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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK 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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Olipudase alfa


HPLSPQGHPA RLHRIVPRLR DVFGWGNLTC PICKGLFTAI NLGLKKEPNV ARVGSVAIKL
CNLLKIAPPA VCQSIVHLFE DDMVEVWRRS VLSPSEACGL LLGSTCGHWD IFSSWNISLP
TVPKPPPKPP SPPAPGAPVS RILFLTDLHW DHDYLEGTDP DCADPLCCRR GSGLPPASRP
GAGYWGEYSK CDLPLRTLES LLSGLGPAGP FDMVYWTGDI PAHDVWHQTR QDQLRALTTV
TALVRKFLGP VPVYPAVGNH ESTPVNSFPP PFIEGNHSSR WLYEAMAKAW EPWLPAEALR
TLRIGGFYAL SPYPGLRLIS LNMNFCSREN FWLLINSTDP AGQLQWLVGE LQAAEDRGDK
VHIIGHIPPG HCLKSWSWNY YRIVARYENT LAAQFFGHTH VDEFEVFYDE ETLSRPLAVA
FLAPSATTYI GLNPGYRVYQ IDGNYSGSSH VVLDHETYIL NLTQANIPGA IPHWQLLYRA
RETYGLPNTL PTAWHNLVYR MRGDMQLFQT FWFLYHKGHP PSEPCGTPCR LATLCAQLSA
RADSPALCRH LMPDGSLPEA QSLWPRPLFC
(Disulfide bridge: 43-119, 46-111, 74-85, 175-180, 181-204, 339-385, 538-542, 548-561)

Olipudase alfa

Xenpozyme, Japan 2022, APPROVALS 2022, 2022/3/28

PEPTIDE, オリプダーゼアルファ (遺伝子組換え)

Alternative Names: Acid sphingomyelinase Niemann Pick disease type B – Sanofi; Acid-sphingomyelinase – Sanofi; GZ-402665; Recombinant human acid sphingomyelinase – Sanofi; rhASM – Sanofi; Sphingomyelinase-C (synthetic human) – Sanofi; Synthetic human sphingomyelinase-C – Sanofi; Xenpozyme

FormulaC2900H4373N783O791S24
CAS927883-84-9
Mol weight63631.0831
EfficacyLysosomal storage disease treatment, Enzyme replacement (acid sphingomyelinase)
CommentEnzyme replacement therapy product
Treatment of Niemann-Pick disease type A/B
  • OriginatorGenzyme Corporation
  • DeveloperSanofi
  • ClassRecombinant proteins; Sphingomyelin phosphodiesterases
  • Mechanism of ActionSphingomyelin-phosphodiesterase replacements
  • Orphan Drug StatusYes – Niemann-Pick diseases
  • RegisteredNiemann-Pick diseases
  • 28 Mar 2022Registered for Niemann-Pick diseases (In adolescents, In children, In adults) in Japan (IV) – First global approval
  • 09 Feb 2022FDA assigns PDUFA action date of (03/07/2022) for Olipudase alfa (In children, In adults) for Niemann-Pick diseases
  • 09 Feb 2022Adverse e

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Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

Olipudase Alfa Improves Lung Function, Spleen Volume in ASMD

https://www.empr.com/home/mpr-first-report/worldsymposium-2021/olipudase-alfa-chronic-visceral-acid-sphingomyelinase-efficacy/embed/#?secret=x9Jl0tjBl4#?secret=4RmoWVLWaQ

Olipudase alfa was associated with significant improvements in clinically relevant disease end points among patients with chronic visceral acid sphingomyelinase (ASM) deficiency (ASMD), according to results from the phase 2/3 ASCEND trial presented at the 17th Annual WORLDSymposium.

ASMD is a rare, debilitating lysosomal storage disease characterized by a deficiency of the enzyme acid sphingomyelinase, which results in the accumulation of sphingomyelin in various tissues of the body. Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM.

The multicenter, randomized, double-blind, placebo-controlled ASCEND trial evaluated the efficacy and safety of olipudase alfa in 36 adults with chronic visceral ASMD. Patients were randomly assigned 1:1 to receive olipudase alfa 3mg/kg intravenously every 2 weeks or placebo for 52 weeks. The coprimary end points were the percent change in spleen volume and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO).

At week 52, treatment with olipudase alfa resulted in a 39.45% reduction in spleen volume, compared with a 0.5% increase for placebo (P <.0001). A decrease in spleen volume of at least 30% was observed in 17 patients (94%) treated with olipudase afla compared with no patients treated with placebo. Additionally, olipudase alfa significantly improved lung function by 22% from baseline compared with 3% for patients receiving placebo (P =.0004), as measured by percent predicted DLCO.

Olipudase alfa also met key secondary end points including a 31.7% reduction in liver volume (vs a 1.4% reduction for placebo; P <.0001) and a 16.8% improvement in mean platelet counts (vs 2.5% with placebo; P =.019) at week 52. Significant improvements in HDL, LDL, AST, ALT, chitotriosidase (54% vs 12% with placebo; P =.0003), and lyso-sphingomyelin (78% vs 6% with placebo) were also observed in the olipudase alfa group at week 52.

With regard to Splenomegaly Related Score, a patient-reported outcome measurement that evaluates patient symptoms associated with an enlarged spleen, findings showed no meaningful difference between olipudase alfa and placebo (-8 point vs -9.3 points, respectively).

As for safety, olipudase alfa was well tolerated with most adverse events being mild to moderate in severity. There were no treatment-related serious adverse events and no adverse event-related discontinuations.

Disclosure: Some authors have declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Reference

Wasserstein M, Arash-Kaps L, Barbato A, et al. Adults with chronic acid sphingomyelinase deficiency show significant visceral, pulmonary, and hematologic improvements after enzyme replacement therapy with olipudase-alfa: 1-year results of the ASCEND placebo-controlled trial. Presented at: 17th Annual WORLDSymposium; February 8-12, 2021. Abstract 265.

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https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-06-14-00-00-2346501

EMA accepts regulatory submission for olipudase alfa, the first potential therapy for ASMD

  • Olipudase alfa has been granted PRIority MEdicines (PRIME) designation in Europe, Breakthrough Therapy designation in the United States, and SAKIGAKE designation in Japan
  • European regulatory decision anticipated second half of 2022

DECEMBER 6, 2021

The European Medicines Agency (EMA) has accepted for review under an accelerated assessment procedure the Marketing Authorization Application (MAA) for olipudase alfa, Sanofi’s investigational enzyme replacement therapy which is being evaluated for the treatment of acid sphingomyelinase deficiency (ASMD). Historically referred to as Niemann-Pick disease (NPD) type A and type B, ASMD is a rare, progressive, and potentially life-threatening disease for which no treatments are currently approved. The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan. If approved, olipudase alfa will become the first and only therapy for the treatment of ASMD.

Today’s milestone has been decades in the making and our gratitude goes to the ASMD community who has stood by us with endless patience while olipudase alfa advanced through clinical development,” said Alaa Hamed, MD, MPH, MBA, Global Head of Medical Affairs, Rare Diseases, Sanofi. “Olipudase alfa represents the kind of potentially life-changing innovation that is possible when industry, medical professionals and the patient community work together toward a common goal.”

The MAA is based on positive results from two separate clinical trials (ASCEND and ASCEND-Peds) evaluating olipudase alfa in adult and pediatric patients with non-central nervous system (CNS) manifestations of ASMD type A/B and ASMD type B.

Olipudase alfa has received special designations from regulatory agencies worldwide, recognizing the innovation potential of the investigational therapy.

“Scientific innovation is the greatest source of hope for people living with diseases like ASMD where there are no approved treatments and is a critical component for ensuring a viable healthcare ecosystem,” said Bill Sibold, Executive Vice President of Sanofi GenzymeAt Sanofi, we have a long history of pioneering scientific innovation, and we remain committed to finding solutions to address unmet medical needs, including those of the rare disease community.”

The EMA awarded olipudase alfa the PRIority MEdicines designation, also known as PRIME, intended to aid and expedite the regulatory process for investigational medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients without treatment options.

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to olipudase alfa. This designation is intended to expedite the development and review of drugs intended to treat serious or life-threatening diseases and conditions. The criteria for granting Breakthrough Therapy designation include preliminary clinical evidence indicating that the molecule may demonstrate substantial improvement on a clinically significant endpoint over available therapies.

In Japan, olipudase alfa was awarded the SAKIGAKE designation, which is intended to promote research and development in Japan for innovative new medical products that satisfy certain criteria, such as the severity of the intended indication. In September, Sanofi filed the J-NDA submission for olipudase alfa.

About ASMD

ASMD results from a deficient activity of the enzyme acid sphingomyelinase (ASM), which is found in special compartments within cells called lysosomes and is required to breakdown lipids called sphingomyelin. If ASM is absent or not functioning as it should, sphingomyelin cannot be metabolized properly and accumulates within cells, eventually causing cell death and the malfunction of major organ systems. The deficiency of the lysosomal enzyme ASM is due to disease-causing variants in the sphingomyelin phosphodiesterase 1 gene (SMPD1). The estimated prevalence of ASMD is approximately 2,000 patients in the U.S., Europe (EU5 Countries) and Japan.

ASMD represents a spectrum of disease caused by the same enzymatic deficiency, with two types that may represent opposite ends of a continuum sometimes referred to as ASMD type A and ASMD type B. ASMD type A is a rapidly progressive neurological form of the disease resulting in death in early childhood due to central nervous system complications. ASMD type B is a serious and potentially life-threatening disease that predominantly impacts the lungs, liver, and spleen, as well as other organs. ASMD type A/B represents an intermediate form that includes varying degrees of neurologic involvement. Patients with ASMD type A/B or ASMD type B were studied in the ASCEND trial program. Another type of NPD is NPD type C, which is unrelated to ASMD.

About olipudase alfa

Olipudase alfa is an investigational enzyme replacement therapy designed to replace deficient or defective ASM, allowing for the breakdown of sphingomyelin. Olipudase alfa is currently being investigated to treat non-CNS manifestations of ASMD. Olipudase alfa has not been studied in ASMD type A patients. Olipudase alfa is an investigational agent and the safety and efficacy have not been evaluated by the FDA, EMA, or any other regulatory authority worldwide.

About Sanofi

Sanofi is dedicated to supporting people through their health challenges. We are a global biopharmaceutical company focused on human health. We prevent illness with vaccines, provide innovative treatments to fight pain and ease suffering. We stand by the few who suffer from rare diseases and the millions with long-term chronic conditions.

With more than 100,000 people in 100 countries, Sanofi is transforming scientific innovation into healthcare solutions around the globe.

///////Olipudase alfa,  japan 2022, APPROVALS 2022, Xenpozyme, PEPTIDE, オリプダーゼアルファ (遺伝子組換え) , ORPHAN DRUG, GZ-402665 , GZ 402665

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Andexanet alfa



(heavy chain)
IVGGQECKDG ECPWQALLIN EENEGFCGGT ILSEFYILTA AHCLYQAKRF KVRVGDRNTE
QEEGGEAVHE VEVVIKHNRF TKETYDFDIA VLRLKTPITF RMNVAPACLP ERDWAESTLM
TQKTGIVSGF GRTHEKGRQS TRLKMLEVPY VDRNSCKLSS SFIITQNMFC AGYDTKQEDA
CQGDAGGPHV TRFKDTYFVT GIVSWGEGCA RKGKYGIYTK VTAFLKWIDR SMKTRGLPKA
KSHAPEVITS SPLK
(light chan)
ANSFLFWNKY KDGDQCETSP CQNQGKCKDG LGEYTCTCLE GFEGKNCELF TRKLCSLDNG
DCDQFCHEEQ NSVVCSCARG YTLADNGKAC IPTGPYPCGK QTLER
(Disulfide bridge: H7-H12, H27-H43, H108-L98, H156-H170, H181-H209, L16-L27, L21-L36, L38-L47, L55-L66, L62-L75, L77-L90)

Andexanet alfa

JAPAN 2022, PEPTIDE

Ondexxya
2022/3/28
Anticoagulant reversal (factor Xa inhibitors)

CAS: 1262449-58-0

アンデキサネットアルファ (遺伝子組換え)

  • Andexanet alfa
  • r-Antidote
  • rfXa Inhibitor Antidote
  • PRT-4445
  • PRT064445

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clotsheart attacksstrokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]

It was approved for medical use in the United States in May 2018.[1] It was developed by Portola Pharmaceuticals.[3]

ndexanet alfa is a recombinant human coagulation Factor Xa that promotes blood coagulation. It was developed by Portola Pharmaceuticals and was approved in in May 2018. It is marketed as Andexxa for intravenous injection or infusion and is indicated for the reversal of anticoagulation in combination with rivaroxaban and apixaban in cases of life-threatening or uncontrolled bleeding. Rivaroxaban and apixaban are Factor Xa inhibitors that promote anticoagulation in situations where blood clotting is unfavourable, such as in deep vein thrombosis and pulmonary embolism. However, the use of these agents is associated with a risk for uncontrollable bleeding episodes that can lead to can cause serious or fatal bleeding. Andexanet alfa is currently under regulatory review by the European Union and is undergoing clinical development in Japan 1.

Andexanet alfa works by binding to Factor Xa inhibitors and prevent them from interacting with endogenous Factor Xa. It displayed high affinity (0.53–1.53 nmol/L) to apixaban, betrixaban, edoxaban and rivaroxaban 1. However, the effectiveness of andexanet alfa on treating bleeding related to any FXa inhibitors other than apixaban and rivaroxaban was not demonstrated, thus such use is limited 7. Its pharmacokinetic properties are not reported to be affected by factor Xa inhibitors 1. Andexanet alfa retains the structural similarity to that of endogenous human factor Xa, but exists in its mature functional form without the need for activation via the intrinsic or extrinsic coagulation pathways 5 and remains catalytically inactive due to structural modification 1. The procoagulation potential of andexanet alfa is eliminated through the removal of a 34-residue fragment containing Gla: via this truncation, andexanet alfa is unable to bind to membrane surfaces and assemble the prothrombinase complex 5. It also prevents andexanet alfa from taking up space on phospholipid surface membranes, so that native FXa may bind and assemble the prothrominase complex 5. The amino acid residue modification from serine to alanine in the binding site of the catalytic domain allows more effective binding to FXa inhibitors and deters the andexanet alfa from converting prothrombin to thrombin 5.

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Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Structure of andexant alfa. Andexanet alfa is a modified activated human factor Xa (FXa) that binds FXa with high affinity and a 1:1 stoichiometric ratio but does not have intrinsic catalytic activity (the amino acid serine at position 419 is replaced by alanine) and lacks the membrane-binding-carboxyglutamic acid domain (Gla domain) of native FX. The Gla domains are responsible for the binding of FXa to phospholipids

Medical uses

Andexanet alfa is used to stop life threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]

There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[4] The only published clinical trial is a prospective, open label, single group study.[5] This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[6] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[7]

Adverse effects

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[8] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa’s procoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[9] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[3][10] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[11]

History[edit]

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[4] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents (“usual care”).[5][12]

Society and culture

Economics

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[13]

References

  1. Jump up to:a b c d e “Andexxa- andexanet alfa injection, powder, lyophilized, for solution”DailyMed. 21 September 2020. Retrieved 12 November 2020.
  2. Jump up to:a b c d e f g “Andexxa Monograph for Professionals”Drugs.com. Retrieved 19 December 2018.
  3. Jump up to:a b Dolgin E (March 2013). “Antidotes edge closer to reversing effects of new blood thinners”Nature Medicine19 (3): 251. doi:10.1038/nm0313-251PMID 23467222S2CID 13340319.
  4. Jump up to:a b Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA (December 2015). “Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”New England Journal of Medicine373 (25): 2413–24. doi:10.1056/NEJMoa1510991PMID 26559317.
  5. Jump up to:a b Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). “Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors”New England Journal of Medicine380 (14): 1326–1335. doi:10.1056/NEJMoa1814051PMC 6699827PMID 30730782.
  6. ^ Justin Morgenstern, “Andexanet Alfa: More garbage science in the New England Journal of Medicine”, First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  7. ^ “A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor”. 11 January 2022.
  8. ^ Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). “Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors”. Blood112 (11): 983. doi:10.1182/blood.V112.11.983.983ISSN 0006-4971.
  9. ^ Kaatz, Scott; Bhansali, Hardik; Gibbs, Joseph; Lavender, Robert; Mahan, Charles E.; Paje, David G. (2017-09-13). “Reversing factor Xa inhibitors – clinical utility of andexanet alfa”Journal of Blood Medicine8: 141–149. doi:10.2147/JBM.S121550PMC 5602457PMID 28979172.
  10. ^ Lu G, Deguzman FR, Hollenbach SJ, et al. (March 2013). “A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa”. Nature Medicine19 (4): 446–51. doi:10.1038/nm.3102PMID 23455714S2CID 11235887.
  11. ^ H. Spreitzer (23 December 2013). “Neue Wirkstoffe – Andexanet Alfa”. Österreichische Apothekerzeitung (in German) (26/2013): 40.
  12. ^ “Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor”ClinicalTrials.gov. 11 January 2022.
  13. ^ “Lexi Comp Drug Information Online”. 24 May 2018.

Further reading

External links

Clinical data
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.comMonograph
License dataUS DailyMedAndexanet_alfa
Routes of
administration
Intravenous injection
ATC codeV03AB38 (WHO)
Legal status
Legal statusUK: POM (Prescription only)US: ℞-only [1]EU: Rx-only
Pharmacokinetic data
MetabolismNot studied
Elimination half-life5 h to 7 h
Identifiers
showIUPAC name
CAS Number1262449-58-0
IUPHAR/BPS7576
DrugBankDB14562
ChemSpidernone
UNIIBI009E452R
KEGGD11029
ChEMBLChEMBL3301583

//////////Andexanet alfa, JAPAN 2022, APPROVALS 2022, アンデキサネットアルファ (遺伝子組換え) , Ondexxya , PRT-4445, PRT064445

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Carotegrast methyl


ChemSpider 2D Image | CAROTEGRAST METHYL | C28H26Cl2N4O5
Carotegrast methyl (JAN).png
2D chemical structure of 401905-67-7

Carotegrast methyl

FormulaC28H26Cl2N4O5
CAS401905-67-7
Mol weight569.4358

PMDA APROVED, CAROGRA, カロテグラストメチル

ON 2022/3/28

Antiasthmatic, Integrin alpha 4 inhibitor

  • An alpha4 integrin antagonist.

