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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Sofpironium bromide


Sofpironium bromide.png

File:Sofpironium bromide.jpg

Sofpironium bromide

ソフピロニウム臭化物

BBI 4000

[(3R)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium-3-yl] (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide

Formula
C22H32NO5. Br
CAS
1628106-94-4
BASE 1628251-49-9
Mol weight
470.3972

PMDA APPROVED JAPAN 2020/9/25, Ecclock

Anhidrotic

Sofpironium Bromide

1-ambo-(3R)-3-{[(R)-(Cyclopentyl)hydroxy(phenyl)acetyl]oxy}-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidinium bromide

C22H32BrNO5 : 470.4
[1628106-94-4]

SYN

PATENT

WO 2018026869

https://patents.google.com/patent/WO2018026869A1/en

Certain glycopyrronium salts and related compounds, as well as processes for making and methods of using these glycopyrronium salts and related compounds, are known. See, for example, US Patent No. 8,558,008, which issued to assignee Dermira, Inc. See also, for example, US Patent No. 2,956,062, which issued to assignee Robins Co Inc. A H. See also, for example, International Patent Application Publication Nos. WO 98/00132 Al and WO 2009/00109A1, both of which list applicant Sepracor, Inc., as well as US Patent Nos. 6,063,808 and 6,204,285, both of which issued to assignee Sepracor, Inc. Certain methods of treating hyperhidrosis using glycopyrronium salts and related compounds are known. See, for example GB 1,080,960. Certain forms of applying glycopyrrolate compounds to a subject are known. See, for example US Patent Nos. 6,433,003 and 8,618,160, both of which issued to assignee Rose U; also US Patent Nos. 7,060,289; 8,252,316; and 8,679,524, which issued to PurePharm, Inc.

[0004] One glycopyrronium salt which is useful in certain medical applications is the following compound:

Figure imgf000003_0001

[0005] As illustrated above, the absolute configuration at the three asymmetric chiral positions is 2R3’R1’RS. This means that the carbon indicated with the number, 2, has the stereochemical R configuration. The carbon indicated with the number, 3′, also has the stereochemical R configuration. The quatemary ammonium nitrogen atom, indicated with a positive charge, may have either the R or the S stereochemical configuration. As drawn, the compound above is a mixture of two diastereoisomers.

[0006] Certain processes for making glycopyrronium salts are known. However, these processes are not as safe, efficient, stereospecific, or stereoselective as the new processes disclosed herein, for example with respect to large-scale manufacturing processes. Certain publications show that higher anticholinergic activity is attributed to the 2R3’R configuration. However, to date, processes for making the 2R3’R isomers, as well as the 2R3’R1’R isomers are low yielding, involve too many reaction steps to be economically feasible, use toxic materials, and/or are not sufficiently stereospecific or stereoselective with respect to the products formed.

EXAMPLE 2

[0179] The below synthetic description refers to the numbered compounds illustrated in FIG. 2. Numbers which refer to these compounds in FIG. 2 are bolded and underlined in this Example.

[0180] Synthesis of R(-)-Cyclopentylmandelic acid (4)

[0181] R(-)-cyclopentylmandelic acid (compound 4) can be synthesized starting with

R(-)-mandelic acid (compound 1) according to Example 1.

[0182] Step 1 : Making Compound 2.

[0183] R(-)-mandelic acid (1) was suspended in hexane and mixed with pivaldehyde and a catalytic amount of trifluoromethanesulfonic acid at room temperature to form a mixture. The mixture was warmed to 36 °C and then allowed to react for about 5 hours. The mixture was then cooled to room temperature and treated with 8% aqueous sodium bicarbonate. The aqueous layer was removed and the organic layer dried over anhydrous sodium sulfate. After filtration and removal of the solvent under vacuum, the crude product was recrystallized to give (5R)-2-(tert-butyl)-5-phenyl-l,3-dioxolan-4-one (compound 2) in 88% yield (per S-enantiomer yield).

[0184] Step 2: Making Compound 3.

[0185] Compound 2 was reacted with lithium hexamethyl disilazide (LiHMDS) in hexane at -78 °C under stirring for one hour. Next, cyclopentyl bromide was added to the reaction mixture including compound 2 and LiHMDS . The reaction was kept cool for about four (4) hours and then slowly warmed to room temperature and allowed to react for at least twelve (12) more hours. The resulting mixture was then treated with 10% aqueous ammonium chloride. The aqueous layer was discarded and the organic layer dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue recrystallized from hexane to give pure product (5R)-2-(tert-butyl)-5-cyclopentyl-5-phenyl- l,3-dioxolan-4-one (3) in 63% yield (per S-enantiomer yield).

[0186] Step 3: Making Compound 4.

[0187] R(-)-cyclopentylmandelic acid (compound 4) was prepared by providing compound 3 in aqueous methanolic potassium hydroxide at 65 °C for four hours. After cooling this mixture to room temperature and removing the methanol under vacuum, the aqueous solution was acidified with aqueous hydrochloric acid. The aqueous solution was then extracted twice with ethyl acetate and the organic phase dried with anhydrous sodium sulfate. After removing the solvent and performing a recrystallization, pure R(-)- cyclopentylmandelic acid (compound 4) was obtained in 62% yield (based on S-enantiomer yield).

[0188] Next, a racemic mixture of l -methyl-3-pyrridinol (20) was provided:

Figure imgf000045_0001

[0189] Synthesis of 2R3 ‘R-glycopyrrolate base (8)

[0190] Step 4: Making Compound 8.

[0191] Enantiomerically pure R(-)-cyclopentylmandelic acid (4) was coupled to racemic l-methyl-3-pyrridinol (20) using 1, 1 -carbonyldiimideazole (CDI) activated esterification to make an enantiomerically pure mixture of the following erythro- and threo- glycopyrrolate bases (compounds 8 and 21, respectively):

Figure imgf000045_0002

[0192] The 2R3’R-glycopyrrolate base (compound 8) was then resolved using the 5- nitroisophthalate salt procedure in Finnish Patent 49713, to provide enantiomerically pure 2R3 Έ. {erythro) as well as pure 2R3 ‘S {threo). In this example, the 2R3 ‘S {threo) was discarded. The 2R3 Έ. {erythro) was separated as stereomerically pure compound 8.

[0193] Step 6: Making Compound 9.

[0194] The glycopyrrolate base, compound 8, was treated in dry acetonitrile with methyl bromoacetate at room temperature under stirring for three (3) hours. The crude product was dissolved in a small volume of methylene chloride and poured into dry ethyl ether to obtain a precipitate. This procedure was repeated three times to provide (3R)-3-((R)- 2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-l -(2-ethoxy-2-oxoethyl)-l-methylpyrrolidin-l – ium bromide, also known as 3′(R)-[R-Cyclopentylphenylhydroxyacetoy]- -ethyl- l ‘methoxycarbonylpyrrolidinium bromide (compound 9) in 89% yield. Compound 9 included the following stereoisomers:

Figure imgf000046_0001

E

Synthesis of 9a, 9b, 13a, and 13b.

Synthesis of 9a, 9b, 13a, and 13b.

Publication Number Title Priority Date Grant Date
US-2019161443-A1 Processes for making, and methods of using, glycopyrronium compounds 2016-08-02

ClinicalTrials.gov

CTID Title Phase Status Date
NCT02058264 A Safety, Tolerability and Preliminary Efficacy Study of BBI-4000 in Subjects With Axillary Hyperhidrosis Phase 1 Completed 2014-09-11

NIPH Clinical Trials Search of Japan

CTID Title Phase Status Date
JapicCTI-184249 A repeatedly applied study of BBI-4000 in patients with primary hyperhidrosis complete 2018-12-13
JapicCTI-184003 A long term safety study of BBI-4000 gel in patients with primary axillary hyperhidrosis complete 2018-06-15
JapicCTI-183948 A confirmatory study of BBI-4000 gel in patients with primary axillary hyperhidrosis complete 2018-05-07
UMIN000020546 A skin irritation study of BBI-4000 in healthy adult males (phase 1) Complete: follow-up complete 2016-01-18

////////////Sofpironium bromide, Ecclock, 2020 APPROVALS, JAPAN 2020, Anhidrotic, ソフピロニウム臭化物 , BBI 4000

CCOC(=O)C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C.[Br-]

Abametapir アバメタピル , абаметапир , أباميتابير , 阿巴甲吡 ,


Abametapir skeletal.svg

Abametapir

アバアバメタピル , абаметапир , أباميتابير 阿巴甲吡 ,

5,5′-dimethyl-2,2′-bipyridine, 6,6′-Bi-3-picoline

  • BRN 0123183
  • HA 44
  • HA-44
  • HA44
Formula
C12H12N2
CAS
1762-34-1
Mol weight
184.2371

Xeglyze, FD APPROVED 24/7/2020

Pediculicide, Metalloproteinase inhibitor
  Disease
Head lice infestation
  • Originator Hatchtech
  • DeveloperDr Reddys Laboratories; Hatchtech
  • ClassAntiparasitics; Heterocyclic compounds; Pyridines; Small molecules
  • Mechanism of ActionChelating agents; Metalloprotease inhibitors
  • Registered Pediculosis
  • 27 Jul 2020Registered for Pediculosis (In adolescents, In children, In infants, In adults) in USA (Topical)
  • 18 Jun 2020FDA assigns PDUFA action date of 12/08/2020 for Abametapir for Pediculosis (Dr Reddy’s Laboratories website, June 2020)
  • 31 Mar 2019Abametapir is still in preregistration phase for Pediculosis in USA

Abametapir is a novel pediculicidal metalloproteinase inhibitor used to treat infestations of head lice.4 The life cycle of head lice (Pediculus capitis) is approximately 30 days, seven to twelve of which are spent as eggs laid on hair shafts near the scalp.2 Topical pediculicides generally lack adequate ovicidal activity,2 including standard-of-care treatments such as permethrin, and many require a second administration 7-10 days following the first to kill newly hatched lice that resisted the initial treatment. The necessity for follow-up treatment may lead to challenges with patient adherence, and resistance to agents like permethrin and pyrethrins/piperonyl butoxide may be significant in some areas.3

Investigations into novel ovicidal treatments revealed that several metalloproteinase enzymes were critical to the egg hatching and survival of head lice, and these enzymes were therefore identified as a potential therapeutic target.1 Abemetapir is an inhibitor of these metalloproteinase enzymes, and the first topical pediculicide to take advantage of this novel target. The improved ovicidal activity (90-100% in vitro) of abemetapir allows for a single administration, in contrast to many other topical treatments, and its novel and relatively non-specific mechanism may help to curb the development of resistance to this agent.1

Abametapir was first approved for use in the United States under the brand name Xeglyze on July 27, 2020.6

Abametapir, sold under the brand name Xeglyze, is a medication used for the treatment of head lice infestation in people six months of age and older.[1][2]

The most common side effects include skin redness, rash, skin burning sensation, skin inflammation, vomiting, eye irritation, skin itching, and hair color changes.[2]

Abametapir is a metalloproteinase inhibitor.[1] Abametapir was approved for medical use in the United States in July 2020.[1][3]

Medical uses

Abametapir is indicated for the topical treatment of head lice infestation in people six months of age and older.[1][2]

History

The U.S. Food and Drug Administration (FDA) approved abametapir based on evidence from two identical clinical trials of 699 participants with head lice.[2] The trials were conducted at fourteen sites in the United States.[2]

The benefit and side effects of abametapir were evaluated in two clinical trials that enrolled participants with head lice who were at least six months old.[2]

About half of all enrolled participants was randomly assigned to abametapir and the other half to placebo.[2] Abametapir lotion or placebo lotion were applied once as a ten-minute treatment to infested hair.[2] The benefit of abametapir in comparison to placebo was assessed after 1, 7 and 14 days by comparing the counts of participants in each group who were free of live lice.[2]

SYN

Ronald Harding, Lewis David Schulz, Vernon Morrison Bowles, “Pediculicidal composition.” WIPO Patent WO2015107384A2, published July, 2015.

References

  1. Jump up to:a b c d e “Xeglyze (abametapir) lotion, for topical use” (PDF)U.S. Food and Drug Administration (FDA). Dr. Reddy’s Laboratories. Inc. Retrieved 25 July 2020.
  2. Jump up to:a b c d e f g h i “Drug Trial Snapshot: Xeglyze”U.S. Food and Drug Administration (FDA). 24 July 2020. Retrieved 6 August 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ “Abametapir: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 25 July 2020.

Further reading

External links

  • “Abametapir”Drug Information Portal. U.S. National Library of Medicine.
Abametapir
Abametapir skeletal.svg
Clinical data
Trade names Xeglyze
Other names Ha44
AHFS/Drugs.com Professional Drug Facts
License data
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration
Topical
Drug class PediculicideMetalloproteinase inhibitor
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.157.434 Edit this at Wikidata
Chemical and physical data
Formula C12H12N2
Molar mass 184.242 g·mol−1
3D model (JSmol)

///////Abametapir, 2020 APPROVALS, FDA 2020, Xeglyze, アバメタピル , абаметапир , أباميتابير 阿巴甲吡 , BRN 0123183, HA 44, head lice

CC1=CC=C(N=C1)C1=CC=C(C)C=N1

Bulevirtide acetate


Bulevirtide acetate

(N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt.

molecular formula C248H355N65O72,

molecular mass is 5398.9 g/mol

ブレビルチド酢酸塩;

APROVED 2020/7/31, EU, Hepcludex

MYR GmbH

Antiviral, Entry inhibitor
  Disease
Hepatitis delta virus infection

Bulevirtide is a 47-amino acid peptide with a fatty acid, a myristoyl residue, at the N-terminus and an amidated C-terminus. The active substance is available as acetate salt. The counter ion acetate is bound in ionic form to basic groups of the peptide molecule and is present in a non-stoichiometric ratio. The chemical name of bulevirtide is (N-Myristoyl-glycyl-L-threonyl-L-asparaginyl-L-leucyl-L-seryl-L-valyl-Lprolyl-L-asparaginyl-L-prolyl-L-leucyl-glycyl-L-phenylalanyl-L-phenylalanyl-L-prolyl-L-aspartyl-L-histidyl-Lglutaminyl-L-leucyl-L-aspartyl-L-prolyl-L-alanyl-L-phenylalanyl-glycyl-L-alanyl-L-asparaginyl-L-seryl-Lasparaginyl-L-asparaginyl-Lprolyl-L-aspartyl-L-tryptophanyl-L-aspartyl-L-phenylalanyl-L-asparaginyl-L-prolylL-asparaginyl-L-lysyl-L-aspartyl-L-histidyl-L-tryptophanyl-L-prolyl-L-glutamyl-L-alanyl-L-asparaginyl-L-lysylL-valylglycinamide, acetate salt. It corresponds to the molecular formula C248H355N65O72, its relative molecular mass is 5398.9 g/mol

Bulevirtide appears as a white or off-white hygroscopic powder. It is practically insoluble in water and soluble at concentrations of 1 mg/ml in 50% acetic acid and about 7 mg/ml in carbonate buffer solution at pH 8.8, respectively. The structure of the active substance (AS) was elucidated by a combination of infrared spectroscopy (IR), mass spectrometry (MS), amino acid analysis and sequence analysis Other characteristics studied included ultraviolet (UV) spectrum, higher order structure (1D- and 2D- nuclear magnetic resonance spectroscopy (NMR)) and aggregation (Dynamic Light Scattering). Neither tertiary structure nor aggregation states of bulevirtide have been identified. With regard to enantiomeric purity, all amino acids are used in L-configuration except glycine, which is achiral by nature. Two batches of bulevirtide acetate were evaluated for enanatiomeric purity and no relevant change in configuration during synthesis was detected.

Bulevirtide is manufactured by a single manufacturer. It is a chemically synthesised linear peptide containing only naturally occurring amino acids. The manufacturing of this peptide is achieved using standard solidphase peptide synthesis (SPPS) on a 4-methylbenzhydrylamine resin (MBHA resin) derivatised with Rink amide linker in order to obtain a crude peptide mixture. This crude mixture is purified through a series of washing and preparative chromatography steps. Finally, the purified peptide is freeze-dried prior to final packaging and storage. The process involves further four main steps: synthesis of the protected peptide on the resin while side-chain functional groups are protected as applicable; cleavage of the peptide from the resin, together with the removal of the side chain protecting groups to obtain the crude peptide; purification; and lyophilisation. Two chromatographic systems are used for purification. No design space is claimed. Resin, Linker Fmoc protected amino acids and myristic acid are starting materials in line with ICH Q11. Sufficient information is provided on the source and the synthetic route of the starting materials. The active substance is obtained as a nonsterile, lyophilised powder. All critical steps and parameters were presented and clearly indicated in the description of the manufacturing process. The process description includes also sufficient information on the type of equipment for the SPPS, in-process controls (IPCs). The circumstances under which reprocessing might be performed were clearly presented. No holding times are proposed. Overall the process is sufficiently described.

The finished product is a white to off white lyophilised powder for solution for injection supplied in single-use vials. Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide. The composition of the finished product was presented. The powder is intended to be dissolved in 1 ml of water for injection per vial. After reconstitution the concentration of bulevirtide net peptide solution in the vial is 2 mg/ml. The components of the formulation were selected by literature review and knowledge of compositions of similar products available on the market at that time, containing HCl, water, mannitol, sodium carbonate, sodium hydrogen carbonate and sodium hydroxide. All excipients are normally used in the manufacture of lyophilisates. The quality of the excipients complies with their respective Ph. Eur monographs. The intrinsic properties of the active substance and the compounding formulation do not support microbiological growth as demonstrated by the stability data. No additional preservatives are therefore needed.

https://www.ema.europa.eu/en/documents/assessment-report/hepcludex-epar-public-assessment-report_en.pdf

Hepcludex is an antiviral medicine used to treat chronic (long-term) hepatitis delta virus (HDV) infection in adults with compensated liver disease (when the liver is damaged but is still able to work), when the presence of viral RNA (genetic material) has been confirmed by blood tests.

HDV is an ‘incomplete’ virus, because it cannot replicate in cells without the help of another virus, the hepatitis B virus. Because of this, patients infected with the virus always also have hepatitis B.

HDV infection is rare, and Hepcludex was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 19 June 2015. For further information on the orphan designation, see EU/3/15/1500.

Hepcludex contains the active substance bulevirtide.

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).[2]

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[2]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[2] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[2]

Bulevirtide was approved for medical use in the European Union in July 2020.[2]

Medical uses

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[2][3]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.[4]

The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[5][6] that can also dock to NTCP, blocking the virus’s entry mechanism.[7]

The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[7]

References

  1. ^ Deterding, K.; Wedemeyer, H. (2019). “Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta”. Aids Reviews21 (3): 126–134. doi:10.24875/AIDSRev.19000080PMID 31532397.
  2. Jump up to:a b c d e f g “Hepcludex EPAR”European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ “Summary of opinion: Hepcludex” (PDF)European Medicines Agency. 28 May 2020.
  4. ^ Francisco, Estela Miranda (29 May 2020). “Hepcludex”European Medicines Agency. Retrieved 6 August 2020.
  5. ^ Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). “The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus”. Journal of Hepatology58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008PMID 23246506.
  6. ^ Abbas Z, Abbas M (August 2015). “Management of hepatitis delta: Need for novel therapeutic options”World Journal of Gastroenterology21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461PMC 4548107PMID 26327754.
  7. Jump up to:a b Spreitzer H (14 September 2015). “Neue Wirkstoffe – Myrcludex B”. Österreichische Apothekerzeitung (in German) (19/2015): 12.

