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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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ZYIL 1


Z 1

CAS 2254433-37-7

Z 1

CAS 2254432-75-0

High probabilty

ZYIL 1

TWO PREDICTIONS

Cryopyrin-associated periodic syndromes

ZYIL-1 is an oral, small-molecule inhibitor of the NLRP3 inflammasome in phase II clinical development at Zydus (formerly known as Cadila Healthcare and Zydus Cadila) for the treatment of cryopyrin-associated periodic syndromes (familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal onset multi-systemic inflammatory disease (NOMID; also known as chronic infantile neurologic cutaneous articular syndrome (CINCA)).

https://clinicaltrials.gov/ct2/show/NCT05186051

Condition or disease Intervention/treatment Phase 2
Cryopyrin Associated Periodic Syndrome

ZYIL1 is expected to show benefit in patients with CAPS. The present study aims to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of ZYIL1 when administered to subjects with CAPS.This is a phase 2a, prospective, open-label study. Primary objective of the study is to determine safety and tolerability profile of twice daily oral administration of ZYIL1 administered for 7 days. The study will be conducted in 3 subjects having CAPS as per eligibility criteria. The study will be divided in three periods: Screening Period; Run-in Period and Study Period.

Zydus announces positive Phase 2 Proof-of-Concept of NLRP3 inhibitor, ZYIL1 in patients with Cryopyrin Associated Periodic Syndrome (CAPS)

https://pipelinereview.com/index.php/2022090781551/Small-Molecules/Zydus-announces-positive-Phase-2-Proof-of-Concept-of-NLRP3-inhibitor-ZYIL1-in-patients-with-Cryopyrin-Associated-Periodic-Syndrome-CAPS.html

First Phase 2 Proof-of-Concept (POC) study demonstrating rapid clinical improvement and remission within days when Cryopyrin Associated Periodic Syndrome (CAPS) patients with flare ups were treated with ZYIL1, a novel oral small molecule NLRP3 inhibitor

Phase 1 study in Healthy Human volunteers published in “Clinical Pharmacology in Drug Development” Journal of American College of Clinical Pharmacology

AHMEDABAD, India I September 07, 2022 I Zydus Lifesciences Ltd. (formerly known as Cadila Healthcare Ltd.), a discovery-driven, global lifesciences company today announced that it has achieved a positive Proof-of-Concept in its Phase 2 clinical study of ZYIL1, in patients with CAPS.

CAPS is a rare, life-long, auto-inflammatory condition, caused by NLRP3 activating mutations and is classified as an orphan disease. The chronic inflammation due to IL-1beta release in CAPS patients leads to urticaria-like rash, fever, arthralgia, and increased risk of amyloidosis. CAPS patients also experience multiple neurological complications like sensorineural hearing loss, migraine, headache, aseptic meningitis and myalgia. Bone deformities and neurological impairments have been reported in Neonatal Onset Multisystem Inflammatory Disease (NOMID), the most severe form of CAPS.

The Phase 2 trial conducted in Australia, evaluated the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZYIL1 in Subjects with Cryopyrin Associated Periodic Syndromes (CAPS) [ClinicalTrials.gov Identifier: NCT05186051]. ZYIL1 showed rapid oral absorption. ZYIL1 is extremely potent (IC50 in nanomolar range) in human whole blood and supressed inflammation caused by the NLRP3 inflammasome. Robust effect on disease biomarkers including CRP, Serum Amyloid A (SAA), IL-6, WBC, was also observed.

ZYIL1 was safe and well-tolerated and there were no Serious Adverse Events (SAE’s) observed in this Phase 2 trial. Liver and kidney function tests also did not show any abnormalities in this Phase 2 trial. CAPS patients with confirmed NLRP3 mutation suffering from CAPS-related flare up, when treated with ZYIL1 in Phase 2 Proof-of-Concept trial showed rapid clinical improvement as early as day 3 which sustained till the end of treatment.

Lauding the positive proof-of-concept results achieved in CAPS patients as a significant milestone, Mr. Pankaj R. Patel, Chairman, Zydus Lifesciences Ltd. said, “As an innovation driven organization, we have been focussed on making a meaningful difference in the lives of patients. This top-line result from the Phase 2 clinical trial has demonstrated for the first time that ZYIL1, an oral small molecule NLRP3 inhibitor is beneficial in treating chronic inflammation in CAPS patients. Zydus is now planning to conduct further pivotal clinical trials and is committed to develop ZYIL1 for patients living with CAPS and other chronic inflammatory diseases.”

Reference:

1.   ClinicalTrials.gov Identifier: NCT04972188 A Phase I, Prospective, Open Label, Multiple Dose Study of ZYIL1 Administered Via Oral Route to Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics In Healthy Adult Subjects

2.   ClinicalTrials.gov Identifier: NCT04731324 A Phase 1, Prospective Open Label, Single

Dose, Single Arm Study of ZYIL1 Administered Via Oral Route to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics in Healthy Adult Human Subjects

3.   ClinicalTrials.gov Identifier: NCT05186051 A Phase 2a, Prospective, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of ZYIL1 in Subjects With Cryopyrin Associated Periodic Syndromes (CAPS)

4.   Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Oral NLRP3 Inflammasome Inhibitor ZYIL1: First-in-human Phase 1 studies (Single Ascending Dose and Multiple Ascending Dose), Clinical Pharmacology in Drug Development, 2022. DOI: 10.1002/cpdd.1162

About Zydus

The Zydus Group with an overarching purpose of empowering people with freedom to live healthier and more fulfilled lives, is an innovative, global lifesciences company that discovers, develops, manufactures, and markets a broad range of healthcare therapies. The group employs over 23000 people worldwide and is driven by its mission to unlock new possibilities in life- sciences through quality healthcare solutions that impact lives. The group aspires to transform lives through path-breaking discoveries. For more details visit www.zyduslife.com

PATENTs

WO2021171230

WO2021111351

WO2021048809, IN202227014064

WO2020148619, EP3911631

WO2019043610, IN202027008328

US2020140382, IN201927046556, WO2018225018

PATENT

Z 1

N-Cyano-N’-[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]-4-methylbenzene-1-sulfonimidoamide

Molecular Formula

C21 H22 N4 O2 S

Molecular Weight

394.49

N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzene sulfonimidamide

      N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfinamide (1.0 eq.) was taken in MeCN (10 mL) under N2 atm. Solid cyanamide (2.1 eq.), potassium tert-butoxide (2 eq.) and N-Chlorosuccinimide (1.2 eq.) were added subsequently. The resulted suspension was stirred further for 3 h at RT. Upon completion of starting material, reaction mixture was concentrated under reduced pressure. it was diluted with Ethyl Acetate (15 mL) and water, layers were separated, aq. layer was back extracted with Ethyl Acetate (15 mL×4), all org. layer was combined and washed with water (15 mL), brine (15 mL), dried it over Na 2SO and conc. under reduced pressure at 45° C. to yield crude product, which was purified by preparative HPLC to afford N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzene sulfonimidamide.
1H NMR (400 MHz, DMSO-d 6): δ=7.91 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 6.78 (s, 1H), 2.75-2.67 (m, 4H), 2.65-2.56 (m, 4H), 2.34 (s, 3H), 1.92-1.83 (m, 4H); MS (ESI): m/z (%)=395.10 (100%) (M+H) +, 393.15 (100%) (M+H)

ACS Medicinal Chemistry Letters (2020), 11(4), 414-418

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.9b00433

NLRP3 inflammasome mediated release of interleukin-1β (IL-1β) has been implicated in various diseases. In this study, rationally designed mimics of sulfonylurea moiety were investigated as NLRP3 inhibitors. Our results culminated into discovery of series of unprecedented N-cyano sulfoximineurea derivatives as potent NLRP3 inflammasome inhibitors. Compound 15 (IC50 = 7 nM) and analogs were found to be highly potent and selective NLRP3 inflammasome inhibitor with good pharmacokinetic profile. These effects translate in vivo, as 15, 29, and 34 significantly inhibit NLRP3 dependent IL-1β secretion…

N’-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide (15). White solid; mp: 228.5 °C; 1H NMR (400 MHz, DMSO-d6): δ = 7.91 (s, 1H, -NHC=O), 7.65 (d, J = 8.0 Hz, 2H, 2 CH arom), 7.27 (d, J = 8.0 Hz, 2H, 2 CH arom), 6.78 (s, 1H, CH arom), 2.75 – 2.67 (m, 4H, 2 CH2), 2.65 – 2.56 (m, 4H, 2 CH2), 2.34 (s, 3H, C6H4-CH3), 1.92 – 1.83 (m, 4H, 2 CH2); 13C NMR and DEPT (100 MHz, DMSO-d6): δ = 158.1 (C, C=O), 142.7 (C), 142.35 (C), 141.0 (C), 137.7 (C), 132.3 (C), 129.1 (CH), 126.9 (CH), 117.6 (CN), 116.7 (CH), 33.0 (CH2), 30.87 (CH2), 25.5 (CH2), 21.3 (CH3); MS (ESI): m/z (%) = 395.10 (100) (M+H)+ ; ESI-Q-TOF-MS: m/z [M+H]+ calcd for [C21H23N4O2S]+ : 395.1542; found: 395.1578; IR (KBr): ν = 3433(N-H), 3230 (N-H), 2949 (CH3), 2191 (CN), 1599 (C=O),, 1531 (N-H), 1323 (CH2-Ar), 1234 (C-N) cm-1

SECOND ONE

PATENT

NLRP3 inflammasome inhibitors reported to be useful for the treatment of cancer, inflammation, neurodegeneration, heteroimmune and autoimmune disease, among others. An exemplified compound (Ex 65 pg 46; EN 1027626) inhibited lipopolysaccharide (LPS)-stimulated IL-1beta production in phorbol 12-myristate 13-acetate (PMA)-differentiated human acute monocytic leukemia THP-1 cells (IC50 = 1.26 nM).

Z 1

N’-Cyano-N-[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidoamide

Molecular Formula

C22 H25 N5 O3 S

Molecular Weight

439.531

 

N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide


(MOL)(CDX)
1H NMR (400 MHz, DMSO): δ=8.75-8.72 (m, 2H), 8.22-8.14 (m, 2H), 6.80 (s, 1H), 5.43 (s, 1H), 2.90-2.60 (m, 8H), 1.99-1.76 (m, 4H), 1.48 (s, 3H), 1.47 (s, 3H); MS (ESI): m/z (%)=439.83 (100%) (M+H) +.

/////////

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old………..

Zydus Cadila gets approval from DCGI for trial of novel molecule ZYIL1

https://www.livemint.com/companies/news/zydus-cadila-gets-approval-from-dcgi-for-trial-of-novel-molecule-zyil1-11607324599234.html

Drug firm Zydus Cadila on Monday said it has received permission from Drugs Controller General of India (DCGI) to initiate phase-1 clinical trial of its novel molecule ZYIL1, indicated for use as an inhibitor for inflammation condition ‘NLRP3’.

In a regulatory filing, Zydus Cadila said “it has received permission to initiate the phase 1 clinical trial of ZYIL1, a novel oral small molecule NLRP3 inhibitor candidate. NLRP3 inflammasomes are involved in the inflammation process”.

This harmful inflammation within the body leads to the onset and development of various kinds of diseases, including Acute Respiratory Distress Syndrome (ARDS), auto-immune diseases, inflammatory diseases, cardiovascular diseases, metabolic disorders, Gastro-intestinal diseases (inflammatory bowel disease), renal diseases and CNS diseases, the company added.

Pankaj R Patel, Chairman, Cadila Healthcare said: “We will study the safety, tolerability, pharmacokinetics and pharmacodynamics of ZYIL1 in this phase I clinical trial in healthy human volunteers. We are committed to developing these pioneering novel treatments to the clinic for the patients in need.”

////////////ZYIL 1. PHASE 2, ZYDUS

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Camizestrant, AZD 9833


img
Unii-jup57A8epz.png

Camizestrant, AZD 9833

AZ 14066724

PHASE 2

CAS: 2222844-89-3
Chemical Formula: C24H28F4N6
Exact Mass: 476.2312
Molecular Weight: 476.5236
Elemental Analysis: C, 60.49; H, 5.92; F, 15.95; N, 17.64

 N-(1-(3-fluoropropyl)azetidin-3-yl)-6-((6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl)pyridin-3-amine

  • AZ14066724
  • AZD-9833
  • AZD9833
  • Camizestrant
  • UNII-JUP57A8EPZ
  • WHO 11592
  • OriginatorAstraZeneca
  • ClassAmines; Antineoplastics; Azetidines; Fluorinated hydrocarbons; Isoquinolines; Pyrazolones; Pyridines; Small molecules
  • Mechanism of ActionSelective estrogen receptor degraders
  • Phase IIIBreast cancer
  • 13 Jun 2022AstraZeneca initiates a phase I drug-drug interaction trial of AZD 9833 Healthy postmenopausal female volunteers, in USA (NCT05438303)
  • 10 Jun 2022AstraZeneca and Quotient Sciences complete the phase I QSC205863 trial in Breast cancer (In volunteers) in United Kingdom (PO, Liquid) (NCT05364255)
  • 03 Jun 2022Safety, efficacy and pharmacokinetics data from the phase I SERENA 1 trial for Breast cancer presented at the 58th Annual Meeting of the American Society of Clinical Oncology (ASCO-2022)
  • Mechanism:selective estrogen receptor degrader
  • Area under investigation:estrogen receptor +ve breast cancer
  • Date commenced phase:Q1 2019
  • Estimated Filing Acceptance:
  • CountryDateUS: EU: Japan: China:

AZD9833 is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, SERD AZD9833 binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells

Camizestrant is an orally available selective estrogen receptor degrader (SERD), with potential antineoplastic activity. Upon administration, camizestrant binds to the estrogen receptor (ER) and induces a conformational change that results in the degradation of the receptor. This prevents ER-mediated signaling and inhibits the growth and survival of ER-expressing cancer cells

SYN

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-0040-1719368

Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist J. Med. Chem. 2020, 63, 14530–14559, DOI: 10.1021/acs.jmedchem.0c01163.

SYN

doi: 10.1021/acs.jmedchem.0c01163.

aReagents and Conditions: (a) n-BuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 1 h, 60%; (b) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 63-74% or isobutyrylaldehyde, Na(OAc)3BH, THF, 0 oC, 56%; (c) benzophenone imine, Pd2dba3, Rac-BINAP, NaOtBu, toluene, 90 oC, then 1 N aq. HCl, 71-85%; (d) nBuLi, THF, −78 oC to 0 oC, 1 h, then 4 N HCl/dioxane, RT, 4 h; e) NH2OH, NH2OH.HCl, EtOH, reflux. 84% over 2 steps; (f) alkyl triflate, DIPEA, 1,4-dioxane, 90 oC, 44-100% or 1-fluorocyclopropane-1- carboxylic acid, HATU, Et3N, DMF, RT, 61%, then BH3.THF, THF, 65 oC, 82%.

[α]26 D -147 (c 2.3, MeOH); 1H NMR (500 MHz, DMSO-d6, 27 °C) 1.08 (d, J = 6.6 Hz, 3H), 1.64 (dp, J = 25.0, 6.3 Hz, 2H), 2.45 (t, J = 6.9 Hz, 2H), 2.73(t, J = 6.8 Hz, 2H), 2.84 (dd, J = 17.1, 8.2 Hz, 1H), 2.96 (dt, J = 19.6, 9.8 Hz, 1H), 3.07 (dd, J = 17.2, 4.6 Hz, 1H), 3.49 (m, 1H), 3.50 – 3.58 (m, 1H), 3.58 – 3.66 (m, 2H), 3.92 (h, J = 6.5 Hz, 1H), 4.44 (dtd, J = 47.4, 6.1, 1.3 Hz, 2H), 4.93 (s, 1H), 6.23 (d, J = 6.9 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 6.83 (dt, J = 8.8, 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 2.8 Hz, 1H), 8.05 (d, J = 1.3 Hz, 1H), 12.97 (s, 1H); 13C NMR (125 MHz, DMSO-d6, 27 °C) 16.2, 28.2 (d, J = 19.4 Hz), 30.1, 43.0, 47.3, 48.7 (q, J = 30.1 Hz), 54.8 (d, J = 5.6 Hz), 61.3 (2C), 67.1, 82.0 (d, J = 161.3 Hz), 107.5, 119.0, 122.4, 123.7, 126.1, 126.2 (q, J = 278.5 Hz), 126.4, 127.5, 131.7, 132.9, 138.5, 142.3, 150.0; 19F NMR (376 MHz, DMSO-d6, 27 °C) -218.1 (1F), -69.7 (3F); m/z (ES+), [M+H]+ = 477, HRMS (ESI) (MH+ ); calcd, 477.2408; found, 477.2390

/////////

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AZD9833 is selective oestrogen receptor degrader (SERD). It works by breaking down the site where oestrogen attaches to the cancer cell. This can help stop or slow the growth of hormone receptor breast cancer. Researchers think that AZD9833 with palbociclib might work better than anastrozole and palbociclib.

