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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Convidicea (Ad5-nCoV)


A vial of Convidecia vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typeViral vector
Clinical data
Trade namesConvidecia
Routes of
administration
IntramuscularIntranasal
ATC codeNone
Legal status
Legal statusFull and Emergency authorizations
Identifiers
DrugBankDB15655

Convidicea (Ad5-nCoV)

Recombinant vaccine (adenovirus type 5 vector)

Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector)

CanSino Biologics, china

see https://covid19.trackvaccines.org/vaccines/2/

AD5-nCOV, trade-named Convidecia, is a single-dose[1] viral vector vaccine for COVID-19 developed by CanSino Biologics. It conducted its Phase III trials in Argentina,[2] Chile,[3] Mexico,[4] Pakistan,[5] Russia,[6] and Saudi Arabia[7] with 40,000 participants.

In February 2021, global data from Phase III trials and 101 COVID cases showed that the vaccine had a 65.7% efficacy in preventing moderate symptoms of COVID-19, and 91% efficacy in preventing severe disease.[8] It has similar efficacy to Johnson & Johnson’s Ad26.COV2.S, another one-shot adenovirus vector vaccine with 66% efficacy in a global trial.[9][1] Convidecia is similar to other viral vector vaccines like AZD1222Gam-COVID-Vac, and Ad26.COV2.S.[10] Its single-dose regimen and normal refrigerator storage requirement (2°to 8 °C) could make it a favorable vaccine option for many countries.[9]

Convidecia is approved for use by some countries in Asia,[11][12][13] Europe,[14][15] and Latin America.[16][17][18] Production capacity for Ad5-NCov should reach 500 million doses in 2021. Manufacturing will take place in China,[19] Malaysia,[13] Mexico,[20] and Pakistan.[21]

Ad5-nCoV is a recombinant adenovirus type-5 vector (Ad5) vaccine currently being investigated for prophylaxis against SARS-CoV-2.1,2 It is being developed by CanSino Biologics Inc., in partnership with the Beijing Institute of Biotechnology, who in March 2020 announced the approval of a phase I clinical trial (ChiCTR2000030906)1 with an expected completion in December 2020. The study will evaluate antibody response in healthy patients between the ages of 18 and 60 who will receive one of three study doses, with follow-up taking place at weeks 2 and 4 and months 3 and 6 post-vaccination.2

  1. Chinese Clinical Trial Register: A phase I clinical trial for recombinant novel coronavirus (2019-COV) vaccine (adenoviral vector) [Link]
  2. Antibody Society: COVID-19 Archives [Link]

Technology

Convidecia is a viral vector vaccine similar to AstraZeneca‘s AZD1222 and Gamaleya‘s Gam-COVID-Vac.[10] Ad5-nCOV can be stored in less extreme cold conditions compared to mRNA vaccines.[22][9]

Efficacy

In February 2021, data released from an interim analysis of Phase III trials with 30,000 participants and 101 COVID cases showed that globally, the vaccine had an efficacy of 65.7% at preventing moderate cases of COVID-19 and 90.98% efficacy at preventing severe cases. In the Pakistan trial subset, the vaccine had an efficacy of 74.8% at preventing symptomatic cases 100% for preventing severe disease.[8]

While the efficacy rates were lower than the Pfizer–BioNTech and Moderna vaccines, its single-dose regimen and normal refrigerator storage requirement (2 to 8 °C) could make it a favorable option for many countries. It has similar efficacy to Johnson & Johnson’s Ad26.COV2.S, another one-shot adenovirus vaccine found to be 66% effective in a global trial.[9][1]

Clinical trials

Phase I-II

In early 2020, Chen Wei led a joint team of the Institute of Biotechnology, the Academy of Military Medical Sciences and CanSino Biologics to develop AD5-nCOV. According to the Chinese state media, the team registered an experimental COVID-19 vaccine for Phase I trial in China on 17 March 2020 to test its safety. The trial was conducted on 108 healthy adults aged 18 to 60 in two medical facilities in WuhanHubei province.[23]

In April, Ad5-nCoV became the first COVID-19 vaccine candidate in the world to begin Phase II trials.[24] The Phase II trial results were published in the peer-reviewed journal The Lancet in August 2020, and noted neutralizing antibody and T cell responses based on statistical analyses of data involving 508 eligible participants.[25] In September, Zeng Guang, chief scientist of the Chinese Center for Disease Control and Prevention said the amount of COVID-19 antibodies in subjects from the Phase I trials remained high six months after the first shot. Zeng said the high levels of antibodies suggested the shots may provide immunity for an extended period of time, although Phase III results were still required.[26] On September 24, CanSino began Phase IIb trials on 481 participants to evaluate the safety and immunogenicity of Ad5-nCoV for children ages 6–17 and elderly individuals ages 56 and above.[27]

In August, China’s National Intellectual Property Administration issued the country’s first COVID-19 vaccine patent to CanSino.[28]

On 16 May 2020, Canadian Prime Minister Justin Trudeau announced Health Canada had approved Phase II trials to be conducted by the Canadian Center for Vaccinology (CCfV) on the COVID-19 vaccine produced by CanSino. Scott Halperin, director of the CCfV said the vaccine would not be the only one going into clinical trials in Canada, and any potential vaccine would not be publicly available until after Phase 3 is complete.[29][30] If the vaccine trials were successful, then the National Research Council would work with CanSino to produce and distribute the vaccine in Canada.[30] In August 2020, the National Research Council disclosed the vaccine had not been approved by Chinese customs to ship to Canada, after which the collaboration between CanSino and the Canadian Center for Vaccinology was abandoned.[31]

Nasal spray trials

In September, CanSino began a Phase I trial in China with 144 adults to determine the safety and immunogenicity of the vaccine to be administered as a nasal spray, in contrast with most COVID-19 vaccine candidates which require intramuscular injection.[32] On June 3, 2021, Chen Wei announced the expansion of clinical trials was approved by the NMPA, in the meantime, they are applying for Emergency Use Listing for the nasal spray.[33]

Phase III

In August, Saudi Arabia confirmed it would begin Phase III trials on 5,000 people for Ad5-nCoV in the cities of Riyadh, Dammam, and Mecca.[7]

In October, Mexico began Phase III trials on 15,000 volunteers.[34][4]

In September, Russia began Phase III trials on 500 volunteers,[35] which Petrovax later received approval from the government to expand to 8,000 more volunteers.[36][6]

In September, Pakistan began Phase III trials on 40,000 volunteers as part of a global multi-center study.[5] As of December, about 13,000 volunteers have participated in trials of Ad5-nCoV.[22]

In November, Chile began Phase III trials on 5,200 volunteers to be managed by University of La Frontera.[37][3]

In December, Argentina’s Fundación Huésped began Phase III trials in 11 health centers in the metropolitan area of Buenos Aires and Mar del Plata.[2]

Combination trials

In April 2021, a new trial was registered in Jiangsu involving one dose of Convidecia followed by a dose of ZF2001 28 or 56 days later using different technologies as a way to further boost efficacy.[38]

Manufacturing

In February, Chen Wei who lead the development of the vaccine, said annual production capacity for Ad5-NCov could reach 500 million doses in 2021.[19]

In February, Mexico received the first batch of active ingredients for Convidecia, which is being packaged in Querétaro by Drugmex.[20]

In Malaysia, final filling and packaging of the vaccine for distribution would be completed by Solution Biologics.[13]

In May, Pakistan began filling and finishing 3 million doses a month at the National Institute of Health, which would be branded as PakVac for domestic distribution.[39]

If the vaccine is approved in Russia, Petrovax said it would produce 10 million doses per month in 2021.[40]

Marketing and deployment

 
  Full authorization  Emergency authorization  Eligible COVAX recipient (ongoing assessment)[41]

See also: List of COVID-19 vaccine authorizations § Convidecia

Asia

On 25 June 2020, China approved the vaccine for limited use by the military.[42] In February 2021, China approved the vaccine for general use.[11]

In February, Malaysia‘s Solution Biologics agreed to supply 3.5 million doses to the government.[43] The doses would be delivered starting in April with 500,000 complete doses, with the rest in bulk to be finished by Solution Biologics.[13]

In October, Indonesia reached an agreement with CanSino to deliver 100,000 doses in November 2020, with the expectation that an additional 15 to 20 million doses would be delivered in 2021.[44]

In February, Pakistan approved the vaccine for emergency use.[45] The country purchased 20 million doses of the vaccine[12] of which the first 3 million doses are to arrive in May.[12]

Europe

In March, Hungary granted emergency use approval for the vaccine.[14]

In March, Moldova authorized use of the vaccine.[46]

North America

In December 2020, Mexico‘s Foreign Minister Marcelo Ebrard signed an agreement for 35 million doses.[47] In February, Mexico approved the vaccine for emergency use.[48] Mexico received active ingredients for 2 million doses with a total of 6 million doses expected to arrive in February.[16]

South America

In June, Argentina approved emergency use of the vaccine and ordered 5.4 million doses.[17]

In June, Brazil announced plans to purchase 60 million doses.[49] In May, Brazil began reviewing the vaccine for emergency use.[50]

In March, Chile signed a deal for 1.8 million doses for delivery between May and June,[51] for which emergency use approval was granted in April.[18]

In June, Ecuador approved emergency use and ordered 6 million doses for delivery between June and August 2021.[52]

References

  1. Jump up to:a b c “It’s not just Johnson & Johnson: China has a single-dose COVID-19 vaccine that has 65% efficacy”Fortune. Retrieved 2021-02-11.
  2. Jump up to:a b “Comenzará en la Argentina un nuevo estudio de vacuna recombinante contra el SARS-CoV-2”infobae (in Spanish). 14 December 2020. Retrieved 2020-12-15.
  3. Jump up to:a b “Gob.cl – Article: Science Minister: “We Work With Maximum Rigor So That Science And Technology Benefit People’S Health””Government of Chile. Retrieved 2020-11-21.
  4. Jump up to:a b “Chinese Covid vaccine trials to be expanded to five more states”Mexico News Daily. 2020-11-10. Retrieved 2020-11-11.
  5. Jump up to:a b “Phase III Trial of A COVID-19 Vaccine of Adenovirus Vector in Adults 18 Years Old and Above – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2020-10-21.
  6. Jump up to:a b Reuters Staff (2020-12-07). “Russia approves clinical trials for Chinese COVID-19 vaccine Ad5-Ncov: Ifax”Reuters. Retrieved 2020-12-07.
  7. Jump up to:a b Eltahir N (9 August 2020). “CanSino to start Phase III trial of COVID-19 vaccine in Saudi”Reuters. Retrieved 9 August 2020.
  8. Jump up to:a b “CanSinoBIO’s COVID-19 vaccine 65.7% effective in global trials, Pakistan official says”Reuters. 8 February 2021. Retrieved 2021-02-08.
  9. Jump up to:a b c d “China’s CanSino Covid Vaccine Shows 65.7% Efficacy”Bloomberg.com. 2021-02-08. Retrieved 2021-02-10.
  10. Jump up to:a b Zimmer C, Corum J, Wee SL (2020-06-10). “Coronavirus Vaccine Tracker”The New York TimesISSN 0362-4331. Retrieved 2020-12-12.
  11. Jump up to:a b Liu R (2021-02-25). “China approves two more domestic COVID-19 vaccines for public use”Reuters. Retrieved 2021-02-26.
  12. Jump up to:a b c “Pakistan purchases over 30 million COVID doses from China: sources”ARY NEWS. 2021-04-25. Retrieved 2021-04-26.
  13. Jump up to:a b c d “Malaysia to receive CanSino vaccine this month | The Malaysian Insight”http://www.themalaysianinsight.com. Retrieved 2021-04-03.
  14. Jump up to:a b Ashok R (2021-03-22). “UPDATE 2-China’s CanSino Biologics COVID-19 vaccine receives emergency use approval in Hungary”Reuters. Retrieved 2021-03-22.
  15. ^ “Membrii NITAG au venit cu recomandări privind utilizarea vaccinurilor împotriva COVID-19 în Republica Moldova”Ministerul Sănătății, Muncii și Protecţiei Sociale. 2021-03-03. Retrieved 2021-05-21.
  16. Jump up to:a b “‘Our gratitude always’: From China’s CanSino, Mexico welcomes biggest vaccine shipment yet”Reuters. 2021-02-11. Retrieved 2021-02-11.
  17. Jump up to:a b “Argentina issues emergency approval to China’s single-dose Cansino COVID-19 vaccine”Reuters. 2021-06-11. Retrieved 2021-06-11.
  18. Jump up to:a b “ISP Approves Emergency Use And Importation Of Cansino Vaccine To Fight COVID-19”Institute of Public Health of Chile. Retrieved 2021-04-08.
  19. Jump up to:a b “China can hit 500-mln-dose annual capacity of CanSinoBIO COVID-19 vaccine this year”finance.yahoo.com. Retrieved 2021-02-28.
  20. Jump up to:a b Solomon DB (2021-02-28). “China’s CanSino says first vaccines packaged in Mexico will be ready in March”Reuters. Retrieved 2021-03-12.
  21. ^ “Pakistan develops homemade anti-Covid vaccine ‘PakVac'”The Express Tribune. 2021-05-24. Retrieved 2021-05-25.
  22. Jump up to:a b Constable P, Hussain S. “Defying fears and skepticism, thousands in Pakistan volunteer for Chinese vaccine trials”The Washington PostISSN 0190-8286. Retrieved 2021-01-01.
  23. ^ Cui J (23 March 2020). “Human vaccine trial gets underway”China Daily. Retrieved 18 April 2020.
  24. ^ Xie J (15 April 2020). “China Announces Phase 2 of Clinical Trials of COVID-19 Vaccine”Voice of America. Retrieved 18 April2020.
  25. ^ Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. (August 2020). “Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial”Lancet396 (10249): 479–488. doi:10.1016/S0140-6736(20)31605-6PMC 7836858PMID 32702299.
  26. ^ O’Brien E (2020-09-25). “Covid Antibodies Endure Over Six Months in China Trial Subjects”http://www.bloomberg.com. Retrieved 2020-09-29.
  27. ^ “Phase IIb Clinical Trial of A COVID-19 Vaccine Named Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2020-10-21.
  28. ^ Yu S (17 August 2020). “China grants country’s first COVID-19 vaccine patent to CanSino: state media”Reuters. Retrieved 17 August 2020.
  29. ^ Bogart N (16 May 2020). “Health Canada approves first clinical trial for potential COVID-19 vaccine”CTV News. Retrieved 7 September 2020.
  30. Jump up to:a b Ryan H (May 16, 2020). “Canada’s first COVID-19 vaccine trials approved for Halifax university”CBC News. Retrieved January 4, 2021.
  31. ^ Cooke A (26 August 2020). “Canadian COVID-19 clinical trial scrapped after China wouldn’t ship potential vaccine”CBC News. Retrieved 7 September 2020.
  32. ^ “A Clinical Trial of a Recombinant Adenovirus 5 Vectored COVID-19 Vaccine (Ad5-nCoV) With Two Doses in Healthy Adults – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 25 September 2020.
  33. ^ Cao X, Liu Y (2021-06-04). “陈薇院士:雾化吸入式新冠疫苗正在申请紧急使用”Sci Tech Daily. Chinanews.com. Retrieved 2021-06-04.
  34. ^ “México recibe el primer lote de la vacuna candidata de CanSino Biologics; alistan pruebas”EL CEO (in Spanish). 2020-11-03. Retrieved 2020-11-03.
  35. ^ “Clinical Trial of Recombinant Novel Coronavirus Vaccine (Adenovirus Type 5 Vector) Against COVID-19 – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2020-10-21.
  36. ^ Bloomberg News (2020-11-25). “Russia’s Richest Man Seeks Global Market for Local Covid-19 Drug – BNN Bloomberg”BNN. Retrieved 2020-11-28.
  37. ^ Yáñez PL (2020-11-15). “Así funcionan las cuatro vacunas que se probarán en Chile”La Tercera. Retrieved 2020-11-17.
  38. ^ “China trials mixing of CanSinoBIO’s and Zhifei Longcom’s COVID-19 vaccines -data”Reuters. 2021-04-19. Retrieved 2021-06-16.
  39. ^ “Covid vaccine: Pakistan starts production of CanSino, China’s single-dose jab”Khaleej Times. Retrieved 2021-05-28.
  40. ^ “Russian Recruits Show ‘No Side Effects’ in Chinese Coronavirus Vaccine Trials”The Moscow Times. 2020-09-21. Retrieved 2020-09-22.
  41. ^ “Status of COVID-19 Vaccines within WHO EUL/PQ evaluation process”World Health Organization (WHO).
  42. ^ Reuters Staff (2020-06-29). “CanSino’s COVID-19 vaccine candidate approved for military use in China”Reuters. Retrieved 2020-12-13.
  43. ^ Reuters Staff (2021-02-04). “Malaysia’s Solution Group to supply 3.5 million doses of CanSino vaccine to government”Reuters. Retrieved 2021-02-04.
  44. ^ Taufiqurrahman M. “Indonesia can be manufacutring hub for COVID-19 vaccine, says Chinese foreign minister”. Jakarta Post. Retrieved 13 October 2020.
  45. ^ Shahzad A (2021-02-12). “Pakistan approves Chinese CanSinoBIO COVID vaccine for emergency use”Reuters. Retrieved 2021-02-12.
  46. ^ “Membrii NITAG au venit cu recomandări privind utilizarea vaccinurilor împotriva COVID-19 în Republica Moldova”Ministerul Sănătății, Muncii și Protecţiei Sociale. 2021-03-03. Retrieved 2021-05-21.
  47. ^ Reuters Staff (2020-12-10). “Mexico agrees to buy 35 million doses of CanSino COVID vaccine”Reuters. Retrieved 2020-12-10.
  48. ^ “Mexico approves China’s CanSino and Sinovac COVID-19 vaccines”Reuters. 10 February 2021.
  49. ^ “Brazil to buy single-shot Chinese COVID-19 vaccine”Reuters. 2021-06-15. Retrieved 2021-06-16.
  50. ^ “Brazil in vaccine talks with Moderna, reviewing CanSino shot”Reuters. 2021-05-19. Retrieved 2021-05-21.
  51. ^ Sherwood D (2021-03-30). “Chile inks deal for 1.8 million doses of CanSino COVID-19 vaccine as inoculation drive plows ahead”Reuters. Retrieved 2021-03-30.
  52. ^ Valencia A. “Ecuador authorizes use of China’s CanSino vaccine against COVID-19”Reuters. Retrieved 2021-06-16.

Further reading

External links

Scholia has a profile for Ad5-nCoV (Q96695265).

/////////Convidicea, Ad5-nCoV, Recombinant vaccine, adenovirus type 5 vector, CanSino Biologics, china, SARS-CoV-2, corona virus, vaccine, covid 19

Convidecia

 
  Full authorization  Emergency authorization  Eligible COVAX recipient (ongoing assessment)[2]

Convidecia is a viral vector vaccine[478] produced by the Chinese company CanSino Biologics and the Beijing Institute of Biotechnology of the Academy of Military Medical Sciences.Full (1)

  1. China[479]

Emergency (8)

  1. Argentina[480]
  2. Chile[481]
  3. Ecuador[482]
  4. Hungary[483][272]
  5. Malaysia[484]
  6. Mexico[436]
  7. Moldova[229]
  8. Pakistan[485]

wdt-17

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Sinovac COVID-19 vaccine, CoronaVac,


sinovac
File:SINOVAC COVID-19 vaccine.jpg

Sinovac COVID-19 vaccine, CoronaVac,

  • PiCoVacc

CoronaVac, also known as the Sinovac COVID-19 vaccine,[1] is an inactivated virus COVID-19 vaccine developed by the Chinese company Sinovac Biotech.[2] It has been in Phase III clinical trials in Brazil,[3] Chile,[4] Indonesia,[5] the Philippines,[6] and Turkey.[7]

It relies on traditional technology similar to BBIBP-CorV and BBV152, other inactivated-virus COVID-19 vaccines in Phase III trials.[8] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[9]

Brazil announced results on 13 January 2021 showing 50.4% effective at preventing symptomatic infections, 78% effective in preventing mild cases needing treatment, and 100% effective in preventing severe cases.[10] Final Phase III results from Turkey announced on 3 March 2021 showed an efficacy of 83.5%.[11] Interim results in Indonesia were announced on 11 January 2021 with an efficacy of 65.3%.[12] A detailed report containing confidence intervals, efficacy by age and side effects has not yet been released.

CoronaVac is being used in vaccination campaigns by certain countries in Asia,[13][14][15] South America,[16][17][18] North America,[19][20] and Europe.[21] In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June 2021.[22] As of March 21, 70 million doses of CoronaVac had been administered worldwide.[23

Technology

CoronaVac is an inactivated vaccine. It uses a similar, more traditional technology as in BBIBP-CorV and BBV152, other inactivated-virus vaccines for COVID-19 in Phase III trials.[24][25] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[26] CoronaVac could remain stable for up to three years in storage, which might offer some advantage in vaccine distribution to regions where cold chains are not developed.[27]

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Efficacy

Empty bottle of CoronaVac

On 7 January 2021, results from Phase III trials in Brazil among 13,000 volunteers revealed the vaccine was 78% effective in preventing symptomatic cases of COVID-19 requiring medical assistance (grade 3 on the WHO Clinical Progression Scale[28]) and 100% effective against moderate and severe infections.[29] After mounting pressure from scientists, Butantan said on 12 January that these rates only included volunteers who had mild to severe cases of COVID-19.[30] The overall efficacy, including asymptomatic cases and symptomatic cases not requiring medical assistance (WHO grade 2), was 50.38%.[31] Of the 220 participants infected, 160 cases were in the placebo group and 60 cases in the group that received CoronaVac.[32]

On 3 March 2021, final Phase III results from Turkey showed an efficacy of 83.5%. The final efficacy rate was based on 41 infections, 32 of which had received a placebo, said Murat Akova, head of the Phase III trials in Turkey. He added the vaccine prevented hospitalization and severe illness in 100% of cases, saying six people who were hospitalized were all in the placebo group. The final results were based on a 10,216 participants, 6,648 of whom received the vaccine as part of the Phase III study that began mid-September. Turkey had announced an interim result with 29 infections in December, which placed the efficacy at 91.25%.[33][34]

On 11 January, Indonesia released Phase III results from an interim analysis of 25 cases which showed an efficacy rate of 65.3% based on data of 1,600 participants in the trial.[35] The trial was conducted in the city of Bandung, and it was not clear how Indonesian scientists made their calculations.[30]

Variability in results

Officials said the lowered figure of 50.4% included “very light” cases of COVID-19 among participants omitted in the earlier analysis. Ricardo Palácios, Medical Director of Instituto Butantan said Sinovac’s relatively low efficacy rate of 50% was due to more rigorous standards for what counts as an infection among trial participants. The Institute included six types of cases in its results: asymptomatic, very mild, mild, two levels of moderate, and severe, while western vaccine makers generally included only mild, moderate, and severe categories. Brazil’s trial was also largely made up of frontline health care workers. “They are more exposed to the virus and may explain the relatively low efficacy rate,” said Yanzhong Huang, a senior fellow for global health at the Council on Foreign Relations.[36]

The release of more definitive data on CoronaVac’s efficacy was delayed because Sinovac needed to reconcile results from different trials using varying protocols.[32] According to Instituto Butantan director Dimas Covas, the Brazilian group was considered more vulnerable to infection and exposure to higher viral loads. In Turkish and Indonesian Phase III trials, the composition of volunteers was similar to that of the general population.[37]

COVID-19 variants

On March 10, Instituto Butantan Director Dimas Covas said CoronaVac was efficient against three variants of COVID-19 in the country; British B.1.1.7, South African 501.V2, and Brazil’s P.1, of which are derived variants P.1 from Manaus state, and P.2 from Rio de Janeiro.[38]

CoronaVac and other inactivated virus vaccines have all parts of the virus. Butantan said this may generate a more comprehensive immune response compared to other vaccines using only a part of the spike protein used by COVID-19 to infect cells. Tests run by Butantan used the serum of vaccinated people, which are placed in a cell culture and subsequently infected with the variants. The neutralization consists of determining whether antibodies generated from the vaccine will neutralize the virus in the culture.[38]

Clinical trials

For broader coverage of this topic, see COVID-19 vaccine.

