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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Evinacumab


(Heavy chain)
EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA ISGDGGSTYY
ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL RNTIFGVVIP DAFDIWGQGT
MVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP
AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF
LGGPSVFLFP PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE
QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS
QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF FLYSRLTVDK
SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK ASSLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H140-L214, H153-H209, H232-H’232, H235-H’235, H267-H327, H373-H431, H’22-H’96, H’140-L’214, H’153-H’209, H’267-H’327, H’373-H’431, L23-L88, L134-L194, L’23-L’88, L’134-L’194)

Evinacumab

エビナクマブ (遺伝子組換え)

Immunoglobulin G4, anti-​(human protein ANGPTL3 (angiopoietin-​like 3)​) (human monoclonal REGN1500 heavy chain)​, disulfide with human monoclonal REGN1500 light chain, dimer

FormulaC6480H9992N1716O2042S46
CAS1446419-85-7
Mol weight146081.9345

Protein Sequence

Sequence Length: 1334, 453, 453, 214, 214multichain; modified (modifications unspecified)

FDA APPROVED,  2021/2/11, EVKEEZA

Antihyperlipidemic, Anti-angiopietin like 3

Monoclonal antibody
Treatment of dyslipidemia

  • REGN 1500
  • REGN-1500
  • REGN1500

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1EVQLVESGGG VIQPGGSLRL SCAASGFTFD DYAMNWVRQG PGKGLEWVSA51ISGDGGSTYY ADSVKGRFTI SRDNSKNSLY LQMNSLRAED TAFFYCAKDL101RNTIFGVVIP DAFDIWGQGT MVTVSSASTK GPSVFPLAPC SRSTSESTAA151LGCLVKDYFP EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS201SLGTKTYTCN VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP251PKPKDTLMIS RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE301QFNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR351EPQVYTLPPS QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT401PPVLDSDGSF FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS451LGK

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence:

1DIQMTQSPST LSASVGDRVT ITCRASQSIR SWLAWYQQKP GKAPKLLIYK51ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNSYSYTFGQ101GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV151DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG201LSSPVTKSFN RGEC

Sequence Modifications

TypeLocationDescription
bridgeCys-22 – Cys-96disulfide bridge
bridgeCys-140 – Cys-214”disulfide bridge
bridgeCys-153 – Cys-209disulfide bridge
bridgeCys-232 – Cys-232′disulfide bridge
bridgeCys-235 – Cys-235′disulfide bridge
bridgeCys-267 – Cys-327disulfide bridge
bridgeCys-373 – Cys-431disulfide bridge
bridgeCys-22′ – Cys-96′disulfide bridge
bridgeCys-140′ – Cys-214”’disulfide bridge
bridgeCys-153′ – Cys-209′disulfide bridge
bridgeCys-267′ – Cys-327′disulfide bridge
bridgeCys-373′ – Cys-431′disulfide bridge
bridgeCys-23” – Cys-88”disulfide bridge
bridgeCys-134” – Cys-194”disulfide bridge
bridgeCys-23”’ – Cys-88”’disulfide bridge
bridgeCys-134”’ – Cys-194”’disulfide bridge

PATENTS

WO 2017024062

 US 20170305999 

Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).[1][2]

Evinacumab is a recombinant human IgG4 monoclonal antibody targeted against angiopoietin-like protein 3 (ANGPTL3) and the first drug of its kind. The ANGPTL family of proteins serve a number of physiologic functions – including involvement in the regulation of lipid metabolism – which have made them desirable therapeutic targets in recent years.2 Loss-of-function mutations in ANGPTL3 have been noted to result in hypolipidemia and subsequent reductions in cardiovascular risk, whereas increases in function appear to be associated with cardiovascular risk, and it was these observations that provided a rationale for the development of a therapy targeted against ANGPTL3.3

In February 2021, evinacumab became the first-and-only inhibitor of ANGPTL3 to receive FDA approval after it was granted approval for the adjunctive treatment of homozygous familial hypercholesterolemia (HoFH) under the brand name “Evkeeza”.8 Evinacumab is novel in its mechanism of action compared with other lipid-lowering therapies and therefore provides a unique and synergistic therapeutic option in the treatment of HoFH.

Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.[2]

Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3).[2] ANGPTL3 slows the function of certain enzymes that break down fats in the body.[2] Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol.[2] Evinacumab was approved for medical use in the United States in February 2021.[2][3]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EvkeezaInjection, solution, concentrate150 mg/1mLIntravenousRegeneron Pharmaceuticals, Inc.2021-02-11Not applicableUS flag 
EVKEEZA™ (evinacumab-dgnb) INJECTION | Regeneron Corporate

History

The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH).[2] In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo.[2] Participants were taking other lipid-lowering therapies as well.[2]

The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24.[2] At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.[2]

The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drugbreakthrough therapy, and priority review designations.[2] The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc.[2]

References

  1. Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761181s000lbl.pdf
  2. Jump up to:a b c d e f g h i j k l m n “FDA approves add-on therapy for patients with genetic form of severely”U.S. Food and Drug Administration (FDA). 11 February 2021. Retrieved 12 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “FDA Approves First-in-class Evkeeza (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol” (Press release). Regeneron Pharmaceuticals. 11 February 2021. Retrieved 12 February 2021 – via PR Newswire.

Further reading

External links

Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetAngiopoietin-like 3 (ANGPTL3)
Clinical data
Trade namesEvkeeza
Other namesREGN1500, evinacumab-dgnb
License dataUS DailyMedEvinacumab
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1446419-85-7
DrugBankDB15354
ChemSpidernone
UNIIT8B2ORP1DW
KEGGD11753
Chemical and physical data
FormulaC6480H9992N1716O2042S46
Molar mass146083.95 g·mol−1

//////////////

#Evinacumab, #Peptide, #APPROVALS 2021, #FDA 2021, #Monoclonal antibody, #dyslipidemia, #エビナクマブ (遺伝子組換え) , #REGN 1500, #REGN-1500, #REGN1500, #Anthony melvin crasto, #world drug tracker. # new drug approvals, #pharma

Tozinameran, Pfizer–BioNTech COVID‑19 vaccine


Covid19 vaccine biontech pfizer 3.jpg

SEQUENCE1

gagaauaaac uaguauucuu cuggucccca cagacucaga gagaacccgc51caccauguuc guguuccugg ugcugcugcc ucuggugucc agccagugug101ugaaccugac caccagaaca cagcugccuc cagccuacac caacagcuuu151accagaggcg uguacuaccc cgacaaggug uucagaucca gcgugcugca201cucuacccag gaccuguucc ugccuuucuu cagcaacgug accugguucc251acgccaucca cguguccggc accaauggca ccaagagauu cgacaacccc301gugcugcccu ucaacgacgg gguguacuuu gccagcaccg agaaguccaa351caucaucaga ggcuggaucu ucggcaccac acuggacagc aagacccaga401gccugcugau cgugaacaac gccaccaacg uggucaucaa agugugcgag451uuccaguucu gcaacgaccc cuuccugggc gucuacuacc acaagaacaa501caagagcugg auggaaagcg aguuccgggu guacagcagc gccaacaacu551gcaccuucga guacgugucc cagccuuucc ugauggaccu ggaaggcaag601cagggcaacu ucaagaaccu gcgcgaguuc guguuuaaga acaucgacgg651cuacuucaag aucuacagca agcacacccc uaucaaccuc gugcgggauc701ugccucaggg cuucucugcu cuggaacccc ugguggaucu gcccaucggc751aucaacauca cccgguuuca gacacugcug gcccugcaca gaagcuaccu801gacaccuggc gauagcagca gcggauggac agcuggugcc gccgcuuacu851augugggcua ccugcagccu agaaccuucc ugcugaagua caacgagaac901ggcaccauca ccgacgccgu ggauugugcu cuggauccuc ugagcgagac951aaagugcacc cugaaguccu ucaccgugga aaagggcauc uaccagacca1001gcaacuuccg ggugcagccc accgaaucca ucgugcgguu ccccaauauc1051accaaucugu gccccuucgg cgagguguuc aaugccacca gauucgccuc1101uguguacgcc uggaaccgga agcggaucag caauugcgug gccgacuacu1151ccgugcugua caacuccgcc agcuucagca ccuucaagug cuacggcgug1201uccccuacca agcugaacga ccugugcuuc acaaacgugu acgccgacag1251cuucgugauc cggggagaug aagugcggca gauugccccu ggacagacag1301gcaagaucgc cgacuacaac uacaagcugc ccgacgacuu caccggcugu1351gugauugccu ggaacagcaa caaccuggac uccaaagucg gcggcaacua1401caauuaccug uaccggcugu uccggaaguc caaucugaag cccuucgagc1451gggacaucuc caccgagauc uaucaggccg gcagcacccc uuguaacggc1501guggaaggcu ucaacugcua cuucccacug caguccuacg gcuuucagcc1551cacaaauggc gugggcuauc agcccuacag agugguggug cugagcuucg1601aacugcugca ugccccugcc acagugugcg gcccuaagaa aagcaccaau1651cucgugaaga acaaaugcgu gaacuucaac uucaacggcc ugaccggcac1701cggcgugcug acagagagca acaagaaguu ccugccauuc cagcaguuug1751gccgggauau cgccgauacc acagacgccg uuagagaucc ccagacacug1801gaaauccugg acaucacccc uugcagcuuc ggcggagugu cugugaucac1851cccuggcacc aacaccagca aucagguggc agugcuguac caggacguga1901acuguaccga agugcccgug gccauucacg ccgaucagcu gacaccuaca1951uggcgggugu acuccaccgg cagcaaugug uuucagacca gagccggcug2001ucugaucgga gccgagcacg ugaacaauag cuacgagugc gacaucccca2051ucggcgcugg aaucugcgcc agcuaccaga cacagacaaa cagcccucgg2101agagccagaa gcguggccag ccagagcauc auugccuaca caaugucucu2151gggcgccgag aacagcgugg ccuacuccaa caacucuauc gcuaucccca2201ccaacuucac caucagcgug accacagaga uccugccugu guccaugacc2251aagaccagcg uggacugcac cauguacauc ugcggcgauu ccaccgagug2301cuccaaccug cugcugcagu acggcagcuu cugcacccag cugaauagag2351cccugacagg gaucgccgug gaacaggaca agaacaccca agagguguuc2401gcccaaguga agcagaucua caagaccccu ccuaucaagg acuucggcgg2451cuucaauuuc agccagauuc ugcccgaucc uagcaagccc agcaagcgga2501gcuucaucga ggaccugcug uucaacaaag ugacacuggc cgacgccggc2551uucaucaagc aguauggcga uugucugggc gacauugccg ccagggaucu2601gauuugcgcc cagaaguuua acggacugac agugcugccu ccucugcuga2651ccgaugagau gaucgcccag uacacaucug cccugcuggc cggcacaauc2701acaagcggcu ggacauuugg agcaggcgcc gcucugcaga uccccuuugc2751uaugcagaug gccuaccggu ucaacggcau cggagugacc cagaaugugc2801uguacgagaa ccagaagcug aucgccaacc aguucaacag cgccaucggc2851aagauccagg acagccugag cagcacagca agcgcccugg gaaagcugca2901ggacgugguc aaccagaaug cccaggcacu gaacacccug gucaagcagc2951uguccuccaa cuucggcgcc aucagcucug ugcugaacga uauccugagc3001agacuggacc cuccugaggc cgaggugcag aucgacagac ugaucacagg3051cagacugcag agccuccaga cauacgugac ccagcagcug aucagagccg3101ccgagauuag agccucugcc aaucuggccg ccaccaagau gucugagugu3151gugcugggcc agagcaagag aguggacuuu ugcggcaagg gcuaccaccu3201gaugagcuuc ccucagucug ccccucacgg cgugguguuu cugcacguga3251cauaugugcc cgcucaagag aagaauuuca ccaccgcucc agccaucugc3301cacgacggca aagcccacuu uccuagagaa ggcguguucg uguccaacgg3351cacccauugg uucgugacac agcggaacuu cuacgagccc cagaucauca3401ccaccgacaa caccuucgug ucuggcaacu gcgacgucgu gaucggcauu3451gugaacaaua ccguguacga cccucugcag cccgagcugg acagcuucaa3501agaggaacug gacaaguacu uuaagaacca cacaagcccc gacguggacc3551ugggcgauau cagcggaauc aaugccagcg ucgugaacau ccagaaagag3601aucgaccggc ugaacgaggu ggccaagaau cugaacgaga gccugaucga3651ccugcaagaa cuggggaagu acgagcagua caucaagugg cccugguaca3701ucuggcuggg cuuuaucgcc ggacugauug ccaucgugau ggucacaauc3751augcuguguu gcaugaccag cugcuguagc ugccugaagg gcuguuguag3801cuguggcagc ugcugcaagu ucgacgagga cgauucugag cccgugcuga3851agggcgugaa acugcacuac acaugaugac ucgagcuggu acugcaugca3901cgcaaugcua gcugccccuu ucccguccug gguaccccga gucucccccg3951accucggguc ccagguaugc ucccaccucc accugcccca cucaccaccu4001cugcuaguuc cagacaccuc ccaagcacgc agcaaugcag cucaaaacgc4051uuagccuagc cacaccccca cgggaaacag cagugauuaa ccuuuagcaa4101uaaacgaaag uuuaacuaag cuauacuaac cccaggguug gucaauuucg4151ugccagccac acccuggagc uagcaaaaaa aaaaaaaaaa aaaaaaaaaa4201aaaagcauau gacuaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa4251aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa

