ORVEPITANT

Molecular Formula:	C31H35F7N4O2
Molecular Weight:	628.624022 g/mol

CAS 579475-18-6

Orvepitant (GW823296)

(2R,4S)-4-[(8aS)-6-oxo-1,3,4,7,8,8a-hexahydropyrrolo[1,2-a]pyrazin-2-yl]-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide

MALEATE

CAS [579475-24-4] MALEATE

MF C31H35F7N4O2.C4H4O4
MW 744.70

https://clinicaltrials.gov/ct2/show/NCT01000493

• Phase IICough; Pruritus
• DiscontinuedAnxiety disorders; Major depressive disorder; Post-traumatic stress disorders

Most Recent Events

• 19 Dec 2015NeRRe Therapeutics terminates a phase II trial in Pruritus in Italy and the United Kingdom (EudraCT2013-002763-25)
• 16 Dec 2013No development reported - Phase-II for Post-traumatic stress disorder in USA (PO)
• 16 Dec 2013No development reported - Phase-II for Major depressive disorder in Canada (PO)

Company	NeRRe Therapeutics Ltd.
Description	Neurokinin 1 (NK1) receptor antagonist
Molecular Target	Neurokinin 1 (NK1) substance P receptor (TACR1)
Mechanism of Action	Neurokinin-1 (NK-1) (Substance P) receptor antagonist
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase II
Standard Indication	Itch
Indication Details	Treat intense pruritus (itch) associated with epidermal growth factor receptor inhibitor (EGFRi) anticancer therapies

 

Start of Phase II study of neurokinin-1 receptor antagonist orvepitant for intense pruritus induced by epidermal growth factor receptor inhibitors

First Clinical Trial for NeRRe Therapeutics

Stevenage, UK, 23 January 2014.
NeRRe Therapeutics Ltd, which is focused on the development of neurokinin (NK) receptor antagonists for a range of indications, is pleased to announce the start of a Phase II study of the novel NK-1 receptor antagonist orvepitant. The proof-of-concept study, results of which are expected in 2015, is investigating orvepitant’s effectiveness as a treatment for the intense pruritus (itch) associated with epidermal growth factor receptor inhibitor (EGFRi) anticancer therapies. The itch intensity experienced by patients can be so severe that their EGFRi dose must be reduced or the treatment withdrawn; also pruritus along with rash has a significant effect on quality of life¹.
The RELIEVE-1 trial is a randomised, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of two daily dose levels of oral orvepitant on EGFRi-induced intense pruritus in oncology subjects. Its primary endpoint is the difference between orvepitant and placebo in reducing the intensity of pruritus over 4 weeks, as measured on a subject-recorded numerical rating scale. RELIEVE-1 is being undertaken in 15 clinical sites in Italy, with Dr Bruno Vincenzi from Università Campus Bio-Medico di Roma as lead investigator. Dr Vincenzi and his colleagues at the centre have pioneered the use NK-1 antagonists as anti-pruritics in this setting². Chemistry, manufacturing and control support for RELIEVE-1 is being provided by Aptuit (Verona) Srl, with clinical operations assistance from the CRO Cromsource.
Dermatologic adverse events such as pruritus are a common feature of targeted anti-cancer therapies, with incidence of this symptom induced by EGFRi^a drugs in clinical trials ranging from 14.6% to 54.9% depending on the specific agent³. Open-label studies in patients suffering from refractory chronic pruritus have indicated that NK-1 receptor antagonism can provide rapid and highly effective relief as well as significantly improving quality of life.^2,4,5,6

Dr Mike Trower, Co-founder & Chief Operating Officer of NeRRe Therapeutics said: 

‘We are very pleased to announce the start of RELIEVE-1, NeRRe’s first clinical trial, in this important area of unmet medical need. There is a strong rationale and a growing body of clinical evidence supporting the potential of orvepitant as an anti-pruritic for this devastating symptom commonly associated with EGFRis. Given its known effects on mood and sleep, orvepitant may also provide additional benefits for patient well-being.’

Dr Emiliangelo Ratti, NeRRe Therapeutics Co-founder added:

‘The intense pruritus induced by EGFRis can lead to significant suffering and poor quality of life, and we believe that a treatment for this troubling side effect would be welcomed by cancer patients and supportive care doctors alike. A successful study of orvepitant in this indication would provide further evidence of the broad therapeutic potential of the NK-1 receptor antagonist mechanism which NeRRe is exploiting in its pipeline.’

–ENDS–

^a This includes monoclonal antibodies that target the extracellular domain of EFGR, small molecule tyrosine kinase (TK) inhibitors, and small molecule dual TK inhibitors.

About NeRRe Therapeutics
NeRRe Therapeutics was formed in December 2012 and is focussed on the development of a portfolio of NK receptor antagonists acquired from GlaxoSmithKline (GSK), which have therapeutic potential in a broad range of indications. NeRRe Therapeutics was co-founded by Drs Emiliangelo Ratti and Mike Trower, both of whom are both former senior leaders of neurosciences drug discovery at GSK with intimate knowledge of the transferred assets and the neurokinin receptor system field. In 2012 NeRRe Therapeutics raised £11.5 million ($18.4 million) in Series A financing from two leading European financial institutions, Novo A/S (www.novo.dk/ventures) and Advent Life Sciences (www.adventventures.com), who are represented by Dr Martin Edwards (Chairman) and Dr Kaasim Mahmood respectively on the company’s Board.
NeRRe (www.nerretherapeutics.com) is based at the state-of-the-art Stevenage Bioscience Catalyst (www.stevenagecatalyst.com), the UK’s first open innovation bioscience campus.

About Orvepitant
Orvepitant is a ‘novel generation’ brain penetrant, selective and potent, small molecule NK-1 receptor antagonist⁷ that features high receptor occupancy and full and long lasting (≥24hrs) central NK-1 receptor occupancy⁸. It has previously completed extensive safety and toxicology studies to support its clinical development; and it has already demonstrated a positive antidepressant effect in a Phase II clinical study together with beneficial effects on sleep⁸.

PATENT

http://www.google.com/patents/EP2297152A1?cl=en

NK1 antagonist compound orvepitant maleate, pharmaceutical formulations comprising this crystalline form, its use in therapy and processes for preparing the same. Background of the invention
WO03/066635 describes a number of diazabicycle derivatives having NK1 activity, including the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro- pyrrolo[1 ,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide (otherwise known as orvepitant).
The structure of the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro- pyrrolo[1 ,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide (otherwise known as orvepitant) is shown in formula (I) below:

