New Drug Approvals

Home » Phase3 drugs

Category Archives: Phase3 drugs

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,059,168 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,205 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,205 other followers

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

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

Remimazolam


Remimazolam.svgChemSpider 2D Image | Remimazolam | C21H19BrN4O2GHUYIIGPWBMOGY-KRWDZBQOSA-N.png

Figure imgf000062_0002

Remimazolam

  • Molecular FormulaC21H19BrN4O2
  • Average mass439.305 Da
3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propionic acid methyl ester
CNS-7056
methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-1-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
methyl 3-[(7S)-12-bromo-3-methyl-9-(pyridin-2-yl)-2,5,8-triazatricyclo[8.4.0.02,6]tetradeca-1(14),3,5,8,10,12-hexaen-7-yl]propanoate
MFCD18633229
UNII:7V4A8U16MB

CAS 308242-62-8 [RN]

PHASE 3, PAION, Anesthesia

4H-Imidazo[1,2-a][1,4]benzodiazepine-4-propanoic acid, 8-bromo-1-methyl-6-(2-pyridinyl)-, methyl ester, (4S)-

7V4A8U16MB
9232
Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate
methyl 3-[(4S)-8-bromo-2-methyl-6-pyridin-2-yl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl]propanoate
D0L5KU; GTPL8442; SCHEMBL13862667; Short-acting sedatives, Therasci; CNS-7056B; CNS-7056X
  1. CNS 7056
  2. methyl 3-(8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazo(1,2-a)(1,4)benzodiazepin-4-yl)propanoate
  3. ONO 2745
  4. ONO-2745
  5. ONO2745

Remimazolam[1] (CNS-7056) is a benzodiazepine derivative drug, developed by PAION, in collaboration with Japanese licensee Ono Pharmaceutical as an alternative to the short-acting imidazobenzodiazepine midazolam, for use in induction of anaesthesia and conscious sedation for minor invasive procedures. Remimazolam was found to be both faster acting and shorter lasting than midazolam, and human clinical trials showed a faster recovery time and predictable, consistent pharmacokinetics, suggesting some advantages over existing drugs for these applications.[2][3]

Remimazolam (CNS-7056) is a water-soluble, rapid and short-acting GABA (A) benzodiazepine (BZ) site receptor agonist in phase III trials at PAION as procedural sedation in patients undergoing colonoscopy or diagnostic endoscopy of the upper gastrointestinal tract, and also with patients undergoing bronchoscopy.

PAION AG and its subsidiary PAION Inc, following its acquisition of CeNeS Pharmaceuticals (following CeNeS’ acquisition of TheraSci ), and licensees Mundipharma , Yichang Humanwell Pharmaceutical , Pendopharm , Cosmo and R-Pharm are developing remimazolam, the lead from a series of short-acting GABA A receptor agonists, as an iv sedative and/or anesthetic for potential use in day case surgical and non-surgical procedures

Image result for remimazolam

(Salt/Parent)
1
Remimazolam [INN]
308242-62-8
2D chemical structure of 308242-62-8
MW: 439.3111
2
Remimazolam besilate
1001415-66-2
2D chemical structure of 1001415-66-2
MW: 597.4875
3
Remimazolam tosylate
1425904-79-5
2D chemical structure of 1425904-79-5
MW: 611.5143

Trials

Phase I[4] and Ib[5] dose-finding studies for procedural sedation with patients recovering faster from remimazolam than midazolam. Phase II trials comparing remimazolam to the standard anesthesia protocols for cardiac surgery and colonoscopy were presented at major conferences in October 2014.[6]

A phase IIa trial comparing remimazolam to midazolam for upper endoscopy was published in December 2014, finding a similar safety profile.[7] Remimazolam was originally discovered in the late 1990s at Glaxo Wellcome in their labs in Research Triangle Park, NC.

BY CHENGDU

WO-2018103119

Novel crystalline forms of hydrobromate salt of remimazolam , processes for their preparation and compositions comprising them are claimed.

Remazolam, whose structure is shown in formula (I), has the chemical name 3-[(4S)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole [1,2] -a] methyl [1,4]benzodiazepin- 4-yl]propanoate.
This compound is currently known as a CNS (Central Nervous System) inhibitor and has sedative, hypnotic, anxiolytic, muscle relaxing, and anticonvulsant effects. It is currently used intravenously in the following clinical treatment programs: preoperative sedation, anxiolysis and forgetfulness during surgery; awake sedation during short-term diagnosis, surgery, or endoscopic procedures; and administration of other anesthetics and analgesia Before and/or at the same time as a component for induction and maintenance of general anesthesia; ICU sedation and the like. It is reported in patent application CN101501019 that the free base stability of the compound is poor, and it is only suitable for storage at a low temperature of 5°C. Under conditions of 40°C/75% relative humidity (open), the sample is deliquescent and discolored, and the content is significantly reduced.
Due to the stability problem of the free base of the compound, researchers from various countries have studied the salts of the compound. For example, patent applications CN101501019B and WO2008/007081A1 respectively report the besylate and ethanesulfonate of the compound of formula (I). And shows that the above salts have good thermal stability, low hygroscopicity, and high water solubility, and that CN104968348A clearly states that the above benzenesulfonates and ethanesulfonates are the most preferred compounds of formula (I). Salts.
Immediately afterwards, CN 103221414B proposes a toxilate salt of a compound of formula (I) and indicates that the toxitic acid salt is less toxic than benzene sulphonate, and the thermal stability, water solubility and the like of certain crystal forms are even higher. For good.
To sort out the existing technology information, you can draw the following related content (Table 1):
Table 1
From the above table, it can be seen that regardless of whether it is a free base of remazolam or a known salt derivative of remazolam, the water solubility is not higher than 11 mg/ml, and only in the slightly soluble range, which will increase The safety risk of its use in clinical use requires resolving and dissolving for a long time during clinical reconstitution. It may also leave insoluble materials, resulting in inaccurate drug dosage and potential safety risks. In addition, it is used for general anesthesia. Indications with a large demand will increase the amount of diluent and cause extreme inconvenience for clinical use. Therefore, the solubility of the known salt derivatives of remazolam is a big disadvantage and needs to be further improved.
The raw material remazolam of the compound of the formula (I) used in the present invention can be obtained by purchasing a commercially available product or can be prepared according to a known method (for example, patent US200,700,934,75A, etc.).
Example 1 Preparation of Form III Hydrobromide Salt of Compound of Formula (I)
Accurately weigh 1.8 g of the compound of formula (I) into a 100 mL three-necked flask, add 8.2 mL of isopropanol and stir to dissolve it completely, then dissolve 0.83 g of 47% aqueous hydrobromic acid in 6.3 mL of isopropanol and drip To the solution of the compound of formula (I) in isopropanol, the crystals were stirred, filtered, and dried at 55°C under reduced pressure to give the hydrobromide salt of the compound of formula (I).
The X-ray diffraction pattern of this crystal is shown in FIG. 1, the DSC and TGA patterns are shown in FIG. 2, and the melting point is 163 DEG C. It is defined that the crystal form is the hydrobromide III crystal form of the compound of Formula (I).

PATENT

WO0069836

Family members of remimazolam’s product case WO0069836 , have production in most of the EU states until May 2020 and expire in the US in April 2020.

PRODUCT PATENT

WO 2000069836

https://encrypted.google.com/patents/WO2000069836A1?cl=en

Inventors Paul L. FeldmanDavid Kendall JungIstvan KaldorGregory J. PacofskyJeffrey A. StaffordJeffrey H. TidwellLess «
Applicant Glaxo Group Limited

Example Ic-8

Methyl 3-[(4S)-8-bromo-l-methyl-6-(2-pyridinyl)-4H-imidazo[l,2- a] [ 1 ,4]benzodiazepin-4-yl]propanoate

Figure imgf000062_0002

A solution of the C7-bromo-benzodiazepine Ex 1-10 (7.31 g, 18.2 mmol) in THF (21 mL) was added to a suspension of NaH (870 mg of 60% oil dispersion, 21.8 mmol) in THF (70 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, warmed to room temperature and stirred for 30 min, then cooled to 0 °C. Bis- morpholinophosphorochloridate (6.48 g, 25.5 mmol) was added, the mixture was allowed to warm to room temperature over 4.5 h, and the mixture was filtered with additional THF (ca. 10 mL). A mixture of the filtrate and DL-l-amino-2-propanol (2.80 mL, 36.4 mmol) was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was diluted with EtOAc (ca. 250 mL), washed with saturated aqueous NaHCO3 (1 x 75 mL), H2O (2 x 75 mL), saturated aqueous NaCl (1 x 75 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19:1 EtOAc-MeOH, gave 3.06 g

(37%) of the adduct as a foam; ESIMS 459 (M+H, base).

A mixture of DMSO (1.88 mL, 26.6 mmol) and oxalyl chloride (1.16 mL, 13.3 mmol) in CH2C12 (40 mL) was stirred at -78 °C for 30 min. A solution of the alcohol prepared above (3.05 g, 6.64 mmol) in CH2C1 (26 mL) was added. The reaction mixture was warmed to -15 °C and stirred 1 h, cooled to -78 °C, treated with

E-3N (5.55 mL, 39.9 mmol), and allowed to warm to room temperature over 3 h. The mixture was diluted with EtOAc (ca. 500 mL), washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (1 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure to give a foam. A mixture of this foam and a catalytic amount ofp-toluenesulfonic acid was stirred at room temperature for 18h, neutralized by the addition of saturated aqueous NaHCO3 and diluted with EtOAc (ca. 500 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 (1 x 100 mL), H2O (2 x 100 mL), saturated aqueous NaCl (1 x 100 mL), dried (Na SO ), and concentrated under reduced pressure. Purification by flash chromatography, elution with 19: 1 EtOAc-

MeOH, gave 2.56 g (88%) of Ic-8 as a foam; 1H NMR (400 MHz, CDC13) δ 8.57 (d, J = 4.6 Hz, lH), 8.17 (d J = 7.8 Hz, IH), 7.79 (dd, J = 7.7, 6.2 Hz, IH), 7.71 (dd, J = 8.6, 2.2 Hz, IH), 7.64 (d, J – 2.2 Hz, IH), 7.34 (dd, J = 7.5, 5.0 Hz, IH), 7.30 (d, J = 8.6 Hz, IH), 6.86 (s, IH), 4.05 (m, 1 H), 3.67 (s, 3H), 2.80 (comp, 4H), 2.34 (s, 3H); ESIMS 461 (M+Na, base), 439 (M+H); Anal, calcd. for C2]H19BrN4O2-0.25 H2O: C,

58.63; H, 4.43; N, 12.62. Found: C, 56.88; H, 4.43; N, 12.23.

Example lc-8 was formulated in an aqueous vehicle at a concentration of 10 mg/ml. Accordingly, 10 mg of compound (and 9 mg NaCl) was dissolved in 0.63 ml of 0.1 N HCl. Slowly and while stirring, 0.37 ml of 0.1 N NaOH was added. Adjustments are made to the dose volume depending on the dose being administered.

PATENT

CN 103232454

https://patents.google.com/patent/CN103232454A/en

The compounds of the following formula I:

[0003]

Figure CN103232454AD00051

Wherein R1 is bromine, R2 and R3 is methyl, [0004] because it contains the specific configuration, W000 / 69836 reported in the compound (60 specification Example Ic-8) is a short-acting central nervous system (CNS) to suppress agents, including having a sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effect.They can be used for intravenous administration in the clinical treatment: preoperative sedation, such as during surgery, and forgetting anxiolytic purposes; in short diagnostic, operative or endoscopic conscious sedation during the procedure; administration of other anesthetics and analgesics before and / or simultaneously, as a component for the induction and maintenance of general anesthesia in; the ICU sedation, according CN101501019A (PA10N, application No. CN200780028964.5) reports, free base of the compound is not very stable, only suitable stored at low temperatures 5 ° C, at 40 ° C / 75% relative humidity (open) condition, the sample storage deliquescence, to the orange color turned yellow, with respect to the initial content and significantly reduced the content of the display. Thus the synthesis of salts of compounds of formula It (the I), hoping to increase the chemical stability thereof, for use in the preparation of medicaments.

[0005] existing CN101501019A and US20100075955A1 (TILBR00K) reported the benzenesulfonate salt of a compound of formula I, ethanesulfonate.CN102964349A (Henry, Application No. 201110456864.0) reported for compounds of formula ITosylate.

[0006] have reported the presence of a compound of formula I or a salt thereof concerns stability, which is disadvantageous for these compounds used in the clinical treatment of related diseases.

HPLC method [A]:

[0022] According to Chinese Pharmacopoeia 2010 Appendix VD High Performance Liquid Chromatography;

[0023] using Daicel Chrialcel OJ-H (5 μ m) 4.6 X 250mm using chiral chromatographic columns (guard column, if necessary Daicel Chrialcel OJ-H column analysis protected 5 μ m4.0 X IOmm, which is Japan Series Cat (Daicel ) brand), hexane: ethanol = 93: 7 (v / v) as the mobile phase, a flow rate of 1.0ml / min, column temperature 40 ° C, detection wavelength 225nm;

Bulk drug preparation of the present invention: [0204] Example 1

[0205] Preparation Example 4 taking the resulting compound of formula I lg, were added to 8ml of ethanol at 50 ° C – lactic acid – water (volume ratio of the three 45: 2: 53) mixed solution was stirred to dissolve; filtration, the filtrate was 5 ° C was allowed to stand at a temperature of 10~12 hours recrystallized, crystals were filtered off, 40 ° C and dried in vacuo; the above operation was repeated once, to give a compound of formula I may be formulated bulk drug used as a pharmaceutical formulation, was recrystallized twice yield rate of 86.1%.Chromatographic purity of product by HPLC 99.22% [B]; R & lt isomer impurity content of 0.39% relative peak area ratio (I / Ix) = 255 HPLC [Method A].

PATENT

EP 2305647

PATENT

WO 2011032692,

See also

References

  1. Jump up^ EP Patent 1183243
  2. Jump up^ Rogers WK, McDowell TS (December 2010). “Remimazolam, a short-acting GABA(A) receptor agonist for intravenous sedation and/or anesthesia in day-case surgical and non-surgical procedures”. IDrugs : the Investigational Drugs Journal13 (12): 929–37. PMID 21154153.
  3. Jump up^ Saari TI, Uusi-Oukari M, Ahonen J, Olkkola KT (March 2011). “Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology”. Pharmacological Reviews63 (1): 243–67. doi:10.1124/pr.110.002717PMID 21245208.
  4. Jump up^ “A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics”. Anesth. Analg.accessdate =115: 274–83. Aug 2012. doi:10.1213/ANE.0b013e31823f0c28PMID 22190555.
  5. Jump up^ “A phase Ib, dose-finding study of multiple doses of remimazolam (CNS 7056) in volunteers undergoing colonoscopy”. Anesth. Analg117: 1093–100. Nov 2013. doi:10.1213/ANE.0b013e3182a705aePMID 24108261.
  6. Jump up^ “Two Scientific Remimazolam Presentations Are Accepted for ASA and ACG Meeting in October 2014”MarketWired. Oct 1, 2014. Retrieved 2014-10-24.
  7. Jump up^ “A Phase IIa, Randomized, Double-Blind Study of Remimazolam (CNS 7056) Versus Midazolam for Sedation in Upper Gastrointestinal Endoscopy”. Anesthesia120: 771–80. Dec 11, 2014. doi:10.1213/ANE.0000000000000548PMID 25502841

PATENTS

WO2016011943A1 *2014-07-232016-01-28李勤耕New benzodiazepine derivative and use thereof

WO2000069836A1 *1999-05-142000-11-23Glaxo Group LimitedShort-acting benzodiazepines
WO2008007081A1 *2006-07-102008-01-17Cenes LimitedShort-acting benzodiazepine salts and their polymorphic forms
CN101501019A *2006-07-102009-08-05Paion英国有限公司Short-acting benzodiazepine salts and their polymorphic forms
WO2012062439A1 *2010-11-082012-05-18Paion Uk Ltd.Dosing regimen for sedation with cns 7056 (remimazolam)
CN102753525A *2009-09-182012-10-24Paion英国有限公司Process for preparing 3-[(4s)-8-bromo-1-methyl-6-(2-pyridinyl)-4h-imidazol[1,2-a][1,4]benzodiazepine-4-yl]propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process
CN102964349A *2011-08-312013-03-13江苏恒瑞医药股份有限公司Tosilate of benzodiazepine derivative, its crystal forms, their preparation method and application
Patent ID

Patent Title

Submitted Date

Granted Date

US9737547 DOSING REGIMEN FOR SEDATION WITH CNS 7056 (REMIMAZOLAM)
2017-01-06
US2015224114 DOSING REGIMEN OF SEDATIVE
2013-08-30
2015-08-13
US2015148338 COMPOSITIONS COMPRISING SHORT-ACTING BENZODIAZEPINES
2013-05-22
2015-05-28
US9777007 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2015-11-23
2016-06-23
US8642588 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2010-03-25
Patent ID

Patent Title

Submitted Date

Granted Date

US2017217965 NEW BENZODIAZEPINE DERIVATIVE AND USE THEREOF
2015-07-22
US9656987 OXIDATION REACTION EXCELLENT IN CONVERSION RATE
2014-03-03
2016-01-14
US9156842 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2010-09-15
2012-12-27
US7435730 Short-acting benzodiazepines
2007-06-14
2008-10-14
US7528127 Short-acting benzodiazepines
2007-06-14
2009-05-05
Patent ID

Patent Title

Submitted Date

Granted Date

US7485635 Short-acting benzodiazepines
2007-04-26
2009-02-03
US2015313913 POSITIVE ALLOSTERIC MODULATORS OF THE GABA-A RECEPTOR IN THE TREATMENT OF AUTISM
2014-02-04
2015-11-05
US9561236 DOSING REGIMEN FOR SEDATION WITH CNS 7056 (REMIMAZOLAM)
2011-11-07
2014-03-20
US2017044135 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2016-10-27
US9512078 PROCESS FOR PREPARING 3-[(4S)-8-BROMO-1-METHYL-6-(2-PYRIDINYL)-4H-IMIDAZO[1, 2-A][1, 4]BENZODIAZEPINE-4-YL]PROPIONIC ACID METHYL ESTER OR THE BENZENE SULFONATE SALT THEREOF, AND COMPOUNDS USEFUL IN THAT PROCESS
2015-09-01
2015-12-24
Patent ID

Patent Title

Submitted Date

Granted Date

US2017217925 PROCESS FOR PREPARING 3-[(S)-7-BROMO-2-(2-OXOPROPYLAMINO)-5-PYRIDIN-2-YL-3H-1, 4-BENZODIAZEPIN-3-YL]PROPIONIC ACID METHYL ESTER
2017-04-14
US9193730 SHORT-ACTING BENZODIAZEPINE SALTS AND THEIR POLYMORPHIC FORMS
2010-04-01
US7473689 Short-acting benzodiazepines
2007-06-14
2009-01-06
US7160880 Short-acting benzodiazepines
2007-01-09
WO0069836 SHORT-ACTING BENZODIAZEPINES
2000-11-23
Remimazolam
Remimazolam.svg
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C21H19BrN4O2
Molar mass 439.304 g/mol
3D model (JSmol)

//////////////CNS-7056 , CNS-7056X , ONO-2745  , CNS 7056 , CNS 7056X , ONO 2745, REMIMAZOLAM, PHASE 3, PHASE 3, PAION, Anesthesia, 308242-62-8

CC1=CN2C3=C(C=C(C=C3)Br)C(=NC(C2=N1)CCC(=O)OC)C4=CC=CC=N4

Advertisements

Fedratinib


Fedratinib structure.svgFedratinib.png

ChemSpider 2D Image | Fedratinib | C27H36N6O3SFigure imgf000121_0001

FEDRATINIB

SAR-302503; TG-101348, 6L1XP550I6, 936091-26-8 [RN], WHO 9707

Molecular Formula: C27H36N6O3S
Molecular Weight: 524.684 g/mol

FLT3, JAK2

http://www.ama-assn.org//resources/doc/usan/fedratinib.pdf

Fedratinib had been in phase III clincial trials by Sanofi for the treatment of myelofibrosis.

However, Sanofi had discontinued this research because of the safety issues. Orphan drug designation was assigned in the U.S. and in Japan for this indication. In 2017, the clinical hold was lifted in the U.S. by Impact Biomedicines.

MYELOFIBROSIS (MF), SANOFI , phase 3

Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-

N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide

N-tert-butyl-3-[[5-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]pyrimidin-4-yl]amino]benzenesulfonamide

USAN (AB-104) FEDRATINIB
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-
pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-
2. N-tert-butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-
yl)amino]benzenesulfonamide

MOLECULAR FORMULA C27H36N6O3S
MOLECULAR WEIGHT 524.7
SPONSOR Sanofi
CODE DESIGNATIONS SAR302503; TG101348
CAS REGISTRY NUMBER……….936091-26-8

WHO 9707

TG-101348 , a dual-acting JAK2/FLT3 small molecule kinase inhibitor, has been evaluated in phase III clinical development at Sanofi (formerly known as sanofi-aventis) for the oral treatment of intermediate-2 or high risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly. However, development of the compound has been discontinued due to safety issues.

In preclinical models of myeloproliferative diseases, TG-101348, administered orally, was shown to reduce V617F-expressing cell populations in a dose-dependent manner without adversely impacting normal hematopoiesis. The reduction of V617F- expressing cell populations correlated with improved survival and reduced morbidity. Orphan drug designation was assigned in the U.S. and in Japan for the treatment of secondary and primary myelofibrosis. In July 2010, TargeGen was acquired by Sanofi. In 2013, orphan drug designation was assigned by the FDA for the treatment of polycythemia vera.

Fedratinib is an orally bioavailable, small-molecule, ATP-competitive inhibitor of Janus-associated kinase 2 (JAK2) with potential antineoplastic activity. Fedratinib competes with JAK2 as well as the mutated form AK2V617F for ATP binding, which may result in inhibition of JAK2 activation, inhibition of the JAK-STAT signaling pathway, and the induction of tumor cell apoptosis. JAK2 is the most common mutated gene in bcr-abl-negative myeloproliferative disorders (MPDs); the mutated form JAK2V617F has a valine-to-phenylalanine modification at position 617 and plays a key role in tumor cell proliferation and survival.

Fedratinib has been used in trials studying the treatment and basic science of Solid Tumor, Myelofibrosis, Renal Impairment, Neoplasm Malignant, and Hepatic Impairment, among others.

Fedratinib (TG101348SAR302503) is an orally available inhibitor of Janus kinase 2 (JAK-2) developed for the treatment of patients with myeloproliferative diseases including myelofibrosis. Fedratinib acts as a competitive inhibitor of protein kinase JAK-2 with IC50=6 nM; related kinases FLT3 and RET are also sensitive, with IC50=25 nM and IC50=17 nM, respectively. Significantly less activity was observed against other tyrosine kinases including JAK3 (IC50=169 nM).[1] In treated cells the inhibitor blocks downstream cellular signalling (JAK-STAT) leading to suppression of proliferation and induction of apoptosis.

Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348. Phase I trial results focused on safety and efficacy of Fedratinib in patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis have been published in 2011.[2]

Fedratinib was originally discovered at TargeGen. In 2010, Sanofi-Aventis acquired TargeGen and continued development of fedratinib until 2013. In 2016, Impact Biomedicines acquired the rights to fedratinib from Sanofi and continued its development for the treatment of myelofibrosis and polycythemia vera. In January 2018, Celgene acquired Impact Biomedicines.[3]

Image result for Fedratinib SYNTHESIS

SYN

WO2007053452A1. +Bioorganic & Medicinal Chemistry Letters, 27(12), 2668-2673; 2017

Condensation of 3-bromo-N-tertbutylbenzylsulfonamide with 2-chloro-5-methyl-pyrimidin-4-ylamine  in the presence of Pd2(dba)3, Xantphos, Cs2CO3 in refluxing dioxane gives sulfonamide derivative , which is coupled with 4-[2-pyrrolidin-1-yl-ethoxy]phenylamine  in AcOH at 150°C to provide the title compound

PRODUCT PATENT

WO2007053452A1.

Inventors Jon Jianguo CaoJohn HoodDan LohseChi Ching MakPherson Andrew McGlenn NoronhaVed PathakJoel RenickRichard M. SollBinqi ZengLess «
Applicant Targegen, Inc.

https://encrypted.google.com/patents/WO2007053452A1?cl=en

EXAMPLE 90. 7V-fe^-Butyl-3-{5-methyl-2-14-(2-pyrrolidm-l-yl-ethoxy)-phenylaminol- pyrimidin-4-ylaminol-benzenesuIfonamide (Compound LVII)

Figure imgf000121_0001

LVII

[0203] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-l-yl- ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 °C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum atnount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).

[0204] 1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J= 5.8 Hz, 2H), 3.99 (t, J= 6.0 Hz, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, IH), 7.90 (s, IH), 8.10-8.15 (m, 2H), 8.53 (s, IH), 8.77 (s, IH). MS (ES+): m/z 525 (M+H)+. it ιr

PATENTS

WO 2013059548

PAPER

Bioorganic & Medicinal Chemistry Letters, 27(12), 2668-2673; 2017

PATENT

WO 2012061833

The compound and the pharmaceutical compositions described herein can be used for treating or delaying development of myelofibrosis in a subject. N-teft-Butyl-3-[(5-methyl-2-{ [4- (2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide has the following chemical structure:

Figure imgf000018_0001

Example 4. Synthesis of TG101348

Example 4.1 N-fer^-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide

(Intermediate)

Example 4.1(a)

Figure imgf000053_0001

1 2 Intermediate

[0162] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1) (0.4 g, 2.8 mmol), 3-bromo-N- teft-butyl-benzenesulfonamide (2) (1.0 g, 3.4 mmol), Pd2(dba¾ (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate

concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.

