CADROFLOXACIN

NDA, Uncategorized Comments Off

May 092016

Cadrofloxacin Structure

Cadrofloxacin , CS 940

3-Quinolinecarboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-1,4-dihydro-7-[(3S)-3-methyl-1-piperazinyl]-4-oxo-, hydrochloride (1:1)

UNII-1YOQ7J9ACY; 153808-85-6; CADROFLOXACIN HYDROCHLORIDE; 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3s)-3-methylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3S)-3-methylpiperazin-1-yl]-4-oxoquinoline-3-carboxylic acid

Molecular Formula:	C₁₉H₂₀F₃N₃O₄
Molecular Weight:	411.37501 g/mol

Company：HengRui (Originator), Daiichi Sankyo (Originator), UBE (Originator)

A quinolone antibiotic potentially for the treatment of bacterial infections.

Research Code CS-940

CAS No. 153808-85-6(FREE)

Cas 128427-55-4(Cadrofloxacin HCl)

HYDROCHLORIDE

Molecular Weight	447.84
Formula	C19H20F3N3O4 • HCl

OriginatorSankyo; Ube Industries
DeveloperSankyo
ClassAntibacterials; Quinolones; Small molecules
Mechanism of ActionType II DNA topoisomerase inhibitors
- 20 Jun 1996An animal study has been added to the Bacterial infections pharmacodynamics section
- 24 Mar 1995Phase-II clinical trials for Bacterial infections in Japan (PO)

Cadrofloxacin hydrochloride was studied for the treatment of bacterial infections.The compound was originally developed by UBE and Daiichi Sankyo. However, this study was discontinued. The compound currently was developed by Hengrui.

SYNTHESIS

Decarboxylation of 3,5,6-trifluoro-4- hydroxyphthalic acid (I) upon heating at 140 C in an autoclave furnished 2,4,5-trifluoro-3-hydroxybenzoic acid (II). This was converted to ethyl ester (III) by refluxing in EtOH in the presence of H2SO4. Condensation of (III) with chlorodifluoromethane and NaH in hot DMF produced the corresponding difluoromethyl ether, and subsequent basic hydrolysis of the ethyl ester yielded 3- (difluoromethoxy) -2, 4,5-trifluorobenzoic acid (IV). Alternatively, acid (II) was converted to acid chloride with SOCl2 and subsequently condensed with ammonia to give amide (V). After formation of the difluoromethyl ether (VI) under similar conditions as above, acid (IV) was obtained by diazotization of the amide function of (VI) in hot sulfuric acid. The difluoromethoxy acid (IV) was also prepared by direct alkylation of hydroxy acid (II) with chlorodifluoromethane in the presence of NaOH in hot DMF. acid (IV) was activated as the corresponding acid chloride (VII) with SOCl2. Condensation of acid chloride (VII) with the magnesium salt of diethyl malonate gave rise to the benzoylmalonate (VIII). Further decarbethoxylation of (VIII) by heating in the presence of p-toluenesulfonic acid yielded keto ester (IX). This was condensed with triethyl orthoformate in the presence of Ac2O to give the ethoxyacrylate (X), which was converted to enamine (XII) by treatment with cyclopropylamine (XI). The target quinolone system (XIII) was then obtained by intramolecular cyclization of (XII) in the presence of NaH. Then, ethyl ester (XII) cleavage using boron trifluoride etherate provided the key quinolonecarboxylic acid boron chelate (XIV)

Route

US5073556A / US5348961A.

1 to 8 of 8

Patent ID	Date	Patent Title
US2011159049	2011-06-30	PHARMACEUTICAL COMPOSITION
US2010330165	2010-12-30	USE OF CHEMOTHERAPEUTIC AGENTS
US2007196504	2007-08-23	PHARMACEUTICAL COMPOSITION
US2007197501	2007-08-23	Use Of Chemotherapeutic Agents
US2007148235	2007-06-28	PHARMACEUTICAL COMPOSITION
US2005152975	2005-07-14	Pharmaceutical composition
US2004022848	2004-02-05	Medicinal composition
US2003045544	2003-03-06	Use of chemotherapeutic agents

//////CS 940, Quinolone antibiotic , CADROFLOXACIN, NDA

CC1CN(CCN1)C2=C(C=C3C(=C2OC(F)F)N(C=C(C3=O)C(=O)O)C4CC4)F

A New Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, from University Of Notre Dame

PRECLINICAL, Uncategorized Comments Off

May 062016

(E)-3-(3-Carboxyphenyl)-2-(4-ethynylstyryl)quinazolin-4(3H)-one

(E)-3-(2-(4-Cyanostyryl)-4-Oxoquinazolin-3(4h)-Yl)benzoic Acid;

1624273-22-8 CAS

NA SALT 1624273-21-7 CAS

INNOVATORS

University Of Notre Dame

Mayland Chang, Shahriar Mobashery, Renee BOULEY INVENTORS

C₂₄H₁₅N₃O₃
Molecular Weight:	393.3942 g/mol

¹H NMR (500 MHz, DMSO-d₆) δ 4.32 (s, 1H), 6.34 (d, J = 15.55 Hz, 1H), 7.35 (d, J = 8.37 Hz, 2H), 7.44 (d, J = 8.37 Hz, 2H), 7.49 (d, J = 7.58 Hz, 1H), 7.55 (t, J = 7.98 Hz, 1H), 7.58 (t, J = 7.78 Hz, 1H), 7.78 (d, J = 8.17 Hz, 1H), 7.87 (m, 3H), 8.05 (d, J = 7.78 Hz, 1H), 8.13 (d, J = 7.98 Hz, 1H).

¹³C NMR (126 MHz, DMSO-d₆) δ 82.70, 83.24, 120.66, 121.04, 122.84, 126.51, 126.81, 127.31, 127.83, 129.98, 130.12, 132.33, 132.39, 133.49, 134.90, 135.21, 137.21, 137.99, 147.36, 151.04, 161.37, 166.58.

HRMS (m/z): [M + H]⁺, calcd for C₂₅H₁₇N₂O₃, 393.1234; found, 393.1250. HRMS (m/z): [M + Na]⁺, calcd for C₂₅H₁₆N₂NaO₃, 415.1053; found, 415.1054.

The emergence of resistance to antibiotics over the past few decades has created a state of crisis in the treatment of bacterial infections.Over the years, β-lactams were the antibiotics of choice for treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of methicillin-resistant S. aureus (MRSA). Presently, vancomycin, daptomycin, linezolid, or ceftaroline are used for treatment of MRSA infections, although only linezolid can be dosed orally. Resistance to all four has emerged. Thus, new anti-MRSA antibiotics are sought, especially agents that are orally bioavailable. a new antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)–one, with potent activity against S. aureus, including MRSA. We document that quinazolinones of our design are inhibitors of cell-wall biosynthesis in S. aureus and do so by binding to dd-transpeptidases involved in cross-linking of the cell wall. quinazolinones possess activity in vivo and are orally bioavailable. This antibiotic holds promise in treating difficult infections by MRSA.

PAPER

Journal of the American Chemical Society (2015), 137(5), 1738-1741.

http://pubs.acs.org/doi/abs/10.1021/jacs.5b00056

Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one

Renee Bouley^†, Malika Kumarasiri^†, Zhihong Peng^†, Lisandro H. Otero^‡, Wei Song^†, Mark A. Suckow^§, Valerie A. Schroeder^§, William R. Wolter^§, Elena Lastochkin^†, Nuno T. Antunes^†, Hualiang Pi^†, Sergei Vakulenko^†, Juan A. Hermoso^‡, Mayland Chang^*^†, and Shahriar Mobashery^*^†

^† Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States

^‡ Department of Crystallography and Structural Biology, Instituto de Química-Física “Rocasolano”, Consejo Superior de Investigaciones Científicas, Madrid, Spain

^§ Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States

J. Am. Chem. Soc., 2015, 137 (5), pp 1738–1741

DOI: 10.1021/jacs.5b00056

Publication Date (Web): January 28, 2015

*mchang@nd.edu, *mobashery@nd.edu

Abstract

In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)–one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.

PATENT

WO 2014138302

http://www.google.com/patents/WO2014138302A1?cl=en

Staphylococcus aureus is a common bacterium found in moist areas of the body and skin. S. aureus can also grow as a biofilm, representing the leading cause of infection after implantation of medical devices. Approximately 29% (78.9 million) of the US population is colonized in the nose with S. aureus, of which 1.5% (4.1 million) is methicillin-resistant S. aureus (MRSA). In 2005, 478,000 people in the US were hospitalized with a S. aureus infection, of these 278,000 were MRSA infections, resulting in 19,000 deaths. MRSA infections have been increasing from 2% of S. aureus infections in intensive care units in 1974 to 64% in 2004, although more recent data report stabilization. Approximately 14 million outpatient visits occur every year in the US for suspected S. aureus skin and soft tissue infections. About 76% of these infections are caused by S. aureus, of which 78% are due to MRSA, for an overall rate of 59%. Spread of MRSA is not limited to nosocomial (hospital-acquired) infections, as they are also found in community-acquired infections. Over the years, β-lactams were antibiotics of choice in treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of

MRSA. Presently, vancomycin, daptomycin or linezolid are agents for treatment of MRSA infections, although only linezolid can be dosed orally. Resistance to all three has emerged. Thus, new anti-MRSA therapeutic strategies are needed, especially agents that are orally bioavailable.

Clinical resistance to β-lactam antibiotics by MRSA has its basis predominantly in acquisition of the mecA gene, which encodes penicillin-binding protein 2a (PBP2a). PBP2a, a cell-wall DD- transpeptidase, is refractory to inhibition by essentially all commercially available β-lactams (ceftaroline is an exception), antibiotics that irreversibly acylate the active-site serine of typical PBPs. PBPs catalyze biosynthesis of the bacterial cell wall, which is essential for the survival of the bacterium. Accordingly, new ηοη-β-lactam antibiotics that inhibit PBP2a are needed to combat drug-resistant strains of bacteria. SUMMARY

Staphylococcus aureus is responsible for a number of human diseases, including skin and soft tissue infections. Annually, 292,000 hospitalizations in the US are due to S. aureus infections, of which 126,000 are related to methicillin-resistant Staphylococcus aureus (MRSA), resulting in 19,000 deaths. A novel structural class of antibiotics has been discovered and is described herein. A lead compound in this class shows high in vitro potency against Gram-positive bacteria comparable to those of linezolid and superior to vancomycin (both considered gold standards) and shows excellent in vivo activity in mouse models of MRSA infection.

The invention thus provides a novel class of ηοη-β-lactam antibiotics, the quinazolinones, which inhibit PBP2a by an unprecedented mechanism of targeting both its allosteric and active sites. This inhibition leads to the impairment of the formation of cell wall in living bacteria. The quinazolinones described herein are effective as anti-MRSA agents both in vitro and in vivo. Furthermore, they exhibit activity against other Gram-positive bacteria. The quinazolinones have anti-MRSA activity by themselves. However, these compounds synergize with β-lactam antibiotics. The use of a combination of a quinazolinone with a β-lactam antibiotic can revive the clinical use of β-lactam antibacterial therapy in treatment of MRSA infections. The invention provides a new class of quinazolinone antibiotics, optionally in combination with other antibacterial agents, for the therapeutic treatment of methicillin- resistant Staphylococcus aureus and other bacteria.

The quinazolinone compounds described herein can be prepared using standard synthetic techniques known to those of skill in the art. Examples of such techniques are described by Khajavi et al. (J. Chem. Res. (S), 1997, 286-287) and Mosley et al. (J. Med. Chem. 2010, 53, 5476-5490). A general preparatory scheme for preparing the compounds described herein, for example, compounds of Formula

wherein each of the variables are as defined for one or more of the formulas described herein, such as Formula (A).

EXAMPLES

Example 1. Compound Preparation

Chemistry. Organic reagents and solvents were purchased from Sigma- Aldrich. ^lH and ¹³C NMR spectra were recorded on a Varian INOVA-500. High-resolution mass spectra were obtained using a Bruker micrOTOF/Q2 mass spectrometer.

2-Methyl-4H-benzo[</| [l,3]oxazin-4-one (3). Anthranilic acid (20 g, 146 mmol) was dissolved in triethyl orthoacetate (45 mL, 245 mmol) and refluxed for 2 h. The reaction mixture was cooled on ice for 4 h to crystallize the intermediate. The resulting crystals were filtered and washed with hexanes to give 3 (17 g, 72% yield). ^lH NMR (500 MHz, CDC1₃) δ 2.47 (s, 3H), 7.50 (t, J= 7.38 Hz, 1H), 7.54 (d, J = 7.98 Hz, 1H), 7.80 (t, J= 7.18 Hz, 1H), 8.18 (d, J= 7.78 Hz, 1H). ¹³C NMR (126 MHz, CDCI3) δ 21.59, 1 16.84, 126.59, 128.42, 128.66, 136.77, 146.61, 159.89, 160.45. HRMS (m/z): [M + H]⁺, calcd for C9H8NO2, 162.0550; found , 162.0555.

2-Methyl-3-(3-carboxyphenyl)-quinazolin-4(3//)-one (4). Compound 3 (2 g, 12.4 mmol) and 3- aminophenol (1.7 g, 12.4 mmol) were suspended in glacial acetic acid (8 mL, 140 mmol), and dissolved upon heating. The reaction was refluxed for 5 h, at which point 5 mL water was added to the cooled reaction mixture. The resulting precipitate was filtered and washed with water, followed by cold ethanol and hexane to give 4 (3.19 g, 92% yield). ^lH (500 MHz, DMSO-d₆) δ 2.87 (s, 3H), 7.52 (t, J= 7.38 Hz, 1H), 7.66-7.73 (m, 3H), 7.84 (t, J= 7.38 Hz, 1H), 8.01 (s, 1H), 8.09 (t, J= 7.58 Hz, 2H). ¹³C NMR (126 MHz, DMSO-de) δ 24.13, 120.48, 126.32, 126.47, 126.72, 129.52, 129.83, 130.01, 132.40, 133.07, 134.67, 138.18, 147.37, 154.13, 161.44, 166.58. HRMS (m/z): [M + H]⁺, calcd for C16H13N2O3 ,

281.0921 ; found, 281.0917.