Sequence Modifications

TypeLocationDescription
modified baseg-1m7g
modified baseg-13′-me
modified basea-2am
uncommon linkg-1 – a-25′->5′ triphosphate

Tozinameran

Pfizer–BioNTech COVID-19 vaccine

トジナメラン (JAN);
コロナウイルス修飾ウリジンRNAワクチン;

RNA (recombinant 5′-​[1,​2-​[(3′-​O-​methyl)​m7G-​(5’→5′)​-​ppp-​Am]​]​-​capped all uridine→N1-​methylpseudouridine-​substituted severe acute respiratory syndrome coronavirus 2 secretory signal peptide contg. spike glycoprotein S1S2-​specifying plus 5′- and 3′-​untranslated flanking region-​contg. poly(A)​-​tailed messenger BNT162b2)​, inner salt

Nucleic Acid Sequence

Sequence Length: 42841106 a 1315 c 1062 g 801 umodified

APPROVED JAPAN Comirnaty, 2021/2/14

CAS 2417899-77-3

5085ZFP6SJ

UNII-5085ZFP6SJ

Bnt-162b2

Bnt162b2

Active immunization (SARS-CoV-2)

Tozinameran is mRNA encoding full length of spike protein analog of SARS-CoV-2

Target Severe acute respiratory syndrome coronavirus 2 spike glycoprotein

Coronavirus disease – COVID-19

FORMROUTESTRENGTH
Injection, suspensionIntramuscular0.23 mg/1.8mL
SuspensionIntramuscular30 mcg
NAMEINGREDIENTSDOSAGEROUTELABELLERMARKETING STARTMARKETING END  
Pfizer-BioNTech Covid-19 VaccinePfizer-BioNTech Covid-19 Vaccine (0.23 mg/1.8mL)Injection, suspensionIntramuscularPfizer Manufacturing Belgium NV2020-12-12Not applicableUS flag 
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
Comirnaty 30 mcgIntramuscularBio N Tech Manufacturing Gmb H2021-01-06Not applicableEU flag 
Pfizer-BioNTech Covid-19 VaccineSuspension30 mcgIntramuscularBiontech Manufacturing Gmbh2020-12-14Not applicableCanada flag 
Pfizer-BioNTech Covid-19 VaccineInjection, suspension0.23 mg/1.8mLIntramuscularPfizer Manufacturing Belgium NV2020-12-12Not applicableUS flag 

The Pfizer–BioNTech COVID‑19 vaccine (pINNtozinameran), sold under the brand name Comirnaty,[13] is a COVID-19 vaccine developed by the German company BioNTech in cooperation with Pfizer. It is both the first COVID-19 vaccine to be authorized by a stringent regulatory authority for emergency use[14][15] and the first cleared for regular use.[16]

It is given by intramuscular injection. It is an RNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a mutated form of the spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles.[17] The vaccination requires two doses given three weeks apart.[18][19][20] Its ability to prevent severe infection in children, pregnant women, or immunocompromised people is unknown, as is the duration of the immune effect it confers.[20][21][22] As of February 2021, it is one of two RNA vaccines being deployed against COVID‑19, the other being the Moderna COVID‑19 vaccine. A third mRNA-based COVID-19 vaccine, CVnCoV, is in late-stage testing.[23]

Trials began in April 2020; by November, the vaccine had been tested on more than 40,000 people.[24] An interim analysis of study data showed a potential efficacy of over 90% in preventing infection within seven days of a second dose.[19][20] The most common side effects include mild to moderate pain at the injection site, fatigue, and headache.[25][26] As of December 2020, reports of serious side effects, such as allergic reactions, have been very rare,[a] and no long-term complications have been reported.[28] Phase III clinical trials are ongoing: monitoring of the primary outcomes will continue until August 2021, while monitoring of the secondary outcomes will continue until January 2023.[18]

In December 2020, the United Kingdom was the first country to authorize the vaccine on an emergency basis,[28] soon followed by the United States, the European Union and several other countries globally.[29][30][6][31][32]

BioNTech is the initial developer of the vaccine, and partnered with Pfizer for development, clinical research, overseeing the clinical trials, logistics, finances and for manufacturing worldwide with the exception of China.[33] The license to distribute and manufacture in China was purchased by Fosun, alongside its investment in BioNTech.[34][35] Distribution in Germany and Turkey is by BioNTech itself.[36] Pfizer indicated in November 2020, that 50 million doses could be available globally by the end of 2020, with about 1.3 billion doses in 2021.[20]

Pfizer has advanced purchase agreements of about US$3 billion for providing a licensed vaccine in the United States, the European Union, the United Kingdom, Japan, Canada, Peru, Singapore, and Mexico.[37][38] Distribution and storage of the vaccine is a logistics challenge because it needs to be stored at temperatures between −80 and −60 °C (−112 and −76 °F),[39] until five days before vaccination[38][39] when it can be stored at 2 to 8 °C (36 to 46 °F), and up to two hours at temperatures up to 25 °C (77 °F)[40][11] or 30 °C (86 °F).[41][42] In February 2021, Pfizer and BioNTech asked the U.S. Food and Drug Administration (FDA) to update the emergency use authorization (EUA) to permit the vaccine to be stored at between −25 and −15 °C (−13 and 5 °F) for up to two weeks before use.[43]

Development and funding

Before COVID-19 vaccines, a vaccine for an infectious disease had never before been produced in less than several years, and no vaccine existed for preventing a coronavirus infection in humans.[44] After the COVID-19 virus was detected in December 2019,[45] the development of BNT162b2 was initiated on 10 January 2020, when the SARS-CoV-2 genetic sequences were released by the Chinese Center for Disease Control and Prevention via GISAID,[46][47][48] triggering an urgent international response to prepare for an outbreak and hasten development of preventive vaccines.[49][50]

In January 2020, German biotech-company BioNTech started its program ‘Project Lightspeed’ to develop a vaccine against the new COVID‑19 virus based on its already established mRNA-technology.[24] Several variants of the vaccine were created in their laboratories in Mainz, and 20 of those were presented to experts of the Paul-Ehrlich-Institute in Langen.[51] Phase I / II Trials were started in Germany on 23 April 2020, and in the U.S. on 4 May 2020, with four vaccine candidates entering clinical testing. The Initial Pivotal Phase II / III Trial with the lead vaccine candidate ‘BNT162b2’ began in July. The Phase III results indicating a 95% effectiveness of the developed vaccine were published on 18 November 2020.[24]

BioNTech received a US$135 million investment from Fosun in March 2020, in exchange for 1.58 million shares in BioNTech and the future development and marketing rights of BNT162b2 in China,[35] Hong Kong, Macau and Taiwan.[52]

In June 2020, BioNTech received €100 million (US$119 million) in financing from the European Commission and European Investment Bank.[53] In September 2020, the German government granted BioNTech €375 million (US$445 million) for its COVID‑19 vaccine development program.[54]

Pfizer CEO Albert Bourla stated that he decided against taking funding from the US government’s Operation Warp Speed for the development of the vaccine “because I wanted to liberate our scientists [from] any bureaucracy that comes with having to give reports and agree how we are going to spend the money in parallel or together, etc.” Pfizer did enter into an agreement with the US for the eventual distribution of the vaccine, as with other countries.[55]

Clinical trials

See also: COVID-19 vaccine § Clinical trials started in 2020

Preliminary results from Phase I–II clinical trials on BNT162b2, published in October 2020, indicated potential for its efficacy and safety.[17][56] During the same month, the European Medicines Agency (EMA) began a periodic review of BNT162b2.[57]

The study of BNT162b2 is a continuous-phase trial in Phase III as of November 2020.[18] It is a “randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals”.[18] The early-stage research determined the safety and dose level for two vaccine candidates, with the trial expanding during mid-2020 to assess efficacy and safety of BNT162b2 in greater numbers of participants, reaching tens of thousands of people receiving test vaccinations in multiple countries in collaboration with Pfizer and Fosun.[20][35]

The Phase III trial assesses the safety, efficacy, tolerability, and immunogenicity of BNT162b2 at a mid-dose level (two injections separated by 21 days) in three age groups: 12–15 years, 16–55 years or above 55 years.[18] For approval in the EU, an overall vaccine efficacy of 95% was confirmed by the EMA.[58] The EMA clarified that the second dose should be administered three weeks after the first dose.[59]

Efficacy endpointVaccine efficacy (95% confidence interval) [%]
After dose 1 to before dose 252.4 (29.5, 68.4)
≥10 days after dose 1 to before dose 286.7 (68.6, 95.4)
Dose 2 to 7 days after dose 290.5 (61.0, 98.9)
≥7 days after dose 2 (subjects without evidence of infection prior to 7 days after dose 2)
Overall95.0 (90.0, 97.9)
16–55 years95.6 (89.4, 98.6)
≥55 years93.7 (80.6, 98.8)
≥65 years94.7 (66.7, 99.9)

The ongoing Phase III trial, which is scheduled to run from 2020 to 2022, is designed to assess the ability of BNT162b2 to prevent severe infection, as well as the duration of immune effect.[20][21][22]

Pfizer and BioNTech started a Phase II/III randomized control trial in healthy pregnant women 18 years of age and older (NCT04754594).[60] The study will evaluate 30 µg of BNT162b2 or placebo administered via intramuscular injection in 2 doses, 21 days apart. The Phase II portion of the study will include approximately 350 pregnant women randomized 1:1 to receive BNT162b2 or placebo at 27 to 34 weeks’ gestation. The Phase III portion of this study will assess the safety, tolerability, and immunogenicity of BNT162b2 or placebo among pregnant women enrolled at 24 to 34 weeks’ gestation. Pfizer and BioNTech announced on 18 February 2021 that the first participants received their first dose in this trial.[61]

Vaccine technology

See also: RNA vaccine and COVID-19 vaccine § Technology platforms

The BioNTech technology for the BNT162b2 vaccine is based on use of nucleoside-modified mRNA (modRNA) which encodes part of the spike protein found on the surface of the SARS-CoV-2 coronavirus (COVID‑19), triggering an immune response against infection by the virus protein.[62]

The vaccine candidate BNT162b2 was chosen as the most promising among three others with similar technology developed by BioNTech.[18][62][56] Prior to choosing BNT162b2, BioNTech and Pfizer had conducted Phase I trials on BNT162b1 in Germany and the United States, while Fosun performed a Phase I trial in China.[17][63] In these Phase I studies, BNT162b2 was shown to have a better safety profile than the other three BioNTech candidates.[63]

Sequence

The modRNA sequence of the vaccine is 4,284 nucleotides long.[64] It consists of a five-prime cap; a five prime untranslated region derived from the sequence of human alpha globin; a signal peptide (bases 55–102) and two proline substitutions (K986P and V987P, designated “2P”) that cause the spike to adopt a prefusion-stabilized conformation reducing the membrane fusion ability, increasing expression and stimulating neutralizing antibodies;[17][65] a codon-optimized gene of the full-length spike protein of SARS-CoV-2 (bases 103–3879); followed by a three prime untranslated region (bases 3880–4174) combined from AES and mtRNR1 selected for increased protein expression and mRNA stability[66] and a poly(A) tail comprising 30 adenosine residues, a 10-nucleotide linker sequence, and 70 other adenosine residues (bases 4175–4284).[64] The sequence contains no uridine residues; they are replaced by 1-methyl-3′-pseudouridylyl.[64]

Composition

In addition to the mRNA molecule, the vaccine contains the following inactive ingredients (excipients):[67][68][8]

The first four of these are lipids. The lipids and modRNA together form nanoparticles. ALC-0159 is a polyethylene glycol conjugate (that is, a PEGylated lipid).[69]

The vaccine is supplied in a multidose vial as “a white to off-white, sterile, preservative-free, frozen suspension for intramuscular injection“.[11][12] It must be thawed to room temperature and diluted with normal saline before administration.[12]

Authorizations

Expedited

The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) gave the vaccine “rapid temporary regulatory approval to address significant public health issues such as a pandemic” on 2 December 2020, which it is permitted to do under the Medicines Act 1968.[70] It was the first COVID‑19 vaccine to be approved for national use after undergoing large scale trials,[71] and the first mRNA vaccine to be authorized for use in humans.[14][72] The United Kingdom thus became the first Western country to approve a COVID‑19 vaccine for national use,[73] although the decision to fast-track the vaccine was criticised by some experts.[74]

On 8 December 2020, Margaret “Maggie” Keenan, 90, from Fermanagh, became the first person to receive the vaccine.[75] In a notable example of museums documenting the pandemic, the vial and syringe used for that first dose were saved acquired by The Science Museum in London for its permanent collection.[76] By 20 December, 521,594 UK residents had received the vaccine as part of the national vaccination programme. 70% had been to people aged 80 or over.[77]