AZD9833 + palbociclib

The patients will receive AZD9833 (75 mg, PO, once daily) + palbociclib (PO, once daily, 125 mg for 21 consecutive days followed by 7 days off treatment) + anastrozole placebo (1 mg, PO, once daily)

SERENA-1: Study of AZD9833 Alone or in Combination in Women With Advanced Breast Cancer. (clinicaltrials.gov)…..https://veri.larvol.com/news/azd9833/drug

P1, N=305, Recruiting, AstraZeneca | Trial primary completion date: Dec 2022 –> Oct 2023

2 months ago

Trial primary completion date

|

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)

|

HER-2 negative

Ibrance (palbociclib) • everolimus • Verzenio (abemaciclib) • capivasertib (AZD5363) • camizestrant (AZD9833)

DescriptionCamizestrant (AZD-9833) is a potent and orally active estrogen receptor (ER) antagonist. Camizestrant is used for the study of ER+ HER2-advanced breast cancer[1].
IC50 & TargetIC50: estrogen receptor (ER)[1]
In VitroCamizestrant is extracted from patent US20180111931A1, example 17[1].MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In VivoCamizestrant (oral administration; 0.2-50 mg/kg; 20 days) exhibits anti-tumour efficacy as a dose-dependent manner in human parental MCF7 mice xenograft[1].
Camizestrant (oral administration; 0.8-40 mg/kg; 30 days) decreases tumor growth as a dose-dependent manner. It gives almost complete tumour growth inhibition at the doses >10 mg/kg in mice[1].
MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Model:Human ESR1 mutant breast cancer patient derived xenograft with CTC174 cells in female NSG mice[1]Dosage:0.8 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kgAdministration:Oral administration; 30 days; once dailyResult:Inhibited tumor growth in a dose-dependent manner.
Clinical TrialNCT NumberSponsorConditionStart DatePhaseNCT04711252AstraZenecaER-Positive HER2-Negative Breast CancerJanuary 28, 2021Phase 3NCT04964934AstraZenecaER-Positive HER2-Negative Breast CancerJune 30, 2021Phase 3NCT04214288AstraZenecaAdvanced ER-Positive HER2-Negative Breast CancerApril 22, 2020Phase 2NCT04588298AstraZenecaHER2-negative Breast CancerNovember 2, 2020Phase 2NCT04541433AstraZenecaER&addition; HER2- Advanced Breast CancerSeptember 29, 2020Phase 1NCT03616587AstraZenecaER&addition; HER2- Advanced Breast CancerOctober 11, 2018Phase 1NCT04546347AstraZeneca|Quotient SciencesHealthy VolunteersSeptember 17, 2020Phase 1NCT04818632AstraZenecaER&addition;, HER2-, Metastatic Breast CancerOctober 11, 2021Phase 1

////////////Camizestrant, AZD 9833, AZ 14066724, UNII-JUP57A8EPZ, WHO 11592, PHASE 2, ASTRA ZENECA, CANCER

C[C@@H]1CC2=C3C(NN=C3)=CC=C2[C@@H](C4=NC=C(NC5CN(CCCF)C5)C=C4)N1CC(F)(F)F

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Danavorexton, TAK 925


str1

Danavorexton Structure.svg

Danavorexton,  TAK 925

2114324-48-8

  • Molecular FormulaC21H32N2O5S
  • Average mass424.554 Da

1-Piperidinecarboxylic acid, 3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-, methyl ester, (2R,3S)-

Methyl (2R,3S)-3-[(methylsulfonyl)amino]-2-[[(cis-4-phenylcyclohexyl)oxy]methyl]-1-piperidinecarboxylate

  • OriginatorTakeda
  • ClassCyclohexanes; Esters; Ethers; Piperidines; Sleep disorder therapies; Small molecules; Sulfonamides
  • Mechanism of ActionOrexin receptor type 2 agonists
  • Orphan Drug StatusYes – Narcolepsy
  • Phase IHypersomnia; Narcolepsy; Respiration disorders; Sleep apnoea syndrome
  • 01 Jun 2022Takeda Pharmaceuticals completes a phase I clinical trials in Respiratory disorder (In adults) in Netherlands (IV) (ISRCTN63027076)
  • 02 Apr 2022Efficacy and safety data from phase a Ib trial in Hypersomnia presented at the 74th Annual Meeting of the American Academy of Neurology 2022 (AAN-2022)
  • 10 Mar 2022Phase-I clinical trials in Sleep apnoea syndrome in Australia (IV) (NCT05180890)

Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist.[1] It is a small-molecule compound and is administered intravenously.[1][2] The compound was found to dose-dependently produce wakefulness to a similar degree as modafinil in a phase 1 clinical trial.[1][3] As of March 2021, danavorexton is under development for the treatment of narcolepsyidiopathic hypersomnia, and sleep apnea.[2][1][4] It is related to another orexin receptor agonist known as TAK-994, the development of which was discontinued for safety reasons in October 2021.[1][5]

PAPER

https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00626

TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.

aReagents and conditions: (a) chiral column separation; (b) RCOCl, Et3N, THF, rt (for 15 and 16); (c) ethyl chlorocarbonate, DIEA, THF, rt (for 17); (d) isocyanatoethane, Et3N, THF, 0 °C−rt (for 18).

Methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4- phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate (16) To a mixture of 14 (58 mg, 0.16 mmol) and Et3N (0.044 mL, 0.32 mmol) in THF (3 mL) was added methyl chlorocarbonate (0.024 mL, 0.32 mmol) at rt. The mixture was stirred at rt overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc, 1:1 to 0:100) to give 16 (64 mg, 0.15 mmol, 95%) as a colorless oil. Crystallization of 16 (1.8 g, 4.1 mmol) from EtOH-H2O gave 16 (1.7 g, 3.9 mmol, 95%) as a white solid. 1H NMR (600 MHz, DMSO-d6) δ 1.40−1.55 (5H, m), 1.56−1.73 (5H, m), 1.87 (1H, brd, J = 13.2 Hz), 1.96 (1H, brd, J = 13.6 Hz), 2.44−2.57 (1H, m), 2.83 (1H, brs), 2.95 (3H, s), 3.40 (1H, brs), 3.53−3.62 (5H, m), 3.73 (1H, brt, J = 9.7 Hz), 3.84 (1H, brs), 4.47 (1H, brs), 7.15 (1H, brt, J = 7.2 Hz), 7.18 (1H, brs), 7.19 (2H, brd, J = 8.1 Hz), 7.27 (2H, brt, J = 7.4 Hz). 13C NMR (151 MHz, DMSO-d6, the minor rotamer’s signals are marked with an asterisk) δ24.05, 24.39*, 26.00, 26.17*, 27.60*, 27.79, 28.68, 30.15*, 37.54, 38.13*, 39.91, 42.99, 51.01, 52.07, 53.90*, 54.49, 61.48, 61.89*, 71.68, 125.68, 126.51, 128.14, 147.34, 155.27*, 156.08. MS (ESI/APCI) mass calculated for [M + H]+ (C21H33N2O5S) requires m/z 424.6, found m/z 425.2. mp 113 °C. Anal. Calcd for C21H32N2O5S: C, 59.41; H, 7.60; N, 6.60. Found: C, 59.45; H, 7.59; N, 6.55. [α] 20 D +16.3 (c 0.1, CHCl3

//////////

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Clinical data
Other namesTAK-925
Routes of
administration
Intravenous[1][2]
Drug classOrexin receptor agonist
Identifiers
showIUPAC name
CAS Number2114324-48-8
PubChem CID130310079
ChemSpider68011464
UNII1QMD83K4YN
ChEMBLChEMBL4650341
Chemical and physical data
FormulaC21H32N2O5S
Molar mass424.56 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

References

  1. Jump up to:a b c d e f Jacobson LH, Hoyer D, de Lecea L (January 2022). “Hypocretins (orexins): The ultimate translational neuropeptides”. J Intern Meddoi:10.1111/joim.13406PMID 35043499.
  2. Jump up to:a b c “Danavorexton – Takeda”Adis Insight. Springer Nature Switzerland AG. Retrieved 7 March 2021.
  3. ^ Evans, R., Hazel, J., Faessel, H., Wu, J., Hang, Y., Alexander, R., … & Hartman, D. (2019). Results of a phase 1, 4-period crossover, placebo-controlled, randomized, single dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-925, a novel orexin 2 receptor agonist, in sleep-deprived healthy adults, utilizing modafinil as an active comparator. Sleep Medicine, 64, S106. https://scholar.google.com/scholar?cluster=10933819770107034612
  4. ^ Evans R, Tanaka S, Tanaka S, Touno S, Shimizu K, Sakui S, et al. (December 2019). “A Phase 1 single ascending dose study of a novel orexin 2 receptor agonist, TAK-925, in healthy volunteers (HV) and subjects with narcolepsy type 1 (NT1) to assess safety, tolerability, pharmacokinetics, and pharmacodynamic outcomes”. Sleep Medicine64: S105–S106. doi:10.1016/j.sleep.2019.11.290.
  5. ^ Tong A (6 October 2021). “Takeda flashes red light on ‘breakthrough’ narcolepsy drug after PhII trials turned up mysterious safety signal”Endpoints News.

External links

///////////////Danavorexton,  TAK 925, ORPHAN DRUG, PHASE 1

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ARIMOCLOMOL


Arimoclomol.svg
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ARIMOCLOMOL

アリモクロモル;

FormulaC14H20ClN3O3
Exact mass313.1193
Mol weight313.7799

CAS 289893-25-0

289893-26-1 (Arimoclomol maleate);

INN 8300

N-[(2R)-2-hydroxy-3-piperidin-1-ylpropoxy]-1-oxidopyridin-1-ium-3-carboximidoyl chloride

BRX 220

Arimoclomol maleate is in a phase III clinical trials by Orphazyme for the treatment of Niemann-Pick disease type C (NP-C). It is also in phase II clinical studies for the treatment of amyotrophic lateral sclerosis (ALS).

Arimoclomol (INN; originally codenamed BRX-345, which is a citrate salt formulation of BRX-220) is an experimental drug developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles, California. In 2011 the worldwide rights to arimoclomol were bought by Danish biotech company Orphazyme ApS.[1] The European Medicines Agency (EMA) and U.S. Food & Drug Administration (FDA) granted orphan drug designation to arimoclomol as a potential treatment for Niemann-Pick type C in 2014 and 2015 respectively.[2][3]

 Fig. 1 Structures of (±)-bimoclomol (1) and (R)-(+)-arimoclomol (2).

Reference:1. WO0179174A1.

Reference:1. Tetrahedron: Asymmetr. 201223, 1564-1570.

PATENT

WO/2022/106614PROCESSES FOR PREPARING ARIMOCLOMOL CITRATE AND INTERMEDIATES THEREOF

The present disclosure provides an optimized four-step process for preparing an ultra-pure composition comprising arimoclomol citrate, i.e. N-{[(2R)-2-hydroxy-3-piperidin-l-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate. The optimized process comprises a plurality of optimized sub-steps, each contributing to an overall improved process, providing the ultra-pure composition comprising arimoclomol citrate. The ultra-pure composition comprising arimoclomol citrate meets the medicines agencies’ high regulatory requirements. An overview of the four-steps process is outlined below:

Step 1: Overview of process for preparing ORZY-01

Step 2: Overview of process for preparing ORZY-03

Step 4: Overview of process for preparing BRX-345 (ORZY-05)

The previously reported two-step synthesis of ORZY-01 as shown below includes a 2 hour reflux in step 1A, followed by purification of intermediate compound (V) to increase the batch quality.

PAPER

https://pubs.rsc.org/en/content/articlehtml/2017/ob/c7ob02578e

DOI: 10.1039/C7OB02578E (Communication) Org. Biomol. Chem., 2017, 15, 9794-9799

SCHEME 1
SCHEME 3
SCHEME 4
 Scheme 1 Synthesis of arimoclomol (2) by reproduction of the published patent route. Reagents and conditions: (a) NH2OH·HCl (1.2 equiv.), NaHCO3 (1.2 equiv.), H2O, rt, 18 h 91%; (b) piperidine (0.9 equiv.), MeOH, 65 °C, quant.; (c) 6, NaOH (1.3 equiv.), EtOH, H2O, 70 °C, 18 h; (d) NaNO2 (1.3 equiv.), conc. HCl, H2O, −5 °C, 2.5 h 51% over 2 steps; (e) (−)-dibenzoyl-L-tartaric acid, EtOH then NaOH, CH2Cl2; (f) citric acid (1.0 equiv.), acetone; (g) supercritical fluid chromatography.
 Scheme 3 Arimoclomol (2) synthesis via chiral glycidyl nosylate synthon. Reagents and conditions: (a) (i) NaH (60% wt), DMF, 0 °C, 0.5 h; (ii) (R)-(−)-glycidyl nosylate (11) (1.06 equiv.), rt, 2 h; (iii) piperidine (1.1 equiv.), 80 °C for 4 h then rt for 18 h, 71%; (b) NaNO2 (1.3 equiv.), conc. HCl, H2O, −5 °C, 2.5 h, 73%.
 Scheme 4 Chiral hydroxylamine route to arimoclomol (2). Reagents and conditions: (a) (i) NaH (60% wt), DMF, 0 °C, 0.5 h; (ii) (R)-(−)-glycidyl nosylate (11) (1.1 equiv.), rt, 2 h, 83%; (b) piperidine (1.05 equiv.), iPrOH, 50 °C, 18 h, quant.; (c) HCl (6 M), 95 °C, 18 h; quant.; (d) Amberlyst A21, MeOH, rt, 4 h, 98%; (e) 3-cyanopyridine-N-oxide (3) (0.8 equiv.), HSCH2CO2H (17) (1.5 equiv.), Et3N, EtOH, 85 °C, 24 h, 75%; (f) NaNO2 (1.3 equiv.), conc. HCl, H2O, −5 °C, 66%.
  1. (R,Z)-3-(N′-(2-Hydroxy-3-(piperidine-1-yl)propoxy)carboximi-oylchloride)pyridine-1-oxide citrate (2-citrate, arimoclomol citrate) was prepared as an off-white amorphous solid (164 mg): m.p. 161–162 °C; [α]20D +8.0° (c = 1, H2O); IR νmax (neat): 3423, 3228, 2949, 2868, 1722, 1589, 1483, 1433, 1307, 1128, 972, 829 cm−11H NMR (600 MHz, d6-DMSO) δ: 8.54 (t, J = 1.5 Hz, 1H), 8.39–8.35 (m, 1H), 7.72–7.68 (m, 1H), 7.55 (dd, J = 8.0, 6.5 Hz, 1H), 4.28 (ddd, J = 17.6, 13.3, 7.4 Hz, 3H), 3.35 (br. s, 2H), 3.13–2.74 (m, 6H), 2.59 (d, J = 15.2 Hz, 2H), 2.56–2.51 (m, 2H), 1.77–1.61 (m, 4H), 1.48 (s, 2H); 13C NMR (151 MHz, d6-DMSO) δ: 176.6, 171.3, 140.5, 136.4, 132.7, 131.5, 126.8, 123.3, 77.8, 71.4, 63.8, 58.7, 53.1, 44.0, 30.7, 23.0, 21.9; HRMS (m/z TOF MS ES+) for C14H20ClN3O3 [M + H]+ calc. 314.1271, observed 314.1263; SFC er purity R[thin space (1/6-em)]:[thin space (1/6-em)]S, >99[thin space (1/6-em)]:[thin space (1/6-em)]1.
  2. (R,Z)-3-(N′-(2-Hydroxy-3-(piperidine-1-yl)propoxy)carboximi-oylchloride)pyridine maleate ((R)-1-maleate, bimoclomol maleate) was prepared as an off-white amorphous solid (70 mg): m.p. 137–138 °C; [α]20D +6.0° (c = 1, MeOH); IR νmax (neat): 3269, 2937, 1577, 1477, 1440, 1348, 1205, 1070, 981, 864 cm−11H NMR (600 MHz, d6-DMSO) δ: 9.09 (s, 1H), 9.01–8.98 (m, 1H), 8.73 (dd, J = 4.8, 1.5 Hz, 1H), 8.24–8.06 (m, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.6 Hz, 1H), 6.02 (d, J = 4.0 Hz, 2H), 5.93 (s, 1H), 4.40–4.21 (m, 3H), 3.60–3.28 (m, 3H), 3.20 (d, J = 11.8 Hz, 1H), 3.12–3.05 (m, 1H), 3.03–2.83 (m, 2H), 1.84–1.55 (m, 5H), 1.38 (s, 1H); 13C NMR (151 MHz, d6-DMSO) δ: 167.1, 151.7, 147.4, 136.0, 135.1, 134.6, 127.9, 123.9, 77.2, 63.1, 58.0, 54.1, 51.1, 22.2, 21.3; HRMS (m/z TOF MS ES+) for C14H20ClN3O2 [M + H]+ calc. 298.1322, observed 298.1319; SFC er purity R[thin space (1/6-em)]:[thin space (1/6-em)]S, 98[thin space (1/6-em)]:[thin space (1/6-em)]2.

(R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide1 – (R)-(+)-Arimoclomol – 2 A solution of (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carbamimidoyl)pyridine-1-oxide 12 (205 mg, 0.70 mmol) in conc. hydrochloric acid (1.1 mL, 13.9 mmol) and water (3 mL) was cooled to -5 °C for 15 minutes. Sodium nitrite (63 mg, 0.91 mmol) in water (0.5 mL) was then added dropwise to the reaction mixture and the reaction was stirred at -5 °C for 2.5 hours. The reaction mixture was made alkaline with NaOH (7 M, 3 mL). An additional 10 mL of water was added followed by DCM (30 mL) containing EtOAc (5 mL) and the organics were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on Biotage Isolera using Biotage SNAP 10 g Si cartridge eluting with gradient elution 0-30% MeOH:DCM both containing 0.1% Et3N to afford the title compound (160 mg, 73% yield) as a colourless semi-solid. Analytical data was consistent with literature values. See ESI section SFC traces for specific enantiomeric ratios of 2 synthesised under the various methodologies quoted in the text. Optical rotation was not determined as it was determined in the ultimate product of this 2·citrate and comparative run times on SFC. 1H NMR (600 MHz, CDCl3) δ: 8.63 (t, J = 1.4 Hz, 1H), 8.16 (ddd, J = 6.4, 1.6, 0.9 Hz, 1H), 7.66 – 7.62 (m, 1H), 7.25 (dd, J = 8.0, 6.6 Hz, 1H), 4.26 (qd, J = 11.3, 5.2 Hz, 2H), 4.07 (dd, J = 9.2, 4.7 Hz, 1H), 2.62 (s, 2H), 2.47 – 2.31 (m, 4H), 1.65 – 1.51 (m, 4H), 1.42 (s, 2H); 13C NMR (151 MHz, CDCl3) δ: 140.3, 137.7, 133.1, 132.5, 125.7, 123.9, 78.7, 64.9, 60.9, 54.8, 25.8, 24.0.

