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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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Lactitol, ラクチトール


Chemical structure of lactitol

Lactitol

Lactitol

ラクチトール;

Formula
C12H24O11
CAS
585-86-4
Mol weight
344.3124

To treat chronic idiopathic constipation (CIC) in adults

FDA 2/12/2020, APPROVED, Pizensy

Lactitol, NS-4, Portolac, Importal

Lactitol
CAS Registry Number: 585-86-4
CAS Name: 4-O-b-D-Galactopyranosyl-D-glucitol
Additional Names: b-galactoside sorbitol; lactit; lactit M; lactite; lactobiosit; lactosit; lactositol
Molecular Formula: C12H24O11
Molecular Weight: 344.31
Percent Composition: C 41.86%, H 7.03%, O 51.11%
Literature References: Polyol sweetener; relative sweetness compared to sucrose is 36%. Prepd by hydrogenation of lactose, q.v.: M. J. B. Senderens, Compt. Rend. 170, 47 (1920); M. L. Wolfrom et al., J. Am. Chem. Soc. 60, 571 (1938). Pharmacology: D. H. Patil et al., Br. J. Nutr. 57, 195 (1987). Crystal structure: J. A. Kanters et al., Acta Crystallogr. C46, 2408 (1990); J. Kivikoski et al., Carbohydr. Res. 223, 45 (1992). Toxicology: E. J. Sinkeldam et al., J. Am. Coll. Toxicol. 11, 165 (1992). Clinical trial in chronic hepatic encephalopathy: O. Riggio et al., Hepatogastroenterology 37, 524 (1990); as a laxative: L. Goovaerts, G. P. Ravelli, Acta Ther. 19, 61 (1993). Review of properties and applications: J. A. van Velthuijsen, J. Agric. Food Chem. 27, 680-686 (1979); of chemistry and use in foods: C. H. den Uyl, Dev. Sweeteners 3, 65-81 (1987).
Properties: Crystals from absolute ethanol, mp 146°. [a]D23 +14° (c = 4 in water). Sol in water, dimethyl sulfoxide, N,N-dimethylformamide; slightly sol in ethanol, ether. Strongly hygroscopic.
Melting point: mp 146°
Optical Rotation: [a]D23 +14° (c = 4 in water)
Derivative Type: Monohydrate
CAS Registry Number: 81025-04-9
Trademarks: Importal (Novartis); Portolac (Zyma)
Properties: White, sweet, odorless, crystalline solid. Non-hygroscopic. mp 94-97° (van Velthuijsen), water of crystallization evaporates 145°-185°; also reported as mp 120° (den Uyl). [a]D22 +12.3°. Soly at 25° (g/100 g solvent): water 206; ethanol 0.75; ether 0.4; DMSO 233; DMF 39; at 50°: water 512; ethanol 0.88; at 75°: water 917.
Melting point: mp 94-97° (van Velthuijsen); mp 120° (den Uyl)
Optical Rotation: [a]D22 +12.3°
Derivative Type: Dihydrate
CAS Registry Number: 81025-03-8
Trademarks: Lacty (CCA Biochem)
Properties: White, sweet, odorless, crystalline powder. Data for food grade, mp 75°. [a]D25 +13.5-15.0°. pH of 10% solution 4.5 – 8.5. 140 g will dissolve in 100 ml water at 25°.
Melting point: mp 75°
Optical Rotation: [a]D25 +13.5-15.0°
Use: Sweetener in food.
Therap-Cat: Laxative. In treatment of hepatic encephalopathy.
Keywords: Laxative/Cathartic

Lactitol is a sugar alcohol used as a replacement bulk sweetener for low calorie foods with approximately 40% of the sweetness of sugar. It is also used medically as a laxative. Lactitol is produced by two manufacturers, Danisco and Purac Biochem.

Applications

MedicalLactitol is used in a variety of low food energy or low fat foods. High stability makes it popular for baking. It is used in sugar-freecandiescookies (biscuits)chocolate, and ice cream. Lactitol also promotes colon health as a prebiotic. Because of poor absorption, lactitol only has 2.4 kilocalories (9 kilojoules) per gram, compared to 4 kilocalories (17 kJ) per gram for typical saccharides. Hence, lactitol is about 60% as caloric as typical saccharides.

Lactitol is listed as an excipient in some prescription drugs.[1][2]

Lactitol is a laxative and is used to prevent or treat constipation,[3] e.g., under the trade name Importal.[4][5]

In February 2020, Lactitol was approved for use in the United States as an osmotic laxative for the treatment of chronic idiopathic constipation (CIC) in adults.[6][7][8]

Lactitol in combination with Ispaghula husk is an approved combination for idiopathic constipation as a laxative and is used to prevent or treat constipation.[medical citation needed]

Safety and health

Lactitol, erythritolsorbitolxylitolmannitol, and maltitol are all sugar alcohols.[medical citation needed] The U.S. Food and Drug Administration (FDA) classifies sugar alcohols as “generally recognized as safe” (GRAS). They are approved as food additives, and are recognized as not contributing to tooth decay or causing increases in blood glucose.Lactitol is also approved for use in foods in most countries around the world.

Like other sugar alcohols, lactitol causes cramping, flatulence, and diarrhea in some individuals who consume it. This is because humans lack a suitable beta-galactosidase in the upper gastrointestinal (GI) tract, and a majority of ingested lactitol reaches the large intestine,[9] where it then becomes fermentable to gut microbes (prebiotic) and can pull water into the gut by osmosis.{[medical citation needed] Those with health conditions should consult their GP or dietician prior to consumption.{[medical citation needed]

History

The U.S. Food and Drug Administration (FDA) approved Pizensy based on evidence from a clinical trial (Trial 1/ NCT02819297) of 594 patients with CIC conducted in the United States.[8] The FDA also considered other supportive evidence including data from Trial 2 (NCT02481947) which compared Pizensy to previously approved drug (lubiprostone) for CIC, and Trial 3 (NCT02819310) in which patients used Pizensy for one year as well as data from published literature.[8]

The benefit and side effects of Pizensy were evaluated in a clinical trial (Trial 1) of 594 patients with CIC.[8] In this trial, patients received treatment with either Pizensy or placebo once daily for 6 months.[8] Neither the patients nor the health care providers knew which treatment was being given until after the trials were completed.[8]

In the second trial (Trial 2) of three months duration, improvement in CSBMs was used to compare Pizensy to the drug lubiprostonewhich was previously approved for CIC.[8] The third trial (Trial 3) was used to collect the side effects in patients treated with Pizensy for one year.[8]

SYN

Lactitol (CAS NO.: 585-86-4), with its other name of 4-O-beta-D-Galactopyranosyl-D-glucitol, could be produced through many synthetic methods.

Following is one of the synthesis routes: Lactitol is obtained by catalytic hydrogenation of lactose (I) in the presence of either, nickel catalysts such as Raney nickel (1-9), or ruthenium catalysts (10). Alternatively, lactose (I) is reduced by employing NaBH(9).

Production Method of Lactitol

CLIP

https://onlinelibrary.wiley.com/doi/full/10.1002/apj.2275

image

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

 

SYNTHESIS

References

  1. ^ “Lactitol (Inactive Ingredient)”Drugs.com. 23 September 2018. Retrieved 24 February 2020.
  2. ^ “Lactitol Monohydrate (Inactive Ingredient)”Drugs.com. 3 October 2018. Retrieved 24 February 2020.
  3. ^ Miller LE, Tennilä J, Ouwehand AC (2014). “Efficacy and tolerance of lactitol supplementation for adult constipation: a systematic review and meta-analysis”Clin Exp Gastroenterol7: 241–8. doi:10.2147/CEG.S58952PMC 4103919PMID 25050074.
  4. ^ “Importal”Drugs.com. 3 February 2020. Retrieved 24 February 2020.
  5. ^ FASS.se (the Swedish Medicines Information Engine). Revised 2003-02-12.
  6. ^ “Pizensy: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 24 February 2020.
  7. ^ “Pizensy- lactitol powder, for solution”DailyMed. 21 February 2020. Retrieved 24 February 2020.
  8. Jump up to:a b c d e f g h “Drug Trial Snapshot: Pizensy”U.S. Food and Drug Administration (FDA). 12 February 2020. Retrieved 4 March 2020. This article incorporates text from this source, which is in the public domain.
  9. ^ Grimble GK, Patil DH, Silk DB (1988). “Assimilation of lactitol, an unabsorbed disaccharide in the normal human colon”Gut29 (12): 1666–1671. doi:10.1136/gut.29.12.1666PMC 1434111PMID 3220306.