Sodium (£^‘)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (2). Compound 4 (1.0 g, 3.6 mmol) and 4-formylbenzonitrile (0.56 g, 4.3 mmol) were suspended in glacial acetic acid (5 mL, 87 mmol), a suspension that dissolved upon heating. The reaction was refluxed for 18 h and 5 mL water was added to the cooled reaction mixture. The resulting precipitate was filtered and washed with water, followed by cold ethanol and hexanes to afford the carboxylic acid (0.77g, 75% yield). HRMS (m/z): [M + H]⁺, calcd for C24H16N3O3, 394.1 186; found 394.1214. The carboxylic acid (0.45 g, 1.1 mmol) was dissolved in hot ethanol, to which sodium 2-ethylhexanoate (0.28 g, 1.7 mmol) was added. The reaction mixture was stirred on ice for 2 h. The precipitate was filtered and washed with cold ethanol. The product was obtained by dissolving the precipitate in about 5 mL of water and subsequent lyophilization of the solution to give 2 as the sodium salt (0.4 g, 85% yield).

¾ NMR (500 MHz, DMSO- de) δ 6.47 (d, J= 15.55 Hz, 1H), 7.59 (m, 3H), 7.74 (d, J= 5.38 Hz, 2H), 7.79 (m, 3H), 7.91 (m, 2H), 8.05 (s, 1H), 8.14 (d, J= 7.78 Hz, 2H).

¹³C NMR (126 MHz, DMSO-de) δ 11 1.56, 1 18.61, 120.76, 123.42, 126.50, 127.01, 127.35, 128.26, 129.99, 130.06, 130.12, 132.33, 132.83, 133.46, 134.89, 136.95, 137.03, 139.25, 147.21, 150.74, 161.25, 166.52.

HRMS (m/z): [M + H]⁺, calcd for C24Hi₅N₃NaO₃, 416.1006; found, 416.0987.

PAPER

http://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b00372

Structure–Activity Relationship for the 4(3H)-Quinazolinone Antibacterials

Renee Bouley^†, Derong Ding^†, Zhihong Peng^†, Maria Bastian^†, Elena Lastochkin^†, Wei Song^†, Mark A. Suckow^‡,Valerie A. Schroeder^‡, William R. Wolter^‡, Shahriar Mobashery^*^†, and Mayland Chang^*^†

^† Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States

^‡ Freimann Life Sciences Center and Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, United States

J. Med. Chem., Article ASAP

DOI: 10.1021/acs.jmedchem.6b00372

Publication Date (Web): April 18, 2016

*S.M.: e-mail, mobashery@nd.edu; phone, 574-631-2933., *M.C.: e-mail, mchang@nd.edu; phone, 574-631-2965.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

We recently reported on the discovery of a novel antibacterial (2) with a 4(3H)-quinazolinone core. This discovery was made by in silico screening of 1.2 million compounds for binding to a penicillin-binding protein and the subsequent demonstration of antibacterial activity againstStaphylococcus aureus. The first structure–activity relationship for this antibacterial scaffold is explored in this report with evaluation of 77 variants of the structural class. Eleven promising compounds were further evaluated for in vitro toxicity, pharmacokinetics, and efficacy in a mouse peritonitis model of infection, which led to the discovery of compound 27. This new quinazolinone has potent activity against methicillin-resistant (MRSA) strains, low clearance, oral bioavailability and shows efficacy in a mouse neutropenic thigh infection model.

NMR

INVENTORS

Renee Bouley

Renee Bouley selected to receive prestigious ACS Predoctoral Fellowship

Published: July 02, 2013

Renee Bouley

Renee Bouley, a third year graduate student in the Department of Chemistry and Biochemistry, has been selected to receive a prestigious American Chemical Society (ACS) Division of Medicinal Chemistry Predoctoral Fellowship. Bouley is one of only four recipients chosen for the 2013-2014 cycle.

This award supports doctoral candidates working in the area of medicinal chemistry who have demonstrated superior achievements as graduate students and who show potential for future work as independent investigators. These fellowships have been awarded annually since 1991 and include one year stipend support and an invitation to present the fellow’s research results at a special awards session at the ACS National Meeting.

Bouley’s work, conducted under the advisement of Shahriar Mobashery, Navari Family Professor in Life Sciences, and Mayland Chang, Research Professor and Director of the Chemistry-Biochemistry-Biology Interface (CBBI) Program, centers around the discovery of a new class of antibiotics that are selective against staphylococcal species of bacteria, including hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA). She has already identified a class of compounds that has in vitro activity against bacteria and demonstrated efficacy in mice. Bouley spent three months in 2012 in the laboratory of Prof. Juan Hermoso at Consejo Superior de Investigaciones Cientificas in Madrid, Spain, where she solved the crystal structure of the lead compound in complex with its target protein. Her studies have shown an unprecedented mechanism of action that opens opportunities for clinical resurrection of β-lactam antibiotics in combination with the new antibiotics. Bouley’s work during her fellowship tenure will explore structural analogs of these compounds with the goal of optimizing their potency in vivo and improving their drug-like properties.

Bouley is already the recipient of a National Institutes of Health Ruth L. Kirschstein National Research Service Award – CBBI (Chemistry-Biochemistry-Biology Interface) Program, a CBBI Research Internship Award, and an American Heart Association Predoctoral Fellowship (declined)………..https://www.linkedin.com/in/renee-bouley-43243215

University of Notre Dame

MAYLAND CHANG

http://chemistry.nd.edu/people/mayland-chang/

MAYLAND CHANG

Research Professor; Director, Chemistry-Biochemistry-Biology Interface (CBBI) Program
Office: 247 NSH
Phone: (574) 631-2965

Dr. Chang obtained B.S. degrees in biological sciences and chemistry from the University of Southern California, and a Ph.D. in chemistry from the University of Chicago. Subsequently, she conducted postdoctoral research at Columbia University as a National Institutes of Health postdoctoral fellow. She joined the faculty of the University of Notre Dame in 2003. Previously, Dr. Chang was Chief Operating Officer of University Research Network, Inc., Senior Scientist with Pharmacia Corporation, and Senior Chemist at Dow Chemical Company. She has characterized the ADME properties of numerous drugs, as well as prepared NDAs, INDs, Investigator’s Brochures, product development plans, and candidate drug evaluations.

Shahriar Mobashery

Navari Professor at University of Notre Dame

The Mobashery research program integrates computation, biochemistry, molecular biology, and the organic synthesis of medically important molecules. Bringing together these different disciplines is required to produce both scientific and medical advances for very difficult, but critically important clinical problems.

http://chemistry.nd.edu/people/shahriar-mobashery/

https://www.linkedin.com/in/shahriar-mobashery-71b67b4b

/////// 1624273-22-8, Antibiotic, (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, methicillin-resistant S. aureus, MRSA, 1624273-21-7, PRECLINICAL

O=C(O)c1cc(ccc1)N3C(=Nc2ccccc2C3=O)/C=C/c4ccc(C#N)cc4

Sun Pharma and Merck & Co. Inc. Enter into Licensing Agreement for Tildrakizumab

Uncategorized Comments Off

May 052016

Tildrakizumab (MK-3222)

Company	Merck & Co. Inc.
Description	Anti-IL-23 antibody
Molecular Target	Interleukin-23 (IL-23)
Mechanism of Action	Antibody
Therapeutic Modality	Biologic: Antibody

Latest Stage of Development	Phase III
Standard Indication	Psoriasis
Indication Details	Treat moderate to severe chronic plaque psoriasis
Regulatory Designation
Partner	Sun Pharmaceutical Industries Ltd.

Tildrakizumab is a monoclonal antibody designed for the treatment of immunologically mediated inflammatory disorders.^[1]

Tildrakizumab was designed to block interleukin-23, a cytokine that plays an important role in managing the immune system and autoimmune disease. Originally developed by Schering-Plough, this drug is now part of Merck‘s clinical program, following that company’s acquisition of Schering-Plough.

Sun Pharmaceutical acquired worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of U.S. $80 million. Upon product approval, Sun Pharmaceutical will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. ^[2]

As of March 2014, the drug was in phase III clinical trials for plaque psoriasis. The two trials will enroll a total of nearly 2000 patients, and preliminary results are expected in June, 2015. ^[3]^[4]

References

http://clinicaltrials.gov/ct2/show/NCT01722331?term=SCH-900222&phase=2&fund=2&rank=2

Sun Pharma and Merck & Co. Inc. Enter into Licensing Agreement for Tildrakizumab, MK 3222

WHITEHOUSE STATION, N.J., and MUMBAI, India, Wednesday, September 17, 2014 (BUSINESS WIRE) – Merck & Co., Inc., (NYSE:MRK), known as MSD outside the United States and Canada, and Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715) through their respective subsidiaries, today announced an exclusive worldwide licensing agreement for Merck’s investigational therapeutic antibody candidate, tildrakizumab, (MK-3222), which is currently being evaluated in Phase 3 registration trials for the treatment of chronic plaque psoriasis, a skin ailment.

Under terms of the agreement, Sun Pharma will acquire worldwide rights to tildrakizumab for use in all human indications from Merck in exchange for an upfront payment of U.S. $80 million. Merck will continue all clinical development and regulatory activities, which will be funded by Sun Pharma. Upon product approval, Sun Pharma will be responsible for regulatory activities, including subsequent submissions, pharmacovigilance, post approval studies, manufacturing and commercialization of the approved product. Merck is eligible to receive undisclosed payments associated with regulatory (including product approval) and sales milestones, as well as tiered royalties ranging from mid-single digit through teen percentage rates on sales.

“Consistent with our previously announced global initiative to sharpen our commercial and R&D focus, including prioritizing our late stage pipeline candidates, we are pleased to enter into this agreement with Sun Pharma to help realize the potential of tildrakizumab for patients with chronic plaque psoriasis,” said Iain D. Dukes, Ph.D., senior vice president, Business Development and Licensing, Merck Research Laboratories.

“Sun Pharma is very pleased to enter into this collaboration with Merck, a recognized leader in the field of inflammatory/immunology therapies, for this late-stage candidate for chronic plaque psoriasis,” said Kirti Ganorkar, senior vice president, Business Development, Sun Pharma. “This collaboration is a part of our strategy towards building our pipeline of innovative dermatology products in a market with strong growth potential.”

The transaction is subject to customary closing conditions, including the requirements under the Hart Scott-Rodino Antitrust Improvements Act.

About Tildrakizumab

Tildrakizumab is an investigational humanized, anti-IL-23p19 monoclonal antibody that binds specifically to IL-23p19 and is therefore designed to selectively block the cytokine IL-23. Human genetics suggest that inhibiting IL-23 is effective for treating inflammatory conditions. In clinical studies for the treatment of chronic plaque psoriasis, tildrakizumab demonstrates efficacy in blocking inflammation by blocking IL-23. Other potential indications, which may be evaluated in future, include psoriatic arthritis and Crohn’s Disease.

Further details of the Phase 3 clinical trials can be found at: http://clinicaltrials.gov

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

About Sun Pharma

Established in 1983, listed since 1994 and headquartered in India, Sun Pharmaceutical Industries Ltd. (Reuters: SUN.BO, Bloomberg: SUNP IN, NSE: SUNPHARMA, BSE: 524715) is an international specialty pharmaceutical company with over 75% sales from global markets. It manufactures and markets a large basket of pharmaceutical formulations as branded generics as well as generics in US, India and several other markets across the world. For the year ending March 2014, overall revenues were at US$2.7 billion, of which US contributed US$1.6 billion. In India, the company is a leader in niche therapy areas of psychiatry, neurology, cardiology, nephrology, gastroenterology, orthopedics and ophthalmology. The company has strong skills in product development, process chemistry, and manufacturing of complex dosage forms. More information about the company can be found at www.sunpharma.com.

Tildrakizumab
Monoclonal antibody
Type	?
Source	Humanized (from mouse)
Target	IL23
Identifiers
CAS Number	1326244-10-3
ATC code	none
ChemSpider	none
Chemical data
Formula	C₆₄₂₆H₉₉₁₈N₁₆₉₈O₂₀₀₀S₄₆
Molar mass	144.4 kg/mol

///////Sun Pharma, Merck & Co. Inc, Licensing Agreement, Tildrakizumab, mk 3222

Processes for Constructing Homogeneous Antibody Drug Conjugates

Uncategorized Comments Off

May 052016

Antibody drug conjugates (ADCs) are synthesized by conjugating a cytotoxic drug or “payload” to a monoclonal antibody. The payloads are conjugated using amino or sulfhydryl specific linkers that react with lysines or cysteines on the antibody surface. A typical antibody contains over 60 lysines and up to 12 cysteines as potential conjugation sites. The desired DAR (drugs/antibody ratio) depends on a number of different factors and ranges from two to eight drugs/antibody. The discrepancy between the number of potential conjugation sites and the desired DAR, combined with use of conventional conjugation methods that are not site-specific, results in heterogeneous ADCs that vary in both DAR and conjugation sites. Heterogeneous ADCs contain significant fractions with suboptimal DARs that are known to possess undesired pharmacological properties. As a result, new methods for synthesizing homogeneous ADCs have been developed in order to increase their potential as therapeutic agents. This article will review recently reported processes for preparing ADCs with improved homogeneity. The advantages and potential limitations of each process are discussed, with emphasis on efficiency, quality, and in vivo efficacy relative to similar heterogeneous ADCs.