Hereinafter any reference to orvepitant refers to the compound of formula (I).
Orvepitant may also be known as: CAS Index name
1-Piperidinecarboxamide, Λ/-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-
2-methylphenyl)-4-[(8aS)-hexahydro-6-oxopyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl]-Λ/-methyl-,
(2RAS) and IUPAC name :
(2R,4S)-Λ/-{(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-
Λ/-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1 ,2-a]pyrazin-2(1 /-/)-yl]-1- piperidinecarboxamide. A preferred salt of this compound is its hydrochloride salt which is otherwise known as orvepitant hydrochloride.
A further preferred salt of this compound is its maleate salt which is otherwise known as orvepitant maleate.
Particularly Example 1 1 C of WO03/066635 describes the synthesis of orvepitant maleate using substantially the same experimental conditions described in the Example 1 in the present patent application.
We have now found that orvepitant maleate can be obtained in a new crystalline form. In particular, we have discovered a form of orvepitant maleate which is anhydrous and crystalline and which surprisingly has particularly good pharmaceutical properties. This is particularly stable and essentially non hygroscopic. It also has good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules.
Example 1 : preparation of orvepitant maleate (Form 2) {(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethyl}methylamine - (2R)-2-hydroxybutanedioic acid (1.8 kg) was added to ethyl acetate (5.4 litres) and 15% w/w sodium carbonate solution (5.4 litres) and was stirred until all solids had dissolved. The organic phase was separated and was washed with water (5.4 litres). Fresh ethyl acetate (6.7 litres) was added and the solution was distilled to 5.4 litres under reduced pressure.
The solution was diluted with ethyl acetate (3.6 litres). The reactor was purged with carbon dioxide and a continuous steady stream of carbon dioxide was maintained. Triethylamine (810 ml) was added over 30 minutes and was rinsed in with ethyl acetate (250 ml). The reaction mixture was stirred for 30 minutes. Chlorotrimethylsilane (850 ml) was added over 30 minutes with cooling to keep the temperature between 17°C and 23°C and was rinsed in with ethyl acetate (250 ml). The reaction mixture was stirred for 30 minutes. Pyridine (720 ml) was added and was rinsed in with ethyl acetate (250 ml). Thionyl chloride (480 ml) was added over 10 minutes and then a rinse of ethyl acetate (500 ml). The reaction mixture was stirred at 20⁰C for 16 hours under a carbon dioxide atmosphere.
28% w/w Racemic malic acid solution (5.3 litres) was added and the mixture was stirred for 15 minutes. The organic phase was separated, diluted with ethyl acetate (1.5 litres) and was washed with water (2 x 2.7 litres) and 20% w/w dibasic potassium phosphate solution (5.6 litres). The solution was distilled under reduced pressure to a total volume of 2.5 litres. Ethyl acetate (5 litres) was added and the solution was redistilled to 3 litres to give a solution of {(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}methylcarbamic chloride.
(2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone - (2S)-hydroxy(phenyl)ethanoic acid (1.2 kg) was added to 15% w/w sodium carbonate solution (4.8 litres) and ethyl acetate (4.8 litres) and the mixture was stirred until solids dissolved. The organic phase was separated and was washed with 20% w/w sodium chloride solution (4 litres). Fresh ethyl acetate (4.8 litres) was added and the solution of (2R)-2-(4-fluoro- 2-methylphenyl)-4-piperidinone was distilled under reduced pressure to a volume of 3 litres. The solution of (2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone was charged to the solution of {(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylcarbamic chloride followed by an ethyl acetate (300 ml) rinse. Triethylamine (857 g) was added followed by ethyl acetate (300 ml) and the mixture was boiled at reflux for 18 hours. The slurry was cooled to 20⁰C and N-acetylpiperazine (240 g) was added. The reaction mixture was stirred for 30 minutes at 20⁰C and was then charged with 28% w/w racemic malic acid solution (3.6 litres). The organic phase was separated and was washed with 20% w/w sodium chloride solution (4.8 litres). Ethyl acetate (4.8 litres) was added and the solution of (2R)-N-{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide was distilled under reduced pressure distillation to a total volume of 3 litres.
(8aS)-hexahydropyrrolo[1 ,2-a]pyrazin-6(2H)-one - (2S)-(acetyloxy)(phenyl)ethanoic acid (1.5 kg) was added to acetonitrile (11.4 litres) and triethylamine (450 g) was added. An acetonitrile (250 ml) rinse was added and the slurry was stirred at 20⁰C for 30 min. Sodium triacetoxyborohydride (900 g) was added and the reaction was cooled to 10⁰C. Formic acid (396 ml) was added to the mixture over 30 min, maintaining the temperature below 15°C. An acetonitrile (250 ml) rinse was added and the reaction was warmed to 20⁰C. The solution of (2R)-N-{(1 R)-1-[3,5- bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1- piperidinecarboxamide in ethyl acetate was added to the reaction mixture and was rinsed in with acetonitrile (1 litre). The reaction was stirred for 16 hours at 20⁰C.
The slurry was distilled to 5 litres under reduced pressure. The mixture was diluted with ethyl acetate (10 litres) and was washed with 13% w/w ammonia solution (2 x 4 litres), and 10% w/w sodium chloride solution (4 litres). The organic solution was distilled to 5 litres under reduced pressure. The solution was diluted with IPA (8 litres) and was distilled under reduced pressure to 5 litres. Further IPA (8 litres) was added and the solution was again distilled to 5 litres.
A solution of maleic acid (248.5 g) in IPA (2.5 litres) was added. The mixture was then seeded with orvepitant maleate A (1 g) and the mixture was aged for 1 hour. Iso-octane (10 litres) was added over 30 min. and the mixture further aged for 1 hour. The slurry was cooled to 7°C and was further aged for 90 minutes. The solid formed was filtered and washed with a 1 :1 mixture of IPA/iso-octane (2 x 3 litres). The resulting solid was dried at 40°C under reduced pressure to give the title compound (1.095kg, 44%). NMR (CD₃OD) δ (ppm) 1.52-1.53 (d, 3H), 1.68-1.78 (m, 1 H), 1.82-1.91 (q, 1 H), 1.95- 2.05 (m, 1 H), 2.16-2.37 (m, 3H), 2.38-2.50 (m, 2H), 2.44 (s, 3H), 2.81-2.87 (t, 1 H),
2.83 (s, 3H), 2.90-2.99 (m, 2H), 3.1 1-3.18 (dt, 1 H), 3.48-3.60 (m, 3H), 3.66-3.69 (d, 1 H), 3.89-3.96 (m, 1 H), 4.15-4.19 (dd, 1 H), 4.33-4.36 (dd , 1 H), 5.40-5.45 (q, 1 H), 6.26 (s, 2H), 6.76-6.81 (dt, 1 H), 6.85-6.88 (dd, 1 H), 7.27-7.31 (dd, 1 H), 7.70 (s, 2H), 7.88 (s, 1 H). (M+H)⁺ Calcd for C₃iH₃₅F₇N₄O 629, found 629.
References:

1. Rosen AC et al. Am J Clin Dermatol. (2013), 14(4):327-33
2. Santini D et al. Lancet Oncol. (2012), 13(10):1020-4
3. Ensslin CJ et al. J Am Acad Dermatol. (2013), 69(5):708-20
4. Duval A, Dubertret L. N Engl J Med. (2009), 1;361(14):1415-6
5. Ständer S et al. PLoS One. (2010), 5(6):e10968
6. Torres T et al. J Am Acad Dermatol. (2012), 66(1):e14-5
7. Di Fabio R et al. Bioorg Med Chem. (2013), 21(21):6264-73
8. Ratti E et al. J Psychopharmacol. (2013), 27(5):424-34

Patent ID	Date	Patent Title
US2015238486	2015-08-27	NOVEL USES
US2014128395	2014-05-08	Novel Method
US2011166150	2011-07-07	Anhydrous Crystal Form Of Ovrepitant Maleate
US2010317666	2010-12-16	Composition Comprising An NK-1 Receptor Antagonist And An SSRI For The Treatment Of Tinnitus And Hearing Loss
US2010152446	2010-06-17	Piperidine Derivatives
US2010105688	2010-04-29	PHARMACEUTICAL COMPOSITIONS COMPRISING 3,5-DIAMINO-6-(2,3-DICHLOPHENYL)-1,2,4-TRIAZINE OR R(-)-2,4-DIAMINO-5-(2,3-DICHLOROPHENYL)-6-FLUOROMETHYL PYRIMIDINE AND AN NK1
US7652012	2010-01-26	2-(R)-(4-fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide maleate and pharmaceutical compositions thereof
US2009326032	2009-12-31	PHARMACEUTICAL COMPOSITIONS COMPRISING NK1 RECEPTOR ANTAGONISTS AND SODIUM CHANNEL BLOCKERS
US2009318530	2009-12-24	PHARMACEUTICAL COMPOSITIONS COMPRISING NK1 RECEPTOR ANTAGONISTS AND SODIUM CHANNEL BLOCKERS
US7189713	2007-03-13	Piperidine derivatives

Patent ID	Date	Patent Title
US7189713	2007-03-13	Piperidine derivatives
US2006287325	2006-12-21	Combinations of paroxetine and 2-(r)-(4-fluoro-2-methyl-phenyl)-4-(s)-((8as)-6-oxo-hexahydro-pyrrolo'1,2-a!-pyrazin-2-yl)-piperidine-1-carboxylicacid'1-(r)-(3,5-bis-trifluoromethyl-phenyl)-
US6384099	2002-05-07	Method for curing polymeric materials, such as those used in dentistry, and for tailoring the post-cure properties of polymeric materials through the use of light source power modulation
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REFERENCES

1: Di Fabio R, Alvaro G, Braggio S, Carletti R, Gerrard PA, Griffante C, Marchioro C, Pozzan A, Melotto S, Poffe A, Piccoli L, Ratti E, Tranquillini E, Trower M, Spada S, Corsi M. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem. 2013 Nov 1;21(21):6264-73. doi: 10.1016/j.bmc.2013.09.001. Epub 2013 Sep 11. PubMed PMID: 24075145.

