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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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BELUMOSUDIL


KD025 structure.png
2-(3-(4-((1H-Indazol-5-yl)amino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide.png
2D chemical structure of 911417-87-3

BELUMOSUDIL

C26H24N6O2

MW 452.5

911417-87-3, SLx-2119, KD-025, KD 025, WHO 11343

2-[3-[4-(1H-indazol-5-ylamino)quinazolin-2-yl]phenoxy]-N-propan-2-ylacetamide

2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide

Belumosudil mesylate | C27H28N6O5S - PubChem

Belumosudil mesylate

KD025 mesylate

2109704-99-4

 

UPDATE FDA APPROVED 7/16/2021 To treat chronic graft-versus-host disease after failure of at least two prior lines of systemic therapy, Rezurock

New Drug Application (NDA): 214783
Company: KADMON PHARMA LLC

200 MG TABLET

FDA approves belumosudil for chronic graft-versus-host disease

On July 16, 2021, the Food and Drug Administration approved belumosudil (Rezurock, Kadmon Pharmaceuticals, LLC), a kinase inhibitor, for adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

Efficacy was evaluated in KD025-213 (NCT03640481), a randomized, open-label, multicenter dose-ranging trial that included 65 patients with chronic GVHD who were treated with belumosudil 200 mg taken orally once daily.

The main efficacy outcome measure was overall response rate (ORR) through Cycle 7 Day 1 where overall response included complete response (CR) or partial response (PR) according to the 2014 criteria of the NIH Consensus Development Project on Clinical Trials in Chronic Graft-versus-Host Disease. The ORR was 75% (95% CI: 63, 85); 6% of patients achieved a CR, and 69% achieved a PR. The median time to first response was 1.8 months (95% CI: 1.0, 1.9). The median duration of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, was 1.9 months (95% CI: 1.2, 2.9). In patients who achieved response, no death or new systemic therapy initiation occurred in 62% (95% CI: 46, 74) of patients for at least 12 months since response.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension.

The recommended dosage of belumosudil is 200 mg taken orally once daily with food.

View full prescribing information for Rezurock.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Australia’s Therapeutic Goods Administration, Health Canada, Switzerland’s Swissmedic, and the United Kingdom’s Medicines and Healthcare products Regulatory Agency.

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. The FDA approved this application 6 weeks ahead of the FDA goal date.

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.

Belumosudil mesylate is an orally available rho kinase 2 (ROCK 2) inhibitor being developed at Kadmon. In 2020, the drug candidate was submitted for a new drug application (NDA) in the U.S., under a real-time oncology review pilot program, for the treatment of chronic graft-versus-host disease (cGVHD). The compound is also in phase II clinical development for the treatment of idiopathic pulmonary fibrosis and diffuse cutaneous systemic sclerosis. Formerly, the company had also been conducting clinical research for the treatment of psoriasis and non-alcoholic steatohepatitis (NASH); however, no further development has been reported for these indications. Originally developed by Nano Terra, the product was licensed to Kadmon on an exclusive global basis in 2011. In 2019, Kadmon entered into a strategic partnership with BioNova Pharmaceuticals and established a joint venture, BK Pharmaceuticals, to exclusively develop and commercialize KD-025 for the treatment of graft-versus-host disease in China. The compound has been granted breakthrough therapy designation in the U.S. for the treatment of cGVHD and orphan drug designations for cGVHD and systemic sclerosis. In the E.U. belumosudil was also granted orphan drug status in the E.U. for the treatment of cGVHD.

Kadmon , under license from NT Life Sciences , is developing belumosudil as mesylate salt, a ROCK-2 inhibitor, for treating IPF, chronic graft-versus-host disease, hepatic impairment and scleroderma. In July 2021, belumosudil was reported to be in pre-registration phase.

Belumosudil (formerly KD025 and SLx-2119) is an experimental drug being explored for the treatment of chronic graft versus host disease (cGvHD), idiopathic pulmonary fibrosis (IPF), and moderate to severe psoriasis. It is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2; ROCK-II).[1] Belumosudil binds to and inhibits the serine/threonine kinase activity of ROCK2. This inhibits ROCK2-mediated signaling pathways which play major roles in pro- and anti-inflammatory immune cell responses. A genomic study in human primary cells demonstrated that the drug also has effects on oxidative phosphorylation, WNT signaling, angiogenesis, and KRAS signaling.[2] Originally developed by Surface Logix, Inc,[1] Belumosudil was later acquired by Kadmon Corporation. As of July 2020 the drug was in completed or ongoing Phase II clinical studies for cGvHD, IPF and psoriasis.[3]

cGvHD is a complication that can follow stem cell or hematopoietic stem cell transplantation where the transplanted cells (graft) attack healthy cells (host). This causes inflammation and fibrosis in multiple tissues. Two cytokines controlled by the ROCK2 signaling pathway, IL-17 and IL-21, have a major role in the cGvHD response. In a 2016 report using both mouse models and a limited human clinical trial ROCK2 inhibition with belumosudil targeted both the immunologic and fibrotic components of cGvHD and reversed the symptoms of the disease.[4] In October 2017 KD025 was granted orphan drug status in the United States for treatment of patients with cGvHD.[5]

IPF is a progressive fibrotic disease where the lining of the lungs become thickened and scarred.[6] Increased ROCK activity has been found in the lungs of humans and animals with IPF. Treatment with belumosudil reduced lung fibrosis in a bleomycin mouse model study.[7] Belumosudil may have a therapeutic benefit in IPF by targeting the fibrotic processes mediated by the ROCK signaling pathway.

Psoriasis is an inflammatory skin condition where patients experiences eruptions and remissions of thickened, erythematous, and scaly patches of skin. Down-regulation of pro-inflammatory responses was observed with KD025 treatment in Phase 2 clinical studies in patients with moderate to severe psoriasis.[8]
“Substance Name:Substance Name: Belumosudil [USAN]”.

PATENT

WO2012040499  

https://patents.google.com/patent/WO2012040499A2/en

PATENT

CN106916145  

https://patents.google.com/patent/CN106916145A/en

WO 2014055996, WO 2015157556

(7) preparation of SLx-2119:
 
N- isopropyls -2- [3- (4- chloro-quinazolines base)-phenoxy group]-acetamide VI is sequentially added in 25mL tube sealings (1.2mmol), 5- Aminoindazoles (1mmol) and DMF (5mL), load onto condensation reflux unit;Back flow reaction is carried out at 100 DEG C, After 2.5h, raw material N- isopropyls -2- [3- (4- chloro-quinazolines base)-phenoxy group]-acetamide VI is monitored by TLC and reacts complete Afterwards, stop stirring, add water after being quenched, organic layer, saturated common salt water washing, anhydrous Na are extracted with ethyl acetate2SO4Dry, be spin-dried for Obtain SLx-2119, brown solid (yield 87%), as shown in figure 1,1H NMR(500MHz,DMSO)δ(ppm):13.12(br, NH,1H),9.98(br,NH,1H),8.61-8.59(m,1H),8.32(s,1H),8.17(s,1H),8.06-8.03(m,2H), 7.97-7.96(m,1H),7.87-7.84(m,1H),7.66-7.61(m,2H),7.44-7.40(m,1H),7.09-7.08(m, 1H), 4.57 (s, 2H), 4.04-3.96 (m, 1H), 1.11 (d, J=5.0Hz, 6H).
 

Patent

WO-2021129589

Novel crystalline polymorphic forms (N1, N2 and N15) of KD-025 (also known as belumosudil ), useful as a Rho A kinase 2 (ROCK-2) inhibitor for treating multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis (IPF), atherosclerosis, non-alcoholic fatty liver and systemic sclerosis. Represents the first filing from Sunshine Lake Pharma or its parent HEC Pharm that focuses on belumosudil.KD-025 is a selective ROCK2 (Rho-associated protein kinase 2, Rho-related protein kinase 2) inhibitor. It has multiple clinical indications such as the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, and Primary pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver, etc., among which many indications are in clinical phase I, and psoriasis and systemic sclerosis are in clinical phase II.
The structure of KD-025 is shown in the following formula (1).

Example 1 Preparation method of crystal form N1 of KD-025[0222]300mg of KD-025 solid was suspended and stirred in 10mL methanol at room temperature. After 22h, it was filtered, suction filtered and placed in a drying oven at 50°C under vacuum overnight to obtain 262mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N1; its X-ray powder diffraction pattern was basically the same as that of Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.

PATENT

WO2006105081 ,

Belumosudil product pat, 

protection in the EU states until March 2026, expires in the US in May 2029 with US154 extension.

Example 82
2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide

[0257] A suspension of 2-(3-(4-(lH-indazol-5-ylamino)qumazolin-2-yl)ρhenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DlEA (24 μL, 0.14 mmol) in dry CH2Cl2 : DMF (2 : 0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added propan-2-amine (5.4 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of propan-2-aminewere added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50 90 rnins) to afford 2-(3-(4-(lH-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide. (40 mg, 0.086 mmol, 61 %).

References

  1. Jump up to:a b Boerma M, Fu Q, Wang J, Loose DS, Bartolozzi A, Ellis JL, et al. (October 2008). “Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin”Blood Coagulation & Fibrinolysis19 (7): 709–18. doi:10.1097/MBC.0b013e32830b2891PMC 2713681PMID 18832915.
  2. ^ Park J, Chun KH (5 May 2020). “Identification of novel functions of the ROCK2-specific inhibitor KD025 by bioinformatics analysis”. Gene737: 144474. doi:10.1016/j.gene.2020.144474PMID 32057928.
  3. ^ “KD025 – Clinical Trials”. ClinicalTrials.gov. Retrieved 25 July 2020.
  4. ^ Flynn R, Paz K, Du J, Reichenbach DK, Taylor PA, Panoskaltsis-Mortari A, et al. (April 2016). “Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism”Blood127 (17): 2144–54. doi:10.1182/blood-2015-10-678706PMC 4850869PMID 26983850.
  5. ^ Shanley M (October 6, 2017). “Therapy to Treat Transplant Complications Gets Orphan Drug Designation”RareDiseaseReport. Retrieved 25 July 2018.
  6. ^ “Pulmonary Fibrosis”. The Mayo Clinic. Retrieved July 25, 2018.
  7. ^ Semedo D (June 5, 2016). “Phase 2 Study of Molecule Inhibitor for Idiopathic Pulmonary Fibrosis Begins”Lung Disease News. BioNews Services, LLC. Retrieved 25 July 2018.
  8. ^ Zanin-Zhorov A, Weiss JM, Trzeciak A, Chen W, Zhang J, Nyuydzefe MS, et al. (May 2017). “Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10”Journal of Immunology198 (10): 3809–3814. doi:10.4049/jimmunol.1602142PMC 5421306PMID 28389592.
 
Clinical data
Routes of
administration
Oral administration (tablets or capsules)
ATC code None
Identifiers
showIUPAC name
CAS Number 911417-87-3 
PubChem CID 11950170
UNII 834YJF89WO
CompTox Dashboard (EPA) DTXSID80238425 
Chemical and physical data
Formula C26H24N6O2
Molar mass 452.518 g·mol−1
3D model (JSmol) Interactive image
showSMILES
showInChI

////////////BELUMOSUDIL, SLx-2119, KD-025, KD 025, WHO 11343, PHASE 2, cGvHD, IPF,  psoriasis, Breakthrough Therapy, Orphan Drug Designation

CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=CC=CC=C3C(=N2)NC4=CC5=C(C=C4)NN=C5

wdt-5

NEW DRUG APPROVALS

ONE TIME

$10.00

Asparaginase erwinia chrysanthemi (recombinant)-rywn


Rylaze

Sequence:

1ADKLPNIVIL ATGGTIAGSA ATGTQTTGYK AGALGVDTLI NAVPEVKKLA51NVKGEQFSNM ASENMTGDVV LKLSQRVNEL LARDDVDGVV ITHGTDTVEE101SAYFLHLTVK SDKPVVFVAA MRPATAISAD GPMNLLEAVR VAGDKQSRGR151GVMVVLNDRI GSARYITKTN ASTLDTFKAN EEGYLGVIIG NRIYYQNRID201KLHTTRSVFD VRGLTSLPKV DILYGYQDDP EYLYDAAIQH GVKGIVYAGM251GAGSVSVRGI AGMRKAMEKG VVVIRSTRTG NGIVPPDEEL PGLVSDSLNP301AHARILLMLA LTRTSDPKVI QEYFHTY

>Protein sequence for asparaginase (Erwinia chrysanthemi) monomer
ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSNM
ASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVVFVAA
MRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNASTLDTFKAN
EEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEYLYDAAIQH
GVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNP
AHARILLMLALTRTSDPKVIQEYFHTY
References:
  1. Therapeutic Targets Database: TTD Biologic drug sequences in fasta format [Link]

Asparaginase erwinia chrysanthemi (recombinant)-rywn

JZP458-201

JZP458

CAS Registry Number 1349719-22-7

Protein Chemical FormulaC1546H2510N432O476S9

Protein Average Weight 140000.0 Da

Rylaze, FDA APPROVED 6/30/2021, BLA 761179

L-Asparaginase (ec 3.5.1.1, L-asparagine amidohydrolase) erwinia chrysanthemi tetramer alpha4Asparaginase (Dickeya chrysanthemi subunit) 

Other Names

  • Asparaginase Erwinia chrysanthemi
  • Crisantaspase
  • Cristantaspase
  • Erwinase
  • Erwinaze
  • L-Asparagine amidohydrolase (Erwinia chrysanthemi subunit)

D733ET3F9O

1349719-22-7

Asparaginase erwinia chrysanthemi [USAN]

UNII-D733ET3F9O

L-Asparaginase (erwinia)

Erwinia asparaginase

L-Asparaginase, erwinia chrysanthemi

Asparaginase (erwinia chrysanthemi)

Erwinase

Asparaginase erwinia chrysanthemi

Erwinaze

Crisantaspase

Crisantaspase [INN]

L-Asparaginase (ec 3.5.1.1, L-asparagine amidohydrolase) erwinia chrysanthemi tetramer alpha4

Asparaginase erwinia sp. [MI]

Asparaginase erwinia chrysanthemi (recombinant) [USAN]

Asparaginase erwinia chrysanthemi (recombinant)

JZP-458

A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3.

NCI: Asparaginase Erwinia chrysanthemi. An enzyme isolated from the bacterium Erwinia chrysanthemi (E. carotovora). Asparagine is critical to protein synthesis in leukemic cells, which cannot synthesize this amino acid due to the absence of the enzyme asparagine synthase. Asparaginase hydrolyzes L-asparagine to L-aspartic acid and ammonia, thereby depleting leukemic cells of asparagine and blocking protein synthesis and tumor cell proliferation, especially in the G1 phase of the cell cycle. This agent also induces apoptosis in tumor cells. The Erwinia-derived product is often used for those patients who have experienced a hypersensitivity reaction to the E. Coli formulation. (NCI Thesaurus)

  • Treatment of Acute Lymphoblastic Leukemia (ALL)
  • Antineoplastic Agents
10MG/0.5MLINJECTABLE;INTRAMUSCULAR

Label (PDF)
Letter (PDF)

Label (PDF)