External links

  •  Media related to Lactitol at Wikimedia Commons
  • “Lactitol”Drug Information Portal. U.S. National Library of Medicine.
Lactitol
Chemical structure of lactitol
Names
IUPAC name

4-O-α-D-Galactopyranosyl-D-glucitol
Other names

Lactitol
Lacty
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.008.698
E number E966 (glazing agents, …)
KEGG
PubChem CID
UNII
Properties
C12H24O11
Molar mass 344.313 g·mol−1
Melting point 146 °C (295 °F; 419 K)
Pharmacology
A06AD12 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒ verify (what is ☑☒ ?)
Infobox references
Lactitol
Clinical data
Trade names Importal, Pizensy
Other names Lactitol Hydrate (JANJP)
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number E966 (glazing agents, …) Edit this at Wikidata
CompTox Dashboard(EPA)
ECHA InfoCard 100.008.698 Edit this at Wikidata
Chemical and physical data
Formula C12H24O11
Molar mass 344.313 g·mol−1
3D model (JSmol)

CLIP

https://www.drugfuture.com/Pharmacopoeia/USP32/pub/data/v32270/usp32nf27s0_m44100.html

Lactitol
Click to View Image

C12H24O11344.31

4-OD-Galactopyranosyl-D-glucitol [585-86-4].
Monohydrate. 362.34 [81025-04-9].
Dihydrate. 380.35 [81025-03-8].
» Lactitol contains not less than 98.0 percent and not more than 101.0 percent of C12H24O11, calculated on the anhydrous basis.
Packaging and storage— Preserve in well-closed containers.
Labeling— Label it to indicate whether it is the monohydrate, the dihydrate, or the anhydrous form.
Water, Method I 921 between 4.5% and 5.5% (monohydrate); between 9.5% and 10.5% (dihydrate); and not more than 0.5% for the anhydrous form.
Residue on ignition 281: not more than 0.5%.
Heavy metals 231 Dissolve 4 g of it in 25 mL of water: the limit is 5 µg per g.
Reducing sugars— Dissolve 500 mg of it in 2.0 mL of water in a 10-mL conical flask. Into a similar flask, pipet 2 mL of a dextrose solution containing 0.5 mg per mL. Concomitantly add 1 mL of alkaline cupric tartrate TS to each solution, heat to boiling, and cool: the lactitol solution shows no more turbidity than that produced in the dextrose solution, in which a reddish brown precipitate forms (0.2%, as dextrose).

Related compounds—

Standard solution— Dissolve an accurately weighed quantity of USP Lactitol RS in water to obtain a solution having a known concentration of about 0.3 mg per mL.
Chromatographic system— Proceed as directed in the Assay, except to chromatograph the Standard solution instead of the Standard preparation.
Test solution— Use the Assay preparation, prepared as directed in the Assay.

Procedure— Separately inject equal volumes (about 25 µL) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. The relative retention times are about 0.53 for lactose, 0.58 for glucose, 0.67 for galactose, 0.72 for lactulitol, 1.0 for lactitol, 1.55 for galactitol, and 1.68 for sorbitol. Calculate the percentages of galactitol, sorbitol, lactulitol, lactose, glucose, and galactose in the portion of Lactitol taken by the formula:

100(CV/W)(rU / rS)

in which C is the concentration, in mg per mL, of USP Lactitol RS in the Standard solution; V is the volume, in mL, of the Test solution; W is the weight, in mg, of Lactitol in the Test solution; rU is the peak response of the relevant related compound, if observed, obtained from the Test solution; and rS is the lactitol peak response obtained from the Standard solution. The total of the percentages of all related compounds is not more than 1.5%.

Assay—

Mobile phase— Use water.
Standard preparation— Dissolve an accurately weighed quantity of USP Lactitol RS in water to obtain a solution having a known concentration of about 10.0 mg per mL.
Assay preparation— Transfer about 1000 mg of Lactitol, accurately weighed, to a 100-mL volumetric flask, dissolve in and dilute with water to volume, and mix.
Chromatographic system (see Chromatography 621)—The liquid chromatograph is equipped with a refractive index detector and a 7.8-mm × 30-cm column that contains packing L34. The column is maintained at 85, and the flow rate is about 0.7 mL per minute. Chromatograph the Standard preparation, and record the peak responses as directed for Procedure: the relative standard deviation for replicate injections is not more than 1.0% for lactitol.

Procedure— Separately inject equal volumes (about 25 µL) of the Standard preparation and the Assay preparation into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the quantity, in mg, of C12H24O11 in the portion of Lactitol taken by the formula:

100C(rU / rS)

in which C is the concentration, in mg per mL, of USP Lactitol RS in the Standard preparation, and rU and rS are the lactitol peak responses obtained from the Assay preparation and the Standard preparation, respectively.

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question Contact Expert Committee
Monograph Elena Gonikberg, Ph.D.
Senior Scientist
1-301-816-8251
(MDGRE05) Monograph Development-Gastrointestinal Renal and Endocrine
Reference Standards Lili Wang, Technical Services Scientist
1-301-816-8129
RSTech@usp.org
USP32–NF27 Page 1263

Pharmacopeial Forum: Volume No. 31(4) Page 1143

Chromatographic Column—

Chromatographic columns text is not derived from, and not part of, USP 32 or NF 27.

//////////////////Lactitol, ラクチトール , APPROVALS 2020, FDA 2020,  NS-4, Portolac, Importal

https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/211281Orig1s000ltr.pdf

Eptinezumab エプチネズマブ;


Fig. 4.7

Eptinezumab

エプチネズマブ;

(Heavy chain)
EVQLVESGGG LVQPGGSLRL SCAVSGIDLS GYYMNWVRQA PGKGLEWVGV IGINGATYYA
SWAKGRFTIS RDNSKTTVYL QMNSLRAEDT AVYFCARGDI WGQGTLVTVS SASTKGPSVF
PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV
TVPSSSLGTQ TYICNVNHKP SNTKVDARVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY ASTYRVVSVL
TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRE EMTKNQVSLT
CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS
VMHEALHNHY TQKSLSLSPG K
(Light chain)
QVLTQSPSSL SASVGDRVTI NCQASQSVYH NTYLAWYQQK PGKVPKQLIY DASTLASGVP
SRFSGSGSGT DFTLTISSLQ PEDVATYYCL GSYDCTNGDC FVFGGGTKVE IKRTVAAPSV
FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL
SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC
(Disulfide bridge: H22-H95, H138-H194, H214-L219, H220-H’220, H223-H’223, H255-H315, H361-H419, H’22-H’95, H’138-H’194, H’214-L’219, H’255-H’315, H’361-H’419, L22-L89, L139-L199, L’22-L’89, L’139-L’199)

Formula
C6352H9838N1694O1992S46
cas
1644539-04-7
Mol weight
143281.2247

Antimigraine, Anti-calcitonin gene-related peptide (GCRP) antibody

Immunoglobulin G1, anti-(calcitonin gene-related peptide) (human-oryctolagus cuniculus monoclonal ALD403 heavy chain), disulfide with human-oryctolagus cuniculus monoclonal ALD403 kappa-chain, dimer

Approved 2020 fda

ALD403, UNII-8202AY8I7H

Humanized anti-calcitonin gene-related peptide (CGRP) IgG1 antibody for the treatment of migraine.

Eptinezumab, sold under the brand name Vyepti, is a medication for the preventive treatment of migraine in adults.[2] It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta.[3][4] It is administered by intravenous infusion every three months.[2]

Image result for Eptinezumab

Eeptinezumab-jjmr was approved for use in the United States in February 2020.[5]

Image result for Eptinezumab

References

  1. ^ “Alder BioPharmaceuticals Initiates PROMISE 2 Pivotal Trial of Eptinezumab for the Prevention of Migraine”. Alder Biopharmaceuticals. 28 November 2016.
  2. Jump up to:a b “Vyeptitm (eptinezumab-jjmr) injection, for intravenous use” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 24 February2020.
  3. ^ Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. (November 2014). “Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial”. The Lancet. Neurology13 (11): 1100–1107. doi:10.1016/S1474-4422(14)70209-1PMID 25297013.
  4. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN)” (PDF)WHO Drug Information. WHO. 31 (1). 2017.
  5. ^ “Vyepti: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 24 February 2020.

External links

Image result for Eptinezumab

Eptinezumab
Monoclonal antibody
Type Whole antibody
Source Humanized
Target CALCACALCB
Clinical data
Trade names Vyepti
Other names ALD403,[1] eeptinezumab-jjmr
License data
Routes of
administration
IV
Drug class Calcitonin gene-related peptide antagonist
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6352H9838N1694O1992S46
Molar mass 143283.20 g·mol−1

Biologics license application submitted for eptinezumab, an anti-CGRP antibody for migraine prevention

Alder BioPharmaceuticals has submitted a biologics license application (BLA) for eptinezumab, a humanized IgG1 monoclonal antibody that targets calcitonin gene-related peptide (CGRP), for migraine prevention. If the US Food and Drug Administration grants approval, Alder will be on track to launch the drug in Q1 2020. The BLA included data from the PROMISE 1 and PROMISE 2 studies, which evaluated the effects of eptinezumab in episodic migraine patients (n=888) or chronic migraine patients (n=1,072), respectively.  In PROMISE 1, the primary and key secondary endpoints were met, and the safety and tolerability were similar to placebo, while in PROMISE 2, the primary and all key secondary endpoints were met, and the safety and tolerability was consistent with earlier eptinezumab studies.