401905-67-7[RN]

L-Phenylalanine, N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1,4-dihydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-, methyl ester

methyl (2S)-2-[(2,6-dichlorophenyl)formamido]-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]phenyl}propanoate

Methyl N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-L-phenylalaninate

Carotegrast Methyl

Methyl (2S)-2-(2,6-dichlorobenzamido)-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}propanoate

C28H26Cl2N4O5 : 569.44
[401905-67-7]

PATENT

WO 2008062859

https://patents.google.com/patent/WO2008062859A1/en

Step 1

(Method 2): The title compound was prepared starting from 2-amino-5-dimethylamino- benzoic acid methyl ester dihydrochloride through the hydrolysis under basic condition To 5.0 g of 2-amino-5-dimethylamino-benzoic acid methyl ester di-hydrochloride, there were added 15 mL of water and 15.6 mL of a 6M aqueous solution of sodium hydroxide and the resulting mixture was heated to 40°C for 2 hours. After the confirmation of the progress of the reaction according to HPLC, the reaction system was cooled to room temperature, a 6M hydrochloric acid aqueous solution was dropwise added to the reaction system to thus neutralize the same and to separate out crystals (pH 4.9) and then the reaction system was stirred at 10°C for 2 hours. The solid thus obtained was isolated through the filtration under reduced pressure, washed with 30 mL of water and then dried under reduced pressure at 60°C for 14 hours. Title compound 3.14 g was obtained as gray-colored solid. The physical properties determined were almost identical to those observed for the same compound prepared in the above-mentioned synthesis example. H-NMR (400MHz, DMSO-d6): δ 8.21 (bs, 3H), 7.10 (d, 1H, J=2.8Hz), 6.97 (dd, 1H, J=9.1, 2.8Hz), 6.70 (d, 1H, J=9.1 Hz), 2.72 (s, 6H); 13C-NMR (100MHz, DMSO-d6): δ168.89, 144.55, 141.61, 123.29, 117.90, 114.78, 110.11,41.95; MS (ESI+): m/z 181.3 (MH+), (ESI-): m/z 179.2 (M-H).

Step 2

Step 1: Synthesis of Nα-(2,6-dichlorobenzoyl) -4-{2-ethoxycarbonylamino-5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester To 1.96 g of 2-amino-5-dimethylaminobenzoic acid, there were added 12 mL of acetonitrile and 5.29 mL of pyridine to form a suspension and then the resulting suspension was cooled to 4°C. To this suspension there was dropwise added 4.17 mL of ethyl chloroformate over 5 minutes and then the mixture was stirred at 25°C for one hour. After confirming the disappearance of the starting material by HPLC, 0.7 mL of ethanol was added to the mixture to thus decompose the excess ethyl chloroformate and the mixture was further stirred for additional one hour. To this reaction solution there were added 4.0 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester and 12 mL of N,Ndimethylformamide, and the resulting mixture was stirred overnight. Subsequently, 48 mL of methanol was drop-wise added, the resulting mixture was stirred at 10°C overnight and then the solid separated from the mixture was isolated through filtration under reduced pressure. The solid was then washed with 8 mL of methanol and dried at 70°C for 5 hours under reduced pressure. Title compound 5.50 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 10.29 (s, 1H), 9.42 (bs, 1H), 9.24 (d, 1H, J=7.9Hz), 7.73 (bs, 1H), 7.62 (d, 2H, J=8.4Hz), 7.48-7.44 (m, 2H), 7.41 (dd, 1H, J=9.5, 6.2Hz), 7.27 (d, 2H,J=8.4Hz), 7.01 (d, 1H, J=2.7Hz), 6.93 (dd, 1H, J=9.1, 2.9Hz), 4.71 (ddd, 1H, J=9.2, 8.1, 5.7Hz), 4.05 (q, 2H, J=7.0Hz), 3.66 (s, 3H), 3.10 (dd, 1H, J=14.0, 5.6Hz), 2.96 (dd, 1H, J=14.0, 9.2Hz), 2.93 (s, 6H), 1.18 (t, 3H, J=7.2Hz); MS (ESI+): m/z 601.2 (MH+) and 623.2 (M+Na), (ESI): m/z 599.1 (M-H).

Step 3

Step2: Synthesis of Na-(2,6-dichlorobenzoyl)-4-{6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine methyl ester To 2.0 g of Na-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonylamino -5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester prepared in above-mentioned step 1, were added 16 mL of N,N-dimethylfbrmamide, 0.8 mL of methanol and 0.91 g of potassium carbonate, followed by the stirring of the resulting mixture at 25°C overnight. To this reaction solution, there was added 0.75 mL of methyl p-toluenesulfonate for subjecting the methyl ester to alkylation at 25~40°C. After confirming the disappearance of the starting material by HPLC, 0.75 mL of acetic acid was added to quench the reaction, 16 mL of water was dropped and the solid was separated. Further, 8 mLof N,N-dimethylformamide/water = 1/1 mixed liquid was added to the resulting mixture, followed by the stirring of the mixture at 25°C. Then the solid thus separated was isolated through filtration under reduced pressure and then washed with 8 mL of water. Thereafter, the isolated solid was dried at 70°C for 4 hours under reduced pressure. Desired compound 1.77 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 9.28 (d, 1H, J=8.1 Hz), 7.48-7.36 (m, 6H), 7.31 (dd, 1H, J=3.0, 9.0Hz), 7.24 (d, 1H, J=3.0Hz), 7.20-7.15 (m, 2H), 4.18 (ddd, 1H, J=10.2, 8.1,4.8Hz), 3.69 (s, 3H), 3.49 (s, 3H), 3.22 (dd, 1H, J=14.1, 4.8Hz), 3.02 (dd, 1H, J=14.2, 10.5Hz), 2.94 (s, 6H); MS (ESI+): m/z 569.2 (MH+) and 591.1 (M+Na), (ESI-): m/z 567.2 (M-H).

PATENT

https://patents.google.com/patent/WO2004074264A1/en

PATENT’ WO 2003070709

https://patents.google.com/patent/WO2003070709A1/en

PATENT

WO 2002016329

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/////////////Carotegrast methyl, CAROGRA, カロテグラストメチル , JAPAN 2022, APPROVALS 2022,

COC(=O)[C@H](Cc1ccc(cc1)N2C(=O)N(C)c3ccc(cc3C2=O)N(C)C)NC(=O)c4c(Cl)cccc4Cl

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Somatrogon


>Somatrogon amino acid sequence
SSSSKAPPPSLPSPSRLPGPSDTPILPQFPTIPLSRLFDNAMLRAHRLHQLAFDTYQEFE
EAYIPKEQKYSFLQNPQTSLCFSESIPTPSNREETQQKSNLELLRISLLLIQSWLEPVQF
LRSVFANSLVYGASDSNVYDLLKDLEEGIQTLMGRLEDGSPRTGQIFKQTYSKFDTNSHN
DDALLKNYGLLYCFRKDMDKVETFLRIVQCRSVEGSCGFSSSSKAPPPSLPSPSRLPGPS
DTPILPQSSSSKAPPPSLPSPSRLPGPSDTPILPQ

Somatrogon

CAS: 1663481-09-1

Protein Chemical FormulaC1359H2125N361O420S7

Protein Average Weight30465.1 Da (Aglycosylated)

NGENLA, JAPAN PMDA APPROVED 2022/1/20

ソマトロゴン;

  • MOD-4023

Replenisher (somatotoropin)

  • OriginatorModigene
  • DeveloperOPKO Health; Pfizer
  • ClassBiological proteins; Growth hormones; Hormonal replacements; Recombinant proteins
  • Mechanism of ActionHuman growth hormone replacements
  • Orphan Drug StatusYes – Somatotropin deficiency
  • RegisteredSomatotropin deficiency
  • 21 Jan 2022Pfizer and OPKO health receives complete response letter from the US FDA for somatrogon in Somatotropin deficiency (In children)
  • 20 Jan 2022Registered for Somatotropin deficiency (In children) in Japan (SC)
  • 01 Dec 2021CHMP issues a positive opinion and recommends approval of somatrogon for Somatotropin deficiency in the European Union

Somatrogon, sold under the brand name Ngenla, is a medication for the treatment of growth hormone deficiency.[1][2] Somatrogon is a glycosylated protein constructed from human growth hormone and a small part of human chorionic gonadotropin which is appended to both the N-terminal and C-terminal.[2]

Somatrogon is a long-acting recombinant human growth hormone used as the long-term treatment of pediatric patients who have growth failure due to growth hormone deficiency.

omatrogon is a long-acting recombinant human growth hormone. Growth hormone is a peptide hormone secreted by the pituitary gland that plays a crucial role in promoting longitudinal growth during childhood and adolescence and regulating metabolic function in adulthood.2 Recombinant growth hormone therapy for growth hormone deficiency and other conditions has been available since 1985, with daily administration being the standard treatment for many years. More recently, longer-acting forms of growth hormone were developed to improve patient adherence and thus, improve the therapeutic efficacy of treatment.1 Somatrogon was produced in Chinese Hamster Ovary (CHO) cells using recombinant DNA technology. It is a chimeric product generated by fusing three copies of the C-terminal peptide (CTP), or 28 carboxy-terminal residues, from the beta chain of human chorionic gonadotropin (hCG) to the N-terminus and C-terminus of human growth hormone.2,6 The glycosylation and the presence of CTPs in the protein sequence prolongs the half-life of somatrogon and allows its once-weekly dosing.6

In October 2021, Health Canada approved somatrogon under the market name NGENLA as the long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone caused by growth hormone deficiency, marking Canada as the first country to approve this drug.4 It is available as a once-weekly subcutaneous injection.5

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About Somatrogon©

Somatrogon©, a long-acting human growth hormone (hGH) molecule, is a once-weekly injectable, created using recombinant technology, for the treatment of pediatric and adult growth hormone deficiency (GHD). The molecule consists of the natural peptide sequence of native growth hormone and the 28 amino acids of the C-Terminus Peptide (CTP) of the human chorionic gonadotropin hormone. This molecule, as compared to current GH replacement therapies, is intended to reduce the injection frequency from a daily to once a week in adults and children with GHD.

Clinical data
Trade namesNgenla
Other namesMOD-4023
Pregnancy
category
AU: B1[1]
Routes of
administration
Subcutaneous injection
ATC codeH01AC08 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]
Identifiers
CAS Number1663481-09-1
DrugBankDB14960
UNII6D848RA61B

Somatrogon© COMPETITIVE ADVANTAGES

In 2014, Pfizer and OPKO entered into a worldwide agreement for the development and commercialization of Somatrogon©. Under the agreement, OPKO is responsible for conducting the clinical program and Pfizer is responsible for registering and commercializing the product.

  • New molecular entity (NME) that maintains natural native sequence of growth hormone
  • Once weekly injection vs. current products requiring daily injections
  • Human growth hormone is used for:
    • Growth hormone deficient children and adults
    • SGA, PWS, ISS
  • Final presentation:
    • Refrigerated, liquid, non-viscous formulation
    • Disposable easy to handle pen injection device with thin needle and small injection volume
  • Orphan drug designation in the U.S. and the EU for children and adults

Somatrogon© PROGRAM STATUS

Phase 3 Pediatric Somatrogon©

  • Phase 3 study in naive growth hormone deficiency pediatric population was completed.

The study was conducted in over 20 countries. This study enrolled and treated 224 pre-pubertal, treatment-naive children with growth hormone deficiency.

  • OPKO and Pfizer Announce Positive Phase 3 Top-Line Results for Somatrogon© during Oct 2019.
  • Achieved Primary Endpoint
    • Somatrogon© was proven non-inferior to daily Genotropin® (somatropin) with respect to height velocity after 12 months
    • Height velocity at 12 months of treatment was higher in the Somatrogon© group (10.12 cm/year) than in the somatropin group (9.78 cm/year)
  • Secondary Endpoints Achieved
    • Change in height standard deviation scores at six and 12 months were higher with Somatrogon© in comparison to somatropin
    • At six months, change in height velocity was higher with Somatrogon© in comparison to somatropin
    • Somatrogon© was generally well tolerated in the study and comparable to that of somatropin dosed once-daily with respect to the types, numbers and severity of the adverse events observed between the treatment arms
  • Children completing this study had the opportunity to enroll in a global, open-label, multicenter, long-term extension study, in which they were able to either continue receiving or switch to Somatrogon© Approximately 95% of the patients switched into the open-label extension study and received Somatrogon© treatment

Phase 3 adults Somatrogon© completed

  • Primary endpoint of change in trunk fat mass from baseline to 26 weeks did not demonstrate a statistical significance between the Somatrogon© treated group and placebo
  • Completed post hoc outlier analysis in June 2017 to assess the influence of outliers on the primary endpoint results
  • Analyses which excluded outliers showed a statistically significant difference between Somatrogon© and placebo on the change in trunk fat mass: additional analyses that did not exclude outliers showed mixed results
  • No safety concerns
  • OPKO and Pfizer have agreed that OPKO may proceed with a pre-BLA meeting with FDA to discuss a submission plan
  • OPKO plans to carry out an additional study in adults using a pen device

Pediatric Somatrogon© registration study in Japan- expected to be completed in Q1 2020

  • 44 patients, comparison of weekly Somatrogon to daily growth hormone.
  • Same pen device, dosage and formulation used in global study.

Somatrogon© Path to Approval

  • BLA submission in US anticipated second half of 2020
    • Completion of analysis of immunogenicity and safety data from pivotal Phase 3 study and open label extension study
  • Two abstracts accepted for oral presentation of data set at the Endo Society’s Annual Meeting in March 2020
    • “Somatrogon© Growth Hormone in the Treatment of Pediatric Growth Hormone Deficiency: Results of the Pivotal Phase 3”
    • “Interpretation of Insulin-like Growth Factor (IGF-1) Levels Following Administration of Somatrogon© (a long acting Growth Hormone-hGH-CTP)”
  • MAA submission in Europe to follow upon completion of open label study demonstrating benefit and compliance with reduced treatment burden
    • Study expected to be completed in Q3 2020

References

Hershkovitz O, Bar-Ilan A, Guy R, et al. In vitro and in vivo characterization of MOD-4023, a long-acting carboxy-terminal peptide (CTP)-modified human growth hormone. Mol Pharm. 2016; 13:631–639 [PDF]

Strasburger CJ, Vanuga P, Payer J, et al. MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults. Eur J Endocrinol. 2017;176:283–294 [PDF]

Zelinska N, Iotova V, Skorodok J, et al. Long-acting CTP-modified hGH (MOD-4023): results of a safety and dose-finding study in GHD children. J Clin Endocrinol Metab. 2017;102:1578–1587 [PDF]

Fisher DM, Rosenfeld RG, Jaron-Mendelson M, et al. Pharmacokinetic and pharmacodynamic modeling of MOD-4023, a long-acting human growth hormone, in GHD Children. Horm Res Paediatr. 2017;87:324–332 [PDF]

Kramer W, Jaron-Mendelson M, Koren R, et al. Pharmacokinetics, Pharmacodynamics and Safety of a Long-Acting Human Growth Hormone (MOD-4023) in Healthy Japanese and Caucasian Adults. Clin Pharmacol Drug Dev. 2017 [in press]

Society and culture

On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ngenla, intended for the treatment of growth hormone deficiency (GHD) in children and adolescents from 3 years of age.[3] The applicant for this medicinal product is Pfizer Europe MA EEIG.[3]

Somatrogon was approved for medical use in Australia in November 2021.[1]

References

  1. Jump up to:a b c d “Ngenla”Therapeutic Goods Administration (TGA). 13 December 2021. Retrieved 28 December 2021.
  2. Jump up to:a b “Pfizer and OPKO Announce Extension of U.S. FDA Review of Biologics License Application of Somatrogon for Pediatric Growth Hormone Deficiency” (Press release). Opko Health. 24 September 2021. Retrieved 18 December 2021 – via GlobeNewswire.
  3. Jump up to:a b “Ngenla: Pending EC decision”European Medicines Agency (EMA). 16 December 2021. Retrieved 18 December 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Further reading

///////////Somatrogon, NGENLA, APPROVALS 2022, JAPAN 2022, ソマトロゴン , MOD-4023, Modigene, OPKO Health,  Pfizer

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Gefapixant citrate


Gefapixant structure.png
ChemSpider 2D Image | Gefapixant | C14H19N5O4S

Gefapixant

  • Molecular FormulaC14H19N5O4S
  • Average mass353.397 Da

1015787-98-0[RN]
10642
AF 217 
5-[(2,4-Diamino-5-pyrimidinyl)oxy]-4-isopropyl-2-methoxybenzenesulfonamide
5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzene- sulfonamide

Gefapixant citrate (JAN/USAN).png

Gefapixant Citrate

FormulaC14H19N5O4S. C6H8O7
CAS2310299-91-1
Mol weight545.5203

APPROVED JAPAN PMDA 2022/1/20, Lyfnua

ゲーファピキサントクエン酸塩

吉法匹生

EfficacyAnalgesic, Anti-inflammatory, Antitussive, P2X3 receptor antagonist
CommentTreatment of disorders associated with purinergic receptor activation

Gefapixant (MK-7264) is a drug which acts as an antagonist of the P2RX3 receptor, and may be useful in the treatment of chronic cough.[1][2][3] It was named in honour of Geoff Burnstock.[4]

Gefapixant is under investigation in clinical trial NCT02397460 (Effect of Gefapixant (AF-219/MK-7264) on Cough Reflex Sensitivity).

PAPER

Organic Process Research & Development (2020), 24(11), 2445-2452.

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00248

A robust, green, and sustainable manufacturing process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. The newly developed commercial process features low process mass intensity (PMI), short synthetic sequence, high overall yield, minimal environmental impact, and significantly reduced API costs. The key innovations are the implementation of a highly efficient two-step methoxyphenol synthesis, an innovative pyrimidine synthesis in flow, a simplified sulfonamide synthesis, and a novel salt metathesis approach to consistently deliver the correct active pharmaceutical ingredient (API) salt form in high purity.

Abstract Image

SYN

Organic Process Research & Development (2020), 24(11), 2478-2490.

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00252

Gefapixant citrate (MK-7264) is a P2X3 antagonist for the treatment of chronic cough. The second generation manufacturing route developed for the Step 3A/3B formylation–cyclization reaction to generate the key intermediate diaminopyrimidine (1) (AF-072) required a significant excess of ethyl formate (EF), potassium tert-butoxide (KOt-Bu), and guanidine•HCl (G•HCl) when both steps were run as batch processes. It was imperative to develop an alternative process that required less of each reagent and generated less carbon monoxide byproducts, as the annual production of the final active pharmaceutical ingredient (API) is expected to be over 50 MT. In addition, the second generation process was misaligned with our company’s strategy of having the best science in place at the first regulatory filing. The final flow–batch process described herein, which features a flow-based formylation combined with a batch cyclization, has been performed on a 500 kg scale and now requires 35% less EF (leading to a 70% reduction in waste carbon monoxide), 38% less KOt-Bu, and 50% less G•HCl. These improvements, along with a twofold increase in concentration, have resulted in a 54% reduction in the step process mass intensity (step-PMI) from the second generation two-step batch–batch process (PMI of 17.16) to the flow–batch process (PMI of 7.86), without sacrificing reaction performance.