Phase I–II

In a Phase II clinical trial completed in July 2020 and published in The Lancet, CoronaVac showed seroconversion of neutralising antibodies for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group.[39]

In May, CoronaVac began Phase I–II trials in China on adults over the age 60, and in September CoronaVac began Phase I–II trials in China on children ages 3–17.[40] Phase II results for older adults published in The Lancet showed CoronaVac was safe and well tolerated in older adults, with neutralising antibody induced by a 3 μg dose were similar to those of a 6 μg dose.[41]

Phase III

Latin America

In late July 2020, Sinovac began conducting a Phase III vaccine trial to evaluate efficacy and safety on 9,000 volunteer healthcare professionals in Brazil, collaborating with Butantan Institute.[42][43] On 19 October, São Paulo Governor João Doria said the first results of the clinical study conducted in Brazil proved that among the vaccines being tested in the country, CoronaVac is the safest, the one with the best and most promising immunization rates.[44] On 23 October, São Paulo announced the creation of six new centers for trials of CoronaVac, increasing the number of volunteers in the trials to 13,000.[45]

Brazil briefly paused Phase III trials on 10 November after the suicide of a volunteer before resuming on 11 November. Instituto Butantan said the suicide had no relation to the vaccine trial.[46][47]

In August, a Phase III trial was started in Chile, headed by Pontifical Catholic University of Chile, which was expected to include 3,000 volunteers between the ages of 18 and 65.[48]

Europe

In September, Turkey began Phase III trials with 13,000 volunteers on a two-dose 14-day interval.[49] The monitoring process for CoronaVac is underway at 25 centers in 12 cities across the country.[50]

The Governor of West Java Ridwan Kamil participating in phase 3 trial of the Sinovac COVID-19 vaccine in Indonesia.

Asia

In August, Sinovac began Phase III trials in Indonesia with Bio Farma in Bandung involving 1,620 volunteers.[51] In November, Padjadjaran University Medical School provided an update that the trials were running smoothly and that “at most, they found a slight body fever which disappeared within two days”.[52]

In October, Saudi Arabia signed an agreement with Sinovac to distribute CoronaVac to 7,000 healthcare workers, after conducting Phase III trials with the Saudi Arabian National Guard.[53]

Manufacturing

Brazilian version of CoronaVac, manufactured by Butantan

In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June. The figure is double the capacity of 1 billion doses in bulk ingredients the firm said it could reach by February.[22]

After Indonesia’s Phase III trials, Bio Farma plans to ramp up production to 250 million doses a year.[54]

On 9 November, São Paulo began building a facility to produce 100 million doses a year.[55] On 10 December, João Doria said Butantan aimed to fill and finish 1 million doses per day on its production line for a vaccination campaign starting 25 January. Doria said 11 Brazilian states have contacted Butantan seeking doses of CoronaVac.[56]

In Malaysia, Pharmaniaga will manufacture, fill, and finish CoronaVac. Pharmaniaga signed a deal to obtain bulk supply of the vaccine as well as technology transfer from Sinovac.[57]

In Egypt, the government was in “advanced stage” discussions with Sinovac to manufacture CoronaVac for local use and export to African countries.[58]

Market and deployment

As of March 21, 70 million doses of CoronaVac had been administered worldwide.[23]

 
show  Full authorizationshow  Emergency authorization  Eligible COVAX recipient (assessment in progress)[80]

South America

São Paulo State Secretary of Health Jean Gorinchteyn (left) and Instituto Butantan chairman Dimas Covas (right) holding single-dose prefilled syringes of CoronaVac, part of the fourth shipment of Sinovac-manufactured vaccine to arrive in Brazil

In Brazil, São Paulo governor João Doria signed a $90 million contract with Sinovac in September to receive the initial 46 million doses of CoronaVac.[81] The price for CoronaVac was announced to be US$10.3 (about R$59).[82] In January, Brazil announced it would obtain 100 million total doses.[83] On 17 January, ANVISA approved emergency use of CoronaVac, with a 54-year-old nurse in São Paulo being the first to receive a vaccine outside of clinical trials in the country.[16] In early February, Brazil said it intends to buy an additional 30 million doses to be produced locally on top of the existing 100 million doses.[84]

In January, Bolivia authorized use of CoronaVac. Butantan Institute had opened negotiations with South American countries to sell the vaccine, which would be produced in São Paulo.[85]

In October, Chile signed an agreement to purchase 20 million doses of CoronaVac[86] which was approved for emergency use on 20 January.[87] By early March, the country had received 10 million doses of CoronaVac and had vaccinated 4.1 million people.[88]

In February, Colombia had purchased 5 million doses of CoronaVac and was in talks for an additional 5 million doses,[89] which had been approved for emergency use on February 5.[90]

In February, Ecuador signed a deal for 2 million doses of CoronaVac which had been approved for emergency use.[91] Chile donated 20,000 doses of CoronaVac to Ecuador on March 6.[92]

In March, Paraguay received a donation of 20,000 doses of CoronaVac from Chile.[92] Paraguay began vaccinations with CoronaVac on March 10.[93]

In January, Uruguay announced the purchased of 1.75 million doses of CoronaVac.[94] The first 192,000 doses arrived on 25 February and vaccinations started on 1 March.[18]

Europe

In March, Albania received 192,000 doses of a first batch of 1 million doses purchased through Turkey.[95]

In November, Turkey signed a contract to buy 50 million doses of CoronaVac.[96] Turkey approved emergency use on 13 January[97] and President Recep Tayyip Erdoğan received his first dose at Ankara City Hospital.[98] In February, Turkey signed a deal for another 50 million doses for a total of 100 million doses.[21] By March 10.7 million doses had been administered, and 852 of the 1.3 million people who had received both doses were later diagnosed with the disease. 53 were hospitalized, but none of those hospitalized were intubated or died.[99]

In December, Ukraine signed a contract to purchase 1.8 million doses of CoronaVac. One dose of CoronaVac would cost 504 hryvnias (around $18).[100] On March 9, Ukraine granted approval for use of CoronaVac.[101]

Asia

On 19 January, Azerbaijan launched its vaccination campaign with CoronaVac. Azerbaijan plans to receive 4 million doses of the vaccine and aims to vaccinate 40% of the population.[102]

In February, Cambodia approved Coronavac[103] for emergency use and later ordered 1.5 million doses to arrive on March 26.[104]

In late August, China approved CoronaVac for emergency use to vaccinate high-risk groups such as medical staff.[105] In early February, China approved CoronaVac for general use.[15]

In December, Hong Kong ordered 7.5 million doses of CoronaVac.[106] The vaccination campaign with CoronaVac began on 26 February.[107]

In August, Indonesia’s Foreign Minister Retno Marsudi said an agreement was signed with Sinovac for 50 million doses,[108] which later increased to 140 million doses.[109] Indonesia approved emergency use authorization on 11 January and[35] President Joko Widodo received the first shot of the vaccine, which would be free for all Indonesian citizens.[13] By March, Indonesia had received 53.5 million doses of CoronaVac.[110]

On 26 January, Malaysia ordered 12 million doses.[57] CoronaVac was approved for emergency use on 2 March.[111] Malaysian Science, Technology and Innovation Minister Khairy Jamaluddin received the first dose with CoronaVac on 18 March as part of the vaccination campaign.[112]

In January, the Philippine’s announced the country had secured 25 million doses.[113] The vaccine was approved on 22 February but not for all health workers as it had lower efficacy when used with health workers compared to healthy individuals aged 18-59. The first 600,000 doses of CoronaVac arrived on 28 February.[114]

Singapore has signed advance purchase agreements for CoronaVac.[115] In February, the first doses arrived in the country.[116]

In early January, Thailand’s Ministry of Public Health announced an order for 2 million doses of CoronaVac,[117] which was approved for emergency use on 22 February.[118] Thailand started its vaccination program on 27 February.[14] In March, Thailand was in talks to purchase an additional 5 million doses.[119]

North America

By March 8, Dominican Republic had vaccinated 400,000 people and had reserved delivery for 10 million additional doses of CoronaVac.[19]

In February, Mexico approved emergency use of CoronaVac.[120] The country has ordered 20 million doses,[121] of which the first 200,000 doses arrived on 20 February.[122] It is currently used as part of the national vaccination campaign.[20]

Africa

In March, Benin received 203,000 doses of CoronaVac with vaccinations to start with health workers and the medically vulnerable.[123]

In March, South Africa’s drug regulator began assessing CoronaVac for use in the country.[124] South African firm Numolux said it could supply 5 million doses once it secured regulatory clearances.[125]

In March, Tunisia’s Ministry of Health approved marketing authorization of CoronaVac in the country.[126]

In March, Zimbabwe approved CoronaVac for emergency use.[127]

Oceania

In March, Fiji said it would be receiving a donation of CoronaVac.[128]

Controversies

Politicization

CoronaVac has been championed by the governor of São PauloJoão Doria, who many believe will challenge Jair Bolsonaro for the presidency in 2022.[129] A political showdown began in October 2020, when Bolsonaro vetoed a deal between the Brazilian health ministry and the São Paulo government for the purchase of 46 million doses of the vaccine.[130] After Instituto Butantan announced CoronaVac’s efficacy rate, Bolsonaro mocked the vaccine’s effectiveness against COVID-19.[131] Critics against the politicization of vaccines have warned that failure to follow international testing and safety protocols risks undermining public trust and can increase people’s hesitancy to inoculation.[129] Doctors in São Paulo said they were struggling to convince patients that CoronaVac would be safe.[132]

In March 2021, the Paraná Pesquisas opinion polling institute found that the vaccines preferred by Brazilians are CoronaVac and the Oxford–AstraZeneca vaccine, chosen by 23.6% and 21.2% of Brazilians interviewed, respectively, against 11.3% of those who would prefer the Pfizer–BioNTech vaccine.[133]

Delays in releasing results

On 23 December 2020, researchers in Brazil said the vaccine was more than 50% effective, but withheld full results at Sinovac’s request, raising questions again about transparency as it was the third delay in releasing results from the trials.[134] São Paulo Health Secretary Jean Gorinchteyn later said the vaccine didn’t reach 90% efficacy. Turkey said its trial showed an estimated efficacy rate of 91.25%, though that was based on only 29 infected cases.[32] When São Paulo state officials announced the protection rate, they declined to provide a more detailed breakdown of the trial, such as information about age groups and side effects of the vaccine.[32] Scientists said the lack of transparency about the data ran the risk of damaging CoronaVac’s credibility, with Brazilians and others world-wide already reluctant to take it.[30] Nikolai Petrovsky, a professor at the College of Medicine and Public Health at Flinders University said, “There is enormous financial and prestige pressure for these trials to massively overstate their results.”[135]

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  97. ^ “Turkey grants emergency authorization to Sinovac’s CoronaVac: Anadolu”Reuters. 13 January 2021. Retrieved 15 January 2021.
  98. ^ “Turkish president gets COVID-19 vaccine”Anadolu Agency. 14 January 2021. Retrieved 20 January 2021.
  99. ^ SABAH, DAILY (12 March 2021). “Few virus infections reported among vaccinated people in Turkey”Daily Sabah. Retrieved 12 March 2021.
  100. ^ “Ukraine signs up for China’s Sinovac vaccine, with doses expected soon”Reuters. 30 December 2020. Retrieved 30 December 2020.
  101. ^ Zinets, Natalia (9 March 2021). “Ukraine approves China’s Sinovac COVID-19 vaccine”Reuters. Retrieved 9 March 2021.
  102. ^ Aliyev, Jeyhun (19 January 2021). “Azerbaijan kicks off COVID-19 vaccination”. Anadolu Agency.
  103. ^ “Cambodian PM okays two more Covid-19 vaccines – Sinovac and AstraZeneca – for emergency use | The Star”http://www.thestar.com.my. Retrieved 19 March 2021.
  104. ^ “Have no fear about shortage of vaccines, 1.5 million doses of Sinovac arriving on March 26”Khmer Times. 19 March 2021. Retrieved 19 March 2021.
  105. ^ “Sinovac’s coronavirus vaccine candidate approved for emergency use in China – source”Reuters. 29 August 2020. Archived from the original on 31 August 2020. Retrieved 30 August 2020.
  106. ^ “Government announces latest development of COVID-19 vaccine procurement” Archived 11 December 2020 at the Wayback Machine (Hong Kong Government Press Releases, 12 December 2020)
  107. ^ “Hong Kong kicks off COVID-19 vaccinations with Sinovac jab”AP NEWS. 26 February 2021. Retrieved 7 March 2021.
  108. ^ “Indonesia books 50 million coronavirus vaccine doses from Sinovac”Reuters. 21 August 2020. Archived from the original on 29 August 2020. Retrieved 21 August 2020.
  109. ^ “Sinovac vaccine has no critical side effects, BPOM says”The Jakarta Post. Retrieved 21 December 2020.
  110. ^ Arkyasa, Mahinda (25 March 2021). “16 Million Sinovac Vaccines Material Arrives in Indonesia”Tempo. Retrieved 25 March 2021.
  111. ^ “Malaysia’s NPRA Approves AstraZeneca, Sinovac Covid-19 Vaccines”. CodeBlue. 2 March 2021. Retrieved 2 March 2021.
  112. ^ Babulal, Veena (18 March 2021). “KJ gets first dose of Sinovac vaccine [NSTTV] | New Straits Times”NST Online. Retrieved 19 March 2021.
  113. ^ “Duque says deal sealed for 25M doses of Sinovac COVID-19 vaccine”GMA News Online. Retrieved 10 January 2021.
  114. ^ “Philippines receives COVID-19 vaccine after delays”AP NEWS. 28 February 2021. Retrieved 28 February 2021.
  115. ^ Chen F (24 December 2020). “Brazil joins ranks of Chinese vaccine backers”Asia Times Online. Retrieved 30 December2020.
  116. ^ “Singapore receives China’s Sinovac vaccine ahead of approval”The Star. 25 February 2021. Retrieved 26 February2021.
  117. ^ “Thailand to get 2 million shots of China’s Sinovac”Bangkok Post. Bangkok Post Public Company. Retrieved 4 January 2021.
  118. ^ “Thailand gives emergency use authorisation for Sinovac’s COVID-19 vaccine – official”Reuters. 22 February 2021. Retrieved 23 February 2021.
  119. ^ Limited, Bangkok Post Public Company. “Thailand in talks to buy another 5m Sinovac shots”Bangkok Post. Retrieved 20 March2021.
  120. ^ “Mexico approves China’s CanSino and Sinovac COVID-19 vaccines”Reuters. 11 February 2021. Retrieved 11 February2021.
  121. ^ Jorgic, Drazen (10 March 2021). “Mexico leans on China after Biden rules out vaccines sharing in short term”Reuters. Retrieved 10 March 2021.
  122. ^ Exteriores, Secretaría de Relaciones. “The Mexican Government receives 200,000 Sinovac COVID-19 vaccines”gob.mx (in Spanish). Retrieved 7 March 2021.
  123. ^ “Lutte contre la Covid-19 : 203.000 doses de vaccins s dont 100.000 offertes par la Chine au Bénin”Concentrées d’informations sur le Bénin et le monde à votre service depuis 2009(in French). 23 March 2021. Retrieved 25 March 2021.
  124. ^ Winning, Alexander. “South Africa’s drugs regulator to start assessing Sinovac COVID-19 vaccine”U.S. Retrieved 12 March2021.
  125. ^ Nijini, Felix (18 March 2021). “Sinovac May Supply South Africa With 5 Million Vaccines: Report – BNN Bloomberg”BNN. Retrieved 19 March 2021.
  126. ^ “Covid: Tunisia approva vaccino cinese Sinovac”Agenzia Nazionale Stampa Associata (in Italian). 5 March 2021. Retrieved 7 March 2021.
  127. ^ Dzirutwe, MacDonald (10 March 2021). “Zimbabwe authorises Sputnik V, Sinovac coronavirus vaccines for emergency use”Reuters. Retrieved 13 March 2021.
  128. ^ “China to donate Sinovac Vaccine to Fiji”Fiji Broadcasting Corporation. Retrieved 17 March 2021.
  129. Jump up to:a b Phillips, Tom (10 November 2020). “Jair Bolsonaro claims ‘victory’ after suspension of Chinese vaccine trial”The Guardian. Retrieved 18 January 2021.
  130. ^ Baptista, Eduardo (11 December 2020). “China-made coronavirus vaccine at heart of political showdown in Brazil”South China Morning Post. Retrieved 18 January 2021.
  131. ^ Carvalho, Daniel (14 January 2021). “‘Is 50% Good?’, Asks Bolsonaro, Mocking Coronavac’s Effectiveness”Folha de S.Paulo. Retrieved 18 January 2021.
  132. ^ Pearson, Samantha; Magalhaes, Luciana (10 November 2020). “Brazil’s Medical Experts Worry Politics Is Hampering Covid-19 Vaccine Progress”The Wall Street Journal. Retrieved 18 January 2021.
  133. ^ “Covid: 70% dos brasileiros não fazem questão de escolher vacina” [Covid: 70% of Brazilians do not make a point of choosing vaccine]. R7.com (in Portuguese). 3 March 2021. Retrieved 9 March2021.
  134. ^ Fonseca P. “Brazil institute says CoronaVac efficacy above 50%, but delays full results”Reuters. Retrieved 25 December 2020.
  135. ^ Hong, Jinshan (12 January 2021). “How Effective Is China’s Sinovac Vaccine? Data Confuse Experts”Bloomberg News. Retrieved 12 January 2021.

External links

Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Routes of
administration
Intramuscular injection
ATC codeNone
Legal status
Legal statusEmergency authorization for use in China, Indonesia, Brazil and Turkey
Identifiers
DrugBankDB15806
Part of a series on the
COVID-19 pandemic
SARS-CoV-2 (virus)COVID-19 (disease)
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 COVID-19 Portal
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Sinovac Biotech Ltd. (Chinese: 北京科兴生物制品有限公司, NasdaqSVA) is a Chinese biopharmaceutical company that focuses on the research, development, manufacture and commercialization of vaccines that protect against human infectious diseases. The company is based in Haidian DistrictBeijing.[2] The company is listed on the NASDAQ but the exchange halted Sinovac’s trading in February 2019 due to a proxy fight.[3][4]

Vaccines

Sinovac’s commercialized vaccines include Healive (hepatitis A), Bilive (combined hepatitis A and B), Anflu (influenza), Panflu (H5N1) and PANFLU.1 (H1N1). Sinovac is currently developing a Universal Pandemic Influenza vaccine and a Japanese encephalitis vaccine.[5][better source needed]

Sinovac is also developing vaccines for enterovirus 71 and human rabies. Its wholly owned subsidiary, Tangshan Yian, is conducting field trials for independently developed inactivated animal rabies vaccines.[citation needed]

COVID-19 vaccine development

Main article: CoronaVac

CoronaVac is an inactivated virus COVID-19 vaccine developed by Sinovac.[6] It has been in Phase III clinical trials in Brazil,[7] Chile,[8] Indonesia,[9] Malaysia,[10] Philippines,[11] and Turkey.[12]

It relies on traditional technology similar to BBIBP-CorV and BBV152, other inactivated-virus COVID-19 vaccines in Phase III trials.[13] CoronaVac does not need to be frozen, and both the vaccine and raw material for formulating the new doses could be transported and refrigerated at 2–8 °C (36–46 °F), temperatures at which flu vaccines are kept.[14]

Brazil announced results on January 13, 2021 showing 50.4% effective at preventing symptomatic infections, 78% effective in preventing mild cases needing treatment, and 100% effective in preventing severe cases.[15] Final Phase III results from Turkey announced on 3 March 2021 showed an efficacy of 83.5%.[16] Interim results in Indonesia were announced on 11 January 2021 with an efficacy of 65.3%.[17]

CoronaVac is being used in vaccination campaigns by certain countries in Asia,[18][19][20] South America,[21][22] and Europe.[23] In March, a Sinovac spokesman told Reuters production capacity for CoronaVac could reach 2 billion doses a year by June 2021.[24] As of 27 February 36 million doses had been administered in total.[25]

See also

References

  1. ^ “China’s Vaccine Front-Runner Aims to Beat Covid the Old-Fashioned Way”Bloomberg. 24 August 2020.
  2. ^ “Home (English)”. Sinovac. Retrieved 2021-03-06. Add: No. 39 Shangdi Xi Road, Haidian District, Beijing, P.R.C. 100085 – Chinese address: “地址:中国· 北京 海淀区上地西路39号北大生物城(100085)”
  3. ^ Dou, Eva (December 4, 2020). “As China nears a coronavirus vaccine, bribery cloud hangs over drugmaker Sinovac”The Washington PostISSN 0190-8286Archived from the original on December 4, 2020. Retrieved 2020-12-06.
  4. ^ Levine, Matt (May 22, 2020). “A Vaccine With a Poison Pill”Bloomberg NewsArchived from the original on June 21, 2020. Retrieved December 6, 2020.
  5. ^ Google Finance, url=https://www.google.com/finance?q=Sinovac
  6. ^ Nidhi Parekh (22 July 2020). “CoronaVac: A COVID-19 Vaccine Made From Inactivated SARS-CoV-2 Virus”. Retrieved 25 July2020.
  7. ^ “New coronavirus vaccine trials start in Brazil”AP News. 21 July 2020. Retrieved 2020-10-07.
  8. ^ “Chile initiates clinical study for COVID-19 vaccine”Chile Reports. 4 August 2020. Retrieved 2020-10-07.
  9. ^ “248 volunteers have received Sinovac vaccine injections in Bandung”Antara News. 30 August 2020. Retrieved 2020-10-07.
  10. ^ “Malaysia Receives China’s Sinovac Vaccine For Regulatory Testing”Bloomberg.com. 2021-02-27. Retrieved 2021-03-02.
  11. ^ “DOH eyes 5 hospitals for Sinovac vaccine Phase 3 clinical trial”PTV News. 16 September 2020. Retrieved 2020-10-07.
  12. ^ “Turkey begins phase three trials of Chinese Covid-19 vaccine”TRT World News. 1 September 2020. Retrieved 2020-10-07.
  13. ^ Zimmer, Carl; Corum, Jonathan; Wee, Sui-Lee. “Coronavirus Vaccine Tracker”The New York TimesISSN 0362-4331. Retrieved 2021-02-12.
  14. ^ “CoronaVac: Doses will come from China on nine flights and can…” AlKhaleej Today (in Arabic). 2020-11-01. Retrieved 2021-02-12.
  15. ^ “Sinovac: Brazil results show Chinese vaccine 50.4% effective”BBC News. 2021-01-13. Retrieved 2021-02-12.
  16. ^ AGENCIES, DAILY SABAH WITH (25 December 2020). “Turkey set to receive ‘effective’ COVID-19 vaccine amid calls for inoculation”Daily Sabah. Retrieved 12 February 2021.
  17. ^ hermesauto (11 January 2021). “Indonesia grants emergency use approval to Sinovac’s vaccine, local trials show 65% efficacy”The Straits Times. Retrieved 12 February 2021.
  18. ^ TARIGAN, EDNA; MILKO, VICTORIA (13 January 2021). “Indonesia starts mass COVID vaccinations over vast territory”Associated Press. Retrieved 15 January 2021.
  19. ^ Aliyev, Jeyhun (19 January 2021). “Azerbaijan kicks off COVID-19 vaccination”. Anadolu Agency.
  20. ^ “China approves Sinovac vaccines for general public use”South China Morning Post. 6 February 2021. Retrieved 6 February2021.
  21. ^ Fonseca, Jamie McGeever, Pedro (17 January 2021). “Brazil clears emergency use of Sinovac, AstraZeneca vaccines, shots begin”Reuters. Retrieved 17 January 2021.
  22. ^ Miranda, Natalia A. Ramos (28 January 2021). “Chile receives two million-dose first delivery of Sinovac COVID-19 vaccine”Reuters. Retrieved 30 January 2021.
  23. ^ “Turkey aims to vaccinate 60 percent of population: Minister – Turkey News”Hürriyet Daily News. Retrieved 12 February 2021.
  24. ^ Liu, Roxanne (2021-03-03). “Sinovac eyes two billion doses in annual capacity of virus vaccine by June”Reuters. Retrieved 2021-03-03.
  25. ^ “Malaysia receives first batch of Sinovac Covid-19 vaccine today”. Bernama. 27 February 2021. Retrieved 27 February 2021– via The Malay Mail.

