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DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution, ........amcrasto@gmail.com..........+91 9323115463, Skype amcrasto64 View Anthony Melvin Crasto Ph.D's profile on LinkedIn Anthony Melvin Crasto Dr.

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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SELETALISIB, селеталисиб , سيلستاليسيب , 司来利塞 ,


Image result for SELETALISIB

Thumb

ChemSpider 2D Image | Seletalisib | C23H14ClF3N6O

DB12706.png

SELETALISIB

CAS 1362850-20-1

UCB-5857 , Plaque psoriasis,Sjoegren’s syndrome,Immunodeficiency disorders

PHASE 3 UCB

23H14ClF3N6O , 482.85

Phosphatidylinositol 3 kinase delta (PI3Kδ) inhibitors

10023
1362850-20-1 [RN]
N-{(1R)-1-[8-Chlor-2-(1-oxido-3-pyridinyl)-3-chinolinyl]-2,2,2-trifluorethyl}pyrido[3,2-d]pyrimidin-4-amine
N—{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}N-(1-oxypyrido-[3,2-d]pyrimidin-4-yl)amine
Pyrido[3,2-d]pyrimidin-4-amine, N-[(1R)-1-[8-chloro-2-(1-oxido-3-pyridinyl)-3-quinolinyl]-2,2,2-trifluoroethyl]-

3-{8-chloro-3-[(1R)-2,2,2-trifluoro-1-({pyrido[3,2-d]pyrimidin-4-yl}amino)ethyl]quinolin-2-yl}pyridin-1-ium-1-olate

селеталисиб [Russian] [INN]
سيلستاليسيب [Arabic] [INN]
司来利塞 [Chinese] [INN]
N-[(1R)-1-[8-chloro-2-(1-oxidopyridin-1-ium-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl]pyrido[3,2-d]pyrimidin-4-amine

Seletalisib has been used in trials studying the treatment and basic science of Primary Sjogren’s Syndrome.

  • Originator UCB
  • Class Anti-inflammatories; Small molecules
  • Mechanism of Action Immunomodulators; Phosphatidylinositol 3 kinase delta inhibitors
  • Phase III Immunodeficiency disorders
  • Phase II Sjogren’s syndrome
  • No development reported Plaque psoriasis
  • 05 Dec 2017 UCB Celltech terminates a phase II trial in Sjogren’s syndrome in France, Spain, United Kingdom, Greece, Sweden, Italy, due to enrolment challenges (PO) (NCT02610543) (EudraCT2014-004523-51)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Plaque-psoriasis in United Kingdom (PO, Capsule)
  • 14 Jun 2017 Pharmacokinetics and pharmacodynamics data from Preclinical and Clinical studies in Immunodeficiency disorders presented at the 18th Annual Congress of the European League Against Rheumatism (EULAR-2017)

SYN

US 9029392

https://patents.google.com/patent/US9029392B2/en

Example 27 N—{(R)-1-[8-Chloro-2-(pyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}N-(1-oxypyrido-[3,2-d]pyrimidin-4-yl)amine

A stirred solution of Example 1 (955 mg, 2.05 mmol) in DCM (40 mL) was cooled to 0° C. MCPBA (410 mg, 1.84 mmol) was added and the mixture was allowed to warm slowly to r.t. over 3 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCOsolution. The aqueous phase was extracted with further DCM and the combined organic fractions were washed with brine, dried Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography (SiO2, 3-60% MeOH in EtOAc) to give the title compound (39 mg, 4%) as a yellow solid. δ(DMSO-d6) 9.64-9.52 (m, 1H), 9.30 (s, 1H), 9.06 (dd, J 4.2, 1.3 Hz, 1H), 8.78-8.71 (m, 2H), 8.67 (dd, J 4.9, 1.6 Hz, 1H), 8.64 (s, 1H), 8.16-8.01 (m, 4H), 7.75-7.69 (m, 1H), 7.52 (ddd, J 7.8, 4.9, 0.7 Hz, 1H), 6.65-6.52 (m, 1H). LCMS (ES+) 483 (M+H)+, RT 1.87 minutes.

AND

PATENT

WO 2012032334

PATENT

WO 2015181053

WO 2015181055

WO 2016170014

PATENT

WO 2017198590

A SPECIFIC TRIFLUOROETHYL QUINOLINE ANALOGUE FOR USE IN THE TREATMENT OF APDS

The present invention relates to the new therapeutic use of a known chemical compound. More particularly, the present invention concerns the use of a specific substituted quinoline derivative comprising a fluorinated ethyl side-chain in the treatment of activated phosphoinositide 3 -kinase delta syndrome (APDS).

N- {(R)- 1 -[8-Chloro-2-(l -oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifiuoroethyl} -pyrido[3,2-JJpyrimidin-4-ylamine is specifically disclosed in WO 2012/032334. The compounds described in that publication are stated to be of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

There is no specific disclosure or suggestion in WO 2012/032334, however, that the compounds described therein might be beneficial in the treatment of APDS.

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as

PASLI (pi ΙΟδ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency), is a serious medical condition that impairs the immune system.

APDS patients generally have reduced numbers of white blood cells (lymphopenia), especially B cells and T cells, compromising their propensity to recognise and attack invading microorganisms, such as viruses and bacteria, and thereby prevent infection. Individuals affected with APDS develop recurrent infections, particularly in the lungs, sinuses and ears. Recurrent respiratory tract infections may gradually lead to bronchiectasis, a condition which damages the passages leading from the windpipe to the lungs (bronchi) and can cause breathing problems. APDS patients may also suffer from chronic active viral infections, including Epstein-Barr virus infections and cytomegalovirus infections.

APDS has also been associated with abnormal clumping of white blood cells, which can lead to enlarged lymph nodes (lymphadenopathy). Alternatively, the white blood cells can build up to form solid masses (nodular lymphoid hyperplasia), usually in the moist lining of the airways or intestines. Whilst lymphadenopathy and nodular lymphoid hyperplasia are benign (noncancerous), APDS also increases the risk of developing a form of cancer called B cell lymphoma.

APDS is a disorder of childhood, typically arising soon after birth. However, the precise prevalence of APDS is currently unknown.

Phosphoinositide 3-kinase delta (ΡΒΚδ) is a lipid kinase which catalyses the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). PI3K5 activates signalling pathways within cells, and is specifically found in white blood cells, including B cells and T cells. PI3K5 signalling is involved in the growth and division (proliferation) of white blood cells, and it helps direct B cells and T cells to mature (differentiate) into different types, each of which has a distinct function in the immune system.

APDS is known to occur in two variants, categorised as APDSl and APDS2.

APDSl is associated with a heterozygous gain-of- function mutation in the PIK3CD gene encoding the PI3K5 protein; whereas APDS2 is associated with loss-of-function frameshift mutations in the regulatory PIK3R1 gene encoding the p85a regulatory subunit of class I phosphoinositide 3-kinase (PI3K) peptides. Both mutations lead to hyperactivated PI3K signalling. See I. Angulo et ah, Science, 2013, 342, 866-871; C.L. Lucas et ah, Nature Immunol, 2014, 15, 88-97; and M-C. Deau et al, J. Clin. Invest., 2014, 124, 3923-3928.

There is currently no effective treatment available for APDS. Because of the seriousness of the condition, and the fact that it arises in infancy, the provision of an effective treatment for APDS would plainly be a highly desirable objective.

It has now been found that N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]- 2,2,2-trifluoroethyl}pyrido[3,2-(i]pyrimidin-4-ylamine is capable of inhibiting the elevation of PI3K signalling in T cells (lymphocytes) from both APDSl and APDS2 patients in the presence or absence of T cell receptor activation.

The present invention accordingly provides N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolinB-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A):

or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of APDS.

The present invention also provides a method for the treatment and/or prevention of APDS, which method comprises administering to a patient in need of such treatment an effective amount of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoro-ethyl}pyrido[3,2-(i]pyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof. The present invention also provides the use of N-{(R)-l-[8-chloro-2-(l-oxypyridin-3-yl)quinolin-3-yl]-2,2,2-trifluoroethyl}pyrido[3,2-JJpyrimidin-4-ylamine of formula (A) as depicted above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of APDS.

PAPER

Journal of Pharmacology and Experimental Therapeutics (2017), 361(3), 429-440.

http://jpet.aspetjournals.org/content/361/3/429

///////////////SELETALISIB, PHASE 3, UCB, селеталисиб سيلستاليسيب 司来利塞 

[O-][N+]1=CC(=CC=C1)C1=NC2=C(Cl)C=CC=C2C=C1[C@@H](NC1=NC=NC2=CC=CN=C12)C(F)(F)F

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Omadacycline tosylate


1075240-43-5.pngChemSpider 2D Image | Omadacycline tosylate | C36H48N4O10S

Image result for Omadacycline tosylate

Omadacycline tosylate

728.8521, C29H40N4O7. C7H8O3S

CAS: 1075240-43-5

389139-89-3 FREE FORM

FDA 2018/10/3, Nuzyra

オマダサイクリントシル酸塩;

UNII-5658Y89YCD

(4S,4aS,5aR,12aS)-4,7-Bis(dimethylamino)-9-{[(2,2-dimethylpropyl)amino]methyl}-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide 4-methylbenzenesulfonate (1:1)
1075240-43-5 [RN]
2-Naphthacenecarboxamide, 4,7-bis(dimethylamino)-9-[[(2,2-dimethylpropyl)amino]methyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4S,4aS,5aR,12aS)-, 4-methylbenzenesulfonate (1:1) (salt)
5658Y89YCD
Amadacycline tosylate
PTK 0796 / PTK-0796
Omadacycline.svg
Omadacycline
FREE FORM, 389139-89-3 FREE FORM

Omadacycline has been used in trials studying the treatment of Bacterial Pneumonia, Bacterial Infections, Community-Acquired Infections, and Skin Structures and Soft Tissue Infections. Omadacycline represents a significant advance over the well-known tetracycline family, and has been shown to be highly effective in animal models at treating increasingly problematic, clinically prevalent infections caused by gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), and by gram-negative, atypical and anaerobic bacteria, including those resistant to currently available classes of antibiotics and known to cause diseases such as pneumonias, urinary tract infections, skin diseases and blood-borne infections in both the hospital and community settings.

Omadacycline (formerly known as PTK-0796)[1] is a broad spectrum antibiotic belonging to the aminomethylcycline subclass[2] of tetracycline antibiotics. In the United States, it was approved in October 2018 for the treatment of community-acquired bacterial pneumonia and acute skin and skin structure infections.

In vitro studies

In vitro studies have shown that omadacycline has activity against a broad range of Gram-positive and select Gram-negativepathogens.[3] Omadacycline has potent in vitro activity against Gram-positive aerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), pencillin-resistant and multi-drug resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococcus. Omadacycline also has antimicrobial activity against common Gram-negative aerobes, some anaerobes, and atypical bacteria such as Legionella and Chlamydia.[4] This activity translated to potent efficacy for omadacycline in an in vivo systemic infection model in mice.[5]

Additional in vitro and in vivo studies of omadacycline metabolism, disposition, and drug interactions show that omadacycline is metabolically stable (i.e., it does not undergo significant biotransformation) and neither inhibits nor interacts with metabolizing enzymes or transporters.[6]

Mechanism of action

The mechanism of action of omadacycline is similar to that of other tetracyclines – inhibition of bacterial protein synthesis. Omadacycline has activity against bacterial strains expressing the two main forms of tetracycline resistance (efflux and ribosomal protection).[7]

Clinical trials

phase 2 study was conducted comparing the safety and efficacy of omadacycline to linezolid for the treatment of complicated skin and skin structure infections. Patients were randomized at 11 sites in the US to receive either omadacycline 100 mg intravenously once daily with an option to transition to 200 mg orally once daily or linezolid 600 mg intravenously twice daily with an option to transition to 600 mg orally twice daily. The results indicated that omadacycline is well-tolerated and has the potential to be an effective treatment in patients with complicated skin and skin structure infections.[8]

In June 2013, the US Food and Drug Administration (FDA) designated the intravenous and oral formulations of omadacycline as a qualified infectious disease product in the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia.[9]

A 650 patient phase 3 registration study comparing omadacycline to linezolid for the treatment of acute bacterial skin and skin structure infections began in June 2015.[10][11]Omadacycline met the primary efficacy endpoint of early clinical response with statistical non-inferiority (10% margin) compared to linezolid, and was generally safe and well-tolerated. The most common treatment-emergent adverse events were gastrointestinal side effects (18.0% for omadacycline vs. 15.8% for linezolid).[12]

A 750 patient phase 3 study comparing omadacycline to moxifloxacin for the treatment of community-acquired bacterial pneumonia began in November 2015.[13] Omadacycline was statistically non-inferior to moxifloxacin at the early clinical response, 72 to 120 hours after therapy was initiated.[14]

In May 2016, a phase 1b study of omadacycline in urinary tract infection was initiated.[15]

In August 2016, a second phase 3 study of omadacycline was initiated in patients with acute bacterial skin and skin structure infections, comparing the efficacy and safety of once-daily, oral omadacycline to that of twice-daily, oral linezolid.[16] In July 2017, analysis of the data showed that all of the primary and secondary endpoints required for submission to the FDA and EMA were met. This was the third phase 3 registration study of omadacycline with favorable results.[17]

Discovery

Omadacycline was invented at Tufts University School of Medicine by a research team led by Mark L. Nelson with Mohamed Ismail while at Tufts and Kwasi Ohemeng and Laura Honeyman at Paratek Pharmaceuticals, Boston. The team applying their chemistry methods to the tetracycline scaffolds created over 3000 new derivatives, leading to the novel third generation compounds omadacycline and sarecycline18[18]

PAPERS

Tetrahedron Letters (2008), 49(42), 6095-6100

str1

PATENTS

WO 2009120389

WO 2009111064

WO 2017165729

WO 2018026987

WO 2018085216

SYNTHESIS BY PHARMACODIA WEBSITE

Omadacyclinewww.pharmacodia.com

Image result for Omadacycline tosylate

Image result for Omadacycline tosylate

Image result for Omadacycline tosylate

REF Omadacyclinewww.pharmacodia.com

Route 3

References

  1. Jump up^ Boggs, Jennifer. “Antibiotic Firm Paratek Joins IPO Queue; Aiming for $92M”bioworld.com. Clarivate Analytics. Retrieved October 17, 2017.
  2. Jump up^ Honeyman, Laura; Ismail, Mohamed; Nelson, Mark L.; Bhatia, Beena; Bowser, Todd E.; Chen, Jackson; Mechiche, Rachid; Ohemeng, Kwasi; Verma, Atul K.; Cannon, E. Pat; MacOne, Ann; Tanaka, S. Ken; Levy, Stuart (2015). “Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline”Antimicrobial Agents and Chemotherapy59 (11): 7044–7053. doi:10.1128/AAC.01536-15PMC 4604364PMID 26349824.
  3. Jump up^ Tanaka, S. Ken (20 June 2016). “In Vitro and In Vivo Assessment of Cardiovascular Effects with Omadacycline”Antimicrobial Agents and Chemotherapy60 (9): 5247–53. doi:10.1128/AAC.00320-16PMC 4997885PMID 27324778.
  4. Jump up^ Villano, Stephen (19 August 2016). “Omadacycline: development of a novel aminomethylcycline antibiotic for treating drug-resistant bacterial infections”Future Microbiology11: 1421–1434. doi:10.2217/fmb-2016-0100. Retrieved 24 August 2016.
  5. Jump up^ MacOne, A. B.; Caruso, B. K.; Leahy, R. G.; Donatelli, J.; Weir, S.; Draper, M. P.; Tanaka, S. K.; Levy, S. B. (February 2014). “In Vitro and in Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline”Antimicrobial Agents and Chemotherapy58 (2): 1127–1135. doi:10.1128/AAC.01242-13PMC 3910882PMID 24295985.
  6. Jump up^ Flarakos, Jimmy (8 August 2016). “Clinical disposition, metabolism and in vitro drug–drug interaction properties of omadacycline”Xenobiotica: 1–15. doi:10.1080/00498254.2016.1213465.
  7. Jump up^ Draper, M. P.; Weir, S.; MacOne, A.; Donatelli, J.; Trieber, C. A.; Tanaka, S. K.; Levy, S. B. (March 2014). “Mechanism of Action of the Novel Aminomethylcycline Antibiotic Omadacycline”Antimicrobial Agents and Chemotherapy58 (3): 1279–1283. doi:10.1128/AAC.01066-13PMC 3957880PMID 24041885.
  8. Jump up^ Noel, G. J.; Draper, M. P.; Hait, H.; Tanaka, S. K.; Arbeit, R. D. (November 2012). “A Randomized, Evaluator-Blind, Phase 2 Study Comparing the Safety and Efficacy of Omadacycline to Those of Linezolid for Treatment of Complicated Skin and Skin Structure Infections”Antimicrobial Agents and Chemotherapy56 (11): 5650–5654. doi:10.1128/AAC.00948-12PMC 3486554PMID 22908151.
  9. Jump up^ “Paratek Pharmaceuticals Announces FDA Grant of Qualified Infectious Disease Product (QIDP) Designation for Its Lead Product Candidate, Omadacycline”prnewsire.com. PR Newswire. January 3, 2013. Retrieved October 17, 2017.
  10. Jump up^ Seiffert, Don (2015). “Paratek presents new trial data for antibiotic as late-stage trials continue”bizjournals.com. American City Business Journals. Retrieved October 17,2017.
  11. Jump up^ “Omadacycline Versus Linezolid for the Treatment of ABSSSI (EudraCT #2013-003644-23)”clinicaltrials.gov. Retrieved 2015-10-13.
  12. Jump up^ “Paratek Announces that Omadacycline Met All Primary and Secondary Efficacy Outcomes Designated by FDA and EMA in a Phase 3 Study in Acute Bacterial Skin Infections; Omadacycline was Generally Safe and Well-Tolerated”finance.yahoo.com. Retrieved 3 July 2016.
  13. Jump up^ “Omadacycline vs Moxifloxacin for the Treatment of CABP (EudraCT #2013-004071-13)”clinicaltrials.gov. Retrieved 2015-10-13.
  14. Jump up^ “Paratek Announces Positive Phase 3 Study of Omadacycline in Community-Acquired Bacterial Pneumonia”http://www.globenewswire.com. April 3, 2017. Retrieved 16 May 2017.
  15. Jump up^ “Paratek Initiates Phase 1b Study of Omadacycline in Urinary Tract Infection”globenewswire.com. May 2, 2016. Retrieved 3 July 2016.
  16. Jump up^ “Paratek Initiates Phase 3 Study of Oral-only Omadacycline in ABSSSI”globenewswire.com. August 15, 2016. Retrieved 15 August 2016.
  17. Jump up^ “Paratek Announces Phase 3 Study of Oral-Only Dosing of Omadacycline Met All Primary and Secondary FDA and EMA Efficacy Endpoints in Acute Bacterial Skin Infections”http://www.globenewswire.com. July 17, 2017. Retrieved 19 July 2017.
  18. Jump up^ Ref: Mark L. Nelson and Kwasi Ohemeng: 4-dedimethylamino tetracycline compounds, United States (US) patent number 7,056,902 (2006)
Omadacycline
Omadacycline.svg
Clinical data
Trade names Nuzyra
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C29H40N4O7
Molar mass 556.66 g·mol−1
3D model (JSmol)

/////////////FDA 2018, Nuzyra, Omadacycline tosylate, Omadacycline, オマダサイクリントシル酸塩 ,PTK-0796, PTK 0796

CC1=CC=C(C=C1)S(O)(=O)=O.[H][C@@]12CC3=C(C=C(CNCC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@]1([H])C2)N(C)C

Golvatinib, ゴルバチニブ


Golvatinib.png

ChemSpider 2D Image | Golvatinib | C33H37F2N7O4

Golvatinib

E-7050, cas 928037-13-2

1-N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1,1-Cyclopropanedicarboxamide, N-[2-fluoro-4-[[2-[[[4-(4-methyl-1-piperazinyl)-1-piperidinyl]carbonyl]amino]-4-pyridinyl]oxy]phenyl]-N’-(4-fluorophenyl)- [ACD/Index Name]
516Z3YP58E
928037-13-2 [RN]
9565
E7050, ゴルバチニブ
Molecular Formula: C33H37F2N7O4
Molecular Weight: 633.701 g/mol
  • N’-[2-fluoro-4-[2-[[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino]pyridin-4-yl]oxyphenyl]-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
    UNII:516Z3YP58E
  • Originator Eisai Co Ltd

  • Class Amides; Antineoplastics; Cyclopropanes; Fluorobenzenes; Piperazines; Piperidines; Pyridines; Small molecules
  • Mechanism of Action Angiogenesis inhibitors; Proto oncogene protein c met inhibitors; Vascular endothelial growth factor receptor-2 antagonists
  • Discontinued Gastric cancer; Glioblastoma; Head and neck cancer; Liver cancer; Malignant melanoma; Solid tumours
  • 15 Nov 2013Eisai completes enrolment in its phase Ib/II trial for Head and neck cancer (second-line combination therapy, late-stage disease) in USA, United Kingdom, South Korea & Ukraine (NCT01332266)
  • 14 Nov 2013Phase-I/II clinical trials in liver cancer (first-line combination therapy, late-stage disease) in Italy & Ukraine (PO)
  • 01 Jul 2013Eisai completes a phase I trial in Solid tumours in Japan (NCT01428141)

Golvatinib is an orally bioavailable dual kinase inhibitor of c-Met (hepatocyte growth factor receptor) and VEGFR-2 (vascular endothelial growth factor receptor-2) tyrosinekinases with potential antineoplastic activity. c-Met/VEGFR kinase inhibitor E7050 binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of tumor cell types and play important roles in tumor cell growth, migration and angiogenesis.

Golvatinib has been investigated for the treatment of Platinum-Resistant Squamous Cell Carcinoma of the Head and Neck.
PATENT
WO 2007023768
WO 2008023698
WO 2008102870
PATENT
WO 2012133416

Method for producing a phenoxy pyridine derivative (3)

The present invention, hepatocyte growth factor receptor (Hepatocyte growth factor receptor; hereinafter, abbreviated as “HGFR”) inhibitory action, antitumor action, anti-tumor agents with such angiogenesis inhibitory activity and cancer metastasis inhibitory action, a cancer metastasis suppressing the method for producing a useful phenoxy pyridine derivatives as agents.

Patent Document 1 has a HGFR inhibitory activity, anti-tumor agents, useful phenoxy pyridine derivative as an angiogenesis inhibitor or cancer metastasis inhibitor has been disclosed.

Figure JPOXMLDOC01-appb-C000004


(In the formula, R 1, .R 2 and R 3 means such as 3-10 membered non-aromatic heterocyclic group, .R 4, R 5, R 6 and R 7 which represents a hydrogen atom, same or different, a hydrogen atom, a halogen atom, .R 8 to mean a C 1-6 alkyl group, .R 9 to mean a hydrogen atom or the like is and 3-10 membered non-aromatic heterocyclic group meaning .n is .X to mean 1 to 2 integer, it refers to a group or a nitrogen atom represented by the formula -CH =.)

As a method for producing the phenoxy pyridine derivative, to the Example 48 of Patent Document 1, N, N-dimethylformamide, triethylamine and benzotriazol-1-yloxytris (dimethylamino) or lower in the presence of a phosphonium hexafluorophosphate discloses that perform the reaction.

Figure JPOXMLDOC01-appb-C000005

Patent Document 2, as a manufacturing method suitable for industrial mass synthesis of the phenoxy pyridine derivative in the presence a condensing agent, production method of reacting an aniline derivative with a carboxylic acid derivative.

Figure JPOXMLDOC01-appb-C000006


(In the formula, R 1, is .R 2, R 3, R 4 and R 5, which means such good azetidin-1-yl group which may have a substituent, the same or different and each represents a hydrogen atom or fluorine It refers to an atom .R 6 means a hydrogen atom or a fluorine atom.)

Patent Document 3, another manufacturing method of the phenoxy pyridine derivative, there is disclosed the manufacturing method shown in the following scheme.

Figure JPOXMLDOC01-appb-C000007


(In the formula, R 1 means a 4- (4-methylpiperazin-1-yl) piperidin-1-yl group or a 3-hydroxy-1-yl group .R 2, R 3, R 4 and R 5 are the same or different, represents a hydrogen atom or a fluorine atom. However, among R 2, R 3, R 4 and R 5, 2 or 3 is a hydrogen atom .R 6 is a hydrogen atom or .R 7 to mean a fluorine atom, .Ar which means a protecting group for the amino group means a phenyl group.)

International Publication No. WO 2007/023768 International Publication No. WO 2008/026577 International Publication No. WO 2009/104520

PATENT
WO 2009104520
Example A-5: Preparation of N- (2-fluoro-4 – {[2 – ({[4- (4-methylpiperazin- 1 –yl) piperidin- 1 – yl] carbonyl} amino) pyridin- oxy} phenyl) -N ‘- (4-fluorophenyl) cyclopropane-1,1 dicarboxamide
[Formula
17] 4- (4-methylpiperazin-1-yl) piperidine-1-carboxylic acid [4- ( To a solution of N, N-dimethylformamide (1 ml) of 4-amino-3-fluorophenoxy) pyridin-2-yl] amide (100 mg) and 1- (4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (78 mg) Triethylamine (71 mg) and O- (7-Azabenzotriazol-1-yl) -N, N, N ‘, N’- tetramethyluronium hexafluorophosphate (HATU) (222 mg) were added and stirred at room temperature for 21 hours. A 1 N sodium hydroxide aqueous solution (2 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 ml). After separation, the organic layer was washed with 5% brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue. The residue was dissolved in ethyl acetate (3 ml) and extracted with 2 N hydrochloric acid (3 ml × 1, 2 ml × 1). The aqueous layer was rendered alkaline with 5 N aqueous sodium hydroxide solution (5.5 ml). After extraction with ethyl acetate and drying over anhydrous magnesium sulfate, the solvent was distilled off to give the title compound (87 mg).
1 H-NMR Spectrum (DMSO-d 6) .Delta. (Ppm): 1.22-1.33 (2H, m), 1.54-1.63 (4H, m), 1.68-1.78 (2H, m), 2.12 (3H , S), 2.12-2.40 (5H, m), 2.40-2.60 (4H, m), 2.68-2.78 (2H, m), 4.06-4.14 (2H, t, J = 8 Hz), 7.22 (2H, m), 6.60 (1H, dd, J = 2.4 Hz, 5.6 Hz), 7.00 (1 H, dd, J = 2.4 Hz, 11.2 Hz), 7.40 (1 H, s), 7.61 (2 H, dd, J = 5.2 Hz, 8 Hz), 7.93 J = 8.8 Hz), 8.13 (1 H, d, J = 5.6 Hz), 9.21 (1 H, s), 9.90 (1 H, brs), 10.55 (1 H, brs).

