Niclosamide

ニクロサミド;

Niclosamide, sold under the brand name Niclocide among others, is a medication used to treat tapeworm infestations.^[2] This includes diphyllobothriasis, hymenolepiasis, 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

References

External links

• “Niclosamide”. Drug Information Portal. U.S. National Library of Medicine.
• Taber, Clarence Wilbur; Venes, Donald; Thomas, Clayton L. (2001). Taber’s cyclopedic medical dictionary. Philadelphia: F.A.Davis Co.
• Niclosamide in the Pesticide Properties DataBase (PPDB)
• “MedlinePlus Drug Information: Niclosamide (Oral)”. MedlinePlus. U.S. National Library of Medicine. 1995-06-23. Archived from the original on 2006-12-16.
• World Health Organization (1995). “Helminths: Cestode (tapeworm) infection: Niclosamide”. WHO model prescribing information : drugs used in parasitic diseases (2nd ed.). World Health Organization (WHO). hdl:10665/41765.

Niclosamide

Niclosamide

Clinical data
Trade names	Niclocide, Fenasal, Phenasal, others[1]
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	By mouth
ATC code	P02DA01 (WHO) QP52AG03 (WHO)
Identifiers
IUPAC name[show]
CAS Number	50-65-7
PubChem CID	4477
DrugBank	DB06803
ChemSpider	4322
UNII	8KK8CQ2K8G
KEGG	D00436
ChEBI	CHEBI:7553
ChEMBL	ChEMBL1448
CompTox Dashboard (EPA)	DTXSID7040362
ECHA InfoCard	100.000.052
Chemical and physical data
Formula	C13H8Cl2N2O4
Molar mass	327.119 g/mol g·mol−1
3D model (JSmol)	Interactive image
Melting point	225 to 230 °C (437 to 446 °F)
SMILES[hide] Clc2cc(ccc2NC(=O)c1cc(Cl)ccc1O)[N+]([O-])=O

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

CHLOROQUINE

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 arthritis, lupus 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

Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. 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.
• Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.^[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]}

• Ampicillin– levels may be reduced by chloroquine;^[23]
• Antacids– may reduce absorption of chloroquine;^[23]
• Cimetidine– may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;^[23]
• Cyclosporine– levels may be increased by chloroquine;^[23] and
• Mefloquine– may increase risk of convulsions.^[23]

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 pK_a 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

Malaria

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 Pfcrt. Verapamil, 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 chlorpheniramine, gefitinib, imatinib, tariquidar 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

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

External links

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

• “Medicines for the Prevention of Malaria While Traveling – Chloroquine (Aralen)” (PDF) (Fact sheet). U.S. Centers for Disease Control and Prevention (CDC).
•  The dictionary definition of chloroquine at Wiktionary

Chloroquine

Clinical data
Pronunciation	/ˈklɔːrəkwɪn/
Trade names	Aralen, other
Other names	Chloroquine phosphate
AHFS/Drugs.com	Monograph
License data	US DailyMed: Chloroquine US FDA: Chloroquine
ATC code	P01BA01 (WHO)
Legal status
Legal status	UK: P (Pharmacy medicines) US: ℞-only
Pharmacokinetic data
Metabolism	Liver
Elimination half-life	1-2 months
Identifiers
IUPAC name[show]
CAS Number	54-05-7
PubChem CID	2719
IUPHAR/BPS	5535
DrugBank	DB00608
ChemSpider	2618
UNII	886U3H6UFF
KEGG	D02366
ChEBI	CHEBI:3638
ChEMBL	ChEMBL76
NIAID ChemDB	000733
CompTox Dashboard (EPA)	DTXSID2040446
ECHA InfoCard	100.000.175
Chemical and physical data
Formula	C18H26ClN3
Molar mass	319.872 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CC

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

EIDD 2801

[(2R,3S,4R,5R)-3,4-dihydroxy-5-[4-(hydroxyamino)-2-oxopyrimidin-1-yl]oxolan-2-yl]methyl 2-methylpropanoate

UNII YA84KI1VEW

Electron microscope image of SARS virus in a tissue culture isolate, courtesy of CDC Public Health Image Library.

The drug EIDD-1931 was effective against SARS and MERS viruses in the laboratory, and a modified version (EIDD-2801) could potentially be valuable against 2019-nCoV.

https://news.emory.edu/stories/2020/02/coronavirus_eidd/index.html

Emory, collaborators testing antiviral drug as potential treatment for coronaviruses

An antiviral compound discovered at Emory University could potentially be used to treat the new coronavirus associated with the outbreak in China and spreading around the globe. Drug Innovation Ventures at Emory (DRIVE), a non-profit LLC wholly owned by Emory, is developing the compound, designated EIDD-2801.

In testing with collaborators at the University of North Carolina at Chapel Hill and Vanderbilt University Medical Center, the active form of EIDD-2801, which is called EIDD-1931, has shown efficacy against the related coronaviruses SARS (Severe Acute Respiratory Syndrome)- and MERS-CoV (Middle East Respiratory Syndrome Coronavirus). Some of the data was recently published in Journal of Virology.

EIDD-2801 is an oral ribonucleoside analog that inhibits the replication of multiple RNA viruses, including respiratory syncytial virus, influenza, chikungunya, Ebola, Venezuelan equine encephalitis virus, and Eastern equine encephalitis viruses.

“We have been planning to enter human clinical tests of EIDD-2801 for the treatment of influenza, and recognized that it has potential activity against the current novel coronavirus,” says George Painter, PhD, director of the Emory Institute for Drug Development (EIDD) and CEO of DRIVE. “Based on the drug’s broad-spectrum activity against viruses including influenza, Ebola and SARS-CoV/MERS-CoV, we believe it will be an excellent candidate.”

“Our studies in the Journal of Virology show potent activity of the EIDD-2801 parent compound against multiple coronaviruses including SARS and MERS,” says Mark Denison, MD, the Stahlman Professor of Pediatrics and director of pediatric infectious diseases at Vanderbilt University School of Medicine.  “It also has a strong genetic barrier to development of viral resistance, and its oral bioavailability makes it a candidate for use during an outbreak.”

“Generally speaking, seasonal flu is still a much more common threat than this coronavirus, however, novel emerging coronaviruses represent a considerable threat to global health as evidenced by the new 2019-nCoV,” said Ralph Baric, PhD, an epidemiology professor at the University of North Carolina’s Gillings School of Global Public Health. “But the reason the new coronavirus is so concerning is that it’s much more likely to be deadly than the flu – fatal for about one in 25 people versus one in 1,000 for the flu.”

The development of EIDD-2801 has been funded in whole or in part with Federal funds from  the National Institute of Allergy and Infectious Diseases (NIAID), under contract numbers HHSN272201500008C and 75N93019C00058, and from the Defense Threat Reduction Agency (DTRA), under contract numbers HDTRA1-13-C-0072 and HDTRA1-15-C-0075, for the treatment of Influenza, coronavirus, chikungunya,  and Venezuelan equine encephalitis virus.

About DRIVE:  DRIVE is a non-profit LLC wholly owned by Emory started as an innovative approach to drug development.  Operating like an early stage biotechnology company, DRIVE applies focus and industry development expertise to efficiently translate discoveries to address viruses of global concern. Learn more at: http://driveinnovations.org/

Emory-discovered antiviral is poised for COVID-19 clinical trials

The nucleoside inhibitor has advantages over Gilead’s remdesivir but has yet to be tested in humans

https://cen.acs.org/biological-chemistry/infectious-disease/Emory-discovered-antiviral-poised-COVID/98/i12?utm_source=Facebook&utm_medium=Social&utm_campaign=CEN&fbclid=IwAR1yIuxNNrelRhKBdPp2hz3oRlqFrDtFYgTPEEORPf1G2R30RIhPIYD9Iwg

Asmall-molecule antiviral discovered by Emory University chemists could soon start human testing against COVID-19, the respiratory disease caused by the novel coronavirus. That’s the plan of Ridgeback Biotherapeutics, which licensed the compound, EIDD-2801, from an Emory nonprofit.

////////EIDD 2801, EMORY, CORONA VIRUS,  COVID 19,

CC(C)C(=O)OC[C@H]2O[C@@H](N1C=CC(=NC1=O)NO)[C@H](O)[C@@H]2O

AZITHROMYCIN

C38H72N2O12,

748.9845

アジスロマイシン;

READ

 

References

1. ^ Jump up to:^ab “Azithromycin Use During Pregnancy”. Drugs.com. 2 May 2019. Retrieved 24 December 2019.
2. ^ Jump up to:^abcdef “Azithromycin International Brands”. Drugs.com. Archived from the original on 28 February 2017. Retrieved 27 February 2017.
3. ^ Jump up to:^{abcdefghijklm} “Azithromycin”. The American Society of Health-System Pharmacists. Archived from the original on 5 September 2015. Retrieved 1 August 2015.
4. ^ Jump up to:^ab “Azithromycin use while Breastfeeding”. Archived from the original on 5 September 2015. Retrieved 4 September 2015.
5. ^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN9780199534845. Archived from the original on 5 March 2016.
6. ^ Jump up to:^ab Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN9783527607495.
7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
8. ^ World Health Organization (2019). Critically important antimicrobials for human medicine (6th revision ed.). Geneva: World Health Organization. hdl:10665/312266. ISBN9789241515528. License: CC BY-NC-SA 3.0 IGO.
9. ^ Jump up to:^ab Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN9781284057560.
10. ^ Jump up to:^ab “Azithromycin”. International Drug Price Indicator Guide. Retrieved 4 September 2015.
11. ^ Jump up to:^ab “NADAC as of 2018-05-23”. Centers for Medicare and Medicaid Services. Retrieved 24 May 2018.
12. ^ “The Top 300 of 2019”. clincalc.com. Retrieved 22 December2018.
13. ^ Taylor SP, Sellers E, Taylor BT (2015). “Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly”. Am. J. Med. 128 (12): 1362.e1–6. doi:10.1016/j.amjmed.2015.07.032. PMID26291905.
14. ^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). “Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults”. Clin. Infect. Dis. 44 Suppl 2: S27–72. doi:10.1086/511159. PMID17278083.
15. ^ Jump up to:^ab “Gonococcal Infections – 2015 STD Treatment Guidelines”. Archived from the original on 1 March 2016.
16. ^ Burton M, Habtamu E, Ho D, Gower EW (2015). “Interventions for trachoma trichiasis”. Cochrane Database Syst Rev. 11 (11): CD004008. doi:10.1002/14651858.CD004008.pub3. PMC4661324. PMID26568232.
17. ^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). “Clinical practice guideline (update): adult sinusitis”. Otolaryngol Head Neck Surg. 152 (2 Suppl): S1–S39. doi:10.1177/0194599815572097. PMID25832968.
18. ^ Hauk L (2014). “AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age”. Am Fam Physician. 89 (8): 676–81. PMID24784128.
19. ^ Neff MJ (2004). “AAP, AAFP release guideline on diagnosis and management of acute otitis media”. Am Fam Physician. 69 (11): 2713–5. PMID15202704.
20. ^ Randel A (2013). “IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis”. Am Fam Physician. 88 (5): 338–40. PMID24010402.
21. ^ The Guardian newspaper: ‘Super-gonorrhoea’ outbreak in Leeds, 18 September 2015Archived 18 September 2015 at the Wayback Machine
22. ^ Lippincott Illustrated Reviews : Pharmacology Sixth Edition. p. 506.
23. ^ Jump up to:^ab “US azithromycin label”(PDF). FDA. February 2016. Archived(PDF) from the original on 23 November 2016.
24. ^ Simoens, Steven; Laekeman, Gert; Decramer, Marc (May 2013). “Preventing COPD exacerbations with macrolides: A review and budget impact analysis”. Respiratory Medicine. 107 (5): 637–648. doi:10.1016/j.rmed.2012.12.019. PMID23352223.
25. ^ Gotfried, Mark H. (February 2004). “Macrolides for the Treatment of Chronic Sinusitis, Asthma, and COPD”. CHEST. 125 (2): 52S–61S. doi:10.1378/chest.125.2_suppl.52S. ISSN0012-3692. PMID14872001.
26. ^ Zarogoulidis, P.; Papanas, N.; Kioumis, I.; Chatzaki, E.; Maltezos, E.; Zarogoulidis, K. (May 2012). “Macrolides: from in vitro anti-inflammatory and immunomodulatory properties to clinical practice in respiratory diseases”. European Journal of Clinical Pharmacology. 68 (5): 479–503. doi:10.1007/s00228-011-1161-x. ISSN1432-1041. PMID22105373.
27. ^ Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles (2012). “Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics”. Mediators of Inflammation. 2012: 584262. doi:10.1155/2012/584262. PMC3388425. PMID22778497.
28. ^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). “Azithromycin anaphylaxis in children”. Int J Immunopathol Pharmacol. 27 (1): 121–6. doi:10.1177/039463201402700116. PMID24674687.
29. ^ Dart, Richard C. (2004). Medical Toxology. Lippincott Williams & Wilkins. p. 23.
30. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). “Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose”. Pharmacotherapy. 26 (1): 147–50. doi:10.1592/phco.2006.26.1.147. PMID16506357.
31. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133.
32. ^ Denise Grady (16 May 2012). “Popular Antibiotic May Raise Risk of Sudden Death”. The New York Times. Archived from the original on 17 May 2012. Retrieved 18 May 2012.
33. ^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). “Azithromycin and the Risk of Cardiovascular Death”. New England Journal of Medicine. 366(20): 1881–90. doi:10.1056/NEJMoa1003833. PMC3374857. PMID22591294.
34. ^ “FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms”. FDA. 12 March 2013. Archived from the original on 27 October 2016.
35. ^ Jump up to:^ab “Archived copy”. Archived from the original on 14 October 2014. Retrieved 10 October 2014.
36. ^ Banić Tomišić, Z. (2011). “The Story of Azithromycin”. Kemija U Industriji. 60 (12): 603–617. ISSN0022-9830. Archived from the original on 8 September 2017.
37. ^ “Azithromycin: A world best-selling Antibiotic”. http://www.wipo.int. World Intellectual Property Organization. Retrieved 18 June 2019.
38. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (April 2013). “U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 368 (15): 1461–1462. doi:10.1056/NEJMc1212055. PMID23574140.
39. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (September 2013). “More on U.S. outpatient antibiotic prescribing, 2010”. The New England Journal of Medicine. 369 (12): 1175–1176. doi:10.1056/NEJMc1306863. PMID24047077.