Example 4.1(b)

Figure imgf000053_0002

SM2 Intermediate[0163] The Intermediate was synthesized from 2,4-dichloro-5-methylpyrimidine (SMI) and N-t- butyl-3-aminobenzenesulfonamide (SM2) in the following steps: (1) Mix MeOH (6.7UOa) and SMI (Combi Blocks) (UOa); (2) Add SM2 (1.15UOa, 082eq) and H20 (8.5UOa); (3) Heat 45°C, 20h, N2, IPC CPL SM2<2%; (4) Cool 20°C; (5) Centrifuge, N2; (6) Wash H20 (2.1UOa) + MeOH (1.7UOa); (7) Mix solid in H20 (4.3UOa) + MeOH (3.4UOa); (8) Centrifuge, N2; (9) Wash H20 (2.1UOa) + MeOH (1.7UOa); and (10) Dry 45°C, vacuum, 15h. Obtained

Intermediate, mass 49.6kg (UOb); Yield 79%; OP: 99.6%.

Example 4.2 N-½ri-Butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l- ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide

Figure imgf000054_0001

Intermediate TG101348

Example 4.2(a)

[0164] A mixture of N-ieri-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)- benzenesulfonamide (Intermediate) (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-l-yl-ethoxy)- phenylamine (3) (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 °C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCC^ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%). ]H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, /=5.8 Hz, 2H), 3.99 (t, 7=6.0 Hz, 2H), 6.79 (d, 7=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

Example 4.2(b)

[0165] N-½ri-Butyl-3-[(5-methyl-2-{ [4-(2-pyrrolidin-l-ylethoxy)phenyl]amino}pyrimidin-4- yl)amino]benzenesulfonamide dihydrochloride monohydrate was prepared from 4-[2-(l- pyrrolidinyl)ethoxy] aniline dihydrochloride (SM3) and Intermediate following steps (A) and (B).

[0166] Step (A), preparation of free base of SM3 (3) from SM3, comprised steps (1) – (9): (1) Solubilize NaOH (0.42UOb) in H20 (9UOb); (2) Cool <20°C, N2; (3) Add TBME (6UOb) then SM3 (Malladi Drugs) (1.06UOb); (4) Mix >20mn then stop; (5) Drain Aq Ph then extract by TBME (3UOb); (6) Combine Or Ph; (7) Concentrate, vacuum, T<40°C, to an Oil; (8) Solubilize in IPA (2.5UOb); and (9) Calculate dry extract 23%.

[0167] Step (B) comprised the steps (1) – (6): (1) Mix IPA (10.5UOb) and Intermediate (UOb); (2) Add free base of SM3 (0.75UOb, 1.33eq/ interm); (3) add HC1 cone (0.413UOb); (4) Heat 70°C, 20h, N2, IPC CPL Interm<2%; (5) Cool <20°C; (2) Centrifuge, N2; (3) Wash IPA (3UOb); (4) Dry 50°C, vacuum, 26h; (5) De-lump in Fitzmill; and (6) polybag (x2) / poly drum. Obtained TG101348 dihydrochloride monohydrate, mass 83.8kg; Yield 98%; OP: 99.5%. Example 5 Capsule Form of TG101348 and Process of Making TG101348

PATENT

WO 2010017122

US 2007259904

WO 2007053452

Paper

JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms.

Treliński J, Robak T.

Curr Med Chem. 2013;20(9):1147-61.

JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation?

Santos FP, Verstovsek S.

Anticancer Agents Med Chem. 2012 Nov;12(9):1098-109. Review.

Octa-arginine mediated delivery of wild-type Lnk protein inhibits TPO-induced M-MOK megakaryoblastic leukemic cell growth by promoting apoptosis.

Looi CY, Imanishi M, Takaki S, Sato M, Chiba N, Sasahara Y, Futaki S, Tsuchiya S, Kumaki S.

PLoS One. 2011;6(8):e23640. doi: 10.1371/journal.pone.0023640. Epub 2011 Aug 10

PATENT

us2007191405

Example 90 N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide (Compound LVII)

Figure US20070191405A1-20070816-C00156

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCOsolution (30 mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SOand filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).

1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

Example 76 N-tert-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide (Intermediate 33)

Figure US20070191405A1-20070816-C00142

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)(0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.

PATENT

https://encrypted.google.com/patents/US20090286789

    Example 90N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benenesulfonamide (Compound LVII)

  • [0308]
    Figure US20090286789A1-20091119-C00143
  • [0309]
    A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in aeetie acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaIICOsolution (30 mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SOand filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
  • [0310]
    1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

PATENT

WO 2015117053

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015117053&recNum=4&maxRec=26794&office=&prevFilter=&sortOption=&queryString=FP%3A%28%22cancer%22%29+AND+EN_ALL%3Anmr&tab=PCTDescription

References

  1. Jump up^ Pardanani, A.; Hood, J.; Lasho, T.; Levine, R. L.; Martin, M. B.; Noronha, G.; Finke, C.; Mak, C. C.; Mesa, R.; Zhu, H.; Soll, R.; Gilliland, D. G.; Tefferi, A. (2007). “TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations”. Leukemia21 (8): 1658–1668. doi:10.1038/sj.leu.2404750PMID 17541402.
  2. Jump up^ Pardanani, A.; Gotlib, J. R.; Jamieson, C.; Cortes, J. E.; Talpaz, M.; Stone, R. M.; Silverman, M. H.; Gilliland, D. G.; Shorr, J.; Tefferi, A. (2011). “Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis”Journal of Clinical Oncology29 (7): 789–796. doi:10.1200/JCO.2010.32.8021PMC 4979099Freely accessiblePMID 21220608.
  3. Jump up^ “Celgene to Acquire Impact Biomedicines, Adding Fedratinib to Its Pipeline of Novel Therapies for Hematologic Malignancies (NASDAQ:CELG)”ir.celgene.com. Retrieved 2018-01-18.

External links

Cited Patent Filing date Publication date Applicant Title
WO2009073575A2 * Nov 28, 2008 Jun 11, 2009 Oregon Health & Science University Methods for treating induced cellular proliferative disorders
US20090088410 * Dec 5, 2008 Apr 2, 2009 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione in combination with other therapies
US20090286789 * Oct 14, 2008 Nov 19, 2009 Targegen, Inc. Bi-Aryl Meta-Pyrimidine Inhibitors of Kinases
Reference
1 * See also references of EP2635282A4
Citing Patent Filing date Publication date Applicant Title
US8604042 Aug 24, 2010 Dec 10, 2013 Targegen, Inc. Bi-aryl meta-pyrimidine inhibitors of kinases
Patent ID

Patent Title

Submitted Date

Granted Date

US8748428 USE OF A PKC INHIBITOR
2011-10-06
US8133900 Use of bi-aryl meta-pyrimidine inhibitors of kinases
2009-11-19
2012-03-13
US8138199 Use of bi-aryl meta-pyrimidine inhibitors of kinases
2009-11-05
2012-03-20
US2016332993 DIAMINOPYRIMIDINE BENZENESULFONE DERIVATIVES AND USES THEREOF
2015-02-02
US7825246 Bi-aryl meta-pyrimidine inhibitors of kinases
2007-11-08
2010-11-02
Patent ID

Patent Title

Submitted Date

Granted Date

US2013243853 COMPOSITIONS AND METHODS FOR TREATING MYELOFIBROSIS
2013-05-06
2013-09-19
US9198911 Methods for Treating Hair Loss Disorders
2013-05-02
2014-03-06
US9089574 ANTIVIRAL JAK INHIBITORS USEFUL IN TREATING OR PREVENTING RETROVIRAL AND OTHER VIRAL INFECTIONS
2012-11-30
2014-11-06
US2014170157 METHOD OF SELECTING THERAPEUTIC INDICATIONS
2012-06-15
2014-06-19
US2011269721 METHODS OF TREATING THALASSEMIA
2011-11-03
Patent ID

Patent Title

Submitted Date

Granted Date

US2016264732 BLOCK COPOLYMERS FOR STABLE MICELLES
2016-03-10
2016-09-15
US9763866 METHODS FOR TREATING HAIR LOSS DISORDERS
2016-03-10
2016-09-08
US9730877 METHODS FOR TREATING HAIR LOSS DISORDERS
2015-08-07
2016-03-03
US9662332 ANTIVIRAL JAK INHIBITORS USEFUL IN TREATING OR PREVENTING RETROVIRAL AND OTHER VIRAL INFECTIONS
2015-07-24
2016-02-25
US2014357557 CYCLODEXTRIN-BASED POLYMERS FOR THERAPEUTIC DELIVERY
2014-05-30
2014-12-04
Patent ID

Patent Title

Submitted Date

Granted Date

US8604042 BI-ARYL META-PYRIMIDINE INHIBITORS OF KINASES
2011-09-01
US8791100 ARYL BENZYLAMINE COMPOUNDS
2011-08-04
US7528143 Bi-aryl meta-pyrimidine inhibitors of kinases
2007-08-16
2009-05-05
US2016346408 IRON STABILIZED MICELLES AS MAGNETIC CONTRAST AGENTS
2016-05-26
US2016303205 Combination Therapies for Lysosomal Storage Diseases
2016-04-13
Fedratinib
Fedratinib structure.svg
Names
IUPAC name

Ntert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide
Other names

SAR302503; TG101348
Identifiers
3D model (JSmol)
Properties
C27H36N6O3S
Molar mass 524.68 g·mol−1
Density 1.247 ± 0.06 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

////////////////FEDRATINIB, SAR-302503,  TG-101348, SANOFI, PHASE 3, TG101348,  SAR302503, TG 101348, SAR 302503, Orphan drug designation 

CC1=CN=C(N=C1NC2=CC(=CC=C2)S(=O)(=O)NC(C)(C)C)NC3=CC=C(C=C3)OCCN4CCCC4

Larotrectinib, ларотректиниб , 拉罗替尼 ,


Image result for LarotrectinibImage result for Larotrectinib

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib

ARRY-470, LOXO-101, PF9462I9HX

Molecular Formula: C21H22F2N6O2
Molecular Weight: 428.444 g/mol
(3S)-N-{5-[(2R)-2-(2,5-Difluorphenyl)-1-pyrrolidinyl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxy-1-pyrrolidincarboxamid
(S)-N-{5-[(R)-2-(2,5-Difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl}-3-hydroxypyrrolidine-1-carboxamide
10360
1223403-58-4 [RN]
UNII:PF9462I9HX
ларотректиниб [Russian] [INN]
拉罗替尼 [Chinese] [INN]
(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide
NTRK-fusion solid tumours
TRK inhibitor
orphan drug designation in the U.S
In 2013, Array Biopharma licensed the product to Loxo Oncology for development and commercialization in the U.S. In 2016, breakthrough therapy designation was received in the U.S. for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments. In 2017, Bayer acquired global co-development and commercialization rights from Loxo Oncology.
  • Originator Array BioPharma
  • Developer Array BioPharma; Loxo Oncology; National Cancer Institute (USA)
  • Class Antineoplastics; Pyrazoles; Pyrimidines; Pyrrolidines; Small molecules
  • Mechanism of Action Tropomyosin-related kinase antagonists
  • Orphan Drug Status Yes – Solid tumours; Soft tissue sarcoma

Highest Development Phases

  • Preregistration Solid tumours
  • Phase II Histiocytosis; Non-Hodgkin’s lymphoma
  • Phase I/II CNS cancer
  • Preclinical Precursor cell lymphoblastic leukaemia-lymphoma

Most Recent Events

  • 29 May 2018 FDA assigns PDUFA action date of 26/11/2018 for larotrectinib for Solid tumors
  • 29 May 2018 Larotrectinib receives priority review status for Solid tumors in the US
  • 29 May 2018 The US FDA accepts NDA for larotrectinib for Solid tumours for review

Image result for LarotrectinibImage result for Larotrectinib

Larotrectinib sulfate

(3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;sulfuric acid

Larotrectinib (LOXO-101) sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).

    • Crystalline Form (I-HS) OF

SULFATE SALT REPORTED IN https://patents.google.com/patent/US20170165267

nmr  http://file.selleckchem.com/downloads/nmr/s796001-loxo-101-methanol-hnmr-selleck.pdf

Figure US20170165267A1-20170615-C00006Figure US20170165267A1-20170615-C00007

Molecular Weight 526.51
Formula C21H22F2N6O2.H2O4S
CAS No. 1223405-08-0
  1. LOXO-101 sulfate
  2. Larotrectinib sulfate
  3. LOXO-101 (sulfate)
  4. 1223405-08-0
  5. UNII-RDF76R62ID
  6. RDF76R62ID
  7. ARRY-470 sulfate
  8. LOXO-101(sulfate)
  9. Larotrectinib sulfate [USAN]
  10. PXHANKVTFWSDSG-QLOBERJESA-N
  11. HY-12866A
  12. s7960
  13. AKOS030526332
  14. CS-5314

LOXO-101 is a small molecule that was designed to block the ATP binding site of the TRK family of receptors, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases. IC50 value: 2 – 20 nM Target: TRKA/B/C in vitro: LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. LOXO-101 is evaluated for off-target kinase enzyme inhibition against a panel of 226 non-TRK kinases at a compound concentration of 1,000 nM and ATP concentrations near the Km for each enzyme. In the panel, LOXO-101 demonstrates greater than 50% inhibition for only one non-TRK kinase (TNK2 IC50, 576 nM). Measurement of proliferation following treatment with LOXO-101 demonstrates a dose-dependent inhibition of cell proliferation in all three cell lines. The IC50 is less than 100 nM for CUTO-3.29 and less than 10 nM for KM12 and MO-91, consistent with the known potency of this drug for the TRK kinase family. [1] LOXO-101 demonstrates potent and highly-selective inhibition of TRKA, TRKB, and TRKC over other kinase- and non-kinase targets. LOXO-101 is a potent, ATP-competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases. [2] in vivo: Athymic nude mice injected with KM12 cells are treated with LOXO-101 orally daily for 2 weeks. Dose-dependent tumor inhibition is observed, demonstrating the ability of this selective compound to inhibit tumor growth in vivo. [1]

Image result for Larotrectinib

DOI

https://doi.org/10.1038/nrd.2018.4

SYNTHESIS

WO 2010048314

Synthesis of larotrectinib

N-Boc-pyrrolidine as starting material The method involves enantioselective deprotonation, transmetalation with ZnCl2, Negishi coupling with 2-bromo-1,4-difluorobenzene,

N-arylation with 5-chloropyrazolo[1,5-a]pyrimidine, nitration, nitro reduction and condensation with CDI and 3(S)-pyrrolidinol.

PRODUCT Patent

WO 2010048314

https://patents.google.com/patent/WO2010048314A1

InventorJulia HaasSteven W. AndrewsYutong JiangGan Zhang

Original AssigneeArray Biopharma Inc.

Priority date 2008-10-22

Example 14


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide

[00423] To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difiuorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z = 429.2 (M+H).

Example 14A


(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolori,5-alpyrimidin-3-yl)- 3 -hydroxypyrrolidine- 1 -carboxamide sulfate

[00424] To a solution of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-3 -hydroxypyrrolidine- 1 -carboxamide (4.5 mg, 0.011 mmol) in methanol (1 mL) at ambient temperature was added sulfuric acid in MeOH (105 μL, 0.011 mmol). The resulting solution was stirred for 30 minutes then concentrated to provide (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3 -hydroxypyrrolidine- 1 -carboxamide sulfate (5.2 mg, 0.0099 mmol, 94 % yield) as a yellow solid.

PATENT

WO 2017201241 

Examples

Preparation of 10:

1)

(R,E)-N-(2,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide (17): Compound 16 and (R)-2-methylpropane-2-sulfinamide (1.05 eq.) were charged to a reactor outfitted with a mechanical stirrer, reflux condensor, J-Kem temperature probe under N2. DCM (3 mL/g of 14) was added (endothermic from 22 °C to about 5 °C) followed by addition of cesium carbonate (0.70 eq.) (exothermic to -50 °C). Once the addition was complete, the reaction mixture was stirred at room temperature for 3 h (slowly cools from about 40 °C). When the reaction was called complete (HPLC) the mixture was filtered through Celite. The Celite pad (0.3 wt eq) was equilibrated with DCM (1 mL/g of 16), and the reaction mixture was poured through the pad. The Celite cake was washed with DCM (2 x 1 mL/g), and the filtrate concentrated partially to leave about 0.5 to 1 mL/g DCM remaining. The orange solution was stored at room temperature (generally overnight) and used directly in the next reaction. (100% yield was assumed).

2)

(R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19): To a reactor equipped with overhead stirring, reflux condensor, under

nitrogen, was added magnesium turnings (2.0 eq), and THF (8 mL/g of 17). The mixture was heated to 40 °C. Dibal-H (25% wt in toluene, 0.004 eq) was added to the solution, and the suspension heated at 40 °C for 25 minutes. A solution of 2-(2-bromoethyl)-l,3-dioxane (18) (2 eq) in THF (4.6 mL/g of 17) was added dropwise to the Mg solution via addition funnel. The solution temperature was maintained < 55 °C. The reaction progress was monitored by GC. When the Grignard formation was judged complete, the solution was cooled to -30 °C, and 17 (1.0 eq, in DCM) was added dropwise via addition funnel. The temperature was kept between -30 °C and -20 °C and the reaction was monitored for completion (FIPLC). Once the reaction was called complete, the suspension (IT = -27.7 °C) was vacuum transferred to a prepared and cooled (10 °C) 10% aqueous citric acid solution (11 mL/g of 17). The mixture temperature rose to 20 °C during transfer. The milky solution was allowed to stir at ambient temperature overnight. MTBE (5.8 mL/g) was added to the mixture, and it was transferred to a separatory funnel. The layers were allowed to separate, and the lower aqueous layer was removed. The organic layer was washed with sat. NaHC03 (11 mL/g) and then sat. NaCl (5.4 mL/g). The organic layer was removed and concentrated to minimum volume via vacuum distillation. MTBE (2 mL/g) was added, and the mixture again concentrated to minimum volume. Finally MTBE was added to give 2 mL/g total MTBE (GC ratio of MTBE:THF was about 9: 1), and the MTBE mixture was heated to 50 °C until full dissolution occurred. The MTBE solution was allowed to cool to about 35 °C, and heptane was added portion -wise. The first portion (2 mL/g) is added, and the mixture allowed to stir and form a solid for 1-2 h, and then the remainder of the heptane is added (8 mL/g). The suspension was allowed to stir for >lh. The solids were collected via filtration through polypropylene filter cloth (PPFC) and washed with 10% MTBE in heptane (4 mL/g. The wet solid was placed in trays and dried in a vacuum oven at 55 °C until constant weight (3101 g, 80.5%, dense white solid, 100a% and 100wt%).

3)

(R)-2-(2,5-difluorophenyl)pyrrolidine (R)-2-hydroxysuccinate (10): To a flask containing 4: 1 TFA:water (2.5 mL/g, pre-mixed and cooled to <35 °C before adding 19) was added (R)-N-((R)-l-(2,5-difluorophenyl)-3-(l,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (19) (1 eq). The mixture temperature rose from 34 °C to 48 °C and was stirred at ambient temperature for 1 h. Additional TFA (7.5 mL/g) was added, followed by triethylsilane (3 eq) over 5 minutes. The biphasic mixture was stirred vigorously under nitrogen for 21 h until judged complete (by GC, <5% of imine). The mixture was then concentrated under vacuum until -10 kg target mass (observed 10.8 kg after concentration). The resulting concentrate was transferred to a separatory funnel and diluted with MTBE (7.5 mL/g), followed by water (7.5 mL/g). The layers were separated. The MTBE layer was back-extracted with 1M HC1 (3 mL/g). The layers were separated, and the aqueous layers were combined in a round-bottomed flask with DCM (8 mL/g). The mixture was cooled in an ice bath and 40% NaOH was charged to adjust the pH to >12 (about 0.5 mL/g; the temperature went from 24 °C to 27 °C, actual pH was 13), and the layers separated in the separatory funnel. The aqueous layer was back-extracted twice with DCM (2 x 4 mL/g). The organic layers were concentrated to an oil (<0.5 mL/g) under vacuum (rotovap) and EtOH (1 mL/g based on product) was added. The yellow solution was again concentrated to an oil (81% corrected yield, with 3% EtOH, 0.2% imine and Chiral HPLC showed 99.7%ee).

Salt formation: To a solution of (R)-2-(2,5-difluorophenyl)pyrrolidine 10 (1 eq) in EtOH (15 mL/g) was added Z)-(+)-Malic Acid (1 eq). The suspension was heated to 70 °C for 30 minutes (full dissolution had occurred before 70 °C was reached), and then allowed to cool to room temperature slowly (mixture was seeded when the temperature was < 40 °C). The slurry was stirred at room temperature overnight, then cooled to <5 °C the next morning. The suspension was stirred at <5 °C for 2h, filtered (PPFC), washed with cold EtOH (2 x 2 mL/g), and dried (50-55 °C) under vacuum to give the product as a white solid (96% based on 91% potency, product is an EtOH solvate or hemi- solvate).

Preparation of the compound of Formula I:

1)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazolo[l,5-a]pyrimidine (11):

Compound 5 and 10 (1.05 eq) were charged to a reactor outfitted with a mechanical stirrer, J-Kem temperature probe, under N2. EtOH and THF (4: 1, 10 mL/g of 5) were added and the mixture was cooled to 15-25 °C. Triethylamine (3.5 eq) was added and the internal temp generally rose from 17.3 – 37.8 °C. The reaction was heated to 50 – 60 °C and held at that temperature for 7 h. Once the reaction is judged complete (HPLC), water (12 mL/g of 5) is added maintaining the temperature at 50 – 60 °C. The heat is removed and the suspension was slowly cooled to 21 °C over two h. After stirring at -21 °C for 2 h, the suspension was centrifuged and the cake was washed with water (3 x 3 mL/g of 5). The solid was transferred to drying trays and placed in a vacuum oven at 50 – 55 °C to give 11.

2)

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-amine fumarate Pt/C hydrogenation (12 fumarate): To a Parr reactor was charged 11 (1.0 eq), 5% Pt/C ~ 50 wt% water (2 mol% Pt / Johnson Matthey B 103018-5 or Sigma Aldrich 33015-9), and MeOH (8 mL/g). The suspension was stirred under hydrogen at 25-30 psi and the temperature was maintained below 65 °C for ~8 h. When the reaction was called complete (HPLC), the reaction was cooled to 15 – 25 °C and the hydrogen atmosphere was replaced with a nitrogen atmosphere. The reaction mixture was filtered through a 2 micron bag filter and a 0.2 micron line filter in series. The filtrate from the Pt/C hydrogenation was transferred to a reactor under nitrogen with mechanical stirring and then MTBE (8 mL/g) and fumaric acid (1.01 eq) were charged. The mixture was stirred under nitrogen for 1 h and solids formed after -15 min. The mixture was cooled to -10 to -20 °C and stirred for 3 h. The suspension was filtered (PPFC), washed with MTBE (-2.5 mL/g), and the solids was dried under vacuum at 20-25 °C with a nitrogen bleed to yield an off-white solid (83% yield).

3)

Phenyl (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5-a]pyrimidin-3-yl)carbamate (13): To a 5 to 15°C solution of 12-fumarate (1.0 eq) in 2-MeTHF (15 mL/g) was added a solution of potassium carbonate (2.0 eq.) in water (5 mL/g) followed by phenyl chloroformate (1.22 eq.) (over 22 min, an exotherm from 7 °C to 11 °C occurred). The mixture was stirred for 2 h and then the reaction was called complete (HPLC). The stirring ceased and the aqueous layer was removed. The organic layer was washed with brine (5 mL/g) and concentrated to ca. 5 mL/g of 2-MeTHF under vacuum and with heating to 40 °C. To the 2-MeTHF solution was added heptanes (2.5 mL/g) followed by seeds (20 mg, 0.1 wt%). This mixture was allowed to stir at room temperature for 2 h (until a solid formed), and then the remainder of the heptanes (12.5 mL/g) was added. The mixture was stirred at ambient temperature for 2 h and then the solids were collected via filtration (PPFC), washed with 4: 1 heptanes :MeTHF (2 x 2 mL/g), and dried to give 13 (96%).

4)

(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate: To a flask containing 13 (1.0 eq) was added a solution of (S)-pyrrolidin-3-ol (1.1 eq.) in EtOH (10 mL/g). The mixture was heated at 50 – 60 °C for 5 h, called complete (HPLC), and then cooled to 20-35 °C. Once <35°C, the reaction was polish-filtered (0.2 micron) into a clean reaction vessel and the mixture was cooled to -5 to 5 °C. Sulfuric acid (1.0 eq.) was added over 40 minutes, the temperature rose to 2 °C and the mixture was seeded. A solid formed, and the mixture was allowed to stir at -5 to 5 °C for 6.5 h. Heptanes (10 mL/g) was added, and the mixture stirred for 6.5 h. The

suspension was filtered (PPFC), washed with 1 : 1 EtOH:heptanes (2 x 2 mL/g), and dried (under vacuum at ambient temperature) to give Formula I (92.3%).

Preparation of the hydrogen sulfate salt of the compound of Formula I:

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)-N-(5- ((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (,S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1 : 1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5 :95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5 :95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide hydrogen sulfate.