PAPER
Journal of Medicinal Chemistry (2017), 60(7), 2973-2982
Patent ID

Title

Submitted Date

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US2015218130 CYCLOPROPYL DICARBOXAMIDES AND ANALOGS EXHIBITING ANTI-CANCER AND ANTI-PROLIFERATIVE ACTIVITIES
2015-01-22
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US9702878 METHOD FOR THE PROGNOSIS AND TREATMENT OF CANCER METASTASIS
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2015-10-15
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2015-12-11
Patent ID

Title

Submitted Date

Granted Date

US8759530 Method for producing phenoxypyridine derivative
2012-03-27
2014-06-24
US2010311972 METHOD FOR PRODUCING PHENOXYPYRIDINE DERIVATIVE
2010-12-09
US7855290 Pyridine derivatives and pyrimidine derivatives (3)
2008-12-25
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US7790885 Process for preparing phenoxypyridine derivatives
2008-09-04
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US2015362495 METHOD FOR THE DIAGNOSIS, PROGNOSIS AND TREATMENT OF PROSTATE CANCER METASTASIS
2013-10-09
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Patent ID

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US9012458 Antitumor Agent Using Compounds Having Kinase Inhibitory Effect in Combination
2011-06-23
2013-05-16
US2009227556 RECEPTOR TYROSINE KINASE INHIBITORS COMPRISING PYRIDINE AND PYRIMIDINE DERIVATIVES
2009-09-10
US7998948 PHARMACEUTICAL COMPOSITION FOR TREATING ESOPHAGEAL CANCER
2009-07-09
2011-08-16
US2017101683 Method for the Prognosis and Treatment of Cancer Metastasis
2014-10-07
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2013-12-20
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Patent ID

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Granted Date

US2016151406 COMBINATION CANCER THERAPY WITH C-MET INHIBITORS AND SYNTHETIC OLIGONUCLEOTIDES
2015-11-19
2016-06-02
US2014275183 AGENT FOR REDUCING SIDE EFFECTS OF KINASE INHIBITOR
2014-05-29
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US2016058751 COMPOSITION AND METHOD FOR TREATING CANCER
2014-03-25
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US2015297604 Combination Products with Tyrosine Kinase Inhibitors and their Use
2013-04-03
2015-10-22
US2015051210 Tyrosine Kinase Inhibitor Combinations and their Use
2013-04-01
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Patent ID

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Submitted Date

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US8481739 NOVEL 3, 5-DISUBSTITUTED-3H-IMIDAZO[4, 5-B]PYRIDINE AND 3, 5- DISUBSTITUTED -3H-[1, 2, 3]TRIAZOLO[4, 5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES
2011-11-17
US8288538 NOVEL PYRIDINE DERIVATIVES AND PYRIMIDINE DERIVATIVES (3)
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US8377938 PHENOXYPYRIDINE DERIVATIVE SALTS AND CRYSTALS THEREOF, AND PROCESS FOR PREPARING THE SAME
2008-12-25
US2012232049 PYRIDINE OR PYRIMIDINE DERIVATIVE HAVING EXCELLENT CELL GROWTH INHIBITION EFFECT AND EXCELLENT ANTI-TUMOR EFFECT ON CELL STRAIN HAVING AMPLIFICATION OF HGFR GENE
2008-02-22
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2011-04-29
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Submitted Date

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US2017240542 NOVEL 3, 5-DISUBSTITUTED-3H-IMIDAZO[4, 5-B]PYRIDINE AND 3, 5-DISUBSTITUTED-3H-[1, 2, 3]TRIAZOLO[4, 5-B] PYRIDINE COMPOUNDS AS MODULATORS OF PROTEIN KINASES
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2012-05-24
2012-10-04

///////////////Golvatinib, phase 2, ゴルバチニブ  ,

CN1CCN(CC1)C2CCN(CC2)C(=O)NC3=NC=CC(=C3)OC4=CC(=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

Savolitinib


ChemSpider 2D Image | Savolitinib | C17H15N9

Savolitinib

CAS 1313725-88-0, Molecular Formula, C17-H15-N9, Molecular Weight, 345.3685

1H-1,2,3-Triazolo(4,5-b)pyrazine, 1-((1S)-1-imidazo(1,2-a)pyridin-6-ylethyl)-6-(1-methyl-1H-pyrazol-4-yl)-

  • AZD-6094
  • AZD6094
  • HMPL-504
  • HMPL504
  • Savolitinib
  • Savolitinib [INN]
  • UNII-2A2DA6857R
  • Volitinib
  • HM 5016504
1H-1,2,3-Triazolo[4,5-b]pyrazine, 1-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-6-(1-methyl-1H-pyrazol-4-yl)-
1-[(1S)-1-(Imidazo[1,2-a]pyridin-6-yl)ethyl]-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine [
2A2DA6857R
9935
Phase III, AstraZeneca
Hutchison China MediTech (Chi-Med), Cancer, kidney (renal cell carcinoma, papillary)

A c-Met kinase inhibitor with antineoplastic activity.

NCI: volitinib. An orally bioavailable inhibitor of the c-Met receptor tyrosine kinase with potential antineoplastic activity. Volitinib selectively binds to and inhibits the activation of c-Met in an ATP-competitive manner, and disrupts c-Met signal transduction pathways. This may result in cell growth inhibition in tumors that overexpress the c-Met protein. C-Met encodes the hepatocyte growth factor receptor tyrosine kinase and plays an important role in tumor cell proliferation, survival, invasion, and metastasis, and tumor angiogenesis; this protein is overexpressed or mutated in a variety of cancers.(NCI Thesaurus)

Savolitinib is an experimental small molecule inhibitor of c-Met. It is being investigated for the treatment of cancer by AstraZeneca.[1] It is in phase II clinical trials for adenocarcinomanon-small cell lung cancer, and renal cell carcinoma.[2]

Savolitinib is a first-in-class inhibitor of c-Met in phase III clinical development at at Hutchison China MediTech (Chi-Med) and AstraZeneca for the treatment of patients with MET-driven, unresectable and locally advanced or metastatic papillary renal cell carcinoma. Phase II trials are also under way for the oral treatment of locally advanced or metastatic pulmonary sarcomatoid carcinoma. AstraZeneca is conducting phase II clinical trials for the treatment of non-small cell lung cancer. Phase I/II trials are ongoing at Samsung Medical Center for the second-line treatment of advanced gastric adenocarcinoma patients with MET amplification.

In 2011, the drug was licensed to AstraZeneca by at Hutchison China MediTech (Chi-Med) for worldwide codevelopment and marketing rights for the treatment of cancer.

Image result for EPITINIB

SYNTHESIS

PAPER

Journal of Organic Chemistry (2018),

Abstract Image

A multidisciplinary approach covering synthetic, physical, and analytical chemistry, high-throughput experimentation and experimental design, process engineering, and solid-state chemistry is used to develop a large-scale (kilomole) Suzuki–Miyaura process. Working against clear criteria and targets, a full process investigation and optimization package is described highlighting how and why key decisions are made in the development of large-scale pharmaceutical processes.

Process Design and Optimization in the Pharmaceutical Industry: A Suzuki–Miyaura Procedure for the Synthesis of Savolitinib

AstraZeneca Pharmaceutical Technology and Development, Macclesfield SK10 2NA, United Kingdom
J. Org. Chem., Article ASAP
DOI: 10.1021/acs.joc.8b02351
Publication Date (Web): October 23, 2018
Copyright © 2018 American Chemical Society
This article is part of the Excellence in Industrial Organic Synthesis 2019 special issue.
Savolitinib (1) were added, and the resulting suspension was cooled to 0 °C over 8 h. After stirring for a further 4 h at 0 °C, the solid was collected via filtration, washed twice with cold s-BuOH (150 kg, 186 L), and dried in vacuo at 40 °C to give Savolitinib (1) as a white crystalline solid (105 kg, 304 mol, 76%): mp 205.9–208.8 °C; 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.62–7.55 (m, 2H), 7.42 (dd, J = 1.7, 9.4 Hz, 1H), 6.45 (q, J= 7.1 Hz, 1H), 3.98 (s, 3H), 2.22 (d, J = 7.1 Hz, 3H); 13C {1H} NMR (DMSO-d6, 101 MHz) δ 147.9, 147.2, 143.9, 141.9, 138.5, 137.4, 133.7, 131.6, 125.4, 124.3, 123.9, 119.4, 117.1, 113.8, 55.5, 40.1, 39.1, 19.6 ppm; HRMS (ESI/Q-ToF) m/z [M + H – N2]+ calcd for C17H16N7 318.1462, found 318.1486.
NMR Summary S6 1H‐NMR
S7 13C‐NMR
S8 HSQC‐DEPT‐NMR
S9 COSY‐NMR
S10 HMBC‐13C/1H‐NMR
S11 NOESY‐NMR
S12 HRMS

PAPER

Journal of Medicinal Chemistry (2014), 57(18), 7577-7589

Abstract Image

HGF/c-Met signaling has been implicated in human cancers. Herein we describe the invention of a series of novel triazolopyrazine c-Met inhibitors. The structure–activity relationship of these compounds was investigated, leading to the identification of compound 28, which demonstrated favorable pharmacokinetic properties in mice and good antitumor activities in the human glioma xenograft model in athymic nude mice.

Discovery of (S)-1-(1-(Imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (Volitinib) as a Highly Potent and Selective Mesenchymal–Epithelial Transition Factor (c-Met) Inhibitor in Clinical Development for Treatment of Cancer

Hutchison MediPharma Limited, Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, 201203, Shanghai, China
J. Med. Chem.201457 (18), pp 7577–7589
DOI: 10.1021/jm500510f
Publication Date (Web): August 22, 2014
Copyright © 2014 American Chemical Society
*E-mail: weiguos@hmplglobal.com. Phone: (+86)-21-20673002.

Preparation of (S)-2-(4-(1-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (30) and (R)-2-(4-(1-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (31)

The racemic compound 44 (prepared by a procedure similar to that described for the synthesis of compound 2 using the corresponding 1-(pyrazolo[1,5-a]pyridin-5-yl)ethanamine instead of quinolin-6-ylmethanamine) (5 mg) was resolved by chiral HPLC to produce optically pure enantiomers 30 (1.0 mg) and 31 (1.9 mg). HPLC resolution conditions: Gilson system, Column: Dicel IA 20 × 250 mm; Mobile phase: n-Hexane/i-PrOH/DEA = 6/4/0.1; Flow rate: 8 mL/min; Detector: 254 nm). Compound 44: Purity: 95.8%, RT 9.28. MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.07 (s, 1H), 8.49–8.47 (m, 2H), 8.26 (s, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.78 (s, 1H), 7.01 (dd, J = 7.2, 2.0 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.47 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95 (t, J = 4.2 Hz, 2H), 2.25 (d, J = 6.8 Hz, 3H). Compound 30: MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.50 (s,1 H), 8.50 (d, J = 7.2 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.01(dd, J = 7.2, 2.0 Hz, 1H), 6.62 (d, J = 1.6 Hz, 1H), 6.48 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95(t, J = 4.2 Hz, 2H), 2.26 (d, J = 6.8 Hz, 3H). Purity: 98.1%, RT 18.44, ee: 96%. Compound 31: MS (m/z): 376 (M + 1)+1H NMR (400 MHz, CD3OD) δ 9.08 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.27 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.01 (dd, J = 7.2, 2.0 Hz,1H), 6.62 (d, J = 2.0 Hz, 1H), 6.48 (q, J = 6.8 Hz, 1H), 4.33 (t, J = 4.2 Hz, 2H), 3.95 (t, J = 4.2 Hz, 2H), 2.26 (d, J = 6.8 Hz, 3H). Purity: 90.7%, RT 24.22, ee: 81%. HPLC analysis conditions: Gilson system, Column: Chiralpak Ia 4.6 mm I.D. × 25 cm L; Mobile phase: n-Hexane/i-PrOH/DEA = 6/4/0.1; Flow rate: 1 mL/min; Detector: 254 nm.

PATENT

WO 2018175251

WO 2018055029

WO 2018024608

WO 2016087680

WO 2016081773

PATENT

JP 2016069348

PATENT

CN 105503906

The present invention provides a triazolopyrazine derivatives, the chemical name (S) -1- (l_ (imidazo [l, 2_a] pyrazin-6-yl) ethane-yl) -6-α _ -1H- pyrazol-4-yl-methyl) -1Η- [1,2,3] triazolo [4,5-b] pyrazine, of formula (I), the

Figure CN105503906AD00041

[0005] This compound is an inhibitor of the activity c -Me t, may be used for treatment or prevention of inhibition of c -Me t sensitive cancers. In the Chinese patent CN 102906092A (W02011 / 079804), discloses the synthesis and use triazolopyrazine derivatives. Prepared by repeating the above patent, the compound powder obtained by detecting an amorphous state. As those skilled in the art, although amorphous higher solubility and dissolution rate than polymorph in most cases, but it is unstable, hygroscopic, readily converted to stable crystalline form.Thus, without the presence of processing stability and poor storage stability shaped, and in the production process, the smaller the bulk density of the particles of amorphous, high surface free energy, are likely to cause aggregation, poor flowability, and a series of powerful elastic deformation of the formulation problem seriously affecting the clinical value of amorphous Drug triazolopyrazine derivatives.

PATENT

CN 105503905

PATENT

WO 2014174478

CN 102127096

PATENT

WO 2011079804

References

Savolitinib
Savolitinib.svg
Clinical data
Synonyms Volitinib
Identifiers
CAS Number
ChemSpider
KEGG
Chemical and physical data
Formula C17H15N9
Molar mass 345.37 g·mol−1
3D model (JSmol)

///////////////Savolitinib, Phase III, AZD-6094, AZD6094, HMPL-504, HMPL504, UNII-2A2DA6857R, Volitinib, HM 5016504

C[C@@H](c1ccc2nccn2c1)n3c4c(ncc(n4)c5cnn(c5)C)nn3

In some embodiments, the c-Met inhibitor is ARQ197 (Tivantinib). Tivantinib has the IUPAC name (3R,4R)-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-2,5-pyrrolidinedione and the following chemical structure:

[0058] In some embodiments, the c-Met inhibitor is EMD1214063 (MSC2156119J; Tepotinib).

Tepotinib has the IUPAC name 3-(1-(3-(5-((1-methylpiperidin-4-yl)methoxy)pyrimidin-2-yl)benzyl)-1,6-dihydro-6-oxopyridazin-3-yl)benzonitrile and the following chemical structure:

[0059] In some embodiments, the c-Met inhibitor is GSK/1363089/XL880 (Foretinib). Foretinib has the IUPAC name N1’-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0060] In some embodiments, the c-Met inhibitor is XL184 (Cabozantinib). Cabozantinib has the IUPAC name N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0061] In some embodiments, the c-Met inhibitor is HMPL-504/AZD6094/volitinib (Savolitinib). Volitinib has the IUPAC name (S)-1-(1-(imidazo[1,2-a]pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine and the following chemical structure:

[0062] In some embodiments, the c-Met inhibitor is MSC2156119J (EMD 1214063, Tepotinib).

Tepotinib has the IUPAC name Benzonitrile, 3-[1,6-dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]- and the following chemical structure:

[0063] In some embodiments, the c-Met inhibitor is LY2801653 (Merestinib). Merestinib has the IUPAC name N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5 yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0064] In some embodiments, the c-Met inhibitor is AMG 337. AMG 337 has the IUPAC name 7-methoxy-N-((6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-1,5-naphthyridin-4-amine and the following chemical structure:

[0065] In some embodiments, the c-Met inhibitor is INCB28060 (Capmatinib). Capmatinib has the IUPAC name 2-fluoro-N-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide and the following chemical structure:

[0066] In some embodiments, the c-Met inhibitor is AMG 458. AMG 458 has the IUPAC name 1-(2-hydroxy-2-methylpropyl)-N-(5-((7-methoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide and the following chemical structure:

[0067] In some embodiments, the c-Met inhibitor is PF-04217903. PF-04217903 has the IUPAC name 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol and the following chemical structure:

[0068] In some embodiments, the c-Met inhibitor is PF-02341066 (Crizotinib). Crizotinib has the IUPAC name (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine and the following chemical structure:

[0069] In some embodiments, the c-Met inhibitor is E7050 (Golvatinib). Golvatinib has the IUPAC name N-(2-fluoro-4-((2-(4-(4-methylpiperazin-1-yl)piperidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and the following chemical structure:

[0070] In some embodiments, the c-Met inhibitor is MK-2461. MK-2461 has the IUPAC name N-((2R)-1,4-Dioxan-2-ylmethyl)-N-methyl-N’-[3-(1-methyl-1H-pyrazol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfamide and the following chemical structure:

[0071] In some embodiments, the c-Met inhibitor is BMS-777607. BMS-777607 has the IUPAC name N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide and the following chemical structure:

[0072] In some embodiments, the c-Met inhibitor is JNJ-38877605. JNJ-38877605 has the IUPAC name 6-(difluoro(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline and the following chemical structure:

Epitinib


str1

Epitinib succinate; HMPL-813; Huposuan yipitini

1203902-67-3, 430.50, C24 H26 N6 O2

1-Piperazinecarboxamide, 4-ethyl-N-[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]-

4-Ethyl-N-[4-[(3-ethynylphenyl)amino]-7-methoxy-6-quinazolinyl]-1-piperazinecarboxamide

Cancer; Glioblastoma; Non-small-cell lung cancer

Epitinib is in phase I clinical trials by Hutchison MediPharma for the treatment of solid tumours.

Epitinib succinate is an oral EGFR tyrosine kinase inhibitor in early clinical development at Hutchison China MediTech (Chi-Med) for the treatment of solid tumors and the treatment of glioblastoma patients with EGFR gene amplification.

  • Originator Hutchison MediPharma
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Epidermal growth factor receptor antagonists
  • Phase I/II Glioblastoma; Non-small cell lung cancer
  • No development reported Oesophageal cancer; Solid tumours
  • 28 May 2018 No recent reports of development identified for preclinical development in Oesophageal-cancer in China (PO)
  • 06 Mar 2018 Hutchison Medipharma plans a phase III pivotal study for Non-small cell lung cancer (NSCLC) patients with brain metastasis in China in 2018
  • 06 Mar 2018 Phase-I/II clinical trials in Glioblastoma (Second-line therapy or greater) in China (PO)

Image result for EPITINIB

PATENT

WO2018210255

https://patentscope2.wipo.int/search/en/detail.jsf;jsessionid=42BB6AE0DA712D6A9C7C741E97BDE64C?docId=WO2018210255&tab=FULLTEXT&office=&prevFilter=&sortOption=Pub+Date+Desc&queryString=&recNum=889&maxRec=71731866

Binding of epidermal growth factor (EGF) to epidermal growth factor receptor (EGFR) activates tyrosine kinase activity and thereby triggers reactions that lead to cellular proliferation. Overexpression and/or overactivity of EGFR could result in uncontrolled cell division which may be a predisposition for cancer. Compounds that inhibit the overexpression and/or overactivity of EGFR are therefore candidates for treating cancer.
The relevant compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide of the present invention has the effect of effectively inhibiting the overexpression and/or overactivity of EGFR. Thus, it is useful in treating diseases associated with overexpression and/or overactivity of EGFR, such as the treatment of cancer.
The phenomenon that a compound could exist in two or more crystal structures is known as polymorphism. Many compounds may exist as various polymorph crystals and also in a solid amorphous form. Until polymorphism of a compound is discovered, it is highly unpredictable (1) whether a particular compound will exhibit polymorphism, (2) how to prepare any such unknown polymorphs, and (3) how are the properties, such as stability, of any such unknown polymorphs. See, e.g., J. Bernstein “Polymorphism in Molecular Crystals” , Oxford University Press, (2002)
Since the properties of a solid material depend on the structure as well as on the nature of the compound itself, different solid forms of a compound can and often do exhibit different physical and chemical properties as well as different biopharmaceutical properties. Differences in chemical properties can be determined, analyzed and compared through a variety of analytical techniques. Those differences may ultimately be used to differentiate among different solid forms. Furthermore, differences in physical properties, such as solubility, and biopharmaceutical properties, such as bioavailability, are also of importance when describing the solid state of a pharmaceutical compound. Similarly, in the development of a pharmaceutical compound, e.g., 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide, the new crystalline and amorphous forms of the pharmaceutical compound are also of importance.
The compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide as well as the preparation thereof was described in patent CN101619043A.
pon extensive explorations and researchs, we have found that compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide can be prepared into succinate salts, the chemical structure of its semisuccinate and monosuccinate being shown by Formula A. Studies have shown that, compared with its free base, the solubility of compound of Formula A is significantly increased, which is beneficial for improving the pharmacokinetic characteristics and in vivo bioavailability of the compound. We have also found that compound of Formula A can exist in different crystalline forms, and can form solvates with certain solvents. We have made extensive studies on the polymorphic forms of compound of Formula A and have finally prepared and determined the polymorphic forms which meet the requirement of pharmaceutical use. Based on these studies, the present invention provides the compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin -6-yl) piperazine-1-carboxamide succinate and the various crystalline forms thereof, solvates and the crystalline forms thereof, which are designated as Form I, Form IV and Form V respectively.
The compound 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide raw material used in the examples were prepared according to CN101619043A.
Example 1 Preparation of Form I of compound of Formula A
The 4-ethyl-N- (4- ( (3-ethynylphenyl) amino) -7-methoxyquinazolin-6-yl) piperazine-1-carboxamide (60g, 0.139mol) was dissolved in 150 times (volume/weight ratio) of tetrahydrofuran (9L) under refluxing. Then the obtained solution was cooled to 50℃, and succinic acid (65.8g, 0.557mol, 4 equivalents) was added in one portion. Then the obtained mixed solution was cooled naturally under stirring. The white precipitate was appeared at about 28℃. After further stirring for 18 hours, the white solid was collected by filtration, and dried at 40℃ under vacuum. A powder sample of 56.7g was obtained (yield 83%) .
1H NMR (400 MHz, cd3od) δ 8.52 (s, 1H) , 8.45 (s, 1H) , 7.93 –7.89 (m, 1H) , 7.77 –7.73 (m, 1H) , 7.35 (t, J = 7.9 Hz, 1H) , 7.24 (dd, J = 5.2, 3.8 Hz, 1H) , 7.19 (s, 1H) , 4.05 (s, 3H) , 3.69 –3.61 (m, 4H) , 3.49 (s, 1H) , 2.71 –2.64 (m, 4H) , 2.60 (q, J = 7.2 Hz, 2H) , 2.53 (s, 2H) , 1.18 (t, J = 7.2 Hz, 3H) .
The obtained powder sample is Form I of compound of Formula A, the X-ray powder diffractogram of which is shown in Figure 1. Peaks (2θ) chosen from the figure has the following values: 6.1, 7.9, 10.2, 11.6, 12.2, 13.6, 15.3, 15.9, 16.6, 17.8, 19.6, 20.4, 21.4, 21.7, 22.3, 23.5, 24.3, and 25.1 degrees, the measured 2θ values each having an error of about ± 0.2 degrees (2θ) , wherein characteristic peaks (2θ) are at 6.1, 7.9, 12.2, 15.3, 15.9, 16.6, and 20.4 degrees. DSC result is given in Figure 2, showing that the melting point range of Form I is about 193.4-197.3℃.
PATENT
PATENT
CN 108863951
PATENT
US 20100009958
PATENT
WO 2010002845

////////////Epitinib , PHASE 1, PHASE 2, Epitinib succinate, HMPL-813,  Huposuan yipitini, 1203902-67-3,

Eluxadoline, エルクサドリン ,элуксадолин ,إيلوكسادولين ,艾沙多林 ,


Eluxadoline.svg

Eluxadoline

  • Molecular FormulaC32H35N5O5
  • Average mass569.651 Da

5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

864821-90-9 CAS

JNJ-27018966

Molecular Formula: C32H35N5O5

Molecular Weight: 569.6508

Agents for Irritable Bowel Syndrome, mu-Opioid Agonists, delta-Opioid Antagonists

Eluxadoline

Trade Name: Viberzi®

Research Code: JNJ-27018966, JNJ27018966, JNJ 27018966

Chemical Name: 5 – [[[(2S) -2-amino-3- [4- (aminocarbonyl) -2,6-dimethylphenyl ] -1- oxopropyl] [(1S) -1- (4-phenyl-1H-imidazol-2-yl) ethyl] amino] methyl] -2-methoxybenzoic acid

MOA: mu opioid receptor agonist, Indication: Irritable bowel syndrome with diarrhea (IBS-D)

Approval Date: May 27, 2015 (US)

Originator: Furiex Pharmaceuticals Inc ( Furiex acquired Eluxadoline from Janssen in 2011 )

Developer: Forest Laboratories Inc. (acquired by Actavis PLC in 2014 )

Eluxadoline, sold under the brand names Viberzi (/vˈbɜːrzi/ vy-BUR-zee) in the US and Truberzi in Europe,[2] is a medication taken by mouth for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).[3]It was approved for use in the United States in 2015.[4] The drug originated from Janssen Pharmaceutica and was developed by Actavis.

Contraindications

This drug is contraindicated in case of having:

Adverse effects

Common adverse effects are constipation and nausea, but rates of discontinuation due to constipation were low for both eluxadoline and placebo. Rare adverse effects: fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effects include pancreatitis with a general incidence of 0.3% – higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%).[6] The risk is even greater in those who do not have a gall bladder and the medication is not recommended in this group.[7]

In March 2017, the U.S. Food and Drug Administration issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder.[8] An FDA review found that in such patients, spasm of the sphincter of Oddi may lead to severe pancreatitis.[9] The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg).[9] Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder.[8]

Interactions

Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein OATP1B1, such as:

Also, concurrent use of other drugs that cause constipation is not preferred, such as:

Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Also, co-administration of eluxadoline with rosuvastatin may increase the risk of rhabdomyolysis.[1]

Pharmacology

Mechanism of action

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist [11] that acts locally in the enteric nervous system, possibly decreasing adverse effects on the central nervous system.[12][13]

Pharmacokinetics

In the in vitro studies, eluxadoline was found to be transported by OAT3 (SLC22A8), OATP1B1 (SLCO1B1) and BSEP (ABCB11) at the highest concentrations tested (400 ng/ml which is 162-fold larger than the observed Cmax of the highest therapeutic dose of 100 mg). However, it was not to be transported by OCT1 POU2F1, OAT1 Organic anion transporter 1, OCT2, OATP1B3 (SLCO1B3), P-gp (P-glycoprotein), or BCRP (ABCG2).

Multidrug resistance-associated protein 2 (MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. Also in the in vitro studies, it was observed that eluxadoline is an in vivo substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of cytochrome P450enzymes was observed.[14]

Following a 100 mg dose of eluxadoline, the Cmax was about 2 to 4 ng/ml and AUC was 12-22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the Cmax by 50% and AUC by 60%.[1]

Chemistry

Synthesis

The synthesis of eluxadoline was extensively discussed in the patent No. WO2006099060 A2, with the title : “Process for the preparation of opioid modulators” which was published in Sept. 2006[15]

A CLIP

5 JAN 2014

Furiex Pharmaceuticals Inc.  more than doubled in its best day of trading after its experimental drug alleviated diarrhea and abdominal pain caused by irritable bowel syndrome in two studies.

The drug eluxadoline met targets for improvements in stool consistency and abdominal pain that were developed in conjunction with U.S. and European regulators, the company said today. Furiex will apply for approval in June, Chairman Fred Eshelman said in an investor call today. He estimated annual sales of $750 million to $1 billion.

“By our math, it looks like a pretty doggone good market,” Eshelman said on the call, noting that there is only one currently approved drug available in the U.S. for the condition.

Diarrhea-predominant irritable bowel syndrome is a chronic disorder that affects about 28 million patients in the U.S. and Europe, Furiex said in the statement.Furiex said it would apply by mid-year for U.S. approval of the drug, eluxadoline, to treat diarrhea-predominant irritable bowel syndrome (IBS-d), a debilitating bowel disorder that affects about 28 million people in the United States and major European markets.

Furiex said it expected to seek European approval in early 2015.

“We believe that there are a lot of patients out there who need this drug. There is a huge unmet need,” Furiex Chief Medical Officer June Almenoff said in a telephone interview.

Currently approved drugs for IBS address constipation associated with the disorder, but there are few options for diarrhea predominant IBS.

Furiex founder and chairman Fred Eshelman said he believes the drug has the potential for blockbuster sales, which he defined as annual sales of between $750 million and $1 billion.

Eluxadoline was tested at two doses against a placebo over the course of 12 weeks to meet requirements by the U.S. Food and Drug Administration, and for 26 weeks for European health regulators, in Phase III studies involving 2,428 patients, Furiex said.

For the combined goal of improvement in abdominal pain and stool consistency for at least half the days in the study, eluxadoline achieved a statistically significant improvement at the 100 milligram and 75 mg doses through 12 weeks in both studies.