External links

Keywords: Antibacterial (Antibiotics); Macrolides.

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

Azithromycin

Clinical data
Trade names	Zithromax, Azithrocin, others[2]
Other names	9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
AHFS/Drugs.com	Monograph
MedlinePlus	a697037
License data	EU EMA: by INN US DailyMed: Azithromycin US FDA: Azithromycin
Pregnancy category	AU: B1 [1] US: B (No risk in non-human studies) [1]
Routes of administration	By mouth (capsule, tablet or suspension), intravenous, eye drop
Drug class	Macrolide antibiotic
ATC code	J01FA10 (WHO) S01AA26 (WHO) J01RA07 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	38% for 250 mg capsules
Metabolism	Liver
Elimination half-life	11–14 h (single dose) 68 h (multiple dosing)
Excretion	Biliary, kidney (4.5%)
Identifiers
IUPAC name[show]
CAS Number	83905-01-5
PubChem CID	55185
IUPHAR/BPS	6510
DrugBank	DB00207
ChemSpider	10482163
UNII	J2KLZ20U1M
KEGG	D07486
ChEBI	CHEBI:2955
ChEMBL	ChEMBL529
NIAID ChemDB	007311
CompTox Dashboard (EPA)	DTXSID8030760
ECHA InfoCard	100.126.551
Chemical and physical data
Formula	C38H72N2O12
Molar mass	748.984 g·mol−1 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] CN(C)[C@H]3C[C@@H](C)O[C@@H](O[C@@H]2[C@@H](C)[C@H](O[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1)[C@@H](C)C(=O)O[C@H](CC)[C@@](C)(O)[C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@]2(C)O)[C@@H]3O

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

Voclosporin

• Molecular FormulaC₆₃H₁₁₁N₁₁O₁₂
• Average mass1214.622 Da

VOCLOSPORIN

Aurinia Pharmaceuticals  (following its merger with  Isotechnika ), in collaboration with licensee  Paladin Labs  (a subsidiary of Endo International plc ),  3SBio ,and  ILJIN , is developing a capsule formulation of the immunosuppressant calcineurin inhibitor peptide voclosporin for the treatment of psoriasis, the prevention of organ rejection after transplantation, autoimmune disease including systemic lupus erythematosus and lupus nephritis, and nephrotic syndrome including focal segmental glomerulosclerosis;

Voclosporin is an experimental immunosuppressant drug being developed by Aurinia Pharmaceuticals. It is being studied as a potential treatment for lupus nephritis (LN) and uveitis.^[1] It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.^[2] Voclosporin was discovered by Robert T. Foster and his team at Isotechnika in the mid 1990s.^[3] Isotechnika was founded in 1993 and merged with Aurinia Pharmaceuticals in 2013.

Initially, voclosporin was a mixture of equal proporations of cis and trans geometric isomers of amino acid-1 modified cyclosporin. Later, in collaboration with Roche in Basel, Switzerland, voclosporin’s manufacturing was changed to yield the predominantly trans isomer which possesses most of the beneficial effect of the drug (immunosuppression) in the treatment of organ transplantation and autoimmune diseases.

Patent

WO-2020082061

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020082061&_cid=P12-K9MDK8-59382-1

Novel crystalline forms of voclosporin  which is a structural analog of cyclosporine A as calcineurin signal-transduction pathway inhibitor useful for treating lupus nephritis.

Voclosporin is a structural analog of cyclosporine A, with an additional single carbon extension that has a double-bond on one side chain. Voclosporin has the chemical name (3S,6S,9S,l2R,l5S,l8S,2lS,24S,30S,33S)-30-Ethyl-33-[(lR,2R,4E)-l-hydroxy-2-methyl-4,6-heptadien-l-yl]-6,9,l8,24-tetraisobutyl-3,2l-diisopropyl-l,4,7,l0,l2,l5,l9,25,28-nonamethyl-l,4,7,l0,l3,l6,l9,22,25,28,3 l-undecaazacyclotritriacontane-2,5,8,l l,l4,l7,20,23,26,29,32-undecone and the following chemical structure:

Voclosporin is reported to be a semisynthetic structural analogue of cyclosporine that exerts its immunosuppressant effects by inhibition of the calcineurin signal-transduction pathway and is in Phase 3 Clinical Development for Lupus Nephritis.

[0003] Voclosporin and process for preparation thereof are known from International Patent Application No. WO 1999/18120.

[0004] Certain mixtures of cis and trans-isomers of cyclosporin A analogs referred to as

ISA_TX247 in different ratios are known from U.S. Patent No. 6,998,385, U.S. Patent No. 7,332,472 and U.S. Patent No. 9,765,119.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Voclosporin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (¹³C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active

pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life.

[0008] For at least these reasons, there is a need for solid state forms (including solvated forms) of Voclosporin and salts thereof.

HPLC method:

Method description

Column: Zorbax SB C18, 1.8 pm, 100×2.1 mm

Mobile phase: A: 38 ACN : 7 TBME : 55 voda : 0.02 H₃P0₄ (V/V/V/V)

B: 70 ACN : 7 TBME : 23 voda : 0.02 H P0₄ (V/V/V/V)

Flow rate: 0.5 mL/min

Gradient

Analysis time: 26 minutes + 3 minutes equilibration

Injection volume: 3.0 pL

Column temperature: 90 °C

Diluent: Ethanol

Detection: UV, 210 nm

EXAMPLES

[0095] The starting material Voclosporin crude may be obtained according to ET.S. Patent No. 6,998,385 ETnless otherwise indicated, the purity is determined by HPLC (area percent). The crude product contained according to HPLC analysis 42.6 % trans-Voclosporin (further only Voclosporin), 40.2 % cis-Voclosporin and 2.9 % Cyclosporin A. The crude Voclosporin was purified by column chromatography on silica gel using a mixture of toluene and acetone 82 : 18 (v/v) as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated, obtaining purified Voclosporin as a white foam. According to HPLC analysis it contained 85.7 % Voclosporin, 3.6 % cis-Voclosporin and 2.6 % Cyclosporin A (further only purified Voclosporin).

[0096] The Voclosporin crude (containing about 42.6 % of Voclosporin) was used for further optimization of the chromatographic separation of cis-Voclosporin and Voclosporin and the effort resulted in improved process for chromatographic separation which includes purification by column chromatography on silica gel using a mixture of toluene and methylisobutylketone 38 : 62 as mobile phase. The fractions were monitored by HPLC. The appropriate fractions were joined and evaporated to a dry residue, weighing 31.0 grams. This residue was not analyzed. The material was dissolved in 25 ml of acetone and then 50 ml of water was added and the solution was let to crystallize for 2 hours in the refrigerator. Then the crystalline product was separated by filtration and dried in vacuum dryer (40 °C, 50 mbar, 12 hours), obtaining 29.6 g of dry product containing 90.6 % of Voclosporin, 0.4 % cis-Voclosporin and 3.7 % Cyclosporin A (further mentioned as final Voclosporin).

Example 1: Preparation of Voclosporin Form A

4.1 grams of Purified Voclosporin was dissolved in acetone and the solution was evaporated to 8.0 grams and the concentrate was diluted by 6 ml of water. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and water 1 : 1 (v/v) and dried on open air obtaining 2.6 grams of crystalline product Form A. Voclosporin form A was confirmed by PXRD as presented in Figure 1.

Example 2: Preparation of Voclosporin Form B

[0097] 1.0 gram of Purified Voclosporin was dissolved in a mixture of 1.5 ml acetone and 3.0 ml n-hexane. The solution was let to crystallize in refrigerator at about 2 °C for 12 hours. The crystalline product was filtered off, washed by a mixture of acetone and hexane 1 : 2 (v/v) and dried on open air obtaining 0.5 grams of crystalline product Form B. Voclosporin form B was confirmed by PXRD as presented in Figure 2.

Example 3: Preparation of Amorphous Voclosporin

[0098] 2.0 grams of Purified Voclosporin was dissolved in 40 ml of hot cyclohexane and the solution was stirred for 12 hours at room temperature. Then the crystalline product was filtered off and washed with 5 ml of cyclohexane and dried on open air, obtaining 1.3 grams of amorphous powder. Amorphous Voclosporin was confirmed by PXRD as presented in Figure 3

Example 4: Preparation of Voclosporin Form C

[0099] Final Voclosporin (2 grams) was dissolved in acetonitrile (20 ml) at 50 °C, water (6 ml) was added with stirring, and the clear solution was allowed to crystallize 5 days at 20 °C. Colorless needle crystals were directly mounted to the goniometer head in order to define the crystal structure. Voclosporin form C was confirmed by X-ray crystal structure determination.

References

External links

• Voclosporin, ClinicalTrials.gov

Voclosporin

Names
IUPAC name (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-Ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methyl-4,6-heptadien-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
Other names VCS, ISA247, Luveniq
Identifiers
CAS Number	515814-01-4
3D model (JSmol)	Interactive image
ChemSpider	5293683
PubChem CID	6918486
InChI[show]
SMILES[show]
Properties
Chemical formula	C63H111N11O12
Molar mass	1214.646 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

REFERENCES

1: Mok CC. Calcineurin inhibitors in systemic lupus erythematosus. Best Pract Res Clin Rheumatol. 2017 Jun;31(3):429-438. doi: 10.1016/j.berh.2017.09.010. Epub 2017 Oct 11. Review. PubMed PMID: 29224682.

2: Dang W, Yin Y, Wang Y, Wang W, Su J, Sprengers D, van der Laan LJW, Felczak K, Pankiewicz KW, Chang KO, Koopmans MPG, Metselaar HJ, Peppelenbosch MP, Pan Q. Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication. Antimicrob Agents Chemother. 2017 Oct 24;61(11). pii: e01095-17. doi: 10.1128/AAC.01095-17. Print 2017 Nov. PubMed PMID: 28807916; PubMed Central PMCID: PMC5655111.

3: Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs. 2017 Jun;22(2):123-136. doi: 10.1080/14728214.2017.1330884. Epub 2017 May 22. Review. PubMed PMID: 28503959.

4: Chow C, Simpson MJ, Luger TA, Chubb H, Ellis CN. Comparison of three methods for measuring psoriasis severity in clinical studies (Part 1 of 2): change during therapy in Psoriasis Area and Severity Index, Static Physician’s Global Assessment and Lattice System Physician’s Global Assessment. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1406-14. doi: 10.1111/jdv.13132. Epub 2015 Apr 27. PubMed PMID: 25917315.

5: Simpson MJ, Chow C, Morgenstern H, Luger TA, Ellis CN. Comparison of three methods for measuring psoriasis severity in clinical studies (Part 2 of 2): use of quality of life to assess construct validity of the Lattice System Physician’s Global Assessment, Psoriasis Area and Severity Index and Static Physician’s Global Assessment. J Eur Acad Dermatol Venereol. 2015 Jul;29(7):1415-20. doi: 10.1111/jdv.12861. Epub 2015 Apr 27. PubMed PMID: 25917214.

6: Maya JR, Sadiq MA, Zapata LJ, Hanout M, Sarwar S, Rajagopalan N, Guinn KE, Sepah YJ, Nguyen QD. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol. 2014;2014:310329. doi: 10.1155/2014/310329. Epub 2014 Apr 24. Review. PubMed PMID: 24868451; PubMed Central PMCID: PMC4020293.

7: Hardinger KL, Brennan DC. Novel immunosuppressive agents in kidney transplantation. World J Transplant. 2013 Dec 24;3(4):68-77. doi: 10.5500/wjt.v3.i4.68. Review. PubMed PMID: 24392311; PubMed Central PMCID: PMC3879526.

8: Ling SY, Huizinga RB, Mayo PR, Larouche R, Freitag DG, Aspeslet LJ, Foster RT. Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin. Br J Clin Pharmacol. 2014 Jun;77(6):1039-50. doi: 10.1111/bcp.12309. PubMed PMID: 24330024; PubMed Central PMCID: PMC4093929.

