What was the drug in Clinical Trial Tragedy In France Jan 2016

BIA 10-2474
cas 1233855-46-3
3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide
1H-​Imidazole-​1-​carboxamide, N-​cyclohexyl-​N-​methyl-​4-​(1-​oxido-​3-​pyridinyl)​-
C₁₆ H₂₀ N₄ O_2, 300.36

Bial-Portela & Ca. S.A.

BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor^[1] developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. The drug was developed to relieve pain,^[2][3] to ease mood and anxiety problems, and to improve movement coordination linked to neurodegenerative illnesses.^[4] It interacts with the human endocannabinoid system.^[5][6] It has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.^[7]

 Synthesis

 WO 2014017938

BIAL – PORTELA & Cª, S.A.
Example 5. 3-(l-(cyclohexyl(methyl)carbamoyl-lfl-imidazol-4-yl)pyridine l-oxide (compound A)

C₁₆H₂₀N₄O                                 C16H20N4O2
MW 284,36                                              MW 300,36
To a solution of N-cyclohexyl-N-methyl-4-(pyridm-3-yl)-lH-imidazole-l-carboxamide in dichioromethane at 25°C was added peracetic acid (38%; the concentration is not critical, and may be varied) in a single portion. The reaction mixture was then maintained at 25°C for at least 20 h, whereupon the reaction was washed four times with water (in some embodiments, the water for the extraction step may be supplemented with a small amount (e.g. 1%) of acetic acid, which helps to promote product solubility in the DCM). The dichioromethane solution was then filtered prior to diluting with 2-propanol. Dichioromethane (50%) was then distilled off under atmospheric pressure, whereupon, 2-propanol was charged at the same rate as the distillate was collected. The distillation was continued until >90% of the dichioromethane was collected. The resulting suspension was then cooled to 20°C and aged for at least 30 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently >80% in several production runs.

PATENT

WO 2012015324
Example 1. Preparation of N-cyclohexyl-N-methyl-4-(pyridin-3yl)-lH-imidazole-l-carboxamide

C₈H₇N₃ C₁₅H_{1 1}N₃0₂ C₁₆H₂₀N₄O
MW 145,16 MW 265,27 MW 284,36
To a suspension of 3-(l/ -imidazol-4-yl)pyridine in tetrahydrofuran (THF) containing pyridine at 25°C was slowly added a solution of phenyl chloroformate in THF over 60 to 90 min. The resulting fine white suspension was then maintained at 25°C for at least 60 min. before the addition of N-methyl- -cyclohexylamine in a single portion, causing the suspension to thin and become yellow in colour. The reaction mixture was then stirred for 90 min. before filtering and washing the filter cake with additional THF. The mother liquors were then maintained at 25°C for at least 18 h, whereupon 65% of the volume of THF was distilled off under atmospheric pressure. The resulting solution was then diluted with 2-propanol and maintained at > 50°C for 10 min. prior to cooling down to 20°C. The resulting suspension was aged at 20°C for 15 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product was washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently around 50% in several production runs.
Example 2. 3-(l-(cyclohexyl(methyl)carbamoyl-l//-imidazol-4-yl)pyridine 1 -oxide (compound A)

C₁₆H₂₀N₄O Ci6H2oN₄0₂
MW 284,36 MW 300,36
To a solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-lH-imidazole-l-carboxamide in dichloromethane at 25°C was added peracetic acid (38%; the concentration is not critical, and may be varied) in a single portion. The reaction mixture was then maintained at 25°C for at least 20 h, whereupon the reaction was washed four times with water. The dichloromethane solution was then filtered prior to diluting with 2-propanol. Dichloromethane (50%) was then distilled off under atmospheric pressure, whereupon, 2-propanol was charged at the same rate as the distillate was collected. The distillation was continued until >90% of the dichloromethane was collected. The resulting suspension was then cooled to 20°C and aged for at least 30 min. prior to cooling to 0°C and aging for a further 60 min. The reaction mixture was then filtered and the product washed with additional 2-propanol, before drying at 50°C under vacuum to afford the title compound as an off-white crystalline solid.
The purity of the product was ascertained by HPLC, with identity confirmable by NMR. The yield was consistently >80% in several production runs. It will be appreciated that this gives an overall yield of compound A many times greater than that achieved in the prior art.
In a further run of this synthesis, in a 2L reactor to a mixture of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-l H- imidazole-l-carboxamide (90 g, 317 mmol) and dichloromethane (1350 ml) was added peracetic acid (84 ml, 475 mmol). The reaction mixture was stirred at 25°C. Completion of the reaction was monitored by HPLC for the disappearance of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-lH- imidazole- 1-carboxamide. After reaction completion a solution of sodium metabisulfite (60.2 g, 317 mmol) in water (270ml) was added to the reaction mixture maintaining the temperature below 30°C. After phase separation the organic phase was washed with water. After phase separation the organic phase was concentrated at atmospheric pressure until 5 vol. Then solvent was swapped to isopropanol (1350 ml) and the suspension was cooled to 0°C during 4 hours and stirred at that temperature for 1 hour. The resulting solid was collected by filtration and was rinsed with water (270 ml) and isopropanol (270 ml) to afford a white crystalline solid in 84.8g (89%).
PATENT
WO 2010074588
Preparation of compound 362 a) N-cyclohexyl-N-methyl-4-(pyridin-3-yl)- 1 H-imidazole- 1 -carboxamide