PATENT

WO 2011003633

https://patents.google.com/patent/WO2011003633A1/en

The present invention concerns a conjugate of a protein having substantial L-asparagine aminohydrolase activity and polyethylene glycol, particularly wherein the polyethylene glycol has a molecular weight less than or equal to about 5000 Da, particularly a conjugate wherein the protein is a L-asparaginase from Erwinia, and its use in therapy.Proteins with L-asparagine aminohydrolase activity, commonly known as L- asparaginases, have successfully been used for the treatment of Acute Lymphoblastic Leukemia(ALL) in children for many years. ALL is the most common childhood malignancy (Avramis and Panosyan, Clin. Pharmacokinet. (2005) 44:367-393).[0003] L-asparaginase has also been used to treat Hodgkin’s disease, acute myelocytic leukemia, acute myelomonocytic leukemia, chronic lymphocytic leukemia, lymphosarcoma, reticulosarcoma, and melanosarcoma (Kotzia and Labrou, J. Biotechnol. 127 (2007) 657-669).The anti-tumor activity of L-asparaginase is believed to be due to the inability or reduced ability of certain malignant cells to synthesize L-asparagine (Kotzia and Labrou, J. Biotechnol. 127 (2007) 657-669). These malignant cells rely on an extracellular supply of L-asparagine. However, the L-asparaginase enzyme catalyzes the hydrolysis of L-asparagine to aspartic acid and ammonia, thereby depleting circulating pools of L-asparagine and killing tumor cells which cannot perform protein synthesis without L-asparagine (Kotzia and Labrou, J. Biotechnol. 127 (2007) 657-669).[0004] L-asparaginase from E. coli was the first enzyme drug used in ALL therapy and has been marketed as Elspar® in the USA or as Kidrolase® and L-asparaginase Medac® in Europe. L- asparaginases have also been isolated from other microorganisms, e.g., an L-asparaginase protein from Erwinia chrysanthemi, named crisantaspase, that has been marketed as Erwinase® (Wriston Jr., J.C. (1985) “L-asparaginase” Meth. Enzymol. 113, 608-618; Goward, CR. et al. (1992) “Rapid large scale preparation of recombinant Erwinia chrysanthemi L-asparaginase”, Bioseparation 2, 335-341). L-asparaginases from other species of Erwinia have also been identified, including, for example, Erwinia chrysanthemi 3937 (Genbank Accession#AAS67028), Erwinia chrysanthemi NCPPB 1125 (Genbank Accession #CAA31239), Erwinia carotovora (Genbank Accession #AAP92666), and Erwinia carotovora subsp. Astroseptica (Genbank Accession #AAS67027). These Erwinia chrysanthemi L-asparaginases have about 91-98% amino acid sequence identity with each other, while the Erwinia carotovora L- asparaginases have approximately 75-77% amino acid sequence identity with the Erwinia chrysanthemi L-asparaginases (Kotzia and Labrou, J. Biotechnol. 127 (2007) 657-669).[0005] L-asparaginases of bacterial origin have a high immunogenic and antigenic potential and frequently provoke adverse reactions ranging from mild allergic reaction to anaphylactic shock in sensitized patients (Wang, B. et al. (2003) “Evaluation of immunologic cross reaction of anti- asparaginase antibodies in acute lymphoblastic leukemia (ALL and lymphoma patients),Leukemia 17, 1583-1588). E. coli L-asparaginase is particularly immunogenic, with reports of the presence of anti-asparaginase antibodies to E. coli L-asparaginase following i.v. or i.m. administration reaching as high as 78% in adults and 70% in children (Wang, B. et al. (2003) Leukemia 17, 1583-1588).[0006] L-asparaginases from Escherichia coli and Erwinia chrysanthemi differ in their pharmacokinetic properties and have distinct immunogenic profiles, respectively (Klug Albertsen, B. et al. (2001) “Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system” Brit. J. Haematol. 115, 983-990). Furthermore, it has been shown that antibodies that developed after a treatment with L-asparaginase from E. coli do not cross react with L-Asparaginase from Erwinia (Wang, B. et al., Leukemia 17 (2003) 1583-1588). Thus, L-asparaginase from Erwinia (crisantaspase) has been used as a second line treatment of ALL in patients that react to E. coli L-asparaginase (Duval, M. et al. (2002) “Comparison of Escherichia co/z-asparaginase with £Vwzmα-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment ofCancer, Children’s Leukemia Group phase 3 trial” Blood 15, 2734-2739; Avramis and Panosyan,Clin. Pharmacokinet. (2005) 44:367-393).[0007] In another attempt to reduce immunogenicity associated with administration of microbial L-asparaginases, an E. coli L-asparaginase has been developed that is modified with methoxy- polyethyleneglycol (mPEG). This method is commonly known as “PEGylation” and has been shown to alter the immunological properties of proteins (Abuchowski, A. et al. (1977) “Alteration of Immunological Properties of Bovine Serum Albumin by Covalent Attachment of Polyethylene Glycol,” J.Biol.Chem. 252 (11), 3578-3581). This so-called mPEG-L- asparaginase, or pegaspargase, marketed as Oncaspar® (Enzon Inc., USA), was first approved in the U.S. for second line treatment of ALL in 1994, and has been approved for first- line therapy of ALL in children and adults since 2006. Oncaspar® has a prolonged in vivo half-life and a reduced immunogenicity/antigenicity.[0008] Oncaspar® is E. coli L-asparaginase that has been modified at multiple lysine residues using 5 kDa mPEG-succinimidyl succinate (SS-PEG) (U.S. Patent No. 4,179,337). SS-PEG is aPEG reagent of the first generation that contains an instable ester linkage that is sensitive to hydro lysis by enzymes or at slightly alkaline pH values (U.S. Patent No. 4,670,417; Makromol. Chem. 1986, 187, 1131-1144). These properties decrease both in vitro and in vivo stability and can impair drug safety.[0009] Furthermore, it has been demonstrated that antibodies developed against L-asparaginase from E. coli will cross react with Oncaspar® (Wang, B. et al. (2003) “Evaluation of immunologic cross-reaction of anti-asparaginase antibodies in acute lymphoblastic leukemia (ALL and lymphoma patients),” Leukemia 17, 1583-1588). Even though these antibodies were not neutralizing, this finding clearly demonstrated the high potential for cross-hypersensitivity or cross-inactivation in vivo. Indeed, in one report 30-41% of children who received pegaspargase had an allergic reaction (Wang, B. et al. (2003) Leukemia 17, 1583-1588).[0010] In addition to outward allergic reactions, the problem of “silent hypersensitivity” was recently reported, whereby patients develop anti-asparaginase antibodies without showing any clinical evidence of a hypersensitivity reaction (Wang, B. et al. (2003) Leukemia 17, 1583-1588). This reaction can result in the formation of neutralizing antibodies to E. coli L-asparaginase and pegaspargase; however, these patients are not switched to Erwinia L-asparaginase because there are not outward signs of hypersensitivity, and therefore they receive a shorter duration of effective treatment (Holcenberg, J., J. Pediatr. Hematol. Oncol. 26 (2004) 273-274).[0011] Erwinia chrysanthemi L-asparaginase treatment is often used in the event of hypersensitivity to E. co/z-derived L-asparaginases. However, it has been observed that as many as 30-50% of patients receiving Erwinia L-asparaginase are antibody-positive (Avramis andPanosyan, Clin. Pharmacokinet. (2005) 44:367-393). Moreover, because Erwinia chrysanthemi L-asparaginase has a significantly shorter elimination half-life than the E. coli L-asparaginases, it must be administered more frequently (Avramis and Panosyan, Clin. Pharmacokinet. (2005) 44:367-393). In a study by Avramis et al., Erwinia asparaginase was associated with inferior pharmacokinetic profiles (Avramis et al., J. Pediatr. Hematol. Oncol. 29 (2007) 239-247). E. coli L-asparaginase and pegaspargase therefore have been the preferred first-line therapies for ALL over Erwinia L-asparaginase.[0012] Numerous biopharmaceuticals have successfully been PEGylated and marketed for many years. In order to couple PEG to a protein, the PEG has to be activated at its OH terminus. The activation group is chosen based on the available reactive group on the protein that will bePEGylated. In the case of proteins, the most important amino acids are lysine, cysteine, glutamic acid, aspartic acid, C-terminal carboxylic acid and the N-terminal amino group. In view of the wide range of reactive groups in a protein nearly the entire peptide chemistry has been applied to activate the PEG moiety. Examples for this activated PEG-reagents are activated carbonates, e.g., p-nitrophenyl carbonate, succinimidyl carbonate; active esters, e.g., succinimidyl ester; and for site specific coupling aldehydes and maleimides have been developed (Harris, M., Adv. Drug – A -DeI. Rev. 54 (2002), 459-476). The availability of various chemical methods for PEG modification shows that each new development of a PEGylated protein will be a case by case study. In addition to the chemistry the molecular weight of the PEG that is attached to the protein has a strong impact on the pharmaceutical properties of the PEGylated protein. In most cases it is expected that, the higher the molecular weight of the PEG, the better the improvement of the pharmaceutical properties (Sherman, M. R., Adv. Drug Del. Rev. 60 (2008), 59-68; Holtsberg, F. W., Journal of Controlled Release 80 (2002), 259-271). For example, Holtsberg et al. found that, when PEG was conjugated to arginine deaminase, another amino acid degrading enzyme isolated from a microbial source, pharmacokinetic and pharmacodynamic function of the enzyme increased as the size of the PEG attachment increased from a molecular weight of 5000Da to 20,000 Da (Holtsberg, F.W., Journal of Controlled Release 80 (2002), 259-271).[0013] However, in many cases, PEGylated biopharmaceuticals show significantly reduced activity compared to the unmodified biopharmaceutical (Fishburn, CS. (2008) Review “The Pharmacology of PEGylation: Balancing PD with PK to Generate Novel Therapeutics” J. Pharm. Sd., 1-17). In the case of L-asparaginase from Erwinia carotovora, it has been observed that PEGylation reduced its in vitro activity to approximately 57% (Kuchumova, A.V. et al. (2007) “Modification of Recombinant asparaginase from Erwinia carotovora with Polyethylene Glycol 5000” Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 1, 230-232). The L-asparaginase from Erwinia carotovora has only about 75% homology to the Erwinia chrysanthemi L-asparaginase (crisantaspase). For Oncaspar® it is also known that its in vitro activity is approximately 50% compared to the unmodified E. coli L-asparaginase.[0014] The currently available L-asparaginase preparations do not provide alternative or complementary therapies— particularly therapies to treat ALL— that are characterized by high catalytic activity and significantly improved pharmacological and pharmacokinetic properties, as well as reduced immunogenicity. L-asparaginase protein has at least about 80% homology or identity with the protein comprising the sequence of SEQ ID NO:1, more specifically at least about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% homology or identity with the protein comprising the sequence of SEQ ID NO:1. SEQ ID NO:1 is as follows:ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGE QFSNMASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTV KSDKPVVFVAAMRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSA RYITKTNASTLDTFKANEEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKV DILYGYQDDPEYLYDAAIQHGVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEELPGLVSDSLNPAHARILLMLALTRTSDPKVIQEYFHTY (SEQ ID NO:1) [0048] The term “comprising the sequence of SEQ ID NO:1” means that the amino-acid sequence of the protein may not be strictly limited to SEQ ID NO:1 but may contain additional amino-acids.ExamplesExample 1 : Preparation of Recombinant Crisantaspase [0100] The recombinant bacterial strain used to manufacture the naked recombinant Erwinia chrysanthemi L-asparaginase protein (also referred to herein as “r-crisantaspase”) was an E. coli BL21 strain with a deleted ansB gene (the gene encoding the endogenous E. coli type II L- asparaginase) to avoid potential contamination of the recombinant Erwinia chrysanthemi L- asparaginase with this enzyme. The deletion of the ansB gene relies on homologous recombination methods and phage transduction performed according to the three following steps:1) a bacterial strain (NMI lOO) expressing a defective lambda phage which supplies functions that protect and recombine electroporated linear DNA substrate in the bacterial cell was transformed with a linear plasmid (kanamycin cassette) containing the kanamycin gene flanked by an FLP recognition target sequence (FRT). Recombination occurs to replace the ansB gene by the kanamycin cassette in the bacterial genome, resulting in a ΛansB strain; 2) phage transduction was used to integrate the integrated kanamycin cassette region from the ΛansB NMI lOO strain to the ansB locus in BL21 strain. This results in an E. coli BL21 strain with a deleted ansB gene and resistant to kanamycin; 3) this strain was transformed with a FLP -helper plasmid to remove the kanamycin gene by homologous recombination at the FRT sequence. The genome of the final strain (BL21 ΛansB strain) was sequenced, confirming full deletion of the endogenous ansB gene.[0101] The E. co/z-optimized DNA sequence encoding for the mature Erwinia chrysanthemi L- asparaginase fused with the ENX signal peptide from Bacillus subtilis was inserted into an expression vector. This vector allows expression of recombinant Erwinia chrysanthemi L- asparaginase under the control of hybrid T5/lac promoter induced by the addition of Isopropyl β- D-1-thiogalactopyranoside (IPTG) and confers resistance to kanamycin.[0102] BL21 ΛansB strain was transformed with this expression vector. The transformed cells were used for production of the r-crisantaspase by feed batch glucose fermentation in Reisenberg medium. The induction of the cell was done 16h at 23°C with IPTG as inducer. After cell harvest and lysis by homogenization in 1OmM sodium phosphate buffer pH6 5mM EDTA (Buffer A), the protein solution was clarified by centrifugation twice at 1500Og, followed by 0.45μm and 0.22μm filtration steps. The recombinant Erwinia chrysanthemi L-asparaginase was next purified using a sequence of chromatography and concentration steps. Briefly, the theoretical isoelectric point of the Erwinia chrysanthemi L-asparaginase (7.23) permits the recombinant enzyme to adsorb to cation exchange resins at pH6. Thus, the recombinant enzyme was captured on a Capto S column (cation exchange chromatography) and eluted with salt gradient in Buffer A. Fractions containing the recombinant enzyme were pooled. The pooled solution was next purified on Capto MMC column (cation exchange chromatography) in Buffer A with salt gradient. . The eluted fractions containing Erwinia chrysanthemi L-asparaginase were pooled and concentrated before protein separation on Superdex 200pg size exclusion chromatography as polishing step. Fractions containing recombinant enzymes were pooled, concentrated, and diafiltered against 10OmM sodium phosphate buffer pH8. The purity of the final Erwinia chrysanthemi L-asparaginase preparation was evaluated by SDS-PAGE (Figure 1) and RP-HPLC and was at least 90%. The integrity of the recombinant enzyme was verified byN-terminal sequencing and LC-MS. Enzyme activity was measured at 37°C using Nessler’s reagent. The specific activity of the purified recombinant Erwinia chrysanthemi L-asparaginase was around 600 U/mg. One unit of enzyme activity is defined as the amount of enzyme that liberates lμmol of ammonia from L-asparagine per minute at 37°C. Example 2: Preparation of 10 kDa mPEG-L- Asparaginase Conjugates[0103] A solution of L-asparaginase from Erwinia chrysanthemi was stirred in a 100 mM sodium phosphate buffer at pH 8.0, at a protein concentration between 2.5 and 4 mg/mL, in the presence of 150 mg/mL or 36 mg/mL 10 kDa mPEG-NHS, for 2 hours at 22°C. The resulting crude 10 kDa mPEG-L-asparaginase was purified by size exclusion chromatography using a Superdex 200 pg column on an Akta purifier UPC 100 system. Protein-containing fractions were pooled and concentrated to result in a protein concentration between 2 and 8 mg/mL. Two 10 kDa mPEG-L-asparaginase conjugates were prepared in this way, differing in their degree of PEGylation as determined by TNBS assay with unmodified L-asparaginase as a reference, one corresponding to full PEGylation (100% of accessible amino groups (e.g., lysine residues and/or the N-terminus) residues being conjugated corresponding to PEGylation of 78% of total amino groups (e.g., lysine residues and/or the N-terminus)); the second one corresponding to partial PEGylation (39% of total amino groups (e.g., lysine residues and/or the N-terminus) or about 50% of accessible amino groups (e.g., lysine residues and/or the N-terminus)) . SDS-PAGE analysis of the conjugates is shown in Figure 2. The resulting conjugates appeared as an essentially homogeneous band and contained no detectable unmodified r-crisantaspase.Example 3: Preparation of 5 kDa mPEG-L-Asparaginase Conjugates[0104] A solution of L-asparaginase from Erwinia chrysanthemi was stirred in a 100 mM sodium phosphate buffer at pH 8.0, at a protein concentration of 4 mg/mL, in the presence of 150 mg/mL or 22.5 mg/mL 5 kDa mPEG-NHS, for 2 hours at 22°C. The resulting crude 5 kDa mPEG-L-asparaginase was purified by size exclusion chromatography using a Superdex 200 pg column on an Akta purifier UPC 100 system. Protein-containing fractions were pooled and concentrated to result in a protein concentration between 2 and 8 mg/mL. Two 5 kDa mPEG-L- asparaginase conjugates were prepared in this way, differing in their degree of PEGylation as determined by TNBS assay with unmodified L-asparaginase as a reference, one corresponding to full PEGylation (100% of accessible amino groups (e.g., lysine residues and/or the N-terminus) being conjugated corresponding to PEGylation of 84% of total amino groups (e.g., lysine residues and/or the N-terminus)); the second one corresponding to partial PEGylation (36% of total amino groups (e.g., lysine residues and/or the N-terminus) or about 43% of accessible amino groups (e.g., lysine residues and/or the N-terminus)). SDS-PAGE analysis of the conjugates is shown in Figure 2. The resulting conjugates appeared as an essentially homogeneous band and contained no detectable unmodified r-crisantaspase.Example 4: Preparation of 2 kDa mPEG-L-Asparaginase Conjugates[0105] A solution of L-asparaginase from Erwinia chrysanthemi was stirred in a 100 mM sodium phosphate buffer pH 8.0 at a protein concentration of 4 mg/mL in the presence of150 mg/mL or 22.5 mg/mL 2 kDa mPEG-NHS for 2 hours at 22°C. The resulting crude 2 kDa mPEG-L-asparaginase was purified by size exclusion chromatography using a Superdex 200 pg column on an Akta purifier UPC 100 system. Protein containing fractions were pooled and concentrated to result in a protein concentration between 2 and 8 mg/mL. Two 2 kDa mPEG-L- asparaginase conjugates were prepared in this way, differing in their degree of PEGylation as determined by TNBS assay with unmodified L-asparaginase as reference, one corresponding to maximum PEGylation (100% of accessible amino groups (e.g., lysine residues and/or the N- terminus) being conjugated corresponding to PEGylation of 86% of total amino groups (e.g., lysine residues and/or the N-terminus)); the second one corresponding to partial PEGylation (47% of total amino groups (e.g., lysine residues and/or the N-terminus) or about 55% of accessible amino groups {e.g., lysine residues and/or the N-terminus)). SDS-PAGE analysis of the conjugates is shown in Figure 2. The resulting conjugates appeared as an essentially homogeneous band and contained no detectable unmodified r-crisantaspase.Example 5: Activity of mPEG-r-Crisantaspase Conjugates[0106] L-asparaginase aminohydrolase activity of each conjugate described in the proceeding examples was determined by Nesslerization of ammonia that is liberated from L-asparagine by enzymatic activity. Briefly, 50μL of enzyme solution were mixed with 2OmM of L-asparagine in a 50 mM Sodium borate buffer pH 8.6 and incubated for 10 min at 37°C. The reaction was stopped by addition of 200μL of Nessler reagent. Absorbance of this solution was measured at 450 nm. The activity was calculated from a calibration curve that was obtained from Ammonia sulfate as reference. The results are summarized in Table 2, below:Table 2: Activity of mPEG-r-crisantaspase conjugates

Figure imgf000031_0001

* the numbers “40%” and “100%” indicate an approximate degree of PEGylation of respectively 40-55% and 100% of accessible amino groups (see Examples 2-4, supra).** the ratio mol PEG / mol monomer was extrapolated from data using TNBS assay, that makes the assumption that all amino groups from the protein (e.g., lysine residues and the N-terminus) are accessible.[0107] Residual activity of mPEG-r-crisantaspase conjugates ranged between 483 and 543 Units/mg. This corresponds to 78-87% of L-asparagine aminohydrolase activity of the unmodified enzyme. Example 6: L-Asparagine-Depleting Effect of Unmodified Crisantaspase

PAPER

Biotechnology and Applied Biochemistry (2019), 66(3), 281-289.  |

https://iubmb.onlinelibrary.wiley.com/doi/10.1002/bab.1723

Crisantaspase is an asparaginase enzyme produced by Erwinia chrysanthemi and used to treat acute lymphoblastic leukemia (ALL) in case of hypersensitivity to Escherichia coli l-asparaginase (ASNase). The main disadvantages of crisantaspase are the short half-life (10 H) and immunogenicity. In this sense, its PEGylated form (PEG-crisantaspase) could not only reduce immunogenicity but also improve plasma half-life. In this work, we developed a process to obtain a site-specific N-terminal PEGylated crisantaspase (PEG-crisantaspase). Crisantaspase was recombinantly expressed in E. coli BL21(DE3) strain cultivated in a shaker and in a 2-L bioreactor. Volumetric productivity in bioreactor increased 37% compared to shaker conditions (460 and 335 U L−1 H−1, respectively). Crisantaspase was extracted by osmotic shock and purified by cation exchange chromatography, presenting specific activity of 694 U mg−1, 21.7 purification fold, and yield of 69%. Purified crisantaspase was PEGylated with 10 kDa methoxy polyethylene glycol-N-hydroxysuccinimidyl (mPEG-NHS) at different pH values (6.5–9.0). The highest N-terminal pegylation yield (50%) was at pH 7.5 with the lowest poly-PEGylation ratio (7%). PEG-crisantaspase was purified by size exclusion chromatography and presented a KM value three times higher than crisantaspase (150 and 48.5 µM, respectively). Nonetheless, PEG-crisantaspase was found to be more stable at high temperatures and over longer periods of time. In 2 weeks, crisantaspase lost 93% of its specific activity, whereas PEG-crisantaspase was stable for 20 days. Therefore, the novel PEG-crisantaspase enzyme represents a promising biobetter alternative for the treatment of ALL.

ADKLPNIVILATGGTIAGSAATGTQTTGYKAGALGVDTLINAVPEVKKLANVKGEQFSN

MASENMTGDVVLKLSQRVNELLARDDVDGVVITHGTDTVEESAYFLHLTVKSDKPVV

FVAAMRPATAISADGPMNLLEAVRVAGDKQSRGRGVMVVLNDRIGSARYITKTNAST

LDTFKANEEGYLGVIIGNRIYYQNRIDKLHTTRSVFDVRGLTSLPKVDILYGYQDDPEY

LYDAAIQHGVKGIVYAGMGAGSVSVRGIAGMRKAMEKGVVVIRSTRTGNGIVPPDEE

LPGLVSDSLNPAHARILLMLALTRTSDPKVIQEYFHTY

Figure S1 – Amino acid sequence of the enzyme crisantaspase without the signal peptide and with the lysines highlighted in red (Swiss-Prot/TrEMBL accession number: P06608|22-348 AA).

……………………………………………………………………………………………………………………………..

As a component of a chemotherapy regimen to treat acute lymphoblastic leukemia and lymphoblastic lymphoma in patients who are allergic to E. coli-derived asparaginase products
Press ReleaseFor Immediate Release:June 30, 2021

FDA Approves Component of Treatment Regimen for Most Common Childhood Cancer

Alternative Has Been in Global Shortage Since 2016

Today, the U.S. Food and Drug Administration approved Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) as a component of a chemotherapy regimen to treat acute lymphoblastic leukemia and lymphoblastic lymphoma in adult and pediatric patients who are allergic to the E. coli-derived asparaginase products used most commonly for treatment. The only other FDA-approved drug for such patients with allergic reactions has been in global shortage for years.

“It is extremely disconcerting to patients, families and providers when there is a lack of access to critical drugs for treatment of a life-threatening, but often curable cancer, due to supply issues,” said Gregory Reaman, M.D., associate director for pediatric oncology in the FDA’s Oncology Center of Excellence. “Today’s approval may provide a consistently sourced alternative to a pivotal component of potentially curative therapy for children and adults with this type of leukemia.”

Acute lymphoblastic leukemia occurs in approximately 5,700 patients annually, about half of whom are children. It is the most common type of childhood cancer. One component of the chemotherapy regimen is an enzyme called asparaginase that kills cancer cells by depriving them of substances needed to survive. An estimated 20% of patients are allergic to the standard E. coli-derived asparaginase and need an alternative their bodies can tolerate.

Rylaze’s efficacy was evaluated in a study of 102 patients who either had a hypersensitivity to E. coli-derived asparaginases or experienced silent inactivation. The main measurement was whether patients achieved and maintained a certain level of asparaginase activity. The study found that the recommended dosage would provide the target level of asparaginase activity in 94% of patients.

The most common side effects of Rylaze include hypersensitivity reactions, pancreatic toxicity, blood clots, hemorrhage and liver toxicity.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with Health Canada, where the application review is pending.

Rylaze received Fast Track and Orphan Drug designations for this indication. Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fulfill an unmet medical need. Orphan Drug designation provides incentives to assist and encourage drug development for rare diseases.

The FDA granted approval of Rylaze to Jazz Pharmaceuticals.

REF

https://www.prnewswire.com/news-releases/jazz-pharmaceuticals-announces-us-fda-approval-of-rylaze-asparaginase-erwinia-chrysanthemi-recombinant-rywn-for-the-treatment-of-acute-lymphoblastic-leukemia-or-lymphoblastic-lymphoma-301323782.html#:~:text=Jazz%20Pharmaceuticals%20Announces,details%20to%20follow

DUBLIN, June 30, 2021 /PRNewswire/ — Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced the U.S. Food and Drug Administration (FDA) approval of Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in pediatric and adult patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase.1 Rylaze is the only recombinant erwinia asparaginase manufactured product that maintains a clinically meaningful level of asparaginase activity throughout the entire duration of treatment, and it was developed by Jazz to address the needs of patients and healthcare providers with an innovative, high-quality erwinia-derived asparaginase with reliable supply.

“We are excited to bring this important new treatment to patients who are in critical need, and we are grateful to FDA for the approval of Rylaze based on its established safety and efficacy profile. We are pleased Rylaze was approved before the trial is complete and are diligently working to advance additional clinical trial data. We are committed to quickly engaging with FDA to evolve the Rylaze product profile with additional dosing options and an IV route of administration,” said Bruce Cozadd, chairman and CEO of Jazz Pharmaceuticals. “Thank you to our collaborators within the Children’s Oncology Group, the clinical trial investigators, patients and their families, and all of the other stakeholders who helped us achieve this significant milestone.”

Rylaze was granted orphan drug designation for the treatment of ALL/LBL by FDA in June 2021. The Biologics Licensing Application (BLA) approval followed review under the Real-Time Oncology Review (RTOR) program, an initiative of FDA’s Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients.

The company expects Rylaze will be commercially available in mid-July.

“The accelerated development and approval of Rylaze marks an important step in bringing a meaningful new treatment option for many ALL patients – most of whom are children – who cannot tolerate E. coli-derived asparaginase medicine,” said Dr. Luke Maese, assistant professor at the University of Utah, Primary Children’s Hospital and Huntsman Cancer Institute. “Before the approval of Rylaze, there was a significant need for an effective asparaginase medicine that would allow patients to start and complete their prescribed treatment program with confidence in supply.”

Recent data from a Children’s Oncology Group retrospective analysis of over 8,000 patients found that patients who did not receive a full course of asparaginase treatment due to associated toxicity had significantly lower survival outcomes – regardless of whether those patients were high risk or standard risk, slow early responders.2

About Study JZP458-201
The FDA approval of Rylaze, also known as JZP458, is based on clinical data from an ongoing pivotal Phase 2/3 single-arm, open-label, multicenter, dose confirmation study evaluating pediatric and adult patients with ALL or LBL who have had an allergic reaction to E. coli-derived asparaginases and have not previously received asparaginase erwinia chrysanthemi. The study was designed to assess the safety, tolerability and efficacy of JZP458. The determination of efficacy was measured by serum asparaginase activity (SAA) levels. The Phase 2/3 study is being conducted in two parts. The first part is investigating the intramuscular (IM) route of administration, including a Monday-Wednesday-Friday dosing schedule. The second part remains active to further confirm the dose and schedule for the intravenous (IV) route of administration.

The FDA approval of Rylaze was based on data from the first of three IM cohorts, which demonstrated the achievement and maintenance of nadir serum asparaginase activity (NSAA) greater than or equal to the level of 0.1 U/mL at 48 hours using IM doses of Rylaze 25 mg/m2. The results of modeling and simulations showed that for a dosage of 25 mg/m2 administered intramuscularly every 48 hours, the proportion of patients maintaining NSAA ≥ 0.1 U/mL at 48 hours after a dose of Rylaze was 93.6% (95% CI: 92.6%, 94.6%).1

The most common adverse reactions (incidence >15%) were abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding and hyperglycemia. In patients treated with the Rylaze, a fatal adverse reaction (infection) occurred in one patient and serious adverse reactions occurred in 55% of patients. The most frequent serious adverse reactions (in ≥5% of patients) were febrile neutropenia, dehydration, pyrexia, stomatitis, diarrhea, drug hypersensitivity, infection, nausea and viral infection. Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received Rylaze. Adverse reactions resulting in permanent discontinuation included hypersensitivity (6%) and infection (3%).1

The company will continue to work with FDA and plans to submit additional data from a completed cohort of patients evaluating 25mg/m2 IM given on Monday and Wednesday, and 50 mg/m2 given on Friday in support of a M/W/F dosing schedule. Part 2 of the study is evaluating IV administration and is ongoing. The company also plans to submit these data for presentation at a future medical meeting.

Investor Webcast
The company will host an investor webcast on the Rylaze approval in July. Details will be announced separately.

About Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn)
Rylaze, also known as JZP458, is approved in the U.S. for use as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL) in pediatric and adult patients one month and older who have developed hypersensitivity to E. coli-derived asparaginase. Rylaze has orphan drug designation for the treatment of ALL/LBL in the United States. Rylaze is a recombinant erwinia asparaginase that uses a novel Pseudomonas fluorescens expression platform. JZP458 was granted Fast Track designation by the U.S. Food and Drug Administration (FDA) in October 2019 for the treatment of this patient population. Rylaze was approved as part of the Real-Time Oncology Review program, an initiative of the FDA’s Oncology Center of Excellence designed for efficient delivery of safe and effective cancer treatments to patients.

The full U.S. Prescribing Information for Rylaze is available at: <http://pp.jazzpharma.com/pi/rylaze.en.USPI.pdf>

Important Safety Information

RYLAZE should not be given to people who have had:

  • Serious allergic reactions to RYLAZE
  • Serious swelling of the pancreas (stomach pain), serious blood clots, or serious bleeding during previous asparaginase treatment

RYLAZE may cause serious side effects, including:

  • Allergic reactions (a feeling of tightness in your throat, unusual swelling/redness in your throat and/or tongue, or trouble breathing), some of which may be life-threatening
  • Swelling of the pancreas (stomach pain)
  • Blood clots (may have a headache or pain in leg, arm, or chest)
  • Bleeding
  • Liver problems

Contact your doctor immediately if any of these side effects occur.

Some of the most common side effects with RYLAZE include: liver problems, nausea, bone and muscle pain, tiredness, infection, headache, fever, allergic reactions, fever with low white blood cell count, decreased appetite, mouth swelling (sometimes with sores), bleeding, and too much sugar in the blood.

RYLAZE can harm your unborn baby. Inform your doctor if you are pregnant, planning to become pregnant, or nursing. Females of reproductive potential should use effective contraception (other than oral contraceptives) during treatment and for 3 months following the final dose. Do not breastfeed while receiving RYLAZE and for 1 week after the final dose.

Tell your healthcare provider if there are any side effects that are bothersome or that do not go away.

These are not all the possible side effects of RYLAZE. For more information, ask your healthcare provider.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088 (1-800-332-1088).

About ALL
ALL is a cancer of the blood and bone marrow that can progress quickly if not treated.3 Leukemia is the most common cancer in children, and about three out of four of these cases are ALL.4  Although it is one of the most common cancers in children, ALL is among the most curable of the pediatric malignancies due to recent advancements in treatment.5,6 Adults can also develop ALL, and about four of every 10 cases of ALL diagnosed are in adults.7  The American Cancer Society estimates that almost 6,000 new cases of ALL will be diagnosed in the United States in 2021.7 Asparaginase is a core component of multi-agent chemotherapeutic regimens in ALL.8  However, asparaginase treatments derived from E. coli are associated with the potential for development of hypersensitivity reactions.9

About Lymphoblastic Lymphoma
LBL is a rare, fast-growing, aggressive subtype of Non-Hodgkin’s lymphoma, most often seen in teenagers and young adults.8 LBL is a very aggressive lymphoma – also called high-grade lymphoma – which means the lymphoma grows quickly with early spread to different parts of the body.10,11

About Jazz Pharmaceuticals plc
Jazz Pharmaceuticals plc (NASDAQ: JAZZ) is a global biopharmaceutical company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing life-changing medicines for people with serious diseases – often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines and novel product candidates, from early- to late-stage development, in neuroscience and oncology. We actively explore new options for patients including novel compounds, small molecules and biologics, and through cannabinoid science and innovative delivery technologies. Jazz is headquartered in Dublin, Ireland and has employees around the globe, serving patients in nearly 75 countries. For more information, please visit www.jazzpharmaceuticals.com and follow @JazzPharma on Twitter.