9: Mayo PR, Ling SY, Huizinga RB, Freitag DG, Aspeslet LJ, Foster RT. Population PKPD of voclosporin in renal allograft patients. J Clin Pharmacol. 2014 May;54(5):537-45. doi: 10.1002/jcph.237. Epub 2013 Nov 30. PubMed PMID: 24243422.

10: Gubskaya AV, Khan IJ, Valenzuela LM, Lisnyak YV, Kohn J. Investigating the Release of a Hydrophobic Peptide from Matrices of Biodegradable Polymers: An Integrated Method Approach. Polymer (Guildf). 2013 Jul 8;54(15):3806-3820. PubMed PMID: 24039300; PubMed Central PMCID: PMC3770487.

11: Ling SY, Huizinga RB, Mayo PR, Freitag DG, Aspeslet LJ, Foster RT. Pharmacokinetics of voclosporin in renal impairment and hepatic impairment. J Clin Pharmacol. 2013 Dec;53(12):1303-12. doi: 10.1002/jcph.166. Epub 2013 Oct 8. PubMed PMID: 23996158.

12: Mayo PR, Huizinga RB, Ling SY, Freitag DG, Aspeslet LJ, Foster RT. Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects. J Clin Pharmacol. 2013 Aug;53(8):819-26. doi: 10.1002/jcph.114. Epub 2013 Jun 4. PubMed PMID: 23736966.

13: Schultz C. Voclosporin as a treatment for noninfectious uveitis. Ophthalmol Eye Dis. 2013 May 5;5:5-10. doi: 10.4137/OED.S7995. Print 2013. PubMed PMID: 23700374; PubMed Central PMCID: PMC3653814.

14: Gomes Bittencourt M, Sepah YJ, Do DV, Agbedia O, Akhtar A, Liu H, Akhlaq A, Annam R, Ibrahim M, Nguyen QD. New treatment options for noninfectious uveitis. Dev Ophthalmol. 2012;51:134-61. doi: 10.1159/000336338. Epub 2012 Apr 17. Review. PubMed PMID: 22517211.

15: Khan IJ, Murthy NS, Kohn J. Hydration-induced phase separation in amphiphilic polymer matrices and its influence on voclosporin release. J Funct Biomater. 2012 Oct 30;3(4):745-59. doi: 10.3390/jfb3040745. PubMed PMID: 24955746; PubMed Central PMCID: PMC4030927.

16: Roesel M, Tappeiner C, Heiligenhaus A, Heinz C. Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis. Clin Ophthalmol. 2011;5:1309-13. doi: 10.2147/OPTH.S11125. Epub 2011 Sep 13. PubMed PMID: 21966207; PubMed Central PMCID: PMC3180504.

17: Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S, Huizinga RB, Meier-Kriesche HU; PROMISE Investigators. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant. 2011 Dec;11(12):2675-84. doi: 10.1111/j.1600-6143.2011.03763.x. Epub 2011 Sep 22. PubMed PMID: 21943027.

18: Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M. Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011 Feb;67(Pt 2):119-23. doi: 10.1107/S0907444910051905. Epub 2011 Jan 15. PubMed PMID: 21245533; PubMed Central PMCID: PMC3045272.

19: Kunynetz R, Carey W, Thomas R, Toth D, Trafford T, Vender R. Quality of life in plaque psoriasis patients treated with voclosporin: a Canadian phase III, randomized, multicenter, double-blind, placebo-controlled study. Eur J Dermatol. 2011 Jan-Feb;21(1):89-94. doi: 10.1684/ejd.2010.1185. PubMed PMID: 21227890.

20: Deuter CM. [Systemic voclosporin for uveitis treatment]. Ophthalmologe. 2010 Jul;107(7):672-5. doi: 10.1007/s00347-010-2217-5. German. PubMed PMID: 20571806.

//////////VOCLOSPORIN, Voclosporin, ISA247, ISAtx 247, ISAtx-247, ISAtx247, Luveniq, LX211,

CC[C@@H]1NC([C@@H](N(C([C@@H](N(C([C@@H](N(C([C@@H](N(C([C@H](NC([C@@H](NC([C@@H](N(C([C@H](C(C)C)NC([C@@H](N(C(CN(C1=O)C)=O)C)CC(C)C)=O)=O)C)CC(C)C)=O)C)=O)C)=O)C)CC(C)C)=O)C)CC(C)C)=O)C)C(C)C)=O)C)[C@@H]([C@@H](C/C=C/C=C)C)O)=O

NARONAPRIDE

860174-12-5

Average: 537.1

C₂₇H₄₁ClN₄O₅

ATI 7505 / ATI-7505

(3R)-1-azabicyclo[2.2.2]octan-3-yl 6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamido)-3-methoxypiperidin-1-yl]hexanoate

 860174-12-5 (free base)   860169-57-9 (HCl)

Naronapride (free base), also known as ATI-7505, is a highly selective, high-affinity 5-HT(4) receptor agonist for gastrointestinal motility disorders. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Investigated for use/treatment in gastroesophageal reflux disease (GERD) and gastroparesis.

Renexxion , presumed to have been spun-out from Armetheon , under license from ARYx Therapeutics is developing naronapride (ATI-7505; phase 2 clinical in February 2020), an analog of the gastroprokinetic 5-HT 4 agonist cisapride identified using ARYx’s RetroMetabolic platform technology (ARM), for the oral treatment of upper GI disorders. In September 2018, this was still the case . PATENT

WO2005068461

NEW PATENT

WO-2020096911

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020096911&tab=PCTDESCRIPTION&_cid=P21-KANOVN-53661-1

Process for preparing trihydrate salt of naronapride  hydrochloride as 5-HT 4 receptor agonist useful for treating gastrointestinal disorders such as dyspepsia, gastroparesis, constipation, post-operative ileus. Appears to be the first filing from the assignee and the inventors on this compound,

In some aspects, provided herein is a method of making a trihydrate form of (3S, 4R, 3’R)-6-[4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-l-yl]-hexanoic acid l-azabicyclo[2.2.2]oct-3’-yl ester di-hydrochloride salt, which has the following formula:

Example 5: NMR Characterization of the Trihydrate

[0282] ^-Nuclear Magnetic Resonance Spectroscopy (‘H-NMR) : Approximately 6 mg of the trihydrate was dissolved in in 1 g of deuterated solvent (dimethylsulfoxide (DMSO)-C45 99.9% d, with 0.05% v/v tetramethyl silane (TMS)). A Varian Gemini 300 MHz FT-NMR spectrometer was used to obtain the ¾-NMK spectrum. A list of the peaks is provided in Table 1 below. A representative ‘H-NMR spectrum is provided in FIG. 6.

Table 1. ‘H-NMR peak list for trihydrate

[0283] ¹³ C-Nuclear Magnetic Resonance Spectroscopy ( ¹³C-NMR ): Approximately 46 mg of the trihydrate was dissolved in 1 mL of deuterated solvent (deuterium oxide, Aldrich, 99.9% D, TPAS 0.75%). The ¹³C-NMR spectrum was obtained using a Varian Gemini 300 MHz FT-NMR spectrometer. A list of the peaks is provided in Table 2 below. A representative ¹³C-NMR spectrum is provided in FIG. 7.

Table 2. ¹³C-NMR peak list for trihydrate

PATENT

US10570127 claiming composition (eg tablet) comprising a trihydrate form of naronapride.

REFERENCES

1: Jiang C, Xu Q, Wen X, Sun H. Current developments in pharmacological therapeutics for chronic constipation. Acta Pharm Sin B. 2015 Jul;5(4):300-9. doi: 10.1016/j.apsb.2015.05.006. Epub 2015 Jun 6. Review. PubMed PMID: 26579459; PubMed Central PMCID: PMC4629408.

2: Buchwald P, Bodor N. Recent advances in the design and development of soft drugs. Pharmazie. 2014 Jun;69(6):403-13. Review. PubMed PMID: 24974571.

3: Mozaffari S, Didari T, Nikfar S, Abdollahi M. Phase II drugs under clinical investigation for the treatment of chronic constipation. Expert Opin Investig Drugs. 2014 Nov;23(11):1485-97. doi: 10.1517/13543784.2014.932770. Epub 2014 Jun 24. Review. PubMed PMID: 24960333.

4: Shin A, Camilleri M, Kolar G, Erwin P, West CP, Murad MH. Systematic review with meta-analysis: highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) in chronic constipation. Aliment Pharmacol Ther. 2014 Feb;39(3):239-53. doi: 10.1111/apt.12571. Epub 2013 Dec 5. Review. PubMed PMID: 24308797.

5: Stevens JE, Jones KL, Rayner CK, Horowitz M. Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. Expert Opin Pharmacother. 2013 Jun;14(9):1171-86. doi: 10.1517/14656566.2013.795948. Epub 2013 May 11. Review. PubMed PMID: 23663133.

6: Tack J, Camilleri M, Chang L, Chey WD, Galligan JJ, Lacy BE, Müller-Lissner S, Quigley EM, Schuurkes J, De Maeyer JH, Stanghellini V. Systematic review: cardiovascular safety profile of 5-HT(4) agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther. 2012 Apr;35(7):745-67. doi: 10.1111/j.1365-2036.2012.05011.x. Epub 2012 Feb 22. Review. PubMed PMID: 22356640; PubMed Central PMCID: PMC3491670.

7: Hoffman JM, Tyler K, MacEachern SJ, Balemba OB, Johnson AC, Brooks EM, Zhao H, Swain GM, Moses PL, Galligan JJ, Sharkey KA, Greenwood-Van Meerveld B, Mawe GM. Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology. 2012 Apr;142(4):844-854.e4. doi: 10.1053/j.gastro.2011.12.041. Epub 2012 Jan 4. PubMed PMID: 22226658; PubMed Central PMCID: PMC3477545.

8: Bowersox SS, Lightning LK, Rao S, Palme M, Ellis D, Coleman R, Davies AM, Kumaraswamy P, Druzgala P. Metabolism and pharmacokinetics of naronapride (ATI-7505), a serotonin 5-HT(4) receptor agonist for gastrointestinal motility disorders. Drug Metab Dispos. 2011 Jul;39(7):1170-80. doi: 10.1124/dmd.110.037564. Epub 2011 Mar 29. PubMed PMID: 21447732.

9: Tack J. Current and future therapies for chronic constipation. Best Pract Res Clin Gastroenterol. 2011 Feb;25(1):151-8. doi: 10.1016/j.bpg.2011.01.005. Review. PubMed PMID: 21382586.

10: Manabe N, Wong BS, Camilleri M. New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders. Expert Opin Investig Drugs. 2010 Jun;19(6):765-75. doi: 10.1517/13543784.2010.482927. Review. PubMed PMID: 20408739.

11: Sanger GJ. Translating 5-HT receptor pharmacology. Neurogastroenterol Motil. 2009 Dec;21(12):1235-8. doi: 10.1111/j.1365-2982.2009.01425.x. Review. PubMed PMID: 19906028.

12: Vakil N. New pharmacological agents for the treatment of gastroesophageal reflux disease. Rev Gastroenterol Disord. 2008 Spring;8(2):117-22. Review. PubMed PMID: 18641594.

13: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.

14: Camilleri M, Vazquez-Roque MI, Burton D, Ford T, McKinzie S, Zinsmeister AR, Druzgala P. Pharmacodynamic effects of a novel prokinetic 5-HT receptor agonist, ATI-7505, in humans. Neurogastroenterol Motil. 2007 Jan;19(1):30-8. PubMed PMID: 17187586.

////////////NARONAPRIDE, ATI 7505, ATI 7505,PHASE 2

CO[C@H]1CN(CCCCCC(=O)O[C@H]2CN3CCC2CC3)CC[C@H]1NC(=O)C1=C(OC)C=C(N)C(Cl)=C1

GST-HG-121

mw 431.4

C23 H29 N07

Fujian Cosunter Pharmaceutical Co Ltd

Preclinical for the treatment of hepatitis B virus infection

This compound was originally claimed in WO2018214875 , and may provide the structure of GST-HG-121 , an HBsAg inhibitor which is being investigated by Fujian Cosunter for the treatment of hepatitis B virus infection; in June 2019, an IND application was planned in the US and clinical trials of the combination therapies were expected in 2020. Fujian Cosunter is also investigating GST-HG-131 , another HBsAg secretion inhibitor, although this appears to be being developed only as a part of drug combination.

WO2017013046A1

PATENT

WO2018214875

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214875&_cid=P21-KB0QYA-12917-1

PATENT

WO-2020103924

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020103924&tab=FULLTEXT&_cid=P21-KB0QP8-09832-1

Novel crystalline forms of 11-oxo-7,11-dihydro-6H-benzo[f]pyrido[1,2-d][1,4]azepine, a hepatitis B surface antigen and HBV replication inhibitor, useful for treating HBV infection.

[0060]

Step H: Compound 9 (15.80 g, 35.95 mmol) was dissolved in dichloromethane (150.00 mL), and trifluoroacetic acid (43.91 mL, 593.12 mmol) was added. The reaction solution was stirred at 10 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure and spin-dried, sodium bicarbonate aqueous solution (100.00 mL) was added, and dichloromethane (100.00 mL) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 10.