On the 26-week measure, the higher dose succeeded in both studies but the lower dose missed statistical significance in one of the two trials, according to initial results released by the company.

The success appeared to be driven by the percentage of patients reporting improvements in diarrhea, which ranged from 30 percent to 37 percent versus 22 percent and 20.9 percent for the placebo groups.

When the composite goal was broken into its two components, researchers found a numerical improvement in pain response rates that did not achieve statistical significance.

The drug appeared to be safe and well-tolerated in both studies, Furiex said. The most commonly reported side effects were constipation and nausea.

The company plans to present a far more detailed analysis of the late stage studies at an upcoming medical meeting.

“We’re very excited about the path ahead and about how this can transform patients’ lives,” Almenoff said.

Mu Delta is a locally active mu opioid receptor agonist and delta opioid receptor antagonist in phase III clinical evaluation at Furiex Pharmaceuticals for the oral treatment of diarrheal predominant irritable bowel syndrome (d-IBS).

The product candidate holds an advantage over currently marketed products for this indication because it acts locally on the enteric nervous system, possibly decreasing adverse effects on the central nervous system. In 2011, fast track designation was assigned in the U.S. for the treatment of d-IBS. In 2011, Mu Delta was licensed to Furiex Pharmaceuticals by Janssen for the treatment of d-IBS, granting an option to Furiex to continue development and commercialization following phase II proof of concept studies.

The opioid receptors were identified in the mid-1970’s, and were quickly categorized into three sub-sets of receptors (mu, delta and kappa). More recently the original three types of receptors have been further divided into sub-types. Also known is that the family of opioid receptors are members of the G-protein coupled receptor (GPCR) super-family. More physiologically pertinent are the well established facts that opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans, and that modulation of the respective receptors can elicit numerous, albeit different, biological effects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269; J. V. Aldrich, “Analgesics”, Burger’s Medicinal Chemistry and Drug Discovery, 5thEdition, Volume 3: Therapeutic Agents, John Wiley & Sons, Inc., 1996, pp. 321-441). In the most current literature, the likelihood of heterodimerization of the sub-classes of opioid receptors has been reported, with respective physiological responses yet undetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development”, Drug Development 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting mu opioid agonist modulators marketed as analgesic agents to attenuate pain (e.g., morphine), as well as peripherally acting mu agonists to regulate motility (e.g., loperamide). Currently, clinical studies are continuing to evaluate medicinal utility of selective delta, mu, and kappa modulators, as well as compounds possessing combined sub-type modulation. It is envisioned such explorations may lead to agents with new utilities, or agents with minimized adverse side effects relative to currently available agents (examples of side effects for morphine includes constipation, respiratory depression, and addiction potential). Some new GI areas where selective or mixed opioid modulators are currently being evaluated includes potential treatment for various diarrheic syndromes, motility disorders (post-operative ileus, constipation), and visceral pain (post operative pain, irritable bowel syndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere and Jean-Louis Junien, “Opioid receptors: Targets for new gastrointestinal drug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, the enkephalins were identified as a set of endogenous opioid ligands (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncating the original pentapeptide enkephalins to simplified dipeptides yielded a series of compounds that maintained opioid activity (Schiller, P. WO 96/06855). However one potential drawback cited for such compounds is the likelihood of their inherent instability (P. W. Schiller et al., Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containing heteroaromatic or heteroaliphatic nuclei were disclosed, however this series is reported showing a different functional profile than that described in the Schiller works. (L. H. Lazarus et al., Peptides 2000, 21, pp. 1663-1671).

Most recently, works around morphine related structures were reported by Wentland, et al, where carboxamido morphine derivatives and it’s analogs were prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters 2001, 11, pp. 623-626). Wentland found that substitution for the phenol moiety of the morphine related structures with a primary carboxamide led anywhere from equal activities up to 40 fold reduced activities, depending on the opioid receptor and the carboxamide. It was also revealed that any additional N-substitutions on the carboxamide significantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosed and are believed to provide advantages over related compounds by providing improved pharmacological profiles.

Opioid receptor modulators, agonists or antagonists are useful in the treatment and prevention of various mammalian disease states, for example pain and gastrointestinal disorders such as diarrheic syndromes, motility disorders including post-operative ileus and constipation, and visceral pain including post-operative pain, irritable bowel syndrome and inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptor modulators. It is a further object of the invention to provide opioid receptor agonists and opioid receptor antagonists. It is an object of the present invention to provide opioid receptor ligands that are selective for each type of opioid receptor, mu, delta and kappa. It is a further object of the present invention to provide opioid receptor ligands that modulate two or three opioid receptor types, mu, delta and kappa, simultaneously.

It is an object of the invention to provide certain instant compounds that are also useful as intermediates in preparing new opioid receptor modulators. It is also an object of the invention to provide a method of treating or ameliorating a condition mediated by an opioid receptor. And, it is an object of the invention to provide a useful pharmaceutical composition comprising a compound of the present invention useful as an opioid receptor modulator.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1 h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid is an opoid receptor modulator (mu receptor agonist and delta receptor antagonist) and may be useful for treating irritable bowel syndrome, pain or other opioid receptor disorders.

5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and methods of making this molecule are disclosed in

US application 2005/02033143. Example 9 of US application 2005/02033143 makes the hydrochloride salt of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

Applicants have discovered a process of making the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid and two novel crystals of this zwitterion. In Applicant’s hands, these novel crystals provide improved properties and can be purified at higher purity. Applicant’s new process results in improved and less costly process manufacturing conditions than the procedure disclosed in US application 2005/02033143.

FIG. 6 is the molecular structure of the zwitterion 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

US7994206

SYNTHESIS OF 5-formyl-2- methoxy-benzoic acid methyl ester

WO2002022612A1

Example 8: 2-Methoxy-5-formylbenzoic acid

Figure imgf000023_0001

Lithium hydroxide (1.04g, 0.043mol, 3eq) in water (lOmL) was added to a stirred solution of methyl 2-methoxy-5-formylbenzoate (2.8g, 0.014mol, leq) in a mixture of tetrahydrofuran (30mL) and methanol (20mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (lOOmL) and the organic solution washed with brine (lOOmL), then extracted with saturated aqueous sodium bicarbonate (3 x lOOmL). The basic solution was washed with ethyl acetate (lOOmL), then acidified to pH 1 with 10% HCl and back extracted with dichloromethane (3 x lOOmL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (2.01g, 77%). 1H NMR (CDC13) δ 9.99 (s, IH, O=C- H), 4.14 (s, 3H, CH3).

ANALOGOUS METHOD TO PREPARE..2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester

USE 5-formyl-2- methoxy-benzoic acid methyl ester  for 3,4- dimethoxybenzaldehyde, TO GET 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester 

Example 4

(3,4-Dimethoxy-benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine

Figure imgf000076_0001
NOTE THIS IS NOT THE COMPD….IT IS REF FOR AN ANALOGOUS PROCEDURE

A solution of 1-(4-phenyl-1 W-imidazol-2-yl)-ethylamine (0.061 g, 0.33 mmol) of Example 3, and 0.55 g (0.33 mmol) of 3,4-dimethoxybenzaldehyde in 5 ml_ of anhydrous methanol was stirred at room temperature for 1 h and then cooled to about 0-100C in an ice bath for 1 h. The reaction was treated carefully with 0.019 g (0.49 mmol) of sodium borohydride in one portion and maintained at about 0-100C for 21 h. Cold 2M aqueous HCI was added dropwise (30 drops), the mixture was stirred for 5 min, and then partially concentrated in vacuo unheated. The residual material was taken up in EtOAc to yield a suspension that was treated with 5 ml_ of cold 3M aqueous NaOH and stirred vigorously until clear. The phases were separated and the aqueous layer was extracted three times additional with EtOAc. The combined extracts were dried over MgSO4, filtered, and concentrated to yield (3,4-dimethoxy- benzyl)-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amine as a light yellow oil (HPLC: 87% @ 254nm and 66% @ 214 nm).

MS (ES+) (relative intensity): 338.1 (100) (M+1)

This sample was of sufficient quality to use in the next reaction without further purification.

SYNTHESIS

WO2006099060A2

In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (IV)

Figure imgf000016_0001

also known as, 5-({[2-amino-3-(4-carbamoyl-2,5-dimethyl-phenyl)- propionyl]-[1 -(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid

Example 1

(S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2.6-dimethyl-phenyl)- propionic acid

Figure imgf000067_0001
Figure imgf000068_0001

STEP A: Trifluoromethanesulfonic acid 4-bromo-3,5-dimethyl-phenyl ester

To a cooled (0°C) solution of 4-bromo-3,5-dimethylphenol (3.05 g, 15.2 mmol) in pyridine (8 ml_) was added trifluoromethanesulfonic anhydride (5.0 g, 17.7 mmol) dropwise. After completion of addition, the resulting mixture was stirred at 0°C for 15 min, and then at room temperature overnight. The reaction was quenched by addition of water, and then extracted with EtOAc. The organic extracts were washed sequentially with water, 2N HCI (2x ), brine, and then dried over MgSO4. Filtration and evaporation to dryness yielded compound 1 b as a colorless oil.

1H NMR (300 MHz, CDCI3): δ 2.45 (6H, s), 7.00 (2H, s).

Step B: 4-Bromo-3,5-dimethylbenzoic acid

Into a solution of compound 1 b (6.57 g, 19.7 mmol) in DMF (65 ml_) were added K2CO3 (13.1 g, 94.7 mmol), Pd(OAc)2 (0.44 g, 1.97 mmol) and 1 ,1′-bis(diphenylphosphino)ferrocene (2.29 g, 4.14 mmol). The resulting mixture was bubbled in gaseous CO for 10 min and was heated to 60°C for 7.5h with a CO(9) balloon. The cooled mixture was partitioned between aqueous NaHCO3 and EtOAc, and filtered. The aqueous phase was separated, acidified with aqueous 6N HCI, extracted with EtOAc, and then dried over Na2SO4. Filtration and concentration of the filtrate yielded crude compound 1c as a brown residue, which was used in the next step without further purification. STEP C: Method A: 4-Bromo-3,5-dimethyl-benzamide

Into a suspension of compound 1c in DCM (40 ml_) was added SOCI2 (3.1 rnL, 42 mmol) and the mixture was heated at reflux for 2 h. Upon removal of the solvent by evaporation, the residue was dissolved in DCM (40 ml_) and then ammonium hydroxide (28% NH3 in water, 2.8 ml_) was added. The reaction mixture was heated at 5O0C for 2 h and concentrated. The residue was diluted with H2O, extracted with EtOAc, and the organic portion was dried over Na2SO4. After filtration and evaporation, the residue was purified by flash column chramotagraphy (eluent: EtOAc) to yield compound 1 d as an off-white solid.

1H NMR (300 MHz, CD3CN): δ 2.45 (6H, s), 5.94 (1 H, br s), 6.71 (1 H, br s), 7.57 (2H, s)

MS(ES+)(relative intensity): 228.0 (100%) (M+1).

Step C: Method B: 4-Bromo-3,5-dimethyl-benzamide

A mixture of compound 1 b (3.33 g, 10 mmol), PdCI2 (0.053 g, 0.3 mmol), hexamethyldisilazane (HMDS, 8.4 ml_, 40 mmol), and DPPP (0.12 g, 0.3 mmol) was bubbled with a gaseous CO for 5 min and then stirred in a CO balloon at 80°C for 4 h. To the reaction mixture was added MeOH (5 ml_). The reaction mixture was stirred for 10 min, diluted with 2N H2SO4 (200 ml_), and then extracted with EtOAc. The EtOAc extract was washed with saturated aqueous NaHCO3, brine, and then dried over Na2SO4. Filtration and evaporation of the resultant filtrate yielded a residue, which was purified by flash column chromatography (eluent: EtOAc) to yield compound 1d as a white solid.

Step D: 2-terf-Butoxycarbonylaminoacrylic acid methyl ester

To a suspension of /V-Boc-serine methyl ester (Compound 1e, 2.19 g, 10 mmol) and EDCI (2.01 g, 10.5 mmol) in DCM (70 ml_) was added CuCI (1.04 g, 10.5 mmol). The reaction mixture was stirred at room temperature for 72 h. Upon removal of the solvent, the residue was diluted with EtOAc, washed sequentially with water and brine and then dried over MgSO4. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :4) to yield compound 1f as a colorless oil.

1H NMR (300 MHz, CDCI3): δ 1.49 (9H, s), 3.83 (3H, s), 5.73 (1 H, d, J = 1.5 Hz), 6.16 (1 H1 S), 7.02 (1 H, s).

STEP E: (2)-2-fert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)acrylic acid methyl ester

A flask charged with compound 1d (0.46 g, 2.0 mmol), compound 1f (0.80 g, 4.0 mmol), tri-o-tolylphosphine (0.098 g, 0.32 mmol) and DMF (8 ml_) was purged with N2(g) 3 times. After the addition of tris(dibenzylideneacetone)dipalladium (0) (0.074 g, 0.08 mmol) and TEA (0.31 ml_, 2.2 mol), the reaction mixture was heated at 110°C for 24 h. At that time, the reaction was quenched by addition of water, and then extracted with EtOAc. The organic phase was washed with 1 N HCI, saturated aqueous NaHCO3, brine, and dried over MgSO4. The mixture was concentrated to a residue, which was purified by flash column chromatography (eluent: EtOAc:hexane~1 :1 to EtOAc only) to yield compound 1g as a white solid.

1H NMR (300 MHz, CD3OD): δ 1.36 (9H, s), 2.26 (6H, s), 3.83 (3H, s), 7.10 (1 H, s), 7.56 (2H, s); 13C NMR (75 MHz, DMSO-d6): δ 17.6, 25.7, 50.2, 78.7, 124.9, 126.4,

128.3, 131.2, 135.2, 135.5, 152.8, 164.3, 169.6;

MS (ES+) (relative intensity): 349.1 (38%)(M+1).

STEP F: (S)-2-ferf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid methyl ester

Into a reactor charged with a solution of compound 1g (0.56 g, 1.6 mmol) in degassed MeOH (80 mL) was added [Rh(COd)(H1R-DIPAMP)J+BF4  under a stream of argon. The reactor was sealed and flushed with H2, stirred at 6O0C under 1000 psi of H2 for 14 days. The crude product was purified by flash column chromatography (eluent: EtOAc:hexane ~1 :1) to yield compound 1 h as a white solid. ee: >99%; 1H NMR (300 MHz, CDCI3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J = 7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1 H, m), 5.12 (1 H, d, J = 8.7 Hz), 5.65 (1 H, br s), 6.09 (1 H, br s), 7.46 (2H, s);

MS(ES+) (relative intensity): 250.9 (100) (M-BoC)+.

STEP G: (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid

Into an ice-cooled solution of compound “I h (0.22 g, 0.63 mmol) in THF (3.5 ml_) was added an aqueous LiOH solution (1 N, 3.5 ml_) and the reaction mixture stirred at 0°C. Upon completion of the reaction, the reaction mixture was concentrated and the aqueous phase was neutralized with cooled aqueous 1 N HCI at 0°C, and then extracted with EtOAc. The combined extracts were dried over Na2SO4 overnight. Filtration and evaporation of the filtrate to dryness yielded compound 1j as a white solid. 1H NMR (300 MHz, DMSO-cfe): δ 1.30 (9H, s), 2.32 (6H, s), 2.95(1 H, dd,

J= 8.8, 13.9 Hz), 3.10 (1 H, dd, J= 6.2, 14.0 Hz), 4.02-4.12 (1 H, m), 7.18-7.23 (2H, m), 7.48 (2H1 s), 7.80 (1 H, s);

MS(ES+) (relative intensity): 236.9 (6) (M-BoC)+.

Example 5

5-((r2-Amino-3-(4-carbamoyl-2.6-dimethyl-phenyl)-propionvn-n-(4-phenyl- 1 H-imidazol-2-yl)-ethvπ-aminol-methyl)-2-methoxy-benzoic acid

Figure imgf000076_0002
Figure imgf000077_0001

STEP A. 2-Methoxy-5-{[1-(4-phenyl-1 W-imidazol-2-yl)-ethylamino]-methyl}- benzoic acid methyl ester

Using the procedures described for Example 4, substituting 5-formyl-2- methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4- dimethoxybenzaldehyde, 2-methoxy-5-{[1 -(4-phenyl-1 H-imidazol-2-yl)- ethylamino]-methyl}-benzoic acid methyl ester was prepared.

STEP B. 5-({[2-ferf-ButoxycarbonylmethyI-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 H-imidazoI-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid methyl ester

Using the procedure of Example 3 for the conversion of Cpd 3d to Cpd 3e, substituting 2-methoxy-5-{[1-(4-phenyl-1 /-/-imidazol-2-yl)-ethylamino]- methylj-benzoic acid methyl ester for Cpd 3d and substituting 2-tert- Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionic acid for 2- tø/t-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 5a was prepared.

STEP C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl]-[1 -(4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2- methoxy-benzoic acid

5-({[2-tørf-Butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)- propionyl]-[1-(4-phenyl-1 H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid methyl ester was dissolved in an ice-chilled (0-10°C), mixed solvent system of THF (10 ml_) and MeOH (5 ml_). A LiOH H2O/water suspension (2.48 M; 3.77 ml_) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3 x 26 ml_). These combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to yield a pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH2CI2 solution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOHZCH2CI2 system as follows: Initial 100% CH2CI2, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 5-({[2-terf- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4- phenyl-1 /-/-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 5b, as a white solid.

STEP D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1 – (4-phenyl-1 W-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A portion of Cpd 5b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 ml_)/THF (5 ml_), filtered, and subsequently treated with gaseous HCI for 15 min. After completion of the HCI addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield Cpd 5c as a white solid di-HCI salt.

Example 2

Racemic 2-terf-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethvl- phenvD-propionic acid

Figure imgf000071_0001

STEP A: Racemic 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid methyl ester

To a reactor charged with a solution of compound 1g (0.68 g, 1.95 mmol) in MeOH (80 mL) was added 10% Pd-C (0.5 g). The reactor was connected to a hydrogenator and shaken under 51 psi of H2 overnight. The mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness to yield compound 2a as a white solid.

The 1H NMR spectrum was identical to that of (S)-2-tert- butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)propionic acid methyl ester, compound 1 h.

STEP B: Racemic 2-terf-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)propionic acid

Following the procedure described for Example 1 , STEP G (preparation of (S)-2-teAt-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)propionic acid), compound 2b – racemic 2-te/?-butoxycarbonylamino-3- (4-carbamoyl-2,6-dimethyl-phenyl)propionic acid – was prepared.

POLYMORPHS

US8609865

Example 1 Preparation of the zwitterion of 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

A 1 L three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and a thermocouple was charged without agitation. 34.2 g of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid (see Example 9 of US 2005/0203143), 340 ml of acetone, and 17 ml of 204 mmolar concentrated HCl were combined in the flask. The stirring was started and the resulting slurry formed a clear solution. This solution was heated to 45° C. under vigorous stirring and aged at this temperature for a period of two hours. After the completion, the reaction mass was cooled to ambient temperature and the supernatant was removed by suction. The vessel along with the residue was rinsed with 20 ml of acetone and then removed as previously. 170 ml of water was added and the reaction mass and was aged under stirring until a homogeneus solution resulted. This solution was then added over a period of ˜½ hr to a solution of 90 ml of 1N NaOH and water. The pH was adjusted to 6.5-7.0 accordingly. The resulting slurry was aged for about 2 hrs at ambient temperature, cooled to 10-15° C., aged at that temperature for about 1 hr, and then filtered. The solid was washed with 10 ml water, air-dried for a period of 4 to 5 hrs, and then placed in a vacuum oven at 50-55° C. until the water content was less than 3%.

Example 2 Preparation of the Form α Crystal

The Form α crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at 0-25% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1-3 respectively.

Example 3 Preparation of the Form β crystal

The Form β crystal can be prepared by storing the zwitterion of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid at greater than 60% relative humidity for 3 days. Representative PXRD, TGA, and DSC data are shown in FIGS. 1, 4, and 5 respectively.

SYNTHESIS

US20050203143

Example 9 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid

Figure US20050203143A1-20050915-C00035

A. 2-Methoxy-5{[1-(4-phenyl-1 H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester.

Using the procedures described for Example 3, substituting 5-formyl-2-methoxy-benzoic acid methyl ester (WO 02/22612) for 3,4-dimethoxybenzaldehyde, 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester was prepared.

B. 5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester.

Using the procedure of Example 1 for the conversion of Cpd 1d to Cpd 1e, substituting 2-methoxy-5-{[1-(4-phenyl-1H-imidazol-2-yl)-ethylamino]-methyl}-benzoic acid methyl ester for Cpd 1 d and substituting 2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl-propionic acid of Example 8 for 2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid, Cpd 9a was prepared.

C. 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[11-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

5-({[2-tert-Butoxycarbonyl methyl-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester was dissolved in an ice-chilled (0-10° C.), mixed solvent system of THF (10 mL) and MeOH (5 mL). A LiOH.H2O/water suspension (2.48 M; 3.77 mL) was added dropwise, then the reaction was allowed to warm to room temperature and stirred overnight. The resulting mixture was cooled in an ice bath and the basic solution was neutralized with 2N citric acid until slightly acidic. The mixture was concentrated under reduced pressure to remove the volatile materials, after which time the remaining aqueous phase was extracted with EtOAc (3×26 mL). These combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to give 2.26 g (146% of theory) of pale yellowish white solid. This crude material was dissolved in a 10% MeOH/CH2Clsolution and adsorbed onto 30 g of silica. The adsorbed material was divided and chromatographed on an ISCO normal phase column over two runs, using a 40 g Redi-Sep column for both runs. The solvent system was a gradient MeOH/CH2Clsystem as follows: Initial 100% CH2Cl2, 98%-92% over 40 min; 90% over 12 min, and then 88% over 13 min. The desired product eluted cleanly between 44-61 min. The desired fractions were combined and concentrated under reduced pressure to yield 1.74 g (113% of theory) of 5-({[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid, Cpd 9b, as a white solid.

D. 5-({[2-Amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid.

A portion of Cpd 9b (0.27g, 0.41 mmol) was dissolved in EtOAc (39 mL)/THF (5 mL), filtered, and subsequently treated with gaseous HCl for 15 min. After completion of the HCl addition, the reaction was slowly warmed to room temperature and a solid precipitate formed. After 5 h the reaction appeared >97% complete by LC (@214 nm; 2.56 min.). The stirring was continued over 3 d, then the solid was collected and rinsed with a small amount of EtOAc. The resulting solid was dried under high vacuum under refluxing toluene for 2.5 h to yield 0.19 g (71%) of desired Cpd 9c as a white solid di-HCl salt.

Example 8 (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester

Figure US20050203143A1-20050915-C00034

A. (S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester. Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol; Sources: Chiramer or RSP AminoAcidAnalogues) and N-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) in dichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol). The resulting solution was stirred at 0° C. for 1 h and slowly warmed to rt. Upon completion, the reaction was quenched by addition of water. The separated organic phase was washed with 1 N NaOH aqueous solution, water and dried over Na2SOovernight. After filtration and evaporation, the residue was purified by flash column chromatography (eluent: EtOAc-hexane: 3:7) to give the desired product (9.74 g, 99%) as a clear oil; 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.39 (6H, s), 3.06 (2H, d, J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m), 5.12 (1H, d, J=8.5 Hz), 6.92 (2H, s); MS (ES+) (relative intensity): 355.8 (100) (M−Boc)+.

B. (S)4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoic acid. To a suspension of (S)-2-tert-butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionic acid methyl ester (9.68 g, 21.3 mmol), K2CO(14.1 g, 0.102 mol), Pd(OAc)(0.48 g, 2.13 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.56 g, 4.47 mmol) in DMF (48 mL) was bubbled in gaseous CO for 15 min. The mixture was heated to 60° C. for 8 h with a CO balloon. The cool mixture was partitioned between NaHCOand EtOAc, and filtered. The aqueous layer was separated, acidified with 10% citric acid aqueous solution, extracted with EtOAc, and finally dried over Na2SO4. Filtration and concentration of the filtrate resulted in a residue. The residue was recrystallized from EtOAc-hexanes to afford the desired product (7.05 g, 94%); 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H, m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS(ES+) (relative intensity): 251.9 (100) (M−Boc)+.

C. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid methyl ester. Into a stirring solution of (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethyl benzoic acid (3.00 g, 8.54 mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36 mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH4Cl (0.92 g, 17.1 mmol). The resulting mixture was stirred at rt for 40 min before being partitioned between aqueous NH4Cl solution and EtOAc. The separated organic phase was washed sequentially with 2N citric acid aqueous solution, saturated aqueous NaHCOsolution, and brine, then dried over Na2SOovernight. After filtration and concentration, the residue was purified by flash column chromatography (eluent: EtOAc) to give the product. (3.00 g, 100%); 1H NMR (300 MHz, CDCl3): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz), 3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, brs), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9 (100) (M−Boc)+.

D. (S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid. Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54 mmol) in THF (50 mL) was added an aqueous LiOH solution (1N, 50 mL) and stirred at 0° C. Upon consumption of the starting materials, the organic solvents were removed and the aqueous phase was neutralized with cooled 1N HCl at 0° C., and extracted with EtOAc, and dried over Na2SOovernight. Filtration and evaporation to dryness led to the title acid (S)-2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionic acid (2.51 g, 87%); 1H NMR (300 MHz, DMSO-d6): δ 1.30 (9H, s), 2.32 (6H, s), 2.95 (1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd, J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s), 7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M−Boc)+.

PAPER

Bioorg Med Chem Lett. 2012 Jul 15;22(14):4869-72.

PATENTS

1.WO 2005090315

2..WO 2006099060

3.WO 2009009480

4. WO 2010062590

5.US 2011263868 *

Patent

https://patentscope2.wipo.int/search/de/detail.jsf;jsessionid=17DB1184234A30C42C287EBFB95A7EF3?docId=WO2018198101&tab=PCTDESCRIPTION&office=&prevFilter=%26fq%3DOF%3AWO&sortOption=Ver%C3%83%C2%B6ffentlichungsdatum+ab&queryString=&recNum=9351&maxRec=3410922

Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2, 6-dimethylphenyl] – 1 -oxopropyl] [( 15)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl] amino] methyl] -2-methoxybenzoic acid, represented by Formula I.

Formula I

Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).

U.S. Patent No. 7,741 ,356 describes a process for the preparation of eluxadoline. U.S. Patent Nos. 7,629,488 and 8,710,256 describe processes for the preparation of intermediates of eluxadoline.

PCT Publication No. WO2009/009480 purportedly discloses forms alpha and beta crystals of eluxadoline and processes thereof. PCT Publication No. WO2009/009480 discloses that form alpha crystals can be prepared by storing the zwitterion of eluxadoline at 0-25% relative humidity (RH) for 3 days and form beta crystals can be prepared by storing the zwitterion of eluxadoline at greater than 60% RH for 3 days.

PCT Publication No. WO2017/015606 purportedly discloses amorphous form, crystalline forms I, II, III and IV, and processes for their preparation and a process for the preparation of form alpha crystal of eluxadoline

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018138274

Eluxadoline is the INN denomination assigned to the compound having lUPAC name 5-({[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propanoyl][(1 S)-1 -(4-phenyl-1 /-/-imidazol-2-yl)ethyl]amino}methyl)-2-methoxybenzoic acid and the formula reported below:

Eluxadoline is a μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist that acts locally in the enteric nervous system. The drug, administered orally, is active locally in the intestine and is able to control gastrointestinal function (Gl) and at the same time to reduce the pain and mitigate the effect of constipation. Its use has been approved for the treatment of diarrhea and abdominal pain in individuals with diarrhea-predominant irritable bowel syndrome (IBS-D).