Abstract Image

SYN

H. REN*, K. M. MALONEY* ET AL. (MERCK & CO., INC., RAHWAY USA) Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 1: Introduction and Process Overview Org. Process Res. Dev. 2020, 24, 2445–2452, DOI: 10.1021/acs.oprd.0c00248.

SYN

https://pubs.acs.org/doi/abs/10.1021/acs.oprd.0c00247

Abstract Image

A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct conversion of the diaryl ether precursor to a sulfonyl chloride intermediate using chlorosulfonic acid, followed by treatment with aqueous ammonia hydroxide, provided the desired sulfonamide in high yield. A pH-swing crystallization allowed for the formation of a transient acetonitrile solvate that enables the rejection of two impurities. After drying, the desired anhydrous free base form was isolated in high yield and purity.

SYN

https://www.sciencedirect.com/science/article/abs/pii/S1566070221000898

Gefapixant is the approved generic name for a compound also known as MK-7264, and prior to that AF-219 and RO-4926219. It is the first-in-class clinically developed antagonist for the P2X3 subtype of trimeric ionotropic purinergic receptors, a family of ATP-gated excitatory ion channels, showing nanomolar potency for the human P2X3 homotrimeric channel and essentially no activity at related channels devoid of P2X3 subunits. As the first P2X3 antagonist to have progressed into clinical studies it has now progressed to the point of successful completion of Phase 3 investigations for the treatment of cough, and the NDA application is under review with US FDA for treatment of refractory chronic cough or unexplained chronic cough. The molecule was discovered in the laboratories of Roche Pharmaceuticals in Palo Alto, California, but clinical development then continued with the formation of Afferent Pharmaceuticals for the purpose of identifying the optimal therapeutic indication for this novel mechanism and establishing a clinical plan for development in the optimal patient populations selected. Geoff Burnstock was a close collaborator and advisor to the P2X3 program for close to two decades of discovery and development. Progression of gefapixant through later stage clinical studies has been conducted by the research laboratories of Merck & Co., Inc., Kenilworth, NJ, USA (MRL; following acquisition of Afferent in 2016), who may commercialize the product once authorization has been granted by regulatory authorities.

PATENT

WO 2008040652

https://patents.google.com/patent/WO2008040652A1/en

Figure imgf000016_0001

SCHEME AExample 1: 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy- benzenesulfonamideThe synthetic procedure used in this Example is outlined in Scheme B.

Figure imgf000027_0001
Figure imgf000028_0001

not isolated

Figure imgf000028_0002
Figure imgf000028_0003

SCHEME BStep 1 2-Isopropyl-4-methoxy-phenolTo a cooled solution of l-(2-hydroxy-5-methoxy-phenyl)-ethanone (10.0 kg) in 79.0 kg of THF was gradually added 46.4 kg of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25°C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours, at which point HPLC (high pressure liquid chromatography) analysis showed more than 98% conversion of l-(2-hydroxy-5-methoxy-phenyl)-ethanone to 2- (1 -hydroxy- 1- methyl-ethyl)-4-methoxy-phenol (not shown in Scheme D). To the stirred solution was then added 10% palladium on carbon (1.02 kg, 50% water wet) suspended in 3.5 kg of THF. The reaction mixture was cooled and placed under a hydrogen atmosphere at 0.34 atmosphere pressure, and concentrated HCl (19.5 kg) was added while maintaining the reaction temperature at 25°C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 44.4 kg water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated by distillation to provide an oil. This oil was dissolved in 2-butanone (20.4 kg) and the crude solution was employed directly in the next step. A 161.8 g aliquot of the solution was concentrated under vacuum to provide 49.5 g of 2-isopropyl-4-methoxyphenol as an oil, projecting to 10.4 kg crude contained product in the bulk 2-butanone solution. 1H NMR (DMSO) delta: 1.14 (d, 6H, J = 6.9 Hz), 3.18 (septet, IH, J = 6.9 Hz), 3.65 (s, 3H), 6.56, (dd, IH, J = 8.6 Hz, 3.1 Hz), 6.67 (d, IH, J = 3.1 Hz), 6.69 (d, IH, 8.6 Hz).Step 2 (2-Isopropyl-4-methoxy-phenoxy)-acetonitrileA stirred slurry of toluene-4-sulfonic acid cyanomethyl ester (13.0 kg), potassium carbonate (13.0 kg) and 2-isopropyl-4-methoxyphenol (9.57 kg) in 79.7 kg of 2-butanone was heated to 55-600C for 4 days, then heated to reflux for 18 hours. The resultant slurry was cooled and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was redissolved in toluene. The toluene solution was extracted with IN KOH, and the organic phase was concentrated by distillation to give 20.6 g of a 1:1 (by weight) solution of (2-isopropyl-4-methoxy-phenoxy)-acetonitrile in toluene, which was used directly in the next step. A aliquot (96.7 g) of this solution was concentrated to dryness to give 50.9 g of crude (2-isopropyl-4-methoxy-phenoxy)- acetonitrile, projecting to a yield of 10.9 kg in the bulk solution: MS (M+H) = 206; 1H NMR (CDCl3) delta: 1.25 (d, J = 6.9 Hz), 3.31 (septet, IH, J = 6.9 Hz), 3.82 (s, 3H), 4.76 (s, 2H), 6.73 (dd. IH, J = 8.8 Hz, 3.1 Hz), 6.87 (d, IH, J = 3.1 Hz), 6.91 (d, IH, J = 8.8 Hz).Step 3 5-(2-Isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine An approximately 1:1 (by weight) solution of 10.6 kg of (2-isopropyl-4-methoxy-phen- oxy) -acetonitrile in toluene was concentrated under reduced pressure and the residue was treated with 10.8 kg of tert-butoxybis(dimethylamino)methane (Brederick’s Reagent). The resulting mixture was dissolved in 20.2 kg of DMF and the solution was heated to 1100C for 2 hours, at which point HPLC analysis showed essentially complete conversion to 3,3-bis-dimethylamino-2-(2-isopropyl-4-methoxy-phenoxy)-propionitrile (not isolated, 1H NMR (CDCl3) delta: 1.21 (d, 3H, J = 7.2 Hz), 1.23 (d, 3H, J = 7.1 Hz), 2.46 (s, 6H), 2.48 (s, 6H), 3.43 (d, IH, J = 5.0 Hz), 3.31 (septet, IH, J = 6.9 Hz), 3.79 (s, 3H), 4.93 (d, IH, J = 5.0 Hz), 6.70 (dd, IH, J = 8.8 Hz, 3.0 Hz), 6.82 (d, IH, J = 3.0 Hz), 6.98 (d, IH, J = 8.8 Hz). The DMF solution was cooled and transferred onto 14.7 kg of aniline hydrochloride. The resulting mixture was heated to 1200C for 22 hours, at which point HPLC analysis showed greater than 97% conversion to 2-(2-isopropyl-4-methoxy-phenoxy)-3- phenylamino-acrylonitrile (not isolated, 1H nmr (CDCl3) delta: 1.31 (d, 6H, J = 6.9 Hz), 3.39 (septet, IH, J = 6.9 Hz), 3.82 (s, 3H), 6.61 (d (br), IH, J = 12.7 Hz), 6.73 (dd, IH, J = 8.9 Hz, 3.1 Hz), 6.88 (d, IH, J = 3.0 Hz), 6.93 (m, 2H), 6.97 (d, IH, J = 8.9 Hz), 7.05 (m, IH), 7.17 (d, IH, J = 12.6 Hz), 7.35 (m. 2H)).The mixture was cooled, diluted with 21.5 kg toluene, then with 72.2 L of water. The organic layer was separated, washed with water, and concentrated by distillation. The concentrate was transferred into 23.8 kg DMF, and the DMF solution was transferred onto 6.01 kg of guanidine carbonate. The resulting mixture was heated to 1200C for 3 days, at which point HPLC analysis showed greater than 95% conversion of 2-(2- isopropyl-4-methoxy-phenoxy)-3-phenylamino-acrylonitrile into 5-(2-Isopropyl-4- methoxy-phenoxy)-pyrimidine-2,4-diamine. The reaction mixture was cooled, diluted with 7.8 kg of EtOAc, then reheated to 600C. Water (75.1 L) was added and the resultant mixture was allowed to cool to ambient temperature. The precipitated solid was collected by filtration, rinsed with isopropanol and dried under vacuum at 50 degrees to give 9.62 kg of 5-(2-isopropyl-4-methoxy- phenoxy)-pyrimidine-2,4-diamine: m.p. 170-171 degrees C; MS (M+H) = 275; H nmr (chloroform) delta: 1.25 (d, 6H, J = 6.9 Hz), 3.30 (septet, IH, J = 6.9 Hz), 3.79 (s, 3H), 4.68 (br, 2H), 4.96 (br, 2H), 6.64 (dd, IH, J = 8.9 Hz, 3.0 Hz), 6.73, d, J = 8.9 Hz), 6.85 (d, IH, J = 3 Hz), 7.47 (s, IH).Step 4 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfon- amide, sulfolane solvate Chlorosulfonic acid (13.82 kg) was added to a slurry of 5-(2-isopropyl-4-methoxy-phen- oxy)-pyrimidine-2,4-diamine (10.07 kg) in sulfolane (50.0 kg) at a rate to maintain an internal pot temperature below 65°C. The reaction mixture was aged at 60-650C for 12 hours, at which point HPCL showed that all 5-(2-isopropyl-4-methoxy-phenoxy)- pyrimidine-2,4-diamine starting material had been converted to 5-(2,4-diamino- pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonic acid. MS (M+H) = 355. Phosphorus oxychloride (3.41 kg) was then added to the reaction mixture at 600C. The reaction mixture was heated to 75°C and aged for 12 hours, at which point HPLC showed that approximately 99% of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy- benzenesulfonic acid had been converted to 5-(2,4-diamino-pyrimidin-5-yloxy)-4-iso- propyl-2-methoxy-benzenesulfonyl chloride. MS (M+H) = 373. The solution of 5-(2,4- diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride was then cooled to around 2°C).To a cooled (ca. 2°C) solution of ammonia (7N) in MeOH (74.1 kg) was added the cooled sulfolane solution of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy- benzenesulfonyl chloride (a homogeneous syrup) at a rate such that the internal temperature did not exceed 23°C. The resultant slurry was stirred for 18 hours at ambient temperature, then filtered on a coarse porosity frit filter. The collected solids were rinsed with MeOH (15.9 kg), then dried under reduced pressure at 700C to a constant weight of 23.90 kg. HPLC showed 97.5% conversion of 5-(2,4-diamino- pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride to 5-(2,4-diamino- pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide sulfolane solvate. H nmr (DMSOd6) delta: 1.26 (d, 6H, J = 6.9 Hz), 2.07 (sym. m, 8H), 2.99 (sym. m, 8H), 3.41 (septet, IH, J = 6.9 Hz), 3.89 (s, 3H), 6.03 (s (br), 2H), 6.58 (s (br), 2H), 7.00 (s, IH), 7.04 (s (br), 2H), 7.08 (s, IH), 7.35 (s, IH). 
Step 5 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzene- sulfonamideA slurry of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfon- amide sulfolane solvate (23.86 kg) in a mixture of ethanol (74.3 kg) and 0.44 N HCl (109.4 kg) was heated to reflux to provide a homogeneous solution of the monohydrochloride salt of 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy- benzenesulfonamide. This solution was filterd while hot, then treated with concentrated ammonium hydroxide (3.4 L) to liberate the free base of 5-(2,4-diamino-pyrimidin-5- yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide. The resultant mixture was cooled slowly to 200C and the crystalline product isolated by filtration. The filter cake was washed with water (20.1 kg) and dried under reduced pressure at 700C to a constant weight of 8.17 kg (57.7% yield based on di-solvate of sulfolane).MP = 281-282 0C.1H nmr (DMSOd6) delta: 1.27 (d, 6H, J = 6.9 Hz), 3.41 (septet, IH, J = 6.9 Hz), 3.89 (s, 3H), 5.87 (s (br), 2H), 6.40 (s (br), 2H), 6.98 (s, IH), 7.01 (s (br), 2H), 7.07 (s, IH), 7.36 (s, IH). 
PATENT 
 US 20080207655https://patents.google.com/patent/US20080207655
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016004358

xample 20

5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-N-methyl-benzenemethylsulfonamide Step 1. 5-(2,4-Diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy- benzenesulfonyl chloride

[211] A mixture of pyrimidine (0.400 g, 1.5 mmol) in 2 ml chlorosulfonic acid was allowed to stir 20 min. The mixture was poured over ice. The precipitate was filtered, washed by cold H2O and dried under vacuum to afford 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonyl chloride (0.515 g, 95%) as a white solid; [MH]+= 373.

PATENT

WO 2017058645

https://patents.google.com/patent/WO2017058645A1/en

PATENTDisclosed herein is a novel process for preparing Compound A, a phenoxy diaminopyrimidine compound of the following formula, or a pharmaceutically acceptable salt thereof:

Figure imgf000004_0001

Compound A.Also disclosed herein are various salts and solvates of Compound A.

Scheme 1

Figure imgf000006_0001
Figure imgf000014_0001

Step 1. Preparation of 4-Bromo-2-isopropylphenol DABCO Co-crystalStep 1. Preparation of 4-Bromo-2-isopropylphenol DABCO Co-crystalThe following 4-bromo-2-isopropylphenol hemi-DABCO co-crystal is obtained in greater than 99% purity and at about 85-92% yield by the following process:

Figure imgf000014_0002

To a solution of 2-isopropyl phenol (75.0 g, 550 mmol) in acetonitrile (225 mL) was added MSA (0.520 g, 5.41 mmol). The mixture was cooled to -10 °C and NBS (98.01 g, 550 mmol) was added in portions while maintaining the internal temperature below 10 °C. The reaction was aged for 30 min to 1 h and then warmed to 20 °C, diluted with water (450 mL), and extracted with toluene (225 mL). The organic layer was sequentially washed with 9 wt% phosphoric acid (150 mL) and 5 wt% NaCl (150 mL). The organic layers were concentrated to roughly 150 mL and filtered into a clean reactor. The mixture was heated to 30-40 °C and n- heptane (28.5 mL) was added followed by DABCO (30.89 g, 275 mmol). The mixture was seeded (a seed can be synthesized from a previous batch of this procedure preformed without seeding) with 4-bromo-2-isopropylphenol hemi-DABCO co-crystal (75 mg, 0.277 mmol), diluted with 52.5 mL of n-heptane, and stirred for 1 h. The slurry was cooled to 20 °C over 1 h and 370 mL of n-heptane is added over 2 h. The slurry was cooled to 5 °C over 2 h, aged for 2 h, filtered, and washed with n-heptane (2 x 75 mL). The solid was dried at 20-25 °C under vacuum to yield 4-bromo-2-isopropylphenol hemi-DABCO co-crystal (134.8 g, 90 %) as a solid. 1H NMR (400 MHz, DMSO-76) d 7.20 (d, J= 2.5 Hz, 1H), 7.13 (dd, J= 8.5, 2.6 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 3.16 (hept, J= 6.9 Hz, 2H), 2.60 (s, 12H), 1.14 (d, J= 6.9 Hz, 12H).The crystallization of step 1 generates 4-bromo-2-isopropylphenol hemi-DABCO co-crystal, bromophenol mono-DABCO co-crystal, or a mixture of bromophenol hemi-DABCO co-crystal and bromophenol mono-DABCO co-crystal. An XRPD pattern of bromophenol hemi- DABCO co-crystal is shown in Figure 1.

The bromo-phenol mono-DABCO co-crystal can be generated in the following procedure:

Figure imgf000015_0001

bromophenol DABCO co-crystalTo a vial with a stir bar was charged DABCO (1.7 g, 15 mmol), phenol (2.5 g, 15 mmol), and 2 mL of n-heptane. The resulting slurry was stirred at 23 °C overnight. The slurry was then filtered and the resulting wet cake was washed with 2 mL of 5 °C n-heptane. The cake was dried under vacuum with nitrogen sweep to afford 4-bromo-2-isopropylphenol mono- DABCO co-crystal (2.9 g, 70% yield) as a solid. 1H NMR (500 MHz, DMSO-76) d 9.65 (s, 1H), 7.20 (s, 1H), 7.14 (d, J= 8.5 Hz, 1H), 6.74 (d, J= 8.5 Hz, 1H), 3.17 (hept, J= 6.8 Hz, 1H), 2.61(s, 12H), 1.15 (d, 7 = 6.9 Hz, 6H).An XRPD pattern of bromophenol mono-DABCO co-crystal is shown in Figure 2.Step 2a. Preparation of 2-Isopropyl-4-Methoxyphenol

The 2-isopropyl-4-Methoxyphenol shown below is obtained at about 92% yield by the following process:

Figure imgf000015_0002

bromophenol DABCO co-crystal methoxy phenolTo a solution of 4-bromo-2-isopropylphenol hemi-DABCO co-crystal (120 g, 442 mmol) in 25 wt% sodium methoxide in methanol (430 g) was added 60 mL of DMF. The solution was pressure purged with nitrogen, copper (I) bromide (3.23 g, 22.5 mmol) was added to the mixture, and the reaction was heated to reflux for 12-16 h. The reaction is cooled to 0-5 °C and quenched with 6M HC1 until the pH of the solution is less than 5. The slurry is diluted with 492 mL of toluene and 720 mL of water to provide a homogeneous solution with a rag between the layers. The aqueous layer is cut to waste. The organic layer is filtered to remove the rag and washed with 240 mL of water to provide 2-isopropyl-4-methoxylphenol (491 g, 13.3 wt%, 89% assay yield) as a solution in toluene. 1H NMR (500 MHz, DMSO-76) d 8.73 (s, 1H), 6.68 (d, J = 8.6 Hz, 1H), 6.66 (d, 7= 3.0 Hz, 1H), 6.55 (dd, 7= 8.6, 3.1 Hz, 1H), 3.65 (s, 3H), 3.17 (hept, j = 6.9 Hz, 1H), 1.14 (d, 7= 6.9 Hz, 6H).Step 2b. Preparation of 2-Isopropyl-4-Methoxyphenol

Alternatively, the methoxy phenol is obtained by the following process:

Figure imgf000016_0001

To a high-pressure vessel were charged 400 mL of anhydrous toluene, Re2(CO)io (3.16 g, 4.84 mmol) and mequinol (100 g, 806 mmol) at RT. The vessel was then degassed with propylene, and charged with propylene (85.0 g, 2.02 mol). The vessel was sealed and heated to 170 °C. Internal pressure was measured near 250 psi. The reaction was stirred at this condition for 72 h. The vessel was then allowed to cool down to 23 °C. The internal pressure was carefully released to 1 atmospheric pressure, and the toluene solution was assayed as 91% and used directly in the next step or isolated as a solid.Step 2a/2b results in anhydrous 2-isopropyl-4-methoxyphenol form 1. An XRPD pattern of the methoxy phenol form 1 is shown in Figure 3.In another embodiment, the product is isolated as a DMAP co-crystal:

Figure imgf000016_0002

To a vial with a stir bar was charged DMAP (3.67 g, 30.1 mmol), 2.5 ml of toluene, and 2-isopropyl-4-methoxylphenol (5.00 g, 30.1 mmol). The reaction mixture was stirred at RT for 5 min, and a homogeneous solution was formed. The reaction mixture was then cooled to 5 °C. Ten mL of n-heptane was slowly charged over 20 min. The resulting slurry was stirred at 5 °C overnight. The slurry was filtered and the resulting wet cake was washed with 3 mL of 5 °C n-heptane. The cake was dried under vacuum with a nitrogen sweep to provide 2- isopropyl-4-methoxylphenol DMAP co-crystal (7.01 g, 81%) as a solid. 1H NMR (500 MHz, DMSO-76) d 8.78 (s, 1H), 8.10 (d, J= 6.1 Hz, 2H), 6.71 – 6.65 (m, 2H), 6.57 (dd, J= 11.3, 6.0 Hz, 3H), 3.66 (s, 3H), 3.17 (hept, J= 6.8 Hz, 1H), 2.95 (s, 6H), 1.14 (d, J= 6.9 Hz, 6H).The crystallization generates anhydrous 2-isopropyl -4-methoxyphenol DMAP co crystal. An XRPD pattern of the 2-isopropyl-4-methoxyphenol DMAP co-crystal is shown in Figure 4.Step 3a. Preparation of the Cvanoether. 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile

The cyanoether is obtained at about 95 % yield by the following process:

Figure imgf000017_0001

A 12-15 wt% solution of 2-isopropyl-4-methoxylphenol (314.3 g, 12 wt%, 226.8 mmol) was concentrated to greater than 50 wt% 2-isopropyl-4-methoxyphenol in toluene under vacuum at 40-50°C. To the solution was added 189 mL of NMP, and the mixture was cooled to 5 °C. Sodium hydroxide (27.2 g, 50 wt% in water, 340 mmol) and chloroacetonitrile (36 g, 340 mmol) were added sequentially to the mixture while maintaining the internal temperature below 10 °C. The reaction was aged for 2 h and then diluted with 150 mL of toluene and 226 mL of water while maintaining the temperature below 10 °C. The mixture was warmed to 20-25 °C, the layers were separated, and the organic layer was washed with 75 mL of 20 wt% NaCl (aq.). The organic layer was and filtered to provide 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile (56.8 g, 74.6 wt%) as a solution in toluene. The filter was washed with NMP to provide additional 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile (27.1 g, 5.0 wt%) as a solution in NMP. The combined yield was about 94 %. 1H NMR (500 MHz, DMSO-i¾) d 7.05 (d, J= 8.8 Hz, 1H), 6.81 (d, 7= 3.0 Hz, 1H), 6.78 (dd, j= 8.8, 3.1 Hz, 1H), 5.11 (s, 2H), 3.73 (s, 3H), 3.20 (hept, j = 6.9 Hz, 1H), 1.17 (d, 7= 6.9 Hz, 6H).Step 3b. Preparation of the Cvanoether. 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile

Alternatively, the cyanoether shown below is obtained at about 92% yield by the following process:

Figure imgf000018_0001

A solution of 2-isopropyl-4-methoxyphenol in toluene (491 g, 13.3 wt%, 393 mmol) was concentrated and solvent switched to acetonitrile under vacuum at 40-50 °C.Potassium carbonate (164.5 g, 1190 mmol) and tetrabutylammonium hydrogensulfate (1.5 g, 4.42 mmol) were added to a separate vessel, and the vessel was pressure purged with nitrogen gas.The solution of phenol in acetonitrile and chloroacetonitrile was added sequentially to the reaction vessel. The vessel was heated to 40 °C and aged for 4 h. The mixture was allowed to cool to 25 °C, and was diluted with 326 mL water. The layers were separated, and the organic layer was washed with 130 mL of 10 wt% NaCl. A solvent switch to toluene was performed under vacuum, and the organic layer was filtered through two 16D Cuno #5 cartridges. The organic layer was concentrated to provide 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile in toluene (128.2 g, 58 wt%, 92% yield).Step 4 Preparation of the Dia inopyrimidine 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2.4-di amineThe diaminopyrimidine is obtained at about 90 % yield by the following process:

Figure imgf000018_0002

A solution of potassium tert-butoxide (44.8 g, 0399 mmol) in NMP (180 mL) was cooled to -10 °C. A solution of 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, the cyanoether, (59.3 g, 61.4 wt%, 177 mmol) in toluene and ethyl formate (26.3 g, 355 mmol) was charged to the base solution while maintaining the internal temperature between -12 °C and -8 °C. After a 3 h age, guanidine hydrochloride (136 g, 1420 mmol) was added to the mixture and the reaction was heated to 115 °C for 6 h. The mixture was allowed to cool to 90 °C, diluted with 200 mL of water, and aged until the reaction mixture was homogeneous (about 30-45 min). After all solids dissolved, vacuum (400 mm Hg) was applied to the reactor to remove toluene. Vacuum was disconnected and the solution was allowed to cool to 85°C. 5-(2-Isopropyl-4- methoxyphenoxy)pyrimidine-2, 4-diamine seed (49.8 mg) (a seed can be synthesized by a route described in U.S. Patent 7,741,484) was charged, the solution was aged for 2 h, 200 mL of water was added, and the batch was allowed to cool to 20 °C over 6 h. The slurry was aged for 10 h at 20 °C, filtered, washed with 2: 1 water :NMP (3 x 100 mL) and water (3 x 100 mL), and dried under vacuum at 50 °C to provide the title compound (42.2 g, 88%) as a solid. 1H NMR (500 MHz, DMSO-r¾) d 7.23 (s, 1H), 6.83 (d, J= 3.0 Hz, 1H), 6.70 (dd, J= 8.9, 3.0 Hz, 1H), 6.63 (d, j= 8.8 Hz, 1H), 6.32 (s, 2H), 5.75 (s, 2H), 3.71 (s, 3H), 3.28 (hept, j= 6.9 Hz, 1H), 1.20 (d, j = 6.9 Hz, 6H); 13C NMR (126 MHz, DMSO-r¾) d 159.7, 157.2, 155.1, 148.4, 144.2, 139.0, 130.4,116.9, 112.5, 111.3, 55.4, 26.57, 22.83.The crystallization of step 4 generates an anhydrous 5-(2-isopropyl-4- methoxyphenoxy)pyrimidine-2, 4-diamine form 1. An XRPD pattern of the 5-(2-isopropyl-4- methoxyphenoxy)pyrimidine-2, 4-diamine form 1 is shown in Figure 5.In one embodiment, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2, 4-diamineNMP solvate 1 is obtained by adding excess amount of 5-(2-isopropyl-4- methoxyphenoxy)pyrimidine-2, 4-diamine form 1 into NMP in a closed vessel to form a suspension. The suspension is stirred at RT until the completion of form transition. The crystals of 5-(2 -isopropyl -4-methoxyphenoxy)pyrimidine-2, 4-diamine NMP solvate 1 can be collected by filtration and measured immediately by XRPD to prevent desolvation. An XRPD pattern of the 5-(2 -isopropyl -4-methoxyphenoxy)pyrimidine-2, 4-diamine NMP solvate 1 is shown in Figure 6.Step 5. Preparation of Compound A Free BaseCompound A free base is obtained at about 91% yield by a process comprising the steps:

Figure imgf000019_0001

To a suspension of 5-(2 -isopropyl -4-methoxyphenoxy)pyrimidine-2, 4-diamine, the diaminopyrimidine, (47.0 g, 171 mmol) in 141 mL of acetonitrile at -10 °C was added chlorosulfonic acid (63.1 mL, 942 mmol) while maintaining the internal temperature below 25 °C. The solution was aged for 1 h at 25 °C and then heated to 45 °C for 12 h. The solution was allowed to cool to 20 °C and added to a solution of 235 mL ammonium hydroxide and 71 mL of acetonitrile at -10 °C while maintaining the internal temperature below 15 °C. The slurry was aged at l0°C for 1 h, heated to 25 °C, and aged for 1 h. The slurry was diluted with 564 mL of water and 188 mL of 50 wt% sodium hydroxide to provide a homogeneous solution that was heated to 35 °C for 2 h. The solution was allowed to cool to 22 °C and the pH of the solution was adjusted to 12.9 with a 2M solution of citric acid. The solution was seeded with Compound A free base (470 mg, 1.19 mmol) (a seed can be synthesized by a route described in U.S. Patent 7,741,484), aged for 2 h, acidified to pH 10.5-11.3 with a 2M solution of citric acid over 5-10 h, and then aged for 2 h. The slurry was filtered, the resulting cake was washed with 90: 10 water: acetonitrile (2 x 118 mL) and water (2 x 235 mL), and dried at 55 °C under vacuum to provide Compound A free base (50.9 g, 91%) as a solid. 1H NMR (500 MHz, DMSO-i¾) d 7.36 (s, 1H), 7.07 (s, 1H), 7.05 – 6.89 (m, 3H), 6.37 (s, 2H), 5.85 (s, 2H), 3.89 (s, 3H), 3.41 (hept, J = 6.6 Hz, 1H), 1.27 (d, J= 6.8 Hz, 6H).The crystallization of step 5 generates anhydrous Compound A free base form 1. In one embodiment, Compound A free base acetonitrile solvate 1 can be prepared by adding excess amount of Compound A free base form 1 into acetonitrile in a closed vessel to form a suspension. The suspension is stirred at 50 °C until the completion of form transition.The crystals of Compound A free base acetonitrile solvate 1 can be collected by filtration and measured immediately by XRPD to prevent desolvation. An XRPD pattern of Compound A free base acetonitrile solvate 1 is shown in Figure 7.Step 6a. Preparation of Compound A Citrate SaltCompound A citrate salt is obtained by a process comprising the steps:

Figure imgf000020_0001

Compound A free base (30.0 g, 84.9 mmol) and glycolic acid (22.6 g, 297 mmol) were added to methanol (360 mL). The solution was heated to 60 °C, aged for 1 h, and filtered through a 0.6 pm filter into a clean vessel. A solution of citric acid (32.6 g, 170 mmol) in 2- propanol (180 mL) at RT was filtered through a 0.6 pm filter into the methanol solution over 30 min while the temperature of the methanol solution was maintained between 58-62 °C. The solution was seeded with Compound A citrate salt (450 mg, 0.825 mmol) (a seed can be synthesized by a route described in patent application number PCT/US17/66562), aged for 1 h, and diluted with 180 mL of 2-propanol over 3 h while the temperature was maintained between 58-62 °C. The slurry was cooled to 50 °C over 3 h. The slurry was filtered at 50 °C, washed with 1 : 1 methanol :2-propanol (120 mL) and 2-propanol (120 mL) at 50 °C, and dried under vacuum at 35 °C to provide Compound A citrate salt (45.1 g, 97%) as a solid. 1H NMR (400 MHz, DMSO-76) d 10.89 (s, 3H), 7.33 (s, 1H), 7.10 (s, 1H), 7.07 (s, 3H), 7.04 (s, 2H), 6.44 (s, 2H), 3.91 (s, 3H), 3.34 (hept, J= 6.7 Hz, 1H), 2.69 (d, 7= 15.3 Hz, 2H), 2.60 (d, 7= 15.3 Hz, 2H), 1.26 (d, 7= 6.9 Hz, 6H). Step 6b. Alternative preparation of Compound A Citrate SaltAlternatively, Compound A citrate salt is obtained by a process comprising the steps:

Figure imgf000021_0001

To a suspension of Compound A citrate salt (4.5 g, 8.25 mmol) in methanol (72 mL) and 2-propanol (36 mL) at 50 °C were added simultaneously through separate 0.6 pm filters a solution of Compound A free base (30.0 g, 84.9 mmol) and glycolic acid (22.6 g, 297 mmol) in 360 mL of methanol at 50 °C and a solution of citric acid (19.5 g, 101 mmol) in 180 mL of 2- propanol at 25 °C over 8 h while maintaining the seed solution temperature of 60 °C. After the simultaneous addition is complete, citric acid (13.2 g, 68.7 mmol) in 180 mL of 2-propanol was added to the slurry over 8 h while the temperature was maintained at 60 °C. The slurry was allowed to cool to 50 °C and aged for 1 h, filtered at 50 °C, washed with 1 : 1 methanol :2- propanol (2 x 120 mL) and 2-propanol (120 mL), and dried under vacuum at 35 °C to provide Compound A citrate salt (45.1 g, 88%) as a solid.The crystallization of step 6a/6b generates anhydrous Compound A citrate form 1. In another embodiment, Compound A citrate methanol solvate 1 can be prepared via a saturated solution of Compound A citrate form 1 in methanol at 50C. The solution is naturally cooled to ambient temperature or evaporated at ambient temperature until the crystals of Compound A citrate methanol solvate 1 can be acquired. An XRPD pattern of Compound A citrate methanol solvate 1 is shown in Figure 8. 
PATENT 
https://patents.google.com/patent/CN111635368B/enPreparation of the Compound Gefapixant of example 11Adding compound 7(16g) and dichloromethane (64mL) into a 250mL three-necked bottle, stirring for dissolving, cooling to below 5 ℃ in an ice bath, dropwise adding a mixed solution of chlorosulfonic acid (21.1g) and dichloromethane (16mL) into the reaction solution, and stirring for 1 hour at the temperature of not higher than 5 ℃; then heating to room temperature and continuing stirring for 10 hours, after the reaction is finished, pouring the reaction liquid into ice water, and quickly separating a water layer; the organic layer was washed once with ice water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product. Dissolving the crude product with 30ml of acetonitrile, and cooling to below 5 ℃; 16ml of ammonia water (25-28%) is dripped into the solution, and after the dripping is finished, the solution is heated to room temperature and stirred for 20 hours. After the reaction is completed, concentrating the reaction solution under reduced pressure to remove acetonitrile, and separating out a white solid; and filtering again, and drying the filter cake at 70 ℃ under reduced pressure for 24h to obtain Gefapixant: white powder (19.50g), yield 94.6%, purity: 97.2 percent.Example 12 purification of the Compound GefapixantAdding a compound Gefapixant (20.77g) into a 500mL reaction bottle, adding 0.44N hydrochloric acid (95.4mL), absolute ethyl alcohol (64.4g) and nitrogen protection, heating to 75 ℃, stirring for dissolving, then carrying out heat preservation and reflux for 1 hour, filtering while hot, after filtering, heating the filtrate again to 60 ℃, dropwise adding ammonia water (25-28 percent and 2.96mL), closing and heating after dropwise adding, slowly cooling to room temperature, and gradually precipitating white solids. And continuously cooling the reaction solution to 20 ℃, keeping the temperature and stirring for 4h, filtering, washing a filter cake with 15ml of water, and performing vacuum drying on the obtained wet product at 60 ℃ for 24h to obtain Gefapixant: white powder (6.58g), yield 53.2%, purity: 99.5 percent.1H NMR(400MHz,DMSO)δ7.37(s,1H),7.08(s,1H),7.02(s,2H),7.00(s,1H),6.43(brs,2H),5.89(s,2H),3.90(s,3H),3.42(m,1H),1.28(d,J=8.0Hz,6H);LC-MS:m/z=354.1[M+H]+。

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References

  1. ^ Muccino D, Green S (June 2019). “Update on the clinical development of gefapixant, a P2X3 receptor antagonist for the treatment of refractory chronic cough”. Pulmonary Pharmacology & Therapeutics56: 75–78. doi:10.1016/j.pupt.2019.03.006PMID 30880151.
  2. ^ Richards D, Gever JR, Ford AP, Fountain SJ (July 2019). “Action of MK-7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation”British Journal of Pharmacology176 (13): 2279–2291. doi:10.1111/bph.14677PMC 6555852PMID 30927255.
  3. ^ Marucci G, Dal Ben D, Buccioni M, Martí Navia A, Spinaci A, Volpini R, Lambertucci C (December 2019). “Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications”. Expert Opinion on Therapeutic Patents29 (12): 943–963. doi:10.1080/13543776.2019.1693542hdl:11581/435751PMID 31726893S2CID 208037373.
  4. ^ Ford, Anthony P.; Dillon, Michael P.; Kitt, Michael M.; Gever, Joel R. (November 2021). “The discovery and development of gefapixant”. Autonomic Neuroscience235: 102859. doi:10.1016/j.autneu.2021.102859.
Clinical data
ATC codeR05DB29 (WHO)
Identifiers
showIUPAC name
CAS Number1015787-98-0
PubChem CID24764487
DrugBankDB15097
ChemSpider58828660
UNII6K6L7E3F1L
KEGGD11349
ChEMBLChEMBL3716057
Chemical and physical data
FormulaC14H19N5O4S
Molar mass353.40 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

////////////Gefapixant, Lyfnua, JAPAN 2022, APPROVALS 2022, ゲーファピキサントクエン酸塩 , MK 7264, 吉法匹生 , AF 217

NEW DRUG APPROVALS

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UPDATE

.WO/2022/060945SOLID STATE FORMS OF GEFAPIXANT AND PROCESS FOR PREPARATION THEREOF

TEVA

Gefapixant, 5-(2, 4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide, has the following chemical structure:

[0003] Gefapixant is a purinergic P2X3 receptor antagonist, and it is developed for the treatment of chronic cough. Gefapixant is also under clinical investigation as a treatment for asthma, interstitial cystitis, musculoskeletal pain, pelvic pain, and sleep apnea syndrome.

[0004] The compound is described in International Publication No. WO 2005/95359.

International Publication No. WO 2008/040652 disclosed a sulfonate solvate of Gefapixant. International Publication Nos. WO 2018/118668 and WO 2019/209607 disclose crystalline forms of Gefapixant as well as Gefapixant salts.

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

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

[0007] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemi cal/phy si cal stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Gefapixant or salts or co-crystals thereof.

NOVAWAX, NVX-CoV2373,


Novavax COVID-19 vaccine reports 89.3% efficacy; protection against UK/South Africa strains

NOVAWAX

NVX-CoV2373

SARS-CoV-2 rS Nanoparticle Vaccine

MCDC OTA agreement number W15QKN-16-9-1002

Novavax COVID-19 vaccine, Coronavirus disease 19 infection

SARS-CoV-2 rS,  TAK 019

Novavax, Inc. is an American vaccine development company headquartered in Gaithersburg, Maryland, with additional facilities in Rockville, Maryland and Uppsala, Sweden. As of 2020, it had an ongoing Phase III clinical trial in older adults for its candidate vaccine for seasonal influenzaNanoFlu and a candidate vaccine (NVX-CoV2373) for prevention of COVID-19.