Step J: Compound 12 (875.00 mg, 1.90 mmol) was dissolved in toluene (20.00 mL) and ethylene glycol dimethyl ether (20.00 mL), and tetrachlorobenzoquinone (1.40 g, 5.69 mmol) was added. The reaction solution was stirred at 120 degrees Celsius for 12 hours. The reaction solution was cooled to room temperature, and a saturated aqueous sodium carbonate solution (50.00 ml) and ethyl acetate (60.00 ml) were added. The mixed solution was stirred at 10-15 degrees Celsius for 20 minutes, and the liquid was separated to obtain an organic phase. Add 2.00 mol/L aqueous hydrochloric acid solution (60.00 mL) to the organic phase, stir at 10-15 degrees Celsius for 20 minutes, and separate the liquid. Wash the organic phase with 2 mol/L aqueous hydrochloric acid solution (60.00 mL×2), separate the liquid, and separate the water phase A 2 mol/L aqueous sodium hydroxide solution (200.00 ml) and dichloromethane (200.00 ml) were added. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 13.

Step K: Compound 13 (600.00 mg, 1.31 mmol) was dissolved in methanol (6.00 mL), and 4.00 mol/L aqueous sodium hydroxide solution (2.00 mL, 6.39 equiv) was added. The reaction solution was stirred at 15 degrees Celsius for 0.25 hours. The reaction solution was adjusted to pH=3-4 with a 1.00 mol/L hydrochloric acid aqueous solution, and then extracted with dichloromethane (50.00 mL×3). The organic phases were combined, washed with saturated brine (50.00 mL), and dried over anhydrous sodium sulfate , Filtered and concentrated under reduced pressure to obtain the compound of formula (I). ee value (enantiomeric excess): 100%.

////////////GST-HG-121, Fujian Cosunter,  Preclinical ,  hepatitis B,  virus infection

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

O=C(O)C1=CN2C(=CC1=O)c3cc(OC)c(OCCCOC)cc3OC[C@H]2C(C)(C)C

DESIDUSTAT

2-(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid

desidustat

Glycine, N-((1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl)carbonyl)-

N-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine

ZYAN1 compound

BCP29692

EX-A2999

ZB1514

CS-8034

HY-103227

A16921

(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Desidustat (INN, also known as ZYAN1) is an investigational drug for the treatment of anemia of chronic kidney disease. Clinical trials on desidustat have been done in India and Australia.^[1] In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed.^[2] It is currently undergoing Phase 3 clinical trials.^[3] Desidustat is being developed for the treatment of anemia, where currently erythropoietin and its analogues are drugs of choice. Desidustat is a prolyl hydroxylase domain (PHD) inhibitor. In preclinical studies, effect of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization.^[4][5] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.^[6]. In January 2020, Zydus entered into licensing agreement with China Medical System Holdings for development and commercialization of Desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of Desidustat in Greater China ^[7]

PATENT

US277539705

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C922CC7937C0B6D7F987FE395E8B6F34.wapp2nB?docId=US277539705&_cid=P21-KCEB8C-83913-1

 (MOL) (CDX)

 (MOL) (CDX)

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, Ethanol (1.25 L) charged at room temperature. 2-iodobenzoic acid (250 g, 1.00 mol) was added in one lot at room temperature. Sulphuric acid (197.7 g, 2.01 mol) was added carefully in to reaction mixture at 20 to 35° C. The reaction mixture was heated to 80 to 85° C. Reaction mixture was stirred for 20 hours at 80 to 85° C. After completion of reaction distilled out ethanol at below 60° C. The reaction mixture was cooled down to room temperature. Water (2.5 L) was then added carefully at 20 to 35° C. The reaction mixture was then charged with Ethyl acetate (1.25 L). After complete addition of ethyl acetate, reaction mixture turned to clear solution. At room temperature it was stirred for 5 to 10 minutes and separated aqueous layer. Aqueous layer then again extracted with ethyl acetate (1.25 L) and separated aqueous layer. Combined organic layer then washed with twice 10% sodium bicarbonate solution (2×1.25 L) and twice process water (2×1.25L) and separated aqueous layer. Organic layer then washed with 30% brine solution (2.5 L) and separated aqueous layer. Concentrated ethyl acetate in vacuo to get ethyl 2-iodobenzoate in 95% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 248.75 (M+H). 1H NMR (CDCl 3): 1.41-1.37 (t, 3H), 4.41-4.35 (q, 2H), 7.71-7.09 (m, 1H), 7.39-7.35 (m, 1H), 7.94-7.39 (m, 1H), 7.96-7.96 (d, 1H). HPLC Purity: 99.27%

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, toluene (1.5 L) was charged at room temperature. Copper (I) iodide (15.3 g, 0.08 mol) was added in one lot at room temperature. Glycine (39.1 g, 0.520 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Ethyl 2-iodobenzoate (221.2 g, 0.801 mol) was added in one lot at room temperature. Tert-butyl (cyclopropylmethoxy)carbamate (150 g, 0.801 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Potassium carbonate (885.8 g, 6.408 mol) and ethanol (0.9 L) were added at 25° C. to 35° C. Reaction mixture was stirred for 30 minutes. The reaction mixture was refluxed at 78 to 85° C. for 24 hours. Reaction mixture was cooled to room temperature and stirred for 30 minutes. The reaction mixture was then charged with ethyl acetate (1.5 L). After complete addition of ethyl acetate, reaction mixture turned to thick slurry. At room temperature it was stirred for 30 minutes and the solid inorganic material was filtered off through hyflow supercel bed. Inorganic solid impurity was washed with ethyl acetate (1.5 L), combined ethyl acetate layer was washed with twice water (2×1.5 L) and separated aqueous layer. Organic layer washed with 30% sodium chloride solution (1.5 L) and separated aqueous layer. Ethyl acetate was concentrated in vacuo to get ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate in 89% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 357.93 (M+Na). 1H NMR (CDCl 3): 0.26-0.23 (m, 2H), 0.52-0.48 (m, 2H), 1.10-1.08 (m, 1H), 1.38-1.35 (t, 3H), 1.51 (s, 9H), 3.78-3.76 (d, J=7.6 Hz, 2H), 4.35-4.30 (q, J=6.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.49-7.47 (m, 2H), 7.78-7.77 (d, 1H). HPLC Purity: 88.07%

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

(MOL) (CDX)

In a 10 L fixed glass assembly, dichloromethane (2.4 L) was charged at room temperature. Ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate (200 g, 0.596 mol) was charged and cooled externally with ice-salt at 0 to 10° C. Methanolic HCl (688.3 g, 3.458 mol, 18.34% w/w) solution was added slowly drop wise, over a period of 15 minutes, while maintaining internal temperature below 10° C. Reaction mixture was warmed to 20 to 30° C., and stirred at 20 to 30° C. for 3 hours. The reaction mixture was quenched with addition of water (3.442 L). Upon completion of water addition, the reaction mixture turn out to light yellow coloured solution. At room temperature it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with Dichloromethane (0.8 L). Combined dichloromethane layer then washed with 20% sodium chloride solution (1.0 L) and separated aqueous layer. Concentrated dichloromethane vacuo to get Ethyl 2-((cyclopropylmethoxy)amino)benzoate in 92% yield, as an oil. MS (ESI-MS): m/z 235.65 (M+H) +. 1H NMR (CDCl 3): 0.35-0.31 (m, 2H), 0.80-0.59 (m, 2H), 0.91-0.85 (m, 1H), 1.44-1.38 (t, 3H), 3.76-3.74 (d, 2H), 4.36-4.30 (q, 2H), 6.85-6.81 (t, 1H), 7.36-7.33 (d, 1H), 7.92-7.43 (m, 1H), 7.94-7.93 (d, 1H), 9.83 (s, 1H). HPLC Purity: 87.62%

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

(MOL) (CDX)

In a 2 L fixed glass assembly, Acetonitrile (0.6 L) was charged at room temperature. Ethyl 2-((cyclopropylmethoxy)amino)benzoate (120 g, 0.510 mol) was charged at room temperature. Ethyl hydrogen malonate (74.1 g, 0.561 mol) was charged at room temperature. Pyridine (161.4 g, 2.04 mol) was added carefully in to reaction mass at room temperature and cooled externally with ice-salt at 0 to 10° C. Phosphorous oxychloride (86.0 g, 0.561 mol) was added slowly drop wise, over a period of 2 hours, while maintaining internal temperature below 10° C. Reaction mixture was stirred at 0 to 10° C. for 45 minutes. The reaction mixture was quenched with addition of water (1.0 L). Upon completion of water addition, the reaction mixture turns out to dark red coloured solution. Dichloromethane (0.672 L) was charged at room temperature and it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with dichloromethane (0.672 L). Combined dichloromethane layer then washed with water (0.400 L) and 6% sodium chloride solution (0.400 L) and separated aqueous layer. Mixture of acetonitrile and dichloromethane was concentrated in vacuo to get Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate in 95% yield, as an oil. MS (ESI-MS): m/z 350.14 (M+H) l. 1H NMR (DMSO-d 6): 0.3-0.2 (m, 2H), 0.6-0.4 (m, 2H), 1.10-1.04 (m, 1H), 1.19-1.15 (t, 3H), 1.29-1.25 (t, 3H), 3.72-3.70 (d, 2H), 3.68 (s, 2H), 4.17-4.12 (q, 2H), 4.25-4.19 (q, 2H), 7.44-7.42 (d, 1H), 7.50-7.46 (t, 1H), 7.68-7.64 (m, 1H), 7.76-7.74 (d, 1H). HPLC Purity: 86.74%

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

(MOL) (CDX)

In a 10 L fixed glass assembly under Nitrogen atmosphere, Methanol (0.736 L) was charged at room temperature. Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate (160 g, 0.457 mol) was charged at room temperature. Sodium methoxide powder (34.6 g, 0.641 mol) was added portion wise, over a period of 30 minutes, while maintaining internal temperature 10 to 20° C. Reaction mixture was stirred at 10 to 20° C. for 30 minutes. The reaction mixture was quenched with addition of ˜1N aqueous hydrochloric acid solution (0.64 L) to bring pH 2, over a period of 20 minutes, while maintaining an internal temperature 10 to 30° C. Upon completion of aqueous hydrochloric acid solution addition, the reaction mixture turned to light yellow coloured slurry. Diluted the reaction mass with water (3.02 L) and it was stirred for another 1 hour. Solid material was filtered off and washed twice with water (2×0.24 L). Dried the compound in fan dryer at temperature 50 to 55° C. for 6 hours to get crude ethyl 1-(cyclopropylmetboxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a solid.

Purification

In a 10 L fixed glass assembly, DMF (0.48 L) was charged at room temperature. Crude ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (120 g) was charged at room temperature. Upon completion of addition of crude compound, clear reaction mass observed. Reaction mixture stirred for 30 minutes at room temperature. Precipitate the product by addition of water (4.8 L), over a period of 30 minutes, while maintaining an internal temperature 25 to 45° C. Upon completion of addition of water, the reaction mixture turned to light yellow colored slurry. Reaction mixture was stirred at 25 to 45° C. for 30 minutes. Solid material was filtered off and washed with water (0.169 L). Dried the product in fan dryer at temperature 50 to 55° C. for 6 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 81% yield, as a solid. MS (ESI-MS): m/z 303.90 (M+H) +. 1H NMR (DMSO-d 6): 0.37-0.35 (m, 2H), 0.59-0.55 (m, 2H), 1.25-1.20 (m, 1H), 1.32-1.29 (t, 3H), 3.97-3.95 (d, 2H), 4.36-4.31 (q, 2H), 7.35-7.31 (in, 1H), 7.62-7.60 (dd, 1H), 7.81-7.77 (m, 1H), 8.06-7.04 (dd, 1H). HPLC Purity: 95.52%

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, tetrahydrofuran (0.5 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (100 g, 0.329 mol) was charged at room temperature. Glycine ethyl ester HCl (50.7 g, 0.362 mol) was charged at room temperature. N,N-Diisopropylethyl amine (64 g, 0.494 mol) was added carefully in to reaction mass at room temperature and heated the reaction mass at 65 to 70° C. Reaction mixture was stirred at 65 to 70° C. for 18 hours. The reaction mixture was quenched with addition of water (2.5 L).

Upon completion of water addition, the reaction mixture turns out to off white to yellow coloured slurry. Concentrated tetrahydrofuran below 55° C. in vacuo and reaction mixture was stirred at 25 to 35° C. for 1 hour. Solid material was filtered off and washed with water (3×0.20 L). Dried the compound in fan dryer at temperature 55 to 60° C. for 8 hours to get crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate as a solid.