About The Children’s Oncology Group (COG)
COG (childrensoncologygroup.org), a member of the NCI National Clinical Trials Network (NCTN), is the world’s largest organization devoted exclusively to childhood and adolescent cancer research. COG unites over 10,000 experts in childhood cancer at more than 200 leading children’s hospitals, universities, and cancer centers across North America, Australia, and New Zealand in the fight against childhood cancer. Today, more than 90% of the 14,000 children and adolescents diagnosed with cancer each year in the United States are cared for at COG member institutions. Research performed by COG institutions over the past 50 years has transformed childhood cancer from a virtually incurable disease to one with a combined 5-year survival rate of 80%. COG’s mission is to improve the cure rate and outcomes for all children with cancer.

Caution Concerning Forward-Looking Statements 
This press release contains forward-looking statements, including, but not limited to, statements related to Jazz Pharmaceuticals’ belief in the potential of Rylaze to provide a reliable therapeutic option for adult and pediatric patients to maximize their chance for a cure, plans for a mid-July 2021 launch of Rylaze, the availability of a reliable supply of Rylaze and other statements that are not historical facts. These forward-looking statements are based on Jazz Pharmaceuticals’ current plans, objectives, estimates, expectations and intentions and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties, which include, without limitation, effectively launching and commercializing new products; obtaining and maintaining adequate coverage and reimbursement for the company’s products; delays or problems in the supply or manufacture of the company’s products and other risks and uncertainties affecting the company, including those described from time to time under the caption “Risk Factors” and elsewhere in Jazz Pharmaceuticals’ Securities and Exchange Commission filings and reports (Commission File No. 001-33500), including Jazz Pharmaceuticals’ Annual Report on Form 10-K for the year ended December 31, 2020 and future filings and reports by Jazz Pharmaceuticals. Other risks and uncertainties of which Jazz Pharmaceuticals is not currently aware may also affect Jazz Pharmaceuticals’ forward-looking statements and may cause actual results and the timing of events to differ materially from those anticipated. The forward-looking statements herein are made only as of the date hereof or as of the dates indicated in the forward-looking statements, even if they are subsequently made available by Jazz Pharmaceuticals on its website or otherwise. Jazz Pharmaceuticals undertakes no obligation to update or supplement any forward-looking statements to reflect actual results, new information, future events, changes in its expectations or other circumstances that exist after the date as of which the forward-looking statements were made.

Jazz Media Contact:
Jacqueline Kirby
Vice President, Corporate Affairs
Jazz Pharmaceuticals plc
CorporateAffairsMediaInfo@jazzpharma.com
Ireland, +353 1 697 2141
U.S. +1 215 867 4910

Jazz Investor Contact:
Andrea N. Flynn, Ph.D.
Vice President, Head, Investor Relations
Jazz Pharmaceuticals plc
investorinfo@jazzpharma.com  
Ireland, +353 1 634 3211

References

  1. Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) injection, for intramuscular use Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.
  2. Gupta S, Wang C, Raetz EA et al. Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group. J Clin Oncol. 2020 Jun 10;38(17):1897-1905. doi: 10.1200/JCO.19.03024
  3. National Cancer Institute. Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version. Available at www.cancer.gov/types/leukemia/patient/adult-all-treatment-pdq. Accessed June 29, 2021
  4. American Cancer Society. Key Statistics for Childhood Leukemia. Available at https://www.cancer.org/cancer/leukemia-in-children/about/key-statistics.html. Accessed June 29, 2021.
  5. American Cancer Society. Cancer Facts & Figures 2019. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html. Accessed June 29, 2021.
  6. Pui C, Evans W. A 50-Year Journey to Cure Childhood Acute Lymphoblastic Leukemia. Seminars in Hematology. 2013;50(3), 185-196.
  7. American Cancer Society. Key Statistics for Acute Lymphocytic Leukemia (ALL). Available at https://cancerstatisticscenter.cancer.org/?_ga=2.8163506.1018157754.1621008457-1989786785.1621008457#!/data-analysis/NewCaseEstimates. Accessed June 29, 2021.
  8. Salzer W, Bostrom B, Messinger Y et al. 2018. Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia. Leukemia & Lymphoma. 59:8, 1797-1806, DOI: 10.1080/10428194.2017.1386305.
  9. Hijiya N, van der Sluis IM. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2016;57(4):748–757. DOI: 10.3109/10428194.2015.1101098.
  10. Leukemia Foundation. Lymphoblastic Lymphoma. Available at https://www.leukaemia.org.au/disease-information/lymphomas/non-hodgkin-lymphoma/other-non-hodgkin-lymphomas/lymphoblastic-lymphoma/. Accessed June 29, 2021.
  11. Mayo Clinic. Acute Lymphocytic Leukemia Diagnosis. Available at https://www.mayoclinic.org/diseases-conditions/acute-lymphocytic-leukemia/diagnosis-treatment/drc-20369083. Accessed June 29, 2021.

SOURCE Jazz Pharmaceuticals plc

Related Links

CLIP

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776285/

An external file that holds a picture, illustration, etc.
Object name is bi-2015-01351t_0006.jpg

/////////////asparaginase erwinia chrysanthemi (recombinant)-rywn, Rylaze, Jazz Pharmaceuticals, JZP458-201, JZP458, FDA 2021, APPROVALS 2021, ORPHAN, Fast TrackAcute Lymphoblastic Leukemia, ALL, Antineoplastic Agents

https://chem.nlm.nih.gov/chemidplus/id/1349719227

https://go.drugbank.com/drugs/DB08886

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Tralokinumab


(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGLSWVRQA PGQGLEWMGW ISANNGDTNY
GQEFQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDS SSSWARWFFD LWGRGTLVTV
SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
EGNVFSCSVM HEALHNHYTQ KSLSLSLGK
(Light chain)
SYVLTQPPSV SVAPGKTARI TCGGNIIGSK LVHWYQQKPG QAPVLVIYDD GDRPSGIPER
FSGSNSGNTA TLTISRVEAG DEADYYCQVW DTGSDPVVFG GGTKLTVLGQ PKAAPSVTLF
PPSSEELQAN KATLVCLISD FYPGAVTVAW KADSSPVKAG VETTTPSKQS NNKYAASSYL
SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS
(Disulfide bridge: H22-H96, H149-H205, H263-H323, H369-H427, H228-H’228, H231-H’231, L22-L87, L136-L195, H136-L213)

Tralokinumab

トラロキヌマブ (遺伝子組換え)

FormulaC6374H9822N1698O2014S44
CAS1044515-88-9
Mol weight143873.2167

EU APPROVED, Adtralza, 2021/6/17

Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody

Tralokinumab is a human monoclonal antibody which targets the cytokine interleukin 13,[1] and is designed for the treatment of asthma and other inflammatory diseases.[2] Tralokinumab was discovered by Cambridge Antibody Technology scientists, using Ribosome Display, as CAT-354[3] and taken through pre-clinical and early clinical development.[4] After 2007 it has been developed by MedImmune, a member of the AstraZeneca group, where it is currently in Ph3 testing for asthma and Ph2b testing for atopic dermatitis.[5][6] This makes it one of the few fully internally discovered and developed drug candidates in AstraZeneca’s late stage development pipeline.

Discovery and development

Tralokinumab (CAT-354) was discovered by Cambridge Antibody Technology scientists[7] using protein optimization based on Ribosome Display.[8] They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims.[7] In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005.[9] On 21 July 2011, MedImmune LLC initiated a Ph2b, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.[10]

In 2016, MedImmune and AstraZeneca were developing tralokinumab for asthma (Ph3) and atopic dermatitis (Ph2b) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued.[9] In July of that year AstraZeneca licensed Tralokinumab to LEO Pharma for skin diseases.[11]

A phase IIb study of Tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.[12]

On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis.[13]

Society and culture

Legal status

On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis.[14]

The applicant for this medicinal product is LEO Pharma A/S.

References

  1. ^ Kopf M, Bachmann MF, Marsland BJ (September 2010). “Averting inflammation by targeting the cytokine environment”. Nature Reviews. Drug Discovery9 (9): 703–18. doi:10.1038/nrd2805PMID 20811382S2CID 23769909.
  2. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Tralokinumab” (PDF). American Medical Association.
  3. ^ Thom G, Cockroft AC, Buchanan AG, Candotti CJ, Cohen ES, Lowne D, et al. (May 2006). “Probing a protein-protein interaction by in vitro evolution” [P]. Proceedings of the National Academy of Sciences of the United States of America103 (20): 7619–24. Bibcode:2006PNAS..103.7619Tdoi:10.1073/pnas.0602341103PMC 1458619PMID 16684878.
  4. ^ May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. (May 2012). “Preclinical development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe uncontrolled asthma”British Journal of Pharmacology166 (1): 177–93. doi:10.1111/j.1476-5381.2011.01659.xPMC 3415647PMID 21895629.
  5. ^ “Pipeline”MedImmune. Retrieved 11 June 2013.
  6. ^ “Studies found for CAT-354”ClinicalTrials.gov. Retrieved 11 June 2013.
  7. Jump up to:a b Human Antibody Molecules for Il-13, retrieved 2015-07-26
  8. ^ Jermutus L, Honegger A, Schwesinger F, Hanes J, Plückthun A (January 2001). “Tailoring in vitro evolution for protein affinity or stability”Proceedings of the National Academy of Sciences of the United States of America98 (1): 75–80. Bibcode:2001PNAS…98…75Jdoi:10.1073/pnas.98.1.75PMC 14547PMID 11134506.
  9. Jump up to:a b “Tralokinumab”Adis Insight. Springer Nature Switzerland AG.
  10. ^ Clinical trial number NCT01402986 for “A Phase 2b, Randomized, Double-blind Study to Evaluate the Efficacy of Tralokinumab in Adults With Asthma” at ClinicalTrials.gov
  11. ^ “AstraZeneca enters licensing agreements with LEO Pharma in skin diseases”.
  12. ^ Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, et al. (January 2019). “Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb”The Journal of Allergy and Clinical Immunology143 (1): 135–141. doi:10.1016/j.jaci.2018.05.029PMID 29906525.
  13. ^ “LEO Pharma starts phase 3 clinical study for tralokinumab in atopic dermatitis”leo-pharma.com. AstraZeneca. 1 July 2016.
  14. ^ “Adtralza: Pending EC decision”European Medicines Agency. 23 April 2021. Retrieved 23 April 2021.
Tralokinumab Fab fragment bound to IL-13. From PDB 5L6Y​.
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetIL-13
Clinical data
ATC codeD11AH07 (WHO)
Identifiers
CAS Number1044515-88-9 
ChemSpidernone
UNIIGK1LYB375A
KEGGD09979
Chemical and physical data
FormulaC6374H9822N1698O2014S44
Molar mass143875.20 g·mol−1
  (what is this?)  (verify)

/////////Tralokinumab, Adtralza, EU 2021, APPROVALS 2021, Antiasthmatic, Anti-inflammatory, Anti-IL-13 antibody, MONOCLONAL ANTIBODY, PEPTIDE, トラロキヌマブ (遺伝子組換え) ,

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Upacicalcet sodium hydrate


Upacicalcet sodium hydrate (JAN).png

Upacicalcet sodium hydrate, ウパシカルセトナトリウム水和物

CAS 2052969-18-1

1333218-50-0 free

PMDA JAPAN APPROVED 2021/6/23, Upasita

Calcium sensing receptor agonist

(2S)-2-amino-3-[(3-chloro-2-methyl-5-sulfophenyl)carbamoylamino]propanoic acid

FormulaC11H13ClN3O6S. Na. xH2O
  • OriginatorAjinomoto Pharma
  • DeveloperSanwa Kagaku Kenkyusho
  • ClassAmines; Chlorobenzenes; Propionic acids; Small molecules; Sulfonic acids; Toluenes
  • Mechanism of ActionCalcium-sensing receptor agonists
  • RegisteredSecondary hyperparathyroidism
  • 25 Jun 2021Chemical structure information added
  • 23 Jun 2021Sanwa Kagaku Kenkyusho and Kissei Pharmaceutical agree to co-promote upacicalcet in Japan for Secondary hyperparathyroidism
  • 23 Jun 2021Registered for Secondary hyperparathyroidism in Japan (IV) – First global approval
Upacicalcet Sodium HydrateMonosodium 3-({[(2S)-2-amino-2-carboxyethyl]carbamoyl}amino)-5-chloro-4-methylbenzenesulfonate hydrateC11H13ClN3NaO6S▪xH2O
[2052969-18-1 , anhydride]

Announcement of Marketing Authorization Approval in Japan and Co-promotion Agreement of UPASITA® IV Injection Syringe for the Treatment of Secondary Hyperparathyroidism in Dialysis Patients

SANWA KAGAKU KENKYUSHO Co., Ltd. (Head Office: Nagoya, President and CEO : Shusaku Isono, Suzuken Group, ; “SANWA KAGAKU”) has received Marketing Authorization approval today for UPASITA® IV Injection Syringes (generic name: Upacicalcet Sodium Hydrate; “UPASITA®”) for the treatment of secondary hyperparathyroidism in patients on hemodialysis.

UPASITA® was created by Ajinomoto Pharmaceuticals Co., Ltd. (currently EA Phama Co., Ltd.) and developed by SANWA KAGAKU for the treatment of secondary hyperparathyroidism under a licensing agreement with EA Pharma. UPASITA® acts on calcium sensing receptor in the parathyroid and suppresses excessive secretions of parathyroid hormones (PTH). UPASITA® is administered by intravenous injection to dialysis patients through dialysis circuit by physicians or medical staffs upon completion of dialysis and such administration is expected to reduce the burden of patients with many oral medications whose drinking water volume is severely restricted.

Regarding provision of medical and drug information, SANWA KAGAKU entered into a co-promotion agreement in Japan with Kissei Pharmaceutical Co., Ltd. (Head Office: Matsumoto, Nagano; Chairman and CEO: Mutsuo Kanzawa ; “Kissei”). SANWA KAGAKU will handle the production, marketing, and distribution of the Product while SANWA KAGAKU and Kissei collaboratively promote it to medical institutions in the field in accordance with the agreement. Through the co-promotion activity in the field, SANWA KAGAKU and Kissei will contribute to the treatment of dialysis patients suffering from secondary hyperparathyroidism.

《Reference》

About secondary hyperparathyroidism (SHPT)
SHTP is one of complications that occur as chronic kidney disease (chronic kidney failure) progresses and is a pathological condition where excessive PTH is secreted by the parathyroid gland. It has been reported that excessive secretion of parathyroid hormone promotes efflux of phosphorus and calcium from the bone into the blood, thereby increasing the risk of developing bone fractures and arteriosclerosis due to calcification of the cardiovascular system and affecting the vital prognosis.

Product Summary of UPASITA® IV Injection Syringe for Dialysis
Brand name:
UPASITA® IV Injection Syringe for Dialysis 25μg
UPASITA® IV Injection Syringe for Dialysis 50μg
UPASITA® IV Injection Syringe for Dialysis 100μg
UPASITA® IV Injection Syringe for Dialysis 150μg
UPASITA® IV Injection Syringe for Dialysis 200μg
UPASITA® IV Injection Syringe for Dialysis 250μg
UPASITA® IV Injection Syringe for Dialysis 300μg

Generic Name (JAN):
Upacicalcet Sodium Hydrate

Date of Marketing Approval:
June 23, 2021

Indications:
Secondary hyperparathyroidism in patients on hemodialysis

Dosage and Administration:
In adults, UPASITA® is usually administered into venous line of the dialysis circuit at the end of dialysis session during rinse back at a dose of 25 μg sodium upacicalcet 3 times a week as a starting dose.
The starting dose can be 50 μg depending on the concentration of serum calcium. Thereafter, the dose may be adjusted in a range from 25 to 300 μg while parathyroid hormone (PTH) and serum calcium level should be carefully monitored in patients.

SYN

WO 2020204117

PATENT

WO 2011108724

WO 2011108690

JP 2013063971

WO 2016194881

JP 6510136 

PATENT

WO 2016194881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016194881&tab=FULLTEXT(Example 1)  Synthesis of
(2S) -2-amino-3-{[(5-chloro-2-hydroxy-3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 1 )
[Chemical formula 14]
CDI 150. 2 g (926.6Mmol, 1.1 eq. vs Boc-DAP-O t Bu) to and stirred at 5 ° C. acetone was added 750mL (3.0L / kg). 250 g (842.6 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, completion of the IC (imidazolylcarbonylation) reaction was confirmed by HPLC. 282.6 g (1263.8 mmol, 1.5 eq.) Of ACHB was added in 3 portions, and the mixture was washed with 125 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 124.5 mL (1432.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1000 mL (4.0 L / kg) of acetone. The filtrate was concentrated to 1018 g (4.1 kg / kg), the temperature was raised to 50 ° C., and 625.0 mL (7187 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 750 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1730 g (6.9 kg / kg) to precipitate a solid. After stirring at 20 ° C. for 14 hours, vacuum filtration was performed. The filtered solid was washed with 500 mL (2.0 L / kg) of acetone and then dried under reduced pressure at 60 ° C. for 6 hours to obtain 201.4 g of the target product (64.5%).
1H-NMR (400MHz, DMSO-d6): δ 8.3 (s, 1H), 8.2 (bs, 3H), 8.1 (d, 1H, J = 2.6Hz), 7.3 (t, 1H, J = 6.0Hz), 7.0 (d, 1H, J = 2.6Hz), 4.0-4.1 (m, 1H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 1H)[0026](Example 2) Synthesis of
(2S) -2-amino-3-{[(3-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 2 )
[Chemical
formula 15] CDI 120.2 g (741.2 mmol, 1. 600 mL (3.0 L / kg) of acetone was added to 1 eq. Vs Boc-DAP-OtBu), and the mixture was stirred at 5 ° C. 200 g (673.9 mmol) of Boc-DAP-OtBu was added in two portions, and the mixture was washed with 100 mL (0.5 L / kg) of acetone. After stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 175.0 g (1010.8 mmol, 1.5 eq.) Of ABS was added in 3 portions and washed with 100 mL (0.5 L / kg) of acetone. After raising the temperature to 30 ° C. and stirring for 18 hours, the completion of the urea conversion reaction was confirmed by HPLC. After cooling to 5 ° C., 99.6 mL (1145.4 mmol, 1.7 eq.) Of concentrated hydrochloric acid was added, and the mixture was stirred for 1 hour. The precipitated unwanted material was filtered and washed with 1400 mL (7.0 L / kg) of acetone. The filtrate was concentrated to 800.1 g (4.0 kg / kg), heated to 50 ° C., and then 500.0 mL (5750.0 mmol, 8.5 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 30 minutes and confirming the completion of deprotection by HPLC, 600 mL of water was added (3.0 L / kg). This liquid was concentrated under reduced pressure to 1653.7 g to precipitate a solid. After aging at 20 ° C. for 15 hours, vacuum filtration was performed. The filtered solid was washed with 400 mL (2.0 L / kg) of acetone and then dried under reduced pressure at room temperature for 6 hours to obtain 140.3 g of the desired product (net 132.2 g, 64.7%).
1H-NMR (400MHz, DMSO-d6): δ 8.8 (s, 1H), 8.2 (bs, 3H), 7.7 (s, 1H), 7.3-7.4 (m, 1H), 7.1-7.2 (m, 2H) , 6.3-6.4 (bs, 1H), 4.0-4.1 (bs, 1H), 3.6-3.7 (bs, 1H), 3.5-3.6 (bs, 1H)[0027](Example 3) Synthesis of
(2S) -2-amino-3-{[(3-chloro-2-methyl-5-sulfophenyl) carbamoyl] amino} propanoic acid (Compound 3 )
[Chemical formula 16]
CDI 14. To 4 g (88.8 mmol, 1.05 eq. Vs Boc-DAP-OtBu), 75 mL (3.0 L / kg vs DAP-OtBu) of acetone was added and stirred at 5 ° C. After adding 25 g (84.3 mmol) of Boc-DAP-OtBu in two portions and stirring for 30 minutes, the completion of the IC reaction was confirmed by HPLC. 26.1 g (118.0 mmol, 1.4 eq.) Of ACTS was added in 3 portions and washed with 25 mL (1.0 L / kg) of acetone. After the temperature was raised to 30 ° C., the mixture was stirred overnight, and the completion of the urea conversion reaction was confirmed by HPLC. After concentrating under reduced pressure at 10 kPa and 40 ° C. until the solvent was completely removed, 37.5 mL (1.5 L / kg) of water and 22.8 mL (257.6 mmol) of concentrated hydrochloric acid were added to perform deprotection for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to 5 ° C., 60 mL (2.4 L / kg) of MeCN was added, and the mixture was stirred overnight. Further, when 120 mL (4.8 L / kg) of MeCN was added, stratification occurred, so 10 mL (0.4 L / kg) of water and 2.5 mL (0.1 L / kg) of MeCN were added. The precipitated solid was filtered under reduced pressure, washed with 60 mL of MeCN / water (1/2), and then dried under reduced pressure at 60 ° C. for 14 hours to obtain 20.1 g of the desired product as a white solid (net18.3 g, yield 61). 0.8%).
1H-NMR (400MHz, DMSO-d6): δ 14.70-13.30 (bs, 1H), 8.27 (bs, 3H), 8.15 (s, 1H), 7.98 (d, 1H, J = 1.6Hz), 7.27 (d , 1H, J = 1.6Hz), 6.82 (t, 1H, J = 6.0Hz), 4.04 (bs, 1H), 3.70-3.60 (m, 1H), 3.60-3.50 (m, 1H), 2.22 (s, 3H)[0028](Example 4) Synthesis of
compound 3 using phenylchloroformate as a carbonyl group-introducing reagent
(Step 1)
[Chemical
formula 17] MeCN 375 mL (7.5 L / kg vs ACTS), Py for 50 g (225.6 mmol) of ACTS. 38.1 mL (473.7 mmol, 2.1 eq.) Was added and stirred at 25 ° C. 29.9 mL (236.8 mmol, 1.05 eq.) Of ClCO 2 Ph (phenyl chloroformate) was added dropwise, and after stirring for 30 minutes, completion of the CM (carbamate) reaction was confirmed by HPLC. 68.9 g (232.4 mmol) of Boc-DAP-OtBu was added, 97.5 mL (699.3 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. The completion of the urea conversion reaction was confirmed by HPLC. Here, 103.5 g of the total amount of 517.43 g was used to move to the next step (down to ACTS 10 g scale).
30 mL of water was added and concentrated to 77.0 g at 40 ° C. and 5 kPa. After 100 mL (10 L / kg) of AcOEt was added and the liquid separation operation was performed, 30 mL of water was added to the organic layer and the liquid separation operation was performed again. The organic layer was concentrated to 47.6 g at 40 ° C. and 10 kPa, and then 15 mL (1.5 L / kg) of AcOEt and 100 mL (10 L / kg) of THF were added. Again, it was concentrated to 50.7 g and THF was added up to 146 g. When it was concentrated again to 35.5 g and added to AcOEt 30 mL (3 L / kg) and THF 100 mL (10 L / kg), a solid was precipitated. It was cooled to 5 ° C. and aged overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of THF, and then dried under reduced pressure at 40 ° C. for 3 hours overnight at 30 ° C. to obtain 24.9 g of the desired product as a white solid (net). 23.0 g, 83.6%).
1 H-NMR (400MHz, DMSO-d6): δ 8.86 (bs, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.25 (d, 1H, J = 1.6Hz), 7.14 (d, 1H, J = 7.6Hz), 6.60 (t, 1H, J = 5.6Hz), 4.00-3.90 (m, 1H), 3.60-3.50 (m, 1H), 3.30-3.20 (m, 1H), 3.15-3.05 (m, 6H), 2.19 (s, 3H), 1.50-1.30 (m, 18H), 1.20-1.10 (m, 9H)