External links

TypePublic
Traded asNasdaqSVA
(American Depository Receipts)
Founded1999; 22 years ago
FounderYin Weidong[1]
HeadquartersBeijing,China
Websitehttp://www.sinovac.com/
Sinovac Biotech
Simplified Chinese北京科兴生物制品有限公司
Traditional Chinese北京科興生物製品有限公司
hideTranscriptionsStandard MandarinHanyu PinyinBěijīng Kē Xìng Shēngwù Zhìpǐn Yǒuxiàn Gōngsī

/////////Sinovac COVID-19 vaccine, CoronaVac, corona virus, covid 19, vaccine, china, Sinovac Biotech, PiCoVacc

#Sinovac COVID-19 vaccine, #CoronaVac, #corona virus, #covid 19, #vaccine, #china, #Sinovac Biotech, #PiCoVacc

BBIBP-CorV, Sinopharm COVID-19 vaccine


Sinopharm COVID-19 vaccine (2021) K (cropped).jpeg

BBIBP-CorV, Sinopharm COVID-19 vaccine

 
CAS Number2503126-65-4
  • Inactivated novel coronavirus (2019-CoV) vaccine (Vero cells)
  • Purified inactivated SARS-CoV-2 Vaccine

ref Lancet Infectious Diseases (2021), 21(1), 39-51.

BBIBP-CorV, also known as the Sinopharm COVID-19 vaccine,[1] is one of two inactivated virus COVID-19 vaccines developed by Sinopharm. In late December 2020, it was in Phase III trials in ArgentinaBahrainEgyptMoroccoPakistanPeru, and the United Arab Emirates (UAE) with over 60,000 participants.[2]

On December 9, the UAE announced interim results from Phase III trials showing BBIBP-CorV had a 86% efficacy against COVID-19 infection.[3] In late December, Sinopharm announced that its internal analysis indicated a 79% efficacy.[4] While mRNA vaccines like the Pfizer–BioNTech COVID-19 vaccine and mRNA-1273 showed higher efficacy of +90%, those present distribution challenges for some nations as they require deep-freeze facilities and trucks. BIBP-CorV could be transported and stored at normal refrigerated temperatures.[5]

BBIBP-CorV shares similar technology with CoronaVac and BBV152, other inactivated virus vaccines for COVID-19 being developed in Phase III trials.[6][7]

BBIBP-CorV is being used in vaccination campaigns by certain countries in Asia,[8][9][10] Africa,[11][12][13] South America,[14][15] and Europe.[16][17][18] Sinopharm expects to produce one billion doses of BBIBP-CorV in 2021.[19] By February 21, Sinopharm said more than 43 million doses of the vaccine had been administered in total.[20]

BBIBP-CorV vaccine contains a SARS-CoV-2 strain inactivated inside Vero Cells. Investigation shows this vaccine induces neutralizing antibodies in several mammalian species while also showing protective efficacy with SARS-CoV-2 challenge in rhesus macaques2. As of August 2020, this vaccine is being tested for prophylaxis against COVID-19 in human clinical trials.

A vaccination certificate of BBIBP-CorV (Beijing Institute of Biological Products, Sinopharm).

Clinical research

Main article: COVID-19 vaccine

Phases I and II

In April 2020, China approved clinical trials for a candidate COVID-19 vaccine developed by Sinopharm‘s Beijing Institute of Biological Products[21] and the Wuhan Institute of Biological Products.[22] Both vaccines are chemically-inactivated whole virus vaccines for COVID-19.

On October 15, the Beijing Institute of Biological Products published results of its Phase I (192 adults) and Phase II (448 adults) clinical studies for the BBIBP-CorV vaccine, showing BBIBP-CorV to be safe and well-tolerated at all tested doses in two age groups. Antibodies were elicited against SARS-CoV-2 in all vaccine recipients on day 42. These trials included individuals older than 60.[21]

On August 13, the Wuhan Institute of Biological Products published interim results of its Phase I (96 adults) and Phase II (224 adults) clinical studies. The report noted the inactivated COVID-19 vaccine had a low rate of adverse reactions and demonstrated immunogenicity, but longer-term assessment of safety and efficacy would require Phase III trials.[22]

BIBP-CorV may have characteristics favorable for vaccinating people in the developing world. While mRNA vaccines, such as the Pfizer–BioNTech COVID-19 vaccine and Moderna COVID-19 vaccine showed higher efficacy of +90%, mRNA vaccines present distribution challenges for some nations, as some may require deep-freeze facilities and trucks. By contrast, BIBP-CorV can be transported and stored at normal refrigeration temperatures.[23] While Pfizer and Moderna are among developers relying on novel mRNA technology, manufacturers have decades of experience with the inactivated virus technology Sinopharm is using.[23]

Phase III

Africa and Asia

On July 16, Sinopharm began conducting a Phase III vaccine trial of 31,000 volunteers in the UAE in collaboration with G42 Healthcare, an Abu Dhabi-based company.[24] By August, all volunteers had received their first dose and were to receive the second dose within the next few weeks.[25] On December 9, UAE’s Ministry of Health and Prevention announced the official registration of BBICP-CorV, after an interim analysis of the Phase III trial showed BBIBP-CorV to have a 86% efficacy against COVID-19 infection.[26] The vaccine had a 99% sero-conversion rate of neutralizing antibodies and 100% effectiveness in preventing moderate and severe cases of the disease.[27]

On September 2, Sinopharm began a Phase III trial in Casablanca and Rabat on 600 people.[28][29] In September, Egypt opened registration for a Phase III trial to last one year and enroll 6,000 people.[30]

In August 2020, Sinopharm began a Phase III clinical trial in Bahrain on 6,000 citizens and resident volunteers.[31][32] In a November update, 7,700 people had volunteered in the trials.[33] Also in late August, Sinopharm began a Phase III clinical trial in Jordan on 500 volunteers at Prince Hamzah Hospital.[34][35]

In Pakistan, Sinopharm began working with the University of Karachi on a trial with 3,000 volunteers.[36]

South America

On September 10, Sinopharm began a Phase III trial in Peru with the long-term goal of vaccinating a total of 6,000 people between the ages of 18 and 75.[37] In October, the trials were expanded to include an additional 6,000 volunteers.[38] On January 26, a volunteer in the placebo group of the vaccine trials had died.[39]

On September 16, Argentina began a Phase III trial with 3,000 volunteers.[40]

Manufacturing

Sinopharm’s Chariman Yang Xioyun has said the company could produce one billion doses in 2021.[19]

In October, Dubai’s G42 Healthcare reached manufacturing agreements to provide UAE and other regional states with BBIBP-CorV, with the UAE producing 75 to 100 million doses in 2021.[41]

In December, Egypt announced an agreement between Sinopharm and Egyptian Holding Company for Biological Products & Vaccines (VACSERA) for the vaccine to be manufactured locally,[42] which would also be exported to other African countries.[43]

In December, AP reported Morocco plans to produce BBIBP-CorV locally.[44]

In March, Serbia announced plans to produce 24 million doses of BBIBP-CorV annually starting in October. The production volume would be sufficient to meet the needs of Serbia and all of its neighbors, deputy prime minister Branislav Nedimović noted.[45]

In March, Belarus was looking to produce BBIBP-CorV locally.[18]

Marketing and Distribution

 
show  Full authorizationshow  Emergency authorizationshow  Received donated doses  Eligible COVAX recipient (assessment in progress)[86]

On February 21, 2021 Sinopharm said more than 43 million doses of BBIBP-CorV had been administered so far, including more than 34 million administered in China and the rest internationally.[20]

Asia

In February, Afghanistan was pledged 400,000 doses of BBIBP-CorV by China.[82]

In November 3, 2020 Bahrain granted emergency use authorization of BBIBP-CorV for frontline workers.[33] In December, Bahrain approved Sinopharm’s vaccine, citing data from Phase III clinical trials that showed an 86% efficacy rate.[87]

In February, Brunei received the first batch of Sinopharm vaccines donated by China.[84]

In January, Cambodia said China would provide a million doses.[88] Cambodia granted emergency use authorization on February 4[89] and started the vaccination campaign on February 10 with the first 600,000 doses.[90]

In China, Sinopharm obtained an EUA in July.[91] In October, it began offering the vaccine for free to students going abroad for higher studies.[92] On December 30, China‘s National Medical Products Administration approved BBIBP-CorV for general use.[93][8] In February, Macau received the first 100,000 doses of 400,000 doses.[94]

In October, Indonesia reached an agreement with Sinopharm to deliver 15 million dual-dose vaccines in 2020.[95]

In February, Iran approved emergency use of BBIBP-CorV,[96] and received the first batch of 250,000 doses on February 28.[97]

In January, Iraq approved BBIBP-CorV for emergency use[98] and has signed agreements for 2 million doses. The first doses arrived on March 2.[99]

In January, Jordan approved BBIBP-CorV for emergency use[100] and started its vaccination campaign on January 13.[101]

In March, Kyrgyzstan received a donation of 150,000 doses of the vaccine.[102]

In January, Laos began vaccinating medical workers at hospitals in Vientiane [103] and received another 300,000 doses in early February.[104]

In March, Lebanon received a donation of 50,000 doses at its request,[105] for which it granted emergency use authorization on March 2.[106]

In March, Maldives granted emergency approval for use. At the time of approval, the country had received 18,000 doses and was awaiting 200,000 additional doses.[107]

In February, Mongolia received a donation of 300,000 doses.[108] On March 10, Governor of Ulaanbaatar D. Sumiyabazar and Deputy Prime Minister S. Amarsaikhan received the first doses of BBIBP-CorV.[109]

In February, Nepal approved the vaccine for emergency use, allowing a donation of 500,000 doses to enter the country.[110]

In December, Pakistan‘s purchased 1.2 million doses,[111] which was approved for emergency use on January 18,[112] and began a vaccination campaign on February 2.[10]

In March, Palestine said it would receive 100,000 doses donated by China.[113]

In March 19, Sri Lanka approved the vaccine for emergency use, allowing a donation of 600,000 doses by China to enter the country.[114]

On 14 September 2020, the United Arab Emirates approved the vaccine for front-line workers following successful interim Phase III trials.[24] In December, the country registered BBIBP-CorV after it reviewed the results of the interim analysis.[26] In March, a small number of people who have reduced immunity against diseases, have chronic illnesses, or belong to high-risk groups have been given a 3rd booster shot.[115]

Africa

In February, Algeria received a donation of 200,000 doses.[83]

Egypt plans to buy 40 million doses of Sinpharm’s vaccine[116] which was approved for regulatory use on January 3.[116] President Abdel Fattah el-Sisi announced a vaccination campaign starting 24 January.[11]

In February, Equatorial Guinea received a donation of 100,000 doses which arrived on February 10. The country began vaccinations on February 15.[56]

In March, Gabon received a donation of 100,000 doses which was the second vaccine approved for use in the country.[117]

Morocco placed orders for 41 million vaccine doses from Sinopharm and 25 million from AstraZeneca, for a total of 66 million doses.[118] Morocco granted emergency use approval on January 23,[119] and the first 500,000 doses arrived on January 27.[12]

In February, Mozambique received a donation of 200,000 doses[120] and planned to start vaccinations on March 8.[121]

In March, Namibia received a donation of 100,000 doses and announced the start of vaccinations in the Khomas and Erongo regions.[122]

In March, Niger received a donation of 400,000 doses with vaccinations to begin on March 27.[123]

In February, Senegal received 200,000 doses in Dakar[124] and began vaccinating health workers on February 22.[125]

In February, Sierra Leone received a donation of 200,000 doses.[126] It was approved for emergency use and vaccinations began on March 15.[127]

In January, Seychelles said it would begin administering vaccinations on January 10 with 50,000 doses it had received as a gift from the UAE.[128]

In March, Republic of the Congo received 100,000 doses with vaccinations prioritizing the medically vulnerable and those over 50.[129]

In February, Zimbabwe purchased 600,000 doses on top of 200,000 doses donated by China,[130] and started vaccinations on February 18.[13] Zimbabwe later purchased an additional 1.2 million doses.[131]

North America

In February, the Dominican Republic ordered 768,000 doses of BBIBP-CorV.[132]

In March, Dominica received 20,000 doses of BBIBP-CorV which it began using in its vaccination campaign on March 4.[133]

In March, Mexico announced it would order 12 million doses of BBIBP-CorV pending approval by its health regulator.[134]

South America

In February, Argentina authorized emergency use of BBIBP-CorV[135] ahead of the arrival of 904,000 doses on February 26.[136]

In February, Bolivia purchased 400,000 doses on top of 100,000 doses donated by China,[137] and started its vaccination campaign on February 26.[15]

In March, Guyana received a donation of 20,000 doses of BBIBP-CorV.[138] Vaccinations were to start on March 7.[139]

In January, Peru purchased 38 million doses of BBIBP-CorV.[140] Peru granted emergency approval for BBIBP-CorV on January 27[141] and started vaccinations on February 9 with the first 300,000 doses.[14]

In March, Venezuela granted approval for BBIBP-CorV to be used in the country.[142] The first 500,000 doses arrived on March 2.[143]

Europe

In February, Belarus received a donation of 100,000 doses[144] and began using the vaccine on March 15.[18]

In January, Hungary became first EU member to approve BBIBP-CorV, signing a deal for 5 million doses.[145] The first 550,000 doses arrived in Budapest on February 16[146] and vaccinations started on February 24.[17] Prime Minister Viktor Orbán was vaccinated with BBIBP-CorV on February 28.[147]

In March, Moldova received 2,000 doses donated by the UAE[148] which will be used to vaccinate doctors at the State University of Mediecne and Pharmacy starting on March 22.[149]

In March 3, Montenegro received a donation of 30,000 doses of BBIBP-CorV.[85]

In February, North Macedonia signed an agreement for 200,000 doses of BBIBP-CorV, with which they hoped to launch their vaccination program later that month.[150]

In January, Serbia received one million doses, making it the first country in Europe to receive BBIBP-CorV.[151] On January 19, Serbia approved the vaccine and Health Minister Zlatibor Lončar became the first person to receive a shot.[16]

Controversies

Lack of public data

Unlike Moderna‘s MRNA-1273OxfordAstraZeneca‘s AZD1222, and Johnson & Johnson‘s Ad26.COV2.S, there is little public information about the Chinese vaccine’s safety or efficacy.[152] The UAE said it had reviewed Sinopharm’s interim data analysis which showed the vaccine was 100% effective to prevent moderate and severe instances of COVID-19, but did not say whether it had independently analyzed the case data in its review. It was unclear how Sinopharm drew conclusions, since the UAE announcement of the approval for BBIBP-CorV noticeably lacked details such as the number of COVID-19 cases in the placebo or active group or the volunteers ages.[153]

As of December 30, 2020, no detailed efficacy data of the vaccine has been released to the public. A Sinopharm executive said detailed data would be released later and published in scientific journals in China and internationally.[8]

Sinopharm president Wu Yonglin said the trial results exceeded the WHO’s requirements, but a director at a large pharmaceutical company in Shanghai expressed skepticism over the trials and the expectation that drug regulators in Bahrain and the UAE would not hold the same standard as the U.S. Food and Drug Administration.[154]

Unauthorized use in Asia

On December 30, Philippine Defense Secretary Delfin Lorenzana said in an interview that at least one minister and president Rodrigo Duterte‘s bodyguards were provided BBIBP-CorV which were “smuggled” but that he felt what happened was “justified”. Brigadier General Jesus Durante, head of the Presidential Security Guard (PSG), said he felt compelled and “took the risk” to have some of his men vaccinated because they provide close-in security to Duterte, who at 75 is highly vulnerable to COVID-19.[155] Ingming Aberia, an author at The Manila Times commented that FDA director-general Enrique Domingo had reason to believe Sinopharm may cause harm to the consuming public given that no COVID-19 vaccine license was issued, but out of “self-preservation”, he would not initiate charges against PSG.[156]

On January 1, Mainichi Shimbun reported that 18 wealthy people, including several owners of leading Japanese companies, have been vaccinated with Sinopharm vaccines since November 2020. The vaccines were brought in by a Chinese consultant close to a senior member of the Chinese Communist Party.[157] The Chinese embassy in Japan later expressed its dissatisfaction at the unverified claims by Japanese news media.[158]

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External links

A vial of the BBIBP-CorV COVID‑19 vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typeInactivated
Clinical data
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusAuthorization for use in BahrainChinaEgyptIraqPakistanSerbiaUnited Arab EmiratesIran (emergency use)
Identifiers
CAS Number2503126-65-4
DrugBankDB15807
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How the Sinopharm Vaccine Works

By Jonathan Corum and Carl ZimmerUpdated March 22, 2021Leer en español

In early 2020, the Beijing Institute of Biological Products created an inactivated coronavirus vaccine called BBIBP-CorV. Clinical trials run by the state-owned company Sinopharm showed that it had an efficacy rate of 79 percent. China approved the vaccine and soon began exporting it to other countries.

A Vaccine Made From Coronaviruses

BBIBP-CorV works by teaching the immune system to make antibodies against the SARS-CoV-2 coronavirus. The antibodies attach to viral proteins, such as the so-called spike proteins that stud its surface.

Spikes

Spike

protein

gene

CORONAVIRUS

To create BBIBP-CorV, the Beijing Institute researchers obtained three variants of the coronavirus from patients in Chinese hospitals. They picked one of the variants because it was able to multiply quickly in monkey kidney cells grown in bioreactor tanks.

Killing the Virus

Once the researchers produced large stocks of the coronaviruses, they doused them with a chemical called beta-propiolactone. The compound disabled the coronaviruses by bonding to their genes. The inactivated coronaviruses could no longer replicate. But their proteins, including spike, remained intact.

Beta-

propiolactone

INACTIVATED

CORONAVIRUS

Inactivated

genes

The researchers then drew off the inactivated viruses and mixed them with a tiny amount of an aluminum-based compound called an adjuvant. Adjuvants stimulate the immune system to boost its response to a vaccine.

Inactivated viruses have been used for over a century. Jonas Salk used them to create his polio vaccine in the 1950s, and they’re the bases for vaccines against other diseases including rabies and hepatitis A.

Prompting an Immune Response

Because the coronaviruses in BBIBP-CorV are dead, they can be injected into the arm without causing Covid-19. Once inside the body, some of the inactivated viruses are swallowed up by a type of immune cell called an antigen-presenting cell.

INACTIVATED

CORONAVIRUS

Engulfing

the virus

ANTIGEN-

PRESENTING

CELL

Digesting

virus proteins

Presenting

virus protein

fragments

HELPER

T CELL

The antigen-presenting cell tears the coronavirus apart and displays some of its fragments on its surface. A so-called helper T cell may detect the fragment. If the fragment fits into one of its surface proteins, the T cell becomes activated and can help recruit other immune cells to respond to the vaccine.

Making Antibodies

Another type of immune cell, called a B cell, may also encounter the inactivated coronavirus. B cells have surface proteins in a huge variety of shapes, and a few might have the right shape to latch onto the coronavirus. When a B cell locks on, it can pull part or all of the virus inside and present coronavirus fragments on its surface.

A helper T cell activated against the coronavirus can latch onto the same fragment. When that happens, the B cell gets activated, too. It proliferates and pours out antibodies that have the same shape as their surface proteins.

ACTIVATED

HELPER

T CELL

INACTIVATED

CORONAVIRUS

Activating

the B cell

Matching

surface proteins

B CELL

SECRETED

ANTIBODIES

Stopping the Virus

Once vaccinated with BBIBP-CorV, the immune system can respond to an infection of live coronaviruses. B cells produce antibodies that stick to the invaders. Antibodies that target the spike protein can prevent the virus from entering cells. Other kinds of antibodies may block the virus by other means.

ANTIBODIES

LIVE

VIRUS

Remembering the Virus

Sinopharm’s clinical trials have demonstrated that BBIBP-CorV can protect people against Covid-19. But no one can yet say how long that protection lasts. It’s possible that the level of antibodies drops over the course of months. But the immune system also contains special cells called memory B cells that might retain information about the coronavirus for years or even decades.

Vaccine Timeline

January, 2020 Sinopharm begins developing an inactivated vaccine against the coronavirus.

June Researchers report the vaccine produces promising results in monkeys. A Phase 1/2 trial shows that the vaccine doesn’t cause any serious side effects and enables people to make antibodies against the coronavirus.

A Sinopharm production plant in Beijing.Zhang Yuwei/Xinhua, via Associated Press

July A Phase 3 trial begins in the United Arab Emirates.

August Phase 3 trials begin in Morocco and Peru.

Preparing a Sinopharm dose in Lima, Peru.Ernesto Benavides/Agence France-Presse

Sept. 14 The U.A.E. gives emergency approval for Sinopharm’s vaccine to use on health care workers. Government officials and others begin to receive it.

November The chairman of Sinopharm says almost a million people in China have received Sinopharm vaccines.

Nov. 3 The ruler of Dubai, Sheikh Mohammed bin Rashid al-Maktoum, announces he received the vaccine.

Sheikh Mohammed before receiving the vaccine.Agence France-Presse

Dec. 9 The U.A.E. gives full approval to BBIBP-CorV, announcing it has an efficacy rate of 86 percent. But the government did not release any details with their announcement, leaving it unclear how they had come to their conclusions.

Dec. 13 Bahrain also approves the vaccine.

Vials of the Sinopharm vaccine at a packaging plant.Zhang Yuwei/Xinhua, via Associated Press

Dec. 30 Sinopharm announces that the vaccine has an efficacy of 79.34 percent, leading the Chinese government to approve it. The company has yet to publish detailed results of their Phase 3 trial.

Jan. 3, 2021 Egypt authorizes the vaccine for emergency use.

Sources: National Center for Biotechnology Information; Science; The Lancet; Lynda Coughlan, University of Maryland School of Medicine; Jenna Guthmiller, University of Chicago.