Purification

In a 2 L fixed glass assembly, Methanol (1.15 L) was charged at room temperature. Crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (100 g) was charged at room temperature. The reaction mass was heated to 65 to 70° C. Reaction mass was stirred for 1 h at 65 to 70° C. Removed heating and cool the reaction mass to 25 to 35° C. Reaction mass stirred for 1 h at 25 to 35° C. Solid material was filtered off and washed with methanol (0.105 L). The product was dried under fan dryer at temperature 55 to 60° C. for 8 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 80% yield, as a solid. MS (ESI-MS): m/z 360.85 (M+H) +. 1H NMR (DMSO-d 6): 0.39 (m, 2H), 0.60-0.54 (m, 2H), 1.23-1.19 (t, 3H), 1.31-1.26 (m, 1H), 4.04-4.02 (d, 2H), 4.18-4.12 (q, 2H), 4.20-4.18 (d, 2H), 7.40-7.36 (m, 1H), 7.70-7.68 (d, 1H), 7.87-7.83 (m, 1H), 8.08-8.05 (dd, 1H), 10.27-10.24 (t, 1H). HPLC Purity: 99.84%

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, methanol (0.525 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (75 g, 0.208 mol) was charged at room temperature. Water (0.30 L) was charged at room temperature. Sodium hydroxide solution (20.8 g, 0.520 mol) in water (0.225 L) was added carefully at 30 to 40° C. Upon completion of addition of sodium hydroxide solution, the reaction mass turned to clear solution. Reaction mixture stirred for 30 minutes at 30 to 40° C. Diluted the reaction by addition of water (2.1 L). Precipitate the solid by addition of hydrochloric acid solution (75 mL) in water (75 mL). Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4×0.375 L). The compound was dried under fan dryer at temperature 25 to 35° C. for 6 hours and then dried for 4 hours at 50 to 60° C. to get (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) +. 1H NMR (DMSO-d 6): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Polymorphic Data (XRPD):

References

1. ^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). “Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers”. Clinical Pharmacokinetics. 57 (1): 87–102. doi:10.1007/s40262-017-0551-3. PMC5766731. PMID28508936.
2. ^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
3. ^ “Zydus Cadila announces phase III clinical trials of Desidustat”. 17 April 2019. Retrieved 20 April 2019 – via The Hindu BusinessLine.
4. ^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). “Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia”. Drug Research. 66 (2): 107–12. doi:10.1055/s-0035-1554630. PMID26367279.
5. ^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). “Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases”. Journal of Medicinal Chemistry. 61 (16): 6964–6982. doi:10.1021/acs.jmedchem.7b01686. PMID29712435.
6. ^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). “Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation”. European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID30458168. S2CID53943666.
7. ^ “Zydus enters into licensing agreement with China Medical System Holdings”. 20 January 2020. Retrieved 20 January 2020 – via Business Standard.

 

 

ANALYSIS

https://patentscope.wipo.int/search/en/result.jsf?inchikey=IKRKQQLJYBAPQT-UHFFFAOYSA-N

• Countries

PCT4

United States of America2

China1

Eurasian Patent Organization1

European Patent Office1

Applicants

CADILA HEALTHCARE LIMITED3

CADILA HEALTHCARE LTD1

PEKING UNIVERSITY1

SCHOLAR ROCK, INC.1

THE SCHEPENS EYE RESEARCH INSTITUTE1

UNIVERSITY HEALTH NETWORK1

Inventors

RANJIT C. DESAI2

VRAJESH PANDYA2

CAPILI, ALLAN1

DAGBAY, KEVIN B.1

DATTA, ABHISHEK1

DESAI RANJIT C1

DONOVAN, ADRIANA1

JIANG CHANGTAO1

KALPESH SHAH1

LERNER, LORENA1

IPC code

A61K6

C07D5

A61P4

A61F1

C07K1

C12N1

C12Q1

G01N1

Publication Dates

20141

20153

20160

20170

20180

20192

2020

1.WO/2020/086736RGMC-SELECTIVE INHIBITORS AND USE THEREOF WO – 30.04.2020 Int.Class A61P 7/06Appl.No PCT/US2019/057687Applicant SCHOLAR ROCK, INC.Inventor NICHOLLS, Samantha Selective inhibitors of repulsive guidance molecule C (RGMc), are described. Related methods, including methods for making, as well as therapeutic use of these inhibitors in the treatment of disorders, such as anemia, are also provided.

2.WO/2020/058882METHODS OF PRODUCING VENOUS ANGIOBLASTS AND SINUSOIDAL ENDOTHELIAL CELL-LIKE CELLS AND COMPOSITIONS THEREOF WO – 26.03.2020 Int.Class C12N 5/071Appl.No PCT/IB2019/057882Applicant UNIVERSITY HEALTH NETWORKInventor KELLER, Gordon Disclosed herein are methods of producing a population of venous angioblast cells from stem cells using a venous angioblast inducing media and optionally isolating a CD34+ population from the cell population comprising the venous angioblast cells, for example using a CD34 affinity reagent, CD31 affinity reagent and/or CD144 affinity reagent, optionally with or without a CD73 affinity reagent as well as methods of further differentiating the venous angioblasts in vitro to produce SEC-LCs and/or in vivo to produce SECs. Uses of the cells and compositions comprising the cells are also described.

3.110876806APPLICATION OF HIF2ALPHA AGONIST AND ACER2 AGONIST IN PREPARATION OF MEDICINE FOR TREATING ATHEROSCLEROSIS CN – 13.03.2020 Int.Class A61K 45/00Appl.No 201911014253.3Applicant PEKING UNIVERSITYInventor JIANG CHANGTAO The invention discloses application of an HIF2alpha agonist and an ACER2 agonist in preparation of a medicine for treating and/or preventing atherosclerosis. Wherein the HIF2alpha agonist can be an adipose cell HIF2alpha agonist, and the ACER2 agonist can be a visceral fat ACER2 enzyme activator. The invention also discloses an application of Roxadustat in preparing a medicine for treating and/orpreventing atherosclerosis. The HIF2alpha agonist, the ACER2 agonist and the Roxadustat can be used for inhibiting or alleviating the occurrence and development of atherosclerosis.

4.20190359574PROCESS FOR THE PREPARATION OF QUINOLONE BASED COMPOUNDS US – 28.11.2019 Int.Class C07D 215/58Appl.No 16421671Applicant CADILA HEALTHCARE LIMITEDInventor Ranjit C. Desai The present invention relates to an improved process for the preparation of quinolone based compounds of general formula (I) using intermediate compound of general formula (XII). Invention also provides an improved process for the preparation of compound of formula (I-a) using intermediate compound of formula (XII-a) and some novel impurities generated during process. Compounds prepared using this process can be used to treat anemia.

5.WO/2019/169172SYSTEM AND METHOD FOR TREATING MEIBOMIAN GLAND DYSFUNCTION WO – 06.09.2019 Int.Class A61F 9/00Appl.No PCT/US2019/020113Applicant THE SCHEPENS EYE RESEARCH INSTITUTEInventor SULLIVAN, David, A. Systems and methods of treating meibomian and sebaceous gland dysfunction. The methods include reducing oxygen concentration in the environment of one or more dysfunctional meibomian and sebaceous glands, thereby restoring a hypoxic status of one or more dysfunctional meibomian and sebaceous glands. The reducing of the oxygen concentration is accomplished by restricting blood flow to the one or more dysfunctional meibomian and sebaceous glands and the environment of one or more dysfunctional meibomian sebaceous glands. The restricting of the blood flow is accomplished by contracting or closing one or more blood vessels around the one or more dysfunctional meibomian or sebaceous glands. The methods also include giving local or systemic drugs that lead to the generation of hypoxia-inducible factors in one or more dysfunctional meibomian and sebaceous glands.

6.201591195ХИНОЛОНОВЫЕ ПРОИЗВОДНЫЕ EA – 30.10.2015 Int.Class C07D 215/58Appl.No 201591195Applicant КАДИЛА ХЕЛЗКЭР ЛИМИТЕДInventor Десаи Ранджит К. Настоящее изобретение относится к новым соединениям общей формулы (I), фармацевтическим композициям, содержащим указанные соединения, применению этих соединений для лечения состояний, опосредованных пролилгидроксилазой HIF, и к способу лечения анемии, включающему введение заявленных соединений

7.2935221QUINOLONE DERIVATIVES EP – 28.10.2015 Int.Class C07D 215/58Appl.No 13828997Applicant CADILA HEALTHCARE LTDInventor DESAI RANJIT C The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. [Formula should be inserted here].

8.20150299193QUINOLONE DERIVATIVES US – 22.10.2015 Int.Class C07D 215/58Appl.No 14652024Applicant Cadila Healthcare LimitedInventor Ranjit C. Desai The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

9.WO/2014/102818NOVEL QUINOLONE DERIVATIVES WO – 03.07.2014 Int.Class C07D 215/58Appl.No PCT/IN2013/000796Applicant CADILA HEALTHCARE LIMITEDInventor DESAI, Ranjit, C. The present invention relates to novel compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation. [Formula should be inserted here].

 

1 / 1

 

Desidustat

Clinical data
Other names	ZYAN1
Identifiers
IUPAC name[show]
CAS Number	1616690-16-4
UNII	Y962PQA4KS
Chemical and physical data
Formula	C16H16N2O6
Molar mass	332.312 g·mol−1
3D model (JSmol)	Interactive image
SMILES[hide] C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
InChI[hide] InChI=1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20) Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

Date

CTID	Title	Phase	Status	Date
NCT04215120	Desidustat in the Treatment of Anemia in CKD on Dialysis Patients	Phase 3	Recruiting	2020-01-02
NCT04012957	Desidustat in the Treatment of Anemia in CKD	Phase 3	Recruiting	2019-12-24

////////// DESIDUSTAT, ZYDUS CADILA, COVID 19, CORONA VIRUS, PHASE 3, ZYAN 1

SELGANTOLIMOD

GS 9688

RN: 2004677-13-6
UNII: RM4GJT3SMQ

Molecular Formula, C14-H20-F-N5-O,

Molecular Weight, 293.344

1-Hexanol, 2-((2-amino-7-fluoropyrido(3,2-d)pyrimidin-4-yl)amino)-2-methyl-, (2R)-

(2R)-2-((2-Amino-7-fluoropyrido(3,2-d)pyrimidin-4-yl)amino)-2-methylhexan-1-ol

Discovery of GS–9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B

Patent ID	Title	Submitted Date	Granted Date
US2019192504	Therapeutic heterocyclic compounds	2018-08-20
US2017281627	TOLL LIKE RECEPTOR MODULATOR COMPOUNDS	2017-04-25
US2017071944	MODULATORS OF TOLL-LIKE RECEPTORS FOR THE TREATMENT OF HIV	2016-09-13
US9670205	TOLL LIKE RECEPTOR MODULATOR COMPOUNDS	2016-03-02

Patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US178076456&tab=PCTDESCRIPTION&_cid=P21-KD1F9D-27923-1

EXAMPLE 63

(MOL) (CDX)

Synthesis of methyl 2-amino-2-methylhexanoate (63A. To a mixture of (2R)-2-amino-2-methylhexanoic acid hydrochloride (50 mg, 0.28 mmol) and (2S)-2-amino-2-methylhexanoic acid hydrochloride (50 mg, 0.28 mmol) in MeOH (5.0 mL) was added (trimethylsilyl) diazomethane in hexanes (2 M, 0.41 mL, 0.83 mmol) dropwise. After 6 h, the reaction was quenched with AcOH (100 μL). The mixture was concentrated in vacuo to provide 63A that was used without further isolation. LCMS (m/z): 159.91 [M+H] +; t R=0.57 min. on LC/MS Method A.

Synthesis of methyl 2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexanoate (63B). To a solution of 84E (120 mg, 0.55 mmol) in THF (5 mL) was added 63A (88 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). After stirring at 80° C. for 18 h, the reaction was cooled to rt, diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na 2SO 4, then filtered and concentrated in vacuo. The crude residue was then diluted with THF (10 mL) and 2,4-dimethoxybenzylamine (0.4 mL, 2.6 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) were added. After stirring at 100° C. for 18 h, the reaction was cooled to rt, diluted with EtOAc (50 mL), washed with water and brine, dried over Na 2SO 4, then filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to provide 63B. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H), 7.36 (s, 1H), 7.28-7.24 (m, 2H), 6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.3, 2.4 Hz, 1H), 4.54 (dd, J=6.2, 2.7 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 2.27-2.16 (m, 1H), 2.02 (s, 1H), 1.71 (s, 3H), 1.34-1.23 (m, 5H), 0.88 (t, J=6.9 Hz, 3H). 19F NMR (376 MHz, Chloroform-d) δ −121.51 (d, J=422.9 Hz). LCMS (m/z): 472.21 [M+H] +; t R=0.91 min. on LC/MS Method A.