2: Ratti E, Bettica P, Alexander R, Archer G, Carpenter D, Evoniuk G, Gomeni R, Lawson E, Lopez M, Millns H, Rabiner EA, Trist D, Trower M, Zamuner S, Krishnan R, Fava M. Full central neurokinin-1 receptor blockade is required for efficacy in depression: evidence from orvepitant clinical studies. J Psychopharmacol. 2013 May;27(5):424-34. doi: 10.1177/0269881113480990. Epub 2013 Mar 28. PubMed PMID: 23539641.

///////Orvepitant, GW823296, PHASE 2, Neurokinin 1 (NK1) receptor antagonist

C[C@@H](N(C)C(=O)N1CC[C@@H](C[C@@H]1c1ccc(F)cc1C)N1CCN2[C@@H](CCC2=O)C1)c1cc(cc(c1)C(F)(F)F)C(F)(F)F

CC1=C(C=CC(=C1)F)C2CC(CCN2C(=O)N(C)C(C)C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)N4CCN5C(C4)CCC5=O

Enasidenib (AG-221)

Enasidenib (AG-221)

1446502-11-9
Chemical Formula: C19H17F6N7O
Exact Mass: 473.13988

AG-221; AG 221; AG221; CC-90007; CC 90007; CC90007; Enasidenib

IUPAC/Chemical Name: 2-methyl-1-((4-(6-(trifluoromethyl)pyridin-2-yl)-6-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,3,5-triazin-2-yl)amino)propan-2-ol

2-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

Agios Pharmaceuticals, Inc. innovator

Enasidenib, aslo known as AG-221 and CC-90007, is a potent and selective IDH2 inhibitor with potential anticancer activity (IDH2 = Isocitrate dehydrogenase 2). The mutations of IDH2 present in certain cancer cells result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). The production of 2HG is believed to contribute to the formation and progression of cancer . The inhibition of mutant IDH2 and its neoactivity is therefore a potential therapeutic treatment for cancer

AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein, making it a highly targeted investigational medicine for the potential treatment of patients with cancers that harbor an IDH2 mutation. AG-221 has received orphan drug and fast track designations from the U.S. FDA. In September 2013, Agios initiated a Phase 1 multicenter, open-label, dose escalation clinical trial of AG-221 designed to assess the safety and tolerability of AG-221 in advanced hematologic malignancies. In October 2014, Agios initiated four expansion cohorts as part of the ongoing Phase 1 study and expanded its development program with the initiation of a Phase 1/2 study of AG-221 in advanced solid tumors. For the detailed information of AG-221, the solubility of AG-221 in water, the solubility of AG-221 in DMSO, the solubility of AG-221 in PBS buffer, the animal experiment (test) of AG-221, the cell expriment (test) of AG-221, the in vivo, in vitro and clinical trial test of AG-221, the EC50, IC50,and affinity,of AG-221, For the detailed information of AG-221, the solubility of AG-221 in water, the solubility of AG-221 in DMSO, the solubility of AG-221 in PBS buffer, the animal experiment (test) of AG-221, the cell expriment (test) of AG-221, the in vivo, in vitro and clinical trial test of AG-221, the EC50, IC50,and affinity,of AG-221,

Agios Announces New Data from Ongoing Phase 1 Dose Escalation and Expansion Trial of AG-221 Showing Durable Clinical Activity in Patients with Advanced Hematologic Malignancies

IDH2-Mutant Inhibitor Shows Durable Responses of More than 15 Months in Patients with Advanced Acute Myeloid Leukemia (AML) and Other Blood Cancers

Proof-of-Concept Demonstrated in Myelodysplastic Syndrome (MDS) and Untreated AML

125-Patient Expansion Cohort and Global Registration-Enabling Program Remain on Track

Company to Host Conference Call and Webcast Today

CAMBRIDGE, Mass. & VIENNA--(BUSINESS WIRE)--Jun. 12, 2015-- Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic disorders of metabolism, today announced new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies. The data will be presented at the 20^th Congress of the European Hematology Association (EHA) taking place June 11-14, 2015 in Vienna.

Data as of May 1, 2015 from 177 patients (104 in dose escalation and 73 from the first four expansion cohorts) with advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than half of the 177 patients remain on treatment. The study had an overall response rate of 40 percent (63 of 158 response-evaluable patients, using the criteria below) and a complete remission rate of 16 percent (26 of 158 response-evaluable patients). Patients responding to AG-221 continue to show durable clinical activity on treatment for more than 15 months, with an estimated 76 percent of responders staying on treatment for six months or longer. The overall safety profile observed was consistent with previously reported data with more than 100 additional patients treated as of the last analysis.

This new data reflects responses in the evaluable population, which includes all patients with a pre-AG-221 screening assessment and day 28 or later response assessment or an earlier discontinuation for any reason. Patients with a screening assessment who were still on treatment, but had not reached the day 28 disease assessment, were excluded.

“The clinical profile of AG-221 continues to be impressive from the perspectives of response rate, durability, safety and unique mechanism of action,” said Courtney DiNardo, M.D., lead investigator and assistant professor, leukemia atUniversity of Texas MD Anderson Cancer Center. “Additionally, it is encouraging to see early proof-of-concept in myelodysplastic syndrome (MDS) and untreated acute myeloid leukemia (AML) given the need for more effective therapies for these patients.”

“As the data from the AG-221 study continue to mature, we are compiling a robust dataset to quickly move this program into global registration studies later this year in collaboration with Celgene,” said Chris Bowden, M.D., chief medical officer of Agios. “We are excited about the speed of enrollment we’ve seen to date in our four expansion cohorts and are on track to enroll our recently announced fifth expansion cohort of 125 patients with relapsed and/or refractory AML. With this progress, we are executing on our strategy to combine speed and breadth to reach people with hematologic malignancies in urgent need of better treatments.”

About the Ongoing Phase 1 Trial for AG-221 in Advanced Hematologic Malignancies

AG-221 is currently being evaluated in an ongoing Phase 1 trial that includes a dose-escalation phase and four expansion cohorts of 25 patients each, evaluating patients with relapsed or refractory AML who are 60 years of age and older and transplant ineligible; relapsed or refractory AML patients under age 60; untreated AML patients who decline standard of care chemotherapy; and patients with other IDH2-mutant positive hematologic malignancies. Data reported here are from patients receiving AG-221 administered from 60 mg to 450 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of May 1, 2015. The median age of these patients is 69 (ranging from 22-90). Treatment with AG-221 showed substantial reduction in the plasma levels of the oncometabolite 2-hydroxglutarate (2HG) to the level observed in healthy volunteers.

Safety Data

A safety analysis was conducted for all 177 treated patients as of May 1, 2015.

• The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, fatigue, increased blood bilirubin and diarrhea.
• The majority of serious adverse events (SAE) were disease related; SAEs possibly related to study drug were reported in 27 patients.
• A maximum tolerated dose (MTD) has not been reached.
• The all-cause 30-day mortality rate was 4.5 percent.

Efficacy Data

Sixty-three out of 158 response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 40 percent as of May 1, 2015.

• Of the 63 patients who achieved an objective response, there were 26 (16 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), two CRs with incomplete hematologic recovery (CRi) and 18 partial remissions (PR).
• Of the 111 patients with relapsed or refractory AML, 46 (41 percent) achieved an objective response, including 20 (18 percent) CRs, one CRp, 16 PRs, eight mCRs and one CRi.
• Of the 22 patients with AML that had not been treated, seven achieved an objective response, including three CRs, two PRs, one mCR and one CRi.
• Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including two CRs, one CRp and four mCRs.
• Responses were durable, with duration on study drug more than 15 months and ongoing. As of the analysis date, an estimated 88 percent of responses lasted three months or longer, and 76 percent of responses lasted six months or longer.