The family of compounds to which eluxadoline belongs is disclosed in patent application WO 2005/090315 A1 , while patent application WO 2006/099060 A2 is directed to processes for the preparation of these compounds.

As generally known, any active principle may exist under amorphous or different crystalline forms (polymorphs), either as pure compound or in forms in which, in the structure of the crystal, are present molecules of water (hydrates) or of another solvent (solvates); besides, in case of hydrates and solvates, the ratio between the number of molecules of active principle and molecules of water or solvent may vary, giving rise to different solid forms of the compound.

Different salts and solid-state forms of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid-state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favourable direction, or improving stability (polymorphic and/or chemical) and shelf-life. These variations in the properties of different salts and solid-state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts, solid-state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which, in turn, may provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.

While not intending to be bound by any theory, certain solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behaviour, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art.

For these reasons, chemical compounds useful in the pharmaceutical field are systematically screened looking for the physical form(s) that present an improved set of production, storage and handling properties, and which result in an improved administration to the patients.

Patent application WO 2009/009480 A2 discloses two crystalline forms of eluxadoline, referred to in the document respectively as Form a and Form β. Form a is characterized by an X-ray powder diffraction pattern having the main peaks at about 10.2°, 1 1.3°, 1 1.8°, 14.0°, 14.3°, 14.7°, 16.1 ° and 18.3° 2Θ, while Form β is characterized by an X-ray powder diffraction pattern having the main peaks at about 1 1.0°, 12.4°, 14.9°, 15.2°, 22.1 °, 25.6°, 27.4°, and 30.4° 2Θ.

Patent application WO 2017/015606 A1 discloses several crystalline forms of eluxadoline, referred to therein as Form I, Form II, Form III, and Form IV. Form I is characterized by an X-ray powder diffraction pattern having peaks at about 6.4°, 7.5°, 9.1 °, 10.0°, and 13.0° 2Θ. Form II is characterized by an X-ray powder diffraction profile having peaks at about 7.2°, 1 1 .6°, 12.1 °, 12.7° and 16.9° 2Θ. Form III is characterized by an X-ray powder diffraction pattern having peaks at about 9.3°, 10.2°, 1 1 .5°, 13.3° and 21.8° 2Θ. Form IV is characterized by an X-ray powder diffraction profile having peaks at about 9.3°, 10.2°, 1 1.5°, 13.3° and 21 .8° 2Θ.

However, no information is provided in any of these documents about any useful

properties from the standpoint of the pharmaceutical industry, neither regarding ease of handling of the forms in the production of formulations nor regarding the storage stability (polymorphic and/or chemical) of eluxadoline when prepared in one of these crystalline forms.

An object of the present invention is the provision of a novel process for the preparation of a polymorphic form a’ of eluxadoline (as defined hereinbelow) which, surprisingly, is polymorphically and chemically stable. Since this polymorphic form represents a valuable product, it is an object that upscaling of this process, in order to meet the needs of industrial-scale production, should be easily accomplishable. It is a further object of the present invention that said novel process should produce high-purity products which must contain as low an amount of possibly harmful compounds as possible.

Surprisingly, it was found that new solvate forms ε of eluxadoline allow for the realization of this process and, thus, of the new polymorphically and chemically stable crystalline form α’. It was found that in terms of the starting material from which the solvate forms ε of eluxadoline can be produced, they are extremely flexible.

Further, it was found that the reaction conditions necessary to produce these solvate forms are highly advantageous in terms of energy consumption in combination with the chemical nature of the solvents used

High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV):

Chemical stability tests were performed using the following HPLC method

Column: XBridge C8 150 X 4.6 mm, 3.5 μηι

Mobile Phase A: 0.1 % (V/V) phosphoric acid aqueous solution

Mobile Phase B: Acetonitrile

Diluent: 1 :1 (V/V) Mixture of Mobile Phases A and B

Flow Rate: 1.3 mL/min

Runtime: 35 min

Column Temperature 30 °C

Autosampler Temperature: Ambient

Injection Volume: 5 μΙ_

Detection: 210 nm

Sample concentration: 0.4 mg/mL

Gradient Program:

PATENT

WO 2018020450

https://patents.google.com/patent/WO2018020450A2/en

Example 1

Preparation of Eluxadoline

Step 1- Preparation of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l- (4-phenyl- lH-imidazol-2-yl)-ethyl]-amino} -methyl)-2-methoxy-benzoic acid

Figure imgf000023_0001

To a stirred solution of 1 -(4-phenyl- lH-imidazole-2-yl)-ethyl amine (20 gm) and 5-formyl-2-methoxy-benzoic acid methyl ester (20 gm) in methanol was added catalytic amount of acetic acid (3 ml). The reaction mixture was cooled at 5°C-10°C and sodium borohydride (4 gm) was added. The reaction mixture was further stirred for 2-3 hours at room temperature. The resultant mixture was diluted with water and then partially concentrated. To this mixture was added 2N HCl solution followed by addition of dichloromethane. The phases were separated and the pH (9-1 1) of aqueous layer was adjusted using 2N NaOH solution; which was further extracted with dichloromethane. The combined organic layers were concentrated under vacuum to afford titled compound as oil (yield: 40 gm).

Step 2- Preparation of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino} -methyl)-2-methoxy- benzoic acid methyl ester

Figure imgf000023_0002

To a stirring mixture of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl-propionic acid (100 gm), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (159.4 gm) and 1- hydroxybenzotriazole (45.4 gm) in dimethylformamide (80 ml) & dichloromethane (1920 ml) was added 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l-(4- phenyl-lH-imidazol-2-yl)-ethyl] -amino }-methyl)-2-methoxy-benzoic acid (step 1 product, 146.6 gm). The resulting mixture was stirred at room temperature for overnight and further diluted with water. The separated organic phase was washed sequentially with aqueous Na2C03 solution, IN HCl solution, water and brine. After concentration, the residue was further dissolved in DCM. The resultant solution was washed sequentially with water & IN HCl solution and then concentrated under vacuum to afford titled compound (yield: 145 gm).

Step 3- Preparation of methyl 5-((2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-(l-(4- phenyl- 1 H-imidazol-2-yl)ethyl) enzoate

Figure imgf000024_0001

To a stirred solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid methyl ester (step -2 product, 20 gm) in THF (80 ml) was added Cone. HCl solution (30 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the mixture was concentrated and resultant residue was diluted with water. The pH (9-10) was adjusted using 3N NaOH solution; and resultant stick mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford titled compound (yield: 18.1 gm).

Step 4- Preparation of Eluxadoline

Figure imgf000025_0001

Into an ice cooled solution of methyl 5-((2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)-N-( 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate (step 3 product, 15 gm) in methanol was added an aqueous lithium hydroxide (3.23 gm in 30 ml water) and resultant mixture was heated at 40°C-45°C. After completion of reaction, mixture was concentrated and further diluted with water. The pH (6-7) was adjusted using 2N citric acid and resultant residue was dissolved in methanol. The resultant solution was added slowly to the acetone and stirring was continued for overnight. The solid precipitated was filtered, washed with acetone and dried to obtain an amorphous form of titled compound (Yield: 3.50 gm).

Example 2

Preparation of Eluxadoline

Step 1 : Preparation of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] – [ 1 -(4-phenyl- 1 W-imidazol-2-yl)-ethyl] -amino } -methyl)-2-methoxy- benzoic acid

Figure imgf000025_0002

Into an ice cooled solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl- 2,6-dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)- 2-methoxy-benzoic acid methyl ester (160 gm) in methanol (800 ml) was added an aqueous solution of lithium hydroxide (29.46 gm in 350 ml water) and resultant mixture was stirred at room temperature for overnight. After completion of reaction, mixture was partially concentrated and further diluted with water. The pH (4-5) was adjusted using 2N citric acid and further stirred for 60 min. The solid precipitated was filtered, washed with water and dried to obtain titled compound (yield: 140 gm). Step 2: Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (step-1 product, 100 gm) in acetone (1200 ml) was added Cone. HC1 solution (50 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the supernatant solution was decanted; resultant residue was rinsed with acetone and further dissolved in water. The pH (6-7) was adjusted using IN NaOH solution and the precipitated was filtered, washed with water and dried to obtain an amorphous form of eluxadoline (yield: 72 gm).

Example 3

Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] – [ 1 -(4-phenyl- 1 -imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (50 gm) in dichloromethane (250 ml) were added solution of Cone. HC1 (50 ml) and water (50 ml). The reaction mixture was heated at 35°C-40°C and further stirred for 10-20 minutes. Tetrahydrofuran (50 ml) & Cone. HC1 (20 ml) were added to the sticky mass and reaction mixture was heated at 40°C for 2 hours. After completion of reaction, the mixture was diluted with water. The pH (6-7) was adjusted using 4N NaOH solution and the obtained sticky mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford eluxadoline (yield: 16 gm).

Example 4

Preparation of amorphous form of eluxadoline Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Water (60 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with water and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 5

Preparation of amorphous form of eluxadoline

Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Acetone (80 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with acetone and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 6

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing acetonitrile (60 ml) and slurried for 24 hours to 25 hours at 50°C. The resultant solid was filtered, and dried to obtain titled compound (Yield: 0.80 gm).

clip

Eluxadoline (Viberzi)

Eluxadoline, originally developed by Janssen and currently marketed by Allergan (formerly Actavis), was approved in May 2015 by the FDA for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D).(60)
Eluxadoline, an orally dosed agent, employs a unique mechanism for IBS-D treatment, as it functions simultaneously as a μ- and κ-opioid receptor agonist and a δ-opioid receptor antagonist,(61) leading to a first-in-class therapy for treatment of IBS-D. Specifically, in animal studies, eluxadoline was found to interact with opioid receptors in the gut, inhibiting neurogenically mediated secretion and reducing intestinal contractility.(62)
Additionally, the treatment led to a decrease in stress-induced acceleration of upper GI transit without causing rebound constipation,(60-62) earning its mark as a first-line therapeutic treatment for IBS-D. In two phase III clinical trials of over 2400 patients with IBS-D, patients taking eluxadoline showed a greater improvement toward the end point (≥30% improvement from their baseline IBS-D score on at least 50% of days treated with eluxadoline) compared to patients treated with placebo.(63)
The synthesis of eluxadoline begins with preparation of advanced coupling component 85, which could be completed via a four-step route from commercially available N-Boc-protected aminoester 83 (Scheme 15).(64) Triflate formation using N-phenyltrifluoromethanesulfinimide in DCM under basic conditions led to nearly quantitative yield of the desired triflate, which was subjected to a carbonylation reaction to yield aryl acid 84 in 94% yield. Employing NH4Cl as a source of ammonia, amidation of 84 took place in the presence of PyBOP/HOBt and DIPEA in DMF. Finally, acid 85 was revealed upon methyl ester saponification with aqueous LiOH in THF. This sequence provided 85 without purification ,and this acid could be used directly as applied in Scheme 16.(64)
Scheme 15. Synthesis of Eluxadoline Intermediate 85
Scheme 16. Synthesis of Eluxadoline (XII)
With coupling component 85 in hand, the synthesis of eluxadoline proceeds as described in Scheme 16 and initiated from a HOBt and EDC·HCl-mediated coupling of commercial N-Cbz-l-alanine (86) with commercial 2-amino acetophenone hydrochloride (87) to provide intermediate 88in 83% yield.(64, 65) Addition of NH4OAc and AcOH to a suspension of 88 in refluxing xylenes furnished the desired imidazole in excellent yield (95%). Submission of this N-Cbz-imidazole to hydrogenation conditions (H2, Pd/C, MeOH) enabled liberation of the free amine to access 89 in quantitative yield following filtration and concentration. From intermediate 89, reductive amination with commercially available aryl aldehyde 90 under standard conditions (NaBH4, MeOH) followed by subsequent coupling of the corresponding crude amine with acid 85 using HOBt/EDC·HCl enabled formation of the carbon framework of eluxadoline (91). Saponification of the ester within 91 with LiOH in MeOH/THF yielded the corresponding acid in quantitative yield. Immediate subjection of this intermediate to acidic conditions (HCl in EtOAc/THF) led to N-Boc cleavage and isolation of eluxadoline (XII) as the bis-HCl salt in 71% yield, requiring no further purification.(64, 65) It should be noted that since this initial report, additional details for the isolation of eluxadoline in high purity in various crystal forms and as a zwitterion have been reported,(66) although most reported routes described isolation of this drug in its HCl salt form.(64, 65)
  1. 60.Garnock-JonesK. P. Eluxadoline: First Global Approval Drugs 2015751305– 1310 DOI: 10.1007/s40265-015-0436-4

  2. 61.DavenportJ. M.CovingtonP.BonifacioL.McIntyreG.VenitzJ. Effect of Uptake Transporters OAT3 and OATP1B1 and Efflux Transporter MRP2 on the Pharmacokinetics of Eluxadoline J. Clin. Pharmacol.201555534– 542 DOI: 10.1002/jcph.442

  3. 62.WadeP. R.PalmerJ. M.McKenneyS.KenigsV.ChevalierK.MooreB. A.MabusJ. R.;SaundersP. R.WallaceN. H.SchneiderC. R.KimballE. S.BreslinH. J.HeW.HornbyP. J.Modulation of Gastrointestinal Function by MuDelta, a Mixed μ Opioid Receptor Agonist/δ Opioid Receptor Antagonist Br. J. Pharmacol. 20121671111– 1125 DOI: 10.1111/j.1476-5381.2012.02068.x

  4. 63.LemboA. J.LacyB. E.ZuckermanM. J.ScheyR.DoveL. S.AndraeD. A.DavenportJ. M.;McIntyreG.LopezR.TurnerL.CovingtonP. S. Eluxadoline for Irritable Bowel Syndrome with DiarrheaN. Engl. J. Med. 2016374242– 253 DOI: 10.1056/NEJMoa1505180

  5. 64.BreslinH. J.CaiC.HeW.KavashR. W. Preparation of Imidazole Derivatives as Opioid Receptor Modulators. WO 20050203143A1, 2005.

  6. 65.caiC.HeW. Process for the Preparation of Amino Acid Derivatives as Opioid Modulators. WO 2006099060A1, 2006.
                   12-24-2010
                          NOVEL COMPOUNDS AS OPIOID RECEPTOR MODULATORS
                    8-32-2010
                          Compounds as opioid receptor modulators
                   6-23-2010
                          Compounds as opioid receptor modulators
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                          PROCESS FOR THE PREPARATION OF OPIOD MODULATORS
                   12-9-2009
                          Process for the preparation of opioid modulators
US7629488 * Mar 6, 2006 Dec 8, 2009 Janssen Pharmaceutica N.V. Process for the preparation of opioid modulators
US7741356 * Mar 14, 2005 Jun 22, 2010 Janssen Pharmaceutica N.V. Compounds as opioid receptor modulators
US7786158 * Oct 24, 2007 Aug 31, 2010 Janssen Pharmaceutica N.V. Compounds as opioid receptor modulators
US7994206 Jul 7, 2008 Aug 9, 2011 Janssen Pharmaceutica, N.V. Crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
CN1950342A Mar 14, 2005 Apr 18, 2007 詹森药业有限公司 Novel compounds as opioid receptor modulators

References

  1. Jump up to:a b c “Viberzi (eluxadoline) Tablets, for Oral Use, CIV. Full Prescribing Information”. Actavis Pharma, Inc. Parsippany, NJ 07054 USA. Retrieved 26 December 2015.
  2. ^ “Truberzi”European Medicines Agency. 29 September 2016.
  3. ^ Fragkos, Konstantinos C (2017-09-25). “Spotlight on eluxadoline for the treatment of patients with irritable bowel syndrome with diarrhea”Clinical and Experimental Gastroenterology10: 229–240. doi:10.2147/ceg.s123621.
  4. ^ “FDA approves two therapies to treat IBS-D”http://www.fda.gov. Retrieved 2015-06-01.
  5. ^ “Viberzi Information from Drugs.com”http://www.drugs.com. Retrieved 2015-06-01.
  6. ^ Limbo AJ, et al. Eluxadoline in Irritable Bowel Syndrome with Diarrhea. NEJM 2016;374:242-53
  7. ^ Commissioner, Office of the (15 March 2017). “Safety Alerts for Human Medical Products – Viberzi (eluxadoline): Drug Safety Communication – Increased Risk of Serious Pancreatitis In Patients Without A Gallbladder”http://www.fda.gov. Retrieved 19 March 2017.
  8. Jump up to:a b Brooks, Megan (March 2017). “FDA: Avoid IBS Drug Viberzi in Patients With No Gallbladder”http://www.medscape.com. Retrieved 2017-09-18.
  9. Jump up to:a b Commissioner, Office of the. “Safety Alerts for Human Medical Products – Viberzi (eluxadoline): Drug Safety Communication – Increased Risk of Serious Pancreatitis In Patients Without A Gallbladder”http://www.fda.gov. Retrieved 2017-09-18.
  10. ^ “bismuth subsalicylate”reference.medscape.com. Retrieved 2016-05-10.
  11. ^ Levy-Cooperman, N; McIntyre, G; Bonifacio, L; McDonnell, M; Davenport, JM; Covington, PS; Dove, LS; Sellers, EM (December 2016). “Abuse Potential and Pharmacodynamic Characteristics of Oral and Intranasal Eluxadoline, a Mixed μ- and κ-Opioid Receptor Agonist and δ-Opioid Receptor Antagonist”The Journal of Pharmacology and Experimental Therapeutics359 (3): 471–481. doi:10.1124/jpet.116.236547PMC 5118645PMID 27647873.
  12. ^ “Actavis Announces FDA Acceptance for Filing of NDA for Eluxadoline”http://www.drugs.com. Retrieved 2015-06-01.
  13. ^ “FDA Approves Viberzi (eluxadoline) for Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults”http://www.drugs.com. Retrieved 2015-06-01.
  14. ^ Davenport, J. Michael; Covington, Paul; Bonifacio, Laura; McIntyre, Gail; Venitz, Jürgen (2015). “Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline”The Journal of Clinical Pharmacology55 (5): 534–542. doi:10.1002/jcph.442ISSN 0091-2700PMC 4402028.
  15. ^ [1], Process of the Preparation of Opioid modulators.

The active ingredient in VIBERZI is eluxadoline, a mu-opioid receptor agonist.

The full chemical name is 5-[[[(2S)-2-amino-3-[4-(aminocarbonyl)-2,6-dimethylphenyl]-1- oxopropyl][(1S)-1-(4-phenyl-1H-imidazol-2-yl)ethyl]amino]methyl]-2-methoxybenzoic acid.

Eluxadoline has a molecular weight of 569.65 and a molecular formula of C32H35N5O5. The chemical structure of eluxadoline is:

VIBERZI (eluxadoline) Structural Formula Illustration

VIBERZI is available as 75 mg and 100 mg tablets for oral administration. In addition to the active ingredient, eluxadoline, each tablet contains the following inactive ingredients: silicified microcrystalline cellulose, colloidal silica, crospovidone, mannitol, magnesium stearate, and Opadry II (partially hydrolyzed polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide yellow, and iron oxide red).

Eluxadoline
Eluxadoline.svg
Eluxadoline ball-and-stick model.png
Clinical data
Trade names Viberzi (US), Truberzi (Europe)
Synonyms JNJ-27018966
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 81%
Elimination half-life 3.7–6 hours
Excretion 82.2% (feces), <1% (urine)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H35N5O5
Molar mass 569.6508 g/mol
3D model (JSmol)
Patent ID

Title

Submitted Date

Granted Date

US2017304268 OPIOID RECEPTOR MODULATOR DOSAGE FORMULATIONS
2017-05-05
US7629488 Process for the preparation of opioid modulators
2006-09-21
2009-12-08
Patent ID

Title

Submitted Date

Granted Date

US9789125 NOVEL CRYSTALS AND PROCESS OF MAKING 5-(-METHYL)-2-METHOXY-BENZOIC ACID
2016-06-02
US9364489 NOVEL CRYSTALS AND PROCESS OF MAKING 5-(-METHYL)-2-METHOXY-BENZOIC ACID
2015-07-22
2016-01-21
US9701647 Tetrazolones as a carboxylic acid bioisosteres
2016-08-10
2017-07-11
US9439888 Tetrazolones as a carboxylic acid bioisosteres
2016-01-25
2016-09-13
US2010036132 PROCESS FOR THE PREPARATION OF OPIOD MODULATORS
2010-02-11
Patent ID

Title

Submitted Date

Granted Date

US9700542 NOVEL COMPOUNDS AS OPIOID RECEPTOR MODULATORS
2015-10-12
2016-02-04
US9675587 OPIOID RECEPTOR MODULATOR DOSAGE FORMULATIONS
2013-03-14
2014-09-18
US9205076 NOVEL COMPOUNDS AS OPIOID RECEPTOR MODULATORS
2014-05-20
2014-09-11
US9115091 Crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2, 6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl—1H-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
2014-08-14
2015-08-25
US8691860 Crystals and process of making 5-({(2-amino-3-(4-carbamoyl-2, 6-dimethyl-phenyl)-propionyl]-[1-(-4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy-benzoic acid
2013-06-24
2014-04-08
Patent ID

Title

Submitted Date

Granted Date

US8772325 Compounds as opioid receptor modulators
2013-10-03
2014-07-08
US8609709 Compounds as opioid receptor modulators
2012-11-30
2013-12-17
US8344011 NOVEL COMPOUNDS AS OPIOID RECEPTOR MODULATORS
2010-12-23
US7786158 Compounds as opioid receptor modulators
2008-04-24
2010-08-31
US7741356 Compounds as opioid receptor modulators
2005-09-15
2010-06-22

//////////////////JNJ-27018966, iberzi, элуксадолин ,إيلوكسادولين ,艾沙多林 ,ELUXADOLINE, FDA 2015, エルクサドリン,

CC1=CC(=CC(=C1CC(C(=O)N(CC2=CC(=C(C=C2)OC)C(=O)O)C(C)C3=NC=C(N3)C4=CC=CC=C4)N)C)C(=O)N

ROLAPITANT, ロラピタント


ROLAPITANT HYDROCHLORIDE

  • Rolapitant HCl
  • Rolapitant hydrochloride
  • Sch 619734
  • SCH619734
  • UNII-57O5S1QSAQ

(5S ,8S)-8-[[(1R)-1-[3 ,5-
Bis(trifluoromethyl)phenyl] ethoxy] methyl]-8-phenyl-1,7-
diazaspiro[4.5]decan-2-one hydrochloride monohydrate.

CAS 914462-92-3

Empirical Formula: C25H26F6N2O2 · HCl · H2O, Molecular Weight:  555

USAN Name: Rolapitant hydrochloride, INN Name:  rolapitantum or rolapitant

CAS Number: 552292-08-7 (rolapitant free base); 914462-92-3 (rolapitant HCl monohydrdate).

ChemSpider 2D Image | rolapitant | C25H26F6N2O2

Rolapitant

  • Molecular FormulaC25H26F6N2O2
  • Average mass500.477 Da
(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluorométhyl)phényl]éthoxy}méthyl)-8-phényl-1,7-diazaspiro[4.5]décan-2-one
1,7-Diazaspiro[4.5]decan-2-one, 8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-, (5S,8S)-
552292-08-7 [RN]
8882
NLE429IZUC
SCH 619734
SCH-619734
Varubi®
UNII-NLE429IZUC
(5S,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one
Rolapitant Hydrochloride Hydrate was approved by the U.S. Food and Drug Administration (FDA) on Sep 1, 2015. It was developed by Tesaro, then marketed as Varubi® by Tesaro in US.
Rolapitant Hydrochloride Hydrate is a selective and competitive antagonist of human substance P/NK1 receptors used to treat chemotherapy-induced nausea and vomiting.
Varubi® is available as tablet for oral use, containing 90 mg of free Rolapitant. The recommended dose is 180 mg approximately 1 to 2 hours prior to the start of chemotherapy.
Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents. Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.
In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy, rolapitant shows no inhibition of CYP3A4, eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h), providing potential opportunities for single- and prechemotherapy-based treatments.
In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.

It is in late-stage trials of its drug rolapitant, which showed promising mid-stage results in reducing nausea and vomiting in patients undergoing chemotherapy

Rolapitant hydrochloride is a tachykinin neurokinin 1 (NK1) antagonist in phase III clinical trials at Tesaro for the prevention of chemotherapy-induced nausea and vomiting (CINV). Phase II clinical trials are also under way at OPKO for this indication. At Merck & Co., phase II clinical studies were also under way for the treatment of chronic idiopathic cough and for the prevention of chemotherapy-induced nausea; however, no recent developments have been reported for these indications.

NK1 is a G-protein coupled receptor found in the central and peripheral nervous systems. Substance P is the endogenous ligand for this receptor, whose activation leads to the production of inositol triphosphate. NK1 is believed to be involved in the emetic response.

The drug candidate was originally developed by Schering-Plough (now Merck & Co.), and in 2009 it was licensed to OPKO for the prevention of nausea and vomiting related to cancer chemotherapy and surgery. In 2010, rolapitant was licensed by OPKO to Tesaro on a worldwide basis for the prevention of chemotherapy-induced nausea and vomiting.

Rolapitant is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM.  (source: Pharmacol Biochem Behav.2012 Mar 31.

Rolapitant is a potent, selective NK1 receptor antagonist that is rapidly absorbed, has a remarkably long half-life (up to180 hours), and appears to have a low potential for drug-drug interactions.  A randomized, multicenter, double-blind, dose-ranging study of rolapitant was conducted with placebo and active control groups. Six hundred nineteen adult women undergoing open abdominal surgery were randomly assigned in equal ratios to 1 of 6 study arms: oral rolapitant in 5-mg, 20-mg, 70-mg, or 200-mg doses; IV ondansetron 4 mg; or placebo, stratified by history of PONV or motion sickness. The primary study endpoint was absence of emetic episodes, regardless of use of rescue medication, at 24 hours after extubation.RESULTS: Groups assigned to rolapitant 20-mg, 70-mg, and 200-mg had a higher incidence of no emesis in comparison with placebo at 24 hours after surgery. A linear relationship between rolapitant dose and primary outcome was seen. The probability of an emetic episode was significantly lower in the rolapitant 70-mg and 200-mg groups in comparison with placebo (P ≤ 0.001 based on the log-rank test). No significant differences were noted between rolapitant and the active control (ondansetron) at 24 hours after surgery, but there was a higher incidence of no emesis (regardless of rescue medication use) in the rolapitant 200- and 70-mg groups at 72 and 120 hours, respectively. CONCLUSION: Rolapitant is superior to placebo in reducing emetic episodes after surgery and reduces the incidence of vomiting in a dose-dependent manner. No differences in side effect profile were observed between rolapitant and placebo.

Rolapitant (INN,[2] trade name Varubi /vəˈrbi/ və-ROO-bee in the US and Varuby in Europe) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor).[3] It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.[4][5][6][7

Medical uses

Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist.[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.[9] Under the European approval, it is contraindicated in combination with St. John’s Wort, which is expected to accelerate inactivation of rolapitant.[8]

Side effects

In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).[9]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.[8]

Interactions

Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphanhave increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.[8]

Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.[8]

Pharmacology

Pharmacodynamics

Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.[10]

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).[8] The stereochemistry of the hydroxyl group is unknown.

Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.[8]

It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.[8]

Chemistry

The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.[10]

Patents

WO 2003051840

PATENT

WO 2008118328

The preparation of diazaspirodecan-2-ones for example, 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one, for example, (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (the compound of Formula I) has been described in U.S. Pat. No. 7,049,320 (the ‘320 patent), issued May 23, 2006, the disclosure of which is incorporated herein in its entirety by reference.

Figure US08552191-20131008-C00001

The compounds described in the ‘320 patent are classified as tachykinin compounds, and are antagonists of neuropeptide neurokinin-1 receptors (herein, “NK-1” receptor antagonists). Other NKreceptor antagonists and their synthesis have been described, for example, those described in Wu et al, Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001); and Rogiers et al, Tetrahedron 57, 8971-8981 (2001) and in published international application no. WO05/100358, each of which are incorporated herein in their entirety by reference.