PATENT

US2017165267

https://patents.google.com/patent/US20170165267

Provided herein is a novel crystalline form of the compound of Formula I:

[0000]

Figure US20170165267A1-20170615-C00001

also known as (S)—N-(5-((R)-2-(2, 5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. In particular, the novel crystalline form comprises the hydrogen sulfate salt of the compound of Formula I in a stable polymorph form, hereinafter referred to as crystalline form (I-HS) and LOXO-101, which can be characterized, for example, by its X-ray diffraction pattern—the crystalline form (I-HS) having the formula:

[0000]

Figure US20170165267A1-20170615-C00002

In some embodiments of the above step (c), the base is an alkali metal base, such as an alkali metal carbonate, such as potassium carbonate.

Figure US20170165267A1-20170615-C00004

Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine Step A—Preparation of sodium pyrazolo[1,5-a]pyrimidin-5-olate

A solution of 1H-pyrazol-5-amine and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (1.05 equiv.) were charged to a round bottom flask outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control. Under mechanical stirring the solids were suspended with 4 vol. (4 mL/g) of absolute EtOH under a nitrogen atmosphere, then charged with 2.1 equivalents of NaOEt (21 wt % solution in EtOH), and followed by line-rinse with 1 vol. (1 mL/g) of absolute EtOH. The slurry was warmed to about 75° Celsius and stirred at gentle reflux until less than 1.5 area % of 1H-pyrazol-5-amine was observed by TRK1PM1 HPLC to follow the progression of the reaction using 20 μL of slurry diluted in 4 mL deionized water and 5 μL injection at 220 nm.

After 1 additional hour, the mixture was charged with 2.5 vol. (2.5 mL/g) of heptane and then refluxed at 70° Celsius for 1 hour. The slurry was then cooled to room temperature overnight. The solid was collected by filtration on a tabletop funnel and polypropylene filter cloth. The reactor was rinsed and charged atop the filter cake with 4 vol. (4 mL/g) of heptane with the cake pulled and the solids being transferred to tared drying trays and oven-dried at 45° Celsius under high vacuum until their weight was constant. Pale yellow solid sodium pyrazolo[1,5-a]-pyrimidin-5-olate was obtained in 93-96% yield (corrected) and larger than 99.5 area % observed by HPLC (1 mg/mL dilution in deionized water, TRK1PM1 at 220 nm).

Step B—Preparation of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one

A tared round bottom flask was charged with sodium pyrazolo[1,5-a]pyrimidin-5-olate that was dissolved at 40-45° Celsius in 3.0 vol. (3.0 mL/g) of deionized water, and then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g deionized water content). Gas chromatography (GC) for residual EtOH (30 μL of solution dissolved in ˜1 mL MeOH) was performed showing less than 100 ppm with traces of ethyl nitrate fumes being observed below upon later addition of HNO3. In some cases, the original solution was charged with an additional 1.5 vol. (1.5 mL/g) of DI water, then concentrated under high vacuum at 65° Celsius in a water-bath on a rotary evaporator until 2.4× weight of starting material was observed (1.4 vol/1.4 mL/g DI water content). Gas chromatograph for residual EtOH (30 μL of solution dissolved in about 1 mL MeOH) was performed showing <<100 ppm of residual EtOH without observing any ethyl nitrate fumes below upon later addition of HNO3.

A round bottom vessel outfitted with a mechanical stirrer, a steam pot, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive Npressure control was charged with 3 vol. (3 mL/g, 10 equiv) of >90 wt % HNOand cooled to about 10° Celsius under a nitrogen atmosphere using external ice-water cooling bath under a nitrogen atmosphere. Using a pressure equalizing addition funnel, the HNO3solution was charged with the 1.75-1.95 volumes of a deionized water solution of sodium pyrazolo[1,5-a]pyrimidin-5-olate (1.16-1.4 mL DI water/g of sodium pyrazolo[1,5-a]pyrimidin-5-olate) at a rate to maintain 35-40° Celsius internal temperature under cooling. Two azeotropes were observed without any ethyl nitrate fumes. The azeotrope flask, the transfer line (if applicable) and the addition funnel were rinsed with 2×0.1 vol. (2×0.1 mL/g) deionized water added to the reaction mixture. Once the addition was complete, the temperature was gradually increased to about 45-50° Celsius for about 3 hours with HPLC showing >99.5 area % conversion of sodium pyrazolo[1,5-a]pyrimidin-5-olate to 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one.

Step C—Preparation of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine

3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one was charged to a round bottom flask outfitted with a mechanical stirrer, a heating mantle, a reflux condenser, a J-Kem temperature probe and an Nadaptor for positive N2pressure control. Under mechanical stirring the solids were suspended with 8 volumes (8 mL/g) of CH3CN, and then charged with 2,6-lutitine (1.05 equiv) followed by warming the slurry to about 50° Celsius. Using a pressure equalizing addition funnel, the mixture was dropwise charged with 0.33 equivalents of POCl3. This charge yielded a thick, beige slurry of a trimer that was homogenized while stirring until a semi-mobile mass was observed. An additional 1.67 equivalents of POClwas charged to the mixture while allowing the temperature to stabilize, followed by warming the reaction mixture to a gentle reflux (78° Celsius). Some puffing was observed upon warming the mixture that later subsided as the thick slurry got thinner.

The reaction mixture was allowed to reflux until complete dissolution to a dark solution and until HPLC (20 μL diluted in 5 mL of CH3CN, TRK1PM1 HPLC, 5 μL injection, 268 nm) confirmed that no more trimer (RRT 0.92) was present with less than 0.5 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one (RRT 0.79) being observed by manually removing any interfering and early eluting peaks related to lutidine from the area integration. On a 1.9 kg scale, 0 area % of the trimer, 0.25 area % of 3-nitropyrazolo[1,5-a]pyrimidin-5(4H)-one, and 99.5 area % of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine was observed after 19 hours of gentle reflux using TRK1PM1 HPLC at 268 [0000]

Figure US20170165267A1-20170615-C00005

Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate Step A—Preparation of tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate

2-bromo-1,4-difluorobenzene (1.5 eq.) was dissolved in 4 volumes of THF (based on weight of tert-butyl 2-oxopyrrolidine-1-carboxylate) and cooled to about 5° Celsius. A solution of 2.0 M iPrMgCl in THF (1.4 eq.) was added over 2 hours to the mixture while maintaining a reaction temperature below 25° Celsius. The solution was allowed to cool to about 5° Celsius and stirred for 1 hour (GC analysis confirmed Grignard formation). A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (1.0 eq.) in 1 volume of THF was added over about 30 min while maintaining a reaction temperature below 25° Celsius. The reaction was stirred at about 5° Celsius for 90 min (tert-butyl 2-oxopyrrolidine-1-carboxylate was confirmed to be less than 0.5 area % by HPLC). The reaction was quenched with 5 volumes of 2 M aqueous HCl while maintaining a reaction temperature below 45° Celsius. The reaction was then transferred to a separatory funnel adding 10 volumes of heptane and removing the aqueous layer. The organic layer was washed with 4 volumes of saturated aqueous NaCl followed by addition of 2×1 volume of saturated aqueous NaCl. The organic layer was solvent-switched to heptane (<1% wt THF confirmed by GC) at a distillation temperature of 35-55° Celsius and distillation pressure of 100-200 mm Hg for 2×4 volumes of heptane being added with a minimum distillation volume of about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55° Celsius yielded a denser solid with the mixture being allowed to cool to room temperature overnight. The slurry was cooled to less than 5° Celsius and filtered through polypropylene filter cloth. The wet cake was washed with 2×2 volumes of heptane. The solids were dried under vacuum at 55° Celsius until the weight was constant, yielding tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate as a white solid at about 75% to 85% theoretical yield.

Step B—Preparation of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole

tert-butyl(4-(2,5-difluorophenyl)-4-oxobutyl)-carbamate was dissolved in 5 vol. of toluene with 2.2 eq. of 12M HCl being added observing a mild exotherm and gas evolution. The reaction was heated to 65° Celsius for 12-24 hours and monitored by HPLC. Upon completion the reaction was cooled to less than 15° Celsius with an ice/water bath. The pH was adjusted to about 14 with 3 equivalents of 2M aqueous NaOH (4.7 vol.). The reaction was stirred at room temperature for 1-2 hours. The mixture was transferred to a separatory funnel with toluene. The aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl. The organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane. The resulting suspension was filtered through a GF/F filter paper and concentrated to a light yellow oil of 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole with a 90% to 100% theoretical yield.

Step C—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine

Chloro-1,5-cyclooctadiene iridium dimer (0.2 mol %) and (R)-2-(2-(diphenylphosphino)phenyl)-4-isopropyl-4,5-dihydrooxazole (0.4 mol %) were suspended in 5 volumes of MTBE (based on 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole) at room temperature. The mixture was stirred for 1 hour and most of the solids dissolved with the solution turning dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5° Celsius and 5-(2,5-difluorophenyl)-3,4-dihydro-2H-pyrrole (1.0 eq.) was added using a 0.5 volumes of MTBE rinse. Diphenylsilane (1.5 eq.) was added over about 20 minutes while maintaining a reaction temperature below 10° Celsius. The reaction was stirred for 30 minutes below 10° Celsius and then allowed to warm to room temperature. The reaction was stirred overnight at room temperature. The completion of the reaction was confirmed by HPLC and then cooled to less than 5° Celsius. The reaction was quenched with 5 volumes of 2M aqueous HCl maintaining temperature below 20° Celsius. After 10 minutes the ice/water bath was removed and the reaction temperature was allowed to increase to room temperature while stirring for 2 hours. The mixture was transferred to a separatory funnel with 3 volumes of MTBE. The aqueous layer was washed with 3.5 volumes of MTBE followed by addition of 5 volumes of MTBE to the aqueous layer while adjusting the pH to about 14 by adding 0.75 volumes of aqueous 50% NaOH. The organic layer was washed with 5 volumes of aqueous saturated NaCl, then concentrated to an oil, and diluted with 3 volumes of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 1 volume of MTBE. The filtrate was concentrated to an oil of (R)-2-(2,5-difluorophenyl)-pyrrolidine with a 95% to 100% theoretical yield and with 75-85% ee.

Step D—Preparation of (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate

(R)-2-(2,5-difluorophenyl)-pyrrolidine (1.0 eq.) was transferred to a round bottom flask charged with 15 volumes (corrected for potency) of EtOH (200 prf). D-malic acid (1.05 eq.) was added and the mixture was heated to 65° Celsius. The solids all dissolved at about 64° Celsius. The solution was allowed to cool to RT. At about 55° Celsius the solution was seeded with (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate (about 50 mg, >97% ee) and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 2×1 volumes of EtOH (200 prf). The solids were dried under vacuum at 55° Celsius, yielding (R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxy-succinate with a 75% to 90% theoretical yield and with >96% ee.

Referring to Scheme 1, suitable bases include tertiary amine bases, such as triethylamine, and K2CO3. Suitable solvents include ethanol, heptane and tetrahydrofuran (THF). The reaction is conveniently performed at temperatures between 5° Celsius and 50° Celsius. The reaction progress was generally monitored by HPLC TRK1PM1.

Figure US20170165267A1-20170615-C00006

Figure US20170165267A1-20170615-C00007

[0247]

Compounds II (5-chloro-3-nitropyrazolo[1,5-a]pyrimidine) and III ((R)-2-(2,5-difluorophenyl)-pyrrolidine (R)-2-hydroxysuccinate, 1.05 eq.) were charged to a round bottom flask outfitted with a mechanical stirrer, a J-Kem temperature probe and an Nadaptor for positive Npressure control. A solution of 4:1 EtOH:THF (10 mL/g of compound II) was added and followed by addition of triethylamine (NEt3, 3.50 eq.) via addition funnel with the temperature reaching about 40° Celsius during addition. Once the addition was complete, the reaction mixture was heated to 50° Celsius and stirred for 0.5-3 hours to yield compound IV.

To a round bottom flask equipped with a mechanical stirrer, a J-Kem temperature probe, and an Ninlet compound IV was added and followed by addition of tetrahydrofuran (10 mL/g of compound IV). The solution was cooled to less than 5° Celsius in an ice bath, and Zn (9-10 eq.) was added. 6M HCl (9-10 eq.) was then added dropwise at such a rate to keep the temperature below 30° Celsius (for 1 kg scale the addition took about 1.5 hours). Once the exotherm subsided, the reaction was allowed to warm to room temperature and was stirred for 30-60 min until compound IV was not detected by HPLC. At this time, a solution of potassium carbonate (K2CO3, 2.0 eq.) in water (5 mL/g of compound IV) was added all at once and followed by rapid dropwise addition of phenyl chloroformate (PhOCOCl, 1.2 eq.). Gas evolution (CO2) was observed during both of the above additions, and the temperature increased to about 30° Celsius after adding phenyl chloroformate. The carbamate formation was stirred at room temperature for 30-90 min. HPLC analysis immediately followed to run to ensure less than 1 area % for the amine being present and high yield of compound VI in the solution.

To the above solution amine VII ((S)-pyrrolidin-3-ol, 1.1 eq. based on theoretical yield for compound VI) and EtOH (10 mL/g of compound VI) was added. Compound VII was added before or at the same time as EtOH to avoid ethyl carbamate impurities from forming. The above EtOH solution was concentrated to a minimum volume (4-5 mL/g) using the batch concentrator under reduced pressure (THF levels should be <5% by GC), and EtOH (10 mL/g of compound VI) was back-added to give a total of 10 mL/g. The reaction was then heated at 50° Celsius for 9-19 hours or until HPLC shows that compound VI is less than 0.5 area %. The reaction was then cooled to room temperature, and sulfuric acid (H2SO4, 1.0 eq. to compound VI) was added via addition funnel to yield compound I-HS with the temperature usually exotherming at about 30° Celsius.

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

PATENT

CN 107987082

PATENT

https://patents.google.com/patent/US20170281632A1/en

WO 2010/048314 discloses in Example 14A a hydrogen sulfate salt of (S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide. WO 2010/048314 does not disclose the particular form of the hydrogen sulfate salt described herein when prepared according to the method of Example 14A in that document. In particular, WO 2010/048314 does not disclose crystalline form (l-HS) as described below.

(S)—N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide having the formula (I):

Figure US20170281632A1-20171005-C00001

Example 1 Preparation of Crystalline Form (I-HS) (Method 1)

(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (0.500 g, 1.17 mmol) was dissolved in EtOH (2.5 mL) and cooled to about 5° Celsius. Concentrated sulfuric acid (0.0636 mL, 1.17 mmol) was added to the cooled solution and stirred for about 10 min, while warming to room temperature. Methyl tert-butyl ether (MTBE) (2 mL) was slowly added to the mixture, resulting in the product gumming out. EtOH (2.5 mL) was then added to the mixture and heated to about reflux until all solids were dissolved. Upon cooling to room temperature and stirring for about 1 hour, some solids formed. After cooling to about 5° Celsius, the solids were filtered and washed with MTBE. After filtration and drying at air for about 15 minutes, (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidi n-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate was isolated as a solid.

Example 2 Preparation of Crystalline Form (I-HS) (Method 2)

Concentrated sulfuric acid (392 mL) was added to a solution of 3031 g of (S)—N-(5-((R)-2-(2, 5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1, 5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in 18322 mL EtOH to form the hydrogen sulfate salt. The solution was seeded with 2 g of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate and the solution was stirred at room temperature for at least 2 hours to form a slurry of the hydrogen sulfate salt. Heptane (20888 g) was added and the slurry was stirred at room temperature for at least 60 min. The slurry was filtered and the filter cake was washed with 1:1 heptane/EtOH. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius).

The dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5:95 w/w solution of water/2-butanone (total weight 41652 g). The mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed. The slurry was filtered, and the filter cake was washed with a 5:95 w/w solution of water/2-butanone. The solids were then dried under vacuum at ambient temperature (oven temperature set at 15° Celsius) to provide the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate.

Example 3 Preparation of Amorphous Form AM(HS)

To a solution of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (9.40 g, 21.94 mmol) in MeOH (220 mL) was slowly added sulfuric acid (0.1 M in MeOH, 219.4 mL, 21.94 mmol) at ambient temperature under rapid stirring. After 30 minutes, the reaction was first concentrated by rotary evaporator to near dryness, then on high vacuum for 48 h to provide amorphous form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (11.37 g, 21.59 mmol, 98.43% yield). LCMS (apci m/z 429.1, M+H).

References

External links

Larotrectinib
Larotrectinib.svg
Identifiers
CAS Number
ChemSpider
UNII
Chemical and physical data
3D model (JSmol)
Patent ID

Patent Title

Submitted Date

Granted Date

US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26
US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
2015-09-04
2016-08-11
Patent ID

Patent Title

Submitted Date

Granted Date

US9447104 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-a]PYRIMIDINE COMPOUNDS
2014-09-18
2015-01-01
US9127013 Method of treatment using substituted pyrazolo[1, 5-a] pyrimidine compounds
2015-01-14
2015-09-08
Patent ID

Patent Title

Submitted Date

Granted Date

US9676783 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
2015-09-04
2016-08-11
US2015073036 NOVEL NTRK1 FUSION MOLECULES AND USES THEREOF
2014-08-29
2015-03-12
US2017114067 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-A] PYRIMIDINE COMPOUNDS
2017-01-05
US2016137654 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2015-11-16
2016-05-19
US2015133429 METHOD OF TREATMENT USING SUBSTITUTED PYRAZOLO[1, 5-a] PYRIMIDINE COMPOUNDS
2015-01-14
2015-05-14
Patent ID

Patent Title

Submitted Date

Granted Date

US2015366866 METHODS OF TREATING CHOLANGIOCARCINOMA
2014-01-17
2015-12-24
US8865698 Method of treatment using substituted pyrazolo[1, 5-a]pyrimidine compounds
2013-07-16
2014-10-21
US8513263 Substituted Pyrazolo[1, 5-a]Pyrimidine Compounds as TRK Kinase Inhibitors
2011-08-11
US2017165267 CRYSTALLINE FORM OF (S)-N-(5-((R)-2-(2, 5-DIFLUOROPHENYL)-PYRROLIDIN-1-YL)-PYRAZOLO[1, 5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE HYDROGEN SULFATE
2017-01-05
US2017260589 POINT MUTATIONS IN TRK INHIBITOR-RESISTANT CANCER AND METHODS RELATING TO THE SAME
2016-10-26

///////////Larotrectinib, UNII:PF9462I9HX, ларотректиниб , 拉罗替尼 , ARRY-470, LOXO-101, PF9462I9HX, phase 3,  Array BioPharma, Loxo Oncology, National Cancer Institute, BAYER, orphan drug designation, breakthrough therapy designation

C1CC(N(C1)C2=NC3=C(C=NN3C=C2)NC(=O)N4CCC(C4)O)C5=C(C=CC(=C5)F)F.OS(=O)(=O)O

Selonsertib, GS-4997, GS-4977


Selonsertib.png

GS-4997, GS-4977, Selonsertib

Selonsertib; 1448428-04-3; GS-4997; UNII-NS3988A2TC; NS3988A2TC; 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]benzamide

  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-[6-[4-(1-methylethyl)-4H-1,2,4-triazol-3-yl]-2-pyridinyl]benzamide
  • 5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-4-methyl-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}benzamide
Molecular Formula: C24H24FN7O
Molecular Weight: 445.502 g/mol
      • NMR  https://file.medchemexpress.com/batch_PDF/HY-18938/Selonsertib-HNMR-25028-MedChemExpress.pdf

str1

Selonsertib is an orally bioavailable inhibitor of apoptosis signal-regulating kinase 1 (ASK1; IC50 = 3.2 nM), which is involved in a variety of conditions, including fibrosis, oxidative stress, and inflammation, among others.1 A formulation containing selonsertib showed antifibrotic activity in a Phase II clinical trial. Clinical trials are ongoing for other conditions, including severe alcoholic hepatitis and nonalcoholic steatohepatitis.

Synonyms
  • GS-4997
  • GS-4977
  • Originator Gilead Sciences
  • Class Benzamides; Cardiovascular therapies; Imidazoles; Pyridines; Triazoles
  • Mechanism of Action MAP kinase kinase kinase 5 inhibitors

Highest Development Phases

  • Phase III Non-alcoholic steatohepatitis
  • Phase II Alcoholic hepatitis; Diabetic nephropathies; Non-alcoholic fatty liver disease; Pulmonary arterial hypertension

Most Recent Events

  • 13 Apr 2018 Efficacy data from a phase II trial in Non-alcoholic fatty liver disease presented at the The International Liver Congress™ 2018 of the European Association for the Study of the Liver (EASL-2018)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 3 phase III trial for Non-alcoholic steatohepatitis in US, Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Malaysia, Mexico, Netherlands, New Zealand, Poland, Portugal, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, Turkey, and United Kingdom (NCT03053050)
  • 13 Apr 2018 Gilead completes enrolment in the STELLAR 4 phase III trial for Non-alcoholic steatohepatitis in the US, Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, India, Israel, Italy, Japan, South Korea, Mexico, New Zealand, Poland, Puerto Rico, Singapore, Spain, Switzerland, Taiwan, and United Kingdom ( NCT03053063)

Apoptosis signal -regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase (“MAP3K”) family that activates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase (Ichijo, H., Nishida, E., e, K., Dijke, P. T., Saitoh, M., Moriguchi, T., Matsumoto, K., Miyazono, K., and Gotoh, Y. (1997) Science, 275, 90-94).

ASK1 is activated by a variety of stimuli including oxidative stress, reactive oxygen species (ROS), LPS, TNF-a, FasL, ER stress, and increased intracellular calcium concentrations (Hattori, K., Naguro, I., Runchel, C, and Ichijo, H. (2009) Cell Comm. Signal. 7: 1-10; Takeda, K., Noguchi, T., Naguro, I., and Ichijo, H. (2007) Annu. Rev. Pharmacol. Toxicol. 48: 1-8.27; Nagai, H., Noguchi, T., Takeda, K., and Ichijo, I. (2007) J. Biochem. Mol. Biol. 40: 1-6).

Phosphorylation of ASK1 protein can lead to apoptosis or other cellular responses depending on the cell type. ASK1 activation and signaling have been reported to play an important role in a broad range of diseases including neurodegenerative, cardiovascular, inflammatory,

autoimmune, and metabolic disorders. In addition, ASK1 has been implicated in mediating organ damage following ischemia and reperfasion of the heart, brain, and kidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al, (2003) Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49).

ROS are reported be associated with increases of inflammatory cytokine production, fibrosis, apoptosis, and necrosis in the kidney. (Singh DK, Winocour P, Farrington K. Oxidative stress in early diabetic nephropathy: fueling the fire. Nat Rev Endocrinol 201 1 Mar;7(3): 176- 184; Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001 Dec 13; 414(6865):813-820; Mimura I, Nangaku M. The suffocating kidney:

tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 2010 Nov; 6(1 1):667- 678).

Moreover, oxidative stress facilitates the formation of advanced glycation end-products (AGEs) that cause further renal injury and production of ROS. (Hung KY, et al. N- acetylcysteine-mediated antioxidation prevents hyperglycemia-induced apoptosis and collagen synthesis in rat mesangial cells. Am J Nephrol 2009;29(3): 192-202).

Tubulointerstitial fibrosis in the kidney is a strong predictor of progression to renal failure in patients with chronic kidney diseases (Schainuck LI, et al. Structural-functional correlations in renal disease. Part II: The correlations. Hum Pathol 1970; 1 : 631-641.).

Unilateral ureteral obstruction (UUO) in rats is a widely used model of tubulointerstitial fibrosis. UUO causes tubulointerstital inflammation, increased expression of transforming growth factor beta (TGF-β), and accumulation of myofibroblasts, which secrete matrix proteins such as collagen and fibronectin. The UUO model can be used to test for a drug’s potential to treat chronic kidney disease by inhibiting renal fibrosis (Chevalier et al., Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy, Kidney International (2009) 75, 1 145-1152.

Thus, therapeutic agents that function as inhibitors of ASK1 signaling have the potential to remedy or improve the lives of patients in need of treatment for diseases or conditions such as neurodegenerative, cardiovascular, inflammatory, autoimmune, and metabolic disorders. In particular, ASK1 inhibitors have the potential to treat cardio-renal diseases, including kidney disease, diabetic kidney disease, chronic kidney disease, fibrotic diseases (including lung and kidney fibrosis), respiratory diseases (including chronic obstructive pulmonary disease (COPD) and acute lung injury), acute and chronic liver diseases.

U.S. Publication No. 2007/0276050 describes methods for identifying AS 1 inhibitors useful for preventing and/or treating cardiovascular disease and methods for preventing and/or treating cardiovascular disease in an animal.

WO2009027283 discloses triazolopyridine compounds, methods for preparation thereof and methods for treating autoimmune disorders, inflammatory diseases, cardiovascular diseases and neurodegenerative diseases.

U.S. Patent Publication No. 2001/00095410A1, published January 13, 201 1, discloses compounds useful as ASK-1 inhibitors. U.S. Patent Publication No. 2001/00095410A1 relates to compounds of Formula (I):

Figure imgf000004_0001
SYN
WO  2016106384

PRODUCT PATENT

WO 2013112741

https://patents.google.com/patent/WO2013112741A1/en

InventorGregory Notte Original AssigneeGilead Sciences, Inc. Priority date 2012-01-27

SCHEME 1

Figure imgf000013_0001

SCHEME 2

 Figure imgf000015_0001

COUPLING

Figure imgf000014_0001Figure imgf000015_0003

GIVES

Figure imgf000015_0002

The name of the compound of the present invention as generated using ChemBioDraw Ultra 11.