(R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide citrate

(R)-(+)- Arimoclomol citrate – 2·citrate (R,Z)-3-(N’-(2-hydroxy-3-(piperidin-1-yl)propoxy)carboximidoyl chloride)pyridine-1-oxide (159 mg, 0.51 mmol) was dissolved in acetone (3 mL) and citric acid (97 mg, 0.51 mmol) was added. The reaction mixture was left to stir at room temperature for 18 hours. After this time the mixture was sonicated and the precipitate was filtered, rinsed with cold acetone (1 mL) and dried under vacuum to afford the title compound (165 mg, 64% yield) as a white amorphous solid. Analytical data was consistent with literature values. m.p. 161-162 °C, Acetone (lit. 163-165 °C, EtOH); [α]D 20 +8.0 (c=1, H2O); IR νmax (neat): 3423, 3228, 2949, 2868, 1722, 1589, 1483, 1433, 1307, 1128, 972, 829 cm-1; 1H NMR (600 MHz, d6-DMSO) δ: 8.54 (t, J = 1.5 Hz, 1H), 8.39 – 8.35 (m, 1H), 7.72 – 7.68 (m, 1H), 7.55 (dd, J = 8.0, 6.5 Hz, 1H), 4.28 (ddd, J = 17.6, 13.3, 7.4 Hz, 3H), 3.35 (br. s, 2H), 3.13 – 2.74 (m, 6H), 2.59 (d, J = 15.2 Hz, 2H), 2.56 – 2.51 (m, 2H), 1.77 – 1.61 (m, 4H), 1.48 (s, 2H); 13C NMR (151 MHz, d6-DMSO) δ: 176.6, 171.3, 140.5, 136.4, 132.7, 131.5, 126.8, 123.3, 77.8, 71.4, 63.8, 58.7, 53.1, 44.0, 30.7, 23.0, 21.9; HRMS (m/z TOF MS ES+) for C14H20ClN3O3 [M+H]+ calc. 314.1271, observed 314.1263; SFC er purity R:S >99:1

Procedure for the conversion of (R)-(+)-Bimoclomol 1 into (R)-(+)-Arimoclomol 2 To a solution of (R)-(+)-bimoclomol (61 mg, 0.21 mmol) in acetone (2 mL) was added benzenesulfonic acid (33 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. Separately to a suspension of hydrogen peroxide-urea adduct (39 mg, 0.41 mmol) in acetonitrile (6 mL) at -5°C (ice-salt bath) was added trifluoroacetic anhydride (58 μL, 0.41 mmol) dropwise. A suspension of (R)-(+)-bimoclomol, 1, benzenesulfonic acid salt, as made above, in acetonitrile (3 mL) was then added dropwise to this solution. The reaction mixture was stirred for 18 hours, whilst slowly warming to room temperature. Aqueous Na2S2O5 solution (0.5 M, 1 mL) was added and the reaction mixture stirred for 1 hour. The reaction mixture was made alkaline with NaOH (7 M) and extracted with DCM (2 x 30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on a Biotage Isolera using Biotage SNAP 10g Si cartridge eluting with gradient elution 0-35% MeOH in DCM to afford the title compound (35 mg, 55% yield) as a colourless semi-solid. Analytical data of the products was consistent with literature and/or previous samples synthesised above.

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Mechanism of action

Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones. Since damaged proteins, called aggregates, are thought to play a role in many diseases, CytRx believes that arimoclomol could treat a broad range of diseases.

Arimoclomol activates the heat shock response.[4][5][6][7][8][9] It is believed to act at Hsp70.[10]

History

Arimoclomol has been shown to extend life in an animal model of ALS[11] and was well tolerated in healthy human volunteers in a Phase I study. CytRx is currently conducting a Phase II clinical trial.[12]

Arimoclomol also has been shown to be an effective treatment in an animal model of Spinal Bulbar Muscular Atrophy (SBMA, also known as Kennedy’s Disease).[13]

Arimoclomol was discovered by Hungarian researchers, as a drug candidate to treat insulin resistance[14][15] and diabetic complications such as retinopathyneuropathy and nephropathy. Later, the compound, along with other small molecules, was screened for further development by Hungarian firm Biorex, which was sold to CytRx Corporation, who developed it toward a different direction from 2003.

References

  1. ^ “CytRx Sells Molecular Chaperone Assets to Orphazyme in Deal Worth $120M | GEN Genetic Engineering & Biotechnology News – Biotech from Bench to Business | GEN”GEN. 17 May 2011.
  2. ^ “European Medicines Agency – – EU/3/14/1376”http://www.ema.europa.eu. Archived from the original on 2017-07-28. Retrieved 2022-02-15.
  3. ^ “Search Orphan Drug Designations and Approvals”http://www.accessdata.fda.gov.
  4. ^ Kalmar B, Greensmith L (2009). “Activation of the heat shock response in a primary cellular model of motoneuron neurodegeneration-evidence for neuroprotective and neurotoxic effects”Cell. Mol. Biol. Lett14 (2): 319–35. doi:10.2478/s11658-009-0002-8PMC 6275696PMID 19183864.
  5. ^ Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L (April 2004). “Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice”. Nat. Med10 (4): 402–5. doi:10.1038/nm1021PMID 15034571S2CID 2311751.
  6. ^ Kalmar B, Greensmith L, Malcangio M, McMahon SB, Csermely P, Burnstock G (December 2003). “The effect of treatment with BRX-220, a co-inducer of heat shock proteins, on sensory fibers of the rat following peripheral nerve injury”. Exp. Neurol184 (2): 636–47. doi:10.1016/S0014-4886(03)00343-1PMID 14769355S2CID 5316222.
  7. ^ Rakonczay Z, Iványi B, Varga I, et al. (June 2002). “Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats”. Free Radic. Biol. Med32 (12): 1283–92. doi:10.1016/S0891-5849(02)00833-XPMID 12057766.
  8. ^ Kalmar B, Burnstock G, Vrbová G, Urbanics R, Csermely P, Greensmith L (July 2002). “Upregulation of heat shock proteins rescues motoneurones from axotomy-induced cell death in neonatal rats”. Exp. Neurol176 (1): 87–97. doi:10.1006/exnr.2002.7945PMID 12093085S2CID 16071543.
  9. ^ Benn SC, Brown RH (April 2004). “Putting the heat on ALS”. Nat. Med10 (4): 345–7. doi:10.1038/nm0404-345PMID 15057226S2CID 11434434.
  10. ^ Brown IR (October 2007). “Heat shock proteins and protection of the nervous system”. Ann. N. Y. Acad. Sci1113 (1): 147–58. Bibcode:2007NYASA1113..147Bdoi:10.1196/annals.1391.032PMID 17656567S2CID 36782230.
  11. ^ Kalmar B, Novoselov S, Gray A, Cheetham ME, Margulis B, Greensmith L (October 2008). “Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS”J. Neurochem107 (2): 339–50. doi:10.1111/j.1471-4159.2008.05595.xPMID 18673445.
  12. ^ “Phase II/III Randomized, Placebo-Controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis – Full Text View – ClinicalTrials.gov”Archived from the original on 11 May 2009. Retrieved 2009-05-18.
  13. ^ Malik B, Nirmalananthan N, Gray A, La Spada A, Hanna M, Greensmith L (2013). “Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy”Brain136 (3): 926–943. doi:10.1093/brain/aws343PMC 3624668PMID 23393146.
  14. ^ Kürthy M, Mogyorósi T, Nagy K, et al. (June 2002). “Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models”. Ann. N. Y. Acad. Sci967 (1): 482–9. Bibcode:2002NYASA.967..482Kdoi:10.1111/j.1749-6632.2002.tb04306.xPMID 12079878S2CID 19585837.
  15. ^ Seböková E, Kürthy M, Mogyorosi T, et al. (June 2002). “Comparison of the extrapancreatic action of BRX-220 and pioglitazone in the high-fat diet-induced insulin resistance”. Ann. N. Y. Acad. Sci967 (1): 424–30. Bibcode:2002NYASA.967..424Sdoi:10.1111/j.1749-6632.2002.tb04298.xPMID 12079870S2CID 23338560.

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Clinical data
Routes of
administration
Oral
ATC codeN07XX17 (WHO)
Legal status
Legal statusInvestigational
Identifiers
showIUPAC name
CAS Number289893-25-0 
PubChem CID208924
ChemSpider21106260 
UNIIEUT3557RT5
KEGGD11374
ChEMBLChEMBL2107726 
CompTox Dashboard (EPA)DTXSID5057701 
Chemical and physical data
FormulaC14H20ClN3O3
Molar mass313.78 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

/////////ARIMOCLOMOL, アリモクロモル , BRX 220, INN 8300, Arimoclomol maleate,  phase III,  clinical,  Orphazyme ,  Niemann-Pick disease type C,   phase II,  amyotrophic lateral sclerosis,  (ALS)

Rabeximod, ROB 803, 


Rabeximod.png
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ChemSpider 2D Image | rabeximod | C22H24ClN5O

Rabeximod, ROB 803

C22H24ClN5O,  409.92

2-(9-chloro-2,3-dimethylindolo[3,2-b]quinoxalin-6-yl)-N-[2-(dimethylamino)ethyl]acetamide

CAS 872178-65-9UNII-J4D3K58W3Z, рабексимод , رابيكسيمود 雷贝莫德 
6H-Indolo[2,3-b]quinoxaline-6-acetamide, 9-chloro-N-[2-(dimethylamino)ethyl]-2,3-dimethyl-
872178-65-9[RN]8866, J4D3K58W3Z

  • OriginatorOxyPharma
  • DeveloperCyxone; University of California
  • ClassAcetamides; Anti-inflammatories; Disease-modifying antirheumatics; Heterocyclic compounds with 4 or more rings; Small molecules
  • Mechanism of ActionCell differentiation modulators; Macrophage inhibitors
  • Phase IICOVID 2019 infections; Rheumatoid arthritis
  • 12 Oct 2021Cyxone terminates a phase-II trial in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)
  • 10 Aug 2021Cyxone completes a phase-II trial in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)
  • 23 Feb 2021Phase-II clinical trials in COVID-2019 infections in Slovakia (PO) (EudraCT2020-004571-41)

SYN

US 20050288296

https://patents.google.com/patent/US20050288296

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 WO 2014140321 

https://patents.google.com/patent/WO2014140321A1/en Example 29-chloro-7V- [2-(dimethylamino)ethyl] -2,3-dimethyl-6H-Indolo [2,3-6] quinoxaline-6- acetamide

Figure imgf000025_0001

This compound was prepared as described in PCT/SE2005/000718 (WO 2005/123741), cf. “Compound E” at page 12 of said WO pamphlet.SYNWO 2005/123741https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2005123741

Compound E

9-Chloro-2,3-dimerthyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo- [2,3-b]quinoxaline (R1=Cl, R2=CH3, X=CO, Y=NH-CH2-CH2-R3; R3=NR5R6;

R5=R6=CH3)

Yield: 58%; 1H-NMR δ: 8.29 (d, 1H), 8.23 (t, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.71

(dd, 1H), 7.61 (d, 1H), 5.09 (s, 2H), 3,16 (q, 2H), 2.47 (s, 6H), 2.28 (t, 2H), 2,12

(s, 6H);

SYN

Rabeximod is an orally administered compound for treatment of moderate or severe active rheumatoid arthritis that is currently undergoing phase II clinical testing in eight European countries.

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

PATENT

The compound rabeximod has been described in European patent application publication EP1756111A1 later granted as EP1756111 B1. The preparation of rabex imod, as compound E, is specifically described in EP1756111A1 as a small-scale process without any description on how to develop a process that can be used for GMP and upscaled. Rabeximod was made in a 58% yield in a small-scale lab pro cess, but no parameters for scaling up have been disclosed.

The objective of the present invention is to provide a process that is suitable for large scale synthesis in good yield, with stable process parameters, and suitable for GMP production.

Experimental

The current process to manufacture Rabeximod involves several process steps as illustrated in below reaction scheme and as described in detail hereunder.

Manufacturing Process OXY001-01 Intermediate

Starting materials: 5-Chloroisatin (CIDO) and 4,5-Dimethyl-1 ,2-phenylenediamine (DAX)

Table 1: Overview Required Raw Materials and Quantities Step 1 

Table 2: Raw Materials Specifications Step 1

Resulting Product (Intermediate): OXY001-01

Batch size: 13.03 kg of OXY001-01

Process description: 4,5-Dimethyl-1 ,2-phenylenediamine (1.1 equivalent) was added to acetic acid (4.7 volumes) in reactor (reactor was running under nitrogen at atmospheric pressure) and stirred up to 3 hours at moderate rate at +20 to +25 °C until clear dark brown solution was formed. 4, 5-Dimethyl-1 ,2-phenylenediamine so lution in acetic acid solution was transferred to intermediate feeding vessel. 5-chloro-isatin (1 .0 equivalent) was added to acetic acid (14.3 volumes) in reactor and stirred while jacket temperature of reactor was adjusted to approximately +150 °C to achieve a reflux temperature for active reflux of solvents. When reflux temperature was reached the 4, 5-Dimethyl-1 ,2-phenylenediamine solution in acetic acid was slowly added over 2-3 hours while distilling acetic acid (4.7 volumes) from the reaction mix ture. A fresh portion of acetic acid (4.7 volumes) was added to the reactor at about the same rate as distillation (4.7 volumes) occurred. After distillation the reaction mixture was stirred at reflux temperature for at least another 2 hours. The expected appearance of content in the reactor was a dark yellow to orange slurry. The reaction mixture was cooled to +65 to +70 °C and filtered using a Nutsche filter using Polyes ter filter cloth (27 pm) or similar as filter media. The filter cake was washed 3 times with fresh ethanol (3 x 4.2 volumes) and 1 time with water (1 x 4.2 volume). After washing the filter cake was dried at +40 to +45 °C for 12 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C resulting in a yellow to orange/brown solid. An in-process control sample was taken and analysed for loss on drying (LOD). LOD should be < 2% (w/w). If the LOD is > 2%, the vacuum tray dryer step was repeated.

Theoretical yield: 18.62 kg

Yield: 70±5% (13.03±0.96kg)

Maximum volume: 216 L

Manufacturing Process OXY001-03 HCI Intermediate

CAC DMEN OXY001-03 HCI

Starting materials: Chloroacetyl chloride (CAC) and N,N-Dimethylethylene diamine (DMEN)

Table 3: Overview Required Raw Materials and Quantities Step 2

a) mol//mol of DMEN; b) kg/kg of DMEN; c) L/kg of DMEN

Table 4: Raw Materials Specifications Step 2

Resulting Product (Intermediate): OXY001-03 HCI

Batch size: 22.6 kg of OXY001 -03 HCI

Process description: Chloroacetyl chloride (1.03 equivalents) was dissolved in ethyl acetate (15 volumes) in reactor (reactor was running under nitrogen at atmos pheric pressure) at +20 °C. The solution was stirred and cooled down to +10 °C.

N,N-dimethylethylene diamine (1.00 equivalent) solution in ethyl acetate (1.0 volume) was slowly charged to the reactor when the temperature reached a range from +10 to +25 °C and at such a rate over 1-2 hours that the internal temperature did not exceed +25 °C. The slurry was stirred for 5 to 30 minutes at +20 to +25 °C and filtered using a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media. The product was washed 3 times on the filter with ethyl acetate (3 x 5 volumes) and dried on the filter for at least 16 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C resulting in an off-white to beige solid.

Theoretical yield: 25.09 kg

Yield: 90±5% (22.6±1 .25 kg)

Maximum volume: 202 L

Manufacturing Process OXY001 Crude


– OXY001 Crude Starting materials: OXY001-01 and OXY001-03 HCI

Table 5: Overview Required Raw Materials and Quantities Step 3

Table 6: Raw/Intermediate Materials Specifications Step 3

Resulting Product: OXY001 Crude (crude rabeximod) Batch size: 11.38 kg of OXY001 Crude

Process description: OXY001-01 (1.0 equivalent) was dissolved in tetrahydrofuran (15.4 volumes) and 50% NaOH aqueous solution (8.0 equivalents in relation to OXY001 -01 ) in reactor (reactor was running under nitrogen at atmospheric pressure) and mixed at +55 to +60 °C up to approximately 1 hour until clear dark red solution was formed. Potassium iodide (0.81 equivalents) was added under vigorous stirring and mixed for 10 to 30 minutes at +55 to +60 °C. OXY001-03 HCI (2.0 equivalents) was added to the solution and mixed for at least 2 hours at +55 to +60 °C. Following completion of the reaction, the mixture was quenched with water (15.4 volumes) and tetrahydrofuran removed (15.4 volumes) by evaporation under reduced pressure. The slurry was cooled to +20 to +25 °C and stirred for 1 hour and filtered with a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media. Resulting cake was washed 3 times with water (3 x 5 volumes) until the pH of the filtrate was between 8-7 and dried on the filter at +40 to +45 °C for at least 12 hours by air suction and additionally in a vacuum tray dryer for 12 hours at +40 °C. Afterwards resulting ma terial was suspended in in tetrahydrofuran (25 volumes) at +45 to +50 °C for at least 1 hour. OXY001 Crude was isolated by filtration with a Nutch filter using Polyamide filter cloth (25 pm) or similar as filter media and washed 2 times on the filter with tetrahydrofuran (2 x 7 volumes). Resulting cake was dried on the filter at +40 to +45 °C for at least 12 hours and additionally in a vacuum tray dryer for 12 hours at +40 °C.

Theoretical yield: 18.96 kg

Yield: 60±5% (11 38±0.95 kg)

Maximum volume: 500 L

Purification of crude Rabeximod:

OXY001 crude (1 .0 equivalent) was dissolved in tetrahydrofuran (10 volumes), water (3 volume), and 2M HCI (1.4 volumes) mixture. The solution was clear filtered and heated to +50 °C. pH of mixture was adjusted to 10-12 by addition of 2M NaOH (1.3 volume). The formed slurry was cooled to +20 to +25 °C and diluted with water (12 volumes).

After stirring for at least 12 hours the slurry was filtered at +20 to +25 °C and washed on the filter with tetrahydrofuran:water (5:2) mixture (2×3 volumes). Rabeximod has a molecular weight of 409.92 g/mol and is isolated as a crystalline free base having a melting point of 259-261 °C.

Batch release results of batches used in Phase 2 and Phase 1 clinical studies are provided in Table 7.

Purity is equal to or above 98% as measured by HPLC.