Alder announced one-year results from the PROMISE 1 study in June 2018, which indicated that, following the first quarterly infusion, episodic migraine patients treated with 300 mg eptinezumab experienced 4.3 fewer monthly migraine days (MMDs) from a baseline of 8 MMDs, compared to 3.2 fewer MMDs for placebo from baseline (p= 0.0001). At one year after the third and fourth quarterly infusions, patients treated with 300 mg eptinezumab experienced further gains in efficacy, with a reduction of 5.2 fewer MMDs compared to 4.0 fewer MMDs for placebo-treated patients.  In addition, ~31% of episodic migraine patients achieved, on average per month, 100% reduction of migraine days from baseline compared to ~ 21% for placebo. New 6-month results from the PROMISE 2 study were also released in June 2018.  These results indicated that, after the first quarterly infusion, chronic migraine patients dosed with 300 mg of eptinezumab experienced 8.2 fewer MMDs, from a baseline of 16 MMDs, compared to 5.6 fewer MMDs for placebo from baseline (p <.0001). A further reduction in MMDs was seen following a second infusion; 8.8 fewer MMDs for patients dosed with 300 mg compared to 6.2 fewer MMDs for those with placebo. In addition, ~ 21% of chronic migraine patients achieved, on average, 100% reduction of MMDs from baseline compared to 9% for placebo after two quarterly infusions of 300 mg of eptinezumab.

If approved, eptinezumab would become the fourth antibody therapeutic for migraine prevention on the US market, following the approval of erenumab-aooe (Aimovig; Novartis), galcanezumab-gnlm (Emgality; Eli Lilly & Company) and fremanezumab-vfrm (Ajovy; Teva Pharmaceuticals) in 2018.

//////////Eptinezumab, Monoclonal antibody, Peptide, エプチネズマブ  , fda 2020, approvals 2020

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.
  3. Jump up to:a b c Rosenzweig, P.; Canal, M.; Patat, A.; Bergougnan, L.; Zieleniuk, I.; Bianchetti, G. (2002). “A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers”. Human Psychopharmacology17 (1): 1–13. doi:10.1002/hup.320PMID 12404702.
  4. ^ Caccia, S (May 2000). “Biotransformation of Post-Clozapine Antipsychotics Pharmacological Implications”. Clinical Pharmacokinetics38 (5): 393–414. doi:10.2165/00003088-200038050-00002PMID 10843459.
  5. ^ Noble, S; Benfield, P (December 1999). “Amisulpride: A Review of its Clinical Potential in Dysthymia”. CNS Drugs12 (6): 471–483. doi:10.2165/00023210-199912060-00005.
  6. Jump up to:a b c “Barhemsys (amisulpride) injection, for intravenous use” (PDF). U.S. Food and Drug Administration (FDA). February 2020. Retrieved 26 February 2020.
  7. Jump up to:a b Pani L, Gessa GL (2002). “The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia”. Molecular Psychiatry7 (3): 247–53. doi:10.1038/sj.mp.4001040PMID 11920152.
  8. Jump up to:a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  9. Jump up to:a b c d e f g Leucht, S; Cipriani, A; Spineli, L; Mavridis, D; Orey, D; Richter, F; Samara, M; Barbui, C; Engel, RR; Geddes, JR; Kissling, W; Stapf, MP; Lässig, B; Salanti, G; Davis, JM (September 2013). “Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis”. Lancet382 (9896): 951–962. doi:10.1016/S0140-6736(13)60733-3PMID 23810019.
  10. Jump up to:a b Brayfield, A, ed. (June 2017). “Amisulpride: Martindale: The Complete Drug Reference”MedicineComplete. Pharmaceutical Press. Retrieved 5 August 2017.
  11. ^ De Silva, V; Hanwella, R (April 2008). “Pharmaceutical patents and the quality of mental healthcare in low- and middle-income countries”. The Psychiatrist32 (4): 121–23. doi:10.1192/pb.bp.107.015651.
  12. ^ “Pipeline”LB Pharmaceuticals. Retrieved 29 August 2019.
  13. ^ “About Us”LB Pharmaceuticals. Retrieved 26 February 2020.
  14. ^ “Data presented at 2017 ECNP meeting (European Neuropsychopharmacology, 2017, 27 (S4), S922-S923)”LB Pharmaceuticals. Retrieved 26 February 2020.
  15. ^ “Building a translational bridge from animals to man for clinical candidate LB-102, a next-generation benzamide antipsychotic (P.101)” (PDF)LB Pharmaceuticals. Retrieved 29 August 2019.
  16. ^ Grattan V, Vaino AR, Prensky Z, Hixon MS (August 2019). “Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D2 and D3, while R Enantiomers Engage 5-HT7”ACS Omega4 (9): 14151–4. doi:10.1021/acsomega.9b02144ISSN 2470-1343PMC 6714530PMID 31497735.
  17. ^ Komossa, K; Rummel-Kluge, C; Hunger, H; Schmid, F; Schwarz, S; Silveira da Mota Neto, JI; Kissling, W; Leucht, S (January 2010). “Amisulpride versus other atypical antipsychotics for schizophrenia”The Cochrane Database of Systematic Reviews (1): CD006624. doi:10.1002/14651858.CD006624.pub2PMC 4164462PMID 20091599.
  18. ^ Leucht, S; Corves, C; Arbter, D; Engel, RR; Li, C; Davis, JM (January 2009). “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis”. Lancet373 (9657): 31–41. doi:10.1016/S0140-6736(08)61764-XPMID 19058842.
  19. ^ Solanki, RK; Sing, P; Munshi, D (October–December 2009). “Current perspectives in the treatment of resistant schizophrenia”Indian Journal of Psychiatry51 (4): 254–60. doi:10.4103/0019-5545.58289PMC 2802371PMID 20048449.
  20. ^ Mouaffak, F; Tranulis, C; Gourevitch, R; Poirier, MF; Douki, S; Olié, JP; Lôo, H; Gourion, D (2006). “Augmentation Strategies of Clozapine With Antipsychotics in the Treatment of Ultraresistant Schizophrenia”. Clinical Neuropharmacology29 (1): 28–33. doi:10.1097/00002826-200601000-00009PMID 16518132.
  21. ^ Nuss, P.; Hummer, M.; Tessier, C. (2007). “The use of amisulpride in the treatment of acute psychosis”Therapeutics and Clinical Risk Management3 (1): 3–11. doi:10.2147/tcrm.2007.3.1.3PMC 1936283PMID 18360610.
  22. Jump up to:a b c Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  23. Jump up to:a b Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Sep 19]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  24. ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  25. ^ McKeage, K; Plosker, GL (2004). “Amisulpride: a review of its use in the management of schizophrenia”. CNS Drugs18 (13): 933–956. doi:10.2165/00023210-200418130-00007ISSN 1172-7047PMID 15521794.
  26. ^ Natesan, S; Reckless, GE; Barlow, KB; Nobrega, JN; Kapur, S (October 2008). “Amisulpride the ‘atypical’ atypical antipsychotic — Comparison to haloperidol, risperidone and clozapine”. Schizophrenia Research105 (1–3): 224–235. doi:10.1016/j.schres.2008.07.005PMID 18710798.
  27. ^ Joint Formulary Committee, BMJ, ed. (March 2009). “4.2.1”. British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
  28. Jump up to:a b c d e Haddad, Peter; Haddad, Peter M.; Dursun, Serdar; Deakin, Bill (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. p. 207–216. ISBN 9780198527480.
  29. ^ Moncrieff J (July 2006). “Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse”. Acta Psychiatrica Scandinavica114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.xPMID 16774655.
  30. ^ Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
  31. ^ Isbister, GK; Balit, CR; Macleod, D; Duffull, SB (August 2010). “Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes”. Journal of Clinical Psychopharmacology30 (4): 391–395. doi:10.1097/JCP.0b013e3181e5c14cPMID 20531221.
  32. ^ Joy, JP; Coulter, CV; Duffull, SB; Isbister, GK (August 2011). “Prediction of Torsade de Pointes From the QT Interval: Analysis of a Case Series of Amisulpride Overdoses”. Clinical Pharmacology & Therapeutics90 (2): 243–245. doi:10.1038/clpt.2011.107PMID 21716272.
  33. Jump up to:a b c Taylor, D; Paton, C; Shitij, K (2012). Maudsley Prescribing Guidelines in Psychiatry(11th ed.). West Sussex: Wiley-Blackwell. ISBN 978-0-47-097948-8.
  34. ^ Levine, M; Ruha, AM (July 2012). “Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management”. CNS Drugs26 (7): 601–611. doi:10.2165/11631640-000000000-00000PMID 22668123.
  35. ^ Roth, BL; Driscol, J. “PDSP Ki Database”Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  36. Jump up to:a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar asat au av aw Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL (2009). “Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo”Psychopharmacology205 (1): 119–28. doi:10.1007/s00213-009-1521-8PMC 2821721PMID 19337725.
  37. Jump up to:a b Maitre, M.; Ratomponirina, C.; Gobaille, S.; Hodé, Y.; Hechler, V. (April 1994). “Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics”. European Journal of Pharmacology256(2): 211–214. doi:10.1016/0014-2999(94)90248-8PMID 7914168.
  38. ^ Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997). “Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity”. J. Pharmacol. Exp. Ther280 (1): 83–97. PMID 8996185.
  39. ^ Blomme, Audrey; Conraux, Laurence; Poirier, Philippe; Olivier, Anne; Koenig, Jean-Jacques; Sevrin, Mireille; Durant, François; George, Pascal (2000), “Amisulpride, Sultopride and Sulpiride: Comparison of Conformational and Physico-Chemical Properties”, Molecular Modeling and Prediction of Bioactivity, Springer US, pp. 404–405, doi:10.1007/978-1-4615-4141-7_97ISBN 9781461368571
  40. ^ “Amisulpride international”Drugs.com. 3 February 2020. Retrieved 26 February 2020.
  41. Jump up to:a b “Active substance: amisulpride” (PDF). 28 September 2017. EMA/658194/2017; Procedure no.: PSUSA/00000167/201701. Retrieved 26 February 2020.
  42. ^ Lecrubier, Y.; et al. (2001). “Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia”. Neuropsychobiology44 (1): 41–46. doi:10.1159/000054913PMID 11408792.
  43. ^ Kaplan, A. (2004). “Psychotropic Medications Around the World”Psychiatric Times21(5).
  44. ^ “Barhemsys: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 26 February 2020.