NVX-CoV2373 is a SARS-CoV-2 rS vaccine candidate and was shown to have high immunogenicity in studies. The vaccine is created from the genetic sequence of COVID-19 and the antigen derived from the virus spike protein is generated using recombinant nanoparticle technology. The vaccine was developed and tested by Novavax. As of May 2020, the company is pursuing a Phase 1 clinical trial (NCT04368988) to test the vaccine.

History

Novavax was founded in 1987. It focused principally on experimental vaccine development, but did not achieve a successful launch up to 2021.[4]

In June 2013, Novavax acquired the Matrix-M adjuvant platform with the purchase of Swedish company Isconova AB and renamed its new subsidiary Novavax AB.[5]

In 2015, the company received an $89 million grant from the Bill & Melinda Gates Foundation to support the development of a vaccine against human respiratory syncytial virus for infants via maternal immunization.[6][7][8][9]

In March 2015 the company completed a Phase I trial for its Ebola vaccine candidate,[10] as well as a phase II study in adults for its RSV vaccine, which would become ResVax.[11] The ResVax trial was encouraging as it showed significant efficacy against RSV infection.[11]

2016 saw the company’s first phase III trial, the 12,000 adult Resolve trial,[11] for its respiratory syncytial virus vaccine, which would come to be known as ResVax, fail in September.[3] This triggered an eighty-five percent dive in the company’s stock price.[3] Phase II adult trial results also released in 2016 showed a stimulation of antigencity, but failure in efficacy.[11] Evaluation of these results suggested that an alternative dosing strategy might lead to success, leading to plans to run new phase II trials.[3] The company’s difficulties in 2016 led to a three part strategy for 2017: cost reduction through restructuring and the termination of 30% of their workforce; pouring more effort into getting ResVax to market; and beginning clinical trials on a Zika virus vaccine.[3]

Alongside the adult studies of ResVax, the vaccine was also in 2016 being tested against infant RSV infection through the route of maternal immunization.[11]

In 2019, late-stage clinical testing of ResVax, failed for a second time, which resulted in a major downturn in investor confidence and a seventy percent reduction in capital value for the firm.[12][13] As a secondary result, the company was forced to conduct a reverse stock split in order to maintain Nasdaq minimum qualification, meaning it was in risk of being delisted.[13]

The company positions NanoFlu for the unmet need for a more effective vaccine against influenza, particularly in the elderly who often experience serious and sometimes life-threatening complications. In January 2020, it was granted fast track status by the U.S. Food and Drug Administration (FDA) for NanoFlu.

External sponsorships

In 2018, Novavax received a US$89 million research grant from the Bill and Melinda Gates Foundation for development of vaccines for maternal immunization.[14]

In May 2020, Novavax received US$384 million from the Coalition for Epidemic Preparedness Innovations to fund early-stage evaluation in healthy adults of the company’s COVID-19 vaccine candidate NVX-CoV2373 and to develop resources in preparation for large-scale manufacturing, if the vaccine proves successful.[15] CEPI had already invested $4 million in March.[15]

Drugs in development

ResVax is a nanoparticle-based treatment using a recombinant F lipoprotein or saponin, “extracted from the Quillaja saponaria [or?] Molina bark together with cholesterol and phospholipid.”[16] It is aimed at stimulating resistance to respiratory syncytial virus infection, targeting both adult and infant populations.[11]

In January 2020, Novavax was given Fast Track status by the FDA to expedite the review process for NanoFlu, a candidate influenze vaccine undergoing a Phase III clinical trial scheduled for completion by mid-2020.[17]

COVID-19 vaccine candidate

See also: NVX-CoV2373 and COVID-19 vaccine

In January 2020, Novavax announced development of a vaccine candidate, named NVX-CoV2373, to establish immunity to SARS-CoV-2.[18] NVX-CoV2373 is a protein subunit vaccine that contains the spike protein of the SARS-CoV-2 virus.[19] Novavax’s work is in competition for vaccine development among dozens of other companies.

In January 2021, the company released phase 3 trials showing that it has 89% efficacy against Covid-19, and also provides strong immunity against new variants.[20] It has applied for emergency use in the US and UK but will be distributed in the UK first.Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 TrialJan 28, 2021 at 4:05 PM ESTDownload PDF

First to Demonstrate Clinical Efficacy Against COVID-19 and Both UK and South Africa Variants

  • Strong efficacy in Phase 3 UK trial with over 50% of cases attributable to the now-predominant UK variant and the remainder attributable to COVID-19 virus
  • Clinical efficacy demonstrated in Phase 2b South Africa trial with over 90% of sequenced cases attributable to prevalent South Africa escape variant
  • Company to host investor conference call today at 4:30pm ET

GAITHERSBURG, Md., Jan. 28, 2021 (GLOBE NEWSWIRE) — Novavax, Inc. (Nasdaq: NVAX), a biotechnology company developing next-generation vaccines for serious infectious diseases, today announced that NVX-CoV2373, its protein-based COVID-19 vaccine candidate, met the primary endpoint, with a vaccine efficacy of 89.3%, in its Phase 3 clinical trial conducted in the United Kingdom (UK). The study assessed efficacy during a period with high transmission and with a new UK variant strain of the virus emerging and circulating widely. It was conducted in partnership with the UK Government’s Vaccines Taskforce. Novavax also announced successful results of its Phase 2b study conducted in South Africa.

“With today’s results from our UK Phase 3 and South Africa Phase 2b clinical trials, we have now reported data on our COVID-19 vaccine from Phase 1, 2 and 3 trials involving over 20,000 participants. In addition, our PREVENT-19 US and Mexico clinical trial has randomized over 16,000 participants toward our enrollment goal of 30,000. NVX-CoV2373 is the first vaccine to demonstrate not only high clinical efficacy against COVID-19 but also significant clinical efficacy against both the rapidly emerging UK and South Africa variants,” said Stanley C. Erck, President and Chief Executive Officer, Novavax. “NVX-CoV2373 has the potential to play an important role in solving this global public health crisis. We look forward to continuing to work with our partners, collaborators, investigators and regulators around the world to make the vaccine available as quickly as possible.”

NVX-CoV2373 contains a full-length, prefusion spike protein made using Novavax’ recombinant nanoparticle technology and the company’s proprietary saponin-based Matrix-M™ adjuvant. The purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike (S) protein and is produced in insect cells. It can neither cause COVID-19 nor can it replicate, is stable at 2°C to 8°C (refrigerated) and is shipped in a ready-to-use liquid formulation that permits distribution using existing vaccine supply chain channels.

UK Phase 3 Results: 89.3% Efficacy

The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65. The primary endpoint of the UK Phase 3 clinical trial is based on the first occurrence of PCR-confirmed symptomatic (mild, moderate or severe) COVID-19 with onset at least 7 days after the second study vaccination in serologically negative (to SARS-CoV-2) adult participants at baseline.

The first interim analysis is based on 62 cases, of which 56 cases of COVID-19 were observed in the placebo group versus 6 cases observed in the NVX-CoV2373 group, resulting in a point estimate of vaccine efficacy of 89.3% (95% CI: 75.2 – 95.4). Of the 62 cases, 61 were mild or moderate, and 1 was severe (in placebo group).

Preliminary analysis indicates that the UK variant strain that was increasingly prevalent was detected in over 50% of the PCR-confirmed symptomatic cases (32 UK variant, 24 non-variant, 6 unknown). Based on PCR performed on strains from 56 of the 62 cases, efficacy by strain was calculated to be 95.6% against the original COVID-19 strain and 85.6% against the UK variant strain [post hoc].

The interim analysis included a preliminary review of the safety database, which showed that severe, serious, and medically attended adverse events occurred at low levels and were balanced between vaccine and placebo groups.

“These are spectacular results, and we are very pleased to have helped Novavax with the development of this vaccine. The efficacy shown against the emerging variants is also extremely encouraging. This is an incredible achievement that will ensure we can protect individuals in the UK and the rest of the world from this virus,” said Clive Dix, Chair, UK Vaccine Taskforce.

Novavax expects to share further details of the UK trial results as additional data become available. Additional analysis on both trials is ongoing and will be shared via prepublication servers as well as submitted to a peer-reviewed journal for publication. The company initiated a rolling submission to the United Kingdom’s regulatory agency, the MHRA, in mid-January.

South Africa Results:   Approximately 90% of COVID-19 cases attributed to South Africa escape variant

In the South Africa Phase 2b clinical trial, 60% efficacy (95% CI: 19.9 – 80.1) for the prevention of mild, moderate and severe COVID-19 disease was observed in the 94% of the study population that was HIV-negative. Twenty-nine cases were observed in the placebo group and 15 in the vaccine group. One severe case occurred in the placebo group and all other cases were mild or moderate. The clinical trial also achieved its primary efficacy endpoint in the overall trial population, including HIV-positive and HIV-negative subjects (efficacy of 49.4%; 95% CI: 6.1 – 72.8).

This study enrolled over 4,400 patients beginning in August 2020, with COVID-19 cases counted from September through mid-January. During this time, the triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa. Preliminary sequencing data is available for 27 of 44 COVID-19 events; of these, 92.6% (25 out of 27 cases) were the South Africa escape variant.

Importantly in this trial, approximately 1/3 of the patients enrolled (but not included in the primary analyses described above) were seropositive, demonstrating prior COVID-19 infection at baseline. Based on temporal epidemiology data in the region, the pre-trial infections are thought to have been caused by the original COVID-19 strain (i.e., non-variant), while the subsequent infections during the study were largely variant virus. These data suggest that prior infection with COVID-19 may not completely protect against subsequent infection by the South Africa escape variant, however, vaccination with NVX-CoV2373 provided significant protection.

“The 60% reduced risk against COVID-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the first COVID-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” says Professor Shabir Maddi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits, and principal investigator in the Novavax COVID-19 vaccine trial in South Africa. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically targeted to the variant, which together with the current vaccine is likely to form the cornerstone of the fight against COVID-19.”

Novavax initiated development of new constructs against the emerging strains in early January and expects to select ideal candidates for a booster and/or combination bivalent vaccine for the new strains in the coming days. The company plans to initiate clinical testing of these new vaccines in the second quarter of this year.

“A primary benefit of our adjuvanted platform is that it uses a very small amount of antigen, enabling the rapid creation and large-scale production of combination vaccine candidates that could potentially address multiple circulating strains of COVID-19,” said Gregory M. Glenn, M.D., President of Research and Development, Novavax. “Combined with the safety profile that has been observed in our studies to-date with our COVID-19 vaccine, as well as prior studies in influenza, we are optimistic about our ability to rapidly adapt to evolving conditions.”

The Coalition for Epidemic Preparedness Innovations (CEPI) funded the manufacturing of doses of NVX-CoV2373 for this Phase 2b clinical trial, which was supported in part by a $15 million grant from the Bill & Melinda Gates Foundation.

Significant progress on PREVENT-19 Clinical Trial in US and Mexico

To date, PREVENT-19 has randomized over 16,000 participants and expects to complete our targeted enrollment of 30,000 patients in the first half of February.  PREVENT-19 is being conducted with support from the U.S. government partnership formerly known as Operation Warp Speed, which includes the Department of Defense, the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) at HHS. BARDA is also providing up to $1.75 billion under a Department of Defense agreement.

PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial | COVID-19) is a Phase 3, randomized, placebo-controlled, observer-blinded study in the US and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 30,000 subjects 18 years of age and older compared with placebo. The trial design has been harmonized to align with other Phase 3 trials conducted under the auspices of Operation Warp Speed, including the use of a single external independent Data and Safety Monitoring Board to evaluate safety and conduct an unblinded review when predetermined interim analysis events are reached.

The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Conference Call

Novavax will host a conference call today at 4:30pm ET. The dial-in numbers for the conference call are (877) 212-6076 (Domestic) or (707) 287-9331 (International), passcode 7470222. A replay of the conference call will be available starting at 7:30 p.m. ET on January 28, 2021 until 7:30 p.m. ET on February 4, 2021. To access the replay by telephone, dial (855) 859-2056 (Domestic) or (404) 537-3406 (International) and use passcode 7470222.

A webcast of the conference call can also be accessed on the Novavax website at novavax.com/events. A replay of the webcast will be available on the Novavax website until April 28, 2021.

About NVX-CoV2373

NVX-CoV2373 is a protein-based vaccine candidate engineered from the genetic sequence of SARS-CoV-2, the virus that causes COVID-19 disease. NVX-CoV2373 was created using Novavax’ recombinant nanoparticle technology to generate antigen derived from the coronavirus spike (S) protein and is adjuvanted with Novavax’ patented saponin-based Matrix-M™ to enhance the immune response and stimulate high levels of neutralizing antibodies. NVX-CoV2373 contains purified protein antigen and can neither replicate, nor can it cause COVID-19. Over 37,000 participants have participated to date across four different clinical studies in five countries. NVX-CoV2373 is currently being evaluated in two pivotal Phase 3 trials: a trial in the U.K that completed enrollment in November and the PREVENT-19 trial in the U.S. and Mexico that began in December.

About Matrix-M™

Novavax’ patented saponin-based Matrix-M™ adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune response.

About Novavax

Novavax, Inc. (Nasdaq: NVAX) is a biotechnology company that promotes improved health globally through the discovery, development and commercialization of innovative vaccines to prevent serious infectious diseases. The company’s proprietary recombinant technology platform combines the power and speed of genetic engineering to efficiently produce highly immunogenic nanoparticles designed to address urgent global health needs. Novavax is conducting late-stage clinical trials for NVX-CoV2373, its vaccine candidate against SARS-CoV-2, the virus that causes COVID-19. NanoFlu™, its quadrivalent influenza nanoparticle vaccine, met all primary objectives in its pivotal Phase 3 clinical trial in older adults and will be advanced for regulatory submission. Both vaccine candidates incorporate Novavax’ proprietary saponin-based Matrix-M™ adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.

For more information, visit www.novavax.com and connect with us on Twitter and LinkedIn.

Candidate: NVX-CoV2373

Category: VAX

Type: Stable, prefusion protein made using Novavax’ proprietary nanoparticle technology, and incorporating its proprietary saponin-based Matrix-M™ adjuvant.

2021 Status: Novavax on March 11 announced final efficacy of 96.4% against mild, moderate and severe disease caused by the original COVID-19 strain in a pivotal Phase III trial in the U.K. of NVX–CoV2373. The study enrolled more than 15,000 participants between 18-84 years of age, including 27% over the age of 65.

The company also announced the complete analysis of its Phase IIb trial in South Africa, showing the vaccine had an efficacy of 55.4% among a cohort of HIV-negative trial participants, and an overall efficacy of 48.6% against predominantly variant strains of SARS-CoV-2 among 147 PCR-positive cases (51 cases in the vaccine group and 96 in the placebo group). Across both trials, NVX-CoV2373 demonstrated 100% protection against severe disease, including all hospitalization and death.

Philippines officials said March 10 that they secured 30 million doses of NVX-CoV2373 through an agreement with the Serum Institute of India, the second vaccine deal signed by the national government, according to Agence France-Presse. The first was with AstraZeneca for 2.6 million doses of its vaccine, developed with Oxford University.

The Novavax vaccine will be available from the third quarter, at a price that has yet to be finalized. The government hopes to secure 148 million doses this year from seven companies—enough for around 70% of its population.

In announcing fourth quarter and full-year 2020 results on March 1, Novavax said it could file for an emergency use authorization with the FDA in the second quarter of 2021. Novavax hopes it can use data from its Phase III U.K. clinical trial in its FDA submission, and expects the FDA to examine data in May, a month after they are reviewed by regulators in the U.K., President and CEO Stanley C. Erck said on CNBC. Should the FDA insist on waiting for U.S. data, the agency may push the review timeline by one or two months, he added.

The company also said that NVX-CoV2373 showed 95.6% efficacy against the original strain of COVID-19 and 85.6% against the UK variant strain, and re-stated an earlier finding that its vaccine met the Phase III trial’s primary endpoint met with an efficacy rate of 89.3%.

Novavax said February 26 that it signed an exclusive license agreement with Takeda Pharmaceutical for Takeda to develop, manufacture, and commercialize NVX-CoV2373 in Japan.

Novavax agreed to transfer the technology for manufacturing of the vaccine antigen and will supply its Matrix-M™ adjuvant to Takeda. Takeda anticipated the capacity to manufacture over 250 million doses of the COVID-19 vaccine per year. Takeda agreed in return to pay Novavax undisclosed payments tied to achieving development and commercial milestones, plus a portion of proceeds from the vaccine.

Takeda also disclosed that it dosed the first participants in a Phase II clinical trial to test the immunogenicity and safety of Novavax’ vaccine candidate in Japanese participants.

Novavax on February 18 announced a memorandum of understanding with Gavi, the Vaccine Alliance (Gavi), to provide 1.1 billion cumulative doses of NVX-CoV2373 for the COVAX Facility. Gavi leads the design and implementation of the COVAX Facility, created to supply vaccines globally, and has committed to working with Novavax to finalize an advance purchase agreement for vaccine supply and global distribution allocation via the COVAX Facility and its partners.

The doses will be manufactured and distributed globally by Novavax and Serum Institute of India (SII), the latter under an existing agreement between Gavi and SII.

Novavax and SK Bioscience said February 15 that they expanded their collaboration and license agreement, with SK finalizing an agreement to supply 40 million doses of NVX-CoV2373 to the government of South Korea beginning in 2021, for an undisclosed price. SK also obtained a license to manufacture and commercialize NVX-CoV2373 for sale to South Korea, as a result of which SK said it will add significant production capacity.

The agreement also calls on Novavax to facilitate technology transfer related to the manufacturing of its protein antigen, its Matrix M adjuvant, and support to SK Bioscience as needed to secure regulatory approval.

Rolling review begins—On February 4, Novavax announced it had begun a rolling review process for authorization of NVX-CoV2373 with several regulatory agencies worldwide, including the FDA, the European Medicines Agency, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), and Health Canada. The reviews will continue while the company completes its pivotal Phase III trials in the U.S. and U.K., and through initial authorization for emergency use granted under country-specific regulations, and through initial authorization for emergency use.

A day earlier, Novavax executed a binding Heads of Terms agreement with the government of Switzerland to supply 6 million doses of NVX-CoV2373, to the country. Novavax and Switzerland plan to negotiate a final agreement, with initial delivery of vaccine doses slated to ship following successful clinical development and regulatory review.

On January 28, Novavax electrified investors by announcing that its COVID-19 vaccine NVX-CoV2373 showed efficacy of 89.3% in the company’s first analysis of data from a Phase III trial in the U.K., where a variant strain (B.1.1.7) accounted for about half of all positive cases.

However, NVX-CoV2373 achieved only 60% efficacy in a Phase IIb trial in South Africa, where that country’s escape variant of the virus (B.1.351, also known as 20H/501Y.V2) was seen in 90% of cases, Novavax said.

