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

May 6, 2016 9:57 am / 1 Comment on A New Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, from University Of Notre Dame

(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

Processes for Constructing Homogeneous Antibody Drug Conjugates

May 5, 2016 10:35 am / 1 Comment on Processes for Constructing Homogeneous Antibody Drug Conjugates

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

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

May 5, 2016 10:32 am / Leave a comment

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

EMA publishes finalised Process Validation Guideline for Biotech Products

May 5, 2016 8:54 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Approximately two years ago the EMA published a draft guideline on process validation for the manufacture of biotech products. Now the final guideline has been published under the title “Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission“.

READ

http://www.gmp-compliance.org/enews_05342_EMA-publishes-finalised-Process-Validation-Guideline-for-Biotech-Prodcts_15435,15373,15298,15250,Z-VM_n.html

The scope of the guideline is to provide guidance on the data to be included in a regulatory submission to demonstrate that the active substance manufacturing process is in a validated state. The guideline focuses on recombinant proteins and polypeptides, their derivates, and products of which they are components (e.g…

View original post 300 more words

Quality Documentation of API mix in the Marketing Authorisation Procedure

May 5, 2016 8:52 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

For different reasons, the manufacture of APIs may sometimes require adding excipients. In the context of an authorisation procedure, this practice reveals to be problematic. Read more here about the data required for the quality documentation of a API mix in an ASMF or a CEP.

http://www.gmp-compliance.org/enews_05334_Quality-Documentation-of-API-mix-in-the-Marketing-Authorisation-Procedure_15339,15332,S-WKS_n.html

The manufacture of APIs sometimes requires adding of one or several excipients like for example an antioxidant or an inert matrix for stabilisation purposes. Occasionally, corresponding mixtures can be manufactured to optimize workability for further processing or filling (e.g. improvement of flowability). Yet, within a marketing authorisation procedure, such an API mix can possibly be accepted differently than the pure API.

To clarify the questions around this topic, EMA’s QWP has published a document entitled “Quality Working Party questions and answers on API mix“. Please find hereinafter a summary of the questions addressed in the document:

What is an API mix?

View original post 476 more words

Galunisertib

May 4, 2016 10:47 am / 3 Comments on Galunisertib

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

http://www.google.co.in/patents/US7872020

	Sreenivasa Reddy Mundla
Original Assignee	Eli Lilly And Company

EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate

Step 1: Preparation of 6-cyano-4-methyl-quinoline hydrochloride

Add 95% ethanol (EtOH) (270 L, 9 vol.), 4-aminobenzonitrile (30.0 kg, 1 equiv) and 2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione, (66.81 kg 1.07 equiv) to a 200 gallon reaction vessel equipped with nitrogen purge, condenser, thermocouple, and overhead agitation. Stir for 2-5 min, then add concentrated hydrochloric acid (HCl) (62.56 L, 3.0 equiv), then heat to 75° C. Dilute methyl vinylketone (33.06 L, 1.5 equiv) in 95% EtOH (30 L, 1 vol.) then add slowly to reaction mixture over 30 min. Monitor for reaction completion by high performance liquid chromatography (HPLC). Add tetrahydrofuran (THF) (11 vol., 330 L), at 75° C., then stir for 1 hour at 60° C. Cool to room temperature and stir for 1 additional hour. Filter on agitated filter/dryer, then rinse with THF (240 L, 8 volumes). Dry overnight under vacuum at 70° C. to give the title compound (42.9 kg, 82.55%).

¹H NMR (DMSO d6): δ=9.047 ppm (d, 4.4 Hz, 1H); 8.865 ppm (d, 1.6 Hz, 1H); 8.262 ppm (d, 8.8 Hz, 1H); 8.170 ppm (dd, 2.2 Hz, 8.8 Hz, 1H); 7.716 ppm (d, 4.4 Hz, 1H); 2.824 ppm (s, 3H). MS ES+: 169.1; Exact: 168.07.