To a stirred suspension of 3-( 1 H-imidazol-4-yl)pyridine dihydrochloride (1.745 g, 8 mmol) in a mixture of tetrahydrofuran (29 mL) and DMF (2.90 mL) was added potassium 2-methylpropan-2-olate (1.795 g, 16.0 mmol) and the mixture was refluxed for 30 minutes. The resulting brown suspension was cooled to room temperature and treated with pyridine (0.979 mL, 12 mmol) and N,N-dimethylpyridin-4-amine (0.098 g, 0.8 mmol), followed by the addition of cyclohexyl(methyl)carbamic chloride (1.476 g, 8.4 mmol). The reaction was heated to 90 ⁰C overnight, whereupon the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried (MgSO^) and filtered. After evaporation, the crude product was chromatographed over silica gel using a dichloromethane/methanol (9:1) mixture. Homogenous fractions were pooled and evaporated to leave a white powder, (160 mg, 7 %).
b) 3-( 1 -(cyclohexyl(methyl)carbamoyl)- 1 H-imidazol-4-yl)pyridine 1 -oxide

To a stirred solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-l H-imidazole- 1 -carboxamide (90 mg, 0.317 mmol) in chloroform (5 mL) was added 3-chlorobenzoρeroxoic acid (149 mg, 0.475 mmol) in one portion. The reaction was allowed to stir at room temperature for 20 h. TLC showed the reaction to be complete and the mixture was evaporated to dryness. The residue was triturated with ether and the resulting white crystals were filtered off and dried in air. Recrystallisation from hot isopropanol gave a white powder (46 mg, 46 %).

Structure and action

French newspaper Le Figaro has obtained Bial study protocol documents listing the the chemical name of BIA-10-2474 as 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.^[8] A Bial news release described BIA-10-2474 as “a long-acting inhibitor of FAAH”.^[9]
Fatty acid amide hydrolase (FAAH) is an enzyme which degrades endocannabinoid neurotransmitters like anandamide,^[10] which relieves pain and can affect eating and sleep patterns.^[11][12] FAAH inhibitors have been proposed for a range of nervous-system disorders including anxiety, alcoholism, pain and nausea.
The Portuguese pharmaceutical company Bial holds several patents on FAAH enzyme inhibitors.^{[12][13][14][15]}
No details of the preclinical testing of this molecule have been made public by the manufacturer Bial. However, the French newspaper Le Figaro has obtained and published an apparently legitimate copy of the full clinical trial protocol (BIA-102474-101).^[8] The protocol presents a summary of what appears to be a full package of pharmacodynamic, pharmacokinetic and toxicological studies that might be expected to support a first-in-man study, including safety pharmacology studies in two species (rat, dog) and repeated dose toxicity studies in four species (13 week sub-chronic studies in mouse, rat, dog and monkey). The summary presented however includes no assessment of the relevance of the animal species selected for study (that is, in terms of physiological and genetic similarities with humans and the mechanism of action of the study drug).
Of note, few adverse events were observed in any of the studies, with the 13-week oral No Observed Adverse Effect Level (NOAEL) varying between 10 mg/kg/day in mice to 75 mg/kg/day in monkeys. The authors suggest that these were the maximum doses tested in these studies, though it is not clear. The authors also report no effects of significance in the animal models used for the CNS safety pharmacology studies, which studied a dose of up to 300 mg/kg/day.^[8]
Notably absent from the protocol are calculations of receptor occupancy; predictions of in vivo ligand binding saturation levels; measures of target affinity; or assessment of the molecule’s activity in non-target tissues or non-target binding interactions as suggested by the European guidance for Phase I studies,^[16] assuming BIA 10-2474 could be considered ‘high risk’).^[8]
The trial protocol makes no reference to chimpanzee studies (only monkeys) which contradicts a previous statement to the media in which the French Health Minister stated that the drug had been tested on animals including chimpanzees.^{[4][17] [18]} Some experts had remarked that drug testing in chimpanzees was unlikely.^[19]
These findings provide no explanation for the type and severity of events observed in Rennes. In describing the rationale for the starting dose, the authors conclude that:

No target organ was identified during toxicology studies and few adverse clinical findings were observed at the highest dose tested. For the single ascending dose part [of the clinical trial], a starting dose of 0.25 mg was judged to be safe for a first-in-human administration. [8]

The protocol defines no starting dose for the multi-dose treatment groups, noting that this will be based on the outcome of the single dose portion of the trial (an approach known as adaptive trial design). The authors note that nonetheless, the starting dose will not exceed 33% of the maximum tolerated dose (MTD) identified in the single dose groups (or 33% of the maximum administered dose if the MTD is not reached).^[8]

Death and serious adverse events during phase I clinical trial

In July 2015 Biotrial, a contract research organization, began testing the drug in a human phase one clinical trial for the manufacturer. The study was approved by French regulatory authority, the Agence Nationale de Sécurité du Médicament (ANSM), on June 26, 2015, and by the Brest regional ethics committee on July 3, 2015.^[20] The trial commenced on July 9, 2015,^[21] in the city of Rennes, and recruited 128 healthy volunteers, both men and women aged 18 to 55. According to French authorities, the study employed a three-stage design with 90 of the volunteers having received the drug during the first two stages of the trial, with no serious adverse events being reported .^[17][20] Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial’s facility for two weeks during which time they would take the drug for ten days and undergo tests.^[22]
In the third stage of the trial evaluating multiple doses, six male volunteers received doses by mouth, starting on 7 January 2016. The first volunteer was hospitalized at the Rennes University Hospital on January 10, became brain dead,^{[17][23][24][25]} and died on January 17.^[26] The other five men in the same dosage group were also hospitalized, in the period of January 10 through January 13^[27] four of them suffering injuries including deep hemorrhagic and necrotic lesions seen on brain MRI.^[7] The six men who were hospitalised were the group which received the highest dose.^[26] A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms “already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap” and were being given corticosteroids to control the inflammation.^[27] The sixth man from the group was not showing adverse effects but had been hospitalized for observation.^[25][28][29] Biotrial stopped the experiment on January 11, 2016.^[4]
No details of the trial have been made public by the manufacturer Bial. The study does not appear in searches of any of the key clinical trial registries, including EudraCT and ClinicalTrials.gov which would normally contain details of approved clinical studies.^{[30][31][32][33]} The trial protocol published by Le Figaro provides extensive detail on what was planned for the study, but many details of the key multi-dose part are not included and were to have been finalised at the conclusion of the single-dose part of the trial.^[8]
The French health minister Marisol Touraine called the event “an accident of exceptional gravity” and promised to investigate the matter.^[4] On January 18 it was reported authorities were investigating if a manufacturing or transport error might be involved.^[34]

Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source.