Figure imgf000012_0001
is 5-(4-cyclopropyl- 1 H-imidazol- 1 -yl)-N-(6-(4-isopropyl-4H- 1 ,2,4-triazol-3 -yl)pyridin-2-yl)-2- fluoro-4-methylbenzamide also known as 5-((4-cyclopropyl-lH-imdazol-l-yl)-2-fluoro-N-(6-(4- isopropyl-4H- 1 ,2,4-triazole-3 -yl)pyridine-2-yl)-4-methylbenzamide.

One method of preparing compounds of formula (I) is shown in Reaction Schemes 1 and 2 below.

Scheme 1

Figure imgf000013_0001

Preparation of Compound A

To a solution of methyl 6-aminopicolinate (432 g, 2.84 mol) in MeOH (5 L) was added NH2NH2.H2O (284 g, 5.68 mol, 2.0 eq.). The reaction mixture was heated under reflux for 3 hr and then cooled to room temperature. The precipitate formed in the mixture was collected by filtration, washed with EA (2 L><2) and then dried in vacuo to give compound A (405 g, 94% yield) as white solid.

Preparation of compound B

A mixture of compound A (405 g, 2.66 mol) in dimethylformamide-dimethylacetal (DMF-DMA) (3.54 L) was heated under reflux for 18 hr, cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in EA (700 mL) and heated at 50°C for 20 min. After being cooled to room temperature, the solid was collected by filtration and dried in vacuo to give compound B (572 g, 82% yield) as white solid.

Preparation of C

To a solution of compound B (572 g, 2.18 mol) in a mixture of CH3CN-AcOH (3.6 L, 4:1) was added propan-2-amine (646 g, 5.0 eq.). The resulting mixture was heated under reflux for 24 hr and then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in water (2.8 L) and 1 N aqueous NaOH was added to a pH of 8.0 H. The precipitate was collected by filtration and the filtrate was extracted with EA (500 mLx3). The combined organic layers were dried over anhydrous Na2S04, and then concentrated to a volume of 150 mL. To this mixture at 0°C was slowly added PE (400 mL) and the resulting suspension was filtered. The combined solid was re-crystallized from EA-PE to give compound C (253 g, 57% yield) as off-white solid.

1H- MR (400 MHz, CDC13): δ 8.24 (s, 1 H), 7.52 (m, 2 H), 6.51 (dd, J = 1.6, 7.2 Hz, 1 H), 5.55 (m, 1 H), 4.46 (bs, 2 H), 1.45 (d, J = 6.8 Hz, 6 H). MS (ESI+) m/z: 204 (M+l)+.

Compound C is a key intermediate for the synthesis of the compound of formula (I). Thus, an object of the present invention is also the provision of the intermediate compound C,

Figure imgf000014_0001

its salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound C is the HC1 addition salt. An example of a protected form of compound C is the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparation and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Scheme 2

Preparation of the Compound of formula (I) continued:

Figure imgf000015_0001
Figure imgf000015_0002

Formula (I)

Compound 6 is a key intermediate for the synthesis of the compound of formula (I). Thus an object of the present invention is also the provision of intermediate compound 6,

Figure imgf000015_0003

6

salts or protected forms thereof, for the preparation of the compound of formula (I). An example of a salt of the compound 6 is the HC1 addition salt. An example of a protected form of the compound 6 is an ester (e.g. methyl, ethyl or benzyl esters) or the carbamate compound such as obtained with Cbz-Cl. Protective groups, their preparations and uses are taught in Peter G.M. Wuts and Theodora W. Greene, Protective Groups in Organic Chemistry, 2nd edition, 1991, Wiley and Sons, Publishers. Step 1 – Preparation of 5-amino-2-fluoro-4-methylbenzonitrile – Compound (2)

The starting 5-bromo-4-fluoro-2-methylaniline (1) (20g, 98 mmol) was dissolved in anhydrous 1-methylpyrrolidinone (100 mL), and copper (I) cyanide (17.6g, 196 mmol) was added. The reaction was heated to 180°C for 3 hours, cooled to room temperature, and water (300 mL) and concentrated ammonium hydroxide (300 mL) added. The mixture was stirred for 30 minutes and extracted with EA (3 x 200 mL). The combined extracts were dried over magnesium sulfate, and the solvent was removed under reduced pressure. The oily residue was washed with hexanes (2 x 100 mL), and the solid dissolved in dichloromethane and loaded onto a silica gel column. Eluting with 0 to 25% EA in hexanes gradient provided 5-amino-2-fluoro- 4-methylbenzonitrile (10.06g, 67.1 mmol). LC/MS (m/z:151 M+1).

Step 2 – Preparation of 5-(2-cvclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile – Compound (3)

5-Amino-2-fluoro-4-methylbenzonitrile (12g, 80mmol) was dissolved in anhydrous N,N- dimethylformamide (160 mL) under nitrogen, and potassium carbonate (13.27g, 96 mmol) and potassium iodide (14.61g , 88mmol) were added as solids with stirring. The reaction was stirred for 5 minutes at room temperature and then bromomethyl cyclopropylketone (20.24 mL, 180 mmol) was added. The reaction mixture was heated to 60°C for 3 hours, and then the solvents removed under reduced pressure. The residue was dissolved in EA (400 mL) and washed with 400 mL of water. The organic layer was dried over magnesium sulfate, and solvent was removed under reduced pressure. The residue was re-dissolved in a minimum amount of EA, and hexanes were added to bring the solution to 3: 1 hexanes: EA by volume. The product precipitated out of solution and was collected by filtration to provide 5-(2-cyclopropyl-2- oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2 mmol). LC/MS (m/z : 233, M+1)

Step 3 – Preparation of 5-(4-cvclopropyl-2-mercapto-lH-imidazol-l -yl)-2-fluoro-4- methylbenzonitrile – Compound (4)

5-(2-Cyclopropyl-2-oxoethylamino)-2-fluoro-4-methylbenzonitrile (14.19g, 61.2mmol) was dissolved in glacial acetic acid (300 mL). Potassium thiocyanate (11.9g, 122.4mmol) was added as a solid with stirring. The reaction mixture was heated to 110°C for 4 hours at which time the solvent was removed under reduced pressure. The residue was taken up in dichloromethane (200 mL) and washed with 200 mL water. The aqueous extract was extracted with (2 x 200 mL) additional dichloromethane, the organic extracts combined and dried over magnesium sulfate. The solvent was removed under reduced pressure and the oily residue was re-dissolved in EA (50 mL) and 150 mL hexanes was added. A dark layer formed and a stir bar was added to the flask. Vigorous stirring caused the product to precipitate as a peach colored solid. The product was collected by filtration, to yield 5-(4-cyclopropyl-2-mercapto-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile, (14.26g, 52.23 mmol). Anal. LC/MS (m/z : 274, M+1)

Step 4 – Preparation of 5-(4-cyclopropyl-lH-imidazol -yl)-2-fluoro-4-methylbenzonitrile – Compound (5)

In a 500 mL three neck round bottom flask was placed acetic acid (96 mL), water (19 mL) and hydrogen peroxide (30%, 7.47 mL, 65.88 mmol). The mixture was heated to 45°C with stirring under nitrogen while monitoring the internal temperature. 5-(4-Cyclopropyl-2- mercapto-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (6.00g, 21.96 mmol) was then added as a solid in small portions over 30 minutes while maintaining an internal temperature below 55°C. When addition of the thioimidazole was complete the reaction was stirred for 30 minutes at a temperature of 45 C, and then cooled to room temperature, and a solution of 20% wt/wt sodium sulfite in water (6 mL) was slowly added. The mixture was stirred for 30 minutes and solvents were removed under reduced pressure. The residue was suspended in 250 mL of water and 4N aqueous ammonium hydroxide was added to bring the pH to ~10. The mixture was extracted with dichloromethane (3 x 200ml), the organics combined, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 20 mL EA, and 80 mL of hexanes were added with stirring. The solvents were decanted off and an oily residue was left behind. This process was repeated and the product, 5-(4-cyclopropyl-lH- imidazol-l-yl)-2-fluoro-4-methylbenzonitrile was obtained as a viscous oil (5.14 g, 21.33 mmol) Anal. LC/MS (m/z: 242, M+1)

Step 5 – Preparation of 5-(4-cvclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzoic acid hydrochloride (6)

5-(4-Cyclopropyl-lH-imidazol-l-yl)-2-fluoro-4-methylbenzonitrile (1 1.21g, 46.50mmol) was placed in a round bottom flask fitted with a reflux condenser, and suspended in 38% hydrochloric acid (200 mL). The mixture was heated to 100°C for 4.5 hours, and then cooled to room temperature. Solvent was removed under reduced pressure to give a pink solid, to which was added 100ml of EA. The solid product was collected by filtration and washed with 3 xlOO mL EA. To the solid product was added 100 mL 10% methanol in dichloromethane, the mixture stirred, and the filtrate collected. This was repeated with 2 more 100ml portions of 10% methanol in dichloromethane. The filtrates were combined and solvent was removed under reduced pressure, to provide crude 5-(4-cyclopropyl-lH-imidazol-l -yl)-2-fluoro-4- methylbenzoic acid hydrochloride. No further purification was carried out (1 1.13g, 37.54mmol). Anal. LC/MS (m/z: 261 , M+1)

Step 6 – Preparation of 5-(4-cvclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-N-(6-(4-isopropyl-4H- l,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide – formula (I)

5-(4-Cyclopropyl- 1 H-imidazol- 1 -yl)-2-fluoro-4-methylbenzoic acid hydrochloride (1.5g,

5.07mmol) was suspended in anhydrous 1 ,2-dichlorom ethane (25 mL) at room temperature. Oxalyl chloride (0.575ml, 6.59mmol) was added with stirring under nitrogen, followed by N,N- dimethylformamide (0.044ml, 0.507mmol). The ; mixture was stirred for 4 hr at room temperature, and then the solvent was removed under reduced pressure. The residue was dissolved in 25 mL anhydrous dichloromethane. 6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2- amine (1.13g, 5.58mmol) (compound C) and 4-dimethylaminopyridine (0.62g, 5.07 mmol) were rapidly added with stirring under nitrogen. The reaction was stirred for 2 hours at room temperature and aqueous saturated NaHC03 (15 mL) was added. The mixture was stirred for 10 minutes, and the layers were separated, and the aqueous layer was washed 1 x 20 mL dichloromethane. The combined organics were dried (MgS04), filtered and concentrated. The residue was dissolved in a minimum amount of CH3CN and water was slowly added until solids precipitated from the mixture. The solid was collected by filtration and dried to give 5-(4- cyclopropyl-lH-imidazol-l -yl)-2-fluoro-N-(6-(4-isopropyl-4H-l ,2,4-triazol-3-yl)pyridin-2-yl)- 4-methylbenzamide in -96% purity (1.28g, 2.88 mmol). Anal. LC/MS (m/z: 446, M+1). The material was further purified by RP-HPLC (reverse phase HPLC) to obtain an analytically pure sample as the HC1 salt.

Figure imgf000018_0001

C24H24FN7O-HCI. 446.2 (M+1). 1H-NMR (DMSO): δ 1 1.12 (s, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.07 (t, J = 8.4 Hz, 1 H), 7.95 (d, J = 6.4 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.59 (d, J = 10.4 Hz, 1H), 5.72 (sept, J = 6.8 Hz, 1H), 2.29 (s, 3H), 2.00-2.05 (m, 1H), 1.44 (d, J = 6.8 Hz, 6H), 1.01-1.06 (m, 2H), 0.85-0.89 (m, 2H).

PATENT

US 9067933

US 20150342943

WO 2016187393

WO 2016025474

WO 2016112305

WO 2017205684

WO 2017210526

WO 2018013936

PAPER

Bioorganic & Medicinal Chemistry Letters (2018), 28(3), 400-404

https://www.sciencedirect.com/science/article/pii/S0960894X17311861?via%3Dihub

https://ars.els-cdn.com/content/image/1-s2.0-S0960894X17311861-mmc1.pdf

PAPER

ACS Medicinal Chemistry Letters (2017), 8(3), 316-320

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00481

https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00481/suppl_file/ml6b00481_si_001.pdf

Abstract Image

Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.

PATENT

FORM I TO IX POLYMORPHS

WO 2016105453

https://patents.google.com/patent/WO2016105453A1/zh-CN

Compound I is known to exhibit ASK1 inhibitory activity and is described in, for example, U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety. Compound I has the formula:

Compound I

Compound I can be synthesized according to the methods described in U.S. Patent No. 8,742,126 or U.S. Provisional Application No. 62/096,391, U.S. Provisional Application No. 62/269,064 and PCT Application PCT/US2015/067511 (filed on even date herewith and titled “Processes for Preparing ASK1 Inhibitors”), all of which are incorporated by reference in their entirety.

The present disclosure provides forms of Compound I and salts, co-crystals, hydrates, and solvates thereof. Also described herein are processes for making the forms of Compound I, pharmaceutical compositions comprising crystalline forms of Compound I and methods for using such forms and pharmaceutical compositions in the treatment of diseases mediated by ASK1 disregulation.

Thus, one embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form I) characterized by an X-ray powder diffractogram comprising the following peaks: 16.7, 21.3, and 22.8 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Kct radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form II) characterized by an X-ray powder diffractogram comprising the following peaks: 11.2, 16.6, and 17.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I Form III) characterized by an X-ray powder diffractogram comprising the following peaks: 5.1, 10.2, and 25.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κ radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIV) characterized by an X-ray powder diffractogram comprising the following peaks: 7.2, 12.6, and 19.3 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormV) characterized by an X-ray powder diffractogram comprising the following peaks: 9.7, 13.3, and 16.4 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVI) characterized by an X-ray powder diffractogram comprising the following peaks: 8.8, 23.2, and 23.5 °2Θ ± 0.2 °2Θ, as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.2, 14.2, and 22.9 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormVIII) characterized by an X-ray powder diffractogram comprising the following peaks: 8.4, 19.3, and 24.3 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is crystalline 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyI-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (Compound I FormIX) characterized by an X-ray powder diffractogram comprising the following peaks: 6.9, 14.3, 23.7, and 24.8 °2Θ ± 0.2 °2Θ as determined on a diffractometer using Cu-Κα radiation at a wavelength of 1.5406 A.

Another embodiment is amorphous 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide.

Some embodiments provided herein relate to crystalline forms of salts or co-crystals of Compound I.

The compound, 5-(4-cyclopropyl-lH-imidazol-l-yl)-N-(6-(4-isopropyl-4H-l,2,4-triazol-3-yl)pyridin-2-yl)-2-fluoro-4-methylbenzamide (also known as 5-((4-cyclopropyl-lH-imidazol-l-yl)-2-fluoro-N-(6-(4-isopropyl-4H-l,2,4-triazole-3-yl)pyridine-2-yl)-4-methylbenzamide)) designated herein as Compound I, has the formula:

Compound I exhibits an EC50 value of about 2 nanomolar in an ASK1 293 cell-based assay. The experimental protocol for this assay is known in the art and is described in U.S. Patent No. 8,742,126, which is hereby incorporated by reference in its entirety.

The present disclosure relates to various crystalline forms of Compound I, and processes for making the crystalline forms. Compound I also provides forms further described herein as “Compound I Form I,” “Compound I Form II,” “Compound I Form III,” “Compound I Form TV,” “Compound I Form V,” “Compound I Form VI,” “Compound I Form VII,” “Compound I Form VIII,” “Compound I Form IX,” and “amorphous Compound I.” In some embodiments, such forms of Compound I may be a solvate or a hydrate.

Additional crystalline forms of Compound I are also further described herein. In some embodiments, crystalline forms of Compound I may include salts or co-crystals of Compound I. Salts or co-crystals of Compound I may have the following formula:

 X

PATENT

WO 2016106384

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016106384&recNum=31&docAn=US2015067511&queryString=EN_ALL:nmr%20AND%20PA:(gilead%20sciences)&maxRec=1065

As described generally above, the disclosure provides in some embodiments processes for making a compound of formula (A).

Scheme 1 represents an exemplary synthesis of a compound of formula (A) and can be carried out according to the embodiments described herein. It is contemplated that the exemplary synthesis shown in Scheme 1 may be particularly advantageous. For example, the synthesis employs less toxic starting materials (i.e., using Compound (H) in place of its corresponding analog having bromide at the tosylate position), avoids toxic reagents (i.e., CuCN), and employs less toxic solvents (i.e., using dichloromethane instead of dichloroethane), including at the final step of the synthesis. The synthesis also can utilize milder reaction conditions (i.e., avoids high temperatures needed for cyanation, etc.), can avoid the use of heavy metals, and can require less purification steps (e.g. avoid column chromatography). The particular reaction conditions and reagents employed in Scheme 1 are discussed below.

Scheme 1


Compound (B)

Scheme 2

Compound (A)

Scheme 3

Compound (E) Compound (A)

EXAMPLES

The compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of compounds described herein, may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g. from Sigma Aldrich or other chemical suppliers. Unless otherwise noted, the starting materials for the following reactions may be obtained from commercial sources.

Example 1: Synthesis of Compound (A)

Compound (C)


MeCN Toluene, /Pr2EtN

Compound (J) Compound (H)

ompound F

(COCI)2, DMF 

Compound (D-a)

Compound (B) J Compound (A) Hydroxytosylation of Compound (J) to form Compound (H)

Compound (J) Compound (H)

Koser’s reagent, PhI(OH)OTs, (1.0 eq.) and acetonitrile (5 vols) are charged to a flask. Cyclopropylmethyl ketone (Compound (J), 1.2 eq.) is charged and the mixture is heated to about 70 °C to about 75 °C. Once the reaction is complete, the contents are cooled and concentrated. The residue is diluted in dichloromethane (about 2.5 vols) and washed with water (2 x about 1 to 2 volumes). The organic phase is concentrated to approximately 1.5 vols and the product is triturated with hexanes (about 1.5 to 2 vols) and concentrated to remove dichloromethane and the distilled volume is replaced with hexanes. The slurry is agitated for about two hours, filtered and washed with hexanes. The solids are dried under vacuum at about 40 °C to afford Compound (H). 1H MR (400 MHz, DMSO-d6): δ 7.82 (d, 2H, J= 8.0 Hz), 7.49 (d, 2H, J= 8.0 Hz), 4.98 (s, 2H), 2.42 (s, 3H), 2.02-2.08 (m, 1H), 0.95-0.91 (m, 2H), 0.89-0.82 (m, 2H). 13C MR (100 MHz, DMSO-de): 202.39, 145.60, 132.76, 130.57, 128.12, 72.98, 21.52, 17.41, 11.39.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Koser’s reagent, alternative reagents may include, but are not limited to, (diacetoxyiodo)benzene organosulfonic acid, (diacetoxyiodo)benzene and p-toluenesulfonic acid, iodosylbenzene/p-toluenesulfonic acid, m-chloroperbenzoic acid/p-toluenesulfonic acid, poly(4-hydroxy tosyloxyiodo)styrenes, N-methyl-O-tosylhydroxylamine, Dess-Martin periodinane/p-toluenesulfonic acid, HlCVp-toluenesulfonic acid, and o-iodoxybenzoic acid/p-toluenesulfonic acid. Various solvents, such as toluene, benzene, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and chloroform, may be employed. The reaction may take place at temperatures that range from about 20 °C to about 100 °C.

Alkylation of Compound (H) with Compound (I) to form Compound (G)

Co

To a mixture of Compound (I) (1.0 equiv) and Compound (H) (1.1 equiv) in toluene (5 vols) is charged iPr2 Et (2.1 equiv). The mixture is heated to about 90 to about 100 °C and aged for about less than 10 hours. Upon completion, the mixture is cooled and diluted with water (about 5 to about 6 vols). The biphasic mixture is separated and the organic solution is washed sequentially with aq. H4C1 (about 27 wt%, about 2 to about 3 vols), aq. NaHC03 (about 9 wt%, about 2 to about 3 vols), and aq. NaCl (about 15 wt%, about 1 vols). The organic solution is dried over Na2S04, filtered, and washed with toluene (about 2 to about 3 vols). The solution is concentrated under vacuum at about 45 °C and the residue is crystallized by the addition of hexane at about 20 °C to about 25 °C and at about 10 °C to about 15 °C. The slurry is filtered, washed with cooled isopropanol (about 1 vol) and dried under vacuum at about 37 °C to about 43 °C to afford Compound (G). 1H NMR(400 MHz, DMSO-d6): δ 7.05 (d, 1H, J= 12.0 Hz), 6.51 (d, lH, J= 8.0 Hz), 5.27 (t, 1H, J= 4.0 Hz), 4.17 (d, 2H, J= 4.0 Hz), 2.21-2.14 (m, 1H), 2.10 (s, 3H), 0.96-0.86 (m, 4H). 13NMR (100 MHz, DMSO-d6): 208.17, 151.63, 149.32, 143.99, 143.97, 123.81, 123.74, 118.13, 117.90, 112.87, 105.09, 104.88, 53.72, 18.33, 17.43, 17.42, 10.85.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organic bases (e.g., DBU and DMAP), alkali metal bases (e.g., NaH), hexamethyldisilazane bases (e.g, sodium, potassium and lithium hexamethyldisilazide), carbonate bases (e.g., Cs2C03, Na2C03), and potassium tert-butoxide. Various solvents, such as THF, MTBE, 2-MeTHF, acetonitrile, dioxane, benzene, DMF, DMAc, NMP, may be employed. The reaction may take place at temperatures that range from about -78 °C to about 100 °C.

Formylation of Compound (G) to form Compound (F)

Acetic anhydride (4 equiv) is added to aqueous formic acid (about 3 to about 4 vols) at about 0 °C to about 5 °C and the mixture is agitated. Compound (G) (1.0 equiv) in DCM (about 3 vols) is charged. The reaction is aged at about 0 to about 5 °C until it is deemed complete. Upon reaction completion, water (about 4 vols) is charged and the mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH with the content temperature maintained between about 0 °C to about 15 °C. The biphasic mixture is separated and the aqueous solution is extracted with dichloromethane (about 6 vols). The organic solution is washed with saturated aqueous NaCl (about 4 vols), dried over Na2S04, and filtered. Compound (F) is carried forward to the next step as a solution in dichloromethane without further purification. 1H MR (400 MHz, DMSO-de): δ (mixture of amide rotamers) 8.17 (s, 1H), 8.14 (s, 1H), 7.61 (d, 1H, J= 8.0 Hz), 7.45 (d, 1H, J= 8.0 Hz), 7.42 (d, 1H, J= 12.0 Hz), 7.33 (d, 1H, J= 12.0 Hz), 4.87 (s, 2H), 4.68 (s, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 2.12-2.03 (m, 1H), 0.98-0.85 (m, 4H). 13C MR (100 MHz, DMSO-de): 206.68 (204.85), 163.71 (163.22), 158.95 (158.69), 156.51 (156.35), 139.09 (139.02), 138.61 (138.53), 137.58 (137.55), 133.35 (133.34), 132.45, 119.02 (118.79), 118.58 (118.36), 105.35 (105.03), 104.77 (104.55), 58.68, 55.40, 17.84 (17.77).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic anhydride and formic acid, acetic acid monoanhydride with carbonic acid or trifluoroacetic anhydride with formic acid may be used. Various solvents, such as chloroform, acetonitrile, isopropyl acetate, or THF, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 40 °C.

Imidazole Cyclization to Form Compound (E)

To a solution of Compound (F) (1.0 equiv) in DCM is charged acetic acid (about 5 vols). The solution is concentrated under vacuum at about 35 °C to remove the bulk of DCM and ammonium acetate (3.9 equiv) is added. The mixture is heated to about 110 °C to about 115 °C and agitated until the reaction is deemed complete. The reaction is cooled, diluted with water (about 10 vols) and iPrOAc (about 6 vols). The mixture is adjusted to about pH 8-9 by the addition of 40-50% aqueous NaOH. The biphasic mixture is separated. Sodium chloride (about 0.3 wt equiv wrt Compound (F)) is charged to the aqueous layer and the aqueous layer is extracted with iPrOAc (about 2 vols). The organic solution is washed with water (about 5 vols) and aq. NaCl (about 10 wt%, about 4 to about 5 vols). The solution is concentrated under vacuum and solvent exchanged to about 2-3 vols Ν,Ν-di methyl acetamide (DMAc). Water (about 5 to about 6 vols) is charged to afford Compound (E) as a slurry. The slurry is filtered and washed sequentially with DMAc/water, water, and hexanes. The resulting solids are dried under vacuum at about 55 °C to afford Compound (E). 1H NMR (400 MHz, DMSO-d6): δ 7.68 (d, 1H, J= 4.0 Hz), 7.64 (d, 1H, J= 1.0 Hz), 7.46 (d, 1H, J= 12.0 Hz), 7.12 (d, 1H, J= 1.0 Hz), 2.12 (s, 3H), 1.85-1.79 (m, 1H), 0.81-0.76 (m, 2H), 0.70-0.66 (2H). 13NMR (100 MHz, DMSO-d6): 159.11, 156.67, 156.67, 143.94, 137.36, 136.19, 136.11, 134.44, 134.41, 131.21, 131.20, 119.05, 118.82, 116.21, 105.56, 105.34, 17.72, 17.71, 9.26, 7.44.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of ammonium acetate, alternative sources of ammonia may be used, including but not limited to ammonium formate and ammonium hydroxide. Various solvents, such as toluene, benzene, and isopropanol, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 120 °C.