Data

/////////////BBIBP-CorV, Sinopharm,  COVID-19 vaccine, china, covid 19, corona virus, vaccine

#BBIBP-CorV, #Sinopharm,  #COVID-19 vaccine, #china, #covid 19, #corona virus, #vaccine

SULCARDINE SULPHATE


Sulcardine.svg

ChemSpider 2D Image | HBI-3000 | C24H33N3O4S

sulcardine, HBI-3000

B 87823

  • Molecular FormulaC24H33N3O4S
  • Average mass459.602 Da

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

Benzenesulfonamide, N-[[4-hydroxy-3,5-bis(1-pyrrolidinylmethyl)phenyl]methyl]-4-methoxy-
N-[4-Hydroxy-3,5-bis(1-pyrrolidinylmethyl)benzyl]-4-methoxybenzenesulfonamide
343935-60-4 [RN]

heart arrhythmia

Sulcardine sulfate,343935-61-5 (Sulcardine sulfate)

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

Synonyms: B-87823; HBI-3000; B87823; HBI3000; B 87823; HBI 3000;N-(4-hydroxy-3,5-bis(pyrrolidin-1-ylmethyl)benzyl)-4-methoxybenzenesulfonamide sulfate
Molecular Formula: C24H35N3O8S2
Molecular Weight: 557.67
  • 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. BaiWei-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).

Figure US06605635-20030812-C00001

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 IKUT 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 Journal13 (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 Pharmacology346 (2–3): 245–253. doi:10.1016/S0014-2999(98)00067-3PMID 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 Pharmacology57 (1): 79–85. doi:10.1097/FJC.0b013e3181ffe8b3PMID 20980921.
  6. ^ Lee, Julia Y.; Gingras, Mireille; Lucchesi, Benedict R. (2010). “HBI-3000 prevents sudden cardiac death in a conscious canine model”. Heart Rhythm7 (11): 1712. doi:10.1016/j.hrthm.2010.09.028.
HBI-3000
Sulcardine.svg
Names
IUPAC name

N-({4-Hydroxy-3,5-bis[(pyrrolidin-1-yl)methyl]phenyl}methyl)-4-methoxybenzene-1-sulfonamide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
Properties
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

////////////////sulcardine sulfate, phase 2, china, HBI 3000, atrial fibrillation, B 87823,

COC1=CC=C(C=C1)S(=O)(=O)NCC2=CC(=C(C(=C2)CN3CCCC3)O)CN4CCCC4

Coblopasvir


img

Coblopasvir.png

Coblopasvir
CAS: 1312608-46-0
Chemical Formula: C41H50N8O8
Molecular Weight: 782.89

UNII-67XWL3R65W

methyl {(2S)-1-[(2S)-2-(4-{4-[7-(2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl)-2H-1,3-benzodioxol-4-yl]phenyl}-1Himidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Carbamic acid, N-((1S)-1-(((2S)-2-(5-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methyl-1-oxobutyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-1,3-benzodioxol-4-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-, methyl ester

hepatitis C virus infection

KW-136

Coblopasvir is an antiviral drug candidate.

Coblopasvir dihydrochloride

CAS 1966138-53-3

C41 H50 N8 O8 . 2 Cl H
 Molecular Weight 855.806
PHASE 3 Beijing Kawin Technology Share-Holding
Hepatitis C virus (HCV), or hepatitis C virus infection, is a chronic blood-borne infection. Studies have shown that 40% of chronic liver diseases are associated with HCV infection, and an estimated 8,000-10,000 people die each year. HCV-related end-stage liver disease is the most common indication for liver transplantation in adults.
In the past ten years, antiviral therapy for chronic liver disease has developed rapidly, and significant improvement has been seen in the treatment effect. However, even with the combination therapy with pegylated IFN-α plus ribavirin, 40% to 50% of patients fail to treat, that is, they are non-responders or relapsers. These patients do not currently have an effective treatment alternative. Because the risk of HCV-related chronic liver disease is related to the duration of HCV infection, and the risk of cirrhosis increases in patients who have been infected for more than 20 years, chronic liver disease often progresses to advanced stages with cirrhosis, ascites, jaundice, and rupture of varicose veins. , Brain disease, and progressive liver failure, and the risk of liver cancer is also significantly increased.
HCV is a enveloped positive-strand RNA virus of the Flaviviridae family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) that encodes a single open reading frame (ORF) of approximately 3,000 amino acids. Mostly polyprotein. In infected cells, cellular and viral proteases cleave this polyprotein at multiple sites to produce viral structural and non-structural (NS) proteins. There are two viral proteases that affect the production of mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B). The first viral protease is cleaved at the NS2-NS3 junction of the polyprotein; the second viral protease is A “NS3 protease” that mediates all subsequent cleavage events at a site downstream of the NS3 position relative to the polyprotein (ie, the site between the C-terminus of NS3 and the C-terminus of the polyprotein). The NS3 protease exhibits cis-activity at the NS3-NS4 cleavage site and, conversely, exhibits trans-activity at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is thought to provide multiple functions, such as acting as a cofactor for the NS3 protease, and may promote membrane localization of NS3 and other viral replicase components. The formation of a complex between NS3 and NS4A may be necessary for NS3-mediated processing events and improves the proteolytic efficiency at all sites recognized by NS3. NS3 protease may also exhibit nucleotide triphosphatase and RNA helicase activity. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. In addition, compounds that inhibit the effects of NS5A in viral replication may be useful for treating HCV.

Beijing Kawin Technology Share-Holding, in collaboration with Beijing Fu Rui Tiancheng Biotechnology and Ginkgo Pharma , is developing coblopasvir as an oral capsule formulation of dihydrochloride salt (KW-136), for treating hepatitis C virus infection. In June 2018, an NDA was filed in China by Beijing Kawin Technology and Sichuan Qingmu Pharmaceutical . In August 2018, the application was granted Priority Review in China . Also, Beijing Kawin is investigating a tablet formulation of coblopasvir dihydrochloride.

PATENT

WO2011075607 , claiming substituted heterocyclic derivatives as HCV replication inhibitors useful for treating HCV infection and liver fibrosis, assigned to Beijing Kawin Technology Share-Holding Co Ltd and InterMune Inc ,

PATENT

CN 108675998

PATENT

WO-2020001089

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020001089&tab=FULLTEXT&_cid=P22-K53D18-32430-1

Novel crystalline and amorphous forms of methyl carbamate compound, particularly coblopasvir dihydrochloride , (designated as Forms H) processes for their preparation, compositions and combinations comprising them are claimed. Also claim is an article or kit comprising a container and a package insert, wherein the container contains coblopasvir dihydrochloride.

Step 7
To a solution of compound 1-IXf (250 mg, 0.31 mmol) in toluene (10.0 mL) was added NH4OAc (4.0 g, 50 mmol) and the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed and the residue was purified by preparative HPLC to give Compound I (43.5 mg, yield 20%) as a white solid. MS (ESI) m / z (M + H) + 783.4.
Example 2 Preparation of a compound of formula II
Compound of formula (I) N-[(2S) -1-[(2S) -2- {4- [7- (4- {2-[(2S) -1-[(2S) -2-[(A Oxycarbonyl) amino] -3-methylbutanoyl] pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl) -2H-1,3-benzodioxo-4-yl] Preparation of -1H-imidazol-2-yl} pyrrolidin-1-yl] -3-methyl-1-oxobutane-2-yl] carbamate dihydrochloride
At room temperature, a solution of the pure product of structural formula I (800 g, 1.0 eq) and ethyl acetate (8 L) were sequentially added to a 20 L bottle and stirred. A 11.2% HCl / ethyl acetate solution (839 g) was added dropwise to the system, the temperature of the system was controlled at 15 ° C to 25 ° C, and the mixture was stirred for more than 3 hours to stop the reaction. The filter cake was filtered with ethyl acetate (2L). Wash the cake, bake the cake at a controlled temperature of 40-60 ° C, sample and test until the ethyl acetate residue is <0.5%, (about 73 hours of baking), to obtain the compound of formula II, off-white solid powder or granules, 774 g, HPLC Purity: 98.65%, yield: 88.5%, tested XRPD as amorphous.

///////////////Coblopasvir , KW-136, hepatitis C virus infection, CHINA, Beijing Kawin Technology, NDA, Phase III

O=C(OC)N[C@@H](C(C)C)C(N1[C@H](C2=NC(C3=CC=C(C4=C5OCOC5=C(C6=CNC([C@H]7N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC7)=N6)C=C4)C=C3)=CN2)CCC1)=O

CK-101


N-[3-[2-[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]anilino]quinazolin-8-yl]phenyl]prop-2-enamide.png

CK-101, RX-518

CAS 1660963-42-7

MF C29 H28 F2 N6 O2
MW 530.57
2-Propenamide, N-[3-[2-[[2,3-difluoro-4-[4-(2-hydroxyethyl)-1-piperazinyl]phenyl]amino]-8-quinazolinyl]phenyl]-

N-[3-[2-[[2,3-Difluoro-4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl]amino]quinazolin-8-yl]phenyl]acrylamide

N-(3-(2-((2,3-Difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide

EGFR-IN-3

UNII-708TLB8J3Y

708TLB8J3Y

AK543910

Suzhou NeuPharma (Originator)
Checkpoint Therapeutics

Non-Small Cell Lung Cancer Therapy
Solid Tumors Therapy

PHASE 2 Checkpoint Therapeutics, Cancer, lung (non-small cell) (NSCLC), solid tumour

RX518(CK-101) is an orally available third-generation and selective inhibitor of certain epidermal growth factor receptor (EGFR) activating mutations, including the resistance mutation T790M, and the L858R and exon 19 deletion (del 19) mutations, with potential antineoplastic activity.

In August 2019, Suzhou Neupharma and its licensee Checkpoint Therapeutics are developing CK-101 (phase II clinical trial), a novel third-generation, covalent, EGFR inhibitor, as a capsule formulation, for the treatment of cancers including NSCLC and other advanced solid tumors. In September 2017, the FDA granted Orphan Drug designation to this compound, for the treatment of EGFR mutation-positive NSCLC; in January 2018, the capsule was being developed as a class 1 chemical drug in China.

CK-101 (RX-518), a small-molecule inhibitor of epidermal growth factor receptor (EGFR), is in early clinical development at Checkpoint Therapeutics and Suzhou NeuPharma for the potential treatment of EGFR-mutated non-small cell lung cancer (NSCLC) and other advanced solid malignancies.

In 2015, Suzhou NeuPharma granted a global development and commercialization license to its EGFR inhibitor program, excluding certain Asian countries, to Coronado Biosciences (now Fortress Biotech). Subsequently, Coronado assigned the newly acquired program to its subsidiary Checkpoint Therapeutics.

In 2017, the product was granted orphan drug designation in the U.S. for the treatment of EGFR mutation-positive NSCLC.

There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

[0003] The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.

[0004] The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of compounds that specifically inhibit the function of a kinase which is essential for processes leading to cancer would be beneficial.

[0005] While such compounds are often initially evaluated for their activity when dissolved in solution, solid state characteristics such as polymorphism are also important. Polymorphic forms of a drug substance, such as a kinase inhibitor, can have different physical properties, including melting point, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process or manufacture a drug substance and the drug product. Moreover, differences in these properties

can and often lead to different pharmacokinetics profiles for different polymorphic forms of a drug. Therefore, polymorphism is often an important factor under regulatory review of the ‘sameness’ of drug products from various manufacturers. For example, polymorphism has been evaluated in many multi-million dollar and even multi-billion dollar drugs, such as warfarin sodium, famotidine, and ranitidine. Polymorphism can affect the quality, safety, and/or efficacy of a drug product, such as a kinase inhibitor. Thus, there still remains a need for polymorphs of kinase inhibitors. The present disclosure addresses this need and provides related advantages as well.

PATENT

WO2015027222

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015027222

PATENT

WO-2019157225

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019157225&tab=PCTDESCRIPTION&_cid=P10-JZNKMN-12945-1

Crystalline form II-VIII of the compound presumed to be CK-101 (first disclosed in WO2015027222 ), for treating a disorder mediated by epidermal growth factor receptor (EGFR) eg cancer.

SCHEME A

Scheme B

General Procedures

Example 1: Preparation of the compound of Formula I (N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide)

[0253] To a solution of l,2,3-trifluoro-4-nitrobenzene (2.5 g, 14 mmol, 1.0 eq.) in DMF (20 mL) was added K2C03 (3.8 g, 28 mmol, 2.0 eq.) followed by 2-(piperazin-l-yl)ethanol (1.8 g, 14 mmol, 1.0 eq.) at 0 °C and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water (200 mL), filtered and dried in vacuo to afford 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 67.5%).

[0254] To a solution of 2-(4-(2,3-difluoro-4-nitrophenyl)piperazin-l-yl)ethanol (2.7 g, 9.0 mmol) in MeOH (30 mL) was added Pd/C (270 mg) and the resulting mixture was stirred at r.t.

overnight. The Pd/C was removed by filtration and the filtrate was concentrated to afford 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (2.39 g, 99% yield) as off-white solid.

[0255] To a solution of 8-bromo-2-chloroquinazoline (15.4 g, 63.6 mmol, 1 eq. ) and (3-aminophenyl)boronic acid (8.7 g, 63.6 mmol, 1 eq.) in dioxane/H20 (200 mL/20 mL) was added Na2C03 (13.5 g, 127.2 mmol, 2 eq.), followed by Pd(dppf)Cl2 (2.6 g, 3.2 mmol, 0.05 eq.) under N2, then the mixture was stirred at 80 °C for 12 h. Then the solution was cooled to r.t.,

concentrated and the residue was purified via column chromatography (PE/EA=3 :2, v/v) to afford 3-(2-chloroquinazolin-8-yl)aniline as yellow solid (8.7 g, 53.7% yield).

[0256] To a solution of 3-(2-chloroquinazolin-8-yl)aniline (8.7 g, 34 mmol, 1 eq.) in DCM ( 200 mL ) cooled in ice-bath was added TEA (9.5 mL, 68 mmol, 2 eq. ), followed by acryloyl chloride (4.1 mL, 51 mmol, 1.5 eq.) dropwise. The resulting mixture was stirred at r.t. for 1 h, then washed with brine, dried over anhydrous N2S04 concentrated and the residue was purified via column chromatography (PE/EA=l : 1, v:v) to afford N-(3-(2-chloroquinazolin-8-yl)phenyl)acryl amide as yellow solid(6.6 g, 65% yield).

[0257] To a suspension of 2-(4-(4-amino-2,3-difluorophenyl)piperazin-l-yl)ethanol (83 mg,

0.32 mmol, 1 eq.) and N-(3-(2-chloroquinazolin-8-yl)phenyl)acrylamide (100 mg, 0.32 mmol, 1 eq.) in n-BuOH (5 mL) was added TFA (68 mg, 0.64 mmol, 2 eq.) and the resulting mixture was stirred at 90 °C overnight. The mixture was concentrated, diluted with DCM (20 mL) , washed with Na2C03 solution (20 mL), dried over anhydrous Na2S04, concentrated and the residue was purified via column chromatography (MeOH/DCM=l/30, v:v) to afford N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide as a yellow solid(l6.3 mg, 9.5% yield). LRMS (M+H+) m/z calculated 531.2, found 531.2. 1H NMR

(CD3OD, 400 MHz) d 9.21 (s, 1 H), 7.19-8.01 (m, 10 H), 8.90 (s, 1 H), 6.41-6.49 (m, 3 H), 5.86 (m, 1 H), 3.98-4.01 (m, 3 H), 3.70-3.76 (m, 3 H), 3.40-3.49 (m, 2 H), 3.37-3.39 (m, 4 H), 3.18 (m, 2H).

Example 2. Preparation of Form I of the compound of Formula I

[0258] Crude compound of Formula I (~30 g, 75% of weight based assay) was dissolved in ethyl acetate (3 L) at 55-65 °C under nitrogen. The resulting solution was filtered via silica gel pad and washed with ethyl acetate (3 L><2) at 55-65 °C. The filtrate was concentrated via vacuum at 30-40 °C to ~2.4 L. The mixture was heated up to 75-85 °C and maintained about 1 hour.

Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and the mixture was then cooled down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with ethyl acetate (60 mL><2). The wet cake was dried via vacuum at 30-40 °C to get (about 16 g) of the purified Form I of the compound of Formula I.

Example 3. Preparation of Form III of the compound of Formula I

[0259] The compound of Formula I (2 g) was dissolved in EtOH (40 mL) at 75-85 °C under nitrogen. n-Heptane (40 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 75-85 °C for 1 hour. Then cooled down to 50-60 °C and maintained about 2 hours. The heat-cooling operation was repeated again and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. The resulting mixture was filtered and washed with EtOH/n-Heptane (1/1, 5 mL><2). The wet cake was dried via vacuum at 30-40 °C to get the purified Form III of the compound of Formula I (1.7 g).

Example 4. Preparation of Form IV of the compound of Formula I The crude compound of Formula I (15 g) was dissolved in ethyl acetate (600 mL) at 75-85 °C under nitrogen and treated with anhydrous Na2S04, activated carbon, silica metal scavenger for 1 hour. The resulting mixture was filtered via neutral Al203 and washed with ethyl acetate (300 mL><2) at 75-85 °C. The filtrate was concentrated under vacuum at 30-40 °C and swapped with DCM (150 mL). n-Heptane (75 mL) was added into this DCM solution at 35-45 °C, and then the mixture was cooled down to 20-30 °C slowly. The resulting mixture was filtered and washed with DCM/n-Heptane (2/1, 10 mL><3). The wet cake was dried via vacuum at 35-40 °C to get the purified Form IV of the compound of Formula I (9.6 g).

Example 5. Preparation of Form V of the compound of Formula I

[0260] Polymorph Form III of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form V.

Example 6. Preparation of Form VI of the compound of Formula I

[0261] The compound of Formula I (1 g) was dissolved in IPA (20 mL) at 75-85 °C under nitrogen. n-Heptane (20 mL) was added dropwise into reaction at 75-85 °C. The mixture was stirred at 45-55 °C for 16 hours. Then heated up to 75-85 °C and maintained about 0.5 hour.

Then cooled down to 45-55 °C for 0.5 hour and continued to cool the mixture down to 20-30 °C and stirred for 3 hours. Filtered and washed with IPA/n-Heptane (1/1, 3 mL><2). The wet cake was dried via vacuum at 75-80 °C for 2 hours to get the purified Form VI of the compound of Formula I.

Example 7. Preparation of Form VIII of the compound of Formula I

[0262] The polymorph Form VI of the compound of Formula I was dried in oven at 80 °C for 2 days to obtain the polymorph Form VIII.

Example 8. X-ray powder diffraction (XRD)

[0263] X-ray powder diffraction (XRD) patterns were obtained on a Bruker D8 Advance. A CuK source (=1.54056 angstrom) operating minimally at 40 kV and 40 mA scans each sample between 4 and 40 degrees 2-theta. The step size is 0.05°C and scan speed is 0.5 second per step.

Example 9. Thermogravimetric Analyses (TGA)

[0264] Thermogravimetric analyses were carried out on a TA Instrument TGA unit (Model TGA 500). Samples were heated in platinum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 60mL/min (sample purge) and 40mL/min (balance purge). The TGA temperature was calibrated with nickel standard, MP=354.4 °C. The weight calibration was performed with manufacturer-supplied standards and verified against sodium citrate dihydrate desolvation.

Example 10. Differential scanning calorimetry (DSC)

[0265] Differential scanning calorimetry analyses were carried out on a TA Instrument DSC unit (Model DSC 1000 or 2000). Samples were heated in non-hermetic aluminum pans from ambient to 300 °C at 10 °C/min with a nitrogen purge of 50mL/min. The DSC temperature was calibrated with indium standard, onset of l56-l58°C, enthalpy of 25-29J/g.

Example 11. Hygroscopicity (DVS)

[0266] The moisture sorption profile was generated at 25°C using a DVS Moisture Balance Flow System (Model Advantage) with the following conditions: sample size approximately 5 to 10 mg, drying 25°C for 60 minutes, adsorption range 0% to 95% RH, desorption range 95% to 0% RH, and step interval 5%. The equilibrium criterion was <0.01% weight change in 5 minutes for a maximum of 120 minutes.

Example 12: Microscopy

[0267] Microscopy was performed using a Leica DMLP polarized light microscope equipped with 2.5X, 10X and 20X objectives and a digital camera to capture images showing particle shape, size, and crystallinity. Crossed polars were used to show birefringence and crystal habit for the samples dispersed in immersion oil.

Example 13: HPLC

[0256] HPLCs were preformed using the following instrument and/or conditions.

///////////////CK-101 , CK 101 , CK101 , phase II , Suzhou Neupharma, Checkpoint Therapeutics ,  Orphan Drug designation, EGFR mutation-positive NSCLC, NSCLC, CANCER, SOLID TUMOUR,  China, RX-518, AK543910

OCCN1CCN(CC1)c5ccc(Nc2nc3c(cccc3cn2)c4cccc(NC(=O)C=C)c4)c(F)c5F

SY-008


Acetic acid;(2S,3R,4S,5S,6R)-2-[[4-[[4-[(E)-4-(2,9-diazaspiro[5.5]undecan-2-yl)but-1-enyl]-2-methylphenyl]methyl]-5-propan-2-yl-1H-pyrazol-3-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol.png

SY-008

CAS 1878218-66-6

FREE FORM 1480443-32-0

SGLT1 inhibitor (type 2 diabetes),

β-D-Glucopyranoside, 4-[[4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)-1-buten-1-yl]-2-methylphenyl]methyl]-5-(1-methylethyl)-1H-pyrazol-3-yl, acetate (1:1)

acetic acid;(2S,3R,4S,5S,6R)-2-[[4-[[4-[(E)-4-(2,9-diazaspiro[5.5]undecan-2-yl)but-1-enyl]-2-methylphenyl]methyl]-5-propan-2-yl-1H-pyrazol-3-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol

4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl beta-D-glucopyranoside acetate

MF H50 N4 O6 . C2 H4 O2

MW 58.8 g/mol,C35H54N4O8

Originator Eli Lilly

  • Developer Eli Lilly; Yabao Pharmaceutical Group
  • Class Antihyperglycaemics; Small molecules
  • Mechanism of Action Sodium-glucose transporter 1 inhibitors
  • Phase I Diabetes mellitus
  • 28 Aug 2018 No recent reports of development identified for phase-I development in Diabetes-mellitus in Singapore (PO)
  • 24 Jun 2018 Biomarkers information updated
  • 12 Mar 2018 Phase-I clinical trials in Diabetes mellitus (In volunteers) in China (PO) (NCT03462589)
  • Eli Lilly is developing SY 008, a sodium glucose transporter 1 (SGLT1) inhibitor, for the treatment of diabetes mellitus. The approach of inhibiting SGLT1 could be promising because it acts independently of the beta cell and could be effective in both early and advanced stages of diabetes. Reducing both glucose and insulin may improve the metabolic state and potentially the health of beta cells, without causing weight gain or hypoglycaemia. Clinical development is underway in Singapore and China.

    As at August 2018, no recent reports of development had been identified for phase-I development in Diabetes-mellitus in Singapore (PO).

Suzhou Yabao , under license from  Eli Lilly , is developing SY-008 , an SGLT1 inhibitor, for the potential oral capsule treatment of type 2 diabetes in China. By April 2019, a phase Ia trial was completed

PATENT

WO 2013169546

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013169546&recNum=43&docAn=US2013039164&queryString=EN_ALL:nmr%20AND%20PA:(ELI%20LILLY%20AND%20COMPANY)%20&maxRec=4416

The present invention is in the field of treatment of diabetes and other diseases and disorders associated with hyperglycemia. Diabetes is a group of diseases that is characterized by high levels of blood glucose. It affects approximately 25 million people in the United States and is also the 7th leading cause of death in U.S. according to the 201 1 National Diabetes Fact Sheet (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the absorption of carbohydrates, such as glucose. More specifically, SGLTl is responsible for transport of glucose across the brush border membrane of the small intestine. Inhibition of SGLTl may result in reduced absorption of glucose in the small intestine, thus providing a useful approach to treating diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives with human SGLTl inhibitory activity which are further disclosed as useful for the prevention or treatment of a disease associated with hyperglycemia, such as diabetes. In addition, WO 201 1/039338 discloses certain pyrazole derivatives with SGLT1/SGLT2 inhibitor activity which are further disclosed as being useful for treatment of bone diseases, such as osteoporosis.