After the United Kingdom, the following countries expedited processes to approve the Pfizer–BioNTech COVID‑19 vaccine for use: Argentina,[78] Australia,[79] Bahrain,[80] Canada,[7][81] Chile,[82] Costa Rica,[83] Ecuador,[82] Hong Kong,[84] Iraq,[85] Israel,[86] Jordan,[87] Kuwait,[88] Mexico,[89] Oman,[90] Panama,[91] the Philippines,[92] Qatar,[93] Saudi Arabia,[32][94] Singapore,[95][96] the United Arab Emirates,[97] and the United States.[10]

The World Health Organization (WHO) authorized it for emergency use.[98]

In the United States, an emergency use authorization (EUA) is “a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID‑19 pandemic”, according to the FDA.[99] Following an EUA issuance, BioNTech and Pfizer are expected to continue the Phase III clinical trial to finalize safety and efficacy data, leading to application for licensure (approval) of the vaccine in the United States.[99][100][101] The United States Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) approved recommendations for vaccination of those aged 16 years or older.[102][103]

Standard

On 19 December 2020, the Swiss Agency for Therapeutic Products (Swissmedic) approved the Pfizer–BioNTech COVID‑19 vaccine for regular use, two months after receiving the application, stating that the vaccine fully complied with the requirements of safety, efficacy and quality. This is the first authorization under a standard procedure.[1][104] On 23 December, a Lucerne resident, a 90-year-old woman, became the first person to receive the vaccine in Switzerland.[105] This marked the beginning of mass vaccination in continental Europe.[106]

On 21 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting conditional marketing authorization for the Pfizer–BioNTech COVID‑19 vaccine under the brand name Comirnaty.[2][107][108] The recommendation was accepted by the European Commission the same day.[107][109]

On February 23, 2021, the Brazilian Health Regulatory Agency approved the Pfizer–BioNTech COVID-19 vaccine under its standard marketing authorization procedure. It became the first COVID-19 vaccine to receive definitive registration rather than emergency use authorization in the country.[110]

Adverse effects

The adverse effect profile of the Pfizer–BioNTech COVID‑19 vaccine is similar to that of other adult vaccines.[20] During clinical trials, the side effects deemed very common[a] are (in order of frequency): pain and swelling at the injection site, tiredness, headache, muscle aches, chills, joint pain, and fever.[68] Fever is more common after the second dose.[68] These effects are predictable and to be expected, and it is particularly important that people be aware of this to prevent vaccine hesitancy.[111]

Severe allergic reaction has been observed in approximately 11 cases per million doses of vaccine administered.[112][113] According to a report by the US Centers for Disease Control and Prevention 71% of those allergic reactions happened within 15 minutes of vaccination and mostly (81%) among people with a documented history of allergies or allergic reactions.[112] The UK’s Medicines and Healthcare products Regulatory Agency (MHRA) advised on 9 December 2020, that people who have a history of “significant” allergic reaction should not receive the Pfizer–BioNTech COVID‑19 vaccine.[114][115][116] On 12 December, the Canadian regulator followed suit, noting that: “Both individuals in the U.K. had a history of severe allergic reactions and carried adrenaline auto injectors. They both were treated and have recovered.”[67]

On 28 January 2021, the European Union published a COVID-19 vaccine safety update which found that “the benefits of Comirnaty in preventing COVID‑19 continue to outweigh any risks, and there are no recommended changes regarding the use the vaccine.”[113][117] No new side effects were identified.[113]

Manufacturing

A doctor holding the Pfizer vaccine

Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe in a three-stage process. The first stage involves the molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. In the United States, this stage is conducted at a small pilot plant in Chesterfield, Missouri[118] (near St. Louis). After four days of growth, the bacteria are killed and broken open, and the contents of their cells are purified over a week and a half to recover the desired DNA product. The DNA is stored in tiny bottles and frozen for shipment. Safely and quickly transporting the DNA at this stage is so important that Pfizer has used its company jet and helicopter to assist.[119]

The second stage is being conducted at plants in Andover, Massachusetts[120] in the United States, and in Germany. The DNA is used as a template to build the desired mRNA strands. Once the mRNA has been created and purified, it is frozen in plastic bags about the size of a large shopping bag, of which each can hold up to 5 to 10 million doses. The bags are placed on special racks on trucks which take them to the next plant.[119]

The third stage is being conducted at plants in Portage, Michigan[121] (near Kalamazoo) in the United States, and Puurs in Belgium. This stage involves combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them.[119] Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids.[122] As of November 2020, the major bottleneck in the manufacturing process was combining mRNA with lipid nanoparticles.[119]

In February 2021, Pfizer revealed this entire sequence initially took about 110 days on average from start to finish, and that the company was making progress on reducing that number to 60 days.[123] Vaccine manufacturers normally take several years to optimize the process of making a particular vaccine for speed and cost-effectiveness before attempting large-scale production.[123] Due to the urgency presented by the COVID-19 pandemic, Pfizer began production immediately with the process by which the vaccine had been originally formulated in the laboratory, then started to identify ways to safely speed up and scale up that process.[123]

BioNTech announced in September 2020 that it had signed an agreement to acquire from Novartis a manufacturing facility in Marburg, Germany, to expand their vaccine production capacity.[124] Once fully operational, the facility would produce up to 750 million doses per year, or over 60 million doses per month. The site will be the third BioNTech facility in Europe which currently produces the vaccine, while Pfizer operates at least four production sites in the United States and Europe.

Advance orders and logistics

Pfizer indicated in its 9 November press release that 50 million doses could be available by the end of 2020, with about 1.3 billion doses provided globally by 2021.[20] In February 2021, BioNTech announced it would increase production by more than 50% to manufacture two billion doses in 2021.[125]

In July 2020, the vaccine development program Operation Warp Speed placed an advance order of US$1.95 billion with Pfizer to manufacture 100 million doses of a COVID‑19 vaccine for use in the United States if the vaccine was shown to be safe and effective.[34][126][127][128] By mid-December 2020, Pfizer had agreements to supply 300 million doses to the European Union,[129] 120 million doses to Japan,[130] 40 million doses (10 million before 2021) to the United Kingdom,[22] 20 million doses to Canada,[131] an unspecified number of doses to Singapore,[132] and 34.4 million doses to Mexico.[133] Fosun also has agreements to supply 10 million doses to Hong Kong and Macau.[134] The Hong Kong government said it would receive its first batch of one million doses by the first quarter of 2021.[135]

BioNTech and Fosun agreed to supply Mainland China with a batch of 100 million doses in 2021, subject to regulatory approval. The initial supply will be delivered from BioNTech’s production facilities in Germany.[136]

The vaccine is being delivered in vials that, once diluted, contain 2.25 ml of vaccine (0.45 ml frozen plus 1.8ml diluent).[101] According to the vial labels, each vial contains five 0.3 ml doses, however excess vaccine may be used for one, or possibly two, additional doses.[101][137] The use of low dead space syringes to obtain the additional doses is preferable, and partial doses within a vial should be discarded.[101][138] The Italian Medicines Agency officially authorized the use of excess doses remaining within single vials.[139] As of 8 January 2021, each vial contains six doses.[68][140][141][138] In the United States, vials will be counted as five doses when accompanied by regular syringes and as six doses when accompanied by low dead space syringes.[142]

Temperature the Pfizer vaccine must be kept at to ensure effectiveness, roughly between −80 and −60 °C (−112 and −76 °F)

Logistics in developing countries which have preorder agreements with Pfizer—such as Ecuador and Peru—remain unclear.[38] Even high-income countries have limited cold chain capacity for ultracold transport and storage of a vaccine that degrades within five days when thawed, and requires two shots three weeks apart.[38] The vaccine needs to be stored and transported at ultracold temperatures between −80 and −60 °C (−112 and −76 °F),[39][22][38][143][144] much lower than for the similar Moderna vaccine. The head of Indonesia‘s Bio Farma Honesti Basyir stated that purchasing the vaccine is out of the question for the world’s fourth-most populous country, given that it did not have the necessary cold chain capability. Similarly, India’s existing cold chain network can only handle temperatures between 2 and 8 °C (36 and 46 °F), far above the requirements of the vaccine.[145][146]

In January 2021, Pfizer and BioNTech offered to supply 50 million doses of COVID‑19 vaccine for health workers across Africa between March and the end of 2021, at a discounted price of US$10 per dose.[147]

Name

BNT162b2 was the code name during development and testing,[17][148] tozinameran is the proposed international nonproprietary name (pINN),[149] and Comirnaty is the brand name.[1][2] According to BioNTech, the name Comirnaty “represents a combination of the terms COVID‑19, mRNA, community, and immunity.”[150][151]

The vaccine also has the common name “COVID‑19 mRNA vaccine (nucleoside-modified)”[2] and may be distributed in packaging with the name Pfizer–BioNTech COVID‑19 Vaccine.”[152]

How the Pfizer-BioNTech Vaccine Works

By Jonathan Corum and Carl ZimmerUpdated Jan. 21, 2021Leer en español

The German company BioNTech partnered with Pfizer to develop and test a coronavirus vaccine known as BNT162b2, the generic name tozinameran or the brand name Comirnaty. A clinical trial demonstrated that the vaccine has an efficacy rate of 95 percent in preventing Covid-19.

A Piece of the Coronavirus

The SARS-CoV-2 virus is studded with proteins that it uses to enter human cells. These so-called spike proteins make a tempting target for potential vaccines and treatments.

Spikes

Spike

protein

gene

CORONAVIRUS

Like the Moderna vaccine, the Pfizer-BioNTech vaccine is based on the virus’s genetic instructions for building the spike protein.

mRNA Inside an Oily Shell

The vaccine uses messenger RNA, genetic material that our cells read to make proteins. The molecule — called mRNA for short — is fragile and would be chopped to pieces by our natural enzymes if it were injected directly into the body. To protect their vaccine, Pfizer and BioNTech wrap the mRNA in oily bubbles made of lipid nanoparticles.

Lipid nanoparticles

surrounding mRNA

Because of their fragility, the mRNA molecules will quickly fall apart at room temperature. Pfizer is building special containers with dry ice, thermal sensors and GPS trackers to ensure the vaccines can be transported at –94°F (–70°C) to stay viable.

Entering a Cell

After injection, the vaccine particles bump into cells and fuse to them, releasing mRNA. The cell’s molecules read its sequence and build spike proteins. The mRNA from the vaccine is eventually destroyed by the cell, leaving no permanent trace.

VACCINE

PARTICLES

VACCINATED

CELL

Spike

protein

mRNA

Translating mRNA

Three spike

proteins combine

Spike

Cell

nucleus

Spikes

and protein

fragments

Displaying

spike protein

fragments

Protruding

spikes

Some of the spike proteins form spikes that migrate to the surface of the cell and stick out their tips. The vaccinated cells also break up some of the proteins into fragments, which they present on their surface. These protruding spikes and spike protein fragments can then be recognized by the immune system.

Spotting the Intruder

When a vaccinated cell dies, the debris will contain many spike proteins and protein fragments, which can then be taken up by a type of immune cell called an antigen-presenting cell.

Debris from

a dead cell

Engulfing

a spike

ANTIGEN-

PRESENTING

CELL

Digesting

the proteins

Presenting a

spike protein

fragment

HELPER

T CELL

The cell presents fragments of the spike protein on its surface. When other cells called helper T cells detect these fragments, the helper T cells can raise the alarm and help marshal other immune cells to fight the infection.

Making Antibodies

Other immune cells, called B cells, may bump into the coronavirus spikes on the surface of vaccinated cells, or free-floating spike protein fragments. A few of the B cells may be able to lock onto the spike proteins. If these B cells are then activated by helper T cells, they will start to proliferate and pour out antibodies that target the spike protein.

HELPER

T CELL

Activating

the B cell

Matching

surface proteins

VACCINATED

CELL

B CELL

SECRETED

ANTIBODIES

Stopping the Virus

The antibodies can latch onto coronavirus spikes, mark the virus for destruction and prevent infection by blocking the spikes from attaching to other cells.

ANTIBODIES

VIRUS

Killing Infected Cells

The antigen-presenting cells can also activate another type of immune cell called a killer T cell to seek out and destroy any coronavirus-infected cells that display the spike protein fragments on their surfaces.

ANTIGEN-PRESENTING CELL Presenting a spike protein fragment ACTIVATED KILLER T CELL INFECTED CELL Beginning to kill the infected cell

Remembering the Virus

The Pfizer-BioNTech vaccine requires two injections, given 21 days apart, to prime the immune system well enough to fight off the coronavirus. But because the vaccine is so new, researchers don’t know how long its protection might last.

First dose, 0.3ml

Second dose, 21 days later

A preliminary study found that the vaccine seems to offer strong protection about 10 days after the first dose, compared with people taking a placebo:

Cumulative incidence of Covid-19 among clinical trial participants 2.5% 2.0 People taking a placebo

1.5 1.0 Second dose First dose People taking the

Pfizer-BioNTech vaccine

0.5

0

1

2

3

4

8

12

16

Weeks after the first dose

It’s possible that in the months after vaccination, the number of antibodies and killer T cells will drop. But the immune system also contains special cells called memory B cells and memory T cells that might retain information about the coronavirus for years or even decades.

For more about the vaccine, see Pfizer’s Covid Vaccine: 11 Things You Need to Know.

Preparation and Injection

Each vial of the vaccine contains 5 doses of 0.3 milliliters. The vaccine must be thawed before injection and diluted with saline. After dilution the vial must be used within six hours.