Upcoming Milestones for AG-221

Agios studies in IDH2-mutated solid and hematologic tumors are ongoing or planned for 2015 to further support development of AG-221.

• Continue to enroll patients in the fifth expansion cohort of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or re-induction treatment, or have relapsed after allogeneic transplantation.
• Initiate combination trials to evaluate AG-221 as a potential frontline treatment for patients with AML and a broad range of hematologic malignancies in the second half of 2015.
• Initiate a global Phase 3 registration-enabling study in relapsed/refractory AML patients that harbor an IDH2 mutation in the second half of 2015.
• Continue dose escalation in the Phase 1/2 trial in patients with advanced solid tumors, including glioma and angioimmunoblastic T-cell lymphoma (AITL) that carry an IDH2 mutation in 2015.

Conference Call Information

Agios will host a conference call and webcast from the congress to review the data on Friday, June 12, 2015, beginning at 8:00 a.m. ET (2:00 p.m. CEST). To participate in the conference call, please dial (877) 377-7098 (domestic) or (631) 291-4547 (international) and refer to conference ID 53010830. The webcast will be accessible live or in archived form under "Events & Presentations" in the Investors and Media section of the company's website at www.agios.com.

About Agios/Celgene Collaboration

AG-221, the IDH1-mutant inhibitor AG-120 and the pan-IDH mutant inhibitor AG-881 are part of Agios' global strategic collaboration with Celgene Corporation. Under the terms of the collaboration, Celgene has worldwide development and commercialization rights for AG-221. Agios continues to conduct clinical development activities within the AG-221 development program and is eligible to receive up to $120 million in payments on achievement of certain milestones and royalties on net sales. For AG-120, Agios retains U.S. development and commercialization rights. Celgene has an exclusive license outside the United States. Celgene is eligible to receive royalties on net sales in the U.S. Agios is eligible to receive royalties on net sales outside the U.S. and up to $120 million in payments on achievement of certain milestones. For AG-881, the companies have a joint worldwide development and 50/50 profit share collaboration, and Agios is eligible to receive regulatory milestone payments of up to $70 million.

About IDH Mutations and Cancer

IDH1 and IDH2 are two metabolic enzymes that are mutated in a wide range of hematologic and solid tumor malignancies, including AML. Normally, IDH enzymes help to break down nutrients and generate energy for cells. When mutated, IDH increases production of an oncometabolite 2-hydroxyglutarate (2HG) that alters the cells' epigenetic programming, thereby promoting cancer. 2HG has been found to be elevated in several tumor types. Agios believes that inhibition of the mutated IDH proteins may lead to clinical benefit for the subset of cancer patients whose tumors carry them.

About Acute Myelogenous Leukemia (AML)

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant, and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH2 mutations are present in about 9 to 13 percent of AML cases.

About Myelodysplastic Syndrome (MDS)

MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the United States each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy and supportive blood products are used to treat MDS.

About Agios Pharmaceuticals, Inc.

Agios Pharmaceuticals is focused on discovering and developing novel investigational medicines to treat cancer and rare genetic disorders of metabolism through scientific leadership in the field of cellular metabolism. In addition to an active research and discovery pipeline across both therapeutic areas, Agios has multiple first-in-class investigational medicines in clinical and/or preclinical development. All Agios programs focus on genetically identified patient populations, leveraging our knowledge of metabolism, biology and genomics. For more information, please visit the company’s website at agios.com.

clips

AG-221, Inhibitor Of IDH2 Mutants

 

COMBATTING CANCER

Agios’s AG-221 team. Front row (from left): Erin Artin, Kate Yen, Fang Wang, Hua Yang, and Lee Silverman. Back row (from left): Michael Su, Stefan Gross, Sam Agresta, Jeremy Travins, Yue Chen, and Lenny Dang.

Credit: Kevin Graham/Agios

The enzyme isocitrate dehydrogenase (IDH) is probably most famous for its role in the central cellular metabolic pathway, the Krebs cycle. The enzyme catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate. One subtype of the enzyme, IDH1, is found in cells’ cytoplasm, and another, IDH2, is found in their mitochondria.

AG-221

Company: Agios Pharmaceuticals
Target: IDH2

People with certain mutations in IDH end up making R-2-hydroxyglutarate (2-HG) instead of α-ketoglutarate. 2-HG is known to make cancer cells flourish. In fact, IDH mutations have been implicated in about 70% of brain cancers and have also been identified in solid tumors and blood cancers, such as acute myeloid leukemia.

Jeremy M. Travins of Agios Pharmaceuticals spoke about how scientists at the company found compounds based on substituted triazines that can cut down on 2-HG production by inhibiting a dimer of mutant IDH2. Using structure-activity relationships and a crystal structure of a lead compound bound to the mutant IDH2 dimer, they managed to develop a clinical candidate: AG-221. It turns out that AG-221 doesn’t bind to the active site of mutant IDH2. Rather, the compound binds to the spot where the two enzymes meet in the dimer.

Hitting this position in just the right way is tricky, Travins explained. Hydrogen-bonding interactions from the triazine and the two amino groups that flank it are critical.

The compound is in Phase I clinical trials, Travins said, and it’s been shown to lower 2-HG levels to those seen in people without cancer. What’s more, he noted, the drug candidate has few side effects, giving patients a higher quality of life than standard chemotherapeutic agents do.
Patent
http://www.google.com/patents/US20130190287
Compound 409—2-methyl-1-(4-(6-(trifluoromethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4-ylamino)-1,3,5-triazin-2-ylamino)propan-2-ol

¹H NMR (METHANOL-d₄) δ 8.62-8.68 (m, 2H), 847-8.50 (m, 1H), 8.18-8.21 (m, 1H), 7.96-7.98 (m, 1H), 7.82-7.84 (m, 1H), 3.56-3.63 (d, J=28 Hz, 2H), 1.30 (s, 6H). LC-MS: m/z 474.3 (M+H)⁺.

Patent ID	Date	Patent Title
US2013190287	2013-07-25	THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE

REFERENCES

1: Caino MC, Altieri DC. Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy. Clin Cancer Res. 2016 Feb 1;22(3):540-5. doi: 10.1158/1078-0432.CCR-15-0460. Epub 2015 Dec 9. PubMed PMID: 26660517; PubMed Central PMCID: PMC4738153.

2: Stein EM. IDH2 inhibition in AML: Finally progress? Best Pract Res Clin Haematol. 2015 Jun-Sep;28(2-3):112-5. doi: 10.1016/j.beha.2015.10.016. Epub 2015 Oct 19. Review. PubMed PMID: 26590767.

3: Rowe JM. Reasons for optimism in the therapy of acute leukemia. Best Pract Res Clin Haematol. 2015 Jun-Sep;28(2-3):69-72. doi: 10.1016/j.beha.2015.10.002. Epub 2015 Oct 22. Review. PubMed PMID: 26590761.

4: Stein EM. Molecular Pathways: IDH2 Mutations-Co-opting Cellular Metabolism for Malignant Transformation. Clin Cancer Res. 2016 Jan 1;22(1):16-9. doi: 10.1158/1078-0432.CCR-15-0362. Epub 2015 Nov 9. PubMed PMID: 26553750.

5: Kiyoi H. Overview: A New Era of Cancer Genome in Myeloid Malignancies. Oncology. 2015;89 Suppl 1:1-3. doi: 10.1159/000431054. Epub 2015 Nov 10. Review. PubMed PMID: 26551625.

6: Tomita A. [Progress in molecularly targeted therapies for acute myeloid leukemia]. Rinsho Ketsueki. 2015 Feb;56(2):130-8. doi: 10.11406/rinketsu.56.130. Japanese. PubMed PMID: 25765792.