Novavax said January 7 it executed an Advance Purchase Agreement with the Commonwealth of Australia for 51 million doses of NVX-CoV2373 for an undisclosed price, with an option to purchase an additional 10 million doses—finalizing an agreement in principle announced in November 2020. Novavax said it will work with Australia’s Therapeutics Goods Administration (TGA), to obtain approvals upon showing efficacy in clinical studies. The company aims to deliver initial doses by mid-2021.

2020 Status: Phase III trial launched—Novavax said December 28 that it launched the pivotal Phase III PREVENT-19 trial (NCT04611802) in the U.S. and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373. The randomized, placebo-controlled, observer-blinded study will assess the efficacy, safety and immunogenicity of NVX-CoV2373 in up to 30,000 participants 18 years of age and older compared with placebo. The trial’s primary endpoint is the prevention of PCR-confirmed, symptomatic COVID-19. The key secondary endpoint is the prevention of PCR-confirmed, symptomatic moderate or severe COVID-19. Both endpoints will be assessed at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2.

Two thirds of the participants will be assigned to randomly receive two intramuscular injections of the vaccine, administered 21 days apart, while one third of the trial participants will receive placebo. Trial sites were selected in locations where transmission rates are currently high, to accelerate the accumulation of positive cases that could show efficacy. Participants will be followed for 24 months following the second injection

PREVENT-19 is being conducted with support from federal agencies involved in Operation Warp Speed, the Trump administration’s effort to promote development and distribution of COVID-19 vaccines and drugs. Those agencies include the Department of Defense (DoD), the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), and the Biomedical Advanced Research and Development Authority (BARDA)—which has committed up to $1.6 billion to Novavax under a DoD agreement (identifier MCDC OTA agreement number W15QKN-16-9-1002).

Novavax is also conducting a pivotal Phase III study in the United Kingdom, a Phase IIb safety and efficacy study in South Africa, and an ongoing Phase I/II trial in the U.S. and Australia. Data from these trials are expected as soon as early first quarter 2021, though timing will depend on transmission rates in the regions, the company said.

Novavax said November 9 that the FDA granted its Fast Track designation for NVX-CoV2373. By the end of November, the company expected to finish enrollment in its Phase III U.K. trial, with interim data in that study expected as soon as early first quarter 2021.

Five days earlier, Novavax signed a non-binding Heads of Terms document with the Australian government to supply 40 million doses of NVX-CoV2373 to Australia starting as early as the first half of 2021, subject to the successful completion of Phase III clinical development and approval of the vaccine by Australia’s Therapeutic Goods Administration (TGA). The vaccine regimen is expected to require two doses per individual, administered 21 days apart.

Australia joins the U.S., the U.K., and Canada in signing direct supply agreements with Novavax. The company is supplying doses in Japan, South Korea, and India through partnerships. Australian clinical researchers led the global Phase I clinical trial in August, which involved 131 Australians across two trial sites (Melbourne and Brisbane). Also, approximately 690 Australians have participated in the Phase II arm of the clinical trial, which has been conducted across up to 40 sites in Australia and the U.S.

Novavax joined officials in its headquarters city of Gaithersburg, MD, on November 2 to announce expansion plans. The company plans to take 122,000 square feet of space at 700 Quince Orchard Road, and has committed to adding at least 400 local jobs, nearly doubling its current workforce of 450 worldwide. Most of the new jobs are expected to be added b March 2021.

Maryland’s Department of Commerce—which has prioritized assistance to life sciences companies—approved a $2 million conditional loan tied to job creation and capital investment. The state has also approved a $200,000 Partnership for Workforce Quality training grant, and the company is eligible for several tax credits, including the Job Creation Tax Credit and More Jobs for Marylanders.

Additionally, Montgomery County has approved a $500,000 grant tied to job creation and capital investment, while the City of Gaithersburg said it will approve a grant of up to $50,000 from its Economic Development Opportunity Fund. The city accelerated its planning approval process to accommodate Novavax’ timeline, given the company’s role in fighting COVID-19 and resulting assistance from Operation Warp Speed, the Trump administration’s effort to accelerate development of COVID-19 vaccines.

On October 27, Novavax said that it had enrolled 5,500 volunteers in the Phase III U.K. trial, which has been expanded from 10,000 to 15,000 volunteers. The increased enrollment “is likely to facilitate assessment of safety and efficacy in a shorter time period,” according to the company.

The trial, which is being conducted with the U.K. Government’s Vaccines Taskforce, was launched in September and is expected to be fully enrolled by the end of November, with interim data expected by early first quarter 2021, depending on the overall COVID-19 attack rate. Novavax has posted the protocol for the Phase III U.K. trial online. The protocol calls for unblinding of data once 152 participants have achieved mild, moderate or severe endpoints. Two interim analyses are planned upon occurrence of 66 and 110 endpoints.

Novavax also said it expects to launch a second Phase III trial designed to enroll up to 30,000 participants in the U.S. and Mexico by the end of November—a study funded through the U.S. government’s Operation Warp Speed program. The patient population will reflect proportional representation of diverse populations most vulnerable to COVID-19, across race/ethnicity, age, and co-morbidities.

The company cited progress toward large-scale manufacturing while acknowledging delays from original timeframe estimates. Novavax said it will use its contract manufacturing site at FUJIFILM Diosynth Biotechnologies’ Morrisville, NC facility to produce material for the U.S. trial.

On September 25, Novavax entered into a non-exclusive agreement with Endo International subsidiary Par Sterile Products to provide fill-finish manufacturing services at its plant in Rochester, MI, for NVX-CoV2373. Under the agreement, whose value was not disclosed, the Rochester facility has begun production of NVX-CoV2373 final drug product, with initial batches to be used in Novavax’ Phase III clinical trial in the U.S. Par Sterile will also fill-finish NVX-CoV2373 vaccine intended for commercial distribution in the U.S.

A day earlier, Novavax launched the U.K. trial. The randomized, placebo-controlled, observer-blinded study to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373 with Matrix-M in up to 10,000 subjects 18-84 years of age, with and without “relevant” comorbidities, over the following four to six weeks, Novavax said. Half the participants will receive two intramuscular injections of vaccine comprising 5 µg of protein antigen with 50 µg Matrix‑M adjuvant, 21 days apart, while half of the trial participants will receive placebo. At least 25% of the study population will be over age 65.

The trial’s first primary endpoint is first occurrence of PCR-confirmed symptomatic COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2. The second primary endpoint is first occurrence of PCR-confirmed symptomatic moderate or severe COVID-19 with onset at least seven days after the second study vaccination in volunteers who have not been previously infected with SARS-CoV-2

“The data from this trial is expected to support regulatory submissions for licensure in the UK, EU and other countries,” stated Gregory M. Glenn, M.D., President, Research and Development at Novavax.

Maryland Gov. Larry Hogan joined state Secretary of Commerce Kelly M. Schulz and local officials in marking the launch of Phase III studies with a tour of the company’s facilities in Gaithersburg: “The coronavirus vaccine candidate that’s been developed by Novavax is one of the most promising in the country, if not the world.”

On August 31, Novavax reached an agreement in principle with the government of Canada to supply up to 76 million doses of NVX-CoV2373. The value was not disclosed. Novavax and Canada did say that they expect to finalize an advance purchase agreement under which Novavax will agree to supply doses of NVX-CoV2373 to Canada beginning as early as the second quarter of 2021.

The purchase arrangement will be subject to licensure of the NVX-CoV2373 by Health Canada, Novavax said. The vaccine is in multiple Phase II clinical trials: On August 24, Novavax said the first volunteers had been enrolled in the Phase II portion of its ongoing Phase I/II clinical trial (NCT04368988), designed to evaluate the immunogenicity and safety of two doses of of NVX-CoV2373 (5 and 25 µg) with and without 50 µg of Matrix‑M™ adjuvant in up to 1,500 volunteers ages 18-84.

The randomized, placebo-controlled, observer-blinded study is designed to assess two dose sizes (5 and 25 µg) of NVX-CoV2373, each with 50 µg of Matrix‑M. Unlike the Phase I portion, the Phase II portion will include older adults 60-84 years of age as approximately half of the trial’s population. Secondary objectives include preliminary evaluation of efficacy. The trial will be conducted at up to 40 sites in the U.S. and Australia, Novovax said.

NVX-CoV2373 is in a pair of Phase II trials launched in August—including a Phase IIb study in South Africa to assess efficacy, and a Phase II safety and immunogenicity study in the U.S. and Australia.

On August 14, the U.K. government agreed to purchase 60 million doses of NVX-CoV2373 from the company, and support its planned Phase III clinical trial in the U.K., through an agreement whose value was not disclosed. The doses are set to be manufactured as early as the first quarter of 2021.

The trial will be designed to evaluate the ability of NVX-CoV2373 to protect against symptomatic COVID-19 disease as well as evaluate antibody and T-cell responses. The randomized, double-blind, placebo-controlled efficacy study will enroll approximately 9,000 adults 18-85 years of age in the U.K., and is expected to start in the third quarter.

Novavax also said it will expand its collaboration with FUJIFILM Diosynth Biotechnologies (FDB), which will manufacture the antigen component of NVX-CoV2373 from its Billingham, Stockton-on-Tees site in the U.K., as well as at U.S. sites in Morrisville, NC, and College Station, TX. FDB’s U.K. sitevis expected to produce up to 180 million doses annually.

On August 13, Novavax said it signed a development and supply agreement for the antigen component of NVX-CoV2373 with Seoul-based SK bioscience, a vaccine business subsidiary of SK Group. The agreement calls for supply to global markets that include the COVAX Facility, co-led by Gavi, the Coalition for Epidemic Preparedness Innovations (CEPI) and the World Health Organization.

Novavax and SK signed a letter of intent with South Korea’s Ministry of Health and Welfare to work toward broad and equitable access to NVX-CoV2373 worldwide, as well as to make the vaccine available in South Korea. SK bioscience agreed to manufacture the vaccine antigen component for use in the final drug product globally during the pandemic, at its vaccine facility in Andong L-house, South Korea, beginning in August. The value of the agreement was not disclosed.

On August 7, Novavax licensed its COVID-19 vaccine technology to Takeda Pharmaceutical through a partnership by which Takeda will develop, manufacture, and commercialize NVX‑CoV2373 in Japan, using Matrix-M adjuvant to be supplied by Novavax. Takeda will also be responsible for regulatory submission to Japan’s Ministry of Health, Labour and Welfare (MHLW).

MHLW agreed to provide funding to Takeda—the amount was not disclosed in the companies’ announcement—for technology transfer, establishment of infrastructure, and scale-up of manufacturing. Takeda said it anticipated the capacity to manufacture over 250 million doses of NVX‑CoV2373 per year.

Five days earlier, Serum Institute of India agreed to license rights from Novavax to NVX‑CoV2373 for development and commercialization in India as well as low- and middle-income countries (LMIC), through an agreement whose value was not disclosed. Novavax retains rights to NVX-CoV2373 elsewhere in the world.

Novavax and Serum Institute of India agreed to partner on clinical development, co-formulation, filling and finishing and commercialization of NVX-CoV2373. Serum Institute will oversee regulatory submissions and marketing authorizations in regions covered by the collaboration. Novavax agreed to provide both vaccine antigen and Matrix‑M adjuvant, while the partners said they were in talks to have the Serum Institute manufacture vaccine antigen in India. Novavax and Seerum Institute plan to split the revenue from the sale of product, net of agreed costs.

A day earlier, Novavax announced positive results from the Phase I portion of its Phase I/II clinical trial (NCT04368988), designed to evaluate two doses of NVX-CoV2373 (5 and 25 µg) with and without Matrix‑M™ adjuvant in 131 healthy adults ages 18-59. NVX-CoV2373, adjuvanted with Matrix-M, elicited robust antibody responses numerically superior to human convalescent sera, according to data submitted for peer-review to a scientific journal.

All participants developed anti-spike IgG antibodies after a single dose of vaccine, Novavax said, many also developing wild-type virus neutralizing antibody responses. After the second dose, all participants developed wild-type virus neutralizing antibody responses. Both anti-spike IgG and viral neutralization responses compared favorably to responses from patients with clinically significant COVID‑19 disease, the company said—adding that IgG antibody response was highly correlated with neutralization titers, showing that a significant proportion of antibodies were functional.

For both dosages of NVX‑CoV2373 with adjuvant, the 5 µg dose performed “comparably” with the 25 µg dose, Novavax said. NVX‑CoV2373 also induced antigen-specific polyfunctional CD4+ T cell responses with a strong bias toward the Th1 phenotype (IFN-g, IL-2, and TNF-a).

Based on an interim analysis of Phase I safety and immunogenicity data, the trial was expanded to Phase II clinical trials in multiple countries, including the U.S. The trial—which began in Australia in May—is being funded by up-to $388 million in funding from the Coalition for Epidemic Preparedness Innovations (CEPI). If the Phase I/II trial is successful, CEPI said, it anticipates supporting further clinical development that would advance NVX-CoV2373 through to licensure.

On July 23, Novavax joined FDB to announce that FDB will manufacture bulk drug substance for NVX-CoV2373, under an agreement whose value was not disclosed. FDB’s site in Morrisville, NC has begun production of the first batch of NVX-CoV2373. Batches produced at FDB’s Morrisville site will be used in Novavax’s planned pivotal Phase III clinical trial, designed to assess NVX-CoV2373 in up to 30,000 participants, and set to start this fall.

The Phase III trial is among R&D efforts to be funded through the $1.6 billion awarded in July to Novavax through President Donald Trump’s “Operation Warp Speed” program toward late-stage clinical trials and large-scale manufacturing to produce 100 million doses of its COVID-19 vaccine by year’s end. Novavax said the funding will enable it to complete late-stage clinical studies aimed at evaluating the safety and efficacy of NVX-CoV2373.

In June, Novavax said biotech investor and executive David Mott was joining its board as an independent director, after recently acquiring nearly 65,000 shares of the company’s common stock. Also, Novavax was awarded a $60 million contract by the U.S. Department of Defense (DoD) for the manufacturing of NVX‑CoV2373. Through the Defense Health Program, the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense Enabling Biotechnologies (JPEO-CBRND-EB) agreed to support production of several vaccine components to be manufactured in the U.S.  Novavax plans to deliver this year for DoD 10 million doses of NVX‑CoV2373 that could be used in Phase II/III trials, or under an Emergency Use Authorization (EUA) if approved by the FDA.

Also in June, AGC Biologics said it will partner with Novavax on large-scale GMP production of Matrix-M– significantly increasing Novavax’ capacity to deliver doses in 2020 and 2021—through an agreement whose value was not disclosed. And Novavax joined The PolyPeptide Group to announce large-scale GMP production by the global CDMO of two unspecified key intermediate components used in the production of Matrix-M.

In May, Novavax acquired Praha Vaccines from the India-based Cyrus Poonawalla Group for $167 million cash, in a deal designed to ramp up Novavax’s manufacturing capacity for NVX-CoV2373. Praha Vaccines’ assets include a 150,000-square foot vaccine and biologics manufacturing facility and other support buildings in Bohumil, Czech Republic. Novavax said the Bohumil facility is expected to deliver an annual capacity of over 1 billion doses of antigen starting in 2021 for the COVID-19 vaccine.

The Bohumil facility is completing renovations that include the addition of Biosafety Level-3 (BSL-3) capabilities. The site’s approximately 150 employees with “significant experience” in vaccine manufacturing and support have joined Novavax, the company said.

On May 11, Novavax joined CEPI in announcing up to $384 million in additional funding for the company toward clinical development and large-scale manufacturing of NVX-CoV2373. CEPI agreed to fund preclinical as well as Phase I and Phase II studies of NVX-CoV2373. The funding multiplied CEPI’s initial $4 million investment in the vaccine candidate, made two months earlier. Novavax’s total $388 million in CEPI funding accounted for 87% of the total $446 million awarded by the Coalition toward COVID-19 vaccine R&D as of that date.

Novavax identified its COVID-19 vaccine candidate in April. The company said NVX-CoV2373 was shown to be highly immunogenic in animal models measuring spike protein-specific antibodies, antibodies that block the binding of the spike protein to the receptor, and wild-type virus neutralizing antibodies. High levels of spike protein-specific antibodies with ACE-2 human receptor binding domain blocking activity and SARS-CoV-2 wild-type virus neutralizing antibodies were also seen after a single immunization.

In March, Emergent Biosolutions disclosed it retained an option to allocate manufacturing capacity for an expanded COVID-19 program under an agreement with Novavax to provide “molecule-to-market” contract development and manufacturing (CDMO) services to produce Novavax’s NanoFlu™, its recombinant quadrivalent seasonal influenza vaccine candidate.

Earlier in March, Emergent announced similar services to support clinical development of Novavax’s COVID-19 vaccine candidate, saying March 10 it agreed to produce the vaccine candidate and had initiated work, anticipating the vaccine candidate will be used in a Phase I study within the next four months. In February, Novavax said it had produced and was assessing multiple nanoparticle vaccine candidates in animal models prior to identifying an optimal candidate for human testing.