A diluted vial of the vaccine at Royal Free Hospital in London.Jack Hill/Agence France-Presse

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External links

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

A vial of the Pfizer–BioNTech COVID‑19 vaccine
Vaccine description
Target diseaseCOVID‑19
TypemRNA
Clinical data
Trade namesComirnaty[1][2]
Other namesBNT162b2, COVID-19 mRNA vaccine (nucleoside-modified)
License dataEU EMAby INNUS DailyMedPfizer-BioNTech_COVID-19_Vaccine
Pregnancy
category
AU: B1[3]
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusAU: S4 (Prescription only) [4][5]CA: Authorized by interim order [6][7]UK: Conditional and temporary authorization to supply [8][9]US: Unapproved (Emergency Use Authorization)[10][11][12]EU: Conditional marketing authorization granted [2]CH: Rx-only[further explanation needed][1]
Identifiers
CAS Number2417899-77-3
PubChem SID434370509
DrugBankDB15696
UNII5085ZFP6SJ
KEGGD11971
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 COVID-19 Portal

/////////

#Tozinameran, #APPROVALS 2021,   #JAPAN 2021,  Comirnaty, #Coronavirus disease, #COVID-19, #BNT162b2 , #BNT162b2, #SARS-CoV-2 Vaccine, #RNA ingredient BNT-162B2, #corona

The Pfizer-BioNTech COVID-19 vaccine (Tozinameran, INN), also known as BNT162b2, is one of four advanced mRNA-based vaccines developed through “Project Lightspeed,” a joint program between Pfizer and BioNTech.2,3 Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. It is designed to induce immunity against SARS-CoV-2, the virus responsible for causing COVID-19.2 The modRNA is formulated in lipid nanoparticles for administration via intramuscular injection in two doses, three weeks apart.1,3

Tozinameran is undergoing evaluation in clinical trials in both the USA (NCT04368728) and Germany (NCT04380701).4,5 Tozinameran received fast track designation by the U.S. FDA on July 13, 2020.6 On December 11, 2020, the FDA issued an Emergency Use Authorization (EUA) based on 95% efficacy in clinical trials and a similar safety profile to other viral vaccines over a span of approximately 2 months.1 Tozinameran was granted an EUA in the UK on December 2, 2020,8 and in Canada on December 9, 20207 for active immunization against SARS-CoV-2.12

Currently, sufficient data are not available to determine the longevity of protection against COVID-19, nor direct evidence that the vaccine prevents the transmission of the SARS-CoV-2 virus from one individual to another.9 Fact sheets for caregivers, recipients, and healthcare providers are now available.10,11

Tozinameran has not yet been fully approved by any country. In both the UK and Canada, Tozinameran is indicated under an interim authorization for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals aged 16 years and older.7,8

On December 11, 2020, the U.S. Food and Drug Administration granted emergency use authorization (EUA) for Tozinameran to prevent COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients aged 16 years and above.9 Safety and immune response information for adolescents 12-15 years of age will follow, and studies to further explore the administration of Tozinameran in pregnant women, children under 12 years of age, and those in special risk groups will be evaluated in the future.1

This vaccine should only be administered where appropriate medical treatment for immediate allergic reactions are immediately available in the case of an acute anaphylactic reaction after vaccine administration.12 Tozinameran administration should be postponed in any individual suffering from an acute febrile illness. Its use should be carefully considered in immunocompromised individuals and individuals with a bleeding disorder or on anticoagulant therapy. Appropriate medical treatment should be readily available in case of an anaphylactic reaction following vaccine administration.7,8

Tozinameran contains nucleoside modified mRNA (modRNA) encapsulated in lipid nanoparticles that deliver the modRNA into host cells. The lipid nanoparticle formulation facilitates the delivery of the RNA into human cells.12 Once inside these cells, the modRNA is translated by host machinery to produce the SARS-CoV-2 spike (S) protein antigen, which is subsequently recognized by the host immune system. Tozinameran has been shown to elicit both neutralizing antibody and cellular immune responses to the S protein, which helps protect against subsequent SARS-CoV-2 infection.7,8

Tozinameran is a nucleoside modified mRNA (modRNA) vaccine encoding an optimized full-length version of the SARS-CoV-2 spike (S) protein, translated and expressed in cells in vaccinated individuals to produce the S protein antigen against which an immune response is mounted. As with all vaccines, protection cannot be guaranteed in all recipients, and full protection may not occur until at least seven days following the second dose.7,8

In U.S. clinical trials, the vaccine was 95% effective in preventing COVID-19; eight COVID-19 cases occurred in the vaccine group and 162 cases occurred in the placebo group. Of the total 170 COVID-19 cases, one case in the vaccine group and three cases in the placebo group were considered to be severe infections.1,9

  1. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Perez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Tureci O, Nell H, Schaefer A, Unal S, Tresnan DB, Mather S, Dormitzer PR, Sahin U, Jansen KU, Gruber WC: Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 10. doi: 10.1056/NEJMoa2034577. [PubMed:33301246]
  2. Gen Eng News: BNT162 vaccine candidates [Link]
  3. BioNTech BNT162 Update [Link]
  4. Clinical Trial NCT04368728 [Link]
  5. Clinical Trial NCT04380701 [Link]
  6. FDA fast track designation: BNT162b1 and BNT162b2 [Link]
  7. Health Canada Interim Product Monograph: BNT162b2 SARS-CoV-2 Vaccine [Link]
  8. MHRA Interim Product Monograph: BNT162b2 SARS-CoV-2 Vaccine [Link]
  9. FDA News Release: FDA Takes Key Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for First COVID-19 Vaccine [Link]
  10. Pfizer: Fact Sheet for Healthcare Providers Administering Vaccine, Pfizer-BioNtech COVID-19 vaccine [Link]
  11. Pfizer: Fact Sheet for Recipients and Caregivers, Pfizer BioNTech COVID-19 vaccine [Link]
  12. FDA Emergency Use Authorization: Full EUA Prescribing information, Pfizer-BioNTech COVID-19 vaccine [Link]
  13.  
    PHASESTATUSPURPOSECONDITIONSCOUNT2Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)12, 3Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)11, 2Active Not RecruitingPreventionCoronavirus Disease 2019 (COVID‑19)11, 2RecruitingTreatmentCoronavirus Disease 2019 (COVID‑19) / Protection Against COVID-19 and Infections With SARS CoV 2 / Respiratory Tract Infections (RTI) / RNA Virus Infections / Vaccine Adverse Reaction / Viral Infections / Virus Diseases1 

Umbralisib


Umbralisib.svg
Umbralisib tosylate (USAN).png
Structure of UMBRALISIB TOSYLATE

Umbralisib tosylate

FormulaC31H24F3N5O3. C7H8O3S
Cas1532533-72-4
FREE 1532533-67-7
Mol weight743.7508

FDA APPR 2021/2/5

ウムブラリシブトシル酸塩;

Treatment of cancer and B-cell related disorders

Antineoplastic

RP-5152; RP-5237; PI3K delta inhibitors (cancer), Rhizen/Incozen; PI3K delta inhibitors (B-cell lymphoma/hematological cancers), Incozen/Rhizen; TGR-1202; TG-1202; RV-1001; umbralisib tosylate; umbralisib; RP-5264; RP-5307; dual PI3Kdelta/CK1 inhibitor (cancer), TG Therapeutics; Ukoniq

Umbralisib (TGR-1202) is an orally available PI3K delta inhibitor, targeting the delta isoform with nanomolar potency and several fold selectivity over the alpha, beta, and gamma isoforms of PI3K. The delta isoform of PI3K is strongly expressed in cells of hematopoietic origin and is believed to be important in the proliferation and survival of B-cell lymphocytes. Inhibition of PI3K delta signaling with umbralisib has demonstrated robust activity in numerous pre-clinical models and primary cells from patients with hematologic malignancies. Umbralisib is currently in Phase 3 clinical development in combination with Ublituximab for patients with hematologic malignancies.

Umbralisib, sold under the brand name Ukoniq, is a medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL).[2] It is taken by mouth.[2]

The most common side effects include increased creatinine, diarrhea-colitis, fatigue, nausea, neutropenia, transaminase elevation, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash.[2]

Umbralisib is a kinase inhibitor including PI3K-delta and casein kinase CK1-epsilon.[2][3][4] Umbralisib was approved for medical use in the United States in February 2021.[2][5]

In April 2019, the FDA granted umbralisib Orphan drug designations for the treatment of nodal MZL, extranodal MZL, and splenic MZL. In January 2019, the FDA granted Breakthrough Therapy Designation for the treatment of MZL in patients who had received at least one prior anti-CD20 regimen, based on the interim data from the MZL umbralisib monotherapy cohort in the UNITY-NHL study. In March 2020, the drug was granted Orphan status for treatment of FL  By June 2019, the confirmation of registration path to submit umbralisib for accelerated approval was obtained from the MZL cohort of the UNITY-NHL Phase IIb trial .

In August 2020, the FDA accepted the NDA for review; the MZL indication (patients with previously treated MZL who have received at least one prior anti-CD20 based regimen) was accepted for Priority Review with a PDUFA date of February 15, 2021, while the FL indication (patients with previously treated FL who have received at least two prior systemic therapies) was accepted for standard review with a PDUFA date of June 15, 2021.

In February 2021, the drug was granted accelerated approval by the FDA for second-line MZL and for fourth-line FL, based on results of UNITY-NHL. At that time, commercial launch was expected in the coming days

Medical uses

Umbralisib is indicated for adults with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen; and adults with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.[2][1]

Umbralisib is a kinase inhibitor. The active pharmaceutical ingredient is umbralisib tosylate with the molecular formula C38H32F3N5O6S and a molecular weight of 743.75 g/mol. The chemical name for umbralisib tosylate is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo [3, 4-d] pyrimidin-1-yl)-ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4- methylbenzenesulfonate and has the following structure:

UKONIQ™ (umbralisib) Structrual Formula Illustration

Umbralisib tosylate is white to light brown powder that is freely soluble in dimethyl sulfoxide, soluble in methanol, and practically insoluble in water. The ionization constant (pKa) of umbralisib tosylate is 2.71.

UKONIQ tablets are for oral administration. Each tablet contains 200 mg of umbralisib free base equivalent to 260.2 mg of umbralisib tosylate. The tablets also contain inactive ingredients: croscarmellose sodium, hydroxypropyl betadex, hydroxypropyl cellulose, magnesium stearate and microcrystalline cellulose.

The tablet coating film consists of FD&C Blue No. 1, FD&C Yellow No. 5, ferric oxide yellow, hypromellose 2910, polydextrose, polyethylene glycol 8000, titanium dioxide and triacetin.
Indications & Dosage

INDICATIONS

Marginal Zone Lymphoma

UKONIQ is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Image result for Umbralisib tosylate

Follicular Lymphoma

UKONIQ is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.

This indication is approved under accelerated approval based on overall response rate [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Adverse effects

The prescribing information provides warnings and precautions for adverse reactions including infections, neutropenia, diarrhea and non-infectious colitis, hepatotoxicity, and severe cutaneous reactions.[2]

History

It has undergone clinical studies for chronic lymphocytic leukemia (CLL).[6][7] Three year data (including follicular lymphoma and DLBCL) was announced June 2016.[8] It is in combination trials for various leukemias and lymphomas, such as mantle cell lymphoma (MCL)[9][10] and other lymphomas.[11]

Umbralisib was granted breakthrough therapy desgination by the U.S. Food and Drug Administration (FDA) for use in people with marginal zone lymphoma (MZL), a type of cancer with no specifically approved therapies.[12]

FDA approval was based on two single-arm cohorts of an open-label, multi-center, multi-cohort trial, UTX-TGR-205 (NCT02793583), in 69 participants with marginal zone lymphoma (MZL) who received at least one prior therapy, including an anti-CD20 containing regimen, and in 117 participants with follicular lymphoma (FL) after at least two prior systemic therapies.[2] The application for umbralisib was granted priority review for the marginal zone lymphoma (MZL) indication and orphan drug designation for the treatment of MZL and follicular lymphoma (FL).[2][13][14][15][16]

SYN

WO 2014071125

clip

First new chemical entity discovered by Indian scientists gets USFDA approval

https://www.businesstoday.in/sectors/pharma/first-new-chemical-entity-discovered-by-indian-scientists-gets-us-fda-approval/story/430693.html

Rhizen has retained commercialisation rights for India while also being the manufacturing and supply partner for Umbralisib. Alembic owns 50 per cent stake in Rhizen

Umbralisib, a novel cancer drug discovered and out-licensed by India’s Alembic Pharmaceuticals and its associate drug discovery company Rhizen Pharmaceuticals, has received the drug regulatory approval for sales in the US market. The drug is touted to be the first new chemical entity (NCE) discovered by Indian scientists to secure a US Food and Drug Administration (FDA) approval.

Switzerland based Rhizen had discovered the molecule in 2012 and two years later was licensed to US based TG Therapeutics, which has worldwide sales rights. Rhizen has retained commercialisation rights for India while also being the manufacturing and supply partner for Umbralisib. Alembic owns 50 per cent stake in Rhizen.