/////////Enasidenib, AG-221,

CC(O)(C)CNC1=NC(C2=NC(C(F)(F)F)=CC=C2)=NC(NC3=CC(C(F)(F)F)=NC=C3)=N1

PF-06260414

PF-06260414
CAS: 1612755-71-1
Chemical Formula: C14H14N4O2S
Exact Mass: 302.0837

PF-06260414; PF 06260414; PF06260414; PF6260414; PF-6260414; PF 6260414.

IUPAC/Chemical Name: (R)-6-(4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)isoquinoline-1-carbonitrile

• 6-[(4R)-4-Methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile

https://clinicaltrials.gov/ct2/show/NCT02070939

• 28 Jul 2015Discontinued - Phase-I for Cachexia in USA (PO)
• 27 Apr 2015Pfizer terminates a phase I trial (In volunteers) in USA (NCT02393807)
• 26 Mar 2015Pfizer plans a phase I pharmacokinetic trial for Healthy volunteers in USA (NCT02393807)

Company	Pfizer Inc.
Description	Selective androgen receptor modulator
Molecular Target	Androgen receptor
Mechanism of Action
Therapeutic Modality

Latest Stage of Development	Phase I
Standard Indication	Cachexia
Indication Details	Treat cachexia

PF-06260414 is a selective androgen receptor modulator, or SARM, which is developed to treat muscle weakening. Testosterone’s anabolic properties help develop muscle mass, and its androgenic activity is associated with reproduction. Improving muscle mass would improve quality of life and may even prolong survival in certain patient populations.
PATENT
WO 2015173684
http://www.google.com/patents/WO2015173684A1?cl=en

The androgen receptor ("AR") is a ligand-activated transcriptional regulatory protein that mediates induction of male sexual development and function through its activity with endogenous androgens. Androgenic steroids play an important role in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth,
spermatogenesis, and the male hair pattern. The endogenous steroidal androgens include testosterone and dihydrotestosterone ("DHT"). Steroidal ligands which bind the AR and act as androgens (e.g. testosterone enanthate) or as antiandrogens (e.g.
cyproterone acetate) have been known for many years and are used clinically.
6-[(4f?)-4-Methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile (Formula I), in its free base form, has the chemical formula C14H14N4SO2 and the following structural formula:

Formula I
Synthesis of 6-[(4f?)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile is disclosed in co-pending international patent application,
PCT/IB2013/060381 , filed 25^th November 2013, and published as WO 2014/087298 on 12^th June 2014, assigned to the assignee of the present invention and which is incorporated herein by reference in its entirety. 6-[(4f?)-4-Methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile is known to be active as a selective androgen receptor modulator (SARM) and, as such, is useful for treating and/or preventing a variety of hormone-related conditions, for example, conditions associated with androgen decline, such as, inter alia, anaemia; anorexia; arthritis; bone disease; musculoskeletal impairment; cachexia; frailty; age-related functional decline in the elderly; growth hormone deficiency; hematopoietic disorders; hormone replacement; loss of muscle strength and/or function; muscular dystrophies; muscle loss following surgery; muscular atrophy; neurodegenerative disease; neuromuscular disease;
obesity; osteoporosis; and, muscle wasting.
Identification of new solid forms of a known pharmaceutical active ingredient provide a means of optimising either the physicochemical, stability, manufacturability and/or bioperformance characteristics of the active pharmaceutical ingredient without modifying its chemical structure. Based on a chemical structure, one cannot predict with any degree of certainty whether a compound will crystallise, under what conditions it will crystallise, or the solid state structure of any of those crystalline forms. The specific solid form chosen for drug development can have dramatic influence on the properties of the drug product. The selection of a suitable solid form is partially dictated by yield, rate and quantity of the crystalline structure. In addition, hygroscopicity, stability, solubility and the process profile of the solid form such as compressibility, powder flow and density are important considerations.

The general reaction schemes provided herein illustrate the preparation of 6-[(4f?)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile (Formula I).

Example 1

Procedure:

Into a 2L 3-neck round bottom flask equipped with a mechanical stirrer, reflux condenser and thermocouple with heating mantle was placed 2-methyltetrahydrofuran (2-MeTHF) (10 mL/g; 8.15 moles; 817 ml_; 702 g) followed by racemic-2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl (BINAP) (0.04 equiv (molar); 14.0 mmol; 8.74 g) and bis(dibenzylideneacetone)palladium (Pd₂(dba)₃) (0.04 equiv (molar); 14.0 mmol;

8.07 g). The mixture was degassed by pulling vacuum and refilling with nitrogen three times then heated to 75 °C for 15 minutes and cooled to ambient temperature. In a separate flask, (S)-3-amino-2-methylpropan-1-ol (1.60 equiv; 561 mmol; 50.0 g, prepared using literature methods, for example as disclosed in EP-A-0,089, 139 published on 21^st September 1983) was dissolved in 2-methyltetrahydrofuran (5 ml_/g;

4.08 moles; 409 ml_; 351 g) and degassed by pulling vacuum and refilling with nitrogen three times. Into the pot containing the catalyst was added 6-(bromoisoquinoline-1- carbonitrile) (1.00 equiv; 351 mmol; 81.75 g) and cesium carbonate (1.6 equiv (molar); 561 mmol; 185 g) in single portions followed by the solution of the aminoalcohol via addition funnel. The reaction mixture was again degassed by pulling vacuum and refilling with nitrogen three times. The reaction was heated to 70 °C for 3 hours. The reaction was cooled to ambient temperature and filtered through a pad of Celite. The contents of the flask were rinsed out with three 100 mL portions of 2-methyltetrahydrofuran. The filtrate was transferred into a 2L round bottom flask equipped with a thermocouple and mechanical stirrer under nitrogen. Silica Gel (Silicylate SiliaMet® Thiol) (0.4 g/g-pure-LR; 544 mmol; 32.7 g) was charged and the flask was stirred at 40 °C overnight. The following morning, the reaction was cooled to < 30 °C and filtered again through Celite. The pad was washed with 100ml_ of 2-methyltetrahydrofuran (or until no yellow color persisted in the filtrate). The filtrate was placed into a 3L round bottom flask equipped with a magnetic stir bar, distillation head (with condenser and receiving flask), and thermocouple. The mixture was heated to 60 °C and placed under vacuum (-450-500 mbar) to distil out 1.3 L total of 2-methyltetrahydrofuran. 500 mL of toluene was added to precipitate the desired product. The heating mantle was removed and the reaction was allowed to reach ambient temperature. The mixture was stirred for 1 hour at ambient temperature and then the solids were collected by vacuum filtration on a sintered glass funnel. The cake was dried overnight on the funnel under vacuum. The following morning, the solids were transferred into an amber bottle and weighed (71.9 g; 298 mmol). The product was used in the next step without further purification.

Example 2

Procedure:

In a 1 L reactor equipped with a temperature probe and overhead stirring was added the product of Example 1 (20.0 g; 1.00 equiv; 82.9 mmol) and 2-methyltetrahydrofuran (2-MeTHF) (30 mL/g-pure-LR; 5.98 moles; 600 mL; 515 g). The reaction mixture was

gently warmed to 40°C to achieve partial solubility. The reaction was cooled to 0°C. Once the reaction reached 0°C methanesulfonyl chloride (MsCI) (1.4 equiv (molar); 1 16 mmol; 8.98 mL; 13.3 g) was added in a single portion followed immediately by triethylamine (TEA) (1.4 equiv (molar); 116 mmol; 16.2 mL; 11.7 g) dropwise via syringe over a period of 15 minutes. The reaction mixture was further stirred for 30 min at 0°C and then warmed to 23°C for 60 minutes. The product (26.47 g; 1.00 equiv; 82.88 mmol; 26.47 g; 100% assumed yield) was then used without purification for the sulfonylation reaction.

Example 3

t-BuOH, 2-MeTHF

o 0 °C to 23 °C o

CI-S-N=C=0 CI-S-NHBoc

0 O

Procedure:

To a solution of t-butyl alcohol (t-BuOH) (1 equiv (molar); 116 mmol; 1 1.0 mL; 8.60 g) in 2-methyltetrahydrofuran (2-MeTHF) (1 M; 1.16 moles; 116 mL; 99.6 g) at 0°C was added chlorosulfonyl isocyanate (116 mmol; 1.00 equiv; 10.1 mL; 16.4 g) dropwise. The homogeneous solution was stirred for 30 minutes at ambient temperature and then used directly in the sulfonylation reaction.