Table 7: Batch release results of Rabeximod drug substance batches used in Phase 1 and phase 2 clinical studies

/////////////////Rabeximod, ROB 803, UNII-J4D3K58W3Z, рабексимод , رابيكسيمود 雷贝莫德 ,OXYPHARMA, PHASE 2, CYXONE

CC1=CC2=C(C=C1C)N=C3C(=N2)C4=C(N3CC(=O)NCCN(C)C)C=CC(=C4)Cl

NEW DRUG APPROVALS

ONE TIME

$10.00

AUPM 170, CA 170, PD-1-IN-1


str1
 https://www.nature.com/articles/s42003-021-02191-1
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str1

(2S,3R)-2-(3-((S)-3-amino-1-(3-((R)-1-amino-2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-3-oxopropyl)ureido)-3-hydroxybutanoic acid

CA-170
GLXC-15291
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PD-1-IN-1 Chemical Structure
Molecular Weight (MW) 360.33
Formula C12H20N6O7
CAS No. 1673534-76-3

N-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-

 AUPM 170, CA 170, AUPM-170, CA-170, PD-1-IN-1

Novel inhibitor of programmed cell dealth-1 (PD-1)

CA-170 (also known as AUPM170 or PD-1-IN-1) is a first-in-class, potent and orally available small molecule inhibitor of the immune checkpoint regulatory proteins PD-L1 (programmed cell death ligand-1), PD-L2 and VISTA (V-domain immunoglobulin (Ig) suppressor of T-cell activation (programmed death 1 homolog; PD-1H). CA-170 was discovered by Curis Inc. and has potential antineoplastic activities. CA-170 selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. Curis is currently investigating CA-170 for the treatment of advanced solid tumours and lymphomas in patients in a Phase 1 trial (ClinicalTrials.gov Identifier: NCT02812875).

References: www.clinicaltrials.gov (NCT02812875); WO 2015033299 A1 20150312.

Aurigene Discovery Technologies Limited INNOVATOR

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CURIS AND AURIGENE ANNOUNCE AMENDMENT OF COLLABORATION FOR THE DEVELOPMENT AND COMMERCIALIZATION OF CA-170

PRESS RELEASE

https://www.aurigene.com/curis-and-aurigene-announce-amendment-of-collaboration-for-the-development-and-commercialization-of-ca-170/

Curis and Aurigene Announce Amendment of Collaboration for the Development and Commercialization of CA-170

– Aurigene to fund and conduct a Phase 2b/3 randomized study of CA-170 in patients with non-squamous non-small cell lung cancer (nsNSCLC) –

– Aurigene to receive Asia rights for CA-170; Curis entitled to royalty payments in Asia –

LEXINGTON, Mass., February 5, 2020 /PRNewswire/ — Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, today announced that it has entered into an amendment of its collaboration, license and option agreement with Aurigene Discovery Technologies, Ltd. (Aurigene). Under the terms of the amended agreement, Aurigene will fund and conduct a Phase 2b/3 randomized study evaluating CA-170, an orally available, dual
inhibitor of VISTA and PDL1, in combination with chemoradiation, in approximately 240 patients with nonsquamous
non-small cell lung cancer (nsNSCLC). In turn, Aurigene receives rights to develop and commercialize CA-170 in Asia, in addition to its existing rights in India and Russia, based on the terms of the original agreement. Curis retains U.S., E.U., and rest of world rights to CA-170, and is entitled to receive royalty payments on potential future sales of CA-170 in Asia.

In 2019, Aurigene presented clinical data from a Phase 2a basket study of CA-170 in patients with multiple tumor types, including those with nsNSCLC. In the study, CA-170 demonstrated promising signs of safety and efficacy in nsNSCLC patients compared to various anti-PD-1/PD-L1 antibodies.

“We are pleased to announce this amendment which leverages our partner Aurigene’s expertise and resources to support the clinical advancement of CA-170, as well as maintain our rights to CA-170 outside of Asia,” said James Dentzer, President and Chief Executive Officer of Curis. “Phase 2a data presented at the European Society for Medical Oncology (ESMO) conference last fall supported the potential for CA-170 to serve as a therapeutic option for patients with nsNSCLC. We look forward to working with our partner Aurigene to further explore this opportunity.”

“Despite recent advancements, patients with localized unresectable NSCLC struggle with high rates of recurrence and need for expensive intravenous biologics. The CA-170 data presented at ESMO 2019 from Aurigene’s Phase 2 ASIAD trial showed encouraging results in Clinical Benefit Rate and Prolonged PFS and support its potential to provide clinically meaningful benefit to Stage III and IVa nsNSCLC patients, in combination with chemoradiation and as oral maintenance” said Kumar Prabhash, MD, Professor of Medical Oncology at Tata Memorial Hospital, Mumbai, India.

Murali Ramachandra, PhD, Chief Executive Officer of Aurigene, commented, “Development of CA-170, with its unique dual inhibition of PD-L1 and VISTA, is the result of years of hard-work and commitment by many people, including the patients who participated in the trials, caregivers and physicians, along with the talented teams at Aurigene and Curis. We look forward to further developing CA-170 in nsNSCLC.”

About Curis, Inc.

Curis is a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, including fimepinostat, which is being investigated in combination with venetoclax in a Phase 1 clinical study in patients with DLBCL. In 2015, Curis entered into a collaboration with Aurigene in the areas of immuno-oncology and precision oncology. As part of this collaboration, Curis has exclusive licenses to oral small molecule antagonists of immune checkpoints including, the VISTA/PDL1 antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as the IRAK4 kinase inhibitor, CA- 4948. CA-4948 is currently undergoing testing in a Phase 1 trial in patients with non-Hodgkin lymphoma.
In addition, Curis is engaged in a collaboration with ImmuNext for development of CI-8993, a monoclonal anti-VISTA antibody. Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at http://www.curis.com.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene’s ROR-gamma inverse agonist AUR-101 is currently in phase 2 clinical development under a US FDA IND. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs  currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/

Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field

Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.

Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions.  In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA.  The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.

In November 2015, preclinical data were reported. Data demonstrated tha the drug rescued and sustained activation of T cells functions in culture. CA-170 resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer. Similar data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA

By August 2015, preclinical data had been reported. Preliminary data demonstrated that in in vitro studies, small molecule PD-L1 antagonists induced effective T cell proliferation and IFN-gamma production by T cells that were specifically suppressed by PD-L1 in culture. The compounds were found to have effects similar to anti-PD1 antibodies in in vivo tumor models

 (Oral Small Molecule PD-L1/VISTAAntagonist)

Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells.  Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor.  It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues.  Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.

In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1.  One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions.  However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment.  Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.

As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation.  CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015.  Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture.  In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile.  Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.

Jan 21, 2015

Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets

— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —

— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —

— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —

— Management to Host Conference Call Today at 8:00 a.m. EST —

LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.

The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.

“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”

Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”

CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement.  Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists.  We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”

In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.

The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.

In addition Curis has agreed to make payments to Aurigene as follows:

  • for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
  • for the third and fourth programs: up to $50 million per program, including $42.5 million per program for  approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
  • for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.

Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule.
About Immune Checkpoint  Modulation and Programmed Death 1 Pathway

Modulation of immune checkpoint pathways has emerged as a highly promising therapeutic approach in a wide range of human cancers. Immune checkpoints are critical for the maintenance of self-tolerance as well as for the protection of tissues from excessive immune response generated during infections. However, cancer cells have the ability to modulate certain immune checkpoint pathways as a mechanism to evade the immune system. Certain immune checkpoint receptors or ligands are expressed by various cancer cells, targeting of which may be an effective strategy for generating anti-tumor activity. Some immune-checkpoint modulators, such as programmed death 1 (PD-1) protein, specifically regulate immune cell effector functions within tissues. One of the mechanisms by which tumor cells block anti-tumor immune responses in the tumor microenvironment is by upregulating ligands for PD-1, such as PD-L1. Hence, targeting of PD-1 and/or PD-L1 has been shown to lead to the generation of effective anti-tumor responses.
About Curis, Inc.

Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.

About Aurigene

Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.

POSTER

STR3
STR3
STR3

WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.

PATENT

WO 2015033299

Inventors

  • SASIKUMAR, Pottayil Govindan Nair
  • RAMACHANDRA, Muralidhara
  • NAREMADDEPALLI, Seetharamaiah Setty Sudarshan

Priority Data

4011/CHE/2013 06.09.2013 IN

Example 4: Synthesis of Co

str1

The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using 
instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.

Pottayil Sasikumar

Pottayil Sasikumar

Murali Ramachandra

Murali Ramachandra

REFERENCES

US20150073024

WO2011161699A227 Jun 201129 Dec 2011Aurigene Discovery Technologies LimitedImmunosuppression modulating compounds
WO2012168944A121 Dec 201113 Dec 2012Aurigene Discovery Technologies LimitedTherapeutic compounds for immunomodulation
WO2013132317A14 Mar 201312 Sep 2013Aurigene Discovery Technologies LimitedPeptidomimetic compounds as immunomodulators
WO2013144704A128 Mar 20133 Oct 2013Aurigene Discovery Technologies LimitedImmunomodulating cyclic compounds from the bc loop of human pd1

http://www.curis.com/pipeline/immuno-oncology/pd-l1-antagonist

http://www.curis.com/images/stories/pdfs/posters/Aurigene_PD-L1_VISTA_AACR-NCI-EORTC_2015.pdf

References:

1) https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-021-00446-4

2) https://www.nature.com/articles/s42003-021-02191-1

3) https://www.esmoopen.com/article/S2059-7029(20)30108-3/fulltext

4) https://www.mdpi.com/1420-3049/24/15/2804

////////Curis, Aurigene,  AUPM 170, CA 170, AUPM-170, CA-170, PD-L1, VISTA antagonist, PD-1-IN-1, phase 2, CANCER

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)[C@@H](C)O)CC(N)=O

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Pralnacasan


Pralnacasan.png

Pralnacasan

VX 740

cas 192755-52-5

(4S,7S)-N-[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1H-pyridazino[1,2-a]diazepine-4-carboxamide

N-[(4S,7S)-4-{[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]carbamoyl}-6,10-dioxo-octahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-yl]isoquinoline-1-carboxamide

 (1S,9S)-N-((2R,3S)-2-Ethoxy-5-oxotetrahydrofuran-3-yl)-9-((isoquinolin-1-ylcarbonyl)amino)-6,10-dioxooctahydro-6-H-pyridazino(1,2-a)(1,2)diazepine-1-carboxamide

6H-Pyridazino(1,2-a)(1,2)diazepine-1-carboxamide, N-((2R,3S)-2-ethoxytetrahydro-5-oxo-3-furanyl)octahydro-9-((1-isoquinolinylcarbonyl)amino)-6,10-dioxo-, (1S,9S)-

  • HMR 3480
  • HMR3480
  • HMR3480/VX-740
  • Pralnacasan
  • UNII-N986NI319S
  • VX 470
  • VX-740

C26H29N5O7, 523.543

NSAID, ICE inhibitor & metastasis inhibitor.пралнаказан [Russian] [INN]برالناكاسان [Arabic] [INN]普那卡生 [Chinese] [INN]

Structure of PRALNACASAN

Pralnacasan is an orally bioavailable pro-drug of a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE).Pralnacasan is a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE, aka Caspase-1). It was originally discovered by Vertex Pharmaceuticals and licensed for development to Aventis Pharma. In 2003 Aventis and Vertex Pharmaceuticals agreed to voluntarily discontinue development based on results from a 9-month animal toxicity trial that showed liver abnormalities due to chronic high doses of pralnacasan. Pralnacasan has also been investigated for the treatment of Partial Epilepsy; advancing to Phase II clinical trials.Pralnacasan is a potent, non-peptide inhibitor of interleukin-1beta converting enzyme (ICE). Pralnacasan is an oral, anti-cytokine drug candidate licensed for development by Aventis Pharma from Vertex Pharmaceuticals. In November 2003, Aventis and Vertex Pharmaceuticals announced that they had voluntarily suspended the phase II clinical trials of pralnacasan due to results from an animal toxicity study that demonstrated liver abnormalities after a nine-month exposure to pralnacasan at high doses. While no similar liver toxicity has been seen to date in human trials, the companies will evaluate the animal toxicity results before proceeding with the phase II clinical program.Pralnacasan inhibits interleukin-1beta converting enzyme (ICE), an enzyme that regulates the production of IL-1 and IFN gamma – intercellular mediators that initiate and sustain the process of inflammation. Inhibiting ICE may be an effective strategy for curtailing damaging inflammatory processes common to a number of acute and chronic conditions, such as rheumatoid arthritis (RA) and osteoarthritis. 
PAPERhttps://pubs.rsc.org/en/content/articlelanding/2017/ob/c7ob01403a/unauth
IDrugs (2003), 6(2), 154-158. 
Chemistry (Weinheim an der Bergstrasse, Germany) (2017), 23(2), 360-369PAPER 
Bioorganic & Medicinal Chemistry Letters (2006), 16(16), 4233-4236.https://www.sciencedirect.com/science/article/abs/pii/S0960894X06006184?

Abstract

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1β converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC50 values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1β production in a whole cell assay (IC50 < 500 nM).

Graphical abstract

Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed and synthesized as selective peptidomimetic inhibitors of interleukin-1β converting enzyme (ICE IC50 values <100 nM).

PAPEROrganic letters (2014), 16(13), 3488-91.https://pubs.acs.org/doi/10.1021/ol501425b

Abstract

Abstract Image

Peptides containing N2-acyl piperazic or 1,6-dehydropiperazic acids can be formed efficiently via a novel multicomponent reaction of 1,4,5,6-tetrahydropyridazines, isocyanides, and carboxylic acids. Remarkably, the reaction’s induced intramolecularity can enable the regiospecific formation of products with N2-acyl piperazic acid, which counters the intrinsic and troublesome propensity for piperazic acids to react at N1 in acylations. The utility of the methodology is demonstrated in the synthesis of the bicyclic core of the interleukin-1β converting enzyme inhibitor, Pralnacasan.
PatentWO 9722619WO 9903852WO 9952935
PATENTWO 2000042061https://patents.google.com/patent/WO2000042061A1/enThe invention particularly relates to the process as defined above in which the compound of formula (I) is 9- (1, 3-dihydro-1,3, dioxo-2H-isoindol-2-yl) -3 ,, 7, 8, 9, 10-hexahydro-6, 10-dioxo-6H-pyridazino- [1,2- a] [1, 2] ethyl diazepine-1-carboxylate:

Figure imgf000010_0001

The invention particularly relates to the process as defined above in which the compound of formula (Iopt) is- (lS-cis) -9- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) – 3,4,7,8,9, 10-hexahydro-β, 10-dioxo -6H-pyridazino- [1,2- a] [1, 2] ethyl diazeρine-1-carboxylate:

Figure imgf000010_0002

The compounds of formula (I) can be generally used for the synthesis of medicaments as indicated in patent EP 94095. The compounds of formulas (II) and (III) and (F) are known and can be prepared according to the experimental method described below.The invention also relates to the application of the process as defined above as an intermediate step for the preparation of a compound of formula (V)

Figure imgf000011_0001

via the compound of formula (Iopt) as defined above, characterized in that this process comprises the steps of the process for the preparation of the compounds of formula (Iopt) from the compounds of formula (II) as defined above.The subject of the invention is also the application as defined above, characterized in that the compound of formula (Iopt) is (lS-cis) -9- (1, 3-dihydro-l, 3-dioxo -2H- isoindol-2-yl) -3,4,7,8,9, 10-hexahydro-6, 10-dioxo-6H- pyridazino- [1,2-a] [1, 2] diazepine-1- ethyl carboxylate