(Step 2)
[Chemical

formula 18] Compound 4 21.64 g (net. 20.0 g, 68 mL of water (3.4 L / kg vs. compound 4) vs. 32.8 mmol) ) Was added, the mixture was stirred at 50 ° C., and 12 mL (135.6 mmol, 4.1 eq.) Of concentrated hydrochloric acid was added dropwise. After stirring for 1 hour, the temperature was raised to 70 ° C. to dissolve the precipitated solid. After confirming the completion of the reaction by HPLC, the mixture was cooled to 50 ° C. and aged for 1 hour, and then cooled to 5 ° C. over 4 hours. The precipitated solid was filtered under reduced pressure, washed with 40 mL (2.0 L / kg) of MeCN / water (2/1), and then dried under reduced pressure at 60 ° C. for 3 hours to obtain 11.2 g of the desired product as a white solid (11.2 g). net 10.5 g, 91.1%).[0029](Example 5)
[Chemical
formula 19] MeCN 10.0 mL (10.0 L / kg vs ACSS), Py 0.75 mL (9.25 mmol, 2.05 eq.) For 1.00 g (4.51 mmol) of ACTS. , And stirred at 8 ° C. After dropping 0.59 mL (4.74 mmol, 1.05 eq.) Of ClCO 2 Ph, raising the temperature to room temperature and stirring for 1 hour, completion of the CM conversion reaction was confirmed by HPLC. 1.33 g (4.51 mmol, 1.0 eq.) Of Boc-DAP-OtBu was added, 1.92 mL (13.76 mmol, 3.05 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 1 hour. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 1.0 mL of water and 2.0 mL of concentrated hydrochloric acid (22.6 mmol, 5.0 eq.) Were added, and the mixture was stirred at 50 ° C. for 4 hours. After confirming the completion of deprotection by HPLC, MeCN 7.5 mL (7.5 L / kg), 1 M HCl aq. After adding 4.5 mL, the mixture was stirred at 5 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 3.0 mL (3.0 L / kg) of MeCN, and then dried at 60 ° C. overnight to obtain 1.28 g of the desired product as a white solid (net 1.18 g, 77). .0%).[0030](Example 6)
(Step 1)
3-({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid ( Synthesis of Compound 5 )
[Chemical formula 20] To
5 g (22.56 mmol) of ACTS, 37.5 mL (7.5 L / kg vs ACTS) of MeCN and 3.81 mL (47.38 mmol, 2.1 eq.) Of Py were added. The mixture was stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the CM reaction was confirmed by HPLC. 5.92 g (23.23 mmol, 1.03 eq.) Of Boc-DAP-OMe was added, 9.75 mL (69.93 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. 0.4 g (1.58 mmol, 0.07 eq.) Of Boc-DAP-OMe and 0.22 mL (1.58 mmol, 0.07 eq.) Of TEA were added, and the completion of the ureaization reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of MeCN and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / MeCN (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the target product as a white solid (772 g of the target product). net 7.20 g, 87.3%).
1H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) , 2.21 (s, 3H)
HRMS (FAB  ): calcd for m / z 364.0369 (MH), found The m / z 364.0395 (MH)

(step 2)
[Formula 21]

compound 5 10.64 g (net Non 10.0 g, To 27.34 mmol), 18 mL of water (1.8 L / kg vs. compound 5 ) was added and stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. The pH was adjusted to 5.8 by adding about 3.55 mL. After confirming the precipitation of the target product by dropping 65 mL (6.5 L / kg) of IPA, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of IPA was added dropwise and aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of IPA, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92. 6%).
1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)[0031](Example 7)
(Step 1)
[Chemical
formula 22] For 10.0 g (45.1 mmol) of ACTS, 50 mL (5.0 L / kg vs ACTS) of MeCN, 7.46 mL (92.5 mmol, 2.05 eq. ) Was added, and the mixture was stirred at 8 ° C. 5.98 mL (47.4 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, the temperature was raised to 25 ° C., and the mixture was stirred for 1 hour, and then the completion of the CM reaction was confirmed by HPLC. 100 ml of acetone (10.0 L / kg vs ACTS) was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 30 mL of acetone (3.0 L / kg vs ACTS), and then dried under reduced pressure at 60 ° C. for 2 hours to obtain 17.8 g of the target product (net 14.4 g as a free form). Quant).
1 H-NMR (400MHz, DMSO-d6): δ 9.76 (bs, 1H), 8.93-8.90 (m, 2H), 8.60-8.50 (m, 1H), 8.10-8.00 (m, 2H), 7.60 (s , 1H), 7.50-7.40 (m, 3H), 7.30-7.20 (m, 3H), 2.30 (s, 3H)

(Step 2)
[Chemical 23]

Compound 6 To 5.0 g (11.9 mmol), 50 ml of acetonitrile and 3.53 g (11.9 mmol) of Boc-DAP-OtBu were added, and the mixture was stirred at 8 ° C. 3.5 ml (25 mmol) of triethylamine was added dropwise, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and 25 ml of ethyl acetate and 5 ml of water were added for extraction. The organic layer was washed with 5 ml of water, the solvent was distilled off, 50 ml of tetrahydrofuran was added, the mixture was cooled to 8 ° C., and aged for 1 hour. The precipitated solid was filtered under reduced pressure, washed with 10 ml of tetrahydrofuran, and dried under reduced pressure at 60 ° C. overnight to obtain 6.3 g of the desired product as a white solid.[0032](Example 8)
[Chemical
formula 24] For 1.08 g (4.89 mmol) of ACTS, 8.1 mL (7.5 L / kg vs ACTS) of MeCN and 827 μL (10.27 mmol, 2.1 eq.) Of Py were added. In addition, it was stirred at room temperature. ClCO 2 Ph 649 μL (5.14 mmol, 1.05 eq.) Was added dropwise, and the mixture was stirred for 30 minutes, and then the completion of the CM conversion reaction was confirmed by HPLC. 1.48 g (5.04 mmol, 1.03 eq.) Of Cbz-DAP-OMe HCl was added, 2.1 mL (15.17 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at room temperature for about 5 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was concentrated until the solvent was completely removed. 15.0 mL of 30% HBr / AcOH was added, and the mixture was stirred at room temperature for 70 minutes, and the completion of deprotection was confirmed by HPLC. After concentration to dryness, 10 mL of water and 4 mL of AcOEt were added to carry out an extraction operation, and then the aqueous layer was stirred at room temperature overnight. The precipitated solid was filtered under reduced pressure, washed with 15 mL of water and 10 mL of AcOEt, and then dried at 40 ° C. for 3 hours to obtain 1.45 g of the desired product as a white solid (58.8%).[0033](Example 9) Synthesis of compound 7 ( methyl ester of compound 1 )
using phenyl chloroformate as a carbonyl group introduction reagent [Chemical  formula 25] MeCN 73 mL (14.6 L) with respect to 5.00 g (22.4 mmol) of ACHB. / Kg vs ACHB), Py 3.8 mL (47 mmol, 2.1 eq.), Was added and stirred at 40 ° C. After adding 3.0 mL (24 mmol, 1.05 eq.) Of ClCO 2 Ph and stirring for 30 minutes, the completion of the CM conversion reaction was confirmed by HPLC. 5.87 g (23 mmol, 1.0 eq.) Of Boc-DAP-OMe was added, washed with a small amount of MeCN, 9.7 mL (70 mmol, 3.1 eq.) Of TEA was added dropwise, and the mixture was stirred at 40 ° C. for 3 hours. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (112 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 7 hours. Further, 1.5 mL (23 mmol, 1.0 eq.) Of MsOH was added, and the reaction was carried out at 50 ° C. overnight. After confirming the completion of deprotection by HPLC, 90 mL of acetone was added to the reaction solution, and the mixture was cooled to room temperature. The precipitated solid was obtained and dried under reduced pressure at 60 ° C. to obtain the desired product. 1 H-NMR (400MHz, DMSO-d6): δ 7.22 (m, 1H), 7.14 (m, 1H), 4.36 (m, 1H), 3.80 (s, 3H), 3.20-3.40 (m, 2H).[0034](Example 10) Synthesis of
compound 5 using 4-chlorophenylchloroformate as a carbonyl group-introducing reagent
[Chemical formula 26] For
5.00 g (22.6 mmol) of ACTS, 73 mL (14.6 L / kg vs ACTS) of MeCN, 3.8 mL (47 mmol, 2.1 eq.) Of Py was added and stirred at 40 ° C. After adding 3.25 mL (23.7 mmol, 1.05 eq.) Of 4-chloroformic acid 4-chlorophenylate and stirring at 40 ° C. for 1.5 hours, completion of the CM conversion reaction was confirmed by HPLC. Add 5.92 g (23.2 mol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 6.94 g of the desired product as a white solid (84.1%).[0035](Example 11) Synthesis of
compound 5 using 4-nitrophenyl chloroformate as a carbonyl group-introducing reagent
[Chemical formula 27]
73 mL (14.6 L / kg vs. ACTS) of MeCN with respect to 5.00 g (22.6 mmol) of ACTS. , Py 3.8 mL (47 mmol, 2.1 eq.), And stirred at 40 ° C. 4.77 mL (23.7 mmol, 1.05 eq.) Of 4-nitrophenyl chloroformate was added dropwise, and the mixture was stirred at 40 ° C. for 3.5 hours, and then the completion of the CM reaction was confirmed by HPLC. Add 5.92 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OMe, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea conversion reaction by HPLC, the mixture was cooled to room temperature. 7.3 mL (113 mmol, 5.0 eq.) Of MsOH was added, the temperature was raised to 50 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of deprotection by HPLC, the reaction solution was cooled to room temperature, 7.5 mL of water was added, the mixture was cooled to 8 ° C., and the mixture was stirred overnight. The precipitated solid was filtered, washed with a small amount of MeCN water, and dried at 60 ° C. overnight to obtain 5.96 g of the desired product as a white solid (72.2%).[0036](Example 12) Synthesis of
compound 3 using Boc-DAP-OH
[Chemical 28]
MeCN 73 mL (14.6 L / kg vs ACTS), Py 3.8 mL, relative to 5.00 g (22.6 mmol) of ACTS. (47 mmol, 2.1 eq.) Was added and stirred at 40 ° C. After adding 3.00 mL (23.8 mmol, 1.05 eq.) Of phenylchloroformate and stirring at 40 ° C. for 0.5 hours, the completion of the CM conversion reaction was confirmed by HPLC (CM conversion reaction product: 4.37 minutes). , ACTS: N.D.). Add 4.75 g (23.2 mmol, 1.0 eq.) Of Boc-DAP-OH, wash with a small amount of MeCN, add 9.7 mL (70 mmol, 3.1 eq.) Of TEA, and stir at 40 ° C. for 2 hours. did. After confirming the completion of the urea-forming reaction by HPLC (urea-forming reaction product: 3.81 minutes, CM-forming reaction product: 0.02 area% vs. urea-forming reaction product), the mixture was cooled to room temperature. By adding 7.3 mL (113 mmol, 5.0 eq.) Of MsOH, raising the temperature to 50 ° C., stirring for 4.5 hours, and further adding 1.5 mL (23 mmol, 1.0 eq.) Of MsOH, stirring for 1 hour. , The formation of the target product was confirmed by HPLC (Compound 3: 2.49 minutes, urea conversion reaction product: 0.50 area vs. compound 3, area of compound 3 with respect to the total area excluding pyridine: 71.0 area).

PATENT

JP 6510136

PATENT

WO 2020204117

Reference Example 1
Synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate sodium (Compound A1) 
(Step 1)
Synthesis of
3 -({[(2S) -2-amino-3-methoxy-3-oxopropyl] carbamoyl} amino) -5-chloro-4-methylbenzene-1-sulfonic acid 3-amino- 37.5 mL (7.5 L / kg vs ACTS) of acetonitrile and 3.81 mL (47.38 mmol, 2.1 eq.) Of pyridine against 5 g (22.56 mmol) of 5-chloro-4-methylbenzenesulfonic acid (ACTS). Was added and stirred at 25 ° C. 2.99 mL (23.68 mmol, 1.05 eq.) Of ClCO 2 Ph was added dropwise, and after stirring for 30 minutes, the completion of the carbamate reaction was confirmed by HPLC. Add 5.92 g (23.23 mmol, 1.03 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 9.75 mL (69.93 mmol, 3.1 eq.) Triethylamine. Was added dropwise, and the mixture was stirred at 25 ° C. for 3 hours. Add 0.4 g (1.58 mmol, 0.07 eq.) Of 3-amino-N- (tert-butoxycarbonyl) -L-alanine methyl ester hydrochloride and 0.22 mL (1.58 mmol, 0.07 eq.) Of triethylamine. Then, the completion of the urea conversion reaction was confirmed by HPLC. 7.32 mL (112.8 mmol, 5.0 eq.) Of methanesulfonic acid was added, the temperature was raised to 50 ° C., and the mixture was stirred for 4 hours. After confirming the completion of deprotection by HPLC, the mixture was cooled to 25 ° C. and 37.5 mL (7.5 L / kg) of acetonitrile and 7.5 mL (1.5 L / kg) of water were added to precipitate a solid. It was cooled to 5 ° C. and aged for 16 hours. The precipitated solid was filtered under reduced pressure, washed with 20 mL (4.0 L / kg) of water / acetonitrile (1/2), and then dried under reduced pressure at 40 ° C. for 5 hours to obtain 7.72 g of the desired product as a white solid (. net 7.20 g, 87.3%).

1 H-NMR (400MHz, DMSO-d6): δ 8.39 (bs, 3H), 8.16 (d, 1H, J = 1.2Hz), 7.90 (d, 1H, J = 1.6Hz), 7.28 (d, 1H, J = 1.6Hz), 6.78 (t, 1H, J = 5.6Hz), 4.20-4.10 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 3.55-3.45 (m, 1H) ), 2.21 (S, 3H)HRMS (FAB  ): Calcd For M / Z 364.0369 (MH & lt;), Found M / Z 364.0395 (MH & lt;) 
(Step 2)
(2)
Compound obtained in step 1 of synthesis of 3-{[(2S) -2-amino-2-carboxyethyl] carbamoylamino} -5-chloro-4-methylbenzenesulfonate . To 64 g (net 10.0 g, 27.34 mmol), 18 mL of water (1.8 L / kg vs. the compound of Step 1) was added, and the mixture was stirred at 8 ° C. 3.42 mL (57.41 mmol, 2.1 eq.) Of a 48% aqueous sodium hydroxide solution was added dropwise, and the mixture was washed with 1.0 mL (1.0 L / kg) of water and then stirred at 8 ° C. for 15 minutes. After confirming the completion of hydrolysis by HPLC, the temperature was raised to 25 ° C. and 48% HBr aq. About 3.55 mL was added to adjust the pH to 5.8. After confirming the precipitation of the desired product by dropping 65 mL (6.5 L / kg) of isopropyl alcohol, the mixture was aged for 1 hour. 81 mL (8.1 L / kg) of isopropyl alcohol was added dropwise and the mixture was aged at 8 ° C. overnight. The precipitated solid was filtered under reduced pressure, washed with 20 mL (2.0 L / kg) of isopropyl alcohol, and then dried under reduced pressure at 40 ° C. for 4 hours to obtain 10.7 g of the desired product as a white solid (net 9.46 g, 92). .6%).
1 H-NMR (400MHz, DMSO-d6): δ8.76 (s, 1H), 7.91 (d, 1H, J = 1.6Hz), 8.00-7.50 (bs, 2H), 7.24 (d, 1H, J = 1.6Hz), 7.20 (t, 1H, J = 5.6Hz), 3.58-3.54 (m, 1H), 3.47-3.43 (m, 1H), 3.42-3.37 (m, 1H), 2.23 (s, 3H)

キッセイ薬品工業株式会社

///////////Upacicalcet sodium hydrate, Upasita, ウパシカルセトナトリウム水和物 , APPROVALS 2021, JAPAN 2021, Upacicalcet

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Meglimin hydrochloride


Imeglimin hydrochloride (JAN).png
Imeglimin.svg

Meglimin hydrochloride

Twymeeg

Formula C6H13N5. HCl
CAS 775351-61-6 (HCl). , C6H14ClN5 191.66CAS 775351-65-0, FREEFORM 155.20
Mol weight 191.6619

AntidiabeticAPPROVED PMDA JAPAN2021/6/23, イメグリミン塩酸塩

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

DB12509

NCGC00378621-02

HY-14771

Q6003719

UNII-UU226QGU97

UU226QGU97

1,3,5-Triazine-2,4-diamine,1,6-dihydro-N,N,6-trimethyl-,(+)-(9CI)

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

Imeglimin [INN]

Emd 387008 (R-imeglimin) HCl

EMD-387008

Imeglimin is an experimental drug being developed as an oral anti-diabetic.[1][2] It is an oxidative phosphorylation blocker that acts to inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion. It will be the first of a new class of anti-diabetic if it is approved.

A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library
A review of phenformin, metformin, and imeglimin - Yendapally - 2020 - Drug Development Research - Wiley Online Library

PATENT

https://patents.google.com/patent/WO2012072663A1/enEXAMPLESExample 1 : Synthesis and isolation of (+)-2-amino-3,6-dihydro-4-dimethylamino-6- methyl-l,3,5-triazine hydrochloride by the process according to the invention

Preliminary step: Synthesis of racemic 2-amino-3,6-dihydro-4-dimethylamino- 6-methyl-l,3,5-triazine hydrochloride:

Figure imgf000013_0001

Metformin hydrochloride is suspended in 4 volumes of isobutanol. Acetaldehyde diethylacetal (1.2 eq.) and para-toluenesulfonic acid (PTSA) (0.05 eq) are added and the resulting suspension is heated to reflux until a clear solution is obtained. Then 2 volumes of the solvent are removed via distillation and the resulting suspension is cooled to 20°C. The formed crystals are isolated on a filter dryer and washed with isobutanol (0.55 volumes). Drying is not necessary and the wet product can be directly used for the next step.Acetaldehyde diethylacetal can be replaced with 2,4,6-trimethyl-l,3,5-trioxane (paraldehyde).- Steps 1 and 2: formation of the diastereoisomeric salt and isolation of the desired diastereoisomer

Figure imgf000013_0002

Racemic 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine hydrochloride wet with isobutanol (obtained as crude product from preliminary step without drying) and L-(+)-Tartaric acid (1 eq.) are dissolved in 2.2 volumes of methanol at 20-40°C. The obtained clear solution is filtered and then 1 equivalent of triethylamine (TEA) is added while keeping the temperature below 30°C. The suspension is heated to reflux, stirred at that temperature for 10 minutes and then cooled down to 55°C. The temperature is maintained at 55°C for 2 hours and the suspension is then cooled to 5- 10°C. After additional stirring for 2 hours at 5-10°C the white crystals are isolated on a filter dryer, washed with methanol (2 x 0.5 Vol) and dried under vacuum at 50°C. The yield after drying is typically in the range of 40-45%

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0001

γ ethanol HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt is suspended in 2 volumes of ethanol and 1.02 equivalents of HCl-gas are added under vacuum (-500 mbar). The suspension is heated to reflux under atmospheric pressure (N2) and 5% of the solvent is removed via distillation. Subsequent filtration of the clear colourless solution into a second reactor is followed by a cooling crystallization, the temperature is lowered to 2°C. The obtained suspension is stirred at 2°C for 3 hours and afterwards the white crystals are isolated with a horizontal centrifuge. The crystal cake is washed with ethanol and dried under vacuum at 40°C. The typical yield is 50-55% and the mother liquors can be used for the recovery of about 25-30%) of (+)-2-amino- 3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate.Example 2: Modification of the solvent of steps 3 and 4

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

Figure imgf000014_0002

HN^NH acetone HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt synthesized according to steps 1 and 2 of example 1 is suspended in 1 volume (based on total amount of (+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt) of acetone at 20°C. To this suspension 1.01 equivalents of 37% Hydrochloric acid are added. The suspension is heated to reflux under atmospheric pressure (N2) and water is added until a clear solution is obtained. 1.5 vol of acetone are added at reflux temperature. The compound starts crystallising and the obtained suspension is kept at reflux for 2 hours followed by a cooling crystallization to 0°C. The obtained suspension is stirred at 0°C for 2 hours and the white crystals are isolated by centrifugation. The crystal cake is washed with isopropanol and dried under vacuum at 40°C in a continuous drying oven.

References

  1. ^ Vuylsteke, V; Chastain, L. M; Maggu, G. A; Brown, C (2015). “Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes”Drugs in R&D15 (3): 227–232. doi:10.1007/s40268-015-0099-3PMC 4561051PMID 26254210.
  2. ^ Dubourg, J; Fouqueray, P; Thang, C; Grouin, JM; Ueki, K (April 2021). “Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial”Diabetes Care44 (4): 952–959. doi:10.2337/dc20-0763PMID 33574125.
 
Names
Preferred IUPAC name(2S)-N6,N6,2-Trimethyl-1,2-dihydro-1,3,5-triazine-4,6-diamine
Identifiers
CAS Number 775351-65-0
3D model (JSmol) Interactive image
ChemSpider 26232690
PubChem CID 24812808
UNII UU226QGU97
CompTox Dashboard (EPA) DTXSID50228237 
showInChI
showSMILES
Properties
Chemical formula C6H13N5
Molar mass 155.205 g·mol−1
Pharmacology
ATC code None
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

/////////Imeglimin hydrochloride, Twymeeg, JAPAN 2021, APPROVALS 2021, Antidiabetic, イメグリミン塩酸塩, ATI DIABETES, DIABETES, Imeglimin

CC1N=C(NC(=N1)N(C)C)N.Cl

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Tucidinostat, Chidamide


Tucidinostat (JAN/USAN/INN).png
Chidamide.svg

Tucidinostat, Chidamide

ツシジノスタット

2021/6/23 PMDA JAPAN APPROVED,

Hiyasta
FormulaC22H19FN4O2
CAS1616493-44-7
Mol weight390.4103

Antineoplastic, Histone deacetylase inhibitor

Chidamide (Epidaza) is a histone deacetylase inhibitor (HDI) developed in China.[1] It was also known as HBI-8000.[2] It is a benzamide HDI and inhibits Class I HDAC1HDAC2HDAC3, as well as Class IIb HDAC10.[3]

Chidamide is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and has orphan drug status in Japan.[2][better source needed] As of April 2015 it is only approved in China.[1]

Chidamide is being researched as a treatment for pancreatic cancer.[4][5][6] However, it is not US FDA approved for the treatment of pancreatic cancer.

Chidamide (Epidaza®), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74 This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis. Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.

Chemical Synthesis

The scalable synthetic approach to chidamide very closely follows the discovery route. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield. Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.

References

  1. Jump up to:a b Lowe D (April 2015). “China’s First Homegrown Pharma”Seeking Alpha.
  2. Jump up to:a b “Chipscreen Biosciences Announces CFDA Approval of Chidamide (Epidaza) for PTCLs in China”. PR Newswire Association LLC.
  3. ^ “HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai”. PR Newswire Association LLC. February 2016.
  4. ^ Qiao Z, Ren S, Li W, Wang X, He M, Guo Y, et al. (April 2013). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells”. Biochemical and Biophysical Research Communications434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059PMID 23541946.
  5. ^ Guha M (April 2015). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews. Drug Discovery14 (4): 225–6. doi:10.1038/nrd4583PMID 25829268S2CID 36758974.
  6. ^ Wang SS (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.
Clinical data
Trade namesEpidaza
Other namesTucidinostat
Identifiers
showIUPAC name
CAS Number1616493-44-7 
PubChem CID9800555
ChemSpider7976319
UNII87CIC980Y0
Chemical and physical data
FormulaC22H19FN4O2
Molar mass390.418 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////Tucidinostat, Antineoplastic, Histone deacetylase inhibitor, ツシジノスタット , Epidaza, Chidamide, APPROVALS 2021, JAPAN 2021

wdt-28

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ZF2001, ZIFIVAX


Republic of Uzbekistan
Oʻzbekiston Respublikasi  (Uzbek)
FlagState emblem

ZF2001

ZIFIVAX

CAS 2609662-31-7 

A COVID-19 vaccine comprising a dimeric form of SARS-CoV-2 receptor-binding domain (RBD) produced in China hamster ovary (CHO) cells and adjuvanted with aluminum hydroxide (Anhui Zhifei Longcom/Institute of Microbiol. China Academy of Sciences)

Recombinant vaccine

Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences

China, Uzbekistan

CHO Cells Recombinant Vaccine

  • ZF-2001
  • ZF-UZ-VAC2001
  • Chinese Academy of Sciences (Originator)
  • Zhifei Longcom (Originator)

Human SARS-CoV-2 (Covid-19 coronavirus) vaccine consisting of recombinant dimer comprising two RBD domains (R319-K527) of the spike glycoprotein of SARS-CoV-2 fused via a disulfide link; expressed in CHO cells

ZF-2001 is a recombinant coronavirus vaccine jointly developed by the Institute of Microbiology of the Chinese Academy of Sciences and Zhifei Longcom. The vaccine became available in 2021 in Uzbekistan under an emergency use authorization for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). The vaccine is currently evaluated in phase III clinical trials.

This vaccine candidate, developed in China, uses SARS-CoV-2 protein subunits that are entirely engineered, created, and secreted by Chinese Hamster Ovary (CHO) cells1. The vaccine candidate is sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. and is undergoing phase I clinical trials to evaluate safety and tolerability.