Table 1. Examples of Heterogeneous ADCs Currently in Clinical Trials for Cancer Indications^a

ADC	Sponsor	Indications	Status	Payload	Linked to	Target
Adcetris	Seattle Genetics	HL and ALCL	approved	MMAE	cysteine	CD30
Kadcyla	Genentech/Roche	breast cancer	approved	DM1	lysine	Her2
inotuzumab ozogamicin	Pfizer	NHL and ALL	Phase III	calicheamicin	lysine	CD22
lorvotuzumab mertansine	Immunogen	SCLC	Phase II	DM1	lysine	CD56
glembatumumab vedotin	Celldex	BC, melanoma	Phase II	MMAE	cysteine	GPNMB
PSMA-ADC	Progenics	prostate	Phase II	MMAE	cysteine	FOLH1
SAR-3419	Sanofi	DLBCL, ALL	Phase II	DM4	lysine	CD19
ABT-414	Abbvie	glioblastoma	Phase II	MMAE	cysteine	EGFR
BT-062	Biotest	mult. myeloma	Phase II	DM4	lysine	CD138
HLL1-Dox	Immunomedics	CLL, MM, NHL	Phase II	doxorubicin	cysteine	CD74
Immu-130	Immunomedics	CRC	Phase II	SN-38	cysteine	CEACAM5
Immu-132	Immunomedics	solid tumors	Phase II	SN-38	cysteine	EGP1
SYD985	Synthon	breast cancer	Phase II	duocarmycin	cysteine	Her2
SAR-3419	Sanofi	DLBCL, ALL	Phase II	DM4	lysine	CD19
IMGN853	ImmunoGen	solid tumors	Phase I	DM4	lysine	FOLR1
IMGN529	ImmunoGen	BCL,CLL, NHL	Phase I	DM1	lysine	CD37
ASG-22M6E	Astellas	solid tumors	Phase I	MMAE	cysteine	nectin-4
AGS-16M8F	Astellas	RCC	Phase I	MMAF	cysteine	AGS16
AMG 172	Amgen	RCC	Phase I	DM1	lysine	CD27L
AMG 595	Amgen	glioblastoma	Phase I	DM1	lysine	EGFR8
BAY94-9343	Bayer	solid tumors	Phase I	DM4	lysine	mesothelin

Source: www.clinicaltrials.gov.

Processes for Constructing Homogeneous Antibody Drug Conjugates

David Y. Jackson^*^†

^† Igenica Biotherapeutics, 863A Mitten Road, Suite 100B, Burlingame, California 94010, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00067

Publication Date (Web): April 14, 2016

*Igenica Biotherapeutics 863A Mitten Road, Suite 100B Burlingame, CA 94010, USA. E-mail: dyjackson@comcast.net. Cell: 650-339-3948.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00067

//////Processes, Constructing, Homogeneous, Antibody Drug Conjugates

Marksans Pharma gets FDA nod for its ANDA for metformin hydrochloride extended release (ER) tablets

Uncategorized Comments Off

May 052016

FDA OK for India’s Marksans Pharma Generic Version of Type 2 Diabetes Drug

Read at

FDA OK for India’s Marksans Pharma Generic Version of Type 2 Diabetes Drug

Diabetes Drug: Latest Diabetes Drug News, Videos – NDTVprofit.ndtv.com/topic/diabetes–drug

Marksans Pharma Gets US Regulator’s Nod For Diabetes Drug … approval from the US Food and Drug Administration (FDA) for its Metformin Hydrochloride tablets, … mainly from sales of its generic versions of the type 2 diabetes drugs Glumetza and Fortamet, … Lupin, Boehringer Ingelheim to Co-Market Linagliptin in India.

METFORMIN HYDROCHLORIDE ANDA (090295)	MARKSANS PHARMA	METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE	METFORMIN HYDROCHLORIDE	500MG	TABLET, EXTENDED RELEASE;ORAL	1	0	AB1
METFORMIN HYDROCHLORIDE	METFORMIN HYDROCHLORIDE	750MG	TABLET, EXTENDED RELEASE;ORAL	1	0	AB

Approval History

2016-04-29

Approval

EARLIAR YEAR

METFORMIN HYDROCHLORIDE ANDA (090888)

Drug Name	Active Ingredient(s)	Strength	Form/Route	Marketing Status	TE Code
METFORMIN HYDROCHLORIDE	METFORMIN HYDROCHLORIDE	500MG	TABLET;ORAL	1	AB
METFORMIN HYDROCHLORIDE	METFORMIN HYDROCHLORIDE	850MG	TABLET;ORAL	1	AB
METFORMIN HYDROCHLORIDE	METFORMIN HYDROCHLORIDE	1GM	TABLET;ORAL	1	AB

Approval History

2012-03-12

Approval

MR. MARK SALDANHA
Promoter And Managing Director

Mr. Mark Saldanha is the Chairman and Managing Director of Marksans. He set out with a vision to create a global pharmaceutical company. Under his able and dynamic leadership, Marksans has grown rapidly to attain newer milestones and the highest level of performance. He is the principal architect for the progress of the organization.

Mr. Mark Saldanha is a science graduate with more than two decades of experience across business and technical functions. He is well versed with the overall management of the company and possesses vast amount of hands-on experience in marketing, production and finance.

His business acumen, entrepreneurial zeal, organizational skills and managerial abilities have enabled Marksans to grow leaps and bounds and spread its wings across the globe.

////////Marksans Pharma, FDAm, ANDA, metformin hydrochloride, extended release (ER) tablets

Oliceridine

Phase 3 drug, Uncategorized Comments Off

May 042016

Oliceridine

N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

A mu-opioid receptor ligand potentially for treatment of acute postoperative pain.

TRV-130; TRV-130A

CAS No.1401028-24-7

Molecular Formula:	C₂₂H₃₀N₂O₂S
Molecular Weight:	386.5508 g/mol

Originator Trevena

Trevena, Inc.

Class Analgesics; Small molecules
Mechanism of Action Beta arrestin inhibitors; Opioid mu receptor agonists

Orphan Drug Status No
On Fast track Postoperative pain
- Phase III Postoperative pain
- Phase II Pain
Most Recent Events
- 09 Mar 2016Trevena intends to submit NDA to US FDA in 2017
- 22 Feb 2016Oliceridine receives Breakthrough Therapy status for Pain in USA
- 19 Jan 2016Phase-III clinical trials in Postoperative pain in USA (IV) (NCT02656875)

Oliceridine (TRV130) is an opioid drug that is under evaluation in human clinical trials for the treatment of acute severe pain. It is afunctionally selective μ-opioid receptor agonist developed by Trevena Inc. Oliceridine elicits robust G protein signaling, with potencyand efficacy similar to morphine, but with far less β-arrestin 2 recruitment and receptor internalization, it displays less adverse effectsthan morphine.^[1]^[2]^[3]

In 2015, the product was granted fast track designation in the U.S. for the treatment of moderate to severe acute pain. In 2016, the compound was granted FDA breakthrough therapy designation for the management of moderate to severe acute pain.

Oliceridine (TRV130) is an intravenous G protein biased ligand that targets the mu opioid receptor. Trevena is developing TRV130 for the treatment of moderate to severe acute pain where intravenous therapy is preferred, with a clinical development focus in acute postoperative pain

TRV 130 HCl is a novel μ-opioid receptor (MOR) G protein-biased ligand; elicits robust G protein signaling(pEC50=8.1), with potency and efficacy similar to morphine, but with far less beta-arrestin recruitment and receptor internalization.

NMR

Oliceridine (TRV130) – Mu Opioid Biased Ligand for Acute Pain

	Target	Indication	Lead Optimization Preclinical Development Phase 1 Phase 2 Phase 3	Ownership
Oliceridine (TRV130)	Mu-receptor	Moderate to Severe Pain	intravenous

Recent TRV130 News

Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits β-arrestin.

When therapeutic doses of morphine are given to patients with pain, the patients report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue.

There is a continuing need for new OR modulators to be used as analgesics. There is a further need for OR agonists as analgesics having reduced side effects. There is a further need for OR agonists as analgesics having reduced side effects for the treatment of pain, immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and/or agents for the treatment of respiratory diseases and cough.

PAPER

Structure activity relationships and discovery of a g protein biased mu opioid receptor ligand, ((3-Methoxythiophen-2-yl)methyl)a2((9R)-9-(pyridin-2-y1)-6-oxaspiro-(4.5)clecan-9-yl)ethylpamine (TRV130), for the treatment of acute severe pain
J Med Chem 2013, 56(20): 8019

Structure–Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain

Xiao-Tao Chen*, Philip Pitis, Guodong Liu, Catherine Yuan, Dimitar Gotchev, Conrad L. Cowan, David H. Rominger,Michael Koblish, Scott M. DeWire, Aimee L. Crombie, Jonathan D. Violin, and Dennis S. Yamashita

Trevena, Inc., 1018 West 8th Avenue, Suite A, King of Prussia, Pennsylvania 19406, United States

J. Med. Chem., 2013, 56 (20), pp 8019–8031

DOI: 10.1021/jm4010829

Publication Date (Web): September 24, 2013

*Phone: 610-354-8840. Fax: 610-354-8850. E-mail: dchen@trevenainc.com.

Abstract

The concept of “ligand bias” at G protein coupled receptors has been introduced to describe ligands which preferentially stimulate one intracellular signaling pathway over another. There is growing interest in developing biased G protein coupled receptor ligands to yield safer, better tolerated, and more efficacious drugs. The classical μ opioid morphine elicited increased efficacy and duration of analgesic response with reduced side effects in β-arrestin-2 knockout mice compared to wild-type mice, suggesting that G protein biased μ opioid receptor agonists would be more efficacious with reduced adverse events. Here we describe our efforts to identify a potent, selective, and G protein biased μ opioid receptor agonist, TRV130 ((R)-30). This novel molecule demonstrated an improved therapeutic index (analgesia vs adverse effects) in rodent models and characteristics appropriate for clinical development. It is currently being evaluated in human clinical trials for the treatment of acute severe pain.

http://pubs.acs.org/doi/abs/10.1021/jm4010829

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl] ethyl})amine ((R)-30)

Using a procedure described in method A, (R)-39e was converted to (R)-30 as a TFA salt. ¹H NMR (400 MHz, CDCl₃) δ 11.70 (brs, 1H), 9.14 (d, J = 66.6, 2H), 8.72 (d, J = 4.3, 1H), 8.19 (td,J = 8.0, 1.4, 1H), 7.70 (d, J = 8.1, 1H), 7.63 (dd, J = 7.0, 5.8, 1H), 7.22 (d, J = 5.5, 1H), 6.78 (d,J = 5.6, 1H), 4.08 (m, 2H), 3.80 (m, 4H), 3.69 (dd, J = 11.2, 8.7, 1H), 2.99 (d, J = 4.8, 1H), 2.51 (t, J = 9.9, 1H), 2.35 (m, 3H), 2.18 (td, J = 13.5, 5.4, 1H), 1.99 (d, J = 14.2, 1H), 1.82 (m, 2H), 1.65 (m, 1H), 1.47 (m, 4H), 1.14 (m, 1H), 0.73 (dt, J = 13.2, 8.9, 1H). LC-MS (API-ES) m/z = 387.0 (M + H).

Patent

WO 2012129495

http://www.google.com/patents/WO2012129495A1?cl=en

Scheme 1: Synthesis of Spirocyclic Nitrile

NCCH₂C0₂CH₃ AcOH, NH₄OAc

1-5 1-6 1-7

Chiral HPLC separation n=1-2

R= phenyl, substituted phenyl, aryl,

Scheme 2: Converting the nitrile to the opioid receptor ligand (Approach 1)

2-4

Scheme 3: Converting the nitrile to the opioid receptor ligand (Approach 2)

1-8B 3-1 3-2 n=1-2

In some embodiments, the same scheme is applied to 1 -7 and 1 -8A. Scheme 4: Synthesis of Non-Spirocyclic Nitrile

4-1 4-2 4-3

KOH, ethylene glycol R= phenyl, substituted phenyl, aryl,

substituted aryl, pyridyl, substituted pyridyl, heat heteroaryl, substituted heteroaryl,

carbocycle, heterocycle and etc.

In some embodiments, 4-1 is selected from the group consisting of

4-1 A 4-1 B 4-1 C 4-1 D 4-1 E

Scheme 5: Synthesis of Other Spirocyclic Derived Opioid Ligands

5-1 5-2 5-3

Scheme 6: Allyltrimethylsilane Approach to Access the Quaternary Carbon Center

RMgX, or RLi

Scheme 7: N-linked Pyrrazole Opioid Receptor Ligand

[(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]ethyl})amine

Into a vial were added 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine (500 mg, 1.92 mmole), 18 mL CH2C12 and sodium sulfate (1.3 g, 9.6 mmole). The 3- methoxythiophene-2-carboxaldehyde (354 mg, 2.4 mmole) was then added, and the misture was stirred overnight. NaBH4 (94 mg, 2.4 mmole) was added to the reaction mixture, stirred for 10 minutes, and then MeOH (6.0 mL) was added, stirred l h, and finally quenched with water. The organics were separated off and evaporated. The crude residue was purified by a Gilson prep HPLC. The desired fractions collected and concentrated and lyophilized. After lyophilization, residue was partitioned between CH2C12 and 2N NaOH, and the organic layers were collected. After solvent was concentrated to half of the volume, 1.0 eq of IN HC1 in Et20 was added,and majority of solvent evaporated under reduced pressure. The solid obtained was washed several times with Et20 and dried to provide [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2- yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine monohydrochloride (336 mg, 41% yield, m/z 387.0 [M + H]+ observed) as a white solid. The NMR for Compound 140 is described herein.

Example 15: Synthesis of [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9- (pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine (Compound 140).

Methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (mixture of E and Z isomers)

A mixture of 6-oxaspiro[4.5]decan-9-one (13.74 g, 89.1 mmol), methylcyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17.mmol) and acetic acid (1.02 ml, 17.8 mmol) in benzene (75 ml) was heated at reflux in a 250 ml round bottom flask equipped with a Dean-Stark and a reflux condenser. After 3h, TLC (25%EtOAc in hexane, PMA stain) showed the reaction was completed. After cooling, benzene (50 ml) was added and the layer was separated, the organic was washed by water (120 ml) and the aqueous layer was extracted by CH2CI2 (3 x 120 ml). The combined organic was washed with sat’d NaHCCb, brine, dried and concentrated and the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 5% EtOAc, 2CV; 5-25%, 14CV; 25-40%,8 CV) gave a mixture of E and Z isomers: methyl 2-cyano-2-[6- oxaspiro[4.5]decan-9-ylidene]acetate ( 18.37 g, 87.8 % yield, m/z 236.0 [M + H]⁺ observed) as a clear oil. -cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate

A solution of 2-bromopyridine (14.4 ml, 150 mmo) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF) at 0°C under N₂, the mixture was then stirred at rt for 3h, copper Iodide(2.59 g, 13.6 mmol) was added and allowed to stir at rt for another 30 min before a solution of a mixture of E and Z isomers of methyl 2-cyano-2-[6-oxaspiro[4.5]decan-9-ylidene]acetate (16 g, 150 mmol) in THF (60 ml) was added in 30 min. The mixture was then stirred at rt for 18h. The reaction mixture was poured into a 200 g ice/2 N HC1 (100 ml) mixture. The product was extracted with Et₂0 (3×300 ml), washed with brine (200 ml), dried (Na₂S0₄) and concentrated. The residual was purified by flash chromatography (100 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV gave methyl 2-cyano-2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetate (15.44 g, 72% yield, m/z 315.0 [M + H]+ observed) as an amber oil .

-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

Ethylene glycol (300 ml) was added to methyl 2-cyano-2-[9-(pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]acetate( 15.43 g, 49 mmol) followed by potassium hydroxide (5.5 g , 98 mmol), the resulting mix was heated to 120oC, after 3 h, the reaction mix was cooled and water (300 ml) was added, the product was extracted by Et20(3 x 400 ml), washed with water(200 ml), dried (Na2S04) and concentrated, the residual was purified by flash chromatography (340 g silica gel column, eluted by EtOAc in hexane: 3% 2CV; 3-25%, 12 CV; 25-40% 6CV to give 2-[9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9- yl]acetonitrile (10.37 g, 82% yield, m/z 257.0 [M + H]+ observed).

-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile

racemic 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile was separated by chiral HPLC column under the following preparative-SFC conditions: Instrument: SFC-80 (Thar, Waters); Column: Chiralpak AD-H (Daicel); column temperature: 40 °C; Mobile phase: Methanol /CO2=40/60; Flow: 70 g/min; Back pressure: 120 Bar; Cycle time of stack injection: 6.0min; Load per injection: 225 mg; Under these conditions, 2-[9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetonitrile (4.0 g) was separated to provide the desired isomer, 2-[(9R)-9-(Pyridin-2-yI)-6- oxaspiro[4.5]decan-9-yl]acetonitrile (2.0 g, >99.5% enantiomeric excess) as a slow- moving fraction. The absolute (R) configuration of the desired isomer was later determined by an X-ray crystal structure analysis of Compound 140. [0240] -[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l-amine

LAH (1M in Et20, 20ml, 20 mmol) was added to a solution of 2-[(9R)-9-(pyridin-2-yl)- 6-oxaspiro[4.5]decan-9-yl]acetonitrile (2.56 g, 10 mmol) in Et20 (100 ml, 0.1M ) at OoC under N₂. The resulting mix was stirred and allowed to warm to room temperature. After 2 h, LCMS showed the reaction had completed. The reaction was cooled at OoC and quenched with water ( 1.12 ml), NaOH (10%, 2.24 ml) and another 3.36 ml of water. Solid was filtered and filter pad was washed with ether (3 x 20 ml). The combined organic was dried and concentrated to give 2-[(9R)-9-(Pyridin-2-yl)-6- oxaspiro[4.5]decan-9-yl]ethan-l -amine (2.44 g, 94% yield, m/z 260.6 [M + H]+ observed) as a light amber oil.

Alternatively, 2-[(9R)-9-(Pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine was prepared by Raney-Nickel catalyzed hydrogenation.

An autoclave vessel was charged with 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4,5]decan-9- yl] acetonitrile and ammonia (7N solution in methanol). The resulting solution was stirred at ambient conditions for 15 minutes and treated with Raney 2800 Nickel, slurried in water. The vessel was pressurized to 30 psi with nitrogen and agitated briefly. The autoclave was vented and the nitrogen purge repeated additional two times. The vessel was pressurized to 30 psi with hydrogen and agitated briefly. The vessel was vented and purged with hydrogen two additional times. The vessel was pressurized to 85-90 psi with hydrogen and the mixture was warmed to 25-35 °C. The internal temperature was increased to 45-50 °C over 30-60 minutes. The reaction mixture was stirred at 45-50 °C for 3 days. The reaction was monitored by HPLC. Once reaction was deemed complete, it was cooled to ambient temperature and filtered through celite. The filter cake was washed with methanol (2 x). The combined filtrates were concentrated under reduced pressure at 40-45 °C. The resulting residue was co-evaporated with EtOH (3 x) and dried to a thick syrupy of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-l -amine.

References

Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS (October 2013). “Structure-Activity Relationships and Discovery of a G Protein Biased μ Opioid Receptor Ligand, [(3-Methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl})amine (TRV130), for the Treatment of Acute Severe Pain”. J. Med. Chem. 56 (20): 8019–31.doi:10.1021/jm4010829. PMID 24063433.
DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD (March 2013). “A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine”. J. Pharmacol. Exp. Ther. 344 (3): 708–17.doi:10.1124/jpet.112.201616. PMID 23300227.
Soergel DG, Subach RA, Sadler B, Connell J, Marion AS, Cowan C, Violin JD, Lark MW (October 2013). “First clinical experience with TRV130: Pharmacokinetics and pharmacodynamics in healthy volunteers”. J Clin Pharmacol 54(3): 351–7. doi:10.1002/jcph.207. PMID 24122908.

External links

Trevena: Oliceridine

Patent ID	Date	Patent Title
US2015246904	2015-09-03	Opioid Receptor Ligands And Methods Of Using And Making Same
US8835488	2014-09-16	Opioid receptor ligands and methods of using and making same
US2013331408	2013-12-12	Opioid Receptor Ligands and Methods of Using and Making Same

Oliceridine
Systematic (IUPAC) name

N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine
Clinical data
Routes of administration	IV
Legal status
Legal status	Investigational New Drug
Identifiers
CAS Number	1401028-24-7
ATC code	none
PubChem	CID 66553195
ChemSpider	30841043
UNII	MCN858TCP0
ChEMBL	CHEMBL2443262
Synonyms	TRV130
Chemical data
Formula	C₂₂H₃₀N₂O₂S
Molar mass	386.55 g·mol⁻¹

////////TRV-130; TRV-130A, Oliceridine, Phase III, Postoperative pain, trevena, mu-opioid receptor ligand, fast track designation, breakthrough therapy designation

COc1ccsc1CNCC[C@]2(CCOC3(CCCC3)C2)c4ccccn4

Galunisertib

Phase 3 drug, Uncategorized Comments Off

May 042016

Galunisertib

A TGF-beta receptor type-1 inhibitor potentially for the treatment of myelodysplastic syndrome (MDS) and solid tumours.

LY-2157299

CAS No.700874-72-2

4-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]quinoline-6-carboxamide

6-Quinolinecarboxamide, 4-[5,6-dihydro-2-(6-methyl-2-pyridinyl)-4H-pyrrolo[1,2-b]pyrazol-3-yl]-

700874-72-2

Molecular FormulaC₂₂H₁₉N₅O
Average mass369.419 Da

4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxamide

4-(2-(6-Methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-6-carboxamide monohydrate

Anal. Calcd for C₂₂H₁₉N₅O·H₂O: C, 68.20; H, 5.46; N, 18.08. Found: C, 68.18; H, 5.34; N, 17.90.

¹H NMR (DMSO-d₆: δ) 1.74 (s, 3H), 2.63 (m, 2H), 2.82 (br s, 2H), 4.30 (t, J = 7.2 Hz, 2H), 6.93 (m, 1H), 7.37 (s, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.56 (m, 1H), 7.58 (m, 1H), 8.04, (s, 1H), 8.04 (d, J = 4.4 Hz, 1H), 8.12 (dd, J = 8.8, 1.6 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 4.4 Hz, 1H).

¹³C NMR (DMSO-d₆: δ) 22.56, 23.24, 25.58, 48.01, 109.36, 117.74, 121.26, 122.95, 126.73, 127.16 (2C), 129.01, 131.10, 136.68, 142.98, 147.20, 148.99, 151.08, 151.58, 152.13, 156.37, 167.47.

IR (KBr): 3349, 3162, 3067, 2988, 2851, 1679, 1323, 864, 825 cm^–1.

HRMS (m/z M + 1): Calcd for C₂₂H₁₉N₅O: 370.1653. Found: 370.1662.

GalunisertibAn orally available, small molecule antagonist of the tyrosine kinase transforming growth factor-beta (TGF-b) receptor type 1 (TGFBR1), with potential antineoplastic activity. Upon administration, galunisertib specifically targets and binds to the kinase domain of TGFBR1, thereby preventing the activation of TGF-b-mediated signaling pathways. This may inhibit the proliferation of TGF-b-overexpressing tumor cells. Dysregulation of the TGF-b signaling pathway is seen in a number of cancers and is associated with increased cancer cell proliferation, migration, invasion and tumor progression.

OriginatorEli Lilly
DeveloperEli Lilly; National Cancer Institute (USA); Vanderbilt-Ingram Cancer Center; Weill Cornell Medical College
ClassAntineoplastics; Pyrazoles; Pyridines; Pyrroles; Quinolines; Small molecules
Mechanism of ActionPhosphotransferase inhibitors; Transforming growth factor beta1 inhibitors
- Phase II/IIIMyelodysplastic syndromes
- Phase IIBreast cancer; Glioblastoma; Hepatocellular carcinoma
- Phase I/IIGlioma; Non-small cell lung cancer; Pancreatic cancer
- Phase ICancer; Solid tumours
Most Recent Events
- 26 Apr 2016Eli Lilly plans a pharmacokinetics phase I trial in Healthy volunteers in United Kingdom (PO) (NCT02752919)
- 16 Apr 2016Pharmacodynamics data from a preclinical study in Cancer presented at the 107th Annual Meeting of the American Association for Cancer Research (AACR-2016)
- 06 Apr 2016Eli Lilly and AstraZeneca plan a phase Ib trial for Pancreatic cancer (Second-line therapy or greater, Metastatic disease, Recurrent, Combination therapy) in USA, France, Italy, South Korea and Spain (PO) (NCT02734160)

Transforming growth factor-beta (TGF-β) signaling regulates a wide range of biological processes. TGF-β plays an important role in tumorigenesis and contributes to the hallmarks of cancer, including tumor proliferation, invasion and metastasis, inflammation, angiogenesis, and escape of immune surveillance. There are several pharmacological approaches to block TGF-β signaling, such as monoclonal antibodies, vaccines, antisense oligonucleotides, and small molecule inhibitors. Galunisertib (LY2157299 monohydrate) is an oral small molecule inhibitor of the TGF-β receptor I kinase that specifically downregulates the phosphorylation of SMAD2, abrogating activation of the canonical pathway. Furthermore, galunisertib has antitumor activity in tumor-bearing animal models such as breast, colon, lung cancers, and hepatocellular carcinoma. Continuous long-term exposure to galunisertib caused cardiac toxicities in animals requiring adoption of a pharmacokinetic/pharmacodynamic-based dosing strategy to allow further development. The use of such a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib. These efforts resulted in an intermittent dosing regimen (14 days on/14 days off, on a 28-day cycle) of galunisertib for all ongoing trials. Galunisertib is being investigated either as monotherapy or in combination with standard antitumor regimens (including nivolumab) in patients with cancer with high unmet medical needs such as glioblastoma, pancreatic cancer, and hepatocellular carcinoma. The present review summarizes the past and current experiences with different pharmacological treatments that enabled galunisertib to be investigated in patients.

Company	Eli Lilly and Co.
Description	Transforming growth factor (TGF) beta receptor 1 (TGFBR1; ALK5) inhibitor
Molecular Target	Transforming growth factor (TGF) beta receptor 1 (TGFBR1) (ALK5)
Mechanism of Action	Transforming growth factor (TGF) beta 1 inhibitor
Therapeutic Modality	Small molecule

Bristol-Myers Squibb and Lilly Enter Clinical Collaboration Agreement to Evaluate Opdivo (nivolumab) in Combination with Galunisertib in Advanced Solid Tumors

Bristol-Myers Squibb and Lilly

NEW YORK & INDIANAPOLIS–(BUSINESS WIRE)– Bristol-Myers Squibb Company (NYSE:BMY) and Eli Lilly and Company (NYSE:LLY) announced today a clinical trial collaboration to evaluate the safety, tolerability and preliminary efficacy of Bristol-Myers Squibb’s immunotherapy Opdivo (nivolumab) in combination with Lilly’s galunisertib (LY2157299). The Phase 1/2 trial will evaluate the investigational combination of Opdivo and galunisertib as a potential treatment option for patients with advanced (metastatic and/or unresectable) glioblastoma, hepatocellular carcinoma and non-small cell lung cancer.

Opdivo is a human programmed death receptor-1 (PD-1) blocking antibody that binds to the PD-1 receptor expressed on activated T-cells. Galunisertib (pronounced gal ue” ni ser’tib) is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body. This collaboration will address the hypothesis that co-inhibition of PD-1 and TGF beta negative signals may lead to enhanced anti-tumor immune responses than inhibition of either pathway alone.