Figure imgf000011_0002

The subject of the invention is also the application of the process as defined above as an intermediate step in the overall process for preparing the compounds of formula (I) and (Iopt) as defined above. Finally, the subject of the invention is, as intermediate compound, the compound of formula (IA) as defined above.Preparation 1 Preparation of bis (phenylmethyl) 1,2-hydrazinecarboxylate1.5 liters of methanol and 25 g of 80% hydrazine monohydrate are placed under nitrogen. Cooled to 0 ° C and then introduced 75 g of benzyl chloroformate and a solution of 93 g of sodium carbonate in 1100 ml of demineralized water. Maintaining the reaction mixture for 1 hour at 0 ° C, drained and washed by displacement with a mixture of 100 ml of methanol and 100 ml of water, then washed by displacement with 500 ml of water at 0 C °. Dried and obtained 107.6 g of the desired product. Preparation 2Preparation of N-phthaloyl-L-glutamic anhydride D (+) 2-tetrahydro-2,6,6-dioxo-2H-pyran-3-yl-1H-isoindole-1,3 (2H) – dione (R)Stage a: N-phthaloyl-L-glutamic acid2- (1, 3-dihydro-1,3, dioxo-2H-isoindole-2-yl) acid – pentanedioic (2S)To a solution of 14.4 g of sodium carbonate in 180 ml of water is added 10 g of L-glutamic acid then 16 g of N-carbethoxyphthalimide (nefkens reagent, commercial). The mixture is stirred at ambient temperature for 2 hours and then extracted with ethyl acetate. The organic phase is evaporated under reduced pressure until a dry extract is obtained and 2.74 g of crude product is obtained. Washing is carried out with sodium bicarbonate, then after return to the acid and extraction with ethyl acetate, 370 mg of expected product and H 2 N-C0 2 Et are isolated. Furthermore, the aqueous phase is brought to pH = 2 with 36% hydrochloric acid at a temperature below 5 ° C and then extracted with ethyl acetate, washed with a saturated chloride solution. sodium, dry, filter and concentrate under reduced pressure until 22.7 g of expected product is obtained in the form of an oil.Mass spectrum (MH)  = 276  Infrared (Nujol):1775 cm “1 (m), 1720 cm ” 1 (F, complex): CO 1611 cm “1 : Aromatic Stage b:To the product obtained in stage a), 160 ml of tetrahydrofuran are added and 18.6 g of DCC (1, 3-Dicyclohexyl-carbodiimide) dissolved in 55 ml of tetrahydrofuran are added dropwise over 30 minutes. Stirred for 1 hour at 15-17 ° C, then filtered, rinsed with tetrahydrofuran, evaporated under reduced pressure until a dry extract is obtained which is taken up in isopropyl ether. After 30 minutes of stirring, the filter is washed and dried. 14.98 g of expected product are obtained. α D = -52.63 λ H NMR (DMSO) 2.12 (m, 1H); 2.61 (m, 1H); 2.98 (dm, 1H); 3.16 (ddd, 1H); 5.48 (dd, 1H); 7.82 (m,> 4H)Example 1: (IS-cis) -9- (1, 3-dihydro-1,3, dioxo-2H-isoindol-2-yl) -3,4,7,8,9,10-hexahydro-6,10 -dioxo-6H-pyridazino- [1,2- a] [1,2] diazepine-1-ethyl carboxylate. Stage a: Preparation of 2,5-dibromopentanoic acid 39 ml of bromine are added to a mixture of 106 g of 5-bromopentanoic acid and 1 ml of phosphorus tribromide. The reaction mixture is brought to 70-80 ° C for 16 h 30. The reaction medium is brought to 100 ° C for 15 minutes and allowed to return to room temperature. 147 g of sought product is obtained.Stage b: Preparation of ethyl 2,5-dibromopentanoate24.37 g of oxalyl chloride are added to a mixture containing 50 g of the acid prepared in the preceding stage, 15 drops of dimethylformamide and 300 ml of dichloromethane. The reaction mixture is kept under stirring at at room temperature, until the reaction is complete. The reaction mixture is cooled to 10 ° C and 50 ml of ethyl alcohol are added. Stirred for 30 minutes at 10 ° C, allowed to return to room temperature and stirred for 3 hours at room temperature. It is brought to dryness and the desired product is obtained. Stage c: CyclizationPreparation of (S) -tetrahydro-1,2,3-pyridazinetricarboxylate of 3-ethyl-1,2-bis (phenylmethyl) and (R) -tetrahydro-1,2,3-pyridazinetricarboxylate of 1,2 -bis (phenylmethyl). A suspension of 12.1 g of ethyl 2,5-dibromopentanoate (stage b) in 50 ml of diglyme is introduced at 20-25 ° C. in a suspension containing 10.42 g of 1,2-hydrazine carboxylate of bis (phenylmethyl) (preparation 1), 65 ml of diglyme and 8.26 g of potassium carbonate. The suspension obtained is heated to 90 ° C. and stirring is continued for 48 hours. Cooled to 20 ° C, poured into a solution containing 50 ml of 2N hydrochloric acid and 150 ml of a mixture of water and ice. Extraction is carried out with ethyl acetate, washing with water and drying. It is filtered, rinsed with ethyl acetate and dried. Finally, the crude product is purified by chromatography on silica, eluting with a heptane / ethyl acetate mixture 40/20 and 10.71 g of sought product is obtained. Stage d: Acylation and hydrogenolysisPreparation of α, (IS) – [3-oxo-3- (tetrahydro-3-ethoxycarbonyl-1 (2H) -pyridazinyl) propyl] -1,3-dihydro-1,3-dioxo-2H-isoindole acid -2-aceticThe mixture consisting of 15g of tetrahydro-1,2,3-pyridazinetricarboxylate of 3-ethyl-1,2-bis (phenylmethyl) is placed under hydrogen pressure (1.3 bar) for 24 hours. R + S mixture as prepared in stage c 150 ml of tetrahydrofuran, 2.5 g of palladium on carbon (10%) and 9.08 g of phthaloylglutamic acid anhydride as prepared according to preparation 2. After filtration, we evaporated under reduced pressure until a dry extract is obtained which is taken up in 100 ml of ethyl acetate and 150 ml of a saturated solution of sodium bicarbonate. It is extracted 3 times and the bicarbonate solution is acidified to pH = 3 with 36% hydrochloric acid. It is extracted 3 times with dichloromethane and washed with water. 13.16 g of crude product are obtained, which product is purified by chromatography on silica, eluting with a toluene / ethyl acetate / acetic acid 20/80 / 1.5 mixture to obtain 12.7 g of the expected product.NMR (250MHz, CDC1 3 ): 1.24 (d, 3H, OCH 2 CH 3 ); 4.12 (q, 2H, OCH 2 CH 3 ); 4.36-4.40 (m, 1H, Hl in alpha or beta position); 4.69-4.92 (m, 1H, H9 in the alpha position); 7.70 – 7.86 H aromatic. Stage el: cyclization with POCl 3– (lS-cis) -9- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) – 3,4,7,8,9, 10-hexahydro-6, 10-dioxo -6H-pyridazino- [1,2- a] [1, 2] ethyl diazepine-1-carboxylate. – (lR-trans) -9- (1, 3-dihydro-1,3, dioxo-2H-isoindol-2-yl) – 3,4,7,8, 9, 10-hexahydro-6,10-dioxo -6H-pyridazino- [1,2-a] [1,2] diazepine-1-ethyl carboxylate.To a solution of 20 ml of dichloroethane heated beforehand to 75 ° C., the following solutions A and B are added over 3 hours: A: 417 mg of the ester prepared in stage d in 4 ml of dichloroethane to which 1 ml of a solution of 1.2 ml of 2,6-lutidine in 5 ml of dichloroethane. B: 1 ml of a solution of 1.9 ml of P0Cl 3 in 10 ml of dichloroethane, then the mixture is stirred for 1 hour at this temperature. Cool to 10 ° C., add demineralized water, extract with dichloromethane and evaporate under reduced pressure to obtain a crude product (0.415 g) which is purified by chromatography on silica eluting with the heptane / dichloromethane mixture. / ethyl acetate 1/1/1. 161.8 mg of the SS diastereoisomer, 126.7 mg of the SR diastereoisomer and 5.8 mg of the SS + SR mixture are isolated. Stage e2: cyclization with POBr 3– (lS-cis) -9- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) – 3,4,7, 8, 9, 10-hexahydro-6, 10-dioxo -6H-pyridazino- [1, 2- a] [1, 2] ethyl diazepine-1-carboxylate. – (lR-trans) -9- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) – 3,4,7, 8, 9, 10-hexahydro-6, 10-dioxo -6H-pyridazino- [1, 2- a] [1, 2] ethyl diazepine-1-carboxylate.To a solution of 20 ml of dichloroethane heated beforehand to 80 ° C., the following solutions A and B are added over 3 hours:A: 417 mg of the ester prepared in stage d in 4 ml of dichloroethane to which 1 ml of a solution of 2.4 ml of 2,6-lutidine in 10 ml of dichloroethane was added. B: 1 ml of a solution of 5.85 g of POBr 3 in 10 ml of dichloroethane, then the mixture is stirred for 1 hour at this temperature. Cool to 10 ° C, add demineralized water, extract with dichloromethane and evaporate under reduced pressure to obtain a crude product (0.419 g) which is purified by chromatography on silica eluting with the heptane / dichloromethane / mixture 1/1/1 ethyl acetate. 163 mg of the SS diastereoisomer, 143 mg of the SR diastereoisomer and 6.2 mg of the SS + SR mixture are isolated.Stage f: deracemization / epimerization – (lS-cis) -9- (1, 3-dihydro-l, 3-dioxo-2H-isoindol-2-yl) – 3,4,7,8, 9, 10-hexahydro -6,10-dioxo-6H-pyridazino- [1, 2- a] [1, 2] ethyl diazepine-1-carboxylate.Is introduced at a temperature of -45 / -48 ° C in one hour 30 minutes, a solution containing 0.029 g of potassium terbutylate and 0.3 ml of dimethylformamide in a mixture containing 0.194 g of the mixture SS + SR prepared in stage d , 1.5 ml of dimethylformamide and 0.75 ml of terbutanol. The mixture is kept stirring for 1 hour and, after cooling to -50 ° C., 0.4 g of powdered ammonium chloride is introduced. Stirred 10 minutes at -45 ° C, add 1 ml of ammonium chloride at 20 ° C and stirred again 10 minutes. 2 ml of water are added after 5 minutes demineralized. Extracted with ethyl acetate, washed with demineralized water, decanted, concentrated and dried. 0.166 g of expected SS diastereoisomer is obtained. ” D = -75.3 ° (1% in methanol) NMR (250MHz, CDC1 3 ): 1.73 (m, 3H, H-2alpha H-3alpha H-3beta; 1.24 (d, 3H, OCH 2 CH 3 ); 2.38 (m, 3H, H2beta, H7alpha, H8 alpha); 2.92 (m, 1H, H4alpha); 3.39 – 3.44 (m, 1H, H8beta); 3.62 (m, 1H, H7beta); 4.23 (m, 2H, OCH 2 CH 3 ); 4.66-4.71 (m, 1H, H4 in beta position); 5.26-5.41 (m, 2H, Hl and H9 in the alpha position); 7.72 – 7.88 H aromatics. 
PATENT 
WO 2000010979https://patents.google.com/patent/WO2000010979A1/en

Figure imgf000020_0002

 formula II, said compound has the structure:

Figure imgf000020_0002

In the synthesis of these inhibitors, the terminal carbon of Ri adjacent the -COOH moiety contains a protecting substituent. Preferably that protecting

substituent is

Figure imgf000020_0003

The synthesis steps from compound H to the inhibitors set forth above involve removal of the protecting substituent on Rx; coupling of the R5-NH- or R5′-NH- moiety in its place; hydrolysis of the R2 group;N .(CJ2)m.—Tand coupling of the amine ( (Ch,2)Rs or -NH-Z)in its place. The removal of the protecting substituent on Ri is typically carried out with hydrazine. The subsequent coupling of the R5-NH- or R5′-NH- moiety is achieved with standard coupling reagents, such as EDC, DCC or acid chloride . Depending upon the nature of R2, its hydrolysis may be achieved with an acid (when R2 is t-butyl), a hydroxide (when R2 is any other alkyl, alkenyl or alkynyl or Ar) or hydrogenolysis (when R2 is an Ar-substituted alkyl, alkenyl or alkynyl) . This produces the corresponding acid from the ester.The acid is then coupled to the amine with standard coupling reagents, such as EDC, DCC or acid chloride .In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. EXAMPLE 1Synthesis of a 7,6 Scaffold for a Caspase InhibitorA.

Figure imgf000022_0001

Compound A’ was dissolved m 5 equivalents of S0C12 and then heated to 80°C for 1 hour. The solution was then cooled to 50°C and 2 equivalents of bromine were added. The solution was incubated at 50°C for an additional 12 hours until the red color disappeared. We then cooled the solution to 10°C and added 4 volumes of water. The solution was then re-heated to 50°C for another hour. We then separated the organic and aqueous layer, washed the organic layer consecutively with water, Na2S0 and then brme, removing the aqueous layer after each washing. The final organic layer was then isolated, dried over Na2S0 and concentrated to produce compound B’ as an amber oil.B.

Figure imgf000022_0002

Compound B’ was treated with 1 equivalent of tert-butanol and 0.1 equivalents of 4- (dimethylammo) – pyπdme a solution of and the resulting solution cooled to 7°C. We then added a solution of 1 equivalent of DCC m toluene while maintaining reaction temperature at less than 22°C. The cooling bath was removed and the reaction was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was then diluted with hexane and cooled to 9°C . The resulting solids were removed by filtration. The filtrate was washed consecutively with 0. IN HC1, water, and then sodium bicarbonate. The filtrate was then dried over sodium sulfate and concentrated in vacuo to afford compound C as a yellow oil.C.

Figure imgf000023_0001

Compound D’ was combined with 1.2 equivalents of compound C and dissolved in DMF at ambient temperature under nitrogen atmosphere. We then added granular sodium sulfate, 2.5 equivalents of LiOH monohydrate, and then 0.1 equivalents Bu4NI to the resulting solution. The reaction temperature was maintained at between 20°C and 30°C and allowed to stir for 16 hours. The reaction mixture was then diluted with ethyl acetate and water and the layers separated. The organic layer was washed with water and then brine, dried over sodium sulfate and concentrated in vacuo to produce an amber oil. This oil was then dissolved in 5 volumes of ethanol at ambient temperature. We then added 2.5 volumes of water. The resulting mixture was allowed to stir until a white solid formed (approximately 5 hours) . The crystallized product was isolated via filtration then dried in vacuo to afford compound E’ as a white solid.D.

Figure imgf000024_0001

We dissolved compound E’ in THF. We then added, at ambient temperature under a nitrogen atmosphere, 0.02 equivalents of triethylamine and 0.01 equivalents of Pd(OAc)2. A solution of 2.5 equivalents of triethylsilane (Et3SiH) in THF was then added and the resulting black solution was allowed to stir for 16 hours to complete the reaction. We then added a saturated, aqueous solution of sodium bicarbonate followed by a solution of compound F’ in THF. After 30 minutes, the layers were separated and the aqueous layer acidified to pH 4.5 with aqueous citric acid. The product in the aqueous layer was then extracted into ethyl acetate. The organic layer was isolated, washed with brine, dried over sodium sulfate and concentrated in vacuo to produce a white foam. This crude product was then recrystallized from MTBE to afford compound G’ as a white powder. E.

Figure imgf000025_0001

Method #1:To a suspension of compound G’ and 0.1 equivalents of DMF m dichloroethane, at 70°C we added 5 equivalents of 2, 6-lutιdme simultaneously with 2.5 equivalents of S0C12 over a period of 3 hours. The reaction was then diluted with toluene and washed consecutively with NaHC03 and br e. The solution was then dried over Na2S04 and concentrated in vacuo to afford compound H’ as a yellow solid.Method #2:To a suspension of compound G’ m dichloroethane, at 70°C, we added 4 equivalents of 2,6- lutid e followed by 2 equivalents of methanesulfonyl chloride. The resulting solution was stirred at 70°C for 12 hours. The reaction was then diluted with toluene and washed consecutively with NaHC03 and brme. The solution was then dried over Na2S04 and concentrated in vacuo to afford compound H’ as a white solid. Method #2 produced a significantly higher yield of H’ as compared to Method #1. EXAMPLE 2 Use of Intermediate H’ to Produce an Inhibitor of ICE A.

Figure imgf000026_0001

t-Butyl-9-amino-6 , 10-dioxo-l ,2,3,4,7,8,9, 10-octahydro-6- H-pyridazino [1 ,2-a] [1 ,2] diazepine-1-carboxylate (GB2,128,984) To a suspension of H’ (107 g, 0.25 mol) in ethanol (900 iriL) was added hydrazine (27 L, 0.55 mol) and the resulting mixture was allowed to stir at ambient temperature. After 4 hours, the reaction was concentrated in vacuo and the resulting white solid was suspended in acetic acid (IL of 2N) and allowed to stir at ambient temperature for 16 hours. The resulting white solid was filtered off and washed with water. The filtrate was made basic by the addition of solid sodium carbonate and the product extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 79 mg of compound I’ as a yellow viscous oil.B.

Figure imgf000026_0002

t-Butyl-9- (isoquinolin-1-oylamino) -6, 10-dioxo- 1,2,3,4,7,8,9, 10-octahydro-6-H-pyridazino [ 1 , 2-a] [1,2] diazepine-1-carboxylate To a solution of the amine I’ (79 g, 0.265 mol) and isoquinolin-1-carboxylic acid (56g, 0.32 mol) in dichloromethane : DMF (400mL: 400mL) was added hydroxybenztriazole (54 g, 0.4 mol) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (74 g, 0.39 mol) and the resulting mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N sodium bisulfate, water, sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to afford 122 g of compound J’ as an orange solid-foam.C.

Figure imgf000027_0001

9- (isoquinolin-1-oylamino) -6, 10-dioxo-l ,2 ,3 ,4 , 7 , 8 , 9 , 10- octahydro-6-H-pyridazino [1 ,2-a] [1,2] diazepine-1- carboxylate A solution of the ester J’ (122 g) in dichloromethane and trifluoroacetic acid (200 mL) was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to a black oil which was then triturated with acetonitrile and ether to afford 98 g of compound K’ as a pale yellow solid. D .