According to the document, BIA 10-2474 is 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.

BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.”

The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.

Six men in a Phase I clinical trial were admitted to the University Hospital Center of Rennes, France, (shown here) because of adverse reactions.Six men in a Phase I clinical trial were admitted to the University Hospital Center of Rennes, France, (shown here) because of adverse reactions.

Credit: Mathieu Pattier/SIPA/Newscom

One man is dead and five men were hospitalized after participating in a Phase I clinical trial in Rennes, France

The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ⁹-tetrahydrocannabinol, the major psychoactive component of marijuana.

Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes.

The most severely affected man was pronounced brain-dead after hospitalization and then died on Jan. 17. Four men remain in the hospital in stable condition. The only man in the high-dose group who had no adverse symptoms has been released from the hospital.
Clinical trials are an essential part of the drug development process. In order to get life-improving and life-saving medicines to patients, they first have to go through an extensive series of tests. Even before a drug makes it to Phase 1 testing, where its safety, dosage amount, and side effects are tested in a small group of humans, it will undergo testing in animals. As a result, it is not common for a medicine undergoing clinical tests to have a very serious adverse effect on a human. This makes you wonder what happened to a group of patients involved in a clinical study in Rennes, France.
According to news reports, a drug undergoing testing in a French clinic has left one person dead, two others with what may be permanent brain damage, and and two others critically ill. The drug has thus far been unnamed, but it appears to have been produced by the Portuguese company Bial. The French health minister has stated the drug acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. It did not contain cannabis or anything derived from it, as was originally reported. All six trial participants were administered the doses simultaneously.
The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. A message on the company’s website stated that they are working with health authorities to understand the cause of the accident, while extending thoughts to the patients and their families. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. Two scientists from the Nottingham Medical School who have worked with FAAH tried over the weekend to try and identify the drug by examining a list of drugs Bial currently has in its pipeline. They believe the culprit is one identified by the codename BIA 10-2474. That same codename appeared on a recruitment form that was given to a volunteer, which was published in a French newspaper. Little more is known about it, and there does not appear to be any entry for it in clinical trial registries.
The French health ministry is reporting the six patients were all in good health prior to taking the oral medicine, which was administered to 90 volunteers. The trial recruited 128 individuals, and the remaining participants received a placebo. Health minister Marisol Touraine, describing the situation as a very serious accident, noted the patients were taking part in a trial in Brittany, Rennes involving a medicine developed by a “European laboratory”, refusing to comment further until additional information became available. She has also asked the Inspector General of Social Affairs to lead an investigation into the circumstances around the trial, which has obviously been suspended. She notes the drug had been tested on animals, including chimpanzees. France’s National Agency for Medicine and Health Products Safety approved the trial on in June 2015.
One thing we do know is that the trial was a Phase 1 clinical study that included 90 healthy volunteers. Regulations that oversee all clinical trials in Europe do attempt to minimize the risk associated with trials, but there is always a risk involved with administering an unapproved medicine to humans. At this time the chief neuroscientist at the hospital where the patients are being treated has said there is no known antidote for the drug.
The drug, administered to men between the ages of 28 and 49, was intended to treat mood disorders such as anxiety. While the men were administered varying doses, the patients who are hospitalized were taking the drug “regularly”.

Old 2006 case

While safety issues like this are rare, they are not unheard of. In 2006, a clinical trial in London left six men ill. All were taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure. Two became critically ill, with one eventually losing all of his fingers and toes. All were told they would have a higher risk of developing cancers or auto-immune diseases.
This of course led many to wonder about the future of trials, and whether the situation could happen again. The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.
However, since patients can fall ill immediately after being administered a medication, certain risks will still exist.
The company that manufactured TGN1412, TeGenero Immuno Therapeutics, later went bankrupt. However the drug was later purchased by a Russian investor and renamed TABO8. TheraMAB, a Russian biotech company, then conducted a new trial of the drug in a much lower dose. A later Phase 2 study was started in patients with Rheumatoid Arthritis.

Other pharmaceutical companies, including Merck, Pfizer, Johnson & Johnson, Sanofi and Vernalis, have previously taken other FAAH inhibitors into clinical trials without experiencing such adverse events (e.g. respectively, MK-4409,^[35][36] PF-04457845, JNJ-42165279,^[37] SSR411298 and V158866.^[38][39] Related enzyme inhibitor compounds such as URB-597 and LY-2183240 have been sold illicitly as designer drugs,^[40][41] all without reports of this type of toxicity emerging, so the mechanism of the toxicity observed with BIA 10-2474 remains poorly understood.
Following the events in Rennes, Janssen announced that it was temporarily suspending dosing in two Phase II clinical trials with its own FAAH inhibitor JNJ-42165279, headlining the decision as “precautionary measure follows safety issue with different drug in class”. Janssen was emphatic that no serious adverse events had been reported in any of the clinical trials with JNJ-42165279 to date. The suspension is to remain in effect until more information is available about the BIA 10-2474 study.^[42]