Example 4

Sulfonylation Reaction Procedure:

A previously prepared solution of the product of Example 3 (1.4 equiv (molar); 1 16 mmol; 116 g) in 2-methyltetrahydrofuran was added to a suspension of the product of Example 2 (1.00 equiv; 82.89 mmol; 26.5 g) at 0°C. The mixture was warmed to ambient temperature over 30 minutes. HPLC analysis revealed the reaction was complete. The reaction was quenched with a 10% sodium carbonate solution (2 equiv

(molar); 165 mmol; 101 mL; 1 17 g) and water (to dissolve salts) (5 L/kg; 7.35 moles; 132 mL; 132 g). The top organic layer was removed and passed through a plug of Carbon (Darco G60) (0.5 g/g) on a filter. A significant improvement in color (dark orange to yellow) was observed. The solution was concentrated to 10 total volumes and used in the next step without purification.

Example 5

Procedure:

A solution of the product of Example 4 (1.OOequiv; 82.9 mmol; 41.3 g) in 2-methyltetrahydrofuran (2-MeTHF) (10ml_/g; 4.12 moles; 413 mL; 355 g) was placed into a 1 L reactor equipped with an overhead stirrer and temperature probe. Next, potassium carbonate (K₂CO₃) (325 mesh) (6 equiv (molar); 497 mmol; 69.4 g) and water (0.0 L/100-g-bulk-LR; 459 mmol; 8.26 mL; 8.26 g) were added and the mixture heated to 40°C (jacket temperature) and stirred overnight. The reaction was cooled to ambient temperature and water (4L/kg-pure-LR; 9.17 moles; 165 mL; 165 g]) was added. The biphasic reaction was stirred for 1 hour at 23 °C. The aqueous layer was extracted and removed. The organic layer was passed through a plug of Carbon (Darco G60) (0.5 g/g-pure-LR; 20.7g) in a disposable filter. The 2-methyltetrahydrofuran solution was switched to a 10 volume solution of toluene via a constant strip-and-replace distillation to no more than 1 % 2-methyltetrahydrofuran. The toluene solution of the reaction product (1.00 equiv; 82.9 mmol; 33.4 g; 100% assumed yield) was used as-is in the next step without further purification.

Example 6

Procedure:

To a 1 L reactor under nitrogen and equipped with overhead stirring and a temperature probe was added the product of Example 5 (1.00 equiv; 78.7 mmol; 33.4 g) as a solution in toluene (10 mL/g-pure-LR; 3.00 moles; 317 ml_; 276 g). Next, trifluoroacetic acid (TFA) (10 equiv (molar); 787 mmol; 59.5 ml_; 89.8 g) was added to the reaction over a period of 1 hour keeping the internal temperature below 30°C. The dark red mixture was stirred for 1 hour. The reaction was quenched at 23 °C by the addition of sodium carbonate (5 equiv (molar); 394 mmol; 240 ml_; 278 g). The reaction was quenched slowly, over a period of 1 hour to form the TFA salt of the product. Once the charge was complete, the mixture was cooled to 0°C, held for 1 hour and filtered. The next morning, the solid product (6-[(4R)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile in its free base form) was weighed (0.89 equiv; 70.0 mmol; 21.2 g; 89.0% yield) and used in the next step without further purification.

Example 7

Crystalline 6-[(4f?)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile free base (Form (1)) was prepared as follows.

In a 1 L 3-neck round bottom flask was added 6-[(4R)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile free base (1.00 equiv; 70.0 mmol; 21.2 g) a magnetic stir bar and acetone (40ml_/g; 1 1.5 moles; 847 ml_; 669 g). The mixture was heated to reflux (approximately 57°C) and stirred for 1 hour. The mixture was concentrated by atmospheric distillation (heating mantle set at 65°C) and 40ml_ of acetone was collected into a graduated cylinder. Next, water (25 mL/g; 29.4 moles; 530 ml_; 530 g) was charged over a period of one hour. The mixture was stirred at ambient temperature for 60min before being cooled to 0°C at 1 °C /min for 1 hour. The solids were collected by filtration in a disposable funnel. Crystalline 6-[(4f?)-4-methyl-1 , 1-dioxido-1 ,2,6-thiadiazinan-2-yl]isoquinoline-1-carbonitrile (Form (1), 0.88 equiv; 61.9 mmol; 18.7 g; 88.3% yield) was dried under vacuum overnight at 40 °C. Typical purity after crystallization is 98%.

PATENT
US 20140155390


Step 1. Synthesis of 6-bromoisoquinoline (#A1). A mixture of 4-bromobenzaldehyde (300.0 g, 1620.0 mmol) and amino acetaldehyde dimethyl acetal (170.4 g, 1620 mmol) in anhydrous toluene (1.5 L) was refluxed under a Dean-Stark condenser for 12 h. The solution was concentrated under vacuum. The residue was dissolved in anhydrous THF and cooled to —10° C. Ethyl chloroformate (193.3 mL, 1782 mmol) was added and stirred for 10 min at −10° C., and then allowed to warm to room temperature. Subsequently trimethyl phosphite (249.6 mL, 1782.0 mmol) was added dropwise to the reaction mixture and stirred for 10 h at room temperature. The solvent was evaporated under vacuum and the residue was dissolved in anhydrous DCM (1.5 L) and stirred for 30 minutes. The reaction mixture was cooled to 0° C., and titanium tetrachloride (1.2 L, 6480 mmol) was added dropwise. The reaction mixture was stirred at 40° C. for 6 days. The reaction mixture was poured into ice and pH was adjusted to 8-9 with aqueous 6N NaOH solution. The suspension was extracted three times with EtOAc. The organic layer was extracted with 3 M HCl. The acidic aqueous solution was adjusted to pH to 7-8 with 3N NaOH solutions and extracted two times with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the product. Crude compound was dissolved in minimum amount of DCM and mixed with pentane to get compound #A1 as light brown solid. Yield: 90 g (35%). R_f: 0.6 (30% EtOAc in petroleum ether).

LCMS m/z=209 (M+1). ¹H NMR (400 MHz, d₆-DMSO): δ 7.82 (m, 2H), 8.11 (d, J=8.8 Hz, 2H), 8.30 (br s, 1H), 8.56 (d, J=6.0 Hz, 1H), 9.35 (s, 1H).
Step 2. Synthesis of 6-bromoisoquinoline 2-oxide (#A2). m-Chloroperoxybenzoic acid (120.0 g, 720.0 mmol) was added to a solution of #A1 (90.0 g, 480.0 mmol) in DCM (500 mL) at room temperature, and the reaction mixture was stirred for 16 h. 1N NaOH was added to the stirred reaction mixture to adjust the pH to 7-8. The layers were separated and the aqueous layer was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to render crude product. The solid product was triturated with the mixture of n-pentane and ethanol (8:2) to get the #A2 as white solid. Yield: 65 g (60%). R_f: 0.2 (EtOAc).
LCMS m/z=225 (M+1). ¹H NMR (400 MHz, d₆-DMSO): δ 7.83 (m, 2H), 7.91 (d, J=6.8 Hz, 1H), 8.21 (dd, J=8.0, 1.2 Hz, 1H), 8.26 (br s, 1H), 8.97 (s, 1H).