Figure imgf000028_0001

K'[IS, 9S (2RS, 3S) ] N-(2-benzyloxγ-5-oxotetrahydrofuran-3- yl) -6 , 10-dιoxo-9- (ιsoquιnolιn-1-oγlamιno) -1,2,3,4,7,8,9, 10-octahydro-6-H-pyrιdazιno [ 1 , 2-a] [1,2] dιazepιne-l-carboxamιde To a solution of (3S, 2RS) 3- allyloxycarbonylammo-2- (4-chlorobenzyl) oxy-5- oxotetrahydrofuran [Bioorg. & Med. Chem. Lett., 2, pp. 615-618 (1992)] (4.4 g, 15.1 mmol) in dichloromethane was added N, N-dimethylbarbituric acid (5.9g, 3.8 mmol) then tetrakispalladium ( 0) tπphenyl phosphme (1.7 g, 1.5 mmol) and the resulting mixture was allowed to stir at ambient temperature for 15 minutes. To the resulting mixture was added the acid, compound K’ (5.0 g, 12.6 mmol), hydroxybenztπazole (2.0 g, 14.8 mmol) then and 1- (3-dιmethylammopropyl) -3-ethylcarbodιιmιde hydrochloride (2.7g, 14 mmol) and the reaction was allowed to stir for 3 hours at ambient temperature. The reaction mixture was then poured into water and extracted with ethyl acetate. The organics were washed with 0.5M sodium bisulfate, water, sodium bicarbonate, br e, dried over magnesium sulfate and concentrated m vacuo to afford 2.6 g of the crude product as a yellow foam. The crude material was purified by column chromatography (Sι02, dichloromethane : acetone 9:1 – 3:1) to afford 1.2 g of the compound L’ . Compound L’ and related compounds that may be synthesized using the method of this invention as an intermediate step are described in WO 97/22619, the disclosure of which is herein incorporated by reference. Those related compounds may be synthesized from the product of the method of this invention, H or H’ , through modifications of the procedure set forth in Example 2. Such modifications are well known in the art. 
PATENTWO 2001083458https://patents.google.com/patent/WO2001083458A2/enScheme IV

Figure imgf000028_0001

C 2 5,> R’==OH (S)-VI-a ** 6 6., R R”==<CI

Figure imgf000028_0002

Example 1

Figure imgf000030_0001

(S) -t-butyl- bis- (1,2-benzyloxycarbonyl) – hexahydropyridazine-3-carboxylate (>90% ee) : To a solution of bis-Cbz hydrazine and (R) -t-butyl-2, 5- dimesylvalerate (from the diol prepared by the method of Schmidt et al., Synthesis, p. 223 (1996)) in DMF was added Na2S04 then TBAF (2.5 equivalents). The resulting reaction mixture was allowed to stir at room temperature for 24 hrs. The reaction was then diluted with ethyl acetate. The organic layer was washed sequentially with 10% citric acid and brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound. The optical purity of the title compound was greater than 90% ee as determined by HPLC using a ChiralPak® AD column and eluting with ethanol at 0.7 ml per minute.Example 2

Figure imgf000030_0002

(S) -t-butyl-bis- (1 ,2-benzyloxycarbonyl) – hexahydropyridazine-3-carboxylate (40% ee) : To a solution of bis-Cbz hydrazine and (R) -t-butyl-2, 5-dimesylvalerate(96.5% ee) in DMF was added Na2S04 then K2C03 (5 equivalents) and TBAI (0.1 equivalents). The resulting reaction mixture was heated at 80°C for 24 hrs. The reaction was allowed to cool and diluted with ethyl acetate. The organic layer was washed sequentially with 10% citric acid and brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound as a 70:30 mixture of the S:R enantiomers (40% ee, as determined by HPLC using a ChiralPak® AD column, eluting with ethanol at 0.7 ml/min) .Example 3

Figure imgf000031_0001

Racemic t-butyl- bis- (1 ,2-benzyloxycarbonyl) – hexahydropyridazine-3-carboxylate: To a solution of bis- Cbz hydrazine and (R) -t-butyl-2, 5-dimesylvalerate (96.5% ee) in THF was added NaH (2 equivalents) . The resulting reaction mixture was stirred at room temperature. The reaction was quenched then diluted with ethyl acetate. The organic layer was washed sequentially with 10% citric acid and brine, dried over anhydrous Na2S04 and concentrated in vacuo to afford the title compound as a racemic mixture.Example 4 A. Deprotection and salt formation

Figure imgf000031_0002

Hexahydro-pyridazine-3-carboxylic acid tert-butyl ester , L-tartaric acid salt (B) : Compound A was combined with 10% Pd/C (10% w/w) in tetrahydrofuran. The resulting suspension was stirred at 60 °C under a hydrogen atmosphere until deprotection complete. The catalyst was removed via filtration, to the filtrate was added L- tartaric acid (1 equivalent) and the resulting solution concentrated in vacuo.B. Enantiomeric Enrichment

Figure imgf000032_0001

The concentrate (B) was taken up in n-butanol(10 volumes), heated to reflux, then allowed to slowly cool to ambient temperature while stirring. The resulting solids were collected via filtration to afford(S) -piperazic acid, t-butyl ester as the tartrate salt (C) in 33% yield.C. Chiral AnalysisCompound (C) was suspended in water and DCM and cooled. We then added NaOH to basify the aqueous layer. The layers were then separated and to the organic layer we added two equivalents of benzyl chloroformate andNaOH. After stirring for 1 hour, the layers were again separated and the organic layer was washed with water.The organic layer was then dried over MgS04 and then concentrated in vacuo to produce the bis-Cbz piperazic acid, t-butyl ester for chiral HPLC analysis. The bis-Cbz piperazic acid, t-butyl ester was applied to a Chiralpak AD HPLC column (Chiral Technologies, Exton, PA) and eluted with ethanol at 0.8 ml/minute. Fractions from the column were quantitate by absorption at 210 nm. The results demonstrated that (S)- piperazic acid, t-butyl ester accounted for 94.5% of the piperazic acid, t-butyl ester present in the preparation.

Example 5 Conversion of Intermediate IV to Intermediate Vl-a Cbzy

Figure imgf000033_0001
Figure imgf000033_0002

IV’ C02t-Bu yi-a C02t-Bu Tetrahydro-pyridazine-l,3-dicarboxylic acid 1-benzyl ester 3-tert-butyl ester (Vl-a) : Compound IV (1 mmol) is combined with toluene and sodium hydroxide (aqueous, 2M, 3 equivalents) and the resulting mixture cooled to 1 °C. A solution of benzylchloroformate (1.05 equivalents) in toluene is added while maintaining the reaction pH at 10 or higher by the addition of sodium hydroxide, as needed. After stirring an additional 1 hour, allow the mixture to warm to room temperature then extract with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and concentrated to afford Vl-a.Example 6 Conversion of Intermediate X to an Inhibitor of ICE

A. Phthalimide removal to form IX-b

Figure imgf000034_0001

X IX-b t-Butyl-9-amino-6 , 10-dioxo-l ,2,3,4,7,8,9, 10-octa ydro-6-H-pyridazino[l,2-a] [1,2] diazepine-1-carboxylate (GB 2,128,984): To a suspension of X (107 g, 0.25 mol) in ethanol (900 mL) was added hydrazine (27 mL, 0.55 mol) and the resulting mixture was allowed to stir at ambient temperature. After 4 hours, the reaction was concentrated in va cuo and the resulting white solid was suspended in acetic acid (1L of 2N) and allowed to stir at ambient temperature for 16 hours. The resulting white solid was filtered off and washed with water. The filtrate was made basic by the addition of solid sodium carbonate and the product extracted with dichloromethane. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in va cuo to afford 79g of compound IX-b as a yellow viscous oil.B. Formation of compound XII

Figure imgf000034_0002

IX-b XII t-Butyl-9- (isoquinolin-1-oylamino) -6 , 10-dioxo- 1,2,3,4,7,8,9, 10-octahydro-6-H-pyridazino [1 , 2-a] [1,2] diazepine-1-carboxylate (XII) : To a solution of IX-b (79 g, 0.265 mol) and isoquinolin-1-carboxylic acid (56g, 0.32 mol) in dichloromethane and DMF (400mL: 00mL) was added hydroxybenzotriazole (54 g, 0.4 mol) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (74 g, 0.39 mol) and the resulting mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N sodium bisulfate, water, sodium bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to afford 122 g of compound XII as an orange solid-foam.t-Butyl ester hydrolysis to form compound XIII

Figure imgf000035_0001

XIII 9- (isoquinolin-1-oylamino) -6 , 10-dioxo-l ,2,3,4,7,8,9, 10- octahydro-6-H-pyridazino [1 , 2-a] [1 , 2] diazepine-1- carboxylate (XIII) : A solution of the ester XII (from step B) (122 g) in dichloromethane and trifluoroacetic acid (200 mL) was allowed to stir at ambient temperature for 16 hours. The reaction mixture was concentrated to a black oil which was then triturated with acetonitrile and ether to afford 98 g of compound XIII as a pale yellow solid.D. Formation of compound 4-b

Figure imgf000035_0002

[1S, 9S (2RS,3S) ]N- (2-benzyloxy-5-oxotetrahydrofuran-3- yl) -6,10-dioxo-9- (isoquinolin-1-oylamino) – 1,2,3,4,7,8,9, 10-octahydro-6-H-pyridazino [1 , 2-a] [1,2] diazepine-1-carboxamide (4-b) : To a solution of (3S, 2RS) 3-allyloxycarbonylamino-2-benzyloxy-5-oxotetrahydrofuran [Bioorq. & Med. Chem. Lett., 2, pp. 615-618 (1992)] (4.4 g, 15.1 mmol) in dichloromethane was added N,N- dimethylbarbituric acid (5.9g, 3.8 mmol) then tetrakispalladium(O) triphenyl phosphine (1.7 g, 1.5 mmol) and the resulting mixture was allowed to stir at ambient temperature for 15 minutes. To the resulting mixture was added the acid, compound XIII (from step C) (5.0 g, 12.6 mmol), hydroxybenzotriazole (2.0 g, 14.8 mmol), then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.7g, 14 mmol) and the reaction was allowed to stir for 3 hours at ambient temperature. The reaction mixture was then poured into water and extracted with ethyl acetate. The organics were washed with 0.5M sodium bisulfate, water, sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo to afford 2.6 g of the crude product as a yellow foam. The crude material was purified by column chromatography (Si02, dichloromethane: acetone 9:1 – 3:1) to afford 1.2 g of the compound 4-b. Compounds of formulae VII and VIII, and related compounds, that may be synthesized using the method of this invention as an intermediate step are described in WO 97/22619 and United States Patent 6,204,261 the disclosure of which is herein incorporated by reference. Those related compounds may be synthesized from the product of the method of this invention, I, IV, or V, through modifications of the procedure set forth in Examples 4 through 6. Such modifications are well known in the art.PATENTUS 6559304https://patents.google.com/patent/US6559304B1PATENTWO 2008074816https://patents.google.com/patent/WO2008074816A1/en

Patent 

Publication numberPriority datePublication dateAssigneeTitleEP0094095A2 *1982-05-121983-11-16F. Hoffmann-La Roche AgBicyclic carboxylic acids and their alkyl and aralkyl estersUS4692438A *1984-08-241987-09-08Hoffmann-La Roche Inc.Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activityWO1993023403A1 *1992-05-151993-11-25Merrell Dow Pharmaceuticals Inc.NOVEL MERCAPTOACETYLAMIDO PYRIDAZO[1,2]PYRIDAZINE, PYRAZOLO[1,2]PYRIDAZINE, PYRIDAZO[1,2-a][1,2]DIAZEPINE AND PYRAZOLO[1,2-a][1,2]DIAZEPINE DERIVATIVES USEFUL AS INHIBITORS OF ENKEPHALINASE AND ACEWO1994011353A1 *1992-11-121994-05-26University College LondonProcess for the preparation of (3r)- and (3s)-piperazic acid derivativesWO1995035308A1 *1994-06-171995-12-28Vertex Pharmaceuticals IncorporatedINHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYMEFamily To Family CitationsUS6204261B11995-12-202001-03-20Vertex Pharmaceuticals IncorporatedInhibitors of interleukin-1β Converting enzyme inhibitorsFR2777888B11998-04-272004-07-16Hoechst Marion Roussel IncNOVEL DERIVATIVES OF ACID (3,4,7,8,9,10-HEXAHYDRO-6,10- DIOXO-6H-PYRIDAZINO [1,2-A] [1,2] DIAZEPINE-1-CARBOXYLIC, THEIR PROCESS OF PREPARATION AND THEIR APPLICATION TO THE PREPARATION OF MEDICINESFR2777889B11998-04-272004-07-09Hoechst Marion Roussel IncNOVEL DERIVATIVES OF OCTAHYDRO-6,10-DIOXO-6H- PYRIDAZINO [1,2-A] [1,2] DIAZEPINE-1-CARBOXYLIC, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO THE PREPARATION OF THERAPEUTICALLY ACTIVE COMPOUNDS 

////////////////Pralnacasan, VX 740, VX 470, HMR 3480, пралнаказан , برالناكاسان , 普那卡生 , 

CCOC1C(CC(=O)O1)NC(=O)C2CCCN3N2C(=O)C(CCC3=O)NC(=O)C4=NC=CC5=CC=CC=C54

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VX 148


img

VX 148

297730-05-3

Name: VX-148
CAS#: 297730-05-3
Chemical Formula: C23H25N5O4
Exact Mass: 435.19065
Molecular Weight: 435.48
Elemental Analysis: C, 63.44; H, 5.79; N, 16.08; O, 14.70

Molecular Weight435.48
FormulaC23H25N5O4
CAS No.297730-05-3 (VX 148);
Chemical NameCarbamic acid, N-[(1S)-1-[3-[[[(4-cyano-3-methoxyphenyl)amino]carbonyl]amino]phenyl]ethyl]-, (1R)-1-(cyanomethyl)propyl ester
  • OriginatorVertex Pharmaceuticals
  • ClassAntipsoriatics
  • Mechanism of ActionInosine monophosphate dehydrogenase inhibitors
  • DiscontinuedPsoriasis; Transplant rejection; Viral infections
  • 13 Nov 2003Interim data from a media release have been added to the adverse events and Skin Disorders therapeutic trials sections
  • 23 May 2003Vertex Pharmaceuticals has completed enrolment in a phase IIa trial for Psoriasis in Iceland
  • 24 Dec 2002Phase-II clinical trials in Psoriasis in Iceland (unspecified route)

VX-148 is a second-generation, orally administered inhibitor of inosine monophosphate dehydrogenase (IMPDH). The IMPDH enzyme plays a key role in regulating immune response and proliferation of specific cell types, including lymphocytes. VX-148 is a developed for the treatment of autoimmune diseases.

Investigated for use/treatment in autoimmune diseases, psoriasis and psoriatic disorders, and viral infection.

VX-148 is a novel, uncompetitive IMPDH inhibitor with a K(i) value of 6 nM against IMPDH type II enzyme. VX-148 is slightly more potent than mycophenolic acid and VX-497 in inhibiting the proliferation of mitogen-stimulated primary human lymphocytes (IC(50) value of ~80 nM). The inhibitory activity of VX-148 is alleviated in the presence of exogenous guanosine. VX-148 does not inhibit proliferation of nonlymphoid cell types such as fibroblasts, indicating selectivity for inhibition of IMPDH activity. VX-148 is orally bioavailable in rats and mice; oral administration of VX-148 inhibits primary antibody response in mice in a dose-dependent manner with an ED(50) value of 38 mg/kg b.i.d. VX-148 significantly prolongs skin graft survival at 100 mg/kg b.i.d. in mice.

SYN

WO 0056331

The intermediate carbamate (V) has been obtained as follows. The reaction of 4-bromo-3-methoxynitrobenzene (I) with CuCN in NMP at 150 C gives 2-methoxy-4-nitrobenzonitrile (II), which is reduced with H2 over Pd/C in ethyl acetate to yield 4-amino-2-methoxybenzonitrile (III). Finally, this compound is condensed with phenyl carbamate (IV) by means of NaHCO3 in ethyl acetate to afford the desired carbamate intermediate (V).

SYN

The reduction of 3-nitroacetophenone (VI) by means of NaBH4 in ethanol gives 1-(3-nitrophenyl)ethanol (VII), which is treated with DPPA and DBU in hot toluene to yield the azido derivative (VIII). The reduction of (VIII) with PPh3 in THF/water affords 1-(3-nitrophenyl)ethylamine (IX) as a racemic mixture that is submitted to optical resolution with L-(+)-tartaric acid to provide the desired (S)-isomer (X). The reduction of the nitro group of (X) by means of H2 over Pd/C in methanol gives 1(S)-(3-aminophenyl)ethylamine (XI), which is condensed with 2(R)-hydroxypentanenitrile (XII) and CDI to yield the carbamate (XIII). Finally, this compound is condensed with intermediate carbamate (V) by means of TEA in hot ethyl acetate to afford the target urea.

  1. Jain J, Almquist SJ, Heiser AD, Shlyakhter D, Leon E, Memmott C, Moody CS, Nimmesgern E, Decker C: Characterization of pharmacological efficacy of VX-148, a new, potent immunosuppressive inosine 5′-monophosphate dehydrogenase inhibitor. J Pharmacol Exp Ther. 2002 Sep;302(3):1272-7. [Article]

////////////VX 148, phase 2

O=C(O[C@H](CC)CC#N)N[C@H](C1=CC=CC(NC(NC2=CC=C(C#N)C(OC)=C2)=O)=C1)C

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VX- ? (3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2- oxo-pyrrolidin-3-yl ] propanamide)


Schembl22118316.png

VX- ?

CAS  2446817-72-5

HYDRATE 2446818-26-2

Acetic acid, 1-​methylethyl ester 2446818-27-3

C21 H20 F N3 O3, 381.4

1H-Indole-3-propanamide, 2-(4-fluorophenyl)-N-[(3S,4R)-4-hydroxy-2-oxo-3-pyrrolidinyl]-

3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2- oxo-pyrrolidin-3-yl ] propanamide

use in treating focal segmental glomerulosclerosis (FSGS) and/or non-diabetic kidney disease (NDKD).

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PATENT

WO/2021/158666

SOLID FORMS OF APOL1 INHIBITOR AND METHODS OF USING SAME

Compound I is disclosed as Compound 87 in U.S. Provisional Application No.62/780,667 filed on December 17, 2018, U.S. Application No. 16/717,099 filed onDecember 17, 2019, and PCT International Application No. PCT/US2019/066746 filed on December 17, 2019, the entire contents of each of which are incorporated herein by reference.

Compound I, which can be employed in the treatment of diseases mediated by APOLl, such as FSGS and NDKD

Example 1. Synthesis of Compound

Preparation of Compound I and Forms Thereof

Compound I Compound I /– PrOAc solvate Form A

n-pentanol/

n-heptane

Compound I

Form B

Step 1. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (C101)

[00156] To a mixture of C104 (100.0 g, 1.0 equiv) and phenyl hydrazine hydrochloride (72.2 g, 1.05 eqiv) was charged AcOH (800 mL, 8 vol). The mixture was agitated and heated to 85 °C for 16 hours. The batch was cooled to 22 °C. A vacuum was applied and the batch distill at <70 °C to ~3 total volumes. The batch was cooled to 19- 25 °C. The reactor was charged with iPrOAc (800 mL, 8 vol) and then charged with water (800 mL, 8 vol). The internal temperature was adjusted to 20 – 25 °C and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and the phases allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. 1 N HC1 (500 mL, 5 vol) was charged to the reactor. The internal temperature was adjusted to 20 – 25 °C, and the

biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. The reactor was charged with 1 N HC1 (500 mL, 5 vol). The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. Water (500 mL, 5 vol) was charged to the reactor. The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. Water (500 mL, 5 vol) was charged to the reactor. The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. The organic phase was distilled under vacuum at <75 °C to 3 total volumes. The reactor was charged with toluene (1000 mL, 10 vol). The organic phase was distilled under vacuum at <75 °C to 5 total volumes. The reactor was charged with toluene (1000 mL, 10 vol). The organic phase was distilled under vacuum at <75 °C to 5 total volumes. The resulting slurry was heated to an internal temperature of 85 °C until complete dissolution of solids was achieved. The mixture was allowed to stir for 0.5 h at 85 °C and then cooled to an internal temperature of 19 – 25 °C over 5 h. The mixture was allowed to stir at 25 °C for no less than 2 h. The slurry was filtered. The filter cake was washed with toluene (1 x 2 vol (200 mL) and 1 x 1.5 vol (150 mL)). The solids were dried under vacuum with nitrogen bleed at 60 °C to afford product C101 (95.03 g, 70%).

