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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYDMSWVRQA PGKGLEWVST ISGGGSYTYY
QDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCASPY YAMDYWGQGT TVTVSSASTK
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)
DIQLTQSPSF LSAYVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW ASTLHTGVPS
RFSGSGSGTE FTLTISSLQP EDFATYYCQH YSSYPWTFGQ GTKLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGLEWVSTISGGGSYTYY
QDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASPYYAMDYWGQGTTVTVSSASTK
GPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS
LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFP
PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS
VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVS
LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFS
CSVMHEALHNHYTQKSLSLSLGK
>Light Chain
DIQLTQSPSFLSAYVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTLHTGVPS
RFSGSGSGTEFTLTISSLQPEDFATYYCQHYSSYPWTFGQGTKLEIKRTVAAPSVFIFPP
SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT
LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
References:
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]

Dostarlimab

Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
FormulaC6420H9832N1680O2014S44
CAS2022215-59-2
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21

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Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

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

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]

History

Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]

References[

  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at ClinicalTrials.gov
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at ClinicalTrials.gov
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – Drugs.com MedNews”Drugs.com. Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at ClinicalTrials.gov
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetPCDP1
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
administration
Intravenous
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2022215-59-2
PubChem SID384585344
DrugBankDB15627
UNIIP0GVQ9A4S5
KEGGD11366
Chemical and physical data
FormulaC6420H9832N1690O2014S44
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021

DEXMETHYLPHENIDATE


Dexmethylphenidate structure.svg

DEXMETHYLPHENIDATE

SynonymsDexmethylphenidate HCl, UNII1678OK0E08, CAS Number19262-68-1, WeightAverage: 269.77
Chemical FormulaC14H20ClNO2

methyl (2R)-2-phenyl-2-[(2R)-piperidin-2-yl]acetate hydrochloride

Thumb
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08

Trade Name:Focalin® / Attenade®MOA:Norepinephrine-dopamine reuptake inhibitorIndication:Attention deficit hyperactivity disorder (ADHD)Status:ApprovedCompany:Novartis (Originator) , CelgeneSales:$365 Million (Y2015); 
$492 Million (Y2014);
$594 Million (Y2013);
$554 Million (Y2012);
$550 Million (Y2011);ATC Code:N06BA11

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-05-26New dosage formFocalin XRAttention deficit hyperactivity disorder (ADHD)Capsule, Extended release5 mg/10 mg/15 mg/20 mg/25 mg/30 mg/35 mg/40 mgNovartis 
2001-11-13Marketing approvalFocalinAttention deficit hyperactivity disorder (ADHD)Tablet2.5 mg/5 mg/10 mgNovartis

Dexmethylphenidate hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on Nov 13, 2001. It was developed and marketed as Focalin® by Novartis in the US.

Dexmethylphenidate hydrochloride is a norepinephrine-dopamine reuptake inhibitor (NDRI). It is indicated for the treatment of attention deficit hyperactivity disorder (ADHD).

Focalin® is available as tablet for oral use, containing 2.5 mg, 5 mg or 10 mg of Dexmethylphenidate hydrochloride. The recommended dose is 10 mg twice daily, at least 4 hours apart.

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Drug Product Name Serdexmethylphenidate and Dexmethylphenidate (SDX/d-MPH)

Dosage Form capsule Strength 26.1/5.2 mg SDX/d-MPH 39.2/7.8 mg SDX/d-MPH 52.3/10.4 mg SDX/d-MPH

Route of Administration oral

Rx/OTC Dispensed Rx

Maximum Daily Dose 52.3 mg serdexmethylphenidate /10.4 mg dmethylphenidate as free base or 56 mg serdexmethylphenidate Chlorid

Dexmethylphenidate, sold under the brand name Focalin among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years.[3] If no benefit is seen after four weeks it is reasonable to discontinue its use.[3] It is taken by mouth.[3] The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours.[4]

Common side effects include abdominal pain, loss of appetite, and fever.[3] Serious side effects may include abusepsychosissudden cardiac deathmaniaanaphylaxisseizures, and dangerously prolonged erection.[3] Safety during pregnancy and breastfeeding is unclear.[5] Dexmethylphenidate is a central nervous system (CNS) stimulant.[6][3] How it works in ADHD is unclear.[3] It is the more active enantiomer of methylphenidate.[3]

Dexmethylphenidate was approved for medical use in the United States in 2001.[1] It is available as a generic medication.[3] In 2018, it was the 156th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[7][8] It is also available in Switzerland.[9]

SYNRoute 1

Reference:1. US6528530B2.

2. J. Org. Chem. 1998, 63, 9628-9629.Route 2

Reference:1. J. Am. Chem. Soc. 1999, 121,6509-6510.Route 3

Reference:1. Org. Process Res. Dev. 201014, 1473–1475.Route 4

Reference:1. J. Med. Chem. 1998, 41,591-601.Route 5

Reference:1. Org. Lett. 19991, 175-178.

2. Organic Syntheses 198563, 206-212.

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.[102][124] The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. “TMP” refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2′R)-(+)-threo-methylphenidate hydrochloride has been published.[125]Methylphenidate synthesis

Methylphenidate synthesis graphic

Method 1: Methylphenidate preparation elucidated by Axten et al. (1998)[126] via Bamford-Stevens reaction.

Methylphenidate synthesis graphic

Method 2: Classic methylphenidate synthesis[127]

Methylphenidate synthesis graphic

Method 3: Another synthesis route of methylphenidate which applies Darzens reaction to obtain aldehyde as an intermediate. This route is significant for its selectivity.SYNhttps://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705SUN

1.9 Synthesis of (R, R), (R, S), (S, S) and (S, R) methyl 2-piperidin-2-yl-phenylacetate hydrochloride (1a1b1c and 1d)

Compound 8a8b8c or 8d (400 mg, 1.3 mmol) was dissolved into methanol solution (15 mL), and then thionyl chloride (1 mL) was added drop-wise. The reaction mixture was stirred for 12 hours and concentrated in vacuum; a white solid was precipitated and filtered to afford the final product. (1a. 0.28 g, 82% yield; 1b. 0.30 g, 84% yield; 1c. 0.31 g, 85% yield; 1d. 0.30 g, 84% yield). The characterization data of the four final products had been reported [2] by us in 2016.

SYN

https://patents.google.com/patent/US20040180928A1/en

  • Dexmethylphenidate, also known as d-threo-methylphenidate, (R,R)-methylphenidate or (R,R)-α-phenyl-2-piperidineacetic acid methyl ester, having the formula:
  • [0029]
    is CNS (central nervous system) stimulant that is chemically and pharmacologically similar to the amphetamines. Dexmethylphenidate’s CNS actions is milder than those of the amphetamines and have more noticeable effects on mental activities than on motor activities.
  • [0030]
    It has been reported by Sporzny (1961) that among racemic mixtures of threo and erythro diastereomers of methylphenidate, only threo-isomer displays stimulant properties. Dexmethylphenidate hydrochloride (i.e. the d-threo enantiomer of methylphenidate hydrochloride) has been reported to be 5 to 38 times more active than the corresponding (S,S)-methylphenidate hydrochloride (Prashad 2000).
  • [0031]
    A commercially available drug is sold under the name Focalin™ (Novartis) and it consists of dexmethylphenidate in the form of the hydrochloride salt. This product is orally administered and clinically used in the treatment of narcolepsy and as adjunctive treatment in children with attention deficit disorder (ADD) and attention-deficit hyperactivity disorder (ADHD).
  • [0032]
    A synthesis of dexmethylphenidate hydrochloride was firstly described in U.S. Pat. No. 2,838,519 and include resolution of erythro-α-phenyl-2-piperidineacetamide to obtain enantiopure (2R,2′S)-α-phenyl-2-piperidineacetamide, which was subjected to epimerization, hydrolysis, and esterification as shown in Scheme 1:
  • [0033]
    Related example of preparation of dexmethylphenidate from erythro-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,936,091.
  • [0034]
    Preparation of dexmethylphenidate through optical resolution of threo-α-phenyl-2-piperidineacetamide was described in U.S. Pat. No. 5,965,734, as shown in Scheme 2:
  • [0035]
    Synthetic methods for the preparation of racemic mixture of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of dexmethylphenidate were described by Panizzon (1944) and Patric (1982) and in U.S. Pat. Nos. 2,507,631, 2,838,519, 2,957,880 and 5,936,091, and in WO 01/27070. These methods include using sodium amide as base in the nucleophilic substitution of chlorine in 2-chloropyridine with phenylacetonitrile followed by hydrolysis of the formed nitrile and reduction of a pyridine ring to a piperidine one by hydrogenation on PtO catalyst, as shown in Scheme 3:
  • [0036]
    Alternatively, 2-bromopyridine was used instead of 2-chloropyridine by Deutsch (1996).
  • [0037]
    In some other methods threo-methylphenidate was used as the raw material for the preparation of dexmethylphenidate. Threo-methylphenidate may be prepared by a several routes, inter alia by the following two processes:
  • [0038]
    i) by esterification of threo-ritalinic acid which may be prepared from erythro-enriched and threo-α-phenyl-2-piperidineacetamides as shown in Scheme 4:
  • [0039]
    ii) by cyclization of easily available 1-(phenylglyoxylyl)piperidine arenesulfonylhydrazone to (R*,R*)-enriched 7-phenyl-1-azabicyclo[4.2.0]octan-8-one and further converting the β-lactam to threo-methylphenidate hydrochloride, as described by Axten (1998), Corey (1965) and Earle (1969) and in WO 99/36403 and shown in Scheme 5:
  • [0040]
    The resolution of threo-methylphenidate to afford dexmethylphenidate was first reported by Patric (1987) which used (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate as the resolving agent. Several new resolutions of threo-methylphenidate have been reported recently by Prashad (1999) and in U.S. Pat. Nos. 6,100,401, 6,121,453, 6,162,919 and 6,242,464 as described in Scheme 6:
  • [0041]
    wherein the chiral acid is one of the following: (R)-(−)-binaphthyl-2,2′-diyl hydrogen phosphate, (−)-menthoxyacetic acid, ditoluoyl-D-tartaric acid or dibenzoyl-D-tartaric acid.
  • [0042]
    Resolution of threo-methylphenidate may be also achieved by enzymatic hydrolysis methods as proposed by Prashad (1998) and in WO 98/25902. Such resolution is described in Scheme 7:
  • [0043]
    Resolution of threo-ritalinic acid hydrochloride with (S)-1-phenylethylamine give complex salt (R,R)-enriched threo-ritalinic acid.HCl.(S)-1-phenylethylamine with 77% ee optical purity of ritalinic acid (U.S. Ser. No. 2002/0019535), Scheme 8: 
  • [0119]
  • [0120]
    Gaseous hydrogen chloride was passed through a boiling solution of (R,R)-N-Boc-ritalinic acid (95.4 g, 299 mmol) in methanol (1.5 L). The mixture was stirred for 12 hours under reflux conditions and concentrated to the volume of 250 mL. Toluene (750 mL) was added to the stirred residue, then methanol lo was removed from boiling suspension under normal pressure. The obtained mixture was stirred overnight at 0-5° C. The precipitated solids were filtered off, washed on the filter with toluene (3×50 mL) and dried under reduced pressure to give 78.4 g (97.2% yield) of dexmethylphenidate hydrochloride as white crystals with mp 222-224° C. and [α]D 25 87.0° (c=1, MeOH).
  • [0117]
  • [0118]
    A mixture of crystalline salt of (R,R)-N-Boc-ritalinic acid and (S)-1-phenylamine with [α]D 20 −28.6° (c=1, MeOH) (133.0 g, 302 mmol), ethyl acetate (1.3 L) and solution of citric acid (164.0 g, 845 mmol) in water (1.3 L) was stirred at 15-25° C. for 1.5 hours. The organic layer was separated, washed lo with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to give 95.4 g (99%) of (R,R)-N-B
  • [0115]
  • [0116]
    (S)-1-Phenylethylamine (113.8 g, 0.94 mol, 0.6 eq) was added dropwise to a stirred solution of N-Boc-threo-ritalinic acid (500 g, 1.57 mol, 1 eq) in ethyl acetate (5 L) for 1 hour at 20-40° C. The mixture was stirred for 1 hour at 40° C. and overnight at 5° C. The precipitated solids were filtered off, washed on the lo filter with cold ethyl acetate (2×500 mL) and dried under reduced pressure to give 380 g of white crystals with [α]D 20−23.3° (c=1, MeOH). The salt was twice recrystallized from aqueous methanol. The precipitated crystals were filtered off, washed on the filter with cold aqueous methanol and dried under reduced pressure to a constant weight to give 265 g (33.5% yield) of salt of (R,R)-N-Boc-ritalinic acid and (S)
  • [0113]
  • [0114]
    A mixture of solution of N-Boc-threo-ritalinic acid sodium salt (1700 g, 4.98 mmol), citric acid (1150 g, 5.98 mmol) and water (5 mL) was stirred at 15-25° C. for 0.5 hour and extracted with ethyl acetate (3×4 L). Combined organic extracts were washed with brine (2×3 L), dried over sodium sulfate, filtered and evaporated under reduced pressure to constant weight to give 1560 g (98.1% yield) of N-Boc-threo-ritalinic acid with mp 133-134° C. (EtOAc/hexane) and 99.8% purity by HPLC.

Medical uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[6]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[6] It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.[6]

CLIP

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride 

Long-Xuan Xing, Cheng-Wu Shen, Yuan-Yuan Sun, Lei Huang, Yong-Yong Zheng,* Jian-Qi Li*

https://onlinelibrary.wiley.com/doi/abs/10.1002/jhet.2705

The present work describes an efficient and commercially viable process for the synthesis of dexmethylphenidate hydrochloride (1), a mild nervous system stimulant. The overall yield is 23% with ~99.9% purity (including seven chemical steps). Formation and control of possible impurities are also described in this report.

An Improved and Efficient Process for the Production of Highly Pure Dexmethylphenidate Hydrochloride - Xing - 2017 - Journal of Heterocyclic Chemistry - Wiley Online Library

(R)-methyl 2-phenyl-2-((R)-piperidin-2-yl)acetate hydrochloride (1). ………… afford 1 as a white solid (107.6 g, 87.3% yield) with 99.50% purity and 99.70% ee. The crude product (107.6 g, 0.4 mol) was further purified by recrystallization from pure water (100 mL) to obtain the qualified product 1 (98.3 g, 91.4% yield) with 99.92 purity and 99.98% ee.

[α] 25 D +85.6 (MeOH, c 1) (lit [4b]. [α] 25 D +84 (MeOH, c 1));

Mp 222-223 C (lit [4b]. Mp 222– 224°C); MS m/z 234 [M + H]+ .

1 H NMR (400Hz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (br, 1H), 8.97 (br, 1H), 7.41-7.26 (m, 5H), 4.18-4.16 (d, J = 9.2Hz, 1H), 3.77-3.75 (m, 1H), 3.66 (s, 3H), 3.25 (m, 1H), 2.94 (m, 1H), 1.67-1.64 (m, 3H), 1.41-1.25 (m, 3H).

13C NMR (100.6 MHz, DMSO-d6) δ 171.3, 134.2, 129.1, 128.6, 128.2, 56.8, 53.3, 52.6, 44.5, 25.7, 21.5, 21.4.

1H-NMR, and 13C-NMR of compound 1………………………………….. 10-11

DEPT,

COSY, NOESY, GHMBC, and HMQC of compound 1……………… 12-14

COSY

NOESY

GHMBC

HMQC

Contraindications

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, ticsglaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.[10]

The US Food and Drug Administration (FDA) gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[11] Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development.[12] In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.[13]

Adverse effects

Part of this section is transcluded from Methylphenidate. (edit | history)

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[14]

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.[15]

The most common adverse effects include appetite lossdry mouthanxiety/nervousnessnausea, and insomniaGastrointestinal adverse effects may include abdominal pain and weight lossNervous system adverse effects may include akathisia (agitation/restlessness), irritabilitydyskinesia (tics), lethargy (drowsiness/fatigue), and dizzinessCardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), and tachycardia (rapid heart rate).[16] Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.[17] Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis.[18]

There is some evidence of mild reductions in height with prolonged treatment in children.[19] This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.[20][21]

Hypersensitivity (including skin rashurticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.[22]

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms.[23] It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania.[24] There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link.[19] Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.[25]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden deathheart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.[26]

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.[27]

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death; the certainty of the evidence was stated as very low and the actual risk might be higher.[28]

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Addiction and dependence[edit]

ΔFosB accumulation from excessive drug use 
Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-FosFosBΔFosBFra1, and Fra2).
Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.[33][34]

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs;[35][36] accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug.[36][37] When used above the medical dose range, stimulants are associated with the development of stimulant psychosis.[38] As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction.[37][39]

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine.[40] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction[41][42][43][44] in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction, or psychological dependence has not been proven and further research is needed.[45]

Biomolecular mechanisms

Further information: Addiction § Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain’s reward system.[39] At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens;[36][39][46] consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction.[36][39][46] However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens.[36][39] Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.[39][46][47]

Overdose

This section is transcluded from Methylphenidate. (edit | history)

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomitingnauseaagitationtremorshyperreflexia, muscle twitching, euphoria, confusion, hallucinations, deliriumhyperthermia, sweating, flushing, headache, tachycardiaheart palpitationscardiac arrhythmiashypertensionmydriasis, and dryness of mucous membranes.[29][30] A severe overdose may involve symptoms such as hyperpyrexiasympathomimetic toxidromeconvulsionsparanoiastereotypy (a repetitive movement disorder), rapid muscle breakdowncoma, and circulatory collapse.[29][30][31] A methylphenidate overdose is rarely fatal with appropriate care.[31] Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.[32]

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychoticsα-adrenoceptor agonists and propofol serving as second-line therapies.[31]

Interactions

This section is transcluded from Methylphenidate. (edit | history)

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations.[48] There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.[49][50][51][52]

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[53][54] not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.[55][54]

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[56]

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.[57]

Mode of activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[58] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[59] Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”[2]

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate.[60][61] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[58][62]

Compd[63]DAT (Ki)DA (IC50)NET (Ki)NE (IC50)
D-TMP1612320639
L-TMP22501600>10K980
DL-TMP1212078851

Pharmacology

Main article: Methylphenidate § Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect (a long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.[64][65]) It has also been demonstrated to reduce ADHD symptoms in both children[66] and adults.[67] d-MPH has a similar side-effect profile to MPH[14] and can be administered without regard to food intake.[68]

 