References

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• 4 Adamson B (January 15, 2016). “Botched Drug Trial Leaves 1 Brain Dead, 5 in Hospital”. ABC, AP. Retrieved January 16, 2016.
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• 6 “France/Monde – Essai thérapeutique : 90 personnes ont pris la molécule”. Ledauphine.com. Retrieved 2016-01-17.
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• 17 “Accident grave dans le cadre d’un essai clinique – Intervention de Marisol Touraine à Rennes”. Ministère des Affaires Sociales, de la Santé et des Droits des Femmes, France. 15 January 2016.
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• Bisogno T, Maccarrone M. Latest advances in the discovery of fatty acid amide hydrolase inhibitors. Expert Opin Drug Discov. 2013 May;8(5):509-22. PMID 23488865 doi: 10.1517/17460441.2013.780021.
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• Shanks KG, Behonick GS, Dahn T, Terrell A. Identification of novel third-generation synthetic cannabinoids in products by ultra-performance liquid chromatography and time-of-flight mass spectrometry. J Anal Toxicol. 2013 Oct;37(8):517-25. PMID 23946450 doi: 10.1093/jat/bkt062.
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• Uchiyama N, Matsuda S, Kawamura M, Shimokawa Y, Kikura-Hanajiri R, Aritake K, Urade Y, Goda Y. Characterization of four new designer drugs, 5-chloro-NNEI, NNEI indazole analog, α-PHPP and α-POP, with 11 newly distributed designer drugs in illegal products. Forensic Sci Int. 2014 Oct;243:1-13. PMID 24769262 doi: 10.1016/j.forsciint.2014.03.013.
• 
  

42. “Janssen Research & Development, LLC Voluntarily Suspends Dosing in Phase 2 Clinical Trials of Experimental Treatment for Mood Disorders”. Janssen.com. 17 January 2016. Retrieved 21 January 2016.

External links

• Bial pipeline
• Urea compounds and their use as faah enzyme inhibitors – Patent
• Selection patent

WO2005073199A1 *	Jan 15, 2005	Aug 11, 2005	Aventis Pharma Gmbh	Indazole derivatives as inhibitors of hormone-sensitive lipases
WO2010074588A2	Dec 23, 2009	Jul 1, 2010	BIAL – PORTELA & Cª, S.A.	Pharmaceutical compounds
WO2012015324A1	Jul 28, 2011	Feb 2, 2012	Bial – Portela & Ca, S.A.	Process for the synthesis of substituted urea compounds
US4051252 *	Nov 24, 1975	Sep 27, 1977	Bayer Aktiengesellschaft	3-aminoindazole-1 and 2-carboxylic acid derivatives
US4331678 *	Jan 14, 1980	May 25, 1982	Fbc Limited	Carbamoyl pyrazole compounds and their pesticidal application
US4973588 *	Feb 10, 1989	Nov 27, 1990	Mitsui Petrochemical Industries, Ltd.	Imidazole derivatives having anti-hypoxia properties
US5578627 *	Oct 27, 1993	Nov 26, 1996	Toyama Chemical Co., Ltd.	1,2-benzoisoxazole derivative or its salt and brain-protecting agent comprising the same

BIA 10-2474

Systematic (IUPAC) name
3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide
Clinical data
Legal status	Investigational New Medicine
Routes of administration	Oral
Identifiers
PubChem	CID: 46831476
Chemical data
Formula	C16H20N4O2 Molecular mass 300.36 g·mol−1 SMILES O=C(N1C=C(C2=C[N+]([O-])=CC=C2)N=C1)N(C3CCCCC3)C

/////////
C1C(CCCC1)N(C)C(=O)n2cc(nc2)c3ccc[n+](c3)O

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cas 915296-00-3

innovator

Elotuzumab (brand name Empliciti, previously known as HuLuc63) is a humanized monoclonal antibody used in relapsed multiple myeloma.^[1] The package insert denotes its mechanism as a SLAMF7-directed (also known as CD 319) immunostimulatory antibody.^[2]

Approvals and indications

In May 2014, it was granted “Breakthrough Therapy” designation by the FDA. ^[3] On November 30, 2015, FDA approved elotuzumab as a treatment for patients with multiple myeloma who have received one to three prior medications.^[1] Elotuzumab was labeled for use with lenalidomide and dexamethasone. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen.^[2]

Elotuzumab is APPROVED for safety and efficacy in combination with lenalidomide and dexamethasone.
Monoclonal antibody therapy for multiple myeloma, a malignancy of plasma cells, was not very clinically efficacious until the development of cell surface glycoprotein CS1 targeting humanized immunoglobulin G1 monoclonal antibody – Elotuzumab. Elotuzumab is currently APPROVED in relapsed multiple myeloma.
Elotuzumab (HuLuc63) binds to CS1 antigens, highly expressed by multiple myeloma cells but minimally present on normal cells. The binding of elotuzumab to CS1 triggers antibody dependent cellular cytotoxicity in tumor cells expressing CS1. CS1 is a cell surface glycoprotein that belongs to the CD2 subset of immunoglobulin superfamily (IgSF). Preclinical studies showed that elotuzumab initiates cell lysis at high rates. The action of elotuzumab was found to be enhanced when multiple myeloma cells were pretreated with sub-therapeutic doses of lenalidomide and bortezomib. The impressive preclinical findings prompted investigation and analysis of elotuzumab in phase I and phase II studies in combination with lenalidomide and bortezomib.
Elotuzumab As Part of Combination Therapy: Clinical Trial Results
Elotuzumab showed manageable side effect profile and was well tolerated in a population of relapsed/refractory multiple myeloma patients, when treated with intravenous elotuzumab as single agent therapy. Lets’ take a look at how elotuzumab fared in combination therapy trials,

In phase I trial of elotuzumab in combination with Velcade/bortezomib in patients with relapsed/refractory myeloma, the overall response rate was 48% and activity was observed in patients whose disease had stopped responding to Velcade previously. The trial results found that elotuzumab enhanced Velcade activity.
A phase I/II trial in combination with lenalidomide and dexamethasone in refractory/relapsed multiple myeloma patients showed that 82% of patients responded to treatment with a partial response or better and 12% of patients showed complete response. Patients who had received only one prior therapy showed 91% response rate with elotuzumab in combination with lenalidomide and dexamethasone.