Step 2. Synthesis of Compound I

[00157] A mixture of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid C101 (50 g, 1.0 equiv), S2 hydrochloride (28.3 g, 1.05 equiv), and CDMT (34.1 g, 1.1 equiv) was charged with 2-MeTHF (200 mL, 4 vol) and DMF (50 mL, 1 vol) and the mixture was agitated. The internal temperature adjusted to <13 °C. The reactor was charged with NMM (64.5 g, 3.5 equiv) over 1 h, while maintaining internal temperature <20 °C. The internal temperature was adjusted to 25 °C and the batch was stirred at that temperature for 14 h. The batch was cooled to 10 °C and charged with water (250 mL, 5 vol) while keeping the internal temperature <20 °C. The batch was then warmed to 20 – 25 °C. Stirring was stopped, and the phases allowed to separate for 10 min. The lower aqueous phase was removed. The aqueous layer was back extracted with 2-MeTHF (2 x 200 mL, 2 x 4 vol) at

20 – 25 °C. The combined organic phases were washed with 1 N HC1 (500 mL, 10 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min. The lower aqueous phase was removed. The organic phases were washed with 0.25 N HC1 (2 x 250 mL, 2 x 5 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min for each wash. Lower aqueous phases were removed after each wash. The organic phase was washed with water (250 mL, 5 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min. The reactor was charged with 20 wt % Nuchar RGC® and stirred for 4 h. The reaction mixture was filtered through a pad of celite®. The reactor and celite® pad were rinsed with 2-MeTHF. The combined organics were distilled under vacuum at <50 °C to 5 total volumes. The reactor was charged with iPrOAc (500 mL, 10 vol). The organic phase was distilled under vacuum at <50 °C to 5 total volumes. The mixture was charged with additional iPrOAc (400 mL, 8 vol) and distillation under vacuum was repeated. The mixture was charged with additional iPrOAc (250 mL, 5 vol), heated to an internal temperature of 75 °C and stirred for 5 h. The slurry was cooled to 25 °C, over 5 h and stirred for no less than 12 h. The slurry was filtered and the filter cake washed with iPrOAc (2 x 50 mL, 2 x 1 vol). The solids were dried under vacuum with nitrogen bleed at 55 – 60 °C to afford Compound I as an iPrOAc solvate (60.38 g including 9.9% w/w iPrOAc, 80.8% yield).

Recrystallization to Form A of Compound I

[00158] Compound I as an iPrOAc solvate (17.16 g after correction for iPrOAc content, 1.0 equiv) was charged to a reactor. A mixture of IP A (77 mL, 4.5 vol) and water (137 mL, 8 vol) were charged to the reactor. The slurry was heated to an internal temperature of 75 °C. The batch was cooled to an internal temperature of 25 °C over 10 h and then stirred at 25 °C for at least 12 h. The slurry was filtered. The filter cake was washed with 36/64 IP A/water (2 x 52 mL, 2 x 3 vol). The solids were dried under vacuum with nitrogen bleed at 60 °C to afford Compound I as a neat, crystalline form (Form A, 15.35 g, 89%).

[00159] The X-ray powder diffractogram of Compound I Form A (FIG. 50) was acquired at room temperature using a PANalytical Empyrean diffractometer equipped with PIXcel ID detector. The peaks are listed in Table A below.

Table A. XRPD of Form A of Compound I

|

I

PATENT

  • WO2020131807

Alternative Preparation I of Compound 87 (Indole preparation route C)

Step 1. Synthesis of 2-(4-fluorophenyl)-lH-indole (C98)

[00401] To a stirred suspension of indole (5 g, 42.7 mmol) and (4- fluorophenyl)boronic acid (8.96 g, 64.0 mmol) in AcOH (200 mL) was

added Pd(OAc)2.Trimer (1.44 g, 6.4 mmol) and the mixture stirred at room temperature for 16 h under 02-balloon pressure. Then the reaction mixture was filtered through a Celite® pad, washed with EtOAc (500 mL). The filtrates were washed with water, sat. NaHC03 solution, brine solution, then dried over Na2S04 and concentrated under reduced pressure. Purification by silica gel chromatography (Gradient: 0-10 % EtOAc in heptane) yielded the product afforded 2-(4-fluorophenyl)-lH-indole (5.5 g, 61 %). ‘H NMR (300 MHz, DMSO-de) 5 11.51 (s, 1H), 7.9 (t, J = 5.4 Hz, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 8.7 Hz, 2H), 7.09 (t, J = 12 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.86 (s, 1H). LCMS m/z 212.4 [M+H]+.

Step 2. Synthesis of methyl (E)-3-[2-(4-fluorophenyl)-lH-indol-3-yl]prop-2-enoate (C99)

[00402] 2-(4-fluorophenyl)-lH-indole (1.0 g, 4.76 mmol) and methyl 3,3-dimethoxypropanoate (0.81 mL, 5.7 mmol) were suspended in dichloromethane (15 mL). Trifluoroacetic acid (2.00 mL, 26 mmol) was added rapidly via syringe, resulting in a clear brown solution. The reaction mixture was heated to 40 °C for three hours. The reaction was diluted with dichloromethane (15 mL) to give an amber solution which was washed with saturated aqueous NaHCCh (25 mL) to yield a bright yellow/light amber biphasic mixture. The phases were separated and the organic layer was washed with saturated NaHCCh (30 mL), then dried (MgSCh) and filtered. The mixture was concentrated under a nitrogen stream overnight. The crude product was obtained as a yellow powder. The product was dissolved in minimum 2-MeTHF and pentane added until the suspension became lightly cloudy. The suspension was allowed to stand overnight, and the precipitate was filtered off. The filter cake was washed with heptane (2 x 15 mL), and dried in vacuo at 40 °C to afford the product as a yellow powder. Methyl (E)-3-[2-(4-fluorophenyl)-lH-indol-3-yl]prop-2-enoate (1.30 g, 86 %). ¾ NMR (300 MHz, Chloroform -if) d 8.41 (s, 1H), 8.01 – 7.95 (m, 1H), 7.92 (d, J = 16.0 Hz,

1H), 7.58 – 7.50 (m, 2H), 7.46 – 7.41 (m, 1H), 7.33 – 7.27 (m, 2H), 7.22 (t, J = 8.6 Hz, 2H), 6.59 (d, J = 16.0 Hz, 1H), 3.79 (s, 3H). LCMS m/z 295.97 [M+H]+.

Step 3. Synthesis of methyl 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoate (CIOO)

[00403] To a solution of methyl (E)-3-[2-(4-fluorophenyl)-lH-indol-3-yl]prop-2-enoate (7 g, 0.02 mol) in EtOAc (350 mL) was added Palladium on carbon (4 g, 10 %w/w, 0.004 mol) and stirred at room temperature for 2 h under an atmosphere of H2 (bladder pressure). The reaction mixture was filtered through a pad of Celite® and washed with EtOAc (400 mL). The filtrates was concentrated to afford methyl 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoate (7.1 g, 100 %). 1H MR (300 MHz, DMSO-<fc) 5 11.2 (s, 1H), 7.65 (q, J = 5.4 Hz, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.36 (t, J = 9.0 Hz, 3H), 7.10 (t, J = 8.1 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 3.53 (s, 3H), 3.10 (t, J = 15.9 Hz, 2H), 2.63 (t, J = 15.9 Hz, 2H). LCMS m/z 298.21 [M+H]+. The product was used directly in the subsequent step without further purification.

Step 4. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (C101)

[00404] To stirred solution of methyl 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoate (14.4 g, 0.05mol) in THF (300 mL), MeOH (300 mL) and H2O (250 mL) was cooled to -10°C. LiOH.H20 (10.1 g, 0.24 mol) was slowly added in a portion-wise manner. The reaction mixture was allowed to stir at room temperature for 16 h. The mixture was

evaporated and ice cold water (200 mL) was added, pH was adjusted to pH- 2 with 1M HC1 (400 mL, Cold solution). The mixture was stirred for 10 minutes, filtered and dried to afford 3-[2-(4-fhiorophenyl)-lH-indol-3-yl]propanoic acid (12.9 g, 94 %). ‘H NMR (400 MHz, DMSCMJ) 5 12.11 (s, 1H), 11.18 (s, 1H), 7.65 (q, J = 5.2 Hz, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.8 Hz, 3H), 7.10 (t, J = 8 Hz, 1H), 7.01 (t, J = 8 Hz, 1H), 3.06 (t, J = 16.4 Hz, 2H), 2.55 (t, J = 16 Hz, 2H). LCMS m/z 284.21 [M+H]+.

Step 5. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2- oxo-pyrrolidin-3-yl ] propanamide (87)

[00405] A mixture of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid C101 (40 g, 120.0 mmol) and (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one (Hydrochloride salt) S2 (23.8 g, 156.0 mmol) in DMF (270 mL) was stirred at room temperature for 5 minutes. CDMT (27.2 g, 154.9 mmol) and NMM (53 mL, 482.1 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was poured into water (140 mL) and then stirred for 1 h at room temperature, then filtered and washing the solids with water (50 mL). The solids were dissolved in 1 : 1 IP A/water (-400 mL, until all solids dissolved) with heating (reflux) and stirring. The mixture was allowed to cool slowly to room temperature overnight. The mixture was cooled to 0 oC and stirred to break up crystals for filtration. The crystals were then filtered off, rinsed with cold 1 : 1 IP A/water to afford a tan solid (45 g). The solid was dissolved in IPA (200 mL) and heated to 80 °C to dissolve the solid. Activated charcoal (10 g) was added and the mixture was heated with stirring for 30 minutes. The mixture was filtered through Celite ® and solvent removed under reduced pressure. A mixture of 40:60 IP A/water (350 mL) was added to the solid and the mixture was heated until all solids dissolved. The mixture was cooled to room temperature over 5 h. Solids precipitated within the mixture. The mixture was then cooled to 0 °C and stirred for 1 h. The solids were filtered off and air dried on funnel for 1 h, then in a vacuum at 55 °C overnight to afford the product. 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (36.6 g, 79 %). ¾ NMR (300 MHz, Methanol-i¾) d 7.63 (ddt, J= 8.6, 5.1, 2.7 Hz, 3H), 7.35 (dt, J= 8.1, 1.0 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.11 (ddd, J= 8.1, 7.0, 1.3 Hz, 1H), 7.03 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 4.34 (td, J= 7.6, 6.8 Hz, 1H), 4.22 (d, J= 7.7 Hz, 1H), 3.55 (dd, J= 9.9, 7.5 Hz, 1H), 3.26 – 3.18 (m, 2H), 3.10 (dd, J= 9.9, 6.8 Hz, 1H), 2.69 – 2.59 (m, 2H). LCMS m/z 382.05 [M+H]+. The

product contained 0.23 % IPA by weight by NMR (1439 ppm IPA by residual solvent analysis). Purity is 99.5 % by (qNMR).

Alternative Preparation II of Compound 87 ( Indole Preparation route D)

Step 1. Synthesis of 5-(4-fluorophenyl)-5-oxo-pentanoic acid (Cl 04)

[00406] To a stirred suspension of AlCb(13.9 g, 0.10 mol) in dichloromethane (50 mL) was added a solution of tetrahydropyran-2,6-dione (5.93 g, 0.05

mol) in dichloromethane (100 mL) at 0 °C over a period of 15 minutes and stirred for 30 min. Then to the reaction mixture was added fluorobenzene (5 g, 0.05 mol) at 0 °C over a period of 15 min, gradually allowed to room temperature and stirred for 16 h. Then the reaction mixture was added to ice water (50 mL) under stirring. The resulting solid was filtered to afford a light yellow solid. The solid was diluted with 3 % NaOH solution (50 mL) and dichloromethane (50 mL). The aqueous layer was separated and acidified with IN HC1 at 0 °C. The mixture was then extracted with EtOAc (100 mL), dried over Na2SC>4, and concentrated under reduced pressure. The solid was then washed with pentane and dried to afford 5-(4-fluorophenyl)-5-oxo-pentanoic acid as an off white solid. (6 g, 53 %). ¾ NMR (300 MHz, DMSO-^) d 12.07 (s, 1H), 8.06 (d, J = 6 Hz, 1H), 8.02 (d, J = 5.4 Hz, 1H), 7.36 (t, J = 8.7 Hz, 2H), 3.06 (t, J = 12 Hz,

2H), 2.31 (t, J = 7.2 Hz, 2H), 1.86-1.78 (m, 2H). LCMS m/z 211.18 [M+H]+.

Step 2. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (Cl 01) [00407] Phenylhydrazine (Hydrochloride salt) (375.7 g, 2.6 mol) was combined with the 5-(4-fluorophenyl)-5-oxo-pentanoic acid (507.7 g, 2.4 mol) in a 12 L three-necked round-bottomed flask equipped with an overhead stirrer, temperature probe, and reflux condenser. AcOH (5 L) was added. The stirring was initiated and ZnCk (605 g, 4.44 mol) was added. The white suspension rapidly thickened after a few minutes (due to formation of the hydrazine intermediate). Approx. 500 mL of extra AcOH was added to aid stirring. The reaction was then heated to 100 °C for three hours. The reaction was cooled to room temperature and poured into water (approx. 6 L). The mixture was extracted with EtOAc (approx 8 L). The extract was washed with water, dried

(MgS04), filtered, and evaporated in vacuo to afford a golden yellow solid. The solid was triturated with approx. 4 L of 10 % EtOAc/DCM and filtered. The filter cake was washed with 50 % dichloromethane/heptane (approx 1 L). The filter cake was dissolved in 40 % EtOAc/dichloromethane (approx. 2L) and filtered over a plug of silica gel. The plug was eluted with 40 % EtOAc/ dichloromethane until the product had been eluted (checked by TLC (25 % EtOAc/ dichloromethane)). The filtrate was evaporated in vacuo to afford 382.6 g of an off-white solid (Crop 1). All filtrates were combined and evaporated in vacuo. The remaining solid was dissolved in 10 %

EtOAc/dichloromethane (approx. 1 L) and chromatographed on a 3 kg silica gel cartridge on the ISCO Torrent (isocratic gradient of 10 % EtOAc/dichloromethane). Product fractions were combined and evaporated in vacuo to afford a yellow solid that was slurried with dichloromethane, cooled under a stream of nitrogen, and filtered. The filter cake was washed with 50 % dichloromethane/heptane and dried in vacuo to afford 244.2 g of product (Crop 2). Altogether, both crops afforded 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (626.8 g, 93 %). ¾ NMR (300 MHz, DMSO-i/e) d 12.15 (s, 1H), 11.20 (s, 1H), 7.74 – 7.62 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.47 – 7.28 (m, 3H), 7.11 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.02 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 3.17 – 2.85 (m, 2H), 2.61 – 2.52 (m, 2H) ppm. 19F NMR (282 MHz, DMSO-i/e) d -114.53 ppm. LCMS m/z 284.15 [M+H]+.

Step 3. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2- oxo-pyrrolidin-3-yl ] propanamide (87)

[00408] A 3-L three neck RBF under nitrogen was equipped with a 150 mL addition funnel and thermocouple, then loaded with 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (77.2 g, 228.6 mmol), (3S,4R)-3-amino-4-hydroxy-pyrrolidin-2-one

(Hydrochloride salt) (36.6 g, 239.9 mmol) and CDMT (44.2 g, 251.7 mmol). DMF (320 mL) was added and the orange slurry was cooled to -5 °C (acetone/brine/dry ice). NMM (88 mL, 800.4 mmol) was added via a funnel over 75 minutes to keep the internal temp <0 °C. The slurry was stirred at between -10 and 0 °C for 1 hour, then allowed to warm to ambient temperature progressively over 2 hours. Additional reagents were added (10 % of the initial quantities), and the mixture was stirred overnight at ambient temperature. Water (850 mL) was added over 60 minutes, maintaining the internal temperature at <25 °C (ice bath). This slow water addition allows for complete dissolution of any visible salt before precipitation of the product. The resulting thick slurry was stirred at ambient temperature overnight. The solid was recovered by filtration and washed with water (3 x 500 mL). The solid was dried under a stream of air at ambient temperature, then purified by crystallization.

Crystallization of 3- [2-( 4-fluorophenyl)-lH-indol-3-yl ]-N-[ ( 3S, 4R)-4-hydroxy-2-oxo- pyrrolidin-3-yl ] propanamide (87)

[00409] Under nitrogen atmosphere, a 2-L, 3 -neck flask equipped with addition funnel and thermocouple was charged with a light brown suspension of the crude 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yljpropanamide (89.5 g) in IPA (225 mL, 2.5 vol). The slurry was heated to 50 °C and water (675 mL, 7.5 vol) was added until near-complete dissolution of solid was observed. The temperature was adjusted to 70 °C-to achieve full dissolution, yielding a clear amber solution. After 30 minutes, the heat source was removed and the mixture was cooled to ambient temperature over the weekend, stirring gently while maintaining the nitrogen atmosphere. The solid was recovered by filtration, washed with IPA:H20 = 1 :2 (2 x 300 mL, 2 x 3.3 vol) dried under a stream of air overnight to afford the product. 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide (84.8 g, 92 %). ¾ NMR (300 MHz, DMSO-^) d 11.19 (s, 1H), 8.23 (d, J= 7.5 Hz, 1H), 7.77 (s, 1H), 7.72 – 7.63 (m, 2H), 7.60 (d, J= 7.8 Hz, 1H), 7.41 -7.31 (m, 3H), 7.12 (ddd, J= 8.1, 7.0, 1.2 Hz, 1H), 7.03 (ddd, J= 8.0, 7.0, 1.1 Hz, 1H), 5.49 (d, J= 5.0 Hz, 1H), 4.20 – 4.06 (m, 2H), 3.38 (s, 1H), 3.11 – 3.00 (m, 2H), 2.92 (dd, J= 9.4, 6.6 Hz, 1H). LCMS m/z 382.15 [M+H]+.