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  34. ^ Nestler EJ (December 2012). “Transcriptional mechanisms of drug addiction”Clinical Psychopharmacology and Neuroscience10 (3): 136–43. doi:10.9758/cpn.2012.10.3.136PMC 3569166PMID 23430970The 35–37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. … As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. … ΔFosB overexpression in nucleus accumbens induces NFκB
  35. ^ Morton WA, Stockton GG (2000). “Methylphenidate Abuse and Psychiatric Side Effects”Prim Care Companion J Clin Psychiatry2 (5): 159–164. doi:10.4088/PCC.v02n0502PMC 181133PMID 15014637.
  36. Jump up to:a b c d e Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 368. ISBN 9780071481274Cocaine, [amphetamine], and methamphetamine are the major psychostimulants of abuse. The related drug methylphenidate is also abused, although it is far less potent. These drugs elicit similar initial subjective effects ; differences generally reflect the route of administration and other pharmacokinetic factors. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
  37. Jump up to:a b Steiner H, Van Waes V (January 2013). “Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants”Prog. Neurobiol100: 60–80. doi:10.1016/j.pneurobio.2012.10.001PMC 3525776PMID 23085425.
  38. ^ Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL (2005). “Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study”Sleep28 (6): 667–72. doi:10.1093/sleep/28.6.667PMID 16477952.
  39. Jump up to:a b c d e f Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (2009). “Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens”Proc. Natl. Acad. Sci. U.S.A106 (8): 2915–20. Bibcode:2009PNAS..106.2915Kdoi:10.1073/pnas.0813179106PMC 2650365PMID 19202072Despite decades of clinical use of methylphenidate for ADHD, concerns have been raised that long-term treatment of children with this medication may result in subsequent drug abuse and addiction. However, meta analysis of available data suggests that treatment of ADHD with stimulant drugs may have a significant protective effect, reducing the risk for addictive substance use (36, 37). Studies with juvenile rats have also indicated that repeated exposure to methylphenidate does not necessarily lead to enhanced drug-seeking behavior in adulthood (38). However, the recent increase of methylphenidate use as a cognitive enhancer by the general public has again raised concerns because of its potential for abuse and addiction (3, 6–10). Thus, although oral administration of clinical doses of methylphenidate is not associated with euphoria or with abuse problems, nontherapeutic use of high doses or i.v. administration may lead to addiction (39, 40).
  40. ^ Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J (2008). “Pharmacotherapy of methamphetamine addiction: an update”Substance Abuse29 (3): 31–49. doi:10.1080/08897070802218554PMC 2597382PMID 19042205.
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  42. ^ Gorelick DA, Gardner EL, Xi ZX (2004). “Agents in development for the management of cocaine abuse”Drugs64 (14): 1547–73. doi:10.2165/00003495-200464140-00004PMID 15233592S2CID 5421657Archived from the original on 1 July 2019. Retrieved 1 July 2019.
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  46. Jump up to:a b c Nestler EJ (December 2013). “Cellular basis of memory for addiction”Dialogues in Clinical Neuroscience15 (4): 431–43. doi:10.31887/DCNS.2013.15.4/enestlerPMC 3898681PMID 24459410Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature has demonstrated that such ΔFosB induction in D1-type NAc neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement … Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.4
  47. ^ Ruffle JK (November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. The American Journal of Drug and Alcohol Abuse40 (6): 428–37. doi:10.3109/00952990.2014.933840PMID 25083822S2CID 19157711
    The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. …
    Conclusions
    ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch(34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.

     Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T (2012). “Epigenetic regulation in drug addiction”. Annals of Agricultural and Environmental Medicine19(3): 491–6. PMID 23020045For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken … In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription
     Robison AJ, Nestler EJ (October 2011). “Transcriptional and epigenetic mechanisms of addiction”Nature Reviews. Neuroscience12 (11): 623–37. doi:10.1038/nrn3111PMC 3272277PMID 21989194ΔFosB has been linked directly to several addiction-related behaviors … Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
  48. ^ “Concerta product monograph” (PDF). Janssen Pharmaceuticals. Archived (PDF) from the original on 28 January 2017. Retrieved 4 December 2016.
  49. ^ Ishii M, Tatsuzawa Y, Yoshino A, Nomura S (April 2008). “Serotonin syndrome induced by augmentation of SSRI with methylphenidate”. Psychiatry and Clinical Neurosciences62 (2): 246. doi:10.1111/j.1440-1819.2008.01767.xPMID 18412855S2CID 5659107.
  50. ^ Türkoğlu S (2015). “Serotonin syndrome with sertraline and methylphenidate in an adolescent”. Clinical Neuropharmacology38(2): 65–6. doi:10.1097/WNF.0000000000000075PMID 25768857.
  51. ^ Park YM, Jung YK (May 2010). “Manic switch and serotonin syndrome induced by augmentation of paroxetine with methylphenidate in a patient with major depression”. Progress in Neuro-Psychopharmacology & Biological Psychiatry34 (4): 719–20. doi:10.1016/j.pnpbp.2010.03.016PMID 20298736S2CID 31984813.
  52. ^ Bodner RA, Lynch T, Lewis L, Kahn D (February 1995). “Serotonin syndrome”. Neurology45 (2): 219–23. doi:10.1212/wnl.45.2.219PMID 7854515S2CID 35190429.
  53. ^ Patrick KS, González MA, Straughn AB, Markowitz JS (2005). “New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder”. Expert Opinion on Drug Delivery2(1): 121–43. doi:10.1517/17425247.2.1.121PMID 16296740S2CID 25026467.
  54. Jump up to:a b Markowitz JS, DeVane CL, Boulton DW, Nahas Z, Risch SC, Diamond F, Patrick KS (2000). “Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol”. Drug Metabolism and Disposition28 (6): 620–4. PMID 10820132.
  55. ^ Markowitz JS, Logan BK, Diamond F, Patrick KS (1999). “Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion”. Journal of Clinical Psychopharmacology19 (4): 362–6. doi:10.1097/00004714-199908000-00013PMID 10440465.
  56. ^ Patrick KS, Straughn AB, Minhinnett RR, Yeatts SD, Herrin AE, DeVane CL, Malcolm R, Janis GC, Markowitz JS (March 2007). “Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics”Clinical Pharmacology and Therapeutics81 (3): 346–53. doi:10.1038/sj.clpt.6100082PMC 3188424PMID 17339864.
  57. ^ Roberts SM, DeMott RP, James RC (1997). “Adrenergic modulation of hepatotoxicity”. Drug Metab. Rev29 (1–2): 329–53. doi:10.3109/03602539709037587PMID 9187524.
  58. Jump up to:a b Markowitz JS, Patrick KS (June 2008). “Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?”. Journal of Clinical Psychopharmacology28 (3 Suppl 2): S54-61. doi:10.1097/JCP.0b013e3181733560PMID 18480678.
  59. ^ Schweri MM, Skolnick P, Rafferty MF, Rice KC, Janowsky AJ, Paul SM (October 1985). “[3H]Threo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters”. Journal of Neurochemistry45 (4): 1062–70. doi:10.1111/j.1471-4159.1985.tb05524.xPMID 4031878S2CID 28720285.
  60. ^ Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, et al. (May 1997). “Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain”Psychopharmacology131 (1): 71–8. doi:10.1007/s002130050267PMID 9181638S2CID 26046917.
  61. ^ Ding YS, Gatley SJ, Thanos PK, Shea C, Garza V, Xu Y, et al. (September 2004). “Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration”. Synapse53 (3): 168–75. CiteSeerX 10.1.1.514.7833doi:10.1002/syn.20046PMID 15236349S2CID 11664668.
  62. ^ Davids E, Zhang K, Tarazi FI, Baldessarini RJ (February 2002). “Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning”. Psychopharmacology160 (1): 92–8. doi:10.1007/s00213-001-0962-5PMID 11862378S2CID 8037050.
  63. ^ Williard RL, Middaugh LD, Zhu HJ, Patrick KS (February 2007). “Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity”. Behavioural Pharmacology18 (1): 39–51. doi:10.1097/FBP.0b013e3280143226PMID 17218796S2CID 20232871.
  64. ^ McGough JJ, Pataki CS, Suddath R (July 2005). “Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder”. Expert Review of Neurotherapeutics5 (4): 437–41. doi:10.1586/14737175.5.4.437PMID 16026226S2CID 6561452.
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  66. ^ Arnold LE, Lindsay RL, Conners CK, Wigal SB, Levine AJ, Johnson DE, et al. (Winter 2004). “A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder”. Journal of Child and Adolescent Psychopharmacology14 (4): 542–54. doi:10.1089/cap.2004.14.542PMID 15662146.
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External links

Clinical data
Trade namesFocalin, Focalin XR, Attenade, others
Other namesd-threo-methylphenidate (D-TMP)
AHFS/Drugs.comMonograph
MedlinePlusa603014
License dataUS DailyMedDexmethylphenidate
Dependence
liability
Physical: None Psychological: High
Routes of
administration
By mouth
ATC codeN06BA11 (WHO)
Legal status
Legal statusAU: S8 (Controlled drug)CASchedule IIIDEAnlage III (Special prescription form required)UK: Class BUS: Schedule II [1][2]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability11–52%
Protein binding30%
MetabolismLiver
Elimination half-life4 hours
ExcretionKidney
Identifiers
showIUPAC name
CAS Number40431-64-9 as HCl: 19262-68-1
PubChem CID154101as HCl: 154100
IUPHAR/BPS7554
DrugBankDB06701 as HCl: DBSALT001458
ChemSpider135807 as HCl: 135806
UNIIM32RH9MFGPas HCl: 1678OK0E08
KEGGD07806 as HCl: D03721 
ChEBICHEBI:51860 
ChEMBLChEMBL827 as HCl: ChEMBL904
CompTox Dashboard (EPA)DTXSID70893769 
Chemical and physical data
FormulaC14H19NO2
Molar mass233.311 g·mol−1
3D model (JSmol)Interactive imageas HCl: Interactive image
showSMILES
showInChI

///////////DEXMETHYLPHENIDATE, FDA 2021, APPROVALS 2021

Cl.[H][C@@](C(=O)OC)(C1=CC=CC=C1)[C@@]1([H])CCCCN1

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Sacituzumab govitecan-hziy


TRODELVY structure
Sacituzumab govitecan.png
Sacituzumab govitecan.png
Sacituzumab Govitecan for Metastatic Triple-Negative Breast Cancer -  National Cancer Institute

Sacituzumab govitecan-hziy

1601.8 g/mol

C76H104N12O24S

(2R)-2-amino-3-[1-[[4-[[1-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[2-[2-[[(2S)-6-amino-1-[4-[[(19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-19-yl]oxycarbonyloxymethyl]anilino]-1-oxohexan-2-yl]amino]-2-oxoethoxy]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylcarbamoyl]cyclohexyl]methyl]-2,5-dioxopyrrolidin-3-yl]sulfanylpropanoic acid

Trodelvy 

  • hRS 7SN38
  • hRS7-SN38
  • IMMU 132
  • IMMU-132

CAS: 1491917-83-9

M9BYU8XDQ6

EX-A4354

UNII-DA64T2C2IO component ULRUOUDIQPERIJ-PQURJYPBSA-N

UNII-SZB83O1W42 component ULRUOUDIQPERIJ-PQURJYPBSA-N

EfficacyAntineoplastic, Topoisomerase I inhibitor
  DiseaseBreast cancer (triple negative)
sacituzumab govitecan-hziy Archives | Access Market Intelligence

Sacituzumab Govitecan is an antibody drug conjugate containing the humanized monoclonal antibody, hRS7, against tumor-associated calcium signal transducer 2 (TACSTD2 or TROP2) and linked to the active metabolite of irinotecan7-ethyl-10-hydroxycamptothecin (SN-38), with potential antineoplastic activity. The antibody moiety of sacituzumab govitecan selectively binds to TROP2. After internalization and proteolytic cleavage, SN-38 selectively stabilizes topoisomerase I-DNA covalent complexes, resulting in DNA breaks that inhibit DNA replication and trigger apoptosis. TROP2, also known as epithelial glycoprotein-1 (EGP-1), is a transmembrane calcium signal transducer that is overexpressed by a variety of human epithelial carcinomas; this antigen is involved in the regulation of cell-cell adhesion and its expression is associated with increased cancer growth, aggressiveness and metastasis.

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https://www.businesswire.com/news/home/20210407006027/en/FDA-Approves-Trodelvy%C2%AE-the-First-Treatment-for-Metastatic-Triple-Negative-Breast-Cancer-Shown-to-Improve-Progression-Free-Survival-and-Overall-Survival?fbclid=IwAR16bUSCbkK98d8j01NNKVnJ-7r8nHSvCOGE4ogCp_Aex79mNh8AOwQFIQc

FDA Approves Trodelvy®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival

– Trodelvy Significantly Reduced the Risk of Death by 49% Compared with Single-Agent Chemotherapy in the Phase 3 ASCENT Study –

– Trodelvy is Under Regulatory Review in the EU and in the United Kingdom, Canada, Switzerland and Australia as Part of Project Orbis April 07, 2021 07:53 PM Eastern Daylight Time

FOSTER CITY, Calif.–(BUSINESS WIRE)–Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has granted full approval to Trodelvy® (sacituzumab govitecan-hziy) for adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. The approval is supported by data from the Phase 3 ASCENT study, in which Trodelvy demonstrated a statistically significant and clinically meaningful 57% reduction in the risk of disease worsening or death (progression-free survival (PFS)), extending median PFS to 4.8 months from 1.7 months with chemotherapy (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001). Trodelvy also extended median overall survival (OS) to 11.8 months vs. 6.9 months (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001), representing a 49% reduction in the risk of death.

Trodelvy is directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including TNBC, where high expression is associated with poor survival and relapse. Prior to the FDA approval of Trodelvy, patients with previously treated metastatic TNBC had few treatment options in this high unmet-need setting. The FDA granted accelerated approval to Trodelvy in April 2020 based on objective response rate and duration of response results in a Phase 1/2 study. Today’s approval expands the previous Trodelvy indication to include treatment in adult patients with unresectable locally advanced or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for metastatic disease.

“Women with triple-negative breast cancer have historically had very few effective treatment options and faced a poor prognosis,” said Aditya Bardia, MD, MPH, Director of Breast Cancer Research Program, Mass General Cancer Center and Assistant Professor of Medicine at Harvard Medical School, and global principal investigator of the ASCENT study. “Today’s FDA approval reflects the statistically significant survival benefit seen in the landmark ASCENT study and positions sacituzumab govitecan-hziy as a potential standard of care for pre-treated TNBC.”

“A metastatic TNBC diagnosis is frightening. As an aggressive and difficult-to-treat disease, it’s a significant advance to have an FDA-approved treatment option with a proven survival benefit for patients with metastatic disease that continues to progress,” said Ricki Fairley, Founder and CEO of Touch, the Black Breast Cancer Alliance. “For far too long, people with metastatic TNBC had very few treatment options. Today’s news continues the progress of bringing more options to treat this devastating disease.”

Among all patients evaluable for safety in the ASCENT study (n=482), Trodelvy had a safety profile consistent with the previously approved FDA label. The most frequent Grade ≥3 adverse reactions for Trodelvy compared to single-agent chemotherapy were neutropenia (52% vs. 34%), diarrhea (11% vs. 1%), leukopenia (11% vs. 6%) and anemia (9% vs. 6%). Adverse reactions leading to treatment discontinuation occurred in 5% of patients receiving Trodelvy.

“Today’s approval is the culmination of a multi-year development program and validates the clinical benefit of this important treatment in metastatic TNBC,” said Merdad Parsey, MD, PhD, Chief Medical Officer, Gilead Sciences. “Building upon this milestone, we are committed to advancing Trodelvy with worldwide regulatory authorities so that, pending their decision, Trodelvy may become available to many more people around the world who are facing this difficult-to-treat cancer.”

Regulatory submissions for Trodelvy in metastatic TNBC have been filed in the United Kingdom, Canada, Switzerland and Australia as part of Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners, as well as in Singapore through our partner Everest Medicines.The European Medicines Agency has also validated a Marketing Authorization Application for Trodelvy in the European Union. All filings are based on data from the Phase 3 ASCENT study.

Trodelvy Boxed Warning

The Trodelvy U.S. Prescribing Information has a BOXED WARNING for severe or life-threatening neutropenia and severe diarrhea; see below for Important Safety Information.

About Trodelvy

Trodelvy (sacituzumab govitecan-hziy) is a first-in-class antibody and topoisomerase inhibitor conjugate directed to the Trop-2 receptor, a protein frequently expressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (TNBC), where high expression is associated with poor survival and relapse.

Trodelvy is also being developed as an investigational treatment for metastatic urothelial cancer, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER 2-) metastatic breast cancer and metastatic non-small cell lung cancer. Additional evaluation across multiple solid tumors is also underway.

About Triple-Negative Breast Cancer (TNBC)

TNBC is an aggressive type of breast cancer, accounting for approximately 15% of all breast cancers. The disease is diagnosed more frequently in younger and premenopausal women and is more prevalent in African American and Hispanic women. TNBC cells do not have estrogen and progesterone receptors and have limited HER 2. Medicines targeting these receptors therefore are not typically effective in treating TNBC.

About the ASCENT Study

The Phase 3 ASCENT study, an open-label, active-controlled, randomized confirmatory trial, enrolled more than 500 patients with relapsed/refractory metastatic triple-negative breast cancer (TNBC) who had received two or more prior systemic therapies (including a taxane), at least one of them for metastatic disease. Patients were randomized to receive either Trodelvy or a chemotherapy chosen by the patients’ treating physicians. The primary efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline, as measured by a blinded, independent, centralized review using RECIST v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS). More information about ASCENT is available at http://clinicaltrials.gov/show/NCT02574455.

Important Safety Information for Trodelvy

BOXED WARNING: NEUTROPENIA AND DIARRHEA

  • Severe, life-threatening, or fatal neutropenia may occur. Withhold TRODELVY for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment. Consider G-CSF for secondary prophylaxis. Initiate anti-infective treatment in patient with febrile neutropenia without delay.
  • Severe diarrhea may occur. Monitor patients with diarrhea and give fluid and electrolytes as needed. Administer atropine, if not contraindicated, for early diarrhea of any severity. At the onset of late diarrhea, evaluate for infectious causes and, if negative, promptly initiate loperamide. If severe diarrhea occurs, withhold TRODELVY until resolved to ≤ Grade 1 and reduce subsequent doses.