“NK-1” receptor antagonists have been shown to be useful therapeutic agents, for example, in the treatment of pain, inflammation, migraine, emesis (vomiting), and nociception. Among many compounds disclosed in the above-mentioned ‘320 patent are several novel diazaspirodecan-2-ones, including the compound of Formula I, which are useful in the treatment of nausea and emesis associated with chemotherapy treatments (Chemotherapy-induced nausea and emesis, CINE).

The synthesis method for preparing the compound of Formula I described in the ‘320 patent generally follows Scheme I in the provision of 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxyl}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one compounds.

Figure US08552191-20131008-C00002
Figure US08552191-20131008-C00003
Figure US08552191-20131008-C00004

The process for the preparation of the compound of Formula I described in the ‘320 patent is carried out in 18 individual steps from commercially available starting materials (see the ‘320 patent at col. 43, line 55 to col. 45, line 20; col. 75. line 55 to col. 80, line 21; col. 90 lines 35 to 63; and col. 98, line 1 to col. 99. line 24). In many steps of the process described in the ‘320 patent, intermediate compounds must be isolated or isolated and purified before use in a subsequent step, often utilizing column chromatography for this purpose.

PATENT

US7049320

Examples 72a and 72b

Figure US07049320-20060523-C00153

Step 1:

Figure US07049320-20060523-C00154

To a solution of crude Compound 53 (19 g) in CH2Cl(300 ml) at RT, DIEA (15 ml, 0.087 mol) was added, followed by triphosgene (4.34 g, 0.015 mol). The mixture was stirred at RT for 18 h and was filtered through a pad of silica. Solvents were removed in vacuum to give crude Compound 60 as yellow oil which was used in the next reaction without further purifications.

Step 2:

Figure US07049320-20060523-C00155

To the crude Compound 60 in THF (200 ml) at 0° C., LiBH(1.26 g, 0.058 mol) was added in small portions. The mixture was stirred at RT for 18 h before quenching with saturated NH4Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (100×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave Compound 61 (12.9 g, 62% overall) as white foam.

Step 3:

Oxalyl chloride (4.2 ml, 0.048 mol) was added to a solution of DMSO (6.8 m[, 0.096) in CH2Cl(300 ml) at −78° C. under N2. The mixture was stirred at −78° C. for 15 min before a solution of Compound 61 (8.5 g, 0.012 mol) in CH2Cl(100 ml) was added. The mixture was stirred at −78° C. for a further 1 h and Et3N (23.5 ml) was added. The cooling bath was removed and the mixture was warmed to RT before it was quenched with saturated NaHCOsolution. Layers were separated and the aqueous was extracted with CH2Cl(150 ml×2). The combined organic layers were dried (MgSO4) and filtered. Removal of solvents in vacuum gave an aldehyde as yellow oil. To a mixture of NaH (1.44 g, 0.036 mol) in THF at 0° C., methyl diethylphosphonoacetate (6.6 ml, 0.036 mol) was added. The mixture was stirred at 0° C. for 15 min and a solution of aldehyde in THF (100 ml) was added. The cooling bath was removed and the mixture was stirred at RT for 1 h. The reaction was quenched with saturated NH4Cl solution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum and purification by column chromatography [hexane-EtOAc, 4:1 (v/v)] gave an ester as white foam. The ester was dissolved in EtOH (100 ml) and a catalytic amount of palladium (1.28 g, 10% on carbon) was added. The mixture was shaken under H(50 psi) for 2 days. Catalytic amount of Pd(OH)(20% on carbon) was then added to the mixture and the mixture was again shaken under H(50 psi) for 5 h. The mixture was filtered through a pad of Celite and solvents were removed in vacuum to give a white foam. The foam was then dissolved in CH2Cl(200 ml) and TFA (8.9 ml, 0.12 mol) was added. The mixture was stirred at RT for 18 h and was cooled at 0° C. before it was neutralized with saturated NaHCOsolution. Water and EtOAc were added to the mixture. Layers were separated and the aqueous layer was extracted with EtOAc (200 ml×2). The combined organic layers were dried (MgSO4) and filtered. Solvents were removed in vacuum to give a yellow oil. The oil was dissolved in CH3OH (50 ml) and a catalytic amount of K2CO(166 mg, 0.0012 mol) was added. The mixture was heated at 60° C. for 2 h. After being cooled to RT, the mixture was filtered through a pad of silica and solvents were removed in vacuum. Purification by column chromatography (EtOAc) gave the mixture of two isomers Example 72a and 72b (2.3 g, 38% overall) as white foam. Separation by HPLC using Chiralcel OD [hexane-isopropanol, 95:5 (v/v)] gave the less polar major isomer Example 72a as white foam. Electrospray MS [M+1]+=501.1. Continuous elution with the same solvent system gave the more polar minor isomer Example 72b as colorless oil.

Electrospray MS [M+1]+=501.1.

PATENT

US8552191

Figure US08552191-20131008-C00028

Figure US08552191-20131008-C00029

Figure US08552191-20131008-C00030

Figure US08552191-20131008-C00031

Figure US08552191-20131008-C00032

Example 6 Preparation of Formula I Compound Salt: (5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride monohydrate

Figure US08552191-20131008-C00033

…………………

Figure US08552191-20131008-C00016

Figure US08552191-20131008-C00017

https://www.google.it/patents/US8552191?hl=it&dq=WO+2008118328&ei=alDCUs-_KYiIrQeg3oCwDw&cl=en

……………

update added

By RTT News,  May 12, 2014,

(RTTNews.com) – TESARO Inc. ( TSRO ) announced positive top-line results from the third and final Phase 3 trial of rolapitant, an investigational neurokinin-1 or NK-1 receptor antagonist in development for the prevention of chemotherapy-induced nausea and vomiting (CINV).

The rolapitant arm in this trial, which enrolled patients receiving cisplatin-based, highly emetogenic chemotherapy or HEC, successfully achieved statistical significance over the standard therapy arm for the primary and all secondary endpoints. The adverse event profile for rolapitant remains consistent with that seen in previous clinical studies.

The third Phase 3 study of rolapitant was an international, multicenter, randomized, double-blind, active-controlled study that enrolled 532 cancer patients receiving cisplatin-based chemotherapy regimens at a dose equal to or greater than 60 mg/m2. Patients were randomized to receive either control, which consisted of a 5-HT3 receptor antagonist plus dexamethasone, or 200 milligrams of oral rolapitant plus control. The rolapitant arm in this study successfully achieved statistical significance over the control arm for the primary endpoint of complete response (CR) in the delayed phase of CINV.

In addition, the rolapitant arm also successfully achieved statistical significance over the control arm for the key secondary endpoints of CR in the acute (0 to 24 hour) and overall (0 to 120 hour) phases of CINV, for the secondary endpoint of no significant nausea, and for all other secondary endpoints.

Safety and tolerability data for patients who received rolapitant were similar to the results for those who received control, and were consistent with earlier clinical studies. The most frequently observed adverse events were balanced across treatment arms and included fatigue, constipation and loss of appetite.

The company noted that preparations continue in support of a submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) in mid-2014.

The oral rolapitant NDA will include data from one Phase 3 study in patients receiving moderately emetogenic chemotherapy (MEC), in addition to one Phase 2 and two Phase 3 trials in patients receiving cisplatin-based, highly emetogenic chemotherapy (HEC), including the trial announced today.

The top-line results of the Phase 3 trial in MEC and the prior Phase 3 trial in HEC were previously announced by TESARO in December 2013.

Rolapitant is an investigational agent and, as such, has not been approved by the U.S. FDA or any regulatory agencies.

CLIP

Rolapitant Hydrochloride Hydrate (Varubi)

Rolapitant hydrochloride hydrate, originally discovered by Schering-Plough and later developed by TESARO, Inc., was approved by the FDA in September 2015 for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in combination with other antiemetic agents.(67) Rolapitant is a highly selective NK-1 receptor antagonist, exhibiting >1000-fold selectivity for NK-1 over human NK-2 and NK-3 receptors in vitro.(68) In contrast to other NK-1 inhibitors that play an essential role in delayed CINV therapy,(69) rolapitant shows no inhibition of CYP3A4,(68)eliminating the need for concern when coadministering with CYP34A substrates. Additionally, rolapitant is an orally active agent with a relatively long half-life (180 h),(68, 70) providing potential opportunities for single- and prechemotherapy-based treatments.(71)
In three large clinical trials involving patients receiving moderately emetogenic chemotherapy (MEC) and highly emetogenic chemotherapy (HEC), subjects using rolapitant as a cotherapy with granisetron and dexamethasone showed a significant improvement in complete response compared to those receiving treatments of granisetron and dexamethasone.(70, 72)
Rolapitant features a fascinating molecular architecture consisting of two tetrasubstituted stereogenic carbon centers situated at the 2- and 5-carbons within a central piperidine ring and a spirocyclic array residing at the 5-position and a phenyl ring and ethereal linkage branching from the 2-position (Scheme 17). The overall synthetic strategy to secure rolapitant hydrochloride hydrate relies upon the union of two advanced chiral building blocks that contain functional groups capable of securing the central piperidine ring. These two key intermediates, pyroglutamate derivative 93 and allylic amine 94, each bear one of the essential stereocenters embedded within the structure of the active pharmaceutical ingredient.(73) The first of these advanced intermediates, amidoaldehyde 93, is generated directly by base-mediated decomposition of pyroglutamic aminal 92, which was prepared according to the route shown in Scheme 18. Subjection of 92 to triethylamine in EtOH/H2O at ambient temperatures led to generation of chiral allyl aldehyde 93, which was not isolated but condensed immediately with amine 94 (Scheme 19) in the presence of refluxing toluene to provide divinyl imine 95, which underwent immediate reduction using NaBH(OAc)3 in AcOH/toluene to furnish the free amine.
The free amine was converted to the corresponding tosylate monohydrate salt and triturated, providing 96 as a white crystalline powder after subjection to TsOH·H2O in i-PrOH/H2O. Divinyl amine 96 could then be reacted with a solution of TsOH in toluene, distilled, and directly combined with a toluene solution of Hoveyda–Grubbs second-generation catalyst (HG-II) under heating conditions, leading to the desired ring-closing metathesis product 97 as the HCl salt (85% yield over two steps) after filtration, distillation, and workup with 12N HCl. Washing of a toluene solution of 97 with aqueous NaOH and subsequent treatment of the resulting organic solution with H2, wet Pd/C, and additional granular activated carbon (Nuchar Aquaguard) led to the fully reduced piperidine product in high yield (95%). Rolapitant hydrochloride hydrate XIII was accessed thereafter by precipitation from a solution of EtOH/i-PrOH/H2O/HCl, providing the product as a white solid (91% yield).(73)
 Figure
Scheme 17. Synthesis of Rolapitant Hydrochloride Hydrate (XIII)
Figure
Scheme 18. Synthesis of Fragment 92 of Rolapitant Hydrochloride Hydrate (XIII)
Figure
Scheme 19. Synthesis of Fragment 94 of Rolapitant Hydrochloride Hydrate (XIII)
Aldehyde precursor 92 was accessed in a four-step sequence starting from commercially available l-pyroglutamic acid 98 (Scheme 18).(73, 74) Condensation of 98 with trimethylacetaldehyde at elevated temperatures in the presence of methanesulfonic acid and NMP prior to careful addition of TFAA led to formation of pyrrolo-oxazolidone 99 in 72% yield. Deprotonation (LHMDS) and stereoselective alkylation of 99 with methyl formate, assisted by addition of copper chloride as a Lewis acid, provided access to carbaldehyde 100 in moderate yield (61%) as a single diastereomer(74) after aqueous workup and crystallization from MTBE.
Wittig olefination of aldehyde 100 (Ph3PCH3Br/LHMDS) followed by aqueous workup and precipitation of triphenylphosphine oxide via addition of MgCl2 constructed an allyl lactone intermediate in 63% yield as an off-white solid, which then immediately underwent partial reduction with LiAlH(Ot-Bu)3to smoothly deliver the key aldehyde precursor 92 in 83% yield as an inconsequential mixture of diastereomers (the stereocenter of consequence arose from the naturally occurring l-pyroglutamic acid 98), which could be employed directly in Scheme 17.(73)
Generation of 94 began with commercially available N-Cbz-(S)-phenylglycine 101 based on reports by O’Donnell and co-workers (Scheme 19).(75) Reaction of 101 with benzaldehyde dimethylacetal under Lewis acid conditions (BF3·Et2O) in diethyl ether led to high yield, diastereoselectivity, and enantioselectivity of trans-disubstituted oxazolidinone 102. In this case, selection of diethyl ether as a solvent was essential, as the use of DCM under similar reaction conditions favored formation of the undesired cis-product. Removal of the most acidic proton within 102 by means of KHMDS in toluene/THF, followed by alkylation with commercially available bromomethyl ether (103) in THF, led to 68% yield of 104 as a single diastereomer.(73, 76)
Reduction of 104 to the corresponding lactol (LiAlH4/Et2O) and subsequent ring opening with KHCO3/H2O in NMP yielded the intermediate aldehyde, which was readily converted to 105 via addition of the crude aldehyde solution to a mixture of Ph3PCH3Br and NaHMDS in toluene.
As described in Scheme 15, triphenylphosphine oxide scavenge by way of MgCl2 enabled generation of crude product in good purity after a simple filtration. TMSI-mediated Cbz removal converted 105to the resulting free amine. Formation of the maleic acid salt enabled the product to be isolated as a crystalline solid in high purity without chromatography. Treatment of the maleate salt with NaOH in toluene provided the free base 94, which was incorporated as previously described in Scheme 17 without the need for additional purification.(73)
  1. 67 . SyedY. Y. Rolapitant: First Global Approval Drugs 2015751941– 1945 DOI: 10.1007/s40265-015-0485-8

  2. 68.DuffyR. A.MorganC.NaylorR.HigginsG. A.VartyG. B.LachowiczJ. E.ParkerE. M. Rolapitant (SCH 619734): A Potent, Selective and Orally Active Neurokinin NK1 Receptor Antagonist with Centrally-mediated Antiemetic Effects in Ferrets Pharmacol., Biochem. Behav. 201210295– 100 DOI: 10.1016/j.pbb.2012.03.021

  3. 69.JanelsinsM. C.TejaniM. A.KamenC.PeoplesA. R.MustianK. M.MorrowG. R. Current Pharmacotherapy for Chemotherapy-induced Nausea and Vomiting in Cancer Patients Expert Opin. Pharmacother. 201314757– 766 DOI: 10.1517/14656566.2013.776541

  4. 70.NavariR. M. Rolapitant for the Treatment of Chemotherapy-induced Nausea and Vomiting Expert Rev. Anticancer Ther. 2015151127– 1133 DOI: 10.1586/14737140.2015.1088787

  5. 71.RomeroD. Chemotherapy Rolapitant – a New and Safer Antiemetic Agent Nat. Rev. Clin. Oncol. 201512,562 DOI: 10.1038/nrclinonc.2015.144

  6. 72.(a) SchwartzbergL. S.ModianoM. R.RapoportB. L.ChasenM. R.GridelliC.UrbanL.PomaA.;AroraS.NavariR. M.SchnadigI. D. Safety and Efficacy of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting after Administration of Moderately Emetogenic Chemotherapy or Anthracycline and Cyclophosphamide Regimens in Patients with Cancer: a Randomised, Active-controlled, Double-blind, Phase 3 Trial Lancet Oncol. 2015161071– 1078 DOI: 10.1016/S1470-2045(15)00034-0

    (b) RapoportB.SchwartzbergL.ChasenM.PowersD.AroraS.;NavariR.SchnadigI. Efficacy and Safety of Rolapitant for Prevention of Chemotherapy-induced Nausea and Vomiting Over Multiple Cycles of Moderately or Highly Emetogenic Chemotherapy Eur. J. Cancer 2016,5723– 30 DOI: 10.1016/j.ejca.2015.12.023

  7. 73.WuG. G.WerneG.FuX.OrrR. K.ChenF. X.CuiJ.SpragueV. M.ZhangF.XieJ.ZengL.;CastellanosL. P.ChenY.PoirierM.MergelsbergI. Process and Intermediates for the Synthesis of 8-[[1-[3,5-bis-(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one Compounds. WO 2010028232A1, 2010.

  8. 74.DikshitD. K.MaheshwariA.PandayS. K. Self Reproduction of Chirality in Pyroglutamates: Reactions at α-Position with Electrophiles Tetrahedron Lett. 1995366131– 6134 DOI: 10.1016/0040-4039(95)01160-J

  9. 75.O’DonnellM. J.FangZ.MaX.HuffmanJ. C. New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the ″Self-regeneration of Stereocenters″ Method: α-Ethyl-α-phenylglycine Heterocycles 1997,46617– 630 DOI: 10.3987/COM-97-S83

  10. 76.PaliwalS.ReichardG. A.WangC.XiaoD.TsuiH.-C.ShihN.-Y.ArredondoJ. D.WrobleskiM. L.;PalaniA. Preparation of Pyrrolidine and Piperidine Derivatives for Therapeutic Use as Neurokinin 1 (NK1) Receptor Antagonists. WO 2003051840A1, 2003.

REF

HETEROCYCLES 1997 46  PG 617 630

Paper | Special issue | Vol 46, No. 1, 1997, pp.617-630
Published online, 1st January, 1970

DOI: 10.3987/COM-97-S83
■ New Methodology for the Synthesis of α,α-Dialkylamino Acids Using the “Self-Regeneration of Stereocenters” Method: α-Ethyl-α-phenylglycine

Martin J. O’Donnell,* Zhiqiang Fang, Xiaojun Ma, and John C. Huffman

*Department of Chemistry, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, U.S.A.

Abstract

The stereoselective room temperature ethylations of protected oxazolidinones from phenylglycine by phase-transfer catalysis or with KOtBu as base are used to prepare optically active α-ethyl-α-phenylglycine.

PATENT

https://patents.google.com/patent/CN106866669A/en

⑴ Route A:

Figure CN106866669AD00041

[0005] ⑵ Route B:

Figure CN106866669AD00051

[0007] (3) Route C:

Figure CN106866669AD00052

[0009] Scheme C, wherein the method further comprises synthesizing Via, namely:

Figure CN106866669AD00061

Won] now, with respect to the other two routes, from the reaction step, time costs, material costs, product yield and product purity of view, comparing the current line C is respected, it is more suitable for production. But even so, there are still a number of route C the following questions:

[0012] [1], the synthesis of compound V, there is a slow reaction, and the reaction was not complete and so on;

[0013] [2], when Via a salt, the desired product is low chiral purity and yield to be improved;

[0014] [3], when VIII recrystallized grain size to be improved.

CLIP

Image result for rolapitant synthesis

References

1: Gan TJ, Gu J, Singla N, Chung F, Pearman MH, Bergese SD, Habib AS, Candiotti KA, Mo Y, Huyck S, Creed MR, Cantillon M; Rolapitant Investigation Group. Rolapitant for the prevention of postoperative nausea and vomiting: a prospective, double-blinded, placebo-controlled randomized trial. Anesth Analg.
2011 Apr;112(4):804-12. Epub 2011 Mar 8. PubMed PMID: 21385988.

2.  Reddy GK, Gralla RJ, Hesketh PJ. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support Cancer Ther. 2006 Apr 1;3(3):140-2. PubMed PMID: 18632487.

3. Drug Data Rep 2003, 25(8): 703

4. A multicenter, randomized, double blind, active-controlled study of the safety and efficacy of rolapitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in subjects receiving moderately emetogenic chemotherapy (NCT01500226)
ClinicalTrials.gov Web Site 2012, February 06

5. Efficacy and safety of rolapitant, a novel NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting in subjects receiving highly emetogenic chemotherapy
48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 9077

6. Proposed international nonproprietary names (Prop. INN): List 97
WHO Drug Inf 2007, 21(2): 160

References

  1. Jump up to:a b “Varubi (rolapitant) Tablets, for Oral Use. Full Prescribing Information” (PDF). TESARO, Inc. 1000 Winter St., #3300, Waltham, MA 02451.
  2. ^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 59” (PDF). World Health Organization. p. 64. Retrieved 5 October 2016.
  3. ^ Duffy, R. A; Morgan, C; Naylor, R; Higgins, G. A; Varty, G. B; Lachowicz, J. E; Parker, E. M (2012). “Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets”. Pharmacol Biochem Behav102 (1): 95–100. doi:10.1016/j.pbb.2012.03.021PMID 22497992.
  4. ^ Jordan, K; Jahn, F; Aapro, M (2015). “Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review”. Ann Oncol26 (6): 1081–90. doi:10.1093/annonc/mdv138PMID 25755107.
  5. ^ Nasir, S. S; Schwartzberg, L. S (2016). “Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting”. Oncology30 (8): 750–62. PMID 27539626.
  6. ^ Rapoport, B; Schwartzberg, L; Chasen, M; Powers, D; Arora, S; Navari, R; Schnadig, I (2016). “Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy”. Eur J Cancer57: 23–30. doi:10.1016/j.ejca.2015.12.023PMID 26851398.
  7. ^ Chasen, M. R; Rapoport, B. L (2016). “Rolapitant for the treatment of chemotherapy-induced nausea and vomiting: a review of the clinical evidence”. Future Oncol12 (6): 763–78. doi:10.2217/fon.16.11PMID 26842387.
  8. Jump up to:a b c d e f g h “Varuby: EPAR – Product Information” (PDF)European Medicines Agency. 2017-05-31.
  9. Jump up to:a b FDA Professional Drug Information on Varubi. Accessed 2017-10-11.
  10. Jump up to:a b “Varuby: EPAR – Public assessment report” (PDF)European Medicines Agency. 2017-05-31.
Rolapitant
Rolapitant.svg
Clinical data
Pronunciation /rˈlæpɪtænt/ roh-LAP-i-tant
Trade names Varubi (US), Varuby (EU)
Synonyms SCH 619734
AHFS/Drugs.com varubi
License data
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability nearly 100%
Protein binding 99.8%
Metabolism CYP3A4
Metabolites C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life 169–183 hours
Excretion Feces (52–89%), urine (9–20%)[1]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C25H26F6N2O2
Molar mass 500.476 g/mol
3D model (JSmol)
/////////////ROLAPITANT, ロラピタント, FDA 2015, Schering-Plough, TESARO,

Selexipag, セレキシパグ ,селексипаг , سيليكسيباق ,


Selexipag.svg

ChemSpider 2D Image | Selexipag | C26H32N4O4S

Selexipag

  • Molecular FormulaC26H32N4O4S
  • Average mass496.622 Da

SelexipagUptravi

475086-01-2 CAS

(C26H32N4O4S, Mr = 496.6 g/mol)

A prostacyclin receptor (PGI2) agonist used to treat pulmonary arterial hypertension (PAH).

NIPPON SHINYAKU….INNOVATOR

セレキシパグ

UNII-5EXC0E384L
селексипаг [Russian] [INN]
سيليكسيباق [Amharic] [INN]
2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methylsulfonyl)acetamide
475086-01-2 [RN]
5EXC0E384L
9231
Acetamide, 2-[4-[(5,6-diphenyl-2-pyrazinyl)(1-methylethyl)amino]butoxy]-N-(methylsulfonyl)-

Selexipag (brand name Uptravi) is a drug developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metaboliteACT-333679 (MRE-269) (the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation.[1]

FDA approves new orphan drug to treat pulmonary arterial hypertension

12/22/2015
On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.

December 22, 2015

On December 21, the U.S. Food and Drug Administration approved Uptravi (selexipag) tablets to treat adults with pulmonary arterial hypertension (PAH), a chronic, progressive, and debilitating rare lung disease that can lead to death or the need for transplantation.

“Uptravi offers an additional treatment option for patients with pulmonary arterial hypertension,” said Ellis Unger, M.D., director of the Office of Drug Evaluation I in the FDA’s Center for Drug Evaluation and Research. “The FDA supports continued efforts to provide new treatment options for rare diseases.”

PAH is high blood pressure that occurs in the arteries that connect the heart to the lungs. It causes the right side of the heart to work harder than normal, which can lead to limitations on exercise ability and shortness of breath, among other more serious complications.

Uptravi belongs to a class of drugs called oral IP prostacyclin receptor agonists. The drug acts by relaxing muscles in the walls of blood vessels to dilate (open) blood vessels and decrease the elevated pressure in the vessels supplying blood to the lungs.

Uptravi’s safety and efficacy were established in a long-term clinical trial of 1,156 participants with PAH. Uptravi was shown to be effective in reducing hospitalization for PAH and reducing the risks of disease progression compared to placebo. Participants were exposed to Uptravi in this trial for a median duration of 1.4 years.

Common side effects observed in those treated with Uptravi in the trial include headache, diarrhea, jaw pain, nausea, muscle pain (myalgia), vomiting, pain in an extremity, and flushing.

Uptravi was granted orphan drug designation. Orphan drug designation provides incentives such as tax credits, user fee waivers, and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Uptravi is marketed by San Francisco-based Actelion Pharmaceuticals US, Inc.

The US FDA granted it Orphan Drug status[2] (for PAH). It was approved by the U.S. FDA on 22 December 2015.[2]

In 2016, the EMA granted marketing authorization in the E.U. for this indication and launch took place shortly after in Germany and the United Kingdom. In Japan, Nippon Shinyaku received approval for the treatment of PAH in 2016.

Selexipag was approved by the U.S. Food and Drug Administration (FDA) on Dec 21, 2015, approved by European Medicine Agency (EMA) on May 12, 2016. It was originally developed by Nippon Shinyaku and then it was licensed to Actelion for co-development. It is marketed as Uptravi® by Actelion in US and EU.

Selexipag is a prostacyclin receptor (PGI2) agonist, which leads to vasodilation in the pulmonary circulation. It is indicated for the treatment of pulmonary arterial hypertension (PAH).

Uptravi® is available as tablets for oral use, containing 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The initial dose is 200 mcg twice daily, and increase the dose by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to 1600 mcg twice daily.

ACT-333679 or MRE-269, the active metabolite of selexipag

SYNTHESIS DEPICT

PATENT

US2012/101276

http://www.google.st/patents/US20120101276?hl=pt-PT&cl=en

The present invention relates to a crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide (hereinafter referred to as “compound A”).

Figure US20120101276A1-20120426-C00001

BACKGROUND OF THE INVENTION

Compound A has an excellent PGI2 agonistic effect and shows a platelet aggregation inhibitory effect, a vasodilative effect, a bronchodilative effect, a lipid deposition inhibitory effect, a leukocyte activation inhibitory effect, etc. (see, for example, in WO 2002/088084 (“WO ‘084”)).