Umbralisib is a novel, next generation, oral, once daily drug for adult patients with relapsed or refractory lymphoma and relapsed or refractory marginal zone lymphoma (MZL) that resists treatments and drugs. Such cancers affect over 3-4 lakh patients in the US every year. The drug is estimated to have a global market worth US$ 1-1.5 billion.

“We are extremely proud of this historic milestone for Rhizen, and of the fact that Umbralisib is the first NCE discovered by Indian scientists to secure a US FDA approval,” said Pranav Amin, Chairman, Rhizen Pharmaceuticals & Managing Director of Alembic Pharmaceuticals.

“We are keen to bring Umbralisib to Indian patients and we plan to initiate activities towards registration and approval there soon,” said Swaroop Vakkalanka, President & CEO of Rhizen Pharmaceuticals.

Ahmedabad-based Zydus Cadila had a few months ago got ‘Fast Track Designation’ by the US Food and Drug Administration (USFDA) for Saroglitazar in the treatment of patients with Primary Biliary Cholangitis (PBC), a liver disorder due to progressive destruction of the bile ducts.

PATENT

WO 2021009509

Umbralisib, having the chemical designation (S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one, is an orally available PI3K delta inhibitor. Umbralisib has the following structure:

Inhibition of PI3K delta signaling with umbralisib has demonstrated activity in several pre-clinical models and primary cells from patients with hematologic malignancies. In a Phase 2 trial, umbralisib provided effective PI3K-delta inhibition and appeared well-tolerated among patients with relapsed/refractory marginal zone lymphoma. Umbralisib is currently in Phase 3 clinical development in combination with ublituximab for patients with hematologic malignancies. Hematologic malignancies are forms of cancer that begin in the cells of blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancer are acute and chronic leukemias, lymphomas, multiple myeloma and myelodysplastic syndromes. Lymphomas can include follicular lymphoma (FL), small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL), among others. Leukemia can include chronic lymphocytic leukemia (CLL), among others. The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to umbralisib for the treatment of patients with follicular lymphoma and for the treatment of patients with nodal, extranodal, and splenic marginal zone lymphoma.

U.S. Patent No. 9,150,579 discloses umbralisib and pharmaceutically acceptable salts thereof, such as 4-methylbenzenesulfonate (also known as tosylate), sulphate, hydrochloride, benzenesulfonate, maleate, and camphor sulfonate salts. U.S. Patent Nos. 9,969,740 and 10,414,773 and U.S. Patent Application Publication No. 2019/0382411 disclose solid state forms of a p-toluenesulfonic acid salt (PTSA) of umbralisib. None of these references disclose an amorphous form of umbralisib monotosylate.

An amorphous form of a compound is considered to be a solid state form that lacks long-range order relative to crystalline solid state forms of the compound. The amorphous form is chemically identical to other crystalline solid state forms but can exhibit different physical properties such as intrinsic solubility, rate of dissolution, density, mechanical property, chemical and physical stability, hygroscopicity, and morphology. The differences in intrinsic solubility also may lead to a difference in the rate of absorption, thus impacting bioavailability. Generally, amorphous compounds have a higher solubility than crystalline compounds.

EXAMPLES

Examples 1-3, which follow herein, provide embodiments of the preparation of amorphous umbralisib monotosylate.

Example 1

Preparation of Amorphous Umbralisib Monotosylate by Dry Grinding of Crystalline Umbralisib Tosylate Salt

Form I of umbralisib tosylate salt is dried under vacuum at about 40 °C in an oven for at least about 3 days to remove any residual ethyl acetate. About 30 mg of the dried umbralisib tosylate salt is ground manually using a mortar (about 6 cm in diameter) and pestle for about 3 minutes. The ground umbralisib tosylate salt is identified as being amorphous by XRPD. FIG. 1 is a representative XPRD pattern for amorphous umbralisib monotosylate prepared according to Example 1.

The amorphous umbralisib monotosylate prepared according to Example 1 is characterized by a Tg of about 51 °C, as depicted in the mDSC thermogram contained in FIG. 2.

A DVS of amorphous umbralisib monotosylate prepared according to Example 1 indicates the sample is hygroscopic, with about a 4% weight change between about 0-90% relative humidity, as depicted in FIG. 3, and less than about a 1% weight change in the sample over three cycles, as depicted in FIG. 4.

An XRPD pattern of the sample after DVS indicates that the sample is still amorphous, as depicted in FIG. 5.

Example 2

Preparation of Amorphous Umbralisib Monotosylate by Dissolution of

Crystalline Umbralisib Tosylate Salt in Methanol and Its Evaporation Therefrom

About 470 mg of Form I of umbralisib tosylate salt is dissolved in about 20 mL of methanol at about 50 °C. A solid umbralisib tosylate salt is obtained by evaporation of the solution under vacuum at about 40 °C in an oven overnight. The isolated product is identified as being amorphous umbralisib monotosylate by XRPD. FIG. 6 is a representative XPRD pattern for amorphous umbralisib monotosylate prepared according to Example 2.

The amorphous umbralisib monotosylate prepared according to Example 2 is characterized by a Tg of about 75 °C, as depicted in the mDSC thermogram contained in FIG. 7.

A TGA of amorphous umbralisib monotosylate prepared according to Example 2 shows about a 0.9% weight loss up to about 120 °C, as depicted in FIG. 8.

A DVS of amorphous umbralisib monotosylate prepared according to Example 2 indicates that the sample is hygroscopic, with about a 4% weight change between about 0-90% relative humidity, as depicted in FIG. 9, with about a 0.5% weight change in the sample over three cycles, as depicted in FIG. 10.

An XRPD pattern of the sample after DVS indicates that the sample is still amorphous, as depicted in FIG. 11.

‘ H NMR is carried out on a sample of amorphous umbralisib monotosylate prepared according to Example 2 in DMSO-d6 which indicates an umbralisib tosylate salt with a 1 :0.9 ratio of free base to acid, as depicted in FIG. 12. The peak at 8.25 ppm is representative of a single proton in the free base and the peaks at 2.30 ppm are the three protons from p-toluenesulfonic acid. A trace amount (about 0.07%) of methanol is observed at 3.16 ppm.

FTIR spectra is collected on amorphous umbralisib monotosylate prepared according to Example 2, as depicted in FIG. 13(a) and on starting crystalline umbralisib tosylate salt, as depicted in FIG. 13(b).

XRPD of amorphous umbralisib monotosylate prepared according to Example 2 after storage at about 40 °C under vacuum conditions for about two weeks indicates that the sample is still amorphous, as depicted in FIG. 14. Further, mDSC of amorphous umbralisib monotosylate after storage at about 40 °C under vacuum conditions for about two weeks indicates that the Tg is increased to about 83 °C, as depicted in FIG. 15.

Example 3

Solution Preparation of Amorphous Umbralisib Monotosylate from Umbralisib

Free Base and p-Toluenesulfonic Acid

Umbralisib free base and p-toluenesulfonic acid are each separately dissolved in MeOH. Specifically, about 72 mg of umbralisib free base is dissolved in about 3mL of MeOH at about 50 °C and about 24 mg of p-toluenesulfonic acid is dissolved in about 0.25 mL of MeOH at about 50 °C. The two solutions are mixed and stirred at room temperature for about 1 hr and then at about 4 °C overnight. The solution is transferred to a vacuum oven at about 40 °C overnight to evaporate the MeOH. Amorphous umbralisib monotosylate, identified by XRPD, is obtained. FIG. 16 is a representative XPRD pattern for amorphous umbralisib monotosylate prepared according to Example 3.

PATENT

WO 2015181728

TGR-1202, chemically known as (S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one, has the following chemical structure:

[04] The preparation of TGR-1202 and its salts is described in International Publication No. WO 2014/006572 and U.S. Patent Publication No. 2014/0011819, each of which is incorporated herein by reference in its entirety for all purposes. TGR-1202 is an investigational drug currently undergoing multiple clinical trials in the area of haematological malignancies.

[05] WO 2014/006572 and US 2014/0011819 describe the synthesis of TGR-1202 (Example B l) and also disclose the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of PI3K.

Example 1: Preparation of the PTSA Salt of TGR-1202 (Form A)

[103] 7100 g of TGR-1202 was charged in a reactor containing 56.8 litres of acetone and stirred at ambient temperature. 4680 g of p-toluene sulphonic acid was added and the reaction mixture was heated at a temperature of 60-65° C for about 6 hours. The solvent was removed by distillation under reduced pressure to obtain a wet residue. The wet residue was degassed and allowed to cool to < 20° C. Approximately 142 litres of diethyl ether was then added and the resulting mixture was stirred overnight, then filtered to obtain a solid mass which was washed with diethyl ether and dried in vacuo to yield a solid mass. The solid mass was re-suspended in diethyl ether, stirred for 6 hours, and then filtered to yield a solid mass which was subsequently dissolved in 56.8 litres of acetone, filtered through a HiFlow bed, and concentrated under reduced pressure. The resulting residue mass was stirred with water overnight, then filtered and vacuum dried to yield 6600 g of the PTSA salt of TGR-1202. HPLC: 99.21% and chiral purity of 99.64:0.36 (S:R).

Example 2: Preparation of the PTSA Salt of TGR-1202 (Form B)

1000 g of TGR-1202 was charged in a reactor containing 8 litres of acetone and stirred at ambient temperature. 666 g of p-toluene sulphonic acid was then added and the reaction mixture was heated at a temperature of 60-65 °C for about 6 hours. The solvent was removed by distillation under reduced pressure to obtain a wet residue. The wet residue was degassed and allowed to cool to < 20° C. Approximately 20 litres of diethyl ether was added and the resulting mixture was stirred overnight, then filtered to obtain a solid mass which was washed with diethyl ether and dried in vacuo to yield a solid mass which was then vacuum dried to yield 1150 g of the PTSA salt of TGR-1202. HPLC: 99.33% and chiral purity: 99.61:0.39 (S:R).

PATENT

WO 2014006572

Intermediate 1

[104] Intermediate 1: 6-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one: To a solution of 2-(l-bromoethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (15.0 g,

40.84 mmol) in DMSO (150 ml), n-butanol (7.5 ml) was added and heated to 120°C for 3h. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (7.90 g, 64%). H-NMR (δ ppm, CDC13, 400 MHz): 7.85 (dd, J = 8.1, 3 Hz, 1H), 7.54 (dd, J = 9.2, 4.2 Hz, 1H), 7.47-7.37 (m, 2H), 7.15-6.98 (m, 3H), 4.74 (quintet, J = 6.8 Hz, 1H), 2.23 (d, J = 7.4 Hz, 1H), 1.54 (d, J = 6.6 Hz, 3H).

Intermediate 2

[105] Intermediate 2: 2-acetyl-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one: DMSO (5.60 ml, 79.14 mmol) was added to dichloromethane (40 ml) cooled to -78°C, followed by oxalyl chloride (3.40 ml, 39.57 mmol). After 10 min. intermediate 1 (6.00 g, 19.78 mmol) in dichloromethane (54 ml) was added dropwise and stirred for 20 min. Triethylamine (12 ml) was added and stirred for lh. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (4.2 g, 71%) which was used as such in the next step.

Intermediate 3

OH

[106] Intermediate 3: (S)-6-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one: To intermediate 2 (2.00 g, 6.66 mmol), R-Alpine borane (0.5M in THF, 20 ml) was added and heated to 60°C for 20h. The reaction mixture quenched with aq. 2N HC1, and

extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (1.51 g, 75%). Enantiomeric excess: 94.2%, enriched in the fast eluting isomer (retention time: 8.78 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 4

[107] Intermediate 4: (R)-l-(6-fluoro-3-(3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl 4-chlorobenzoate: To a solution of intermediate 3 (1.45 g, 4.78 mmol) in THF (15 ml), 4-chlorobenzoic acid (0.748 g, 4.78 mmol) and triphenylphosphine (1.88 g, 7.17 mmol) were added and heated to 45 C followed by diisopropylazodicarboxylate (1.4ml, 7.17 mmol). After lh, the reaction mixture was concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (1.81 g, 86%) which was used without purification in the next step.

Intermediate 5

Method A

[108] Intermediate 5: (R)-6-fluoro-3-(3-fluorophenyl)-2-(l-hydroxyethyl)-4H-chromen-4-one: To intermediate 4 (1.75 g, 3.96 mmol) in methanol (17 ml) cooled to 10°C, potassium carbonate (0.273 g, 1.98 mmol) was added and stirred for 30 min. The reaction mixture was concentrated, acidified with 2N HC1 solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (1.05 g, 87%). Enantiomeric excess: 93.6%, enriched in the late eluting isomer (retention time: 11.12 min.) as determined by HPLC on a chiralpak AD-H column.

Method B:

[109] Step-1 : (R)-2-(l-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one : To l-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl)ethanone (11.00 g, 44.31 mmol ) in dichloromethane, HATU (33.7 g, 88.63 mmol) and R-(+)2-benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirred for 10 min. Triethylamine (66.7 ml, 0.47 mol) was added dropwise and stirred at RT for 24h. The reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (10.5 g, 60%). ‘H-NMR (δ ppm, CDC13, 400 MHz): 7.85 (dd, J = 8.1,3 Hz, 1H), 7.58 (dd, J = 9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.07 (m, 1H), 6.99-6.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J = 6.4 Hz, 3H).