CONTRAINDICATIONS

  • Severe hypersensitivity to TRODELVY

WARNINGS AND PRECAUTIONS

Neutropenia: Dose modifications may be required due to neutropenia. Neutropenia occurred in 62% of patients treated with TRODELVY, leading to permanent discontinuation in 0.5% of patients. Grade 3-4 neutropenia occurred in 47% of patients. Febrile neutropenia occurred in 6%.

Diarrhea: Diarrhea occurred in 64% of all patients treated with TRODELVY. Grade 3 diarrhea occurred in 12% of patients. Neutropenic colitis occurred in 0.5% of patients. Withhold TRODELVY for Grade 3-4 diarrhea and resume when resolved to ≤ Grade 1. At onset, evaluate for infectious causes and if negative, promptly initiate loperamide, 4 mg initially followed by 2 mg with every episode of diarrhea for a maximum of 16 mg daily. Discontinue loperamide 12 hours after diarrhea resolves. Additional supportive measures (e.g., fluid and electrolyte substitution) may also be employed as clinically indicated. Patients who exhibit an excessive cholinergic response to treatment can receive appropriate premedication (e.g., atropine) for subsequent treatments.

Hypersensitivity and Infusion-Related Reactions: TRODELVY can cause severe and life-threatening hypersensitivity and infusion-related reactions, including anaphylactic reactions. Hypersensitivity reactions within 24 hours of dosing occurred in 37% of patients. Grade 3-4 hypersensitivity occurred in 1% of patients. The incidence of hypersensitivity reactions leading to permanent discontinuation of TRODELVY was 0.4%. Pre-infusion medication is recommendedObserve patients closely for hypersensitivity and infusion-related reactions during each infusion and for at least 30 minutes after completion of each infusion. Medication to treat such reactions, as well as emergency equipment, should be available for immediate use.

Nausea and Vomiting: Nausea occurred in 67% of all patients treated with TRODELVY. Grade 3-4 nausea occurred in 5% of patients. Vomiting occurred in 40% of patients and Grade 3-4 vomiting occurred in 3% of these patients. Premedicate with a two or three drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy-induced nausea and vomiting (CINV). Withhold TRODELVY doses for Grade 3 nausea or Grade 3-4 vomiting and resume with additional supportive measures when resolved to Grade ≤ 1. Additional antiemetics and other supportive measures may also be employed as clinically indicated. All patients should be given take-home medications with clear instructions for prevention and treatment of nausea and vomiting.

Increased Risk of Adverse Reactions in Patients with Reduced UGT1A1 Activity: Individuals who are homozygous for the uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1)*28 allele are at increased risk for neutropenia, febrile neutropenia, and anemia and may be at increased risk for other adverse reactions with TRODELVY. The incidence of Grade 3-4 neutropenia in genotyped patients was 69% in patients homozygous for the UGT1A1*28, 48% in patients heterozygous for the UGT1A1*28 allele and 46% in patients homozygous for the wild-type allele. The incidence of Grade 3-4 anemia in genotyped patients was 24% in patients homozygous for the UGT1A1*28 allele, 8% in patients heterozygous for the UGT1A1*28 allele, and 10% in patients homozygous for the wild-type allele. Closely monitor patients with known reduced UGT1A1 activity for adverse reactions. Withhold or permanently discontinue TRODELVY based on severity of the observed adverse reactions in patients with evidence of acute early-onset or unusually severe adverse reactions, which may indicate reduced UGT1A1 function.

Embryo-Fetal Toxicity: Based on its mechanism of action, TRODELVY can cause teratogenicity and/or embryo-fetal lethality when administered to a pregnant woman. TRODELVY contains a genotoxic component, SN-38, and targets rapidly dividing cells. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TRODELVY and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TRODELVY and for 3 months after the last dose.

ADVERSE REACTIONS

In the ASCENT study (IMMU-132-05), the most common adverse reactions (incidence ≥25%) were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain. The most frequent serious adverse reactions (SAR) (>1%) were neutropenia (7%), diarrhea (4%), and pneumonia (3%). SAR were reported in 27% of patients, and 5% discontinued therapy due to adverse reactions. The most common Grade 3-4 lab abnormalities (incidence ≥25%) in the ASCENT study were reduced hemoglobin, lymphocytes, leukocytes, and neutrophils.

DRUG INTERACTIONS

UGT1A1 Inhibitors: Concomitant administration of TRODELVY with inhibitors of UGT1A1 may increase the incidence of adverse reactions due to potential increase in systemic exposure to SN-38. Avoid administering UGT1A1 inhibitors with TRODELVY.

UGT1A1 Inducers: Exposure to SN-38 may be substantially reduced in patients concomitantly receiving UGT1A1 enzyme inducers. Avoid administering UGT1A1 inducers with TRODELVY

Please see full Prescribing Information, including BOXED WARNING.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Sacituzumab govitecan, sold under the brand name Trodelvy, is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate indicated for the treatment of metastatic triple-negative breast cancer (mTNBC) in adult patients that have received at least two prior therapies.[1][2]

The most common side effects are nauseaneutropeniadiarrheafatigueanemiavomitingalopecia (hair loss), constipationdecreased appetiterash and abdominal pain.[1][2] Sacituzumab govitecan has a boxed warning about the risk of severe neutropenia (abnormally low levels of white blood cells) and severe diarrhea.[1][2] Sacituzumab govitecan may cause harm to a developing fetus or newborn baby.[1] Women are advised not to breastfeed while on sacituzumab govitecan and 1 month after the last dose is administered.[3]

The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[4]

Mechanism

Sacituzumab govitecan is a conjugate of the humanized anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.[5] Each antibody having on average 7.6 molecules of SN-38 attached.[6] SN-38 is too toxic to administer directly to patients, but linkage to an antibody allows the drug to specifically target cells containing Trop-2.

Sacituzumab govitecan is a Trop-2-directed antibody and topoisomerase inhibitor drug conjugate, meaning that the drug targets the Trop-2 receptor that helps the cancer grow, divide and spread, and is linked to topoisomerase inhibitor, which is a chemical compound that is toxic to cancer cells.[1] Approximately two of every ten breast cancer diagnoses worldwide are triple-negative.[1] Triple-negative breast cancer is a type of breast cancer that tests negative for estrogen receptors, progesterone receptors and human epidermal growth factor receptor 2 (HER2) protein.[1] Therefore, triple-negative breast cancer does not respond to hormonal therapy medicines or medicines that target HER2.[1]

Development

Immunomedics announced in 2013, that it had received fast track designation from the US Food and Drug Administration (FDA) for the compound as a potential treatment for non-small cell lung cancer, small cell lung cancer, and metastatic triple-negative breast cancer. Orphan drug status was granted for small cell lung cancer and pancreatic cancer.[7][8] In February 2016, Immunomedics announced that sacituzumab govitecan had received an FDA breakthrough therapy designation (a classification designed to expedite the development and review of drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition) for the treatment of patients with triple-negative breast cancer who have failed at least two other prior therapies for metastatic disease.[9][10]

History

Sacituzumab govitecan was added to the proposed INN list in 2015,[11] and to the recommended list in 2016.[12]

Sacituzumab govitecan-hziy was approved for use in the United States in April 2020.[1][13][14][2]

Sacituzumab govitecan-hziy was approved based on the results of IMMU-132-01, a multicenter, single-arm clinical trial (NCT01631552) of 108 subjects with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease.[1][14][2] Of the 108 patients involved within the study, 107 were female and 1 was male.[15] Subjects received sacituzumab govitecan-hziy at a dose of 10 milligrams per kilogram of body weight intravenously on days one and eight every 21 days.[14][15] Treatment with sacituzumab govitecan-hziy was continued until disease progression or unacceptable toxicity.[15] Tumor imaging was obtained every eight weeks.[14][2] The efficacy of sacituzumab govitecan-hziy was based on the overall response rate (ORR) – which reflects the percentage of subjects that had a certain amount of tumor shrinkage.[1][14] The ORR was 33.3% (95% confidence interval [CI], 24.6 to 43.1). [1][14][15] Additionally, with the 33.3% of study participants who achieved a response, 2.8% of patients experienced complete responses.[15] The median time to response in patients was 2.0 months (range, 1.6 to 13.5), the median duration of response was 7.7 months (95% confidence interval [CI], 4.9 to 10.8), the median progression free survival was 5.5 months, and the median overall survival was 13.0 months.[15] Of the subjects that achieved an objective response to sacituzumab govitecan-hziy, 55.6% maintained their response for six or more months and 16.7% maintained their response for twelve or more months.[1][14]

Sacituzumab govitecan-hziy was granted accelerated approval along with priority reviewbreakthrough therapy, and fast track designations.[1][14] The U.S. Food and Drug Administration (FDA) granted approval of Trodelvy to Immunomedics, Inc.[1]

References

  1. Jump up to:a b c d e f g h i j k l m n o “FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 22 April 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f “Drug Trial Snapshot: Trodelvy”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 29 April 2020. This article incorporates text from this source, which is in the public domain.
  3. ^ (PDF)https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Missing or empty |title= (help)
  4. ^ “New Drug Therapy Approvals 2020”U.S. Food and Drug Administration (FDA). 31 December 2020. Retrieved 17 January2021.  This article incorporates text from this source, which is in the public domain.
  5. ^ Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. 2015
  6. ^ “Novel Agents are Targeting Drivers of TNBC”http://www.medpagetoday.com. 28 June 2016.
  7. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  8. ^ “Sacituzumab govitecan Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 22 April 2020.
  9. ^ “New Therapy Shows Early Promise, Continues to Progress in Triple-Negative Breast Cancer”Cure Today.
  10. ^ “U.S. Food and Drug Administration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients With Triple-Negative Breast Cancer”(Press release). Immunomedics. 5 February 2016. Retrieved 25 April 2020 – via GlobeNewswire.
  11. ^ World Health Organization (2015). “International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 113”. WHO Drug Information29 (2): 260–1. hdl:10665/331080.
  12. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 151–3. hdl:10665/331046.
  13. ^ “Trodelvy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 April 2020.
  14. Jump up to:a b c d e f g h “FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer”U.S. Food and Drug Administration (FDA). 22 April 2020. Retrieved 23 April 2020.  This article incorporates text from this source, which is in the public domain.
  15. Jump up to:a b c d e f “Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer”The New England Journal of Medicine.

Further reading

External links

 
Monoclonal antibody
Type?
SourceHumanized (from mouse)
TargetTrop-2
Clinical data
Trade namesTrodelvy
Other namesIMMU-132, hRS7-SN-38, sacituzumab govitecan-hziy
AHFS/Drugs.comMonograph
MedlinePlusa620034
License dataUS DailyMedSacituzumab_govitecan
Pregnancy
category
Contraindicated
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
CAS Number1491917-83-9
PubChem CID91668186
DrugBankDB12893
ChemSpidernone
UNIIM9BYU8XDQ6
KEGGD10985
Chemical and physical data
FormulaC76H104N12O24S
Molar mass1601.79 g·mol−1
3D model (JSmol)Interactive image
showSMILES
show 

//////////sacituzumab govitecan-hziy, fda 2021, approvals 2021, Trodelvy , hRS 7SN38, hRS7-SN38, IMMU 132, IMMU-132, MONOCLONAL ANTIBODY, Sacituzumab govitecan, sacituzumab govitecan-hziy, CANCER, MONOCLONAL ANTIBODIES

#sacituzumab govitecan-hziy, #fda 2021, #approvals 2021, #Trodelvy , #hRS 7SN38, #hRS7-SN38, #IMMU 132, #IMMU-132, #MONOCLONAL ANTIBODY, #Sacituzumab govitecan, #sacituzumab govitecan-hziy, #CANCER, #MONOCLONAL ANTIBODIES

CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)OC(=O)OCC5=CC=C(C=C5)NC(=O)C(CCCCN)NC(=O)COCC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCN6C=C(N=N6)CNC(=O)C7CCC(CC7)CN8C(=O)CC(C8=O)SCC(C(=O)O)N)C2=NC9=C1C=C(C=C9)O

wdt-14

NEW DRUG APPROVALS

ONE TIME

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Dasiglucagon


Dasiglucagon.png
2D chemical structure of 1544300-84-6
str1

Dasiglucagon

Treatment of Hypoglycemia in Type 1 and Type 2 Diabetes Patients

FormulaC152H222N38O50
CAS1544300-84-6
Mol weight3381.6137

FDA APPROVED,  2021/3/22, Zegalogue

Zealand Pharma A/S

UNIIAD4J2O47FQ

HypoPal rescue pen

SVG Image
IUPAC CondensedH-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr-OH
SequenceHSQGTFTSDYSKYLDXARAEEFVKWLEST
HELMPEPTIDE1{H.S.Q.G.T.F.T.S.D.Y.S.K.Y.L.D.[Aib].A.R.A.E.E.F.V.K.W.L.E.S.T}$$$$
IUPACL-histidyl-L-seryl-L-glutaminyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-alpha-methyl-alanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alpha-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-alpha-glutamyl-L-seryl-L-threonine

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-2-methylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid

. [16-(2-methylalanine)(S>X),17-L-alanine(R>A),20-L-α-glutamyl(Q>E),21-L-αglutamyl(D>E),24-L-lysyl(Q>K),27-L-α-glutamyl(M>E),28-L-serine(N>S)]human glucagon

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L- phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L- lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L- arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L- valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl

ZP-4207

His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-aib-Ala-Arg-Ala-Glu-Glu-Phe-Val-Lys-Trp-Leu-Glu-Ser-Thr

L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-alpha-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-alpha-glutamyl-L-alphaC152 H222 N38 O50L-Threonine, L-histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-Molecular Weight3381.61

Other Names

  • L-Histidyl-L-seryl-L-glutaminylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-tyrosyl-L-seryl-L-lysyl-L-tyrosyl-L-leucyl-L-α-aspartyl-2-methylalanyl-L-alanyl-L-arginyl-L-alanyl-L-α-glutamyl-L-α-glutamyl-L-phenylalanyl-L-valyl-L-lysyl-L-tryptophyl-L-leucyl-L-α-glutamyl-L-seryl-L-threonine
  • Developer Beta Bionics; Zealand Pharma
  • ClassAntihyperglycaemics; Antihypoglycaemics; Peptides
  • Mechanism of ActionGlucagon receptor agonists
  • Orphan Drug StatusYes – Hypoglycaemia; Congenital hyperinsulinism
  • RegisteredHypoglycaemia
  • Phase IIICongenital hyperinsulinism
  • Phase II/IIIType 1 diabetes mellitus
  • 22 Mar 2021Registered for Hypoglycaemia (In children, In adolescents, In adults, In the elderly) in USA (SC) – First global approval
  • 22 Mar 2021Zealand Pharma anticipates the launch of dasiglucagon in USA (SC, Injection) in June 2021
  • 22 Mar 2021Pooled efficacy and safety data from three phase III trials in Hypoglycaemia released by Zealand Pharma

NEW DRUG APPROVALS

one time

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PATENTS

WO 2014016300

US 20150210744

PAPER

Pharmaceutical Research (2018), 35(12), 1-13

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.[1]

The most common side effects include nausea, vomiting, headache, diarrhea, and injection site pain.[1]

Dasiglucagon was approved for medical use in the United States in March 2021.[1][2][3] It was designated an orphan drug in August 2017.[4]

Dasiglucagon is under investigation in clinical trial NCT03735225 (Evaluation of the Safety, Tolerability and Bioavailability of Dasiglucagon Following Subcutaneous (SC) Compared to IV Administration).

Medical uses

Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.[1][2]

Contraindications

Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.[1]

References

  1. Jump up to:a b c d e f https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214231s000lbl.pdf
  2. Jump up to:a b “Dasiglucagon: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 22 March 2021.
  3. ^ “Zealand Pharma Announces FDA Approval of Zegalogue (dasiglucagon) injection, for the Treatment of Severe Hypoglycemia in People with Diabetes” (Press release). Zealand Pharma. 22 March 2021. Retrieved 22 March 2021 – via GlobeNewswire.
  4. ^ “Dasiglucagon Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 10 August 2017. Retrieved 22 March 2021.

External links

  • “Dasiglucagon”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03378635 for “A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects” at ClinicalTrials.gov
  • Clinical trial number NCT03688711 for “Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM” at ClinicalTrials.gov
  • Clinical trial number NCT03667053 for “Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children” at ClinicalTrials.gov
Clinical data
Trade namesZegalogue
AHFS/Drugs.comZegalogue
License dataUS DailyMedDasiglucagon
Routes of
administration
Subcutaneous
Drug classGlucagon receptor agonist
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number1544300-84-6
PubChem CID126961379
DrugBankDB15226
UNIIAD4J2O47FQ
KEGGD11359
Chemical and physical data
FormulaC152H222N38O50
Molar mass3381.664 g·mol−1
3D model (JSmol)Interactive image

///////////Dasiglucagon, FDA 2021,  APPROVALS 2021, Zegalogue, ダシグルカゴン, ZP 4207, ZP-GA-1 Hypoglycemia, Type 1, Type 2 , Diabetes Patients, Zealand Pharma A/S, Orphan Drug Status,  Hypoglycaemia, Congenital hyperinsulinism,  HypoPal rescue pen, DIABETES

#Dasiglucagon, #FDA 2021,  #APPROVALS 2021, #Zegalogue, #ダシグルカゴン, #ZP 4207, ZP-GA-1 #Hypoglycemia, #Type 1, #Type 2 , #Diabetes Patients, #Zealand Pharma A/S, #Orphan Drug Status,  #Hypoglycaemia, #Congenital hyperinsulinism,  #HypoPal rescue pen, #DIABETESSMILES

  • C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CNC=N7)N)O

Lisocabtagene maraleucel


U.S. FDA Accepts Priority Review for Lisocabtagene Maraleucel R/R Large B-Cell Lymphoma - Onco'ZineLisocabtagene maraleucel (liso-cel; JCAR017; Anti-CD19 CAR T-Cells) is an investigational chimeric antigen receptor (CAR) T-cell therapy designed to target CD19, [1][2] which is a surface glycoprotein expressed during normal B-cell development and maintained following malignant transformation of B cells. [3][4][5] Liso-cel CAR T-cells aim to target and CD-19 expressing cells through a CAR construct that includes an anti-CD19 single-chain variable fragment (scFv) targeting domain for antigen specificity, a transmembrane domain, a 4-1BB costimulatory domain hypothesized to increase T-cell proliferation and persistence, and a CD3-zeta T-cell activation domain. [1][2][6][7][8][9] The defined composition of liso-cel may limit product variability; however, the clinical significance of defined composition is unknown. [1][10] Image Courtesy: 2019/2020 Celgene/Juno Therapeutics / Bristol Meyers Squibb.