Crystallization of 3- [2-( 4-fluorophenyl)-lH-indol-3-yl J-N-[ ( 3S, 4R)-4-hydroxy-2-oxo- pyrrolidin-3-yl ] propanamide (87)

[00410] A 2-L, 3-neck flask equipped with addition funnel and thermocouple was charged with a light brown suspension of the crude 3-[2-(4-fluorophenyl)-lH-indol-3- yl]-N-[(3S,4R)-4-hydroxy-2-oxo-pyrrolidin-3-yl]propanamide in IPA (225 mL, 1 vol). The slurry was heated to 50 °C and water (675 mL, 3 vol) was added until near- complete dissolution of solid observed (mL). Temperature was increased to 70 °C under nitrogen (full dissolution, yielding a clear amber solution). After 30 minutes, the heat was removed and the mixture cooled to ambient temperature over the weekend, stirring gently under nitrogen atmosphere. The solid was recovered by filtration and washed with IPAiLLO = 1 :2 (2 x 300 mL).The solid was dried under a stream of air overnight to afford the product. 3-[2-(4-fluorophenyl)-lH-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxo- pyrrolidin-3-yl]propanamide (84.8 g, 92 %). ¾ NMR (300 MHz, DMSO-i/e) d 11.19 (s, 1H), 8.23 (d, J= 7.5 Hz, 1H), 7.77 (s, 1H), 7.72 – 7.63 (m, 2H), 7.60 (d, J= 7.8 Hz,

1H), 7.41 – 7.31 (m, 3H), 7.12 (ddd, J= 8.1, 7.0, 1.2 Hz, 1H), 7.03 (ddd, 7= 8.0, 7.0,

1.1 Hz, 1H), 5.49 (d, J= 5.0 Hz, 1H), 4.20 – 4.06 (m, 2H), 3.38 (s, 1H), 3.11 – 3.00 (m, 2H), 2.92 (dd, J= 9.4, 6.6 Hz, 1H). LCMS m/z 382.15 [M+H]+.

Large Scale Preparation of Compound 87

/- PrOAc solvate Form A

Step 1. Synthesis of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid (C101)

[00411] To a mixture of C104 (100.0 g, 1.0 equiv) and phenyl hydrazine hydrochloride (72.2 g, 1.05 eqiv) was charged AcOH (800 mL, 8 vol). The mixture was agitated and heated to 85 °C for 16 hours. The batch was cooled to 22 °C. A vacuum was applied and the batch distill at <70°C to ~3 total volumes. The batch was cooled to 19- 25 °C. The reactor was charged with iPrOAc (800 mL, 8 vol) and then charged with water (800 mL, 8 vol). The internal temperature was adjusted to 20 – 25 °C and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and the phases allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. 1 N HC1 (500 mL, 5 vol) was charged to the reactor. The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. The reactor was charged with 1 N HC1 (500 mL, 5 vol). The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h.

Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. Water (500 mL, 5 vol) was charged to the reactor.

The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. Water (500 mL, 5 vol) was charged to the reactor. The internal temperature was adjusted to 20 – 25 °C, and the biphasic mixture was stirred for no less than 0.5 h. Stirring was stopped and phases were allowed to separate for no less than 0.5 h. The lower aqueous layer was removed. The organic phase was distilled under vacuum at <75 °C to 3 total volumes. The reactor was charged with toluene (1000 mL, 10 vol). The organic phase was distilled under vacuum at <75 °C to 5 total volumes. The reactor was charged with toluene (1000 mL, 10 vol). The organic phase was distilled under vacuum at <75 °C to 5 total volumes. The resulting slurry was heated to an internal temperature of 85 °C until complete dissolution of solids was achieved. The mixture was allowed to stir for 0.5 h at 85 °C and then cooled to an internal temperature of 19 – 25 °C over 5 h. The mixture was allowed to stir at 25 °C for no less than 2 h. The slurry was filtered. The filter cake was washed with toluene (1 x 2 vol (200 mL) and 1 x 1.5 vol (150 mL)). The solids were dried under vacuum with nitrogen bleed at 60 °C to afford product C101 (95.03 g, 70%).

Purification of Compound 87 by Recrystallization to Form A

[00412] Compound 87 as an iPrOAc solvate (17.16 g after correction for iPrOAc content, 1.0 equiv) was charged to a reactor. A mixture of IP A (77 mL, 4.5 vol) and water (137 mL, 8 vol) were charged to the reactor. The slurry was heated to an internal temperature of 75 °C. The batch was cooled to an internal temperature of 25 °C over 10 h and then stirred at 25 °C for at least 12 h. The slurry was filtered. The filter cake was washed with 36/64 IP A/water (2 x 52 mL, 2 x 3 vol). The solids were dried under vacuum with nitrogen bleed at 60 °C to afford Compound 87 as a neat, crystalline form (Form A, 15.35 g, 89%).

Synthetic Procedure

[00413] A mixture of 3-[2-(4-fluorophenyl)-lH-indol-3-yl]propanoic acid C101 (50 g, 1.0 equiv), S2 hydrochloride (28.3 g, 1.05 equiv), and CDMT (34.1 g, 1.1 equiv) was charged with 2-MeTHF (200 mL, 4 vol) and DMF (50 mL, 1 vol) and the mixture was agitated. The internal temperature adjusted to <13 °C. The reactor was charged with NMM (64.5 g, 3.5 equiv) over 1 h, while maintaining internal temperature <20 °C. The internal temperature was adjusted to 25 °C and the batch was stirred at that temperature for 14 h. The batch was cooled to 10 °C and charged with water (250 mL, 5 vol) while keeping the internal temperature <20 °C. The batch was then warmed to 20 – 25 °C. Stirring was stopped, and the phases allowed to separate for 10 min. The lower aqueous phase was removed. The aqueous layer was back extracted with 2-MeTHF (2 x 200 mL, 2 x 4 vol) at 20 – 25 °C. The combined organic phases were washed with 1 N HC1 (500 mL, 10 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min. The lower aqueous phase was removed. The organic phases were washed with 0.25 N HC1 (2 x 250 mL, 2 x 5 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min for each wash. Lower aqueous phases were removed after each wash. The organic phase was washed with water (250 mL, 5 vol) at 20 – 25 °C by mixing for 10 min and settling for 10 min. The reactor was charged with 20 wt % Nuchar RGC® and stirred for 4 h. The reaction mixture was filtered through a pad of celite®. The reactor and celite® pad were rinsed with 2-MeTHF. The combined organics were distilled under vacuum at <50 °C to 5 total volumes. The reactor was charged with iPrOAc (500 mL, 10 vol). The organic phase was distilled under vacuum at <50 °C to 5 total volumes. The mixture was charged with additional iPrOAc (400 mL, 8 vol) and distillation under vacuum was repeated. The mixture was charged with additional iPrOAc (250 mL, 5 vol), heated to an internal

temperature of 75 °C and stirred for 5 h. The slurry was cooled to 25 °C, over 5 h and stirred for no less than 12 h. The slurry was filtered and the filter cake washed with iPrOAc (2 x 50 mL, 2 x 1 vol). The solids were dried under vacuum with nitrogen bleed at 55 – 60 °C to afford Compound 87 as an iPrOAc solvate (60.38 g including 9.9% w/w iPrOAc, 80.8% yield).

Form A of Compound 87

[00414] Compound 87 hydrate form was converted to the dehydrated, neat crystalline form (Form A) after drying.

Hydrate Form A of Compound 87

[00415] A mixture of IP A (4.5 vol) and water (8 vol) was added to compound 87

(iPrOAc solvate containing ~2.5 – 11 wt% iPrOAc, 1.0 equiv). The slurry was heated to an internal temperature of 75 °C and filtered hot. The filtrate was cooled to 25 °C for at least 12 h. The slurry was filtered. The filter cake was washed with 36/64 IP A/water (2 x 3 vol). The solids were dried under vacuum with nitrogen bleed at 55 – 60 °C. The product was isolated as Hydrate form.

IPAC Solvate of Compound 87:

[00416] The large scale synthesis described above provided an iPrOAc solvate containing ~2.5 – 11 wt% iPrOAc after drying.

Amorphous Form of Compound 87

[00417] ~lg of compound 87 was dissolved in 22mL of acetone. The solution was evaporated using a Genevac. The resulted solid was dried at 60C under vacuum overnight. The dried solid was amorphous form.

Publication Number TitlePriority Date Grant Date
WO-2020131807-A1Inhibitors of apol1 and methods of using same2018-12-17 
US-2020377479-A1Inhibitors of apol1 and methods of using same2018-12-17

///////////

O=C(N[C@@H]1C(=O)NC[C@H]1O)CCc1c2ccccc2[NH]c1c1ccc(F)cc1

SIMILAR

https://d4crq6wjnrm5a.cloudfront.net/drugs/720/5842720.png?Expires=1629119288&Policy=eyJTdGF0ZW1lbnQiOlt7IlJlc291cmNlIjoiaHR0cHM6Ly9kNGNycTZ3am5ybTVhLmNsb3VkZnJvbnQubmV0L2RydWdzLzcyMC81ODQyNzIwLnBuZyIsIkNvbmRpdGlvbiI6eyJEYXRlTGVzc1RoYW4iOnsiQVdTOkVwb2NoVGltZSI6MTYyOTExOTI4OH19fV19&Signature=cF-TptDVLQjX2ZetNPD5u1xkA-2MNWfoDI-idPuhS-blf-hpPJxOxXvstTNlxr0CfZBAGZwTR0LgoB5iSQzJJyu2NJXiXipepG0~Svx6zY6NdmxVK37PO7nzv61f9zTO-vjTUW4g0oiXzENMdRkJsansf2XgskWiwa-9piD0gV02R9jO2E9mmjtLygU5JlbJsfui91rsPYVHkW7qJQLVliePDWNXO4ykZpeGwy0N2UXxfphEgm3WsBDE1TomCJDgMZBY37ewn3Bk83lH2DBBb~EhC80sRaJr4mEcOkbdVI3hWISDfz-14L-A2tY0JQ8JOdpth31dNVYZIQZcsI-qZA__&Key-Pair-Id=APKAJYXZOHSJHO6RX3UQ

predicted

VX 147

cas 2446816-88-0 predicted

O=C(N[C@@H]1C(=O)NC[C@H]1O)CCc1c2cc(F)cc(F)c2[NH]c1c1ccc(F)cc1

  • OriginatorVertex Pharmaceuticals
  • ClassSmall molecules; Urologics
  • Mechanism of ActionApolipoprotein L1 inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • Phase IIFocal segmental glomerulosclerosis
  • Phase IKidney disorders

Most Recent Events

  • 14 Apr 2020Phase-II clinical trials in Focal segmental glomerulosclerosis in USA (PO) (EudraCT2020-000185-42) (NCT04340362)
  • 31 Dec 2019Vertex Pharmaceuticals completes phase I clinical trial in Focal segmental glomerulosclerosis and Kidney disorders (In volunteers) in USA (PO)
  • 05 Aug 2019Vertex Pharmaceuticals plans a phase II proof-of-concept trial for focal segmental glomerulosclerosis in 2020
NCT Number  ICMJENCT04340362
Other Study ID Numbers  ICMJEVX19-147-101
2020-000185-42 ( EudraCT Number )

ONO-2910


Figure JPOXMLDOC01-appb-C000058
Schembl21647748.png

ONO-2910

CAS 2410177-35-2

3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid

3- [2-[(E) -5- [3- (benzenesulfonamido) phenyl] penta-4-enoxy] phenyl] propanoic acidC26 H27 N O5 S465.56Benzenepropanoic acid, 2-[[(4E)-5-[3-[(phenylsulfonyl)amino]phenyl]-4-penten-1-yl]oxy]-

ONO Pharmaceuticals is developing ONO-2910 , the lead from a program of novel transient receptor potential cation channel 4/5 inhibitors, for treating peripheral neuropathy. In April 2021, a phase II trial in patients with diabetic polyneuropathy was initiated.

PATENT

CN112513011-BENZENE DERIVATIVE

Example 84: 3-[2-[(E)-5-[3-(Benzenesulfonamido)phenyl]pent-4-enyloxy]phenyl]propionic acid
        [Chemical formula 52]
         
        To a solution of the compound (146 mg) produced in Example 83 in THF (0.5 mL) and methanol (0.1 mL), 1M aqueous lithium hydroxide solution (0.5 mL) was added, and the mixture was stirred at 50°C for 8 hours. 1M hydrochloric acid was added to make it acidic, and it was extracted with ethyl acetate. After drying the organic layer over sodium sulfate, it was concentrated under reduced pressure to obtain the title compound (105 mg) having the following physical properties.
        HPLC retention time (min): 1.10
         1 H-NMR(CD 3 OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61,2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45-7.49, 7.55, 7.75 -7.78.
wdt-5

NEW DRUG APPROVALS

ONE TIME

$10.00

PATENT

WO-2021153690

Novel crystalline forms of 3-[2-[(E)-5-[3-(benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid act as neuroprotective, useful for treating neurological disorders eg chronic inflammatory demyelinating polyneuritis, Guillain-Barre syndrome and allergic angiitis.Example 1:
Sulfuric acid (0.26 mL) is added to a solution of isopropyl 3- (2-hydroxyphenyl) propanoate 3,4-dihydrocoumarin (50.0 g) in isopropyl alcohol (500 mL), and the reaction mixture is mixed at room temperature for 2 hours. Stirred. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (73.2 g) having the following physical properties.
1 1 H-NMR (CDCl 3 ): δ 1.20, 2.66-2.70, 2.87-2.91, 4.95-5.08, 6.86-6.91, 7.06-7.15, 7.35.

Example 2: Isopropyl 3- (2- (pent-4-in-1-yloxy) phenyl) propanoate In a solution of the compound (3.00 g) prepared in Example 1 in N, N-dimethylacetamide (25 mL) at room temperature. Cesium carbonate (9.39 g) was added at the same temperature, and the mixture was stirred at the same temperature for 15 minutes. 5-Chloro-1-pentyne (CAS Registry Number: 14267-92-6) (1.63 g) was added to the reaction solution at room temperature, and the mixture was stirred at 60 ° C. for 3 hours. Water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 → 5: 1) to give the title compound (2.40 g) having the following physical property values.
HPLC retention time (minutes): 1.13.Example 3: Isopropyl (E) -3- (2-((5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) penta-4-en-1-yl) Il) Oxy) Phenyl) Propanoate In
a heptane (2 mL) solution of the compound (1.00 g) prepared in Example 2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1. 17 g) and 4-dimethylaminobenzoic acid (60.2 mg) were added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give the title compound (503 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.38.Example 3 (1):
Pyridine (0.95 mL), N, N-dimethyl in a solution of N- (3-bromophenyl) benzenesulfonamide 3-bromoaniline (1.02 g) in dichloromethane (20 mL) at 0 ° C. Aminopyridine (hereinafter abbreviated as DMAP) (72.4 mg) and benzenesulfonyl chloride (1.10 g) were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 2: 1) to give the title compound (1.96 g) having the following physical properties. rice field.
HPLC retention time (minutes): 0.98.
Example 4: Isopropyl (E) -3-(2-((5- (3- (phenylsulfonamide) phenyl) penta-4-en-1-yl) oxy) phenyl) propanoate The
compound prepared in Example 3. In a solution of (180 mg) in THF (3 mL), the compound (168 mg) prepared in Example 3 (1), chloro (2-dicyclohexylphosphino-2′, 4′, 6′-triisopropyl-1,1′- Biphenyl) [2- (2′-amino-1,1′-biphenyl)] palladium (II) (0.035 g) and a 2M tripotassium phosphate aqueous solution (0.67 mL) were added, and the mixture was stirred at 60 ° C. for 1 hour. .. The reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (113 mg) having the following physical characteristics.
HPLC retention time (minutes): 1.24 
Example 5: 3- [2-[(E) -5- [3- (benzenesulfonamide) phenyl] penta-4-enoxy] phenyl] propanoic acid 
[Chemical 2]

 A 1 M aqueous lithium hydroxide solution (0.5 mL) was added to a solution of the compound (146 mg) prepared in Example 4 in THF (0.5 mL) and methanol (0.1 mL), and the mixture was stirred at 50 ° C. for 8 hours. It was acidified by adding 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (105 mg) having the following physical characteristics.
Form: Amorphous
HPLC retention time (minutes): 1.101
1 H-NMR (CD 3 OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45-7.49, 7.55, 7.75-7.78.

PATENT

WO2020027150

https://patents.google.com/patent/WO2020027150A1/en

Example 83: Isopropyl (E) -3- (2-((5- (3- (phenylsulfonamido) phenyl) penta-4-en-1-yl) oxy) phenyl) propanoate The compound prepared in Example 82 Compound (168 mg) prepared in Example 9 and chloro (2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl) [180 mg) in THF (3 mL) solution were added. 2- (2′-Amino-1,1′-biphenyl)] palladium (II) (0.035 g) and a 2M aqueous solution of tripotassium phosphate (0.67 mL) were added, and the mixture was stirred at 60 ° C. for 1 hour. After cooling the reaction solution to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1 → 2: 1) to give the title compound (113 mg) having the following physical data.
HPLC retention time (min): 1.24.Example 84: 3- [2-[(E) -5- [3- (benzenesulfonamido) phenyl] penta-4-enoxy] phenyl] propanoic acid

Figure JPOXMLDOC01-appb-C000058

To a solution of the compound prepared in Example 83 (146 mg) in THF (0.5 mL) and methanol (0.1 mL) was added a 1 M aqueous lithium hydroxide solution (0.5 mL), and the mixture was stirred at 50 ° C. for 8 hours. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (105 mg) having the following physical data.
HPLC retention time (min): 1.10
1 H-NMR (CD 3 OD): δ 1.95-2.03, 2.41-2.46, 2.57-2.61, 2.92-2.95, 4.03-4.06, 6.24, 6.36, 6.86, 6.90-6.95, 7.06-7.08, 7.11-7.19, 7.45 -7.49, 7.55, 7.75-7.78.

///////////ONO-2910, ONO 2910, PHASE 2,

O=S(=O)(Nc1cc(\C=C\CCCOc2ccccc2CCC(=O)O)ccc1)c1ccccc1

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