References

  1. ^ “Company Overview of Novavax, Inc”Bloomberg.comArchived from the original on 24 February 2017. Retrieved 2 June2019.
  2. ^ https://www.globenewswire.com/news-release/2021/03/01/2184674/0/en/Novavax-Reports-Fourth-Quarter-and-Full-Year-2020-Financial-Results-and-Operational-Highlights.html
  3. Jump up to:a b c d e Bell, Jacob (November 14, 2016). “Novavax aims to rebound with restructuring, more trials”BioPharma Dive. Washington, D.C.: Industry Dive. Archived from the original on 2017-03-29. Retrieved 2017-03-28.
  4. ^ Thomas, Katie; Twohey, Megan (2020-07-16). “How a Struggling Company Won $1.6 Billion to Make a Coronavirus Vaccine”The New York TimesISSN 0362-4331. Retrieved 2021-01-29.
  5. ^ Taylor, Nick Paul (3 June 2013). “Novavax makes $30M bid for adjuvant business”FiercePharmaArchived from the original on 14 September 2016. Retrieved 9 September 2016.
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Further reading

External links

General References

  1. Novavax Pipeline Page [Link]
  2. Novavex News Release [Link]
TypePublic
Traded asNasdaqNVAX
Russell 2000 Component
IndustryBiotechnology
Founded1987; 34 years ago [1]
HeadquartersGaithersburg, Maryland,United States
Area servedWorldwide
Key peopleStanley Erck (CEO)
ProductsVaccines
RevenueIncrease $475.2 Million (2020)[2]
Number of employees500+[3]
Websitewww.novavax.com 

The Novavax COVID-19 vaccine, codenamed NVX-CoV2373, and also called SARS-CoV-2 rS (recombinant spike) protein nanoparticle with Matrix-M1 adjuvant, is a COVID-19 vaccine candidate developed by Novavax and Coalition for Epidemic Preparedness Innovations (CEPI). It requires two doses[1] and is stable at 2 to 8 °C (36 to 46 °F) (refrigerated).[2]

Description

NVX-CoV2373 has been described as both a protein subunit vaccine[3][4][5] and a virus-like particle vaccine,[6][7] though the producers call it a “recombinant nanoparticle vaccine”.[8]

The vaccine is produced by creating an engineered baculovirus containing a gene for a modified SARS-CoV-2 spike protein. The baculovirus then infects a culture of Sf9 moth cells, which create the spike protein and display it on their cell membranes. The spike proteins are then harvested and assembled onto a synthetic lipid nanoparticle about 50 nanometers across, each displaying up to 14 spike proteins.[3][4][8]

The formulation includes a saponin-based adjuvant.[3][4][8]

Development

In January 2020, Novavax announced development of a vaccine candidate, codenamed NVX-CoV2373, to establish immunity to SARS-CoV-2.[9] Novavax’s work is in competition for vaccine development among dozens of other companies.[10]

In March 2020, Novavax announced a collaboration with Emergent BioSolutions for preclinical and early-stage human research on the vaccine candidate.[11] Under the partnership, Emergent BioSolutions will manufacture the vaccine at large scale at their Baltimore facility.[12] Trials have also taken place in the United Kingdom, and subject to regulatory approval, at least 60 million doses will be manufactured by Fujifilm Diosynth Biotechnologies in Billingham for purchase by the UK government.[13][14] They also signed an agreement with Serum Institute of India for mass scale production for developing and low-income countries.[15] It has also been reported, that the vaccine will be manufactured in Spain.[16] The first human safety studies of the candidate, codenamed NVX-CoV2373, started in May 2020 in Australia.[17][18]

In July, the company announced it might receive $1.6 billion from Operation Warp Speed to expedite development of its coronavirus vaccine candidate by 2021—if clinical trials show the vaccine to be effective.[19][20] A spokesperson for Novavax stated that the $1.6 billion was coming from a “collaboration” between the Department of Health and Human Services and Department of Defense,[19][20] where Gen. Gustave F. Perna has been selected as COO for Warp Speed. In late September, Novavax entered the final stages of testing its coronavirus vaccine in the UK. Another large trial was announced to start by October in the US.[21]

In December 2020, Novavax started the PREVENT-19 (NCT04611802) Phase III trial in the US and Mexico.[22][full citation needed][23]

On 28 January 2021, Novavax reported that preliminary results from the United Kingdom trial showed that its vaccine candidate was more than 89% effective.[24][2] However, interim results from a trial in South Africa showed a lower effectiveness rate against the 501.V2 variant of the virus, at around 50-60%.[1][25]

On 12 March 2021, they announced their vaccine candidate was 96.4% effective in preventing the original strain of COVID-19 and 86% effective against the U.K variant. It proved 55% effective against the South African variant in people without HIV/AIDS. It was also 100% effective at preventing severe illness.[citation needed]

Deployment

On 2 February 2021, the Canadian Prime Minister Justin Trudeau announced that Canada has signed a tentative agreement for Novavax to produce millions of doses of its COVID-19 vaccine in Montreal, Canada, once it’s approved for use by Health Canada, making it the first COVID-19 vaccine to be produced domestically.[26]

References

  1. Jump up to:a b Wadman M, Jon C (28 January 2021). “Novavax vaccine delivers 89% efficacy against COVID-19 in UK—but is less potent in South Africa”Sciencedoi:10.1126/science.abg8101.
  2. Jump up to:a b “New Covid vaccine shows 89% efficacy in UK trials”BBC News. 28 January 2021. Retrieved 28 January 2021.
  3. Jump up to:a b c Wadman M (November 2020). “The long shot”Science370 (6517): 649–653. Bibcode:2020Sci…370..649Wdoi:10.1126/science.370.6517.649PMID 33154120.
  4. Jump up to:a b c Wadman M (28 December 2020). “Novavax launches pivotal U.S. trial of dark horse COVID-19 vaccine after manufacturing delays”Sciencedoi:10.1126/science.abg3441.
  5. ^ Parekh N (24 July 2020). “Novavax: A SARS-CoV-2 Protein Factory to Beat COVID-19”Archived from the original on 22 November 2020. Retrieved 24 July 2020.
  6. ^ Chung YH, Beiss V, Fiering SN, Steinmetz NF (October 2020). “COVID-19 Vaccine Frontrunners and Their Nanotechnology Design”ACS Nano14 (10): 12522–12537. doi:10.1021/acsnano.0c07197PMC 7553041PMID 33034449.
  7. ^ Medhi R, Srinoi P, Ngo N, Tran HV, Lee TR (25 September 2020). “Nanoparticle-Based Strategies to Combat COVID-19”ACS Applied Nano Materials3 (9): 8557–8580. doi:10.1021/acsanm.0c01978PMC 7482545.
  8. Jump up to:a b c “Urgent global health needs addressed by Novavax”Novavax. Retrieved 30 January 2021.
  9. ^ Gilgore S (26 February 2020). “Novavax is working to advance a potential coronavirus vaccine. So are competitors”Washington Business JournalArchived from the original on 16 March 2020. Retrieved 6 March 2020.
  10. ^ “COVID-19 vaccine tracker (click on ‘Vaccines’ tab)”. Milken Institute. 11 May 2020. Archived from the original on 6 June 2020. Retrieved 12 May 2020. Lay summary.
  11. ^ Gilgore S (10 March 2020). “Novavax’s coronavirus vaccine program is getting some help from Emergent BioSolutions”Washington Business JournalArchived from the original on 9 April 2020. Retrieved 10 March 2020.
  12. ^ McCartney R. “Maryland plays an outsized role in worldwide hunt for a coronavirus vaccine”Washington PostArchived from the original on 7 May 2020. Retrieved 8 May 2020.
  13. ^ Boseley S, Davis N (28 January 2021). “Novavax Covid vaccine shown to be nearly 90% effective in UK trial”The Guardian. Retrieved 29 January 2021.
  14. ^ Brown M (14 August 2020). “60m doses of new covid-19 vaccine could be made in Billingham – and be ready for mid-2021”TeesideLive. Reach. Retrieved 29 January 2021.
  15. ^ “Novavax signs COVID-19 vaccine supply deal with India’s Serum Institute”Reuters. 5 August 2020.
  16. ^ “Spain, again chosen to produce the vaccine to combat COVID-19”This is the Real Spain. 18 September 2020.
  17. ^ Sagonowsky E (11 May 2020). “Novavax scores $384M deal, CEPI’s largest ever, to fund coronavirus vaccine work”FiercePharmaArchived from the original on 16 May 2020. Retrieved 12 May 2020.
  18. ^ “Novavax starts clinical trial of its coronavirus vaccine candidate”. CNBC. 25 May 2020. Archived from the original on 26 May 2020. Retrieved 26 May 2020.
  19. Jump up to:a b Thomas K (7 July 2020). “U.S. Will Pay $1.6 Billion to Novavax for Coronavirus Vaccine”The New York TimesArchived from the original on 7 July 2020. Retrieved 7 July 2020.
  20. Jump up to:a b Steenhuysen J (7 July 2020). “U.S. government awards Novavax $1.6 billion for coronavirus vaccine”ReutersArchived from the original on 14 September 2020. Retrieved 15 September 2020.
  21. ^ Thomas K, Zimmer C (24 September 2020). “Novavax Enters Final Stage of Coronavirus Vaccine Trials”The New York TimesISSN 0362-4331Archived from the original on 28 September 2020. Retrieved 28 September 2020.
  22. ^ Clinical trial number NCT04611802 for “A Study Looking at the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults at Risk for SARS-CoV-2” at ClinicalTrials.gov
  23. ^ “Phase 3 trial of Novavax investigational COVID-19 vaccine opens”National Institutes of Health (NIH). 28 December 2020. Retrieved 28 December 2020.
  24. ^ Lovelace B (28 January 2020). “Novavax says Covid vaccine is more than 89% effective”CNBC.
  25. ^ Facher L, Joseph A (28 January 2021). “Novavax says its Covid-19 vaccine is 90% effective in late-stage trial”Stat. Retrieved 29 January 2021.
  26. ^ “Canada signs deal to produce Novavax COVID-19 vaccine at Montreal plant”CP24. 2 February 2021. Retrieved 2 February2021.
Vaccine description
TargetSARS-CoV-2
Vaccine typeSubunit
Clinical data
Other namesNVX-CoV2373
Routes of
administration
Intramuscular
ATC codeNone
Identifiers
DrugBankDB15810
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UPDATE

SARS-CoV-2 Spike glycoprotein vaccine antigen nvx-cov2373

SARS-CoV-2 rS;
Novavax Covid-19 vaccine (TN);
Nuvaxovid (TN)

SARS-CoV-2 rS;
組換えコロナウイルス (SARS-CoV-2) ワクチン;
コロナウイルス(SARS-CoV-2)スパイク糖タンパク質抗原nvx-cov2373ワクチン;
SARS-CoV-2 Spike glycoprotein vaccine antigen nvx-cov2373;
SARS-CoV-2 rS

APPROVED JAPAN Nuvaxovid, 2022/4/19

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TOLVAPTAN


TOLVAPTAN

的合成

N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide

Formula C26H25ClN2O3 
Mol. mass 448.941 g/mol

150683-30-0 CAS NO

+ form  331947-66-1 Rform

OPC-41061

Otsuka…..innovator

UPDATE 2022

Tolvaptan sodium phosphate, Samtasu,

トルバプタンリン酸エステルナトリウム
2022/3/28 JAPAN PPROVED
Formula
C26H24ClN2O6P. 2Na
CAS
 
Mol weight
572.8849

Tolvaptan sodium phosphate (JAN).png

Tolvaptan sodium phosphate

disodium;[(5R)-7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-2,3,4,5-tetrahydro-1-benzazepin-5-yl] phosphate

European Medicines Agency (EMA) Accepts Otsuka’s Marketing Authorisation Application (MAA) for Tolvaptan, an Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD)

•Tolvaptan was discovered by Otsuka in Japan and, if approved by the EMA, would become the first pharmaceutical therapy in Europe for patients with ADPKD
•ADPKD is an inherited genetic disease that causes cyst growth in the kidneys, which gradually impairs their functioning. There is no current pharmaceutical treatment option
•Otsuka’s development of tolvaptan as a treatment for ADPKD illustrates the company’s commitment to address significant patient needs for diseases that traditionally have not been a priority for the pharmaceutical industry

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. announced today that the European Medicines Agency (EMA) has accepted the submission of a marketing authorisation application (MAA) for the potential approval of tolvaptan for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine.

http://www.pharmalive.com/ema-accepts-otsukas-maa-for-tolvaptan

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP).

Tolvaptan is (±)-4′-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl) carbonyl]-otolu-m-toluidide. The empirical formula is C26H25ClN2O3. Molecular weight is 448.94. The chemical structure is:

SAMSCA® (tolvaptan) Structural Formula Illustration

SAMSCA tablets for oral use contain 15 mg or 30 mg of tolvaptan. Inactive ingredients include corn starch, hydroxypropyl cellulose, lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose and FD&C Blue No. 2 Aluminum Lake as colorant.

SEE NEW UPDATE AT END OF PAGE

Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.

ChemSpider 2D Image | Tolvaptan | C26H25ClN2O3

Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]

Tolvaptan was first approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, then approved by the European Medicines Agency (EMA) on August 3, 2009 and approved by Pharmaceuticals and Medical Devices Agency of Japan on Feb 4, 2013. It was developed and marketed as Samsca® by Otsuka in the US, DE and JP.

UPDATED

Tolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the V2-receptor that is 1.8 times that of native arginine vasopressin (AVP) and that is 29 times greater than for the V1a-receptor. When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations. It is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia [serum sodium < 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction], including patients with heart failure, cirrhosis, and syndrome of inappropriate antidiuretic hormone (SIADH).

Samsca® is available as tablet for oral use, containing 7.5 mg/15 mg/30 mg of free Tolvaptan. The recommended starting dose is 15 mg once daily and it may be increased at intervals ≥ 24 hr to 30 mg once daily, and to a maximum of 60 mg once daily as needed to raise serum sodium.

 
 

Synthesis Reference

Bandi Parthasaradhi Reddy, “PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES.” U.S. Patent US20130190490, issued July 25, 2013.

US20130190490

Route 1

Reference:1. US5258510A.

Route 4

Reference:1. CN102060769B.

Route 5
 
 

SYN

SYN

Chemical synthesis:[5] Tolvaptan.png

 

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxy1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Figure US20130190490A1-20130725-C00001

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. Pat. No. 5,258,510.

Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro-1H-1-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-1-p-toluenesulfonyl-1H-1-benzazepine, and then reacted with polyphospholic acid. According to the journal, 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine can be prepared by reacting 1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation oftolvaptan can be prepared by the reduction of 7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

Biooganic and Medicinal Chemistry I (2007) 6455-6458, Biooganic andMedicinal Chemistry 14 (2000) 2493-2495 reported in the literature of the intermediate 2 – carboxylic acid -5 – (2 – methyl-benzoylamino) toluene synthesis method,

5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.

……………………………………….

PATENT

CN102382053AFigure CN102382053AD00031

……………………………………………..

PATENT

CN102060769

Figure CN102060769BC00021

Synthesis of Intermediate III: 1.

Example

  2-methyl-4-nitrobenzoic acid (available from Alfa Aesar Tianjin Chemical Co., purity> 99%, 25g,

0.14mol) was added to a 250ml reaction flask, is reacted with thionyl chloride under reflux conditions for 3h, thionyl chloride was distilled off under reduced pressure to give 2-methyl-4-nitrobenzoyl chloride (26.Sg, light yellow oily liquid), without purification, was used directly in the next step.

  Intermediate II (20g, 0.1moI) and 2_ methyl _4_ nitrobenzoylchloride (22.4g, 0.llmol) was added to a 250ml reaction flask. Dichloromethane (50ml), cooled to ice bath with stirring to dissolve O~5 ° C, was slowly added dropwise N- methylmorpholine (11.2g, 0.llmol), Bi dropwise with stirring while, at room temperature the reaction 4h. TLC [developing solvent: ethyl acetate – petroleum ether (I: I), hereinafter] is displayed after completion of the reaction, saturated aqueous sodium bicarbonate (20ml), stirred for lOmin, filtered, the filter cake with dichloromethane (15ml X 2 ) washing. The filtrate and washings were combined, washed with saturated sodium chloride solution (30ml X 3), dried over anhydrous sodium sulfate and filtered. The filtrate under reduced pressure to recover the solvent, the residue was recrystallized from anhydrous methanol to give a white powder 111 (27.5g, 75.2%), mp 154.8 ~155.6 ° C. Purity 97.9% (HPLC normalization method).

Synthesis of Intermediate IV:

Intermediate III (10g, 28mmol) was added to a 250ml reaction flask, concentrated hydrochloric acid (40ml) and ethanol (50ml), with stirring, was slowly added dropwise stannous chloride (20g, 88mmol) in ethanol (40ml) . Bi room temperature drops 5h. After TLC showed completion of the reaction, ethanol was distilled off under reduced pressure to about 70ml, the residue was -10 ° C -0 ° C allowed to stand overnight to cool. Filtered, and the filter cake was washed with water poured into water (40ml) in. Plus 20% sodium hydroxide solution (approximately 60ml) was adjusted to pH 9. Filtered, washed with ethanol and recrystallized to give a pale yellow powdered solid IV (6.3g, 68.7%), mp 190.4~191.1 ° C. Purity 97.2% (HPLC normalization method).

Synthesis of intermediate V:

  Intermediate IV (5g, 15mmol) and triethylamine (2.3g, 23mmol) was added followed by IOOml reaction flask was added dichloromethane (30ml), stir until dissolved. Solution of o-methylbenzoyl chloride (2.8g, 18mmol), dropwise at room temperature completion of the reaction Ih0 TLC showed the reaction was complete was poured into ice-water (about 40ml) in, (20ml X 3) and extracted with dichloromethane, the combined organic phases, and saturated sodium chloride solution successively (25ml X 3), dried over anhydrous sodium sulfate and filtered with 5% hydrochloric acid (25ml X 3). The filtrate under reduced pressure to recover the solvent (about 50ml), dried over anhydrous methanol residue – petroleum ether (2: 1) and recrystallized to give white crystals of Intermediate V (6.2g, 90.9%), mp 121.1 ~123.6 ° C. Purity 98.6% (HPLC normalization method).

Synthesis of tolvaptan: Example 4

Intermediate V (5g, Ilmmol) IOOml added to the reaction flask, was added anhydrous methanol (25ml), stirred and then added portionwise sodium borohydride (0.65g, 17mmol) to the reaction mixture, addition was complete the reaction at room temperature lh. After TLC showed the reaction was complete, the methanol recovered under reduced pressure (approximately 20ml), the residue was added methylene chloride (25ml), (25mlX3) and washed with saturated sodium chloride solution. Anhydrous sodium sulfate and filtered, and the filtrate under reduced pressure to recover the solvent, the residue with absolute methanol – petroleum ether (2: 1) and recrystallized tolvaptan white crystals (4.85g, 96.6%), mp 220.1~221.5 ° C. Purity 99.2% (HPLC normalization method). ES1-HRMS (C26H25C1N203, m / z) found (calc): 447.1476 (447.1481) [MH] – “

…………..

PATENT

http://www.google.com/patents/WO2012046244A1?cl=en

Tolvaptan is chemically, N-[4-[(7-chloro-2,3,4,5-tetrahydro-5-hydroxylH-l- benzazepin- 1 -yl)carbonyl]-3-methylphenyl]-2-methylbenzamide. Tolvaptan is represented by the following structure:

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.

Tolvaptan and its process for preparation were disclosed in U.S. patent no. 5,258,510. Processes for the preparation of 7-chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5- one, 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine and 7-chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine were reported in Bioorganic & medicinal chemistry 7 (1999), 1743-1754. According to the journal, 7-chloro-2,3,4,5-tetrahydro-lH-l- benzazepin-5-one can be prepared by reacting 7-chloro-4-ethoxycarbonyl-5-oxo-N-p- toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine with acetic acid in the presence of hydrochloric acid and water to obtain 7-chloro-5-oxo-2,3,4,5-tetrahydro-l-p- toluenesulfonyl-lH-l-benzazepine, and then reacted with polyphospholic acid.

According to the journal, 7-chloro- 1 -(2 -methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine can be prepared by reacting 7-chloro-5-oxo-2,3,4,5- tetrahydro-lH-l-benzazepine with 2-methyl-4-nitobenzoyl chloride in the presence of triethylamine.

According to the journal, 7-chloro- l-[2-methyl-4-[(2- methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine can be prepared by reacting l-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- lH-l-benzazepine with 2-methylbenzoylchloride in the presence of triethylamine.