REF https://www.oncozine.com/u-s-fda-accepts-priority-review-for-lisocabtagene-maraleucel-r-r-large-b-cell-lymphoma/

Lisocabtagene maraleucel

リソカブタゲンマラルユーセル;

JCAR 017

STN# BLA 125714

  • Adoptive immunotherapy agent JCAR 017
  • Autologous anti-CD19 scFv/4-1BB/CD3ζ/CD28 chimeric antigen receptor-expressing CD4+/CD8+ central memory T cell JCAR 017
  • CAR T-cell JCAR 017

FDA 2021, 2021/2/24, BREYANZI

Juno Therapeutics

Antineoplastic, Anti-CD19 CAR-T cell

An immunotherapeutic autologous T cell preparation expressing a chimeric antigen receptor (CAR) specific to the CD19 antigen (Juno Therapeutics, Inc., Seattle, Washington, USA – FDA Clinical Trial Data)

  • For the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Lisocabtagene maraleucel, sold under the brand name Breyanzi, is a cell-based gene therapy used to treat large B-cell lymphoma.[1][3]

Side effects of lisocabtagene maraleucel include hypersensitivity reactions, serious infections, low blood cell counts and a weakened immune system.[3]

Lisocabtagene maraleucel, a chimeric antigen receptor (CAR) T cell therapy, is the third gene therapy approved by the U.S. Food and Drug Administration (FDA) for certain types of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL).[3] Lisocabtagene maraleucel was approved for medical use in the United States in February 2021.[1][3]

U.S. Food and Drug Administration Approves Bristol Myers Squibb's Breyanzi (lisocabtagene maraleucel), a New CAR T Cell Therapy for Adults with Relapsed or Refractory Large B-cell Lymphoma | Business Wire

Medical uses

Lisocabtagene maraleucel is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.[1][3]

Lisocabtagene maraleucel is not indicated for the treatment of people with primary central nervous system lymphoma.[3]

Adverse effects

The labeling carries a boxed warning for cytokine release syndrome (CRS), which is a systemic response to the activation and proliferation of CAR T cells, causing high fever and flu-like symptoms and neurologic toxicities.[3]

History

The safety and efficacy of lisocabtagene maraleucel were established in a multicenter clinical trial of more than 250 adults with refractory or relapsed large B-cell lymphoma.[3] The complete remission rate after treatment with lisocabtagene maraleucel was 54%.[3]

The FDA granted lisocabtagene maraleucel orphan drugregenerative medicine advanced therapy (RMAT) and breakthrough therapy designations.[3] Lisocabtagene maraleucel is the first regenerative medicine therapy with RMAT designation to be licensed by the FDA.[3] The FDA granted approval of Breyanzi to Juno Therapeutics Inc., a Bristol-Myers Squibb Company.[3]

SYN

WO 2018156680

WO 2018183366

Saishin Igaku (2018), 73(11), 1504-1512.

WO 2019148089

WO 2019220369

Leukemia & Lymphoma (2020), 61(11), 2561-2567.

WO 2020097350

WO 2020086943

Journal of Immunotherapy (2020), 43(4), 107-120.

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel

CLIP

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma

On February 5, 2021, the Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc.) for the treatment of adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Lisocabtagene maraleucel is a CD19-directed chimeric antigen receptor (CAR) T cell immunotherapy. It consists of autologous T cells that are genetically modified to produce a CAR protein, allowing the T cells to identify and eliminate CD19-expressing normal and malignant cells.

Efficacy was evaluated in TRANSCEND (NCT02631044), a single-arm, open label, multicenter trial that evaluated lisocabtagene maraleucel, preceded by lymphodepleting chemotherapy, in adults with R/R large B-cell lymphoma after at least two lines of therapy.

Of the 192 patients evaluable for response, the overall response rate (ORR) per independent review committee assessment was 73% (95% CI: 67, 80) with a complete response (CR) rate of 54% (95% CI: 47, 61). The median time to first response was one month. Of the 104 patients who achieved CR, 65% had remission lasting at least 6 months and 62% had remission lasting at least 9 months. The estimated median duration of response (DOR) was not reached (95% CI: 16.7 months, NR) in patients who achieved a CR. The estimated median DOR among patients with partial response was 1.4 months (95% CI: 1.1, 2.2).

Cytokine release syndrome (CRS) occurred in 46% of patients (Grade 3 or higher, 4%) and neurologic toxicity occurred in 35% (Grade 3 or higher, 12%). Three patients had fatal neurologic toxicity. Other Grade 3 or higher adverse reactions included infections (19%) and prolonged cytopenias (31%). FDA approved lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy because of the risk of fatal or life-threatening CRS and neurologic toxicities.

The recommended regimen is a single dose containing 50 to 110 x 106 CAR-positive viable T cells with a 1:1 ratio of CD4 and CD8 components, administered by IV infusion and preceded by fludarabine and cyclophosphamide for lymphodepletion. Lisocabtagene maraleucel is not indicated for the treatment of patients with primary central nervous system lymphoma.

References

  1. Jump up to:a b c d “Lisocabtagene maraleucel”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.
  2. ^ https://www.fda.gov/media/145711/download
  3. Jump up to:a b c d e f g h i j k l “FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma”U.S. Food and Drug Administration (FDA) (Press release). 5 February 2021. Retrieved 5 February 2021.  This article incorporates text from this source, which is in the public domain.

External links

Clinical data
Trade namesBreyanzi
Other namesJCAR017
License dataUS DailyMedLisocabtagene_maraleucel
Routes of
administration
Intravenous
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
UNII7K2YOJ14X0
KEGGD11990
ChEMBLChEMBL4297236

///////////Lisocabtagene maraleucel, BREYANZI, FDA 2021, APPROVALS 2021, リソカブタゲンマラルユーセル , Juno Therapeutics, JCAR 017, STN# BLA 125714

#Lisocabtagene maraleucel, #BREYANZI, #FDA 2021, #APPROVALS 2021, #リソカブタゲンマラルユーセル , #Juno Therapeutics, #JCAR 017, #STN# BLA 125714

Casimersen


Casimersen

カシメルセン;

RNA, [P-​deoxy-​P-​(dimethylamino)​]​(2′,​3′-​dideoxy-​2′,​3′-​imino-​2′,​3′-​seco)​(2’a→5′)​(C-​A-​A-​m5U-​G-​C-​C-​A-​m5U-​C-​C-​m5U-​G-​G-​A-​G-​m5U-​m5U-​C-​C-​m5U-​G)​, 5′-​[P-​[4-​[[2-​[2-​(2-​hydroxyethoxy)​ethoxy]​ethoxy]​carbonyl]​-​1-​piperazinyl]​-​N,​N-​dimethylphosphonamid​ate]

FormulaC268H424N124O95P22
CAS1422958-19-7
Mol weight7584.4307

FDA 2021/2/25 , Amondys 45, Antisense oligonucleotide
Treatment of Duchenne muscular dystrophy

Nucleic Acid Sequence

Sequence Length: 224 a 7 c 5 g 6 umodified

  • Exon-45: NG-12-0064
  • SRP-4045
  • WHO 10354

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping.[1][2][3][4] It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO).[1]

The most common side effects include upper respiratory tract infections, cough, fever, headache, joint pain and throat pain.[2]

Casimersen was approved for medical use in the United States in February 2021,[1][2] and it is the first FDA-approved targeted treatment for people who have a confirmed mutation of the DMD gene that is amenable to skipping exon 45.[2]

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder characterized by a lack of functional dystrophin protein, which leads to progressive impairment of ambulatory, pulmonary, and cardiac function and is invariably fatal. A related, albeit a less severe, form of muscular dystrophy known as Becker muscular dystrophy (BMD) is characterized by shortened and partially functional dystrophin protein production. Although corticosteroids effectively slow disease progression in both DMD and BMD patients, they do not address the underlying molecular pathogenesis.1,2,3

The application of antisense oligonucleotides in DMD patients with specific mutations allows for exon skipping to produce truncated BMD-like dystrophin proteins, which restore partial muscle function and slow disease progression.1,2,4,5,7 Casimersen is a phosphorodiamidate morpholino oligonucleotide (PMO); PMOs are oligonucleotides in which the five-membered ribofuranosyl ring is replaced with a six-membered morpholino ring, and the phosphodiester links between nucleotides are replaced with a phosphorodiamidate linkage.6,7 In this manner, PMOs are much less susceptible to endo- and exonucleases and exhibit drastically reduced metabolic degradation compared to traditional synthetic oligonucleotides.6 Casimersen is the most recent in a line of approved PMOs for treating DMD, including eteplirsen and viltolarsen. However, the specific mutations, and hence the precise exon skipping, targeted by each is different.

Casimersen was granted accelerated FDA approval on February 25, 2021, based on data showing an increase in dystrophin levels in skeletal muscle of patients treated with casimersen; this approval is contingent on further verification in confirmatory trials. Casimersen is currently marketed under the tradename AMONDYS 45™ by Sarepta Therapeutics, Inc.7

Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients confirmed to have a DMD gene mutation amenable to exon 45 skipping. This indication represents an accelerated approval based on observed efficacy; continued approval for this indication may be contingent on the verification of safety and efficacy in a confirmatory trial.7

Medical uses

Casimersen is indicated for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.[1][2]

History

Casimersen was evaluated in a double-blind, placebo-controlled study in which 43 participants were randomized 2:1 to receive either intravenous casimersen or placebo.[2] All participants were male, between 7 and 20 years of age, and had a genetically confirmed mutation of the DMD gene that is amenable to exon 45 skipping.[2]

The U.S. Food and Drug Administration (FDA) granted the application for casimersen fast trackpriority review, and orphan drug designations.[2][5] The FDA granted the approval of Amondys 45 to Sarepta Therapeutics, Inc.[2]

Pharmacodynamics

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA, preventing its inclusion in mature mRNA and allowing the production of an internally truncated dystrophin protein in patients who would normally produce no functional dystrophin. Due to the need for continuous alteration of mRNA splicing and its relatively short half-life, casimersen is administered weekly.7 Although casimersen is associated with mostly mild adverse effects, animal studies suggest a potential for nephrotoxicity, which has also been observed after administration of some oligonucleotides.4,7 Measurement of glomerular filtration rate before starting casimersen is advised. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting therapy. They should be measured monthly (urine dipstick) or every three months (serum cystatin C and urine protein-to-creatinine ratio) during treatment. Creatinine levels are not reliable in muscular dystrophy patients and should not be used. Any persistent alteration in kidney function should be further investigated.7

Mechanism of action

Duchenne muscular dystrophy (DMD) is an X-linked recessive allelic disorder that results in the absence of functional dystrophin, a large protein comprising an N-terminal actin-binding domain, C-terminal β-dystroglycan-binding domain, and 24 internal spectrin-like repeats.1,2,3 Dystrophin is vital for normal muscle function; the absence of dystrophin leads to muscle membrane damage, extracellular leakage of creatinine kinase, calcium influx, and gradual replacement of normal muscle tissue with fibrous and adipose tissue over time.1,2 DMD shows a characteristic disease progression with early functional complaints related to abnormal gait, locomotion, and falls that remain relatively stable until around seven years of age. The disease then progresses rapidly to loss of independent ambulatory function, ventilatory insufficiency, and cardiomyopathy, with death typically occurring in the second or third decade of life.1,2,3

The human DMD gene contains 79 exons spread over approximately 2.4 million nucleotides on the X chromosome.1 DMD is associated with a variety of underlying mutations, including exon duplications or deletions, as well as point mutations leading to nonsense translation through direct production of an in-frame stop codon, frameshift production of an in-frame stop codon, or aberrant inclusion of an intronic pseudo-exon with the concomitant production of an in-frame stop codon.1,2 In all cases, no functional dystrophin protein is produced. Becker muscular dystrophy (BMD) is a related condition with in-frame mutations that result in the production of a truncated but partially functional dystrophin protein. BMD patients, therefore, have milder symptoms, delayed disease progression, and longer life expectancy compared to DMD patients.1,2,3

Casimersen is an antisense phosphorodiamidate morpholino oligonucleotide designed to bind to exon 45 of the DMD pre-mRNA and prevent its inclusion within the mature mRNA before translation.4,7 It is estimated that around 8% of DMD patients may benefit from exon 45 skipping, in which the exclusion of this exon results in the production of an internally truncated and at least partly functional dystrophin protein.4,7,5 Although fibrotic or fatty muscle tissue developed previously cannot be improved, this therapy aims to slow further disease progression through the production of partially functional dystrophin and alleviation of the pathogenic mechanism of muscle tissue necrosis.1,2

TARGETACTIONSORGANISM
ADMD gene (exon 45 casimersen target site)binderHumans

Absorption

DMD patients receiving IV doses of 4-30 mg/kg/week revealed exposure in proportion to dose with no accumulation of casimersen in plasma with once-weekly dosing. Following a single IV dose, casimersen Cmax was reached by the end of infusion. Inter-subject variability, as measured by the coefficient of variation, ranged from 12-34% for Cmax and 16-34% for AUC.7

Pre-clinical studies in nonhuman primates (cynomolgus monkeys) investigated the pharmacokinetics of once-weekly casimersen administered at doses of 5, 40, and 320 mg/kg. On days 1 and 78, the 5 mg/kg dose resulted in a Cmax of 19.5 ± 3.43 and 21.6 ± 5.60 μg/mL and an AUC0-t of 24.9 ± 5.17 and 26.9 ± 7.94 μg*hr/mL. The 40 mg/kg dose resulted in a Cmax of 208 ± 35.2 and 242 ± 71.1 μg/mL and an AUC0-t of 283 ± 68.5 and 320 ± 111 μg*hr/mL. Lastly, the 320 mg/kg dose resulted in a a Cmax of 1470 ± 88.1 and 1490 ± 221 μg/mL and an AUC0-t of 1960 ± 243 and 1930 ± 382 μg*hr/mL.4

Volume of distribution

Casimersen administered at 30 mg/kg had a mean steady-state volume of distribution (%CV) of 367 mL/kg (28.9%).7

Protein binding

Casimersen binding to human plasma proteins is not concentration-dependent, ranging from 8.4-31.6%.7

Metabolism

Casimersen incubated with human hepatic microsomal preparations is metabolically stables and no metabolites are detected in plasma or urine.7

Route of elimination

Casimersen is predominantly (more than 90%) excreted in the urine unchanged with negligible fecal excretion.7

Half-life

Casimersen has an elimination half-life of 3.5 ± 0.4 hours.7

Clearance

Casimersen administered at 30 mg/kg has a plasma clearance of 180 mL/hr/kg.7

NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
Amondys 45Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2021-02-25Not applicableUS flag 

Synthesis Reference

Diane Elizabeth Frank and Richard K. Bestwick, “Exon skipping oligomers for muscular dystrophy.” U.S. Patent US20190262375A1, issued August 29, 2019.

PATENT

https://patents.google.com/patent/WO2017205879A2/en

also

WO 2021025899 

References

  1. Jump up to:a b c d e “Amondys 45- casimersen injection”DailyMed. Retrieved 1 March 2021.
  2. Jump up to:a b c d e f g h i j “FDA Approves Targeted Treatment for Rare Duchenne Muscular Dystrophy Mutation”U.S. Food and Drug Administration (FDA) (Press release). 25 February 2021. Retrieved 25 February 2021.  This article incorporates text from this source, which is in the public domain.
  3. ^ “Sarepta Therapeutics Announces FDA Approval of Amondys 45 (casimersen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 45” (Press release). Sarepta Therapeutics. 25 February 2021. Retrieved 25 February 2021 – via GlobeNewswire.
  4. ^ Rodrigues M, Yokota T (2018). “An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases”. Exon Skipping and Inclusion Therapies. Methods in Molecular Biology. 1828. Clifton, N.J. pp. 31–55. doi:10.1007/978-1-4939-8651-4_2ISBN 978-1-4939-8650-7PMID 30171533.
  5. ^ “Casimersen Orphan Drug Designations and Approvals”U.S. Food and Drug Administration (FDA). 4 June 2019. Retrieved 25 February 2021.

General References

  1. Wein N, Alfano L, Flanigan KM: Genetics and emerging treatments for Duchenne and Becker muscular dystrophy. Pediatr Clin North Am. 2015 Jun;62(3):723-42. doi: 10.1016/j.pcl.2015.03.008. Epub 2015 Apr 20. [PubMed:26022172]
  2. Verhaart IEC, Aartsma-Rus A: Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3. [PubMed:31147635]
  3. Mercuri E, Bonnemann CG, Muntoni F: Muscular dystrophies. Lancet. 2019 Nov 30;394(10213):2025-2038. doi: 10.1016/S0140-6736(19)32910-1. [PubMed:31789220]
  4. Carver MP, Charleston JS, Shanks C, Zhang J, Mense M, Sharma AK, Kaur H, Sazani P: Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates. J Neuromuscul Dis. 2016 Aug 30;3(3):381-393. doi: 10.3233/JND-160157. [PubMed:27854228]
  5. Rodrigues M, Yokota T: An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases. Methods Mol Biol. 2018;1828:31-55. doi: 10.1007/978-1-4939-8651-4_2. [PubMed:30171533]
  6. Smith CIE, Zain R: Therapeutic Oligonucleotides: State of the Art. Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:605-630. doi: 10.1146/annurev-pharmtox-010818-021050. Epub 2018 Oct 9. [PubMed:30285540]
  7. FDA Approved Drug Products: AMONDYS 45 (casimersen) injection [Link]

External links

Clinical data
Trade namesAmondys 45
Other namesSRP-4045
License dataUS DailyMedCasimersen
Routes of
administration
Intravenous
Drug classAntisense oligonucleotide
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number1422958-19-7
DrugBankDB14984
UNIIX8UHF7SX0R
KEGGD11988
Chemical and physical data
FormulaC268H424N124O95P22
Molar mass7584.536 g·mol−1

////////////Casimersen, FDA 2021, APPROVALS 2021, カシメルセン , Exon-45: NG-12-0064, SRP-4045, WHO 10354, Amondys 45, Antisense oligonucleotide, Duchenne muscular dystrophy

#Casimersen, #FDA 2021, #APPROVALS 2021, #カシメルセン , #Exon-45: NG-12-0064, #SRP-4045, #WHO 10354, #Amondys 45, #Antisense oligonucleotide, #Duchenne muscular dystrophy

Sequence:

1caaugccauc cuggaguucc ug

Sequence Modifications

TypeLocationDescription
modified basec-15′-ester
modified basec-1modified cytidine
modified basea-2modified adenosine
modified basea-3modified adenosine
modified baseu-4m5u
modified baseu-4modified uridine
modified baseg-5modified guanosine
modified basec-6modified cytidine
modified basec-7modified cytidine
modified basea-8modified adenosine
modified baseu-9modified uridine
modified baseu-9m5u
modified basec-10modified cytidine
modified basec-11modified cytidine
modified baseu-12m5u
modified baseu-12modified uridine
modified baseg-13modified guanosine
modified baseg-14modified guanosine
modified basea-15modified adenosine
modified baseg-16modified guanosine
modified baseu-17modified uridine
modified baseu-17m5u
modified baseu-18modified uridine
modified baseu-18m5u
modified basec-19modified cytidine
modified basec-20modified cytidine
modified baseu-21m5u
modified baseu-21modified uridine
modified baseg-22modified guanosine
uncommon linkc-1 – a-2unavailable
uncommon linka-2 – a-3unavailable
uncommon linka-3 – u-4unavailable
uncommon linku-4 – g-5unavailable
uncommon linkg-5 – c-6unavailable
uncommon linkc-6 – c-7unavailable
uncommon linkc-7 – a-8unavailable
uncommon linka-8 – u-9unavailable
uncommon linku-9 – c-10unavailable
uncommon linkc-10 – c-11unavailable
uncommon linkc-11 – u-12unavailable
uncommon linku-12 – g-13unavailable
uncommon linkg-13 – g-14unavailable
uncommon linkg-14 – a-15unavailable
uncommon linka-15 – g-16unavailable
uncommon linkg-16 – u-17unavailable
uncommon linku-17 – u-18unavailable
uncommon linku-18 – c-19unavailable
uncommon linkc-19 – c-20unavailable
uncommon linkc-20 – u-21unavailable
uncommon linku-21 – g-22unavailable

Fosdenopterin hydrobromide


Fosdenopterin hydrobromide.png
FOSDENOPTERIN HYDROBROMIDE

Fosdenopterin hydrobromide

FDA APPR 2021/2/26, NULIBRY

BBP-870/ORGN001

a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.