There is a need for alternative drugs and treatment for diabetes. The present invention provides certain novel inhibitors of SGLTl which may be suitable for the treatment of diabetes.

Accordingly, the present invention provides a compound of Formula II:

Preparation 1

Synthesis of (4-bromo-2-methyl-phenyl)methanol.

Scheme 1, step A: Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in

tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under the reduced pressure to give a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). 1H NMR (CDCI3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).

Alternative synthesis of (4-bromo-2-methyl-phenyl)methanol.

Borane-dimethyl sulfide complex (2M in THF; 1 16 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.1 13 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3 °C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5°C, and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHC03 solution (200 mL) and dried over Na2S04. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+l-18).

Preparation 2

Synthesis of 4-bromo- l-2-methyl-benzene.

Scheme 1, step B: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and

-Cl-

dimethylformamide (0.025 mol, 2.0 mL) at 0°C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. XH NMR (CDC13): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).

Alternative synthesis of 4-bromo- 1 -chloromethyl-2-methyl-benzene. Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further

methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (IN; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2S04. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). XH NMR (300.1 1 MHz, CDC13): δ 7.36-7.30 (m, 2H), 7.18 (d, J= 8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).

Preparation 3

Synthesis of 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol.

Scheme 1, step C: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0°C. After 30 min at room temperature, add a solution of 4-bromo- l-chloromethyl-2-methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70 °C overnight (18 hours). Add 1.0 M HC1 (20 mL) to quench the reaction.

Extract with ethyl acetate (200 mL), wash extract with water (200 rnL) and brine (200 mL), dry over a2S04, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120 °C for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40 °C to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+l), 309.0 (M-l).

Alternative synthesis of 4-r(4-bromo-2-methyl-phenyl)methyl1-5-isopropyl- !H-pyrazol- 3-oL

A solution of 4-bromo- 1 -chloromethyl-2-methyl-benzene (13.16 g, 59.95 mmoles) in acetonitrile (65.8 mL) is prepared. Potassium carbonate (24.86 g, 179.9 mmol), potassium iodide (1 1.94 g, 71.94 mmol) and methyl 4-methyl-3-oxo valerate (8.96 mL; 62.95 mmol) are added. The resulting mixture is stirred at ambient temperature for 20 hours. Hydrochloric acid (2N) is added to give pH 3. The solution is extracted with ethyl acetate (100 ml), the organic phase is washed with brine (100 ml) and dried over Na2S04. The mixture is filtered and concentrated under reduced pressure. The residue is dissolved in toluene (65.8 mL) and hydrazine monohydrate (13.7 mL, 0.180 mol) is added. The resulting mixture is heated to reflux and water is removed using a Dean and Stark apparatus. After 3 hours the mixture is cooled to 90 °C and additional hydrazine monohydrate (13.7 mL; 0.180 mol) is added and the mixture is heated to reflux for 1 hour. The mixture is cooled and concentrated under reduced pressure. The resulting solid is triturated with water (200 mL), filtered and dried in a vacuum oven over P2O5 at 60°C. The solid is triturated in iso-hexane (200 mL) and filtered to give the title compound (14.3 g; 77.1% yield). MS (m/z): 309/31 1 (M+l).

Preparation 4

Synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra- O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step D: To a 1L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (20 g, 64.7 mmol), alpha-D-glucopyranosyl bromide tetrabenzoate (50 g, 76 mmol), benzyltributylammonium chloride (6 g, 19.4 mmol), dichloromethane (500 mL), potassium carbonate (44.7 g, 323 mmol) and water (100 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (500mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to yield the title compound (37 g, 64 mmol). MS (ml 2): 889.2 (M+l), 887.2 (M-l).

Preparation 5

Synthesis of 4- {4-[( lis)-4-hydroxybut- 1 -en- 1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- 1H- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step E: Add 3-buten-l-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90 °C for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+l).

Preparation 6

Synthesis of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step F: Add 3,3,3-triacetoxy-3-iodophthalide (134 mg, 0.96 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (280 mg, 0.32 mmol) and sodium bicarbonate (133.8 mg, 1.6 mmol) in dichloromethane (20 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (270 mg, 0.31 mmol). MS (m/z): 876.5 (M+l), 874.5 (M-l).

Preparation 7

Synthesis of tert-butyl 2- {(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 1, step G: Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4- {4-[(lis)-4-oxybut- 1 -en-1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2-dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol).

MS (m/z): 1115.6 (M+1).

Preparation 8

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D- glucopyranoside dihydrochloride.

Scheme 1, step H: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 0.6 mL, 2.4 mmol) to a solution of tert-butyl 2-{(3is)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (275 mg, 0.25 mmol) in dichloromethane (5 mL). After overnight (18 hours) at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (258 mg, 0.24 mmol). MS (m/z): 1015.6 (M+l).

Example 1

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 1, step I: Add sodium hydroxide (0.5 mL, 0.5 mmol, 1.0 M solution) to a solution of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride (258 mg, 0.24 mmol) in methanol (2 mL). After 2 hours at 40 °C, concentrate to remove the solvent under reduced pressure to give a residue, which is purified by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 um C18XBridge ODB column, solvent A – 1¾0 w NH4HCO3 @ pH 10, solvent B – MeCN to yield the title compound as a solid (46 mg, 0.08 mmol). MS (m/z): 598.8 (M+l), 596.8 (M-l).

 Preparation 9

Synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra- O-acetyl-beta-D-glucopyranoside.

Scheme 2, step A: To a 1 L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (24 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammomum chloride (5 g, 15.5 mmol), dichloromethane (250 mL), potassium carbonate (32 g, 323 mmol) and water (120 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (450 mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (36.5 g, 57 mmol). MS (m/z): 638.5 (M+l), 636.5 (M-l).

Alternative synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Reagents 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (24.0 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (4.94 g, 15.52 mmol), potassium carbonate

(32.18 g, 232.9 mmol), dichloromethane (250 mL) and water (120 mL) are combined and the mixture is stirred at ambient temperature for 18 hours. The mixture is partitioned between dichloromethane (250 mL) and water (250 mL). The organic phase is washed with brine (250 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (eluting with 10% ethyl acetate in dichloromethane to 70% ethyl acetate in dichloromethane) to give the title compound (36.5 g, 74% yield). MS (m/z): 639/641 (M+l).

Preparation 10

Synthesis of 4- {4-[( lis)-4-hydroxybut- 1 -en- 1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- 1H- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Scheme 2, step B: Add 3-buten-l-ol (6.1 mL, 70 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90 °C for 2 hours, cool, and concentrate to remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (7.5 g, 11.9 mmol). MS (m/z): 631.2 (M+l), 629.2 (M-l).

Preparation 11

Synthesis of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Scheme 2, step C: Add 3,3,3-triacetoxy-3-iodophthalide (2.1g, 4.76 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside ( 1.5 g, 2.38 mmol) and sodium bicarbonate (2 g, 23.8 mmol) in dichloromethane (50 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL), wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (0.95 g, 1.51 mmol). MS (m/z): 628.8(M+1), 626.8 (M-l).

Preparation 12

Synthesis of tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 2, Step D: Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4- {4-[(lis)-4-oxybut- 1 -en-1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2-dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol).

MS (m/z): 866.8, 867.8 (M+l), 864.8, 865.8 (M-l).

Preparation 13

Synthesis oftert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,8- diazaspiro[4.5]decane-8-carboxylate.

The title compound is prepared essentially by the method of Preparation 12. S (m/z): 852.8, 853.6 (M+l), 850.8, 851.6 (M-l).

Preparation 14

Synthesis oftert-butyl 9-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-3,9- diazaspiro[5.5]undecane-3-carboxylate.

The title compound is prepared essentially by the method of Preparation 12. S (m/z): 866.8, 867.6 (M+l), 864.8, 865.6 (M-l).

Preparation 15

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranoside dihydrochloride.

Scheme 2, step E: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 1.5 mL, 5.8 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]- lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 0.58 mmol) in dichloromethane (20 mL). After 2 hours at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (480 mg, 0.57 mmol).

MS (m/z): 767.4 (M+l).

Preparation 16

Synthesis of 4-{4-[(lE)-4-(2,8-diazaspiro[4.5]dec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5- (propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

dihydrochloride.

The title compound is prepared essentially by the method of Preparation 15. MS (m/z): 752.8, 753.8 (M+1), 750.8 (M-1).

First alternative synthesis of Example 1

First alternative synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en- 2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 2, step F: Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (480 mg, 0.24 mmol). After 18 hours (overnight) at room temperature, concentrate to dryness under reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 urn C18XBridge ODB column, solvent A – H20 w NH4HCO3 @ pH 10, solvent B – MeCN to yield the title compound as a solid (50 mg, 0.08 mmol).

MS (m/z): 598.8 (M+1), 596.8 (M-1). 1H MR (400.31 MHz, CD3OD): δ 7.11 (d, J=1.3

Hz, 1H), 7.04 (dd, J=1.3,8.0 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 15.8 Hz, 1H), 6.16 (dt, J= 15.8, 6.3 Hz, 1H), 5.02 (m, 1H), 3.81 (d, J= 11.7 Hz, 1H), 3.72 (d, J= 16.8 Hz, 1H), 3.68 (d, J= 16.8 Hz, 1H) , 3.64 (m, 1H), 3.37-3.29 (m, 4H), 2.79 (m, 1H), 2.72 (t, J= 5.8 Hz, 4H), 2.44-2.33 (m, 6H), 2.30 (s, 3H), 2.26 ( broad s, 2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.36 (m, 2H), 1.1 1 (d, J= 7.0 Hz, 3H), 1.10 (d, J= 7.0 Hz, 3H).

Example 2

Synthesis of 4- {4-[(lE)-4-(2,8-diazaspiro[4.5]dec-2-yl)but-l-en-l-yl]-2-methylbi

(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

O H

The title compound is prepared essentially by the method of the first alternative synthesis of Example 1. MS (m/z): 584.7 (M+l), 582.8 (M-l).

Example 3

Synthesis of 4- {4-[( 1 E)-4-(3 ,9-diazaspiro[5.5]undec-3 -yl)but- 1 -en- 1 -yl]-2- methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl beta-D-glucopyranoside.

The title compound is prepared essentially by first treating the compound of Prearation 14 with HC1 as discussed in Preparation 15 then treating the resulting hydrochloride salt with triethyl amine as discussed in the first alternative synthesis of Example 1. MS (m/z): 598.8, 599.8 (M+l), 596.8, 597.8 (M-l).

Example 1 Preparation 17

Synthesis of tert-butyl 4-but-3- nyl-4,9-diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step A: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSC^, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). iH MR (300.11 MHz, CDC13): δ 3.43-3.31 (m, 4H),

2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.44 (s, 17H).

Preparation 18

Synthesis of tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]- 4,9-diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step B: Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5, 5-tetramethyl-1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65 °C for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ~4cm thick pad of silica gel, eluting with dichloromethane (2 x 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield), !H NMR (300.1 1 MHz, CDC13): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H),

3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70 – 1.13 (m, 29H).

Preparation 19

Synthesis of tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D- glucopyranosyl)oxy]- lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step C: A solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (20 g, 31.3 mmol), tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (16.3 g, 37.5 mmol) and potassium carbonate (12.97 g, 93.82 mmol) in tetrahydrofuran (200 mL) and water (40 mL) is degassed for 15 min by bubbling nitrogen gas through it. Pd(OAc)2 (140 mg, 625 μιηοΐ) and 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-l, r-biphenyl (0.596 g, 1.25 mmol) are added and the reaction is heated to reflux for 16 h. The solution is cooled to ambient temperature and methanol (200 mL) is added. After 30 minutes the solvent is removed under reduced pressure. The mixture is partitioned between ethyl acetate (500 mL) and brine (500 ml) adding aqueous MgS04 (1M; 500 ml) to aid the phase separation. The layers are separated and the organic layer is dried over MgS04 and filtered through a 10 cm pad of silica gel, eluting with ethyl acetate (-1.5 L). The filtrate is discarded and the silica pad is flushed with 5% MeOH in THF (2 L). The methanolic filtrate is concentrated under reduced pressure to give the title compound (20. lg, 92%).

MS (m/z): 699 (M+l).

Second alternative Synthesis of Example 1

Second alternative synthesis of 4- {4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l- yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 3, step D: Trifluoroacetic acid (32.2 mL; 0.426 mol) is added to a solution of tert-butyl 2- {(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (14.87 g; 21.28 mmol) in dichloromethane (149 mL) cooled in iced water. The solution is allowed to warm to room temperature. After 30 minutes, the mixture is slowly added to ammonia in MeOH (2M; 300 mL), applying cooling as necessary to maintain a constant temperature. The solution is stirred at room temperature for 15 min. The mixture is concentrated under reduced pressure and the residue is purified using SCX-2 resin. The basic filtrate is concentrated under reduced pressure and the residue is triturated/sonicated in ethyl acetate, filtered and dried. The resulting solid is dissolved in MeOH (200ml) and concentrated in vacuo. This is repeated several times give the title compound (12.22 g, yield 96%). MS (m/z): 599 (M+l). [a]D20 = -12 ° (C=0.2, MeOH).

PATENT

WO 2015069541

https://patents.google.com/patent/WO2015069541A1

4-{4-[(1 E)-4-(2,9-DIAZASPIRO[5.5]UNDEC-2-YL)BUT-1 -EN-1

-YL]-2-METHYLBENZYL}-5-(PROPAN-2-YL)-1 H-PYRAZOL-3-YL

BETA-D- GLUCOPYRANOSIDE ACETATE

The present invention relates to a novel SGLT1 inhibitor which is an acetate salt of a pyrazole compound, to pharmaceutical compositions comprising the compound, to methods of using the compound to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compound.

The present invention is in the field of treatment of diabetes and other diseases and disorders associated with hyperglycemia. Diabetes is a group of diseases that is characterized by high levels of blood glucose. It affects approximately 25 million people in the United States and is also the 7th leading cause of death in U.S. according to the 2011 National Diabetes Fact Sheet (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the absorption of carbohydrates, such as glucose. More specifically, SGLT1 is responsible for transport of glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 may result in reduced absorption of glucose in the small intestine, thus providing a useful approach to treating diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives with human SGLT1 inhibitory activity which are further disclosed as useful for the prevention or treatment of a disease associated with hyperglycemia, such as diabetes. In addition, WO 2011/039338 discloses certain pyrazole derivatives with SGLT1/SGLT2 inhibitor activity which are further disclosed as being useful for treatment of bone diseases, such as osteoporosis.

There is a need for alternative drugs and treatment for diabetes. The present invention provides an acetate salt of a pyrazole compound, which is an SGLT1 inhibitor, and as such, may be suitable for the treatment of certain disorders, such as diabetes. Accordingly, the present invention provides a compound of Formula I:

Figure imgf000003_0001

or hydrate thereof.

Figure imgf000008_0001

Preparation 1

(4-bromo-2-methyl-phenyl)methanol

Figure imgf000009_0001

Scheme 1, step A: Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in

tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under the reduced pressure to give a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). !H NMR (CDCI3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).

Alternative synthesis of (4-bromo-2-methyl-phenyl)mefhanol.

Borane-dimethyl sulfide complex (2M in THF; 116 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.113 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3 °C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5°C, and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHC03 solution (200 mL) and dried over Na2S04. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+l-18).

Preparation 2

4-bromo- 1 -chloromethyl -2 -methyl -benzene

Figure imgf000009_0002

Scheme 1, step B: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4- bromo-2 -methyl -phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0°C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. !H NMR (CDC13): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).

Alternative synthesis of 4-bromo-l-chloromethyl-2-methyl -benzene. Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further

methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (IN; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na2S04. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). !H NMR (300.11 MHz, CDC13): δ 7.36-7.30 (m, 2H), 7.18 (d, J= 8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).

Preparation 3

4- [(4-bromo-2-methyl-phenyl)methyl] -5 -isopropyl- lH-pyrazol-3 -ol

Figure imgf000010_0001

Scheme 1, step C: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0°C. After 30 min at room temperature, add a solution of 4-bromo-l-chloromethyl-2- methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70 °C overnight (18 hours). Add 1.0 M HC1 (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na2S04, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120 °C for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40 °C to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+l), 309.0 (M-l). Alternative synthesis of 4-[(4-bromo-2-methyl-phenyl)methyl] -5 -isopropyl- lH-pyrazol-

3-ol.

A solution of 4-bromo-l-chloromethyl-2-methyl-benzene (13.16 g, 59.95 mmoles) in acetonitrile (65.8 mL) is prepared. Potassium carbonate (24.86 g, 179.9 mmol), potassium iodide (11.94 g, 71.94 mmol) and methyl 4-methyl-3-oxovalerate (8.96 mL; 62.95 mmol) are added. The resulting mixture is stirred at ambient temperature for 20 hours. Hydrochloric acid (2N) is added to give pH 3. The solution is extracted with ethyl acetate (100 ml), the organic phase is washed with brine (100 ml) and dried over Na2S04. The mixture is filtered and concentrated under reduced pressure. The residue is dissolved in toluene (65.8 mL) and hydrazine monohydrate (13.7 mL, 0.180 mol) is added. The resulting mixture is heated to reflux and water is removed using a Dean and Stark apparatus. After 3 hours the mixture is cooled to 90 °C and additional hydrazine monohydrate (13.7 mL; 0.180 mol) is added and the mixture is heated to reflux for 1 hour. The mixture is cooled and concentrated under reduced pressure. The resulting solid is triturated with water (200 mL), filtered and dried in a vacuum oven over P2Os at 60°C. The solid is triturated in iso-hexane (200 mL) and filtered to give the title compound (14.3 g; 77.1% yield). MS (m/z): 309/311 (M+l).

Preparation 4

4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl- beta-D-glucopyranoside

Figure imgf000012_0001

Scheme 1, step D: To a 1L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5- isopropyl-lH-pyrazol-3-ol (20 g, 64.7 mmol), alpha-D-glucopyranosyl bromide tetrabenzoate (50 g, 76 mmol), benzyltributylammonium chloride (6 g, 19.4 mmol), dichloromethane (500 mL), potassium carbonate (44.7 g, 323 mmol) and water (100 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (500mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to yield the title compound (37 g, 64 mmol). MS (m/z): 889.2 (M+l), 887.2 (M-l).

Preparation 5

4- {4- [(lis)-4-hydroxybut- 1 -en- 1 -yl] -2-methylbenzyl } -5 -(propan-2-yl)- lH-pyrazol-3-yl

2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside

Figure imgf000012_0002

Scheme 1, step E: Add 3-buten-l-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4- bromo-2-methylbenzyl)-5 -(propan-2-yl)- lH-pyrazol-3 -yl 2,3 ,4,6-tetra-O-benzoyl-beta-D- glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90 °C for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+l).

Preparation 6

4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside

Figure imgf000013_0001

Scheme 1, step F: Add 3,3,3-triacetoxy-3-iodophthalide (134 mg, 0.96 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (280 mg, 0.32 mmol) and sodium bicarbonate (133.8 mg, 1.6 mmol) in dichloromethane (20 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (270 mg, 0.31 mmol). MS (m/z): 876.5 (M+l), 874.5 (M-l).

Preparation 7

tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate

Figure imgf000014_0001

Scheme 1, step G: Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2- dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol).

MS (m/z): 1115.6 (M+l).

Preparation 8

4- {4- [( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan- 2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride

Figure imgf000014_0002

Scheme 1, step H: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 0.6 mL, 2.4 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3- [(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4- yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (275 mg, 0.25 mmol) in dichloromethane (5 mL). After overnight (18 hours) at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (258 mg, 0.24 mmol). MS (m/z): 1015.6 (M+l).

Figure imgf000016_0001

Preparation 9

4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl- beta-D-glucopyranoside.

Figure imgf000017_0001

Scheme 2, step A: To a 1 L flask, add 4-[(4-bromo-2-methyl-phenyl)mefhyl]-5- isopropyl-lH-pyrazol-3-ol (24 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D- glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (5 g, 15.5 mmol), dichloromethane (250 mL), potassium carbonate (32 g, 323 mmol) and water (120 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (450 mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (36.5 g, 57 mmol). MS (m/z): 638.5 (M+l), 636.5 (M-l).

Alternative synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Reagents 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (24.0 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (4.94 g, 15.52 mmol), potassium carbonate (32.18 g, 232.9 mmol), dichloromethane (250 mL) and water (120 mL) are combined and the mixture is stirred at ambient temperature for 18 hours. The mixture is partitioned between dichloromethane (250 mL) and water (250 mL). The organic phase is washed with brine (250 mL), dried over Na2S04, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (eluting with 10% ethyl acetate in dichloromethane to 70% ethyl acetate in dichloromethane) to give the title compound (36.5 g, 74% yield). MS (m/z): 639/641 (M+l). Preparation 10

4- {4- [(lis)-4-hydroxybut- 1 -en- 1 -yl] -2-methylbenzyl } -5 -(propan-2-yl)- lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

Figure imgf000018_0001

Scheme 2, step B: Add 3-buten-l-ol (6.1 mL, 70 mmol) to a solution of 4-(4- bromo-2-methylbenzyl)-5 -(propan-2-yl)- 1 H-pyrazol-3 -yl 2,3 ,4,6-tetra-O-acetyl-beta-D- glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90 °C for 2 hours, cool, and concentrate to remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (7.5 g, 11.9 mmol) MS (m/z): 631.2 (M+l), 629.2 (M-l).

Preparation 11

4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

Figure imgf000018_0002

Scheme 2, step C: Add 3,3,3-triacetoxy-3-iodophthalide (2.1g, 4.76 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside ( 1.5 g, 2.38 mmol) and sodium bicarbonate (2 g, 23.8 mmol) in dichloromethane (50 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL), wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (0.95 g, 1.51 mmol). MS (m/z): 628.8(M+1), 626.8 (M-l).

Preparation 12a

tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)oxy] -lH-pyrazol-4-yl}methyl)phenyl]but-3-en- 1 -yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate

Figure imgf000019_0001

Scheme 2, Step D: Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2- dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol).

MS (m/z): 866.8, 867.8 (M+l), 864.8, 865.8 (M-l).

Preparation 13

4- {4- [( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan- 2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride

Figure imgf000020_0001

Scheme 2, step E: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 1.5 mL, 5.8 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6- tetra-0-acetyl-beta-D-glucopyranosyl)oxy] – lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 – yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 0.58 mmol) in dichloromethane (20 mL). After 2 hours at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (480 mg, 0.57 mmol).

MS (m/z): 767.4 (M+l).

Scheme 3

Figure imgf000021_0001

Preparation 14

tert-butyl 4-but-3-ynyl-4,9-diazas iro[5.5]undecane-9-carboxylate

Figure imgf000021_0002

Scheme 3, step A: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgS04, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). lH NMR (300.11 MHz, CDC13): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.44 (s, 17H).

Preparation 15

tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9- diazaspiro[5.5]undecane-9-carboxylate

Figure imgf000022_0001

Scheme 3, step B: Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65 °C for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ~4cm thick pad of silica gel, eluting with dichloromethane (2 x 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield). 1H NMR (300.11 MHz, CDCI3): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H), 3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70 – 1.13 (m, 29H).