Phase I/II trials of the antibody drug has been very impressive and the drug is currently into Phase III trials. Two phase III trials are investigating whether addition of elotuzumab with Revlimid and low dose dexamethasone would increase the time to disease progression. Another phase III trial (ELOQUENT 2) is investigating and comparing safety and efficacy of lenalidomide plus low dose dexamethasone with or without 10mg/kg of elotuzumab in patients with relapsed/refractory multiple myeloma.
Elotuzumab is being investigated in many other trials too. It is being evaluated in combination with Revlimid and low-dose dexamethasone in multiple myeloma patients with various levels of kidney functions, while another phase II study is investigating elotuzumab’s efficacy in patients with high-risk smoldering myeloma.
The main target of multiple myeloma drug development is to satisfy the unmet need for drugs that would improve survival rates. Elotuzumab is an example that mandates much interest in this area and should be followed with diligence.

On November 30, 2015, the U. S. Food and Drug Administration approved elotuzumab (EMPLICITI, Bristol-Myers Squibb Company) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies.

Elotuzumab is a monoclonal antibody directed against Signaling Lymphocyte Activation Molecule Family 7 (SLAMF7). SLAMF7 is present on myeloma cells and is also present on natural killer cells.

The approval was based on a multicenter, randomized, open-label, controlled trial evaluating progression-free survival (PFS) and overall response rate (ORR) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 prior lines of therapy.  A total of 646 patients were randomized (1:1) to receive elotuzumab in combination with lenalidomide and dexamethasone (n=321) or lenalidomide plus dexamethasone alone (n=325).  Patients continued treatment until disease progression or the development of unacceptable toxicity.

The trial demonstrated a statistically significant improvement in both PFS and ORR, the trial’s co-primary endpoints.  The median PFS in the elotuzumab-containing arm was 19.4 months and 14.9 months in the lenalidomide plus dexamethasone alone arm (hazard ratio 0.70, 95% CI: 0.57, 0.85; p = 0.0004).  The ORR in the elotuzumab-containing arm was 78.5% (95% CI: 73.6, 82.9) compared to 65.5% (95% CI: 60.1, 70.7) in the lenalidomide plus dexamethasone alone arm (p=0.0002).

The safety data reflect exposure in 318 patients to elotuzumab in combination with lenalidomide and dexamethasone and 317 patients to lenalidomide plus dexamethasone. The most common adverse reactions (greater than or equal to 20%), with an increased rate in the elotuzumab arm compared to the control arm, were fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, and pneumonia.

Other important adverse reactions include infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with determination of complete response.  As elotuzumab is an IgG kappa monoclonal antibody, it can be detected in the serum protein electrophoresis and immunofixation assays used to assess response.

Serious adverse events occurred in 65.4% of patients in the elotuzumab-containing arm compared to 56.5% in the lenalidomide plus dexamethasone alone arm. The most common serious adverse reactions were pneumonia, pyrexia, respiratory tract infection, anemia, pulmonary embolism, and acute renal failure.

The recommended dose and schedule for elotuzumab is 10 mg/kg intravenously every week for the first two cycles and every 2 weeks, thereafter, until disease progression or unacceptable toxicity with lenalidomide 25 mg daily orally on days 1 through 21.  Dexamethasone is administered as follows: In weeks with elotuzumab infusion, dexamethasone is to be administered in divided doses, 8 mg intravenously prior to infusion and 28 mg orally; in weeks without elotuzumab infusion, dexamethasone is to be administered 40 mg orally.  Pre-medication with an H1 blocker, H2 blocker, and acetaminophen should be administered prior to elotuzumab infusion.

Elotuzumab is being approved prior to the Prescription Drug User Fee Act (PDUFA) goal date of February 29, 2016.  This application was granted priority review and had breakthrough therapy designation.  A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Full prescribing information is available at:  http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761035s000lbl.pdf

Empliciti’s Cost
Empliciti will be sold in the U.S. in two vials sizes: A smaller vial that contains 300 mg of the drug, and a larger vial that contains 400 mg.
Bristol-Myers Squibb has informed The Beacon that the wholesale price per vial of Empliciti will be $1,776 for the 300 mg vial and $2,368 for the 400 mg vial.
Using these prices and an assumed patient weight of between 154 and 176 pounds, Empliciti will cost $18,944 per four-week cycle for each of the first two cycles of treatment, and $9,472 per cycle there­after. This means, in turn, that Empliciti’s cost per year will be $142,080 in the first year and $123,136 in subsequent years.
In comparison, Velcade costs between $4,800 and $8,500 per four-week cycle, depending on how often it is dosed. Ninlaro costs $8,670 per four-week cycle. And Kyprolis costs $10,500 per four-week cycle at the standard (20 – 27 mg/m²) dose.
Additional details about the FDA approval of Empliciti can be found in this press release from the FDA, a related press release from Bristol-Myers Squibb and AbbVie, and the full Empliciti prescribing information.
The results of the ELOQUENT-2 trial were published in Lonial, S. et al., “Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma,” The New England Journal of Medicine, June 2, 2015 (abstract). Slides from the ASCO presentation summarizing the ELOQUENT-2 results can be viewed here (PDF, courtesy of Dr. Lonial). This Beacon news article provides an in-depth look at the trial results.

Elotuzumab

Monoclonal antibody
Type	Whole antibody
Source	Humanized
Target	SLAMF7 (CD319)
Clinical data
Trade names	Empliciti
Pregnancy category	US: X (Contraindicated) X (used with lenalidomide)
Legal status	US: ℞-only
Routes of administration	IV
Pharmacokinetic data
Bioavailability	100% (IV)
Identifiers
CAS Number	915296-00-3
ATC code	None
IUPHAR/BPS	8361
UNII	1351PE5UGS
Chemical data
Formula	C6476H9982N1714O2016S42
Molecular mass	145.5 kDa

References

1 “Press Announcement—FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma”. U.S. Food and Drug Administration. Retrieved 3 December 2015.
2“Empliciti (elotuzumab) for Injection, for Intravenous Use. Full Prescribing Information” (PDF). Empliciti (elotuzumab) for US Healthcare Professionals. Bristol-Myers Squibb Company, Princeton, NJ 08543 USA.
3 “Bristol-Myers Squibb and AbbVie Receive U.S. FDA Breakthrough Therapy Designation for Elotuzumab, an Investigational Humanized Monoclonal Antibody for Multiple Myeloma” (Press release). Princeton, NJ & North Chicago, IL: Bristol-Myers Squibb. 2014-05-19. Retrieved 2015-02-05.