Step 2: Preparation of 2-(6-cyano-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone

Combine the 6-cyano-4-methyl-quinoline (28 kg) and THF (9.5 vol.) and cool to 5° C. Add sodium t-butoxide solid (3.3 equiv.) in portions to the cooled slurry to keep the batch temperature ≦25° C. Stir the resulting mixture at 20° C. for 30 min. To a separate vessel, charge with liquid 6-methyl-2-pyridinecarboxylic acid, methyl ester (1.5 equiv.) and dilute with THF (2.0 vols.). The 6-methyl-2-pyridinecarboxylic acid, methyl ester solution is slowly added (20-40 min) while maintaining a temperature of ≦25° C. Stir the reaction mixture for 2 hours at 20° C. and monitor by HPLC/TLC (thin layer chromatography on silica gel) to confirm reaction completion. In a separate vessel, dilute 1.03 kg conc. HCl per kg of 2-(6-cyano-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone with 7.7 vol water. Cool both the reaction mixture and the HCl solution to 5° C. Perform a pH adjustment on the reaction mixture by the slow addition of the acid solution, keeping the temperature <15° C. Acid solution is added until the pH of the mixture is 8.0-9.0. After the pH endpoint is obtained, extract the mixture with ethyl acetate (7 vol.). Wash the organic layer with an aqueous sodium chloride/sodium bicarbonate solution [0.78 kg sodium chloride per kg of 2-(6-cyano-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl) -ethanone, and 0.20 kg of sodium bicarbonate (NaHCO₃) per kg of 2-(6-cyano-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl)-ethanone in 6.6 vol.]. Distill the organic layer at one atmosphere to remove THF and ethylacetate (EA) until 5 vol. of concentrated solution remains. Using methanol (10 vol.) perform a solvent exchange to methanol using a constant add/distill operation while maintaining 5 vol. Add warm methanol (MeOH) (10 vol. @ 60° C.). Cool the solution to 50° C., then add seed crystals obtained by Preparation 2. Cool the mixture gradually to 5° C., stir for 1 hour, and filter. Wash the product cake with chilled methanol (5 vols. @ 5° C.) and dry under vacuum at 40° C. until a loss on drying (LOD) specification of <1% is satisfied. Gives the title compound (31.6 kg, 81%).

¹H NMR (CDCl₃): δ=8.978 ppm (d, 4.4 Hz, 1H); 8.627 ppm (d, 1.6 Hz, 1H); 8.199 ppm (d, 8.8 Hz, 1H); 7.874 ppm (d, 7.7 Hz, 1H); 7.837 ppm (dd, 2.2 Hz, 8.8 Hz, 1H); 7.759 ppm (t, 7.7 Hz, 1H); 7.546 ppm (d, 4.4 Hz, 1H); 7.416 ppm (d, 7.7 Hz, 1H); 5.036 ppm (s, 2H); 2.720 ppm (s, 3H). MS ES+: 288.1; Exact: 287.11.

Step 3a: Preparation of 1-(amino)-2-pyrrolidinone, p-toluene sulfonate

Combine 1-[(Diphenylmethylene)amino]-2-pyrrolidinone (35.36 g, 134 mmoles) with 15 volumes of toluene (530 mL) in a 1 L reaction flask, add 1 equiv of water (2.43 g, 134.9 mmoles) and heat to 40° C. Add 1 equiv of p-toluensulfonic acid monohydrate (25.978 g, 133.8 mmoles). Monitor reaction by TLC, then cool to 20-25° C. Filter the slurry and rinse the filter cake with 3 volumes of toluene (105 mL). Dry to a constant weight in a vacuum dryer at 50° C. to give the title compound (36.14 g, 99.2%).

¹H NMR (DMSO): δ=7.472 ppm (dt, 8.2 Hz, 1.9Hz, 2H); 7.112 ppm (m, 2H); 3.472 ppm (t, 7.0 Hz, 2H); 2.303 ppm (m, 5H); 2.012 ppm (m, 2H). MS: ES+=179; 157. ES−=171. Exact: 272.08.