Carboxylation o Compound (E) to form Compound (D)

Compound (E) then 15 10 25 c Compound (D)

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered, washed with water (about 4 vols), isopropanol (about 4 vols), followed by n-heptane (about 6 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Conversion o Compound (D) to form Compound (D-a)

Compound (D) Compound (D-a)

To a mixture of Compound (D) (1.0 equiv) in methanol (about 4 vols) at about 15 °C to about 25 °C is charged concentrated HC1 (1.1 equiv relative to Compound (D)). The mixture is aged until most of the Compound (D) is dissolved, seeded with Compound (D-a) (0.005 equiv), which was formed according to the procedure outlined above, and MTBE (about 3 vols relative to the amount of seed) is charged slowly. The slurry is aged, filtered, and rinsed with MTBE (5 vols) and the solids are dried under vacuum at about 40 °C to afford Compound (D-a). 1H MR (400 MHz, DMSO-de): δ 9.34 (s, 1H), 8.00 (d, 1H, J= 8.0 Hz), 7.76 (d, 1H, J= 2.0 Hz), 7.54 (d, 1H, J= 12.0 Hz), 2.25 (s, 3H), 2.08-2.01 (m, 1H), 1.05-1.00 (m, 2H), 0.92-0.88 (m, 2H). 13C MR QOO MHz, DMSO-d6): 164.08, 164.05, 162.73, 160.14, 142.11, 142.01, 137.11, 135.91, 131.14, 131.11, 130.73, 120.19, 119.96, 118.78, 118.39, 118.27, 17.71, 8.24, 6.13.

Carboxylation o Compound (E) to form Compound (D) Hydrate

Compound (E) then 15 10 25 °c Compound (D) Hydrate

A mixture of Compound (E) (1.0 equiv) in THF (about 15 vols) was cooled to about -10 to about 0 °C and a solution of iPrMgCl (2.0 M in THF, 1.2 equiv) was charged slowly to maintain the internal temperature below about 5 °C. The mixture was stirred for about 1 hour at about -5 to about 5 °C after which C02 was bubbled slowly into the mixture (exothermic). The addition is continued until the exotherm subsides and the internal temperature typically increases to about 15 to about 25 °C after the addition. Upon reaction completion, the mixture is concentrated under vacuum to approximately 3 vols and water (about 6 to about 7 vols) is added, followed by about 1 vol 6 M HC1. MTBE (about 10 vols) is added and the biphasic mixture is separated. A solution of 6 M HC1 is added slowly to the aqueous layer to adjust the pH (initially at > 10) to approximately 4.8. The mixture is seeded with Compound (D) (if necessary), which was formed according to the procedure outlined above, and the resultant slurry is cooled slowly to about 0 °C to about 5 °C and aged. The slurry is filtered and washed with water (about 4 vols). The solids are dried under vacuum at about 40 °C to afford Compound (D) hydrate. 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13NMR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases, including but not limited to organolithium bases (e.g., MeLi, «-BuLi, t-BuLi, and sec- uLi) and Grignard bases (e.g., MeMgCl, «-BuMgCl, and PhMgCl). Various solvents, such as 2-MeTHF, dioxane, MTBE, and Et20, may be employed. The reaction may initially take place at temperatures that range from about -20 °C to about 40 °C and then continue at temperature that range from about -10 °C to about 50 °C.

Acid Chloride Formation Using Compound (D-a) to Form Compound (B)

Compound (B)

To a mixture of Compound (D-a) (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (about 1.7 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D-a), compound (D) may be used. Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various

solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

Acid Chloride Formation Using Compound (D) Hydrate to Form Compound (B)

To a mixture of Compound (D) hydrate (1.0 equiv), DCM (about 10 vols) and DMF (0.1 equiv), a solution of oxalyl chloride (1.2 equiv) was slowly charged to maintain the internal temperature below about 30 °C. The mixture was stirred for about 1 hour at about 20 °C after which time the mixture is distilled to about about 4 vols total volume. DCM (about 5 vols) is repeatedly charged and the mixture distilled to about 4 vols total volume. DCM is then charged to bring the total volume to about 12 vols of Compound (B). The solution is carried forward to the next step without further purification.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (D) hydrate, compound (D) may be used.

Additionally, in lieu of oxalyl chloride and DMF, thionyl chloride, PC15, and PCI3 may be used. Various solvents, such as MeCN, THF, and MTBE, may be employed. In some embodiments, additives may be used, including but not limited to trimhetylsilyl chloride, water, HC1, or tetrabutyl ammonium chloride. The reaction may take place at temperatures that range from about -20 °C to about 40 °C.

mide Bond Formation to form Compound (A)

Compound (C) 15 to 25 °C Compound (A)

Compound (C) was synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety.

To a solution of Compound (B) (about 1 equiv in about 12 vols DCM) was charged diisopropylethyl amine (1.0 equiv) followed by Compound (C) (1.05 equiv). Upon reaction completion, 5% aqueous sodium hydroxide (about 5 vols) is added and the layers of the biphasic mixture are separated. A solution of 10% aqueous citric acid (about 2 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. Water (about 5 vols) is charged to the organic layer and the layers of the biphasic mixture are separated. The organic solution is filtered, and the solution is solvent swapped to about 15% DCM in EtOH under vacumm at about 45 °C. The mixture is seeded with about 0.001 equiv of Compound (A), which was synthesized as described by U.S. Patent No. 8,742,126, and the resultant slurry is aged at about 45 °C. An additional 2-3 vols solvent is distilled in vacuo and then heptane (about 10 vols) is charged slowly and the slurry is aged, cooled to about 20 °C, filtered and washed with 1 :2 EtOH:heptane (about 3 vols). The solids are dried under vacuum at about 40 °C to afford Compound (A). Characterization data for Compound (A) matches that disclosed in U.S. Patent No. 8,742,126.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to Et3N, pyridine, and DMAP. Various solvents, such as 2-MeTHF, toluene, MTBE, and chloroform, may be employed. The reaction may take place at temperatures that range from about 0 °C to about 40 °C.

In lieu of Compound (B), Compound (D) or activated esters thereof may be employed.

Coupling reagents may also be employed; non-limiting examples of such reagents include

propane phosphonic acid anhydride (T3P®), Ι, -carbonyldiimidazole, EDC/HOBt or other imide coupling reagents, isobutylchloroformate (to generate an isobutyl ester), and pivoyl chloride (to generate a pivalate ester).

Example 2: Alternative Synthesis of Compound (D)


ompound (K) Compound (L)

Compound (D)

Coupling of Compound (K) and Compound (L-a) to provide Compound (D)

Compound (K) Compound (L-a) Compound (D)

Compound 2-1 Compound 2-2

Compound (L-a) (1.0 eq), Compound (K) (1.5 eq), potassium phosphate (5.0 eq), copper

(I) oxide (0.05 eq), and 8-hydroxyquinoline, Compound 2-2 (0.2 eq) were combined with degassed DMSO (about 6 vols). The reaction mixture was heated to about 95 °C to about 105 °C and stirred for about 22 h. Upon reaction completion, the mixture was cooled to ambient temperature and diluted with water (about 6 vols) and isopropyl acetate (about 5 vols). The aqueous layer was washed with isopropyl acetate (about 5 vols), and the pH was adjusted to about 6 by the addition of 8 M HC1. The solution was seeded with about about 0.003 equiv of Compound (D) seed, which was synthesized as described in U.S. Patent No. 8,742, 126, and the pH was further adjusted to pH about 4.8. The resultant slurry was cooled to about 0 °C for about 2 h, filtered, and washed with cold dilute HC1 (pH about 4.8, about 2 vols) and cold isopropyl alcohol (about 2 vols) to provide Compound (D). 1H NMR (400 MHz, DMSO-d6): δ 7.69 (d,

1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative bases may be used, including but not limited to carbonate bases (such as CS2CO3, K2C03, and Na2C03). In lieu of Cu20, alternative catalysts may be used, such as CuOAc, Cul, CuBr, and [(CuOTf)2-benzene complex]. Non-limiting examples of alternative ligands include phenanthroline ligands (such as 4,7-dimethoxy-l, 10-phenanthroline (Compound 2-1) and 1,10-phenanthroline), aminoarenethiols (such as 2-((dimethylamino)methyl)benzenethiol), oxime-phospine oxides, phosphoramidites, 2-aminopyrimidine diols (such as 2-aminopyrimidine-4,6-diol), and oxime-phosphine oxides (such as 2-hydroxybenzaldehyde oxime). In some embodiments, additives may be used, including but not limited to polyethyleneglycol and/or water, Et4NHC03, and cetryltrimethylammonium bromide.

In lieu of Compound (L-a), alternative starting material can be used, including but not limited to 5-bromo-2-fluoro-4-methylbenzoic acid, 2-fluoro-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)benzoic acid, and 2-fluoro-4-methyl-5-(tosyloxy)benzoic acid. Additionally, in lieu of the free base of Compound (K), various salts of Compound (K) may be used, such as the besylate salt.

Various solvents may be used, including but not limited to DMF, DMAc, DMSO, butyronitrile, xylenes, EtCN, dioxane, and toluene. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (L-b) with Compound (K) to provide Compound (D)

Compound (L-b) Compound (K) Compound (D)

Compound (L-b) (1 equiv), Compound (K) (1.2 equiv), and Cu(OAc)2 (1 equiv) was added methanol (about 20 vols) followed by pyridine (2.2 equiv). The mixture was then stirred at about 23 °C for about 16 h, then at about 45 °C for about 4 h.The reaction mixture was diluted with methanol (about 60 vols), filtered though a pad of celite and concentrated in vacuo to afford Compound (D) . 1H MR (400 MHz, DMSO-d6): δ 7.69 (d, 1H, J= 2.0 Hz), 7.67 (d, 1H, J= 8.0 Hz), 7.40 (d, 1H, J= 8.0 Hz), 7.15 (d, 1H, J= 2.0 Hz), 2.20 (s, 3H), 1.87-1.80 (m, 1H), 0.81-0.77 (m, 2H), 0.71-0.67 (m, 2H). 13C MR (100 MHz, DMSO-d6): 164.52, 164.48, 161.68, 159.12, 143.95, 141.63, 141.53, 137.34, 133.21, 133.18, 129.70, 119.85, 119.61, 118.08, 117.97, 116.25, 18.02, 9.21, 7.48.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of Compound (L-b), 2-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid may be used. In lieu of Compound (K), the besylate salt of Compound (K) may be used.

Various copper reagents can be employed, such as Cu(OTf)2, Cu20, and CuBr.

Alternative bases include but are not limited to triethylamine and N,N-diisopropylethylamine. Various solvents, such as DCM and DMF, may be employed. The reaction may take place at temperatures that range from about 23 °C to about 100 °C and under an atmosphere of oxygen or nitrogen.

Example 3: Alternative Synthesis of Compound (C)

C


Compound (C)

Coupling of Compound (O) with Compound (N-a) to form Compound (M)

Compound (O) Compound (N-a)

Compound (M)

To a mixture of Compound (O) (1.0 equiv), Compound (N-a) (1.6 equiv), PdCl2(PPh3)2 (65 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (10 mL). The mixture

was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 10 vols), washed with water (about 10 vols) and the layers of the biphasic mixture were separated. The organic layer was dried over MgS04 and concentrated in vacuo. The crude residue was purified by silica gel chromatography to afford Compound (M). 1H NMR (400

MHz, DMSO-de): δ 8.95 (s, 1H), 8.16-8.04 (m, 2H), 7.67 (d, 1H, J= 8.4 Hz), 5.34 (sep, 1H, J = 6.6 Hz), 1.50 (d, 6H, 6.6 Hz). 13NMR (100 MHz, DMSO-d6): 149.90, 149.58, 148.36, 144.11, 141.62, 125.27, 122.92, 48.91, 23.42.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Conversion of Compound (M) to form Compound (C)

Compound (M) Compound (C)

To a mixture of Compound (M) (1.0 equiv), Pd(OAc)2 (2.0 mol%), rac-BINAP (3.0 mol%), and Cs2C03 (1.4 equiv), was charged dioxane (about 9 vols) followed by benzophenone imine (2.0 equiv). The mixture was degassed, sealed and then heated to about 75 °C to about 85 °C under nitrogen. After a period of about 20 hours, the mixture was cooled to ambient temperature, and HC1 (6 M, about 8 vols) was charged until the pH of the reaction mixture was about 1 to about 2. The solution was maintained at ambient temperature for about 15 minutes, then NaOH (30 wt.%, about 1 to about 2 vols) was charged until the pH of the reaction mixture was about 8-9. The reaction mixture was concentrated in vacuo, slurried in MeOH (about 22 vols), and filtered to remove gross solids, which were washed with MeOH (2 x about 3 vols). The resulting solution was concentrated in vacuo, adsorbed onto celite and purified by silica gel chromatography to provide compound (C). LRMS [M+H]+: 204.08.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp, Pd(OAc)2/PPh3, Pd(OAc)2/dppe, Pd2dba3/dppf,

Pd2dba3/CyJohnPhos, Pd2dba3/P(t-Bu)3. Various ammonia sources may be used such as

LiHMDS or ammonium hydroxide. Various carbonate bases (e.g. K2C03 or Na2C03) or phosphate bases such as K3P04 may be used. Various solvents, such as THF, DMAc, DMSO, and NMP, may be employed. The reaction may take place at temperatures that range from about 75 °C to about 150 °C and pressures ranging from about 15 to about 50 psig.

Example 4: Alternative Synthesis of Compound (C)

Co 
mpound (O)

Compound (C)

Coupling of Compound (O) with Compound (P-a) to form Compound (C)

C


)

To a mixture of Compound (O) (1.0 equiv), Compound (P-a) (1.0 equiv), PdCl2(PPh3)2 (10 mol%), Cs2C03 (2.0 equiv), and Cul (4.7 mol%) was charged dioxane (about 20 vols). The mixture was degassed and then heated to about 95 °C to about 105 °C. After a period of about 20 to about 40 hours, the mixture was cooled to ambient temperature. The reaction mixture was diluted with EtOAc (about 40 vols) and the organic layer was washed with water (about 40 vols) The layers of the biphasic mixture were separated and the aqueous phase was extracted with

EtOAc (about 40 vols). The combined organic phases were concentrated in vacuo. To the residue was charged IPA (about 20 vols), and the resulting suspension was stirred at about 40 °C to about 50 °C for about 1 h and then stirred at ambient temperature for about 16 h. The suspension was cooled to about 5 °C, filtered and washed with cold IPA (about 4 vols). The resulting solids were dried at about 40 °C to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, J= 8.0 Hz), 1.42 (d, 6H, J= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, including but not limited to: Pd(PPh3)4, Pd2dba3/PPh3, Pd(OAc)2/dppf, Pd2dba3/dppp; Pd(OAc)2/PPh3; Pd(OAc)2/dppe; Pd2dba3/dppf, Pd(OAc) 2/(m-tolyl)3P, Pd(OAc)2/JohnPhos; PdCl2dppf, Pd(OAc)2/(o-tolyl)3P; PdCl2(AmPhos)2; Pd(OAc) 2/(cyclohexanlyl)3P. Various bases may be used, such as a carbonate base (e.g. K2C03 or Na2C03). Various solvents, such as DMF, DMAc, DMSO, butyronitrile, and NMP, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 150 °C.

Coupling of Compound (O) with Compound (P-b) to form Compound (C)

Co


)

A solution of Compound (O) (1.0 equiv) in THF (about 20 vols) was degassed with nitrogen. The solution was cooled to about -55 °C to about -70 °C and a solution of n-BuLi (1.6 M solution in hexane, 1.0 equiv) was added over about 15 to about 20 minutes. The suspension was stirred for about 15 to about 25 minutes at about -55 °C to about -60 °C, followed by the slow addition of ZnCl2 (0.5 M solution in THF, 1 equiv). The suspension was stirred for about 30 minutes and warmed to ambient temperature. To a separate flask was charged Compound (P-b) (1.0 equiv) and Pd(PPh3)4 (231 mg, 4.4 mol%) in dioxane (about 20 vols). The mixture was degassed and transferred to the flask containing the organozinc intermediate. The mixture was sealed and heated to about 115 °C to about 125 °C for about 15 hours then cooled to ambient temperatureThe reaction mixture was concentrated in vacuo at ambient temperature and triturated with MTBE (about 10 mL) to afford Compound (C). 1H NMR (400 MHz, DMSO-d6): δ 8.77 (s, 1H), 7.51 (t, 1H, J= 8.0 Hz), 7.18 (d, 1H, J= 4.0 Hz), 6.53 (d, 1H, J= 8.0 Hz), 6.17 (s, 1H), 5.53 (sep, 1H, 7= 8.0 Hz), 1.42 (d, 6H, 7= 8.0 Hz). 13NMR (100 MHz, DMSO-d6): 159.59, 151.18, 146.25, 142.97, 138.41, 111.90, 108.88, 48.12, 23.55.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, for the metallation, in lieu of n-BuLi, other organolithium reagents (such as t-BuLi, MeLi, and s-BuLi) or Grignard reagents (such as iPrMgCl and PhMgCl) may be used. In lieu of 1 equivalent of ZnCl2, 0.5 equivalent of ZnCl2 or ZnCl2 with LiCl, ZnBr2, or Znl2 can be used. Alternative solvents to THF can include 2-MeTHF, MTBE, or Et20, and this reaction may take place at temperatures that range from about -78 °C to about -40 °C.

Additionally, during the coupling reaction, alternative catalysts may be other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as Pd(PPh3)4.

Various solvents, such as NMP, THF, butyronitrile, and toluene, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 140 °C.

Example 5: Alternative Synthesis for Compound (D) 

Compound (E) Compound (Q) Compound (D)

Carboalkoxylation to form Compound (Q)

CO (1 atm)

Compound (E)

Compound (Q)

To a reaction flask was added 1-butanol (7 volumes). Compound (E) (1 equiv) was added followed by K2C03 (1.5 equiv) and Pd(dppf)Cl2 (0.02 equiv) and the reaction was placed under a CO atmostphere. The reaction mixture was heated at about 90 °C until reaction completion. The reaction contents were cooled to ambient temperature, the reaction mixture was filtered through a pad of Celite to remove solids, and then rinsed forward with EtOAc. The mother liquor was washed with water and brine, and dried over Na2S04, filtered, and concentrated to afford Compound (Q). Purification by flash chromatography afforded Compound (Q): 1H MR (400 MHz, CDC13) δ 7.77 (d, J = 6.7 Hz, 1H), 7.39 (s, 1H), 7.08 (d, J= 10.8 Hz, 1H), 6.74 (s, 1H), 4.31 (t, J= 6.6 Hz, 2H), 2.20 (s, 3H), 1.87 (m, 1H), 1.73 (tt, J= 6.7, 6.6 Hz, 3H), 1.43 (tq, J= 7.3, 7.4 Hz), 0.94 (t, J= 7.4 Hz, 3H), 0.88 (m, 2H), 0.79 (m, 2H); Exact mass for Ci8H22N202F [M+H], 317.2. Found [M+H], 317.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(dppf) or Pd(OAc)2 with PPh3, xantphos, tBu3P-HBF4, dppe, dppb, dpcb, tBu-dppf, and (Ad)2P(nBu). Alternative bases can be used, such as other carbonate bases (such as Cs2C03, and Na2C03), NaOAc, KOAc, or organic bases such as TMEDA, Et3N, and iPr2NEt. Various solvents may be employed, such as 1-butanol with other co-solvents (e.g. DMF). The reaction may take place at temperatures that range from about 70 °C to about 115 °C and at CO pressures of about 5 to about 50 psig.

Hydrolysis of Compound (Q) to Compound (D)

Compound (Q) Compound (D)

To a reaction flask was added Compound (Q) (1.0 equiv) and MeOH (7 volumes). A 25% NaOH solution (5 equiv) was then added dropwise. Consumption of Compound (D) was observed after about 1.5 hours at which point the pH of the solution was carefully adjusted to about 1 by the addition of 6 N HC1. Methanol was removed under vacuum to afford a solid which was isolated by filtration. The crude product was first triturated in THF and then filtered. This solid was then triturated in CH2Cl2/MeOH (9: 1) and filtered. Concentration of the mother liquor afforded Compound (D). 1H MR (400 MHz, CD3OD) δ 8.87 (s, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.43 (s, 1H), 7.31 (d, J= 1 1.5 Hz, lH), 2.21 (s, 3H), 1.96 (m, 1H), 1.04 (m, 2H), 0.81 (m, 2H); LRMS: Calculated mass for C14H14N2O2F [M+H], 261.1. Found [M+H], 261.

Alternative reagents and reaction conditions to those disclosed above may also be employed.

For example, an alternative hydroxide base, including but not limited to KOH, LiOH, and CsOH, may be used in lieu of NaOH. Various solvents may be employed, such as THF, EtOH, and 2-propanol. The reaction may take place at temperatures that range from about 0 °C to about 50 °C.

Example 6: Alternative Synthesis of Compound (A)

Com ound C

(A)

Compound (E) (1 equiv.), Compound (C) (1 equiv.), DMF (about 16 vols), Et3N (1.5 equiv.), Pd(OAc)2 (0.02 equiv.), and Ad2P(«-Bu) (0.04 equiv.) were combined and the contents were purged with N2 followed by CO and then pressurized with CO (20 psi). The reaction mixture was heated to about 95 °C to about 105 °C. After about 24 hours, the reaction was allowed to cool to about 20 °C to about 30 °C to afford Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative catalysts may be used. Non-limiting examples include other Pd (II) complexes or Pd(0) complexes with trialkyl or triarylphosphine ligands, such as

PdCl2(PPh3)2, PdCl2(A-Phos)2 or Pd(OAc)2 with PPh3. Alternative bases can be used, including but not limited to other organic bases (such as iPr2NEt and TMEDA) and inorganic bases (such as NaOAc, KOAc, Na2C03, and Cs2C03). Various solvents, NMP, dioxane, and toluene, may be employed. The reaction may take place at temperatures that range from about 90 °C to about 120 °C and at CO pressures of about 20 psig to about 60 psig.

Example 7: Alternative Synthesis of Compound (A)

Compound (A)

Compound (D) (1.0 equiv), Compound (C) (1.05 equiv), 4-(dimethylamino)pyridine (1.0 equiv), ethyl acetate (about 4 V) and diisopropylethylamine (1.2 equiv) were combined and the resulting slurry was charged T3P® as a 50 wt% solution in ethyl acetate (2.0 equiv) over about 3 min at about 20 °C. During the addition, a small exotherm was observed. The mixture was stirred at about 20 °C for about 24 h. After reaction completion, 0.5 M aqueous hydrochloric acid (about 5 vols was added, and the mixture was stirred for about 15 min. Stirring was then stopped, and the phases were allowed to separate. Then, the aqueous phase was reintroduced to the reactor. The pH of the aqueous solution was then adjusted to about 7 with a 5 wt% solution of aqueous sodium hydroxide (about 12 vols). The resulting slurry was stirred for about 12 h at about 20 °C and then filtered, and the reactor was rinsed forward with water (about 3 vols). The filter cake was washed with isopropanol (2 vols), and the resulting solids were dried under vacuum at about 45 °C to provide Compound (A).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of T3P®, other coupling reagents may be used, including but not limited to Ι, Γ-carbonyldiimidazole, isobutyl chloroformate, pivoyl chloride, EDC-HCl/HOBt, thionyl chloride, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride. Alternative bases may be used, including but not limited organic amines (such as trialkyl amine bases (for example, triethylamine), N-methyl morpholine, and the like) and carbonates (such as lithium carbonates, sodium carbonates, cesium carbonates, and the like). Various solvents, such as DCM, THF, DMF, ethyl acetate, MTBE, toluene, MP, DMAc, acetonitrile, dichloroethane,

2-MeTHF, and cyclopentyl methyl ether, may be employed. The reaction may take place at temperatures that range from about -10 °C to about 60 °C or from about 0 °C to about 30 °C.

Example 8: Alternative Synthesis of Compound (C)

Compound (8-b)

The mixture of Compound (8-a) and Compound (8-b) is dissolved in about 10 volumes of process water. The solution is heated to about 80 °C, and the solution is allowed to age for about 6 hours. Upon reaction completion, the solution is cooled to about 60 °C. The reaction mixture is seeded with 0.001 equiv of Compound (C), which was obtained by suitable means, and cooled to about 0 °C. Compound (C) is filtered from the cold aqueous solution to yield the product.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, instead of the mixture of Compuond (8-a) and (8-b), the reaction may be carried out with Compound (8-a) or Compound (8-b). Additionally, other organic acids may be used, including but not limited to acetic acid and trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, MP, and 2-MeTHF, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

rnative Synthesis of Compound (C)

Compound (9-c)

Compound (C) may be synthesized as described in U.S. Patent No. 8,742, 126, which is hereby incorporated by reference in its entirety. Additionally, when starting with Compound (9-a), it was found that Compound (C) may be formed through two additional intermediates, Compound (9-b) and Compound (9-c). LRMS for Compound (9-b): Calculated mass, C14H14N2O2F [M+H], 235.1; Found [M+H], 235.9. LRMS for Compound (9-c): Calculated mass, C14H14N2O2F [M+H], 207.1; Found [M+H], 208.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in lieu of acetic acid, other organic acids may be used, including but not limited to trifluoroacetic acid. Various solvents, such as toluene, dimethylacetamide, NMP, 2-MeTHF, acetic acid, and water, may be employed. The reaction may take place at

temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 10: Alternative Synthesis of Compou

Compound (10-a) Compound (C)

Compound (10-a) (1 equiv), toluene (about 20 vols), N-isopropylformamide (3.00 equiv), isopropylamine (3.00 equiv) and trifluoroacetic acid (2.50 equiv) were sequentially

combined. The vial was sealed and heated to about 100 °C. After about 22 h, the vial was cooled to room temperature and the contents were analyzed by HPLC. Compound (C) was observed by HPLC.

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, other organic acids may be used, including but not limited to acetic acid. Various solvents, such as dimethylacetamide, MP, and acetic acid, may be employed. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 100 °C.