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Merck’s Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP)

ote


Indoline 7  as in ACS MEDCHEM LETTERS, DOI: 10.1021/acsmedchemlett.5b00404
and
eg 10 as in WO2015054088
(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.
1H-​Indole-​1-​ethanol, 2,​3-​dihydro-​3-​[3-​(trifluoromethoxy)​phenyl]​-​3-​[[3-​ (trifluoromethoxy)​phenyl]​methyl]​-​α-​(trifluoromethyl)​-​, (αR)​-
cas 1699732-96-1 R ISOMER

MF C₂₆ H₂₀ F₉ N O_3, MW 565.43

Merck Sharp & Dohme Corp. INNOVATOR

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from ¹H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK–PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

chemical compounds that inhibit cholesterol ester transfer protein (CETP) and are expected to have utility in raising HDL-C, lowering LDL-C, and in the treatment and prevention of atherosclerosis.
see………….http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.5b00404
http://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.5b00404/suppl_file/ml5b00404_si_001.pdf

Discovery of Novel Indoline Cholesterol Ester Transfer Protein Inhibitors (CETP) through a Structure-Guided Approach

Jonathan E. Wilson^*†, Ravi Kurukulasuriya†, Mikhail Reibarkh‡, Maud Reiter, Aaron Zwicker, Kake Zhao†, Fengqi Zhang†, Rajan Anand†, Vincent J. Colandrea, Anne-Marie Cumiskey§, Alejandro Crespo‡, Ruth A. Duffy§, Beth Ann Murphy§, Kaushik Mitra∥, Douglas G. Johns⊥, Joseph L. Duffy†, and Petr Vachal†

^†Department of Medicinal Chemistry and ^‡Department of Structural Chemistry, Merck Research Laboratories, Merck & Co, Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

^§Department of Pharmacology, ^∥Department of Drug Metabolism and Pharmacokinetics, and ^⊥Department of Biology, Merck Research Laboratories, Merck & Co, Inc., P.O. Box 2000, Kenilworth, New Jersey 07033, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.5b00404

Publication Date (Web): January 4, 2016

Copyright © 2016 American Chemical Society

*E-mail: jonathan_wilson@merck.com.

 PATENT

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=5D4A5D79894298F5BC0A664CF54B61E9.wapp2nB?docId=WO2013028382&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Atherosclerosis and its clinical consequences, including coronary heart disease
(CHD), stroke and peripheral vascular disease, represent a truly enormous burden to the health care systems of the industrialized world. In the United States alone, approximately 13 million patients have been diagnosed with CHD, and greater than one half million deaths are attributed to CHD each year. Further, this toll is expected to grow over the next quarter century as an epidemic in obesity and diabetes continues to grow.
It has long been recognized that in mammals, variations in circulating lipoprotein profiles correlate with the risk of atherosclerosis and CHD. The clinical success of HMG-CoA reductase inhibitors, especially the statins, in reducing coronary events is based on the reduction of circulating low density lipoprotein cholesterol (LDL-C), levels of which correlate directly with an increased risk for atherosclerosis. More recently, epidemiologic studies have
demonstrated an inverse relationship between high density lipoprotein cholesterol (HDL-C) levels and atherosclerosis, leading to the conclusion that low serum HDL-C levels are associated with an increased risk for CHD.
Metabolic control of lipoprotein levels is a complex and dynamic process involving many factors. One important metabolic control in man is the cholesteryl ester transfer protein (CETP), a plasma glycoprotein that catalyzes the movement of cholesteryl esters from HDL to the apoB containing lipoproteins, especially VLDL (see Hesler, C.B., et. al. (1987) Purification and characterization of human plasma cholesteryl ester transfer protein. J. Biol. Chem. 262(5), 2275-2282)). Under physiological conditions, the net reaction is a heteroexchange in which CETP carries triglyceride to HDL from the apoB lipoprotein and transports cholesterol ester from HDL to the apoB lipoprotein.
In humans, CETP plays a role in reverse cholesterol transport, the process whereby cholesterol is returned to the liver from peripheral tissues. Intriguingly, many animals do not possess CETP, including animals that have high HDL levels and are known to be resistant to coronary heart disease, such as rodents (see Guyard-Dangremont, V., et. al, (1998)
Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility, Comp. Biochem. Physiol. B Biochem. Mol. Biol. 120(3), 517-525). Numerous epidemiologic studies correlating the effects of natural variation in CETP activity with respect to coronary heart disease risk have been performed, including studies on a small number of known human null mutations (see Hirano, K.-L, Yamashita, S. and Matsuzawa, Y. (2000) Pros and cons of inhibiting cholesteryl ester transfer protein, Curr. Opin. Lipidol. 11(6), 589-596). These studies have clearly demonstrated an inverse correlation between plasma HDL-C concentration and CETP activity (see Inazu, A., et. al. (2000) Cholesteryl ester transfer protein and atherosclerosis, Curr. Opin. Lipidol. 11(4), 389-396), leading to the hypothesis that pharmacologic inhibition of CETP lipid transfer activity may be beneficial to humans by increasing levels of HDL-C while lowering LDL-C.
Despite the significant therapeutic advance that statins such as simvastatin and atorvastatin represent, statins only achieve a risk reduction of approximately one-third in the treatment and prevention of atherosclerosis and ensuing atherosclerotic disease events.
Currently, few pharmacologic therapies are available that favorably raise circulating levels of HDL-C. Certain statins and some fibrates offer modest HDL-C gains. Niacin provides an effective therapy for raising HDL-C but suffers from patient compliance issues, due in part to side effects such as flushing. Drugs that inhibit CETP (CETP inhibitors) have been under development with the expectation that they will effectively raise HDL cholesterol levels and also reduce the incidence of atherosclerosis in patients. Torcetrapib was the first drug that was tested in a long-term outcomes clinical trial. The clinical trial of torcetrapib was terminated early due to a higher incidence of mortality in patients to whom torcetrapib and atorvastatin were administered concomitantly compared with patients who were treated with atorvastatin alone. The cause of the increased mortality is not completely understood, but it is not believed to be associated with the CETP inhibiting effects of the drug.
Two other drug candidates, dalcetrapib and anacetrapib, are currently being tested in Phase III clinical trials, including large scale outcomes trials. Data from the recently completed DEFINE Phase III trial of anacetrapib are promising. Patients who were being treated with anacetrapib along with baseline statin therapy showed an increase of HDL-C of 138% and a decrease of LDL-C of 40%> compared with patients who were treated with just a statin. See: N. Engl. J. Med. 2010: 363: 2406-15. The data in the DEFINE trial were sufficient to indicate that an increase in mortality for patients treated with anacetrapib is unlikely. Additional drug candidates are still being sought that may have properties that are advantageous compared with the CETP inhibitors that have so far been studied or are currently being studied. Such properties may include, for example, higher potency, reduced off-target activity, better pharmacodynamics, higher bioavailability, or a reduced food effect compared with many of the highly lipophilic compounds that have so far been studied. “Food effect” refers to the variability in exposure to the active drug that occurs depending on when the patient had last eaten, whether or not the drug is administered with food, and the fat content of the food.