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]

Patent

Publication numberPriority datePublication dateAssigneeTitle
US4052445A *1975-02-011977-10-04Deutsche Gold- Und Silber-Scheideanstalt Vormals RoesslerProcess for the production of alkyl sulfonic acids
Family To Family Citations
FR2415099B11978-01-201981-02-20Ile De France
US20100105755A1 *2008-09-122010-04-29Auspex Pharmaceuticals, Inc.Substituted benzamide modulators of dopamine receptor

Non-Patent

Title
Jeyakumar et al. (Tetrahedron Letters 47 (2006) 4573-4576) *
Sato et al. (Tetrahedron 57 (2001) 2469-2476) *
WO2019113084A1 *2017-12-052019-06-13Sunovion Pharmaceuticals Inc.Crystal forms and production methods thereof
Family To Family Citations
CN102807516A *2012-08-162012-12-05四川省百草生物药业有限公司Intermediate in amisulpride and method for preparing amisulpride by using intermediate
CN103819383A *2012-11-192014-05-28上海美迪西生物医药有限公司Synthesis method for amisulpride
CN103319385B *2013-06-182015-07-08苏州诚和医药化学有限公司Method for synthesizing 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid
CN103450058B *2013-09-182015-10-14广安凯特医药化工有限公司A kind of preparation method of amisulpride acid
CN103553989B *2013-11-082015-03-11苏州诚和医药化学有限公司Synthetic method of 2-methoxyl-4-amino-5-ethyl sulfuryl methyl benzoate
CN104725292B *2015-03-232017-07-25湖北荆江源制药股份有限公司A kind of preparation method of (S) () Amisulpride
CN105237422A *2015-09-062016-01-13南京理工大学Synthetic method of 4-amino-5-chloro-2-methoxyl benzoic acid

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

Rimegepant sulfate, リメゲパント硫酸塩;


ChemSpider 2D Image | Rimegepant | C28H28F2N6O3

Rimegepant.svg

Rimegepant

  • Molecular FormulaC28H28F2N6O3
  • Monoisotopic mass534.219116 Da
1289023-67-1 [RN]
1-Piperidinecarboxylic acid, 4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-, (5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl ester
9751
BMS 927711

Antimigraine, Calcitonin receptor-like receptor antagonist

Treatment of migraine

Rimegepant sulfate.png

str1

Structure of RIMEGEPANT SULFATE

Rimegepant sulfate (USAN)

リメゲパント硫酸塩;

Formula
(C28H28F2N6O3)2. H2SO4. 3H2O
CAS
1374024-48-2
Mol weight
1221.2386

Nurtec ODT, FDA 2020, 2020/2/27 fda approved

Biohaven Pharmaceuticals developed Rimegepant, also known as BMS-927711, acquired in 2016 from Bristol-Myers Squibb, Rimegepant, also known as BMS-927711. Rimegepant is a potent, selective, competitive and orally active calcitonin gene-related peptide (CGRP) antagonist in clinical trials for treating migraine. Rimegepant has shown in vivo efficacy without vasoconstrictor effect; it is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Rimegepant is a medication for the treatment of an acute migraine with or without aura (a sensory phenomenon or visual disturbance) in adults. However, it is not to be used prophylactically. In the US, it is marketed under the brand name, Nurtec ODT.[1]

It is not indicated for the preventive treatment of migraine.[1] It is taken by mouth, to dissolve on the tongue.[1] It takes effect within an hour and can provide relief for up to 48 hours, according to Biohaven. It is not a narcotic and has no addictive potential, and consequently will not be designated a controlled substance. It works by blocking CGRP receptors. 86% of patients did not require additional rescue medication within 24 hours of a single dose of Nurtec. All this info was obtained from a press release from Biohaven. (https://www.prnewswire.com/news-releases/biohavens-nurtec-odt-rimegepant-receives-fda-approval-for-the-acute-treatment-of-migraine-in-adults-301013021.html)

Rimegepant was approved for use in the United States as of February 27th, 2020 by the U.S. Food and Drug Administration (FDA) to be produced and marketed by Biohaven Pharmaceuticals.[2]

Charlie Conway

Charlie Conway, Chief Scientific Officer at Biohaven Pharmaceuticals

Vlad Coric, M.D.

Vlad Coric, M.D., CEO at Biohaven

No alternative text description for this image

 

clip

https://www.biohavenpharma.com/investors/news-events/press-releases/02-27-2020

BIOHAVEN’S NURTEC™ ODT (RIMEGEPANT) RECEIVES FDA APPROVAL FOR THE ACUTE TREATMENT OF MIGRAINE IN ADULTS
– First and only calcitonin gene-related peptide (CGRP) receptor antagonist available in a fast-acting orally disintegrating tablet (ODT)- A single oral dose of NURTEC ODT 75 mg can provide fast pain relief and return patients to normal function within one hour, and deliver sustained efficacy that lasts up to 48 hours for many patients- 86 percent of patients treated with a single dose of NURTEC ODT did not use a migraine rescue medication within 24 hours- Biohaven to host investor conference call on Friday, February 28, 2020 at 8:00 am ET

NEW HAVEN, Conn., Feb. 27, 2020 /PRNewswire/ — Biohaven Pharmaceutical Holding Company Ltd. (NYSE: BHVN) today announced that the U.S. Food and Drug Administration (FDA) has approved NURTEC™ ODT (rimegepant) for the acute treatment of migraine in adults. NURTEC ODT is the first FDA-approved product for Biohaven, a company dedicated to advancing innovative therapies for neurological diseases.

Nurtec™ ODT convenient 8-count package

NURTEC™ ODT Convenient 8-count Package

 NURTEC™ ODT zoom in showing one individual quick-dissolving tablet (not actual size)

A single quick-dissolving tablet of NURTEC ODT can provide fast pain relief and return patients to normal function within one hour, and deliver sustained efficacy that lasts up to 48 hours for many patients. NURTEC ODT disperses almost instantly in a person’s mouth without the need for water, offering people with migraine a convenient, discreet way to take their medication anytime and anywhere they need it. NURTEC ODT is not indicated for the preventive treatment of migraine. Biohaven expects topline results from its prevention of migraine trial later this quarter.

Vlad Coric, M.D., CEO of Biohaven commented, “The FDA approval of NURTEC ODT marks an important milestone for the migraine community and a transformative event for Biohaven. Millions of people suffering from migraine are often not satisfied with their current acute treatment, at times having to make significant tradeoffs because of troublesome side effects and reduced ability to function. NURTEC ODT is an important new oral acute treatment for migraine that offers patients the potential to quickly reduce and eliminate pain and get back to their lives.” Dr. Coric added, “We believe NURTEC ODT will be the first of many innovative Biohaven medicines to become available to treat devastating neurological diseases, a therapeutic category many other companies have abandoned. We are dedicated to helping patients with these conditions, who often have limited or no treatment options, live better, more productive lives.”

NURTEC ODT, with its novel quick-dissolve oral tablet formulation, works by blocking CGRP receptors, treating a root cause of migraine. NURTEC ODT is not an opioid or narcotic, does not have addiction potential and is not scheduled as a controlled substance by the U.S. Drug Enforcement Administration.