Step 3b and 3c: Preparation of Intermediates 1-[(6-methyl-pyridin-2-yl)-2-(6-cyano-quinolin-4-yl) -ethylideneamino]-pyrrolidin-2-one and 3-(6-cyano-quinolin-4-yl)-2-(6-methyl-pyridin-2-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Into a 3-neck, 1 L flask equipped with mechanical stirring, a Dean-Stark condenser, thermocouple and N₂purge charge 2-(6-cyano-quinolin-4-yl)-1-(6-methyl-pyridin-2-yl) -ethanone (25 g, 1 equiv), 1-(amino)-2-pyrrolidinone, p-toluene sulfonate (27.3 g, 1 equiv), dimethylformamide (DMF) (150 mL, 6 vol), toluene (250 mL, 10 vol) and 2,6-lutidine (26 mL, 1 vol). Heat the mixture to reflux and periodically remove water from the trap. Monitor the reaction by HPLC or TLC analysis (5% MeOH/methylene chloride, silica). After 4 hours, most of the ketone is converted into 1-[(6-methyl-pyridin-2-yl)-2-(6-cyano-quinolin-4-yl)-ethylideneamino]-pyrrolidin-2-one as indicated by TLC.

Cool the reaction mixture to 50 to 55° C. and charge potassium carbonate (K₂CO₃) (20.42 g, 1.66 equiv) into the reaction mixture over a couple of minutes and heat the reaction mixture back up to reflux. Continue to remove the water collected in the trap and monitor the reaction by HPLC for the disappearance of hydrazone. After completion of reaction distill off most of the toluene (total distillate is 350 mL) until the reaction mixture reaches a temperature of 145° C. Cool the reaction mixture to ˜30° C. and dilute with water (450 mL) and stir for 1.5 hours at room temperature (RT). Filter the formed product by filtration and rinse the cake with water 200 mL. After 1 hour under vacuum, and then dried in a vacuum oven at 70° C. to a consistent weight. The dried solid weighed 28.5 g, 93.2% yield and the purity by HPLC is 97%. The product is used as is in the next step.

¹H NMR (CDCl₃): δ=9.018 ppm (d, 4.5 Hz, 1H); 8.233 ppm (d, 8.7 Hz, 1H); 8.198 ppm (dd, 0.5 Hz, 1.8 Hz, 1H); 7.808 ppm (dd, 1.8 Hz, 8.8 Hz, 1H); 7.483-7.444 ppm (m, 2H); 7.380 ppm (d, 7.9 Hz, 1H); 6.936 ppm (d, 7.6 Hz, 1H); 4.422 ppm (t, 7.2 Hz, 2H); 2.970-2897 ppm (m, 2H); 2.776 ppm (p, 7.2 Hz, 2H); 2.065 ppm (s, 3H). MS ES+: 352.4 Exact: 351.15.

Step 4: Preparation of 2-(6-methyl-pyridin-2-yl)-3-(6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, monohydrate

Slurry 3-(6-cyano-quinolin-4-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole (25.515 kg) and potassium carbonate (0.2 eq.) in 6 volumes of dimethyl sulfoxide (DMSO). Add dilute hydrogen peroxide solution [35% hydrogen peroxide (1.25 eq.) to 0.5 volumes of purified water] to the slurry over 2-3.3 hours while maintaining the temperature between 20-38° C. Monitor the reaction by HPLC (1 hour). Add sodium sulfite (0.6 eq.) to 9.1 volumes of purified water. Add the product slurry to dilute sodium sulfite solution [sodium sulfite (0.6 eq.) in 9.1 volumes of purified water] while maintaining a temperature of 20-39° C., stir this slurry for 1-2 hours to ensure all remaining hydrogen peroxide is completely neutralized. Check for peroxide. Add 1.08 vol. of 32.1% HCl Food Grade to this slurry and stir for 20-30 min. Add activated charcoal (10% by wt.) to the solution and stir for 20-40 minutes. Filter the crude product (mostly monohydrate), rinsing the cake with purified water. Add 1.05 vol. of methanol to the filtrate. Add 5.5 vol. of 2N sodium hydroxide to the filtrate while maintaining a temperature of 20-30° C. Stir the slurry for 20-30 min. Ensure pH is >8.