Synthesis of 2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (63C). To a solution of 63B (104 mg, 0.22 mmol) in THF (5 mL) was added lithium aluminum hydride in Et 2O (2M, 0.30 mL, 0.60 mmol). After 5 h the reaction was quenched with H 2O (1 mL) and 2M NaOH (aq), and then filtered. The mother liquor was then diluted with EtOAc (30 mL), washed with sat. Rochelle’s salt solution (25 mL), H 2O (25 mL), and brine (25 mL), dried over Na 2SO 4, then filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to provide 63C. 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J=2.5 Hz, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.2, 2.4 Hz, 1H), 4.57-4.52 (m, 2H), 3.84 (s, 3H), 3.79 (s, 4H), 3.75 (s, 2H), 1.92 (d, J=14.1 Hz, 1H), 1.74 (t, J=12.6 Hz, 1H), 1.40-1.37 (m, 3H), 1.32 (td, J=13.4, 12.4, 6.3 Hz, 4H), 0.91 (t, J=7.0 Hz, 3H). 19F NMR (377 MHz, Chloroform-d) δ −121.34. LCMS (m/z): 444.20 [M+H] +; t R=0.94 min. on LC/MS Method A

Synthesis of 2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (63). To 63C (22 mg, 0.05 mmol) was added TFA (3 mL). After 30 minutes, the reaction mixture was diluted with MeOH (5 mL). After stirring for 18 h, the mixture was filtered and concentrated in vacuo. Co-evaporation with MeOH (×3) provided 63 as a TFA salt. 1H NMR (400 MHz, MeOH-d 4) δ 8.53 (d, J=2.4 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 3.95 (s, 1H), 3.70 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13.9, 10.9, 5.3 Hz, 1H), 1.96-1.86 (m, 1H), 1.53 (s, 3H), 1.42-1.28 (m, 6H), 0.95-0.87 (m, 3H). 19F NMR (377 MHz, MeOH-d 4) δ −77.47, −118.23 (d, J=8.6 Hz). LCMS (m/z): 294.12 [M+H] +; t R=0.68 min. on LC/MS Method A.

EXAMPLE 64

(MOL) (CDX)

Synthesis of (S)-2-amino-2-methylhexan-1-ol (64A). To (2S)-2-amino-2-methylhexanoic acid hydrochloride (250 mg, 1.4 mmol, supplied by Astatech) in THF (5 mL) was added borane-tetrahydrofuran complex solution in THF (1M, 5.5 mL) dropwise over 5 minutes. After 24 h, the reaction was quenched with MeOH (1 mL) and concentrated in vacuo. The residue was taken up in DCM (10 mL), filtered, and concentrated in vacuo to provide crude 64A. LCMS (m/z): 131.92 [M+H] +; t R=0.57 min. on LC/MS Method A.

Synthesis of (S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (64). To a solution of 43B (140 mg, 78 mmol) and 64A (125 mg, 0.95 mmol) in NMP (7.5 mL), was added DBU (0.35 mL, 2.4 mmol) followed by BOP (419 mg, 0.95 mmol). After 16 h, the reaction mixture was subjected to prep HPLC (Gemini 10u C18 110A, AXIA; 10% aq. acetonitrile—50% aq. acetonitrile with 0.1% TFA, over 20 min. gradient) to provide, after removal of volatiles in vacuo, 64 as a TFA salt. 1H NMR (400 MHz, MeOH-d 4) δ 8.55 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 7.64 (dd, J=8.7, 2.5 Hz, 1H), 3.97 (d, J=11.2 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13.9, 10.8, 5.2 Hz, 1H), 1.92 (ddd, J=13.6, 10.9, 5.4 Hz, 1H), 1.54 (s, 4H), 1.40-1.31 (m, 5H), 1.00-0.85 (m, 3H). 19F NMR (377 MHz, MeOH-d 4) δ −77.62, −118.22 (d, J=8.7 Hz). LCMS (m/z) 294.09 [M+H] +; t R=0.79 min. on LC/MS Method A.

EXAMPLE 65

(MOL) (CDX)

Synthesis of (R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (65A). To a solution of 19B (112 mg, 0.48 mmol) in THF (5 mL) was added 61E (100 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). After stirring at 80° C. for 18 h, 2,4-dimethoxybenzylamine (0.75 mL, 5.0 mmol) was added and the mixture was heated to 100° C. After 18 h, the reaction was cooled to rt, diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over Na 2SO 4, then filtered and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexanes-EtOAc to provide 65A LCMS (m/z): 509.30[M+H] +; t R=0.89 min. on LC/MS Method A.

Synthesis of (R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (65). To 65A (21 mg, 0.04 mmol) was added TFA (3 mL). After 30 minutes, the mixture was concentrated in vacuo and the residue co-evaporated with MeOH (10 mL×3). The resulting residue was suspended in MeOH (10 mL), filtered, and concentrated in vacuo to provide 65 as a TFA salt. 1H NMR (400 MHz, MeOH-d 4) δ 8.59 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H), 3.52 (d, J=14.0 Hz, 1H), 2.22-2.10 (m, 1H), 1.96 (s, 3H), 1.95-1.87 (m, 1H), 1.54 (s, 3H), 1.34 (dd, J=7.5, 3.9 Hz, 5H), 0.94-0.89 (m, 3H). 19F NMR (377 MHz, MeOH-d 4) δ −77.91. LCMS (m/z): 351.29 [M+H] +; t R=0.69 min. on LC/MS Method A.

 

 

/////////////GS 9688, SELGANTOLIMOD

CCCC[C@@](C)(CO)Nc1nc(N)nc2cc(F)cnc12

MK 5204

 (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-21-[(2R)-2-amino-2,3,3-trimethylbutoxy]-20-(5-carbamoyl-1,2,4-triazol-1-yl)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid

MW 695.97

C40 H65 N5 O5

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0960894X20304686

Abstract

patent

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43243783&tab=PCTDESCRIPTION&_cid=P22-KD34BU-17225-1

Patent ID	Title	Submitted Date	Granted Date
US8188085	Antifungal agents	2010-05-06	2012-05-29

ungal infection is a major healthcare problem, and the incidence of hospital-acquired fungal diseases continues to rise. Severe systemic fungal infection in hospitals (such as candidiasis, aspergillosis, histoplasmosis, blastomycosis and coccidioidomycosis) is commonly seen in neutropaenic patients following chemotherapy and in other oncology patients with immune suppression, in patients who are immune-compromised due to Acquired Immune Deficiency Syndrome (AIDS) caused by HIV infection, and in patients in intensive care. Systemic fungal infections cause ˜25% of infection-related deaths in leukaemics. Infections due to Candida species are the fourth most important cause of nosocomial bloodstream infection. Serious fungal infections may cause 5-10% of deaths in patients undergoing lung, pancreas or liver transplantation. Treatment failures are still very common with all systemic mycoses. Secondary resistance also arises. Thus, there remains an increasing need for effective new therapy against mycotic infections.

Enfumafungin is a hemiacetal triterpene glycoside that is produced in fermentations of a Hormonema spp. associated with living leaves of Juniperus communis (U.S. Pat. No. 5,756,472; Pelaez et al., Systematic and Applied Microbiology, 23:333-343, 2000; Schwartz et al., JACS, 122:4882-4886, 2000; Schwartz, R. E., Expert Opinion on Therapeutic Patents, 11(11):1761-1772, 2001). Enfumafungin is one of the several triterpene glycosides that have in vitro antifungal activities. The mode of the antifungal action of enfumafungin and other antifungal triterpenoid glycosides was determined to be the inhibition of fungal cell wall glucan synthesis by their specific action on (1,3)-β-D-glucan synthase (Onishi et al., Antimicrobial Agents and Chemotherapy, 44:368-377, 2000; Pelaez et al., Systematic and Applied Microbiology, 23:333-343, 2000). 1,3-β-D-Glucan synthase remains an attractive target for antifungal drug action because it is present in many pathogenic fungi which affords broad antifungal spectrum and there is no mammalian counterpart and as such, compounds inhibiting 1,3-β-D-Glucan synthase have little or no mechanism-based toxicity.

SIMILAR BUT NOT SAME

METHOXY EXAMPLE

Example 8

(1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[3-(methoxycarbonyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (EXAMPLE 8A) and (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3-dimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(methoxycarbonyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (EXAMPLE 8B)

(MOL) (CDX)

Methyl 1,2,4-triazole-3-carboxylate (27.1 mg, 0.213 mmol) and BF 3OEt 2 (54 μl, 0.426 mmol) were added to a stirred solution of Intermediate 6 (25.9 mg, 0.043 mmol) in 1,2-dichloroethane (0.43 ml). The reaction mixture was a light yellow suspension that was heated at 50° C. for 7.5 hr and then stirred at room temperature for 64 hr. The solvent was evaporated and the resulting residue was placed under high vacuum. The residue was dissolved in methanol and separated using a single HPLC run on a 19×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The HPLC fractions of the faster eluting regioisomer were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give EXAMPLE 8A (8.9 mg, 10.97 μmol) as a white solid. The HPLC fractions of the slower eluting regioisomer were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from ethanol and benzene to give EXAMPLE 8B (1.5 mg, 1.85 μmol) as a white solid.

Example 8A

1H NMR (CD 3OD, 600 MHz, ppm) δ 0.76 (s, 3H, Me), 0.76 (d, 3H, Me), 0.79 (d, 3H, Me), 0.83 (d, 3H, Me), 0.85 (d, 3H, Me), 0.88 (s, 3H, Me), 0.88 (s, 3H, Me), 0.89 (d, 3H, Me), 1.16 (s, 3H, Me), 1.20 (s, 3H, Me), 1.22-1.35 (m), 1.39-1.44 (m), 1.47-1.65 (m), 1.78-2.02 (m), 2.10-2.22 (m), 2.46 (dd, 1H, H13), 2.66 (d, 1H), 2.83 (s, 1H, H7), 3.48 (d, 1H), 3.50 (d, 1H), 3.53 (dd, 1H), 3.60 (d, 1H), 3.77 (d, 1H), 3.92 (d, 1H), 3.95 (s, 3H, COOMe), 5.48 (dd, 1H, H5), 5.61-5.68 (m, 1H, H14), 8.77 (broad s, 1H, triazole).

Mass Spectrum: (ESI) m/z=697.42 (M+H).

Example 8B

1H NMR (CD 3OD, 600 MHz, ppm) δ 0.76 (s, 3H, Me), 0.76 (d, 3H, Me), 0.79 (s, 3H, Me), 0.79 (d, 3H, Me), 0.82 (d, 3H, Me), 0.85 (d, 3H, Me), 0.88 (s, 3H, Me), 0.89 (d, 3H, Me), 1.13 (s, 3H, Me), 1.20 (s, 3H, Me), 1.22-1.36 (m), 1.39-1.44 (m), 1.47-1.55 (m), 1.59-1.65 (m), 1.72-1.96 (m), 2.10-2.22 (m), 2.46 (dd, 1H, H13), 2.78 (d, 1H), 2.84 (s, 1H, H7), 3.48 (d, 1H), 3.50 (d, 1H), 3.55 (dd, 1H), 3.62 (d, 1H), 3.93 (d, 1H), 3.98 (d, 1H), 3.99 (s, 3H, COOMe), 5.47 (dd, 1H, H5), 6.53-6.59 (m, 1H, H14), 8.14 (s, 1H, triazole).

Mass Spectrum: (ESI) m/z=697.42 (M+H).

1. EP-2326172-B1

US-20100113439-A1

/////////////MK 5204, BM178545

NC(=O)c6ncnn6[C@@H]1C[C@]45COC[C@@](C)([C@H]1OC[C@](C)(N)C(C)(C)C)[C@@H]5CC[C@H]3C4=CC[C@@]2(C)[C@H](C(=O)O)[C@](C)(CC[C@@]23C)[C@H](C)C(C)C

CC(C)C(C)C1(CCC2(C3CCC4C5(COCC4(C3=CCC2(C1C(=O)O)C)CC(C5OCC(C)(C(C)(C)C)N)N6C(=NC=N6)C(=O)N)C)C)C

BAY 1895344

BAY-1895344

BAY-1895344 (hydrochloride)

1876467-74-1

1876467-74-1(free base)

s8666, CCG-268786, CS-7574, HY-101566A

BAY-1895344 hydrochloride is a potent, orally available and selective ATR inhibitor, with IC₅₀ of 7 nM. Anti-tumor activity.