NURTEC ODT may offer an alternative treatment option, particularly for patients who experience inadequate efficacy, poor tolerability, or have a contraindication to currently available therapies. More than 3,100 patients have been treated with rimegepant with more than 113,000 doses administered in clinical trials, including a one-year long-term safety study. In the pivotal Phase 3 trial, NURTEC ODT was generally well tolerated; the most common adverse reaction was nausea (2%) in patients who received NURTEC ODT compared to 0.4% of patients who received placebo.

Mary Franklin, Executive Director of the National Headache Foundation commented, “Everyone knows someone living with migraine, yet it remains an invisible disease that is often overlooked and misunderstood. Almost all people with migraine need an acute treatment to stop a migraine attack as it occurs, which can happen without warning. The approval of NURTEC ODT is exciting for people with migraine as it provides a new treatment option to help people regain control of their attacks and their lives.”

Peter Goadsby, M.D., Ph.D., Professor of Neurology and Director of the King’s Clinical Research Facility, King’s College Hospital commented, “I see many patients in my practice whose lives are disrupted by migraine, afraid to go about everyday life in case of a migraine attack. Many feel unsure if their acute treatment will work and if they can manage the side effects. With the FDA approval of NURTEC ODT, there is renewed hope for people living with migraine that they can get back to living their lives without fear of the next attack.”

The FDA approval of NURTEC ODT is based on results from the pivotal Phase 3 clinical trial (Study 303) and the long-term, open-label safety study (Study 201). In the Phase 3 trial, NURTEC ODT achieved statistical significance on the regulatory co-primary endpoints of pain freedom and freedom from most bothersome symptom (MBS) at two hours post dose compared to placebo. NURTEC ODT also demonstrated statistical superiority at one hour for pain relief (reduction of moderate or severe pain to no pain or mild pain) and return to normal function. The benefits of pain freedom, pain relief, return to normal function and freedom from MBS were sustained up to 48 hours for many patients. Importantly, these benefits were seen with only a single dose of NURTEC ODT. Eighty-six percent of patients treated with NURTEC ODT did not require rescue medication (e.g. NSAIDS, acetaminophen) within 24 hours post dose. The long-term safety study assessed the safety and tolerability of rimegepant with multiple doses used over up to one year. The study evaluated 1,798 patients, who used rimegepant 75 mg as needed to treat migraine attacks, up to one dose per day. The study included 1,131 patients who were exposed to rimegepant for at least six months, and 863 who were exposed for at least one year, all of whom treated an average of at least two migraine attacks per month. The safety of treating more than 15 migraines in a 30-day period has not been established.

NURTEC ODT is contraindicated in patients with a history of hypersensitivity to rimegepant, NURTEC ODT, or to any of its components. Hypersensitivity reactions with dyspnea and severe rash, including delayed serious hypersensitivity days after administration, occurred in less than 1% of subjects taking NURTEC ODT in clinical studies.

Biohaven Conference Call Information
Biohaven is hosting a conference call and webcast on Friday, February 28, 2020, at 8:00 a.m. ET.  Participants are invited to join the conference by dialing 877-407-9120 (toll-free) or 412-902-1009 (international). To access the audio webcast with slides, please visit the “Events & Presentations” page in the Investors section of the Company’s website.

Biohaven’s Commitment to Patient Access 
Biohaven is committed to supporting the migraine community by eliminating barriers to medication access. The company has launched a patient support program. For more information and to enroll, please call 1-833-4-NURTEC or visit www.nurtec.com.

NURTEC ODT will be available in pharmacies in early March 2020 in packs of eight tablets. Each eight tablet pack covers treatment of eight migraine attacks with one dose, as needed, up to once daily.  Sample packs containing two tablets will also be made available to healthcare providers. Patients with migraine should discuss with their primary care provider or neurologist whether NURTEC ODT is appropriate for them.

About NURTEC ODT
NURTEC™ ODT (rimegepant) is the first and only calcitonin gene-related peptide (CGRP) receptor antagonist available in a quick-dissolve ODT formulation that is approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine in adults. The activity of the neuropeptide CGRP is thought to play a causal role in migraine pathophysiology. NURTEC ODT is a CGRP receptor antagonist that works by reversibly blocking CGRP receptors, thereby inhibiting the biologic activity of the CGRP neuropeptide. The recommended dose of NURTEC ODT is 75 mg, taken as needed, up to once daily. For more information about NURTEC ODT, visit www.nurtec.com.

About Migraine
Nearly 40 million people in the U.S. suffer from migraine and the World Health Organization classifies migraine as one of the 10 most disabling medical illnesses. Migraine is characterized by debilitating attacks lasting four to 72 hours with multiple symptoms, including pulsating headaches of moderate to severe pain intensity that can be associated with nausea or vomiting, and/or sensitivity to sound (phonophobia) and sensitivity to light (photophobia). There is a significant unmet need for new acute treatments as more than 90 percent of migraine sufferers are unable to work or function normally during an attack.

About CGRP Receptor Antagonism
Small molecule CGRP receptor antagonists represent a novel class of drugs for the treatment of migraine. This unique mode of action potentially offers an alternative to current agents, particularly for patients who have contraindications to the use of triptans, or who have a poor response to triptans or are intolerant to them.

What is NURTEC ODT? 
NURTEC™ ODT (rimegepant) is indicated for the acute treatment of migraine with or without aura in adults.

No alternative text description for this image

Raising the “flag of freedom from migraine” over Biohaven headquarters in New Haven CT

Mechanism of action

Rimegepant is a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist.[3]

PATENTS

WO 2011046997

PATENT

WO 2012050764

https://patents.google.com/patent/WO2012050764A1

The disclosure generally relates to a synthetic process for preparing compounds of formula I including the preparation of chemical intermediates useful in this process. CGRP inhibitors are postulated to be useful in pathophysiologic conditions where excessive CGRP receptor activation has occurred. Some of these include neurogenic vasodilation, neurogenic inflammation, migraine, cluster headache and other headaches, thermal injury, circulatory shock, menopausal flushing, and asthma. CGRP antagonists have shown efficacy in human clinical trials. See Davis CD, Xu C. Curr Top Med Chem. 2008 8(16):1468-79; Benemei S, Nicoletti P, Capone JG, Geppetti P. Curr Opin Pharmacol 2009 9(1):9-14. Epub 2009 Jan 20; Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, Leibensperger H, Froman S, Assaid C, Lines C, Koppen H, Winner PK. Lancet. 2008 372:2115. Epub 2008 Nov 25; Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM; Neurology 2008 70: 1304. Epub 2007 Oct 3.

CGRP receptor antagonists have been disclosed in PCT publications WO 2004/092166, WO 2004/092168, and WO 2007/120590. The compound (5S,6S,9R)- 5-amino-6-(2,3-difluorophenyl)-6,7,8!9-tetrahydiO-5H-cyclohepta[b]pyridin-9-yl 4- (2-oxo-2,3-dihydiO-lH-imidazo[4,5-b]pyridin-l-yl)piperidine-l-carboxylate is an inhibitor of the calcitonin gene-related peptide (CGRP) receptor.

Figure imgf000004_0001
Figure imgf000005_0001

cheme 1 illustrates a synthesis of formula I compounds. heme 1,

Figure imgf000011_0001

DESCRIPTION OF SPECIFIC EMBODIMENTS

Figure imgf000012_0001

( 6S, 9R)-6~ (2, 3 -difluorophenyl)-9-(triisopropylsiIyloxy) – 6, 7, 8, 9-tetrahydro-5H- cyclohepta[b]pyridin-5 -amine. To a 100 mL hastelloy autoclave reactor was charged (6S,9R)-6-(2,3-difluorophenyl)-9-(triisopiOpylsilyloxy)-6,7,8,9-tetrahydi -5H- cyclohepta[b]pyridin-5-one (5.00 g, 1 1.22 mmol), 1,4-dioxane (50 mL) and titanium tetra(isopropoxide) (8.33 mL, 28.11 mmol). The reactor was purged three times with nitrogen and three times with ammonia. After the purge cycle was completed, the reactor was pressurized with ammonia to 100 psig. The reaction mixture was heated to 50°C (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig ammonia and 50°C for 20 h. The mixture was then cooled to 20°C then 5 % Pd/Alumina (1.0 g, 20 wt%) was charged to the autoclave reactor. The reactor was purged three times with nitrogen and three times with hydrogen. After the purged cycle completed, the reactor was pressurized with hydrogen to 100 psig and mixture was heated to 50°C (jacket temperature) and stirred at a speed to ensure good mixing. The reaction mixture was aged at 100 psig H2 and 50°C for 23h (reactor pressure jumped to -200 psig due to soluble ammonia in the mixture). The mixture was then cooled to 20 °C then filtered then transferred to a 100 ml 3-necked flask. To the mixture water (0.55 mL) was added drop wise, which resulted in yellow slurry. The resulting slurry was stirred for 30 mm then filtered, then the titanium dioxide cake was washed with 1,4-dioxane (30 mL). The filtrate was collected and the solvent was removed. The resulting oil was dissolved in isopropanol (40 mL). To the solution ~5N HC1 in isopropanol (9.0 ml) was added drop wise resulting in a thick slurry. To the slurry isopropyi acetate (60 ml) was added and heated to 45 °C for 10 min and then cooled to 22 °C over approximately 3 h to afford a white solid (3.0 g, 51.5 %). Ή NMR (500 MHz, CD3OD)