ZF2001, trade-named ZIFIVAX, is an adjuvanted protein subunit COVID-19 vaccine developed by Anhui Zhifei Longcom in collaboration with the Institute of Microbiology at the Chinese Academy of Sciences.[1][2] As of December 2020, the vaccine candidate was in Phase III trials with 29,000 participants in ChinaEcuadorMalaysiaPakistan, and Uzbekistan.[3][4]

ZF2001 employs technology similar to other protein-based vaccines in Phase III trials from NovavaxVector Institute, and Medicago.[5] It is administered in 3 doses over a period of 2 months.[6]

ZF2001 was first approved for use in Uzbekistan and later China.[7][8] Production capacity is expected to be one billion doses a year.[6] Phase II results published in The Lancet on the three dose administration showed seroconversion rates of neutralizing antibodies of between 92% to 97%.[9]

Anhui Zhifei Longcom Biopharmaceuticals began a phase 3 clinical trial for its recombinant protein vaccine candidate in December, according to the WHO. State-run China Global Television Network in November reported that a one-year trial would take place in Uzbekistan and aim to recruit 5,000 volunteers. Anhui Zhifei is a unit of private firm Chongqing Zhifei Biological Products. It is co-developing the vaccine with the Chinese Academy of Sciences, a government institution.

Emergency Use Authorization received in UZ by Zhifei Longcom for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19)

Description

As described in Cell, the CoV spike receptor-binding domain (RBD) is an attractive vaccine target for coronaviruses but is constrained by limited immunogenicity, however a dimeric form of MERS-CoV RBD offers greater protection. The RBD-dimer significantly increases neutralizing antibodies compared to a conventional monomeric form and protected mice against MERS-CoV infection. CoV RBD-dimer have been produced at high yields in pilot scale production.[10]

Rather than injecting a whole virus, subunit vaccines contains virus particles specially selected to stimulate an immune response. Because the fragments are incapable of causing disease, subunit vaccines are considered very safe.[11] Subunit vaccines in widespread use include the Hepatitis B vaccine and Pertussis vaccine. However, as only a few viral components are included in the vaccine which does not display the full complexity of the virus, their efficacy may be limited.[12] Subunit vaccines are delivered alongside adjuvants and booster doses may be required.[11]

According to industry experts, production for this kind of vaccine is stable and reliable, and easier to achieve large-scale industrial production at home and overseas. However it was noted it can be very inconvenient for people to come back for a second and third dose.[6]

figure2

ZF2001 (Anhui Zhifei Longcom Biopharmaceutical/Chinese Academy of Medical Sciences)

The latest subunit vaccine candidate to enter Phase 3 clinical studies is the adjuvanted RBD-dimeric antigen designed by Anhui Zhifei Longcom Biopharmaceutical and the Institute of Microbiology of the Chinese Academy of Medical Sciences. Phase 3 clinical study was launched on December104 and will be initially carried out in China and Uzbekistan while Indonesia, Pakistan and Ecuador will follow as study sites (Clinical Trial Identifier: NCT04646590 and Registration Number: ChiCTR2000040153). The design of the study involves recruitment of 22,000 volunteers from China and 7000 subjects outside China for a total of 29,000 volunteers. There are still no published results on this candidate, however data from its Phase 2 placebo-controlled clinical trial (Clinical Trial Identifier: NCT04466085) conducted on a total of 900 participants ranging from 18 to 59 years old suggest that a 2 or 3 dose regimen is evaluated. Each immunization will be separated by the next by 4 weeks.

Development

Phase I and II trials and results

In June, Longcom began a double-blind, randomized, placebo parallel controlled Phase I trial with 50 participants aged 18–59 in Chongqing divided into low-dose, high-dose, and placebo groups.[13]

In July, Longcom began a randomized, double-blind, placebo-controlled Phase II trial with 900 participants aged 18–59 in ChangshaHunan divided into low-dose, high-dose, and placebo groups.[14] In August, an additional Phase II trial was launched with 50 participants aged 60 and above.[15][1]

In Phase II results published in The Lancet, on the two-dose schedule, seroconversion rates of neutralizing antibodies after the second dose were 76% (114 of 150 participants) in a 25 μg group and 72% (108 of 150) in a 50 μg group. On the three-dose schedule, seroconversion rate of neutralizing antibodies after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. 7 to 14 days after the administration of the third dose, the GMTs of neutralizing antibodies reached levels that were significantly higher than observed in human convalescent serum of recovering COVID-19 patients, especially in the 25 μg group.[9]

Phase III trials

In December, Longcom began enrollment of a Phase III randomized, double-blind, placebo-controlled clinical trial for 29,000 participants, including 750 participants between 18-59 and 250 participants 60 and older in China and 21,000 participants between 18-59 and 7,000 participants 60 and older outside China.[16][17]

In December, Malaysia‘s MyEG announced it would conduct Phase III trials. If the trials were successful, MyEG would be the sole distributor of ZF2001 in Malaysia for 3 years.[4]

In December, Uzbekistan began a year-long Phase III trial of ZF2001 with 5,000 volunteers between 18 and 59.[18][19]

In December, Ecuador‘s Minister of Health, Juan Carlos Zevallos announced Phase III trials would involve between 5,000 and 8,000 volunteers.[20]

In February, Pakistan‘s Drug Regulatory Authority (DRAP) approved Phase III trials with approximately 10,000 participants to be conducted at UHS Lahore, National Defense Hospital, and Agha Khan Hospital.[21]

Discussions to begin Phase III trials are also underway in Indonesia.[17][22]

COVID-19 Variants

In February, lab studies of twelve serum samples taken from recipients of BBIBP-CorV and ZF2001 retained neutralizing activity against the Beta variant although with weaker activity than against the original virus.[23] For ZF-2001, geometric mean titers declined by 1.6-fold, from 106.1 to 66.6, which was less than antisera from mRNA vaccine recipients with a 6-folds decrease.[24] Preliminary clinical data from Novavax and Johnson & Johnson also showed they were less effective in preventing COVID-19 in South Africa, where the new variant is widespread.[23]

Manufacturing

The company’s vaccine manufacturing facility was put into use in September.[17] In February 2021, Pu Jiang, General Manager of Zhifei Longcom, said the company had an annual production capacity of 1 billion doses.[6]

Marketing and deployment

 
  Full authorization  Emergency authorization

See also: List of COVID-19 vaccine authorizations § RBD-Dimer

On March 1, Uzbekistan granted approval for ZF2001 (under tradename ZF-UZ-VAC 2001) after having taken part in the Phase III trials.[8] In March, Uzbekistan received 1 million doses and started vaccinations in April.[25] By May, a total of 3 million doses had been delivered.[26]

On March 15, China approve of ZF2001 for emergency use after being approved by Uzbekistan earlier in the month.[7]

References

  1. Jump up to:a b “Anhui Zhifei Longcom: RBD-Dimer – COVID19 Vaccine Tracker”covid19.trackvaccines.org. Retrieved 27 December2020.
  2. ^ “COVID-19 Vaccine: ZIFIVAX by Anhui Zhifei Longcom Biopharma, Institute of Microbiology Chinese Academy of Sciences”covidvax.org. Retrieved 27 December 2020.
  3. ^ “Fifth Chinese Covid-19 vaccine candidate ready to enter phase 3 trials”South China Morning Post. 20 November 2020. Retrieved 27 December 2020.
  4. Jump up to:a b Ying TP (7 December 2020). “MYEG to conduct phase 3 clinical trial for China’s Covid-19 vaccine in Msia | New Straits Times”NST Online. Retrieved 27 December 2020.
  5. ^ Zimmer C, Corum J, Wee SL (10 June 2020). “Coronavirus Vaccine Tracker”The New York TimesISSN 0362-4331. Retrieved 27 December 2020.
  6. Jump up to:a b c d “China’s production bottleneck ‘could be eased with latest Covid-19 vaccine'”South China Morning Post. 17 March 2021. Retrieved 18 March 2021.
  7. Jump up to:a b Liu, Roxanne (15 March 2021). “China IMCAS’s COVID-19 vaccine obtained emergency use approval in China”Reuters. Retrieved 15 March 2021.
  8. Jump up to:a b Mamatkulov, Mukhammadsharif (1 March 2021). “Uzbekistan approves Chinese-developed COVID-19 vaccine”Reuters. Retrieved 2 March 2021.
  9. Jump up to:a b Yang, Shilong; Li, Yan; Dai, Lianpan; Wang, Jianfeng; He, Peng; Li, Changgui; Fang, Xin; Wang, Chenfei; Zhao, Xiang; Huang, Enqi; Wu, Changwei (24 March 2021). “Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials”The Lancet Infectious Diseases0doi:10.1016/S1473-3099(21)00127-4ISSN 1473-3099PMC 7990482PMID 33773111.
  10. ^ Dai L, Zheng T, Xu K, Han Y, Xu L, Huang E, et al. (August 2020). “A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS”Cell182 (3): 722–733.e11. doi:10.1016/j.cell.2020.06.035PMC 7321023PMID 32645327.
  11. Jump up to:a b “What are protein subunit vaccines and how could they be used against COVID-19?”http://www.gavi.org. Retrieved 27 December2020.
  12. ^ Dong Y, Dai T, Wei Y, Zhang L, Zheng M, Zhou F (October 2020). “A systematic review of SARS-CoV-2 vaccine candidates”Signal Transduction and Targeted Therapy5 (1): 237. doi:10.1038/s41392-020-00352-yPMC 7551521PMID 33051445.
  13. ^ Clinical trial number NCT04445194 for “Phase I Clinical Study of Recombinant Novel Coronavirus Vaccine” at ClinicalTrials.gov
  14. ^ Clinical trial number NCT04466085 for “A Randomized, Blinded, Placebo-controlled Trial to Evaluate the Immunogenicity and Safety of a Recombinant New Coronavirus Vaccine (CHO Cell) With Different Doses and Different Immunization Procedures in Healthy People Aged 18 to 59 Years” at ClinicalTrials.gov
  15. ^ Clinical trial number NCT04550351 for “A Randomized, Double-blind, Placebo-controlled Phase I Clinical Trial to Evaluate the Safety and Tolerability of Recombinant New Coronavirus Vaccines (CHO Cells) in Healthy People Aged 60 Years and Above” at ClinicalTrials.gov
  16. ^ Clinical trial number NCT04646590 for “A Phase III Randomized, Double-blind, Placebo-controlled Clinical Trial in 18 Years of Age and Above to Determine the Safety and Efficacy of ZF2001, a Recombinant Novel Coronavirus Vaccine (CHO Cell) for Prevention of COVID-19” at ClinicalTrials.gov
  17. Jump up to:a b c “Another Chinese Covid-19 vaccine enters late-stage human trials with a plan to produce 300 million doses annually”Business Insider. Retrieved 27 December 2020.
  18. ^ Reuters Staff (11 November 2020). “Uzbekistan to carry out late-stage trial of Chinese COVID-19 vaccine candidate”Reuters. Retrieved 27 December 2020.
  19. ^ “Uzbekistan poised to start trials on Chinese COVID-19 vaccine | Eurasianet”eurasianet.org. Retrieved 27 December 2020.
  20. ^ “Ecuador participará en ensayos de una vacuna china contra el covid-19”CNN (in Spanish). 29 December 2020. Retrieved 23 January 2021.
  21. ^ “China’s third vaccine enters Pakistan”The Nation. 15 February 2021. Retrieved 28 February 2021.
  22. ^ “Covid vaccine tracker: How do the leading jabs compare?”http://www.ft.com. 23 December 2020. Retrieved 27 December 2020.
  23. Jump up to:a b Liu, Roxanne (3 February 2021). “Sinopharm’s COVID-19 vaccine remained active against S.Africa variant, effect reduced – lab study”Reuters. Retrieved 29 March 2021.
  24. ^ Huang, Baoying; Dai, Lianpan; Wang, Hui; Hu, Zhongyu; Yang, Xiaoming; Tan, Wenjie; Gao, George F. (2 February 2021). “Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines”bioRxiv: 2021.02.01.429069. doi:10.1101/2021.02.01.429069.
  25. ^ uz, Kun. “Uzbekistan receives 1 million doses of ZF-UZ-VAC 2001 vaccine”Kun.uz. Retrieved 28 March 2021.
  26. ^ Romakayeva, Klavdiya (18 May 2021). “Uzbekistan receives third batch of Chinese-Uzbek COVID-19 vaccine”Trend.Az. Retrieved 19 May 2021.

 

Vaccine description
TargetSARS-CoV-2
Vaccine typeProtein subunit
Clinical data
Trade namesZIFIVAX
Routes of
administration
Intramuscular
ATC codeNone
Identifiers
DrugBankDB15893
Part of a series on the
COVID-19 pandemic
COVID-19 (disease)SARS-CoV-2 (virus)
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 COVID-19 portal

////////ZF2001, ZIFIVAX, corona virus, covid 19, SARS-CoV-2ZF 2001, ZF-UZ-VAC2001, Uzbekistan, approvals 2021

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Estetrol


Skeletal formula of estetrol
Estetrol (USAN).png

Estetrol

エステトロール;

FormulaC18H24O4
CAS15183-37-6
Mol weight304.3808

FDA 4/15/2021, To prevent pregnancy, Nextstellis

New Drug Application (NDA): 214154
Company: MAYNE PHARMA

Label (PDF)
Letter (PDF)
Review

Label (PDF)

PATENT

https://patents.google.com/patent/EP1562976B1/en

Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol.Recently, estetrol has been found effective as an estrogenic substance for use in HRT, disclosure of which is given in the Applicant’s co-pending application WO 02/094276 . Estetrol is a biogenic estrogen that is endogeneously produced by the fetal liver during human pregnancy. Other important applications of estetrol are in the fields of contraception, therapy of auto-immune diseases, prevention and therapy of breast and colon tumors, enhancement of libido, skin care, and wound healing as described in the Applicant’s co-pending applications WO 02/094276 , WO 02/094279 , WO 02/094278 , WO 02/094275 , EP 1511496 A1 EP 1511498 A1 , WO 03/041718 , WO 03/018026 , EP 1526856 A1 and WO 04/0278032 .[0004]The synthesis of estetrol and derivatives thereof on a laboratory scale basis is known in the art: Fishman J., Guzik H., J. Org. Chem. 33, 3133 – 3135 (1968); Nambara T. et al., Steroids 27, 111 – 121 (1976); or Suzuki E. et al., Steroids 60, 277 – 284(1995).[0005]

Fishman J., Guzik H., J. Org. Chem. 33, 3133 – 3135 (1968) discloses a successful synthesis of estetrol from an estrone derivative (compound (III); cf. for a synthesis of compound (III) Cantrall, E.W., Littell, R., Bernstein, S. J. Org. Chem 29, 214 – 217 (1964)). In a first step, the carbonyl group at C17 of compound (III) was reduced with LiAlH4 to estra-1,3,5(10),15-tetraene-3,17-diol (compound VIa) that was isolated as the diacetate (compound VIb). Compound VIb was subjected to cis-hydroxylation of the double bond of ring D by using OsO4 which resulted into the formation of estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound Ib) that under heating with K2CO3 in methanol produces estetrol (Scheme 1).

Figure imgb0001

[0006]

The overall yield of this three step process is, starting from estrone derivative III, only about 7%. It is worth noting that the protected derivative 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IV) could be cis-hydroxylated to its 15α,16α-diol derivative (compound Va), but that thereafter the dioxolane group could not be removed (p-toluene sulfonic acid in acetone at room temperature) or that the hydrolysis (aqueous sulfuric acid in warm dioxane) of the dioxolane group resulted in a mixture containing a multitude of products (Scheme 2).

Figure imgb0002

[0007]Nambara T. et al., Steroids 27, 111 – 121 (1976) discloses another synthesis of estetrol wherein estrone is the starting material. The carbonyl group of estrone is first protected by treatment with ethylene glycol and pyridine hydrochloride followed by acetylation of the hydroxy group at C3. The next sequence of steps involved a bromination/base catalyzed dehydrobromination resulting into the formation of 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol (compound IVa). This compound IVa was subsequently acetylated which produced 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IVb). In a next step, the dioxolane group of compound IVb was hydrolysed by using p-toluene sulfonic acid to compound Vb, followed subsequently by reduction of the carbonyl group at C17 (compound Vc) and oxidation of the double bond of ring D thereby forming estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound VIb). See Scheme 3.[0008]

Suzuki E. et al., Steroids 60, 277 – 284 (1995) also discloses the synthesis of estetrol by using compound Vb of Nambara T. et al. as starting material. The carbonyl group at C17 of this compound was first reduced followed by acetylation yielding estra-1,3,5(10),15-tetraene-3,17-diol-3,17-diacetate (compound 2b). The latter was subjected to oxidation with OsO4 which provided estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound 3b) in 46% yield.

Figure imgb0003

[0009]According to the Nambara T. et al. and Suzuki E. et al., the synthesis of estetrol can be performed with a yield of approximately 8%, starting from estrone.0010]

Poirier D., et al., Tetrahedron 47, 7751 – 7766 (1991) discloses the following compounds which were prepared according to methods that have been used to prepare similar compounds:

Figure imgb0004

[0011]Dionne, P. et al., Steriods 62, 674 – 681 (1997) discloses the compound shown above wherein R is either methyl or t-butyldimethylsilyl.[0012]Magnus, P. et al., J. Am. Chem. Soc. 120, 12486 -12499 (1998) discloses that the main methods for the synthesis of α,β-unsaturated ketones from saturated ketones are (a) halogenation followed by dehydrohalogenation, (b) utilising sulphur or selenium derivatives, (c) DDQ and (d) utilizing palladium(II) complexes.[0013]Furthermore, it has also been found that by following the prior art methods mentioned above, estetrol of high purity was obtained only in low yield when using an acetyl group as a protecting group for the 3-hydroxy group of estra-1,3,5(10),15-tetraen-3-ol-17-one, in particular because its sensitivity to hydrolysis and solvolysis. In particular, the lability of the acetyl group lead not only to an increased formation of byproducts during the reactions, but also during chromatography and crystallisation for purification of intermediate products when protic solvents such as methanol were used. Therefore, it is difficult to isolate purified estetrol and intermediates thereof in good yield.

Example 7 3-Benzyloxy-estra-1,3,5 (10),15-tetraen-17-ol (compound 5; A = benzyl)

[0088]To a solution of 3-benzyl-dehydroestrone (compound 6; A = benzyl; 58 g, 162 mmol) in a mixture of MeOH (900 mL) and THF (200 mL) at room temperature was added CeCl3 heptahydrate (66.4 g, 178 mmol). After stirring for 1 h the mixture was cooled to 0-5°C using an ice/water bath. Then NaBH4 (12.2 g, 324 mmol) was added in small portions maintaining a temperature below 8°C. After stirring for 2 h at 0-5°C (TLC showed the reaction to be complete) 1 N NaOH (300 mL) and DCM (1 L) were added and the mixture was stirred for ½ h at room temperature. The layers were separated and the aqueous layer was extracted with DCM (200 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give an off-white solid (55.0 g, 152.8 mmol, 94%) TLC: Rf = 0.25 (heptanes/ethyl acetate = 4:1); HPLC-MS: 93% β-isomer, 2% α-isomer; DSC: Mp. 149.7°C, purity 96.6%; 1H-NMR (200 MHz, CDCl3) δ 7.48 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.85 (dd, 1H, J1 = 2.8 Hz, J2 = 8.6 Hz), 6.81 (d, 1H, J = 2.4 Hz), 6.10 (d, 1H, J = 5.8 Hz), 5.79 (dd, 1H, J1 = 1.8 Hz, J2 = 3.4 Hz), 5.11 (s, 2H), 4.48 (d, 1H, J = 7.6), 2.96 (m, 2H), 2.46 – 1.64 (m, 9H), 0.93 (s, 3H) ppm.

Example 8 17-Acetyloxy-3-benzyloxy-estra-1,3,5 (10),15-tetraene (compound 4; A = benzyl, C = acetyl)

[0089]A solution of 3-Benzyloxy-estra-1,3,5 (10),15-tetraen-17-ol (compound 5; A = benzyl; 55.0 g, max. 153 mmol) in pyridine (400 mL) was treated with Ac2O (50 mL, 0.53 mol) and 4-dimethylaminopyridine (1.5 g, 12.3 mmol). The mixture was stirred for 2 h at room temperature (TLC showed the reaction to be complete). It was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL), washed with water (200 mL) and brine (150 mL), dried (Na2SO4) and concentrated in vacuo to yield a yellow solid (54.0 g, 49.8 mmol, 88%). The product was purified by recrystallization from heptanes/ EtOAc/ EtOH (1:0.5:1) to afford a white solid (45.0 g, 112 mmol, 73%) TLC: Rf = 0.6 (heptanes/ethyl acetate = 4/1); HPLC-MS: 98% β-isomer, 1% α-isomer, 1.3% ß-estradiol; DSC: Mp. 122.8°C, purity 99.8%; 1H-NMR (200 MHz, CDCl3) δ 7.44 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.86 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.80 (d, 1H, J = 2.6 Hz), 6.17 (d, 1H, J = 5.8 Hz), 5.78 (dd, 1H, J1 = 1.4 Hz, J2 = 3.2 Hz), 5.45 (m, 1H), 5.11 (s, 2H), 2.96 (m, 2H), 2.40 – 1.54 (m, 10H), 2.18 (s, 3H), 0.93 (s, 3H) ppm.

Example 9 17-Acetyl-3-Benzyl estetrol (compound 3; A = benzyl, C = acetyl)

[0090]OsO4 on PVP (9 g, ~5% w/w OsO4 on PVP, prepared according to Cainelli et al. Synthesis, 45 – 47 (1989) was added to a solution of 17-Acetyloxy-3-benzyloxy-estra-1,3,5 (10),15-tetraene (compound 4; A = benzyl, C = acetyl; 45 g, 112 mmol) in THF (450 mL) and the mixture was heated to 50°C. Trimethylamine-N-oxide dihydrate (24.9 g, 224 mmol) was added portion-wise over 2 h. After stirring for 36 h at 50°C (TLC showed the reaction to be complete) the reaction mixture was cooled to room temperature. The solids were filtered off, washed with THF (100 mL) and the filtrate was concentrated. The residue was taken up in EtOAc (250 mL) and water (250 mL) was added. The aqueous layer was acidified with 1 N HCl (ca. 10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with heptanes/EtOAc (1:1, 100 mL), stirred for 2 h and the resulting white precipitate was filtered off to give the product as a white solid (41 g, 94 mmol, 84%). The product was purified by recrystallization from heptanes/ ethyl acetate/ EtOH (2:1:1) three times to afford a white solid (21 g, 48.2 mmol, 43%). HPLC-MS: 99.5% βαα-isomer; DSC: Mp. 159.3°C, purity 98.7%; 1H-NMR (200 MHz, CDCl3) δ 7.49 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.84 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.81 (d, 1H, J = 2.4 Hz), 5.11 (s, 2H), 4.45 (d, 1H, J = 4.4), 4.11 (m, 3H), 3.12 (m, 1H) 2.95 (m, 2H), 2.46 -1.64 (m, 10H), 2.24 (s, 3H), 0.93 (s, 3H) ppm.

Example 10 17-Acetyl estetrol (compound 2; C = acetyl)

[0091]To a solution of 17-acetyl-3-benzyl estetrol (compound 3; A = benzyl, C = acetyl; 21 g, 48.2 mmol) in MeOH (600 mL, HPLC-grade) was added a preformed suspension of 10% Palladium on activated carbon (2 g) in methanol (50 mL). The mixture was placed under an atmosphere of H2 at 1 atm and stirred for 24 h (TLC showed the reaction to be completed) at room temperature. It was filtered over Celite® and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give 17-acetyl estetrol as a white solid (15 g, 43.4 mmol, 90%). TLC: Rf = 0.2 (heptanes/ethyl acetate = 1/1); HPLC-MS: 99.2%, DSC: Mp. 212.2°C, purity 98.9%; 1H-NMR (200 MHz, CD3OD) δ 7.14 (d, 1H, J = 8.0 Hz), 6.60 (dd, 1H, J1 = 2.6 Hz, J2 = 8.8 Hz), 6.56 (d, 1H, J = 2.4 Hz), 4.81 (dd, 1H, J1 = 3.4 Hz, J2 = 6.4 Hz), 4.07 (m, 3H), 3.12 (m, 1H), 2.85 (m, 2H), 2.37 – 1.37 (m, 10H), 2.18 (s, 3H), 0.91 (s, 3H) ppm.