External links

Bulevirtide
Clinical data
Trade names Hepcludex
Other names MyrB, Myrcludex-B[1]
License data
Routes of
administration
Subcutaneous injection
ATC code
  • None
Legal status
Legal status
  • EU: Rx-only [2]
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////Bulevirtide acetate, ブレビルチド酢酸塩 , orphan designation, MYR GmbH, PEPTIDE, EU 2020, 2020 APPROVALS

Nifurtimox


Nifurtimox.svg

Nifurtimox

Formula
C10H13N3O5S
CAS
23256-30-6
Mol weight
287.2923

FDA APPROVED, 2020/8/6, LAMPIT

Antiprotozoal
  Disease
Chagas disease

IUPAC Name

3-methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1lambda6-thiomorpholine-1,1-dione

SMILES

CC1CS(=O)(=O)CCN1\N=C\C1=CC=C(O1)[N+]([O-])=O
SYN
Danong Chen, Glenn Rice. 2013. Novel formulations of nitrofurans including nifurtimox with enhanced activity with lower toxicity.US20150140089A1
  • OriginatorBayer
  • ClassAntiprotozoals; Nitrofurans; Small molecules; Thiamorpholines; Thiazines
  • Mechanism of ActionDNA damage modulators
  • RegisteredChagas disease
  • 07 Aug 2020Registered for Chagas disease (In adolescents, In children, In infants) in USA (PO)
  • 31 Jan 2020Preregistration for Chagas disease (In infants, In children, In adolescents) in USA (PO)
  • 29 Jan 2020Bayer completes a phase I trial in Chagas disease in Argentina (PO) (NCT03334838)
Title: Nifurtimox
CAS Registry Number: 23256-30-6
CAS Name: 3-Methyl-N-[(5-nitro-2-furanyl)methylene]-4-thiomorpholinamine 1,1-dioxide
Additional Names: 4-[(5-nitrofurfurylidene)amino]-3-methylthiomorpholine-1,1-dioxide; tetrahydro-3-methyl-4-[(5-nitrofurfurylidene)amino]-2H-1,4-thiazine 1,1-dioxide; 1-[(5-nitrofurfurylidene)amino]-2-methyltetrahydro-1,4-thiazine 4,4-dioxide
Manufacturers’ Codes: Bay 2502
Trademarks: Lampit (Bayer)
Molecular Formula: C10H13N3O5S
Molecular Weight: 287.29
Percent Composition: C 41.81%, H 4.56%, N 14.63%, O 27.85%, S 11.16%
Literature References: Prepn from 5-nitrofurfural and 4-amino-3-methyltetrahydro-1,4-thiazine 1,1-dioxide: Herlinger et al., DE 1170957 corresp to US 3262930 (1964 and 1966 to Bayer). Series of articles on pharmacology and clinical findings: Arzneim.-Forsch. 22, 1563-1642 (1972). Toxicity data: K. Hoffmann, ibid. 1590.
Properties: Orange-red crystals from dil acetic acid, mp 180-182°. LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann).
Melting point: mp 180-182°
Toxicity data: LD50 in mice, rats (mg/kg): 3720, 4050 by gavage (Hoffmann)
Therap-Cat: Antiprotozoal (Trypanosoma).
Keywords: Antiprotozoal (Trypanosoma).

Nifurtimox, sold under the brand name Lampit, is a medication used to treat Chagas disease and sleeping sickness.[1][4] For sleeping sickness it is used together with eflornithine in nifurtimox-eflornithine combination treatment.[4] In Chagas disease it is a second-line option to benznidazole.[5] It is given by mouth.[1]

Common side effects include abdominal pain, headache, nausea, and weight loss.[1] There are concerns from animal studies that it may increase the risk of cancer but these concerns have not be found in human trials.[5] Nifurtimox is not recommended in pregnancy or in those with significant kidney or liver problems.[5] It is a type of nitrofuran.[5]

Nifurtimox came into medication use in 1965.[5] It is on the World Health Organization’s List of Essential Medicines.[4] It is not available commercially in Canada.[1] It was approved for medical use in the United States in August 2020.[3] In regions of the world where the disease is common nifurtimox is provided for free by the World Health Organization (WHO).[6]

Chagas disease, caused by a parasite known as Trypanosoma cruzi (T.cruzi), is a vector-transmitted disease affecting animals and humans in the Americas. It is commonly known as American Trypanosomiasis.11

The CDC estimates that approximately 8 million people in Central America, South America, and Mexico are infected with T. cruzi, without symptoms. If Chagas disease is left untreated, life-threatening sequelae may result.11

Nifurtimox, developed by Bayer, is a nitrofuran antiprotozoal drug used in the treatment of Chagas disease. On August 6 2020, accelerated FDA approval was granted for its use in pediatric patients in response to promising results from phase III clinical trials. Continued approval will be contingent upon confirmatory data.10 A convenient feature of Bayer’s formulation is the ability to divide the scored tablets manually without the need for pill-cutting devices.10

Medical uses

Nifurtimox has been used to treat Chagas disease, when it is given for 30 to 60 days.[7][8] However, long-term use of nifurtimox does increase chances of adverse events like gastrointestinal and neurological side effects.[8][9] Due to the low tolerance and completion rate of nifurtimox, benznidazole is now being more considered for those who have Chagas disease and require long-term treatment.[5][9]

In the United States nifurtimox is indicated in children and adolescents (birth to less than 18 years of age and weighing at least 2.5 kilograms (5.5 lb) for the treatment of Chagas disease (American Trypanosomiasis), caused by Trypanosoma cruzi.[2]

Nifurtimox has also been used to treat African trypanosomiasis (sleeping sickness), and is active in the second stage of the disease (central nervous system involvement). When nifurtimox is given on its own, about half of all patients will relapse,[10] but the combination of melarsoprol with nifurtimox appears to be efficacious.[11] Trials are awaited comparing melarsoprol/nifurtimox against melarsoprol alone for African sleeping sickness.[12]

Combination therapy with eflornithine and nifurtimox is safer and easier than treatment with eflornithine alone, and appears to be equally or more effective. It has been recommended as first-line treatment for second-stage African trypanosomiasis.[13]

Pregnancy and breastfeeding

Use of nifurtimox should be avoided in pregnant women due to limited use.[5][8][14] There is limited data shown that nifurtimox doses up to 15 mg/kg daily can cause adverse effects in breastfed infants.[15] Other authors do not consider breastfeeding a contraindication during nifurtimox use.[15]

Side effects

Side effects occur following chronic administration, particularly in elderly people. Major toxicities include immediate hypersensitivity such as anaphylaxis and delayed hypersensitivity reaction involving icterus and dermatitis. Central nervous system disturbances and peripheral neuropathy may also occur.[8]

Contraindications

Nifurtimox is contraindicated in people with severe liver or kidney disease, as well as people with a background of neurological or psychiatric disorders.[5][16][20]

Mechanism of action

Nifurtimox forms a nitro-anion radical metabolite that reacts with nucleic acids of the parasite causing significant breakdown of DNA.[8] Its mechanism is similar to that proposed for the antibacterial action of metronidazole. Nifurtimox undergoes reduction and creates oxygen radicals such as superoxide. These radicals are toxic to T. cruzi. Mammalian cells are protected by presence of catalaseglutathioneperoxidases, and superoxide dismutase. Accumulation of hydrogen peroxide to cytotoxic levels results in parasite death.[8]

Manufacturing and availability

A bottle of nifurtimox

Nifurtimox is sold under the brand name Lampit by Bayer.[3] It was previously known as Bayer 2502.

Nifurtimox is only licensed for use in Argentina and Germany,[citation needed] where it is sold as 120-mg tablets. It was approved for medical use in the United States in August 2020.[3]

Research

Nifurtimox is in a phase-II clinical trial for the treatment of pediatric neuroblastoma and medulloblastoma.[21]

SYN

Nifurtimox

Synthesis of Essential Drugs

2006, Pages 559-582

Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine (37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsul-fide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives 2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox [58,59].

58. H. Herlinger, K.H. Heinz, S. Petersen, M.Bock, Ger. Pat. 1.170.957 (1964).

59. H. Herlinger, K.H. Heinz, S. Petersen, M. Bock, U.S. Pat. 3.262.930 (1966)

References

  1. Jump up to:a b c d e f “Nifurtimox (Systemic)”Drugs.com. 1995. Archived from the original on 20 December 2016. Retrieved 3 December 2016.
  2. Jump up to:a b “Lampit (nifurtimox) tablets, for oral use” (PDF)U.S. Food and Drug Administration(FDA). Bayer HealthCare Pharmaceuticals Inc. Retrieved 6 August 2020.
  3. Jump up to:a b c d “Lampit: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 6 August 2020.
  4. Jump up to:a b c World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. Jump up to:a b c d e f g h Bern, Caryn; Montgomery, Susan P.; Herwaldt, Barbara L.; Rassi, Anis; Marin-Neto, Jose Antonio; Dantas, Roberto O.; Maguire, James H.; Acquatella, Harry; Morillo, Carlos (2007-11-14). “Evaluation and Treatment of Chagas Disease in the United States”JAMA298 (18): 2171–81. doi:10.1001/jama.298.18.2171ISSN 0098-7484PMID 18000201.
  6. ^ “Trypanosomiasis, human African (sleeping sickness)”World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December2016.
  7. ^ Coura JR, de Castro SL (2002). “A critical review of Chagas disease chemotherapy”Mem Inst Oswaldo Cruz97 (1): 3–24. doi:10.1590/S0074-02762002000100001PMID 11992141.
  8. Jump up to:a b c d e f g h “Nifurtimox Drug Information, Professional”http://www.drugs.comArchivedfrom the original on 2016-11-08. Retrieved 2016-11-09.
  9. Jump up to:a b Jackson, Yves; Alirol, Emilie; Getaz, Laurent; Wolff, Hans; Combescure, Christophe; Chappuis, François (2010-11-15). “Tolerance and Safety of Nifurtimox in Patients with Chronic Chagas Disease”Clinical Infectious Diseases51 (10): e69–e75. doi:10.1086/656917ISSN 1058-4838PMID 20932171.
  10. ^ Pepin J, Milord F, Mpia B, et al. (1989). “An open clinical trial of nifurtimox for arseno-resistant T. b. gambiense sleeping sickness in central Zaire”. Trans R Soc Trop Med Hyg83(4): 514–7. doi:10.1016/0035-9203(89)90270-8PMID 2694491.
  11. ^ Bisser S, N’Siesi FX, Lejon V, et al. (2007). “Equivalence Trial of Melarsoprol and Nifurtimox Monotherapy and Combination Therapy for the Treatment of Second-Stage Trypanosoma brucei gambiense Sleeping Sickness”J Infect Dis195 (3): 322–329. doi:10.1086/510534PMID 17205469.
  12. ^ Pepin J (2007). “Combination Therapy for Sleeping Sickness: A Wake-Up Call”J Infect Dis195 (3): 311–13. doi:10.1086/510540PMID 17205466.
  13. ^ Priotto G, Kasparian S, Mutombo W, et al. (July 2009). “Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiensetrypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial”. Lancet374(9683): 56–64. doi:10.1016/S0140-6736(09)61117-Xhdl:10144/72797PMID 19559476.
  14. ^ Schaefer, Christof; Peters, Paul W. J.; Miller, Richard K. (2014-09-17). Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment. Academic Press. ISBN 9780124079014Archived from the original on 2017-09-08.
  15. Jump up to:a b “Nifurtimox use while Breastfeeding | Drugs.com”http://www.drugs.comArchived from the original on 2016-11-08. Retrieved 2016-11-07.
  16. Jump up to:a b c “Parasites – American Trypanosomiasis (also known as Chagas Disease)”U.S. Centers for Disease Control and Prevention (CDC)Archived from the original on 2016-11-06. Retrieved 2016-11-09.
  17. Jump up to:a b Forsyth, Colin J.; Hernandez, Salvador; Olmedo, Wilman; Abuhamidah, Adieb; Traina, Mahmoud I.; Sanchez, Daniel R.; Soverow, Jonathan; Meymandi, Sheba K. (2016-10-15). “Safety Profile of Nifurtimox for Treatment of Chagas Disease in the United States”Clinical Infectious Diseases63 (8): 1056–1062. doi:10.1093/cid/ciw477ISSN 1537-6591PMC 5036918PMID 27432838.
  18. ^ Castro, José A.; de Mecca, Maria Montalto; Bartel, Laura C. (2006-08-01). “Toxic side effects of drugs used to treat Chagas’ disease (American trypanosomiasis)”. Human & Experimental Toxicology25 (8): 471–479. doi:10.1191/0960327106het653oaISSN 0960-3271PMID 16937919.
  19. Jump up to:a b Estani, Sergio Sosa; Segura, Elsa Leonor (1999-09-01). “Treatment of Trypanosoma cruzi infection in the undetermined phase. Experience and current guidelines of treatment in Argentina”Memórias do Instituto Oswaldo Cruz94: 363–365. doi:10.1590/S0074-02761999000700070ISSN 0074-0276PMID 10677756.
  20. ^ “Chagas disease”World Health OrganizationArchived from the original on 2014-02-27. Retrieved 2016-11-08.
  21. ^ Clinical trial number NCT00601003 for “Study of Nifurtimox to Treat Refractory or Relapsed Neuroblastoma or Medulloblastoma” at ClinicalTrials.gov. Retrieved on July 10, 2009.

External links

  • “Nifurtimox”Drug Information Portal. U.S. National Library of Medicine.
Nifurtimox
Nifurtimox.svg
Nifurtimox 3D.png
Clinical data
Trade names Lampit[1]
Other names Bayer 2502[1]
AHFS/Drugs.com Drugs.com archive
Lampit
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low
Metabolism Liver (Cytochrome P450 oxidase (CYP) involved)
Elimination half-life 2.95 ± 1.19 hours
Excretion Kidney, very low
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.041.377 Edit this at Wikidata
Chemical and physical data
Formula C10H13N3O5S
Molar mass 287.29 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 180 to 182 °C (356 to 360 °F)

///////////Nifurtimox, LAMPIT, 2020 APPROVALS, FDA 2020, ニフルチモックス, CHAGAS DISEASE, ANTI PROTOZOAL

Imlifidase


MDSFSANQEI RYSEVTPYHV TSVWTKGVTP PANFTQGEDV FHAPYVANQG WYDITKTFNG
KDDLLCGAAT AGNMLHWWFD QNKDQIKRYL EEHPEKQKIN FNGEQMFDVK EAIDTKNHQL
DSKLFEYFKE KAFPYLSTKH LGVFPDHVID MFINGYRLSL TNHGPTPVKE GSKDPRGGIF
DAVFTRGDQS KLLTSRHDFK EKNLKEISDL IKKELTEGKA LGLSHTYANV RINHVINLWG
ADFDSNGNLK AIYVTDSDSN ASIGMKKYFV GVNSAGKVAI SAKEIKEDNI GAQVLGLFTL
STGQDSWNQT N

Imlifidase

イムリフィダーゼ;

Formula
C1575H2400N422O477S6
CAS
1947415-68-0
Mol weight
35070.8397

EMA APPROVED, 2020/8/25, Idefirix

Pre-transplant treatment to make patients with donor specific IgG eligible for kidney transplantation
Immunosuppressant, Immunoglobulin modulator (enzyme)

Imlifidase is under investigation in clinical trial NCT02854059 (IdeS in Asymptomatic Asymptomatic Antibody-Mediated Thrombotic Thrombocytopenic Purpura (TTP) Patients).

Imlifidase, brand name Idefirix, is a medication for the desensitization of highly sensitized adults needing kidney transplantation, but unlikely to receive a compatible transplant.[1]

Imlifidase is a cysteine protease derived from the immunoglobulin G (IgG)‑degrading enzyme of Streptococcus pyogenes.[1] It cleaves the heavy chains of all human IgG subclasses (but no other immunoglobulins), eliminating Fc-dependent effector functions, including CDC and antibody-dependent cell-mediated cytotoxicity (ADCC).[1] Thus, imlifidase reduces the level of donor specific antibodies, enabling transplantation.[1]

The benefits with imlifidase are its ability to convert a positive crossmatch to a negative one in highly sensitized people to allow renal transplantation.[1] The most common side effects are infections and infusion related reactions.[1]

In June 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Imlifidase.[1][2]

Medical uses

Per the CHMP recommendation, imlifidase will be indicated for desensitization treatment of highly sensitized adult kidney transplant people with positive crossmatch against an available deceased donor.[1] The use of imlifidase should be reserved for people unlikely to be transplanted under the available kidney allocation system including prioritization programmes for highly sensitized people.[1]

History

Imlifidase was granted orphan drug designations by the European Commission in January 2017, and November 2018,[3][4] and by the U.S. Food and Drug Administration (FDA) in both February and July 2018.[5][6]

In February 2019, Hansa Medical AB changed its name to Hansa Biopharma AB.[4]

References

  1. Jump up to:a b c d e f g h i “Imlifidase: Pending EC decision”European Medicines Agency (EMA). 25 June 2020. Retrieved 26 June 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “New treatment to enable kidney transplant in highly sensitised patients”European Medicines Agency (Press release). 26 June 2020. Retrieved 26 June 2020.  This article incorporates text from this source, which is in the public domain.
  3. ^ “EU/3/16/1826”European Medicines Agency (EMA). 12 January 2017. Retrieved 27 June 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “EU/3/18/2096”European Medicines Agency (EMA). 13 February 2019. Retrieved 27 June 2020.  This article incorporates text from this source, which is in the public domain.
  5. ^ “Imlifidase Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 3 July 2018. Retrieved 27 June 2020.
  6. ^ “Imlifidase Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 14 February 2018. Retrieved 27 June 2020.

Further reading

External links

  • “Imlifidase”Drug Information Portal. U.S. National Library of Medicine.
Imlifidase
Clinical data
Pronunciation im lif’ i dase
Trade names Idefirix
Other names HMED-IdeS
Routes of
administration
Intravenous
ATC code
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C1575H2400N422O477S6
Molar mass 35071.36 g·mol−1

//////////Imlifidase, Idefirix, PEPTIDE, イムリフィダーゼ , 2020 APPROVALS, EMA 2020, EU 2020

Pralsetinib


Pralsetinib.png

ChemSpider 2D Image | trans-N-{(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl}cyclohexanecarboxamide | C27H32FN9O2

Pralsetinib

Formula
C27H32FN9O2
CAS
2097132-94-8
Mol weight
533.6005
Cyclohexanecarboxamide, N-[(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]-, cis
2097132-94-8 [RN]
BLU-667
BS-15942

Other Names

  • cis-N-[(1S)-1-[6-(4-Fluoro-1H-pyrazol-1-yl)-3-pyridinyl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]cyclohexanecarboxamide
  • BLU 123244
  • BLU 667
  • Pralsetinib
  • X 581238
  • cis-N-{(1S)-1-[6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl]ethyl}-1-methoxy-4-{4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}cyclohexane-1-carboxamide

N-[(1S)-1-[6-(4-fluoropyrazol-1-yl)pyridin-3-yl]ethyl]-1-methoxy-4-[4-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]cyclohexane-1-carboxamide

FDA APPROVED GAVRETO, 2020/9/4

Pralsetinib, sold under the brand name Gavreto, is a medication for the treatment of metastatic RET fusion-positive non-small cell lung cancer (NSCLC).[1] Pralsetinib is a tyrosine kinase inhibitor. It is taken by mouth.[1]

The most common adverse reactions include increased aspartate aminotransferase (AST), decreased hemoglobin, decreased lymphocytes, decreased neutrophils, increased alanine aminotransferase (ALT), increased creatinine, increased alkaline phosphatase, fatigue, constipation, musculoskeletal pain, decreased calcium, hypertension, decreased sodium, decreased phosphate, and decreased platelets.[1]

Pralsetinib was approved for medical use in the United States in September 2020.[1][2][3][4]

Medical uses

Pralsetinib is indicated for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test.[1][4]

History

Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) with 220 participants aged 26-87 whose tumors had RET alterations.[1][4] Identification of RET gene alterations was prospectively determined in local laboratories using either next generation sequencing, fluorescence in situ hybridization, or other tests.[1] The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1.[1] The trial was conducted at sites in the United States, Europe and Asia.[4]

Efficacy for RET fusion-positive NSCLC was evaluated in 87 participants previously treated with platinum chemotherapy.[1] The ORR was 57% (95% CI: 46%, 68%); 80% of responding participants had responses lasting 6 months or longer.[1] Efficacy was also evaluated in 27 participants who never received systemic treatment.[1] The ORR for these participants was 70% (95% CI: 50%, 86%); 58% of responding participants had responses lasting 6 months or longer.[1]

The US Food and Drug Administration (FDA) granted the application for pralsetinib priority revieworphan drug, and breakthrough therapy designations[1]and granted approval of Gavreto to Blueprint Medicines.[1]

PATENT

US 20170121312

https://patents.google.com/patent/US20170121312A1/en

    • Step 7: Synthesis of (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (Compound 129) and (1S,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (Compound 130)

    • [0194]
      Figure US20170121312A1-20170504-C00094
    • [0195]
      The title compounds were prepared from methyl 1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxylate (192 mg, 0.53 mmol) using the same two-step procedure (hydrolysis and amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (190 mg), which was then dissolved in 6 mL methanol and purified by SFC (ChiralPak AD-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 2.5 mL injections, 70 mL/min). Peak 1 was concentrated to give (1R,4S)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexanecarboxamide (29 mg, 10%) as a white solid. Peak 2 was concentrated to give (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)cyclohexane-carboxamide (130 mg, 46%) as a white solid.

Example 6. Synthesis of Compound 149Step 1: Synthesis of Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate

    • [0196]
      Figure US20170121312A1-20170504-C00095
    • [0197]
      Methyl 4-iodo-1-methoxycyclohexanecarboxylate (3.37 g, 11.3 mmol) was dissolved in dimethylacetamide (38 mL) in a pressure vessel under a stream of N2. Rieke Zinc (17.7 mL of a 50 mg/mL suspension in THF, 13.6 mmol) was added quickly via syringe, and the vessel was capped and stirred at ambient temperature for 15 minutes. The vessel was opened under a stream of Nand 2,4-dichloro-6-methylpyrimidine (1.84 g, 11.3 mmol) was added followed by PdCl2dppf (826 mg, 1.13 mmol). The vessel was capped and heated to 80° C. for one hour, then cooled to room temperature. The reaction mixture was diluted with EtOAc, filtered through celite, and the filtrate was washed with H2O (3×), brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 50% EtOAc-hexanes) to give methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (74 mg, 2.2%) as a colorless oil. MS (ES+) C14H19ClN2Orequires: 298, found: 299 [M+H]+.