δ ppm 8.89 (d, J= 5.3, 1H), 8,42 (bs, 1H), 8.05 (bs, 1H), 7.35 (dd, J= 8.19 , 16.71), 7.2 (bs, 2H), 7.22 (m, 1H) 7.15 (m, 1H), 5.7 (dd, J = 1.89, J = 8.51), 5.4 (m, 1H), 3.5 ( m, 1H), 1.9-2.5 (B, 4h) 1.4 (sept, J = 15.13,3H), 1.2 (t, J= Ί.5Ί 18H); 13C NMR (125 MHz, CD3OD) δ 153.5, 151.6, 151.5, 151.3, 149.4, 143.4, 135.03, 129.8, 129.8, 127.8, 126.8, 126.4, 118.6, 72.4, 54.1, 41.4, 34.3, 32.3, 25.4, 18.6, 18.5, 13.7, 13.6, 13.5, 13.3.

Example 2

Figure imgf000013_0001

(6S,9R)-5-cmino-6-(2 -difluorophenyl)-6, 7,8,9-tetrahydro~5H-cyclohepta[b^ 9-o To a 250 ml flask was charged (6S,9R)-6-(253-difluoiOphenyl)-9-

(tnisopiOpylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-amine di HC1 salt (15 g, 25.88 mtnol) and a solution of isopropanol: water (45 mL : 15 mL). The mixture was heated to 82 °C for 6h then dried via azeotropic distillation at atmospheric pressure using isopropanol until the KF was less than < 3 %. After fresh isopropanol (25 ml) was added, the mixture was heated to 70 °C and then isopropyl acetate (45 ml) was added that resulting in a white slurry. The slurry cooled to 22 °C for 15 min to afford a white solid (9.33 g, 99%). 1H NMR (500 MHz CD3OD) δ 8.77 (d, J= 5.7 Hz, 1H), 8.47 (d, J= 7.9 Hz, 1H), 8.11 (dd, J= 6.0, 8.2 Hz, 1H), 7.21-7.32 (m, 3H), 5.53 (dd, J= 3.8, 9.8 Hz, 1H) 5.33 (d, J = 9.8 Hz, 1H), 3.5 (bm, 1H), 2.25- 2.40 (m, 2H), 2.15 (bm, 1H), 1.90 (bm, 1H); 13C NMR (125 MHz, MeOD) δ 159.4, 153.9, 151.9 and 151.8, 149.7, 143.6, 141.8, 135.7, 130.6, 127.7, 126.8, 1 18.9, 70.0, 54.9, 42.2, 34.5, 33.4. Example 3

Figure imgf000014_0001

(5S, 6S, 9R)-5-amino-6-(2, 3-difluorophenyl)-6, 7>8,9-tetrahydro-5H- cyclohepta[b ]pyridin-9~yl~4-(2-oxo-2, 3-dihydro-lH-imidazo[4, 5-b ]pyridin-l- yl)piperidine-l-carboxylate. To a round bottom flask was charged (5S,6S,9R)-5- amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol dihydrochloride (1.00 g, 2.73 mmol) and dichloromethane (15 mL). A solution of sodium carbonate (0.58 g, 5.47 mmol), 20 wt% aqueous sodium chloride (5 mL), and water (10 mL) was added and the biphasic mixture was aged for 30 min. The phases were allowed to separate and the organic stream was retained. The dichloromethane solvent was then switched with azeotropic drying to tetrahydrofuran, with a final volume of (15 mL). At 20 °C was added, l-(l-(lH~imidazole-l-carbonyl)piperidin- 4-yl)-lH-imidazo[4,5-b]pyridin-2(3H)-one (0.95 g, 3.01 mmol), followed by a 20 wt% potassium ter/-butoxide solution in THF (4 mL, 6.20 mmol). The thin slurry was aged for lh, and then the reaction was quenched with the addition of 20 wt% aqueous sodium chloride (5 mL) and 20 wt% aqueous citric acid (2.5 mL). The layers were allowed to separate and the organic rich layer was retained. The organic layer was washed with 20 wt% aqueous sodium chloride (1 mL). The organic tetrahydrofuran stream was then concentrated in vacuo to afford an oil which was resuspended in dichloromethane (20 mL) and dried with MgS04. The

dichloromethane stream was concentrated in vacuo to afford an oil, which was crystallized from ethanohheptane to afford a white solid (1.14 g, 78.3%). LCMS: [M+H] = 535: 1H MR (600 MHz, 6-DMSO) δ 11.58 (IH, bs), 8.45 (IH, bd), 8.03 (IH, d, J= 7.3 Hz), 7.91 (IH, bs), 7.54 (IH, bd), 7.36 (IH, bm), 7.34 (IH, bm), 7.28 (IH, m), 7.21 (IH, m), 7.01 (IH, bs), 6.01 (IH, dd, J= 3.2, 9.8 Hz), 4.48 (IH, d, J= 9.5 Hz), 4.43 (IH, bm), 4.38 (IH, bm), 4.11 (IH, bm), 3.08 (IH, bm), 2.93 (IH, bm), 2.84 (IH, m), 2.62 (IH, bm), 2.20 (2H, bm), 2.13 (IH, bm), 2.12 (IH, bm), 1.75 (IH, bm), 1.72 (1H, bm), 1.66 (1H, bm); C NMR (125 MHz, i/6-DMSO) δ 156.6, 154.2, 153.0, 149.8, 148.1, 146.4, 143.5, 139.6, 137.4, 134.0, 132.8, 124.7, 124.5, 123.3, 122.2, 116.3, 115.0, 114.3, 73.7, 52.8, 50.0, 43.8, 43.3, 32.0, 30.3, 28.6; nip 255°C.

Example 4

Figure imgf000015_0001

l-(l-(lH^mdazole-l-carbonyl)piperidin-4-yl)-lH-imidazo

To a round bottom flask was added, Ι,Γ-carbonyldiimidazole (8.59 g, 51.4 mmoi), diisopropylethylamine (12.6 mL, 72.2 mmol) and tetrahydrofuran (100 niL). This mixture was warmed to 40°C and aged for 10 min, after which l-(piperidin-4-yl)-lH- imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (10 g, 34,3 mmol) was added. The slurry was aged at 40 °C for 3 h, and then upon reaction completion, the solvent was swapped to acetonitrile which afforded an off white solid (9.19 g, 85.9%). LCMS: [M+H] = 313; Ή NMR (400 MHz, 6-DMSO) δ 11.58 (1H, s), 8.09 (1H, s), 7.97 (1H, d, J= 8.0 Hz), 7.73 (1H, d, J= 4.0 Hz), 7.53 (1H, s), 7.05 (1H, s), 7.00 (1H, dd, J= 4.0, 8.0 Hz), 4.52, (1H, dd, J= 8.0, 12.0 Hz), 4.05 (2H, bd, J= 8,0 Hz), 3.31 (2H, m), 2.34 (2H, m), 1.82 (2H, bd, J = 12.0 Hz); 13C NMR (100 MHz, i/6~DMSO) δ 153.0, 150.4, 143.4, 139.8, 137.2, 128.9, 123.0, 1 18.7, 116.4, 115.2, 49.3, 45.1 , 28.5; mp 226°C.

Example 5

Figure imgf000015_0002

l-(l-(lH-imidazole-l-carbonyl)piperidin-4-yl)-lH-imidazo[4,5

To a 250 ml round bottom flask was added 3-N-piperidin-4-ylpyridine-2, 3 -diamine dihydrochloride (10 g, 52 mmol) and acetonitrile (100 mL). Triethyl amine (11.44 g, 1 13 mmol) and 1 , -Carbonyldiimidazole (18.34 g, 113 mmol) were added at ambient temperature and the mixture was stirred for 2 h. The solvent was evaporated under vacuum to—30 ml reaction volume and isopropyl acetate (50 mL) was added into the resulting sluny at 40°C. The slurry was cooled to 10-15 °C and then stirred for 1 h to afford an off white solid (10 g, 85%).