“Advanced solid tumors represent a serious unmet medical need among patients with cancer,” said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. “Our clinical collaboration with Lilly underscores Bristol-Myers Squibb’s continued commitment to explore combination regimens from our immuno-oncology portfolio with other mechanisms of action that may accelerate the development of new treatment options for patients.”

“Combination therapies will be key to addressing tumor heterogeneity and the inevitable resistance that is likely to develop to even the most promising new tailored therapies,” said Richard Gaynor, M.D., senior vice president, Product Development and Medical Affairs, Lilly Oncology. “To that end, having multiple cancer pathways and technology platforms will be critical in an era of combinations to ensure sustainability beyond any single asset.”

The study will be conducted by Lilly. Additional details of the collaboration were not disclosed.

About Galunisertib

Galunisertib (pronounced gal ue” ni ser’tib) is Lilly’s TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumors growth, suppresses the immune system, and increases the ability of tumors to spread in the body.

Immune function is suppressed in cancer patients, and TGF beta worsens immunosuppression by enhancing the activity of immune cells called T regulatory cells. TGF beta also reduces immune proteins, further decreasing immune activity in patients

Galunisertib is currently under investigation as an oral treatment for advanced/metastatic malignancies, including Phase 2 evaluation in hepatocellular carcinoma, myelodysplastic syndromes (MDS), glioblastoma, and pancreatic cancer.

PATENT

WO 2004048382

The disclosed invention also relates to the select compound of Formula II:

Formula II

2-(6-methyl-pyridin-2-yI)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[l,2- bjpyrazole and the phannaceutically acceptable salts thereof.

The compound above is genetically disclosed and claimed in PCT patent application PCT/US02/11884, filed 13 May 2002, which claims priority from U.S. patent application U. S . S .N. 60/293 ,464, filed 24 May 2001 , and incorporated herein by reference. The above compound has been selected for having a surprisingly superior toxicology profile over the compounds specifically disclosed in application cited above.

The following scheme illustrates the preparation of the compound of Formula II.

Scheme II

Cs₂C0₃

The following examples further illustrate the preparation of the compounds of this invention as shown schematically in Schemes I and II. Example 1

Preparation of 7-(2-morpholin-4-yI-ethoxy)-4-(2-pyridin-2-yl-5,6-dihydro-4H- pyrroIo[l,2-b]pyrazol-3-yl)-q inoline

A. Preparation of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)- 7-[2-(tetrahydropyran-2-yIoxy)ethoxy]quinoIine

Heat 4-(2-pyridm-2-yl-5,6-dihydro-4H-pyrrolo[l,2-b]pyrazol-3-yl)-quinolin-7-ol (376 mg, 1.146 mmol), cesium carbonate (826 mg, 2.54 mmol), and 2-(2- bromoethoxy)tetrahydro-2H-pyran (380 μL, 2.52 mmol) in DMF (5 mL) at 120 °C for 4 hours. Quench the reaction with saturated sodium chloride and then extract with chloroform. Dry the organic layer over sodium sulfate and concentrate in vacuo. Purify the reaction mixture on a silica gel column eluting with dichloromethane to 10% methanol in dichloromethane to give the desired subtitled intermediate as a yellow oil (424 mg, 81%). MS ES⁺m/e 457.0 (M+l).

EXAMPLE 2

Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazole

A. Preparation of 6-bromo-4-methyI-quinoline

Stir a solution of 4-bromo-phenylamine (1 eq), in 1,4-dioxane and cool to approximately 12 °C. Slowly add sulfuric acid (2 eq) and heat at reflux. Add methyl vinyl ketone (1.5 eq) drop wise into the refluxing solution. Heat the solution for 1 hour after addition is complete. Evaporate the reaction solution to dryness and dissolve in methylene chloride. Adjust the solution to pH 8 with 1 M sodium carbonate and extract three times with water. Chromatograph the residue on SiO (70/30 hexane/ethyl acetate) to obtain the desired subtitled inteπnediate. MS ES+ m e = 158.2 (M+l). B. Preparation of 6-methyl-pyridine-2-carboxylic acid methyl ester

Suspend 6-methyl-pyridine-2-carboxylic acid (10 g, 72.9 mmol) in methylene chloride (200 mL). Cool to 0 °C. Add methanol (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)

(18.2 g, 94.8 mmol). Stir the mixture at room temperature for 6 hours, wash with water and brine, and dry over sodium sulfate. Filter the mixture and concentrate in vacuo.

Chromatograph the residue on SiO₂ (50% ethyl acetate/hexanes) to obtain the desired subtitled intermediate, 9.66 g (92%), as a colorless liquid. 1H NMR (CDC1₃) 6 7.93-7.88 (m, IH), 7.75-7.7 (m, IH), 7.35-7.3 (m, IH), 4.00 (s, 3H), 2.60 (s, 3H).

C. Preparation of 2-(6-bromo-quinoIin-4-yl)-l-(6-methyl-pyridin-2-yl)-ethanone Dissolve 6-bromo-4-methyl-quinoline (38.5 g, 153 mmol) in 600 mL dry THF.

Cool to -70° C and treat with the dropwise addition of 0.5 M potassium hexamethyldisilazane (KN(SiMe )₂ (400 mL, 200 mmol) over 2 hours while keeping the temperature below -65 °C. Stir the resultant solution at -70°C for 1 hour and add a solution of 6-methylpyridine-2-carboxylic acid methyl ester (27.2, 180 mmol) in 100 mL dry THF dropwise over 15 minutes. During the addition, the mixture will turn from dark red to pea-green and form a precipitate. Stir the mixture at -70°C over 2 hours then allow it to warm to ambient temperature with stirring for 5 hours. Cool the mixture then quench with 12 N HC1 to pH=l . Raise the pH to 9 with solid potassium carbonate. Decant the solution from the solids and extract twice with 200 mL ethyl acetate. Combine the organic extracts, wash with water and dry over potassium carbonate. Stir the solids in 200 mL water and 200 mL ethyl acetate and treat with additional potassium carbonate. Separate the organic portion and dry with the previous ethyl acetate extracts. Concentrate the solution in vacuo to a dark oil. Pass the oil through a 300 mL silica plug with methylene chloride then ethyl acetate. Combine the appropriate fractions and concentrate in vacuo to yield an amber oil. Rinse the oil down the sides of the flask with methylene chloride then dilute with hexane while swirling the flask to yield 38.5 g (73.8 %) of the desired subtitled intermediate as a yellow solid. MS ES+ = 341 (M+l)v D. Preparation of l-[2-(6-bromo-quinolin-4-yI)-l-(6-methyl-pyridin-2-yl)- ethylideneamino]-pyrrolidin-2-one

Stir a mixture of 2-(6-bromo-quinolin-4-yl)-l-(6-methyl-pyridin-2-yl)-ethanone (38.5 g, 113 mmol) and 1-aminopyrrolidinone hydrochloride (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 A unactivated sieves. Continue stirring an additional 13 h and add 10-15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. MS ES⁺ = 423 (M+l).

E. Preparation of 6-bromo-4-[2-(6-methyl-pyridin-2-yι)-5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl]-quinoline

To a mixture of (1.2 eq.) cesium carbonate and l-[2-(6-bromo-qumolin-4-yl)-l- (6-methyl-pyridin-2-yl)-ethylideneamino]-pyrrolidin-2-one (33.3 g, 78.7 mmol) add 300 mL dry N,N-dimethylformamide. Stir the mixture 20 hours at 100°C. The mixture may turn dark during the reaction. Remove the N,N-dimethylformamide in vacuo. Partition the residue between water and methylene chloride. Extract the aqueous portion with additional methylene chloride. Filter the organic solutions through a 300 mL silica plug, eluting with 1.5 L methylene chloride, 1.5 L ethyl acetate and 1.5 L acetone. Combine the appropriate fractions and concentrate in vacuo. Collect the resulting precipitate by filtration to yield 22.7 g (71.2%) of the desired subtitled intermediate as an off-white solid. MS ES⁺ = 405 (M+l).

F. Preparation of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinoline-6-carboxylic acid methyl ester

Add 6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinoline (22.7 g, 45 mmol) to a mixture of sodium acetate (19 g, 230 mmol) and the palladium catalyst [1,1 ‘- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (850 mg, 1.04 mmol) in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphere and stir while warming to 90° C over 1 hour and with constant charging with additional carbon monoxide. Allow the mixture to cool over 8 hours, recharge again with carbon monoxide and heat to 90 °C. The pressure may rise to about 75 PSI. The reaction is complete in about an hour when the pressure is stable and tic (1 : 1 toluene/acetone) shows no remaining bromide. Partition the mixture between methylene chloride (600 mL) and water (1 L). Extract the aqueous portion with an additional portion of methylene chloride (400 mL.) Filter the organic solution through a 300 mL silica plug and wash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discard the acetone portion. Combine appropriate fractions and concentrate to yield 18.8 g (87.4%) of the desired subtitled intermediate as a pink powder. MS ES⁺ = 385 (M+l).

G. Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yι)-5,6- dihydro-4H-pyrrolo[l,2-b]pyrazole

Warm a mixture of 4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[l,2- b]pyrazol-3-yl]-quinolme-6-carboxylic acid methyl ester in 60 mL 7 N ammonia in methanol to 90 °C in a stainless steel pressure vessel for 66 hours. The pressure will rise to about 80 PSI. Maintain the pressure for the duration of the reaction. Cool the vessel and concentrate the brown mixture in vacuo. Purify the residual solid on two 12 g Redi- Pak cartridges coupled in series eluting with acetone. Combine appropriate fractions and concentrate in vacuo. Suspend the resulting nearly white solid in methylene chloride, dilute with hexane, and filter. The collected off-white solid yields 1.104 g (63.8%) of the desired title product. MS ES⁺ = 370 (M+l).

PAPER

http://pubs.acs.org/doi/abs/10.1021/op4003054

Application of Kinetic Modeling and Competitive Solvent Hydrolysis in the Development of a Highly Selective Hydrolysis of a Nitrile to an Amide

Jeffry K. Niemeier*, Roger R. Rothhaar*, Jeffrey T. Vicenzi, and John A. Werner

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States

Org. Process Res. Dev., 2014, 18 (3), pp 410–416

DOI: 10.1021/op4003054

Publication Date (Web): February 11, 2014

*Telephone: (317) 276-2066. E-mail: niemeier_jeffry_k@lilly.com (J.K.N.)., *Telephone: (317) 433-3769. E-mail: rrothhaar@lilly.com(R.R.R.).

Abstract

A combination of mechanism-guided experimentation and kinetic modeling was used to develop a mild, selective, and robust hydroxide-promoted process for conversion of a nitrile to an amide using a substoichiometric amount of aqueous sodium hydroxide in a mixed water and N-methyl-2-pyrrolidone solvent system. The new process eliminated a major reaction impurity, minimized overhydrolysis of the product amide by selection of a solvent that would be sacrificially hydrolyzed, eliminated genotoxic impurities, and improved the intrinsic safety of the process by eliminating the use of hydrogen peroxide. The process was demonstrated in duplicate on a 90 kg scale, with 89% isolated yield and greater than 99.8% purity.

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US2014348889	2014-11-27	Compositions and Methods for Treating and Preventing Neointimal Stenosis
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US2014127228	2014-05-08	INHIBITION OF TGFBETA SIGNALING TO IMPROVE MUSCLE FUNCTION IN CANCER
US2014128349	2014-05-08	ADMINISTERING INHIBITORS OF TGFBETA SIGNALING IN COMBINATION WITH BENZOTHIAZEPINE DERIVATIVES TO IMPROVE MUSCLE FUNCTION IN CANCER PATIENTS
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US7872020	2011-01-18	TGF-[beta] inhibitors
US7834029	2010-11-16	QUINOLINYL-PYRROLOPYRAZOLES
US7265225	2007-09-04	Quinolinyl-pyrrolopyrazoles

REFERENCES

1: Rodón J, Carducci M, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I, Sicart E, Gueorguieva I, Cleverly A, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J. Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer. Invest New Drugs. 2014 Dec 23. [Epub ahead of print] PubMed PMID: 25529192.

2: Kovacs RJ, Maldonado G, Azaro A, Fernández MS, Romero FL, Sepulveda-Sánchez JM, Corretti M, Carducci M, Dolan M, Gueorguieva I, Cleverly AL, Pillay NS, Baselga J, Lahn MM. Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study. Cardiovasc Toxicol. 2014 Dec 9. [Epub ahead of print] PubMed PMID: 25488804.

3: Rodon J, Carducci MA, Sepulveda-Sanchez JM, Azaro A, Calvo E, Seoane J, Brana I, Sicart E, Gueorguieva I, Cleverly AL, Sokalingum Pillay N, Desaiah D, Estrem ST, Paz-Ares L, Holdoff M, Blakeley J, Lahn MM, Baselga J. First-in-Human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma. Clin Cancer Res. 2014 Nov 25. pii: clincanres.1380.2014. [Epub ahead of print] PubMed PMID: 25424852.

4: Huang C, Wang H, Pan J, Zhou D, Chen W, Li W, Chen Y, Liu Z. Benzalkonium Chloride Induces Subconjunctival Fibrosis Through the COX-2-Modulated Activation of a TGF-β1/Smad3 Signaling Pathway. Invest Ophthalmol Vis Sci. 2014 Nov 18;55(12):8111-22. doi: 10.1167/iovs.14-14504. PubMed PMID: 25406285.

5: Cong L, Xia ZK, Yang RY. Targeting the TGF-β receptor with kinase inhibitors for scleroderma therapy. Arch Pharm (Weinheim). 2014 Sep;347(9):609-15. doi: 10.1002/ardp.201400116. Epub 2014 Jun 11. PubMed PMID: 24917246.