PCT publication no. WO 2007/026971 disclosed a process for the preparation of tolvaptan can be prepared by the reduction of 7-chloro- l-[2-methyl-4-(2- methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one with sodium borohydride.

7-Chloro-2,3,4,5-tetrahydro-lH-l-benzazepin-5-one is a key intermediate for the preparation of tolvaptan.

 SYNTHESIS CONSTRUCTION

to1

TO0

to2

to3

to4

to5

Reference example 1 :

Preparation of methyl 5-chloro-2-nitrobenzoate

Potassium carbonate (515 gm) was added to a solution of 5-chloro-2-nitro benzoic acid (500 gm) in acetone (2750 ml) at room temperature. Dimethyl sulphate (306.5 gm) was added to the reaction mixture slowly and heated to reflux for 30 minutes. The reaction mass was filtered and then concentrated to obtain a residual mass. The residual mass was poured to the ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual solid of methyl 5- chloro-2-nitrobenzoate (534 gm). Reference example 2:

Preparation of methyl 2-amino-5-chlorobenzoate

A mixture of methyl 5-chloro-2-nitrobenzoate (534 gm) as obtained in reference example 1 and concentrated hydrochloric acid (2250 ml) was added to ethyl acetate (1120 ml). To the reaction mixture was added a solution of tin chloride (1680 gm) in ethyl acetate (2250 ml). The reaction mass was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with aqueous sodium hydroxide solution (2650 ml). The separated aqueous layer was extracted with ethyl acetate and then concentrated to obtain a residual solid of methyl 2- amino-5-chlorobenzoate (345 gm). Reference example 3:

Preparation of methyl 5-chIoro-2-(N-p-toluenesulfonyl)aminobenzoate

To a solution of methyl-2-amino-5-chloro benzoate (345 gm) as obtained in reference example 2 in pyridine (1725 ml) was added p-toluenesulfonyl chloride (425 gm). The reaction mixture was stirred for 2 hours at room temperature and poured to the ice water. The separated solid was filtered and dried to obtain 585 gm of methyl 5- chloro-2-(N-p-toluenesulfonyl)aminobenzoate.

Reference example 4:

Preparation of methyl 5-chloro-2-[N-(3-ethoxycarbonyI)propyI-N-p- toluenesulfonyl] aminobenzoate

Methyl 5-chloro-2-(N-p-toluenesulfonyl)aminobenzoate (585 gm) as obtained in reference example 3, ethyl-4-bromo butyrate (369.6 gm) and potassium carbonate (664 gm) in dimethylformamide (4400 ml) were added at room temperature. The contents were heated to 120°C and maintained for 2 hours. The reaction mass was poured into water and filtered. The solid obtained was dried to give 726 gm of methyl 5-chloro-2-[N- (3 -ethoxycarbonyl)propyl-N-p-toluenesulfonyl] aminobenzoate.

Reference example 5:

Preparation of 7-chloro-4-ethoxycarbonyI-5-oxo-N-p-toluenesufonyl-2,3,4,5- tetrahydro-lH-l-benzazepine

To a heated mixture of potassium tetrabutoxide (363 gm) in toluene (1000 ml) at 70°C was added portion wise methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p- toluenesulfonyl]aminobenzoate (726 gm) as obtained in reference example 4. The contents were heated to reflux and maintained for 30 minutes. The reaction mass was then cooled to room temperature and then poured to the ice water. The layers were separated and the aqueous layer was extracted with toluene. The solvent was distilled off under reduced pressure to obtain a residual solid of 7-chloro-4-ethoxycarbonyl-5-oxo-N- p-toluenesufonyl-2,3,4,5-tetrahydro-lH-l-benzazepine (455 gm).

Example 1:

Preparation of 7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine

7-Chloro-4-ethoxycarbonyl-5-oxo-N-p-toluenesufonyl-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (455 gm) as obtained in reference example 5 was added to aqueous sulfuric acid (80%, 2275 ml). The contents heated to 75°C and maintained for 2 hours. The reaction mass was then cooled to room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 7.5 to 8.0 with sodium hydroxide solution (2575 ml). The solid obtained was collected by filtration and dried to give 160 gm of 7- chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 -benzazepine.

Example 2:

Preparation of 7-chIoro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l- benzazepine

7-Chloro-5-oxo-2,3,4,5-tetrahydro-lH-l -benzazepine (160 gm) as obtained in example 1 was dissolved in methylene dichloride (480 ml) and then added aqueous sodium bicarbonate solution (20%, 68.75 gm). The reaction mixture was then cooled to 0 to 5°C and then added 2-methyl-4-nitrobenzoylchloride (180 gm) slowly. The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (170 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The solvent was distilled off under reduced pressure to obtain a residual mass. To the residual mass was dissolved in isopropyl alcohol (7300 ml) and maintained for 2 hours at reflux temperature. The separated solid was filtered and dried to obtain 250 gm of 7-chloro-l-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-lH-l-benzazepine. Example 3:

Preparation of l-(4-amino-2-methylbenzoyl)-7-chIoro-5-oxo-2,3,4,5-tetrahydro-lH- 1-benzazepine

7-Chloro- 1 -(2-methyl-4-nitrobenzoyl)-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (250 gm) as obtained in example 2 was dissolved in methanol (575 ml) and then added a solution of tin chloride (630 gm) in methanol (1130 ml). The reaction mixture was stirred for 16 hours at room temperature and then poured to the ice water. The pH of the reaction mass was adjusted to 8.0 to 9.0 with sodium hydroxide solution (1250 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under vacuum to obtain a residual solid of l-(4- amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 -benzazepine (185 gm).

Example 4:

Preparation of 7-chloro-l-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-dxo- 2,3,4,5-tetrahydro-lH-l-benzazepine

1 -(4-Amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3 ,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm) as obtained in example 3 was dissolved in methylene chloride (4000 ml) and then added sodium bicarbonate solution (10%, 47.3 gm). The reaction mass was cooled to 0 to 5°C and then added 2-methyl benzoyl chloride (95.7 gm) slowly. -The pH of the reaction mass was adjusted to 7.0 to 8.0 with aqueous sodium bicarbonate solution (120 ml). The separated aqueous layer was extracted with methylene chloride and then concentrated to obtain a residual solid of 7-chloro-l-[2- methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro- 1 H- 1 – benzazepine (185 gm). Example 5:

Preparation of tolvaptan

7-Chloro- 1 -[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5- tetrahydro-lH-1 -benzazepine (63 gm) as obtained in example 4 was dissolved in methanol (570 ml) and then added sodium borohydride (2.07 gm) at room temperature. The reaction mass was stirred for 1 hour and pH of the reaction mass was adjusted to 6.0 to 7.0 with hydrochloric acid solution (1%, 630 ml). The separated solid was filtered and dried to obtain 57 gm of tolvaptan.

……………….

t1.

Process used to prepare Tolvaptan involves condensing 7-chloro-1, 2, 3, 4-tetrahydro-benzo[b]azepin-5-one with 2-methyl, 4-nitro benzoyl chloride, followed by reduction using SnCl2/HCl catalyst resulting in amine which is then condensed with o-toluoyl chloride followed by reduction with sodium borohydride to give Tolvaptan

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SYN 1

Synthetic Reference

Cordero-Vargas, Alejandro; Quiclet-Sire, Beatrice; Zard, Samir Z. A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan. Bioorganic & Medicinal Chemistry. Volume 14. Issue 18. Pages 6165-6173. 2006.

SYN 2

Synthetic Reference

Torisawa, Yasuhiro; Abe, Kaoru; Muguruma, Yasuaki; Fujita, Shigekazu; Ogawa, Hidenori; Utsumi, Naoto; Miyake, Masahiro. Process for preparation of benzoylaminobenzoylbenzazepinones by reaction of benzazepinones with benzoylaminophenyl halides in the presence of carbonylating agents. Assignee Otsuka Pharmaceutical Co.,

SYN 3

Synthetic Reference

Zard, Samir; Cordero Vargas, Alejandro; Sire, Beatrice. Improved process for the preparation of benzazepines and their derivatives. Assignee Centre National de la Recherche Scientifique CNRS, Fr.; Ecole Polytechnique. FR 2867187. (2005).

SYN 4

Synthetic Reference

Gao, Junlong; Li, Peng; Liu, Kai; Guo, Dapeng. Method for preparing high-purity Tolvaptan intermediate. Assignee Jiangsu Hengrui Medicine Co., Ltd., Peop. Rep. China. CN 108503586. (2018).

SYN 5

Synthetic Reference

Han, Shin; Jeon, Seong Hyeon; Lee, Shin Yoon. Improved method for preparing synthetic intermediates for tolvaptan. Assignee Hexa Pharmatec Co., Ltd., S. Korea. JP 2018012690. (2018).

SYN 6

Synthetic Reference

Guo, Xinfu; Wang, Qiang; Liu, Zhaoguo; Wang, Zhipeng. Preparation method of tolvaptan. Assignee Tianjin Taipu Pharmaceutical Co., Ltd., Peop. Rep. China. CN 106883175. (2017).

SYN 7

Synthetic Reference

Lixin, Juanzi; Li, Jianzhi; Ma, Xilai; Chi, Wangzhou; Liu, Hai; Hu, Xuhua; Zheng, Xiaoli; Zhai, Zhijun; Li, Jianxun. Process for the preparation of tolvaptan. Assignee Shanghai Tianci International Pharmaceutical Co., Ltd., Peop. Rep. China. CN 105753735. (2016).

STR8

Synthetic Reference

Patel, Dhaval J.; Shah, Tejas C.; Singh, Manoj Kumar. A process for the preparation of tolvaptan. Assignee Cadila Healthcare Limited, India. IN 2012MU01559. (2014).

STR9

Synthetic Reference

Sethi, Madhuresh Kumar; Rawat, Vijendrasingh; Thirunavukarasu, Jayaprakash; Yerramala, Raja Krishna; Kumar, Anish. Improved process for the preparation of tolvaptan. Assignee Matrix Laboratories Ltd., India. IN 2011CH01303. (2013).

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t2 t3 t4

Title: Tolvaptan
CAS Registry Number: 150683-30-0
CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide
Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine
Manufacturers’ Codes: OPC-41061
Molecular Formula: C26H25ClN2O3
Molecular Weight: 448.94
Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%
Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549; eidem, US 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).
Properties: Colorless prisms, mp 225.9°.
Melting point: mp 225.9°
Therap-Cat: In treatment of congestive heart failure.
Keywords: Vasopressin Receptor Antagonist.

  1. Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205.
  2.  Otsuka Maryland Research Institute, Inc.
  3. Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963PMID 15113814.
  4. (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
  5. Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
  6. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
  • Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.

G. R. Belum, V. R. Belum, S. K. Chaitanya Arudra, and B. S. N. Reddy, “The Jarisch-Herxheimer reaction: revisited,” Travel Medicine and Infectious Disease, vol. 11, no. 4, pp. 231–237, 2013.
H. D. Zmily, S. Daifallah, and J. K. Ghali, “Tolvaptan, hyponatremia, and heart failure,” International Journal of Nephrology and Renovascular Disease, vol. 4, pp. 57–71, 2011.
M. N. Ferguson, “Novel agents for the treatment of hyponatremia: a review of conivaptan and tolvaptan,” Cardiology in Review, vol. 18, no. 6, pp. 313–321, 2010.
H. Ogawa, H. Miyamoto, K. Kondo, et al., US5258510, 1993.
K. Kondo, H. Ogawa, H. Yamashita et al., “7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5- tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist,” Bioorganic and Medicinal Chemistry, vol. 7, no. 8, pp. 1743–1754, 1999.

WO2012046244A1 * Aug 23, 2011 Apr 12, 2012 Hetero Research Foundation Process for preparing tolvaptan intermediates
CN102060769A * Dec 20, 2010 May 18, 2011 天津药物研究院 Preparation method of tolvaptan
CN102060769B Dec 20, 2010 Sep 18, 2013 天津药物研究院 Preparation method of tolvaptan
US9024015 Aug 23, 2011 May 5, 2015 Hetero Research Foundation Process for preparing tolvaptan intermediates
Cited Patent Filing date Publication date Applicant Title
CN101817783A May 12, 2010 Sep 1, 2010 天津泰普药品科技发展有限公司 Method for preparing tolvaptan intermediate
WO2007026971A2 Sep 1, 2006 Mar 8, 2007 Otsuka Pharma Co Ltd Process for preparing benzazepine compounds or salts thereof
Reference
1   Cordero-Vargas, Alejandro
2   Kondo, Kazumi et al.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist.《Bioorganic & Medicinal Chemistry》.1999,1743-1757.
3   Quiclet-Sire, Beatrice
4   Torisawa, Yasuhiro et al.Aminocarbonylation route to tolvaptan.《Bioorganic & Medicinal Chemistry Letters》.2007,6455-6458.
5   Zard, Samir Z.A flexible approach for the preparation of substituted benzazepines: Application to the synthesis of tolvaptan.《Bioorganic & Medicinal Chemistry》.2006,6165-6173.

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CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)OP(=O)([O-])[O-])C.[Na+].[Na+]

////////////UPDATE 2022

Tolvaptan
(RS)-Tolvaptan Structural Formula V1.svg
Tolvaptan ball-and-stick model.png
Clinical data
Trade names Samsca, Jinarc, Jynarque, others
Other names OPC-41061
AHFS/Drugs.com Monograph
MedlinePlus a609033
License data
Pregnancy
category
  • UK: Contraindicated
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unknown (40% absorbed)
Protein binding 99%
Metabolism Liver (CYP3A4-mediated)[7]
Elimination half-life 12 hours (terminal)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.219.212 Edit this at Wikidata
Chemical and physical data
Formula C26H25ClN2O3
Molar mass 448.95 g·mol−1
3D model (JSmol)
 ☒check (what is this?)  (verify)

Tolvaptan, sold under the brand name Samsca among others, is an aquaretic drug that functions as a selective, competitive vasopressin receptor 2 (V2) antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failurecirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca.[8] Tolvaptan, as Jynarque, was granted approval for medical use in the United States in April 2018.[9]

The U.S. Food and Drug Administration (FDA) granted tolvaptan a fast track designation for clinical trials investigating its use for the treatment of polycystic kidney disease.[10] The FDA granted Jynarque an orphan drug designation in April 2012, for the treatment of autosomal dominant polycystic kidney disease.[11]

Tolvaptan is available as a generic medication.[12]

Medical uses

Tolvaptan (Samsca) is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.[13]

Tolvaptan (Jynarque) is indicated to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).[14]

Side effects

The FDA has determined that tolvaptan should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure.[15] When using to treat hyponatremia, it may cause too rapid correction of hyponatremia resulting in fatal osmotic demyelination syndrome.[16]

Pharmacology

Tolvaptan is a selective vasopressin V2 receptor antagonist.[13][14]

Chemistry

Tolvaptan is a racemate, a 1:1 mixture of the following two enantiomers:[17]

Enantiomers of tolvaptan
(R)-Tolvaptan Structural Formula V1.svg
(R)-Tolvaptan
CAS number: 331947-66-1
(S)-Tolvaptan Structural Formula V1.svg
(S)-Tolvaptan
CAS number: 331947-44-5

References

  1. ^ “Samsca 15 mg tablets – Summary of Product Characteristics (SmPC)”(emc). Retrieved 14 December 2020.
  2. ^ “Jinarc 15 mg tablets – Summary of Product Characteristics (SmPC)”(emc). 21 April 2020. Retrieved 14 December 2020.
  3. ^ “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”DailyMed. 31 March 2020. Retrieved 14 December 2020.
  4. ^ “Samsca- tolvaptan tablet”DailyMed. 26 October 2020. Retrieved 14 December 2020.
  5. ^ “Samsca EPAR”European Medicines Agency (EMA). Retrieved 14 December 2020.
  6. ^ “Jinarc EPAR”European Medicines Agency (EMA). Retrieved 14 December 2020.
  7. ^ Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther10 (3): 165–71. doi:10.1177/107424840501000304PMID 16211205S2CID 39158242.
  8. ^ “Drug Approval Package: Samsca (Tolvaptan) Tablets NDA #022275”U.S. Food and Drug Administration (FDA). 21 July 2009. Retrieved 15 August 2020Lay summary (PDF). {{cite web}}Cite uses deprecated parameter |lay-url= (help)
  9. ^ “Drug Approval Package: Jynarque (tolvaptan)”U.S. Food and Drug Administration (FDA). 8 June 2018. Retrieved 15 August 2020.
  10. ^ “Otsuka Maryland Research Institute, Inc. Granted Fast Track Designation For Tolvaptan In PKD”Medical News Today. Healthline Media UK Ltd. Retrieved 6 December 2018.
  11. ^ “Tolvaptan Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 6 April 2012. Retrieved 15 August 2020.
  12. ^ “Drugs@FDA: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 15 August 2020.
  13. Jump up to:a b “Samsca- tolvaptan tablet”DailyMed. 28 May 2019. Retrieved 15 August 2020.
  14. Jump up to:a b “Jynarque- tolvaptan kit Jynarque- tolvaptan tablet”DailyMed. 31 March 2020. Retrieved 15 August 2020.
  15. ^ “U.S. Food and Drug Administration.” Samsca (Tolvaptan): Drug Safety Communication. N.p., 30 Apr. 2013. Web. 1 June 2014. <http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm>[dead link]
  16. ^ Goodman & Gilman’s the pharmacological basis of therapeutics. Brunton, Laurence L, Knollmann, Björn C, Hilal-Dandan, Randa (Thirteenth ed.). New York. 5 December 2017. ISBN 9781259584732OCLC 994570810.
  17. ^ Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, ISBN 978-3-946057-10-9, S. 222.

Further reading

External links

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

Synthesis

Synthesis of Tolvaptan
Fugure 1: Synthesis of Tolvaptan

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Title: Tolvaptan

CAS Registry Number: 150683-30-0

CAS Name: N-[4-[(7-Chloro-2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide

Additional Names: 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine

Manufacturers’ Codes: OPC-41061

Molecular Formula: C26H25ClN2O3

Molecular Weight: 448.94

Percent Composition: C 69.56%, H 5.61%, Cl 7.90%, N 6.24%, O 10.69%

Literature References: Nonpeptide arginine vasopressin V2 receptor antagonist. Prepn: H. Ogawa et al., WO 9105549eidemUS 5258510 (1991, 1993 both to Otsuka); K. Kondo et al., Bioorg. Med. Chem. 7, 1743 (1999). Pharmacology: Y. Yamamura et al., J. Pharmacol. Exp. Ther. 287, 860 (1998). Clinical trial in heart failure: M. Gheorghiade et al., J. Am. Med. Assoc. 291, 1963 (2004).

Properties: Colorless prisms, mp 225.9°.

Melting point: mp 225.9°

Therap-Cat: In treatment of congestive heart failure.

Keywords: Vasopressin Receptor Antagonist.

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