Example 11: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (11 -b) Compound (C)

Compound (10-a) (1.0 equiv), toluene (about 12 volumes), 79 wt% 

dimethylformimidamide (3.0 equiv), isopropylamine (3.0 equiv) and trifluoroacetic acid 2.5 equiv) were combined and heated to about 100 °C. After about 22 h, the reaction mixture was cooled to room temperature. The mixture was seeded with Compound (C), which was obtained by suitable means, and cooled to about 0 °C. After about 30 min, the heterogeneous mixture was filtered and the vial was rinsed forward with toluene (about 25 vols). The solid was collected and dried under vacuum at about 40 °C to provide Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, organic acids may be used, including but not limited to acetic acid. Various solvents, such as acetic acid, dimethylacetamide, and NMP, may be employed.

Alternative organic amines may also be added. The reaction may take place at temperatures that range from about 80 °C to about 110 °C or about 90 °C to about 100 °C.

Example 12: Alternative Synthesis of Compound (C)

Compound (10-a) Compound (C)

A suitable reactor fitted with a reflux condenser was charged with acyl hydrazide (1 equiv), toluene (6 volumes), isopropylamine (7.20 equiv) andN.N-dimethylformamide dipropyl acetal (2.70 equiv). To the resulting slurry was charged acetic acid (1.50 equiv) over about 2 min at about 20 °C. During the addition, an exotherm was observed. The mixture was heated to about 95 °C for about 20 h. After reaction completion, the mixture was concentrated under vacuum at about 80 °C. The mixture was diluted with water (10 volumes), and the resulting biphasic solution was concentrated under vacuum at about 80 °C. Water was added (3 volumes), and the solution is heated to about 85 °C. The resulting solution was cooled to about 60 °C and seeded with Compound (C), which was obtained by suitable means. The resulting slurry was aged for about 30 min and then cooled to about 20 °C over about 1 h and aged for about 15 h. The resulting slurry was cooled to about 5 °C and aged for about 3 h. The cold slurry is filtered and the reactor is rinsed forward with cold water (15 mL). The resulting solids were dried under vacuum at about 40 °C to give Compound (C).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative formamide reagents may be used, such as dimethyl formamide diethyl acetal, dimethyl formamide diisopropyl acetal, dimethyl formamide disec-butyl acetal, dimethyl formamide diisobutyl acetal, and the like. Other organic acids may be used, including but not limited to trifluoroacetic acid, chloroacetic acid, and methanesulfonic acid. Various solvents, such as acetic acid, dimethylacetamide, 2-MeTHF, NMP, isobutyl acetate, isobu

Phase 2 Data for Selonsertib in Nonalcoholic Steatohepatitis (NASH) Presented at The Liver Meeting® 2016

— Results Demonstrate Improvement in Fibrosis Stage among NASH Patients with Moderate to Severe Fibrosis —

BOSTON–(BUSINESS WIRE)–Nov. 14, 2016– Gilead Sciences (Nasdaq:GILD) today announced detailed results from an open-label Phase 2 trial evaluating the investigational apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997) alone or in combination with the monoclonal antibody simtuzumab (SIM) in patients with nonalcoholic steatohepatitis (NASH) and moderate to severe liver fibrosis (fibrosis stages F2 or F3). The data demonstrate regression in fibrosis that was, in parallel, associated with reductions in other measures of liver injury in patients treated with selonsertib for 24 weeks. These data were presented in a late-breaking abstract session at The Liver Meeting® 2016 in Boston (#LB-3).

Patients receiving selonsertib demonstrated improvements in several measures of liver disease severity, including fibrosis stage, progression to cirrhosis, liver stiffness (measured by magnetic resonance elastography, MRE) and liver fat content (measured by magnetic resonance imaging (MRI)-proton density fat fraction, PDFF). Data for these efficacy endpoints are summarized in the table below. As no differences were observed between combination and monotherapy, results are presented for selonsertib (18 mg and 6 mg) with/without SIM and for SIM alone. Additionally, patients with fibrosis improvement demonstrated reductions in hepatic collagen content, liver biochemistry (e.g., serum ALT) and the apoptosis marker, cytokeratin-18, supporting the biological activity of selonsertib.

Endpoint (Week 24) Selonsertib

18 mg ± SIM

Selonsertib 
6 mg ± SIM

SIM
Fibrosis Improvement ≥1 Stage from Baseline* 43% (n=13/30) 30% (n=8/27) 20% (n=2/10)
Progression to Cirrhosis 3% (n=1/30) 7% (n=2/27) 20% (n=2/10)
≥15% Reduction in Liver Stiffness by MRE 20% (n=5/25) 32% (n=7/22) 0% (n=0/7)
≥30% Reduction in Liver Fat by MRI-PDFF 26% (n=8/31) 13% (n=3/24) 10% (n=1/10)

*Fibrosis staged according to the NASH Clinical Research Network (CRN) classification by a central pathologist blinded to treatment group.

Selonsertib demonstrated no dose-related increases in treatment-emergent adverse events or serious adverse events. Headache, nausea and sinusitis were the most common adverse events in patients receiving selonsertib.

“Currently, no approved treatments exists for NASH, and patients with advanced fibrosis would potentially benefit from new options to halt and/or reverse the progression of their disease,” said Rohit Loomba, MD, MHSc, lead study author and Director, NAFLD Research Center, Director of Hepatology, Professor of Medicine, Vice Chief, Division of Gastroenterology, University of California San Diego School of Medicine. “After only 24 weeks of therapy, selonsertib exhibited promising anti-fibrotic activity in this study, which was the first known multi-center NASH clinical trial to use centrally-assessed MRE, MRI-PDFF, in addition to liver biopsy as endpoints. Based on these data, selonsertib represents an important investigational drug candidate for further clinical trials in patients with NASH and significant fibrosis.”

Other Gilead NASH data being presented at The Liver Meeting include results from Phase 1 studies evaluating the investigational selective, non-steroidal Farnesoid X receptor (FXR) agonist GS-9674. Data from a Phase 1 study demonstrated the biological activity and safety profile of GS-9674 in healthy volunteers and support the evaluation of this compound in patients with NASH and cholestatic liver disorders (#1077 and #1140). Phase 2 studies with GS-9674 are ongoing in patients with NASH, primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Additionally, preclinical data for the combination of selonsertib and GS-9674 in a rodent model of advanced fibrosis suggested that the combination of selonsertib and GS-9674 resulted in greater anti-fibrotic activity than either agent alone (#1588). These preclinical data support clinical evaluation of combination approaches with selonsertib and GS-9674 in patients with NASH and advanced fibrosis.

Selonsertib, GS-9674 and simtuzumab have not been determined to be safe or efficacious.

About Selonsertib and the Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

This Phase 2, randomized, open-label trial evaluated the safety, tolerability and efficacy of selonsertib alone or in combination with SIM in 72 patients with NASH and fibrosis stages F2 (n=25) or F3 (n=47). Eligible patients were randomized (2:2:1:1:1) to receive selonsertib 6 mg (n=20), selonsertib 18 mg (n=22), selonsertib 6 mg plus SIM 125 mg (n=10), selonsertib 18 mg plus SIM 125 mg (n=10) or SIM 125 mg alone (n=10) for 24 weeks. Selonsertib was administered orally once daily and SIM was administered via weekly subcutaneous injection.

About Gilead’s Clinical Programs in NASH

Gilead is advancing a pipeline of novel investigational therapies for the treatment of NASH with advanced fibrosis. Gilead is currently planning or conducting Phase 2 and Phase 3 clinical trials evaluating single-agent and combination therapy approaches against multiple core pathways associated with NASH – metabolic dysfunction, inflammation and fibrosis. Compounds in development include the ASK1 inhibitor, selonsertib; the FXR agonist, GS-9674; and an inhibitor of acetyl-coA carboxylase (ACC), GS-0976, currently being evaluated in a Phase 2 study in patients with NASH.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

 

Patent ID

Patent Title

Submitted Date

Granted Date

US2016166556 METHODS OF TREATING PULMONARY HYPERTENSION
2015-08-11
2016-06-16
US2015342943 METHODS OF TREATING LIVER DISEASE
2015-05-29
2015-12-03
US9771328 Processes for preparing ASK1 inhibitors
2017-01-23
2017-09-26
US9586933 Processes for preparing ASK1 inhibitors
2015-12-22
2016-08-25
US8742126 Apoptosis signal-regulating kinase inhibitor
2013-01-24
2014-06-03
Patent ID

Patent Title

Submitted Date

Granted Date

US9643956 SOLID FORMS OF AN ASK1 INHIBITOR
2015-12-22
2016-09-29
US9750730 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2016-04-27
2016-08-18
US2017273952 METHODS OF TREATING LIVER DISEASE
2015-09-22
US9333197 APOPTOSIS SIGNAL-REGULATING KINASE INHIBITOR
2014-04-16
2014-08-14
US8552196 Apoptosis signal-regulating kinase inhibitors
2012-09-13
2013-10-08

/////////Selonsertib,  GS-4997, PHASE 3, GILEAD, GS-4997, GS-4977

CC1=C(C=C(C(=C1)F)C(=O)NC2=CC=CC(=N2)C3=NN=CN3C(C)C)N4C=C(N=C4)C5CC5

GFT 505, Elafibranor, элафибранор , إيلافيبرانور , 依非兰诺 


Image result for Elafibranor

ChemSpider 2D Image | (E)-Elafibranor | C22H24O4SElafibranor.pngChemSpider 2D Image | Elafibranor | C22H24O4S

(E)-Elafibranor

  • Molecular FormulaC22H24O4S
  • Average mass384.489 Da

Elafibranor

CAS 824932-88-9  E Z MIXTURE USAN

CAS 923978-27-2 E ISOMER INN

2-(2,6-Dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropanoic acid

Elafibranor(GFT505)
GFT505;GFT-505;GFT 505
UNII:2J3H5C81A5
(E)-Elafibranor
2-(2,6-Dimethyl-4-{(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropanoic acid
2-(2,6-Dimethyl-4-{(1E)-3-[4-(methylsulfanyl)phenyl]-3-oxo-1-propen-1-yl}phenoxy)-2-methylpropansäure
2J3H5C81A5
CAS 923978-27-2 E ISOMER INN
Acide 2-(2,6-diméthyl-4-{(1E)-3-[4-(méthylsulfanyl)phényl]-3-oxo-1-propén-1-yl}phénoxy)-2-méthylpropanoïque[French] [ACD/IUPAC Name]
GFT505
Propanoic acid, 2-[2,6-dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methyl-
UNII-2J3H5C81A5
(E)-2-(2,6-Dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenoxy)-2-methylpropanoic acid
элафибранор[Russian][INN]
إيلافيبرانور[Arabic][INN]
依非兰诺[Chinese][INN]
UNII-2J3H5C81A5
Treatment of Non-Alcoholic Steato-Hepatitis, Reducing Cardiometabolic Risk Factors in Patients with Diabetes and Pre-Diabetes
InventorJean DelhomelKarine Caumont-Bertrand Current Assignee Genfit
Priority date 2002-07-08  EXPIRY 2032 JULY
OTHERS
US7385082
US8058308
CN 106674069
WO 2016127019
WO 2018060373
WO 2018060372
INNOVATOR Genfit SA
Image result for Genfit SA
FAST TRACK FDA
Fibrosis; Primary biliary cirrhosis; Cholangitis; Obesity; Non-alcoholic steatohepatitis; Lipid metabolism disorder; Cancer; Non-insulin dependent diabetes; Crohns disease
Genfit is developing elafibranor (GFT-505; structure shown), a PPAR alpha and delta agonist with antioxidant properties and an anti-inflammatory action, for the potential oral treatment of non-alcoholic steatohepatitis (NASH) dyslipidemia, type 2 diabetes, atherogenic dyslipidemia, abdominal obesity and primary biliary cholangitis (PBC)

REGULATORY

In November 2016, the EMA approved elafibranor’s Pediatric Investigation Plan (PIP) . In February 2017, the company expected to obtain conditional marketing authorization for elafibranor in NASH during the course of the second half of 2019 or first half of 2020 .

In February 2014, the FDA granted Fast Track designation for GFT-505 for the treatment of NASH

PHASE III

In March 2015, the company was planning to begin a late stage phase III trial in patients with seriously Ill NASH (expected n = 2,000)

EUROPE

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001857-PIP01-15/pip_001493.jsp&mid=WC0b01ac058001d129

Active substance Elafibranor
Decision number P/0237/2016
PIP number EMEA-001857-PIP01-15
Pharmaceutical form(s) Capsule, hard; Coated tablet
Condition(s)/indication(s) Treatment of non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH)
Route(s) of administration Oral use
PIP applicant Genfit SA
France
Tel.+33 320164000
Fax +33 320164001
Email: contact@genfit.com
Decision type P: decision agreeing on a investigation plan, with or without partial waiver(s) and or deferral(s)
Doubts on drug substance
  • Elafibranor
  • GFT 505
  • GFT-505
  • UNII-2J3H5C81A5

scifinder refers to CAS Registry Number 923978-27-2 as E isomer

  • 2-[2,6-Dimethyl-4-[(1E)-3-[4-(methylthio)phenyl]-3-oxo-1-propen-1-yl]phenoxy]-2-methylpropanoic acid
  • GFT 505

SYNTHESIS

6 STEPS

WO 2005005369, WO 2004005233

SYN 2

CN106674069

Solubility (25°C)

In vitro DMSO 76 mg/mL (197.66 mM)
Ethanol 76 mg/mL (197.66 mM)
Water Insoluble

Biological Activity

Description Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α(PPAR-alpha) and peroxisome proliferator-activated receptor-δ(PPAR-δ). It improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation.
Targets
PPARα [1]
()
PPARδ [1]
()
In vitro GFT505 is a novel PPAR modulator that shows a preferential activity on PPAR-α and concomitant activity on PPAR-δ[2].
In vivo Elafibranor (GFT505) is a dual PPARα/δ agonist that has demonstrated efficacy in disease models of nonalcoholic fatty liver disease (NAFLD)/NASH and liver fibrosis. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. Elafibranor confers liver protection by acting on several pathways involved in NASH pathogenesis, reducing steatosis, inflammation, and fibrosis. GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression[1].

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Elafibranor (code name GFT505) is a multimodal and pluripotent medication for treatment of atherogenic dyslipidemia for an overweight patient with or without diabetes. It is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.

Elafibranor (INN,[2] code name GFT505) is an experimental medication that is being studied and developed by Genfit for the treatment of cardiometabolic diseases including diabetesinsulin resistancedyslipidemia, and non-alcoholic fatty liver disease (NAFLD).[3][4][5]

Elafibranor is a dual PPARα/δ agonist.[6][7]

Elafibranor is an agonist of the peroxisome proliferator-activated receptor-α(PPAR-alpha) and peroxisome proliferator-activated receptor-δ(PPAR-δ). It improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation

FT505 is an oral treatment that acts on the 3 sub-types of PPAR (PPARa, PPARg, PPARd) with a preferential action on PPARa. It has a sophisticated mechanism of action. It is able to differentially recruit cofactors to the nuclear receptor, which subsequently lead to differential regulation of genes and biological effect. Therefore, the ability to identify and profile the activity of selective nuclear receptor modulator (SNuRMs) is a powerful approach to select innovative drug candidates with improved efficacy and diminished side effects. These pluripotent and multimodal molecules have significant positive effects on obesity, insulin-resistance and diabetes, atherosclerosis, inflammation, and the lipid triad (increasing of HDL cholesterol, lowering of triglycerides and LDL cholesterol).

Clinical studies

Administered to over 800 patients and healthy volunteers to date, elafibranor has demonstrated:

  • beneficial properties for non-alcoholic steatohepatitis (NASH)[8]
  • improvement of insulin sensitivity and glucose homeostasis[9]

Phase 2b (GOLDEN) results were published online in Gastroenterology in February 2016[10] and will be fully available in the paper version in May 2016.

As of February 2016, elafibranor has completed 8 clinical trials and a phase III is in progress.[11]

Pre-clinical studies

Efficacy on histological NASH parameters (steatosis, inflammation, fibrosis) in animal disease models — anti-fibrotic activities.[12]

The absence of safety concern has been confirmed in a full toxicological package up to 2-year carcinogenicity studies and cardiac studies (in mice).[13]

PATENT

20060142611 or 20050176808

Patent

US20070032543

https://patents.google.com/patent/US20070032543A1/en

    Compound 29: 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-carboxydimethylmethyloxyphenyl]prop-2-en-1-one

  • Figure US20070032543A1-20070208-C00178
  • This compound was synthesized from 1-[4-methylthiophenyl]-3-[3,5-dimethyl-4-isopropyloxycarbonyldimethylmethyloxyphenyl]prop-2-en-1-one (compound 28) according to general method 5 described earlier.
  • Purification was made by chromatography on silica gel (elution: dichloromethane/methanol 98:2).
  • 1H NMR DMSO-dδppm: 1.39 (s, 6H), 2.22 (s, 6H), 2.57 (s, 3H), 7.40 (d, J=8.55 Hz, 2H), 7.57 (s, 2H), 7.62 (d, J=15.5 Hz, 1H), 7.83 (d, J=15.5 Hz, 1H), 8.1 (d, J=8.55 Hz, 2H), 12.97 (s, 1H).
  • MS (ES-MS): 383.3 (M−1).

PATENT

WO 2016127019

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=FD673C8170C27624DC7C0E0C9420AD23.wapp2nB?docId=WO2016127019&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

CN 106674069

https://patents.google.com/patent/CN106674069A/enhttps://patents.google.com/patent/CN106674069A/en

The liver is one of the most important organs of the body, is one of the highest organ of risk. Many factors can lead to liver disease. For example, drinking too much can lead to cirrhosis, excessive medication can lead to liver damage and even obesity can lead to fatty liver. Thus, the pharmaceutical treatment of fatty liver diseases has become a hot spot of bio-pharmaceutical development.

French Genf biopharmaceutical company said recently that the US Food and Drug Administration has agreed to continue the development of peroxisome proliferator-activated receptor α / δ dual agonist GFT505, and begin Phase IIb study in the United States. GFT 505 is expected to rule early diagnosis of fatty liver, heart disease and its complications, prevention and treatment of diabetes-related lipid hyperlipidemia. French Food and Drug Administration approval to a detailed in-depth far for preclinical and clinical data were analyzed based. Experts expressed the Authority, GFT505 to ensure safe operation and research and can lead to liver cancer or liver cirrhosis related biomarkers all favorable. GFT505 structure as shown in formula III.

Figure CN106674069AD00061

GFT505 Intermediate I is a key intermediate GFT505III, the existing technology (e.g., Patent Document 1 ^ 1 ^ 20060142611 or 20050176808) are synthesized by the method of 4-methylthio-acetophenone and 3,5 dimethyl-4-hydroxybenzaldehyde GFT505 condensation of intermediate IV, with 2-bromo-iso-butyric acid tert-butyl ester obtained. Process GFT505 Intermediate I Z double bond configuration is a type, but the 4-methylthio-acetophenone and 3,5_-dimethyl-4-hydroxybenzaldehyde condensation process, the formation of a double bond, it is difficult GFT505 avoid intermediate IV of formula Z, E mixtures of formula, and then 2-bromo-iso-butyric acid tert-butyl ester to give GFT505 intermediate II, R is also of formula Z, E mixtures of formula. E-isomer and Z-type polarity very close to the crystallization purification difficult, very precise product by column chromatography is not suitable for industrial production.

Figure CN106674069AD00062

 Accordingly, a need to find an efficient synthesis, reducing the content of Z-isomer impurities to improve the purity and yield of the products, and to avoid use of column chromatography purification process difficult industrialization.

The present invention provides a method for the preparation of intermediate I GFT505, comprising the steps of: an organic solvent, a compound II with an alkali metal t-butoxide isomerization reaction to give intermediate I GFT505; the said compound II is a double bond in Z / E mixtures, according GFT505 intermediate I is a compound of formula E; the double bonds in Z / E mixtures of formula Z refers to the product from 0.1% to 99.0% of the total mass of the mixture (including 0.1%, comprising 99.0%); the compound of formula E E means that the content of the compound of formula more than 99.0% (including 99.0%);

Figure CN106674069AD00071

 In reaction I of the preparation of intermediates GFT505, the organic solvent is preferably a protic solvent, a polar aprotic organic solvent non-polar solvent, more preferably a non-polar solvent. The protic solvent is preferably & ~ (: 4 alcoholic solvent; the & ~ (: t-butanol 4 alcoholic solvent preferably the polar aprotic organic solvent is preferably C 1-C4 nitrile solvents, &. ~ C6 ketone solvents, C1-C4 one or more 4 sulfone amide solvents and C1-C solvent. C1-C4 of the nitrile solvents preferably acetonitrile. the C 1-C6 ketone solvent preferably acetone and / or methyl isobutyl ketone. C1-C4 of the amide-based solvent is preferably N, N- dimethylformamide. C 1-C4 of the sulfone solvent is preferably dimethylsulfoxide. the said nonpolar solvent is preferably aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent preferably toluene.

Example 1: Preparation of intermediate IV GFT505 (refer to Patent W02011 / 144579)

Figure CN106674069AD00091

 A mixture of 4-mercapto-acetophenone (50g, 0.30 Imo 1), 3,5- dimethyl-4-hydroxybenzaldehyde (45g, 0.30 Imo 1) was added to a methanol solution of hydrogen chloride in 200ml (4moI / L) , 20 ~ 30 ° C for 3 hours, cooled to 0 ~ 10 ° C, stirred for 1 hour, filtered and dried to give 83g GFT505 intermediate (IV) as a yellow solid in 93% yield.

Example 2: Preparation of intermediate IV GFT505 (refer to Patent W02011 / 144579)

A mixture of 4-mercapto-acetophenone (I 9Kg, 114mo 1), 3,5- dimethyl-4-hydroxybenzaldehyde (I 7.1Kg, 114mo 1) was added to a methanol solution of hydrogen chloride in 76L (4mol / L ), 20 ~ 30 ° C for 3 hours, cooled to 0 ~ 10 ° C, stirred for 1 hour, centrifuged, 40 ° C and dried under vacuum for 12 hours to obtain 31.6Kg GFT505 intermediate (IV) as a yellow solid, yield 93% . LCMS: m / z = 299 (M + H) +.

Example 3: GFT505 intermediate II preparation (Ref US2006 / 142611)

Figure CN106674069AD00092

 The GFT505 Intermediate IV (78.8g, 0.263mol) was added to the reaction flask was added acetonitrile (480 ml of), potassium carbonate (54.5g, 0.395mol), tert-butyl 2-bromo-isobutyrate (39.3 g, 0.176mol), heated to 75 ~ 85 ° C for 10 hours, additional potassium carbonate (54.5g, 0.395mol), 2_ tert-butyl bromoisobutyrate (39.3g, 0.176mol) 10 hours, refed with potassium carbonate (54 · 5g, 0 · 395mol), 2- tert-butyl bromoisobutyrate (39 · 3g, 0 · 176mol) for 10 hours, until completion of the reaction compound, and concentrated under reduced pressure to dryness, was added 800g 400g of dichloromethane and water, layers were separated, washed with water, the organic phase dried over anhydrous sodium sulfate, filtered, the organic phase was concentrated to dryness, ethyl acetate and petroleum ether to give a solid compound II 81. Ig, yield 70% 〇

Example 4: GFT505 intermediate II preparation (Ref US2006 / 142611)

The GFT505 Intermediate IV (30Kg, 100mol) was added to acetonitrile (183L) was added potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14 · 9Kg, 66 · 8mol), was heated to 75 ~ 85 ° C for 10 hours, additional potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14.9Kg, 66.8mol) for 10 hours, refed with potassium carbonate (21Kg, 152mol), 2- tert-butyl bromoisobutyrate (14.9Kg, 66.8mol) for 10 hours, until the reaction was complete compound, 45 ~ 55 ° C was slowly concentrated under reduced pressure to distilled off, water was added and 300Kg 160Kg dichloromethane , the organic layer was separated out, IOOKg IOOKg water and washed with 10% concentration of aqueous sodium chloride solution (the mass concentration refers to the percentage by mass of the total mass of sodium chloride aqueous solution), 15 to 25 ° C was slowly distilled off under reduced pressure to concentrate. Ethyl acetate was added IOOKg was heated to 75 ~ 85 ° C a clear solution was added heptane 180Kg, cooled to stirred 15 ~ 25 ° C for 2-3 hours. Centrifugation, washed with n-heptane 40Kg, 40 ~ 50 ° C was dried in vacuo for 12 hours to obtain 31.6Kg GFT505 intermediate II, R a yield of 71.6%. LC-MS: m / z = 441 (M + H) + square

Example 5: Preparation of Intermediate I GFT505

Figure CN106674069AD00101

Compound II (81 · lg, 0.184mol) was added to 400g of toluene, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (26.8g, 0.279mol), heated to 50 ~ 60 ° C for 2 hours , 400g of water was added, layers were separated, washed with water, the organic phase concentrated to dryness under reduced pressure, methanol was added to 200ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (-0 · 08MPa ~ -0 · IMPa ) was dried in vacuo for 12 hours to give a yellow solid 78.8g GFT505 intermediate I, a yield of 97.0% APLC: 99.23% (in terms of E-form, Z configurational isomers accounted for 0.085%, largest other single impurity 0.41%).