Step 3. Synthesis of 6-bromoisoquinoline-1-carbonitrile (#A3). Trimethylsilyl cyanide (52.0 mL, 580.0 mmol) was added dropwise to the stirred solution of #A2 (65.0 g, 290.0 mmol) and DBU (50.0 mL, 348.0 mmol) in THF (500 mL) at room temperature over a period of 15 minutes. The reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the solution was extracted with DCM. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude product. The product was purified by column chromatography using silica gel (100-200 mesh) with 0-4% EtOAc in petroleum ether as an eluent to give #A3 as white solid. Yield: 41 g (61%). R_f: 0.6 (30% EtOAc in petroleum ether).
LCMS m/z=233 (M+1). ¹H NMR (400 MHz, d₆-DMSO): δ 8.07 (dd, J=11.2, 2.0 Hz, 1H), 8.21 (m, 2H), 8.55 (br s, 1H), 8.77 (d, J=7.6 Hz, 1H).
A General Procedure to Prepare Intermediates of #A4, #A5, #A6 and #1, #2, #3, #4, #6, #7.
Step 4. A solution of #A3 (1 eq.) in toluene (50 mL) was degassed by bubbling with argon gas for 15 min and then Pd₂dba₃ (0.03 eq.), BINAP (0.06 eq.) and Cs₂CO₃(3 eq.) were added to the solution followed by the addition aminoalcohol (2 eq.). The mixture was heated at 100° C. under argon atmosphere for 3 h. Reaction mixture was cooled to room temperature, diluted with EtOAC and washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated to get crude product. The crude compounds were purified by silica gel (100-200 mesh) column chromatography by using 0-5% MeOH in DCM. Yields: 25-45%.
Step 5. MsCl (1 eq.) was added dropwise to a solution of #A4 (1 eq.) and Et₃N (2 eq.) in DCM (10 mL) at 0° C. and was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM, washed with water and brine. The organic layer was dried over Na₂SO₄ and concentrated. Crude products were used in next step without further purification.
Step 6. t-Butanol (2 eq.) was slowly added to a solution of chloro sulfonyl isocyanate (2 eq.) in toluene (1 mL/1 mmol) at 0° C. The reaction mixture was stirred at room temperature for 45 min. This solution (t-butyl chlorosulfonylcarbamate) was then added to a solution of #A5 (1 eq.) and DIPEA (4 eq.) in THF and stirred at room temperature for 12 h. Reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with water, brine, then dried over anhydrous Na₂SO₄ and concentrated. Crude products were purified by silica gel (100-200 mesh) column chromatography using 0-40% EtOAc in petroleum ether.
Step 7. TFA was added to a solution of #A6 (1 eq.) in DCM (8 mL) at 0° C. and stirred at room temperature for 2 h. Reaction mixture was concentrated, diluted with water, neutralized with sat. aq. NaHCO₃ soln. then extracted with DCM. The organic layer was washed with water and dried over Na₂SO₄ then concentrated. The crude products were purified by triturating with DCM and pentane to provide the compound. In the case of racemic materials, the enantiomers were separated by chiral preparative HPLC.
Column: CHIRALPAK IA, 4.6 mm×250, 5 μm; Mobile phase: n-Hexane: EtOH (65:35) (For X3: 35:65; For X2: 70:30); Flow rate: 1 mL/min; Eluent: EtOH.

EXAMPLE 16-[(3S)-3-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl]isocluinoline-1-carbonitrile (#1; R═CH3)

LCMS m/z=289.1 (M+1). ¹H NMR (400 MHz, d₆-DMSO): δ 1.37 (d, J=6.3 Hz, 3H), 3.27 (m, 1H), 3.74 (m, 1H), 4.63 (m, 1H), 7.17 (d, J=5.7 Hz, 1H), 7.72 (m, 1H), 7.89 (dd, J=10.7, 2.1 Hz, 1H), 8.26 (m, 2H), 8.62 (d, J=5.7 Hz, 1H).

PATENT

WO 2015181676

example 9

6 - [(3S) -3-methyl-1, 1 -dioxido-1, 2,5-thiadiazolidin-2-carbonitrile 1-yl1naphthalene

(Stereochemistry is arbitrarily Assigned)

LCMS m / z = 286.0 (M - H). ¹ H NMR (400 MHz, cf ₆ -DMSO): δ 1 .31 (d, J = 6.2 Hz, 3H), 3.13 - 3.25 (m, 1H), 3.71 (dt, J = 12.5, 6.8 Hz, 1H), 4.49 - 4.62 (m, 1H), 7.62 - 7.70 (m, 1H), 7.75 - 7.83 (m, 2H), 7.99 (t, J = 7.8 Hz, 1H), 8.07 (d, J = 6.6 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H). Chiral HPLC purity: 99.1% (retention time 17.12 minutes)

Step 1. Synthesis of amino ester (# D1). Thionylchlride (8.5 mL, 1 16.5 mmol) Was added to the solution of amino acid (4.0 g, 38.8 mmol) in MeOH (170 mL) at 0 ° C, and the reaction mixture Was Stirred for 6 h at room temperature. The reaction Was monitored by TLC, and after-disappearance of the starting material It was cooled to room temperature and solid NaHC0 ₃ Was added. The reaction mixture Was filtered, concentrated in vacuo and the resulting and residue Was triturated with diethyl ether to crude obtenir # D1 (4 g, 90%) as a white solid. R _f : 0.4 (f-BuOH: AcOH: H ₂ 0 (4: 0.5: 0.5)).

GCMS m / z 1 17.1 (M +). ¹ H NMR (400 MHz, cf ₆ -DMSO): δ 1.17 (d, J = 6.8Hz, 3H), 2.83 - 2.88 (m, 2H), 3.03 - 3.05 ( m, 1H), 3.65 (s, 3H), 8.02 - 8.30 (br s, 3H).

Step 2. Synthesis of aminoalcohol (# D2). # D1 (2.0 g, 13.0 mmol) Was added

portionwise to a suspension of LiAlH ₄ (1.4 g, 39.2 mmol) in THF (75 mL) under nitrogen atmosphere at 0 ° C. The reaction mixture Was Stirred for 30 minutes and allowed to stir Then at room temperature for Reviews another 30 minutes. The reaction mixture Was Refluxed for 2 h, And Then It was cooled to -10 ° C and quenched with ice cold water Carefully (1.4 mL). 10% NaOH solution (2.8 mL) and ice cold water (4.2 mL) Were added, and the mixture Was Stirred for 15 minutes. It was filtered, and the filtrate washed with EtOAc (3 x 100 mL), dried over anhydrous Na ₂ S0 ₄ and Concentrated under vacuum to obtenir # D2 (1.2 g, 86%) as a pale yellow liquid. R _f: 0.2 (20% MeOH in DCM).

¹ H NMR (400 MHz, cf ₆ -DMSO): δ 0.78 (d, J = 6.8Hz, 3H), 1.46 - 1.54 (m, 1H), 2.41 -2.45 (m, 2H), 2.50 - 2.54 (m , 1H), 3.22 - 3.34 (m, 4H).

Step 3. Synthesis of coupling product (# D3). K ₃ P0 ₄ (6.1 g, 28.8 mmol), BINAP (0.44 g, 0.72 mmol) and Pd ₂ (dba) ₃ (0.32.0 g, 0.36 mmol) Was added to the degassed

suspension of 6-bromo-1 -cyanoisoquinoline # A3 (1.7 g, 7.2 mmol), # D2 (1.2 g, 14.5 mmol) in DMSO at room temperature. The reaction mixture Was heated at 105 ° C for 2 h. The reaction Was cooled to room temperature, water (500 mL) Followed by EtOAc (100 mL) Were added, and the mixture Was Stirred for 10 minutes. The biphasic mixture Was filtered through a Celite ™ pad and washed with EtOAc (100 mL). The organic layer Was separated, and the aqueous layer Was Extracted with EtOAc (3 x 100 mL). The combined organic layers Were dried over anhydrous Na ₂ S0 ₄ , concentrated under Reduced pressure to get a crude material. Reviews This was purified by column chromatography on 100-200 mesh silica gel, using 50-70% EtOAc in petroleum ether as the eluent to obtenir # D3 (0.5 g, 48.5%) as a yellow solid. R _f : 0.4 (60% EtOAc in petroleum ether).

LCMS m / z = 242.0 (M + H). ¹ H NMR (400 MHz, cf ₆ -DMSO): δ 0.97 (d, J = 6.4Hz, 3H), 1.87 - 1.99 (m, 1H), 2.92 - 2.99 (m, 1H), 3.20 - 3.27 (m, 1H), 3.38 - 3.42 (m, 2H), 4.59 (t, J = 5.2 Hz, 1H), 6.77 (d, J = 2.0, 1H ), 7.01 (t, J = 5.6 Hz, 1H), 7.34 (dd, J = 9.2 Hz, J = 2.0 Hz, 1H), 7.73 (d, J = 6.0 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 8.312 (d, J = 6.0 Hz, 1H).