Filter the slurry, and rinse the cake with purified water. Suspend the wet cake in 28 vol. of a 75%/25% acetone/purified water solution. Heat this slurry to reflux (60° C.) and stir for 30-45 minutes after the product dissolves. Filter the product solution. Start the distillation, and add milled seed when the pot temperature reaches 63° C. Continue distilling until the distillate volume is 50% of the initial volume. Cool the slurry to 20-25° C. over 90 minutes. Then cool the slurry to 0-5° C. over 30-40 minutes. Stir for 2-3 hours at 0-5° C. Filter the slurry and rinse the product cake on the filter with purified water. Dry the product under vacuum at 45° C. to furnish the title compound (25.4 kg, 90%). Water content by Karl Fischer of 4.6% in monohydrate. Theory: 4.65%.

¹H NMR (CDCl₃): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16.

Alternatively, the monohydrate of the present invention can be prepared by recrystallization of 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole.

EXAMPLE 2 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole monohydrate

Suspend 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole in 28 vol. of a 75%/25% acetone/purified water solution. Heat this slurry to reflux (60° C.) and stir for 30-45 minutes after the product dissolves. Filter the product solution. Start the distillation, and add milled seed when the pot temperature reaches 63° C. Continue distilling until the distillate volume is 50% of the initial volume. Cool the slurry to 20-25° C. over 90 minutes. Then cool the slurry to 0-5° C. over 30-40 minutes. Stir for 2-3 hours at 0-5° C. Filter the slurry and rinse the product cake on the filter with purified water. Dry the product under vacuum at 45° C. to furnish the title compound. The reaction yield is >80%. Product purity is >98% with low total related substances.

Alternatively, the monohydrate of the present invention can be prepared by reslurrying of 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole.

EXAMPLE 3 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole monohydrate

Prepare 2-(6-Methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate by stirring the compound or active pharmaceutical ingredient (API) in 10 volumes of water at room temperature for 1-2 hours, filtering, and drying at 45° C. under vacuum.

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.

WO2002094833A1	13 May 2002	28 Nov 2002	Eli Lilly And Company	Novel pyrrole derivatives as pharmaceutical agents
WO2004048382A1	10 Nov 2003	10 Jun 2004	Eli Lilly And Company	Quinolinyl-pyrrolopyrazoles
WO2004048383A1	12 Nov 2003	10 Jun 2004	Eli Lilly And Company	Mixed lineage kinase modulators

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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.

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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

Oliceridine

May 4, 2016 10:45 am / Leave a comment

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

Elpamotide

May 3, 2016 11:44 am / Leave a comment

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

Boldenone Undecylenate

May 3, 2016 11:43 am / Leave a comment

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

Cebranopadol hemicitrate, セブラノパドール

May 2, 2016 2:03 pm / Leave a comment

Cebranopadol hemicitrate, GRT-6005

Grünenthal GmbH innovator

SYNTHESIS COMING WATCH OUT………. Glitter Glitter Glitter Glitter

A mu-opioid agonist for treatment of neuropathic pain and pain due to osteoarthritis.

CAS No.863513-92-2(Cebranopadol Hemicitrate)

CAS 863513-91-1(FREE FORM)

Spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-, trans

MF C₂₄ H₂₇ F N₂ O, MW, 378.48

Spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine, 6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-, (1α,4β)-

Cebranopadol (GRT-6005) is a novel opioid analgesic of the benzenoid class which is currently under development internationally by Grünenthal, a German pharmaceutical company, and its partner Depomed, a pharmaceutical company in the United States, for the treatment of a variety of different acute and chronic pain states.^[1]^[2]^[3] As of November 2014, it is in phase III clinical trials. Cebranopadol is unique in its mechanism of action as an opioid, binding to and activating all four of the opioid receptors; it acts as afull agonist of the nociceptin receptor (K_i = 0.9 nM; EC₅₀ = 13.0; IA = 89%), μ-opioid receptor (K_i = 0.7 nM; EC₅₀ = 1.2; IA = 104%), and δ-opioid receptor (K_i = 18 nM; EC₅₀ = 110; IA = 105%), and as a partial agonist of the κ-opioid receptor (K_i = 2.6 nM; EC₅₀ = 17; IA = 67%).^[1] The ED50 values of 0.5-5.6 µg/kg when introduced IV & 25.1 µg/kg after oral administration.^[4]