Preparation 16

tert-butyl 2-{(3£’)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D-glucopyranosyl)oxy]-lH- pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl} -2,9-diazaspiro [5.5]undecane-9-carboxylate

Figure imgf000023_0001

Scheme 3, step C: A solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (20 g, 31.3 mmol), tert- butyl 4-[(£)-4-(4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)but-3 -enyl] -4,9- diazaspiro[5.5]undecane-9-carboxylate (16.3 g, 37.5 mmol) and potassium carbonate (12.97 g, 93.82 mmol) in tetrahydrofuran (200 mL) and water (40 mL) is degassed for 15 min by bubbling nitrogen gas through it. Pd(OAc)2 (140 mg, 625 μιηοΐ) and 2- dicyclohexylphosphino-2′,4′,6′-tri-i -propyl- Ι, -biphenyl (0.596 g, 1.25 mmol) are added and the reaction is heated to reflux for 16 h. The solution is cooled to ambient temperature and methanol (200 mL) is added. After 30 minutes the solvent is removed under reduced pressure. The mixture is partitioned between ethyl acetate (500 mL) and brine (500 ml) adding aqueous MgS04 (1M; 500 ml) to aid the phase separation. The layers are separated and the organic layer is dried over MgS04 and filtered through a 10 cm pad of silica gel, eluting with ethyl acetate (-1.5 L). The filtrate is discarded and the silica pad is flushed with 5% MeOH in THF (2 L). The methanolic filtrate is concentrated under reduced pressure to give the title compound (20. lg, 92%).

MS (m/z): 699 (M+l).

Figure imgf000024_0001
Figure imgf000024_0002

Preparation 17

tert-butyl 4- [(E)-4- [4- [(3 -hydroxy-5-isopropyl- 1 H-pyrazol-4-yl)methyl] -3 -methyl- phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate

Figure imgf000024_0003

Scheme 4, step A: Add tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (35.8 kg, 82.4 mol) in methanol (130 L) to a solution of (4-[(4-bromo-2-methyl-phenyl)methyl]-5- isopropyl-lH-pyrazol-3-ol (23.9 kg, 77.3 mol) in methanol (440 L) at room temperature. Add water (590 L) and tripotassium phosphate (100 kg, 471.7 mol) and place the reaction under nitrogen atmosphere. To the stirring solution, add a suspension of

tris(dibenzylideneacetone) dipalladium (1.42 kg, 1.55 mol) and di-tert- butylmethylphosphonium tetrafluoroborate (775 g, 3.12 mol) in methanol (15 L). The resulting mixture is heated at 75 °C for 2 hours. Cool the mixture and filter over diatomaceous earth. Rinse the the filter cake with methanol (60 L), and concentrate the filtrate under reduced pressure. Add ethyl acetate (300 L), separate the layers, and wash the organic layer with 15% brine (3 x 120 L). Concentrate the organic layer under reduced pressure, add ethyl acetate (300 L), and stir the mixture for 18 to 20 hours. Add heptane (300 L), cool the mixture to 10 °C, and stir the mixture for an additional 18 to 20 hours. Collect the resulting solids by filtration, rinse the cake with ethyl acetate/heptane (2:3, 2 x 90 L), and dry under vacuum at 40°C to give the title compound (29.3 kg, 70.6% yield) as a white solid. lH NMR (400 MHz, CD3OD): δ 7.14 (s, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.92 (d, J= 7.6 Hz, 1H), 6.39 (d, J= 16.0 Hz, 1H), 6.25-6.12 (m, 1H), 3.63 (s, 2H), 3.45-3.38 (bs, 3H), 3.34 (s, 3 H), 3.33 (s, 3H), 2.85-2.75 (m, 1H), 2.49-2.40 (m, 5 H), 2.33 (s, 3H), 1.68-1.62 (m, 2H), 1.60-1.36 (m, 15H), 1.11 (s, 3H), 1.10 (s, 3H).

Preparation 12b

Alterternative preparation of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3- [(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but- 3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate.

Figure imgf000025_0001

Scheme 4, step B: Combine tert-butyl 4-[(E)-4-[4-[(3-hydroxy-5-isopropyl-lH- pyrazol-4-yl)methyl] -3-methyl-phenyl]but-3 -enyl] -4,9-diazaspiro [5.5]undecane-9- carboxylate (17.83 kg, 33.2 moles), acetonitrile (180 L), and benzyltributylammonium chloride (1.52 kg, 4.87 moles) at room temperature. Slowly add potassium carbonate (27.6 kg, 199.7 moles) and stir the mixture for 2 hours. Add 2,3,4,6-tetra-O-acetyl-alpha- D-glucopyranosyl bromide (24.9 kg, 60.55 mol), warm the reaction mixture to 30°C and stir for 18 hours. Concentrate the mixture under reduced pressure and add ethyl acetate (180 L), followed by water (90 L). Separate the layers, wash the organic phase with 15% brine (3 x 90 L), concentrate the mixture, and purify using column chromatography over silica gel (63 kg, ethyl acetate/heptanes as eluent (1 :2→1 :0)) to provide the title compound (19.8 kg, 94% purity, 68.8% yield) as a yellow foam, !H NMR (400 MHz, CDC13): δ 7.13 (s, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 16.0,

1H), 6.25-6.13 (m, 1H), 5.64 (d, J= 8.0 Hz, 1H), 5.45-5.25 (m, 2H), 5.13-4.95 (m, 2H), 4.84-4.76 (m, 1H), 4.25-4.13 (m, 2H), 4.10-4.00 (m, 2H), 3.90-3.86 (m, 1H), 3.58-3.50 (m, 2H), 3.40-3.22 (m, 4H), 2.89-2.79 (m, 1H), 2.10-1.90 (m, 18 H), 1.82 (s, 3H), 1.62- 0.82 (m, 22H).

Preparation 18

2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl} -2,9- diazaspiro[5.5]undecane

Figure imgf000026_0001

Scheme 4, step C: Combine tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)- 3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4- yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (19.6 kg, 22.6 moles) with dichloromethane (120 L) and cool to 0°C. Slowly add trifluoroacetic acid (34.6 L, 51.6 kg, 452 moles) and stir for 9 hours. Quench the reaction with ice water (80 L), and add ammonium hydroxide (85-90 L) to adjust the reaction mixture to pH (8- 9). Add dichloromethane (120 L), warm the reaction mixture to room temperature, and separate the layers. Wash the organic layer with water (75 L), brine, and concentrate under reduced pressure to provide the title compound (16.2 kg, 95.0% purity, 93% yield) as a yellow solid. lH NMR (400 MHz, CDC13): δ 7.08 (s, IH), 6.99 (d, J= 8.0 Hz, IH),

6.76 (d, J= 7.6 Hz, IH), 6.38 (d, J=15.6 Hz, IH), 6.00-5.83 (m, IH), 5.31 (d, J= 7.6 Hz, IH), 5.25-5.13 (m, 4H), 4.32 (dd, J= 12.8, 9.2 Hz, IH), 4.14 (d, J= 11.2 Hz, IH), 3.90 (d, J= 10.0 Hz, IH), 3.75-3.50 (m, 3H), 3.30-3.00 (m, 5 H), 2.85-2.75 (m, IH), 2.70-2.48 (m, 3H), 2.25 (s, IH), 2.13-1.63 (m, 19H), 1.32-1.21 (m, IH), 1.14 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).

Example 1

Hydrated crystalline 4- {4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but- 1 -en- 1 -yl]-2- methylbenzyl} -5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside acetate

First alternative preparation of 4-{4-[(l£’)-4-(2.9-diazaspiro[5.5]undec-2-yl)but-l-en-l- yl]-2-methylbenzyl| -5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside (free base).

Figure imgf000027_0001

Scheme 1, step I: Add sodium hydroxide (0.5 mL, 0.5 mmol, 1.0 M solution) to a solution of 4- {4-[( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} – 5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride (258 mg, 0.24 mmol) in methanol (2 mL). After 2 hours at 40°C, concentrate to remove the solvent under reduced pressure to give a residue, which is purified by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 μιη C18XBridge ODB column, solvent A – H.0 with NH4HCO3 @ pH 10, solvent B – MeCN to yield the title compound (free base) as a solid (46 mg, 0.08 mmol). MS (m/z): 598.8 (M+l), 596.8 (M-l).

Second alternative preparation of 4-{4-r(l-£’)-4-(2.9-diazaspiror5.51undec-2-yl)but-l-en- 1 -yl] -2-methylbenzyl I -5 -(propan-2-yl)- lH-pyrazol-3 -yl beta-D-glucopyranoside (free base).

Figure imgf000028_0001

Scheme 2, step F: Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4- {4-[( lJE)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl } -5 – (propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (480 mg, 0.24 mmol). After 18 hours (overnight) at room temperature, concentrate to dryness under reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 μιη C18XBridge ODB column, solvent A – H20 with NH4HCO3 @ pH 10, solvent B – MeCN to yield the title compound (free base) as a solid (50 mg, 0.08 mmol).

MS (m/z): 598.8 (M+l), 596.8 (M-l). 1H NMR (400.31 MHz, CD3OD): δ 7.11 (d, J=1.3

Hz, 1H), 7.04 (dd, J=l .3,8.0 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 15.8 Hz, 1H), 6.16 (dt, J= 15.8, 6.3 Hz, 1H), 5.02 (m, 1H), 3.81 (d, J= 11.7 Hz, 1H), 3.72 (d, J= 16.8 Hz, 1H), 3.68 (d, J= 16.8 Hz, 1H) , 3.64 (m, 1H), 3.37-3.29 (m, 4H), 2.79 (m, 1H), 2.72 (t, J= 5.8 Hz, 4H), 2.44-2.33 (m, 6H), 2.30 (s, 3H), 2.26 ( broad s, 2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.36 (m, 2H), 1.11 (d, J= 7.0 Hz, 3H), 1.10 (d, J= 7.0 Hz, 3H).

Third alternative preparation of 4-{4-[(l£,)-4-(2,9-diazaspiro[5.51undec-2-yl)but-l-en-l- yll-2-methylbenzyl|-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 3, step D: Trifluoroacetic acid (32.2 mL; 0.426 mol) is added to a solution of tert-butyl 2-{(3JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate (14.87 g; 21.28 mmol) in dichloromethane (149 mL) cooled in iced water. The solution is allowed to warm to room temperature. After 30 minutes, the mixture is slowly added to ammonia in MeOH (2M; 300 mL), applying cooling as necessary to maintain a constant temperature. The solution is stirred at room temperature for 15 min. The mixture is concentrated under reduced pressure and the residue is purified using SCX-2 resin. The basic filtrate is concentrated under reduced pressure and the residue is triturated/sonicated in ethyl acetate, filtered and dried. The resulting solid is dissolved in MeOH (200mL) and concentrated in vacuo. This is repeated several times to give the title compound (free base) (12.22 g, yield 96%). MS (m/z): 599 (M+l); [a]D 20 = -12 ° (C=0.2, MeOH).

Preparation of final title compound, hydrated crystalline 4-{4-|YlE)-4-(2.9- diazaspiro [5.5|undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl I -5-(propan-2-vD- 1 H-pyrazol-3 – yl beta-D-glucopyranoside acetate.

Figure imgf000029_0001

4- {4- [(1 E)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl } -5 – (propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside (902 mg) is placed in a round bottom flask (100 mL) and treated with wet ethyl acetate (18 mL). [Note – wet ethyl acetate is prepared by mixing ethyl acetate (100 mL) and dionized water (100 mL). After mixing, the layers are allowed to separate, and the top wet ethyl acetate layer is removed for use. Acetic acid is a hydrolysis product of ethyl acetate and is present in wet ethyl acetate.] The compound dissolves, although not completely as wet ethyl acetate is added. After several minutes, a white precipitate forms. An additional amount of wet ethyl acetate (2 mL) is added to dissolve remaining compound. The solution is allowed to stir uncovered overnight at room temperature during which time the solvent partially evaporates. The remaining solvent from the product slurry is removed under vacuum, and the resulting solid is dried under a stream of nitrogen to provide the final title compound as a crystalline solid. A small amount of amorphous material is identified in the product by solid-state NMR. This crystalline final title compound may be used as seed crystals to prepare additional crystalline final title compound.

Alternative preparation of final title compound, hvdrated crystalline 4-{4-[(lE)-4-(2.,9- diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl I -5-(propan-2-yl)- 1 H-pyrazol-3 – yl beta-D-glucopyranoside acetate.

Under a nitrogen atmosphere combine of 4-{4-[(lE)-4-(2,9-diazaspiro[5.5]undec- 2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan-2-yl)- 1 H-pyrazol-3-yl 2,3,4,6-tetra-O- acetyl-beta-D-glucopyranoside (2.1 kg, 2.74 mol), methanol (4.4 L), tetrahydrofuran (4.2 L), and water (210 mL). Add potassium carbonate (460 g, 3.33 moles) and stir for four to six hours, then filter the reaction mixture to remove the solids. Concentrate the filtrate under reduced pressure, then add ethanol (9.0 L) followed by acetic acid (237 mL, 4.13 mol) and stir at room temperature for one hour. To the stirring solution add wet ethyl acetate (10 L, containing approx. 3 w/w% water) slowly over five hours, followed by water (500 mL). Stir the suspension for twelve hours and add wet ethyl acetate (4.95 L, containing approx. 3 w/w% water) over a period of eight hours. Stir the suspension for twelve hours and add additional wet ethyl acetate (11.5 L, containing approx. 3 w/w% water) slowly over sixteen hours. Stir the suspension for twelve hours, collect the solids by filtration and rinse the solids with wet ethyl acetate (3.3 L, containing approx. 3 w/w% water). Dry in an oven under reduced pressure below 30°C to give the title compound as an off-white crystalline solid (1.55 kg, 2.35 mol, 96.7% purity, 72.4 w/w% potency, 68.0% yield based on potency). HRMS (m/z): 599.3798 (M+l).

PATENT

CN105705509

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN175101669&tab=PCTDESCRIPTION

The present invention is in the field of treatment of diabetes and other diseases and conditions associated with hyperglycemia. Diabetes is a group of diseases characterized by high blood sugar levels. It affects approximately 25 million people in the United States, and according to the 2011 National Diabetes Bulletin, it is also the seventh leading cause of death in the United States (US Department of Health and Human Resources Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the uptake of carbohydrates such as glucose. More specifically, SGLT1 is responsible for transporting glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 can result in a decrease in glucose absorption in the small intestine, thus providing a useful method of treating diabetes.

Alternative medicines and treatments for diabetes are needed. The present invention provides an acetate salt of a pyrazole compound which is an SGLT1 inhibitor, and thus it is suitable for treating certain conditions such as diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives having human SGLT1 inhibitory activity, which are also disclosed for use in the prevention or treatment of diseases associated with hyperglycemia, such as diabetes. Moreover, WO 2011/039338 discloses certain pyrazole derivatives having SGLT1/SGLT2 inhibitor activity, which are also disclosed for use in the treatment of bone diseases such as osteoporosis.


PATENT

WO-2019141209

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019141209&tab=FULLTEXT&_cid=P10-JYNZF2-05384-1

Diabetes is a group of lifelong metabolic diseases characterized by multiple causes of chronic hyperglycemia. Long-term increase in blood glucose can cause damage to large blood vessels and microvessels and endanger the heart, brain, kidney, peripheral nerves, eyes, feet and so on. According to the statistics of the World Health Organization, there are more than 100 complications of diabetes, which is the most common complication, and the incidence rate is also on the rise. The kidney plays a very important role in the body’s sugar metabolism. Glucose does not pass through the lipid bilayer of the cell membrane in the body, and must rely on the glucose transporter on the cell membrane. Sodium-coupled glucose co-transporters (SGLTs) are one of the transporters known to be responsible for the uptake of carbohydrates such as glucose. More specifically, SGLT1 is responsible for transporting glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 results in a decrease in glucose absorption in the small intestine and can therefore be used in the treatment of diabetes.
Ellerelli has developed a novel SGLTs inhibitor for alternative drugs and treatments for diabetes. CN105705509 discloses the SGLTs inhibitor-pyrazole compound, which has the structure shown in the following formula (1):
str1
It is well known for drug production process has strict requirements, the purity of pharmaceutical active ingredients will directly affect the safety and effectiveness of drug quality. Simplified synthetic route optimization, and strictly control the purity of the intermediates has a very important role in improving drug production, quality control and optimization of the dosage form development.
CN105705509 discloses a method for synthesizing a compound of the formula (1), wherein the intermediate compound 2-{(3E)-4-[3-methyl4-({5-(propyl-2-yl)) is obtained by the step B in Scheme 4. -3-[(2,3,4,6-tetra-acetyl-β-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3- Tert-butyl-1-enyl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound obtained in Preparation Example 12b) was obtained as a yellow foam, yield 68.6%, purity 94 %, this step involves silica gel column purification, low production efficiency, high cost, and poor quality controllability; the intermediate 2-{(3E)-4-[3-methyl 4-({5- (prop-2-yl)-3-[(2,3,4,6-tetra-acetyl-β-D-glucopyranosyl)oxy)-1H-pyrazol-4-yl}methyl) Phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane (Compound obtained in Preparation Example 18) as a yellow solid with a purity of 95.0%; The resulting intermediate compounds were all of low purity. Moreover, CN105705509 produces a compound of formula (1) having a purity of 96.7% as described in the publications of the publications 0141 and 0142. The resulting final compound is not of high purity and is not conducive to subsequent drug preparation.

Process for preparing pyranoglucose-substituted pyrazole compound, used as a pharmaceutical intermediate in SGLT inhibitor for treating diabetes.

Example 1
626 g of the compound of the formula (16), 6 L of acetonitrile, 840 g of cesium carbonate and 1770 g of 2,3,4,6-tetra-O-pivaloyl-α-D-glucosyl bromide (formula (17) The compound is sequentially added to the reaction vessel, heated to 40 ° C to 45 ° C, and reacted for 4 to 5 hours, then cooled to 20 to 25 ° C, filtered, and the obtained solid is rinsed once with acetonitrile; the filter cake is dissolved with 8 L of ethyl acetate and 10 L of water. After the liquid separation, the organic phase was concentrated to about 3 L, 10 L of acetonitrile was added, and the mixture was stirred for 12 h to precipitate a solid, which was filtered. The filter cake was rinsed with acetonitrile and dried under vacuum at 60 ° C for 24 h to give white crystals, 652 g of compound of formula (9c). The yield was 61%, the HPLC purity was 98.52%, and the melting point was 180.0-182.1 °C. 1 H NMR (400 MHz, MeOD) (see Figure 1): δ 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.39 (d, J=15.6,1H), 6.19-6.12 (m,1H), 5.59 (d, J=8.4 Hz, 1H), 5.40-5.35 (t, J=9.6 Hz, 1H), 5.17-5.06 (m, 2H) , 4.18-4.14 (dd, J = 12.4 Hz, 4.4 Hz, 1H), 4.10-4.06 (dd, J = 12.4 Hz, 1.6 Hz, 1H), 3.92-3.89 (dd, J = 10 Hz, 2.4 Hz, 1H) , 3.64-3.54 (dd, J=20 Hz, 16.8 Hz, 2H), 3.31-3.30 (m, 4H), 2.86-2.79 (m, 1H), 2.37-2.29 (m, 11H), 1.63-1.38 (m, 17H), 1.15-1.05 (m, 42H). MS (m/z): 1035.7 (M+H).
640 g of the compound of the formula (9c) and 6.4 L of ethyl acetate were successively added to the reaction vessel, and the temperature was lowered to 15 ° C to 20 ° C. 1176 g of p-toluenesulfonic acid monohydrate was added in portions for 2 to 3 hours; after the reaction was over, 3.5 L of a 9% potassium hydroxide aqueous solution was added, and the mixture was stirred for 10 minutes, and the aqueous phase was discarded. The organic phase was washed successively with 3.5 L of 9% and 3.5 L of 3% aqueous potassium hydroxide and concentrated to 2.5 L. 21L of n-heptane was added to the residue, and the mixture was stirred for 12 hours; filtered, and the filter cake was rinsed with n-heptane; the filter cake was dried under vacuum at 60 ° C for 24 h to obtain white crystals, p-toluene of the compound of formula (10c). The sulfonate salt was 550 g, the yield was 80%, the purity was 97.59%, and the melting point was 168.0-169.2 °C. 1 H NMR (400 MHz, MeOD) (see Figure 2): δ 7.72 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 15.6, 1H), 6.19-6.12 (m, 1H), 5.60 (d, J = 8.0 Hz, 1H) ), 5.41-5.37 (t, J = 9.6 Hz, 1H), 5.17-5.06 (m, 2H), 4.18-4.14 (dd, J = 12.4 Hz, 4.0 Hz, 1H), 4.10-4.07 (d, J = 11.6Hz, 1H), 3.94-3.91 (dd, J=7.2Hz, 2.8Hz, 1H), 3.64-3.54 (dd, J=20.0Hz, 16.8Hz, 2H), 3.31-3.30 (m, 4H), 2.86 -2.79 (m, 1H), 2.49-2.29 (m, 14H), 1.78-1.44 (m, 8H), 1.15-1.05 (m, 42H). MS (m/z): 935.7 (M+H).
82.6 g of potassium hydroxide, 5.5 L of absolute ethanol and 550 g of the p-toluenesulfonate of the compound of the formula (10c) were sequentially added to the reaction vessel, and stirred at 45 to 50 ° C for about 4 hours. The temperature was lowered to 20 to 25 ° C, filtered, and the solid was rinsed with ethanol. The filtrate and the eluent were combined, and 65 g of acetic acid was added thereto, followed by stirring for 15 min. The reaction solution was concentrated under reduced pressure to about 1.5 L, and then 52 g of acetic acid was added. After stirring for 20 min, 4.5 L of ethyl acetate containing 3% water and 160 mL of purified water were added dropwise. After the dropwise addition, continue stirring for 3 to 4 hours. Filter and filter cake was rinsed with ethyl acetate containing 3% water. The solid was transferred to a reaction kettle, 500 mL of water was added and stirred for 18 h. After filtration, the filter cake was washed successively with water and an ethanol/ethyl acetate mixed solvent. The filter cake was dried under vacuum at 35 to 40 ° C for 4 hours to obtain a white solid, 245 g of compound of formula (1), yield 75%, purity 99.55%. 1 H NMR (400 MHz, MeOD) (see Figure 3): δ 7.11 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.39 (d, J=16.0,1H), 6.20-6.13 (dt, J=15.6 Hz, 6.8 Hz, 1H), 5.03-5.01 (m, 1H), 3.83 (d, J=11.2, 1H), 3.71-3.59 (m, 3H), 3.35-3.30 (m, 4H), 3.09-3.06 (t, J = 6 Hz, 4H), 2.87-2.77 (m, 1H), 2.49-2.31 (m, 6H), 2.30 (s, 3H), 2.26(s, 2H), 1.90 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.65 (m, 2H), 1.44-1.43 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), MS (m/z): 599.5 (M+H).
Example 2
5.00 kg of the maleate salt of the compound of the formula (16), 40 L of tetrahydrofuran, 5.47 kg of potassium phosphate and 11.67 kg of 2,3,4,6-tetra-O-pivaloyl-α-D-glucosyl bromide The compound (formula (17)) is sequentially added to the reaction vessel, heated to 40 to 45 ° C, and reacted for 4 to 5 hours, then cooled to 15 to 25 ° C, filtered, and the solid was rinsed once with tetrahydrofuran. The filter cake was dissolved in 36 L of ethyl acetate and 20 L of water and then separated. The organic phase was concentrated to ca. 18 L, 64 L acetonitrile was added and stirred for 15 h. Filtration, the filter cake was rinsed with acetonitrile, and dried under vacuum at 60 ° C for 24 h to give white crystals of the compound of formula (9c), 4.50 kg, yield 57%, HPLC purity 99.19%.
4.45 kg of the compound of the formula (9c) and 45 L of butyl acetate were sequentially added to the reaction vessel, and the temperature was lowered to 15 ° C to 20 ° C. 4.13 kg of methanesulfonic acid was added in portions and the reaction was carried out for 2 to 3 hours. 22 L of a 9% aqueous potassium hydroxide solution was added, stirred for 10 min, and the liquid phase was discarded. The organic phase was washed successively with 10 L of 9%, 4.5 L of 10% and 2 L of 2.5% aqueous potassium hydroxide and concentrated to 15 L. 68 L of n-heptane was added to the residue, and the mixture was stirred for further 12 h. Filtered and the filter cake was rinsed once with n-heptane. The solid was dried under vacuum at 60 ° C for 24 h to obtain white crystals. The methanesulfonic acid salt of the compound of formula (10c) was 4.37 kg, yield 99%, purity 97.94%.
0.73 kg of potassium hydroxide, 43 L of methanol and 4.30 kg of the compound of the formula (10c) were sequentially added to the reaction vessel, and stirred at 45 to 50 ° C for 4 hours. The temperature was lowered to 20 to 25 ° C, filtered, and 0.56 kg of acetic acid was added to the filtrate, and the mixture was stirred for 15 minutes. The reaction solution was concentrated to about 15 L under reduced pressure, and 0.40 g of acetic acid was added. After stirring for 10 min, 39 L of 3% water in ethyl acetate and 1.3 L of purified water were added dropwise. After the dropwise addition, stirring was continued for about 2 hours. Filter and filter cake was rinsed once with ethyl acetate containing 3% water. The solid was transferred to a reaction kettle, and 3.5 L of water was added and stirred for 18 h. After filtration, the filter cake was washed successively with water and an ethanol/ethyl acetate mixed solvent. The cake was vacuum dried at 35 to 40 ° C to give a white solid. Compound (1) (1), 1.84 g, yield 67%, purity 99.65%.
Patent ID Title Submitted Date Granted Date
US9573970 4–5-(PROPAN-2-YL)-1H-PYRAZOL-3-YL BETA-D GLUCOPYRANOSIDE ACETATE 2014-10-30 2016-07-28

/////////////SY-008 , SY 008 , SY008, ELI LILY, PHASE 1, GLT1 inhibitor, type 2 diabetes, Yabao Pharmaceutical, CHINA, DIABETES

CC(=O)O.Cc5cc(\C=C\CCN2CCCC1(CCNCC1)C2)ccc5Cc3c(nnc3C(C)C)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O

Cc5cc(\C=C\CCN2CCCC1(CCNCC1)C2)ccc5Cc3c(nnc3C(C)C)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4
O

Fluazolepali, 氟唑帕利 , Fluzoparib


Fluazolepali

CAS  2170504-09-1

Fluzoparib; SHR-3162, (HS10160)

  • HS 10160
  • SHR 3162

An orally available inhibitor of poly(ADP-ribose) polymerase 1 and 2 (PARP-1/2) for treatment of solid tumors (Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China)

Fluazolepali, developed by Hengrui and Howson, is intended for the treatment of recurrent ovarian cancer, triple-negative breast cancer, advanced gastric cancer and other advanced solid tumors. Currently, the drug has been introduced into China for recurrent ovarian cancer. Clinical stage.