6: Gueorguieva I, Cleverly AL, Stauber A, Sada Pillay N, Rodon JA, Miles CP, Yingling JM, Lahn MM. Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. Br J Clin Pharmacol. 2014 May;77(5):796-807. PubMed PMID: 24868575; PubMed Central PMCID: PMC4004400.

7: Oyanagi J, Kojima N, Sato H, Higashi S, Kikuchi K, Sakai K, Matsumoto K, Miyazaki K. Inhibition of transforming growth factor-β signaling potentiates tumor cell invasion into collagen matrix induced by fibroblast-derived hepatocyte growth factor. Exp Cell Res. 2014 Aug 15;326(2):267-79. doi: 10.1016/j.yexcr.2014.04.009. Epub 2014 Apr 26. PubMed PMID: 24780821.

8: Giannelli G, Villa E, Lahn M. Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma. Cancer Res. 2014 Apr 1;74(7):1890-4. doi: 10.1158/0008-5472.CAN-14-0243. Epub 2014 Mar 17. Review. PubMed PMID: 24638984.

9: Dituri F, Mazzocca A, Peidrò FJ, Papappicco P, Fabregat I, De Santis F, Paradiso A, Sabbà C, Giannelli G. Differential Inhibition of the TGF-β Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-β Receptor Type II. PLoS One. 2013 Jun 27;8(6):e67109. Print 2013. PubMed PMID: 23826206; PubMed Central PMCID: PMC3694933.

10: Bhola NE, Balko JM, Dugger TC, Kuba MG, Sánchez V, Sanders M, Stanford J, Cook RS, Arteaga CL. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013 Mar 1;123(3):1348-58. doi: 10.1172/JCI65416. Epub 2013 Feb 8. PubMed PMID: 23391723; PubMed Central PMCID: PMC3582135.

11: Bhattachar SN, Perkins EJ, Tan JS, Burns LJ. Effect of gastric pH on the pharmacokinetics of a BCS class II compound in dogs: utilization of an artificial stomach and duodenum dissolution model and GastroPlus,™ simulations to predict absorption. J Pharm Sci. 2011 Nov;100(11):4756-65. doi: 10.1002/jps.22669. Epub 2011 Jun 16. PubMed PMID: 21681753.

12: Bueno L, de Alwis DP, Pitou C, Yingling J, Lahn M, Glatt S, Trocóniz IF. Semi-mechanistic modelling of the tumour growth inhibitory effects of LY2157299, a new type I receptor TGF-beta kinase antagonist, in mice. Eur J Cancer. 2008 Jan;44(1):142-50. Epub 2007 Nov 26. PubMed PMID: 18039567.

References

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539082/

http://www.ncbi.nlm.nih.gov/pubmed/26057634

https://clinicaltrials.gov/ct2/show/NCT0242334

Bhattachar, Shobha N.; Journal of Pharmaceutical Sciences 2011, 100(11), 4756-4765

Investigational new drugs (2015), 33(2), 357-70.

//////////TGF-β, TGF-βRI kinase inhibitor, ALK5, galunisertib, LY2157299, cancer, clinical trials, PHASE 3

CC1=CC=CC(=N1)C2=NN3CCCC3=C2C4=C5C=C(C=CC5=NC=C4)C(=O)N

Boldenone Undecylenate

Uncategorized Comments Off

May 032016

Boldenone Undecylenate

cas 13103-34-9,

C₃₀ H₄₄ O_{3, 452.67}

Androsta-1,4-dien-3-one, 17-[(1-oxo-10-undecenyl)oxy]-, (17β)-

Androsta-1,4-dien-3-one, 17β-hydroxy-, 10-undecenoate (7CI,8CI)
(17β)-17-[(1-Oxo-10-undecenyl)oxy]androsta-1,4-dien-3-one
10-Undecenoic acid, ester with 17β-hydroxyandrosta-1,4-dien-3-one (8CI)
Ba 29038
Ba 9038

Boldefarm
Boldenone 10-undecenoate
Boldenone undecylenate
Equipoise
Parenabol
Vebonol

Boldenone undec-10-enoate; 17b-[(1-Oxo-10-undecenyl)oxy]-androsta-1,4-dien-3-one; 17b-Hydroxyandrosta-1,4-dien-3-one 10-undecenoate

CAS # 13103-34-9, Boldenone undecylenate, Boldenone undec-10-enoate, 17b-[(1-Oxo-10-undecenyl)oxy]-androsta-1,4-dien-3-one, 17b-Hydroxyandrosta-1,4-dien-3-one 10-undecenoate

PATENT

http://www.google.com/patents/CN104327143A?cl=en

Boldenone (17β- hydroxy-1,4-dien-3-one male steroid, CAS: 846-48-0) The structural formula is:

Boldenone (Boldenone) is a derivative of testosterone, with a strong ability to support enhanced blood vessels, increase muscle, highlighting the blood vessels, increase appetite and other clinical role.

Domestic remain alcohol fermentation Preparation of 4- androstenedione (4AD) and 1,4-androstenedione (ADD), the company is numerous, very adequate supply of raw materials. Cheap and easily available 4AD and ADD steroid hormone drugs as key intermediates wide range of applications. Boldenone is an existing technology to the two aforementioned materials are prepared, in particular: (1) from 4-androstenedione as starting material Boldenone, synthetic route is as follows: C

After the above process route of the first reduction step of the reduction reaction of a 4- substrate androstenedione is added in one solvent dissolved in methanol, and then control the temperature dropping reducing a solution of potassium borohydride reduction reaction. According to this operation and the order of addition, the reduction reaction selectivity, impurities, must be introduced in the subsequent selective oxidation processes to ensure product quality; dehydrogenation process uses a chemical method dehydrogenation need to use more expensive as the dehydrogenation reagent DDQ using bio-dehydrogenation there is a long process cycle, easy contamination and other defects. There is a whole process line production process, long period, poor selectivity, multi-product, active manganese dioxide need freshly prepared, high production costs low.

(2) 1,4 androstenedione as a starting material Boldenone. Since ADD structure contains 3-one and two-keto-17-one, although I, 4- diene in the presence of the male left, increasing the structural stability of the three keto group, but still can not avoid the reduction reaction due 3 position ketone group is reduced to generate a 3-hydroxy-products. In order to avoid the reduction process due to 3-hydroxy-keto group is reduced to generate impurities, Chinese patent CN103030677A use of three-one ether of protection and then be prepared to restore technical solutions, synthetic route is as follows:

Said routing reduction step, a reduction reaction substrate ether solvent such as methanol was added at once dissolved and then put into a reducing agent, sodium borohydride, thanks in advance 3 ether ketone way of protection, in reducing Reaction to avoid the formation of by-products. Compared with the traditional 4-androstenedione route, eliminating the above process dehydrogenation reaction step, but there are still many steps, long period, higher production costs and other issues.

[0005] In recent years, adding different metal ions in the reduction reaction in order to improve the selectivity of the reduction reaction gradually attracted people’s attention. By participating in a metal borohydride multi carbonyl precursor compound remaining reduction reaction was added CeCl3 · 6H20, CoCl2 · 6H20, CdCl2 · (5/2) H20, CuCl, Cufc the like, to selectively reducing a compound of the structure in different positions keto, thereby obtaining reduced product having a different regioselectivity and stereoselectivity. In order to achieve the 1, 4_ androstenedione preparation Boldenone selective reduction objectives, technical personnel respectively potassium borohydride, sodium borohydride, boron and zinc borohydride as a reducing agent in the reduction reaction were added to the different After the metal ion, in accordance with a first reduction reaction substrate 1, 4_ androstenedione is added in one solvent dissolved, adding metal ions, the reducing agent added in the order reduction reaction. According to the above operation and the addition order, no matter how varying the process parameters have not been able to better achieve the selective reduction of 17-keto purposes.

[0006] Preparation Boldenone prior art process route, the reduction reactions using first reduction reaction substrate added in one solvent to dissolve, then add the reducing agent addition sequence and addition manner. Multi-keto-reduction reaction of the compound according to this method, there is a poor selectivity, multi-product of the state. In order to get qualified products often require the introduction of the first steps were selective oxidation or reduction reaction is not required to protect the keto group in the preparation process route, and then turn reduction, deprotection steps. Preparation prior Boldenone increased reaction step, extend the production cycle, improve the generation costs.

Synthetic route of the present invention are as follows:

Example always 350ml of methanol was added and the reaction vial IOOml water, cooled with stirring to -10 ° C, 4. 5g of sodium borohydride was added. Then added to -KTC~_5 ° C graded crushed through a 20 mesh processed 50gl, 4- androstenedione, androstenedione added 1,4_ time of 20 minutes ~ 30 minutes. Canada finished continue to -KTC~_5 ° C the reaction was stirred 0.5 hours. The reaction mixture was added a pre-cooled to square ° C~5 ° C water, continuing to 0 ° C~5 ° C was stirred for 0.5 hours, suction filtered, and dried to give 49. 7g of crude product. The crude product is then mixed with methanol and ethyl acetate solvent crystallization to give 47. 6g Boldenone, HPLC purity of 98.6%.

References

Analytical Chemistry (Washington, DC, United States) (2011), 83(4), 1243-1251.

///////Boldenone Undecylenate

Elpamotide

PEPTIDES, Phase 3 drug, Uncategorized Comments Off

May 032016

Elpamotide str drawn bt worlddrugtracker

Elpamotide

L-Arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-alpha-aspartylglycyl-L-asparaginyl-L-arginyl-L-isoleucine human soluble (Vascular Endothelial Growth Factor Receptor) VEGFR2-(169-177)-peptide

MF C₄₇ H₇₆ N₁₆ O₁₃

Molecular Weight, 1073.2164

L-Isoleucine, L-arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-α-aspartylglycyl-L-asparaginyl-L-arginyl-

10: PN: WO2008099908 SEQID: 10 claimed protein
14: PN: WO2009028150 SEQID: 1 claimed protein
18: PN: JP2013176368 SEQID: 18 claimed protein
1: PN: WO2009028150 SEQID: 1 claimed protein
2: PN: WO2010027107 TABLE: 1 claimed sequence

6: PN: WO2013133405 SEQID: 6 claimed protein
8: PN: US8574586 SEQID: 8 unclaimed protein
8: PN: WO2004024766 SEQID: 8 claimed sequence
8: PN: WO2010143435 SEQID: 8 claimed protein

A neoangiogenesis antagonist potentially for the treatment of pancreatic cancer and biliary cancer.

OTS-102

CAS No.673478-49-4, UNII: S68632MB2G

Company	OncoTherapy Science Inc.
Description	Angiogenesis inhibitor that incorporates the KDR169 epitope of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1; VEGFR-2)
Molecular Target	Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2) (KDR/Flk-1)
Mechanism of Action	Angiogenesis inhibitor; Vaccine
Therapeutic Modality	Preventive vaccine: Peptide vaccine

Originator OncoTherapy Science
Class Cancer vaccines; Peptide vaccines
Mechanism of Action Cytotoxic T lymphocyte stimulants

16 Jun 2015 No recent reports on development identified – Phase-II/III for Pancreatic cancer (Combination therapy) and Phase-II for Biliary cancer in Japan (SC)
09 Jan 2015 Otsuka Pharmaceutical announces termination of its license agreement with Fuso Pharmaceutical for elpamotide in Japan
01 Feb 2013 OncoTherapy Science and Fuso Pharmaceutical Industries complete a Phase-II trial in unresectable advanced Biliary cancer and recurrent Biliary cancer (combination therapy) in Japan (UMIN000002500)

Elpamotide str drawn bt worlddrugtracker

Elpamotide , credit kegg

Elpamotide is a neoangiogenesis inhibitor in phase II clinical trials at OncoTherapy Science for the treatment of inoperable advanced or recurrent biliary cancer. Phase III clinical trials was also ongoing at the company for the treatment of pancreas cancer, but recent progress report for this indication are not available at present.

Consisting of VEGF-R2 protein, elpamotide is a neovascular inhibitor with a totally novel mechanism of action. Its antitumor effect is thought to work by inducing strong immunoreaction against new blood vessels which provide blood flow to tumors. The drug candidate only act against blood vessels involved in tumor growth and is associated with few adverse effects.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival

The vaccine candidate was originally developed by OncoTherapy Science. In January 2010, Fuso Pharmaceutical, which was granted the exclusive rights to manufacture and commercialize elpamotide in Japan from OncoTherapy Science, sublicensed the manufacturing and commercialization rights to Otsuka Pharmaceutical. In 2015, the license agreement between Fuso Pharmaceutical and OncoTherapy Science, and the license agreement between Fuso Pharmaceutical and Otsuka Pharmaceutical terminated.

WO 2010143435

US 8574586

WO 2012044577

WO 2010027107

WO 2013133405

WO 2009028150

WO 2008099908

WO 2004024766

PATENT

WO2013133405

The injectable formulation containing peptides, because peptides are unstable to heat, it is impossible to carry out terminal sterilization by autoclaving. Therefore, in order to achieve sterilization, sterile filtration step is essential. Sterile filtration step is carried out by passing through the 0.22 .mu.m following membrane filter typically absolute bore is guaranteed. Therefore, in the stage of pre-filtration, it is necessary to prepare a peptide solution in which the peptide is completely dissolved. However, peptides, since the solubility characteristics by its amino acid sequence differs, it is necessary to select an appropriate solvent depending on the solubility characteristics of the peptide. In particular, it is difficult to completely dissolve the highly hydrophobic peptide in a polar solvent, it requires a great deal of effort on the choice of solvent. It is also possible to increase the solubility by changing the pH, or depart from the proper pH range as an injectable formulation, in many cases the peptide may become unstable.

　In recent years, not only one type of peptide, the peptide vaccine formulation containing multiple kinds of peptides as an active ingredient has been noted. Such a peptide vaccine formulation is especially considered to be advantageous for the treatment of cancer.