Specifically, compound A is useful as preventive or therapeutic agents for transient ischemic attack (TIA), diabetic neuropathy, diabetic gangrene, peripheral circulatory disturbance (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, vibration syndrome, Raynaud’s disease), connective tissue disease (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue disease, vasculitic syndrome), reocclusion/restenosis after percutaneous transluminal coronary angioplasty (PTCA), arteriosclerosis, thrombosis (e.g., acute-phase cerebral thrombosis, pulmonary embolism), hypertension, pulmonary hypertension, ischemic disorder (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), glomerulonephritis, diabetic nephropathy, chronic renal failure, allergy, bronchial asthma, ulcer, pressure ulcer (bedsore), restenosis after coronary intervention such as atherectomy and stent implantation, thrombocytopenia by dialysis, the diseases in which fibrosis of organs or tissues is involved [e.g., Renal diseases (e.g., tuburointerstitial nephritis), respiratory diseases (e.g., interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease), digestive diseases (e.g., hepatocirrhosis, viral hepatitis, chronic pancreatitis and scirrhous stomachic cancer), cardiovascular diseases (e.g, myocardial fibrosis), bone and articular diseases (e.g, bone marrow fibrosis and rheumatoid arthritis), skin diseases (e.g, cicatrix after operation, scalded cicatrix, keloid, and hypertrophic cicatrix), obstetric diseases (e.g., hysteromyoma), urinary diseases (e.g., prostatic hypertrophy), other diseases (e.g., Alzheimer’s disease, sclerosing peritonitis; type I diabetes and organ adhesion after operation)], erectile dysfunction (e.g., diabetic erectile dysfunction, psychogenic erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic renal failure, erectile dysfunction after intrapelvic operation for removing prostata, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease, intestinal tuberculosis, ischemic colitis and intestinal ulcer associated with Behcet disease), gastritis, gastric ulcer, ischemic ophthalmopathy (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden hearing loss, avascular necrosis of bone, intestinal damage caused by administration of a non-steroidal anti-inflammatory agent (e.g., diclofenac, meloxicam, oxaprozin, nabumetone, indomethacin, ibuprofen, ketoprofen, naproxen, celecoxib) (there is no particular limitation for the intestinal damage so far as it is damage appearing in duodenum, small intestine and large intestine and examples thereof include mucosal damage such as erosion and ulcer generated in duodenum, small intestine and large intestine), and symptoms associated with lumbar spinal canal stenosis (e.g., paralysis, dullness in sensory perception, pain, numbness, lowering in walking ability, etc. associated with cervical spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis, diffuse spinal canal stenosis or sacral stenosis) etc. (see, for example, in WO ‘084, WO 2009/157396, WO 2009/107736, WO 2009/154246, WO 2009/157397, and WO 2009/157398).

In addition, compound A is useful as an accelerating agent for angiogenic therapy such as gene therapy or autologous bone marrow transplantation, an accelerating agent for angiogenesis in restoration of peripheral artery or angiogenic therapy, etc. (see, for example, in WO ‘084).

Production of Compound A

Compound A can be produced, for example, according to the method described in WO ‘084, and, it can also be produced according to the production method mentioned below.

Figure US20120101276A1-20120426-C00002

Step 1:

6-Iodo-2,3-diphenylpyrazine can be produced from 6-chloro-2,3-diphenylpyrazine by reacting it with sodium iodide. The reaction is carried out in the presence of an acid in an organic solvent (e.g., ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or their mixed solvent). The acid to be used is, for example, acetic acid, sulfuric acid, or their mixed acid. The amount of sodium iodide to be used is generally within a range of from 1 to 10 molar ratio relative to 6-chloro-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the acid to be used, but may be generally within a range of from 60° C. to 90° C. The reaction time varies depending on the kinds of the solvent and the acid to be used and on the reaction temperature, but may be generally within a range of from 9 hours to 15 hours.

Step 2:

5,6-Diphenyl-2-[(4-hydroxybutyl(isopropyl)amino]pyrazine can be produced from 6-iodo-2,3-diphenylpyrazine by reacting it with 4-hydroxybutyl(isopropyl)amine. The reaction is carried out in the presence of a base in an organic solvent (e.g., sulfolane, N-methylpyrrolidone, N,N-dimethylimidazolidinone, dimethyl sulfoxide or their mixed solvent). The base to be used is, for example, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate or their mixed base. The amount of 4-hydroxybutyl(isopropyl)amine to be used may be generally within a range of from 1.5 to 5.0 molar ratio relative to 6-iodo-2,3-diphenylpyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from 170° C. to 200° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 5 hours to 9 hours.

Step 3:

Compound A can be produced from 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine by reacting it with N-(2-chloroacetyl)methanesulfonamide. The reaction is carried out in the presence of a base in a solvent (N-methylpyrrolidone, 2-methyl-2-propanol or their mixed solvent). The base to be used is, for example, potassium t-butoxide, sodium t-butoxide or their mixed base. The amount of N-(2-chloroacetyl)methanesulfonamide to be used may be generally within a range of from 2 to 4 molar ratio relative to 5,6-diphenyl-2-[4-hydroxybutyl(isopropyl)amino]pyrazine, preferably within a range of from 2 to 3 molar ratio. The reaction temperature varies depending on the kinds of the solvent and the base to be used, but may be generally within a range of from −20° C. to 20° C. The reaction time varies depending on the kinds of the solvent and the base to be used and on the reaction temperature, but may be generally within a range of from 0.5 hours to 2 hours.

The compounds to be used as the starting materials in the above-mentioned production method for compound A are known compounds, or can be produced by known methods.

PATENT

WO 2002088084

and

http://www.google.fm/patents/WO2009157398A1?cl=en

PAPER

Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   21  p. 6692 – 6704

compd 31

PAPER

Bioorganic and Medicinal Chemistry, 2007 ,  vol. 15,   24  p. 7720 – 7725

Full-size image (5 K)2a is the drug

N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.

http://www.sciencedirect.com/science/article/pii/S0968089607007614

PATENT

WO 2011024874

A. Preparation of
Compound A Compound A can be produced , for example, by the method described in Patent Document 1, but can also be produced by the production method described below.
[
Step 2]
6-iodo-2,3-diphenylpyrazine can be produced by reacting 6-chloro-2,3-diphenylpyrazine with sodium iodide. This reaction is carried out in an organic solvent (for example, ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, or a mixed solvent thereof) in the presence of an acid. As the acid to be used, for example, acetic acid, sulfuric acid, or a mixed acid thereof can be mentioned. The amount of sodium iodide used is, for example, suitably in the range of 1 mole to 10 moles, preferably in the range of 2 time moles to 3 times the amount of 1 mole of 6-chloro-2,3-diphenylpyrazine . The reaction temperature varies depending on the raw materials used and the type of acid, but is usually carried out within the range of 60 ° C. to 90 ° C. The reaction time varies depending on the starting materials used, the type of acid and the reaction temperature, but it is usually within the range of 9 hours to 15 hours.Step 2
5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine can be prepared by reacting 6-iodo-2,3-diphenylpyrazine with 4-hydroxybutyl (isopropyl) amine. This reaction is carried out in an organic solvent (for example, sulfolane, N-methylpyrrolidone, N, N-dimethylimidazolidinone, dimethylsulfoxide or a mixed solvent thereof) in the presence of a base. Examples of the base used include sodium hydrogencarbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate, and mixed bases thereof. The amount of 4-hydroxybutyl (isopropyl) amine to be used is, for example, suitably in the range of 1.5 mol to 5.0 mol per 1 mol of 6-iodo-2,3-diphenylpyrazine, It is within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of 170 ° C. to 200 ° C. The reaction time varies depending on the type of raw materials and base used and the reaction temperature, but it is usually within the range of 5 hours to 9 hours.Step 3
Compound A can be prepared by reacting 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] pyrazine with N- (2-chloroacetyl) -methanesulfonamide. This reaction is carried out in an organic solvent (N-methylpyrrolidone, 2-methyl-2-propanol or a mixed solvent thereof) in the presence of a base. Examples of the base to be used include potassium t-butoxide, sodium t-butoxide or mixed bases thereof. The amount of N- (2-chloroacetyl) -methanesulfonamide used is, for example, 2 to 4 mol per 1 mol of 5,6-diphenyl-2- [4-hydroxybutyl (isopropyl) amino] It is suitable within the range, and preferably within the range of 2 mol to 3 mol. The reaction temperature varies depending on the type of raw material and base used, but is usually carried out within the range of -20 ° C. to 20 ° C. The reaction time varies depending on the kinds of raw materials and bases used and the reaction temperature, but it is usually within the range of 0.5 hour to 2 hours.Each compound used as a raw material in the above-mentioned production method of compound A is a known compound or can be produced according to a known method.

[0016]
B. Preparation of salt of the present invention The salt of the
present invention can be obtained, for example, by the following method.
The salt of the present invention can be prepared by dissolving the compound A in an appropriate solvent (for example, an ether solvent (for example, dimethoxyethane, tetrahydrofuran), an ester solvent (for example, isopropyl acetate), an aromatic hydrocarbon (for example, toluene), acetonitrile After dissolving and adding a desired base, if necessary, the mixed solution is left to stand at room temperature or under cooling in the state of concentrating or stirring or leaving it stationary. The precipitate formed is collected by filtration , Followed by washing with an appropriate solvent to obtain the desired salt of the present invention. When cooling, not only cooling but also gradual cooling or rapid cooling may be effective in obtaining good crystals. It is also effective to obtain good crystals by adding an ether solvent (for example, t-butyl methyl ether), an ester solvent (for example, ethyl acetate), and an aromatic hydrocarbon (for example, toluene) There are cases.The amount of the solvent used for dissolving the compound A is suitably in the range of 10 ml to 300 ml with respect to the compound A 1 g, for example.
The amount of the base to be used for preparing the salt of the present invention is suitably in the range of 0.5 mol to 1.2 mol with respect to the mol of the compound A 1.
Further, the salt of the present invention, which is a crystal, can be obtained by, for example, the method described in Examples described later.

Example 1 t- butylamine Form I crystal of the salt
Compound A (40 mg) with 0.5mL dimethoxyethane (hereinafter, referred to as. “DME”) was dissolved in, and t- butylamine (1.1 eq) were added, 25 1 ° C. at 8 it was stirred for hours. Thereafter, the reaction solution was added t- butyl methyl ether (1mL), at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, I-form crystals of t- butylamine salt ( 3 to afford 9.9mg). B Powder X-ray diffraction spectrum of type I crystal obtained t- butylamine salt using the apparatus shown in Figure 1.
Melting point: 152.5 ℃
elemental analysis (C 3 0 H 4 3 N 5 O 4 S + 0.0 3 H 2 as O)
calculated value (%) C: 6 3 .1 8 H: 7 . 6 1 N: 12 .2 8 measured value (%) C: 6 2. 8 5 H: 7 . 6 4 N: 12.52 1 H-NMR (DMSO-D 6 ): delta 8 .15 (s, 1H), 7 .55 – 7 . 8 0 (M, 2H), 7 .10- 7 . .45 (M, 10H), 4 7 . 0-4 8 5 (M, 1H), 3 . 6 6 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 3 (s, 3 H), 1.50-1. 7 5 (M, 4H), 1.2 3 (s, 9H), 1.22 (D, 6 H)
Example 2 I-form crystal of the potassium salt
Compound A tetrahydrofuran with (40mg) 12mL (hereinafter, referred to as. “THF”) was dissolved in, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added, 40 ℃ It was heated and stirred in for 15 minutes. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. After repeated two more times this step, at -20 ° C. 3 and held hours. The resulting precipitated crystals were collected by filtration under reduced pressure, and dried to obtain Form I crystal of the potassium salt. B Powder X-ray diffraction spectrum of type I crystal of the obtained potassium salt using the apparatus shown in Fig. 1 H-NMR (DMSO-D 6 ): delta 8 .14 (s, 1H), 7 .1 8 – 7 . 3 8 . (M, 10H), 4 7 . 2-4 8 4 (M, 1H) , 3 . 6 5 (s, 2H), 3 .4 7 (t, 2H), 3 .45 (t, 2H), 2. 7 2 (s, 3 H), 1.55-1. 7 0 ( M, 4H), 1.2 3 (D, 6 H)
Example 3  II-form crystals of the potassium salt
Compound A with (40mg) was dissolved in THF and 12mL, 0.1M aqueous potassium hydroxide solution (1.1 eq) was added and heated with stirring for 15 min at 40 ℃. After that, it was evaporated under reduced pressure, the solvent. The residue it was added ethyl acetate (200μL). While shaking the mixture heated to 50 ° C. 8 was allowed to cool to 25 ℃ over hours. This operation was repeated two more times, at -20 ° C. 3 and held hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, after drying, 40 ℃, relative humidity 7 while 5% of thermo-hygrostat 7 left for days to give crystalline Form II of the potassium salt. B Powder X-ray diffraction spectrum of crystalline Form II of the resulting potassium salt using the apparatus Fig 3 is shown in.

Example 4 III type crystal of the potassium salt
Compound A , in addition to (100mg) acetonitrile (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (1.1 eq) was added and stirred for 200 minutes at 20 ℃. While stirring the mixture 7 after a heated stirring for 1 hour to 0 ° C., and then cooled to 10 ℃ over 10 hours. Further heated while the mixture 6 is heated to 0 ℃, t- butyl methyl ether (0. 3 after adding mL), cooled to 20 ℃ over 10 hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried, III type crystal of the potassium salt ( 7 to afford 5mg). The powder X-ray diffraction spectrum of the type III crystal of the obtained potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, of about 7 endothermic peak was observed at around 4 ° C..
Elemental analysis (C 2 6 H 3 1 N 4 O 4 . SK + 0 7 8 H 2 as O)
calculated value (%) C: 5 6 .91 H: 5.9 8 N: 10.21
measured value (%) C: 5 6 . 6 1 H: 5.55 N:. 10 3 6

EXAMPLE 5 IV-type crystal of the potassium salt
Compound A , in addition to (50mg) and ethyl acetate (1mL), and stirred with heating, Compound A was dissolved, followed by cooling to 20 ℃. To a solution 3 .5M potassium hydroxide / ethanol solution (2.2 eq) was added and 2 at 20 ° C. 3 and stirred for hours. It was collected by filtration the precipitated crystals produced, under reduced pressure, and dried to obtain Form IV crystal of the potassium salt (41mg). The powder X-ray diffraction spectrum of crystalline Form IV of the resulting potassium salt using R unit is shown in FIG. Furthermore, in differential scanning calorimetry, an endothermic peak was observed at around approximately 91 ℃.

Paper

J Med Chem 2015, 58(18): 7128

PATENT

WO 2018008042

https://patents.google.com/patent/WO2018008042A1/en

The present invention relates to an improved and novel processes for the preparation of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide compound of formula- 1 , which is represented by the following structural formula- l .

Figure imgf000003_0001

Formula-

The present invention also relates to novel crystalline forms of the compound of formula- 1 and process for the preparation thereof.

Background of the Invention:

2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide is known as Selexipag. It is developed by Nippon Shinyaku under the brand name of Uptravi®, for the treatment of pulmonary arterial hypertension.

2- {4-[(5,6-diphenylpyTazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide was firstly described in US7205302B2 herein after referred as US ‘302. The said patent also describes its process for the preparation. According to this process the final product was obtained with low yield and purity.

US8791 122 (herein after referred as US’ 122) patent describes crystalline form-I, II and III of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N-(methylsulfonyl) acetamide. Because of drug compounds having, for example, improved stability, solubility, shelf life and in vivo pharmacology, are consistently sought, there is an ongoing need for new or pure salts, hydrates, solvates and polymorphic forms of existing drug molecules. The novel crystalline forms of 2- {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy} -N- (methylsulfonyl) acetamide described herein help meet this requirement.

US ‘ 122 patent describes amorphous form of the compound of formula- 1 . This patent does not disclose any detailed process for amorphous form and PXRD pattern of amorphous compound of formula- 1 .

Figure imgf000019_0001

Examples:

Example-1 Preparation of 4-((5)6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol compound of formula-8

A mixture of 5-chloro-2,3-diphenylpyrazine (25 gm) compound of formula-7a and 4- (isopropyl amino)butan- 1 -ol (108 gm) was heated to 190-195°C and stirred the reaction i mixture for 10- 12 hours at same temperature. Cooled the reaction mixture to 25-35°C. To this reaction mixture n-heptane followed by water were added slowly at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filter the precipitated solid, washed with water and dried to get the title compound.

Yield: 30 gm.

Example-2: Preparation of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetate

Potassium hydroxide solution (96.6 gm of potassium hydroxide dissolved in 175 ml of water) was added to the mixture of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan- l -ol (25 gm) and toluene ( 175 ml) at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C. Tert-butyl bromoacetate (94 gm) was slowly added to the reaction mixture at 0-5°C and stirred the reaction for 60 minutes at same temperature. Raised the temperature of the reaction mixture to 25-30°C and maintained for 60 minutes. Both the aqueous and organic layers were separated. The aqueous layer was extracted with toluene and combined the organic layers. Organic layer was washed with hydrochloric acid solution followed by with aqueous sodium bicarbonate solution. Organic layer was dried with sodium sulphate and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Yield: 29 gm.

Example-3: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid compound of formula-6

Aqueous sodium hydroxide solution (7.5 gm of sodium hydroxide was dissolved in 80 ml of water) was added to the solution of tert-butyl 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl) amino)butoxy)acetate (30 gm) in methanol (290 ml) at 30-35°C. Heated the reaction mixture to reflux temperature and stirred for 3 hours at the same temperature. Distilled off solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30°C. Water was added to the obtained compound and acidified the reaction mixture using diluted hydrochloric acid at the same temperature. Extracted the reaction mixture with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and dried with sodium sulphate. Distilled off the solvent from the organic layer under reduced pressure. Diisopropyl ether (60 ml) was added to the obtained compound at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid, washed with diisopropyl ether and dried to get the title compound.

Yield: 19 gm.

Example-4: Preparation of 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropy.)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Triethylamine (9.6 gm) was added to the mixture of 2-(4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butoxy)acetic acid (10 gm), dichloro methane (100 ml), N,N- dicyclohexylcarbodiimide (4.9 gm), hydroxybenzotriazole (3.5 gm) and methane sulfonamide (3.39 gm) at 25-30°C and stirred the reaction mixture for 12 hours at the same temperature. Filtered the unwanted compounds from the reaction mixture and washed with dichloromethane. The organic layer was washed with water, followed by with aqueous citric acid solution and then washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (20 ml) and carbon (1 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4.5 gm.

Example-5: Preparation of 2-{4-f(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}- N-(methylsulfonyl) acetamide compound of formula-1

Sodium t-butoxide (96.6 gm) was added to the mixture of n-methy pyrrolidinone (125 ml) and 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (25 gm) compound of formula-8 at 0-5°C and stirred the reaction for 20 minutes at the same temperature. 2-chloro- N-(methylsulfonyl)acetamide (23.7 gm) was slowly added to the reaction mixture at 0-5°C and raise the temperature of the reaction mixture to 25-30°C. Stirred the reaction mixture for 10-12 hours at 25-30°C and water was added to it at the same temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution and distilled off the solvent from the organic layer under reduced pressure. To this residue ethyl acetate (50 ml) and carbon (2.5 gm) were added at 25-30°C and stirred the reaction mixture for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. The obtained filtrate was slowly added to the mixture of n-heptane and water at 25-30°C and stirred for 10 hours. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 14 gm.

Example-6: Preparation of 2-chIot*o- -(methylsulfonyl)acetamide

A mixture of methane sulfonamide (100 gm) and chloroacetyl chloride (356.4 gm) was heated to reflux temperature and stirred it for 10 hours at the same temperature. Cooled the reaction mixture to – 10 to -5°C and stirred it for 2 hours at the same temperature. Filtered the precipitated, solid, washed with toluene followed by n-heptane and dried to get the title compound.

Yield: 175 gm.

ExampIe-7: Purification of the compound of formula-1

Methanol (20 ml) was added to the compound of formula-1 (2 gm) at 25-30°C and heated to reflux temperature. Dichloromethane (3 ml) was added to the reaction mixture at reflux temperature and stirred for 15 minutes at the same temperature. Filtered the reaction mixture, distilled off the solvent from the filtrate under reduced pressure to get the title compound. Yield: 2 gm

Example-8: Preparation of N-isopropyI-5,6-diphenylpyrazin-2-amine (Formula-4) Isopropyl bromide (5.5 gm) was added to the mixture of 2-amino -5,6-diphenylpyrazine ( 10 gm), potassium tert-butoxide (9 gm) and dimethylformamide (50 ml) at 25-30°C, slowly heated to 80-85°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 10- 15°C, diluted the reaction mixture with water and stirred it for 2 hours at the same temperature. Filtered the obtained solid and dried to get the title compound.

Yield: 9.5 gm

ExampIe-9: Preparation of N-isopropyl-5,6-diphenylpyrazin-2-amine (Formula-4)

A mixture of 5-chloro-2,3-diphenylpyrazine ( 10 gm), isopropyl amine (7.5 gm) and potassium carbonate (10.5 gm) and dioxane (50 ml) were heated to 40-45°C and stirred the reaction mixture for 12 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C, diluted with water and extracted with dichloromethane. Combined the organic layers was washed with aqueous sodium hydrochloride solution and dried over anhydrous sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure to provide the title compound.

Yield: 9 gm

Example-10: Preparation of 2-(4-chlorobutoxy)aceticacid (Formula-5a)

2-bromoaceticacid (10 gm) was slowly added to a mixture of l-chlorobutan-4-ol (7.2 gm), potassium carbonate (26.5 gm) and acetonitrile (50 ml) at 25-30°C. The reaction mixture was heated to 75-80°C and stirred the reaction mixture for 6 hours at same temperature. The reaction mixture was cooled to 25-30°C and diluted with , water. Acidified the reaction mixture using diluted hydrochloric acid at 25-30°C. The reaction mixture extracted with dichloromethane. Combined the organic layers was dried over anhydrous sodium sulphate and distilled off the solvent under reduced pressure to provide the title compound.

Yield: 10.5 gm.

Example-11: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino) butoxy)acetic acid (formula-6)

A mixture of N-isopropyl-5,6-diphenylpyrazin-2-amine (8 gm), potassium carbonate (7.5 gm) and acetonitrile (40 ml) was stirred for 1 hr at 25-30°C. A solution of 2-(4-chlorobutoxy) aceticacid (5.4 gm) in acetonitrile (15 ml) was slowly added to the reaction mixture at 25- 30°C. Heated the reaction mixture to reflux and stirred for 12 hours at the same temperature. The reaction mixture was cooled to 10-15°C and diluted with wateT. Acidified the reaction mixture using diluted hydrochloric acid and extracted the reaction mixture using ethyl acetate. Combined the organic layers and dried over sodium sulphate. Distilled off the solvent completely from the organic layer to get the title compound.

Yield: 8.5 gm

Example-12: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyt)amino)butoxy)- N-(methylsulfonyl)acetamide (formula-1)

A mixture of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid (5 gm), HATU (5.4 gm), triethylamine (1.5 gm) and dimethylformamide (20 ml) was stirred for 1 hr at 5-10°C under nitrogen atmosphere. Methane sulfonamide (5.2 gm) was slowly added to the reaction mixture at 5-10°C and stirred for 12 hrs at the same temperature. The reaction mixture was diluted with water and stirred for 2 hrs. The precipitated solid was filtered and dried to get the title compound.

Yield: 4.5 gm

Example-13: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (Formula-12)

To the mixture of 4-((5,6-diphenylpyrazin-2-yI)(isopropyl)amino)butan-l-ol ( 10 gm), tetrabutyl ammoniumbromide (0.2 gm), potassium carbonate (7.6 gm) and acetone (50 mL), chloroacetonitrile (3.2 gm) was added at 25-30°C. Heated the reaction mixture to reflux temperature and stirred the reaction mixture for 6 hrs at the same temperature. The reaction mixture was cooled to 10- 15°C and filtered the reaction mixture. Distilled off the solvent completely from the filtrate to get the tile compound.

Yield: 9 gm

Example-14: Preparation of 2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy) acetic acid (formula-6)

Sodium hydroxide (3.5 gm) was added to a solution of 2-(4-((5,6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetonitrile (8 gm) in methanol (60 ml) and water (30 ml). The reaction mixture was heated to 65-70°C and maintained for 6 hrs. The reaction mixture was cooled to 10°C, acidified with diluted hydrochloric acid and stirred at same temperature for 2 hr. The obtained solid was filtered and dried to provide the title compound.

Yield: 7.5 gm

Example-15: Preparation of 2-chloro-N-(methylsulfonyl)acetamide (Formula-16)

The mixture of methane sulfonamide (50 gm) and chloroacetyl chloride (92 gm) was heated to 1 10-1 15°C and stirred the reaction mixture for 7 hours at the same temperature. The reaction mixture was cooled to 25-30°C and dichloromethane was added to the reaction mixture at the same temperature. Cooled the reaction mixture to 15-20°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with dichloromethane. The obtained solid was recrystallized using dichloromethane to get pure title compound. Yield: 80 gm. M.R.: U0- 1 15°C. Purity by HPLC: 98.85%.

Example-16: Preparation of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

The mixture of 5-chloro-2,3-diphenylpyrazine ( 100 gm) and 4-(isopropylamino)butan-l -ol (245.5 gm) was heated to 190-195°G and stirred the reaction mixture for 12 hours at the same temperature. The reaction was cooled to 25-30°C and n-heptane was added to the reaction mixture. The reaction mixture was further cooled to 10-15°C, water was slowly added to the reaction mixture and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. Dichloromethane (300 ml) was added to the obtained solid and stirred for 5 minutes. Both the organic and aqueous layers were separated. The organic layer was dried with sodium sulphate, distilled off the solvent from the organic layer completely under reduced pressure and co-distilled with n-heptane. 400 ml of n-heptane was added to the obtained compound at 25-30°C, heated the reaction mixture to 45-50°C and stirred for 30 minutes at the same temperature. The reaction mixture was cooled to 15-20°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound.

Yield: 82 gm. M.R.: 100-105°C. Purity by HPLC: 95.4%.

Example-17: Purification of 4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butan-l-ol (Formula-8)

n-Heptane (750 ml) was slowly added to pre-cooled solution of 4-((5,6-diphenylpyrazin-2- yl)(isopropyl)amino)butan- l -ol (100 gm) in acetone (250 ml) was cooled to 0-5°C. Stirred the reaction mixture for 4 hours at the same tempereature. Filtered the precipitated solid, washed with n-heptane and dried to get the pure title compound.

Yield: 54 gm. Purity by HPLC: 99.92%.

Example-18: Preparation of crystalline form-L of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of pre-cooled n-heptane at 0- 5°C. Stirred the reaction mixture for 6 hr at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 9 gm; PXRD of the obtained compound is depicted in figure- 10 and DSC thermogram is depicted in figure- 1 1. Example-19: Preparation of crystalline form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of pre-cooled n-heptane at 0- 5°C. Stirred the reaction mixture for 36 hours at 0-5°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm; PXRD of the obtained compound is depicted in figure-7, its IR is depicted in figure-8 and its DSC is depicted in figure-9.

Example-20: Preparation of crystalline form-P of compound of formula-1

Melting the compound of formula-1 (10 gm) at 140-145°C under reduced pressure for 15 minutes. The above obtained oily residue was added to 100 ml of n-heptane at 30-40°C.

Stirred the reaction mixture for 36 hours at 30-40°C. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 9 gm; PXRD of the obtained compound is similar to the figure-7.

Example-21 : Preparation of amorphous form of compound of formula-1

Melting the compound of formula-1 ( 10 gm) at 140- 145°C under reduced pressure for 15 minutes and the above obtained oily residue was cooled to 0-5°C. Unload the obtained compound and dried to get the title compound. Yield: 9 gm; Purity by HPLC: 99.74%. PXRD of the obtained compound is depicted in figure-5 and IR is depicted in figure-6.

Exaniple-22: Preparation of crystalline form-I of compound of formula-1

Melting the compound of formula-1 (5 gm) at 140-145°C under reduced pressure for 15 minutes. 50 ml of n-heptane was added to the above obtained oily residue at 115-120°C.

Stirred the reaction mixture for 20 minutes at 1 15- 120°C. Cooled the reaction mixture to 25-

30°C and stirred for 60 minutes at the same temperature. Further cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 60 minutes at the same temperature. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound.

Yield: 4 gm; Purity by HPLC: 99.68%.

PATENT

CN 108675964

PATENT

CN 106316967

PATENT

WO 2017029594

PATENT

US8791122

Form-I  II  III

https://patents.google.com/patent/US8791122B2/en

Figure US08791122-20140729-C00002

PATENT

https://patents.google.com/patent/WO2018022704A1/en

Selexipag has the chemical name 2-{4-[(5,6-diphenylpyrazin-2- yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide. Selexipag has the following chemical structure:

Figure imgf000002_0001

[0004] Selexipag is being developed by Actelion and Nippon Shinyaku for the treatment of arteriosclerosis obliterans, pulmonary hypertension and Raynaud’s disease secondary to systemic sclerosis.