Example 11 Estetrol

[0092]17-Acetyl-estetrol (compound 2; C = acetyl; 15 g, 43.4 mmol) and K2CO3 (6 g, 43.4 mmol) were suspended in MeOH (500 mL, HPLC-grade) and stirred for 4 h at room temperature (TLC showed the reaction to be complete). The solvents were evaporated in vacuo. Water (200 mL) and CHCl3 (70 mL) were added and the mixture was stirred and neutralized with 0.1 N HCl (50 mL). The product was collected by filtration, washed with water (100 mL) and CHCl3 (100 mL) to give estetrol as a white solid (12.2 g, 40.1 mmol, 92.5%, overall yield from estrone 10.8%) after drying at 40°C in an air-ventilated oven. TLC: Rf = 0.05 (heptanes/ethyl acetate = 1/1); HPLC-MS: 99.1%, DSC: Mp. 243.7°C, purity 99.5%; 1H-NMR (200 MHz, CD3OD) δ 7.14 (d, 1H, J = 8.6 Hz), 6.61 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.56 (d, 1H, J = 2.4 Hz), 4.83 (m, 1H), 3.93 (m, 3H), 3.50 (d, 1H, J = 5.2), 3.38 (m, 2H), 2.84 (m, 2H), 2.32 (m, 3H), 1.97 (m, 1H), 1.68 – 1.24 (m, 5H), 0.86 (s, 3H) ppm.

SYN

https://www.tandfonline.com/doi/abs/10.1080/13697130802054078?journalCode=icmt20

Estetrol (E4), or oestetrol, is a weak estrogen steroid hormone, which is found in detectable levels only during pregnancy in humans.[1][2] It is produced exclusively by the fetal liver.[1] Estetrol is closely related to estriol (E3), which is also a weak estrogen that is found in high quantities only during pregnancy.[1][2] Along with estradiol (E2), estrone (E1), and E3, estetrol (E4) is a major estrogen in the body, although only during pregnancy.[1]

In addition to its role as a natural hormone, estetrol is under clinical development for use as a medication, for instance in hormonal contraception (in combination with drospirenone) and as menopausal hormone therapy; for information on estetrol as a medication, see the estetrol (medication) article.

Biological function

Estetrol is an estrogen and has estrogenic effects in various tissues.[1] Estetrol interacts with nuclear Estrogen Receptor (ERα) in a manner identical to that of the other estrogens and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs).[3][4] So far the physiological function of estetrol is unknown. The possible use of estetrol as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal estetrol plasma levels during pregnancy this appeared not to be feasible.[5][6][7][8][9]

Biological activity

Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen.[10][11] It has moderate affinity for ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively.[10][12] As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ.[10][12] The estrogen has low affinity for the ERs relative to estradiol, and both estetrol and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects to estradiol.[10] The affinity of estetrol for the ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol.[10] Estetrol shows high selectivity for the ERs.[10][12]

Biochemistry

Biosynthesis

Estetrol is synthesized during pregnancy only in the fetal liver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase.[13][14][15] Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step.[16] It appears in maternal urine at around week 9 of pregnancy.[2] After birth the neonatal liver rapidly loses its capacity to synthesize estetrol because these two enzymes are no longer expressed.

Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine.[17][18] During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy.[1]

Distribution

In terms of plasma protein binding, estetrol is moderately bound to albumin, and is not bound to sex hormone-binding globulin (SHBG).[19][20]

Metabolism

Estetrol undergoes no phase I metabolism by CYP P450 enzymes.[10] It is conjugated via glucuronidation and to a lesser extent sulfation and then excreted.[10][21]

Excretion

Estetrol is excreted mostly or completely in urine.[21][10]

Chemistry

See also: List of estrogens

vteStructures of major endogenous estrogensChemical structures of major endogenous estrogensEstrone (E1)Estradiol (E2)Estriol (E3)Estetrol (E4)The image above contains clickable linksNote the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is a naturally occurring estrane steroid and derivative of estrin (estratriene).[10][11] It has four hydroxyl groups, which explains the abbreviation E4.[10][11]

Synthesis

Chemical syntheses of estetrol have been published.[22]

History

Estetrol was discovered in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, via isolation from the urine of pregnant women.[10][23]

References

  1. Jump up to:a b c d e f Holinka CF, Diczfalusy E, Coelingh Bennink HJ (May 2008). “Estetrol: a unique steroid in human pregnancy”. J. Steroid Biochem. Mol. Biol110 (1–2): 138–43. doi:10.1016/j.jsbmb.2008.03.027PMID 18462934.
  2. Jump up to:a b c Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991
  3. ^ Abot, Anne; Fontaine, Coralie; Buscato, Mélissa; Solinhac, Romain; Flouriot, Gilles; Fabre, Aurélie; Drougard, Anne; Rajan, Shyamala; Laine, Muriel; Milon, Alain; Muller, Isabelle (2014). “The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation”EMBO Molecular Medicine6 (10): 1328–1346. doi:10.15252/emmm.201404112ISSN 1757-4676PMC 4287935PMID 25214462.
  4. ^ Foidart, JM; et al. (2019). “30th Annual Meeting of The North America Menopause Society September 25 – 28, 2019, Chicago, IL”Menopause26 (12): 1445–1481. doi:10.1097/GME.0000000000001456ISSN 1530-0374.
  5. ^ J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.
  6. ^ D. Tulchinsky, F.D. Frigoletto, K.J. Ryan, J. Fishman, Plasma estetrol as an index of fetal well-being, J. Clin. Endocrinol. Metab. 40 (1975) 560-567
  7. ^ A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.
  8. ^ N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.
  9. ^ N. Kundu, M. Wachs, G.B. Iverson, L.P. Petersen, Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies, Obstet. Gynecol. 58 (1981) 276-281.
  10. Jump up to:a b c d e f g h i j k l Coelingh Bennink HJ, Holinka CF, Diczfalusy E (2008). “Estetrol review: profile and potential clinical applications”. Climacteric. 11 Suppl 1: 47–58. doi:10.1080/13697130802073425PMID 18464023.
  11. Jump up to:a b c Visser M, Coelingh Bennink HJ (March 2009). “Clinical applications for estetrol” (PDF). J. Steroid Biochem. Mol. Biol114(1–2): 85–9. doi:10.1016/j.jsbmb.2008.12.013PMID 19167495.
  12. Jump up to:a b c Visser M, Foidart JM, Coelingh Bennink HJ (2008). “In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism”. Climacteric. 11 Suppl 1: 64–8. doi:10.1080/13697130802050340PMID 18464025.
  13. ^ J. Schwers, G. Eriksson, N. Wiqvist, E. Diczfalusy, 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn, Biochim. Biophys. Acta. 100 (1965) 313-316
  14. ^ J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.
  15. ^ S. Mancuso, G. Benagiano, S. Dell’Acqua, M. Shapiro, N. Wiqvist, E. Diczfalusy, Studies on the metabolism of C-19 steroids in the human foeto-placental unit, Acta Endocrinol. 57 (1968) 208-227.
  16. ^ Jerome Frank Strauss; Robert L. Barbieri (2009). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 262–. ISBN 1-4160-4907-X.
  17. ^ J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253
  18. ^ J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.
  19. ^ Visser M, Holinka CF, Coelingh Bennink HJ (2008). “First human exposure to exogenous single-dose oral estetrol in early postmenopausal women”. Climacteric. 11 Suppl 1: 31–40. doi:10.1080/13697130802056511PMID 18464021.
  20. ^ Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ (2008). “Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells”. Climacteric. 11 Suppl 1: 41–6. doi:10.1080/13697130701851814PMID 18464022.
  21. Jump up to:a b Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ (2015). “Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives”Eur J Contracept Reprod Health Care20 (6): 463–75. doi:10.3109/13625187.2015.1068934PMC 4699469PMID 26212489.
  22. ^ Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M (2008). “A new route of synthesis of estetrol”. Climacteric. 11 Suppl 1: 59–63. doi:10.1080/13697130802054078PMID 18464024.
  23. ^ Hagen AA, Barr M, Diczfalusy E (June 1965). “Metabolism of 17-beta-oestradiol-4-14-C in early infancy”. Acta Endocrinol49: 207–20. doi:10.1530/acta.0.0490207PMID 14303250.
Names
Preferred IUPAC name(1R,2R,3R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
Other namesOestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Identifiers
CAS Number15183-37-6 
3D model (JSmol)Interactive image
ChEBICHEBI:142773
ECHA InfoCard100.276.707 
KEGGD11513
PubChem CID27125
UNIIENB39R14VF 
CompTox Dashboard (EPA)DTXSID50164888 
showSMILES
Properties
Chemical formulaC18H24O4
Molar mass304.386 g/mol
Solubility in water1.38 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

//////////estetrol, Nextstellis, fda 2021, approvals 2021

NEW DRUG APPROVALS

one time

$10.00

Drospirenone


Drospirenone.svg

Drospirenone

FDA APPROVED 4/15/2021, To prevent pregnancy Nextstellis

New Drug Application (NDA): 214154
Company: MAYNE PHARMALabel (PDF)
Letter (PDF)
ReviewLabel (PDF)DrospirenoneCAS Registry Number: 67392-87-4 
CAS Name: (2¢S,6R,7R,8R,9S,10R,13S,14S,15S,16S)-1,3¢,4¢,6,7,8,9,10,11,12,13,14,15,16,20,21-Hexadecahydro-10,13-dimethylspiro[17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene-17,2¢(5¢H)-furan]-3,5¢(2H)-dione 
Additional Names: 6b,7b,15b,16b-dimethylene-3-oxo-4-androstene-[17(b-1¢)-spiro-5¢]perhydrofuran-2¢-one; 6b,7b,15b,16b-dimethylen-3-oxo-17a-pregn-4-ene-21,17-carbolactone; dihydrospirorenone 
Manufacturers’ Codes: ZK-30595 
Molecular Formula: C24H30O3Molecular Weight: 366.49Percent Composition: C 78.65%, H 8.25%, O 13.10% 
Literature References: Synthetic progestogen exhibiting antimineralocorticoid and antiandrogenic activity. Prepn: R. Wiechert et al.,DE2652761eidem,US4129564 (both 1978 to Schering AG); D. Bittler et al.,Angew. Chem.94, 718 (1982). HPLC determn in human plasma: W. Krause, U. Jakobs, J. Chromatogr.230, 37 (1982). Pharmacological profile: P. Muhn et al.,Contraception51, 99 (1995). Review of synthesis: H. Laurent et al.,J. Steroid Biochem.19, 771-776 (1983); of pharmacology and clinical experience: W. Oelkers, Mol. Cell. Endocrinol.217, 255-261 (2004). 
Properties: mp 201.3°. [a]D22 -182° (c = 0.5 in chloroform). uv (methanol): 265 nm (e 19000). 
Melting point: mp 201.3° 
Optical Rotation: [a]D22 -182° (c = 0.5 in chloroform) 
Derivative Type: Mixture with ethinyl estradiolTrademarks: Angeliq (Schering AG); Yasmin (Schering AG)Literature References: Clinical trial as oral contraceptive: K. S. Parsey, A. Pong, Contraception61, 105 (2000); in treatment of menopausal symptoms: R. Schürmann et al., Climacteric7, 189 (2004). 
Therap-Cat: Progestogen. In combination with estrogen as oral contaceptive and in treatment of menopausal symptoms.Keywords: Progestogen; Contraceptive (Oral).SYNhttps://www.sciencedirect.com/science/article/abs/pii/S0039128X15002135

Abstract

A general methodology for the synthesis of different steroidal 17-spirolactones is described. This method uses lithium acetylide of ethyl propiolate as the three carbon synthon and the method was successfully applied for the process development of drospirenone.

Graphical abstract

SYN

Steroid Hormones

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Drospirenone–Yaz

The synthesis of drospirenone (27.4.12) is believed to have been described for the first time in Wiechert et al [79], with a total yield of approximately 2 to 3% via the pathway presented in Scheme 27.4.

Each compound produced after each reaction step was purified by column chromatography.

Androsta-5,15-diene-3-ol-17-one was methylenated at the 15,16-position (27.4.13) and reacted with organometallic reagent (3,3-dimethoxypropyl)lithium prepared from 3-bromo-1,1-dimethoxypropane (27.4.14) and lithium in THF to produce the tertiary alcohol (27.4.15), which on short-term reflux with toluenesulfonic acid in acetone transformed to cyclic 21,17-hemiacetal (27.4.16). Oppenanuer oxidation with aluminium isopropoxide in excess of cyclohexanone in toluene was brought to mild oxidation of both secondary alcohol groups, and the simultaneous isomerization of the 5,6 double bond to the 4,5 position produced the compound (27.4.17). The last was oxidized with Jones reagent—chromic trioxide in diluted sulfuric acid—producing conjugated diene-one (27.4.18). Corey methylenation of the obtained product with dimethyloxosulfonium methylide in DMSO containing sodium hydride produced the final compound, the desired drospirenone (27.4.12).

The following patents and publications [80-83], which differ slightly from one another, disclose similar processes for preparing drospirenone and are presented in Scheme 27.5.

In Scheme 27.5, drospirenone (27.4.12) is prepared by converting the key starting compound (27.4.19) into the corresponding chloride (27.4.20) via reaction with triphenylphosphine and tetrachloromethane under mild conditions. Reductive dechlorination with Zn in acetic acid in THF tetrahydrofuran produced 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one (27.4.21). The pivaloyl protecting group of the last was removed with the mixture of potassium hydroxide and sodium perchlorate in THF/methanol mixture to produce the diol (27.4.22). Simmons–Smith cyclopropanation reaction was applied to this compound. For that purpose, solution of (27.4.22) in dimethyl Cellosolve was stirred at 80°C with zinc-copper couple and methylene iodide, which produced the desired compound (27.4.23). The compound (27.4.23) underwent ethinylation with propargyl alcohol using potassium methylate in THF as a base to produce the 1,4-butindiol derivative (27.4.24). The triple bond of the 1,4-butindiol derivative (27.4.24) was hydrogenated in aTHF/methanol/pyridine mixture in the presence of palladium on carbon to produce the 1,4-butanediol derivative (27.4.25). The obtained compound underwent oxidation–lactonization at 50°C using a solution of CrO3 in water and pyridine to produce the desired drospirenone (27.4.12).

Several other synthetic routes for the production of drospirenone have been proposed [84-96], one of which [96] is presented in Scheme 27.6.

According to Scheme 27.6, a mixture of the key starting ketodiol (27.4.26), synthesis of which was described previously [84], with ethyl propiolate in THF was added to a solution of lithium hexamethyldisilylamide to produce, after quenching with acetic acid and saturated ammonium chloride solution, ethinyl alcohol (27.4.27). This product was hydrogenated on H2-Pd/C catalyst to produce ethyl 4-hydroxybutanoate (27.4.28). The 3-hydroxy group in the obtained product was oxidized to the keto group with (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl, resulting in the compound (27.4.29). Treatment of the last with potassium hydroxide in a methanol–water mixture affects both hydrolysis of the ester group and dehydration of 5-hydroxy substituent. Acidification of the resulting intermediate results in drospirenone (27.4.12).

Drospirenone is a unique synthetic progestogen derived from 17α-spirolactone; it has a pharmacological profile very similar to that of endogenous progesterone. Drospirenone prevents ovulation and is used in contraceptive pills; it is also used as a postmenopausal hormone replacement. Drospirenone provides reliable and well-tolerated contraception and effective treatment of menopause. It has progestational, antialdosterone, and antiandrogenic properties, but is devoid of any estrogenic, androgenic, glucocorticoid, antiglucocorticoid, and mineralocorticoid activities. The affinity of drospirenone for the mineralocorticoid receptor makes it an antagonist of aldosterone, which is not only important in the renin–angiotensin–aldosterone system, but also means it acts directly on the cardiovascular system. It is progestin with antimineralocorticoid property that acts to suppress gonadotropins. It is thus able to prevent excessive sodium loss and regulate blood pressure. Drospirenone slightly decreases body weight and blood pressure and shares many pharmacodynamic properties with progesterone [97-110].

PATENT

https://patents.google.com/patent/US8334375B2/enDrospirenone is a synthetic steroid with progestin, anti-mineral corticoid and anti androgen activity. Drospirenone is currently being used as a synthetic progestin in oral contraceptive formulations. A regioselective synthesis for drospirenone has been described (see e.g., Angew. Chem. 94, 1982, 718) that uses the 17 keto derivative (1) as a key intermediate.

Figure US08334375-20121218-C00001

The synthesis of intermediate (1) and the transformation of intermediate (1) into drospirenone has been described in, for example, U.S. Published Patent Application Nos. 2009/0023914; 20080207575; 2008/0200668; 2008/0076915, 20070049747, and 20050192450; U.S. Pat. Nos. 6,933,395; 6,121,465, and 4,129,564, European Patent No. 0 075 189 and PCT Publication No. WO 2006/061309, all of which are incorporated herein by reference. Many of these routes introduce the required C3 side chain in the 17 position of intermediate (1). These conversions are usually carried out with carbanions, such as propargylalcohol, trimethylsulfoxonium iodide, or the use of the anion generated from a suitably protected derivative of 1-bromopropionaldehyde. After oxidation of the 3-hydroxy substituent to a 3-keto group, and the oxidative formation of the 17-spirolactone, the 3-keto-5-hydroxy-17-spirolactone is transformed via acid catalysis into drospireneone. If the oxidation is performed under acidic conditions at elevated temperatures, the oxidation and elimination can be run without isolation of the intermediate products.Most of these procedures rely on the acid-catalyzed elimination of the 5-hydroxy group in the last step of the synthesis. It has been documented that 15,16-methylene-17-spirolactones are prone to undergo rearrangement to generate the inverted 17-spirolactone under mild acidic conditions (see, for example, Tetrahedron Letters, Vol. 27, No 45, 5463-5466) in considerable amounts. This isomer has very similar physical chemical properties, and typically requires chromatographic separation or repeated fractional recrystallizations to purify the product. This isomerization can make these approaches less desirable from an economical point of view.FIG. 1Experimental Example

Figure US08334375-20121218-C00022

A solution of compound (1) (5 g; 15.2 mmol) and tert-butyldimethyl (2-propynyloxy)silane (2.83 g, 16.7 mmol) in 75 ml of dry THF was added dropwise through an addition funnel to a precooled slurry of potassium tert-butoxide (8.49 g, 75.7 mmol) at −10 C. A thick white precipitate is formed during the addition and the resulting mixture was stirred for an hour at 0 C. TLC analysis (70% EtOAc/Hexanes) showed completion of the reaction and showed a less polar product. The reaction was quenched by the addition of ice water (100 ml) and neutralized by adding acetic acid (4.3 ml). The THF layer was separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (2×100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford compound (2a) (7.5 g, 99.2%) as a solid which was used in the next step without any purification.NMR (CDCl3) δ 0.139 (s, 6H, S1—CH3), 0.385 (m, 1H), 0.628 (m, 1H), 0.857 (s, 18-Me), 0.896 (s, 19-Me), 0.918 (s, 3H, Si—CH3), 0.927 (s, 6H, Si—CH3), 4.05 (s, 1H), 4.428 (s, 2H, —O—CH2) FTIR (ATR): 3311, 3017, 2929, 2858, 2270, 1058 cm−1

Figure US08334375-20121218-C00023

Compound (2a) (5 g, 9.98 mmol) was dissolved in 100 ml of ethyl acetate in a Parr hydrogenation bottle and was mixed with 10% palladium on charcoal (1 g, 0.09 mmol). This mixture was hydrogenated on a Parr apparatus at a pressure of 20 psi for 90 minutes. The catalyst was filtered and washed with ethyl acetate. The solvent was removed in vacuo to afford compound (3a) as a colorless foam (5.01 g, 99%).NMR (CDCl3) δ 0.0758 (s, 6H, Si—CH3), 0.283 (m, 1H), 0.628 (m, 1H), 0.856 (s, 18-Me), 0.893 (s, 19-Me), 0.918 (s, 9H, Si—CH3), 3.69 (m, 2H), 4.05 (s, 1H). FTIR (ATR): 3374, 3017, 2929, 2858, 1259, 1091, 1049, 835 cm−1

Figure US08334375-20121218-C00024

Chromium trioxide (4.95 g, 49.5 mmol) was added to a solution of pyridine (7.83 g, 99.05 mmol) in anhydrous dichloromethane (100 ml). The resulting mixture was stirred for 15 minutes during which time the color changed to burgundy. A solution of compound (1a) (5 g, 9.90 mmol) in 50 ml of dichloromethane was added and the mixture was stirred at room temperature for 6 h. The excess oxidizing agent was quenched by adding isopropanol. The reaction mixture was diluted with MTBE (50 ml) and was passed through a short pad of Celite. The solid was washed again with 2:1 MTBE-CH2Cl(50 ml x2). The solvent was removed in vacuo to give a residue which was dissolved in 100 ml of EtOAc, was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford compound (4a) as a pale yellow foam (4.5 g, 90.3%).NMR (CDCl3) δ 0.08 (s, 6H, Si—CH3), 0.31 (m, 1H), 0.914 (s, 9H, Si—CH3), 0.931 (s, 6H, 18-Me, 19-Me) 3.70 (m, 2H). FTIR (ATR): 3399, 3022, 2950, 2929, 2862, 1708, 1649, 1259, 1041 cm−1

Figure US08334375-20121218-C00025

A solution of compound (4a) (5 g, 9.94 mmol) in 50 ml of MeOH was refluxed with NaOH (397 mg, 9.94 mmol) for 3 h. When the reaction was over, as shown by TLC, the reaction mixture was cooled to room temperature and added to ice cold water (150 ml). The mixture was extracted with ethyl acetate (3×50 mL). The combined EtOAc layers were washed with water (100 ml) brine (50 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford compound (5) as a colorless amorphous solid (4.5 g, 92%).NMR (CDCl3) δ 0.05 (s, 6H, Si—CH3), 0.296 (m, 1H), 0.886 (s, 9H, Si—CH3), 0.908 (s, 3H, 18-Me), 1.07 (s, 3H, 19-Me), 3.68 (m, 2-H), 5.95 (s, 1H). FTIR (ATR): 3450, 3009, 2950, 2858, 1653, 1603, 1095 cm−1

Figure US08334375-20121218-C00026

A solution of compound (5a) (5 g, 9.94 mmol) in 30 ml of acetone was cooled to −15 C as a 2.7M solution of Jones reagent (3.68 ml, 9.94 mmol) was added drop wise. The reaction mixture was stirred at 0 C for 2 h, during this time TLC showed completion of the reaction. The reaction was quenched by adding isopropanol and diluted with water. The reaction mixture was extracted with EtOAc. The combined EtOAc layers were washed with water, sat. NaHCOand brine. The EtOAc layers were dried over sodium sulfate and solvent was removed by vacuum to afford crude drospirenone as a pale yellow foam (3 g, 82%) Recrystallization from acetone-hexane gave 1.5 g of pure drospirenone as white solid.NMR (CDCl3) δ 0.0548 (m, 1H), 0.88 (m, 1H), 1.008 (s, 3H, 18-Me), 1.11 (s, 3H, 18-Me), 6.03 (s, 1H). FTIR (ATR): 3025, 2971, 2942, 1763, 1654, 1590, 1186 cm−1FIG. 2Experimental Example

Figure US08334375-20121218-C00027

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a thermocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warned to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2b) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00028

Compound (2b) (5.0 g, 11.67 mmol) was dissolved in THF (50 mL) and 5% Pd/C (622 mg, 0.29 mmol Pd) was added and the mixture was shaken at 15 psi Hfor 2 hours. The mixture was diluted with ethyl acetate (25 mL) and filtered through a pad of Celite. The filter pad was washed with ethyl acetate (3×25 mL) and the filtrate was evaporated to dryness to afford 5.0 g (99.1%) of triol (7b) as a stable foam.

Figure US08334375-20121218-C00029

Compound (7a) (5.0 g, 11.56 mmol) was dissolved in dichloromethane (50 mL) and the solution was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (45.16 mg, 0.29 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (11.17 mL, 23.12 mmol) in water (8.0 mL) containing potassium bicarbonate (833 mg, 8.32 mmol). The mixture was allowed to warm to 0 C for 1.25 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (15.0 mL) solution of sodium phosphate (1.27 g, 7.75 mmol) and sodium metabisulfite (1.10 g, 5.78 mmol). The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate, filtered, and evaporated to give 4.88 g (98.08%) of ketone (8b) as a stable foam.