ホスデノプテリン臭化水素酸塩水和物;
FormulaC10H14N5O8P. 2H2O. HBr
CAS2301083-34-9DIHYDRATE
Mol weight480.1631

2301083-34-9

(1R,10R,12S,17R)-5-amino-11,11,14-trihydroxy-14-oxo-13,15,18-trioxa-2,4,6,9-tetraza-14λ5-phosphatetracyclo[8.8.0.03,8.012,17]octadeca-3(8),4-dien-7-one;dihydrate;hydrobromide

1,3,2-DIOXAPHOSPHORINO(4′,5′:5,6)PYRANO(3,2-G)PTERIDIN-10(4H)-ONE, 8-AMINO-4A,5A,6,9,11,11A,12,12A-OCTAHYDRO-2,12,12-TRIHYDROXY-, 2-OXIDE, HYDROBROMIDE, HYDRATE (1:1:2), (4AR,5AR,11AR,12AS)-

CYCLIC PYRANOPTERIN MONOPHOSPHATE MONOHYDROBROMIDE DIHYDRATE

(4aR,5aR,11aR,12aS)-8-Amino-2,12,12-trihydroxy-4a,5a,6,7,11,11a,12,12aoctahydro-2H-2lambda5-(1,3,2)dioxaphosphinino(4′,5′:5,6)pyrano(3,2-g)pteridine-2,10(4H)-dione, hydrobromide (1:1:2)

1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide, hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-

1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide,hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-

ALXN1101 HBrUNII-X41B5W735TX41B5W735TD11780

Nulibry Approved for Molybdenum Cofactor Deficiency Type A - MPR
Thumb
ChemSpider 2D Image | Cyclic pyranopterin monophosphate | C10H14N5O8P
Cyclic pyranopterin monophosphate.svg

C10H14N5O8P, Average: 363.223

150829-29-1

  • ALXN-1101
  • WHO 11150
  • Synthesis ReferenceClinch K, Watt DK, Dixon RA, Baars SM, Gainsford GJ, Tiwari A, Schwarz G, Saotome Y, Storek M, Belaidi AA, Santamaria-Araujo JA: Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. J Med Chem. 2013 Feb 28;56(4):1730-8. doi: 10.1021/jm301855r. Epub 2013 Feb 19.

Fosdenopterin (or cyclic pyranopterin monophosphatecPMP), sold under the brand name Nulibry, is a medication used to reduce the risk of death due to a rare genetic disease known as molybdenum cofactor deficiency type A (MoCD-A).[1]

Adverse effects

The most common side effects include complications related to the intravenous line, fever, respiratory infections, vomiting, gastroenteritis, and diarrhea.[1]

Mechanism of action

People with MoCD-A cannot produce cyclic pyranopterin monophosphate (cPMP) in their body.[1] Fosdenopterin is an intravenous medication that replaces the missing cPMP.[1][2] cPMP is a precursor to molybdopterin, which is required for the enzyme activity of sulfite oxidasexanthine dehydrogenase/oxidase and aldehyde oxidase.[3]

History

Fosdenopterin was developed by José Santamaría-Araujo and Guenter Schwarz at the German universities TU Braunschweig and the University of Cologne.[4][5]

The effectiveness of fosdenopterin for the treatment of MoCD-A was demonstrated in thirteen treated participants compared to eighteen matched, untreated participants.[1][6] The participants treated with fosdenopterin had a survival rate of 84% at three years, compared to 55% for the untreated participants.[1]

The U.S. Food and Drug Administration (FDA) granted the application for fosdenopterin priority reviewbreakthrough therapy, and orphan drug designations along with a rare pediatric disease priority review voucher.[1] The FDA granted the approval of Nulibry to Origin Biosciences, Inc., in February 2021.[1] It is the first medication approved for the treatment of MoCD-A.[1]

References

  1. Jump up to:a b c d e f g h i j “FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A”U.S. Food and Drug Administration (FDA) (Press release). 26 February 2021. Retrieved 26 February 2021.  This article incorporates text from this source, which is in the public domain.
  2. ^ DrugBank DB16628 . Accessed 2021-03-05.
  3. ^ Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (April 2004). “The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor”The Journal of Biological Chemistry279 (16): 15994–9. doi:10.1074/jbc.M311815200PMID 14761975.
  4. ^ Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Gröne HJ, et al. (June 2004). “Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli”Human Molecular Genetics13 (12): 1249–55. doi:10.1093/hmg/ddh136PMID 15115759.
  5. ^ Tedmanson S (5 November 2009). “Doctors risk untried drug to stop baby’s brain dissolving”TimesOnline.
  6. ^ Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. (November 2015). “Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study”. Lancet386 (10007): 1955–63. doi:10.1016/S0140-6736(15)00124-5PMID 26343839S2CID 21954888.

External links

Molybdenum cofactor deficiency (MoCD) is an exceptionally rare autosomal recessive disorder resulting in a deficiency of three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde oxidase.1 Signs and symptoms begin shortly after birth and are caused by a build-up of toxic sulfites resulting from a lack of SOX activity.1,5 Patients with MoCD may present with metabolic acidosis, intracranial hemorrhage, feeding difficulties, and significant neurological symptoms such as muscle hyper- and hypotonia, intractable seizures, spastic paraplegia, myoclonus, and opisthotonus. In addition, patients with MoCD are often born with morphologic evidence of the disorder such as microcephaly, cerebral atrophy/hypodensity, dilated ventricles, and ocular abnormalities.1 MoCD is incurable and median survival in untreated patients is approximately 36 months1 – treatment, then, is focused on improving survival and maintaining neurological function.

The most common subtype of MoCD, type A, involves mutations in MOCS1 wherein the first step of molybdenum cofactor synthesis – the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP) – is interrupted.1,3 In the past, management strategies for this disorder involved symptomatic and supportive treatment,5 though efforts were made to develop a suitable exogenous replacement for the missing cPMP. In 2009 a recombinant, E. coli-produced cPMP was granted orphan drug designation by the FDA, becoming the first therapeutic option for patients with MoCD type A.1

Fosdenopterin was approved by the FDA on Februrary 26, 2021, for the reduction of mortality in patients with MoCD type A,5 becoming the first and only therapy approved for the treatment of MoCD. By improving the three-year survival rate from 55% to 84%,7 and considering the lack of alternative therapies available, fosdenopterin appears poised to become a standard of therapy in the management of this debilitating disorder.

Fosdenopterin replaces an intermediate substrate in the synthesis of molybdenum cofactor, a compound necessary for the activation of several molybdenum-dependent enzymes including sulfite oxidase (SOX).1 Given that SOX is responsible for detoxifying sulfur-containing acids and sulfites such as S-sulfocysteine (SSC), urinary levels of SSC can be used as a surrogate marker of efficacy for fosdenopterin.7 Long-term therapy with fosdenopterin has been shown to result in a sustained reduction in urinary SSC normalized to creatinine.7

Animal studies have identified a potential risk of phototoxicity in patients receiving fosdenopterin – these patients should avoid or minimize exposure to sunlight and/or artificial UV light.7 If sun exposure is necessary, use protective clothing, hats, and sunglasses,7 in addition to seeking shade whenever practical. Consider the use of a broad-spectrum sunscreen in patients 6 months of age or older.8

Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder in which patients are deficient in three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde dehydrogenase.1 The loss of SOX activity appears to be the main driver of MoCD morbidity and mortality, as the build-up of neurotoxic sulfites typically processed by SOX results in rapid and progressive neurological damage. In MoCD type A, the disorder results from a mutation in the MOCS1 gene leading to deficient production of MOCS1A/B,7 a protein that is responsible for the first step in the synthesis of molybdenum cofactor: the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP).1,4

Fosdenopterin is an exogenous form of cPMP, replacing endogenous production and allowing for the synthesis of molybdenum cofactor to proceed.7

  1. Mechler K, Mountford WK, Hoffmann GF, Ries M: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015 Dec;17(12):965-70. doi: 10.1038/gim.2015.12. Epub 2015 Mar 12. [PubMed:25764214]
  2. Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, Konig K, McGregor TL, Font-Montgomery E, Santamaria-Araujo JA, Santra S, Vaidya M, Vierzig A, Wassmer E, Weis I, Wong FY, Veldman A, Schwarz G: Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet. 2015 Nov 14;386(10007):1955-63. doi: 10.1016/S0140-6736(15)00124-5. Epub 2015 Sep 3. [PubMed:26343839]
  3. Iobbi-Nivol C, Leimkuhler S: Molybdenum enzymes, their maturation and molybdenum cofactor biosynthesis in Escherichia coli. Biochim Biophys Acta. 2013 Aug-Sep;1827(8-9):1086-101. doi: 10.1016/j.bbabio.2012.11.007. Epub 2012 Nov 29. [PubMed:23201473]
  4. Mendel RR: The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. [PubMed:23539623]
  5. FDA News Release: FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A [Link]
  6. OMIM: MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A (# 252150) [Link]
  7. FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
  8. Health Canada: Sun safety tips for parents [Link]

SYN

Journal of Biological Chemistry (1995), 270(3), 1082-7.

https://linkinghub.elsevier.com/retrieve/pii/S0021925818829696

PATENT

WO 2005073387

PATENT

WO 2012112922

PAPER

 Journal of Medicinal Chemistry (2013), 56(4), 1730-1738

https://pubs.acs.org/doi/10.1021/jm301855r

Abstract Image

Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and d-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.

str1
str2
str3
str4

PAPER

 European Journal of Organic Chemistry (2014), 2014(11), 2231-2241.

https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/ejoc.201301784

Abstract

The first synthesis of an oxygen‐stable analogue of the natural product cyclic pyranopterin monophosphate (cPMP) is reported. In this approach, the hydropyranone ring is annelated to pyrazine by a sequence comprising ortho‐lithiation/acylation of a 2‐halopyrazine, followed by nucleophilic aromatic substitution. The tetrose substructure is introduced from the chiral pool, from D‐galactose or D‐arabitol.

image

Abstract

Molybdenum cofactor (Moco) deficiency is a lethal hereditary metabolic disease. A recently developed therapy requires continuous intravenous supplementation of the biosynthetic Moco precursor cyclic pyranopterin monophosphate (cPMP). The limited stability of the latter natural product, mostly due to oxidative degradation, is problematic for oral administration. Therefore, the synthesis of more stable cPMP analogues is of great interest. In this context and for the first time, the synthesis of a cPMP analogue, in which the oxidation‐labile reduced pterin unit is replaced by a pyrazine moiety, was achieved starting from the chiral pool materials D‐galactose or D‐arabitol. Our synthesis, 13 steps in total, includes the following key transformations: i) pyrazine lithiation, followed by acylation; ii) closure of the pyrane ring by nucleophilic aromatic substitution; and iii) introduction of phosphate.

Patent

https://patents.google.com/patent/US9260462B2/en

Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate; cPMP), MPT, and adenylated MPT. Mutations in the Moco biosynthetase genes result in the loss of production of the molybdenum dependent enzymes sulfite-oxidase, xanthine oxidoreductase, and aldehyde oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity. Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, untreatable seizures, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.

It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis (see U.S. Pat. No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the availability of the therapeutic active agent.

Scheme 3.

Figure US09260462-20160216-C00133

Scheme 4.

Figure US09260462-20160216-C00140

(I).

Figure US09260462-20160216-C00141

 Scheme 6.

Figure US09260462-20160216-C00142

 (I).

Figure US09260462-20160216-C00143

Scheme 8.

Figure US09260462-20160216-C00144

(I).

Figure US09260462-20160216-C00145

 Scheme 10.

Figure US09260462-20160216-C00146

EXAMPLESExample 1Preparation of Precursor Z (cPMP)

Figure US09260462-20160216-C00214
Figure US09260462-20160216-C00215

Experimental

Air sensitive reactions were performed under argon. Organic solutions were dried over anhydrous MgSOand the solvents were evaporated under reduced pressure. Anhydrous and chromatography solvents were obtained commercially (anhydrous grade solvent from Sigma-Aldrich Fine Chemicals) and used without any further purification. Thin layer chromatography (t.l.c.) was performed on glass or aluminum sheets coated with 60 F254 silica gel. Organic compounds were visualized under UV light or with use of a dip of ammonium molybdate (5 wt %) and cerium(IV) sulfate 4H2O (0.2 wt %) in aq. H2SO(2M), one of I(0.2%) and KI (7%) in H2SO(1M), or 0.1% ninhydrin in EtOH. Chromatography (flash column) was performed on silica gel (40-63 μm) or on an automated system with continuous gradient facility. Optical rotations were recorded at a path length of 1 dm and are in units of 10−1 deg cmg−1; concentrations are in g/100 mL. 1H NMR spectra were measured in CDCl3, CD3OD (internal Me4Si, δ 0 ppm) or D2O(HOD, δ 4.79 ppm), and 13C NMR spectra in CDCl(center line, δ 77.0 ppm), CD3OD (center line, δ 49.0 ppm) or DMSO d(center line δ 39.7 ppm), D2O (no internal reference or internal CH3CN, δ 1.47 ppm where stated). Assignments of 1H and 13C resonances were based on 2D (1H—1H DQF-COSY, 1H—13C HSQC, HMBC) and DEPT experiments. 31P NMR were run at 202.3 MHz and are reported without reference. High resolution electrospray mass spectra (ESI-HRMS) were recorded on a Q-TOF Tandem Mass

Spectrometer. Microanalyses were performed by the Campbell Microanalytical Department, University of Otago, Dunedin, New Zealand.

A. Preparation of (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one mono hydrate (1)

2,5,6-Triamino-3,4-dihydropyrimidin-4-one dihydrochloride (Pfleiderer, W.; Chem. Ber. 1957, 90, 2272; Org. Synth. 1952, 32, 45; Org. Synth. 1963, Coll. Vol. 4, 245, 10.0 g, 46.7 mmol), D-galactose phenylhydrazone (Goswami, S.; Adak, A. K. Tetrahedron Lett. 2005, 46, 221-224, 15.78 g, 58.4 mmol) and 2-mercaptoethanol (1 mL) were stirred and heated to reflux (bath temp 110° C.) in a 1:1 mixture of MeOH—H2O (400 mL) for 2 h. After cooling to ambient temperature, diethyl ether (500 mL) was added, the flask was shaken and the diethyl ether layer decanted off and discarded. The process was repeated with two further portions of diethyl ether (500 mL) and then the remaining volatiles were evaporated. Methanol (40 mL), H2O (40 mL) and triethylamine (39.4 mL, 280 mmol) were successively added and the mixture seeded with a few milligrams of 1. After 5 min a yellow solid was filtered off, washed with a little MeOH and dried to give 1 as a monohydrate (5.05 g, 36%) of suitable purity for further use. An analytical portion was recrystallized from DMSO-EtOH or boiling H2O. MPt 226 dec. [α]D 20 +135.6 (c1.13, DMSO). 1H NMR (DMSO d6): δ 10.19 (bs, exchanged D2O, 1H), 7.29 (d, J=5.0 Hz, slowly exchanged D2O, 1H), 5.90 (s, exchanged D2O, 2H), 5.33 (d, J=5.4 Hz, exchanged D2O, 1H), 4.66 (ddd, J˜5.0, ˜1.3, ˜1.3 Hz, 1H), 4.59 (t, J=5.6 Hz, exchanged D2O, 1H), 4.39 (d, J=10.3 Hz, exchanged D2O, 1H), 3.80 (bt, J˜1.8 Hz, exchanged D2O, 1H), 3.70 (m, 1H), 3.58 (dd, J=10.3, 3.0 Hz, 1H), 3.53 (dt, J=10.7, 6.4 Hz, 1H), 3.43 (ddd, J=11.2, 5.9, 5.9 Hz, 1H), 3.35 (t, J=6.4 Hz, 1H), 3.04 (br m, 1H). 13C NMR (DMSO dcenter line 6 39.7): δ 156.3 (C), 150.4 (C), 148.4 (C), 99.0 (C), 79.4 (CH), 76.5 (CH), 68.9 (CH), 68.6 (CH), 60.6 (CH2), 53.9 (CH). Anal. calcd. for C10H15N5O5H2O 39.60; C, 5.65; H, 23.09; N. found 39.64; C, 5.71; H, 22.83; N.