[110] Step-2 : (R)-2-(l-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (10.5 g, 26.69 mmol) in dichloromethane (110 ml) cooled to 0°C, aluminium chloride (5.35 g, 40.03 mmol) was added portionwise and stirred at RT for 6h. The reaction mixture was quenched with 2N HC1 solution, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the desired intermediate as a yellow solid (6.1 g, 76%). Enantiomeric excess: 97.7%, enriched in the late eluting isomer (retention time: 11.12 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 13

[121] Intermediate 13: 3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine: To a solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (11.0 g, 42.14 mmol) in DMF 110 ml), ethanol (55 ml) and water (55 ml), intermediate 12 (23.4 g, 84.28 mmol) and sodium carbonate (13.3 g, 126.42 mmol) were added and degassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.10 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12h, the reaction mixture was filtered though celite, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound as light brown solid (3.2 g, 26% yield) which is used as such for the next step.

Example Bl

(S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

[127] To a solution of intermediate 13 (0.134 g, 0.494 mmol) in THF (2.0 ml), intermediate 5 (0.150 g, 0.494 mmol) and triphenylphosphine (0.194 g, 0.741 mml) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate ( 0.15 ml, 0.749 mmol) was added heated to 45°C. After 2h, the reaction mixture was quenched with with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as an off-white solid (0.049 g, 20 %). MP: 139-142°C. Mass : 571.7 (M H-NMR (δ ppm, CDC13, 400 MHz): 8.24 (s, 1H), 7.85 (dd, J = 8.2,3.1 Hz, 1H), 7.50-7.29 (m, 5H), 7.14 (t, J = 8.4 Hz, 1H), 7.02 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.11 (q, J = 7.1 Hz, 1H), 5.40 (s, 2H), 4.66 (quintet, J = 6.1 Hz, 1H), 2.00 (d, J = 7.1Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H). Enantiomeric excess: 89.8% as determined by HPLC

on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 10.64min.).

PATENT

US 2014/0011819 describe the synthesis of TGR-1202 (Example B l)

PATENT

US 20150290317

US 20150174263

WO 2014071125

WO 2014006572

WO 2013188763*

References

  1. Jump up to:a b c d e f “Ukoniq (umbralisib) tablets, for oral use” (PDF). TG Therapeutics.
  2. Jump up to:a b c d e f g h i j “FDA grants accelerated approval to umbralisib for marginal zone lymphoma and follicular lymphoma”U.S. Food and Drug Administration (FDA). 5 February 2021. Retrieved 5 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ Lunning M, Vose J, Nastoupil L, Fowler N, Burger JA, Wierda WG, et al. (November 2019). “Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia”Blood134 (21): 1811–20. doi:10.1182/blood.2019002118PMC 7042665PMID 31558467.
  4. ^ Burris HA, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, et al. (April 2018). “Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study”. Lancet Oncology19 (4): 486–96. doi:10.1016/S1470-2045(18)30082-2PMID 29475723.
  5. ^ “TG Therapeutics Announces FDA Accelerated Approval of Ukoniq (umbralisib)” (Press release). TG Therapeutics. 5 February 2021. Retrieved 5 February 2021 – via GlobeNewswire.
  6. ^ Inman S (19 March 2016). “Novel BTK, PI3K Inhibitors on Horizon for Relapsed CLL”OncLive. Archived from the original on 1 May 2016.
  7. ^ “Therapy Focus –- TG Could Benefit From Zydelig Setback”Seeking Alpha. 29 March 2016.
  8. ^ “TG Therapeutics, Inc. Announces First Patient Enrolled in the Registration-Directed UNITY-DLBCL Phase 2b Trial”. TG Therapeutics Inc. June 2016.
  9. ^ Clinical trial number NCT02268851 for “A Phase I/Ib Safety and Efficacy Study of the PI3K-delta Inhibitor TGR-1202 and Ibrutinib in Patients With CLL or MCL” at ClinicalTrials.gov
  10. ^ “Follow-Up Data for Combination of TGR-1202 (umbralisib) plus Ibrutinib in Patients with Relapsed or Refractory CLL and MCL”(Press release). TG Therapeutics. 14 June 2017 – via Globenewswire.
  11. ^ Clinical trial number NCT02793583 for “Study to Assess the Efficacy and Safety of Ublituximab + TGR-1202 With or Without Bendamustine and TGR-1202 Alone in Patients With Previously Treated Non-Hodgkin’s Lymphoma (UNITY-NHL)” at ClinicalTrials.gov
  12. ^ Columbus G (22 January 2019). “FDA Grants Umbralisib Breakthrough Designation for Marginal Zone Lymphoma”OncLive. Archived from the original on 23 January 2019.
  13. ^ “Orphan Treatment of extranodal marginal zone lymphoma”U.S. Food and Drug Administration (FDA). 11 April 2019. Retrieved 5 February 2021.
  14. ^ “Orphan Treatment of splenic marginal zone lymphoma”U.S. Food and Drug Administration (FDA). 11 April 2019. Retrieved 5 February 2021.
  15. ^ “Orphan Treatment of Follicular Lymphoma”U.S. Food and Drug Administration (FDA). 11 April 2019. Retrieved 5 February2021.
  16. ^ “Orphan Treatment of nodal marginal zone lymphoma”U.S. Food and Drug Administration (FDA). 11 April 2019. Retrieved 5 February 2021.

External links

Clinical data
Trade namesUkoniq
Other namesRP5264; TGR-1202
License dataUS DailyMedUmbralisib
Pregnancy
category
Not recommended[1]
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Pharmacokinetic data
MetabolismCYP2C9, CYP3A4, and CYP1A2[1]
Elimination half-life91 h[1]
ExcretionFeces, urine[1]
Identifiers
IUPAC name[show]
CAS Number1532533-67-7
PubChem CID72950888
DrugBankDB14989
ChemSpider34979945
UNII38073MQB2A
ChEMBLChEMBL3948730
Chemical and physical data
FormulaC31H24F3N5O3
Molar mass571.560 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CC(C)OC1=C(C=C(C=C1)C2=NN(C3=NC=NC(=C23)N)C(C)C4=C(C(=O)C5=C(O4)C=CC(=C5)F)C6=CC(=CC=C6)F)F

Feb. 9, 2021 04:45 UTC Rhizen Pharmaceuticals AG Announces That Its Partnered Asset, Umbralisib (UKONIQ™), Has Received US FDA Accelerated Approval for Adult Patients With Relapsed or Refractory MZL & FL

Umbralisib (UKONIQ™) granted accelerated approval by US FDA for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL), follicular lymphoma (FL).

Umbralisib, a novel next generation inhibitor of PI3K delta & CK1 epsilon, was discovered by Rhizen Pharmaceuticals and subsequently licensed to TG Therapeutics, who led the asset’s clinical development.

Rhizen and its affiliate Alembic Pharma to support TG Therapeutics towards UKONIQ’s commercialization as its manufacturing & supply partner; Rhizen plans to register and commercialize Umbralisib in India.

BASEL, Switzerland–(BUSINESS WIRE)–Rhizen Pharmaceuticals, a clinical-stage oncology-focused biopharmaceutical company, today announced that its novel next generation PI3K-delta inhibitor, Umbralisib, which was licensed to TG Therapeutics (NASDAQ:TGTX), has secured US FDA accelerated approval for the treatment of:

adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20 based regimen, and

adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy.

Accelerated approval was granted for these indications, under a priority review (MZL), based on the results of the Phase 2 UNITY-NHL Trial (NCT02793583); in MZL, an ORR of 49% with 16% complete responses and in FL an ORR of 43% with 3% complete responses were achieved, respectively. Umbralisib was earlier granted Breakthrough Therapy Designation (BTD) for the treatment of MZL and orphan drug designation (ODD) for the treatment of MZL and FL.

Umbralisib is a novel, next generation, oral, once daily, inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon and was discovered by Rhizen Pharma and subsequently licensed to TG Therapeutics (NASDAQ:TGTX) at an IND stage (TGR 1202) in 2012. In 2014, both parties entered into a licensing agreement as a part of which TGTX obtained worldwide rights and Rhizen has retained commercialization rights for India while also being the manufacturing and supply partner for Umbralisib.

Swaroop Vakkalanka, President & CEO of Rhizen Pharmaceuticals said: “Umbralisib’s approval offers MZL & FL patients a new treatment option and is a huge validation of Rhizen’s drug discovery & development capabilities. This is a momentous occasion in Rhizen’s journey as a successful biotech that speaks of the true ability of our team to discover & develop safe and effective therapies that can last the rigors of drug development. Further, we are keen to bring Umbralisib to Indian patients and we plan to initiate activities towards registration and approval there soon.”

Pranav Amin, Chairman, Rhizen Pharmaceuticals & Managing Director of Alembic Pharmaceuticals Ltd said: “We are extremely proud of this historic milestone for Rhizen, and of the fact that Umbralisib is the first NCE discovered by Indian scientists to secure a US FDA approval. We are committed to working together with TG Therapeutics and Rhizen Pharma to ensure uninterrupted supply of UKONIQ™. Umbralisib is the first discovery asset to come out of Rhizen’s R&D efforts and this approval heralds the promise of the rest of Rhizen’s deep pipeline and continuing efforts.”

About Umbralisib:

Umbralisib is the first and only oral inhibitor of phosphoinositide 3 kinase (PI3K) delta and casein kinase 1 (CK1) epsilon. PI3K-delta is known to play an important role in supporting cell proliferation and survival, cell differentiation, intercellular trafficking and immunity and is expressed in both normal and malignant B-cells. CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies. Umbralisib is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) who have received at least three prior lines of systemic therapy. These indications are approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. More information on Umbralisib or UKONIQ™ can be found at https://www.tgtherapeutics.com/prescribing-information/uspi-ukon.pdf.

About Alembic Pharmaceuticals Ltd:

Alembic Pharmaceuticals Limited, a vertically integrated research and development pharmaceutical company, has been at the forefront of healthcare since 1907. Headquartered in India, Alembic is a publicly listed company that manufactures and markets generic pharmaceutical products all over the world. Alembic’s state of the art research and manufacturing facilities are approved by regulatory authorities of many developed countries including the USFDA. Alembic is one of the leaders in branded generics in India. Alembic’s products that are marketed through a marketing team of over 5000 are well recognized by doctors and patients.

Information about Alembic can be found at http://www.alembicpharmaceuticals.com/.

(Reuters: ALEM.NS) (Bloomberg: ALPM) (NSE: APLL TD) (BSE: 533573)

About Rhizen Pharmaceuticals A.G.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel onco-therapeutics. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways. Rhizen is headquartered in Basel, Switzerland. For additional information, please visit http://www.rhizen.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210208005742/en/ Contacts

////////////ウムブラリシブトシル酸塩 , Umbralisib, fda 2021, 2021 approvals, TGR 1202, TGR-1202-101, RP 5264, Umbralisib tosylate, RP-5307 , TGR-1202, TGR-1202 PTSA, FU8XW5V3FS , RP-5264, AK173784, 

old post pasted

rp-5264.png

   TGR 1202, TGR-1202-101, RP 5264, UmbralisibAK173784;(S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one(S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one,2-[(1S)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one CAS TOSYLATE 1532533-72-4 Umbralisib tosylateCAS 1532533-67-7, 1514919-95-9

Molecular Formula:C31H24F3N5O3
Molecular Weight:571.54917 g/mol

RP-5307
TGR-1202
TGR-1202 PTSA
FU8XW5V3FS (UNII code)
RP-5264 (free base)

A PI3K inhibitor potentially for treatment of chronic lymphocytic leukemia, leukemia,lymphoma,B-cell

TGR‐1202, a next generation PI3K-δ delta inhibitor. TGR-1202 (RP-5264) is a highly specific, orally available, PI3K delta inhibitor, targeting the delta isoform with nanomolar potency and several fold selectivity over the alpha, beta, and gamma isoforms of PI3K.

TG Therapeutics, under license from Rhizen Pharmaceuticals, is developing TGR-1202 (structure shown; formerly RP-5264), a lead from a program of PI3K delta inhibitors, for the potential oral treatment of hematological cancers including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), B-cell lymphoma and mantle cell lymphoma (MCL)

Incozen Therapeutics Pvt Ltd

TG Therapeutics

TGR-1202 potential to perform as the best PI3K inhibitor in its class and the possible superiority of TG-1101 over Rituxan®.

 Rhizen Pharmaceuticals S.A.
DescriptionPhosphoinositide 3-kinase (PI3K) delta inhibitor

Leukemia, chronic lymphocytic  PHASE 3, TG Therapeutics

Orphan Drug

Umbralisib is a novel phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor under development at TG Therapeutics in phase III clinical trials, in combination with ublituximab, for the treatment of chronic lymphocytic leukemia (CLL) and for the treatment of diffuse large B-cell lymphoma (DLBCL). The company refers to the combination regimen of ublituximab and TGR-1202 as TG-1303. The drug is also in phase II clinical development for the oral treatment of hematologic malignancies, as a single agent or in combination therapy. Phase I clinical trials are ongoing in patients with select relapsed or refractory solid tumors, such as adenocarcinoma of the pancreas, adenocarcinoma of the colon, rectum, gastric and GE junction cancer, and GI Stromal Tumor (GIST).