In February 2019, a randomized, double-blind, controlled, multicenter, phase III clinical study (CTR20190294) of flazopril capsule versus placebo for maintenance of recurrent ovarian cancer was initiated in China and was sponsored by Hengrui Medicine.

Jiangsu Hansoh Pharmaceutical , in collaboration with  Jiangsu Hengrui Medicine , is developing an oral capsule formulation of fluazolepali (fluzoparib; SHR-3162), a small molecule inhibitor to PARP-1 and PARP-2, for the treatment of solid tumors including epithelial ovarian, fallopian tube or primary peritoneal, breast and gastric cancer.

  • Originator Jiangsu Hengrui Medicine Co.
  • Class Antineoplastics
  • Mechanism of Action Poly(ADP-ribose) polymerase 1 inhibitors; Poly(ADP-ribose) polymerase 2 inhibitors
  • Phase II Ovarian cancer
  • Phase I Breast cancer; Fallopian tube cancer; Gastric cancer; Peritoneal cancer; Solid tumours
  • 09 Jul 2019 Jiangsu HengRui Medicine initiates a phase I trial in Solid tumors in China (NCT04013048) [14C]-Fluzoparib
  • 01 Jul 2019 Jiangsu HengRui Medicine plans a phase I drug-drug interaction trial (In volunteers) in China (PO) (NCT04011124)
  • 12 Jun 2019 Jiangsu HengRui Medicine completes a phase I trial in Gastric cancer (Combination therapy, Recurrent, Metastatic disease, Second-line therapy or greater, Late-stage disease) in China (PO) (NCT03026881)

Fluzoparib (SHR 3162) is a selective poly [ADP-ribose] polymerase 1 (PARP1) and poly [ADP-ribose] polymerase 2 inhibitor (PARP2), being developed by Jiangsu HengRui Medicine, for the treatment of cancer. PARP enzymes play a vital role in repair of DNA damage and maintaining genomic stability. Fluzoparib inhibits PARP enzymes and induces DNA-double strands breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Clinical development for ovarian cancer, breast cancer, fallopian tube cancer, peritoneal cancer, gastric cancer and solid tumours is underway in China and Australia.

An orally available inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2, with potential antineoplastic activity. Upon oral administration, fluzoparib inhibits PARP 1 and 2 activity, which inhibits PARP-mediated repair of damaged DNA via the base excision repair (BER) pathway, enhances the accumulation of DNA strand breaks, promotes genomic instability, and leads to an induction of apoptosis. The PARP family of proteins catalyze post-translational ADP-ribosylation of nuclear proteins, which then transduce signals to recruit other proteins to repair damaged DNA. PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. Check for active clinical trials using this agent. (NCI Thesaurus)

PATENT

WO-2019137358

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019137358&tab=FULLTEXT&_cid=P20-JYI5A2-54836-1

Process for preparing heterocyclic compounds (presumed to be fluazolepali ) and its intermediates as PARP inhibitors useful for treating cancer.

Example 1

The compound and 5.0kg of 10% palladium on carbon 250g, 80L of methanol was added to the kettle at 0.4MPa, 24h 25 ℃ hydrogenation reaction. The palladium carbon was removed by filtration, the filter cake was washed with methanol, and the filtrate was collected, evaporated to dryness under reduced pressure, and ethyl acetate (20 L) was added to the concentrate, and the mixture was stirred and evaporated, and then cooled to 0° C. ~3, stirring, filtration, filter cake and then adding 20 L of ethyl acetate, pulping at room temperature for 3 to 4 h, filtration, vacuum drying at 45 ° C for 6-8 h to obtain 5.5 kg of compound 3 solid, yield 91.7%, HPLC purity 99.69%.
Example 2
According to the method of Example 19 of CN102686591A, 2 g of the compound 3 and 2.79 g of the compound 4 were charged to obtain 3.6 g of the compound of the formula I in a yield of 87.8%.
Example 3
At room temperature, 2.0 g of compound 2 (prepared according to the method disclosed in WO2009025784) was dissolved in 30 mL of isopropanol, and concentrated sulfuric acid was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 150 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the sulfate solid of Compound 2 could not be obtained.
Example 4
1. At room temperature, 1.11 g of compound 2 was dissolved in 10 mL of isopropanol, and 15% phosphoric acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried under vacuum. Compound 2 phosphate solid 1.46 g, yield 87.1%, HPLC purity 99.72%.
Example 5
At room temperature, 1.28 g of compound 2 was dissolved in 10 mL of isopropanol, and 20% acetic acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 100 mL of n-hexane, and continued. After stirring at room temperature, no solid precipitated, and the acetate solid of Compound 2 could not be obtained.
Example 6
1.05g of compound 2 was dissolved in 10mL of isopropanol at room temperature, and the pH was adjusted to 3 by adding 15% citric acid/isopropanol solution while stirring. At room temperature, no solid precipitated; the reaction solution was poured into 100 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the citrate solid of Compound 2 could not be obtained.
Example 7
1.12 g of compound 2 was dissolved in 10 mL of isopropanol at room temperature, and 0.74 g of maleic acid was added thereto with stirring. The mixture was stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried in vacuo to obtain the maleate salt of compound 2. 1.51 g, yield 84.6%.

PATENT

WO2019109938

claiming synergistic combination comprising PARP inhibitor fluazolepali and apatinib mesylate .

PATENT

WO 2018005818

WO 2018129553

WO 2018129559

WO 2018208968

WO 2018213732

WO 2018191277

WO 2018201096

WO 2018085469

WO 2018085468

WO 2019090227

WO 2019133697

WO 2019067978

WO 2019071123

WO 2019090141

///////////Fluazolepali, Jiangsu Hansoh Pharmaceutical,  Jiangsu Hengrui Medicine, fluzoparib,  SHR-3162, 氟唑帕利 , Phase II,  Ovarian cancer, HS10160, CHINA, HS 10160

https://med.sina.com/article_detail_103_2_64751.html

HS 10340


HS-10340

CAS 2156639-66-4

MF C26 H31 N7 O5
MW 521.57
1,8-Naphthyridine-1(2H)-carboxamide, N-[5-cyano-4-[[(1R)-2-methoxy-1-methylethyl]amino]-2-pyridinyl]-7-formyl-3,4-dihydro-6-[(tetrahydro-2-oxo-1,3-oxazepin-3(2H)-yl)methyl]-
(R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl)-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

CAS 2307670-65-9

Jiangsu Hansoh Pharmaceutical Group Co Ltd

Being investigated by Jiangsu Hansoh, Shanghai Hansoh Biomedical and Changzhou Hengbang Pharmaceutical ; in June 2018, the product was being developed as a class 1 chemical drug in China.

Useful for treating liver cancer, gastric cancer and prostate cancer.

Use for treating cancers, liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma and rhabdomyosarcoma

The fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor and includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.
FGFR4, a member of the FGFR receptor family, forms dimers on the cell membrane by binding to its ligand, fibroblast growth factor 19 (FGF19), and the formation of these dimers can cause critical tyrosine in FGFR4’s own cells. The phosphorylation of the amino acid residue activates multiple downstream signaling pathways in the cell, and these intracellular signaling pathways play an important role in cell proliferation, survival, and anti-apoptosis. FGFR4 is overexpressed in many cancers and is a predictor of malignant invasion of tumors. Decreasing and reducing FGFR4 expression can reduce cell proliferation and promote apoptosis. Recently, more and more studies have shown that about one-third of liver cancer patients with continuous activation of FGF19/FGFR4 signaling pathway are the main carcinogenic factors leading to liver cancer in this part of patients. At the same time, FGFR4 expression or high expression is also closely related to many other tumors, such as gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and the like.
The incidence of liver cancer ranks first in the world in China, with new and dead patients accounting for about half of the total number of liver cancers worldwide each year. At present, the incidence of liver cancer in China is about 28.7/100,000. In 2012, there were 394,770 new cases, which became the third most serious malignant tumor after gastric cancer and lung cancer. The onset of primary liver cancer is a multi-factor, multi-step complex process with strong invasiveness and poor prognosis. Surgical treatments such as hepatectomy and liver transplantation can improve the survival rate of some patients, but only limited patients can undergo surgery, and most patients have a poor prognosis due to recurrence and metastasis after surgery. Sorafenib is the only liver cancer treatment drug approved on the market. It can only prolong the overall survival period of about 3 months, and the treatment effect is not satisfactory. Therefore, it is urgent to develop a liver cancer system treatment drug targeting new molecules. FGFR4 is a major carcinogenic factor in liver cancer, and its development of small molecule inhibitors has great clinical application potential.
At present, some FGFR inhibitors have entered the clinical research stage as anti-tumor drugs, but these are mainly inhibitors of FGFR1, 2 and 3, and the inhibition of FGFR4 activity is weak, and the inhibition of FGFR1-3 has hyperphosphatemia. Such as target related side effects. Highly selective inhibitor of FGFR4 can effectively treat cancer diseases caused by abnormal FGFR4 signaling pathway, and can avoid the side effects of hyperphosphatemia caused by FGFR1-3 inhibition. Highly selective small molecule inhibitors against FGFR4 in tumor targeted therapy The field has significant application prospects.
SYN

PATENT

WO2017198149

where it is claimed to be an FGFR-4 inhibitor for treating liver and prostate cancers, assigned to Jiangsu Hansoh Pharmaceutical Group Co Ltd and Shanghai Hansoh Biomedical Co Ltd .

PATENT

WO2019085860

Compound (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-) 1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (shown as Formula I). The compound of formula (I) is disclosed in Hausen Patent PCT/CN2017/084564, the compound of formula I is a fibroblast growth factor receptor inhibitor, and the fibroblast growth factor receptor (FGFR) belongs to the receptor tyrosine kinase transmembrane receptor. The body includes four receptor subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. FGFR regulates various functions such as cell proliferation, survival, differentiation and migration, and plays an important role in human development and adult body functions. FGFR is abnormal in a variety of human tumors, including gene amplification, mutation and overexpression, and is an important target for tumor-targeted therapeutic research.

[0003]
Example 1: Preparation of a compound of formula (I)

[0048]
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol

[0049]

[0050]
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .

[0051]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);

[0052]
MS m/z (ESI): 310.2 [M+H] + .

[0053]
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone

[0054]

[0055]
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).

[0056]
MS m/z (ESI): 336.2 [M+H] + .

[0057]
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate

[0058]

[0059]
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .

[0060]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);

[0061]
MS m/z (ESI): 456.2 [M+H] + .

[0062]
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis

[0063]

[0064]
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).

[0065]
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);

[0066]
MS m/z (ESI): 568.3 [M+H] + .

[0067]
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide

[0068]

[0069]
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).

[0070]
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);

[0071]
MS m/z (ESI): 522.2 [M+H] + .

PATENT

WO-2019085927

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019085927&tab=FULLTEXT

Novel crystalline salt (such as hydrochloride, sulfate, methane sulfonate, mesylate, besylate, ethanesulfonate, oxalate, maleate, p-toluenesulfonate) forms of FGFR4 inhibitor, particularly N-[5-cyano-4-[[(1R)-2-methoxy-1-methyl-ethyl]amino]-2-pyridyl]-7-formyl-6-[(2-oxo-1,3-oxazepan-3-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide (designated as Forms I- IX), compositions comprising them and their use as an FGFR4 inhibitor for the treatment of cancer such as liver cancer, gastric cancer, prostate cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, colon cancer and glioma or rhabdomyosarcoma are claimed.

Example 1: Preparation of a compound of formula (I)
First step 4-(((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butane Preparation of 1-propanol
2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-carbaldehyde (1.0 g, 4.2 mmol), 4-aminobutyl at room temperature l-ol (0.45g, 5.1mmol) was dissolved in DCE (15mL), stirred for 2 hours, followed by addition of NaBH (OAc) . 3 (1.35 g of, 6.4 mmol), stirred at room temperature overnight. The reaction was treated with CH 2 CI 2 was diluted (100 mL), the organic phase was washed with water (10mL) and saturated brine (15mL), and dried over anhydrous sodium sulfate, and concentrated by column chromatography to give compound 4 – (((2- ( Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino)butan-1-ol (0.9 g, 69%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.13 (S, IH), 5.17 (S, IH), 4.84 (S, IH), 3.73 (S, 2H), 3.66-3.49 (m, 2H), 3.42 ( s, 6H), 3.40-3.36 (m, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.68-2.56 (m, 2H), 1.95-1.81 (m, 2H), 1.74-1.55 (m, 4H);
MS m/z (ESI): 310.2 [M+H] + .
The second step is 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3- Preparation of oxazepine-2 ketone
4-(((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)amino) in an ice water bath Butan-1-ol (0.6 g, 1.94 mmol) was dissolved in DCE (15 mL), then bis(trichloromethyl) carbonate (0.22 g, 0.76 mmol) was added and triethylamine (0.78 g, 7.76) was slowly added dropwise. Methyl) and then stirred at room temperature for 3 hours. The reaction temperature was raised to 80 ° C, and the reaction was carried out at 80 ° C for 6 hours. After the reaction was cooled to room temperature, it was diluted with CH 2 Cl 2 (100 mL), and the organic phase was washed sequentially with water (10 mL) and brine (15 mL) Drying with sodium sulfate, concentration and column chromatography to give the compound 3-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl) )methyl)-1,3-oxazepin-2-one (0.37 g, 57%).
MS m/z (ESI): 336.2 [M+H] + .
The third step is phenyl 7-(dimethoxymethyl)-6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1, Preparation of 8-naphthyridin-1(2H)-carboxylate
3-((2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-1,3-oxan -2-one (670mg, 2mmol), diphenyl carbonate (643mg, 3mmol) mixing in of THF (15 mL), N 2 in an atmosphere, cooled to -78 deg.] C, was added dropwise LiHMDS in THF (4mL, 4mmol) was Naturally, it was allowed to react to room temperature overnight. After adding saturated aqueous NH 4 Cl (100 mL), ethyl acetate (100 mL×2), EtOAc. Methyl)-6-((3-carbonylmorpholino)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (432 mg, 47%) .
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 7.56 (S, IH), 7.38 (m, 2H), 7.21 (m, 3H), 5.22 (S, IH), 4.77 (S, 2H), 4.16 (m, 2H), 3.95 (m, 2H), 3.39 (s, 6H), 3.25 (m, 2H), 2.84 (t, J = 6.5 Hz, 2H), 1.87 (m, 2H), 1.64 (m, 4H);
MS m/z (ESI): 456.2 [M+H] + .
The fourth step: (R)-N-(5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl) -6-((2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide synthesis
(R)-6-Amino-4-((1-methoxypropan-2-yl)amino) nicotinenitrile (30 mg, 0.14 mmol), phenyl 7-(dimethoxymethyl)-6- ( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxylate (60 mg, 0.13 Methyl acetate was dissolved in THF (5 mL), cooled to -78 ° C under N 2atmosphere, and a solution of THF (0.3 mL, 0.3 mmol) of LiHMDS was added dropwise to the reaction mixture. After adding a saturated aqueous solution of NH 4 Cl (50 mL), EtOAc (EtOAc) (5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-((2-carbonyl-1) 3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 86%).
1H NMR (400MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 7.60 (s, 2H), 5.41 (s, 1H), 5.12 (d, J = 7.8 Hz, 1H), 4.73 (s, 2H), 4.20-4.11 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 1H), 3.52-3.48 (m, 7H), 3.46-3.42 (m, 1H), 3.39 (s, 3H), 3.26-3.21 (m, 2H), 2.83 (t, J = 6.2 Hz, 2H), 2.03-1.95 (m, 2H), 1.91-1.83 (m, 2H), 1.67-1.62 (m , 2H), 1.31 (d, J = 6.6 Hz, 3H);
MS m/z (ESI): 568.3 [M+H] + .
Step 5: (R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2) Synthesis of -carbonyl-1,3-oxoheptyl-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide
(R)-N-(5-Cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-( (2-carbonyl-1,3-oxazepine-3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1(2H)-carboxamide (65 mg, 0.12 mmol) Dissolved in THF/water (volume ratio: 11/4, 4.5 mL), concentrated HCl (0.45 mL, 5.4 mmol), and allowed to react at room temperature for 2 h. Saturated NaHC03 . 3 solution (50mL), (50mL × 2 ) and extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to give the title compound (R) -N- ( 5-cyano-4-((1-methoxypropan-2-yl)amino)pyridin-2-yl)-7-formyl-6-((2-carbonyl-1,3-oxazepine) 3-yl)methyl)-3,4-dihydro-1,8-naphthyridin-1 (2H)-carboxamide (30 mg, 51%).
. 1 H NMR (400 MHz, CDCl3 . 3 ) [delta] 13.57 (S, IH), 10.26 (S, IH), 8.17 (S, IH), 7.71 (S, IH), 7.63 (S, IH), 5.27 (S, 1H), 4.95 (s, 2H), 4.19-4.12 (m, 2H), 4.11-4.04 (m, 2H), 3.94 (s, 1H), 3.52 (m, 1H), 3.48-3.37 (m, 4H) , 3.33 – 3.28 (m, 2H), 2.93 (t, J = 6.3 Hz, 2H), 2.04 (m, 2H), 1.93-1.85 (m, 2H), 1.73 (m, 2H), 1.39-1.28 (m , 3H);
MS m/z (ESI): 522.2 [M+H] + .

///////////HS-10340 , HS 10340 , HS10340, CANCER, Jiangsu Hansoh, Shanghai Hansoh Biomedical,  Changzhou Hengbang, CHINA,  liver cancer, gastric cancer, prostate cancer, skin cancer, ovary cancer, lung cancer, breast cancer, colon cancer, glioma,  rhabdomyosarcoma

C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CCS(=O)(=O)O.C[C@H](COC)Nc1cc(ncc1C#N)NC(=O)N4CCCc3cc(CN2CCCCOC2=O)c(C=O)nc34

CS 3001


str1

CS-3001

BB 7, VX 033

CAS 2159116-56-8
Propanoic acid, 2-[[5-bromo-4-(3-cyclopropyl-5,5-difluoro-4,5,6,7-tetrahydrobenzo[c]thien-1-yl)-4H-1,2,4-triazol-3-yl]thio]-2-methyl-
Molecular Weight, 478.37

C17 H18 Br F2 N3 O2 S2

CStone Pharmaceuticals Co Ltd, JUNE 2018 IND FILED CHINA

URAT1 inhibitor – useful for treating hyperuricemia and gout.