B. Preparation of Compounds 2 (a or b) and 3 (a, b or c)

Di-tert-butyl dicarbonate (10.33 g, 47.3 mmol) and DMAP (0.321 g, 2.63 mmol) were added to a stirred suspension of 1 (1.5 g, 5.26 mmol) in anhydrous THF (90 mL) at 50° C. under Ar. After 20 h a clear solution resulted. The solvent was evaporated and the residue chromatographed on silica gel (gradient of 0 to 40% EtOAc in hexanes) to give two product fractions. The first product to elute was a yellow foam (1.46 g). The product was observed to be a mixture of two compounds by 1H NMR containing mainly a product with seven Boc groups (2a or 2b). A sample was crystallized from EtOAc-hexanes to give 2a or 2b as a fine crystalline solid. MPt 189-191° C. [α]D 20 −43.6 (c 0.99, MeOH). 1H NMR (500 MHz, CDCl3): δ 5.71 (t, J=1.7 Hz, 1H), 5.15 (dt, J=3.5, ˜1.0, 1H), 4.97 (t, J=3.8, 1H), 4.35 (br t, J=˜1.7, 1H), 4.09-3.97 (m, 3H), 3.91 (m, 1H), 1.55, 1.52, 1.51, 1.50, 1.45 (5s, 45H), 1.40 (s, 18H). 13C NMR (125.7 MHz, CDCl3): δ 152.84 (C), 152.78 (C), 151.5 (C), 150.9 (C), 150.7 (2×C), 150.3 (C), 149.1 (C), 144.8 (C), 144.7 (C), 118.0 (C), 84.6 (C), 83.6 (C), 83.5 (C), 82.7 (3×C), 82.6 (C), 76.3 (CH), 73.0 (CH), 71.4 (CH), 67.2 (CH), 64.0 (CH2), 51.4 (CH), 28.1 (CH3), 27.8 (2×CH3), 27.7 (CH3), 27.6 (3×CH3). MS-ESI+ for C45H72N5O19 +, (M+H)+, Calcd. 986.4817. found 986.4818. Anal. calcd. for C45H71N5O19H2O 54.39; C, 7.39; H, 6.34; N. found 54.66; C, 7.17; H, 7.05; N. A second fraction was obtained as a yellow foam (2.68 g) which by 1H NMR was a product with six Boc groups present (3a, 3b or 3c). A small amount was crystallized from EtOAc-hexanes to give colorless crystals. [α]D 2O −47.6 (c, 1.17, CHCl3). 1H NMR (500 MHz, CDCl3): δ 11.10 (br s, exchanged D2O, 1H), 5.58 (t, J=1.8 Hz, 1H), 5.17 (d, J=3.4 Hz, 1H), 4.97 (t, J=3.9 Hz, 1H), 4.62 (s, exchanged D2O, 1H), 4.16 (dd, J=11.3, 5.9 Hz, 1H), 4.12 (dd, J=11.3, 6.4 Hz, 1H), 3.95 (dt, J=6.1, 1.1 Hz, 1H), 3.76 (m, 1H), 1.51, 1.50, 1.49, 1.48, 1.46 (5s, 54H). 13C NMR (125.7 MHz, CDCl3): δ 156.6 (C), 153.0 (C), 152.9 (C), 151.9 (C), 150.6 (C), 149.4 (2×C), 136.2 (C), 131.8 (C), 116.9 (C), 85.0 (2×C), 83.3 (C), 82.8 (C), 82.49 (C), 82.46 (C), 73.3 (CH), 71.5 (CH), 67.2 (CH), 64.5 (CH2), 51.3 (CH), 28.0, 27.72, 27.68, 27.6 (4×CH3). MS-ESI+ for C40H64N5O17 +, (M+H)+calcd. 886.4287. found 886.4289.

C. Preparation of Compound 4a, 4b or 4c

Step 1—The first fraction from B above containing mainly compounds 2a or 2b (1.46 g, 1.481 mmol) was dissolved in MeOH (29 mL) and sodium methoxide in MeOH (1M, 8.14 mL, 8.14 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.

Step 2—The second fraction from B above containing mainly 3a, 3b or 3c (2.68 g, 3.02 mmol) was dissolved in MeOH (54 mL) and sodium methoxide in MeOH (1M, 12.10 mL, 12.10 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.

The products from step 1 and step 2 above were combined and chromatographed on silica gel (gradient of 0 to 15% MeOH in CHCl3) to give 4a, 4b or 4c as a cream colored solid (1.97 g). 1H NMR (500 MHz, DMSO d6): δ 12.67 (br s, exchanged D2O, 1H), 5.48 (d, J=5.2 Hz, exchanged D2O, 1H), 5.43 (t, J=˜1.9 Hz, after D2O exchange became a d, J=1.9 Hz, 1H), 5.00 (br s, exchanged D2O, 1H), 4.62 (d, J=5.7 Hz, exchanged D2O, 1H), 4.27 (d, J=6.0 Hz, exchanged D2O, 1H), 3.89 (dt, J=5.2, 3.8 Hz, after D2O became a t, J=3.9 Hz, 1H), 3.62 (dd, J=6.0, 3.7 Hz, after D2O exchange became a d, J=3.7 Hz, 1H), 3.52-3.39 (m, 4H), 1.42 (s, 9H), 1.41 (s, 18H). 13C NMR (125.7 MHz, DMSO d6): δ 157.9 (C), 151.1, (C), 149.8 (2×C), 134.6 (C), 131.4 (C), 118.8 (C), 83.5 (2×C), 81.3 (C), 78.2 (CH), 76.5 (CH), 68.1 (CH), 66.8 (CH), 60.6 (CH2), 54.4 (CH), 27.9 (CH3), 27.6 (2×CH3). MS-ESI+ for C25H40N5O11 +, (M+H)+ calcd. 586.2719. found 586.2717.

D. Preparation of Compound 5a, 5b or 5c

Compound 4a, 4b or 4c (992 mg, 1.69 mmol) was dissolved in anhydrous pyridine and concentrated. The residue was dissolved in anhydrous CH2Cl(10 mL) and pyridine (5 mL) under a nitrogen atmosphere and the solution was cooled to −42° C. in an acetonitrile/dry ice bath. Methyl dichlorophosphate (187 μL, 1.86 mmol) was added dropwise and the mixture was stirred for 2 h 20 min. Water (10 mL) was added to the cold solution which was then removed from the cold bath and diluted with ethyl acetate (50 mL) and saturated NaCl solution (30 mL). The organic portion was separated and washed with saturated NaCl solution. The combined aqueous portions were extracted twice further with ethyl acetate and the combined organic portions were dried over MgSOand concentrated. Purification by silica gel flash column chromatography (eluting with 2-20% methanol in ethyl acetate) gave the cyclic methyl phosphate 5a, 5b or 5c (731 mg, 65%). 1H NMR (500 MHz, CDCl3,): δ 11.72 (bs, exchanged D2O, 1H), 5.63 (t, J=1.8 Hz, 1H), 5.41 (s, exchanged D2O, 1H), 4.95 (d, J=3.2 Hz, 1H), 4.70 (dt, J=12.4, 1.8 Hz, 1H), 4.42 (dd, J=22.1, 12.1 Hz, 1H). 4.15 (q, J=3.7 Hz, 1H), 3.82 (s, 1H), 3.75 (s, 1H), 3.58 (d, J=11.7 Hz, 3H), 2.10 (bs, exchanged D20, 1H+H2O), 1.50 (s, 9H), 1.46 (s, 18H). 13C NMR (125.7 MHz, CDCl3, centre line δ 77.0): δ 157.5 (C), 151.2 (C), 149.6 (2×C), 134.5 (C), 132.3 (C), 117.6 (C), 84.7 (2×C), 82.8 (C), 77.3 (CH), 74.8 (d, J=4.1 Hz, CH), 69.7 (CH2), 68.8 (d, J=4.1 Hz, CH), 68.6 (d, J=5.9 Hz, CH), 56.0 (d, J=7.4 Hz, CH3), 51.8 (CH), 28.1 (CH3), 27.8 (CH3). MS-ESI+ for C26H40N5NaO13P+ (M+Na)+, calcd. 684.2252. found 684.2251.

E. Preparation of Compound 6a, 6b or 6c

Compound 5a, 5b or 5c (223 mg, 0.34 mmol) was dissolved in anhydrous CH2Cl(7 mL) under a nitrogen atmosphere. Anhydrous DMSO (104 μL, 1.46 mmol) was added and the solution was cooled to −78° C. Trifluoroacetic anhydride (104 μL, 0.74 mmol) was added dropwise and the mixture was stirred for 40 min. N,N-diisopropylethylamine (513 μL, 2.94 mmol) was added and the stirring was continued for 50 min at −78° C. Saturated NaCl solution (20 mL) was added and the mixture removed from the cold bath and diluted with CH2Cl(30 mL). Glacial acetic acid (170 μL, 8.75 mmol) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous phase was washed with CH2Cl(10 mL). The combined organic phases were washed with 5% aqueous HCl, 3:1 saturated NaCl solution:10% NaHCOsolution and saturated NaCl solution successively, dried over MgSO4, and concentrated to give compound 6a, 6b or 6c (228 mg, quant.) of suitable purity for further use. 1H NMR (500 MHz, CDCl3): δ 5.86 (m, 1 H), 5.07 (m, 1 H), 4.70-4.64 (m, 2 H), 4.49-4.40 (m, 1 H), 4.27 (m, 1 H), 3.56, m, 4 H), 1.49 (s, 9 H), 1.46 (s, 18 H) ppm. 13C NMR (500 MHz, CDCl3): δ 157.5 (C), 151.1 (C), 150.6 (2 C), 134.6 (C), 132.7 (C), 116.6 (C), 92.0 (C), 84.6 (2 C), 83.6 (C), 78.0 (CH), 76.0 (CH), 70.4 (CH2), 67.9 (CH), 56.2 (CH3) δ6.0 (CH), 28.2 (3CH3), 26.8 (6 CH3) ppm. 31P NMR (500 MHz, CDCl3): δ−6.3 ppm.

F. Preparation of compound 7: (4aR,5aR,11aR,12aS)-1,3,2-Dioxaphosphorino[4′,5′:5,6]pyrano[3,2-g]pteridin-10(4H)-one,8-amino-4-a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-2-oxide

Compound 6a, 6b or 6c (10 mg, 14.8 μmol was dissolved in dry acetonitrile (0.2 mL) and cooled to 0° C. Bromotrimethylsilane (19.2 μL, 148 μmol) was added dropwise and the mixture was allowed to warm to ambient temperature and stirred for 5 h during which time a precipitate formed. HCl(aq) (10 μl, 37%) was added and the mixture was stirred for a further 15 min. The mixture was centrifuged for 15 min (3000 g) and the resulting precipitate collected. Acetonitrile (0.5 mL) was added and the mixture was centrifuged for a further 15 min. The acetonitrile wash and centrifugation was repeated a further two times and the resulting solid was dried under high vacuum to give compound 7 (4 mg, 75%). 1H NMR (500 MHz, D2O): δ 5.22 (d, J=1.6 Hz, 1H), 4.34 (dt, J=13, 1.6 Hz, 1H), 4.29-4.27 (m, 1H), 4.24-4.18 (m, 1H), 3.94 (br m, 1H), 3.44 (t, J=1.4 Hz, 1H). 31P NMR (500 MHz, D2O): δ −4.8 MS-ESI+ for C10H15N5O8P+, (M+H)+calcd. 364.0653. found 364.0652.

Example 2Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. Coli in the In vitro Synthesis of Moco

In vitro synthesis of Moco was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. Moco synthesis also involved the use of the purified components E. coli MPT synthase, gephyrin, molybdate, ATP, and apo-sulfite oxidase. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. The assay is based on the conversion of cPMP into MPT, the subsequent molybdate insertion using recombinant gephyrin and ATP, and finally the reconstitution of human apo-sulfite oxidase.

As shown in FIG. 1, Moco synthesis from synthetic cPMP was confirmed, and no differences in Moco conversion were found in comparison to E. coli purified cPMP.

Example 3Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. coli in the In vitro Synthesis of MPT

In vitro synthesis of MPT was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. MPT synthesis also involved the use of in vitro assembled MPT synthase from E. coli. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. Three repetitions of each experiment were performed and are shown in FIGS. 2 and 3.

As shown in FIGS. 2 and 3, MPT synthesis from synthetic cPMP confirmed, and no apparent differences in MPT conversion were found when compared to E. coli purified cPMP. A linear conversion of cPMP into MPT is seen in all samples confirming the identity of synthetic cPMP (see FIG. 2). Slight differences between the repetitions are believed to be due to an inaccurate concentration determination of synthetic cPMP given the presence of interfering chromophores.

Example 4Preparation of Precursor Z (cPMP)

A. Preparation of Starting Materials

Figure US09260462-20160216-C00216

B. Introduction of the protected Phosphate

Figure US09260462-20160216-C00217


The formation of the cyclic phosphate using intermediate [10] (630 mg) gave the desired product [11] as a 1:1 mixture of diastereoisomers (494 mg, 69%).

Figure US09260462-20160216-C00218

C. Oxidation and Overall Deprotection of the Molecule

Oxidation of the secondary alcohol to the gem-diol did prove successful on intermediate [12], but the oxidized product [13] did show significant instability and could not be purified. For this reason, deprotection of the phosphate was attempted before the oxidation. However, the reaction of intermediate [11] with TMSBr led to complete deprotection of the molecule giving intermediate [14]. An attempt to oxidize the alcohol to the gem-diol using Dess-Martin periodinane gave the aromatized pteridine [15].

Oxidation of intermediate [11] with Dess-Martin periodinane gave a mixture of starting material, oxidized product and several by-products. Finally, intermediate [11] was oxidized using the method described Example 1. Upon treatment, only partial oxidation was observed, leaving a 2:1 mixture of [11]/[16]. The crude mixture was submitted to the final deprotection. An off white solid was obtained and analyzed by 1H-NMR and HPLC-MS. These analyses suggest that cPMP has been produced along with the deprotected precursor [11].

Because the analytical HPLC conditions gave a good separation of cPMP from the major impurities, this method will be repeated on a prep-HPLC in order to isolate the final material.

CLIP

BridgeBio Pharma And Affiliate Origin Biosciences Announces FDA Acceptance Of Its New Drug Application For Fosdenopterin For The Treatment Of MoCD Type A

Application accepted under Priority Review designation with Breakthrough Therapy Designation and Rare Pediatric Disease Designation previously grantedThere are currently no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury for infants and children.This is BridgeBio’s first NDA acceptanceSAN FRANCISCO, September 29, 2020 – BridgeBio Pharma, Inc. (Nasdaq: BBIO) and affiliate Origin Biosciences today announced the US Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for fosdenopterin (previously BBP-870/ORGN001), a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.The NDA has been granted Priority Review designation. Fosdenopterin has previously been granted Breakthrough Therapy Designation and Rare Pediatric Disease Designation in the US and may be eligible for a priority review voucher if approved. It received Orphan Drug Designation in the US and Europe. This is BridgeBio’s first NDA acceptance.“We want to thank the patients, families, scientists, physicians and all others involved who helped us reach this critical milestone,” said BridgeBio CEO and founder Neil Kumar, Ph.D. “MoCD Type A is a devastating disease with a median survival of less than four years and we are eager for our investigational therapy to be available to patients, who currently have no approved treatment options. BridgeBio exists to help as many patients as possible afflicted with genetic diseases, no matter how rare. We are grateful that the FDA has accepted our first NDA for priority review and we look forward to submitting our second NDA later this year for infigratinib for second line treatment of cholangiocarcinoma.”About Fosdenopterin
Fosdenopterin is being developed for the treatment of patients with MoCD Type A. Currently, there are no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury with a median survival between 3 to 4 years. Fosdenopterin is a first-in-class cPMP hydrobromide dihydrate and is designed to treat MoCD Type A by replacing cPMP and permitting the two remaining MoCo synthesis steps to proceed, with activation of MoCo-dependent enzymes and elimination of sulfites.About Molybdenum Cofactor Deficiency (MoCD) Type A
MoCD Type A is an ultra-rare, autosomal recessive, inborn error of metabolism caused by disruption in molybdenum cofactor (MoCo) synthesis which is vital to prevent buildup of s-sulfocysteine, a neurotoxic metabolite of sulfite. Patients are often infants with severe encephalopathy and intractable seizures. Disease progression is rapid with a high infant mortality rate.Those who survive beyond the first few month’s experience profuse developmental delays and suffer the effects of irreversible neurological damage, including brain atrophy with white matter necrosis, dysmorphic facial features, and spastic paraplegia. Clinical presentation that can be similar to hypoxic-ischemic encephalopathy (HIE) or other neonatal seizure disorders may lead to misdiagnosis and underdiagnosis. Immediate testing for elevated sulfite levels and S-sulfocysteine in the urine and very low serum uric acid may help with suspicion of MoCD.About Origin Biosciences
Origin Biosciences, an affiliate of BridgeBio Pharma, is a biotechnology company focused on developing and commercializing a treatment for Molybdenum Cofactor Deficiency (MoCD) Type A. Origin is led by a team of veteran biotechnology executives. Together with patients and physicians, the company aims to bring a safe, effective treatment for MoCD Type A to market as quickly as possible. For more information on Origin Biosciences, please visit the company’s website at www.origintx.com.

About BridgeBio Pharma
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development. For more information visit bridgebio.com.