[0005] Selexipag is disclosed in US 7,205,302. US 8,791,122, US 9,284,280 and US 2014- 0155414 disclose polymorphs of Selexipag, denominated forms I, II and III. WO

2017/040872 discloses form IV and V of Selexipag.

xample 1: Preparation of Selexipag

[00126] A. Route 1

[00127] Crude Selexipag can be obtained by any method known in the art, for example by the method described in US 7,205,302 or according to the following.

[00128] B. Route 2

[00129] Step a: Preparation of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino)butan-l-ol

[00130] To 50 g (0.161 mol) of 5-bromo-2,3-diphenylpyrazine, 116 g (0.884 mol, 5.5 eq/mol) of 4-(isopropylamino)-butan-l-ol and 13.33 g of KI (0.080 mol, 0.5 Eq/mol) were added. The reaction mixture was stirred, warmed and then heated up to 140°C for about 18- 20 hrs. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to room temperature. After the reaction was completed, the following work up step was performed:

[00131] Option 1 : Ethyl acetate was added (500 mL, 10 vol) and the organic phase was washed with water (150 mL, 3 vol). The organic phase was separated and aqueous phase was extracted with ethyl acetate (150 mL, 3 vol). The organic phases were joined and washed with water (200 mL, 2 vol) three times.

[00132] The solvent was distilled off under vacuum at not more than (“NMT”) 40°C until 1 vol (oil appearance).

[00133] Option 2: The material (mixture) was dissolved in acetone (250 mL, 5 vol), the solution obtained was cooled down to 0°C to 5°C and anti-solvent / water was added (1000 mL, 20 vol) for 40 minutes, then the suspension was stirred for about 30 minutes at about 0°C-5°C. The solid material was filtered and washed with water (200 mL, 4 vol). Crude wet product was obtained as yellow solid yielding 101.8 % WY (87 % MY), HPLC purity 90.8% on area at this stage.

[00134] The crude material, obtained in either of the above described options, was purified through crystallization from acetone :«-heptane as follows: to a solution of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol crude in acetone (175 mL, 3.5 vol) at 0°C – 5°C, hexane (600 mL, 12 vol) dropwise in about 120 min was added, then the precipitated mixture was cooled down to about -10°C and stirred for about 60 min. The product was filtered off and washed with hexane (250 mL, 5 vol) and dried under vacuum at 25°C. Pure product was obtained as yellowish solid yielding overall 77.2%, (66.5% MY), HPLC purity 98.2% on area.

[00135] Step b: Preparation (2-bromo-N-(methylsulfonyl)-acetamide)

[00136] To a suspension of 50 g (0.526 mol) of methanesulfonamide in toluene (625 mL, 12.5 vol) and isopropyl acetate (625 mL, 12.5 vol), 159.1 g (0.789 mol) of bromo-acetyl- bromide (“BAB”) was added under nitrogen atmosphere. The reaction mixture was heated up to about 90°C for about 8 hours under a nitrogen stream. The reaction was monitored by TLC up to completion (starting material about 1% by TLC). The reaction mixture was cooled down to about 40°C and concentrated under vacuum until 10 volumes. Subsequently, toluene was added (250 mL, 5 vol) and distilling off solvents is carried out at NMT 30°C until 10 volumes. Then was added dichloromethane (100 mL, 2 vol) and the mixture was cooled down at 0°C and is stirred for 90 min. The solid was filtered and washed with

dichloromethane (100 mL, 2 vol). Crude product was obtained as beige solid material yielding 187% WY (83% MY), HPLC purity 99.2% at this stage. [00137] The crude material (83 g) was purified through re-slurring with dichloromethane (166 mL, 2 vol; preferably 332 mL, 4 vol) by stirring at about 32°C for about 60 min. The crystallization mixture was cooled down to about 0°C-5°C and stirring for 30 min, filtered off and washed with dichloromethane (100 mL, 2 vol). Subsequently, the material was dried at 35°C for 24 hours. Pure and dried material was obtained as white off solid yielding overall 173%, (77% MY), HPLC purity 99.6 % on area.

[00138] Step c: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino]butoxy]-N-(methylsulfonyl)-acetamide) – Selexipag

[00139] To 10 g (0.028 mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl)amino) butan-l-ol was added a strong base (6.0 eq/mol), previously suspended in an appropriate solvent, within a range of from -10°C to 40°C under a nitrogen atmosphere and stirred for 60 min. Then, a solution of 17.9 g (3.0 eq/mol) of 2-bromo-N-(methylsulfonyl)-acetamide, previously dissolved in the same solvent, is added dropwise within a range of from 120 tol 80 min, controlling the exothermic temperature. The reaction was monitored by TLC up to completion. Subsequently, the mixture reaction was cooled down around 5°C and water is added by controlling the exotherm (NMT 15°C). Finally, an acetic acid solution was added and the suspension was stirred for about 60 min at 0°C -5°C. The product (crude) was filtered off and washed with water. An amorphous solid was obtained. The crude product was purified by crystallization from ethanol:THF.

[00140] Step d: Purification of Selexipag

[00141] Crude Selexipag can be purified by crystallization in an organic solvent for example alcohols such as ethanol, iso-amyl alcohol, iso-propyl alcohol, butanol; ethers such as tetrahydrofuran, hydrocarbons such as heptane and mixed solvents thereof.

[00142] C. Route 3

[00143] 33.3 g (0.297 mol, 6.0 eq/mol) of potassium tert-butoxide were dissolved in DMF (2.8 vol) in a flask (500 mL) under nitrogen atmosphere and stirred for 15 min. Then, a solution of 17.9 g (0.049 mol, 1.0 eq/mol) of 4-((5,6-diphenyl-pyrazin-2-yl)(isopropyl) amino) butan-l-ol (SLX-4) dissolved in DMF (1.2 vol) was added in one portion. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C at 150 rpm Then, a solution of 32.1 g (0.15 mol, 3.0 Eq/mol) of 2-bromo-N-(methylsulfonyl)- acetamide (SLX-9), previously dissolved in DMF (1.3 vol), was added dropwise for 120 minutes by controlling the temperature (exothermic process).

[00144] The reaction mixture was quenched with cool water (0.33 vol), transferred into a flask of more capacity (1000 mL) and placed in an ice bath. Cool water (38.32 vol) was added to the reaction mixture and the pH was adjusted to 5.0 with AcOH (0.33 vol). The mixture was stirred at 300 rpm for 40 min. Then, the flask with the reaction mixture was stored in the refrigerator at 8°C. After 8h, the solid was filtered and washed with cool water (5 vol, 2 times). The crude product (yellow solid) was drained (i.e. dried) for 30 min and was stored at 8°C.

Example 2: Preparation of crystalline Selexipag Form IV

[00145] A. Route 1

[00146] 3.0 g of Selexipag was dissolved in dimethylformamide (“DMF”) (12 mL, 4 vol). The obtained solution was added dropwise to a pre-cooled acetic acid solution (0.06 M, 120 mL, from 2°C to 8°C) to obtain a suspension. The suspension was stirred within a range of from 2°C to 8°C for 30 min; then the material was filtered, washed with water (10 mL, 3.3 vol) and drained (i.e. dried) for 10 minutes. The solid material (amorphous) was suspended in heptane (25 mL, 7.5 vol) and the obtained suspension was stirred for 30 minutes at room temperature. The material was filtered, washed with heptane (20 mL, 6.6 vol) and drained (i.e. dried) under vacuum for at least 30 minutes at room temperature to obtain the Form IV Crystal.

[00147] B. Route 2

[00148] Crude Selexipag (1.0 g, amorphous solid, obtained from the synthesis) was dissolved in ethyl acetate (5 vol, 5 mL), then water was added (10 vol, 10 mL) into the solution, the mixture was stirred for about 10 minutes and the pH was adjusted to a range of from 8.0 to 9.0 by titration with K2CO3 solution. The phases were separated; the pH of the aqueous phase was adjusted to a range of from 3.5 to 5.0 by titration with acetic acid. Then, ethyl acetate (10 vol, 10 mL) was added into the aqueous phase, the obtained mixture was stirred and the phases were separated. The organic phase was distilled off under reduced pressure (from 2 to 3 volumes), and a solution was obtained. The obtained concentrated solution was quickly added to a mixture (suspension) of Form IV in ^-heptane (17 mL, 17 vol), over a period of less than 5 minutes, (the suspension temperature was of from 15°C to 25°C), and a suspension was obtained. The obtained suspension was stirred (155rpm) for 90 minutes at a temperature of from 0°C to 5°C. The suspension was filtered, washed with heptane, squeezed for 15 minutes and dried at 25°C, under vacuum, for about 14 hours. The product was analyzed by PXRD – Form IV was obtained.

[00149] The above procedure can be performed by dissolving the crude amorphous starting material in any suitable organic solvent, for example ester solvent. Example 3: Preparation of (2-[4-[(5,6-diphenyl-2-pyrazinyl)(l- methylethyl)amino] butoxy] -N-(methylsulfonyl)-acetamide) – Selexipag

Figure imgf000024_0001

SLX-4 SLX-9 SLX-6

[00150] 9.2 grams (0.082 mol, 5.9 eq/mol) of potassium tert-butoxide were combined with DMF (2.7 vol, 13.5 mL) in a flask (50 mL) under nitrogen atmosphere and a suspension was formed and was stirred for 20 min. Then, 5.0 g (0.014 mol, 1.0 eq/mol) of 4-((5,6-diphenyl- pyrazin-2-yl)(isopropyl)amino)butan-l-ol (SLX-4) as solid powder was added under nitrogen atmosphere. The reaction mixture was stirred for 60 min within a temperature range from 20°C to 25°C and at 170 rpm. Then, a solution of 8.9 g (0.041 mol, 3.0 eq/mol) of 2-bromo- N-(methylsulfonyl)-acetamide (SLX-9), previously dissolved in DMF (1.3 vol, 6.5 mL), was added dropwise for 120 minutes by controlling the temperature (exothermic process). After the end of addition, the reaction was completed, and the reaction mixture was quenched with cold water (0.5 vol, 2.5 mL), subsequently transferred into a flask of more capacity (500 mL) and placed into an ice bath. Cold water (40 vol, 200 mL) was added into the suspension and the pH was adjusted within the range from 4.0 to 5.0 with acetic acid. The obtained mixture was stirred for 120 min. The crude amorphous product was collected by filtration and washed twice with cold water (5 vol, 25 mL). The product was drained (i.e. dried) for 30 min and isolated as a yellow-brown solid which was stored within the range from 2°C to 8°C for approximately 17 hours. Then, the crude amorphous material was dissolved in ethyl acetate (15 vol, 75 mL) and water was added into the solution (30 vol, 150 mL). The pH was adjusted from 8.0 to 9.0 by addition of potassium carbonate solution, the phases were separated and the aqueous phase was washed twice with ethyl acetate (7.5 vol, 37.5 mL). The pH of the final aqueous phase was adjusted to a range from 4.0 to 5.0 with acetic acid. Then, ethyl acetate was added (30 vol, 150 mL) and the phases were separated. The organic phase was washed twice with water (7.5 vol, 37.5 mL). The organic phase was distilled off under reduced pressure (from 6 to 7 volumes, or from 6 to 15 volumes) and a solution was obtained.

[00151] In a different flask (capacity of 250 mL with a PTFE stirrer blade), a suspension of 0.05 g of Selexipag Form IV in ^-heptane (30 volumes, 150 mL) was stirred for 60 minutes within the range 0°C to 5°C and this suspension was added into the above ethyl acetate concentrated solution at room temperature over a period of less than 5 minutes. The final suspension was cooled down to 0°C to 5°C and stirred (220 rpm) for 120 minutes. The solid product was filtered off and washed twice with cold heptane (5 vol, 25 mL). The product was drained (i.e. dried) overnight. The product was analyzed by PXRD – Form VI was obtained, PXRD pattern is depicted in Figure 1.

PATENT

CN105949135

https://patents.google.com/patent/CN105949135A/en

Figure CN105949135AD00052

Example 1

[0027] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0028] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] butanol -1_ (20 (^, 0.09111 〇1) and tert-butyl bromoacetate (21 · lg, 0 llmol) solution. The reaction was stirred for 2 hours to burn dichloromethane (90mL), was added tetrabutylammonium chloride (0.72g, 2.6mmol), potassium hydroxide (7.3g, 0.13mol) and water (12.0g), the reaction mixture was 25 ° C The reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl yl) aminobutoxy] acetate, as a pale yellow oil (26.6 g of), a yield of 89.0%, the reaction formula of this step is as follows:

[0029]

Figure CN105949135AD00071

[0030] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0031] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (26. (^, 0.075! 11〇1) was dissolved in methanol (50 mL), was added sodium hydroxide solution (NaOH = 3 · 3g, 0 · 08mol; water 9 · 0g), was heated to 80 ° C for 6 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid (20.7 g of), a yield of 95.0%, the reaction formula of this step is as follows:

Figure CN105949135AD00081

[0033] C) Preparation of 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0034] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (20 (^, 0.07 11〇1) and a hoot “-.! P sitting carbonyldiimidazole (14.0g, 0.09mo 1 ) was dissolved in tetrahydro-thiopyran Misaki (70 mL), with stirring, was added methyl sulfonamide (7.9g, 0.08mol), the reaction mixture was 90 ° C the reaction stirred for 18 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (21.2 g), yield 83.7%, the reaction formula of this step is as follows:

Figure CN105949135AD00082

[0036] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (20 (^, 0.055111〇1. ) and dissolved in methanol (1101 ^), trifluoroacetic acid (6.88,0.06111〇1), 65 ° (: the reaction stirred for 6 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (200 mL), cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in methanol (40 mL), was added 5 – chloro-2,3-diphenyl-pyrazine (16 · 0g, 0 · 06mol), N, N- diisopropylethylamine (15 · 5g, 0 · 12mol), the reaction mixture was stirred reactor 8 100 ° C hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (25.0 g of), a yield of 92.3%, the reaction step formula as follows:

[0037]

Figure CN105949135AD00083

[0038] Example 2

[0039] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0040] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (23 (^, 0.10111 〇1) and tert-butyl bromoacetate (25 · 2g, 0 · 13mol) was dissolved. burning in 1,2-dichloroethane (110mL), was added tetrabutylammonium bromide (1 · lg, 3 · 5mmol), sodium hydroxide (6.4g, 0.16mol) and water (14.0g), the reaction mixture was 30 ° C The reaction was stirred for 3 hours, the reaction solution was concentrated by rotary evaporation to dryness under reduced pressure and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxy butoxycarbonyl) (isopropyl) aminobutoxy] acetate, as a pale yellow oil (30.3 g of), a yield of 88.2%, the reaction of the present step is the same formula as in Example 1;

[0041] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0042] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (30. (^, 0.09! 11〇1) was dissolved in ethanol (85 mL), was added potassium hydroxide solution ( 1 (! = 5.78,0.10111〇1 01; 128 water), heated to 75 ° (: 7 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (23.5 g of), a yield of 93.7%, the reaction of the present step is the same formula as in Example 1;

[0043] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0044] [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (23 (^, 0.08 11〇1) and Chi ^ -! Dicyclohexyl carbodiimide (22. lg, 0. llmol) was dissolved in chloroform (120 mL), with stirring, was added methyl sulfonamide (9.8g, 0. lOmol), the reaction mixture was 80 ° C the reaction stirred for 19 hours, the reaction solution was concentrated by rotary evaporation to dryness, ethyl acetate was added and extracted dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide, off-white the solid (24.8 g of), a yield of 85.0%, the reaction of the present step is the same formula as in Example 1;

[0045] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (24 (^, 0.065111〇1. ) and dissolved in ethanol (1601 ^), trifluoroacetic acid (9 (^, 0.08111〇1.), 70 ° (: the reaction was stirred for 7 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (260 mL of), cooled crystallization to 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in ethanol (90 mL) , 5-chloro-2,3-diphenyl-pyrazine (! 11〇1 21.8 8,0.08), triethylamine (14.98,0.15111〇1), the reaction mixture was 100 ° (: The reaction was stirred for 18 hours, the reaction solution cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (29.6 g of), a yield of 91.0%, the reaction of the present step is the same formula as in Example 1 .

[0046] Example 3

[0047] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0048] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (12g, 0.05mol) and t-butyl bromoacetate (12.1g, 0.06mol) was dissolved in chloroform (70mL), was added tetrabutylammonium iodide (0 · 5g, 1 · 3mmol), lithium hydroxide (1 · 7g, 0 · 07mol) and water (6.5 g of), the reaction mixture was stirred 20 ° C for 4 hours, the reaction solution under reduced pressure concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxygen yl] acetate, as a pale yellow oil (15.6 g of), a yield of 86.8%, the reaction of the present step is the same formula as in Example 1;

[0049] B) Preparation of [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0050] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (15.0g, 0.04mol) was dissolved in isopropanol (40mL), was added a solution of lithium hydroxide (LiOH = 1 · 3g, 0 · 05mol; water 6 · 0g), was heated to 70 ° C for 8 hours, cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl) aminobutyrate oxy] acetic acid as an off-white solid (11.7 g), 93.0% yield, this step is the same reaction scheme of Example 1;

[0051] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0052] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (11 (^, 0.04! 11〇1) and 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide (8.38,0.05111〇1) was dissolved in acetonitrile (4〇1111 ^), with stirring, was added methyl sulfonamide (5.] ^, 0.05mol), the reaction mixture was 95 ° C the reaction stirred for 22 hours, The reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (11.7 g), yield 84.2%, the reaction of the present step is the same formula as in Example 1;

[0053] D) Preparation of SIPA Seiler: 2- [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (11 (^, 0.03111〇1. ) and dissolved in dichloromethane (601 ^), trifluoroacetic acid (4.48,0.04111〇1), 50 ° (: the reaction was stirred for 10 hours to water (120 mL completion of the reaction, the reaction liquid was added to a stirred), cooled to crystallization 0 ° C for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), and then dissolved in tert-butanol (40 mL ), 5-chloro-2,3-diphenyl-pyrazine (9.68,0.036 11〇1), 4-dimethylaminopyridine (8.18,0.07111〇1), the reaction mixture was 110 ° (:! reaction was stirred for 14 hours the reaction was cooled to room temperature, water (15 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (13.5 g of), a yield of 90.5%, the reaction in this step is the same formula Example 1.

[0054] Example 4

[0055] A) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate:

[0056] 4 – [(tert-butoxycarbonyl) (isopropyl) amino] -1-butanol (15 (^, 0.065111〇1) and t-butyl bromoacetate (17.78,0.09111〇1) was dissolved in toluene (701] 11 ^), was added tetrabutylammonium hydrogen sulfate (0.888,2.61] 11] 1〇1), potassium carbonate (15.2 area, 0.1 lmol) and water (9.5 g of), the reaction mixture was stirred 40 ° C for 1.5 hours, the reaction solution was concentrated under reduced pressure and rotary evaporated to dryness and extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, a mixed solvent of ethanol and recrystallized from isopropanol to give [4- (tert-butoxycarbonyl) (isopropyl propyl) aminobutoxy] acetate, as a pale yellow oil (19.6 g of), in the same reaction formula in this step a yield of 87.5% in Example 1;

[0057] B) Preparation of [4_ (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid:

[0058] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetate (19 (^, 0.055! 11〇1) was dissolved in tert-butanol (60 mL), hydroxide solution of cesium (CsOH = 11. lg, 0.07mol; water, 8.0 g), the reaction was heated to 75 ° C for 6.5 hours cooled to room temperature, after treatment and purification, to give [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] acetic acid, an off-white solid (15.0 g of), a yield of 94.2%, the reaction of the present step is the same formula as in Example 1;

[0059] C) Preparation of 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide:

[0060] [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] acetic acid (15.0g, 0.05mol) and diazabicyclo 1,8_

[5.4.0] – | -7- dilute (9.5 region, 0.06111〇1) was dissolved in toluene (8〇1111 ^), with stirring, was added methyl sulfonamide (5.7 region, 0.06mo 1), the reaction mixture was 105 ° C for 16 hours, the reaction solution was concentrated by rotary evaporation to dryness, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness, recrystallized from methanol to give 2- [4- (tert-butoxycarbonyl) (isopropyl ) aminobutoxy] -N- (methylsulfonyl) acetamide as an off-white solid (16.6 g of), 87.3% yield, this step is the same reaction scheme of Example 1;

[0061] D) Preparation of SIPA Seiler: 2- [4- (tert-butoxycarbonyl) (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide (16 (^, 0.04111〇. 1) and dissolved in ethyl acetate (^ 1,301,111), trifluoroacetic acid (5.78,0.051] 1〇1), 80 <€ the reaction was stirred for 5 hours to complete the reaction, the reaction was added dropwise to a stirred solution of water (150 mL), was cooled to 0 ° C crystallization for 3 hours and filtered to give the intermediate compound (2- [4- (isopropyl) aminobutoxy] -N- (methylsulfonyl) acetamide), then dissolved in isopropanol (50 mL), was added 5-chloro-2,3-diphenyl-pyrazine (13.58,0.05 11〇1!), a hoot dimethylaniline (12.28,0.10111〇1), the reaction mixture was 95 ° (: The reaction was stirred 12 hours, the reaction was cooled to room temperature, water (40 mL), cooled to -10 ° C crystallization for 3 hours and filtered to give SIPA game music, as a white solid (19.7 g of), a yield of 91.0%, the reaction step formula in Example 1.

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

Selexipag (C26H32N4O4S, Mr = 496.6 g/mol) ist ein Diphenylpyrazin-Derivat. Es wird in der Leber zum aktiven Metaboliten ACT-333679 (MRE-269) biotransformiert. Selexipag unterscheidet sich strukturell von Prostazyklin und anderen Prostazylin-Rezeptor-Agonisten.

References

 

  1. Kuwano et al. NS-304, an orally available and long-acting prostacyclin receptor agonist prodrug. J Pharmacol Exp Ther 2007;322:1181-1188.
  2. Kuwano et al. A long-acting and highly selective prostacyclin receptor agonist prodrug, NS-304, ameliorates rat pulmonary hypertension with unique relaxant responses of its active form MRE-269 on rat pulmonary artery. J Pharmacol Exp Ther 2008;326:691-699.
  3. Simonneau G, Lang I, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N. Selexipag, an oral, selective IP receptor agonist for the treatment of pulmonary arterial hypertension Eur Respir J 2012; 40: 874-880
  4. Mubarak KK. A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension. Respir Med 2010;104:9-21.
  5. Sitbon, O.; Morrell, N. (2012). “Pathways in pulmonary arterial hypertension: The future is here”. European Respiratory Review 21 (126): 321–327. doi:10.1183/09059180.00004812PMID 23204120.
  6. Publication numberPriority datePublication dateAssigneeTitle
    WO2016193994A12015-05-292016-12-08Megafine Pharma (P) Ltd.Amorphous selexipag and process for preparation thereof
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    WO2018008042A1 *2016-07-052018-01-11Maithri Drugs Private LimitedNovel process for the preparation of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl)amino]butoxy}-n-(methylsulfonyl)acetamide and novel polymorphs thereof
    WO2018015974A12016-07-202018-01-25Mylan Laboratories LimitedPolymorphic forms and amorphous solid dispersion of selexipag
    WO2018022704A12016-07-262018-02-01Teva Pharmaceuticals International GmbhCrystalline form vi of selexipag
    WO2018078383A12016-10-272018-05-03Cipla LimitedPharmaceutical composition comprising amorphous selexipag
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    WO2009107736A1 *2008-02-282009-09-03日本新薬株式会社Fibrosis inhibitor
    CN106279047A2015-05-132017-01-04上海适济生物科技有限公司Preparation method of prostacyclin receptor agonist
    WO2017029594A1 *2015-08-172017-02-23Dr. Reddy’s Laboratories LimitedProcesses for preparation of selexipag and its amorphous form
    WO2017042828A3 *2015-09-102017-04-27Megafine Pharma (P) Ltd.Process for the preparation of selexipag
    EP3192502A12016-01-152017-07-19Sandoz AgPharmaceutical composition of selexipag
    WO2017168401A1 *2016-04-012017-10-05Honour (R&D)Process for the preparation of diphenylpyrazine derivatives
    CN105949135A *2016-05-102016-09-21湖南欧亚生物有限公司Synthetic method of selexipag
    EP3335699A12016-12-152018-06-20H e x a l AktiengesellschaftSelexipag formulation in liquisolid system
Patent Submitted Granted
Methods of identifying critically ill patients at increased risk of development of organ failure and compounds for the treatment hereof [US8877710] 2009-12-30 2014-11-04
Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same [US8791122] 2010-06-25 2014-07-29
COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2015057325] 2013-03-26 2015-02-26
INHIBITION OF NEOVASCULARIZATION BY SIMULTANEOUS INHIBITION OF PROSTANOID IP AND EP4 RECEPTORS [US2014275200] 2014-03-05 2014-09-18
INHIBITION OF NEOVASCULARIZATION BY INHIBITION OF PROSTANOID IP RECEPTORS [US2014275238] 2014-03-05 2014-09-18
Fibrosis inhibitor [US8889693] 2014-04-10 20
Patent Submitted Granted
Heterocyclic compound derivatives and medicines [US7205302] 2004-05-27 2007-04-17
METHODS OF IDENTIFYING CRITICALLY ILL PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ORGAN FAILURE AND COMPOUNDS FOR THE TREATMENT HEREOF [US2014322207] 2014-07-11 2014-10-30
THERAPEUTIC COMPOSITIONS CONTAINING MACITENTAN [US2014329824] 2014-07-18 2014-11-06
Sustained Release Composition of Prostacyclin [US2014303245] 2012-08-10 2014-10-09
COMPOUNDS CAPABLE OF MODULATING/PRESERVING ENDOTHELIAL INTEGRITY FOR USE IN PREVENTION OR TREATMENT OF ACUTE TRAUMATIC COAGULOPATHY AND RESUSCITATED CARDIAC ARREST [US2013261177] 2011-09-30 2013-10-03
METHODS OF TREATMENT OF PATIENTS AT INCREASED RISK OF DEVELOPMENT OF ISCHEMIC EVENTS AND COMPOUNDS HEREOF [US2013040898] 2011-04-29 2013-02-14
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Selexipag
Selexipag.svg
Names
IUPAC name

2-{4-[(5,6-diphenylpyrazin-2-yl)(propan-2-yl)amino]butoxy}-N-(methanesulfonyl)acetamide
Other names

ACT-293987, NS-304
Identifiers
475086-01-2 Yes
ChEMBL ChEMBL238804 
ChemSpider 8089417 Yes
7552
Jmol interactive 3D Image
KEGG D09994 Yes
PubChem 9913767
UNII P7T269PR6S Yes
Properties
C26H32N4O4S
Molar mass 496.6 g·mol−1

//////////ACT-333679,  MRE-269, Selexipag, セレキシパグ , UNII-5EXC0E384L, селексипаг سيليكسيباق Orphan Drug, fda 2015, NS 304,  ACT 293987,  Uptravi, EU 2016, 

CC(C)N(CCCCOCC(=O)NS(=O)(=O)C)C1=CN=C(C(=N1)C2=CC=CC=C2)C3=CC=CC=C3

Selexipag (Uptravi)

Selexipag and its active metabolite, the corresponding carboxylic acid, are nonprostanoid prostaglandin I2 (PGI-2) receptor agonists (Scheme 8).(24) The N-methylsulfonamide within selexipag is hydrolyzed to the corresponding carboxylic acid in vivo by hepatic microsomes at a rate which provides a slow-release pharmacological effect.(24) The compound was originally discovered by Nippon Shinyaki and later licensed to Actelion for development. The drug was approved in 2015 and first launched for the oral treatment of pulmonary arterial hypertension (PAH) in the U.S. in 2016 to delay disease progression and reduce the risk of hospitalization.(25)
Figure
The synthesis of selexipag began with condensation of commercially available benzil (51) and glycinamide hydrochloride in the presence of concentrated sodium hydroxide in refluxing MeOH to yield hydroxypyrazine 52. This compound was subsequently converted to 5-chloro-2,3-diphenylpyrazine (53) upon treatment with refluxing POCl3 in the presence of a catalytic amount of H2SO4.(26) Chloride 53 was then subjected to neat 4-(isopropylamino)-1-butanol (54, prepared by the reductive alkylation of 4-amino-1-butanol and acetone with hydrogen over PtO2 in EtOH) at 190 °C to give aminopyrazinyl alcohol 55 in 56% yield as colorless crystals. Alcohol 55 was alkylated with tert-butyl bromoacetate using Bu4NHSO4 as a phase-transfer catalyst and 40% aqueous KOH in benzene to give ester 56. Although it is particularly unusual to employ benzene on a production scale, these are the only reported conditions for this transformation. The crude ester 56 was then saponified using methanolic sodium hydroxide to yield the corresponding carboxylic acid 57 in 62% as pale-yellow crystals in two steps from compound 55. Finally, the carboxylic acid 57 was coupled with methanesulfonamide in the presence of CDI and DBU in THF to give selexipag (VI) in 77% yield.(27
  1. 24.AsakiT.KuwanoK.MorrisonK.GatfieldJ.HamamotoT.ClozelM. Selexipag: An Oral and Selective IP Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension J. Med. Chem. 2015,587128– 7137 DOI: 10.1021/acs.jmedchem.5b00698

  2. 25.Skoro-SajerN.LangI. M. Selexipag for the Treatment of Pulmonary Arterial Hypertension Expert Opin. Pharmacother. 201415429– 436 DOI: 10.1517/14656566.2014.876007

  3. 26.KarmasG.SpoerriP. E. The Preparation of Hydroxypyrazines and Derived Chloropyrazines J. Am. Chem. Soc. 1952741580– 1584 DOI: 10.1021/ja01126a070

  4. 27.AsakiT.HamamotoT.SugiyamaY.KuwanoK.KuwabaraK. Structure-activity Studies on Diphenylpyrazine Derivatives: a Novel Class of Prostacyclin Receptor Agonists Bioorg. Med. Chem. 2007,156692– 6704 DOI: 10.1016/j.bmc.2007.08.010

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder


 

FDA approves first treatment Firdapse (amifampridine) for Lambert-Eaton myasthenic syndrome, a rare autoimmune disorder

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/UCM627093.htm?utm_campaign=11282018_PR_FDA%20approves%20treatment%20for%20LEMS&utm_medium=email&utm_source=Eloqua

 

November 28, 2018

Release

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a rare autoimmune disorder that affects the connection between nerves and muscles and causes weakness and other symptoms in affected patients. This is the first FDA approval of a treatment for LEMS.