NMR https://file.selleckchem.com/downloads/nmr/S866603-BAY-1895344-hnmr-selleck.pdf

Biological Activity

In vitro, BAY 1895344 was shown to be a very potent and highly selective ATR inhibitor (IC50 = 7 nM), which potently inhibits proliferation of a broad spectrum of human tumor cell lines (median IC50 = 78 nM). In cellular mechanistic assays BAY 1895344 potently inhibited hydroxyurea-induced H2AX phosphorylation (IC50 = 36 nM). Moreover, BAY 1895344 revealed significantly improved aqueous solubility, bioavailability across species and no activity in the hERG patch-clamp assay. BAY 1895344 also demonstrated very promising efficacy in monotherapy in DNA damage deficient tumor models as well as combination treatment with DNA damage inducing therapies.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models

Journal of Medicinal Chemistry  2020, 63, 13, 7293-7325 (Article)

Publication Date (Web):June 5, 2020DOI: 10.1021/acs.jmedchem.0c00369

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.0c00369

2-[(3R)-3-Methylmorpholin-4-yl]-4-(1-methyl-1Hpyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-naphthyridine (BAY 1895344). Sulfonate 67 (500 mg, 0.95 mmol), 1- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (68) (415 mg, 1.90 mmol), 2 M aq K2CO3 solution (1.4 mL), and Pd(PPh3)2Cl2 (67 mg, 0.094 mmol) were solubilized in DME (60 mL). The reaction mixture was stirred for 20 min at 130 °C under microwave irradiation. After cooling to rt, the mixture was filtered through a silicon filter and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica gel, hexane/EtOAc gradient 0–100%, followed by EtOAc/EtOH 9:1). The desired fractions were concentrated under reduced pressure and solubilized in concd H2SO4 (5 mL). The mixture was stirred for 3 h at rt. The mixture was then poured into ice and basified using solid NaHCO3. The suspension was filtered and the solid was stirred with EtOH at 40 °C, filtered, and dried under reduced pressure to give BAY 1895344 (280 mg, 0.75 mmol, 78%). LC-MS [Method 2]: Rt = 0.99 min. MS (ESI+): m/z = 376.1 [M+H]+ . 1H NMR (400 MHz, DMSO-d6): δ = 13.44 (br s, 1H, pyrazole-NH), 8.35 (d, J = 5.32 Hz, 1H, naphthyridine), 7.56–7.68 (m, 3H, pyrazole, naphthyridine), 7.42 (br s, 1H, pyrazole), 7.27 (d, J = 5.58 Hz, 1H, naphthyridine), 6.59 (d, J = 2.03 Hz, 1H, pyrazole), 4.60–4.69 (m, 1H, morpholine), 4.23 (br d, J = 11.66 Hz, 1H, morpholine), 4.00–4.09 (m, 1H, morpholine), 3.78–3.85 (m, 1H, morpholine), 3.75 (m, 4H, methyl, morpholine), 3.69–3.74 (m, 1H, morpholine), 3.57 (m, 1H, morpholine), 1.30 (d, J = 6.59 Hz, 3H, methyl). 13C NMR (125 MHz, DMSO-d6): δ = 156.5, 145.2, 140.0, 139.6, 139.5, 138.2, 137.4, 137.4, 125.7, 117.1, 115.5, 108.2, 107.7, 70.3, 66.1, 47.3, 39.7, 37.2, 13.3. ESI-HRMS: m/z [M+H]+ calcd for C20H22N7O: 376.1886, found: 376.1879. [α]D –80.8 ± 1.04 (1.0000 g/ 100 mL CHCl3).

References

Identification of potent, highly selective and orally available ATR inhibitor BAY 1895344 with favorable PK properties and promising efficacy in monotherapy and combination in preclinical tumor models
Ulrich T, et al. AACR. 2017 July;77(13 Suppl):Abstract nr 983.

ATR inhibitor BAY 1895344 shows potent anti-tumor efficacy in monotherapy and strong combination potential with the targeted alpha therapy Radium-223 dichloride in preclinical tumor models
Antje Margret Wengner, et al. AACR 2017 July;77(13 Suppl):Abstract nr 836.

////////////s8666, CCG-268786, CS-7574, HY-101566A, BAY-1895344, BAY 1895344

CC1COCCN1C2=NC3=C(C=CN=C3C4=CC=NN4)C(=C2)C5=CC=NN5C

Diquafosol

• Molecular FormulaC₁₈H₂₆N₄O₂₃P₄
• Average mass790.307 Da

Diquafosol (tradename Diquas) is a pharmaceutical drug for the treatment of dry eye disease. It was approved for use in Japan in 2010.^[1] It is formulated as a 3% ophthalmic solution of the tetrasodium salt.

Its mechanism of action involves agonism of the P2Y2 purinogenic receptor.^[2]

SYN

INS-365 can also been obtained by the following ways: 4) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with bis(tributylammonium) pyrophosphate (II) by means of CDI, followed by purification by semipreparative ion璭xchange chromatography. 5) Dimerization of uridine-5′-monophosphate tributyl-ammonium salt (I) with pyrophosphoryl chloride (III) in pyridine, followed by chromatographic purification as before. 6) Condensation of uridine (IV) with POCl3 and bis(tributylammonium) pyrophosphate (II) by means of tributylamine in trimethyl phosphate, followed by chromatographic purification as before. 7) Dimerization of uridine-5′-diphosphate tributylammonium salt (V) by means of CDI in DMF, followed by purification over Dowex 50Wx4 Na+. 8) Condensation of uridine-5′-triphosphate tributylammonium salt (VI) with uridine-5′-monophosphate tributyl-ammonium salt (I) by means of DCC in DMF, followed by chromatographic purification as before. 9) Reaction of uridine-5′-monophosphate tributylammonium salt (I) with CDI in DMF, followed by condensation with uridine-5′-triphosphate (VI) and chromatographic purification as before.

CLIP

• China

Route 1

Reference：1. WO9905155A2.

Route 2

Reference：1. WO1999005155.

2. Bioorg. Med. Chem. Lett. 2001, 11, 157-160.

Route 3

Reference：1. WO1999005155.

Route 4

Reference：1. WO2014103704.

SYN

Practical and Efficient Approach to the Preparation of Diquafosol Tetrasodium

• • Pengfei Xu

Cite this: Org. Process Res. Dev. 2020, XXXX, XXX, XXX-XXX

Publication Date:June 30, 2020

https://doi.org/10.1021/acs.oprd.0c00209

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.0c00209/suppl_file/op0c00209_si_001.pdf

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00209

A scalable and practical route to synthesize the P2Y2 receptor agonist diquafosol tetrasodium has been described. Diquafosol tetrasodium was obtained via a four-step process starting from commercially available 5′-uridylic acid disodium salt. The whole procedure gives the target product in a 45% overall yield with high purity (>99%). Key steps in this process including isolation of impurities and the target product by using anion-exchange resin are discussed in detail. The optimized process has been successfully demonstrated on a large scale to support the development of diquafosol tetrasodium in China.

References

1. ^ “Santen and Inspire Announce Approval of DIQUAS for Dry Eye Treatment in Japan”. April 16, 2010.
2. ^ Pendergast, W; Yerxa, BR; Douglass Jg, 3rd; Shaver, SR; Dougherty, RW; Redick, CC; Sims, IF; Rideout, JL (2001). “Synthesis and P2Y receptor activity of a series of uridine dinucleoside 5′-polyphosphates”. Bioorganic & Medicinal Chemistry Letters. 11 (2): 157–60. doi:10.1016/S0960-894X(00)00612-0. PMID 11206448.

Diquafosol

Names
IUPAC name [[[[(2R,3S,4R,5R)-5-(2,4-Dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methoxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl] [(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxy-tetrahydrofuran-2-yl]methyl hydrogen phosphate
Other names P1,P4-Bis(5′-uridyl) tetraphosphate; INS-365; Diquafosol tetrasodium
Identifiers
CAS Number	59985-21-6  211427-08-6 (tetrasodium salt)
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1767408 ChEMBL221326
ChemSpider	130647 130646 (tetrasodium salt)
IUPHAR/BPS	1736
PubChem CID	148197 148196 (tetrasodium salt)
UNII	7828VC80FJ
CompTox Dashboard (EPA)	DTXSID40208689
InChI[show]
SMILES[show]
Properties
Chemical formula	C18H26N4O23P4
Molar mass	790.306 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

///////////// INS 365, Diquafosol, INS-365,  DE 089,  KPY 998, JAPAN 16

59985-21-6 (Diquafosol ); 211427-08-6 (Diquafosol Tetrasodium);

sulcardine, HBI-3000

B 87823

• Molecular FormulaC₂₄H₃₃N₃O₄S
• Average mass459.602 Da

N-[[4-hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)phenyl]methyl]-4-methoxybenzenesulfonamide

heart arrhythmia

CAS No. : 343935-61-5 (Sulcardine sulfate)

• Originator Jiangsu Furui Pharmaceuticals; Shanghai Institute of Materia Medica
• Developer HUYA Bioscience International; Jiangsu Furui Pharmaceuticals
• Class Antiarrhythmics; Small molecules
• Mechanism of ActionIon channel antagonists

• Phase I Atrial fibrillation
• No development reported Arrhythmias

• 13 Mar 2020 Chemical structure information added
• 28 Feb 2020 No recent reports of development identified for preclinical development in Arrhythmias in USA (IV)
• 16 Dec 2019 Adverse events data from a phase I trial in Atrial fibrillation (In volunteers) presented at the American Heart Association Scientific Sessions 2019 (AHA-2019)

HUYA Bioscience , under license from Shanghai Institute of Materia Medica (SIMM), is developing sulcardine (HBI-3000, oral, i.v, heart arrhythmia), a myocardial ion channel inhibitory compound, for the treatment of arrhythmia; In September 2016, the drug was still in phase II development, as of August 2020, the company website states that a phase II trial was pending in China.

HBI-3000 (sulcardine sulfate) is an experimental drug candidate that is currently in phase II of human clinical trials as an antiarrhythmic agent.^{[1][needs update]} Clinical investigation will test the safety and efficacy of HBI-3000 as a treatment for both atrial and ventricular arrhythmias.^[2]

The molecular problem

Anti-arrhythmic medication is taken to treat irregular beating of the heart. This irregular beating results from a deregulation of the initiation or propagation of the electrical stimulus of the heart. The most common chronic arrhythmia is atrial fibrillation.^[3] There is an increased incidence of atrial fibrillation in the elderly and some examples of complications include heart failure exacerbation, hypotension and thrombembolic events.^[3]

Most anti-arrhythmic medications exert their effects by decreasing the permeability of potassium ion channels (IKr) in heart cells. These potassium channel blockers delay ventricular repolarization and prolong action potential duration (APD; the prolongation of the electrical stimulus within heart cells). These changes can lower heart rate, eliminate atrial fibrillation, and ultimately sudden cardiac death.^[4][5]

Mechanism of action in ventricular myocytes

Ventricular myocytes are heart muscle cells found in the lower chambers of the heart. Heart rate is dependent on the movement of an electrical stimulus through the individual heart cells. This is mediated by the opening of ion channels on cell surfaces. HBI-3000 exerts its effects on the heart by inhibiting multiple ion channels (INa-F, INa-L, ICa-L and IKr), but predominantly the INa-L ion channel . By decreasing the ion permeability of these channels, HBI-3000 slightly prolongs APD (due to IKr); however, unlike pure IKr channel blockers, it is self-limited (due to the decreased permeability of INa-L and ICa-L). This is similar to the medications ranolazine and amiodarone.^[5] HBI-3000 suppresses early afterdepolarizations (EADs; a change in the normal net flow of ions during repolarization), does not produce any electrical abnormalities, and displays minimally pronounced prolongation of APD during a slow heart rate (i.e. stimulated at a slower frequency). Pronounced prolongation of APD during a slow heart rate can lead to proarrythmias. Overall, HBI-3000 seems to have a low proarrhythmic risk. The effect of HBI-3000 on contractility and cardiac conduction requires further investigation.^[5]

Studies

Animal model

In a canine model, the intravenous injection of HBI-3000 demonstrated to be an effective anti-arrhythmic and anti-fribrillatory agent.^[6]

Cellular isolation

The administration of HBI-3000 to isolated heart muscle cells demonstrated the potential to improve arrhythmias while having low proarrhythmic risk.^[5]

Human studies

Jiangsu Furui Pharmaceuticals Co., Ltd is currently recruiting participants in their study.^[1][

PAPER

 Acta Pharmacologica Sinica 2012

Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent

D. Bai, Wei-zhou Chen, +6 authors Y. Wang

http://www.simm.cas.cn/wyp/wyp_lw/201804/W020180420480084769998.pdf

N-[3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl]-4-methoxybenzenesulfamide (sulcardine, 6f) and the sulfate (sulcardine sulfate) (1) To a suspension of 4-hydroxybenzylamine (133 g, 1.08 mol) in DMF (500 mL) was added dropwise 4-methoxybenzensul-fonyl chloride (206 g, 1.00 mol) in DMF (320 mL) over a period of 30 min at 0–10 °C with stirring, followed by the addition of triethylamine (158 mL, 1.12 mol) over 30 min at the same temperature. The stirring was continued for an additional 1.5 h at room temperature. The reaction mixture was poured into ice-water (5 L). After stirring for 10 min, the suspension was allowed to stand for 2 h. The solid was filtered, washed with water (300 mL×3), and dried in a desiccator over anhydrous calcium chloride, yielding N-(4-hydroxybenzyl)-4-methoxybenzenesulfamide (11) (248 g, 85%) as a white solid, mp 160–162 °C. The authentic sample was obtained by recrystallization from ethyl acetate, mp 161–162 °C. 1 H NMR (CD3OD) δ 3.70 (s, 3H), 3.76 (s, 2H), 6.48 (d, J=8.4 Hz, 2H), 6.82(d, J=8.4 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H). EIMS (m/z): 293 (M+ ), 254, 195, 185, 171, 155, 149, 122 (100), 107, 99, 77, 65. Anal. (C14H15NO4S) C, H, N.