Clinical data
Trade namesNulibry
Other namesPrecursor Z, ALXN1101
License dataUS DailyMedFosdenopterin
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
showIUPAC name
CAS Number150829-29-1
PubChem CID135894389
DrugBankDB16628
ChemSpider17221217
UNII4X7K2681Y7
KEGGD11779
ChEMBLChEMBL2338675
CompTox Dashboard (EPA)DTXSID90934067 
Chemical and physical data
FormulaC10H14N5O8P
Molar mass363.223 g·mol−1
3D model (JSmol)Interactive image
hideSMILESNC1=NC(=O)C2=C(N[C@@H]3O[C@@H]4COP(=O)(O)O[C@@H]4C(O)(O)[C@@H]3N2)N1
hideInChIInChI=1S/C10H14N5O8P/c11-9-14-6-3(7(16)15-9)12-4-8(13-6)22-2-1-21-24(19,20)23-5(2)10(4,17)18/h2,4-5,8,12,17-18H,1H2,(H,19,20)(H4,11,13,14,15,16)/t2-,4-,5+,8-/m1/s1Key:CZAKJJUNKNPTTO-AJFJRRQVSA-N

//////////Fosdenopterin hydrobromide, ホスデノプテリン臭化水素酸塩水和物 , ALXN1101 HBrUNII-X41B5W735TX41B5W735TD11780, BBP-870/ORGN001, Priority Review designation, Breakthrough Therapy Designation, Rare Pediatric Disease Designation, Orphan Drug Designation, molybdenum cofactor deficiency, ALXN-1101, WHO 11150, FDA 2021, APPROVALS 2021

#Fosdenopterin hydrobromide, #ホスデノプテリン臭化水素酸塩水和物 , #ALXN1101 HBr, #UNII-X41B5W735TX41B5W735T, #D11780, #BBP-870/ORGN001, #Priority Review designation, #Breakthrough Therapy Designation, #Rare Pediatric Disease Designation, #Orphan Drug Designation, #molybdenum cofactor deficiency, #ALXN-1101, #WHO 11150, #FDA 2021, #APPROVALS 2021

C1C2C(C(C3C(O2)NC4=C(N3)C(=O)NC(=N4)N)(O)O)OP(=O)(O1)O.O.O.Br

Melphalan flufenamide hydrochloride


Melphalan flufenamide.svg.HCl

Melphalan flufenamide hydrochloride

メルファランフルフェナミド塩酸塩;

L-Phenylalanine, 4-[bis(2-chloroethyl)amino]-L-phenylalanyl-4-fluoro-, ethyl ester, hydrochloride

FormulaC24H30Cl2FN3O3. HCl
CAS380449-54-7
Mol weight534.8786

FDA APPROVED PEPAXTO, 2021/2/26

EfficacyAntineoplastic, Alkylating agent
  DiseaseMultiple myeloma
  • Ethyl (2S)-2-[(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanamido]-3-(4-fluorophenyl)propanoate
  • J 1
  • J 1 (prodrug)
  • L-Melphalanyl-L-p-fluorophenylalanine ethyl ester
  • Melflufen
  • Melphalan flufenamide
  • Pepaxto
  • Prodrug J 1
ChemSpider 2D Image | Melflufen | C24H30Cl2FN3O3

Melflufen

мелфалана флуфенамид [Russian] [INN]ميلفالان فلوفيناميد [Arabic] [INN]氟美法仑 [Chinese] [INN]380449-51-4[RN]
9493Ethyl 4-[bis(2-chloroethyl)amino]-L-phenylalanyl-4-fluoro-L-phenylalaninate
F70C5K4786L-Phenylalanine, 4-[bis(2-chloroethyl)amino]-L-phenylalanyl-4-fluoro-, ethyl ester

Melphalan flufenamide, sold under the brand name Pepaxto, is an anticancer medication used to treat multiple myeloma.[3][4]

The most common adverse reactions include fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.[3]

Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) that exerts a targeted delivery of melphalan in cells with high expression of aminopeptidases, such as aminopeptidase N, which has been described as over-expressed in human malignancies.Aminopeptidase N plays a functional role in malignant angiogenesis.

Melphalan flufenamide was approved for medical use in the United States in February 2021.[4][5]

Medical uses

Melphalan flufenamide is indicated in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma, with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody.[3][4]

Metabolism

Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard.[6] Its biological half-life is 10 minutes in vitro.

Origin and development

Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) with a targeted delivery within tumor cells of melphalan, a widely used classical chemotherapeutic belonging to a group of alkylating agents developed more than 50 years ago. Substantial clinical experience has been accumulated about melphalan since then. Numerous derivatives of melphalan, designed to increase the activity or selectivity, have been developed and investigated in vitro or in animal models.[7] Melphalan flufenamide was synthesized, partly due to previous experience of an alkylating peptide cocktail named Peptichemio[8] and its anti-tumor activity is being investigated.

Pharmacology

Compared to melphalan, melphalan flufenamide exhibits significantly higher in vitro and in vivo activity in several models of human cancer.[9][10][11][12][13][14][15][16] A preclinical study, performed at Dana–Farber Cancer Institute, demonstrated that melphalan flufenamide induced apoptosis in multiple myeloma cell lines, even those resistant to conventional treatment (including melphalan).[17] In vivo effects in xenografted animals were also observed, and the results confirmed by M Chesi and co-workers – in a unique genetically engineered mouse model of multiple myeloma – are believed to be predictive of clinical efficacy.[18]

Structure

Chemically, the drug is best described as the ethyl ester of a dipeptide consisting of melphalan and the amino acid derivative para-fluoro-L-phenylalanine.

Pharmacokinetics

Pharmacokinetic analysis of plasma samples showed a rapid formation of melphalan; concentrations generally exceeded those of melphalan flufenamide during ongoing infusion. Melphalan flufenamide rapidly disappeared from plasma after infusion, while melphalan typically peaked a few minutes after the end of infusion. This suggests that melphalan flufenamide is rapidly and widely distributed to extravasal tissues, in which melphalan is formed and thereafter redistributed to plasma.[19]

This rapid disappearance from plasma is likely due to hydrolytic enzymes.[20] The Zn(2+) dependent ectopeptidase (also known as alanine aminopeptidase), degrades proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N is frequently overexpressed in tumors and has been associated with the growth of different human cancers suggesting it as a suitable target for anti-cancerous therapy.[21]

Adverse effects

In a human Phase 1 trial, no dose-limiting toxicities (DLTs) were observed at lower doses. At doses above 50 mg, reversible neutropenias and thrombocytopenias were observed, and particularly evident in heavily pretreated patients.[22] These side-effects are shared by most chemotherapies, including alkylating agents in general.

Drug interactions

No drug interaction studies have been reported. Several in vitro studies indicate that melphalan flufenamide may be successfully combined with standard chemotherapy or targeted agents.[23][24]

Therapeutic efficacy

In a Phase 1/2 trial, in solid tumor patients refractory to standard therapy, response evaluation showed disease stabilization in a majority of patients.[25][26] In relapsed and refractory multiple-myeloma (RRMM) patients, promising activity was seen in heavily pre-treated RRMM patients where conventional therapies had failed; the median Progression-Free Survival was 9.4 months and the Duration of Response was 9.6 months.[27] An overall response rate of 41% and a clinical benefit rate of 56% were also shown, with similar results seen across patient populations regardless of their refractory status. Hematologic toxicity was common, but manageable with cycle prolongations, dose modifications and supportive therapy, and non-hematologic treatment-related adverse events were infrequent.

History

Efficacy was evaluated in HORIZON (NCT02963493), a multicenter, single-arm trial.[3] Eligible patients were required to have relapsed refractory multiple myeloma.[3] Patients received melphalan flufenamide 40 mg intravenously on day 1 and dexamethasone 40 mg orally (20 mg for patients ≥75 years of age) on day 1, 8, 15 and 22 of each 28-day cycle until disease progression or unacceptable toxicity.[3] Efficacy was evaluated in a subpopulation of 97 patients who received four or more prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody.[3]

The application for melphalan flufenamide was granted priority review and orphan drug designations.[3]

Society and culture

Names

Melphalan flufenamide is the International nonproprietary name (INN).[28]

PAPER

 Organic Process Research & Development (2019), 23(6), 1191-1196.

https://pubs.acs.org/doi/pdf/10.1021/bk-2020-1369.ch005

Ethyl (2S)-2-[(2S)-2-amino-3-[bis-(2-chloroethyl)amino]phenyl]propaneamido]-3-(4-fluorophenyl)propanoate hydrochloride, (melphalan flufenamide or Melflufen), is an alkylating agent intended for the treatment of multiple myeloma. Initially only milligram quantities were synthesized, following a route starting from pharmaceutical-grade melphalan. Along with the pharmaceutical development, adjustments were made to the original medicinal chemistry route. This resulted in material for early clinical trials, but it became obvious that further development was necessary. Development resulted in a route in which two phenyl alanine derivatives were coupled to give a dipeptide. This intermediate was further manipulated to give an aniline which could be converted into the desired compound melflufen. The aniline derivative was converted to the corresponding N,Nbis-chloroethylaniline using chloroacetic acid and borane. Deprotection and conversion to the hydrochloride gave melflufen in good yield and excellent purity. Production was performed without chromatography at multi-kilogram scale to supply the API for Phase III studies and commercial validation batches.

PAPER

Antineoplastics

R.S. Vardanyan, V.J. Hruby, in Synthesis of Essential Drugs, 2006

Melphalan

Melphalan, l-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine (30.2.1.13), is a structural analog of chlorambucil in which the butyric acid fragment is replaced with an aminoacid fragment, alanine. This drug is synthesized from l-phenylalanine, the nitration of which with nitric acid gives 4-nitro-l-phenylalanine (30.2.1.8). Reacting this with an ethanol in the presence of hydrogen chloride gives the hydrochloride of 4-nitro-l-phenylalanine ethyl ester (30.2.1.9), the amino group of which is protected by changing it to phthalamide by a reaction with succinic anhydride to give 30.2.1.10. The nitro group in this molecule is reduced to an amino group using palladium on calcium carbonate as a catalyst. The resulting aromatic amine (30.2.1.11) is then reacted with ethylene oxide, which forms a bis-(2-hydroxyethyl)-amino derivative (30.2.1.12). The hydroxy groups in this molecule are replaced with chlorine atoms upon reaction with thionyl chloride, after which treatment with hydrochloric acid removes the phthalamide protection, giving melphalan (30.2.13) [47–50].

Melaphalan is used intravenously and orally to treat multiple myeloma and cancers of the breast, neck, and ovaries. A synonym of this drug is alkeran.

The racemic form of this drug, d,l-3-[p-[bis-(2-chloroethyl)amino]phenyl]alanine, is also widely used under the name sarcolysine or racemelfalan.
PATENT WO 2001096367PAPEROncology Research (2003), 14(3), 113-132PATENTWO 2016180740https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016180740

Alkylating agents, such as drugs derived from nitrogen mustard, that is bis(2-chloroethyl)amine derivatives, are used as chemotherapeutic drugs in the treatment of a wide variety of cancers. Melphalan, or p-bis-(2-chloroethyl)-amino-L-phenylalanine (compound (Id), CAS No. 148-82-3), is an alkylating agent which is a conjugate of nitrogen mustard and the amino acid phenylalanine (US 3,032,584). Melphalan is used clinically in the treatment of metastatic melanomas, but has limited efficacy, dose-limiting toxicities and resistance can develop.

Melphalan flufenamide ethyl ester (L-melphalanyl-L-p-fluorophenylalanine ethyl ester, melflufen, compound (Ib)) is a derivative of melphalan conjugated to the amino acid phenylalanine, creating a dipeptide (WO 01/96367):

The monohydrochloride salt of melflufen (L-melphalanyl-L-p-fluorophenylalanine ethyl ester monohydrochloride; hydrochloride salt of (Ib); CAS No. 380449-54-7) is referred to as melflufen hydrochloride.

When studied in cultures of human tumor cells representing approximately 20 different diagnoses of human cancers, including myeloma, melflufen showed 50- to 100-fold higher potency compared with that of melphalan (http://www.oncopeptides.se/products/melflufen/ accessed 26 March 2015). Data disclosed in Arghya, et al, abstract 2086 “A Novel Alkylating Agent Melphalan Flufenamide Ethyl Ester Induces an Irreversible DNA Damage in Multiple Myeloma Cells” (2014) 5th ASH Annual Meeting and Exposition, suggest that melflufen triggers a rapid, robust and irreversible DNA damage, which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Melflufen is currently undergoing phase I/IIa clinical trials in multiple myeloma.

A process for preparing melflufen in hydrochloride salt form is described in WO 01/96367, and is illustrated in Scheme 1, below. In that process N-tert-butoxycarbonyl-L-melphalan is reacted with p-fluorophenylalanine ethyl ester to give N-tert-butoxycarbonyl-L-melphalanyl-L-p-fluorophenylalanine ethyl ester. After purification by gradient column chromatography the yield of that step is 43%.

Scheme 1. Current route to melflufen (in hydrochloride salt form)

As shown in Scheme 1, the known process for preparing melflufen (in hydrochloride salt form) uses the cytotoxic agent melphalan as a starting material, and melflufen is synthesised in a multistep sequence. Melphalan is highly toxic, thus the staring materials and all of the intermediates, and also the waste stream generated, are extremely toxic. That is a major disadvantage in terms of safety, environmental impact and cost when using the process on a large scale. Therefore, an improved and safer method is highly desired, especially for production of melflufen on a large scale. Further, the purity of commercially available melphalan is poor due to its poor stability, the yield in each step of the process is poor, and purity of the final product made by the known process is not high.

A process for preparing melphalan is described in WO 2014/141294. In WO 2014/141294 the step to introduce the bis(2-chloroethyl) group into the molecule comprises conversion of a primary phenyl amine to a tertiary phenyl amine diol, by reaction with ethylene oxide gas. This gives a 52.6% yield. The amine diol is then converted to a bis(2-chloroethyl) phenylamine by reaction with phosphoryl chloride. Using ethylene oxide, or chloroethanol, to convert an aromatic amine to the corresponding bis-(2-hydroxy ethyl) amine, followed by

chlorination of that intermediate, is a common technique for producing aromatic bis-(2-chloroethyl) amines. It is also known to start from a chloroarene and let it undergo a SNAr-reaction with diethanolamine. The present inventors have applied those methods to produce melflufen (in its salt form), shown in Scheme 2 below.

Scheme 2. Alternative pathways to melflufen

The inventors have found that using ethylene oxide in THF (route (a) of Scheme 2), no alkylation occurs at 55 °C; increasing the temperature to 60 °C lead to the dialkylated intermediate being formed, but the reaction was very slow. To increase yield and reaction rate the reaction would require high temperatures, but this would cause increased pressure so that the reaction would need be performed in a pressure reactor. Such conditions are likely lead to formation of side products. Similar reaction conditions but using a 50:50 mixture of ethylene oxide and acetic acid (route (b) of Scheme 2) lead to faster reaction times but formation of side products. Using potassium carbonate and chloroethanol (route (c) of Scheme 2) also lead to formation of side product, possibly due to the chloroethanol undergoing partial trans-esterification with the ethyl ester.

The inventors also attempted chlorination of the di-alkylated compound. Chlorination of the bis-(2-hydroxyethyl) compound (4) of Scheme 2 using thionyl chloride in dichloromethane led to significant de-protected side product formation. Chlorination of the bis-(2-hydroxyethyl) compound (4) of Scheme 2 using POCl3 required high temperature and long

reaction times. In addition, both thionyl chloride and POCl3 are challenging to handle at large scale due to safety concerns. The inventors also converted the bis-(2-hydroxyethyl) compound (4) of Scheme 2 to the corresponding dimesylate by treatment with methanesulfonyl chloride and triethylamine. The dimesylate was treated then with sodium chloride in DMF at 120 °C. However, the crude product of this reaction contained significant side products making this route unsuitable to be used economically at scale.

In summary, none of these routes were found to be suitable for large scale production of high purity melflufen. They do not work well for the synthesis of melflufen, resulting in poor yields and are inefficient. Further, the routes shown in Scheme 2 require multiple steps to form the N, N-bis-chloroethyl amine and use toxic reagents.

Example 1 – Synthesis of compound (VIc)

To a reactor with overhead stirring, equipped with nitrogen inlet and reflux condenser, was charged Boc-nitrophenylalanine (compound (IVc)) (35.0 g, 112.8 mmol, 1 eq.), followed by acetone (420 mL), N-methylmorpholine (43.4 mL, 394.8 mmol, 3.5 eq.), fluoro-L-phenylalanine ethyl ester hydrochloride (compound (V)) (28.5 g, 115 mmol, 1.02 eq.), EDC (23.8 g, 124.1 mmol, 1.1 eq.) and HOBt·H2O (1.7 g, 11.3 mmol, 0.1 eq.). The slurry was stirred at room temperature for 18.5 h which led to full consumption of compound (IVc) according to HPLC. Water (180 mL) and 2-MeTHF (965 mL) were charged. Approximately 640 g solvent was then removed by evaporation (TJ: 35 °C) from the clear two phase orange mixture. 360 mL 2-MeTHF was then added and evaporated off twice. The water phase was acidified to pH 3 via addition of 58 mL 2 M sulfuric acid. The organic layer was heated to 35-40 °C and was then sequentially washed with water (90 mL), twice with saturated aqueous NaHCO3 solution (90 mL) and then brine (90 mL) and finally water (90 mL). To the 2-MeTHF dissolved product was added heptane (270 mL) drop wise at 35-40 °C before the mixture was allowed to reach room temperature overnight with stirring. Another 135 mL heptane was added drop wise before the beige slurry was cooled to 10 °C. The product was isolated and was rinsed with 100 mL cold 2-MeTHF/heptane 6/4. Product compound (VIc) was stored moist (82.5 g). A small sample of the product was analyzed by limit of detection (LOD) which revealed the solid to contain 43.8% solvent residues. Based on this, the purified product was obtained in a yield of 82 %. The purity was determined by HPLC to be: 99.4 area%.

1 H-NMR (300 MHz, DMSO-D6) δ 8.48 (broad d, 1H, J=7.5 Hz), 8.16 (2H, d, J=8.7 Hz), 7.55 (2H, d, J=9 Hz), 7.28 (2H, dd, J=8,7, 8.1 Hz), 7.12-7.02 (3H, m), 4.49 (1H, dd, J=14.4, 7.2 Hz), 4.32-4.24 (1 H, m), 4.04 (2H, dd, J=14.4, 7.2 Hz), 3.08-2.95 (3H,m), 2.84 (1H, dd, J=13.2, 10.8 Hz), 1.27 (s, 9H), 1.11 (3H, t, J=7.2Hz)

13C-NMR (75 MHz, DMSO-D6) δ 171.4 (C=O), 171.2 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.2 (C=O), 146.6 (C), 146.2 (C), 133.1 (C), 131.1 (2 carbon, CH, d, J=8.3 Hz), 130.6 (2 carbon, CH), 123.1 (C), 114.9 (2 carbon, CH, J=20.4 Hz), 78.1 (C), 60.6 (CH2), 55.1 (CH), 53.6 (CH), 37.3 (CH2), 35.9 (CH2), 28.0 (3 carbons, CH3), 14.0 (CH3)

Example 2 – Synthesis of compound (IIc)

To a hydrogenation autoclave was added wet solid product compound (VIc) (approximately 4.9 g dry weight, 9.7 mmol, 1 eq.), 2-MeTHF (75 mL) and 3 w/w% of a 5% Pd/C-catalyst (147 mg, 50% moist). The reaction mixture was degased with nitrogen and then 1 barg hydrogen gas was charged. Stirring was set to 600 rpm and TJ to 36 °C. The reaction was completed in four hours, The hydrogenation autoclave was rinsed with 10 mL 2-MeTHF and the rinsing portion was added to the reaction solution in the E-flask. Charcoal (250 mg, 5 wt%) was then added and the resulting mixture was stirred for 15 minutes at room temperature before it was filtered. The filter was rinsed with 10 mL 2-MeTHF and the rinsing portion was added to the filter. The light yellow/pink filtrate contained white precipitated product. The slurry was heated to approximately 40 °C to dissolve the solid before heptane (42 mL) was added drop wise during one hour. The heating was turned off and the mixture was allowed to reach room temperature with overnight stirring. Additional 21 mL heptane was the added before the mixture was cooled to approximately 7 °C (ice/water bath). The solid was isolated and was washed through with 10 mL cold 2-MeTHF/heptane 6/4. The moist solid (5.7 g) was vacuum dried at 35 °C overnight which gave a dry weight of

compound (IIc) of 4.2 g which corresponds to a yield of 91 %. The purity was determined by HPLC to be 99.1 area%.