In 2016, orphan drug designation was assigned to the compound in the U.S. for the treatment of CLL. In 2017, additional orphan drug designation was granted in the U.S. for the treatment of CLL and DLBCL, in combination with ublituximab.

Originated by Rhizen Pharmaceuticals, the product was jointly developed by Rhizen Pharmaceuticals and TG Therapeutics since 2012. In 2014, exclusive global development and commercialization rights (excluding India) were licensed to TG Therapeutics.

CLINICAL TRIALS……….https://clinicaltrials.gov/search/intervention=TGR-1202

B-cell lymphoma; Chronic lymphocytic leukemia; Hematological neoplasm; Hodgkins disease; Mantle cell lymphoma; Non-Hodgkin lymphoma

Phosphoinositide-3 kinase delta inhibitor

rp-5264.png

SYNTHESIS

str1
str1

Rhizen Pharmaceuticals Announces Out-licensing Agreement for TGR-1202, a Novel Next Generation PI3K-delta Inhibitor

Rhizen to receive upfront payment of $8.0 million — Rhizen to retain global manufacturing and supply rights — Rhizen to retain development and commercialization for India

Rhizen to retain development and commercialization for India

http://globenewswire.com/news-release/2014/09/23/667853/10099642/en/Rhizen-Pharmaceuticals-Announces-Out-licensing-Agreement-for-TGR-1202-a-Novel-Next-Generation-PI3K-delta-Inhibitor.html?parent=794070#

September 23, 2014 09:00 ET | Source: Rhizen Pharmaceuticals SA

La Chaux-de-Fonds, Switzerland, Sept. 23, 2014 (GLOBE NEWSWIRE) — Rhizen Pharmaceuticals S.A. today announced an out-licensing agreement for TGR-1202, a novel next generation PI3K-delta inhibitor. TG Therapeutics exercised its option for early conversion to a licensing agreement from a 50:50 joint venture partnership.

In exchange for this licensing agreement, TG Therapeutics will pay Rhizen an upfront payment of $8.0 million ($4.0 million in cash and $4.0 million in TG Therapeutics common stock).  In addition to the upfront payment, Rhizen will be eligible to receive regulatory filing, approval and sales based milestones in the aggregate of approximately $240 million, and tiered royalties based on net sales.

Swaroop Vakkalanka, Ph.D. and President of Rhizen stated, “We are extremely happy and take pride in discovering a novel, next generation, once-daily PI3K-delta inhibitor under active development led by TG Therapeutics.  We are encouraged by the progress of TRG-1202 to date, and the speed at which TG Therapeutics is developing the asset in various hematological malignancies.  We look forward to the day this novel drug reaches cancer patients in need of new and safe therapies.”

About Rhizen Pharmaceuticals S.A.:

Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel therapeutics for the treatment of cancer, immune and metabolic disorders.  Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways.  Rhizen is headquartered in La-Chaux-de-Fonds, Switzerland.  For additional information, please visit Rhizen’s website, www.rhizen.com.

TGR-1202.with Idelalisib and IPI-145 (left to right) for comparison.

TGTX structure
Idelalisib Struture
IPI-145 Structure

IPI 145

PATENTS

WO 2011055215

http://www.google.com/patents/WO2011055215A2?cl=en

Figure imgf000106_0001
  

PATENT

WO 2015181728

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015181728

TGR-1202, chemically known as (S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one, has the following chemical structure:

Example 1: Preparation of the PTSA Salt of TGR-1202 (Form A)

7100 g of TGR-1202 was charged in a reactor containing 56.8 litres of acetone and stirred at ambient temperature. 4680 g of p-toluene sulphonic acid was added and the reaction mixture was heated at a temperature of 60-65° C for about 6 hours. The solvent was removed by distillation under reduced pressure to obtain a wet residue. The wet residue was degassed and allowed to cool to < 20° C. Approximately 142 litres of diethyl ether was then added and the resulting mixture was stirred overnight, then filtered to obtain a solid mass which was washed with diethyl ether and dried in vacuo to yield a solid mass. The solid mass was re-suspended in diethyl ether, stirred for 6 hours, and then filtered to yield a solid mass which was subsequently dissolved in 56.8 litres of acetone, filtered through a HiFlow bed, and concentrated under reduced pressure. The resulting residue mass was stirred with water overnight, then filtered and vacuum dried to yield 6600 g of the PTSA salt of TGR-1202. HPLC: 99.21% and chiral purity of 99.64:0.36 (S:R).

Example 2: Preparation of the PTSA Salt of TGR-1202 (Form B)

1000 g of TGR-1202 was charged in a reactor containing 8 litres of acetone and stirred at ambient temperature. 666 g of p-toluene sulphonic acid was then added and the reaction mixture was heated at a temperature of 60-65 °C for about 6 hours. The solvent was removed by distillation under reduced pressure to obtain a wet residue. The wet residue was degassed and allowed to cool to < 20° C. Approximately 20 litres of diethyl ether was added and the resulting mixture was stirred overnight, then filtered to obtain a solid mass which was washed with diethyl ether and dried in vacuo to yield a solid mass which was then vacuum dried to yield 1150 g of the PTSA salt of TGR-1202. HPLC: 99.33% and chiral purity: 99.61:0.39 (S:R).

Table 1 lists the XRPD pattern peaks and relative peak intensities for the products of Examples 1 and 2.

TABLE 1

The tablet composition comprising a PTSA salt of TGR-1202 prepared according to Example 2 exhibited a Cmax about 2.5 fold and an area under the curve (AUC) about 1.9 fold greater than that of the tablet composition comprising a PTSA salt of TGR-1202 prepared according to Example 1. The results are provided in Table 8 below.

TABLE 8

PATENT

WO 2014071125

http://www.google.com/patents/WO2014071125A1?cl=en

formula (A) that is a ΡΒΚδ selective inhibitor,

Figure imgf000004_0001

(A)

Synthesis of Compound of Formula A

Unless otherwise stated, purification implies column chromatography using silica gel as the stationary phase and a mixture of petroleum ether (boiling at 60-80°C) and ethyl acetate or dichloromethane and methanol of suitable polarity as the mobile phases. The term “RT” refers to ambient temperature (25-28°C).

Intermediate 1 : 2-( l-bromoethyl)-6-fluoro-3-f3-fluorophenyl)-4H-chromen-4-one

Step-1 [l-(5-Fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl)ethanone]: 3- Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 ml dichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles) and DMF (3 drops) were added at 0°C and stirred for 30 min. The solvent was evaporated and dissolved in 25 ml dichloromethane. To this mixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to 0°C. At 0°C A1C13 (7.95 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 hours. The reaction mixture was quenched by the addition of 2N HC1, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate :petroleum ether to afford the title compound as colorless solid (4.5 g, 45% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.34 (s, 1H), 7.75 (dd, J=9.4, 3.1 Hz, 1H), 7.42 (m, 2H), 7.12 (m, 3H), 7.05 (dd, J=9.0, 4.5 Hz, 1H), 4.47 (s, 2H).

Step-2 [2-Ethyl-6-fiuoro-3-(3-fluorophenyl)-4H-chromen-4-one]: l-(5-Fluoro-2- hydroxyphenyl)-2-(3-fluorophenyl)ethanone obtained from Step-1 (3.00 g, 12.08 mmoles) was placed in a round bottom flask and to this triethylamine (25 ml) and propionic anhydride (4.92 g, 37.82 mmoles) were added, and the mixture was refluxed for 24 hours. After cooling to RT, the reaction mixture was acidified by the addition of IN HC1 solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate :petroleum ether to afford the title compound as off-yellow solid (1.80 g, 52% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 7.80 (m, 1H), 7.76 (m, 2H), 7.51 (dd, J=8.0, 6.4 Hz), 7.22 (m, 1H), 7.18 (m, 2H), 2.56 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H).

Step-3: To a solution of 2-Ethyl-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one obtained from Step-2 (1.80 g, 6.28 mmoles) in carbon tetrachloride (20 ml), N- bromosuccinimide (1.11 g, 6.28 mmoles) was added and heated to 80°C. Azobisisobutyronitrile (10 mg) was added to the reaction mixture at 80°C. After 12 hours, the reaction mixture was cooled to RT, diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford the crude title compound as yellow solid (1.25 g, 55% yield). 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 7.91 (dd, J=9.2, 4.3 Hz, 1H), 7.81 (dt, j=8.2, 2.8 Hz, 1H), 7.74 (dd, J=8.3, 3.1 Hz, 1H), 7.57 (m, 1H), 7.32 (dt, J=8.5, 2.4 Hz, 1H), 7.19 (m, 2H), 5.00 (q, J=6.8 Hz, 1H), 1.97 (d, J=6.8 Hz, 3H).

Intermediate 2: 6-fluoro-3-f3-fluorophenyl)-2-fl-hvdroxyethyl)-4H-chromen-4-one

Figure imgf000052_0001

To a solution of Intermediate 1 (15.0 g, 40.84 mmol) in DMSO (150 ml), n-butanol (7.5 ml) was added and heated to 120°C for 3 hours. The reaction mixture was cooled to RT, quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (7.90 g, 64%). 1H-NMR (δ ppm, CDC13, 400 MHz): 7.85 (dd, J = 8.1, 3 Hz, 1H), 7.54 (dd, J = 9.2, 4.2 Hz, 1H), 7.47-7.37 (m, 2H), 7.15-6.98 (m, 3H), 4.74 (quintet, J= 6.8 Hz, 1H), 2.23 (d, J = 7.4 Hz, 1H), 1.54 (d, J = 6.6 Hz, 3H).

Intermediate 3 : 2-acetyl-6-fluoro-3-( 3-fluorophenyl)-4H-chromen-4-one

Figure imgf000052_0002

DMSO (5.60 ml, 79.14 mmol) was added to dichloromethane (40 ml), and cooled to – 78°C, followed by oxalyl chloride (3.40 ml, 39.57 mmol). After 10 min., intermediate 2 (6.00 g, 19.78 mmol) in dichloromethane (54 ml) was added dropwise and stirred for 20 min.

Triethylamine (12 ml) was added and stirred for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (4.2 g, 71%) which was used as such in the next step.

Intermediate 4: fS)-6-fluoro-3-f3-fluorophenyl)-2-fl-hvdroxyethyl)-4H-chromen-4-one

Figure imgf000053_0001

To intermediate 3 (2.00 g, 6.66 mmol), R-Alpine borane (0.5 M in THF, 20 ml) was added and heated to 60°C for 20 hours. The reaction mixture quenched with 2N HC1, and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (1.51 g, 75%).

Enantiomeric excess: 94.2%, enriched in the fast eluting isomer (retention time: 8.78 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 5: fR)-l-f6-fluoro-3-f3-fluorophenyl)-4-oxo-4H-chromen-2-yl)ethyl 4- chlorobenzoate

Figure imgf000053_0002

To a solution of intermediate 4 (1.45 g, 4.78 mmol) in THF (15 ml), 4-chlorobenzoic acid (0.748 g, 4.78 mmol) and triphenylphosphine (1.88 g, 7.17 mmol) were added and heated to 45°C followed by diisopropylazodicarboxylate (1.4 ml, 7.17 mmol). After 1 hour, the reaction mixture was concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as an off-white solid (1.81 g, 86%) which was used without purification in the next step. Intermediate 6: fR)-6-fluoro-3-f3-fluorophenyl)-2-fl-hvdroxyethyl)-4H-chromen-4-one

Figure imgf000054_0001

Method A

Intermediate 5 (1.75 g, 3.96 mmol) in methanol (17 ml) was cooled to 10°C, potassium carbonate (0.273 g, 1.98 mmol) was added and stirred for 30 min. The reaction mixture was concentrated, acidified with 2N HCl solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow solid (1.05 g, 87% yield). Enantiomeric excess: 93.6%>, enriched in the late eluting isomer (retention time: 11.12 min.) as determined by HPLC on a chiralpak AD-H column.

Method B

Step-1 [(R)-2-(l-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one]: To l-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl)ethanone (11.00 g, 44.31 mmol) in dichloromethane, HATU (33.7 g, 88.63 mmol) and R-(+)2-benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirred for 10 min. Triethylamine (66.7 ml, 0.47 mol) was added dropwise and stirred at RT for 24 hours. The reaction mixture was quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:

petroleum ether to afford the title compound as a yellow solid (10.5 g, 60%> yield). 1H-NMR (δ ppm, CDCls, 400 MHz): 7.85 (dd, J = 8.1,3 Hz, 1H), 7.58 (dd, J = 9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.07 (m, 1H), 6.99-6.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J = 6.4 Hz, 3H).

Step-2: (R)-2-(l-(benzyloxy)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one obtained in Step-1 (10.5 g, 26.69 mmol) in dichloromethane (110 ml) was cooled to 0°C, aluminium chloride (5.35 g, 40.03 mmol) was added portionwise and stirred at RT for 6 hours. The reaction mixture was quenched with 2N HCl solution, extracted with dichloromethane, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford intermediate 6 a yellow solid (6.1 g, 76% yield). Enantiomeric excess: 97.7%, enriched in the late eluting isomer (retention time: 11.12 min.) as determined by HPLC on a chiralpak AD-H column.