(2) A mixture of 11 (230 g, 0.78 mmol), pyrrolidine (200 mL, 2.44 mol) and 36% aqueous formaldehyde (250 mL, 3.30 mol) in ethanol (800 mL) was stirred under reflux for 8 h. The reaction mixture was concentrated under vacuum to dryness. The resulting oil residue was dissolved in chloroform (350 mL), and the solution was washed with water (300 mL×3). Under stirring, the organic layer was mixed with water (300 mL), and then concentrated hydrochloric acid (approximately 165 mL) was added portionwise at 0-10 °C to adjust the pH of the aqueous phase to ~2. The aqueous phase was washed with chloroform (200 mL) and then mixed with additional chloroform (300 mL). Under stirring, the two-phase mixture was treated portionwise with 25%–28% aqueous ammonia (~300 mL) to adjust the pH of the aqueous phase to 9–10. The organic layer was separated, and the aqueous layer was further extracted with chloroform (200 mL×2). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to dryness. The oily residue was treated with acetone (45 mL) and isopropyl ether (290 mL), and the mixture was heated under reflux until the suspension became a solution. The solution was cooled to room temperature, seeded with an authentic sample, and allowed to stand at 0°C overnight. The solid was filtered and dried under vacuum, yielding product 6f (290 g, 81%) as a yellowish solid, mp 96–98 °C. The authentic sample was obtained by preparative TLC or column chromatography (silica gel; CHCl3:MeOH:25% NH4OH=92:7:1). The compound could be recrystallized from ethanol-water, mp 101–102 °C. 1 H NMR (CDCl3) δ 1.77–1.86 (m, 8H), 2.53–2.63 (m, 8H), 3.68 (s, 4H), 3.86 (s, 3H), 3.97 (s, 2H), 6.86 (s, 2H), 6.95 (d, J=8.7 Hz, 2H), 7.78 (d, J=8.6 Hz 2H). EIMS (m/z): 459 (M+ ), 390, 388, 202, 171, 148, 107, 84, 70 (100). Anal. (C24H33N3O4S) C, H, N.

(3) Under stirring, the Mannich base 6f (150.5 g, 0.327 mol) was mixed with 2 mol/L H2SO4 (172 mL, 0.344 mol), and the mixture was heated at 80 °C until the solid dissolved. The solution was cooled to room temperature, seeded with an authentic sample, and the sulfate of 6f was formed as crystals. To the stirred mixture was added anhydrous ethanol (520 mL), and the mixture was allowed to stand at 0°C for 24 h. The solid was filtered, washed with ethanol, and recrystallized with 80% ethanol (250 mL). The sulfate was dried over concentrated sulfuric acid in a desiccator, giving the sulfate of 6f (143 g, 71%) as a trihydrate, mp 125–140°C. 1 H NMR (D2O) δ 2.00–2.13 (m, 4H), 2.14–2.25 (m, 4H), 3.12–3.22 (m, 4H), 3.45– 3.55 (m, 4H), 3.90 (s, 3H), 4.20 (s, 2H), 4.33 (s, 4H), 7.06 (d, J=8.7 Hz, 2H), 7.28 (s, 2H), 7.66 (d, J=8.9 Hz, 2H). 13C NMR (D2O) δ 24.7, 47.6, 55.7, 56.1, 58.1, 116.6, 122.5, 131.3, 132.3, 133.3, 136.0, 155.8, 164.8. EIMS (m/z): 459, 390, 388, 202, 171, 148, 107, 84, 70 (100). Anal. (C24H33N3O4S∙H2SO4∙3H2O) C, H, N, S.

PATENT

Preparation of sulcardine sulfate salt has been reported in U.S. Patent No. 6,605,635.

https://patents.google.com/patent/US6605635

Synthesis and antiarrhythmic activities of changrolin (1) have been reported (Liangquan Li, et al., Scientia Sinica, 1979, 7, 723; Weizhou Chen, et al., Acta Pharmaceutica Sinica, 1979, 14, 710). Thereafter, investigations of the chemical structural modifications and the physiological activities have successively been carried out by domestic and foreign scientists (Cunji Sun, et al., Acta Pharmaceutica Sinica, 1981, 16, 564; 1986, 21, 692; Mulan Lin, et al., ibid., 1982, 17, 212; D. M. Stout, et al. J. Med. Chem., 1983, 26, 808; 1984, 27, 1347; 1985, 28, 295; 1989, 32, 1910; R. J. Chorvat, et al., ibid., 1993, 36, 2494).

Changrolin is an effective antiarrhythmic agent. Ventricular premature beats disappear 2-3 days after oral administration of changrolin to patients suffering from arrhythmia; I.v. injection or instillaton may result in significant reduction or even disappearence of ventricular premature beats and ventricular tachycardia. However, oral administration of changrolin for a period of over one month may cause a reversible pigmentation on the skin of patients, which gradually retrogresses after ceasing the administration. This pigmentation is associated to the subcutaneous oxidation of certain structural moieties in changrolin molecule or to its instability in solution.

EXAMPLE 1N-[3,5-bis(1-Piperidinomethyl)-4-hydroxy]phenyl-1-naphthalenesulfonamide (B-87836)

(1) To a solution of 4-aminophenol (4.5 g) in dioxane (20 ml) was added dropwise a solution of 1-naphthalenesulfonyl chloride (4.4 g) in dioxane (20 ml). The mixture was further stirred at room temperatue for 4.5 hours and poured into water. The precipitate was collected by filtration, recrystallized from ethanol and decolored with activated carbon to give N-(ρ-hydroxyphenyl)-1-naphthalenesulfonamide (4.2 g), mp 195-196° C.

(2) A mixture of N-(ρ-hydroxyphenyl)-1-naphthalenesulfonamide (2.0 g), 37% aqueous formaldehyde (4.5 g) and piperidine (5.6 g) in ethanol (100 ml) was heated to reflux for 50 hours. The ethanol was removed by evaporation in vacuo and chloroform was added to the residue. The organic layer was washed with water then dried over anhydrous Na₂SO₄. Then the chloroform was removed in vacuo and the residue was triturated in water to give a solid, which was then recrystallized from ethanol to give the titled product (1.4 g), mp 197-198° C.

¹HNMR(CDCl₃): 1.30-1.50(m, 12H), 2.10-2.21(m, 8H), 3.28(s, 4H), 6.45(s, 2H), 7.24-8.04(m, 6H), 8.56(m, 1H). Elemental analysis (C₂₈H₃₅N₃O₃S ): Calcd. (%): C, 68.12; H, 7.15; N, 8.51. Found (%): C, 67.96; H, 7.16; N, 8.56.

PATENT

WO-2020159959

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020159959&tab=PCTDESCRIPTION&_cid=P11-KDSBL9-99100-1

Novel crystalline forms of acid salts of sulcardine useful for treating arrhythmia and atrial fibrillation.

4-Methoxy-N-(3,5-bis-(l-pyrrolidinylmethyl)-4-hydroxybenzyl)benzene sulfonamide (or N-(4-hydroxy-3,5-bis(pyrrolidin-l-ylmethyl)benzyl)-4-methoxybenzenesulfonamide), also known as sulcardine, and its salts, such as sulcardine sulfate, constitute a group of compounds with potent anti -arrhythmic activity. Sulcardine is a multi-ion channel blocker that specifically inhibits iNa-Peak, iNa-Late, Ica,L, and Ixrwith similar in vitro potencies (and Ito and IK_UT to a lesser degree) in human atrial cardiomyocytes and represents what may be the sole example of a substituted sulfonamide class of anti-arrhythmic. Sulcardine salts can be used as an intravenous injectable or as oral doses for the treatment of arrhythmias, including supraventricular tachyarrhythmia, premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, and atrial fibrillation. See, e.g ., U.S. Patent Nos. 8,541,464 and 8,637,566. Preparation of sulcardine sulfate salt has been reported in U.S. Patent No. 6,605,635.

[0004] In addition, the evidence to date suggests that one advantage of sulcardine and its salts is that they lack significant pro-arrhythmic activity, as demonstrated in rigorous preclinical safety models, including a post-MI sudden-death conscious canine model and the validated rabbit ventricular wedge model. Additionally, it has been shown that they do not significantly increase defibrillation threshold, nor increase defibrillation failure risk in a post-MI canine model as was seen with flecainide. On the basis of these data, sulcardine and salts, with their very low apparent pro-arrhythmic potential, could potentially be used to treat acute and recurrent atrial fibrillation in the presence of organic heart disease, prolonged QR syndrome, and ventricular arrhythmias, including premature ventricular contractions (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF), in either acute- or chronic-administration settings owing to their ability to be formulated into intravenous and oral dosing formulations.

Sulcardine has a chemical name of 4-methoxy-N-(3,5-bis-(l-pyrrolidinylmethyl)- 4-hydroxybenzyl)benzene sulfonamide (or N-(4-hydroxy-3,5-bis(pyrrolidin-l-ylmethyl)benzyl)-4-methoxybenzenesulfonamide), and has the following structure:

[0062] Sulcardine sulfate has the following structure:

[0063] Sulcardine sulfate can exist in a hydrated form. One such form is a trihydrate.

HPLC analysis was performed on a Dionex Ultimate 3000 instrument with the following parameters:

Column: Phenomenex Luna C18, 150×4.6mm, 5pm

Column Temperature: 30°C

Mobile Phase A: 0.2% Phosphoric Acid

Mobile Phase B: Methanol

Diluent: 50:50 MeOH:H₂0

Runtime: 12 minutes

Flow Rate: l.OmL/min

Injection Volume: 5pL

Detection: 237 nm

Gradient:

EXAMPLE 2 – PREPARATION OF FREE BASE AND SCREENING

[00348] Sulcardine sulfate trihydrate was dissolved in ethyl acetate (16 vol.) and saturated sodium bicarbonate solution (16 vol.). The biphasic solution was transferred to a separating funnel and the layers separated. The organic layer was dried over sodium sulfate and then the solvent was removed by rotary evaporation and the resulting oil dried under vacuum at ambient temperature for ca. 3 hr. FIG. 4 is an XRPD pattern of the resulted amorphous sulcardine free base. In all cases, the initial screening work detailed below was performed on 10 mg of sulcardine free base. All XRPD diffractograms were compared with sulcardine sulfate trihydrate, sulcardine free base and relevant counterions and found to be distinct.

Patent

WO2020123824

claiming treatment of atrial fibrillation (AF) by intravenously administering sulcardine sulfate .

PATENT

US6605635

References

1. ^ Jump up to:^a b Jiangsu Furui Pharmaceuticals (November 5, 2010). “Efficacy and safety of sulcardine sulfate tablets in patients with premature ventricular contractions”. ClinicalTrials.gov. U.S. National Library of Medicine. Retrieved 2019-12-20.
2. ^ “HUYA Bioscience Int’l announces clinical trial milestones in China for promising new anti-arrhythmic compound; Data supports desirable safety profile” (Press release). San Francisco, California: HUYA Bioscience International. Retrieved 2019-12-20.
3. ^ Jump up to:^a b Mashal, Abdallah; Katz, Amos; Shvartzman, Pesach (2011). “Atrial fibrillation: A primary care cross-sectional study”. Israel Medical Association Journal. 13 (11): 666–671. PMID 22279699.
4. ^ Farkas, András; Leprán, István; Papp, Julius Gy. (1998). “Comparison of the antiarrhythmic and the proarrhythmic effect of almokalant in anaesthetised rabbits”. European Journal of Pharmacology. 346 (2–3): 245–253. doi:10.1016/S0014-2999(98)00067-3. PMID 9652366.
5. ^ Jump up to:^a b c d Guo, Donglin; Liu, Que; Liu, Tengxian; Elliott, Gary; Gingras, Mireille; Kowey, Peter R.; Yan, Gan-Xin (2011). “Electrophysiological properties of HBI-3000: A new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes”. Journal of Cardiovascular Pharmacology. 57 (1): 79–85. doi:10.1097/FJC.0b013e3181ffe8b3. PMID 20980921.
6. ^ Lee, Julia Y.; Gingras, Mireille; Lucchesi, Benedict R. (2010). “HBI-3000 prevents sudden cardiac death in a conscious canine model”. Heart Rhythm. 7 (11): 1712. doi:10.1016/j.hrthm.2010.09.028.

HBI-3000

Names
IUPAC name N-({4-Hydroxy-3,5-bis[(pyrrolidin-1-yl)methyl]phenyl}methyl)-4-methoxybenzene-1-sulfonamide
Identifiers
CAS Number	343935-60-4  343935-61-5 (sulfate)
3D model (JSmol)	Interactive image
ChemSpider	8318784
PubChem CID	10143275
UNII	4Q5HLV8HG1  4NDN0NJZ62 (sulfate)
InChI[hide] InChI=1S/C24H33N3O4S/c1-31-22-6-8-23(9-7-22)32(29,30)25-16-19-14-20(17-26-10-2-3-11-26)24(28)21(15-19)18-27-12-4-5-13-27/h6-9,14-15,25,28H,2-5,10-13,16-18H2,1H3 Key: SYZGIWXQGIBJGN-UHFFFAOYSA-N InChI=1/C24H33N3O4S/c1-31-22-6-8-23(9-7-22)32(29,30)25-16-19-14-20(17-26-10-2-3-11-26)24(28)21(15-19)18-27-12-4-5-13-27/h6-9,14-15,25,28H,2-5,10-13,16-18H2,1H3 Key: SYZGIWXQGIBJGN-UHFFFAOYAK
SMILES[hide] O=S(=O)(c1ccc(OC)cc1)NCc2cc(c(O)c(c2)CN3CCCC3)CN4CCCC4
Properties
Chemical formula	C24H33N3O4S
Molar mass	459.61 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references