1H-NMR (300 MHz, DMSO-D6) δ 8.26 (1H, d, J=7.5Hz), 7.26 (dd, 2H, J=8.1, 5.7 Hz), 7.09 (2H, t, J=8.7 Hz), 6.86 (2H, d, J=8.1 Hz), 6.71 (1H, d, J=8.7 Hz), 6.45 (1H, d, J=8.1 Hz), 4.87 (2H, s), 4.45 (1H, dd, J=14.4, 7.5 Hz), 4.07-4.00 (3H, m), 3.06-2.91 (2H, m), 2.71 (1H, dd, J=13.8, 3.9 Hz), 2.54-2.46 (1H, m), 1.31 (s, 9H), 1.11 (3H, t, J=6.9 Hz).

13C-NMR (75 MHz, DMSO-D6) δ 171.4 (C=O), 171.2 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.1 (C=O), 146.9 (C), 133.2 (C, d, J=3.0 Hz), 131.1 (2 carbon, CH, d, J=8.3 Hz), 129.5 (2 carbon, CH), 124.8 (C), 114.8 (2 carbon, CH, J=21.1 Hz), 113.6 (2 carbon, CH), 77.9 (C), 60.5 (CH2), 56.0 (CH), 53.5 (CH), 36.7 (CH2), 35.9 (CH2), 28.1 (3 carbons, CH3), 13.9 (CH3)

The present inventors have repeated Example 2 several times using crude compound (VIc) or recrystallised compound (VIc) (purity: 99.1 area%) as starting material and varying various reaction conditions, e.g. pressure of H2, w/w% of Pd/C, solvent and temperature. The crude purity (97.2 area%) was a slightly higher when recrystallized compound (VIc) was used as starting material than when using crude compound (VIc), in which case the crude purity is generally 95-96 area%. Final yield and purity is also slightly higher than when starting from crude compound (VIc) (98-98.5 area%).

The present inventors have also repeated Example 2 several times varying the Pd/C w/w%, temperature, pressure of H2 and concentration using 2-MeTHF as the solvent. A high conversion of Compound (VIc) (>99.5 area%) was achieved for Pd/C w/w% from 3 to 6 bar; temperature ranges from 30 to 40 °C, H2 pressure from 1 to 6 barg, and for varying reaction concentrations. The resulting crude purity was similar in all attempts (95.3-96.2 area%), as was the purity of the isolated product after crystallization from 2-MeTHF/heptane (98.0-98.5 area%).

Example 3 – Preparation of compound (IIIc)

(i) carried out using BH3SMe2 in the presence of chloroacetic acid salt

In a 0.5 L dried reactor with overhead stirrer, compound (IIc) (6.99 g, 14.76 mmol) was added, followed by anhydrous tetrahydrofuran (46 mL), chloroacetic acid (36.3 g, 383.8 mmol), chloroacetic acid sodium salt (17.2 g, 147.6 mmol) at TI=5-13°C. A solution of

BH3SMe2 (14.6 g, 191.9 mmol, 18.2 mL) was then added over 45 minutes. After the addition, the reaction temperature was adjusted to TI=25-30°C and kept for 2 hr after reaching this temperature. The reaction was slowly quenched with ethanol (17.7 g, 383.8 mmol, 22.4 mL) and was stirred overnight at TJ=5°C and then slowly diluted with distilled water (138 mL) to precipitate the product, compound (IIIc). The temperature was adjusted to TI=15°C and the stirring rate was increased before addition of a solution of aqueous K2CO3 (8.0 M, 27 mL) to pH = 7.0-7.5. The reaction slurry was collected on a filter and reaction vessel and filter-cake were washed with water (2×40 mL). The filter-cake was re-slurred in water (200 mL) for 1 hr at TJ=20°C and then filtered again. Washing with water (50 mL), followed by drying at TJ=35°C under high vacuum, produced the crude white product, compound (IIIc), in 7.85 g (88.8%) uncorrected yield. HPLC purity 97.5 area %.

Crude compound (IIIc) (7.5 gram) prepared according to the described procedure was charged to a reactor and washed down with 2-MeTHF (80 mL). Heating at TJ=50°C dissolved the substance. Heptane (80 mL) was added with stirring at TI=45-50°C and then stirred before adjusting the temperature to TJ=10°C. The precipitated solid was collected by filtration and dried at TJ=35°C under high vacuum which produced white product, compound (IIIc), in 6.86 g (91.5%). HPLC purity 99.1 area %.

1H-NMR (300 MHz, DMSO-D6) δ 8.30 (1H, d, J=7.8 Hz), 7.26 (2H, dd, J=8.1, 6 Hz), 7.09-7.05 (3H, m), 6.79 (1H, d, J=8.9 Hz), 6.63 (2H, d, J=8.4 Hz), 4.49-4.42 (1H, dd, J=14.7, 7.5 Hz), 4.07-3.99 (3H, m), 3.68 (8H, s), 3.06-2.91 (2H, m), 2.76 (1H, dd, J=13.8, 4.2 Hz), 2.56 (1H, m), 1.29 (9H, s), 1.1 (3H, t, J=6.6 Hz)

13C-NMR (75 MHz, DMSO-D6) δ 172.1 (C=O), 171.3 (C=O), 161.2 (C-F, d, J=242.3 Hz), 155.2 (C=O), 144.7 (C), 133.2 (C, d, J=3.0 Hz), 131.1 (2 carbon, CH, d, J=7.5 Hz), 130.2 (2 carbon, CH), 126.1 (C), 114.9 (2 carbon, CH, J=21.1 Hz), 111.6 (2 carbon, CH), 78.0 (C), 60.6 (CH2), 55.9 (CH), 53.5 (CH), 52.2 (CH2), 41.2 (CH2), 36.4 (CH2), 35.9 (CH2), 28.1 (3 carbons, CH3), 14.0 (CH3)

(ii) Carried out using BH3SMe2 in the presence of chloroacetic acid salt

In a 0.5 L dried reactor with overhead stirrer, compound (IIe) (7.5 g, 15.84 mmol) was added, followed by 2-MeTHF (150 mL). The mixture was heated to 45 °C to form a clear solution. The solution was cooled to 4 °C and chloroacetic acid (38.9 g, 411.8 mmol), followed by chloroacetic acid sodium salt (18.4 g, 158.4 mmol) was added at TI=5-13°C. A solution of BH3SMe2 (15.6 g, 205.9 mmol, 19.5 mL) was then added over 90 minutes. After the addition, the reaction temperature was adjusted to TI=20-25°C and kept for 5 hr after reaching this temperature. The reaction was slowly quenched with water at TI=15-25 °C (150 g, 8333 mmol, 150 mL), pH=3.5 in water phase, and left overnight without stirring at TI=6 °C.

Product, compound (IIIc), had precipitated out in the organic phase and the temperature was adjusted to TI=35 °C while stirring, and two clear phases formed. The phases were allowed to separate and the water phase was removed. The organic phase was washed three times with 20% NaCl(aq). pH in the three water phases were: 1.7, 1.1, and 1.1. After the removal of the third water phase, the organic phase was transferred to a round bottom flask and concentrated to half its volume on an evaporator. Product, compound (IIIc), started to precipitate out and the product slurry was allowed to mature at 6 °C for 19 hr. The slurry was collected on a filter and round bottom flask and filter-cake were washed with 2-MeTHF:n-heptane (2×40 mL), followed by drying at TJ=35 °C under high vacuum, to produce the crude white product, compound (IIIc), in 8.3 g (87.6%) uncorrected yield. HPLC purity 99.4 area % .

(iii) Carried out using borane-tetrahydrofuran in the presence of chloroacetic acid salt

In a 100 mL dried round bottom flask with magnet stirrer bar, compound (IIc) (0.75 g, 1.58 mmol) was added under a slow nitrogen flow followed by anhydrous tetrahydrofuran (6 mL), chloroacetic acid (3.89 g, 41.2 mmol), and chloroacetic acid sodium salt (1.84 g, 15.8 mmol). At TI=5-13°C °C a 1 M solution of BH3THF (20.6 mmol, 20.6 mL) was added over 30

minutes. After the addition the reaction temperature was adjusted between TI=23-28 °C and kept for 2 hr after reaching this temperature. In process control sample (HPLC) indicated in-complete reaction and the jacket temperature was set to TJ=40°C and when the internal temperature reached TI=40°C the reaction was kept at this temperature for 2 hr when in-process sample (HPLC) showed 6.7 area% starting material, 7.1% acylation adduct

(impurity) and 84.1% compound (IIIc). The reaction was progressed at TI=23°C and left for 4 days before slowly quenched with ethanol (2.4 g, 3 mL). Water (100 mL) was added and the pH adjusted with 1 M aqueous K2CO3 to pH 7. The reaction slurry was collected on a filter and reaction vessel and filter-cake were washed with water (2×20 mL) followed by drying at TJ=35°C under high vacuum produced the crude colorless product in 0.85 g (89.6%) uncorrected yield. HPLC purity was 94.3 area %, with one major impurity attributed to a chloroacylation adduct of the starting material in 3.8 area %.

(iv) Carried out using BH3SMe2 without addition of chloroacetic acid salt

In a 100 mL dried round bottom flask with magnet stirrer bar, compound (IIc) (0.75 gram, 1.58 mmol) was added under a slow nitrogen flow followed by anhydrous tetrahydrofuran (6 mL) and chloroacetic acid (3.89 g, 41.2 mmol). At TI=5-16°C a solution of BH3SMe2 (1.56 g, 20.6 mmol, 2.0 mL) was added over 30. After the addition the reaction temperature was adjusted between TI=25°C and kept for 2.5 h after reaching this temperature. A process control sample (HPLC) indicated melflufen (Compound (Ib)), the Boc-deprotected form of Compound (IIIc), in 66 area %. The reaction was slowly quenched with ethanol (2.9 g, 3.7 mL). The pH of the reaction was adjusted with 1 M aqueous K2CO3 solution to pH=8, followed by addition of EtOAc (40 mL). Layers were separated and the aqueous layer re-extracted with EtOAc (50 mL). The organic layers were combined and reduced at <30 mbar / 35°C to an oil. The oil was re-distilled from EtOAc (30 mL) twice and the residue was dried at TJ=23°C / 5 mbar to leave 1.6 g brownish oil. HPLC purity of Compound (Ib) was 66.1 area %.

Example 4 – Preparation of compound (Ib) as hydrochloride salt

Boc-melflufen (compound (IIIc)) (5.0 g, 8.3 mmol) was charged to a round bottomed flask, equipped with magnet stirrer bar, and nitrogen inlet. 1.3 M HCl (anhydrous) in ethanol (64 mL, 83.5 mmol, 10 eq.) was added. After 19 h the conversion was 99.4%. The solvents were partially distilled at TJ=33°C on a rotary evaporator, followed by the addition of ethanol (18 mL). This was repeated twice. Seed crystals were added and after 30 minutes product had precipitated. The slurry was stirred for 21 h and was then concentrated. Methyl tert-butyl ether (MTBE) (108 mL) was added at room temperature with an even rate over 30 minutes. After 100 minutes of stirring at room temperature the precipitate was collected by vacuum filtration and washed with 2×25 mL ethanol: MTBE (1:6). Drying was performed overnight at TJ=35°C / 5 mbar in vacuum oven. Yield of compound (Ib) in the form of its hydrochloride salt, 4.0 g (90%). HPLC-purity 98.7 area%.

1H-NMR (300 MHz, MeOH-D4) δ 7.26 (2H, dd, J=8.4, 8.1 Hz), 7.17 (2H, d, J=8.4 Hz), 7.02 (2H, dd, J=9, 8.4 Hz), 6.74 (2H, d, J=8.4 Hz), 4.69 (1H, dd, J=7.8, 6.3 Hz), 4.15 (2H, dd, J=14.1, 7.2 Hz), 4.04 (1H, dd, J=8.4, 5.4 Hz), 3.76 (4H, dd, J=6.3, 6 Hz), 3.67 (4H, dd, 6.6, 5.7 Hz), 3.17 (2H, dd, J=14.4, 6 Hz), 3.06-2.88 (2H, m), 1.22 (3H, t, J=7.2 Hz)

13C-NMR (75 MHz, MeOH-D4) δ 172.2 (C=O), 169.8 (C=O), 163.4 (C-F, d, J=244.5 Hz), 147.4 (C), 133.9 (C, d, J=3 Hz), 132.1 (2 carbon, CH, d, J=7.5 Hz), 131.8 (2 carbon, CH), 123.4 (C), 116.2 (2 carbon, CH, d, J=21.9 Hz), 113.7 (2 carbon, CH), 62.6 (CH2), 55.6 (CH), 55.5 (CH), 54.3 (CH2), 41.6 (CH2), 37.6 (CH2), 37.6 (CH2), 14.5 (CH3)

Example 4 was repeated successfully in the presence ethyl acetate and with varying concentrations of HCl from 1.3 M to 2.5 M and at varying temperatures from 6 °C to room temperature.PAPERhttps://pubs.acs.org/doi/10.1021/acs.oprd.9b00116 Organic Process Research & Development (2019), 23(6), 1191-1196.Melflufen is a novel cytostatic currently in phase III clinical trials for treatment of multiple myeloma. Development of a process suitable for production is described. The two key features of the novel method are late introduction of the alkylating pharmacophore and an improved method for formation of the bis-chloroethyl group.

Abstract Image

1H NMR spectrum of L-Phenylalanine, 4-[bis(2-chloroethyl)amino]-L-phenylalanyl-4-fluoro-, ethyl ester, hydrochloride (1) (in D4–MeOH).

13C NMR spectrum of L-Phenylalanine, 4-[bis(2-chloroethyl)amino]-L-phenylalanyl-4-fluoro-, ethyl ester, hydrochloride (1) (in D4–MeOH).

References

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  23. ^ Wickström, M; Haglund, C; Lindman, H; Nygren, P; Larsson, R; Gullbo, J (2008). “The novel alkylating prodrug J1: Diagnosis directed activity profile ex vivo and combination analyses in vitro”. Investigational New Drugs26 (3): 195–204. doi:10.1007/s10637-007-9092-1PMID 17922077S2CID 19915448.
  24. ^ Chauhan, D; Ray, A; Viktorsson, K; Spira, J; Paba-Prada, C; Munshi, N; Richardson, P; Lewensohn, R; Anderson, K. C. (2013). “In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells”Clinical Cancer Research19 (11): 3019–31. doi:10.1158/1078-0432.CCR-12-3752PMC 4098702PMID 23584492.
  25. ^ Berglund, Åke; Ullén, A; Lisyanskaya, A; Orlov, S; Hagberg, H; Tholander, B; Lewensohn, R; Nygren, P; Spira, J; Harmenberg, J; Jerling, M; Alvfors, C; Ringbom, M; Nordström, E; Söderlind, K; Gullbo, J (2015). “First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies”. Investigational New Drugs33 (6): 1232–41. doi:10.1007/s10637-015-0299-2PMID 26553306S2CID 8207569.
  26. ^ Viktorsson, K; Shah, C. H.; Juntti, T; Hååg, P; Zielinska-Chomej, K; Sierakowiak, A; Holmsten, K; Tu, J; Spira, J; Kanter, L; Lewensohn, R; Ullén, A (2016). “Melphalan-flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma”Molecular Oncology10 (5): 719–34. doi:10.1016/j.molonc.2015.12.013PMC 5423156PMID 26827254.
  27. ^ https://ash.confex.com/ash/2015/webprogram/Paper85666.html
  28. ^ World Health Organization (2012). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 67”. WHO Drug Information26 (1): 72. hdl:10665/109416.

External links

  • “Melphalan flufenamide”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02963493 for “A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients (HORIZON)” at ClinicalTrials.gov
Clinical data
Trade namesPepaxto
Other namesMelflufen, 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine ethyl ester, J1[1][2]
License dataUS DailyMedMelphalan_flufenamide
Legal status
Legal statusUS: ℞-only [3]
Pharmacokinetic data
MetabolismAminopeptidase hydrolysis, Spontaneous hydrolyisis on N-mustard
Elimination half-life10 min in vitro[medical citation needed]
Identifiers
showIUPAC name
CAS Number380449-51-4
PubChem CID9935639
DrugBankDB16627
ChemSpider8111267
UNIIF70C5K4786
ChEMBLChEMBL4303060
Chemical and physical data
FormulaC24H30Cl2FN3O3
Molar mass498.42 g·mol−1
3D model (JSmol)Interactive image
hideSMILESCCOC(=O)[C@H](CC1=CC=C(C=C1)F)NC(=O)[C@H](CC2=CC=C(C=C2)N(CCCl)CCCl)N
hideInChIInChI=1S/C24H30Cl2FN3O3/c1-2-33-24(32)22(16-18-3-7-19(27)8-4-18)29-23(31)21(28)15-17-5-9-20(10-6-17)30(13-11-25)14-12-26/h3-10,21-22H,2,11-16,28H2,1H3,(H,29,31)/t21-,22-/m0/s1Key:YQZNKYXGZSVEHI-VXKWHMMOSA-N

//////////Melphalan flufenamide hydrochloride, Melphalan flufenamide, FDA 2021,  APPROVALS 2021,  PEPAXTO, メルファランフルフェナミド塩酸塩 , J 1

#Melphalan flufenamide hydrochloride, #Melphalan flufenamide, #FDA 2021,  #APPROVALS 2021,  #PEPAXTO, メルファランフルフェナミド塩酸塩 , #J 1

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

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

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SYNTHESIS

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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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