PATENT

US 20130225636

EP 2815749

PAPER

 Journal of Medicinal Chemistry (2012), 55(23), 10644-10651.

https://pubs.acs.org/doi/full/10.1021/jm3013147

Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe the design, synthesis, and preclinical characterization of a highly potent, oral CGRP receptor antagonist BMS-927711 (8). Compound 8 has good oral bioavailability in rat and cynomolgus monkey, attractive overall preclinical properties, and shows dose-dependent activity in a primate model of CGRP-induced facial blood flow. Compound 8 is presently in phase II clinical trials.

PAPER

Organic letters (2015), 17(24), 5982-5.

https://pubs.acs.org/doi/full/10.1021/acs.orglett.5b02921

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi–Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.

History

Originally discovered at Bristol-Myers Squibb,[4] it was under development by Biohaven Pharmaceuticals and is now also being marketed in the US by the same company after receiving FDA approval late February 2020.[5]

References

  1. Jump up to:a b c “Nurtec ODT (rimegepant) orally disintegrating tablets, for sublingual or oral use” (PDF). February 2020. Retrieved 27 February 2020.
  2. ^ “Nurtec ODT: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 28 February 2020.
  3. ^ Diener HC, Charles A, Goadsby PJ, Holle D (October 2015). “New therapeutic approaches for the prevention and treatment of migraine”. The Lancet. Neurology14 (10): 1010–22. doi:10.1016/S1474-4422(15)00198-2PMID 26376968.
  4. ^ “Rimegepant – Biohaven Pharmaceuticals Holding Company”Adis Insight. Springer Nature Switzerland AG.
  5. ^ “Rimegepant (BHV-3000) – for acute treatment of Migraine”. Biohaven Pharmaceuticals.

External links

Rimegepant
Rimegepant.svg
Clinical data
Trade names Nurtec ODT
Other names BHV-3000, BMS-927711
License data
Routes of
administration
By mouth
Drug class calcitonin gene-related peptide receptor antagonist
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
Chemical and physical data
Formula C28H28F2N6O3
Molar mass 534.568 g·mol−1
3D model (JSmol)

//////////Rimegepant , リメゲパント硫酸塩, Rimegepant sulfate,  migraine, BMS-927711, fda 2020

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

1: Nakagawa H, Nemoto O, Yamada H, Nagata T, Ninomiya N. Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis. J Dermatol. 2018 Jun;45(6):701-709. doi: 10.1111/1346-8138.14322. Epub 2018 Apr 17. PubMed PMID: 29665062; PubMed Central PMCID: PMC6001687.

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.

8: Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, Noji S, Shiozaki M, Matsuo A, Shinozaki Y, Matsushita M. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015 Jan;64(1):41-51. doi: 10.1007/s00011-014-0782-9. Epub 2014 Nov 12. PubMed PMID: 25387665; PubMed Central PMCID: PMC4286029.

/////////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

CC1CN(C12CCN(C2)C3=NC=NC4=C3C=CN4)C(=O)CC#N

Dotinurad ドチヌラド


Dotinurad.png

2D chemical structure of 1285572-51-1

Dotinurad

ドチヌラド

(3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2H-1,3-benzothiazol-3-yl)methanone

Formula
C14H9Cl2NO4S
CAS
1285572-51-1
Mol weight
358.1966

PMDA, Urece, APROVED JAPAN 2020/1/23, Antihyperuricemic
305EB53128UNII-305EB53128

1285572-51-1,

VOFLAIHEELWYGO-UHFFFAOYSA-N

HY-109031

CS-0030545

Dotinurad is a urate transporter inhibitor.

Patents

WO 2011040449

https://patents.google.com/patent/WO2011040449A1/en

Uric acid is produced by metabolizing a purine produced by the degradation of a nucleic acid in the body and adenosine triphosphate (ATP), which is an energy source of the living body, to xanthine, and further undergoes oxidation by xanthine oxidase or xanthine dehydrogenase. In humans, uric acid (dissociation constant pKa = 5.75) is the final metabolite of purines and exists in the body as free forms or salts.

Uric acid is normally excreted in the urine, but when uric acid production exceeds excretion and blood uric acid increases, hyperuricemia occurs. If a state in which the blood level of uric acid exceeds the upper limit of solubility (about 7 mg / dL) continues for a long period of time, crystals of urate (usually sodium salt) precipitate. 
In the blood, the precipitated crystals deposit on cartilage tissue and joints, form precipitates and become gouty nodules, causing acute gouty arthritis, and then transition to chronic gouty arthritis. 
When uric acid crystals are precipitated in urine, renal disorders such as interstitial nephritis (gouty kidney), urinary calculi, and the like are caused. After the seizures of acute gouty arthritis have subsided, drug therapy is given along with lifestyle improvement guidance to correct hyperuricemia. 
Correcting hyperuricemia and appropriately managing uric acid levels are also important in preventing acute gouty arthritis, gouty kidneys, urinary tract stones, and the like.

Hyperuricemia is considered to be associated with a high rate of lifestyle-related diseases such as obesity, hyperlipidemia, impaired glucose tolerance, and hypertension (see Non-Patent Document 1 (pp7-9)). Increased serum uric acid levels are positively related to cardiovascular mortality, and higher serum uric acid levels increase mortality due to ischemic heart disease. It has been suggested that it is associated with the risk of death from disease (see Non-Patent Document 2). 
Furthermore, serum uric acid levels have also been shown to be a powerful risk factor for myocardial infarction and stroke (see Non-Patent Document 3). To date, hyperuricemia is obesity, hyperlipidemia, dyslipidemia, impaired glucose tolerance, diabetes, metabolic syndrome, kidney disease (eg, renal failure, urine protein, end-stage renal disease (ESRD), etc.), heart It is known to be associated with vascular diseases (for example, hypertension, coronary artery disease, carotid artery disease, vascular endothelial disorder, arteriosclerosis, cardiac hypertrophy, cerebrovascular disease, etc.) or risk factors of these diseases (Non-Patent Documents 2 to 11) reference). In cerebrovascular dementia, it has also been reported that the concentration of uric acid in the cerebrospinal cord is increased (see Non-Patent Document 12).

Under such circumstances, it has been suggested that the treatment for lowering the blood uric acid level may delay the progression of kidney disease and reduce the risk of cardiovascular disease (Non-Patent Documents 5, 8, 13, 14), it has been reported that it should also be applied to asymptomatic hyperuricemia (see Non-Patent Document 14).

Therefore, reducing the blood uric acid level in the above-mentioned diseases is effective for the treatment or prevention of these diseases, and is considered to be important in terms of preventing recurrence of cardiovascular accidents and maintaining renal function.

The main factors that increase blood uric acid levels include excessive uric acid production and decreased uric acid excretion. Therefore, as a method for lowering blood uric acid level, it is conceivable to suppress the production of uric acid or promote the excretion of uric acid, and allopurinol is a drug having the former mechanism of action (uric acid production inhibitor). Benzbromarone, probenecid, JP-A 2006-176505 (Patent Document 1) and the like are known as drugs having the latter mechanism of action (uric acid excretion promoters).

According to the Japanese guidelines for treatment of hyperuricemia and gout, in principle, uric acid excretion-promoting agents are applied to hyperuricemia-reducing types and uric acid production-inhibiting agents are applied to excessive uric acid production types, respectively. (See Non-Patent Document 1 (pp31-32)).

In Japan, it is said that about 60% of hyperuricemia patients have a reduced uric acid excretion type, and about 25% are a mixed type of reduced uric acid excretion type and excessive uric acid production type (Non-patent Document 15). About 85% of the patients showed a decrease in uric acid excretion, and the average value of uric acid clearance was significantly lower than that of healthy individuals even in patients with excessive uric acid production, and the decrease in uric acid excretion was fundamental in all gout patients. Is also reported (Non-Patent Document 16). 
Therefore, in hyperuricemia (especially gout), treatment for patients with reduced uric acid excretion is considered to be important, and the existence significance of uric acid excretion promoters is extremely large.

Among the major uric acid excretion promoters, probenecid is weakly used and is rarely used because of its gastrointestinal tract disorders and interactions with other drugs. On the other hand, severe liver damage has been reported for benzbromarone, which has a strong uric acid excretion promoting action and is widely used in Japan as a uric acid excretion promoting drug (see Non-Patent Document 17). 
Benzbromarone or its analogs inhibit mitochondrial respiratory chain enzyme complex activity, uncoupling action, respiration inhibition, fatty acid β oxidation inhibition, mitochondrial membrane potential reduction, apoptosis, generation of reactive oxygen species, etc. Has been suggested to be involved in the development of liver damage (see Non-Patent Documents 18 and 19). Hexahydrate, which is the active body of benzbromarone, is also toxic to mitochondria. 
Furthermore, benzbromarone has an inhibitory action on cytochrome P450 (CYP), which is a drug metabolizing enzyme. In particular, the inhibition against CYP2C9 is very strong, suggesting the possibility of causing a pharmacokinetic drug interaction (non-) (See Patent Documents 20 and 21).