Cebranopadol shows highly potent and effective antinociceptive and antihypertensive effects in a variety of different animal modelsof pain.^[1] Notably, it has also been found to be more potent in models of chronic neuropathic pain than acute nociceptive paincompared to selective μ-opioid receptor agonists.^[1] Relative to morphine, tolerance to the analgesic effects of cebranopadol has been found to be delayed (26 days versus 11 days for complete tolerance).^[1] In addition, unlike morphine, cebranopadol has not been found to affect motor coordination or reduce respiration in animals at doses in or over the dosage range for analgesia.^[1] As such, it may have improved and prolonged efficaciousness and greater tolerability in comparison to currently available opioid analgesics.^[1]

As an agonist of the κ-opioid receptor, cebranopadol may have the capacity to produce psychotomimetic effects and other adverse reactions at sufficiently high doses, a property which could potentially limit its practical clinical dosage range.^[5]

Cebranopadol (trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine) is a novel analgesic nociceptin/orphanin FQ peptide (NOP) and opioid receptor agonist [K_i (nM)/EC₅₀(nM)/relative efficacy (%): human NOP receptor 0.9/13.0/89; human mu-opioid peptide (MOP) receptor 0.7/1.2/104; human kappa-opioid peptide receptor 2.6/17/67; human delta-opioid peptide receptor 18/110/105]. Cebranopadol exhibits highly potent and efficacious antinociceptive and antihypersensitive effects in several rat models of acute and chronic pain (tail-flick, rheumatoid arthritis, bone cancer, spinal nerve ligation, diabetic neuropathy) with ED₅₀ values of 0.5−5.6 µg/kg after intravenous and 25.1 µg/kg after oral administration. In comparison with selective MOP receptor agonists, cebranopadol was more potent in models of chronic neuropathic than acute nociceptive pain. Cebranopadol’s duration of action is long (up to 7 hours after intravenous 12 µg/kg; >9 hours after oral 55 µg/kg in the rat tail-flick test). The antihypersensitive activity of cebranopadol in the spinal nerve ligation model was partially reversed by pretreatment with the selective NOP receptor antagonist J-113397[1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one] or the opioid receptor antagonist naloxone, indicating that both NOP and opioid receptor agonism are involved in this activity. Development of analgesic tolerance in the chronic constriction injury model was clearly delayed compared with that from an equianalgesic dose of morphine (complete tolerance on day 26 versus day 11, respectively). Unlike morphine, cebranopadol did not disrupt motor coordination and respiration at doses within and exceeding the analgesic dose range. Cebranopadol, by its combination of agonism at NOP and opioid receptors, affords highly potent and efficacious analgesia in various pain models with a favorable side effect profile.

Almost 20 years ago, a new member of the opioid receptor family and its endogenous agonist were described (Meunier et al., 1995; Reinscheid et al., 1995). Because of its partial homology to the opioid receptors [mu-opioid peptide (MOP) receptor, delta-opioid peptide (DOP) receptor, kappa-opioid peptide (KOP) receptor] and its insensitivity to the prototypical opioid agonist and antagonist ligands morphine and naloxone, this receptor was initially termed opioid receptor-like receptor, ORL1. Subsequently, it was renamed the nociceptin/orphanin FQ peptide (NOP) receptor after its endogenous ligand nociceptin, and it is now considered to be a non-opioid member of the opioid receptor family (Cox et al., 2009). At a cellular level, the actions of the NOP receptor are broadly similar to those of the opioid receptors (Chiou et al., 2007; Lambert, 2008). Although NOP receptors are clearly expressed at all levels of the pain pathways, it is thought that NOP and MOP receptors are not colocalized in the same neurons and may, thus, have independent actions in at least partly distinct neuronal networks (Monteillet-Agius et al., 1998).