　The peptide vaccine formulation for the treatment of cancer, to induce a specific immune response to the cancer cells, containing the T cell epitope peptides of the tumor-specific antigen as an active ingredient (e.g., Patent Document 1). Tumor-specific antigens these T-cell epitope peptide is derived, by exhaustive expression analysis using clinical samples of cancer patients, for each type of cancer, specifically overexpressed in cancer cells, only rarely expressed in normal cells It never is one which has been identified as an antigen (e.g., Patent Document 2). However, even in tumor-specific antigens identified in this way, by a variety of having the cancer cells, in all patients and all cancer cells, not necessarily the same as being highly expressed. That is, there may be a case in which the cancer in different patients can be an antigen that is highly expressed cancer in a patient not so expressed. Further, even in the same patient, in the cellular level, cancer cells are known to be a heterogeneous population of cells (non-patent document 1), another even antigens expressed in certain cancer cells in cancer cells may be the case that do not express. Therefore, in one type of T-cell epitope peptide vaccine formulations containing only, there is a possibility that the patient can not be obtained a sufficient antitumor effect is present. Further, even in patients obtained an anti-tumor effect, the cancer cells can not kill may be present. On the other hand, if the vaccine preparation comprising a plurality of T-cell epitope peptide, it is likely that the cancer cells express any antigen. Therefore, it is possible to obtain an anti-tumor effect in a wider patient, the lower the possibility that cancer cells can not kill exists.

　The effect of the vaccine formulation containing multiple types of T-cell epitope peptide as described above, the higher the more kinds of T-cell epitope peptides formulated. However, if try to include an effective amount of a plurality of types of T cell peptide, because the peptide content of the per unit amount is increased, to completely dissolve the entire peptide becomes more difficult. Further, because it would plurality of peptides having different properties coexist, it becomes more difficult to maintain all of the peptide stability.

　For example, in European Patent Publication No. 2111867 (Patent Document 3), freeze-dried preparation of the vaccine formulation for the treatment of cancer comprising a plurality of T-cell epitope peptides have been disclosed. This freeze-dried preparation, in the preparation of peptide solution before freeze drying, each peptide depending on its solubility properties, are dissolved in a suitable solvent for each peptide. Furthermore, when mixing the peptide solution prepared in order to prevent the precipitation of the peptide, it is described that mixing the peptide solution in determined order. Thus, to select a suitable solvent for each peptide, possible to consider the order of mixing each peptide solution is laborious as the type of peptide increases.

In order to avoid difficulties in the formulation preparation, as described above, a vaccine formulation comprising one type of T-cell epitope peptides, methods for multiple types administered to the same patient is also contemplated. However, when administering plural kinds of vaccine preparation, it is necessary to vaccination of a plurality of locations of the body, burden on a patient is increased. Also peptide vaccine formulation, the DTH (Delayed Type Hypersensitivity) skin reactions are often caused called reaction after inoculation. Occurrence of skin reactions at a plurality of positions of the body, increases the discomfort of the patient. Therefore, in order to reduce the burden of patients in vaccination is preferably a vaccine formulation comprising a plurality of T-cell epitope peptide. Further, even when the plurality of kinds administering the vaccine formulation comprising a single type of epitope peptides, when manufacturing each peptide formulation is required the task of selecting an appropriate solvent for each peptide.

Patent Document 1: International Publication No. WO 2008/102557
Patent Document 2: International Publication No. 2004/031413 Patent
Patent Document 3: The European Patent Publication No. 2111867

PATENT

https://www.google.com/patents/US8574586

PATENT

///////////Elpamotide, A neoangiogenesis antagonist, pancreatic cancer and biliary cancer, OTS-102, OncoTherapy Science Inc, peptide

CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)N)NC(=O)CNC(=O)[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CCCNC(=N)N)N

ASP 3026

Uncategorized Comments Off

May 022016

ASP3026

ASP3026;

CAS 1097917-15-1; ASP-3026; ASP 3026; UNII-HP4L6MXF10;

N2-[2-Methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-1,3,5-triazine-2,4-diamine;

2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine

(N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel selective inhibitor of the fusion protein EML4-ALK.

¹H NMR (CDCl₃, 400 MHz) (ppm) = 1.31 (d, 6H, J = 6.8 Hz), 1.58–1.80 (m, 4H), 1.90–2.04 (m, 2H), 2.16–2.84 (m, 12H), 3.18–3.32 (m, 1H), 3.66–3.76 (m, 2H), 3.88 (s, 3H), 6.48–6.60 (m, 2H), 7.18–7.26 (m, 1H), 7.50–7.72 (m, 2H), 7.86–7.92 (dd, 1H, J = 1.2 Hz, J = 7.6 Hz), 8.06–8.16 (m, 1H), 8.28–8.48 (m, 1H), 8.48–8.62 (m, 1H), 9.28 (s, 1H).

Molecular Formula:	C₂₉H₄₀N₈O₃S
Molecular Weight:	580.7447 g/mol

ASP3026 is a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts.

ASP-3026 was studied in P1 clinical trials at Astellas Pharma for the oral treatment of advanced solid tumors and advanced B-cell lymphoma. In 2014 the product was discontinued by Astellas due to strategic reasons

JP 2012153674

WO 2012102393

WO 2011145548

WO 2009008371

PATENT

WO2012102393

The compound of the formula (1) has an excellent EML4-ALK fusion protein and inhibitory activity of the kinase of the mutant EGFR protein, we are already reported to be useful as an active ingredient of a pharmaceutical composition for cancer treatment (Patent Document 1). Further, it is the compound of formula (1) there are five polymorphs shown as A01 ~ A05 type, among others A04 type crystal is in finding reported that the most stable type crystals (Japanese Patent Document 2).
[Formula 1] 　a compound of formula (1) described in Patent Document 1 production method of (Patent Document 1 of Example 23), referring to Production Examples and Examples described in this document, the reaction formula (I) It is shown in. That is, 2,4-dichloro-1,3,5-triazine (hereinafter, may be referred to as “compound of formula (15)”.), 2- (isopropylsulfonyl) aniline (hereinafter, “the formula (8) sometimes referred to compound “.) using, by reacting according to the method described in production example 7 of this document, to give compounds of formula (14) to (production example 22 of Patent Document 1), then , the resulting compound of formula (14), a known method (e.g., International Publication No. 2005/016894 pamphlet reference) was prepared by 2-methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] aniline (hereinafter, may be referred to as “formula (13) compounds of.”) is used to react according to the method described in example 1 of the document, and the target it is a method for producing a compound of formula (1) to.

[Formula 2]

Patent Document 1: International Publication No. 2009/008371 pamphlet
Patent Document 2: WO 2011/145548 pamphlet

Example 1
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² Synthesis of methyl Any compound of formula (10))
　4,4 – N and dimethoxy piperidine monohydrochloride (35.9 g), N-dimethylformamide and (75 mL) were mixed, and the mixed solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (57.5 mL) was added It was. It was separately prepared here 5-fluoro-2-nitroanisole (30.0 g) and N, N-dimethylformamide (30 mL) was stirred for 5 hours at room temperature. Water (120 mL) was added at room temperature to the reaction mixture, after stirring for 4 hours, the precipitated crystals were collected by filtration. The resulting crystals N, N-dimethylformamide and a mixed solution of water (1: 1) (60mL) , water (60 mL), was further washed sequentially with water (60 mL), and dried under reduced pressure at 40 ° C. to give 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (49.9 g, 96.1% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of

　4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine and (45.0 g) in tetrahydrofuran and a (225 mL) were mixed, 5% palladium carbon (about 50% wet product, 4.5 g) to this mixed solution was added at room temperature, under a hydrogen atmosphere (2.4821×10 ⁵ Pa), and the mixture was stirred for 5 hours and a half at room temperature. Then filtered off and palladium-carbon, washed with tetrahydrofuran (90mL), was concentrated under reduced pressure filtrate until total volume of about 90mL obtain a slurry. After the slurry was stirred for 1 hour at 40 ° C., n- heptane (135 mL) was added and after stirring for 1 hour at 40 ° C., cooled to 0 ° C., was added n- heptane (405 mL), precipitated crystals It was collected by filtration.The obtained crystals were washed with a mixed solution of tetrahydrofuran (9 mL) and n- heptane (54 mL), and dried in vacuo at 40 ℃, 4- (4,4- dimethoxy-1-yl) -2-methoxy to give aniline (37.9g, 93.7% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric chloride (25.0 g), sodium bicarbonate (13.7 g), were mixed 2- (isopropylsulfonyl) aniline (29.7 g) and acetone (200 mL), and stirred at room temperature for 25 hours. After adding water (200 mL) at room temperature the reaction mixture was stirred for 19 hours, the precipitated crystals were collected by filtration. The resulting crystals acetone and a mixed solution of water (1: 1) was washed with (100 mL), and dried in vacuo at 40 ° C., 4,6-dichloro-N- [2-(propane-2-sulfonyl) to give phenyl] -1,3,5-triazin-2-amine (45.1g, 95.8% yield) as crystals.
D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (40.0 g) was mixed with tetrahydrofuran (400 mL), to this mixed solution 4- (4,4-dimethoxy-piperidin-1 yl) -2-methoxyaniline (32.2 g) and N, N- diisopropylethylamine (16.38g) was stirred for 4 hours at room temperature.Thereafter, isopropyl acetate (40 mL), then extracted by adding a mixed solution of potassium carbonate (2.0 g) and water (40 mL). The obtained organic layer was concentrated under reduced pressure until the total volume of about 200 mL, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (4 mg), to give a slurry and stirred for about 15 minutes. The slurry n- heptane (200 mL) was added and filtered off cooled to 18 hours with stirring to precipitate crystals to 0 ° C.. The resulting crystals were washed with a mixed solution of tetrahydrofuran (40 mL) and n- heptane (40 mL), and dried in vacuo at 40 ° C., 6- Chloro -N- [4- (4,4- dimethoxy-piperidine – 1-yl) -2-methoxyphenyl] -N ‘- [2- (the propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (61.4 g, 92.4% yield) It was obtained as a crystal.
D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI-: 575,577

The fourth alternative process (e.g. without using a seed crystal) 6-Chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane 2-sulfonyl) phenyl] (a Lv is Cl, R-1,3,5-triazine-2,4-diamine ¹ and R ² none is methyl, the formula (5) synthesis of compound of)
4 , and mixed 6-dichloro -N- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (23.0 g) in tetrahydrofuran (230 mL), to this mixed solution 4- (4,4-dimethoxy-1-yl) -2-methoxyaniline (18.5 g) and N, N- diisopropylethylamine (12.7 mL) was stirred for 2 hours at room temperature. Thereafter, isopropyl acetate (57.5 mL), then extracted by adding potassium carbonate (5.75 g) and a mixed solution of water (115 mL). The resulting organic layer was concentrated under reduced pressure. The resulting residue is added and stirred in tetrahydrofuran (50mL) to obtain a slurry. After stirring for 1 hour at the slurry was added tetrahydrofuran (75 mL) and n- heptane (75mL) 40 ℃, cooled to 0 ° C., and stirred for a further 18 hours.Thereafter, n- heptane (50 mL) was added, and the precipitated crystals were collected by filtration. The resulting crystals tetrahydrofuran and n- heptane mixed solution (5: 7) After washing with (24 mL), and dried in vacuo at 40 ° C., 6- chloro-N- [4- (4,4-dimethoxy piperidin-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (30.6g, 80.0% yield ) was obtained as a crystal.

The fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino ) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (60.0 g), tetrahydrofuran (540 mL) and 10% palladium carbon (about 50% wet product, 10.7 g) and mixed, N to the mixture, added to N- diisopropylethylamine (16.11g) and 2-propanol (60 mL), under a hydrogen atmosphere (2.4131X10 ^{5 of 5} Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (120 mL), the resulting filtrate activated carbon (12.0 g) was added to, and stirred at room temperature overnight. Then filtered off and the activated carbon, and washed with tetrahydrofuran (120mL), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane – to obtain a solution containing 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added a mixed solution of 35% hydrochloric acid (21.7 g) and water (120 mL), and stirred for 21 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (35.9 g) and water (120 mL), and extracted. Activated carbon (12.0 g) was added to the obtained organic layer was stirred for 16 h, filtered, washed with activated carbon in tetrahydrofuran (120 mL). The filtrate obtained total amount was concentrated under reduced pressure to approximately 120 mL. After addition of acetone (180 mL) to the resulting mixture, as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5 after stirring for 1 hour and inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (60 mg), water (480 mL) was stirred for 20 hours was added, and the precipitated crystals were collected by filtration . The obtained crystals were washed with a mixed solution of acetone (36 mL) and water (96 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – was obtained sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (45.8g, 88.7% yield (yield in a continuous two steps)) as crystals .
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Fifth Step N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine 2,4-diamine (R ¹ and R ² is methyl any formula (4) of compound) synthesis of
6-chloro-N- [4- (4,4-dimethoxy-1-yl) – 2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (5.0 g), tetrahydrofuran (45 mL), 2-propanol (5mL ), 10% palladium-carbon (about 50% wet product, 1.0 g) were mixed, added N, N- diisopropylethylamine (1.81 mL) to this mixed solution, under a hydrogen atmosphere (2.4821X10 ^{5 of 5} Pa), 40 ° C. in and the mixture was stirred for 5 hours and a half. Filtration of the palladium-carbon was washed with tetrahydrofuran (10 mL), and extraction was performed with 10% brine (20 mL). The resulting organic layer was concentrated under reduced pressure. Acetone to the concentrated residue (10 mL), was added diisopropyl ether (40 mL), it was collected by filtration stirred precipitated crystals 30 minutes. The obtained crystals were washed with diisopropyl ether (20 mL), and dried in vacuo at 40 ℃, N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl]-N’- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.31 g, 91.6% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 1.80 (4H, dd, J = 5.5,5.7Hz), 3.15 (6H, s), 3.21 (4H, dd, J = 5.5,5.7Hz) , 3.77 (3H, s), 6.50 (1H, dd, J = 2.5,8.7Hz), 6.62 (1H, d, J = 2.5Hz), 7.25-7.28 (1H, m), 7.34 (1H, d, J 8.7 Hz =), 7.58 (1H, br), 7.77-7.79 (1H, yd), 8.28 (1H, s), 8.49 (1H, br), 8.63 (1H, br), 9.25 (1H, br)
ESI +: 543