Example 18 as in patent

(R)- 1,1, 1 -trifluoro-3-((R)-4-(3-trifluoromethoxy)benzyl)-2-(3-(l, 1 ,2,2,-tetrafluoroethoxy)phenyl)-3,4- dihydroquinoxalin- 1 (2H)-yl)propan-2-ol
SPA: 15 nM
Example 18 was prepared from 2-bromo-l-(3-(l , 1 ,2,2,-tetrafluoroethoxy)phenyl)ethanone in three steps, using the reactions detailed in Schemes A6, A2 and Al . Spectral data are as follows: 1H NMR (400 MHz, CDC1₃) £2.70 (bd, J=4.1 Hz, IH), 3.24 (dd, J=l 1.3, 3.4 Hz, IH), 3.34 (dd, J=15.5, 9.7 Hz, IH), 3.58 (dd, J=l 1.3, 3.3 Hz, IH), 3.86 (d, J=15.4 Hz, IH), 4.20 (d, J=15.7 Hz, IH), 4.40 (d, J=15.8 Hz, IH), 4.46 (m, IH), 4.927 (t, J=3.3 Hz, IH), 5.90 (tt, J=53.1 , 2.7 Hz, IH), 6.59 (d, J= 7.9 Hz, IH), 6.72 (m, 2H), 6.84 (m, 2H), 6.92 (d, J=7.6 Hz, IH), 7.20 (m, 2H), 7.35 (t, J=7.9 Hz, IH), MS m/z = 613.03.
Scheme A12

Methyl 3 – { 1 – [(R)-3 ,3 ,3 -trifluoro-2-hy droxypropyl] -4- [3 -(trifluoromethoxy) benzyl]-l,2,3,4-tetrahydroquinoxalin-2-yl}benzoate (700 mg, 1.262 mmol) is made as described in Example 16 but with one stereochemical center unresolved. The compound was dissolved in MeOH (12.6mL), lithium hydroxide monohydrate (530 mg, 12.62 mmol) was added, and the reaction mixture was heated to 60°C for 4 hours. The crude mixture was dissolved in saturated ammonium chloride solution and extracted into EtOAc, the organic phase was dried with anhydrous magnesium sulfate, filtered, concentrated, and purified on a silica gel column with a 0-100% Hex/EtOAc gradient. The major peak was concentrated to afford 3-{l-[(R)-3,3,3-trifluoro-2-hydroxypropyl]-4-[3-(trifluoromethoxy)benzyl]-l,2,3,4-tetra-hydroquinoxalin-2-yl} benzoic acid. MS m/z = 541.09.

1H and 13C NMR spectra for compound 7

(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.

Patent
WO2015054088
http://google.com/patents/WO2015054088A1?cl=en
Scheme Al

Scheme A2

Scheme A3

R = Ar, NR_2l C0₂R, CN, S0₂Me
es
es

SEE EXAMPLE ………SIMILAR BUT NOT SAME

Example 1. (2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. This material was prepared according to Scheme Al, as described below.

3-(3-(trifluoromethyl)phenyl)indolin-2-one. Oxindole (1.598 g, 12 mmol), 3-bromo-a,a,a-trifluoromethyltoluene (2.009 ml, 14.40 mmol), potassium carbonate (3.32 g, 24.00 mmol), Pd₂dba₃ (0.220 g, 0.240 mmol), and 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.458 g, 0.960 mmol) were combined in THF (12 ml) and the mixture was degassed with nitrogen. The solution was then heated to 80 °C for 18h. The mixture was cooled to room temperature, filtered through silica eluting with ethyl acetate, and concentrated. The material was then purified by silica gel chromatography (Biotage lOOg SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethyl)phenyl)indolin-2-one as a white solid.
1H NMR (500 MHz) δ 8.58 (s, 1H), 7.61 (d, J=7 Hz, 1H), 7.53-7.45 (m, 3H), 7.33-7.29 (m, 1H), 7.16 (d, J=7 Hz, 1H), 7.10 (m, 1H), 7.01-6.90 (m, 1H), 4.73 (s, 1H).