The role of the NOP receptor in pain and analgesia has remained unclear for some time owing to inconsistent findings in early reports using nociceptin to activate the receptor. Being a peptide, nociceptin was administered locally into the central nervous system (CNS) where it produced both pronociceptive and antinociceptive effects when administered supraspinally (Meunier et al., 1995; Calo and Guerrini, 2013). Remarkably, when administered into the spinal cord of rodents and nonhuman primates, nociceptin consistently produced antinociceptive effects (Ko et al., 2009; Sukhtankar and Ko, 2013). Subsequent studies of systemic administration of nonpeptide NOP receptor agonists revealed that such compounds were effective analgesics in animal pain models. Although evidence for antinociceptive and antihyperalgesic effects in rodents is limited and inconsistent (Jenck et al., 2000; Reiss et al., 2008), Ko et al. (2009) demonstrated impressive antinociceptive and antiallodynic potency and efficacy using the NOP receptor agonist Ro64-6198 in Rhesus monkeys. Potency and efficacy were comparable with those of alfentanil but with a complete absence of alfentanil-associated side effects such as itching/scratching and respiratory depression and no evidence of reinforcing effects (Ko et al., 2009; Podlesnik et al., 2011).

Currently, strong MOP receptor agonists are the most effective drugs for the treatment of moderate to severe acute and chronic pain. However, although these drugs provide potent analgesia, they also carry the risk of severe side effects such as respiratory depression, nausea, vomiting, and constipation, and their use may lead to physical dependence and tolerance (Zöllner and Stein, 2007). In addition, opioids are considered to have limited efficacy in treating chronic nociceptive and neuopathic pain owing to a reduction in the already low therapeutic index (Rosenblum et al., 2008; Labianca et al., 2012). For these reasons, there is an unmet medical need for potent and well-tolerated analgesics for the treatment of moderate to severe chronic nociceptive and neuropathic pain.

As NOP and opioid receptor agonists modulate pain and nociception via distinct yet related targets, combining both mechanisms may constitute an interesting and novel approach for the development of innovative analgesics. Notably, a supra-additive interaction between intrathecal morphine and intrathecal nociceptin has been described in rodents (Courteix et al., 2004), as well as an enhancement of the antinociceptive effect of systemic morphine by systemic administration of Ro64-6198 (Reiss et al., 2008). Furthermore, a synergistic effect of concurrent NOP and MOP receptor activation without significant side effects has been demonstrated in nonhuman primates after systemic administration (Cremeans et al., 2012). At the same time, activation of NOP receptors has been proposed to counteract supraspinal opioid activity; in animal studies, NOP receptor agonists do not generate typical opioid-like side effects and may even ameliorate opioid-related side effects when administered concurrently with an opioid agonist (Ko et al., 2009; Rutten et al., 2010; Toll, 2013). Thus, a combination of NOP and opioid receptor activation may be particularly suited to provide potent analgesia with reduced opioid-like side effects.

To explore the potential benefits of NOP and opioid receptor coactivation, novel compounds acting as agonists on both NOP and opioid receptors have been designed (Molinari et al., 2013; Zaveri et al., 2013). This article describes the preclinical pharmacology of cebranopadol, a potent NOP and opioid receptor agonist derived from a novel chemical series of spiro[cyclohexane-dihydropyrano[3,4-b]indol]-amines (S. Schunk, K. Linz, C. Hinze, S. Frormann, S. Oberbörsch, B. Sundermann, S. Zemolka, W. Englberger, T. Germann, T. Christoph, B.Y. Kögel, W. Schröder, S. Harlfinger, D. Saunders, A. Kless, H. Schick, and H. Sonnenschein, submitted manuscript) that was developed by Grünenthal (Aachen, Germany) and is currently in clinical development for the treatment of severe chronic pain……..http://jpet.aspetjournals.org/content/349/3/535.full

WO 2013170968

WO 2013170966

WO 2013170971

WO 2013170972

WO 2013170970

WO 2013170969

WO 2013170967

WO 2004043967

US 20130150590

PAPER

ACS Medicinal Chemistry Letters (2014), 5(8), 857-862.

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

^†Departments of Medicinal Chemistry, ^‡Preclinical Drug Safety, ^§Molecular Pharmacology, ^∥Pain Pharmacology,^⊥Pharmacokinetics, and ^#Discovery Informatics, Global Drug Discovery, Grünenthal Innovation, Grünenthal GmbH, D-52099 Aachen, Germany

^○ ASCA GmbH Angewandte Synthesechemie Adlershof, Magnusstr. 11, 12489 Berlin, Germany

ACS Med. Chem. Lett., 2014, 5 (8), pp 857–862

DOI: 10.1021/ml500117c

Publication Date (Web): June 24, 2014

*(S.S.) E-mail: stefan.schunk@grunenthal.com.