The compound was originally claimed in WO2017202291 , covering thiophene derivative URAT1 inhibitors, useful for treating hyperuricemia and gouty arthritis, assigned to Medshine Discovery Inc , but naming the inventors.and has been reported in some instances to be a URAT1 modulator. In June 2018, an IND application was filed in

Uric acid is a product of the metabolism of terpenoids in animals. For humans, due to the lack of uric acid enzymes that continue to oxidatively degrade uric acid, uric acid is excreted in the human body as the final product of sputum metabolism through the intestines and kidneys. Renal excretion is the main pathway for uric acid excretion in humans. The upper limit of the normal range of uric acid concentration in the human body is: male 400 μmol/L (6.8 mg/dL) and female 360 μmol/L (6 mg/dL). Abnormal uric acid levels in the human body are often due to an increase in uric acid production or a decrease in uric acid excretion. Conditions associated with abnormal levels of uric acid include hyperuricemia, gout, and the like.
Hyperuricemia refers to a disorder in which the metabolism of substances in the human body is disordered, resulting in an increase or decrease in the synthesis of uric acid in the human body, and an abnormally high level of uric acid in the blood. Gouty arthritis refers to the fact that when uric acid is more than 7 mg/dL in human blood, uric acid is deposited as a monosodium salt in the joints, cartilage and kidneys, causing excessive reaction (sensitivity) to the body’s immune system and causing painful inflammation. The general site of attack is the big toe joint, ankle joint, knee joint and so on. Red, swollen, hot, and severe pain in the site of acute gout attacks, usually in the midnight episode, can make people wake up from sleep. In the early stages of gout, the attack is more common in the joints of the lower extremities. Hyperuricemia is the pathological basis of gouty arthritis. The use of drugs to lower blood uric acid concentration is one of the commonly used methods to prevent gouty arthritis.
In Europe and the United States, the onset of hyperuricemia and gout disease is on the rise. Epidemiological studies have shown that the incidence of gouty arthritis accounts for 1-2% of the total population and is the most important type of arthritis in adult males. Bloomberg estimates that there will be 17.7 million gout patients in 2021. In China, the survey showed that among the population aged 20 to 74, 25.3% of the population had a high blood uric acid content and 0.36% had gout disease. At present, clinical treatment drugs mainly include 1) inhibition of uric acid-producing drugs, such as xanthine oxidase inhibitor allopurinol and febuxostat; 2) uric acid excretion drugs, such as probenecid and benzbromarone; 3) Inflammation inhibitors, such as colchicine. These drugs have certain defects in treatment, poor efficacy, large side effects, and high cost are some of the main bottlenecks in their clinical application. It has been reported that 40%-70% of patients with serum uric acid levels do not meet the expected therapeutic goals (<6mg/dL) after receiving standard treatment.
As a uric acid excretion agent, its mechanism of action is to reduce the reabsorption of uric acid by inhibiting the URAT1 transporter on the brush-like edge membrane of the proximal convoluted tubule. Uric acid is a metabolite of sputum in the body. It is mainly filtered by glomerulus in the original form, reabsorbed and re-secreted by the renal tubules, and finally excreted through the urine. Very few parts can be secreted into the intestinal lumen by mesenteric cells. The S1 segment of the proximal convoluted tubule is a site of uric acid reabsorption, and 98% to 100% of the filtered uric acid enters the epithelial cells through the uric acid transporter URAT1 and the organic anion transporter OAT4 on the brush epithelial cell border of the tubular epithelial cells. The uric acid entering the epithelial cells is reabsorbed into the capillaries around the tubules via the renal tubular basement membrane. The S2 segment of the proximal convoluted tubule is the site of re-secretion of uric acid, and the amount secreted is about 50% of the excess of the small filter. The uric acid in the renal interstitial enters the epithelial cells first through the anion transporters OAT1 and OAT3 on the basal membrane of the tubular epithelial cells. The uric acid entering the epithelial cells passes through another anion transporter MRP4 on the brush border membrane and is discharged into the small lumen. The S3 segment of the proximal convoluted tubule may be a reabsorption site after uric acid secretion, and the amount of reabsorption is about 40% of the excess of the microsphere filtration, and similar to the first step of reabsorption, URAT1 may be a key reabsorption transporter. Therefore, if the urate transporter URAT1 can be significantly inhibited, it will enhance the excretion of uric acid in the body, thereby lowering blood uric acid level and reducing the possibility of gout attack.
In December 2015, the US FDA approved the first URAT1 inhibitor, Zurampic (Leinurad). The 200 mg dose was approved in combination with xanthine oxidase inhibitor XOI (such as Febuxostat, etc.) for the treatment of hyperuricemia and gouty arthritis, but the combination was compared with the xanthine oxidase inhibitor alone. The effect is not very significant. The Zurampic 400 mg dose was not approved due to significant toxic side effects at high doses (the incidence of renal-related adverse events, especially the incidence of kidney stones). Therefore, the FDA requires the Zurampic label to be filled with a black box warning to warn medical staff Zulampic of the risk of acute kidney failure, especially if it is not used in conjunction with XOI. If the over-approved dose uses Zurampic, the risk of kidney failure is even greater. high. At the same time, after the FDA asked for the listing of Zurampic, AstraZeneca continued its investigation of kidney and cardiovascular safety. Therefore, the development of a new type of safe blood-supplemented uric acid drug has become a strong demand in this field.
WO2009070740 discloses Leinurad, which has the following structure:
SYN
PATENT

WO-2019101058

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019101058&tab=FULLTEXT&maxRec=1000

Novel crystalline forms of URAT1 inhibitor (designated as Forms A and B) are claimed. The compounds are disclosed to be useful for treating hyperuricemia and gouty arthritis.

Novel crystalline forms of a URAT1 inhibitor, designated as Forms A and B, and their preparation.

Example 1: Preparation of a compound of formula (I)
synthetic route:
Step 1: Synthesis of Compound 2
In a three-necked flask (10 L), 4.5 L of dimethyl sulfoxide was added, and potassium t-butoxide (836.66 g, 7.46 mol, 2 eq) was added with stirring, and stirring was continued for 10 minutes until the dissolution was clear, and then cooled to an ice water bath. The internal temperature of the reaction solution was 20-25 °C. To the above solution, a solution of Compound 1 (500.05 g, 3.73 mol, 1 eq) in dimethyl sulfoxide (500 mL) was added dropwise, and the mixture was stirred for 30 minutes, and then carbon disulfide (283.86 g, 3.73 mol, 1 eq) was added dropwise thereto. ), after the completion of the dropwise addition, the reaction was stirred for 30 minutes. Further, ethyl bromoacetate (1250 g, 7.46 mol, 2 eq) was added dropwise thereto, and the mixture was stirred for further 2 hours. Finally, potassium carbonate (515.52 g, 7.46 mol, 1 eq) was added, and the temperature was raised to an internal temperature of 65 ° C, and the reaction was further stirred for 8 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The reaction solution was diluted with ethyl acetate (10 L), and then 1M hydrochloric acid (2 L) and water (2 L) were added and stirred for 10 minutes, and the mixture was allowed to stand. The aqueous layer was separated and the organic phase was washed with water (2L×3). The combined aqueous layers were extracted with ethyl acetate (3L). All organic phases were combined and washed with saturated brine (2 L×2). The organic phase was dried over an appropriate amount of anhydrous sodium sulfate, and then filtered, and then evaporated. On the same scale, 6 batches were fed in parallel, and the combined black and red oily products were obtained. After the crude product was allowed to stand for 72 hours, a large amount of solid was precipitated, ethanol (2 L) was added thereto, stirred for 30 minutes, filtered, and the cake was collected and dried in vacuo to give Compound 2. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 4.32 (Q, J = 7.2 Hz, 2H), 4.19 (Q, J = 7.2 Hz, 2H), 3.56 (S, 2H), 3.25 (T, J = 6.8Hz , 2H), 3.19 (t, J = 14.4 Hz, 2H), 2.26-2.17 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); MS m/z = 364.8 [M+H] + .
Step 2: Synthesis of Compound 3
Compound 2 (241.00 g, 0.66 mol) was dissolved in ethanol (1 L) and placed in an autoclave (5 L), and Raney nickel (120 g) was added under argon atmosphere, followed by the addition of ethanol (2 L). The autoclave was charged and replaced with argon three times, then replaced with hydrogen three times, hydrogen was charged to a pressure of 2.0 MP in the autoclave, stirred and heated to an internal temperature of 85 ° C for 28 hours. The reaction was stopped, the reaction system was cooled to room temperature, the reaction solution was filtered, and the filter cake was washed three times with ethanol, 0.5 L each time. The filtrates were combined and then dried to give compound 3. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 7.09 (S, IH), 4.26 (Q, J = 7.2 Hz, 2H), 3.20 (T, J = 6.8Hz, 2H), 3.12 (T, J = 14.4Hz , 2H), 2.20-2.10 (m, 2H), 1.30 (t, J = 6.8 Hz, 3H); MS m/z = 247.0 [M+H] + .
Step 3: Synthesis of Compound 4
Compound 3 (406.2 g, 1.65 mol, 1 eq) was dissolved in acetonitrile (6 L), then N-bromosuccinimide (1484.2 g, 6.60 mol, 4 eq) was slowly added, and the obtained reaction mixture was at 23 to 25 ° C. The reaction was stirred for 12 hours. After the reaction was completed, the reaction liquid was concentrated to about 1.0 L. The solid was removed by filtration, and a saturated solution of sodium hydrogensulfite (1 L) was added to the filtrate and stirred for 10 min. Add acid ethyl ester and extract three times, 2L each time. The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (3 L) was added to the residue, and the mixture was stirred at 30 ° C for 30 minutes. After filtration, the filter cake was washed 5 times with petroleum ether, 200 mL each time, until no product remained in the filter cake. Combine all the organic phases and spin dry to obtain a crude product. Petroleum ether (100 mL) was added to the crude product, stirred well, filtered, and filtered, and then dried in vacuo. . 1 H NMR (400 MHz, CDCl3 . 3) [delta]: 4.24 (Q, J = 7.2 Hz, 2H), 3.19 (T, J = 6.8Hz, 2H), 2.95 (T, J = 14.4Hz, 2H), 2.17-2.07 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).
Step 4: Synthesis of Compound 5
Compound 4 (340.21 g, 1.05 mol), cyclopropylboronic acid (108.12 g, 1.26 mol), anhydrous potassium phosphate (444.98 g, 2.10 mol), palladium acetate (12.03 g, 53.58 mmol) and 2-dicyclohexyl Phospho-2′,4′,6′-triisopropylbiphenyl (23.86 g, 50.05 mmol) was added to a mixed solvent of toluene and water (10:1, 3.4 L/340 mL), and the reaction flask was replaced with nitrogen. After that, place it in an oil bath. The reaction solution was heated at an internal temperature of 80 ° C, and the reaction was stirred at this temperature for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and tris-thiocyanic acid (6.51 g, suspended in ethanol (34 mL)) was added to the reaction mixture and stirred for 0.5 hour. On a similar scale (300.00 g of compound 4), 5 batches were fed in parallel and combined. After filtration, the organic phase was separated and the aqueous phase was extracted with ethyl acetate (250mL). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to yield crude crude oil. After the crude product was allowed to stand for 20 hours, a yellow solid was precipitated, and petroleum ether (3 L) was added thereto and stirred for 1 hour. Filtration and drying of the filter cake in vacuo gave compound 5. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 4.29 (Q, J = 7.2 Hz, 2H), 3.23 (T, J = 6.4Hz, 2H), 3.16 (T, J = 14.8 Hz, 2H), 2.24-2.18 (m, 2H), 1.95-1.85 (m, 1H), 1.35 (t, J = 6.8 Hz, 3H), 1.09-1.07 (m, 2H), 0.77-0.75 (m, 2H).
Step 5: Synthesis of Compound 6
Compound 5 (619.27 g, 2.16 mol) was added to a mixed solution of ethanol and water (3 L/3 L) of sodium hydroxide (173.55 g, 4.33 mol), and the reaction liquid was heated to an internal temperature of 60 ° C to stir the reaction 3 hour. After the reaction was completed, the reaction solution was cooled to room temperature. On a similar scale (750.17 g of compound 5), 1 batch was fed in parallel and combined. The combined reaction solution was extracted with petroleum ether (4 L). The organic phase was separated and the organic phase was backwashed twice with water (1.5L x 2). The aqueous phases were combined and concentrated under reduced pressure to remove ethanol. Water was added to the aqueous phase to dilute to 13 L, and then slowly added with dilute hydrochloric acid (3 M) to adjust to pH = 2, and a large amount of pale yellow solid precipitated. Filter and filter cake with water (3.0L x 2). After draining, the filter cake was collected and dried under vacuum at 60 ° C to give Compound 6. . 1 H NMR (400 MHz, DMSO-D . 6 ) [delta]: 12.79 (brs, IH), 3.23 (T, J = 14.8 Hz, 2H), 3.07 (T, J = 6.8Hz, 2H), 2.27-2.20 (m, 2H), 2.19-2.02 (m, 1H), 1.09-1.04 (m, 2H), 0.68-0.66 (m, 2H).
Step 6: Synthesis of Compound 7
Compound 6 (641.27 g, 2.48 mol), triethylamine (754.07 g, 7.45 mol) and diphenyl azide (1025.34 g, 3.73 mol) were added to t-butanol (6.5 L) with stirring. The reaction solution was heated in a 100 ° C oil bath for 16 hours. After the reaction was completed, it was cooled to room temperature. On a similar scale (650.00 g of compound 6), 4 batches were fed in parallel and combined. The reaction mixture was combined and concentrated under reduced pressure to remove t-butyl alcohol. The remaining black residue was dissolved with ethyl acetate (10L). Dry with an appropriate amount of anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give a crude brown solid. Petroleum ether (8 L) was added to the crude product and stirred for 2 hours. After filtration, the filter cake was rinsed with petroleum ether (1 L) in portions, and the filter cake was vacuum dried in a vacuum oven at 60 ° C to obtain Compound 7. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 6.31 (brs, IH), 3.11 (T, J = 14.8 Hz, 2H), 2.66 (T, J = 6.8Hz, 2H), 2.23-2.15 (m, 2H) , 1.82-1.75 (m, 1H), 1.51 (s, 9H), 0.94-0.90 (m, 2H), 0.68-0.65 (m, 2H).
Step 7: Synthesis of Compound 8
Compound 7 (1199.17 g, 3.64 mol) was added to ethyl acetate (2 L), and then stirred and then ethyl acetate (4L, 16. The reaction solution was reacted at 15 ° C for 2.5 hours, and then placed in a 40 ° C warm water bath to continue the reaction for 2 hours. After the reaction was completed, a large amount of dark red solid precipitated. Filter and filter cake was rinsed with ethyl acetate (2.0 L). The filter cake was dried under vacuum in a vacuum oven at 60 ° C to give compound 8. . 1 H NMR (400 MHz, DMSO-D . 6 ) [delta]: 3.17 (T, J = 14.8 Hz, 2H), 2.82 (T, J = 6.8Hz, 2H), 2.25-2.15 (m, 2H), 2.00-1.94 ( m, 1H), 0.99-0.95 (m, 2H), 0.58-0.54 (m, 2H); MS m/z = 229.8 [M+H-HCl] + .
Step 8: Synthesis of Compound 9
In a 3 L three-necked flask, Compound 8 (301.25 g) was added to tetrahydrofuran (600 mL), and the mixture was cooled to an internal temperature of 0 to 10 ° C under ice-cooling. Diisopropylethylamine (635.72 g) was added dropwise, and after completion of the dropwise addition, the ice water bath was removed, and the mixture was stirred at an internal temperature of 10 to 15 ° C for about 10 minutes. Filter and filter cake was washed with tetrahydrofuran (100 mL x 2). The filtrates were combined to give a solution A for use.
Tetrahydrofuran (2 L) was added to a 5 L reaction flask containing thiophosgene (257.48 g). The mixture was stirred and cooled to an internal temperature of 0 to 10 ° C in an ice water bath, and the solution A was slowly added dropwise thereto, and the dropwise addition was completed within about 5.5 hours, and stirring was continued for 10 minutes. After the reaction was completed, it was filtered, and the filter cake was washed with tetrahydrofuran (150 mL × 2). The filtrate was combined and concentrated under reduced pressure to remove solvent. Tetrahydrofuran (400 mL) was added to the residue, which was dissolved to give a solution B.
The hydrazine hydrate (112.94 g) was added to tetrahydrofuran (2.5 L), and the mixture was cooled to an internal temperature of 5 to 10 ° C under ice-cooling. Solution B was added dropwise, and the addition was completed for about 2 hours, and stirring was continued for 10 minutes. After the reaction was completed, the reaction was stopped. The ice water bath was removed, N,N-dimethylformamide dimethyl acetal (333.45 g) was added, and the mixture was heated to an internal temperature of 60 to 65 ° C, and the reaction was stopped after the heat retention reaction for 3 hours.
The reaction solution was dried to dryness, and ethyl acetate (2 L) and purified water (1L) were added to the residue, and the mixture was stirred. The pH was adjusted to 5-6 with 10% hydrobromic acid, stirring was continued for 5 minutes, and allowed to stand for 10 minutes. Dispense and separate the aqueous phase. The organic phase was washed with pure water (500 mL x 2). The combined aqueous phases were extracted with EtOAc (1 mL). The desiccant was removed by filtration, and the filtrate was concentrated to dryness to dryness. n-Heptane (2.0 L) and tert-butyl methyl ether (150 mL) were added to the crude product, and the mixture was stirred ( stirring speed 550 rpm) for 18 hours. Filter and filter cake was washed with n-heptane (150 mL). The filter cake was collected and the filter cake was dried under vacuum at 60 ° C to give compound 9. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 7.82 (S, IH), 3.20 (T, J = 14.8 Hz, 2H), 2.74 (T, J = 6.8Hz, 2H), 2.28-2.10 (m, 2H) , 1.98-1.82 (m, 1H), 1.06-1.02 (m, 2H), 0.75-0.71 (m, 2H); MS m/z = 313.9 [M+H] + .
Step 9: Synthesis of Compound 10
Acetonitrile (3 L) was placed in a 5 L three-necked flask. Compound 9 (303.25 g) and potassium carbonate (261.83 g) were added first with stirring. Further, methyl 2-bromoisobutyrate (203.85 g) was added, and the reaction system was replaced with nitrogen, and then heated to an internal temperature of 60 to 65 ° C, and the reaction was kept for about 2 hours. After the completion of the reaction, the heating was stopped, and the mixture was naturally cooled to 15 to 20 ° C under stirring. Filter and filter cake was washed with ethyl acetate (100 mL x 3). The filtrate was combined and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography (mobile phase: ethyl acetate / n-heptane = 1:5 to 2:1). . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 8.20 (S, IH), 3.68 (S, 3H), 3.19 (T, J = 14.4Hz, 2H), 2.57 (T, J = 6.8Hz, 2H), 2.22 -2.12 (m, 2H), 1.93-1.83 (m, 1H), 1.67 (s, 6H), 1.08-1.03 (m, 2H), 0.73-0.69 (m, 2H); MS m/z = 414.0 [M +H] + .
Step 10: Synthesis of Compound 11
Acetonitrile (3.17 L) was placed in a 5 L three-necked flask. Under stirring, compound 10 (317.22 g) and thiocarbonyldiimidazole (26.94 g) were added, and the mixture was stirred at 16 to 20 ° C for 5 minutes. N-bromosuccinimide (158.60 g) was added and stirred for about 30 minutes with heat. After the reaction was over, the reaction was stopped. Filtration and concentration of the filtrate under reduced pressure afforded crude crude. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc This crude product was dissolved in ethyl acetate (3.50 L) and washed with purified water (700 mL×4). The organic phase was separated and the organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated to dryness to give Compound 11. . 1 H NMR (400 MHz, CDCl3 . 3 ) [delta]: 3.73 (S, 3H), 3.22 (T, J = 14.4Hz, 2H), 2.53 (T, J = 6.8Hz, 2H), 2.24-2.14 (m, 2H) , 1.95-1.91 (m, 1H), 1.71 (d, J = 4.4 Hz, 6H), 1.11-1.07 (m, 2H), 0.78-0.74 (m, 2H); MS m/z = 491.7 [M+H ] + ,493.7[M+H+2] + .
Step 11: Synthesis of a compound of formula (I)
Tetrahydrofuran (1.2 L) was added to a 5 L reaction flask, and Compound 11 (243.03 g) was added with stirring. After the solution was dissolved, pure water (1.2 L) was added, and then lithium hydroxide monohydrate (125.46 g) was added, and the mixture was stirred at 20 to 25 ° C for about 2.5 hours. After the reaction was completed, the reaction was stopped. The reaction solution was concentrated under reduced pressure at 40 ° C to remove organic solvent. Pure water (1 L) was added to the residue, and the mixture was extracted with t-butyl methyl ether (300 mL). The aqueous phase was placed in a 10 L three-necked flask and cooled to 5 to 10 ° C in an ice bath. The pH was adjusted to 2 to 3 with a 40% hydrobromic acid solution, and a large amount of a pale yellow solid precipitated. Stirring was continued for 30 minutes, and the pH was again measured to be 2-3. Stirring was continued for 20 minutes and filtered. The filter cake was washed with pure water (150 mL x 3). The filter cake was collected, pure water (1500 mL) was added, and the mixture was beaten at room temperature for 1 hour. After filtration, the filter cake was washed with pure water (150 mL × 2), and the filter cake was collected and dried under vacuum at 40 ° C for 3 hours to obtain a compound of the formula (I). . 1 H NMR (400 MHz, the CD . 3 the OD) [delta]: 3.27 (T, J = 15.6Hz, 2H), 2.60-2.47 (m, 2H), 2.27-2.17 (m, 2H), 2.10-2.03 (m, IH) , 1.68 (d, J = 1.2 Hz, 6H), 1.15.10.10 (m, 2H), 0.80-0.71 (m, 2H); MS m/z = 477.99 [M+H] + , 480.1 [M+H+ 2] + .
Example 2: Preparation of Form A of Compound of Formula (I)
The compound of the formula (I) (50 mg) was added to a glass bottle, and methanol (0.4 mL) was added thereto, followed by stirring to a suspension or a solution. The suspension sample was placed in a thermomixer (40 ° C), shaken at 40 ° C for 60 hours, and then centrifuged to collect a sample. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The above sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystal form of the final product having a crystalline form of the compound of the formula (I).
The compound of the formula (I) (50 mg) was added to a glass bottle, and ethyl acetate (0.4 mL) was added and stirred to a suspension or a solution. The suspension sample was placed in a thermomixer (40 ° C), shaken at 40 ° C for 60 hours, and then centrifuged to collect a sample. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The above sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystal form of the final product having a crystalline form of the compound of the formula (I).
Example 3: Preparation of Form B of Compound of Formula (I)
The compound of the formula (I) (50 mg) was added to a glass bottle, tetrahydrofuran (0.4 mL) was added, and the mixture was stirred to dissolve. The above-mentioned lysed sample was volatilized at room temperature, centrifuged, and the sample was collected. The collected sample was dried in a vacuum oven (40 ° C) overnight, and its crystalline form was examined by XRPD to obtain a crystalline form of the final product in the form of Form B of the compound of formula (I).
Example 4: Solubility test of Form A of the compound of formula (I)
1. Preparation of diluent and mobile phase
Diluent: Accurately measure 300mL of pure water and 100mL of pure acetonitrile, mix in a 1L glass bottle, ultrasonic degassing for 10 minutes and then set aside.
Mobile phase A: 0.1% phosphoric acid aqueous solution

For example, remove 2.0 mL of phosphoric acid into 2000 mL of water, sonicate for 10 minutes, mix, and let cool to room temperature as mobile phase A.

Mobile phase B: acetonitrile.
2. Preparation of the reference solution (using the A crystal form itself as a control sample)
Accurately weigh 5 mg of Form A, place it in a sample vial, add 10 mL of diluent, sonicate for 5 minutes, then cool to room temperature and mix well, and mark it as working reference solution STD-1.
Accurately weigh 5 mg of Form A, place it in a sample vial, add 10 mL of diluent, sonicate for 5 minutes, then cool to room temperature and mix well, and mark it as working reference solution STD-2.
3. Preparation of linear solution
The above working reference solution STD-1 was diluted 1 time, 10 times, 100 times, 1000 times and 2000 times, and recorded as linear solutions L1, L2, L3, L4 and L5.
4. Solubility test
Accurately weigh 6mg of A crystal form into 8mL glass bottle, then accurately add 3mL different solvent (0.1N hydrochloric acid solution, 0.01N hydrochloric acid solution, purified water, pH3.8 buffer solution, pH4.5 buffer solution, pH5 .5 buffer solution, pH 6.0 buffer solution, pH 7.4 buffer solution, pH 6.8 buffer solution), made into a suspension. A stir bar was added to the above suspension, and the mixture was thoroughly stirred at 37 ° C in the dark. After stirring, the solids in the pH 7.4 buffer solution and the pH 6.8 buffer solution were all dissolved, and 6 mg of the A crystal form was accurately weighed, added to the buffer solution, and thoroughly stirred again to prepare a suspension. After stirring for 4 hours and 24 hours, the sample was centrifuged, and the solution was filtered through a filter and the concentration thereof was measured by HPLC. The HPLC analysis method is shown in Table 3.
Table 3: HPLC analysis methods

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