Intermediate I the preparation of GFT505: 6 cases of  Embodiment

Figure CN106674069AD00102

Compound II (31Kg, 70.5mol) was added to 153Kg of toluene, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (10 · 3Kg, 107mol), warmed to 50 ~ 60 ° C for 2 hours, 160Kg of water, layered, and water IOOKg IOOKg mass concentration of the aqueous solution was washed with 10% sodium chloride (the concentration refers to the percentage by mass of the total mass of sodium chloride aqueous solution), 40 ~ 50 ° C Save concentrated under pressure to slowly distilled off, methanol was added to 60Kg, cooled to 0 ~ 10 ° C, stirred for 1 hour, centrifuged, washed with methanol 20Kg, 40 ~ 50 ° C (-0.08MPa ~ -0.1 MPa) was dried under vacuum for 12 hours to give 30.4 Kg GFT505 yellow solid intermediate I, 1.0 yield 98%. LC-MS: m / z = 441 (M + H) +; HPLC: 99 · 50% E configuration similar terms, Z configurational isomers accounted for 0.082%, largest other single impurity of 0.32%.

7  Example: Preparation of Intermediate I GFT505

 The compound II (8.0g, 0.018mol) was added to 64g tert-butanol, cooled to 10 ~ 20 ° C, was added potassium tert-butoxide (6.05g, 0.054mol), heated to 70 ~ 80 ° C Reaction 4 to 5 hours, was added 200g of water, 60g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.62g yellow solid GFT505 intermediate I, a yield of 95.2% dHPLC: 99.36% (in terms of E-form, Z configurational isomers accounted for 0.079%, single largest other 0.42% impurities).

Example 8: Preparation of Intermediate I GFT505

Compound II (8.Og, 0.018mo 1) was added to 16g N, N- dimethylformamide, cooled to 10 ~ 20 ° C, was added sodium tert-butoxide (2.17g, 0.023mol), heated to the reaction 90 ~ 100 ° C for 1-2 hours, was added 100g of water, 60g extracted twice with isopropyl acetate, the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to O-HTC, stirred for 1 hour, filtered, 40 ~ 50 ° C (-0.08MPa ~ -0 IMPa.) was dried in vacuo for 12 hours to give 7.34g yellow solid GFT505 intermediate I, a yield of 91.7% APLC: 99.21% E configuration similar terms, Z configurational isomers accounted 0.097%, the largest single other impurities 0.48%).

9  Example: Preparation of Intermediate I GFT505

The compound II (8.0g, 0.018mol) was added to 160g of acetonitrile, cooled to 10 ~ 20 ° C, was added lithium t (7.21g, 0.090mol) butanol, warmed to 40 ~ 50 ° C the reaction 9-10 hours, was added 160g of water, 90g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to 0-10 ° C, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.29g yellow solid GFT505 intermediate I, a yield of 91.1% dHPLC: 99.16% (in terms of E-form, Z configurational isomers accounted for 0.089%, largest other single impurity 0.49 %).

10  Example: Preparation of Intermediate I GFT505

The compound II (8.0g, 0.018mol) was added to 28g of dimethyl sulfoxide, cooled to 10 ~ 20 ° C, was added potassium t-butoxide (5.04g, 0.045mol), heated to 60 ~ 70 ° C the reaction 3 to 4 hours, was added 100g of water, 60g extracted twice with isopropyl acetate, and the organic phase concentrated to dryness under reduced pressure, methanol was added 20ml, cooled to O-UTC, stirred for 1 hour, filtered, 40 ~ 50 ° C (_ 0.08 MPa ~ -0.1 MPa) was dried in vacuo for 12 hours to give 7.33g yellow solid GFT505 intermediate I, a yield of 91.6% dHPLC: 99.46% (in terms of E-form, Z configurational isomers accounted for 0.077%, largest single impurity other 0.27%).

Preparation of GFT505III: 11 cases of Embodiment

Figure CN106674069AD00111

 The GFT505 Intermediate I (77.9g, 0.177mol, may be prepared as described in Example 10) was added to the reaction flask was added 790g of dichloromethane was added trifluoroacetic acid (209.7g, 1.84mol), 20 ~ 30 ° C the reaction for 5-6 hours, concentrated to dryness, was added 600ml ethyl acetate and 600ml of water, layers were separated, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated to a small volume the organic phase, 10-20 ° C for 2 hours crystallization, filtration, under -0.08MPa ~ -0.1 MPa, 40 ° C ~ 50 ° C was dried in vacuo 12 hours to give 60.1 g as a yellow solid. 25〇1 yellow solid was recrystallized from ethyl acetate to give 52.98 ^ as a yellow solid 6? 505 (111), a yield of 77.8%.

 LC-MS: m / z = 385 (M + H) +; HPLC: 99 · 86%, largest single impurity 0.5 06%.

GFT505III prepared: Example 12 Embodiment

The GFT505 Intermediate I (30Kg, 68.2mol, may be prepared as described in Example 9) was added to 307Kg dichloromethane was added trifluoroacetic acid (80.8Kg, 709mol), 20-30 ° C the reaction 5-6 h, concentrated to dryness, ethyl acetate and water 197Kg 231Kg, layered, and water IOOKg IOOKg concentration of 10 mass% aqueous sodium chloride concentration (which refers to the quality of the aqueous solution of sodium chloride percentage of total mass) washing, 40 ~ 50 ° C to about 80Kg concentrated under reduced pressure, cooled to IO ~ 20 ° C for 2 hours crystallization, centrifugation was washed with ethyl acetate 20Kg, at -0.08MPa ~ -O.IMPa, 40 ~ 50 ° C was dried in vacuo for 12 hours to give a yellow solid was 23.2Kg. As a yellow solid was obtained as a yellow solid GFT505III 20.9Kg 82Kg recrystallized from ethyl acetate, 5.8 79% yield. LCMS: m / z = 385 (M + H) +; HPLC: 99 · 95%, largest single impurity 0.5 03%.

Patent ID

Patent Title

Submitted Date

Granted Date

US9221751 USE OF 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES FOR TREATING LIVER DISORDERS
2014-10-24
2015-02-19
US8058308 SUBSTITUTED 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES THEREOF
2011-08-04
2011-11-15
US8106097 COMPOSITION BASED ON SUBSTITUTED 1, 3-DIPHENYLPROP-2-EN-1-ONE DERIVATIVES, PREPARATION AND USES THEREOF
2010-05-13
2012-01-31
US7566737 Combinations of substituted 1, 3-diphenylprop-2-EN-1-one derivatives with other therapeutically active ingredients
2007-02-08
2009-07-28
US7943661 Substituted 1, 3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof
2005-08-11
2011-05-17

References

  1. Jump up^ Cariou, B.; Zair, Y.; Staels, B.; Bruckert, E. (2011). “Effects of the New Dual PPAR / Agonist GFT505 on Lipid and Glucose Homeostasis in Abdominally Obese Patients with Combined Dyslipidemia or Impaired Glucose Metabolism”Diabetes Care34 (9): 2008–2014. doi:10.2337/dc11-0093PMC 3161281Freely accessiblePMID 21816979.
  2. Jump up^ “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74” (PDF). World Health Organization. p. 10. Retrieved 9 November 2016.
  3. Jump up^ “Advanced Compound Status” (Press release). Genfit.
  4. Jump up^ “GFT505 Broadens Its Therapeutic Potential” (PDF) (Press release). Retrieved 31 Mar 2013.
  5. Jump up^ Cariou, Bertrand; Staels, Bart (2014-10-01). “GFT505 for the treatment of nonalcoholic steatohepatitis and type 2 diabetes”. Expert Opinion on Investigational Drugs23 (10): 1441–1448. doi:10.1517/13543784.2014.954034ISSN 1744-7658PMID 25164277.
  6. Jump up^ US Patent No. 7655641 “96 dpi image of original patent USPTO 7655641” (PDF). Retrieved 31 Mar 2013.
  7. Jump up^ “GFT-505” (PDF). Drugs of the Future37 (8): 555–559. 2012.[permanent dead link]
  8. Jump up^ Staels, Bart; Rubenstrunk, Anne; Noel, Benoit; Rigou, Géraldine; Delataille, Philippe; Millatt, Lesley J.; Baron, Morgane; Lucas, Anthony; Tailleux, Anne (2013-12-01). “Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis”Hepatology58 (6): 1941–1952. doi:10.1002/hep.26461ISSN 1527-3350.
  9. Jump up^ Cariou, Bertrand; Hanf, Rémy; Lambert-Porcheron, Stéphanie; Zaïr, Yassine; Sauvinet, Valérie; Noël, Benoit; Flet, Laurent; Vidal, Hubert; Staels, Bart (2013-05-28). “Dual Peroxisome Proliferator–Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects”Diabetes Care36: DC_122012. doi:10.2337/dc12-2012ISSN 0149-5992PMC 3781493Freely accessiblePMID 23715754.
  10. Jump up^ “Elafibranor, an Agonist of the Peroxisome Proliferator-activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening – Gastroenterology”http://www.gastrojournal.org. Retrieved 2016-03-08.
  11. Jump up^ clinical trials involving GFT505
  12. Jump up^ Quintero, Pablo; Arrese, Marco (2013-12-01). “Nuclear control of inflammation and fibrosis in nonalcoholic steatohepatitis: therapeutic potential of dual peroxisome proliferator-activated receptor alpha/delta agonism”. Hepatology58 (6): 1881–1884. doi:10.1002/hep.26582ISSN 1527-3350PMID 23787705.
  13. Jump up^ Hanf, Rémy; Millatt, Lesley J.; Cariou, Bertrand; Noel, Benoit; Rigou, Géraldine; Delataille, Philippe; Daix, Valérie; Hum, Dean W.; Staels, Bart (2014-11-01). “The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects”. Diabetes & Vascular Disease Research11 (6): 440–447. doi:10.1177/1479164114548027ISSN 1752-8984PMID 25212694.

External links

Elafibranor
Elafibranor.svg
Clinical data
Synonyms GFT505, SureCN815512
ATC code
  • None
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C22H24O4S
Molar mass 384.489 g/mol
3D model (JSmol)

/////////////////Elafibranor, E Elafibranor,  923978-27-2,  GFT-505,  UNII-2J3H5C81A5, GFT505, GFT 505, элафибранор إيلافيبرانور 依非兰诺 , PHASE 3, FAST TRACK 

CC1=CC(=CC(=C1OC(C)(C)C(=O)O)C)C=CC(=O)C2=CC=C(C=C2)SC

PF-04965842


PF-04965842, >=98% (HPLC).png

img

2D chemical structure of 1622902-68-4

PF-04965842

UNII: 73SM5SF3OR

CAS Number 1622902-68-4, Empirical Formula  C14H21N5O2S, Molecular Weight 323.41

N-[cis-3-(Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide,

N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide

1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide

PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor

THE US

In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD

PHASEIII

In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD

PRODUCT PATENT

Pub. No.: WO/2014/128591 International Application No.: PCT/IB2014/058889
Publication Date: 28.08.2014 International Filing Date: 11.02.2014

EXPIRY  Roughly 2034

form powder
color white to beige
solubility DMSO: 10 mg/mL, clear
storage temp. room temp
    Biochem/physiol Actions
    • PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
  • Originator Pfizer
  • Class Skin disorder therapies; Small molecules
  • Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

  • Phase IIIAtopic dermatitis
  • DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

  • 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
  • 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
  • 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

Image result for PF-04965842

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).

Figure

Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018

 

 

INTERMEDIATE

CN 105732637

ONE STEP

CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

Image result for PF-04965842

Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis

Wednesday, February 14, 2018 8:30 am EST

Dateline:

NEW YORK

Public Company Information:

NYSE:
PFE
US7170811035
“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the J AK1 A topic D ermatitis E fficacy and Safety (JADE) global development program.

“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1

About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership

PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:

  • PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
  • PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
  • PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis

Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  and www.pfizer.com .

Image result for PF-04965842

# # # # #

1 Food and Drug Administration Fact Sheet Breakthrough Therapies at https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htmaccessed on January 25, 2018

PATENT

CA 2899888

PATENT

WO 2014128591

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=6767BBB5964A985E88C9251B6DF3182B.wapp2nB?docId=WO2014128591&recNum=233&maxRec=8235&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3Apfizer&tab=PCTDescription

PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)

BROWN, Matthew Frank; (US).
FENWICK, Ashley Edward; (US).
FLANAGAN, Mark Edward; (US).
GONZALES, Andrea; (US).
JOHNSON, Timothy Allan; (US).
KAILA, Neelu; (US).
MITTON-FRY, Mark J.; (US).
STROHBACH, Joseph Walter; (US).
TENBRINK, Ruth E.; (US).
TRZUPEK, John David; (US).
UNWALLA, Rayomand Jal; (US).
VAZQUEZ, Michael L.; (US).
PARIKH, Mihir, D.; (US)

COMPD 2

str1

Example 2 : N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane- l -sulƒonamide

This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93 : 7) to afford the title compound as a tan sol id (78% yield). 1NMR (400 MHz, DMSO-d6): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d, 1 H), 6.61 (d, 1 H), 4.81-4.94 (m, 1 H), 3.47-3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 2.14-2.27 (m, 2 H) 1.60- 1.73 (m, 2 H) 0.96 (t, 3 H). LC/MS (exact mass) calculated for C14H21N5O2S;

323.142, found (M + H+); 324.1.

PAPER

 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

Abstract Image

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01598

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (25)

Compound 48a·2HBr …………..was collected by filtration, washed with 2:1 EtOH/H2O (100 mL), and again dried overnight in a vacuum oven at 40 °C.
1H NMR (400 MHz, DMSO-d6): 11.64 (br s, 1H), 8.12 (s, 1 H), 7.50 (d, J = 9.4 Hz, 1H), 7.10–7.22 (m, 1H), 6.65 (dd, J= 1.8, 3.3 Hz, 1H), 4.87–4.96 (m, 1H), 3.53–3.64 (m, 1H), 3.27 (s, 3H), 2.93–2.97 (m, 2H), 2.57–2.64 (m, 2H), 2.20–2.28 (m, 2H), 1.65–1.74 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.

SchmiederG.DraelosZ.PariserD.BanfieldC.CoxL.HodgeM.KierasE.Parsons-RichD.MenonS.SalganikM.PageK.PeevaE. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study Br. J. Dermatol. 2017DOI: 10.1111/bjd.16004

Compound 25N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).

REFERENCES

1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012

 2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

/////////////////PF-04965842, PF 04965842, PF04965842, PF 4965842, Phase 3, Atopic dermatitis, PFIZER, Breakthrough Therapy Designation

CCCS(=O)(N[C@H]1C[C@@H](N(C)C2=C3C(NC=C3)=NC=N2)C1)=O

CCCS(=O)(=O)N[C@@H]1C[C@@H](C1)N(C)c2ncnc3[nH]ccc23

JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,


2D chemical structure of 1200493-78-2imgChemSpider 2D Image | atabecestat | C18H14FN5OS

Atabecestat, JNJ-54861911

Cas 1200493-78-2

367.40, C18 H14 F N5 O S

2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-
  • N-[3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-2-pyridinecarboxamide
  • Atabecestat
  • атабецестат [Russian] [INN]
    أتابيسيستات [Arabic] [INN]

Atabecestat is a beta-secretase inhibitor drug candidate.

(S)-N-(3-(2-amino-4-methyl-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide

JNJ-54861911
N-{3-[(4S)-2-Amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-cyano-2-pyridinecarboxamide
2-Pyridinecarboxamide, N-[3-[(4S)-2-amino-4-methyl-4H-1,3-thiazin-4-yl]-4-fluorophenyl]-5-cyano-

WO 2017111042, 1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Image result

Structure of JNJ54861911.
Credit: Tien Nguyen/C&EN

Presented by: Yuji Koriyama, associate director at Shionogi & Co.

Target: β-site amyloid presursor protein cleaving enzyme 1 (BACE1), an enzyme whose buildup is implicated in Alzheimer’s disease

Disease: Alzheimer’s disease

Reporter’s notes: Presented by Koriyama, who told the audience he was attending the ACS National Meeting for the first time, JNJ-5486911 joins dozens of clinical candidates from many companies in Phase II and III trials to treat Alzheimer’s disease. Researchers started with a hit that inhibited BACE1 with approximately 2,600 nM affinity and advanced the program until finally reaching a compound with roughly 1 nM affinity. The compound is being jointly developed by Shionogi & Co. and Janssen Pharmaceuticals.

  • Originator Shionogi
  • Developer Janssen Research & Development
  • Class Antidementias; Small molecules
  • Mechanism of Action Amyloid precursor protein secretase inhibitors

Highest Development Phases

  • Phase II/III Alzheimer’s disease

Most Recent Events

  • 16 Jul 2017 Pharmacodynamics data from preclinical trials in Alzheimer’s disease presented at the Alzheimer’s Association International Conference (AAIC-2017)
  • 15 Dec 2016 Biomarkers information updated
  • 01 Jun 2016 Janssen Research & Development completes a phase I pharmacokinetic interaction trial in Healthy volunteers in Germany (PO) (NCT02611518)
  • Image result for Janssen Research & Development

SYNTHESIS

PATENTS

WO 2009151098

Applicants: SHIONOGI & CO., LTD. [JP/JP]; 1-8, Doshomachi 3-chome, Chuo-ku, Osaka-shi, Osaka 5410045 (JP) (For All Designated States Except US).
HORI, Akihiro [JP/JP]; (JP) (For US Only).
YONEZAWA, Shuji [JP/JP]; (JP) (For US Only).
FUJIKOSHI, Chiaki [JP/JP]; (JP) (For US Only).
MATSUMOTO, Sae [JP/JP]; (JP) (For US Only).
KOORIYAMA, Yuuji [JP/JP]; (JP) (For US Only).
UENO, Tatsuhiko [JP/JP]; (JP) (For US Only).
KATO, Terukazu [JP/JP]; (JP) (For US Only)
Inventors: HORI, Akihiro; (JP).
YONEZAWA, Shuji; (JP).
FUJIKOSHI, Chiaki; (JP).
MATSUMOTO, Sae; (JP).
KOORIYAMA, Yuuji; (JP).
UENO, Tatsuhiko; (JP).
KATO, Terukazu; (JP)

PATENT

WO 2011071057

PATENT

WO 2017175855

PATENT

WO 2017111042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017111042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Scheme 1-D
[Chem. 27]

Example 1-4
Preparation of Compound 15
[Chem. 31]

Compound 12 (3.0 g, 20.3 mmol) was dissolved in N-methylpyrrolidone (18 mL), and the solution was cooled to 5°C. Thionyl chloride (3.1 g, 26.1 mmol) was added to obtain a solution of Compound 13.
To a suspension of Compound 11 (5.0 g, 16.8 mmol) in ethyl acetate (50 mL) were added sodium bicarbonate (3.5 g, 42.0 mmol) and water (50 mL), and the mixture was stirred for 5 min at 20°C.
The layers were separated, and the organic layer was concentrated to 10 g under reduced pressure. N-Methylpyrrolidone (5 mL) and 35% hydrochloric acid (0.9 g) were added, and the mixture was cooled to 3°C. The solution of Compound 13 and N-methylpyrrolidone (1.5 mL) were added to obtain a solution of Compound 15.
The solution of Compound 15 was added to a mixture of water (15 mL) and ethyl acetate (10 mL). After stirring the mixture for 1 hour, triethylamine (14.8 g, 14.6 mmol), N-methylpyrrolidone (1.5 mL) and water (5 mL) were added and further stirred for 1 hour. Water (45 mL) was added, and the mixture was stirred for 1 hour, filtered and dried to obtain crystals of Compound 15 (Crystalline Form I, 5.71 g, 92.4%).

Compound 15
1H-NMR (CDCl3) δ: 1.71 (3H, s), 4.06 (3H, s), 6.29 (2H, d, J = 2.4 Hz), 7.07 (1H, dd, J = 11.3, 8.8 Hz), 7.65 (2H, dd, J = 6.8, 2.8 Hz), 7.86 (1H, ddd, J = 8.8, 4.1, 2.8 Hz), 8.19 (1H, dd, J = 8.1, 2.0 Hz), 8.43 (1H, d, J = 8.1 Hz), 8.89 (1H, d, J = 2.0 Hz), 9.81 (1H, s).
[α]D -11.8±1.0° (DMSO, 23°C, c=0.518)

Example 1-5
To a suspension of Compound 11 (1831 g, 6.2 mol) in ethyl acetate (18L) were added sodium bicarbonate (1293 g, 15.4 mol) and water (18L), and the mixture was stirred for 5 min at 20°C. The layers were separated, and the organic layer was concentrated to 3.8 kg under reduced pressure to obtain a concentrated solution of Compound 14.
Compound 12 (912 g, 6.2 mol) was dissolved in N-methylpyrrolidone (64L), and the solution was cooled to 4°C. Thionyl chloride (951 g, 8.0 mol) was added, and the mixture was stirred for 30 min. The concentrated solution of Compound 14 was added to obtain a solution of Compound 15.
The solution of Compound 15 and N-methylpyrrolidone (1.6 L) were added to water (18 L), and the mixture was stirred for 40 min at 25°C. 24% sodium hydroxide in water (5 kg), sodium bicarbonate (259 g, 3.1 mmol) and water (2.7 L) were added to the mixture. The mixture was stirred for 1 hour, filtered and dried to obtain crystals (metastable Form II) of Compound 15 (1.93 kg, 85.4%).

Example 1-3
Preparation of Compound 11
[Chem. 30]

A suspension of Compound 9 (20.0 g, 29.0 mmol) in N,N-dimethylacetamide (30 mL) was cooled to 5°C. 1,8-diazabicyclo(5,4,0)-7-undecene (39.7 g, 260.8 mmol) was added, and the mixture was stirred for 22 hours. Water (70 mL) was added to afford a solution of Compound 10.

To a mixture of ethyl acetate (200 mL), water (40 mL) and 62% sulfuric acid (12.7 g) was added the solution of Compound 10, and the mixture was cooled to 10°C. 15% sulfuric acid (3.7 g) was added, and the mixture was warmed to 20°C. The layers were separated, and the organic layer was washed with 5% sodium chloride in water (95 g). The layers were separated, and the organic layer was concentrated in vacuo to 42 mL. Ethyl acetate (20 mL) and 50% potassium carbonate in water (20 g) were added, and the mixture was warmed to 40°C. 4-chlorobenzenethiol (6.29 g, 43.5 mmol) and ethyl acetate (11 mL) were added, and the mixture was stirred for 1 hour. After cooling to 20°C, ethyl acetate (100 mL), water (68 mL) and 15% hydrochloric acid (42.6 g) were added. The layers were separated, and ethyl acetate (149 mL) and 20% potassium carbonate in water (40.5 g) were added to the aqueous layer. The layers were separated, and the organic layer was washed with water (100 mL). The layers were separated, and the organic layer was concentrated to 20 mL. Acetic acid (1.7 g, 29.0 mmol) was added, and the mixture was cooled to 5°C and stirred for 90 min, filtered and dried to afford 7.19 g of crystals of Compound 11 (yield: 83.4%, optical purity of (S)-isomer: 100%).

Compound 11
1H-NMR (DMSO-d6) δ: 6.74 (1H, dd, J=11.86, 8.56 Hz), 6.62 (1H, dd, J=6.97, 2.93 Hz), 6.35-6.40 (2H, m), 6.11 (1H, dd, J=9.60, 4.71 Hz), 1.90 (3H, s), 1.49 (3H, s).

The optical purity was determined as follows.
(Sample Preparation)
25 mg of Compound 11 was weighed and dissolved in a solvent to prepare a 50 mL sample solution.

(Method)
Using liquid chromatography, the peak area was determined by automatic integration method for each of (R)- and (S)-isomers of Compound 11.

(Conditions)
Detector: ultraviolet absorptiometer (wave length: 230 nm)
Column: CHIRALCEL OD-RH, φ4.6×150 mm, 5 μm, (Daicel Corporation)
Column Temp.: constant at around 40°C
Mobile Phase: water/acetonitrile (LC grade)/methanol (LC grade)/triethylamine (1320:340:340:1)
Flow Rate: 1.0 mL/min (retention time of Compound 11: about 8 min for (R)-isomer, about 9 min for (S)-isomer)
Time span of measurement: over 15 min from the sample injection
Injection Volume: 10 μL
Sample Cooler Temp.: constant at around 25°C
Autoinjector Rinse Solution: water/acetonitrile (1:1)

http://www.shionogi.co.jp/en/

Image result for HORI, Akihiro SHIONOGI

//////////////JNJ-54861911, Atabecestat , атабецестат , أتابيسيستات ,Phase III , Alzheimer’s disease, DEMENTIA, Shionogi, Developer,  Janssen Research & Development

C[C@]1(C=CSC(N)=N1)c3cc(NC(=O)c2ccc(C#N)cn2)ccc3F

ELECLAZINE, элеклазин , إيليكلازين , 依来克秦 , REVISITED


Eleclazine.pngChemSpider 2D Image | eleclazine | C21H16F3N3O3

ELECLAZINE

GS-6615

Molecular Formula: C21H16F3N3O3
Molecular Weight: 415.372 g/mol

1443211-72-0

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one

7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

1,4-Benzoxazepin-5(2H)-one, 3,4-dihydro-4-(2-pyrimidinylmethyl)-7-[4-(trifluoromethoxy)phenyl]-

Eleclazine; UNII-PUY08529FK; 1443211-72-0; GS-6615; PUY08529FK; 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-on

элеклазин [Russian] [INN]
إيليكلازين [Arabic] [INN]
依来克秦 [Chinese] [INN]
  • Phase III Long QT syndrome
INGREDIENT UNII CAS
Eleclazine Hydrochloride 4R1JP3Q4HI 1448754-43-5

Eleclazine has been used in trials studying the treatment of LQT2 Syndrome, Long QT Syndrome, Ischemic Heart Disease, Ventricular Arrhythmia, and Long QT Syndrome Type 3, among others.