Step 2: Synthesis of tert-Butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate

    • [0198]
      Figure US20170121312A1-20170504-C00096
    • [0199]
      Methyl 4-(2-chloro-6-methylpyrimidin-4-yl)-1-methoxycyclohexane-1-carboxylate (70.5 mg, 0.236 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (69.8 mg, 0.354 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (20.0 mg, 0.2 equiv.), Pd2(dba)(21.6 mg, 0.1 equiv.), and potassium acetate (70 mg, 0.71 mmol) were combined in a vial under nitrogen and 0.98 mL dioxane was added. The reaction mixture was heated to 115° C. for 2 h, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, filtered through celite, concentrated onto silica gel, and the resulting residue was purified by flash-column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-hexanes) to give tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (48 mg, 44%) as a yellow oil. MS (ES+) C23H33N5Orequires: 459, found: 460 [M+H]+.

Step 3: Synthesis of 1-Methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid

    • [0200]
      Figure US20170121312A1-20170504-C00097
    • [0201]
      Lithium hydroxide monohydrate (13 mg, 0.31 mmol) was added to a solution of tert-butyl 3-((4-(4-methoxy-4-(methoxycarbonyl)cyclohexyl)-6-methylpyrimidin-2-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate (47.7 mg, 0.104 mmol) in THF/MeOH/H2O (17:1:1, 1.8 mL). The reaction mixture was heated to 60° C. and stirred for 16 h. The reaction mixture was then cooled to ambient temperature and concentrated to give crude 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, crude) which was used in the subsequent amide coupling without any further purification. MS (ES+) C17H23N5Orequires: 345, found: 346 [M+H]+.

Step 4: Synthesis of (1s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (Compound 149)

    • [0202]
      Figure US20170121312A1-20170504-C00098
    • [0203]
      The title compound was prepared from 1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxylic acid (57 mg, 0.104 mmol) using the same procedured (amide coupling) outlined in Synthetic Protocols 1 and 2, with PyBOP as the amide coupling reagent instead of HATU. The products were initially isolated as a mixture of diastereomers (36 mg), which was then dissolved in 6 mL methanol-DCM (1:1) and purified by SFC (ChiralPak IC-H 21×250 mm, 40% MeOH containing 0.25% DEA in CO2, 1.0 mL injections, 70 mL/min). Peak 1 was an undesired isomer, and Peak 2 was concentrated to give (1 s,4R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-1-methoxy-4-(6-methyl-2-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)cyclohexane-1-carboxamide (13.4 mg, 24%) as a white solid.

Synthesis of IntermediatesExample 7. Synthesis of Ketone and Boronate IntermediatesA. Methyl 1-methoxy-4-oxocyclohexane-1-carboxylate

    • [0204]
      Figure US20170121312A1-20170504-C00099
    • [0205]
      The title compound was prepared as described in WO 2014/130810 A1 page 86.

B. Ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0206]
      Figure US20170121312A1-20170504-C00100

Step 1: Synthesis of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate

    • [0207]
      A solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol) in CHBr(3234 g, 1280 mmol) was cooled to 0° C. and potassium hydroxide (57.5 g, 1024 mmol) in EtOH (300 mL) was added dropwise over 2.5 hrs. After stirring the mixture for 23 h, the mixture was concentrated, and the residue was partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product, which was purified by flash column chromatography on silica gel (gradient elution, PE:EA=15:1 to 10:1) to obtain the title compound (18.0 g).

Step 2: Synthesis of ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate

    • [0208]
      To a solution of ethyl 8-ethoxy-1,4-dioxaspiro[4.5]decane-8-carboxylate (10 g, 43 mmol) in 1,4-dioxane (250 mL) was added aqueous HCl (6 M, 92.5 mL), and the mixture was stirred for 23 h at ambient temperature. The mixture was then diluted with H2O and extracted with EtOAc.
    • [0209]
      The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography on silica gel (PE:EA=15:1) to obtain the product (8.0 g). 1H NMR (400 MHz, DMSO) δ 4.20-4.13 (m, 2H), 3.43 (q, J=6.9 Hz, 1H), 2.48-2.39 (m, 1H), 2.24-2.12 (m, 2H), 2.10-2.01 (m, 1H), 1.22 (t, J=7.1 Hz, 2H), 1.17 (t, J=7.0 Hz, 2H).

C. Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0210]
      Figure US20170121312A1-20170504-C00101

Step 1: Synthesis of ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate

    • [0211]
      A solution of methylmagnesium bromide (3M, 109.8 mL, 329.4 mmol) was added dropwise to a suspension of CuCN (14.75 g, 164.7 mmol) in diethyl ether (50 mL) at 0° C. The mixture was stirred for 30 min at 0° C. and then cooled to −78° C. The solution of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate (10 g, 54.9 mmol) in diethyl ether (10 mL) was then added dropwise. The mixture was stirred between −40° C. to −20° C. for 2 h, then was warmed to ambient temperature for 16 h. The reaction mixture was carefully added to a saturated solution of ammonium chloride. The aqueous layer was extracted twice with diethyl ether, and the organic layers were combined. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE:EA=10:1) to give ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g).

Step 2: Synthesis of ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

    • [0212]
      Ethyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate (1.16 g, 5.85 mmol) and DIPEA (3.03 g, 23.4 mmol) were dissolved in dry toluene (2 mL) and heated at 45° C. for 10 minutes. Trifluoromethanesulfonic anhydride (6.61 g, 23.4 mmol) in DCM (20 mL) was added dropwise over 10 min and the mixture was heated at 45° C. for 2 h. The mixture was allowed to cool to room temperature, concentrated, diluted with water (60 mL) and extracted with DCM (2×40 mL). The organic layer was washed with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (1 g).

Step 3: Synthesis of ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0213]
      Ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.03 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.15 g, 4.54 mmol), Pd(dppf)Cl(73.5 mg, 0.09 mmol) and potassium acetate (891 mg, 9.08 mmol) were suspended in 1,4-dioxane (20 mL). The reaction mixture was flushed with nitrogen, then heated to 100° C. for 2 h. The mixture was cooled to room temperature, filtered, and concentrated, and the resulting brown oil was purified by flash column chromatography on silica gel (gradient elution, 0 to 100% ethyl acetate-petroleum ether) to afford ethyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (618 mg).

D. Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

    • [0214]
      Figure US20170121312A1-20170504-C00102
    • [0215]
      Ethyl 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate was prepared using the same synthetic protocol as described above using ethyl 2-methyl-4-oxocyclohexane-1-carboxylate as the starting material.

E. Methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0216]
      Figure US20170121312A1-20170504-C00103

Step 1: Synthesis of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate

    • [0217]
      A mixture of acrylaldehyde (120 g, 2.14 mol), methyl methacrylate (200 g, 2.00 mol) and hydroquinone (2.2 g, 20 mmol) were heated in a sealed steel vessel at 180° C. for one h. The mixture was then cooled to ambient temperature and concentrated. The residue was purified by silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=100:1 to 80:1) to give methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (70 g, 22% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 6.38 (d, J=6.4 Hz, 1H), 4.73-4.70 (m, 1H), 3.76 (s, 3H), 2.25-2.22 (m, 1H), 1.99-1.96 (m, 2H), 1.79-1.77 (m, 1H), 1.49 (s, 3H).

Step 2: Synthesis of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate

    • [0218]
      To a solution of methyl 2-methyl-3,4-dihydro-2H-pyran-2-carboxylate (20.0 g, 128 mmol) in anhydrous tetrahydrofuran (200 mL) was added borane (67 mL, 1 M in tetrahydrofuran) dropwise at −5° C. The reaction mixture was stirred at 0° C. for 3 hours. This reaction was monitored by TLC. The mixture was quenched by a solution of sodium acetate (10.5 g, 128 mmol) in water (15 mL). Then the mixture was treated with 30% hydrogen peroxide solution (23.6 g, 208.2 mmol) slowly at 0° C. and stirred at 30° C. for 3 h. The mixture was then partitioned between saturated sodium sulfite solution and tetrahydrofuran. The aqueous layer was further extracted with tetrahydrofuran (2×). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (gradient elution, petroleum ether:ethyl acetate=10:1 to 1:1) to give crude methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18 g, crude) as a pale yellow oil, which used directly for next step.

Step 3: Synthesis of methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate

    • [0219]
      To a solution of methyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate (18.0 g, 103 mmol) in anhydrous dichloromethane (200 mL) was added PCC (45.0 g, 209 mmol) in portions. The reaction mixture was stirred at ambient temperature until TLC indicated the reaction was completed. Petroleum ether (500 mL) was then added and the mixture was filtered. The filter cake was washed with petroleum ether (100 mL), and the filtrate was concentrated under vacuum to give methyl 2-methyl-5-oxotetrahydro-2H-pyran-2-carboxylate (15 g, 84% yield) as a pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ 4.25 (d, J=17.6 Hz, 1H), 4.07 (d, J=17.6 Hz, 1H), 3.81 (s, 3H), 2.52-2.44 (m, 3H), 2.11-2.04 (m, 1H), 1.53 (s, 3H).

Example 8. Synthesis of Iodide IntermediatesA. Methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0220]
      Figure US20170121312A1-20170504-C00104

Step 1: Synthesis of methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate

    • [0221]
      Methyl 1-methoxy-4-oxocyclohexanecarboxylate (4.00 g, 21.5 mmol) was dissolved in methanol (100 mL) and the solution was cooled to 0° C. Sodium borohydride (2.03 g, 53.7 mmol) was added in portions over 20 min. The reaction mixture was stirred for 30 min, then was quenched by addition of aqueous saturated NH4Cl solution. The quenched reaction mixture was evaporated to remove the MeOH, then the aqueous suspension was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield a residue that was purified by flash-column chromatography on silica gel (gradient elution, 5% to 100% ethyl acetate-hexanes) to afford methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 49.5%) as a colorless oil. MS (ES+) C9H16Orequires: 188, found: 211 [M+Na]+.

Step 2: Synthesis of methyl 1-methoxy-4-iodocyclohexane-1-carboxylate

    • [0222]
      Methyl 1-methoxy-4-hydroxycyclohexane-1-carboxylate (2.00 g, 10.6 mmol) was dissolved in THF (20 mL) and imidazole (723 mg, 10.6 mmol) and triphenylphosphine (3.34 g, 12.8 mmol) were added. The mixture was cooled to 0° C., and then a solution of iodine (3.24 g, 12.8 mmol) in THF (10 mL) was added dropwise over 15 min. The reaction mixture was allowed to warm to ambient temperature and was then stirred for 2 days, after which it was poured over saturated sodium thiosulfate solution and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was triturated with hexane (40 mL, stir for 20 min). The mixture was filtered, and the filtrate was evaporated to provide a residue that was purified by flash-column chromatography on silica gel (gradient elution, 0 to 30% ethyl acetate-hexanes) to give the title compound (2.37 g, 75%) as a pale yellow oil. MS (ES+) C9H15IOrequires: 298, found: 299 [M+H]+.

B. Ethyl 1-ethoxy-4-iodocyclohexane-1-carboxylate

    • [0223]
      Figure US20170121312A1-20170504-C00105
    • [0224]
      The title compound was prepared as described above using ethyl 1-ethoxy-4-oxocyclohexane-1-carboxylate as a starting material. C11H19IOrequires: 326, found: 327 [M+H].

Example 9. Synthesis of Amine IntermediatesA. (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

    • [0225]
      Figure US20170121312A1-20170504-C00106

Step 1: Synthesis of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one

    • [0226]
      4-Fluoro-1H-pyrazole (4.73 g, 55 mmol) and potassium carbonate (17.27 g, 125 mmol) were combined and stirred in N,N-dimethylformamide (41.7 mL) for 10 minutes in an open sealed tube before addition of 2-bromo-5-acetylpyridine (10 g, 50 mmol). The reaction tube was sealed and stirred for 20 hours at 100° C. The reaction mixture was then cooled to room temperature and poured into water (˜700 mL). The mixture was sonicated and stirred for 20 minutes, after which a beige solid was isolated by filtration, washed with small amounts of water, and dried to yield 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.81 g, 96% yield). MS: M+1=206.0.

Step 2: Synthesis of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide

    • [0227]
      To a stirred room temperature solution of 1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-one (9.806 g, 47.8 mmol) in THF (96 mL) was added (R)-(+)-t-Butylsulfinamide (5.79 g, 47.8 mmol) followed by titanium (IV) ethoxide (21.8 g, 96 mmol). The solution was stirred at 75° C. on an oil bath for 15 hours. The reaction solution was cooled to room temperature and then to −78° C. (external temperature) before the next step. To the −78° C. solution was added dropwise over nearly 55 minutes L-Selectride (143 mL of 1N in THF, 143 mmol). During addition, some bubbling was observed. The reaction was then stirred after the addition was completed for 15 minutes at −78° C. before warming to room temperature. LC-MS of sample taken during removal from cold bath showed reaction was completed. The reaction was cooled to −50° C. and quenched slowly with methanol (˜10 mL), then poured into water (600 mL) and stirred. An off-white precipitate was removed by filtration, with ethyl acetate used for washes. The filtrate was diluted with ethyl acetate (800 mL), the layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated down. The crude was purified by silica gel chromatography to yield (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.5 g, 99% purity, 70.3% yield) as a light yellow solid. MS: M+1=311.1.

Step 3: Synthesis of (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine

  • [0228]
    A solution of (R)—N—((S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (10.53 g, 33.9 mmol)) in methanol (79 mmol) and 4N HCl/dioxane (85 mL, 339 mmol) was stirred for 2.5 hours, at which point LC-MS showed reaction was complete. The reaction solution was poured into diethyl ether (300 mL) and a sticky solid was formed. The mixture was treated with ethyl acetate (200 mL) and sonicated. The solvents were decanted, and the sticky solid was treated with more ethyl acetate (˜200 mL), sonicated and stirred. The bulk of the sticky solid was converted to a suspension. A light yellow solid was isolated by filtration, washed with smaller amounts of ethyl acetate, and dried to yield (S)-1-(6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)ethan-1-amine (7.419 g, 78% yield). LC-MS confirmed desired product in high purity. MS: M+1=207.1.

PATENT

CN 111440151

PATENT

CN 111362923

References

  1. Jump up to:a b c d e f g h i j k l m n “FDA approves pralsetinib for lung cancer with RET gene fusions”U.S. Food and Drug Administration (FDA). 4 September 2020. Retrieved 8 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “Blueprint Medicines Announces FDA Approval of Gavreto (pralsetinib) for the Treatment of Adults with Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer” (Press release). Blueprint Medicines. 4 September 2020. Retrieved 8 September 2020 – via PR Newswire.
  3. ^ “Roche announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer”Roche (Press release). 7 September 2020. Retrieved 8 September 2020.
  4. Jump up to:a b c d “Drug Trial Snapshot: Gavreto”U.S. Food and Drug Administration. 4 September 2020. Retrieved 16 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Pralsetinib
Clinical data
Trade names Gavreto
Other names BLU-667
License data
Pregnancy
category
  • US: N (Not classified yet)
Routes of
administration
By mouth
Drug class Tyrosine kinase inhibitor
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C27H32FN9O2
Molar mass 533.612 g·mol−1
3D model (JSmol)

Roche buys into Blueprint’s RET inhibitor

The deal positions pralsetinib to compete against Lilly’s Retevmo

by Lisa M. Jarvis
JULY 18, 2020 | APPEARED IN VOLUME 98, ISSUE 28
09828-buscon2-pral.jpg

Roche is investing $775 million in cash and equity for access to Blueprint Medicines’ oncology drug candidate pralsetinib, which is under review by the US Food and Drug Administration.

Pralsetinib is a small-molecule inhibitor of RET alterations—rare genetic fusions or mutations that occur at low levels across lung, thyroid, and many other cancers.

The drug will go up against Eli Lilly and Company’s Retevmo, an RET inhibitor that received FDA approval in May for certain lung and thyroid cancers. Lilly acquired Retevmo in its $8 billion purchase of Loxo Oncology in 2019, a deal to obtain Loxo’s pipeline of small molecules for genetically defined tumors.

But SVB Leerink analyst Andrew Berens points out that Retevmo has side effects: it can cause an irregular heart rhythm called QT prolongation and hemorrhagic events. That leaves room for pralsetinib, which Roche will be better able to get in front of oncologists, Berens argues. In addition to a vast commercial network, Roche brings diagnostic tools to help identify cancer patients whose tumors feature RET alterations.

The FDA has a deadline of Nov. 23 to decide on approving the drug for lung cancer.

Roche’s move lowers the likelihood of a takeover of Blueprint, which had appeared on many investors’ short lists of acquisition targets. “We were surprised by the profuse language framing this deal as ensuring Blueprint’s independence,” Piper Sandler stock analyst Christopher J. Raymond told investors in a note.

//////////Pralsetinib, GAVRETO, 2020 APPROVALS, FDA 2020

CC1=CC(=NN1)NC2=NC(=NC(=C2)C)C3CCC(CC3)(C(=O)NC(C)C4=CN=C(C=C4)N5C=C(C=N5)F)OC

Clascoterone


Cortexolone 17α-propionate.svg

Clascoterone

(1R,3aS,3bR,9aR,9bS,11aS)-1-(2-hydroxyacetyl)-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl propanoate

Formula
C24H34O5
CAS
19608-29-8
Mol weight
402.5238

FDA APPROVED, 2020/8/26, Winlevi

クラスコステロン;

Anti-acne, Androgen receptor antagonist

Clascoterone, sold under the brand name Winlevi, is an antiandrogen medication which is used topically in the treatment of acne.[1][2][3] It is also under development for the treatment of androgen-dependent scalp hair loss.[2] The medication is used as a cream by application to the skin, for instance the face and scalp.[3]

Clascoterone is an antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone.[4][5] It shows no systemic absorption when applied to skin.[3]

The medication, developed by Cassiopea and Intrepid Therapeutics,[2] was approved by the US Food and Drug Administration (FDA) for acne in August 2020.[6][7]

Medical uses

Clascoterone is indicated for the topical treatment of acne vulgaris in females and males age 12 years and older.[1][8] It is applied to the affected skin area in a dose of 1 mg cream (or 10 mg clascoterone) twice per day, once in the morning and once in the evening.[1] The medication should not be used ophthalmicallyorally, or vaginally.[1]

Available forms

Clascoterone is available in the form of a 1% (10 mg/g) cream for topical use.[1]

Contraindications

Clascoterone has no contraindications.[1]

Side effects

The incidences of local skin reactions with clascoterone were similar to placebo in two large phase 3 randomized controlled trials.[1][9] Suppression of the hypothalamic–pituitary–adrenal axis (HPA axis) may occur during clascoterone therapy in some individuals due to its cortexolone metabolite.[1][8] HPA axis suppression as measured by the cosyntropin stimulation test was observed to occur in 3 of 42 (7%) of adolescents and adults using clascoterone for acne.[1][8] HPA axis function returned to normal within 4 weeks following discontinuation of clascoterone.[1][8] Hyperkalemia (elevated potassium levels) occurred in 5% of clascoterone-treated individuals and 4% of placebo-treated individuals.[1]

Pharmacology

Pharmacodynamics

Clascoterone is an steroidal antiandrogen, or antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT).[1][4][5] In a bioassay, the topical potency of the medication was greater than that of progesteroneflutamide, and finasteride and was equivalent to that of cyproterone acetate.[10] Likewise, it is significantly more efficacious as an antiandrogen than other AR antagonists such as enzalutamide and spironolactone in scalp dermal papilla cells and sebocytes in vitro.[5]\

Pharmacokinetics

Steady-state levels of clascoterone occur within 5 days of twice daily administration.[1] At a dosage of 6 g clascoterone cream applied twice daily, maximal circulating levels of clascoterone were 4.5 ± 2.9 ng/mL, area-under-the-curve levels over the dosing interval were 37.1 ± 22.3 h*ng/mL, and average circulating levels of clascoterone were 3.1 ± 1.9 ng/mL.[1] In rodents, clascoterone has been found to possess strong local antiandrogenic activity, but negligible systemic antiandrogenic activity when administered via subcutaneous injection.[10] Along these lines, the medication is not progonadotropic in animals.[10]

The plasma protein binding of clascoterone is 84 to 89% regardless of concentration.[1]

Clascoterone is rapidly hydrolyzed into cortexolone (11-deoxycortisol) and this compound is a possible primary metabolite of clascoterone based on in-vitro studies in human liver cells.[1][8] During treatment with clascoterone, cortexolone levels were detectable and generally below or near the low limit of quantification (0.5 ng/mL).[1] Clascoterone may also produce other metabolites, including conjugates.[1]