Figure US08334375-20121218-C00030

Compound (8b) was added to a methanol (10 mL) solution containing 8.0 M KOH solution (6.3 mL, 50.36 mmol) preheated to 60 C. The solution was heated at reflux for 2.5 hours. The mixture was chilled in an ice bath and treated with acetic acid (36 mL) and water (5.0 mL). The solution was stirred at 50-60 C for 15 hours. The volatiles were evaporated in vacuo and the acetic acid solution was poured into cold water (150 mL) to give a white precipitate. The aqueous mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were washed with water (2×), saturated sodium bicarbonate solution, and brine. The combined ethyl acetate extract was dried over sodium sulfate. Evaporation of the solvent gave a yellow foam. Trituration of the foam with acetone/hexane followed by evaporation gave 4.27 g (92.62%) of a light yellow solid. Recrystallization of the solid from acetone/hexanes gave 3.07 g of drospirenone with an HPLC purity of 99.66%. Evaporation of the mother liquor and recrystallization of the residue affords an additional 0.54 g of slightly impure drospirenone.FIG. 3Experimental Example

Figure US08334375-20121218-C00031

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a thermocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warmed to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2c) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00032

Propiolate adduct (2c) (5.86 g, 13.67 mmol) was suspended in dichloromethane (60 mL). The mixture was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (54 mg, 0.35 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (13.2 mL, 27.34 mmol) in water (8.0 mL) containing potassium bicarbonate (985 mg, 9.84 mmol). During the addition of the hypochlorite solution, a 5-8 C temperature rise was observed and the mixture became yellow. The mixture was allowed to warm to at 0 C for 2 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (150 mL) solution of sodium phosphate (1.50 g, 9.16 mmol) and sodium metabisulfite (1.30 g, 6.84 mmol). Once again, a temperature rise of 5-8 C was observed and the yellow color was quenched. The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate and the bulk of the solvent was evaporated in vacuo. Upon the observation of solids in the mixture during the evaporation, the evaporation was discontinued and the residue in the flask diluted with MTBE (35 mL). While stirring, the mixture was slowly diluted with hexanes (35 mL). The mixture was then chilled in an ice bath for 30 min. The solid was filtered, washed with 25% MTBE/hexane, and dried to give intermediate (9c) (4.98 g, 85.31%) as a white solid.NMR (CDCl3) δ 0.462 (q, 1H), 0.699 (m, 1H), 0.924 (s, 18-Me), 0.952 (s, 19-Me), 1.338 (t, J=7 Hz, OCH2CH 3), 2.517 (d, 1H), 3.021 (d, 1H), 4.269 (t, OCH 2CH3) ppm. FTIR (ATR): 3493, 3252, 2948, 2226, 1697, 1241 cm−1.

Figure US08334375-20121218-C00033

Alkynyl ketone (9c) (5.37 g, 12.59 mmol) was dissolved in THF (27 mL) in a 250 mL shaker bottle. 5% Pd/C (670 mg, 2.5 mol %) was added to the solution and the mixture was shaken under a hydrogen pressure of 15 psi. Over approximately 30 min, there was observed a rapid up take of hydrogen. The pressure was continually adjusted to 15 psi until the uptake of hydrogen ceased and was shaken for a total of 1.5 hrs. The mixture was diluted with a small amount of methanol and filtered through Celite. The filter pad was washed with methanol (ca. 3×25 mL).NMR (CDCl3) δ 0.353 (q, 1H), 0.704 (m, 2H), 0.930 (s, 18-Me), 0.933 (s, 19-Me), 1.279 (t, J=7 Hz, OCH2CH 3), 2.480 (d, 1H), 2.672 (m, 2H), 3.981 (d, 1H), 4.162 (t, OCH 2CH3) ppm. FTIR (ATR): 3465, 2946, 1712, cm−1.

Figure US08334375-20121218-C00034

The filtrate containing compound (8c) described above, was added in one portion to a methanol (10 mL) solution containing 8.0 M KOH solution (6.3 mL, 50.36 mmol) preheated to 60 C. The solution was heated at reflux for 2.5 hours. The mixture was chilled in an ice bath and treated with acetic acid (36 mL) and water (5.0 mL). The solution was stirred at 50-60 C for 15 hours. The volatiles were evaporated in vacuo and the acetic acid solution was poured into cold water (150 mL) to give a white precipitate. The aqueous mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were washed with water (2×), saturated sodium bicarbonate solution, and brine. The combined ethyl acetate extract was dried over sodium sulfate. Evaporation of the solvent gave a yellow foam. Trituration of the foam with acetone/hexane followed by evaporation gave 4.27 g (92.62%) of a light yellow solid. Recrystallization of the solid from acetone/hexanes gave 3.07 g of drospirenone with an HPLC purity of 99.66%. Evaporation of the mother liquor and recrystallization of the residue affords an additional 0.54 g of slightly impure drospirenone.FIG. 4Experimental Example

Figure US08334375-20121218-C00035

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a theiniocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warmed to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2d) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00036

Propiolate adduct (2d) (5.86 g, 13.67 mmol) was suspended in dichloromethane (60 mL). The mixture was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (54 mg, 0.35 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (13.2 mL, 27.34 mmol) in water (8.0 mL) containing potassium bicarbonate (985 mg, 9.84 mmol). During the addition of the hypochlorite solution, a 5-8 C temperature rise was observed and the mixture became yellow. The mixture was allowed to warm to at 0 C for 2 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (15.0 mL) solution of sodium phosphate (1.50 g, 9.16 mmol) and sodium metabisulfite (1.30 g, 6.84 mmol). Once again, a temperature rise of 5-8 C was observed and the yellow color was quenched. The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate and the bulk of the solvent was evaporated in vacuo. Upon the observation of solids in the mixture during the evaporation, the evaporation was discontinued and the residue in the flask diluted with MTBE (35 mL). While stirring, the mixture was slowly diluted with hexanes (35 mL). The mixture was then chilled in an ice bath for 30 min. The solid was filtered, washed with 25% MTBE/hexane, and dried to give intermediate (9d) (4.98 g, 85.31%) as a white solid.NMR (CDCl3) δ 0.462 (q, 1H), 0.699 (m, 1H), 0.924 (s, 18-Me), 0.952 (s, 19-Me), 1.338 (t, J=7 Hz, OCH2CH 3), 2.517 (d, 1H), 3.021 (d, 1H), 4.269 (t, OCH 2CH3) ppm. FTIR (ATR): 3493, 3252, 2948, 2226, 1697, 1241 cm−1.

Figure US08334375-20121218-C00037

Compound (9d) (5.0 g) was dissolved in methanol (50 mL) and treated with 1.0 N sulfuric acid (10 mL). The mixture was heated to reflux for 3 hours, cooled, and neutralized through the addition of saturated sodium bicarbonate solution. Most of the methanol was evaporated in vacuo at ambient temperature and diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give 4.95 g of unsaturated ketone (10d) as a stable foam.

Figure US08334375-20121218-C00038

Compound (10d) (5.0 g, 12.24 mmol) was dissolved in degassed benzene (50 mL) and treated with chlorotris(triphenylphosphine)rhodium (I) (283.1 mg, 0.31 mmol and the resulting mixture was stirred in a hydrogen atmosphere for 10 hours. The solution was evaporated, reconstituted in 50% ethyl acetate/hexanes, and passed through a short column of neutral alumina. Evaporation of the solvent gave 4.95 g of (11d) as a stable foam.

Figure US08334375-20121218-C00039

Compound (11d) (4.95 g, 12.01 mmol) was dissolved in 10% aqueous methanol (50 mL) and solid potassium carbonate (4.98 g, 36.04 mmol) was added. The mixture was stirred at room temperature for 30 min and the bicarbonate was neutralized through the addition of acetic acid (2.06 mL, 36.04 mmol). The methanol was evaporated in vacuo at ambient temperature and diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give 4.10 g (93%) of a semi solid. The material was dissolved in dichloromethane and evaporated in vacuo to give a stable foam. The foam was dissolved in ethyl acetate (5 mL) and allowed to stand overnight. The resulting solid was filtered, washed with cold ethyl acetate, and dried in vacuo to afford 2.86 g (66%) of pure drospirenone.FIG. 5Experimental Example 1

Figure US08334375-20121218-C00040

A dichloromethane (50 mL) solution of ketodiol (1) (5.0 g, 15.13 mmol) was treated with ethyl vinyl ether (7.24 mL, 75.65 mmol), followed by the addition of pyridinium tosylate (380 mg, 1.15 mmol). The solution was stirred at room temperature for 30 min. The dichloromethane solution was washed with water (2×), brine, and dried over sodium sulfate. Following filtration, evaporation of the solvent gave 6.14 g of the 3-protected compound (1e) as a stable foam.

Figure US08334375-20121218-C00041

Compound (1e) (6.14 g, 15.13 mmol) was dissolved in DMSO/THF (15 mL/15 mL), treated with trimethylsulfonium iodide (4.63 g, 22.70 mmol) and the mixture was chilled to −15 C. The mixture was treated portion wise with potassium t-butoxide (3.23 g, 28.82 mmol). The mixture was stirred at −15 C for 45 min and then poured into ice/water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 6.21 g (98.42%) of oxirane (12e) as a stable foam.

Figure US08334375-20121218-C00042

A THF (30 mL) solution of di-isopropyl amine (12.02 mL, 85.03 mmol) was chilled to −40 C and treated with butyl lithium (2.5 M/hexanes, 34.01 mL, 85.03 mmol) and the mixture was stirred for 15 min. A THF (5 mL) solution of acetonitrile (4.7 mL, 90.79 mmol) was added dropwise to the in situ generated lithium di-isopropylamide (LDA) solution to give a slurry of the acetonitrile anion. After stirring for 15 min at −40° C., compound (12e) (6.21 g, 14.91 mmol) as a THF (25 mL) solution was added dropwise over 10 min. The mixture was stirred for 30 min and then quenched through the addition of saturated ammonium chloride solution (210 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (3×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 7.07 g of the addition product (13e) as a tacky foam.

Figure US08334375-20121218-C00043

Compound 13e (5.0 g, 10.93 mmol) was dissolved in acetone (25 mL) and chilled to 0 C. The stirred solution was treated dropwise with 2.7M chromic acid (Jones Reagent) (7.0 mL, 18.91 mmol). After 1.5 hrs, the excess Cr (VI) was quenched through the addition of 2-propanol until the green color of Cr (IV) was evident. Water (300 mL) was added and the mixture was stirred until all the chromium salts were dissolved. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 3.83 g (96%) of ketone (14e) as a stable foam.

Figure US08334375-20121218-C00044

Compound (14e) (3.83 g, 10.48 mmol) was dissolved in methanol (38 mL) and treated with 8.0 M KOH solution (7.0 mL, 56 mmol) and the mixture was heated at reflux for 5 hours. The mixture was cooled to 0 C and treated with acetic acid (15 mL) and water (6 mL) and the mixture was stirred at 50 C for 6 hours. The solvents were evaporated in vacuo and the residue was diluted with water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 3.76 g (94%) of crude drospirenone as a stable foam. The crude drospirenone was dissolved in 60% ethyl acetate/hexanes and passed through a short column of neutral alumina (10× w/w) and the column was eluted with the same solvent. Following evaporation of the solvent, 2.58 g (65%) of crystalline drospirenone was obtained. Recrystallization from acetone/hexanes afforded pure drospirenone.FIG. 5Experimental Example 2

Figure US08334375-20121218-C00045

Intermediate (1) (5 g, 15.13 mmol) was dissolved in DMSO/THF (50 mL/50 mL), treated with trimethylsulfonium iodide (4.63 g, 22.70 mmol), and the mixture was chilled to −15 C. The mixture was treated portion wise with potassium t-butoxide (5.03 g, 43.88 mmol). The mixture was stirred at −15 C for 45 min and then poured into ice/water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.11 g (98%) of oxirane (12f) as a stable foam.

Figure US08334375-20121218-C00046

A THF (30 mL) solution of di-isopropyl amine (12.02 mL, 85.03 mmol) was chilled to −40 C and treated with butyl lithium (2.5 M/hexanes, 34.01 mL, 85.03 mmol) and the mixture was stirred for 15 min. A THF (5 mL) solution of acetonitrile (4.7 mL, 90.79 mmol) was added dropwise to the above lithium di-isopropylamide (LDA) solution to give a slurry of the acetonitrile anion. After stirring for 15 min at −40 C, compound (12f) (5.11 g, 14.83 mmol) as a THF (75 mL) solution was added dropwise over 10 min. The mixture was stirred for 30 min and then quenched through the addition of saturated ammonium chloride solution (300 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (3×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.75 g of addition product (13f) as a tacky foam.

Figure US08334375-20121218-C00047

Compound 13f (5.75 g, 14.95 mmol) was dissolved in acetone (25 mL) and chilled to 0 C. The stirred solution was treated dropwise with 2.7M chromic acid (Jones Reagent) until the orange color of Cr (VI) persisted. After 1.5 hrs, the excess Cr (VI) was quenched through the addition of 2-propanol until the green color of Cr (IV) was evident. Water (300 mL) was added and the mixture was stirred until all the chromium salts were dissolved. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.5 g (96%) of ketone (14f) as a stable foam.

Figure US08334375-20121218-C00048

Compound (14f) (5.5 g, 14.38 mmol) was dissolved in methanol (50 mL) and treated with 8.0 M KOH solution (9.35 mL, 74.77 mmol) and the mixture was heated at reflux for 5 hours. The mixture was cooled to 0 C and treated with acetic acid (25 mL) and water (10 mL) and the mixture was stirred at 50 C for 6 hours. The solvents were evaporated in vacuo and the residue was diluted with water (300 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 4.95 g (94%) of crude drospirenone as a stable foam. The crude drospirenone was dissolved in 60% ethyl acetate/hexanes and passed through a short column of neutral alumina (10× w/w) and the column was eluted with the same solvent. Following evaporation of the solvent, 3.43 g (65%) of crystalline drospirenone was obtained. Recrystallization from acetone/hexanes afforded pure drospirenone.

Drospirenone is a progestin medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses.[1][7] It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others.[7][2] The medication is taken by mouth.[2][1]

Common side effects include acneheadachebreast tendernessweight increase, and menstrual changes.[2] Rare side effects may include high potassium levels and blood clots, among others.[2][8] Drospirenone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[1] It has additional antimineralocorticoid and antiandrogenic activity and no other important hormonal activity.[1] Because of its antimineralocorticoid activity and lack of undesirable off-target activity, drospirenone is said to more closely resemble bioidentical progesterone than other progestins.[9][10]

Drospirenone was patented in 1976 and introduced for medical use in 2000.[11][12] It is available widely throughout the world.[7] The medication is sometimes referred to as a “fourth-generation” progestin.[13][14] It is available as a generic medication.[15] In 2018, a formulation of drospirenone with ethinylestradiol was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[16][17]

Medical uses

Drospirenone (DRSP) is used by itself as a progestogen-only birth control pill, in combination with the estrogens ethinylestradiol (EE) or estetrol (E4), with or without supplemental folic acid (vitamin B9), as a combined birth control pill, and in combination with the estrogen estradiol (E2) for use in menopausal hormone therapy.[2] A birth control pill with low-dose ethinylestradiol is also indicated for the treatment of moderate acnepremenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation).[18][19] For use in menopausal hormone therapy, E2/DRSP is specifically approved to treat moderate to severe vasomotor symptoms (hot flashes), vaginal atrophy, and postmenopausal osteoporosis.[20][21][22] The drospirenone component in this formulation is included specifically to prevent estrogen-induced endometrial hyperplasia.[23] Drospirenone has also been used in combination with an estrogen as a component of hormone therapy for transgender women.[24][25]

Studies have found that EE/DRSP is superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life.[26][27] E2/DRSP has been found to increase bone mineral density and to reduce the occurrence of bone fractures in postmenopausal women.[28][23][29][30] In addition, E2/DRSP has a favorable influence on cholesterol and triglyceride levels and decreases blood pressure in women with high blood pressure.[29][30] Due to its antimineralocorticoid activity, drospirenone opposes estrogen-induced salt and water retention and maintains or slightly reduces body weight.[31]

Available forms

Drospirenone is available in the following formulations, brand names, and indications:[32][33]

Contraindications

Contraindications of drospirenone include renal impairment or chronic kidney diseaseadrenal insufficiency, presence or history of cervical cancer or other progestogen-sensitive cancersbenign or malignant liver tumors or hepatic impairment, undiagnosed abnormal uterine bleeding, and hyperkalemia (high potassium levels).[2][45][46] Renal impairment, hepatic impairment, and adrenal insufficiency are contraindicated because they increase exposure to drospirenone and/or increase the risk of hyperkalemia with drospirenone.[2]

Side effects

Adverse effects of drospirenone alone occurring in more than 1% of women may include unscheduled menstrual bleeding (breakthrough or intracyclic) (40.3–64.4%), acne (3.8%), metrorrhagia (2.8%), headache (2.7%), breast pain (2.2%), weight gain (1.9%), dysmenorrhea (1.9%), nausea (1.8%), vaginal hemorrhage (1.7%), decreased libido (1.3%), breast tenderness (1.2%), and irregular menstruation (1.2%).[2]

High potassium levels

Drospirenone is an antimineralocorticoid with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected.[45] In women with mild or moderate chronic kidney disease, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitorsangiotensin II receptor antagonistspotassium-sparing diureticsheparin, antimineralocorticoids, or nonsteroidal anti-inflammatory drugs), a potassium level should be checked after two weeks of use to test for hyperkalemia.[45][47] Persistent hyperkalemia that required discontinuation occurred in 2 out of around 1,000 women (0.2%) with 4 mg/day drospirenone alone in clinical trials.[2]

Blood clots

Birth control pills containing ethinylestradiol and a progestin are associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).[48] The incidence is about 4-fold higher on average than in women not taking a birth control pill.[48] The absolute risk of VTE with ethinylestradiol-containing birth control pills is small, in the area of 3 to 10 out of 10,000 women per year, relative to 1 to 5 out of 10,000 women per year not taking a birth control pill.[49][50] The risk of VTE during pregnancy is 5 to 20 in 10,000 women per year and during the postpartum period is 40 to 65 per 10,000 women per year.[50] The higher risk of VTE with combined birth control pills is thought to be due to the ethinylestradiol component, as ethinylestradiol has estrogenic effects on liver synthesis of coagulation factors which result in a procoagulatory state.[8] In contrast to ethinylestradiol-containing birth control pills, neither progestogen-only birth control nor the combination of transdermal estradiol and an oral progestin in menopausal hormone therapy is associated with an increased risk of VTE.[8][51]

Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE.[8] Birth control pills containing progestins such as desogestrelgestodene, drospirenone, and cyproterone acetate have been found to have 2- to 3-fold the risk of VTE of birth control pills containing levonorgestrel in retrospective cohort and nested case–control observational studies.[8][49] However, this area of research is controversial, and confounding factors may have been present in these studies.[8][49][52] Other observational studies, specifically prospective cohort and case control studies, have found no differences in risk between different progestins, including between birth control pills containing drospirenone and birth control pills containing levonorgestrel.[8][49][52][53] These kinds of observational studies have certain advantages over the aforementioned types of studies, like better ability to control for confounding factors.[53] Systematic reviews and meta-analyses of all of the data in the mid-to-late 2010s found that birth control pills containing cyproterone acetate, desogestrel, drospirenone, or gestodene overall were associated with a risk of VTE of about 1.3- to 2.0-fold compared to that of levonorgestrel-containing birth control pills.[54][55][49]

Androgenic progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation.[56][57][58][59] As a result, more androgenic progestins, like levonorgestrel and norethisterone, may oppose the procoagulatory effects of ethinylestradiol and result in a lower increase in risk of VTE.[8][60] Conversely, this would be the case less or not at all with progestins that are less androgenic, like desogestrel and gestodene, as well as progestins that are antiandrogenic, like drospirenone and cyproterone acetate.[8][60]

In the early 2010s, the FDA updated the label for birth control pills containing drospirenone and other progestins to include warnings for stopping use prior to and after surgery, and to warn that such birth control pills may have a higher risk of blood clots.[46]

Breast cancer

Drospirenone has been found to stimulate the proliferation and migration of breast cancer cells in preclinical research, similarly to certain other progestins.[61][62] However, some evidence suggests that drospirenone may do this more weakly than certain other progestins, like medroxyprogesterone acetate.[61][62] The combination of estradiol and drospirenone has been found to increase breast density, an established risk factor for breast cancer, in postmenopausal women.[63][64][65]

Data on risk of breast cancer in women with newer progestins like drospirenone are lacking at present.[66] Progestogen-only birth control is not generally associated with a higher risk of breast cancer.[66] Conversely, combined birth control and menopausal hormone therapy with an estrogen and a progestogen are associated with higher risks of breast cancer.[67][66][68]

Overdose

These have been no reports of serious adverse effects with overdose of drospirenone.[2] Symptoms that may occur in the event of an overdose may include nauseavomiting, and vaginal bleeding.[2] There is no antidote for overdose of drospirenone and treatment of overdose should be based on symptoms.[2] Since drospirenone has antimineralocorticoid activity, levels of potassium and sodium should be measured and signs of metabolic acidosis should be monitored.[2]

Interactions

Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may influence the levels and efficacy of drospirenone.[2] Treatment for 10 days with 200 mg twice daily ketoconazole, a strong CYP3A4 inhibitor among other actions, has been found to result in a moderate 2.0- to 2.7-fold increase in exposure to drospirenone.[2] Drospirenone does not appear to influence the metabolism of omeprazole (metabolized via CYP2C19), simvastatin (metabolized via CYP3A4), or midazolam (metabolized via CYP3A4), and likely does not influence the metabolism of other medications that are metabolized via these pathways.[2] Drospirenone may interact with potassium-sparing medications such as ACE inhibitorsangiotensin II receptor antagonistspotassium-sparing diureticspotassium supplementsheparinantimineralocorticoids, and nonsteroidal anti-inflammatory drugs to further increase potassium levels.[2] This may increase the risk of hyperkalemia (high potassium levels).[2]

Pharmacology

Pharmacodynamics

Drospirenone binds with high affinity to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity to the androgen receptor (AR), and with very low affinity to the glucocorticoid receptor (GR).[1][69][70][4] It is an agonist of the PR and an antagonist of the MR and AR, and hence is a progestogenantimineralocorticoid, and antiandrogen.[1][69][4][62] Drospirenone has no estrogenic activity and no appreciable glucocorticoid or antiglucocorticoid activity.[1][69][4][62]

Progestogenic activity

Drospirenone is an agonist of the PR, the biological target of progestogens like progesterone.[1][69] It has about 35% of the affinity of promegestone for the PR and about 19 to 70% of the affinity of progesterone for the PR.[1][3][62] Drospirenone has antigonadotropic and functional antiestrogenic effects as a result of PR activation.[1][69] The ovulation-inhibiting dosage of drospirenone is 2 to 3 mg/day.[72][73][1][74] Inhibition of ovulation occurred in about 90% of women at a dose of 0.5 to 2 mg/day and in 100% of women at a dose of 3 mg/day.[75] The total endometrial transformation dose of drospirenone is about 50 mg per cycle, whereas its daily dose is 2 mg for partial transformation and 4 to 6 mg for full transformation.[1][76][75] The medication acts as a contraceptive by activating the PR, which suppresses the secretion of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium.[77][2]

Due to its antigonadotropic effects, drospirenone inhibits the secretion of the gonadotropinsluteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses gonadal sex hormone production, including of estradiolprogesterone, and testosterone.[1][78][3] Drospirenone alone at 4 mg/day has been found to suppress estradiol levels in premenopausal women to about 40 to 80 pg/mL depending on the time of the cycle.[78] No studies of the antigonadotropic effects of drospirenone or its influence on hormone levels appear to have been conducted in men.[79][80][81] In male cynomolgus monkeys however, 4 mg/kg/day oral drospirenone strongly suppressed testosterone levels.[69]

Antimineralocorticoid activity

Drospirenone is an antagonist of the MR, the biological target of mineralocorticoids like aldosterone, and hence is an antimineralocorticoid.[69] It has about 100 to 500% of the affinity of aldosterone for the MR and about 50 to 230% of the affinity of progesterone for the MR.[1][3][71][62] Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid than spironolactone in animals.[69][75][82] Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity.[83][2] It has been said that the pharmacological profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.[69] Drospirenone is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone.[1] For comparison to progesterone, a 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of spironolactone.[84] Both drospirenone and progesterone are actually weak partial agonists of the MR in the absence of mineralocorticoids.[4][3][62]