Abstract

In a previous communication, our efforts leading from 1 to the identification of spiro[cyclohexane-dihydropyrano[3,4-b]indole]-amine 2a as analgesic NOP and opioid receptor agonist were disclosed and their favorable in vitro and in vivo pharmacological properties revealed. We herein report our efforts to further optimize lead 2a, toward trans-6′-fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3′H)-pyrano[3,4-b]indol]-4-amine (cebranopadol, 3a), which is currently in clinical development for the treatment of severe chronic nociceptive and neuropathic pain.

http://pubs.acs.org/doi/abs/10.1021/ml500117c?source=chemport&journalCode=amclct

MP 258-282 DEG CENT

October the family Grünenthal GmbH celebrated its longtime employee in Aachen-Eilendorf. Proud 680 years of service …

PATENT

http://www.google.com/patents/US7547707

Example 24 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added to the reaction mixture and the mixture was stirred for 30 min. The organic phase was separated, and the aqueous phase which remained was extracted with MC (3×60 ml). The combined organic phases were washed with water (2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added to the solid residue obtained after the solvent had been distilled off, and the mixture was heated, and stirred for 15 hours. The solid contained in the suspension was filtered off with suction and dried. 955 mg of the more non-polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole were obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hot ethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2 mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystals precipitated out at the boiling point. After cooling to approx. 5° C., the mixture was left to stand for 2 h. The solid formed was filtered off with suction. 640 mg of the hemicitrate were obtained as a white solid (m.p. 258-282° C.).

Example 25 1,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole hemicitrate, More Polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and 2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1 mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture was stirred at RT for 16 h. For working up, the mixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC (3×20 ml). The combined organic phases were dried with sodium sulfate and evaporated. The residue (364 mg of white solid) was suspended in hot ethanol (20 ml), and a similarly hot solution of citric acid (185 mg, 0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolved completely and no longer precipitated out even on cooling to approx. 5° C. Ethanol was removed on a rotary evaporator and the hemicitrate of the more polar diastereoisomer of 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole was obtained in this way in a yield of 548 mg as a white solid (m.p. 148-155° C.).

24	hemicitrate	more non-polar diastereomer

25	hemicitrate	more polar diastereomer

PATENT

WO 2013113690

(1 r,4r)-6′-fluoro-N,N- dimethyl-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1 ,1 ‘-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):

http://www.google.com/patents/WO2013113690A1?cl=en

PATENT

http://www.google.com/patents/WO2008040481A1?cl=en

see A4

PATENT

http://www.google.com/patents/US20130231381

One particular drug that is of great interest for use in treating cancer pain (and other acute, visceral, neuropathic and chronic pain pain disorders) is (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine. This drug is depicted below as the compound of formula (I).

The solid forms of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4b]indol]-4-amine that are known so far are not satisfactory in every respect and there is a demand for advantageous solid forms

A) Synthesis of Crystalline Form A100 mg (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine [crystalline form D according to D)] was suspended in 0.5 mL TBME. The suspension was stirred at RT for six days. The resulting solid was filtered out and dried in air. A crystalline solid of crystalline form A was obtained and characterized by FT Raman, TG-FTIR and PXRD.

……………………

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

http://pubs.acs.org/doi/full/10.1021/ml500117c

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/ml500117c

synthesis…………http://pubs.acs.org/doi/suppl/10.1021/ml500117c/suppl_file/ml500117c_si_001.pdf

6′-Fluoro-4′,9′-dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane-1,1′(3’H)-pyrano[3,4-
b]indol]-4-amine, trans-, 2-hydroxy-1,2,3-propanetricarboxylate (2:1)

hemicitrate were obtained as a white solid (mp 258-282 °C).1H-NMR (300 MHz; DMSO-d6): 1.75-1.87 (m, 4 H); 2.14 (s, 6 H); 2.27 (t, 2 H); 2.61-
2.76 (m,6 H); 3.88 (t, 2 H); 6.86 (dt, 1 H); 7.10 (dd, 1 H); 7.30-7.43 (m, 6 H); 10.91 (br
s, 1 H).