The elimination of clascoterone has not been fully characterized in humans.[1]

Chemistry

Clascoterone, also known as cortexolone 17α-propionate or 11-deoxycortisol 17α-propionate, as well as 17α,21-dihydroxyprogesterone 17α-propionate or 17α,21-dihydroxypregn-4-en-3,20-dione 17α-propionate, is a synthetic pregnane steroid and a derivative of progesterone and 11-deoxycortisol (cortexolone).[11] It is specifically the C17α propionate ester of 11-deoxycortisol.[10]

An analogue of clascoterone is 9,11-dehydrocortexolone 17α-butyrate (CB-03-04).[12]

History

C17α esters of 11-deoxycortisol were unexpectedly found to possess antiandrogenic activity.[10] Clascoterone, also known as cortexolone 17α-propionate, was selected for development based on its optimal drug profile.[10] The medication was approved by the US Food and Drug Administration (FDA) for the treatment of acne in August 2020.[6]

Two large phase 3 randomized controlled trials evaluated the effectiveness of clascoterone for the treatment of acne over a period of 12 weeks.[1][8][9] Clascoterone decreased acne symptoms by about 8 to 18% more than placebo.[1][9] The defined treatment success endpoint was achieved in about 18 to 20% of individuals with clascoterone relative to about 7 to 9% of individuals with placebo.[1][8][9] The comparative effectiveness of clascoterone between males and females was not described.[1][9]

A small pilot randomized controlled trial in 2011, found that clascoterone cream decreased acne symptoms to a similar or significantly greater extent than tretinoin 0.05% cream.[8][13] No active comparator was used in the phase III clinical trials of clascoterone for acne.[8] Hence, it’s unclear how clascoterone compares to other therapies used in the treatment of acne.[8]

The FDA approved clascoterone based on evidence from two clinical trials (Trial 1/NCT02608450 and Trial 2/NCT02608476) of 1440 participants 9 to 58 years of age with acne vulgaris.[14] The trials were conducted at 99 sites in the United States, Poland, Romania, Bulgaria, Ukraine, Georgia, and Serbia.[14]

Participants applied clascoterone or vehicle (placebo) cream twice daily for 12 weeks.[14] Neither the participants nor the health care providers knew which treatment was being given until after the trial was completed.[14] The benefit of clascoterone in comparison to placebo was assessed after 12 weeks of treatment using the Investigator’s Global Assessment (IGA) score that measures the severity of disease (on a scale from 0 to 4) and a decrease in the number of acne lesions.[14]

Society and culture

Names

Clascoterone is the generic name of the drug and its INN and USAN.[11][15]

Research

Clascoterone has been suggested as a possible treatment for hidradenitis suppurativa (acne inversa), an androgen-dependent skin condition.[16]

PATENT

https://patents.google.com/patent/EP2503005B1/en

  • Cortexolone derivatives in which the hydroxyl group at position C-17α is esterified with short chain aliphatic or aromatic acids and the derivatives of the corresponding 9,11-dehydro derivative, are known to have an antiandrogenic effect.
  • [0002]
    EP 1421099 describes cortexolone 17α-propionate and 9,11-dehydro-cortexolone-17-α-butanoate regarding a high antiandrogenic biological activity demonstrated both “in vitro” and “in vivo” on the animal.
  • [0003]
    US3530038 discloses the preparation of a crystalline form of cortexolone-17α-propionate having a melting point of 126-129 °C and an IR spectrum with bands at (cm-1): 3500, 1732, 1713, 1655 and 1617.
  • [0004]
    A method for obtaining the above mentioned derivatives is described by Gardi et al. (Gazz. Chim. It. 63, 43 1,1963) and in the United States patent US3152154 providing for the transformation of cortexolone, or transformation of 9,11-dehydrocortexolone, in the intermediate orthoester using orthoesters available in the market as a mixture of aprotic solvents such as cyclohexane and DMF, in presence of acid catalysis (ex. PTSA.H20). The intermediate orthoester thus obtained can be used as is or upon purification by suspension in a solvent capable of solubilising impurities, preferably in alcohols. The subsequent hydrolysis in a hydroalcoholic solution, buffered to pH 4-5 preferably in acetate buffer, provides the desired monoester.
  • [0005]

    Such synthesis is indicated in the diagram 1 below

    Figure imgb0001
  • [0006]
    However, the monoesters thus obtained were, in the reaction conditions, unstable and, consequently hard to manipulate and isolate (R. Gardi et al Tetrahedron Letters, 448, 1961). The instability is above all due to the secondary reaction of migration of the esterifying acyl group from position 17 to position 21.
  • [0007]
    It is thus known that in order to obtain the above mentioned monoesters with a chemical purity in such a manner to be able to proceed to the biological tests, it is necessary to use, at the end of the synthesis, a purification process which is generally performed by means of column chromatography.
  • [0008]
    Furthermore, US3152154 describes how the hydrolysis of the diester in a basic environment is not convenient due to the formation of a mixture of 17α,21-diol, of 17- and 21 -monoesters, alongside the initial non-reacted product.
  • [0009]
    Now, it has been surprisingly discovered that an alcoholysis reaction using a lipase from Candida as a biocatalyst can be usefully applied during the preparation of 17α monoesters of cortexolone, or its 9,11-dehydroderivatives.
  • [0010]

    As a matter of fact, it has been discovered that such enzymatic alcoholysis of the 17,21-diester of the cortexolone, or of its derivative 9,11-dehydro, selectively occurs in position 21 moving to the corresponding monoester in position 17, as shown in diagram 2 below:

    Figure imgb0002
  • [0011]
    The chemoselectivity of the special enzymatic reaction in alcoholysis conditions, according to the present invention, opens new perspectives for preparation, at industrial level with higher yields, of 17α-monoesters with respect to the methods already indicated in literature.
  • [0012]
    The diesters serving as a substrate for the reaction of the invention can be prepared according to the prior art, for example following the one described in B.Turner, (Journal of American Chemical Society, 75, 3489, 1953) which provides for the esterification of corticosteroids with a linear carboxylic acid in presence of its anhydride and PTSA monohydrate.

EXAMPLES

    • Example 1

Alcoholysis with CCL of cortexolone 17α, 21-dipropionate

      • [0055]
        Add butanol (0.4g, 5.45 mmoles) and CCL (17.4g, 3.86 U/mg, FLUKA) to a solution of cortexolone-17α,21-dipropionate (0.5g, 1.09 mmoles) in toluene (50ml). Maintain the mixture under stirring, at 30 °C, following the progress of the reaction in TLC (Toluene/ethyl acetate 6/4) until the initial material is dissolved (24h). Remove the enzyme by means of filtration using a Celite layer. Recover the cortexolone 17α-propionate (0.437, 99%) after evaporation under low pressure. Through crystallisation, from diisopropyl ether you obtain a product with a purity >99% in HPLC.
      • [0056]
        1H-NMR (500MHz, CDCl3) relevant signals δ (ppm) 5.78 (br s, 1 H, H-4), 4.32 (dd, 1 H, H-21), 4.25 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 1.17 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C

Example 2 (comparative)

      • [0057]
        According to the method described in example 1 prepare cortexolone-17α-butanoate.
      • [0058]
        1H-NMR relevant signals δ (ppm) 5.78 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.23 (s, 3H, CH3-19), 0.97 (t, 3H, CH3), 0.73 (s, 3H. CH3-18). P.F. 134-136 °C

Example 3 (comparative)

According to the method described in the example prepare cortexolone-17α-valerate.

      • [0059]
        1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 4.32 (dd, 1H, H-21), 4.26 (dd, 1H, H-21), 1.22 (s, 3H, CH3-19), 0.95 (t, 3H, CH3), 0.72 (s, 3H, CH3-18). P.f. 114 °C (diisopropyl ether).

Example 4 (comparative)

According to the method described in the example prepare 9, 11-dehydro-cortexolone-17α-butanoate.

      • [0060]
        1H-NMR relevant signals δ (ppm) 5.77 (br s, 1H, H-4), 5.54 (m, 1H, H-9), 4.29 (dd, 1H, H-21), 4.24 (dd, 1H, H-21), 1.32 (s, 3H, CH3-19), 0.94(t, 3H, CH3), 0.68 (s, 3H, CH3-18). P.f. 135-136 °C (acetone/hexane).

Example 5

Alcoholysis with CALB of cartexolone-17α, 21-dipropionate

      • [0061]
        Dissolve cortexolone, 17α, 2-dipropionate (0.5g, 1.09 mmoles) in acetonitrile (40ml), add CALB (2.3g, 2.5 U/mg Fluka) and octanol (0.875ml). Leave the mixture under stirring, at 30 °C, for 76 hrs. Remove the enzyme by means of filtration using a paper filter. Once the solvents evaporate, recover a solid (0.4758) which upon analysis 1H-NMR shall appear made up of cortexolone-17α-propionate at 91%.

Example 6

Crystallisation

      • [0062]
        Add the solvent (t-butylmethylether or diisopropylether) to the sample according to the ratios indicated in Table 3. Heat the mixture to the boiling temperature of the solvent, under stirring, until the sample dissolves completely. Cool to room temperature and leave it at this temperature, under stirring, for 6 hours. Filter using a buchner funnel and maintain the solid obtained, under low pressure, at a room temperature for 15 hours and then, at 40°C, for 5 hours.

Example 7 (comparative)

Precipitation

      • [0063]
        Disslove the sample in the suitable solvent (dichloromethane, acetone, ethyl acetate or ethanol) according to the ratios indicated in table 3 and then add the solvent, hexane or water, according to the ratios indicated in table 3, maintaining the mixture, under stirring, at room temperature. Recover the precipitate by filtration using a buchner funnel and desiccate as in example 6.

Example 8.

Obtaining a pharmaceutical form containing the medication in a defined crystalline form.

  • [0064]
    Prepare a fluid cream containing 2 % cetylic alcohol, 16% glyceryl monostearate, 10% vaseline oil, 13 % propylene glycol, 10% polyethylenglycol with low polymerization 1.5% polysorbate 80 and 47.5 % purified water. Add 1 g of cortexolone 17α-propionate of crystalline form III to 100 g of this cream and subject the mixture to homogenisation by means of a turbine agitator until you obtain homogeneity. You obtain a cream containing a fraction of an active ingredient dissolved in the formulation vehicle and a non-dissolved fraction of an active ingredient, present as a crystal of crystalline form III. This preparation is suitable for use as a formulation vehicle for skin penetration tests on Franz cells, where a coefficient of penetration in the range of 0.04 to 0.03 cm/h is observed on the preparation.

References

  1. 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 “Winlevi (clascoterone) cream, for topical use”(PDF). Cassiopea. Retrieved 9 September 2020.
  2. Jump up to:a b c http://adisinsight.springer.com/drugs/800026561
  3. Jump up to:a b c Kircik LH (July 2019). “What’s new in the management of acne vulgaris”Cutis104(1): 48–52. PMID 31487336.
  4. Jump up to:a b Rosette C, Rosette N, Mazzetti A, Moro L, Gerloni M (February 2019). “Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro”. J Drugs Dermatol18 (2): 197–201. PMID 30811143.
  5. Jump up to:a b c Rosette C, Agan FJ, Mazzetti A, Moro L, Gerloni M (May 2019). “Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro”. J Drugs Dermatol18 (5): 412–418. PMID 31141847.
  6. Jump up to:a b “Cassiopea Receives FDA Approval for Winlevi (clascoterone cream 1%), First-in-Class Topical Acne Treatment Targeting the Androgen Receptor”Cassiopea (Press release). Retrieved 2020-08-30.
  7. ^ “Winlevi: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 9 September 2020.
  8. Jump up to:a b c d e f g h i j Barbieri, John S. (2020). “A New Class of Topical Acne Treatment Addressing the Hormonal Pathogenesis of Acne”. JAMA Dermatology156 (6): 619–620. doi:10.1001/jamadermatol.2020.0464ISSN 2168-6068PMID 32320045.
  9. Jump up to:a b c d e Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, Mazzetti A (April 2020). “Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials”JAMA Dermatol156 (6): 621–630. doi:10.1001/jamadermatol.2020.0465PMC 7177662PMID 32320027.
  10. Jump up to:a b c d e f Celasco G, Moro L, Bozzella R, Ferraboschi P, Bartorelli L, Quattrocchi C, Nicoletti F (2004). “Biological profile of cortexolone 17alpha-propionate (CB-03-01), a new topical and peripherally selective androgen antagonist”. Arzneimittelforschung54 (12): 881–6. doi:10.1055/s-0031-1297043PMID 15646372.
  11. Jump up to:a b https://chem.nlm.nih.gov/chemidplus/rn/19608-29-8
  12. ^ Celasco G, Moroa L, Bozzella R, Ferraboschi P, Bartorelli L, Di Marco R, Quattrocchi C, Nicoletti F (2005). “Pharmacological profile of 9,11-dehydrocortexolone 17alpha-butyrate (CB-03-04), a new androgen antagonist with antigonadotropic activity”. Arzneimittelforschung55 (10): 581–7. doi:10.1055/s-0031-1296908PMID 16294504.
  13. ^ Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G (2011). “Cortexolone 17α-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0·05% cream”. Br. J. Dermatol165 (1): 177–83. doi:10.1111/j.1365-2133.2011.10332.xPMID 21428978S2CID 38404925.
  14. Jump up to:a b c d e “Drug Trial Snapshot: Winlevi”U.S. Food and Drug Administration (FDA). 26 August 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.
  15. ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information33 (3): 106. hdl:10665/330879.
  16. ^ Der Sarkissian SA, Sun HY, Sebaratnam DF (August 2020). “Cortexolone 17 α-proprionate for hidradenitis suppurativa”. Dermatol Ther: e14142. doi:10.1111/dth.14142PMID 32761708.

External links

  • “Clascoterone”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02608450 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (25)” at ClinicalTrials.gov
  • Clinical trial number NCT02608476 for “A Study to Evaluate the Safety and Efficacy of CB-03-01 Cream, 1% in Subjects With Facial Acne Vulgaris (26)” at ClinicalTrials.gov
Clascoterone
Cortexolone 17α-propionate.svg
Clinical data
Trade names Winlevi
Other names CB-03-01; Breezula; 11-Deoxycortisol 17α-propionate; 17α-(Propionyloxy)-
deoxycorticosterone; 21-Hydroxy-3,20-dioxopregn-4-en-17-yl propionate
License data
Routes of
administration
Topical (cream)
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.810 Edit this at Wikidata
Chemical and physical data
Formula C24H34O5
Molar mass 402.531 g·mol−1
3D model (JSmol)

/////////Clascoterone, クラスコステロン , FDA 2020, 2020 APPROVALS, ANTI ACNE

[H][C@@]12CC[C@](OC(=O)CC)(C(=O)CO)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C

Copper Cu 64 dotatate, 銅(Cu64)ドータテート;


Copper dotatate Cu-64.png

2D chemical structure of 1426155-87-4

Figure imgf000004_0001

Copper Cu 64 dotatate

銅(Cu64)ドータテート;

UNII-N3858377KC

N3858377KC

Copper 64-DOTA-tate

Copper Cu-64 dotatate

Copper dotatate Cu-64

Diagnostic (neuroendocrine tumors), Radioactive agent

Formula
C65H86CuN14O19S2. 2H
CAS:
 1426155-87-4
Mol weight
1497.1526

FDA APPROVED 2020. 2020/9/3. Detectnet

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-10-(carboxylatomethyl)-7-(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;copper-64(2+)

Cuprate(2-)-64Cu, (N-(2-(4,10-bis((carboxy-kappaO)methyl)-7-(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl-kappaN1,kappaN4,kappaN7,kappaN10)acetyl)-D-phenylalanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-threonyl-L-cysteinyl-L-threoni

Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adults.[1]

Common side effects include nausea, vomiting and flushing.[2]

It was approved for medical use in the United States in September 2020.[1][2]

History

The U.S. Food and Drug Administration (FDA) approved copper Cu 64 dotatate based on data from two trials that evaluated 175 adults.[3]

Trial 1 evaluated adults, some of whom had known or suspected NETs and some of whom were healthy volunteers.[3] The trial was conducted at one site in the United States (Houston, TX).[3] Both groups received copper Cu 64 dotatate and underwent PET scan imaging.[3] Trial 2 data came from the literature-reported trial of 112 adults, all of whom had history of NETs and underwent PET scan imaging with copper Cu 64 dotatate.[3] The trial was conducted at one site in Denmark.[3] In both trials, copper Cu 64 dotatate images were compared to either biopsy results or other images taken by different techniques to detect the sites of a tumor.[3] The images were read as either positive or negative for presence of NETs by three independent image readers who did not know participant clinical information.[3]

PATENT

https://patents.google.com/patent/WO2013029616A1/en

PATENT

https://patents.google.com/patent/US20140341807

  • Known imaging techniques with tremendous importance in medical diagnostics are positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), single photon computed tomography (SPECT) and ultrasound (US). Although today’s imaging technologies are well developed they rely mostly on non-specific, macroscopic, physical, physiological, or metabolic changes that differentiate pathological from normal tissue.
  • [0003]
    Targeting molecular imaging (MI) has the potential to reach a new dimension in medical diagnostics. The term “targeting” is related to the selective and highly specific binding of a natural or synthetic ligand (binder) to a molecule of interest (molecular target) in vitro or in vivo.
  • [0004]
    MI is a rapidly emerging biomedical research discipline that may be defined as the visual representation, characterization and quantification of biological processes at the cellular and sub-cellular levels within intact living organisms. It is a novel multidisciplinary field, in which the images produced reflect cellular and molecular pathways and in vivo mechanism of disease present within the context of physiologically authentic environments rather than identify molecular events responsible for disease.
  • [0005]
    Several different contrast-enhancing agents are known today and their unspecific or non-targeting forms are already in clinical routine. Some examples listed below are reported in literature.
  • [0006]
    For example, Gd-complexes could be used as contrast agents for MRI according to “Contrast Agents I” by W. Krause (Springer Verlag 2002, page one and following pages). Furthermore, superparamagnetic particles are another example of contrast-enhancing units, which could also be used as contrast agents for MRI (Textbook of Contrast Media, Superparamagnetic Oxides, Dawson, Cosgrove and Grainger Isis Medical Media Ltd, 1999, page 373 and following pages). As described in Contrast Agent II by W. Krause (Springer Verlag 2002, page 73 and following pages), gas-filled microbubbles could be used in a similar way as contrast agents for ultrasound. Moreover “Contrast Agents II” by W. Krause (Springer Verlag, 2002, page 151 and following pages) reports the use of iodinated liposomes or fatty acids as contrast agents for X-Ray imaging.
  • [0007]
    Contrast-enhancing agents that can be used in functional imaging are mainly developed for PET and SPECT.
  • [0008]
    The application of radiolabelled bioactive peptides for diagnostic imaging is gaining importance in nuclear medicine. Biologically active molecules which selectively interact with specific cell types are useful for the delivery of radioactivity to target tissues. For example, radiolabelled peptides have significant potential for the delivery of radionuclides to tumours, infarcts, and infected tissues for diagnostic imaging and radiotherapy.
  • [0009]
    DOTA (1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10tetraazacyclododecane) and its derivatives constitute an important class of chelators for biomedical applications as they accommodate very stably a variety of di- and trivalent metal ions. An emerging area is the use of chelator conjugated bioactive peptides for labeling with radiometals in different fields of diagnostic and therapeutic nuclear oncology.
  • [0010]
    There have been several reports in recent years on targeted radiotherapy with radiolabeled somatostatin analogs.
  • [0011]
    US2007/0025910A1 discloses radiolabled somatostatin analogs primarily based on the ligand DOTA-TOC. The radionucleotide can be (64)Copper and the somatostatin analog may be octreotide, lanreotide, depreotide, vapreotide or derivatives thereof. The compounds of US2007/0025910A1 are useful in radionucleotide therapy of tumours.
  • [0012]
    US2007/0025910A1 does not disclose (64)Cu-DOTA-TATE. DOTA-TATE and DOTA-TOC differ clearly in affinity for the 5 known somatostatin receptors (SST1-SST2). Accordingly, the DOTA-TATE has a 10-fold higher affinity for the SST2 receptor, the receptor expressed to the highest degree on neuroendocrine tumors. Also the relative affinity for the other receptor subtypes are different. Furthermore, since 177Lu-DOTATATE is used for radionuclide therapy, only 64Cu-DOTATATE and not 64Cu-DOTATOC can be used to predict effect of such treatment by a prior PET scan.
  • [0013]
    There exists a need for further peptide-based compounds having utility for diagnostic imaging techniques, such as PET.