Due to its antimineralocorticoid activity, drospirenone increases natriuresis, decreases water retention and blood pressure, and produces compensatory increases in plasma renin activity as well as circulating levels and urinary excretion of aldosterone.[3][85][1] This has been shown to occur at doses of 2 to 4 mg/day.[3] Similar effects occur during the luteal phase of the menstrual cycle due to increased progesterone levels and the resulting antagonism of the MR.[3] Estrogens, particularly ethinylestradiol, activate liver production of angiotensinogen and increase levels of angiotensinogen and angiotensin II, thereby activating the renin–angiotensin–aldosterone system.[3][1] As a result, they can produce undesirable side effects including increased sodium excretion, water retention, weight gain, and increased blood pressure.[3] Progesterone and drospirenone counteract these undesirable effects via their antimineralocorticoid activity.[3] Accumulating research indicates that antimineralocorticoids like drospirenone and spironolactone may also have positive effects on adipose tissue and metabolic health.[86][87]

Antiandrogenic activity

Drospirenone is an antagonist of the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT).[1][3] It has about 1 to 65% of the affinity of the synthetic anabolic steroid metribolone for the AR.[1][3][4][62] The medication is more potent as an antiandrogen than spironolactone, but is less potent than cyproterone acetate, with about 30% of its antiandrogenic activity in animals.[1][88][69][75] Progesterone displays antiandrogenic activity in some assays similarly to drospirenone,[3] although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.[89][1][4]

Drospirenone shows antiandrogenic effects on the serum lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women.[3] The medication does not inhibit the effects of ethinylestradiol on sex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins like levonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate.[3][1][74] SHBG levels are significantly higher with ethinylestradiol and cyproterone acetate than with ethinylestradiol and drospirenone, owing to the more potent antiandrogenic activity of cyproterone acetate relative to drospirenone.[90] Androgenic progestins like levonorgestrel have been found to inhibit the procoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis of coagulation factors, whereas this may occur less or not at all with weakly androgenic progestins like desogestrel and antiandrogenic progestins like drospirenone.[8][60][56][57][58][59]

Other activity

Drospirenone stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[91] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[91] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[66]

Pharmacokinetics

Absorption

The oral bioavailability of drospirenone is between 66 and 85%.[1][3][4] Peak levels occur 1 to 6 hours after an oral dose.[1][3][2][82] Levels are about 27 ng/mL after a single 4 mg dose.[2] There is 1.5- to 2-fold accumulation in drospirenone levels with continuous administration, with steady-state levels of drospirenone achieved after 7 to 10 days of administration.[1][2][3] Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL.[2] With the combination of 30 μg/day ethinylestradiol and 3 mg/day drospirenone, peak levels of drospirenone after a single dose are 35 ng/mL, and levels at steady state are 60 to 87 ng/mL at peak and 20 to 25 ng/mL at trough.[3][1] The pharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg.[2][3] Intake of drospirenone with food does not influence the absorption of drospirenone.[2]

Distribution

The distribution half-life of drospirenone is about 1.6 to 2 hours.[3][1] The apparent volume of distribution of drospirenone is approximately 4 L/kg.[2] The plasma protein binding of drospirenone is 95 to 97%.[2][1] It is bound to albumin and 3 to 5% circulates freely or unbound.[2][1] Drospirenone has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these plasma proteins in the circulation.[1]

Metabolism

The metabolism of drospirenone is extensive.[3] It is metabolized into the acid form of drospirenone by opening of its lactone ring.[1][2] The medication is also metabolized by reduction of its double bond between the C4 and C5 positions and subsequent sulfation.[1][2] The two major metabolites of drospirenone are drospirenone acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system.[2][3] Neither of these metabolites are known to be pharmacologically active.[2] Drospirenone also undergoes oxidative metabolism by CYP3A4.[2][3][5][6]

Elimination

Drospirenone is excreted in urine and feces, with slightly more excreted in feces than in urine.[2] Only trace amounts of unchanged drospirenone can be found in urine and feces.[2] At least 20 different metabolites can be identified in urine and feces.[3] Drospirenone and its metabolites are excreted in urine about 38% as glucuronide conjugates, 47% as sulfate conjugates, and less than 10% in unconjugated form.[3] In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.[3]

The elimination half-life of drospirenone is between 25 and 33 hours.[2][3][1] The half-life of drospirenone is unchanged with repeated administration.[2] Elimination of drospirenone is virtually complete 10 days after the last dose.[3][2]

Chemistry

See also: SpirolactoneList of progestogens § Spirolactone derivatives, and List of steroidal antiandrogens § Spirolactone derivatives

vteChemical structures of spirolactonesSpirolactone structuresProgesteroneSpirolactoneCanrenoneSpironolactoneDrospirenoneSpirorenoneThe image above contains clickable linksChemical structures of progesterone and spirolactones (steroid-17α-spirolactones).

Drospirenone, also known as 1,2-dihydrospirorenone or as 17β-hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone, is a synthetic steroidal 17α-spirolactone, or more simply a spirolactone.[7][92] It is an analogue of other spirolactones like spironolactonecanrenone, and spirorenone.[7][92] Drospirenone differs structurally from spironolactone only in that the C7α acetylthio substitution of spironolactone has been removed and two methylene groups have been substituted in at the C6β–7β and C15β–16β positions.[93]

Spirolactones like drospirenone and spironolactone are derivatives of progesterone, which likewise has progestogenic and antimineralocorticoid activity.[94][95][96] The loss of the C7α acetylthio group of spironolactone, a compound with negligible progestogenic activity,[97][98] appears to be involved in the restoration of progestogenic activity in drospirenone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity similarly to drospirenone.[99]

History

Drospirenone was patented in 1976 and introduced for medical use in 2000.[11][12] Schering AG of Germany has been granted several patents on the production of drospirenone, including WIPO and US patents, granted in 1998 and 2000, respectively.[100][101] It was introduced for medical use in combination with ethinylestradiol as a combined birth control pill in 2000.[11] Drospirenone is sometimes described as a “fourth-generation” progestin based on its time of introduction.[13][14] The medication was approved for use in menopausal hormone therapy in combination with estradiol in 2005.[20] Drospirenone was introduced for use as a progestogen-only birth control pill in 2019.[2] A combined birth control pill containing estetrol and drospirenone was approved in 2021.[102]

Society and culture

Generic names

Drospirenone is the generic name of the drug and its INNUSANBAN, and JAN, while drospirénone is its DCF.[7] Its name is a shortened form of the name 1,2-dihydrospirorenone or dihydrospirenone.[7][92] Drospirenone is also known by its developmental code names SH-470 and ZK-30595 (alone), BAY 86-5300BAY 98-7071, and SH-T-00186D (in combination with ethinylestradiol), BAY 86-4891 (in combination with estradiol), and FSN-013 (in combination with estetrol).[7][92][103][104][105][106][102]

Brand names

Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world.[7] Among others, it is marketed in combination with ethinylestradiol under the brand names Yasmin and Yaz, in combination with estetrol under the brand name Nextstellis, and in combination with estradiol under the brand name Angeliq.[7][102]

Availability

See also: List of progestogens available in the United States

Drospirenone is marketed widely throughout the world.[7]

Generation

Drospirenone has been categorized as a “fourth-generation” progestin.[62]

Litigation

Many lawsuits have been filed against Bayer, the manufacturer of drospirenone, due to the higher risk of venous thromboembolism (VTE) that has been observed with combined birth control pills containing drospirenone and certain other progestins relative to the risk with levonorgestrel-containing combined birth control pills.[52]

In July 2012, Bayer notified its stockholders that there were more than 12,000 such lawsuits against the company involving Yaz, Yasmin, and other birth control pills with drospirenone.[107] They also noted that the company by then had settled 1,977 cases for US$402.6 million, for an average of US$212,000 per case, while setting aside US$610.5 million to settle the others.[107]

As of July 17, 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone.[108] This is in addition to around 10,000 claims that Bayer has already settled without admitting liability.[108] These claims of VTE have amounted to US$1.97 billion.[108] Bayer also reached a settlement for arterial thromboembolic events, including stroke and heart attacks, for US$56.9 million.[108]

Research

See also: Estetrol/drospirenone and Ethinylestradiol/drospirenone/prasterone

A combination of ethinylestradiol, drospirenone, and prasterone is under development by Pantarhei Bioscience as a combined birth control pill for prevention of pregnancy in women.[109] It includes prasterone (dehydroepiandrosterone; DHEA), an oral androgen prohormone, to replace testosterone and avoid testosterone deficiency caused by suppression of testosterone by ethinylestradiol and drospirenone.[109] As of August 2018, the formulation is in phase II/III clinical trials.[109]

Drospirenone has been suggested for potential use as a progestin in male hormonal contraception.[79]

Drospirenone has been studied in forms for parenteral administration.[110][111][112][113]

References

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  2. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai ajak al am an ao ap aq ar as at au “Slynd- drospirenone tablet, film coated”DailyMed. Retrieved 17 April 2021.
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  99. ^ Hertz R, Tullner WW (1958). “Progestational activity of certain steroid-17-spirolactones”. Proc. Soc. Exp. Biol. Med99 (2): 451–2. doi:10.3181/00379727-99-24380PMID 13601900S2CID 20150966.
  100. ^ WO patent 9806738, Mohr, Jörg-Thorsten & Klaus Nickisch, “PROCESS FOR PRODUCING DROSPIRENONE (6ss,7ss;15ss,16ss-DIMETHYLENE-3-OXO-17 alpha -PREGN-4-EN-21,17-CARBOLACTONE, DRSP), AS WELL AS 7 alpha -(3-HYDROXY-1-PROPYL)-6ss,7ss;15ss,16ss-DIMETHYLENE-5ss-ANDROSTANE-3ss,5,17ss-TRIOL (ZK 92836) AND 6ss,7ss;15ss,16ss-DIMETHYLENE-5ss HYDROXY-5-OXO-17 alpha -ANDROSTANE-21, 17-CARBOLACTONE”, issued 1998-02-19, assigned to Shering AG
  101. ^ US patent 6121465, Mohr, Joerg-Thorston & Klaus Nickisch, “Process for production drospirenone and intermediate products of the process”, issued 2000-09-19, assigned to Scheiring AG and Bayer Schering Pharma
  102. Jump up to:a b c “Drospirenone/Estetrol – Mithra Pharmaceuticals – AdisInsight”.
  103. ^ “Ethinylestradiol/drospirenone – AdisInsight”.
  104. ^ “Ethinylestradiol/drospirenone/folic acid – AdisInsight”.
  105. ^ “Drospirenone/ethinylestradiol low-dose – Bayer HealthCare Pharmaceuticals – AdisInsight”.
  106. ^ “Estradiol/drospirenone – Bayer HealthCare Pharmaceuticals – AdisInsight”.
  107. Jump up to:a b Feeley, Jef; Kresge, Naomi (July 31, 2012). “Bayer’s Yasmin lawsuit settlements rise to $402.6 million”Bloomberg News. New York. Retrieved November 11, 2012.
  108. Jump up to:a b c d AG, Bayer. “Quarterly Reports of Bayer”http://www.bayer.com.
  109. Jump up to:a b c “Drospirenone/estradiol/prasterone – ANI Pharmaceuticals/Pantarhei Bioscience – AdisInsight”adisinsight.springer.com.
  110. ^ Nippe S, General S (September 2011). “Parenteral oil-based drospirenone microcrystal suspensions-evaluation of physicochemical stability and influence of stabilising agents”. Int J Pharm416 (1): 181–8. doi:10.1016/j.ijpharm.2011.06.036PMID 21729745.
  111. ^ Nippe S, General S (November 2012). “Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release”. Eur J Pharm Sci47 (4): 790–800. doi:10.1016/j.ejps.2012.08.009PMID 22940138.
  112. ^ Nippe S, Preuße C, General S (February 2013). “Evaluation of the in vitro release and pharmacokinetics of parenteral injectable formulations for steroids”. Eur J Pharm Biopharm83 (2): 253–65. doi:10.1016/j.ejpb.2012.09.006PMID 23116659.
  113. ^ Nippe S, General S (April 2015). “Investigation of injectable drospirenone organogels with regard to their rheology and comparison to non-stabilized oil-based drospirenone suspensions”. Drug Dev Ind Pharm41 (4): 681–91. doi:10.3109/03639045.2014.895375PMID 24621345S2CID 42932558.

Further reading

External links

Clinical data
PronunciationDroe-SPY-re-nown
Trade namesAlone: Slynd
With estradiol: Angeliq
With ethinylestradiol: Yasmin, Yasminelle, Yaz, others
With estetrol: Nextstellis
Other namesDihydrospirenone; Dihydrospirorenone; 1,2-Dihydrospirorenone; MSp; SH-470; ZK-30595; LF-111; 17β-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone
AHFS/Drugs.comProfessional Drug Facts
License dataUS DailyMedDrospirenone
Routes of
administration
By mouth[1]
Drug classProgestogenProgestinAntimineralocorticoidSteroidal antiandrogen
ATC codeG03AC10 (WHO)
G03AA12 (WHOG03FA17 (WHO) (combinations with estrogens)
Legal status
Legal statusAU: S4 (Prescription only)US: ℞-only [2]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability66–85%[1][3][4]
Protein binding95–97% (to albumin)[2][1][3]
MetabolismLiver (mostly CYP450-independent (reductionsulfation, and cleavage of lactone ring), some CYP3A4 contribution)[3][5][6]
Metabolites• Drospirenone acid[2]
• 4,5-Dihydrodrospirenone 3-sulfate[2]
Elimination half-life25–33 hours[2][3][1]
ExcretionUrinefeces[2]
Identifiers
showIUPAC name
CAS Number67392-87-4 
PubChem CID68873
DrugBankDB01395 
ChemSpider62105 
UNIIN295J34A25
KEGGD03917 
ChEBICHEBI:50838 
ChEMBLChEMBL1509 
CompTox Dashboard (EPA)DTXSID7046465 
ECHA InfoCard100.060.599 
Chemical and physical data
FormulaC24H30O3
Molar mass366.501 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

//////////drospirenone, Nextstellis, ZK 30595, FDA 2021, APPROVALS 2021

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Samidorphan


Samidorphan structure.svg
852626-89-2.png

Samidorphan

サミドルファン;

FormulaC21H26N2O4
CAS852626-89-2
Mol weight370.4421

FDA  APPROVED 5/28/2021 Lybalvi

  • ALKS 33
  • ALKS-33
  • RDC-0313
  • RDC-0313-00

Product Ingredients

Thumb
ChemSpider 2D Image | Samidorphan L-malate | C25H32N2O9

UNII0AJQ5N56E0

CAS Number1204592-75-5

WeightAverage: 504.536
Monoisotopic: 504.210780618

Chemical FormulaC25H32N2O9

INGREDIENTUNIICASINCHI KEY
Samidorphan L-malate0AJQ5N56E01204592-75-5RARHXUAUPNYAJF-QSYGGRRVSA-N

IUPAC Name(1R,9R,10S)-17-(cyclopropylmethyl)-3,10-dihydroxy-13-oxo-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2,4,6-triene-4-carboxamide; (2S)-2-hydroxybutanedioic acid

MOA:mu-Opioid antagonist; delta-Opioid partial agonist; kappa-Opioid partial agonistsIndication:Alcohol dependence

New Drug Application (NDA): 213378
Company: ALKERMES INChttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213378Orig1s000,%20Orig2s000ltr.pdf

To treat schizophrenia in adults and certain aspects of bipolar I disorder in adults

LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist.

Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine. The molecular formula of olanzapine is: C17H20N4S and the molecular weight is 312.44 g/mol. It is a yellow crystalline powder and has pKa values of 7.80 and 5.44. The chemical structure is:

Olanzapine Structural Formula - Illustration

Samidorphan L-malate is morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4, 14-dihydroxy-6-oxo-, (2S)-2-hydroxybutanedioate. The molecular formula of samidorphan L-malate is C21H26N2O4 • C4H6O5 and the molecular weight is 504.54 g/mol. It is a white to off-white crystalline powder and has pKa values of 8.3 (amine) and 10.1 (phenol). The chemical structure is:

Samidorphan Structural Formula - Illustration

LYBALVI is intended for oral administration and is available as film-coated, bilayer tablets in the following strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg of olanzapine and samidorphan (equivalent to 13.6 mg of samidorphan L-malate).

Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating ingredients include hypromellose, titanium dioxide, triacetin, and color additives [iron oxide yellow (5 mg/10 mg); iron oxide yellow and iron oxide red (10 mg/10 mg); FD&C Blue No. 2/ indigo carmine aluminum lake (15 mg/10 mg); iron oxide red (20 mg/10 mg)].

  • to treat schizophrenia
  • alone for short-term (acute) or maintenance treatment of manic or mixed episodes that happen with bipolar I disorder
  • in combination with valproate or lithium to treat manic or mixed episodes that happen with bipolar I disorder

Olanzapine is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes.5,6 Samidorphan is a novel opioid antagonist structurally related to naltrexone, with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing.1,5,11 Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate olanzapine-induced weight gain and metabolic dysfunction.5,6

Samidorphan was first approved as a variety of fixed-dose combination tablets with olanzapine by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.11

Samidorphan (INNUSAN) (developmental code names ALKS-33RDC-0313), also known as 3-carboxamido-4-hydroxynaltrexone,[2] is an opioid antagonist that preferentially acts as an antagonist of the μ-opioid receptor (MOR). It is under development by Alkermes for the treatment of major depressive disorder and possibly other psychiatric conditions.[3]

Development

Samidorphan has been investigated for the treatment of alcoholism and cocaine addiction by its developer, Alkermes,[4][5] showing similar efficacy to naltrexone but possibly with reduced side effects.

However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist buprenorphine, as an antidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as euphoria or substance dependence being evident.[6][7]

Samidorphan is also being studied in combination with olanzapine, as ALKS-3831 (olanzapine/samidorphan), for use in schizophrenia.[8] A Phase 3 study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone.[9] The combination is now under review for approval by the US Food and Drug Administration.[10]

Pharmacology

Pharmacodynamics

The known activity profile of samidorphan at the opioid receptors is as follows:[11][12]

As such, samidorphan is primarily an antagonist, or extremely weak partial agonist of the MOR.[11][12] In accordance with its in vitro profile, samidorphan has been observed to produce some side effects that are potentially consistent with activation of the KOR such as somnolencesedationdizziness, and hallucinations in some patients in clinical trials at the doses tested.[13]

SYNPATENT

WO2006052710A1.

https://patents.google.com/patent/WO2006052710A1/enExample 1 -Synthesis of 3-Carboxyamido-4-hvdroxy-naltrexone derivative 3

Figure imgf000020_0001

(A) Synthesis of 3-Carboxyamido-naltrexone 2[029] The triflate 11 of naltrexone was prepared according to the method of Wentland et al. (Bioorg. Med. Chem. Lett. 9, 183-187 (2000)), and the carboxamide 2 was prepared by the method described by Wentland et al. [(Bioorg. Med. Chem. Lett. ϋ, 623-626 (2001); and Bioorg. Med. Chem. Lett. 11, 1717-1721 (2001)] involving Pd-catalyzed carbonylation of the triflate 11 in the presence of ammonia and the Pd(O) ligand, DPPF ([l,l’-bis(diphenylρhosphino)ferrocene]) and DMSO.(B) Synthesis of 3-Carboxyamido-4-hydroxy-naltrexone derivative 3[030] Zinc dust (26 mg, 0.40 mmol) was added in portions to a solution of 2 (50 mg, 0.14 mmol) in HCl (37%, 0.2 mL) and AcOH (2 mL) at reflux. After heating at reflux for a further 15 min, the reaction was cooled by the addition of ice/water (10 mL) and basified (pH=9) with NH3/H2O, and the solution was extracted with EtOAc (3×10 mL). The organic extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2, CH2Cl2, CH3OH : NH3/H2O = 15:1:0.01) to give compound 3 as a foam (25 mg, 50%). 1H NMR (CDC13) δl3.28(s, IH, 4-OH), 7.15(d, IH, J=8.1, H-2), 6.47(d, IH, J=8.4, H- 1), 6.10(br, IH, N-H), 4.35(br, IH, N-H), 4.04(dd,lH, J=I.8, 13.5, H-5), 3.11( d, IH, J=6), 2.99( d, IH, J=5.7), 2.94( s, IH), 2.86( d, IH, J= 6), 2.84-2.75(m, 2H), 2.65-2.61(m, 2H), 2.17-2.05(m, IH), 1.89-1.84(m, 2H), 0.85(m, IH), 0.56-0.50(m, 2H), 0.13-0.09(m, 2H). [α]D25= -98.4° (c=0.6, CH2Cl2). MS m/z (ESI) 371(MH+).

Paper

 Bioorg. Med. Chem. Lett. 200010, 183-187.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X99006708

Abstract

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For μ and κ opioid receptorssecondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures.

PAPER

Bioorg. Med. Chem. Lett. 200111, 1717-1721.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X01002785

Abstract

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH2 analogues of morphine and naltrexone. High affinity (Ki=34 and 1.7 nM) for μ opioid receptors was seen, however, the new targets were 39- and 11-fold less potent than morphine and naltrexone, respectively.

Abstract

High-affinity binding to μ opioid receptors has been identified in a series of novel 3-carboxamido analogues of morphine and naltrexone.

References

  1. ^ Turncliff R, DiPetrillo L, Silverman B, Ehrich E (February 2015). “Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers”. Clinical Therapeutics37 (2): 338–48. doi:10.1016/j.clinthera.2014.10.001PMID 25456560.
  2. ^ Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack, JM (April 2005). “Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone”. Bioorganic & Medicinal Chemistry Letters15 (8): 2107–10. doi:10.1016/j.bmcl.2005.02.032PMID 15808478.
  3. ^ “Samidorphan”Adis Insight. Springer Nature Switzerland AG.
  4. ^ Hillemacher T, Heberlein A, Muschler MA, Bleich S, Frieling H (August 2011). “Opioid modulators for alcohol dependence”. Expert Opinion on Investigational Drugs20 (8): 1073–86. doi:10.1517/13543784.2011.592139PMID 21651459.
  5. ^ Clinical trial number NCT01366001 for “ALK33BUP-101: Safety and Pharmacodynamic Effects of ALKS 33-BUP Administered Alone and When Co-administered With Cocaine” at ClinicalTrials.gov
  6. ^ “ALKS 5461 drug found to reduce depressive symptoms in Phase 1/2 study”.
  7. ^ “Investigational ALKS 5461 Channels ‘Opium Cure’ for Depression”.
  8. ^ LaMattina J (15 January 2013). “Will Alkermes’ Antipsychotic ALKS-3831 Become Another Tredaptive?”Forbes.
  9. ^ Correll, Christoph U.; Newcomer, John W.; Silverman, Bernard; DiPetrillo, Lauren; Graham, Christine; Jiang, Ying; Du, Yangchun; Simmons, Adam; Hopkinson, Craig; McDonnell, David; Kahn, René S. (2020-08-14). “Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study”American Journal of Psychiatry177 (12): 1168–1178. doi:10.1176/appi.ajp.2020.19121279ISSN 0002-953X.
  10. ^ “FDA Panel: Some Risk OK for Olanzapine Combo With Less Weight Gain”http://www.medpagetoday.com. 2020-10-09. Retrieved 2021-01-23.
  11. Jump up to:a b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4.
  12. Jump up to:a b Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). “Syntheses of novel high affinity ligands for opioid receptors”Bioorganic & Medicinal Chemistry Letters19 (8): 2289–94. doi:10.1016/j.bmcl.2009.02.078PMC 2791460PMID 19282177.
  13. ^ McElroy SL, Guerdjikova AI, Blom TJ, Crow SJ, Memisoglu A, Silverman BL, Ehrich EW (April 2013). “A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder”The International Journal of Eating Disorders46(3): 239–45. doi:10.1002/eat.22114PMID 23381803.

External links

 
Clinical data
Other namesALKS-33, RDC-0313; 3-Carboxamido-4-hydroxynaltrexone
Routes of
administration
Oral
Pharmacokinetic data
Elimination half-life7–9 hours[1]
Identifiers
showIUPAC name
CAS Number852626-89-2 
PubChem CID11667832
ChemSpider23259667
UNII7W2581Z5L8
KEGGD10162 
Chemical and physical data
FormulaC21H26N2O4
Molar mass370.449 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////////samidorphan, サミドルファン, ALKS 33, ALKS-33, RDC-0313, RDC-0313-00, APPROVALS 2021, FDA 2021, Lybalvi

SMILESO[C@@H](CC(O)=O)C(O)=O.NC(=O)C1=CC=C2C[C@H]3N(CC4CC4)CC[C@@]4(CC(=O)CC[C@@]34O)C2=C1O

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