Furthermore, although a nitrogen-containing fused ring compound having a URAT1 inhibitory action, which is a kind of uric acid transporter, and having a structure similar to that of the compound of the present invention is described in JP-A-2006-176505 (Patent Document 1), the effect is sufficient. In addition, no practical uric acid excretion promoter has been developed yet.

Recently, it has been found that the uric acid excretion promoting action depends on the urinary concentration of a drug having the same action, that is, the uric acid excretion promoting drug is excreted in the urine and exhibits a medicinal effect (Patent Document 2). Non-Patent Documents 22 and 23). 
Therefore, a stronger pharmacological effect is expected if it is a uric acid excretion promoter that is excreted more in the urine, but the above existing uric acid excretion promoters have a very low concentration in urine, and a satisfactory activity can be obtained sufficiently. I can’t say that.

Regarding the urinary excretion of drugs, it is assumed that the administered drug is excreted as it is as an unchanged form or converted into an active metabolite and excreted. In the latter case, the active metabolite is produced. There is a risk that the individual difference in the amount becomes large, and in order to obtain stable drug efficacy and safety, a drug excreted as an unchanged substance is more desirable.

As described above, there is a demand for the development of a highly safe pharmaceutical having a high unchanged body urine concentration and a remarkable uric acid excretion promoting action as compared with existing uric acid excretion promoting drugs.

JP 2006-176505 A WO2005 / 121112

Treatment Guidelines for Hyperuricemia and Gout (1st Edition) pp7-9 and pp31-32, Gout and Nucleic Acid Metabolism, Volume 26, Supplement 1, 2002 Japan Gout and Nucleic Acid Metabolism Society JAMA 283: 2404-2410 (2000) Stroke 37: 1503-1507 (2006) Nephrology 9: 394-399 (2004) Semin. Nephrol. 25: 43-49 (2005)J. Clin. Hypertens. 8: 510-518 (2006) J. Hypertens. 17: 869-872 (1999) Curr. Med. Res. Opin. 20: 369-379 (2004) Curr. Pharm. Des. 11: 4139-4143 (2005)Hypertension 45: 991-996 (2005) Arch. Intern. Med. 169: 342-350 (2009) J. Neural. Transm. Park Dis. Dement. Sect. 6: 119-126 (1993) Am. J. Kidney Dis. 47: 51-59 (2006) Hyperuricemia and gout 9: 61-65 (2001) Japanese clinical trials 54: 3230-3236 (1996) Japanese clinical trial 54: 3248-3255 (1996) J. Hepatol. 20: 376-379 (1994) J. Hepatol. 35: 628-636 (2001) Hepatology 41: 925-935 (2005) Saitama Medical University Journal (J. Saitama. Med. School) 30: 187-194 (2004) Drug Metab. Dispos. 31: 967-971 (2003) 42nd Annual Meeting of the Japanese Gout and Nucleic Acid Metabolism General Assembly Program / Abstracts, p59 (2009) ACR 2008 Annual Scientific Meeting, No. 28

Figure JPOXMLDOC01-appb-I000003

Figure JPOXMLDOC01-appb-I000004

Figure JPOXMLDOC01-appb-I000005

Figure JPOXMLDOC01-appb-I000006

Figure JPOXMLDOC01-appb-I000007

Figure JPOXMLDOC01-appb-I000008

PATENT

JP 2011074017

PATENT

WO 2018199277

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018199277

//////////Dotinurad, Antihyperuricemic, JAPAN 2020, 2020 APPROVALS , ドチヌラド  , VOFLAIHEELWYGO-UHFFFAOYSA-NHY-109031CS-0030545

C1N(C2=CC=CC=C2S1(=O)=O)C(=O)C3=CC(=C(C(=C3)Cl)O)Cl

Teprotumumab-trbw


Image result for teprotumumab-trbw

Tepezza (teprotumumab-trbw)

Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease

UNIIY64GQ0KC0A

CAS number1036734-93-6

R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001

Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).

FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020

Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.

“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”

Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.

Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.

The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.

The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.

The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.

Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]

The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]

It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.

Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphomanon-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.

Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough TherapyOrphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]

In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]

History[edit]

Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]

Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]

The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]

References

  1. Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ https://clinicaltrials.gov/ct2/show/NCT01868997
  3. ^ http://adisinsight.springer.com/drugs/800015801
  4. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  5. ^ http://adisinsight.springer.com/drugs/800015801
  6. ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
  7. ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”The New England Journal of Medicine376 (18): 1748–1761. doi:10.1056/NEJMoa1614949PMC 5718164PMID 28467880.
  8. ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”Horizon Pharma plc. Retrieved 22 March 2019.
  9. ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”Horizon Therapeutics plc. Retrieved 27 August 2019.

External links

Teprotumumab
Monoclonal antibody
Type Whole antibody
Source Human
Target IGF-1R
Clinical data
Other names teprotumumab-trbw, RG-1507
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard 100.081.384 Edit this at Wikidata
Chemical and physical data
Formula C6476H10012N1748O2000S40
Molar mass 145.6 kg/mol g·mol−1

/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza,  Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS,  active thyroid eye disease, Teprotumumab

https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease

Avapritinib, アバプリチニブ , авапритиниб , أفابريتينيب ,


Image result for Avapritinib

Avapritinib.png

ChemSpider 2D Image | avapritinib | C26H27FN10

Avapritinib

BLU-285, BLU285

Antineoplastic, Tyrosine kinase inhibitor

アバプリチニブ

авапритиниб [Russian] [INN]
أفابريتينيب [Arabic] [INN]

(1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine

(1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl}-5-pyrimidinyl)ethanamine
10613
1703793-34-3 [RN]
513P80B4YJ
5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-
(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine
(αS)-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-5-pyrimidinemethanamine
Formula
C26H27FN10
CAS
1703793-34-3
Mol weight
498.558
No. Drug Name Active Ingredient Approval Date FDA-approved use on approval date*
1. Ayvakit avapritinib 1/9/2020 To treat adults with unresectable or metastatic gastrointestinal stromal tumor (GIST)

PRIORITY; Orphan, 

Avapritinib, sold under the brand name Ayvakit, is a medication used for the treatment of tumors due to one specific rare mutation: It is specifically intended for adults with unresectable or metastatic ( y) gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.[1]

Common side effects are edema (swelling), nauseafatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairmentvomitingdecreased appetitediarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal painconstipationrash. and dizziness.[1]

Ayvakit is a kinase inhibitor.[1]

History

The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020.[1] The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation.[1] The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.[1]

Avapritinib was approved based on the results from the Phase I NAVIGATOR[2][3] clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation.[1] Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity.[1] The recommended dose was determined to be 300 mg once daily.[1] The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).[1] For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response.[1] For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response.[1] While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).[1]

PATENT

WO 2015057873

https://patents.google.com/patent/WO2015057873A1/en

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Figure imgf000080_0001
Figure imgf000080_0002

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

Figure imgf000081_0001

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na2S04, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C25H22FN90 requires: 483, found: 484 [M + H]+.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

Figure imgf000081_0002

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l- methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5- yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C29H3iFN10OS requires: 586, found: 587 [M + H]+.

Step 3: Synthesis of (lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

Figure imgf000082_0001

(lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na2S04, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C3oH35FN10OS requires: 602, found: 603 [M + H]+. Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

Figure imgf000083_0001

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1- /] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4- yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C26H27FN10requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]+.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- 1 -yl)pyrimidin- -yl)ethanamine:

Figure imgf000083_0002

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH- pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (lS,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C26H27FN10 requires: 498, found: 499 [M + H]+.

References

  1. Jump up to:a b c d e f g h i j k l m “FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors”U.S. Food and Drug Administration (FDA) (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.  This article incorporates text from this source, which is in the public domain.
  2. ^ “Blueprint Medicines Announces FDA Approval of AYVAKIT (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor”Blueprint Medicines Corporation (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.
  3. ^ “Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy”Blueprint Medicines Corporation (Press release). 15 November 2018. Archived from the original on 10 January 2020. Retrieved 9 January 2020.

Further reading

  • Wu CP, Lusvarghi S, Wang JC, et al. (July 2019). “Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines”. Mol. Pharm16 (7): 3040–3052. doi:10.1021/acs.molpharmaceut.9b00274PMID 31117741.
  • Gebreyohannes YK, Wozniak A, Zhai ME, et al. (January 2019). “Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors”. Clin. Cancer Res25 (2): 609–618. doi:10.1158/1078-0432.CCR-18-1858PMID 30274985.

External links

Avapritinib
Clinical data
Trade names Ayvakit
Other names BLU-285, BLU285
License data
Routes of
administration
By mouth
Drug class Antineoplastic agents
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C26H27FN10
Molar mass 498.570 g·mol−1
3D model (JSmol)

///////Avapritinib, 2020 APPROVALS, PRIORITY, Orphan, BLU-285, BLU285, FDA 2020,  Ayvakit, アバプリチニブ  , авапритиниб أفابريتينيب 

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