Figure US20140341807A1-20141120-C00001

    • EXAMPLE
  • [0033]
    Preparation of “Cu-Dotatate-DOTA-TATE
  • [0034]
    64Cu was produced using a GE PETtrace cyclotron equipped with a beamline. The 64Cu was produced via the 64Ni (p,n) 64Cu reaction using a solid target system consisting of a water cooled target mounted on the beamline. The target consisted of 64Ni metal (enriched to >99%) electroplated on a silver disc backing. For this specific type of production a proton beam with the energy of 16 MeV and a beam current of 20 uA was used. After irradiation the target was transferred to the laboratory for further chemical processing in which the 64Cu was isolated using ion exchange chromatography. Final evaporation from aq. HCl yielded 2-6 GBq of 64Cu as 64CuCl2 (specific activity 300-3000 TBq/mmol; RNP >99%). The labeling of 64Cu to DOTA-TATE was performed by adding a sterile solution of DOTA-TATE (0.3 mg) and Gentisic acid (25 mg) in aq Sodium acetate (1 ml; 0.4M, pH 5.0) to a dry vial containing 64CuCl2 (˜1 GBq). Gentisic acid was added as a scavenger to reduce the effect of radiolysis. The mixture was left at ambient temperature for 10 minutes and then diluted with sterile water (1 ml). Finally, the mixture was passed through a 0.22 μm sterile filter (Millex GP, Millipore). Radiochemical purity was determined by RP-HPLC and the amount of unlabeled 64Cu2+ was determined by thin-layer chromatography. All chemicals were purchased from Sigma-Aldrich unless specified otherwise. DOTA-Tyr3-Octreotate (DOTA-TATE) was purchased from Bachem (Torrance, Calif.). Nickel-64 was purchased in +99% purity from Campro Scientific Gmbh. All solutions were made using Ultra pure water (<0.07 μSimens/cm). Reversed-phase high pressure liquid chromatography was performed on a Waters Alliance 2795 Separations module equipped with at Waters 2489 UV/Visible detector and a Caroll Ramsey model 105 S-1 radioactivity detector—RP-HPLC column was Luna C18, HST, 50×2 mm, 2.5 μm, Phenomenex. The mobile phase was 5% aq. acetonitrile (0.1% TFA) and 95% aq. acetonitrile (0.1% TFA).
  • [0035]
    Thin layer chromatography was performed with a Raytest MiniGita Star TLC-scanner equipped with a Beta-detector. The eluent was 50% aq methanol and the TLC-plate was a Silica60 on Al foil (Fluka). Ion exchange chromatography was performed on a Dowex 1×8 resin (Chloride-form, 200-400 mesh).

References

  1. Jump up to:a b “FDA approval letter” (PDF). 3 September 2020. Retrieved 5 September 2020.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b “RadioMedix and Curium Announce FDA Approval of Detectnet (copper Cu 64 dotatate injection) in the U.S.” (Press release). Curium. 8 September 2020. Retrieved 9 September 2020 – via GlobeNewswire.
  3. Jump up to:a b c d e f g h “Drug Trials Snapshots: Detectnet”U.S. Food and Drug Administration (FDA). 3 September 2020. Retrieved 10 September 2020.  This article incorporates text from this source, which is in the public domain.

External links

Coppers Coming | Cu 64 dotatate injection is coming soonThe emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The emerging role of copper-64 radiopharmaceuticals as cancer theranostics  - ScienceDirect

The FDA has approved copper Cu 64 dotatate injection (Detectnet) for the localization of somatostatin receptor–positive neuroendocrine tumors (NETs), according to an announcement from RadioMedix Inc. and Curium Pharma.1

The positron emission tomography (PET) diagnostic agent is anticipated to launch immediately, according to Curium. Doses will be accessible through several nuclear pharmacies or through the nuclear medicine company.

“Detectnet brings an exciting advancement in the diagnosis of NETs for healthcare providers, patients, and their caregivers,” Ebrahim Delpassand MD, CEO of RadioMedix, stated in a press release. “The phase 3 results demonstrate the clinical sensitivity and specificity of Detectnet which will provide a great aid to clinicians in developing an accurate treatment approach for their [patients with] NETs.”

Copper Cu 64 dotatate adheres to somatostatin receptors with highest affinity for subtype 2 receptors (SSTR2). Specifically, the agent binds to somatostatin receptor–expressing cells, including malignant neuroendocrine cells; these cells overexpress SSTR2. The agent is a positron-producing radionuclide that possesses an emission yield that permits PET imaging.

“Perhaps most exciting is that the 12.7-hour half-life allows Detectnet to be produced centrally and shipped to sites throughout the United States,” added Delpassand. “This will help alleviate shortages or delays that have been experienced with other somatostatin analogue PET agents.”

Two single-center, open-label studies confirmed the efficacy of the diagnostic agent, according to Curium.2 In Study 1, investigators conducted a prospective analysis of 63 patients, which included 42 patients with known or suspected NETs according to histology, conventional imaging, or clinical evaluations, and 21 healthy volunteers. The majority of the participants, or 88% (n = 37) had a history of NETs at the time that they underwent imaging. Just under half of patients (44%; n = 28) were men and the majority were white (86%). Moreover, patients had a mean age of 54 years.

Images produced by the PET agent were interpreted to be either positive or negative for NET via 3 independent readers who had been blinded to the clinical data and other imaging information. Moreover, the results from the diagnostic agent were compared with a composite reference standard that was comprised of 1 oncologist’s blinded evaluation of patient diagnosis based on available histopathology results, reports of conventional imaging that had been done within 8 weeks before the PET imaging, as well as clinical and laboratory findings, which involved chromogranin A and serotonin levels.

Additionally, the percentage of patients who tested positive for disease via composite reference as well as through PET imaging was used to quantify positive percent agreement. Conversely, the percentage of participants who did not have disease per composite reference and who were determined to be negative for disease per PET imaging was used to quantify negative percent agreement.

Results showed that the percent reader agreement for positive detection in 62 scans was 91% (95% CI, 75-98) and negative detection was 97% (95% CI, 80-99). For reader 2, these percentages were 91% (95% CI, 75-98) and 80% (95% CI, 61-92), respectively, for 63 scans. Lastly, the percent reader agreement for reader 3 in 63 scans was 91% (95% CI, 75-98) positive and 90% (95% CI, 72-97) negative.

Study 2 was a retrospective analysis in which investigators examined published findings collected from 112 patients; 63 patients were male, while 43 were female. The mean age of patients included in the analysis was 62 years. All patients had a known history of NETs. Results demonstrated similar performance with the PET imaging agent.

In both safety and efficacy trials, a total of 71 patients were given a single dose of the diagnostic agent; the majority of these patients had known or suspected NETs and 21 were healthy volunteers. Adverse reactions such as nausea, vomiting, and flushing were reported at a rate of less than 2%. In all clinical experience that has been published, a total of 126 patients with a known history of NETs were given a single dose of the PET diagnostic agent. A total of 4 patients experienced nausea immediately after administration.

“Curium is excited to bring the first commercially available Cu 64 diagnostic agent to the US market,” Dan Brague, CEO of Curium, North America, added in the release. “Our unique production capabilities and distribution network allow us to deliver to any nuclear pharmacy, hospital, or imaging center its full dosing requirements first thing in the morning, to provide scheduling flexibility to the institution and its patients. We look forward to joining with healthcare providers and our nuclear pharmacy partners to bring this highly efficacious agent to the market.”

References
1. RadioMedix and Curium announce FDA approval of Detectnet (copper Cu 64 dotatate injection) in the US. News release. RadioMedix Inc and Curium. September 8, 2020. Accessed September 9, 2020. https://bit.ly/3m6iC0q.
2. Detectnet. Prescribing information. Curium Pharma; 2020. Accessed September 9, 2020. https://bit.ly/32eZxS3.

///////////////Copper Cu 64 dotatate, 銅(Cu64)ドータテート , FDA 2020, 2020 APPROVALS, Diagnostic, neuroendocrine tumors, Radioactive agent,

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)O)C(=O)NC(C(C)O)C(=O)O)O.[Cu+2]

Amisulpride, アミスルプリド ,


71675-85-9.png

ChemSpider 2D Image | Amisulpride | C17H27N3O4S

Amisulpride.svg

Amisulpride

FDA 2020, Barhemsys APPROVED, 2020/2/27

Name
Amisulpride (INN);
Deniban (TN);
Solian (TN)
アミスルプリド;
Formula
C17H27N3O4S
CAS
71675-85-9
Mol weight
369.479

Antipsychotic, Dopamine receptor antagonist, Neuropsychiatric agent

amisulpride(标准品)

275-831-7 [EINECS]
Synthesis ReferenceUS4401822
4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide
Amisulpride
CAS Registry Number: 71675-85-9
CAS Name: 4-Amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxybenzamide
Additional Names: 4-amino-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-o-anisamide; aminosultopride
Manufacturers’ Codes: DAN-2163
Trademarks: Deniban (Synthelabo); Socian (Synthelabo); Solian (Synthelabo); Sulamid (Baldacci)
Molecular Formula: C17H27N3O4S
Molecular Weight: 369.48
Percent Composition: C 55.26%, H 7.37%, N 11.37%, O 17.32%, S 8.68%
Literature References: Dopamine receptor antagonist. Prepn: M. Thominet et al., BE 872585eidem, US 4401822 (1979, 1983 both to Soc. d’Etudes Sci. Ind. de l’Ile-de-France).
Crystal structure: H. L. DeWinter et al., Acta Crystallogr. C46, 313 (1990). Psychopharmacology: G. Perrault et al., J. Pharmacol. Exp. Ther. 280, 73 (1997). HPLC determn in plasma and urine: B. Malavasi et al., J. Chromatogr. B 676, 107 (1996). Series of articles on pharmacology and clinical efficacy in schizophrenia: Int. Clin. Psychopharmacol. 12, Suppl. 2, S11-S36 (1997).
Properties: Crystals from acetone, mp 126-127°. LD50 in male mice (mg/kg): 56-60 i.v.; 175-180 i.p.; 224-250 s.c.; 1024-1054 orally (Thominet).
Melting point: mp 126-127°
Toxicity data: LD50 in male mice (mg/kg): 56-60 i.v.; 175-180 i.p.; 224-250 s.c.; 1024-1054 orally (Thominet)
Therap-Cat: Antipsychotic.
Keywords: Antipsychotic; Benzamides; Dopamine Receptor Antagonist.
Amisulpride (trade name Solian) is an antipsychotic drug sold by Sanofi-Aventis.  but is approved for use in Europe and Australia for the treatment of psychoses and schizophrenia. Additionally, it is approved in Italy for the treatment of dysthymia (under the brand name Deniban). Amisulpride is a selective dopamine antagonist.

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses orally and intramuscularly to treat schizophrenia and acute psychotic episodes. It is sold under the brandnames Barhemsys[6] (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic).[2] It is also used to treat dysthymia.[7]

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.[8][9][10] It has also been found to be modestly more effective in treating schizophrenia than the typical antipsychotics.[9]

Amisulpride is approved for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.[6]

Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynapticdopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorized to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.[7]

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available.[11] It is marketed in all English-speaking countries except for Canada and the United States.[10] A New York City based company, LB Pharmaceuticals, has announced the ongoing development of LB-102, also known as N-methyl amisulpride, an antipsychotic specifically targeting the United States.[12][13] A poster presentation at European Neuropsychopharmacology[14] seems to suggest that this version of amisulpride, known as LB-102 displays the same binding to D2, D3 and 5HT7 that amisulpride does.[15][16]

Medical uses

Schizophrenia

In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, amisulpride was ranked second and demonstrated high effectiveness. 11% more effective than olanzapine (3rd), 32-35% more effective than haloperidolquetiapine, and aripiprazole, and 25% less effective than clozapine (1st).[9] Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia.[17][18] Amisulpride augmentation, similarly to sulpirideaugmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia.[19][20] Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.[21]

Contraindications

Amisulpride’s use is contraindicated in the following disease states[2][22][8]

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.[2]

Adverse effects

Very Common (≥10% incidence)[1]
  • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisiaparkinsonism). Produces a moderate degree of EPS; more than aripiprazole (not significantly, however), clozapine, iloperidone (not significantly), olanzapine (not significantly), quetiapine (not significantly) and sertindole; less than chlorpromazine (not significantly), haloperidol, lurasidone (not significantly), paliperidone (not significantly), risperidone (not significantly), ziprasidone (not significantly) and zotepine (not significantly).[9]
Common (≥1%, <10% incidence)[1][2][23][22][8]
  • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.)
  • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine)[9]
  • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
– constipation
– dry mouth
– disorder of accommodation
– Blurred vision
Rare (<1% incidence)[1][2][23][22][8]

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood-brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%[24]) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2receptors including those in the anterior pituitary.[25][26]

  • Somnolence. It produces minimal sedation due to its absence of cholinergic, histaminergic and alpha adrenergic receptor antagonism. It is one of the least sedating antipsychotics.[9]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[27] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[28] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[28] Less commonly there may be a felling of the world spinning, numbness, or muscle pains.[28] Symptoms generally resolve after a short period of time.[28]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[29] It may also result in reoccurrence of the condition that is being treated.[30] Rarely tardive dyskinesia can occur when the medication is stopped.[28]

Overdose

Torsades de pointes is common in overdose.[31][32] Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).[33][34]

Interactions

Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopramvenlafaxinebupropionclozapinetricyclic antidepressantssertindoleziprasidone, etc.),[33] reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.[33]

Pharmacology

Pharmacodynamics

Amisulpride and its relatives sulpiridelevosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).[37]Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constantsof 3.0 and 3.5 nM, respectively.[36] Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.[2]

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).[39]

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychoticproperties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM).[36] Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice.[36] The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride.[36] These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.[36]

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist.[36] The clinical implications of this, if any, are unclear.[36] In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.[36]

Society and culture

Brand names

Brand names include: Amazeo, Amipride (AU), Amival, Solian (AUIERUUKZA), Soltus, Sulpitac (IN), Sulprix (AU), Midora (RO) and Socian (BR).[40][41]

Availability

Amisulpride was not approved by the Food and Drug Administration for use in the United States until February 2020, but it is used in Europe,[41]Israel, Mexico, India, New Zealand and Australia[2] to treat psychosis and schizophrenia.[42][43]

Amisulpride was approved for use in the United States in February 2020.[44][6]

CLIP

Dopamine receptor antagonist. Prepn: M. Thominet et al., BE 872585; eidem, U.S. Patent 4,401,822 (1979, 1983 both to Soc. d’Etudes Sci. Ind. de l’Ile-de-France).

CLIP

4-Amino-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-(ethylsulfonyl)-o-anisamide, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, the acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid affords 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone producing methyl 2-methoxy-5-acetaminobenzoate (III). Secondly, nitration of (III) with HNOin acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). Next, the diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI), which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) in the presence of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII). At last, this compound is reduced with H2 over Raney-Ni in ethanol.

Production Route of Amisulpride

CLIP

BE 0872585; ES 476755; FR 2415099; GB 2083458; JP 54145658; US 4294828; US 4401822

Alkylation of 2-methoxy-4-amino-5-mercaptobenzoic acid (X) with diethyl sulfate acid Na2CO3 gives 2-methoxy-4-amino-5-ethylthiobenzoic acid (XI), which is oxidized with H2O2 in acetic acid yielding 2-methoxy-4-amino-5-(ethylsulfonyl)benzoic acid (XII). Finally, this compound is condensed with (VII) by means of ethyl chloroformate.

CLIP

FR 2460930

Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III). Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). The diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI), which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) by means of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII). Finally, this compound is reduced with H2 over Raney-Ni in ethanol.

CLIP

Treatment of thiourea (I) with iodomethane provided S-methylthiouronium iodide (II). This was further condensed with N-methylpiperazine (III) to afford the intermediate piperazine-1-carboxamidine (IV)

CLIP

Regioselective lithiation of 1,2,4-trichlorobenzene (V) with n-BuLi at -60 C, followed by quenching of the resultant organolithium compound (VI) with N,N-dimethylformamide yielded 2,3,5-trichlorobenzaldehyde (VII) (1), which was then reduced with NaBH4 to provide alcohol (VIII). Bromination of (VIII) using PBr3 afforded compound (IX), whose bromide atom was displaced with KCN to give the trichlorophenylacetonitrile (X). Claisen condensation of (X) with ethyl formate in the presence of NaOEt furnished the oxo nitrile sodium enolate (XI), which was subsequently O-alkylated with iodomethane yielding the methoxy acrylonitrile (XII). Finally, cyclization of (XII) with the piperazine-1-carboxamidine (IV) in EtOH gave rise to the target pyrimidine derivative

PATENT

https://patents.google.com/patent/US20130096319A1/en

Amisulpride is represented by the formula (I) as given below.

Figure US20130096319A1-20130418-C00001

The product patent U.S. Pat. No. 4,401,822 describes preparation of amisulpride as shown in scheme (I)

Figure US20130096319A1-20130418-C00002

The synthesis of amisulpride involves oxidation of 2-methoxy-4-amino-5-ethyl-thio benzoic acid (III) using acetic acid and hydrogen peroxide at 40-45° C. for few hours to obtain 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV). In our attempt to repeat this reaction, we found that almost 22 hours were required for completion and the purity of compound (IV) was 87.6%.

    • [0006]
      Thus, the product patent method suffers from the disadvantages such as high reaction time, low yield and low purity.
    • [0007]
      Liu Lie et al, Jingxi Huagong Zhongjianti 2008, 38 (3), 29-32 describes the process for the preparation of 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) as shown in scheme (II).
    • Figure US20130096319A1-20130418-C00003
    • [0008]
      4-amino salicylic acid (VI) is treated with dimethyl sulphate in the presence of potassium hydroxide and acetone to give 4-amino-2-methoxy-methyl benzoate in 4 hours, which is further treated with potassium thiocynate to give compound of formula (VIII). 4-Amino-2-,methoxy-5-thiocyanatobenzoate (VIII) is treated with bromoethane to give 4-amino-5-ethylthio-2-methoxy benzoic acid (IX) which is further converted to 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) via oxidation with hydrogen peroxide and acetic acid.
    • [0009]
      The yield of conversion of compound (VIII) to compound (IX) is 57% and the overall yield of compound (IV) from compound (VI) is 24% only. Thus, the above process suffers from the disadvantages such as low yield and in that it uses bromoethane which is skin and eye irritant and has carcinogenic effects.
    • [0010]
      Therefore, there is, an unfulfilled need to provide industrially feasible process for the preparation of 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) and amisulpride (I) with higher purity and yield, since it is one of the key intermediates in the manufacture of amisulpride.