3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin-2-one . 3 -Trifluoromethoxy-benzylbromide (0.204 ml, 1.255 mmol) was added to a mixture of 3-(3-(trifluoromethyl)-phenyl)indolin-2-one (290 mg, 1.046 mmol) and potassium carbonate (289 mg, 2.092 mmol) (sodium carbonate may be used in place of potassium carbonate) in DMA (2.5 ml). The mixture was stirred at r.t. for 16h. The reaction was diluted with ethyl acetate and washed with water (3×5 mL). The organic layer was dried with Na₂S0₄, filtered, and concentrated. The products were then purified by silica gel chromatography (Biotage 50g SNAP cartridge; 0-40%> ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-2-one .
1H NMR (500 MHz) δ 7.79 (s, 1H), 7.73 (d, J=7 Hz, 1H), 7.62-7.60 (m, 2H), 7.51 (t, J=7 Hz, 1H), 7.26- 7.22 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 7.11 (m, 1H), 6.97 (m, 1H), 6.92 (m, 1H), 6.78 (m, 1H), 6.73 (s, 1H), 3.77 (d, J=13 Hz, 1H), 3.49 (d, J=13 Hz, 1H).
LCMS m/z = 451.8 (M+H)

3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. Borane tetrahydrofuran complex (1.673 ml, 1.673 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indolin-2-one (302 mg, 0.669 mmol) in THF (1.5 ml). The mixture was heated to 70 °C for 20h. The reaction was cooled to room temperature and quenched with saturated NH₄C1 solution, and this mixture was stirred vigorously for 20 minutes. The product was extracted with ethyl acetate. The extracts were dried over Na₂S0₄, filtered, and concentrated. The product was purified by silica gel chromatography (Biotage 25g SNAP cartridge, 0-50% ethyl acetate in hexanes) to provide 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline. This material may also be used without purification in the final step of the sequence, epoxide opening.
1H NMR (500 MHz) δ 7.66 (s, IH), 7.59 (d, J=7 Hz, IH), 7.53 (d, J=7 Hz, IH), 7.45 (t, J=8 Hz, IH), 7.18-7.13 (m, 2H), 7.04 (d, J=8 Hz, IH), 6.98 (d, J=7 Hz, IH), 6.81 (t, J=7.5 Hz, IH), 6.71 (m, 2H), 6.60 (s, IH), 3.83 (m, IH), 3.75-3.73 (m, 2H), 3.46 (d, J=13 Hz, IH), 3.41 (d, J=13 Hz, IH).
= 437.9 (M+H)

(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)-phenyl)indolin-l-yl)propan-2-ol. (S)-2-(trifluoromethyl)oxirane (81 μΐ, 0.933 mmol) was added to a solution of 3-(3-(trifluoromethoxy)benzyl)-3-(3-(trifluoromethyl)phenyl)indoline (136 mg, 0.311 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (412 μΐ, 3.91 mmol). The reaction was stirred at room temperature overnight. The solvent was removed and the product was purified by silica gel chromatography (Biotage 25 g SNAP cartridge; 0-25% ethyl acetate in hexanes) to provide (2R)- 1 ,1,1 -trifluoro-3 -(3 -(3 -(trifluoromethoxy)benzyl)-3 -(3 -(trifluoromethyl)phenyl)indolin- 1 -yl)propan-2-ol.
1H NMR (500 MHz) (mixture of diastereomers) δ 7.72 (s, 0.5 H), 7.69 (s, 0.5 H), 7.65 (d, J=6.5 Hz, 0.5 H), 7.61 (d, J=7.5 Hz, 0.5 H), 7.56 (s, 1H), 7.50 (m, 1H), 7.25-7.17 (m, 2H), 7.07 (broad s, 2H), 6.91-6.89 (m, 1H), 6.79-6.75 (m, 1H), 6.53 (m, 2H), 4.00 (broad s, 1H), 3.83 (d, J= 9 Hz, 0.5H), 3.77 (d, J=9 Hz, 0.5H), 3.59-3.55 (m, 1H), 3.45-3.43 (m, 1H), 3.39-3.29 (m, 2H), 3.21-3.15 (m, 1H), 2.32 (m, 0.5H), 2.15 (m, 0.5H).
LCMS m/z = 549.8 (M+H)
Examples 1-25, in the table below, were prepared according to Scheme Al in a

SEE EG 10…….(2R)- 1,1,1 -trifluoro-3-(3-(3-(trifluoromethoxy)benzyl)-3-(3- (trifluoromethoxy)-phenyl)indolin-l-yl)propan-2-ol.

ABOUT AUTHOR

Jonathan Wilson

Associate Principal Scientist at Merck

https://www.linkedin.com/in/jonathan-wilson-23206523

Experience

Associate Principal Scientist

Merck

October 2013 – Present (2 years 4 months)

Senior scientist

Merck

May 2009 – October 2013 (4 years 6 months)

Postdoctoral researcher

Princeton University

October 2007 – May 2009 (1 year 8 months)

Associate Medicinal Chemist

Merck

2000 – 2002 (2 years)

Education

Massachusetts Institute of Technology

Ph.D., Organic Chemistry

2002 – 2007

Oberlin College

B. A., Chemistry

1996 – 2000

///////CETP inhibition, cholesterol ester transfer protein, HDL,  indoline,  tetrahydroquinoxaline, merck, discovery
c21ccccc1N(C[C@@]2(c3cccc(c3)OC(F)(F)F)Cc4cc(ccc4)OC(F)(F)F)C(C(F)(F)F)O
FC(F)(F)Oc1cccc(c1)C3(CN(C[C@@H](O)C(F)(F)F)c2ccccc23)Cc4cccc(OC(F)(F)F)c4



///////////see..........http://newdrugapprovals.org/2016/01/06/mercks-novel-indoline-cholesterol-ester-transfer-protein-inhibitors-cetp/