13C-NMR (75.47 MHz; DMSO-d6): 22.1; 27.6; 30.2 (2 C); 38.0 (2 C); 43.1; 58.8 (2 C,
overlap); 71.5; 72.2; 102.3 (2JC,F = 23 Hz); 105.6 (3JC,F = 4 Hz); 108.3 (2JC,F = 26 Hz);

112.0 (3JC,F = 10 Hz); 126.5; 126.6; 126.7 (2 C); 127.4 (2 C); 132.4; 138.7; 141.5;
156,7 (1JC,F = 231 Hz); 171.3 (2 C), 175.3.HPLC-MS: m/z 378.9 [M + H]+

PATENTS

US20120034297 *	Aug 4, 2011	Feb 9, 2012	Gruenenthal Gmbh	Pharmaceutical dosage forms comprising 6′-fluoro-(N-methyl- or N,N-dimethyl-)-4-phenyl-4′,9′-dihydro-3’H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine
US20130012563 *	Jul 6, 2012	Jan 10, 2013	Gruenenthal Gmbh	Crystalline (1r,4r)-6′-fluoro-n,n-dimethyl-4-phenyl-4′,9′-dihydro-3’h-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine

WO2004043967A1	Nov 5, 2003	May 27, 2004	Otto Aulenbacher	Spirocyclic cyclohexane derivatives
WO2008040481A1	Sep 26, 2007	Apr 10, 2008	Gruenenthal Gmbh	MIXED ORL 1/μ AGONISTS FOR TREATING PAIN

References

Linz K, Christoph T, Tzschentke TM; et al. (June 2014). “Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist”. J. Pharmacol. Exp. Ther. 349 (3): 535–48. doi:10.1124/jpet.114.213694.PMID 24713140.
Schunk S, Linz K, Hinze C; et al. (August 2014). “Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol”. ACS Med Chem Lett 5 (8): 857–62.doi:10.1021/ml500117c. PMID 25147603.
Lambert DG, Bird MF, Rowbotham DJ (September 2014). “Cebranopadol: a first in-class example of a nociceptin/orphanin FQ receptor and opioid receptor agonist”. Br J Anaesth114: 364–6. doi:10.1093/bja/aeu332. PMID 25248647.
Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. Journal of Pharmacol Exp Ther. 2014 Jun;349(3):535-48. doi: 10.1124/jpet.114.213694
Pfeiffer A, Brantl V, Herz A, Emrich HM (August 1986). “Psychotomimesis mediated by kappa opiate receptors”. Science 233 (4765): 774–6. doi:10.1126/science.3016896.PMID 3016896.
Expert Opinion on Investigational Drugs (2015), 24(6), 837-844
Journal of Pharmacology and Experimental Therapeutics (2014), 349(3), 535-548,
External links
- About Cebranopadol – Oceanic Program
- Cebranopadol Search Results – ClinicalTrials.gov

Cebranopadol
Systematic (IUPAC) name

(1r,4r)-6’-fluoro-N,N-dimethyl-4-phenyl-4’,9’-dihydro-3’H-spiro[cyclohexane-1,1’-pyrano[3,4-b]indol]-4-amine
Pharmacokinetic data
Biological half-life	~4.5 hours
Identifiers
CAS Number	863513-91-1
ATC code	None
PubChem	CID 11848225
ChemSpider	29398942
Chemical data
Formula	C₂₄H₂₇FN₂O
Molar mass	378.482 g/mol

////Cebranopadol hemicitrate, GRT-6005, Cebranopadol, セブラノパドール

CN([C@]1(CC[C@]2(OCCc3c2[nH]c4c3cc(cc4)F)CC1)c5ccccc5)C

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

PAPER

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

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WO 2012129495

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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

Elpamotide , credit kegg

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Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

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PATENT

Discovery of a Potent Analgesic NOP and Opioid Receptor Agonist: Cebranopadol

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