Sixth Step 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (equation (3) a compound of) synthesis of
N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (4.0 g), and tetrahydrofuran (36 mL) and 2-propanol (4 mL) solution of 35% hydrochloric acid containing (1.44 g) a mixture of water (4 mL) was added on, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (2.4 g) and water (4 mL), and extracted.The resulting organic layer was concentrated under reduced pressure. After stirring for 30 minutes by addition of acetone (12 mL) and water (4 mL) to the concentrated residue, add water (28 mL) was stirred for 1 hour, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of acetone (8 mL) and tetrahydrofuran (3 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – give sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (3.42g, 99.2% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (20.0 g), methyl piperazine (8.07 g), were mixed in toluene (200 mL) and acetic acid (9.0 mL), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (17.06 g), and stirred at room temperature for 20 hours. To the reaction mixture, water (60 mL) and methanol (20 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (20 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (200 mL). Methanol (220 mL) to the resulting aqueous layer, a mixed solution of sodium hydroxide (9.68 g) and water (48 mL) was added, as a seed crystal, N-{2-methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (2.0mg) inoculated, after stirring at room temperature for 1.5 hours, add water (220 mL), further stirred for 2 hours at room temperature, the precipitated crystals were collected by filtration. The resulting crystals were washed with a mixed solution of methanol (40mL) and water (40mL), and then dried under reduced pressure at 50 ℃, N- {2- methoxy-4- [4- (4-methyl-piperazine -1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (20.15g, 86.1% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

Alternatively 1 (Example not using seed crystals) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N seventh step ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (compound of formula (1))

　1- [3-methoxy-4 – ({4- [2 – (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), methyl piperazine (2.02 g), toluene (50 mL) and acetic acid (1.5 mL) were mixed and stirred at room temperature for 1 hour. To this mixture solution was added sodium triacetoxyborohydride (4.72 g), and stirred at room temperature for 18 hours. To the reaction mixture, water (15 mL) and methanol (5 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (5 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (50 mL). The resulting aqueous layer methanol (55 mL), a mixed solution was added sodium hydroxide (2.0 g) and water (10 mL), was stirred for 62 hours at room temperature, add water (55 mL), at room temperature for a further 2 hours stirring, the formed crystals were separated by filtration. The obtained crystals were washed with a mixed solution of methanol (5 mL) and water (5 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin–1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.56g, 78.0% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581
alternative seventh step 2 (example using reducing catalyst) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane -2 – sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine synthesis of compounds of formula (1)
1- [3-methoxy-4 – ({4- [2- (propan-2 sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), tetrahydrofuran (30 mL), methylpiperazine (1.81 g) and 10% palladium carbon (about 50 % wet product, were mixed 0.8 g), under a hydrogen atmosphere (2.4821X10 ^{5 of 5}Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (10 mL), the resulting filtrate was concentrated under reduced pressure. To the concentrated residue 2-butanone (9 mL) was added, followed by stirring at 60 ° C. 30 minutes, cooled slowly, at 30 ° C. n-heptane (9 mL) was added, and stirred for 19 hours at room temperature, the precipitated crystals were collected by filtration did.The resulting crystals of 2-butanone and (1 mL) was washed with a mixture of n- heptane (1 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methyl piperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (3.09 g, yield: 88.0%) was obtained.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine by recrystallization purification steps (formula (1 compound of))
(the a method) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (8.80 g), 2-butanone (211 mL) after mixing and confirmation of dissolution and stirring at 65 ° C. 30 minutes for clarifying filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 17 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (7.88 g, 89.5% yield, purity 99.4%) was obtained as a A04 type crystal (A04 type ratio 98.9%).

(B method): N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazine-2,4-diamine (8.80g), was mixed activated carbon (0.88 g) and 2-butanone (211 mL), after stirring for 1 hour at 75 ° C., was subjected to activated carbon filtration .The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 16 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (6.60 g, 75.0% yield, purity 99.3%) was obtained as A04 type crystal (A04 type ratio 100%).

Example 2
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² is methyl Any formula (Compound 10)) Synthesis of
4,4 – dimethoxy piperidine monohydrochloride (69.9kg) and N, N-dimethylformamide (125.7kg) was mixed, to this mixed solution 1,8-diazabicyclo [5.4.0] undec-7-ene and (117.3kg) N It was added N- dimethylformamide (17.0kg). N of separately prepared here 5-fluoro-2-nitroanisole (60.0kg), the N- dimethylformamide (57.0kg) was added at room temperature, N, N- dimethylformamide (29.0 kg) solution was added 5 hours It stirred. At room temperature with a seed crystal of 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (about 6 g) was added to the reaction mixture was stirred at room temperature for 14 hours. Water (240 kg) was added at room temperature to the reaction mixture, after stirring for 22 hours, the precipitated crystals were collected by filtration. The obtained crystals N, washed with a mixed solution of N- dimethylformamide (56.9kg) and water (60kg), washed twice with water (120 kg), and dried in vacuo at 50 ° C., 4, 4 – to give dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (99.7kg, 96.0% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of
4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine (99.0kg), 5% palladium carbon (about 50% wet product, 10.5 kg), were mixed at room temperature in tetrahydrofuran (440 kg), under a hydrogen atmosphere (200 ~ 300 kPa ), and stirred at room temperature for 3 hours. Then filtered off and palladium-carbon, tetrahydrofuran and washed with (180.5Kg), the filtrate was concentrated under reduced pressure until the total volume of about 220L, as a seed crystal 4- (4,4-dimethoxy-1-yl) – crystals of 2-methoxyaniline was inoculated (approximately 10g). To the resulting slurry n- heptane (205.4kg) was added at 40 ° C., after stirring for 1 h, was stirred and cooled to 0 ° C. 16 hours. To this slurry was added n- heptane (613.5kg), After stirring for 2 hours, the crystals were collected by filtration. The obtained crystals were washed with a mixed solution of tetrahydrofuran (17.8 kg) and n- heptane (81.5kg), and dried in vacuo at 50 ℃, 4- (4,4- dimethoxy-1-yl) -2 – give methoxyaniline (84.1kg, 94.5% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric acid chloride (40.0kg) and acetone (249.2kg) was mixed at a 17 ℃. Sodium hydrogen carbonate in the mixed solution (21.9 kg), 2-a (isopropylsulfonyl) aniline (47.5Kg) was added, and stirred at room temperature for 23 hours. After adding to the reaction mixture water (320 kg) at room temperature, and stirred for 3.5 hours, the precipitated crystals were collected by filtration. After washing the obtained crystals with a mixed solution of acetone (63.0kg) and water (80 kg), and dried in vacuo at 50 ° C., 4,6-dichloro -N- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazin-2-amine (71.6kg, 95.1% yield) was obtained as crystals.

D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (70.9 kg) in tetrahydrofuran (611.1kg) was mixed at room temperature, to this mixed solution 4- (4,4-dimethoxy-piperidine 1-yl) -2-methoxyaniline (57.1kg), N, N- diisopropylethylamine (29.1 kg) was stirred for 4 hours at room temperature. Thereafter, isopropyl acetate (61.0kg), then extracted by adding potassium carbonate (3.6 kg) and a mixed solution of water (71 kg).The resulting organic layer total amount was concentrated under reduced pressure at an external temperature of about 40 ° C. to approximately 360 L, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2 – methoxyphenyl] -N ‘- [2- was inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 7 g) to give a slurry. To this slurry of 2-propanol (111.0kg), n- heptane (243.1kg) was added and after cooling for 2 hours at room temperature, was collected by filtration stirred precipitated crystals were cooled to 0 ℃ 18 hours. The resulting crystals tetrahydrofuran (74.9kg), 2- propanol (44.6kg), was washed with a mixed solution of n- heptane (97.6kg), and then dried under reduced pressure at 50 ℃, 6- chloro -N- [ 4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine It was obtained (108.9kg, 92.4% yield) as crystals.

D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI -: 575,577
fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazine – 2-yl} amino) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (108.2kg), tetrahydrofuran (866.0kg), 10% palladium carbon (about 50% wet goods, 23.3 kg) were mixed, N to this mixed solution was added to N- diisopropylethylamine (28.9 kg) and 2-propanol (85.5kg), under a hydrogen atmosphere (100 ~ 300kPa), 4 hours at 40 ° C. did. Filtration of the palladium-carbon was washed with tetrahydrofuran (193.3kg), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane -2 – to obtain a solution containing a sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added 35% hydrochloric acid (39.1 kg) of mixed solution of water (217kg), and stirred for 15 hours at room temperature. To the reaction mixture, added potassium carbonate (64.8kg) and a mixed solution of water (217kg), and extracted. Activated carbon (10.8 kg) was added to the obtained organic layer and stirred for 17 hours at room temperature, filtered and washed activated carbon with tetrahydrofuran (96.0kg). The resulting filtrate was concentrated under reduced pressure until the total volume of about 380L at 40 ° C.. After the resultant mixture was added acetone (257.1Kg), as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] 1,3,5 – after stirring for 1 hour was inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (approximately 11g), the addition of water (865Kg) was stirred for 15 hours, the precipitated crystals were collected by filtration did. The obtained crystals were washed with a mixed solution of acetone (50.9kg) and Tsunemizu (173 kg), and dried in vacuo at 50 ℃, 1- [3- methoxy-4 – ({4- [2- (propane 2-sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (82.9kg, 89.0% yield (yield in a continuous two steps)) as crystals Obtained.

D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (60.1kg), methylpiperazine (24.2kg), was mixed with toluene (500 kg) and acetic acid (28.4kg), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (51.4kg), and stirred at room temperature for 17 hours. To the reaction mixture, methanol (47.5kg) and water (180.1kg) was added, extraction to give an organic layer and an aqueous layer 1. The organic layer was re-extracted by adding water (60.0kg), to obtain an aqueous layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (523.4kg). The resulting aqueous layer methanol (522.3kg), a mixed solution of 48% sodium hydroxide (60.6kg) and water (112.7kg) was added, as a seed crystal N- {2- methoxy-4- [4- (4 – methyl-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (about 6 g) were inoculated, after stirring at room temperature for 2 hours, added water (660.2kg), further stirred for 3.5 hours at room temperature, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of methanol (104.4kg) and water (132.0kg), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.2kg, yield: 77.1 %) was obtained as A06-form crystals.

D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , purification step by recrystallization 5-triazine-2,4-diamine (compound of formula (1))
N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.3kg), activated charcoal (5.4 kg), 2-butanone (1046.1 kg) were mixed, stirred for 1 hour at 75 ° C., was subjected to active carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume approximately until 430L normal pressure concentrated and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 5 g), after stirring for 3 hours, It was cooled to 5 ℃ at a rate of 20 ℃ / h, and the precipitated crystals were collected by filtration. After washing with the resulting crystals were cooled in 5 of 5 ° C. 2-butanone (220L), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (42.6kg, 78.5% yield, purity 99.5%) was obtained as A04-form crystals (A04 type ratio 100%).

Ken Jones, president and chief executive officer, Astellas Pharma Europe

Paper

Organic Process Research & Development (2015), 19(12), 1966-1972

Strategy for Controlling Polymorphism of Di(Arylamino) Aryl Compound ASP3026 and Monitoring Solution Structures via Raman Spectroscopy

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., 2015, 19 (12), pp 1966–1972

DOI: 10.1021/acs.oprd.5b00208

Publication Date (Web): October 23, 2015

*E-mail:kazuhiro.takeguchi@astellas.com. Tel.: +81-293-23-5459. Fax: +81-293-23-5993.

Abstract

ASP3026(N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date, and the most stable polymorph (A04) was selected for designing solid formulations. The influence of crystallization process parameters on nucleation of A03 and A04 was clarified for process development. A04 was obtained at relatively high temperatures and A03 at relatively low temperatures, regardless of the superaturation ratio. A03 and A04 were therefore able to be selectively obtained via temperature control, possibly due to temperature-dependent variations in the concentrations of conformers in solution. The relationship between polymorphs and solution structures before nucleation was investigated using in situ Raman spectroscopy. The relationship with the intensity ratios of nine Raman bands of both polymorphs and ASP3026 solution structures was investigated in detail. Our findings suggest that the solution structure shifted from a structure similar to that of A04 to one similar to that of A03 with decreasing temperature.

Chairman of Astellas Pharma Inc. Mr. Masafumi Nogimori is conferred with Netherlands Honor – ‘Officer in the Order of Oranje-Nassau’

PAPER

Effect of Temperature and Solvent of Solvent-Mediated Polymorph Transformation on ASP3026 Polymorphs and Scale-up

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00068

Publication Date (Web): April 28, 2016

*Telephone: +81-293-23-5459. Fax: +81-293-23-5993; e-mail:kazuhiro.takeguchi@astellas.com.

Abstract

ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date. Process development was conducted for large-scale pilot plant manufacturing, and obtaining the desired polymorph A04 was key after a synthetic route of ASP3026 was selected for scale-up. The effects of temperature and solvent species on induction time of polymorph transformation were investigated using in situ Raman spectroscopy, and selective transformation conditions of A02 to A03 and A04 were examined in detail. A04 was obtained at high temperatures using highly polar non-hydrogen-bond-donating solvents, while A03 was obtained at low temperatures using low-polarity or hydrogen-bond-donating solvents. Further, the desired polymorph A04 was successfully obtained in high purity in first stage scale-up manufacturing. Given these findings, this method of solvent-mediated polymorph transformation may aid in process development for obtaining desired polymorphs.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00068

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