SUMMARY OF THE INVENTION

The present invention is related to a novel process for the preparation of amisulpride (I) that involves: (i) methylation of 4-amino-salicylic-acid (VI) with dimethyl sulphate and base, optionally in presence of TBAB to obtain 4-amino-2-methoxy methyl benzoate (VII) and (ii) oxidation of 4-amino-2-methoxy-5-ethyl thio benzoic acid (IX) or 4-amino-2-methoxy-5-ethyl thio methyl benzoate (X) with oxidizing agent in the presence of sodium tungstate or ammonium molybdate to give 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid (IV) or 2-methoxy-4-amino-5-ethyl-sulfonyl methyl benzoate (XI) respectively.
    • Example 13

    • [0097]
      Preparation of crude amisulpride
    • [0098]
      To a stirring mixture of 4-amino-2-methoxy-5-ethyl sulphonyl benzoic acid (IV) and acetone (5.0 L) at 0-5° C., triethyl amine (0.405 Kg) was added and stirred followed by addition of ethyl chloroformate (0.368 Kg). N-ethyl-2-amino methyl pyrrolidine (0.627 Kg) was added to the reaction mass at 5-10° C. Temperature of reaction mass was raised to 25-30° C. and stirred for 120 min. To the same reaction mass triethyl amine (0.405 Kg) and ethyl chloroformate (0.368 Kg) was added with maintaining the temperature. Reaction mass was stirred for 120 min. After completion of reaction, water (4.0 L) was added. Reaction mass was filtered and washed with water (2.0 L). Filtrate was collected and water was added (9.0 L). pH of the reaction mass was adjusted to 10.8-11.2 by using 20% NaOH solution. Reaction mass was stirred for 240-300 min, filtered and washed with water. Solid was dried under vacuum
    • [0099]
      Yield : 70%
    • [0100]
      Purity: 98%

Example 14

  • [0101]
    Purification of amisulpride
  • [0102]
    Amisulpride (1 kg) was charged in acetone (6 liters) and the reaction mixture was heated till a clear solution was obtained. Slurry of activated carbon (0.1 kg in 1 liter) was added in acetone. The reaction mass was stirred at 50-55 ° C. for 60 minutes and filtered hot. The filtrate was concentrated and further heated to dissolve the solid. The reaction mass was cooled to 0-5° C., stirred and filtered. The precipitated solid was washed with acetone and dried.
  • [0103]
    Yield: 750 gm (75%)
  • [0104]
    HPLC purity: 99.8% (quantitative)
  • [0105]
    M.P.: 125° C.
  • [0106]
    DSC: shows endotherm at 133° C.
  • [0107]
    Particle size: d10=0.637, d50=6.0, d90=13.325 microns

CLIP

https://watermark.silverchair.com/bmw186.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAmEwggJdBgkqhkiG9w0BBwagggJOMIICSgIBADCCAkMGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQM_rfBl_qrJE7Y7K67AgEQgIICFOQ9ug62uUxOD4oCuuUGlGD3N04qUgCHew1O5UIyknvohf-_QUaJclqSZM6k5UhPTLgjkYyVMVgS04HMcDKUVXr1cMUfV6cExwayFb8z3MQUF4Ny6s8hPuAMJO4XsTm4qh0nnEykHwgMonNWdDr32D4B7NuEVwGE_5Z-d1yQvAdkNeCmEbHIaue3OTiocWodCsAv8yUdnXf1AtreXJkvsiAQtk4oCddsM_a2njiXJAc-VcFgTImCvsaCY-_eWT91Dc3gb7fpEAJSPLl06xx30GziAvF_hl5P33TaMFmVm_p-0rJGWi-_x92Tlo1CkuR1N1oWlcnuBSPqKeX3tbMO3phnIYtbDPycftd6UKI2f9-zyMRHgSId4xJCpaxvy6fndrWZ1qrHTyQLt_XqncL7zD8aYHER67kV3g30ZgAtcivHoMSHj9h4wGD5WLZ5-M4cZ0dpUyKx3E2njYBEBe0LNQyqDmP8HKpM_RBN2C2nuD2h1fJkiwf2kLAdlBC6gOhjl60XqU_7ARJZf_86kR3OhUJ5f8Ey2R-k3zwDHEc3tU10AlEky9ne-UWVHGjOCd9L-SV-eXfjOnaERGw9EHahxajGBCRuqa07-BtbV0mr53AKyaS5YUTQ2EZ7P3WarhImsJpYiQxWAuSlYn2F11RTMu_KjP7-DMXbX6pcq20axI2NNwrBtfsDXFbQWZ8q9R0FYGsUS90

References

  1. Jump up to:a b c d “Amisulpride 100 mg Tablets – Summary of Product Characteristics (SmPC)”(emc). 5 July 2019. Retrieved 26 February 2020.
  2. Jump up to:a b c d e f g h i j k “Solian tablets and solution product information” (PDF)TGA eBusiness Services. Sanofi-Aventis Australia Pty Ltd. 27 September 2019. Retrieved 26 February2020.
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External links

Amisulpride
Amisulpride.svg
Amisulpride-xtal-1990-ball-and-stick-model.png
Clinical data
Trade names Solian, Barhemsys, others
Other names APD421
AHFS/Drugs.com International Drug Names
License data
Pregnancy
category
  • AU: C
Routes of
administration
By mouthintravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 48%[3][2]
Protein binding 16%[2]
Metabolism Hepatic (minimal; most excreted unchanged)[2]
Elimination half-life 12 hours[3]
Excretion Renal[3] (23–46%),[4][5]Faecal[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.068.916 Edit this at Wikidata
Chemical and physical data
Formula C17H27N3O4S
Molar mass 369.48 g/mol g·mol−1
3D model (JSmol)

  1. Rosenzweig P, Canal M, Patat A, Bergougnan L, Zieleniuk I, Bianchetti G: A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol. 2002 Jan;17(1):1-13. [PubMed:12404702]
  2. Moller HJ: Amisulpride: limbic specificity and the mechanism of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Oct;27(7):1101-11. [PubMed:14642970]
  3. Weizman T, Pick CG, Backer MM, Rigai T, Bloch M, Schreiber S: The antinociceptive effect of amisulpride in mice is mediated through opioid mechanisms. Eur J Pharmacol. 2003 Oct 8;478(2-3):155-9. [PubMed:14575800]
  4. Leucht S, Pitschel-Walz G, Engel RR, Kissling W: Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am J Psychiatry. 2002 Feb;159(2):180-90. [PubMed:11823257]
  5. Rehni AK, Singh TG, Chand P: Amisulpride-induced seizurogenic effect: a potential role of opioid receptor-linked transduction systems. Basic Clin Pharmacol Toxicol. 2011 May;108(5):310-7. doi: 10.1111/j.1742-7843.2010.00655.x. Epub 2010 Dec 22. [PubMed:21176108]

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Non-Patent

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///////////////Amisulpride, アミスルプリド , 标准品 , FDA 2020, 2020 APPROVALS, Barhemsys, SOLIAN,  Antipsychotic, Benzamides,  Dopamine Receptor Antagonist,

CCN1CCCC1CNC(=O)C1=CC(=C(N)C=C1OC)S(=O)(=O)CC

Delgocitinib


Image result for japan animated flag

Delgocitinib.png

2D chemical structure of 1263774-59-9

img

Delgocitinib

デルゴシチニブ

3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile

1,6-Diazaspiro(3.4)octane-1-propanenitrile, 3-methyl-beta-oxo-6-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)-, (3S,4R)-

3-((3S,4R)-3-methyl-6-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)-1,6-diazaspiro(3.4)octan-1-yl)-3-oxopropanenitrile

Formula
C16H18N6O
CAS
1263774-59-9
Mol weight
310.3537

Approved, Japan 2020, Corectim, 2020/1/23, atopic dermatitis, Japan Tobacco (JT)
Torii

UNII-9L0Q8KK220, JTE-052, LP-0133, ROH-201, 9L0Q8KK220, LEO 124249ALEO 124249HY-109053

CS-0031558D11046GTPL9619JTE-052AJTE052

Image result for Corectim

Delgocitinib, also known as LEO-124249 and JTE052, is a potent and selective JAK inhibitor. JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation.

Delgocitinib is a JAK inhibitor first approved in Japan for the treatment of atopic dermatitis in patients 16 years of age or older. Japan Tobacco is conducting phase III clinical trials for the treatment of atopic dermatitis in pediatric patients. Leo is developing the drug in phase II clinical trials for the treatment of inflammatory skin diseases, such as atopic dermatitis, and chronic hand eczema and for the treatment of discoid lupus erythematosus. Rohto is evaluating the product in early clinical development for ophthalmologic indications.

In 2014, the drug was licensed to Leo by Japan Tobacco for the development, registration and marketing worldwide excluding Japan for treatment of inflammatory skin conditions. In 2016, Japan Tobacco licensed the rights of co-development and commercialization in Japan to Torii. In 2018, Japan Tobacco licensed the Japanese rights of development and commercialization to Rohto for the treatment of ophthalmologic diseases.

PATENTS

WO 2018117151
IN 201917029002

IN 201917029003

IN 201917029000

PATENTS

WO 2011013785

https://patents.google.com/patent/WO2011013785A1/en

[Production Example 6]: Synthesis of Compound 6

Figure JPOXMLDOC01-appb-C000103

(1) Optically active substance of 2-benzylaminopropan-1-ol

Figure JPOXMLDOC01-appb-C000104

To a solution of (S)-(+)-2-aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) in ethanol (500 ml) was added 5% palladium carbon (5.0 g) at room temperature and normal pressure. Hydrogenated for 8 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (111.2 g). 
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.27 (4H, m), 7.23-7.18 (1H, m), 4.53-4.47 (1H, m), 3.76 (1H, d, J = 13.5 Hz) , 3.66 (1H, d, J = 13.5 Hz), 3.29-3.24 (2H, m), 2.65-2.55 (1H, m), 1.99 (1H, br s), 0.93 (3H, d, J = 6.4 Hz) .

(2) Optically active substance of [benzyl- (2-hydroxy-1-methylethyl) -amino] acetic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000105

To a mixture of optically active 2-benzylaminopropan-1-ol (111.2 g), potassium carbonate (111.6 g) and N, N-dimethylformamide (556 ml) cooled to 0 ° C., tert-butyl bromoacetate was added. Ester (109 ml) was added dropwise over 20 minutes and stirred at room temperature for 19.5 hours. The mixture was acidified to pH 2 by adding 2M aqueous hydrochloric acid and 6M aqueous hydrochloric acid, and washed with toluene (1000 ml). The separated organic layer was extracted with 0.1 M aqueous hydrochloric acid (300 ml). The combined aqueous layer was adjusted to pH 10 with 4M aqueous sodium hydroxide solution and extracted with ethyl acetate (700 ml). The organic layer was washed successively with water (900 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted again with ethyl acetate (400 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (160.0 g). 
1 H-NMR (DMSO-D 6 ) δ: 7.37-7.26 (4H, m), 7.24-7.19 (1H, m), 4.26 (1H, dd, J = 6.9, 3.9 Hz), 3.76 (1H, d, J = 14.1 Hz), 3.68 (1H, d, J = 13.9 Hz), 3.45-3.39 (1H, m), 3.29-3.20 (1H, m), 3.24 (1H, d, J = 17.2 Hz), 3.13 ( 1H, d, J = 17.0 Hz), 2.84-2.74 (1H, m), 1.37 (9H, s), 0.96 (3H, d, J = 6.8 Hz).

(3) Optically active substance of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000106

(3)-(1) Optically active form of [benzyl- (2-chloro-1-methylethyl) -amino] acetic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000107

To a solution of [benzyl- (2-hydroxy-1-methylethyl) -amino] acetic acid tert-butyl ester optically active substance (160.0 g) cooled to 0 ° C. in chloroform (640 ml) was added thionyl chloride (50.0 ml). Was added dropwise and stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (1000 ml) and chloroform (100 ml) were added and stirred. The separated organic layer was washed with a saturated aqueous sodium chloride solution (500 ml), and the aqueous layer was extracted again with chloroform (450 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (172.9 g). 
1 H-NMR (CDCl 3 ) δ: 7.40-7.22 (5H, m), 4.05-3.97 (0.4H, m), 3.93-3.81 (2H, m), 3.70-3.65 (0.6H, m), 3.44- 3.38 (0.6H, m), 3.29 (0.8H, s), 3.27 (1.2H, d, J = 2.4 Hz), 3.24-3.15 (0.6H, m), 3.05-2.99 (0.4H, m), 2.94 -2.88 (0.4H, m), 1.50 (1.2H, d, J = 6.4 Hz), 1.48 (3.6H, s), 1.45 (5.4H, s), 1.23 (1.8H, d, J = 6.8 Hz) .

(3)-(2) Optically active form of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000108

[Benzyl- (2-chloro-1-methylethyl) -amino] acetic acid tert-butyl ester optically active substance (172.9 g) was dissolved in N, N-dimethylformamide (520 ml) and stirred at 80 ° C. for 140 minutes. did. The reaction mixture was cooled to 0 ° C., water (1200 ml) was added, and the mixture was extracted with n-hexane / ethyl acetate (2/1, 1000 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted again with n-hexane / ethyl acetate (2/1, 600 ml). The combined organic layers were concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50/1 to 40/1) to give the title compound (127.0 g ) 
1 H-NMR (CDCl 3 ) δ: 7.37-7.29 (4H, m), 7.28-7.23 (1H, m), 4.05-3.97 (1H, m), 3.91 (1H, d, J = 13.5 Hz), 3.86 (1H, d, J = 13.7 Hz), 3.29 (2H, s), 3.03 (1H, dd, J = 13.9, 6.6 Hz), 2.91 (1H, dd, J = 13.9, 6.8 Hz), 1.50 (3H, d, J = 6.4 Hz), 1.48 (9H, s).

(4) Optically active substance of 1-benzyl-3-methylazetidine-2-carboxylic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000109

To a solution of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester optically active substance (60.0 g) cooled to −72 ° C. and hexamethylphosphoramide (36.0 ml) in tetrahydrofuran (360 ml), Lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 242 ml) was added dropwise over 18 minutes, and the temperature was raised to 0 ° C. over 80 minutes. A saturated aqueous ammonium chloride solution (300 ml) and water (400 ml) were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (500 ml), and the separated aqueous layer was extracted again with ethyl acetate (300 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50/1 to 4/1). To give the title compound (50.9 g). 
1 H-NMR (CDCl 3 ) δ: 7.34-7.21 (5H, m), 3.75 (1H, d, J = 12.6 Hz), 3.70-3.67 (1H, m), 3.58 (1H, d, J = 12.6 Hz ), 3.05-3.01 (1H, m), 2.99-2.95 (1H, m), 2.70-2.59 (1H, m), 1.41 (9H, s), 1.24 (3H, d, J = 7.1 Hz).

(5) Optically active substance of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester

Figure JPOXMLDOC01-appb-C000110

1-Benzyl-3-methylazetidine-2-carboxylic acid tert-butyl ester optically active substance (43.5 g) and di-tert-butyl dicarbonate (38.2 g) in tetrahydrofuran / methanol (130 ml / 130 ml) solution 20% Palladium hydroxide carbon (3.5 g) was added thereto, and hydrogenated at 4 atm for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (48.0 g). 
1 H-NMR (DMSO-D 6 ) δ: 4.44 (1H, d, J = 8.8 Hz), 3.99-3.77 (1H, m), 3.45-3.37 (1H, m), 3.00-2.88 (1H, m) , 1.45 (9H, s), 1.40-1.30 (9H, m), 1.02 (3H, d, J = 7.2 Hz).

(6) Optically active substance of 3-methyl-2- (3-methyl-but-2-enyl) -azetidine-1,2-dicarboxylic acid di-tert-butyl ester

Figure JPOXMLDOC01-appb-C000111

Optically active substance (48.0 g) of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester cooled to -69 ° C. and 1-bromo-3-methyl-2-butene (25.4 ml) Lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 200 ml) was added to a tetrahydrofuran solution (380 ml). The reaction mixture was warmed to −20 ° C. in 40 minutes and further stirred at the same temperature for 20 minutes. A saturated aqueous ammonium chloride solution (200 ml) and water (300 ml) were successively added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1,500 ml). The separated organic layer was washed successively with water (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 15/1 to 8/1) to give the titled compound (44.5 g). 
1 H-NMR (CDCl 3 ) δ: 5.29-5.21 (1H, m), 3.77-3.72 (1H, m), 3.49-3.44 (1H, m), 2.73-2.52 (3H, m), 1.76-1.74 ( 3H, m), 1.66-1.65 (3H, m), 1.51 (9H, s), 1.43 (9H, s), 1.05 (3H, d, J = 7.3 Hz).

(7) Optically active substance of 3-methyl-2- (2-oxoethyl) azetidine-1,2-dicarboxylic acid di-tert-butyl ester

Figure JPOXMLDOC01-appb-C000112

3-methyl-2- (3-methyl-but-2-enyl) -azetidine-1,2-dicarboxylic acid di-tert-butyl ester optically active substance (44.5 g) in chloroform / cooled to −70 ° C. An ozone stream was passed through the methanol solution (310 ml / 310 ml) for 1 hour. To this reaction mixture, a solution of triphenylphosphine (44.7 g) in chloroform (45 ml) was added little by little, and then the mixture was warmed to room temperature. To this mixture were added saturated aqueous sodium thiosulfate solution (200 ml) and water (300 ml), and the mixture was extracted with chloroform (500 ml). The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (95.0 g). This product was subjected to the next step without further purification. 
1 H-NMR (DMSO-D 6 ) δ: 9.65 (1H, t, J = 2.6 Hz), 3.79-3.74 (1H, m), 3.45-3.40 (1H, m), 2.99-2.80 (3H, m) , 1.46 (9H, s), 1.34 (9H, s), 1.06 (3H, d, J = 7.2 Hz).

(8) Optically active substance of 2- (2-benzylaminoethyl) -3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester

Figure JPOXMLDOC01-appb-C000113

To a solution of the residue (95.0 g) obtained in (7) in tetrahydrofuran (300 ml) was added benzylamine (34 ml) at room temperature, and the mixture was stirred for 2 hours. The mixture was cooled to 0 ° C., sodium triacetoxyborohydride (83.3 g) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (300 ml) was added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1/3, 600 ml). The separated organic layer was washed with water (300 ml) and saturated aqueous sodium chloride solution (200 ml), and then extracted twice with 5% aqueous citric acid solution (300 ml, 200 ml) and three times with 10% aqueous citric acid solution (250 ml × 3). . The combined aqueous layers were basified to pH 10 with 4M aqueous sodium hydroxide solution and extracted with chloroform (300 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (46.9 g). 
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.26 (4H, m), 7.22-7.17 (1H, m), 3.74-3.65 (2H, m), 3.61 (1H, t, J = 7.8 Hz) , 3.28 (1H, t, J = 7.5 Hz), 2.76-2.66 (2H, m), 2.57-2.45 (1H, m), 2.15 (1H, br s), 2.05-1.89 (2H, m), 1.42 ( 9H, s), 1.27 (9H, s), 0.96 (3H, d, J = 7.1 Hz).

(9) Optically active substance of 2- (2-benzylaminoethyl) -3-methylazetidine-2-dicarboxylic acid dihydrochloride

Figure JPOXMLDOC01-appb-C000114

2- (2-Benzylaminoethyl) -3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester optically active substance (46.5 g), 4M hydrochloric acid 1,4-dioxane (230 ml) and water (4.1 ml) was mixed and stirred at 80 ° C. for 2 hours. The mixture was concentrated under reduced pressure, azeotroped with toluene, and then slurry washed with n-hexane / ethyl acetate (1/1, 440 ml) to give the title compound (30.1 g). 
1 H-NMR (DMSO-D 6 ) δ: 10.24 (1H, br s), 9.64 (2H, br s), 8.90 (1H, br s), 7.58-7.53 (2H, m), 7.47-7.41 (3H , m), 4.21-4.10 (2H, m), 4.02-3.94 (1H, m), 3.46-3.37 (1H, m), 3.20-3.10 (1H, m), 2.99-2.85 (2H, m), 2.69 -2.54 (2H, m), 1.10 (3H, d, J = 7.2 Hz).

(10) Optically active substance of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octan-5-one

Figure JPOXMLDOC01-appb-C000115

To a solution of 2- (2-benzylaminoethyl) -3-methylazetidine-2-dicarboxylic acid dihydrochloride optically active substance (29.1 g) and N, N-diisopropylethylamine (65 ml) in chloroform (290 ml), At room temperature, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (41.3 g) was added and stirred for 4 hours. To this reaction mixture were added saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (100 ml), and the mixture was extracted with chloroform (200 ml). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 to 10/1) to give the titled compound (21.3 g). 
1 H-NMR (DMSO-D 6 ) δ: 7.38-7.31 (2H, m), 7.30-7.22 (3H, m), 4.52 (1H, d, J = 14.8 Hz), 4.29 (1H, d, J = 14.8 Hz), 3.35-3.27 (2H, m), 3.22-3.17 (1H, m), 3.05 (2H, dd, J = 9.5, 4.0 Hz), 2.77-2.66 (1H, m), 2.16-2.10 (1H , m), 1.96-1.87 (1H, m), 0.94 (3H, d, J = 7.1 Hz).

(11) Optically active substance of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000116

Concentrated sulfuric acid (4.8 ml) was slowly added dropwise to a suspension of lithium aluminum hydride (6.8 g) in tetrahydrofuran (300 ml) under ice cooling, and the mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octan-5-one optically active substance (21.3 g) in tetrahydrofuran (100 ml) at the same temperature. Stir for 45 minutes. Water (7.0 ml), 4M aqueous sodium hydroxide solution (7.0 ml) and water (14.0 ml) were sequentially added to the reaction mixture, and the mixture was stirred as it was for 30 minutes. To this mixture was added anhydrous magnesium sulfate and ethyl acetate (100 ml), and the mixture was stirred and filtered through celite. Di-tert-butyl dicarbonate (23.4 g) was added to the filtrate at room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure to a half volume and washed twice with a saturated aqueous ammonium chloride solution (200 ml × 2). N-Hexane (200 ml) was added to the separated organic layer, and the mixture was extracted 5 times with a 10% aqueous citric acid solution. The separated aqueous layer was basified with 4M aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1 to 20/1) to give the titled compound (15.6 g). 
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.27 (4H, m), 7.26-7.21 (1H, m), 3.84-3.69 (1H, m), 3.62-3.47 (2H, m), 3.19- 3.05 (1H, m), 3.02-2.92 (1H, m), 2.76-2.69 (1H, m), 2.47-2.24 (4H, m), 1.95-1.77 (1H, m), 1.36 (9H, s), 1.03 (3H, d, J = 7.0 Hz).

(12) Optically active substance of 3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester

Figure JPOXMLDOC01-appb-C000117

20% of optically active form of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester (10.0 g) in tetrahydrofuran / methanol (50 ml / 50 ml) solution Palladium hydroxide on carbon (2.0 g) was added and hydrogenated at 4 atm for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (7.3 g). 
1 H-NMR (DMSO-D 6 ) δ: 3.88-3.71 (1H, m), 3.44-3.06 (2H, m), 3.02-2.64 (4H, m), 2.55-2.38 (1H, m), 2.31- 2.15 (1H, m), 1.81-1.72 (1H, m), 1.37 (9H, s), 1.07 (3H, d, J = 7.0 Hz).