Step 4. Methanesulfonated coupling product (# D4). Triethylamine (0.44 mL, 3.1 mmol) Was added to a solution of # D3 (0.50 g, 2.0 mmol) in DCM at 0 ° C.

Methanesulfonylchloride (0.25 mL, 3.1 mmol) Was added over 10 minutes, and the reaction mixture Was Stirred for 1 h at room temperature. After disappearance of the starting material by TLC, It was diluted with DCM and washed with water. The organic layer Was separated, dried over Na ₂ S0 ₄ , concentrated under pressure to obtenir Reduced crude # D4 (0.6 g, crude) as yellow solid. Reviews This was used for next step Without Any purification. R _f : 0.6 (50% EtOAc in petroleum ether).

LCMS m / z = 320.0 (M + H). ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.17 (d, J = 6.8Hz, 3H), 2.32 - 2.37 (m, 1H), 3.06 (s, 3H), 3.26 - 3.41 (m, 2H), 4.16 - 4.20 (m, 1H), 4.33 - 4.37 (m, 1H), 4.75 (br s, 1H), 6.70 (d, J = 2.4, 1 H), 7.09 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.57 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H).

Step 5. cyclized and uncyclized intermediates (# D5, D6 #). Chlorosulfonyl isocyanate (1.2 mL, 13.1 mmol) Was added dropwise to a solution of f-BuOH (1.4 mL, 13.1 mmol) in toluene (4.0 mL) at -5 ° C. The reaction mixture Was Stirred at room temperature for 20 minutes, And Then THF (1 mL) Was added to the resulting suspension to obtenir clear solution. In Reviews another flask, DIPEA (2.3 mL, 13.1 mmol) Was added to a solution of # D4 (0.6 g, 2.6 mmol crude) in dry THF (3 mL). The Above Prepared reagent (CIS0 ₂ NH-Soc) Was added to this reaction mixture dropwise at room temperature over a period of 20 minutes. The resulting and reaction mixture Was Then Stirred for 16 h at room temperature. The mixture Was diluted with EtOAc (100 mL) and washed with water (100 mL). The aqueous layer Was washed with EtOAc (2 x 100 mL), combined all the organic layers, dried over Na ₂ S0 ₄ , concentrated under Reduced pressure to obtenir the crude product (LCMS shows Desired # D6 and uncyclized # D5. This crude Was purified by column chromatography on 100-200 mesh silica gel, using 10-30% EtOAc in petroleum ether as an eluent to obtenir Desired # D6 (0.35 g, 47.8%), and uncyclized # D5 (0.22 g, crude).

The uncyclized # D5 (0.22 g, crude) Was Dissolved in THF (1 mL) and DIPEA (0.6 ml) Was added to the solution. The reaction mixture Was Stirred Reviews another for 12 h at room temperature. After qui time, It was diluted with EtOAc (100 mL) and washed with water (100 mL). The aqueous layer Was washed with EtOAc (2 x 100 mL), combined all the organic layers, dried over Na ₂ S0 ₄ , concentrated under pressure to obtenir Reduced crude product. Was this crude purified by column chromatography on 100-200 mesh silica gel, using 10-30% EtOAc in petroleum ether as an eluent to obtenir Desired # D6 (1 .1 g, 13.2%). Total amount of # D6 Was (0.5 g, 60% for two steps, 82% purity LCMS). R _f : 0.8 (60% EtOAc in petroleum ether).

LCMS m / z = 403.1 (M + H). ¹ H NMR (400 MHz, CDCl3): δ 1 .04 (d, J = 6.8 Hz, 3H), 1 .50 (s, 9H), 2.38 - 2.48 ( m, 1H), 3.65 - 3.82 (m, 2H), 3.92 - 4.02 (m, 1H), 4.30 - 4.38 (m, 1H), 7.79 - 7.81 (m, 1H), 7.86 - 7.88 (m , 2H), 8.34 - 8.37 (d, J = 9.2 Hz, 1H), 8.67 (d, J = 6.0 Hz, 1H).

Step 6. Racemate # D7 and final products (# 10, # 11). TFA (5 mL) Was added to a solution of # D6 (0.15 g, 0.37 mmol) in DCM (100 mL) at 0 ° C. The reaction mixture Was Stirred for 1 h at 0 ° C. The solution Was Neutralized with saturated aqueous NaHC03 solution at 0 ° C. The mixture Was diluted with water, Extracted with DCM (3 x 100 mL). The combined organic layers Were dried over anhydrous Na ₂ S0 ₄ and Concentrated under pressure Reduced to obtenir racemic # D7 (0.10 mg, 73%).

LCMS m / z = 303.0 (M + H). R _f : 0.3 (60% EtOAc in petroleum ether).

Enantiomeric separation: # D7 Was Submitted for chiral separation to obtenir final compounds # 10 (0.015 mg) and # 11 (0.016 mg).

Column: CHIRALPAK IA, 4.6 χ 250 mm, 5 m; Mobile phase: n-Hexane / / -PrOH / DCM (60% / 15% / 15%); Flow rate: 0.8 mL / min.

example 10

6 - [(4R) -4-methyl-1, 1 -dioxido-1, 2,6-thiadiazinan-2-yl1isoquinoline-1-carbonitrile (# 10; R = (R) -CH ₃ )

LCMS m / z = 303.0 (M + 1). ¹ H NMR (400 MHz, cf ₆ -DMSO): δ 0.98 (d, J = 6.4Hz, 3H), 2.22 - 2.26 (m, 1H), 3.16 - 3.22 (m, 1H), 3.34 - 3.39 (m, 1H), 3.59 - 3.65 (m, 1H), 3.77 - 3.81 (m, 1H), 7.75 - 7.79 (m, 1H, Disappeared in D20 exchange), 7.95 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 8.06 (d, J = 1 .6 Hz, 1H), 8.23 - 8.27 (m, 2H), 8703 (d, J = 5.2 Hz, 1H). R _f : 0.3 (60% EtOAc in petroleum ether). Chiral HPLC purity: 98.2% (retention time on January 1 .43 minutes).

CLIP

PF-06260414, A Treatment For Muscle Diseases

PF-06260414

Company: Pfizer
Target: Androgen receptors
Disease: Muscular dystrophy, atrophy, sarcopenia

Chekler

 

 

There aren’t many options when it comes to treating weakening muscles caused either by a disease such as muscular dystrophy or atrophy or by sarcopenia, the natural muscle weakening that comes with age. Doctors’ primary option is to give patients testosterone—a hormone with serious unwanted side effects on reproductive organs, the liver, and kidneys.

Morris

 

Credit: Pfizer

Owens

 

Pfizer’s Eugene Chekler spoke about PF-06260414, a selective androgen receptor modulator, or SARM, the company developed to treat muscle weakening. The idea, Chekler told C&EN, was to develop a nonsteroidal small molecule that would target androgen receptors but wouldn’t have any of testosterone’s negative side effects.

Gilbert

 

 

Testosterone’s anabolic properties help develop muscle mass, and its androgenic activity is associated with reproduction. To discover their SARM, Pfizer’s scientists used a novel screening strategy in which they decoupled anabolic and androgenic properties in vitro, Chekler said. Compounds that performed well in the muscle assay but had little effect in an assay that predicts androgenic response were developed further.

PF-06260414’s key pharmacophore is an isoquinoline with a pendant cyano group. The molecule also features a cyclic sulfuric diamide. It has completed Phase I clinical trials. “The market potential for this kind of treatment is huge,” Chekler said. “Improving muscle mass would improve quality of life and may even prolong survival in certain patient populations.”

Many answers from a first in human (FIH) study: Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PF-06260414 in healthy Western and Japanese males
Annu Meet Am Soc Clin Pharmacol Ther (ASCPT) (March 8-12, San Diego) 2016, Abst PI-021

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