“There has been a long-standing need for a treatment for this rare disorder,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Patients with LEMS have significant weakness and fatigue that can often cause great difficulties with daily activities.”

In people with LEMS, the body’s own immune system attacks the neuromuscular junction (the connection between nerves and muscles) and disrupts the ability of nerve cells to send signals to muscle cells. LEMS may be associated with other autoimmune diseases, but more commonly occurs in patients with cancer such as small cell lung cancer, where its onset precedes or coincides with the diagnosis of cancer. The prevalence of LEMS is estimated to be three per million individuals worldwide.

The efficacy of Firdapse was studied in two clinical trials that together included 64 adult patients who received Firdapse or placebo. The studies measured the Quantitative Myasthenia Gravis score (a 13-item physician-rated categorical scale assessing muscle weakness) and the Subject Global Impression (a seven-point scale on which patients rated their overall impression of the effects of the study treatment on their physical well-being). For both measures, the patients receiving Firdapse experienced a greater benefit than those on placebo.

The most common side effects experienced by patients in the clinical trials were burning or prickling sensation (paresthesia), upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, elevated liver enzymes, back pain, hypertension and muscle spasms. Seizures have been observed in patients without a history of seizures. Patients should inform their health care provider immediately if they have signs of hypersensitivity reactions such as rash, hives, itching, fever, swelling or trouble breathing.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Firdapse also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Firdapse to Catalyst Pharmaceuticals, Inc.

///////////Priority Review,  Breakthrough Therapy,  Firdapse,  Orphan Drug designation, fda 2018, amifampridine

VIXOTRIGINE, раксатригин , راكساتريجين , 维索曲静 ,


Raxatrigine.svg

Vixotrigine.png

VIXOTRIGINE

  • Molecular FormulaC18H19FN2O2
  • Average mass314.354 Da
  • раксатригин , راكساتريجين , 维索曲静 ,
(5R)-5-{4-[(2-Fluorobenzyl)oxy]phényl}-L-prolinamide
10287
2-Pyrrolidinecarboxamide, 5-[4-[(2-fluorophenyl)methoxy]phenyl]-, (2S,5R)-
934240-30-9 [RN]
QQS4J85K6Y
Raxatrigine
UNII:QQS4J85K6Y

Vixotrigine (INNUSAN), formerly known as raxatrigine (INNUSAN), is an analgesic which is under development by Convergence Pharmaceuticals for the treatment of lumbosacral radiculopathy (sciatica) and trigeminal neuralgia (TGN).[1][2][3] Vixotrigine was originally claimed to be a selective central Nav1.3 blocker, but was subsequently redefined as a selective peripheral Nav1.7 blocker.[4]Following this, vixotrigine was redefined once again, as a non-selective voltage-gated sodium channel blocker.[4] As of January 2018, it is in phase III clinical trials for trigeminal neuralgia and is in phase II clinical studies for erythromelalgia and neuropathic pain.[5] It was previously under investigation for the treatment of bipolar disorder, but development for this indication was discontinued.[5]

WO2018085521 , claiming novel dosage regimen, assigned to Biogen Inc and Biogen Ma Inc , naming a different team. Biogen, following the acquisition of Convergence Pharmaceuticals , that previously acquired clinical assets from GlaxoSmithKline , is developing vixotrigine ( phase 2 , in November 2018), a voltage-gated sodium channel 1.7 inhibitor, for treating neuropathic pain associated with trigeminal neuralgia, and small fibre neuropathy

PATENT

WO 2011/029762.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011029762

Preparation 1 : Methyl 4-(2-fluorobenzyloxy)benzoate (P1)

Methylparaben (8.85 g, 58.19 mmol) and K2CO3 (16.1 g, 1 16.38 mmol) were stirred in acetonitrile (100 mL) for 5 minutes and then 2-fluorobenzyl bromide (10 g, 52.9 mmol) was added. The suspension was heated to 50-55 °C and held for 2 hours. The mixture was then cooled to 20-25 °C, filtered, and the filtrate solution concentrated to a thick residue. The residue was then dissolved in CH2CI2, washed with a 1 M Na2CO3 solution, dried over Na2SO4, and concentrated to a solid. The solid was then stirred vigorously for 1 hour in just enough hexanes to allow for agitation (~40 mL) and then cooled to 0-5 °C. After 15 minutes, the product was isolated by filtration and washed with -25 mL of hexanes. After drying under vacuum, 1 was isolated as a white solid (13.1 g, 87% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.96-7.90 (2H, m), 7.57 (2H, apparent td, J = 7.7, 1.8 Hz),

7.48-7.39 (1 H, m), 7.30-7.21 (2H, m), 7.17-7.12 (2H, m), 5.22 (2H, s), 3.81 (3H, s).

13C NMR (100 MHz, DMSO-d6) δ 166.2, 162.4, 160.8 (d, J = 247 Hz), 131.6, 131.1 (d, J = 3.8

Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.5 (d, J = 14.1 Hz), 122.6, 1 15.8 (d, J =

21.0 Hz), 115.0, 64.2 (d, J = 3.4 Hz), 52.2.

LRMS (m/e) : 261.3 [MH]+.

Preparation 2: 4-(2-fluorobenzyloxy)benzoic acid (P2).

Methyl 4-(2-fluorobenzyloxy)benzoate (P1 , 10.0 g, 26.9 mmol) was dissolved in methanol (60 mL) and THF (90 mL). A 45 wt% potassium hydroxide solution (20 mL) was then added and

the resulting exotherm was controlled by a water bath. After 1.5 days at 20-25 °C the solution became a thick suspension. Using a water bath to control the exotherm, 20 mL of concentrated HCl was added. The mixture was then concentrated to remove the THF and methanol and 150 mL water was added. The solid was isolated by filtration and washed with 50 mL water. After drying under vacuum, the title compound was isolated as a white crystalline solid (9.4 g, 99% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.95-7.89 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.16-7.10 (2H, m), 5.22 (2H, s).

13C NMR (100 MHz, DMSO-d6) δ 167.3, 162.1 , 160.8 (d, J = 246 Hz), 131.7, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.3 Hz), 124.9 (d, J = 3.4 Hz), 123.8, 123.6, 115.8 (d, J = 21.0 Hz), 114.9, 64.2 (d, J = 3.4 Hz).

LRMS (m/e) 247.2 [MH]+.

Preparation 3: 4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3).

4-(2-fluorobenzyloxy)benzoic acid (P2, 5.5 g, 22.3 mmol) was suspended in thionyl chloride (16.5 mL) and heated to 65 °C and held for 3 hours during which time the reactor was kept under a slow sweep of nitrogen. The mixture was then concentrated to a thick oil under hi vac to remove all traces of residual thionyl chloride. The residue was then diluted in CH2CI2 (20 mL) and cooled to 0 °C. In a separate flask, a solution of diaza(1 ,3)bicycle[5.4.0]undecane (DBU, 8.0 mL, 8.15 g, 53.52 mmol) and N-methoxy-N-methyl amine hydrochloride (2.61 g, 26.76 mmol) in CH2CI2 (20 mL) was made and slowly added to the solution at 0 °C. After warming to 20-25 °C, the mixture was washed with 1 M HCl and then with a saturated NaHCO3 solution. After drying over Na2SO4, the solution was concentrated to a thick residue. The mixture was then purified by flash column chromatography eluting with 0→ 100% EtOAc/hexanes (gradient). Concentration of the fractions containing the title compound gave an oil that crystallized upon standing (6.0 g, 93% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.66-7.62 (2H, m), 7.58 (2H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.41 (1 H, m), 7.30-7.23 (2H, m), 7.12-7.07 (2H, m), 5.20 (2H, s), 3.55 (3H, s), 3.25 (3H, s).

13C NMR (100 MHz, DMSO-d6) δ 168.9, 168.0 (d, J = 246 Hz), 163.0, 131.2 (d, J = 3.8 Hz), 130.9 (d, J = 8.2 Hz), 130.4, 126.9, 124.9 (d, J = 3.4 Hz), 123.8 (d, J = 14.8 Hz), 115.8 (d, J = 21.0 Hz), 114.4, 64.0 (d, J = 3.8 Hz), 60.9, 33.8.

LRMS (m/e) 290.3 [MH]+.

Preparation 4: 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4).

4-(2-fluorobenzyloxy)-N-methyl-N-methoxybenzamide (P3, 6.0 g, 20.7 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. A 1.0 M solution of vinyl magnesium bromide in THF (31 mL, 31 mmol) was added and the cold bath was removed. Upon warming to 20-25 °C, the mixture was poured into a vigorously stirred solution of 1 M HCl. The resulting mixture was extracted twice with CH2CI2. The combined organic layers were then washed with 1 M HCl, then with a saturated NaHCO3 solution, dried over Na2SO4, and concentrated to a thick residue. The product was purified by flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 4 gave an oil that crystallized upon standing (4.83 g, 91% yield).

1H NMR (400 MHz, DMSO-d6) δ 8.06-8.01 (2H, m), 7.59 (1 H, apparent td, J = 7.5, 1.7 Hz), 7.48-7.38 (2H, m), 7.30-7.22 (2H, m), 7.21-7.16 (2H, m), 6.32 (1 H, dd, J = 17.0, 2.0 Hz), 5.92 (1 H, dd, J = 10.5, 2.0 Hz), 5.26 (2H, s).

13C NMR (100 MHz, DMSO-d6) δ 188.3, 162.6, 160.8 (d, J = 246 Hz), 132.5, 131.3, 131.2 (d, J = 3.8 Hz), 131.0 (d, J = 8.2 Hz), 130.3, 129.7, 124.9 (d, J = 3.1 Hz), 123.6 (d, J = 14.4 Hz), 115.8 (d, J = 21.0 Hz), 115.2, 64.3 (d, J = 3.4 Hz).

LRMS (m/e) 257.3 [MH]+.

Preparation 6: Ethyl-5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2- carboxylate (P5)

(S)-4-lsopropyl-2-[(S)-2-(diphenylphosphino) ferrocen-1-yl]oxazoline (18.8 mg, 0.039 mmol) and Cu(MeCN)4PF6 (14.5 mg, 0.039 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (5.0 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -78 °C and a solution of 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one (P4, 2.0 g, 7.80 mmol) and ethyl N-(diphenylmethylidene)glycinate (2.29 g, 8.58 mmol) in THF (15 mL total volume) was added over 1-2 minutes. After 3-5 minutes, a solution of DBU (5.9 mg, 0.039 mmol) in THF (0.5 mL total volume) was added. The solution was then stirred for 8-12 hours at -78 °C. The reaction mixture was then warmed to 0-5 °C and 1 M H2SO4 (aq., 25 mL) was then added. The reaction mixture was then warmed to 20-25 °C and mixed vigorously for 2 hours. The mixture was then poured into a rapidly stirring solution of NaHCO3 (saturated, enough to bring the pH to≥ 7.0). After 5minut.es of stirring, the mixture was extracted twice with TBME and the organic extracts were pooled, dried over Na2SO4, and concentrated to near dryness. The resulting residue was purified by flash column chromatography eluting with 0→ 40% acetone/hexanes (gradient). Concentration of the fractions containing the title compound gave a crystalline solid (2.23 g, 84% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.85-7.80 (2H, m), 7.58 (1H, apparent td, J = 7.5, 1.7 Hz), 7.47-7.41 (1 H, m), 7.30-7.22 (2H, m), 7.13-7.09 (2H, m), 5.21 (2H, s), 4.82-4.76 (1 H, m), 4.14 (2H, q, J = 7.1 Hz), 3.13-3.02 (1 H, m), 2.98-2.87 (1 H, m), 2.32-2.21 (1 H, m), 2.09-1.98 (1 H, m), 1.22 (3H, t, J = 7.02 Hz).

13C NMR (100 MHz, DMSO-d6) δ 174.8, 173.1 , 160.8 (d, J = 246 Hz), 160.6, 131.1 (d, J = 3.8 Hz), 130.9 (d, J = 8.3 Hz), 130.0, 127.1 , 124.9 (d, J = 3.1 Hz), 123.9 (d, J = 14.4 Hz), 1 15.8 (d, J = 21.0 Hz), 115.0, 74.2, 64.0 (d, J = 3.8 Hz), 60.7, 35.3, 26.6, 14.4.

LRMS (m/e) 342.4 [MH]+.

Preparation 6: 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6).

1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one may be prepared from N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide using analogous procedures as those described above for the preparation of P4. N-methyl-N-(methyloxy)-4-[(phenylmethyl)oxy]benzamide may be prepared according to procedures known from the literature (Cowart, M. et. al. J. Med. Chem. 2005, 48, 38).

1H NMR (400 MHz, DMSO-d6) δ 8.05-8.00 (2H, m), 7.50-7.32 (6H, m), 7.18-7.14 (2H, m),

6.32 (1 H, dd, J = 16.9, 2.1 Hz), 5.92 (1 H, dd, J = 10.5, 2.1 Hz), 5.23 (2H, s).

13C NMR (100 MHz, DMSO-d6) d 188.3, 162.8, 136.8, 132.5, 131.3, 130.1 , 129.6, 128.9,

128.4, 128.2, 115.3, 69.9.

LRMS (m/e) 239.3 [MH]+.

Praparation 7a and 7b Ethyl (2R)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7a) and Ethyl (2S)-2-[(diphenylmethylidene)amino]-5-(4-[2-fluorobenzyloxy]phenyl)-5-oxopentanoate (P7b).

 

The Ligand (according to Table 1 below reported, 0.0084 mmol) and Cu(MeCN)4PF6 (3.13 mg, 0.0084 mmol) were added to a dried, nitrogen swept reaction vessel. Anhydrous, degassed, BHT inhibited THF (0.4 mL) was then added and the mixture was stirred for 30 minutes at 20-25 °C. The resulting solution was then cooled to -20 to -21 °C and a solution of 1-{4-[(phenylmethyl)oxy]phenyl}-2-propen-1-one (P6, 100mg, 0.42 mmol) and ethyl N-(diphenylmethylidene)glycinate (123.5 mg, 0.462 mmol) in THF (0.5 mL total volume) was added over 1-2 minutes. After 1-5 minutes, a solution of DBU (1.27 mg, 0.0084 mmol) in THF (0.1 mL total volume) was added. The solution was then stirred for 8-12 hours at -20 to -25 °C. After this time the reactions were complete and an aliquot of each reaction mixture was diluted in 10% iPrOH / hexanes and analyzed by chiral HPLC. An analytically pure sample was obtained by subjecting the concentrated reaction mixture to flash column chromatography eluting with 0→ 40% acetone hexanes (gradient). Concentration of the fractions containing 7a and 7b (94:6) gave a thick syrup (187 mg, 88% yield).

1H NMR (400 MHz, DMSO-d6) δ 7.91-7.86 (2H, m), 7.54-7.32 (13H, m), 7.13-7.07 (4H, m), 5.20 (2H, s), 4.11-4.05 (2H, m), 4.02 (1 H, dd, J = 8.0, 4.8 Hz), 3.01-2.91 (2H, m), 2.27-2.21 (1 H, m), 2.14-2.08 (1 H, m), 1.16 (3H, t, J = 7.2 Hz).

13C NMR (100 MHz, DMSO-d6) δ 197.3, 171.2, 170.0, 162.1 , 138.8, 136.5, 135.6, 130.5, 130.1 , 129.6, 128.7, 128.6, 128.5, 128.2, 128.1 , 128.0, 127.7, 127.3, 114.6, 69.4, 63.8, 60.5, 33.6, 27.7, 14.0.

Example 1: (5R)-5-(4-[2-fluorobenzyioxy]phenyl)-L-prolinamide (E1)

A mixture of 5% Pt/C (Johnson Mathey B102022-5, 100 mg) was added to a solution of Ethyl -5-(4-[2-fluorobenzyloxy]phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate (P5, obtained as above reported, 1.0 g, 2.93 mmol) in ethanol (12 mL). Acetic acid (1.2 ml.) was then added and the reaction vessel was purged with N2 and then H2. The mixture was hydrogenated at 50 psi of H2 at 15-20 °C for at least 2h. Upon completion of the reaction (monitored by H2 uptake), the mixture was filtered through celite, then through a 0.2 μm PTFE filter and concentrated to approximately 1.5 mL. The mixture was diluted with 1 :1 iPrOAc/TBME and washed with a saturated solution of NaHCO3. After concentrating the organics to a thick residual oil (986mg, 98% crude yield; LCMS retention time 2.04 minutes, calculated 344.4 [MH]+, found 344.3 [MH]+), a solution of ammonia in methanol (ca 7 M) was added in two portions (4 mL initially and then 1 mL after ~10 hrs). After the additions were complete, the reaction stirred for at least 24 hrs at 15-20 °C. Upon completion of the reaction, the mixture was concentrated to dryness. The solid was suspended in a mixture of toluene/TBME 1 :1 (~4 mL) at 18-23 °C with vigorous mixing. After 2hrs at 18-23 °C, the mixture was cooled to 0-5 °C and held for 1 hr. The solid was isolated by filtration and washed with TBME (~4 mL). Drying the solid in a vacuum oven at approximately 40 °C gave the title compound as an off white-solid (720 mg, 78% yield from P5).

Analysis of the sample obtained, performed on CHIRALCEL OJ analytical HPLC column (10% iPrOH/hexanes, 1 mL/min, rt), revealed the presence in minor amounts of (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide (enantiomer of the title compound); retention times: (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide 36.3 min (1.2%), E1 41.8 min (98.8%).

1H NMR (400 MHz, DMSO-d6) δ 7.55 (1 H, apparent td, J = 7.6, 1.6 Hz), 7.45-7.32 (4H, m), 7.29-7.21 (2H, m), 7.14 (1 H, br. s), 7.00-6.95 (2H, m), 5.12 (2H, s), 4.10 (1 H, dd, J = 9.4, 5.8 Hz), 3.56 (1 H, dd, J = 9.4, 4.4 Hz), 2.14-1.96 (2H, m), 1.92-1.82 (1 H, m), 1.47-1.36 (1 H, m). 13C NMR (100 MHz, DMSO-d6) δ 177.1 , 160.3 (d, J = 246 Hz), 157.0, 137.1 , 130.6 (d, J = 3.8 Hz), 130.3 (d, J = 8.3 Hz), 127.6, 124.5 (d, J = 3.4 Hz), 124.0 (d, J = 14.4 Hz), 115.3 (d, J = 21.0 Hz), 114.4, 63.5 (d, J = 3.8 Hz), 61.7, 59.9, 34.1 , 30.4.

Example 2: (5R)-5-(4-[2-fluorobenzyloxy]phenyl)-L-prolinamide hydrochloride (E2)

To a solution of E1 ( 72 mg, 0.23 mmol) in a mixture of ethyl acetate (1.0 ml) and methanol (1.0 ml) was added 4M HCl in 1 ,4-dioxane (57.5 uL, 0.23 mmol) at 0°C. The mixture was stirred for 1.5h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (75 mg, 93% yield).

1H NMR (300 MHz, DMSO-d6) δ 10.89 (1 H, br. s), 8.12 (1 H, s), 8.1 1 (1 H, br. s), 7.73 (1 H, s), 7.60-7.39 (4H, m), 7.30-7.21 (2H, m), 7.13-7.06 (2H, m), 5.18 (2H, s), 4.66-4.56 (1 H, m), 4.36-4.28 (1 H, m), 2.42-1.94 (4H, m).

PATENT

WO-2018213686

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018213686&tab=PCTDESCRIPTION&maxRec=1000

Novel crystalline forms of vixotrigine and their anhydrous form or solvates (designated as Forms A-C), processes for their preparation and composition comprising them are claimed.

The hydrochloride salt of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, herein referred to as the compound of formula (I):

(I)

is described in WO 2007/042239 as having utility in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels. The synthetic preparation of (2S, 5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide hydrochloride is described in both WO 2007/042239 and WO 2011/029762.

However, there is a need for the development of crystalline forms of such a-carboxamide pyrrolidine derivatives, which have desirable pharmaceutical properties

Example 1 : (5/?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride (E1 )

. HCI

The compound of Example 1 may be prepared as described in Example 2,

Procedures 1 to 5 of WO 2007/042239.

Example 2: (5 ?)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide hydrochloride Form 1 (Anhydrous A) (E2)

25.0 mg of Example 1 was added to a 3 mL scintillation vial. THF (2.00 mL) was added and the resulting suspension stirred for 10 minutes. The suspension was filtered through a 0.45 μηι PTFE filter and the filtrate vial placed inside a 20 mL scintillation vial. Hexanes (2 mL) were placed in the outer vial, the entire system sealed and stored at room temperature for 3 days, after which time a crop of colorless crystals was evident in the 3 mL vial. One of these crystals was selected for a single crystal X-ray diffraction experiment. Full characterisation is shown in Figures 1 and 2 and Tables 1 and 2 below

References

  1. Jump up^ Convergence Pharmaceuticals. “CNV1014802 – Convergence Pharmaceuticals”.
  2. Jump up^ Stephen McMahon; Martin Koltzenburg; Irene Tracey; Dennis C. Turk (1 March 2013). Wall & Melzack’s Textbook of Pain: Expert Consult – Online. Elsevier Health Sciences. p. 508. ISBN 0-7020-5374-0.
  3. Jump up^ Bagal, Sharan K.; Chapman, Mark L.; Marron, Brian E.; Prime, Rebecca; Ian Storer, R.; Swain, Nigel A. (2014). “Recent progress in sodium channel modulators for pain”. Bioorganic & Medicinal Chemistry Letters24 (16): 3690–9. doi:10.1016/j.bmcl.2014.06.038ISSN 0960-894XPMID 25060923.
  4. Jump up to:a b Keppel Hesselink, Jan M. (2017). “Moving targets in sodium channel blocker development: the case of raxatrigine: from a central NaV1.3 blocker via a peripheral NaV1.7 blocker to a less selective sodium channel blocker”. Journal of Medicine and Therapeutics1 (1). doi:10.15761/JMT.1000104ISSN 2399-9799.
  5. Jump up to:a b https://adisinsight.springer.com/drugs/800027679

External links

Vixotrigine – AdisInsight

Vixotrigine
Raxatrigine.svg
Clinical data
Synonyms Raxatrigine; CNV1014802; GSK-1014802; BIIB 074
Routes of
administration
By mouth
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C18H19FN2O2
Molar mass 314.354 g/mol
3D model (JSmol)
Patent ID

Title

Submitted Date

Granted Date

US2017304265 Paroxysmal Extreme Pain Disorder Treatment
2015-10-02
US2017096708 DIAGNOSTIC METHOD
2015-06-03
Patent ID

Title

Submitted Date

Granted Date

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2015-12-23
US9006271 5-[5-[2-(3, 5-BIS(TRIFLUOROMETHYL)PHENYL)-2-METHYLPROPANOMETHYLPROPANOYLMETHYLAMINO]-4-(4-FLUORO-2-METHYLPHENYL)]-2-PYRIDINYL-2-ALKYL-PROLINAMIDE AS NK1 RECEPTOR ANTAGONISTS
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2014-06-24
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2015-10-02
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Patent ID

Title

Submitted Date

Granted Date

US8093268 PHARMACEUTICAL COMPOSITIONS COMPRISING 2-METHOXY-5-(5-TRIFLUOROMETHYL-TETRAZOL-1-YL-BENZYL)-(2S-PHENYLPIPERIDIN-3S-YL-)
2010-05-06
2012-01-10
US2010105688 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
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2010-04-29
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2009-12-24
US7655693 Compounds
2008-11-13
2010-02-02
Patent ID

Title

Submitted Date

Granted Date

US7855218 Compounds
2008-12-11
2010-12-21
US2017340646 Methods and Compositions for Decreasing Gastric Emptying
2017-08-18
US9763955 Methods and Compositions for Decreasing Gastric Emptying
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2012-11-20
2014-09-02
US8143306 Methods of treating bipolar disorders
2011-04-28
2012-03-27
Patent ID

Title

Submitted Date

Granted Date

US8633214 Spiro (piperidine-4, 2′-pyrrolidine)-1-(3, 5-trifluoromethylphenyl) methylcarboxamides as NK1 tachikynin receptor antagonists
2012-11-21
2014-01-21
US8344005 5-[5-[2-(3, 5-BIS(Trifluoromethyl)Phenyl)-2-MethylpropanoMethylpropanoylmethylamino]-4-(4-Fluoro-2-Methylphenyl)]-2-Pyridinyl-2-Alkyl-Prolinamide As NK1 Receptor Antagonists
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US8367692 Spiro (Piperidine-4, 2′-Pyrrolidine)-1-(3, 5-Trifluoromethyl Phenyl) Methylcarboxamides As NK1 Tachikynin Receptor Antagonists
2011-03-03
US8153623 Compounds
2010-12-23
2012-04-10
US2009286836 Novel Compounds
2009-11-19

////////////VIXOTRIGINE, раксатригин , راكساتريجين , 维索曲静 , QQS4J85K6Y, Raxatrigine, UNII:QQS4J85K6Y

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