(13) Optical activity of 3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester body

Figure JPOXMLDOC01-appb-C000118

The optically active substance (6.9 g) of 3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester was converted into 4-chloro-7H-pyrrolo [2,3-d] pyrimidine ( 4.3 g), potassium carbonate (7.7 g) and water (65 ml) and stirred for 4 hours at reflux. The mixture was cooled to room temperature, water (60 ml) was added, and the mixture was extracted with chloroform / methanol (10/1, 120 ml). The organic layer was washed successively with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. To this mixture, silica gel (4 g) was added, stirred for 10 minutes, filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethyl acetate = 1/1, then chloroform / methanol = 50/1 to 20/1) to give the title compound (10.0 g). Obtained. 
1 H-NMR (DMSO-D 6 ) δ: 11.59 (1H, br s), 8.09 (1H, s), 7.12-7.09 (1H, m), 6.64-6.59 (1H, m), 4.09-3.66 (5H , m), 3.39-3.21 (1H, m), 2.64-2.44 (2H, m), 2.27-2.06 (1H, m), 1.36 (3H, s), 1.21 (6H, s), 1.11 (3H, d , J = 6.5 Hz).

(14) Optically active form of 4- (3-methyl-1,6-diazaspiro [3.4] oct-6-yl) -7H-pyrrolo [2,3-d] pyrimidine dihydrochloride

Figure JPOXMLDOC01-appb-C000119

Optically active form of 3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester (9 0.5 g), 4M hydrochloric acid 1,4-dioxane (50 ml), chloroform (50 ml) and methanol (100 ml) were mixed and stirred at 60 ° C. for 30 minutes. The mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (9.3 g). 
1 H-NMR (DMSO-D 6 ) δ: 12.91 (1H, br s), 9.97-9.64 (2H, m), 8.45-8.35 (1H, m), 7.58-7.47 (1H, m), 7.04-6.92 (1H, m), 4.99-4.65 (1H, m), 4.32-3.21 (7H, m), 3.04-2.90 (1H, m), 2.46-2.31 (1H, m), 1.27 (3H, d, J = 6.0 Hz).

(15) 3- [3-Methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] oct-1-yl] -3-oxo Optically active form of propionitrile

Figure JPOXMLDOC01-appb-C000120

4- (3-Methyl-1,6-diazaspiro [3.4] oct-6-yl) -7H-pyrrolo [2,3-d] pyrimidine dihydrochloride optically active substance (8.8 g) was converted to 1- The mixture was mixed with cyanoacetyl-3,5-dimethylpyrazole (6.8 g), N, N-diisopropylethylamine (20 ml) and 1,4-dioxane (100 ml) and stirred at 100 ° C. for 1 hour. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol (10/1). The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 30/1 to 9/1). The residue obtained by concentration under reduced pressure was slurry washed with n-heptane / ethanol (2/1, 90 ml) to obtain a solid (7.3 g). The solid was slurried again with n-heptane / ethanol (5/1, 90 ml) to give the title compound as crystals 1 (6.1 g). 
1 H-NMR (DMSO-D 6 ) δ: 11.60 (1H, br s), 8.08 (1H, s), 7.11 (1H, dd, J = 3.5, 2.4 Hz), 6.58 (1H, dd, J = 3.4 , 1.9 Hz), 4.18-4.14 (1H, m), 4.09-3.93 (3H, m), 3.84-3.73 (1H, m), 3.71 (1H, d, J = 19.0 Hz), 3.66 (1H, d, J = 18.7 Hz), 3.58 (1H, dd, J = 8.2, 6.0 Hz), 2.70-2.58 (2H, m), 2.24-2.12 (1H, m), 1.12 (3H, d, J = 7.1 Hz). 
[Α] D = + 47.09 ° (25 ° C., c = 0.55, methanol)

1-Butanol (39 ml) was added to the obtained crystal 1 (2.6 g), and the mixture was heated and stirred at 100 ° C. After complete dissolution, the solution was cooled to room temperature by 10 ° C. every 30 minutes and further stirred at room temperature overnight. The produced crystals were collected by filtration, washed with 1-butanol (6.2 ml), and dried under reduced pressure to give crystals 2 (2.1 g) of the title compound.

PATENTS

WO 2017006968

WO 2018117152

WO 2018117151

PATENT

WO 2018117153

https://patentscope.wipo.int/search/zh/detail.jsf?docId=WO2018117153&tab=FULLTEXT

Janus kinase (JAK) inhibitors are of current interest for the treatment of various diseases including autoimmune diseases, inflammatory diseases, and cancer. To date, two JAK inhibitors have been approved by the U.S. Food & Drug Administration (FDA). Ruxolitinib has been approved for the treatment of primary myelofibrosis and polycythemia vera (PV), and tofacitinib has been approved for the treatment of rheumatoid arthritis. Other JAK inhibitors are in the literature. The compound 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile (Compound A) (see structure below) is an example of a spirocyclic JAK inhibitor reported in U.S. Pat. Pub. Nos. 2011/0136778 and International Pat. Pub. No. PCT/JP2016/070046.
[Chem. 1]

Step A. Preparation of S-MABB-HC (Compound [5])
[Chem. 2]

Step 1
[Chem. 3]
S-BAPO [1] (35.0 g, 212 mmol) was added to water (175 mL) at room temperature under nitrogen atmosphere. To the resulting suspension were added toluene (53 mL) and potassium carbonate (32.2 g, 233 mmol) at room temperature. To the resulting solution was added dropwise TBBA (434.4 g, 223 mmol) at room temperature, and then the used dropping funnel was washed with toluene (17 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at 65°C for 21 hours, and then cooled to room temperature. After toluene (105 mL) was added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The organic layer was washed with water (175 mL), aqueous layer was removed, and then the solvent was removed out of the organic layer in vacuo. Toluene (105 mL) was added to the residue and the toluene solution was concentrated. The operation was repeated two more times to give a toluene solution of S-BBMO [2] (74.0 g, 212 mmol in theory). The given toluene solution of S-BBMO was used in the next step, assuming that the yield was 100 %.
A crude product of S-BBMO which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.36-7.13 (5H, m), 4.26 (1H, dd, J = 6.8, 3.9 Hz), 3.72 (2H, dd, J = 14.2, 6.8 Hz), 3.47-3.38 (1H, m), 3.30-3.08 (3H, m), 2.79 (1H, sext, J = 6.8 Hz), 1.35 (9H, s), 0.96 (3H, d, J = 6.8 Hz).
MS: m/z = 280 [M+H] +

[0134]
Step 2
[Chem. 4]
To the toluene solution of S-BBMO [2] (74.0 g, 212 mmol) were added toluene (200 mL), tetrahydrofuran (35 mL), and then triethylamine (25.7 g, 254 mmol) at room temperature under nitrogen atmosphere. To the mixture was added dropwise methanesulfonyl chloride (26.7 g, 233 mmol) at 0°C, and then the used dropping funnel was washed with toluene (10 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours and further at 65°C for 22 hours, and then cooled to room temperature. After sodium bicarbonate water (105 mL) was added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The organic layer was washed with water (105 mL), aqueous layer was removed, and then the solvent was removed out of the organic layer in vacuo. Toluene (105 mL) was added to the residue, and the toluene solution was concentrated. The operation was repeated two more times to give a toluene solution of R-BCAB [3] (75.3 g, 212 mmol in theory). The given toluene solution of R-BCAB was used in the next step, assuming that the yield was 100 %.
A crude product of R-BCAB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.28-7.11 (5H, m), 4.24-4.11 (1H, m), 3.80 (2H, d, J = 3.6 Hz), 3.24 (2H, d, J = 3.6 Hz), 2.98-2.78 (2H, m), 1.46-1.37 (12H, m).
MS: m/z = 298 [M+H] +

[0135]
Step 3
[Chem. 5]
To the toluene solution of R-BCAB [3] (75.3 g, 212 mmol) were added tetrahydrofuran (88.0 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (42.0 mL) at room temperature under nitrogen atmosphere. To the resulting solution was added dropwise a solution of lithium bis(trimethylsilyl)amide /tetrahydrofuran (195 mL, 233 mmol) at 0°C, and then the used dropping funnel was washed with tetrahydrofuran (17.0 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour, and then warmed to room temperature. After water (175 mL) and toluene (175 mL) were added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The resulting organic layer was washed with aqueous ammonium chloride (175 mL) and then water (175 mL), and the solvent was removed out of the organic layer in vacuo. Ethyl acetate (175 mL) was added to the residue and the ethyl acetate solution was concentrated. The operation was repeated two more times to give an ethyl acetate solution of S-MABB [4] (66.5 g, 212 mmol in theory). The given ethyl acetate solution of S-MABB was used in the next step, assuming that the yield was 100 %.
A crude product of S-MABB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.28-7.25 (10H, m), 3.75 (1H, d, J = 12.7 Hz), 3.68 (1H, d, J = 1.4 Hz), 3.66 (1H, d, J = 6.7 Hz), 3.46 (2H, d, J = 12.7 Hz), 3.30-3.17 (2H, m), 2.95 (1H, dd, J = 6.2, 1.2 Hz), 2.77 (1H, dd, J = 6.1, 2.2 Hz), 2.65-2.55 (1H, m), 2.48-2.40 (2H, m), 1.35 (9H, s), 1.35 (9H, s), 1.12 (3H, d, J = 7.2 Hz), 1.09 (3H, d, J = 6.2 Hz).
MS: m/z = 262 [M+H] +

[0136]
Step 4
[Chem. 6]
To the ethyl acetate solution of S-MABB [4] (66.5 g, 212 mmol in theory) were added ethyl acetate (175 mL) and active carbon (3.5 g) under nitrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. The active carbon was removed by filtration, and the residue on the filter was washed with ethyl acetate (175 mL). The washings were added to the filtrate. To the solution was added S-MABB-HC crystal (17.5 mg) that was prepared according to the method described herein at 0°C, and then 4 M hydrogen chloride/ethyl acetate (53.0 mL, 212 mmol) was dropped thereto at 0°C. The reaction mixture was stirred at 0°C for 17 hours, and then the precipitated solid was collected on a filter, and washed with ethyl acetate (70 mL). The resulting wet solid was dried in vacuo to give S-MABB-HC [5] (48.3 g, 162 mmol, yield: 76.4 %).
S-MABB-HC which was prepared by the same process was measured about NMR, MS, and Cl-content.
1H-NMR (DMSO-d 6) δ: 11.08 (1H, br s), 10.94 (1H, br s), 7.52-7.42 (10H, m), 5.34 (1H, t, J = 8.4 Hz), 4.90 (1H, br s), 4.45-4.10 (5H, m), 3.92-3.49 (3H, br m), 3.10-2.73 (2H, br m), 1.35 (9H, s), 1.29 (9H, s), 1.24 (3H, d, J = 6.7 Hz), 1.17 (3H, d, J = 7.4 Hz).
MS: m/z = 262 [M+H-HCl] +
Cl content (ion chromatography): 11.9 % (in theory: 11.9 %).

[0137]
Step B. Preparation of S-MACB-HC (Compound [6])
[Chem. 7]
To a solution of S-MABB-HC [5] (5.0 g, 16.8 mmol) in methanol (15.0 mL) was added 5 % palladium carbon (made by Kawaken Fine Chemicals Co., Ltd., PH type, 54.1 % water-content 1.0 g) at room temperature under nitrogen atmosphere. The reaction vessel was filled with hydrogen, the reaction mixture was stirred at hydrogen pressure of 0.4 MPa at room temperature for 12 hours, the hydrogen in the reaction vessel was replaced with nitrogen, and then the 5 % palladium carbon was removed by filtration. The reaction vessel and the 5 % palladium carbon were washed with methanol (10 mL). The washings were added to the filtrate to give a methanol solution of S-MACB-HC [6] (24.8 g, 16.8 mmol in theory). The given methanol solution of S-MACB-HC was used in the next step, assuming that the yield was 100 %.
A crude product of S-MACB-HC which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 9.60 (br s, 1H), 4.97 (d, 1H, J = 9.2 Hz), 4.61 (d, 1H, J = 8.4 Hz), 4.01 (dd, 1H, J = 10.0, 8.4 Hz), 3.78-3.74 (m, 1H), 3.54 (dd, 1H, J = 9.6, 8.4 Hz), 3.35 (dd, 1H, J = 10.0, 6.0 Hz), 3.15-3.03 (m, 1H), 3.00-2.88 (m, 1H), 1.49 (s, 9H), 1.47 (s, 9H), 1.22 (d, 3H, J = 6.8 Hz), 1.14 (d, 3H, J = 7.2 Hz).
MS: m/z = 172 [M+H] + (free form)

[0138]
Step C. Preparation of S-ZMAB (Compound [7])
[Chem. 8]
To the methanol solution of S-MACB-HC [6] (24.8 g, 16.8 mmol in theory) was added dropwise N,N-diisopropylethylamine (4.8 g, 36.9 mmol) at room temperature under nitrogen atmosphere, and then the used dropping funnel was washed with tetrahydrofuran (2.5 mL) and the washings were added to the reaction mixture. To the resulting reaction mixture was added dropwise benzyl chloroformate (3.0 g, 17.6 mmol) at 0°C, and then the used dropping funnel was washed with tetrahydrofuran (2.5 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C for 1 hour, and then the solvent was removed in vacuo. After toluene (25.0 mL) and an aqueous solution of citric acid (25.0 mL) was added to the residue and then the mixture was stirred, the organic layer was separated out. The resulting organic layer was washed with sodium bicarbonate water (25.0 mL) and then water (25.0 mL), and the solvent in the organic layer was removed out of the organic layer in vacuo. Toluene (15.0 mL) was added to the residue and the toluene solution was concentrated. The operation was repeated one more time to give a toluene solution of S-ZMAB [7] (6.9 g, 16.8 mmol in theory). The given toluene solution of S-ZMAB was used in the next step, assuming that the yield was 100 %.
A crude product of S-ZMAB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.38-7.28 (m, 10H), 5.16-5.04 (m, 4H), 4.60 (d, 1H, J = 9.2 Hz), 4.18-4.12 (m, 2H), 4.04 (t, 1H, J = 8.6 Hz), 3.66 (dd, 1H, J = 7.6, 7.2 Hz), 3.50 (dd, 1H, J = 8.0, 5.2 Hz), 3.05-2.94 (m, 1H), 2.60-2.50 (m, 1H), 1.43 (br s, 18H), 1.33 (d, 3H, J = 6.5 Hz), 1.15 (d, 3H, J = 7.2 Hz).
MS: m/z = 328 [M+Na] +.

[0139]
Step D. Preparation of RS-ZMBB (Compound [8])
[Chem. 9]
To the toluene solution of S-ZMAB [7] (6.9 g, 16.8 mmol) was added tetrahydrofuran (15.0 mL) at room temperature under nitrogen atmosphere. A solution of lithium bis(trimethylsilyl)amide/tetrahydrofuran (14.7 mL, 17.6 mmol) was added dropwise to the toluene solution at -70°C. The used dropping funnel was washed with tetrahydrofuran (2.5 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at -70°C for 6 hours, and then a solution of TBBA (3.4 g, 17.6 mmol) in tetrahydrofuran (2.5 mL) was added dropwise to the reaction mixture at -70°C. The used dropping funnel was washed with tetrahydrofuran (2.5 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at -70°C for 1 hour, and then warmed to room temperature. To the reaction mixture were added an aqueous ammonium chloride (25 mL) and toluene (25 mL) and then the mixture was stirred, the organic layer was separated out. The resulting organic layer was washed with an aqueous solution of citric acid (25 mL, x 2), sodium bicarbonate water (25 mL), and then water (25 mL), and then the solvent was removed out of the organic layer in vacuo. Acetonitrile (15 mL) was added to the residue and the acetonitrile solution was concentrated. The operation was repeated two more times. Acetonitrile (15 mL) and active carbon (0.25 g) were added to the residue, the mixture was stirred at room temperature for 2 hours. The active carbon was removed by filtration, and the reaction vessel and the residue on the filter was washed with acetonitrile (10 mL). The washings were added to the filtration, and then the filtration was concentrated in vacuo to give an acetonitrile solution of RS-ZMBB [8] (13.2 g, 16.8 mmol in theory). The given acetonitrile solution of RS-ZMBB was used in the next step, assuming that the yield was 100 %.
A crude product of RS-ZMBB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.38-7.29 (m, 5H), 5.09-4.96 (m, 2H), 3.91 (t, 0.4H, J = 8.0 Hz), 3.79 (t, 0.6H, J = 8.0 Hz), 3.55 (t, 0.4H, J = 7.2 Hz), 3.46 (t, 0.6H, J = 7.5 Hz), 3.14-3.04 (m, 1H), 2.83-2.72 (m, 2H), 1.38 (br s, 9H), 1.37 (br s, 3.6H), 1.34 (br s, 5.4H), 1.12-1.09 (m, 3H).
MS: m/z = 420 [M+H] +.

[0140]
Step E. Preparation of RS-ZMAA-DN . 2H 2 O (Compound [9])
[Chem. 10]
To the acetonitrile solution of RS-ZMBB [8] (13.2 g, 16.8 mmol in theory) was added acetonitrile (15 mL) at room temperature under nitrogen atmosphere. p-Toluenesulfonic acid mono-hydrate (6.4 g, 33.6 mmol) was added to the solution at room temperature. The reaction mixture was stirred at 50°C for 12 hours, and then cooled to room temperature, and water (7.5 mL) was added dropwise to the reaction mixture. The reaction mixture was cooled to 0°C, and then 4 mol/L aqueous sodium hydroxide (17.6 mL, 70.5 mmol) was added dropwise thereto. After stirring the reaction mixture at room temperature for 1 hour, acetonitrile (75 mL) was added dropwise thereto at room temperature, and the reaction mixture was stirred for 3 hours. The precipitated solid was collected on a filter, and washed with a mixture of acetonitrile : water = 4 : 1 (10 mL) and then acetonitrile (10 mL). The resulting wet solid was dried in vacuo to give RS-ZMAA-DN .2H 2O [9] (5.2 g, 13.4 mmol, yield: 85.4 %).
RS-ZMAA-DN .2H 2O which was prepared by the same process was measured about NMR, MS, Na-content, and water-content.
1H-NMR (DMSO-d 6) δ: 7.32-7.22 (m, 5H), 4.97 (d, 1H, J = 12.7 Hz), 4.84 (d, 1H, J = 12.7 Hz), 3.79 (t, 1H, J = 8.0 Hz), 3.29 (d, 1H, J = 14.8 Hz), 3.16-3.12 (m, 1H), 2.17-2.09 (m, 2H), 1.07 (d, 3H, J = 6.9 Hz).
MS: m/z = 352 [M+H] + (anhydrate)
Na content (ion chromatography): 13.3 % (after correction of water content)(13.1 % in theory)
Water content (Karl Fischer’s method): 9.8 % (9.3 % in theory)

[0141]
Step F. Preparation of RS-ZMAA (Compound [10])
[Chem. 11]
To 1 mol/L hydrochloric acid (180 mL) were added RS-ZMAA-DN .2H 2O [9] (30 g, 77.5 mmol) and acetonitrile (60 mL), and the mixture was stirred at room temperature for about 15 minutes. After ethyl acetate (240 mL) was added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The organic layer was washed with 10 % brine (60 mL x 2). The organic layer was stirred with magnesium sulfate (6 g), the magnesium sulfate was removed by filtration, and the residue on the filter was washed with ethyl acetate (60 mL). The filtrate and the washings are combined, and the solvent was removed out in vacuo. Tetrahydrofuran (240 mL) was added to the residue and the tetrahydrofuran solution was concentrated. The operation was repeated two more times. Tetrahydrofuran (60 mL) was added to the residue to give a tetrahydrofuran solution of RS-ZMAA [10]. The given tetrahydrofuran solution of RS-ZMAA was used in the next step, assuming that the yield was 100 %.
RS-ZMAA which was prepared by the same process was measured about NMR and MS.
1H-NMR (DMSO-D 6) δ: 7.35-7.28 (m, 5H), 5.06-4.94 (m, 2H), 3.86 (dt, 1H, J = 48.4, 7.9 Hz), 3.50 (dt, 1H, J = 37.9, 7.4 Hz), 3.16-3.02 (br m, 1H), 2.91-2.77 (br m, 2H), 1.08 (d, 3H, J = 6.9 Hz)
MS: m/z = 308 [M+H] +.