Intermediate 7: 4-bromo-2-fluoro-l-isopropoxybenzene

Figure imgf000055_0001

To a solution of 4-bromo-3-fluorophenol (10 g, 52.35 mmol) in THF (100ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6 g, 78.52 mmol) were added and heated to 45°C followed by diisopropylazodicarboxylate (15.4 ml, 78.52 mmol). The mixture was refluxed for 1 hour, concentrated and the residue was purified by column

chromatography with ethyl acetate: petroleum ether to afford the title compound as a colorless liquid (13.1 g, 99% yield), which was used without purification in the next step.

Intermediate 8: 2-f3-fluoro-4-isopropoxyphenyl)-4,4,5.,5-tetramethyl-l,3i2-dioxaborolane

Figure imgf000055_0002

Potassium acetate (10.52 g, 107.2 mmol) and bis(pinacolato)diboron (15 g, 58.96 mmol) were added to a solution of intermediate 7 (10.52 g, 107.2 mmol) in dioxane (125 ml), and the solution was degassed for 30 min. [l, -Bis(diphenylphosphino)ferrocene]dichloro palladium(II) CH2CI2 (4.4 g, 5.36 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12 hours, the reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow oil (13.9g, 99%) which was used without purification in the next step.

Intermediate 9: 3-f3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3.,4-dlpyrimidin-4-amine

Figure imgf000055_0003

To a solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (11.0 g, 42.14 mmol) in DMF (110 ml), ethanol (55 ml) and water (55 ml), intermediate 8 (23.4 g, 84.28 mmol) and sodium carbonate (13.3 g, 126.42 mmol) were added and degassed for 30 min.

Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.10 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12 hours, the reaction mixture was filtered through celite, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound as light brown solid (3.2 g, 26% yield) which is used as such for the next step.

(RS)- 2-fl-f4-amino-3-f3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3.,4-(ilpyrimi(iin-l- yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

To a solution of intermediate 9 (0.080 g, 0.293 mmol) in DMF (2 ml), potassium carbonate (0.081 g, 0.587 mmol) was added and stirred at RT for 10 min. To this mixture intermediate 1 (0.215 g, 0.587 mmol) was added and stirred for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as a pale yellow solid (0.045 g). MP: 175-177°C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 8.20 (s, 1H), 7.85 (dd, J = 81, 3.0 Hz, 1H), 7.48-7.33 (m, 5H), 7.14 (t, J= 8.3 Hz, 1H), 7.02 (m, 2H), 6.90 (m, 1H), 6.10 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H), 4.64 (quintet, J = 6.0 Hz, 1H), 1.99 (d, J = 7.1 Hz, 3H), 1.42 (d, J= 6.1 Hz, 6H).

fS)-2-fl-f4-amino-3-f3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3.,4-(ilpyrimi(iin-l- yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (“S-isomer”)

To a solution of intermediate 9 (0.134 g, 0.494 mmol) in THF (2.0 ml), intermediate 6 (0.150 g, 0.494 mmol) and triphenylphosphine (0.194 g, 0.741 mml) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate (0.15 ml, 0.749 mmol) was added heated to 45°C. After 2 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as an off-white solid (0.049 g, 20 % yield). MP: 139-142°C. Mass: 571.7 (M+). Enantiomeric excess: 89.8% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 10.64 min.). fR)-2-fl-f4-amino-3-f3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3.,4-(ilpyrimi(iin-l- yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-ehromen-4-one

To a solution of intermediate 8 (0.284 g, 0.989 mmol) in THF (5.0 ml), intermediate 4 (0.250 g, 0.824 mmol) and tris(4-methoxy)phenylphosphine (0.435 g, 1.23 mml) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate (0.25 ml, 1.23 mmol) was added stirred at RT. After 12 hours, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate :

petroleum ether to afford the title compound as an off-white solid (0.105 g, 22 % yield). MP: 145-148°C. Mass: 571.7 (M+). Enantiomeric excess: 95.4% as determined by HPLC on a chiralpak AD-H column, enriched in the late eluting isomer (retention time = 14.83 min.).

PATENT

  

WO 2014006572

http://www.google.com/patents/WO2014006572A1?cl=en

Figure imgf000005_0001B1 IS DESIRED

(S)-2- (l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-6- fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (compound-B l)

Intermediate 11

[119] Intermediate 11: 4-bromo-2-fluoro-l-isopropoxybenzene:To a solution of 4-bromo-2- fluorophenol (lOg, 52.35 mmol) in THF (100ml), isopropyl alcohol (4.8ml, 62.62 mmol) and triphenylphosphine (20.6g, 78.52 mmol) were added and heated to 45 C followed by diisopropylazodicarboxylate (15.4ml, 78 52 mmol). The mixture was refluxed for lh, concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a colourless liquid (13. lg, 99%) which was used without purification in the next step. Intermediate 12

[120] Intermediate 12: 2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane: Potassium acetate (10.52 g, 107.2 mmol) and bis(pinacolato)diboron (15g, 58.96 mmol) were added to a solution of intermediate 11 (10.52 g, 107.2 mmol) in dioxane (125 ml), and the solution was degassed for 30 min. [1,1 ‘- Bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH2Cl2 (4.4g, 5.36 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12h the reaction mixture was filtered through celite and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a yellow oil (13.9g, 99%) which was used without purification in the next step.

Intermediate 13

[121] Intermediate 13: 3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-4- amine: To a solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (11.0 g, 42.14 mmol) in DMF 110 ml), ethanol (55 ml) and water (55 ml), intermediate 12 (23.4 g, 84.28 mmol) and sodium carbonate (13.3 g, 126.42 mmol) were added and degassed for 30 min. Tetrakis(triphenylphosphine)palladium(0) (2.4 g, 2.10 mmol) was added under nitrogen atmosphere and heated to 80°C. After 12h, the reaction mixture was filtered though celite, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was triturated with diethyl ether, filtered and dried under vacuum to afford the title compound as light brown solid (3.2 g, 26% yield) which is used as such for the next step.

Example Bl

(S)-2-(l-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

[127] To a solution of intermediate 13 (0.134 g, 0.494 mmol) in THF (2.0 ml), intermediate 5 (0.150 g, 0.494 mmol) and triphenylphosphine (0.194 g, 0.741 mml) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate ( 0.15 ml, 0.749 mmol) was added heated to 45°C. After 2h, the reaction mixture was quenched with with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate : petroleum ether to afford the title compound as an off-white solid (0.049 g, 20 %). MP: 139- 142°C. Mass : 571.7 (M H-NMR (δ ppm, CDC13, 400 MHz): 8.24 (s, 1H), 7.85 (dd, J = 8.2,3.1 Hz, 1H), 7.50-7.29 (m, 5H), 7.14 (t, J = 8.4 Hz, 1H), 7.02 (m, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.11 (q, J = 7.1 Hz, 1H), 5.40 (s, 2H), 4.66 (quintet, J = 6.1 Hz, 1H), 2.00 (d, J = 7.1Hz, 3H), 1.42 (d, J = 6.1 Hz, 6H). Enantiomeric excess: 89.8% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time = 10.64min.).

PATENT

US 2014/0011819 describe the synthesis of TGR-1202 (Example B l)

http://www.google.co.in/patents/US20140011819

Example B1 (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one

  •  To a solution of intermediate 13 (0.134 g, 0.494 mmol) in THF (2.0 ml), intermediate 5 (0.150 g, 0.494 mmol) and triphenylphosphine (0.194 g, 0.741 mml) were added and stirred at RT for 5 min. Diisopropylazodicarboxylate (0.15 ml, 0.749 mmol) was added heated to 45° C. After 2 h, the reaction mixture was quenched with with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as an off-white solid (0.049 g, 20%). MP: 139-142° C. Mass: 571.7 (M+).1H-NMR (δ ppm, CDCl3, 400 MHz): 8.24 (s, 1H), 7.85 (dd, J=8.2, 3.1 Hz, 1H), 7.50-7.29 (m, 5H), 7.14 (t, J=8.4 Hz, 1H), 7.02 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 6.11 (q, J=7.1 Hz, 1H), 5.40 (s, 2H), 4.66 (quintet, J=6.1 Hz, 1H), 2.00 (d, J=7.1 Hz, 3H), 1.42 (d, J=6.1 Hz, 6H). Enantiomeric excess: 89.8% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time=10.64 min)

4-Methylbenzenesulfonate Salt of Compound B1 (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate

  •  
  • (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one 4-methylbenzenesulfonate: To (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (22.7 g, 39.69 mmol) in isopropanol (600 ml), p-toluenesulphonic acid (8.30 g, 43.66 mmol) was added and refluxed for 1 h. The reaction mixture was concentrated, co-distilled with petroleum ether and dried. To the residue water (300 ml) was added and stirred for 30 min. The solid was filtered, washed with petroleum ether and dried under vacuum to afford the title compound as off-white solid (28.2 g, 95%). MP: 138-141° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.11 (s, 1H), 7.85 (dd, J=8.0, 3.0 Hz, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.51 (dd, J=9.3, 4.3 Hz, 1H), 7.45 (dd, J=7.5, 3.1 Hz, 1H), 7.42-7.31 (m, 3H), 7.29 (m, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.16 (t, J=8.3 Hz, 1H), 7.08 (dt, J=8.5, 2.5 Hz, 1H), 6.97 (br s, 1H), 6.88 (br s, 1H), 6.11 (q, J=7.2 Hz, 1H), 4.67 (quintet, J=6.0 Hz, 1H), 2.36 (s, 3H), 2.03 (d, J=7.1 Hz, 3H), 1.43 (d, J=6.0 Hz, 6H). Mass: 572.4 (M++1-PTSA). Enantiomeric excess: 93.4% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time=12.35 min.)

Sulphate Salt of Compound B1 (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one sulfate

  •  (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one sulphate: To (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one (15.0 g, 26.24 mmol) in isopropanol (600 ml) was cooled to 0° C. To this Sulphuric acid (2.83 g, 28.86 mmol) was added and stirred at room temperature for 24 h. The reaction mass was filtered and washed with petroleum ether and dried under vacuum. To the solid, water (150 ml) was added and stirred for 30 min. The solid was filtered, washed with petroleum ether and dried under vacuum to afford the title compound as off-white solid (13.5 g, 76%). MP: 125-127° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.11 (s, 1H), 7.85 (dd, J=8.0, 3.0 Hz, 1H), 7.51 (dd, J=9.2, 4.2 Hz, 1H), 7.45-7.31 (m, 3H), 7.29 (m, 1H), 7.15 (t, J=8.3 Hz, 1H), 7.08 (dt, J=8.5, 2.4 Hz, 1H), 6.96 (br s, 1H), 6.88 (br s, 1H), 6.09 (q, J=7.1 Hz, 1H), 4.676 (quintet, J=6.1 Hz, 1H), 2.01 (d, J=7.1 Hz, 3H), 1.42 (d, J=6.1 Hz, 6H). Mass: 572.2 (M++1-H2SO4). Enantiomeric excess: 89.6% as determined by HPLC on a chiralpak AD-H column, enriched in the fast eluting isomer (retention time=12.08 min.)
  •  Various other acid addition salts of compound B1 were prepared as provided in Table 1.
  •  TABLE 1   Melting  PointAcidMethod of preparation(° C.) Hydro-Compound B1 (1 eq.) dissolved in THF,130-132chloricexcess HCl/Et2O was added, the clearacidsolution obtained was evaporated completely. The residue obtained was washed with water.p-Compound B1 (1 eq.) dissolved in138-141° C.Toluene-isopropyl alcohol (IPA), refluxed forsulfonic30 min., acid (1.1 eq.) in IPA was added,acidthe clear solution obtained was evaporated completely. The residue obtained was washed with water.Benzene-Compound B1 (1 eq.) dissolved in IPA,170-172sulphonicrefluxed for 30 min., acid(1.1 eq.) in IPAacidwas added, the clear solution not obtained, the residue was evaporated completely and was washed with water.MaleicCompound B1 (1 eq.) dissolved in IPA,107-109acidrefluxed for 30 min., acid (1.1 eq.) in IPA was added, the clear solution not obtained, the residue was evaporated completely and was washed with water.CamphorCompound B1 (1 eq.) dissolved in IPA,120-121sulfonicrefluxed for 30 min., acid (1.1 eq.) in IPAacidwas added, the clear solution not obtained, the residue was evaporated completely and was washed with water.SulphuricCompound B1 (1 eq.) dissolved in IPA,125-127acidrefluxed for 30 min., acid(1.1 eq.) in IPA was added, the clear solution obtained was evaporated completely. The residue obtained was washed with water.

REFERENCES

WO 2014/006572 and U.S. Patent Publication No. 2014/0011819,

http://www.tgtherapeutics.com/O’ConnorTGR202Single%20AgentEHA&Lugano2015.pdf

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PatentSubmittedGranted
NOVEL SELECTIVE PI3K DELTA INHIBITORS [US2014011819]2013-07-022014-01-09
Treatment Of Cancers Using PI3 Kinase Isoform Modulators [US2014377258]2014-05-302014-12-25

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CC(C)OC1=C(C=C(C=C1)C2=NN(C3=C2C(=NC=N3)N)C(C)C4=C(C(=O)C5=C(O4)C=CC(=C5)F)C6=CC(=CC=C6)F)F

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