[0142]
Step G. Preparation of RS-ZMOO (Compound [11])
[Chem. 12]
To the tetrahydrofuran solution of RS-ZMAA [10] (25.8 mmol in theory) was added tetrahydrofuran (50 mL) under nitrogen atmosphere. Boron trifluoride etherate complex (4.40 g) was added dropwise thereto at 0°C to 5°C. The used dropping funnel was washed with tetrahydrofuran (5 mL) and the washings were added to the reaction mixture. To the reaction mixture was added dropwise 1.2 mol/L borane-tetrahydrofuran complex (43.0 mL) at 0°C to 5°C, and the reaction mixture was stirred at 0°C to 5°C for about 30 minutes, and then further stirred at room temperature overnight. To the reaction mixture was added dropwise 1.2 mol/L borane-tetrahydrofuran complex (21.1 mL) at 0°C to 5°C, and then the reaction mixture was stirred at room temperature overnight. After stirring, water (40 mL) was added dropwise to the reaction mixture at 0°C to 15°C. To the reaction mixture was added sodium bicarbonate (5.42 g) at 0°C to 15°C. The sodium bicarbonate left in the vessel was washed with water (10 mL), and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, and then toluene (50 mL) was added thereto and the reaction mixture was further stirred. The organic layer was separated out. The resulting organic layer was washed with 10 % brine (20 mL x 1), a mixture (x 3) of 5 % sodium bicarbonate water (20 mL) and 10 % brine (20 mL), a mixture (x 1) of 5 % aqueous potassium hydrogensulfate (10 mL) and 10 % brine (10 mL), and then 10 % brine (20 mL x 2). The organic layer was stirred with magnesium sulfate (8.9 g), the magnesium sulfate was removed by filtration, and the residue on the filter was washed with toluene (20 mL). The washings were added to the filtration, and then the filtrate was concentrated in vacuo. To the concentrated residue was added toluene (80 mL). The solution was concentrated in vacuo, and toluene (15 mL) was added thereto to give a toluene solution of RS-ZMOO [11]. The given toluene solution of RS-ZMOO was used in the next step, assuming that the yield was 100 %.
RS-ZMOO which was prepared by the same process was measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.39-7.30 (m, 5H), 5.10 (s, 2H), 4.15-4.01 (br m, 2H), 3.83-3.73 (br m, 3H), 3.48 (dd, 1H, J = 8.3, 6.4 Hz), 2.59-2.50 (br m, 1H), 2.46-2.40 (br m, 1H), 2.07-1.99 (m, 1H), 1.14 (d, 3H, J = 7.2 Hz)
MS: m/z = 280 [M+H]+.

[0143]
Step H. Preparation of RS-ZMSS (Compound [12])
[Chem. 13]
To the toluene solution of RS-ZMOO [11] (23.7 mmol in theory) was added toluene (55 mL) under nitrogen atmosphere. And, triethylamine (5.27 g) was added dropwise thereto at -10°C to 10°C, and the used dropping funnel was washed with toluene (1.8 mL) and the washings were added to the reaction mixture. To this reaction mixture was added dropwise methanesulfonyl chloride (5.69 g) at -10°C to 10°C, and then the used dropping funnel was washed with toluene (1.8 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at 0°C to 10°C for about 2 hours, and then water (28 mL) was added dropwise thereto at 0°C to 20°C. The reaction mixture was stirred at 0°C to 20°C for about 30 minutes, and then, the organic layer was separated out. The resulting organic layer was washed twice with 10 % brine (18 mL). The organic layer was stirred with magnesium sulfate (2.75 g), the magnesium sulfate was removed by filtration, and the residue on the filter was washed with toluene (18 mL). The washings were added to the filtrate, and then the solvent was removed from the filtrate in vacuo. To the concentrated residue was added toluene up to 18 mL to give a toluene solution of RS-ZMSS [12]. The given toluene solution of RS-ZMSS was used in the next step, assuming that the yield was 100 %.
RS-ZMSS which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-D 6) δ: 7.37-7.27 (br m, 5H), 5.10-4.98 (m, 2H), 4.58-4.22 (br m, 4H), 3.84 (dt, 1H, J = 45.6, 8.1 Hz), 3.48-3.33 (br m, 1H), 3.17-3.10 (m, 6H), 2.81-2.74 (br m, 1H), 2.22-2.12 (m, 2H)
MS: m/z = 436 [M+H] +.

[0144]
Step I. Preparation of SR-ZMDB (Compound [13])
[Chem. 14]
To a toluene solution of RS-ZMSS [12] (23.7 mmol in theory) was added toluene (55 mL) under nitrogen atmosphere. And, benzylamine (17.8 g) was added dropwise thereto at room temperature, and the used dropping funnel was washed with toluene (9.2 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at room temperature for about 1 hour, at 55°C to 65°C for about 3 hours, and then at 70°C to 80°C for 6 hours. After the reaction mixture was cooled to room temperature, 10 % NaCl (28 mL) was added dropwise thereto, and the reaction mixture was stirred at room temperature for about 30 minutes. After toluene (37 mL) was added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The resulting organic layer was washed with a mixture (x 2) of 10 % brine (18 mL) and acetic acid (2.84 g), and then 10 % brine (11 mL, x 1). The solvent of the organic layer was removed in vacuo to a half volume, and acetic anhydride (1.45 g) was added to the concentrated residue at room temperature. The mixture was stirred for about 3 hours. To the reaction mixture were added dropwise a solution of potassium hydrogensulfate (3.87 g) and water (92 mL) at room temperature. The reaction mixture was stirred, and then the aqueous layer was separated out. The resulting aqueous layer was washed with toluene (18 mL), and toluene (73 mL) and then sodium bicarbonate (6.56 g) were added to the aqueous layer at room temperature, and the mixture was stirred. The organic layer was separated out, and washed with 10 % brine (11 mL). The organic layer was stirred with magnesium sulfate (2.75 g), the magnesium sulfate was removed by filtration. The residue on the filter was washed with toluene (18 mL), and the washings were added to the filtrate, and then the filtrate was concentrated in vacuo. Toluene (44 mL) was added to the concentrated residue to give a toluene solution of SR-ZMDB [13]. The given toluene solution of SR-ZMDB was used in the next step, assuming that the yield was 100 %.
1H-NMR (CDCl 3) δ: 7.35-7.20 (m, 10H), 5.08 (d, 2H, J = 23.6 Hz), 3.94 (q, 1H, J = 7.9 Hz), 3.73-3.42 (br m, 2H), 3.30-3.23 (m, 1H), 3.05 (dd, 1H, J = 19.7, 9.5 Hz), 2.79 (dt, 1H, J = 69.6, 6.1 Hz), 2.57-2.32 (br m, 4H), 1.96-1.89 (m, 1H), 1.09 (d, 3H, J = 6.9 Hz)
MS: m/z = 351 [M+H] +.

[0145]
Step J. Preparation of SR-MDOZ (Compound [14])
[Chem. 15]
To a solution of 1-chloroethyl chloroformate (3.72 g) in toluene (28 mL) was added dropwise the toluene solution of SR-ZMDB [13] (23.7 mmol in theory) at 0°C to 10°C under nitrogen atmosphere, and then the used dropping funnel was washed with toluene (4.6 mL) and the washings were added to the reaction mixture. To the reaction mixture was added triethylamine (718 mg) at 0°C to 10°C, and the reaction mixture was stirred at 15°C to 25°C for about 2 hours. Then, methyl alcohol (46 mL) was added to the reaction mixture, and the mixture was stirred at 50°C to 60°C for additional about 2 hours. The solvent of the reaction mixture was removed in vacuo to a volume of about less than 37 mL. To the concentrated residue was added dropwise 2 mol/L hydrochloric acid (46 mL) at 15°C to 20°C, and the mixture was stirred, and the aqueous layer was separated out. The resulting aqueous layer was washed with toluene (28 mL, x 2). To the aqueous layer were added 20 % brine (46 mL) and tetrahydrofuran (92 mL), and then 8 mol/L aqueous sodium hydroxide (18 mL) was added dropwise thereto at 0°C to 10°C. The organic layer was separated out from the reaction mixture, washed with 20 % brine (18 mL, x 2), and then the solvent of the organic layer was removed in vacuo. To the concentrated residue was added tetrahydrofuran (92 mL), and the solution was concentrated in vacuo. The operation was repeated one more time. The concentrated residue was dissolved in tetrahydrofuran (92 mL). The solution was stirred with magnesium sulfate (2.75 g), and the magnesium sulfate was removed by filtration. The residue on the filter was washed with tetrahydrofuran (28 mL), the washings were added to the filtrate, and the filtrate was concentrated in vacuo. The volume of the concentrated residue was adjusted to about 20 mL with tetrahydrofuran to give a tetrahydrofuran solution of SR-MDOZ [14] (net weight: 4.01 g, 15.4 mol, yield: 65.0 %).
SR-MDOZ which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.37-7.28 (m, 5H), 5.08 (dd, 2H, J = 16.8, 12.8 Hz), 4.00 (dd, 1H, J = 17.1, 8.3 Hz), 3.40-3.31 (m, 1H), 3.24 (d, 1H, J = 12.7 Hz), 3.00 (dd, 1H, J = 54.9, 12.4 Hz), 2.87-2.57 (m, 3H), 2.47-2.27 (m, 1H), 1.91-1.80 (m, 1H), 1.14 (d, 3H, J = 7.2 Hz)
MS: m/z = 261 [M+H] +.

[0146]
Step K. Preparation of SR-MDOZ-OX (Compound [15])
[Chem. 16]
Under nitrogen atmosphere, oxalic acid (761 mg) was dissolved in tetrahydrofuran (40 mL), and the tetrahydrofuran solution of SR-MDOZ [14] (3.84 mmol in theory) was added dropwise to the solution of oxalic acid at room temperature. To the solution was added SR-MDOZ-OX crystal (1 mg) that was prepared according to the method described herein at room temperature, and the mixture was stirred at room temperature for about 3.5 hours to precipitate the crystal. To the slurry solution was added dropwise the tetrahydrofuran solution of SR-MDOZ (3.84 mmol) at room temperature, and the mixture was stirred at room temperature for about 1 hour. The slurry solution was heated, and stirred at 50°C to 60°C for about 2 hours, and then stirred at room temperature overnight. The slurry solution was filtrated, and the wet crystal on the filter was washed with tetrahydrofuran (10 mL), dried in vacuo to give SR-MDOZ-OX [15] (2.32 g, 6.62 mol, yield: 86.2 %).
SR-MDOZ-OX which was prepared by the same process was measured about NMR, MS, and elementary analysis.
1H-NMR (DMSO-D 6) δ: 7.37-7.30 (m, 5H), 5.15-5.01 (m, 2H), 3.92 (dt, 1H, J = 43.5, 8.4 Hz), 3.48-3.12 (br m, 5H), 2.67-2.56 (m, 1H), 2.46-2.35 (m, 1H), 2.12-2.05 (m, 1H), 1.13 (d, 3H, J = 6.9 Hz)
MS: m/z = 261 [M+H] +
elementary analysis: C 58.4wt % , H 6.4wt % , N 7.9 % wt % (theoretically, C 58.3wt % , H 6.3wt % , N 8.0wt % )

[0147]
Step L. Preparation of SR-MDPZ (Compound [16])
[Chem. 17]
To SR-MDOZ-OX [15] (12.0 g, 34.2 mmol) were added ethanol (36 mL), water (72 mL), CPPY [20] (5.36 g, 34.9 mmol), and then K 3PO 4 (21.8 g, 103 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80°C for 5 hours, and then cooled to 40°C. Toluene (120 mL) was added thereto at 40°C, and the organic layer was separated out. The resulting organic layer was washed with 20 % aqueous potassium carbonate (48 mL), followed by washing twice with water (48 mL). The solvent of the organic layer was then removed in vacuo. tert-butanol (60 mL) was added to the residue and the tert-butanol solution was concentrated. The operation was repeated two more times. tert-Butanol (36 mL) was added to the concentrated residue to give a solution of SR-MDPZ [16] in tert-butanol (61.1 g, 34.2 mmol in theory). The given tert-butanol solution of SR-MDPZ was used in the next step, assuming that the yield was 100 %.
SR-MDPZ which was prepared by the same process was isolated as a solid from a mixture of ethyl acetate and n-heptane, and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.41-7.26 (br m, 3H), 7.22-7.08 (br m, 3H), 6.64-6.51 (br m, 1H), 5.07-4.91 (br m, 2H), 4.09-3.67 (br m, 5H), 3.47-3.32 (br m, 1H), 2.67-2.55 (br m, 2H), 2.21-2.15 (br m, 1H), 1.11 (d, 3H, J = 6.9 Hz).
MS: m/z = 378 [M+H] +

[0148]
Step M. Preparation of SR-MDOP (Compound [17])
[Chem. 18]
To the solution of SR-MDPZ [16] in tert-butanol (34.2 mmol in theory) were added ammonium formate (10.8 g, 171 mmol), water (60 mL), and 10 % palladium carbon (made by Kawaken Fine Chemicals Co., Ltd., M type, 52.6 % water-content, 1.20 g) under nitrogen atmosphere. The reaction mixture was stirred at 40°C for 13 hours, and then cooled to room temperature, and the resulting precipitate was removed by filtration. The reaction vessel and the residue on the filter were washed with tert-butanol (24 mL), the washings was added to the filtrate, and 8 M aqueous sodium hydroxide (25.7 mL, 205 mmol) and sodium chloride (13.2 g) were added to the filtrate. The reaction mixture was stirred at 50°C for 2 hours, and then toluene (84 mL) was added thereto at room temperature, and the organic layer was separated out. The resulting organic layer was washed with 20 % brine (60 mL), stirred with anhydrous sodium sulfate, and then the sodium sulfate was removed by filtration. The residue on the filter was washed with a mixture of toluene : tert-butanol = 1 : 1 (48 mL), the washings was added to the filtrate, and the filtrate was concentrated in vacuo. To the concentrated residue was added toluene (60 mL), and the solution was stirred at 50°C for 2 hours, and then the solvent was removed in vacuo. To the concentrated residue was added toluene (60 mL) again, and the solution was concentrated. To the concentrated residue was added toluene (48 mL), and the solution was stirred at room temperature for 1 hour, and then at ice temperature for 1 hour. The precipitated solid was collected on a filter, and washed with toluene (24 mL). The resulting wet solid was dried in vacuo to give SR-MDOP [17] (7.07 g, 29.1 mmol, yield: 84.8 %).
SR-MDOP which was prepared by the same process was measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.57 (br s, 1H), 8.07 (s, 1H), 7.10 (d, 1H, J = 3.2 Hz), 6.58 (d, 1H, J = 3.2 Hz), 3.92-3.59 (br m, 4H), 3.49 (dd, 1H, J = 8.3, 7.2 Hz), 2.93 (dd, 1H, J = 7.2, 6.1 Hz), 2.61-2.53 (m, 2H), 2.12-2.01 (br m, 2H), 1.10 (d, 3H, J = 6.9 Hz).
MS: m/z = 244 [M+H] +.

[0149]
Step N. Preparation of Compound A mono-ethanolate (Compound [18])
[Chem. 19]
Under nitrogen atmosphere, acetonitrile (60 mL) and triethylamine (416 mg, 4.11 mmol) were added to SR-MDOP [17] (5.00 g, 20.5 mmol), and to the solution was added dropwise a solution of DPCN [21] (3.69 g, 22.6 mmol) in acetonitrile (35 mL) at 45°C, and then the used dropping funnel was washed with acetonitrile (5.0 mL) and the washings were added to the reaction mixture. The reaction mixture was stirred at 45°C for 3 hours, and then cooled to room temperature. After 5 % sodium bicarbonate water (25 mL), 10 % brine (25 mL), and ethyl acetate (50 mL) were added to the reaction mixture and then the mixture was stirred, the organic layer was separated out. The solvent of the organic layer was removed out in vacuo. Tetrahydrofuran (50 mL) was added to the residue and the tetrahydrofuran solution was concentrated. The operation was repeated three more times. To the concentrated residue was added tetrahydrofuran (50 mL), and water was added the solution to adjust the water content to 5.5 %. The resulting precipitate was removed by filtration. The reaction vessel and the residue on the filter were washed with tetrahydrofuran (15 mL), the washings were added to the filtrate, and the solvent was removed out of the filtrate in vacuo. To the concentrated residue were added ethanol (50 mL) and Compound A crystal (5.1 mg) that was prepared according to the method described in the following Example 15. The mixture was stirred at room temperature for 1 hour, and concentrated in vacuo. To the residue was ethanol (50 mL), and the solution was concentrated again. To the concentrated residue was added ethanol (15 mL), and the solution was stirred at room temperature for 1 hour. The precipitated solid was collected on the filter, and washed with ethanol (20 mL). The resulting wet solid was dried in vacuo to give Compound A mono-ethanolate [18] (6.26 g, 17.6 mmol, yield: 85.5 %).
Compound A mono-ethanolate which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.3 Hz), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.34 (t, 1H, J = 5.1 Hz), 4.16 (t, 1H, J = 8.3 Hz), 4.09-3.92 (m, 3H), 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 3.44 (dq, 2H, J = 6.7, 5.1 Hz), 2.69-2.60 (m, 2H), 2.23-2.13 (br m, 1H), 1.12 (d, 3H, J = 7.1 Hz), 1.06 (t, 3H, J = 6.7 Hz).
MS: m/z = 311 [M+H] +

[0150]
Step O. Purification of Compound A (Compound [19])
[Chem. 20]
Compound A mono-ethanolate [18] (4.00 g, 11.2 mmol) and n-butanol (32 mL) were mixed under nitrogen atmosphere, and the mixture was dissolved at 110°C. The mixture was cooled to 85°C, and Compound A crystal (4.0 mg) that was prepared according to the method described herein was added thereto, and the mixture was stirred at 85°C for 2 hours, at 75°C for 1 hour, and then at room temperature for 16 hours. The precipitated solid was collected on a filter, and washed with n-butanol (8.0 mL) and then ethyl acetate (8.0 mL). The resulting wet solid was dried in vacuo to give Compound A [19] (3.18 g, 10.2 mmol, yield: 91.3 %).
Compound A which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.5 Hz), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.16 (t, 1H, J = 8.3 Hz), 4.09-3.93 (m, 3H), 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 2.69-2.59 (m, 2H), 2.23-2.13 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).
MS: m/z = 311 [M+H] +

[0151]
Using Compound A, which was prepared by the same method, the single crystal X-ray analysis was carried out.
(1) Preparation of Single crystal
To 10 mg of Compound A in a LaPha ROBO Vial(R) 2.0 mL wide-mouthed vial was added 0.5 mL of chloroform. The vial was covered with a cap, in which Compound A was completely dissolved. In order to evaporate the solvent slowly, a hole was made on the septum attached in the cap with a needle of a TERUMO(R) syringe, and the vial was still stood at room temperature. The resulting single crystal was used in the structural analysis.
(2) Measuring instrument
Beam line: SPring-8 BL32B2
Detector: Rigaku R-AXIS V diffractometer
(3) Measuring method
The radiant light of 0.71068Å was irradiated to the single crystal to measure X-ray diffraction data.
(4) Assay method
Using the X-ray anomalous scattering effect of the chlorine atom in the resulting Compound A chloroform-solvate, the absolute configuration of Compound A was identified as (3S,4R). Based on the obtained absolute configuration of Compound A, the absolute configurations of each process intermediate were identified.

REFERENCES

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2: Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2018 Feb;178(2):424-432. doi: 10.1111/bjd.16014. Epub 2018 Jan 15. PubMed PMID: 28960254.

3: Tanimoto A, Shinozaki Y, Yamamoto Y, Katsuda Y, Taniai-Riya E, Toyoda K, Kakimoto K, Kimoto Y, Amano W, Konishi N, Hayashi M. A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. Exp Dermatol. 2018 Jan;27(1):22-29. doi: 10.1111/exd.13370. Epub 2017 Jul 3. PubMed PMID: 28423239.

4: Nomura T, Kabashima K. Advances in atopic dermatitis in 2015. J Allergy Clin Immunol. 2016 Dec;138(6):1548-1555. doi: 10.1016/j.jaci.2016.10.004. Review. PubMed PMID: 27931536.

5: Amano W, Nakajima S, Yamamoto Y, Tanimoto A, Matsushita M, Miyachi Y, Kabashima K. JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation. J Dermatol Sci. 2016 Dec;84(3):258-265. doi: 10.1016/j.jdermsci.2016.09.007. Epub 2016 Sep 13. PubMed PMID: 27665390.

6: Tanimoto A, Shinozaki Y, Nozawa K, Kimoto Y, Amano W, Matsuo A, Yamaguchi T, Matsushita M. Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis. BMC Musculoskelet Disord. 2015 Nov 6;16:339. doi: 10.1186/s12891-015-0802-0. PubMed PMID: 26546348; PubMed Central PMCID: PMC4636776.

7: Amano W, Nakajima S, Kunugi H, Numata Y, Kitoh A, Egawa G, Dainichi T, Honda T, Otsuka A, Kimoto Y, Yamamoto Y, Tanimoto A, Matsushita M, Miyachi Y, Kabashima K. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol. 2015 Sep;136(3):667-677.e7. doi: 10.1016/j.jaci.2015.03.051. Epub 2015 Jun 24. PubMed PMID: 26115905.

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/////////Delgocitinib, デルゴシチニブ   , JAPAN 2020, 2020 APPROVALS, Corectim, UNII-9L0Q8KK220, JTE-052, 9L0Q8KK220, LEO 124249ALEO 124249HY-109053CS-0031558D11046GTPL9619JTE-052AJTE052, LP-0133 , ROH-201, atopic dermatitis

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