In 2015, orphan drug designation was assigned to the product by the FDA for the treatment of congenital long QT syndrome.

  • Originator Gilead Sciences
  • Class Antiarrhythmics; Ischaemic heart disorder therapies; Pyrimidines; Small molecules; Vasodilators
  • Mechanism of Action Sodium channel antagonists

Highest Development Phases

  • Phase III  Long QT syndrome
  • Phase II/III Hypertrophic cardiomyopathy
  • Phase II Ventricular arrhythmias
  • No development reported Ischaemic heart disorders

Most Recent Events

  • 15 Nov 2017 Gilead Sciences presents safety and adverse events data from a phase III trial in Long QT syndrome type 3 at the 90th Annual Scientific Sessions of the American Heart Association (AHA-2017)
  • 11 Nov 2017 Efficacy data from the phase II TEMPO trial in Ventricular arrthymmia presented at the 90th Annual Scientific Sessions of the American Heart Association
  • 17 Feb 2017 Gilead Sciences terminates a phase II/III trial in Hypertrophic cardiomyopathy in Australia, France, Germany, Israel, Italy, Netherlands, USA and United Kingdom (NCT02291237)
  • Gilead Sciences was developing eleclazine (GS-6615), a late sodium current inhibitor, for the potential oral (tablet) treatment of hypertrophic cardiomyopathy and arrhythmias including long QT-3 (LQT3) syndrome.

Image result

Image result for Long QT syndrome

Image result for Long QT syndrome

Image result for Long QT syndrome

Image result for Long QT syndrome

Image result for Long QT syndrome

Long QT syndrome

The late sodium current (INaL) is a component of the fast Na+ current of cardiac myocytes and neurons. Late sodium current in cardiac cells is small compared with the fast component, but it may make a large contribution to sodium loading during each cardiac cycle. Impaired sodium channel function contributes to pathologic increase of the late sodium current, sodium overload, and sodium-induced calcium overload by way of the sodium-calcium exchanger. Calcium overload causes impaired diastolic relaxation, which increases diastolic wall tension, increases myocardial oxygen demand, reduces myocardial blood flow and oxygen supply, microvascular perfusion, and worsens ischemia and angina. Many common neurological and cardiac conditions are associated with abnormal (INaL) augmentation, which contributes to the pathogenesis of both electrical and contractile dysfunction in mammals. Inhibiting the late sodium current can lead to reductions in elevated intracellular calcium levels, which, in turn, may lead to reduced tension in the heart wall and reduced oxygen requirements for the heart muscle. Inhibition of cardiac late sodium current is a strategy used to suppress arrhythmias and sodium -dependent calcium overload associated with myocardial i schemia and heart failures. Thus, compounds that selectively inhibit the iate sodium current (INaL) in mammals may be useful in treating such disease states.

Eleclazine (4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)pheny l)-3,4-dihydrobenzo[b]oxepin-5(2H)-one]; CAS # 144321 1-72-0) is an inhibitor of the late sodium current, Eleclazine is being investigated for the treatment of cardiomyopathy, specifically hypertrophic cardiomyopathy, as well as additional cardiovascular indications, including angina, heart failure, atrial fibrillation (AF), ischemic heart disorders, atrial premature beats (APBs), myocardial isch mia, and arrhythmias.

Eleclazine

Eleclazine shows a shortening of the QTc interval (the time interval between the start of the Q-wave and the end of T-wave in the electrical cycle of the heart) in patients with QT-3 (LQT3) sydrome. LQTS is a genetic disorder that prolongs the heart’s QTc interval and can cause life-threatening cardiac arrhythmias. Therefore, eleclazine is also being investigated for treatment of long QT syndrome.

Eleclazine may be metabolized in the liver and may be subject to extensive cytochrome P450-mediated oxidative metabolism. Eleclazine is metabolized predominantly by N-dealkylation, and elimination is principally in the bile and gastrointestinal tract. The primary metabolite of eleclazine is GS-623134

Adverse effects associated with eleclazine may include dizziness, dry mouth, nausea, weakness, ringing in ears, tremors, and the like. Additionally, some metabolites of eleclazine, particularly the metabolite GS 623134, may have undesirable side effects.

PATENT

PRODUCT, WO 2013112932, WO 2013006485

WO 2013006463

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013006463&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WO 2013006463 , ( US8962610 ) hold protection in the EU states until 2032 and in US until 2033 with US154 extension.

PATENT

WO 2015017661

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015017661

Provided herein is a method for reducing the prolongation of the QT interval in a human patient, said method comprising administering to the patient an effective amount of Compound 1:

Example 1: 4-(pyrimidin-2-ylmethyl)-7-(4-(trifluoromethoxy)phenyl)-3,4- dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 1)

To a solution of Compound 1-A (20 g, 0.083 mol, 1 eq.) and Compound 1-B (25 g, 0.15 mol, 1.8 eq.) in DMF (150 mL), NaOH solution (20 mL, 10 M, 5 eq.) was slowly added at room temperature (slightly exothermic) and stirred at r.t. for 10 min, followed by heating at 95 °C for 2 h. After cooling the reaction mixture, ethyl acetate (200 mL) was added and the organic layer was separated. The organics was washed with water (20 mL), brine, dried over sodium sulphate and concentrated.

The residue was dissolved in 1,4-dioxane (50 mL) and to this 4 N HCl in dioxane (50 mL) and cone. HCl ( 2 mL) was added and stirred at room temperature for 4 h, filtered the precipitate, washed with ethyl acetate and dried. Compound 1-C was obtained (30 g) as a light yellow solid.

To the bromide (15 g, 0.04 mol, 1 eq), boronic acid (12.5 g, 0.06 mol, 1.5 eq) and potassium carbonate (22 g, 0.16 mol, 4 eq) in a round bottom flask, solvent (150 mL, toluene/isopropanol/water : 2/1/1) was added and stirred under nitrogen for 10 min. To the above solution the palladium catalyst (1 g, 0.012 mol, 0.02 eq) was added and heated at 85 °C for 2h. The reaction mixture was diluted with ethyl acetate, separated the organic layer and filtered the organic layer through a plug of celite and silica gel and concentrated. Column purification on silica gel using ethyl acetate/hexane as eluent provided Compound 1 (13 g).

To a solution of Compound 1 (26 g) in 1,4-dioxane (25 mL), 4N HCl/dioxane (25 mL) was added followed by cone. HCl (2 mL) and stirred at room temperature for 4h. Solvent was distilled off, dichlorom ethane was added and distilled off and to the residue, ethyl acetate (150 mL) was added and stirred at room temperature overnight and filtered the precipitate, washed with ethyl acetate, hexane and dried under vacuum. Compound 1-HCl obtained (24.8 g) was a white solid.

1H-NMR (CDCl3) 5 8.72 (d, 2H, J= 5.2 Hz), 8.17 (d, 1H, J= 2.4 Hz), 7.59-7.63 (m, 3H), 7.26 (d, 2H, J= 3.2 Hz), 7.22 (t, 1H, J= 4.8 Hz), 7.10 (d, 1H, J= 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J= 5.0 Hz); MS m/z 416.1 (M+H).

PATENT

WO-2018048977

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018048977&redirectedID=true

Novel deuterated analogs of a substituted oxazepin compounds, particularly eleclazine and their salts, esters, prodrugs and solvates and compositions and combinations comprising them are claimed. Also claim is their use for treating a late sodium current-mediated disorder, such as acute coronary syndrome, angina, congestive heart disease, myocardial infraction, diabetes, ischemic heart disorders, inflammatory diseases and cancers.

EXAMPLE 1- COMPARATIVE

[00297] 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluorome4hoxy)phenyl]-2,3,4,5-tetrahydro-l,4- benzoxazepin-5-one [Eleclazine]

[00299] To a solution of 5-bromo-2-hydroxybenzoate (10 g, 43.28 mmol, 1.00 equiv) in DMA (100 ml.) was added potassium carbonate (9 g, 65, 12 mmol, 1.50 equiv) and 2-chloroacetonitrile (3.4 mL, 1.25 equiv). The resulting suspension was stirred overnight. The solids were filtered out. The filtrate was washed with water. The resulting solution was extracted with ethyl acetate (3 x 50 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford 1 1 g (94%) of methyl 5-bromo-2-(cyanomethoxy)benzoate as a white solid, LC-MS: m/z = 270 [M+H]+.

[00300] Step 2: 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one

[00301] To a solution of 5-bromo-2-(cyanomethoxy)benzoate [Example 1 , Step 1 ] (4 g, 14.81 mmol, 1.00 equiv) in methanol (50 mL) was added saturated aq. NIL (4 mL) and Raney-Ni (2 mL) under a H2 atmosphere. The resulting solution was stirred overnight at room temperature. The catalyst was filtered out. The filtrate was concentrated under vacuum. The residue was purifsed by SiCte chromatography eluted with ethyl acetate/petroleum ether (1 : 1 ) to afford 530 mg (15%) of 7-bromo-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as a yellow solid. LC-MS: m/z = 242 [M+H]+.

[00302] Step 3 : 7-bromo-4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5- one

[00303] To a solution of 7-bromo-2,3,4,5-tetrahydro- l ,4-benzoxazepin-5-one [Example 1, Step 2] (530 mg, 2.19 mmol, 1.00 equiv) and 2-(chloromethyl)pyrimidine hydrochloride (650 mg, 3.96 mmol, 1.80 equiv) in DMF (10 mL), was slowly added a NaOH solution (0.55 mL, 10 M, 2.50 equiv), which was stirred at room temperature for 10 min. Then the mixture was stirred at 95°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added and the organic layer was separated. The organic layers were washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford 600 mg (82%) of 7-bromo- 4-(pyrimidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4-benzoxazepin-5-one as light yellow oil . LC-MS: m/z = 334 [M+H]+.

[00304] Step 4: 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydro- 1 ,4-benzoxazepin-5-one

[00305] To a solution of 7-bromo-4-(pyriraidin-2-ylmethyl)-2,3,4,5-tetrahydro-l,4- benzoxaze- pin-5-one [Example 1, Step 3] (277 mg, 0.83 mmol, 1.00 equiv) in Toluene/iPrOH/thO (2: 1 : 1, 4 mL) was added potassium carbonate (459 mg, 3.32 mmol, 4.00 equiv) and [4-(trifluoromethoxy)phenyl]boronic acid (257 mg, 1.25 mmol, 1.50 equiv). The mixture was stirred for 10 min at room temperature. Then Pd(dppf)Ch (12 mg, 0.02 equiv) was added to the solution. The mixture was stirred at 85°C for 2 h. After cooling the reaction mixture, ethyl acetate (30 mL) was added, and the organic layer was separated. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, Sum, 19*150mm; mobile phase, Water (10 mmol/L NH4HCO3) and CH3CN (50,0% CH3CN up to 52.0% in 7 min); Detector, UV 254, 220nra to afford 190 mg (55%) of 4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydro-1,4- benzoxazepin-5-one as a white solid. LC-MS: m/z = 416 [M+H]+

[00306] 1H NMR (400 MHz, Chloroform-t/) δ 8.75-8.74 (m, 2H), 8.20-8. 19 (m, IH), 7.66- 7,61 (m, 3H), 7,29-7,28 (m, IH), 7.27-7.26 (m, IH), 7.24-7.23 (m, I H), 7.13-7.1 1 (m, IH), 5.12 (s, 2H), 4.60-4.57 (m, 2H), 3.81 -3.78 (m, 2H).

PAPER

Journal of Medicinal Chemistry (2016), 59(19), 9005-9017

Abstract Image

Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia–ventricular fibrillation (VT–VF). We will describe structure–activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1(ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S–T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INainhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties

Medicinal Chemistry, Drug Metabolism, §Drug Safety Evaluation, Formulation and Process Development, and Structural Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States
# Biology, Gilead Sciences Inc., 7601 Dumbarton Circle, Fremont, California 94555, United States
J. Med. Chem.201659 (19), pp 9005
7-(4-(Trifluoromethoxy)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one 4
Compound 4 HCl obtained (24.8 g) was obtained as a white solid. Anal. HPLC 100% (6.78 min).
 
 1H NMR (CDCl3) δ 8.72 (d, 2H, J = 5.2 Hz), 8.17 (d, 1H, J = 2.4 Hz), 7.59–7.63 (m, 3H), 7.26 (d, 2H, J = 3.2 Hz), 7.22 (t, 1H, J = 4.8 Hz), 7.10 (d, 1H, J = 8.4 Hz), 5.10 (s, 2H), 4.56 (t, 2H, J = 5.0 Hz), 3.77 (t, 2H, J = 5.0 Hz). LCMS m/z 416.1 (M + H).
HRMS-ESI+: [M + H]+ calcd for C21H16F3N3O3, 416.1217; found, 416.1215.
PAPER
Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions
Scientific Reports (2017), 7, (1), 1-11.
PATENT
US 20180064726
PATENTS
Patent ID

Patent Title

Submitted Date

Granted Date

US9126989 COMPOUND AND METHODS FOR TREATING LONG QT SYNDROME
2014-07-31
2015-02-05
US9193694 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2013-09-26
2014-05-15
US9125916 METHODS OF TREATING HYPERTROPHIC CARDIOMYOPATHY
2014-07-28
2015-02-05
US2016332976 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2016-05-02
US2015283149 METHODS OF TREATING PATIENTS HAVING IMPLANTABLE CARDIAC DEVICES
2015-03-20
2015-10-08
Patent ID

Patent Title

Submitted Date

Granted Date

US2015045305 COMBINATION THERAPIES USING LATE SODIUM ION CHANNEL BLOCKERS AND POTASSIUM ION CHANNEL BLOCKERS
2013-01-25
2015-02-12
US2016332977 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2016-05-02
US9598435 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2015-10-01
2016-04-07
US2015225384 PROCESSES FOR PREPARING FUSED HETEROCYCLIC ION CHANNEL MODULATORS
2015-02-13
2015-08-13
US9273038 SOLID FORMS OF AN ION CHANNEL MODULATOR
2015-02-12
2015-08-13
Patent ID

Patent Title

Submitted Date

Granted Date

US9676760 FUSED HETEROCYCLIC COMPOUNDS AS ION CHANNEL MODULATORS
2016-05-11
US8697863 Fused heterocyclic compounds as ion channel modulators
2013-03-07
2014-04-15
US8586732 Fused heterocyclic compounds as ion channel modulators
2012-06-29
2013-11-19
US2017007617 INTRAVENOUS FORMULATIONS OF A LATE SODIUM CURRENT INHIBITOR
2016-07-06
US2014329755 COMBINATION THERAPY FOR THE TREATMENT OF ARRHYTHMIAS OR HEART FAILURE
2014-04-30
2014-11-06

/////////////////ELECLAZINE, GS-6615, GS 6615, элеклазин إيليكلازين 依来克秦 Phase III,  Long QT syndrome, orphan drug designation, Long QT syndrome

C1COC2=C(C=C(C=C2)C3=CC=C(C=C3)OC(F)(F)F)C(=O)N1CC4=NC=CC=N4

LASMIDITAN


Lasmiditan skeletal.svg

LASMIDITAN, COL-144 , LY-573144

613677-28-4 HYDROCHLORIDE
439239-90-4 (free base)

2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide

2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide

CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

UNII:760I9WM792

Lasmiditan succinate; UNII-W64YBJ346B; Lasmiditan succinate [USAN]; W64YBJ346B; 439239-92-6; Lasmiditan succinate (USAN)

Lasmiditan succinate.png

Molecular Formula: C42H42F6N6O8
Molecular Weight: 872.822 g/mol

Lasmiditan (COL-144) is an investigational drug for the treatment of acute migraine. It is being developed by Eli Lilly and is in phase III clinical trials. It is a first-in-class “neurally acting anti-migraine agent” ditan.

WO-2018010345,  from Solipharma and the inventor on this API. Eli Lilly , following its acquisition of CoLucid Pharmaceuticals , is developing lasmiditan, a 5-HT 1f agonist, for treating acute migraine.

WATCH THIS SPACE, SYNTHESIS COMING………..

noname01

 

SYN 2

noname01

Mechanism of action

Lasmiditan is a serotonin receptor agonist that, like the unsuccessful LY-334,370, selectively binds to the 5-HT1F receptor subtype. A number of triptans have been shown to act on this subtype as well, but only after their affinity for 5-HT1B and 5-HT1D has been made responsible for their anti-migraine activity. The lack of affinity for these receptors might result in fewer side effects related to vasoconstriction compared to triptans in susceptible patients, such as those with ischemic heart diseaseRaynaud’s phenomenon or after a myocardial infarction,[1] although a 1998 review has found such side-effects to rarely occur in patients taking triptans.[2][3]

Discovery and development

Lasmiditan was discovered by Eli Lilly and Company and was out-licensed to CoLucid Pharmaceuticals in 2006, until CoLucid was bought by Eli Lilly in 2017 to reacquire the drug.[4] The drug is protected by patents until 2031.[5]

Phase II clinical trials for dose finding purposes were completed in 2007 for an intravenous form[6] and in early 2010 for an oral form.[7]Two separate Phase III clinical trials for the oral version are currently ongoing under special protocol agreements with the US Food and Drug Administration (FDA). Eli Lilly has stated that they intend to submit a new drug application to the FDA in early 2018.[5]

As of 2017, three phase III clinical trials have been completed or are in progress. The SPARTAN trial compares placebo with 50, 100, and 200 mg of lasmiditan.[8] SAMURAI compared placebo with 100 and 200 mg doses of lasmidatin. In 2016, CoLucid announced that the trial had met its primary and secondary endpoints of patients being pain-free two hours after dosing.[5] GLADIATOR is an open-labelstudy comparing 100 and 200 mg doses of lasmidatin in patients that received the drug as part of a prior trial.[9] In August 2017 topline results from the SPARTAN trial showed that the drug induced met its primary and secondary endpoints in the trial. The primary result showed a statistically significant improvement in pain relief relative to placebo 2 hours after the first dose. The secondary result showed a statistically significantly greater percentage of patients were free of their most bothersome symptom (MBS) compared with placebo at two hours following the first dose. [10]

Novel crystalline forms of a 5-HT1F receptor agonist, particularly lasmiditan – designated as Forms 1-3 and A-D – processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating anxiety, fatigue, depression, premenstrual syndrome, trauma syndrome, memory loss, dementia (including Alzheimer’s), autism, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, epilepsy, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania.

Biological Activity

Lasmiditan (also known as COL-144 and LY573144) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.

In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370.

In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis).

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Image result for LASMIDITAN

Image result for LASMIDITAN

PATENT

WO 03084949

https://www.google.co.in/patents/WO2003084949A1?cl=en

8. 2,4,6-Trifluoro-N-[6-(l -methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000035_0001

Combine 2-amino-6-(l-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1 ,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (lOg), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255°C (dec).

Examples

21. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide

Figure imgf000049_0001

Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a solution of 2-amino-(6-(l- methylpiperidin-4-ylcarbonyl)-pyridine (7g, 31.96 mmol, 1 eq) in anhydrous THF (100 mL) under a nitrogen atmosphere. Add 2,4,6-triflubenzoylchloride (7.46g, 5 mL, 38.35 mmol, 1.20 eq) dropwise at room temperature. After 2 hrs., add additional 2,4,6- triflubenzoylchloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) to the reaction mixture and agitate the mixture for an additional 3 hrs. Quench the reaction with distilled water (10 mL) and 30%o NaOH (15 mL). Stir the resulting biphasic system for 1 hour and then separate the phases. Extract the organic fraction by adding H2O (75 mL) and acetic acid (12 mL), followed by cyclohexane (70 mL). Wash the organic fraction with H2O (50 mL) containing acetic acid (1 mL). Combine all the aqueous fractions and washes and neutralize the mixture with 30% NaOH (15 mL). Extract with methyl-tert- butyl ether (MTBE) (3×50 mL). Combine the organic fractions and dry with MgSO4, filter, concentrate under reduce pressure, and vacuum dry at room temperature, to obtain the title compound as a light-brown solid (11.031 g, 91 % yield).

Mass spectrum, (Electrospray) m/z = 378 (M+l); Η NMR (250 MHz, Chloroform-D) ppm 1.54 (m, 2 H) 2.02 (m, 2 H) 2.13 (t, J=l 1.48 Hz, 2 H) 2.29 (s, 3 H) 2.80 (m, J=l 1.96 Hz, 1 H) 3.56 (m, 1 H) 4.26 (d, J=7.87 Hz, 1 H) 6.17 (d, J=8.50 Hz, 1 H) 6.75 (m, 2 H) 7.45 (t, J=7.87 Hz, 1 H) 7.53 (m, 1 H) 7.95 (s, 1 H); 13C-NMR: (62.90 MHz, Chloroform-D) ppm 202.78; 162.6 (dm C-F-couplings); 162.0 (m C-F-couplings); 160.1 (m C-F-couplings); 158.1 ; 150.0; 139.7; 1 19.3; 1 17.9; 1 10.2 (m C-F-couplings); 100.9 (m C-F-couplings); 55.2; 46.5; 41.9; 28.1

22. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000049_0002

Dissolve 2,4,6-trifluoro-N-[6-(l-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide – free base (5g, 23.26mmol) in isopropanol (50 mL) at room temperature and add a solution of 3.3 M diethylether/HCl (8 mL). Heat the reaction mixture under reflux for 30 minutes. Cool the reaction mixture to room temperature and agitate for 2 hrs. Filter the resulting white precipitate and rinse with isopropanol (5 mL). Dry the residual solid under reduce pressure at 40°C overnight to obtain the title compound (5.12 g, 93% yield). M.p. 223-224°C (sublimation); Η NMR (400 MHz, d6-DMSO) d ppm 1.94 (m, 2 H) 2.14 (m, J=11.15 Hz, 2 H) 2.74 (s, 3 H) 2.99 (m, J=9.19 Hz, 2 H) 3.49 (m, J=1 1.15 Hz, 2 H) 3.77 (m, 1 H) 7.41 (t, J=8.71 Hz, 2 H) 7.78 (d, J=7.43 Hz, 1 H) 8.10 (t, J=7.92 Hz, 1 H) 8.37 (d, J=6.85 Hz, 1 H) 10.50 (s, 1 H) 1 1.51 (s, 1 H); 13C-NMR: (100.61 MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m, C-F-couplings); 150.4; 150.1; 140.2; 118.5; 1 18.2; 11 1.9; 101.3 (t, C-F couplings); 52.8; 42.6; 25.2

23. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide hemi-succinate salt

Figure imgf000050_0001

Add succinic acid (0.25g, 2.148 mmol, 0.5eq) to a solution of 2,4,6-trifluoro-N-[6-

(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide – free base (1.62g, 4.297 mmol, leq) in acetone (16.2 mL), at room temperature. Warm the solution under reflux for 30 minutes. Cool the solution to room temperature and filter off the resulting white precipitate. Rinse the precipitate with acetone (0.2 mL) and dry under vacuum at 50°C for 16 hours to provide the title compound (1.5g, 80% yield). M.p. 198.5°C; mass spectrum (Electrospray) m/z = 495.45

The following examples are prepared by combinatorial chemistry techniques as follows:

Examples 24-54

Figure imgf000050_0002

Combine R-acid (300 μL of 0.5M solution in dimethylformamide (DMF)), HATU (57 mg, 0.15 mmol), collidine (19 μL, 0.15 mmol), 2-amino-(6-(l-methylpiperidin-4- ylcarbonyl)-pyridine and DMF (1.5 mL), and agitate for 48 hr. Dilute the reaction mixture with 10% acetic acid in methanol (0.5 L). Load the resulting reaction mixture onto a 2 g SCX column. Wash the column thoroughly with methanol and then elute with 1 M ammonia in methanol. Concentrate the eluent and further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 24-54.

Examples 55-58

Figure imgf000051_0001

Heat R-acid chloride (300 μL of 0.5M solution in pyridine) to 55°C, add 2-amino- (6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine), and continue heating the reaction mixture for 24 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 55-58.

Examples 59-71

Figure imgf000051_0002

Heat 2-amino-(6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine) to 55°C then add R-acid chloride (0.10 mmol), heat for 2 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high-throughput mass guided chromatography. This procedure is repeated in parallel for examples 59-71.

PATENT

WO 2018010345

Lasmiditan, also known as COL-144, LY573144, is a 5-HT 1F receptor agonist. Can be used to inhibit neuronal protein extravasation, to treat or prevent migraine in patients with diseases or conditions associated with other 5-HT 1F receptor dysfunction. The chemical name is 2,4,6-trifluoro-N- [6 – [(1 -methylpiperidin-4-yl) carbonyl] -pyridin- 2-yl] -benzamide, which has the chemical structure shown below I) shows:
Lasmiditan is a new and selective 5-HT 1F receptor agonist. It acts against migraine and other 5-HT 1F receptor related diseases by enhancing 5-HT 1F receptor activation while avoiding vasoconstrictive activity and inhibiting neuronal protein extravasation such as Migraine (including migraine, migraine headache, neurovascular headache), general pain, trigeminal neuralgia, anxiety, panic disorder, depression, post traumatic syndrome, dementia and the like.
Patent document CN100352817C reports on Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride and the synthetic preparation thereof, and discloses the mass spectra of Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride, 1 H-NMR, 13 C -NMR detection data and the melting points of Lasmiditan hemisuccinate and Lasmiditan hydrochloride. The inventor of the present invention has found that Lasmiditan, which is obtained according to the preparation method of Example 17 and Example 21 in CN100352817C, is a light brown oily amorphous substance, which has the defects of instability, moisture absorption and poor morphology.
Example 8 of patent document CN100352817C reports the preparation of Lasmiditan hydrochloride, which mentions Lasmiditan free base as an oily substance. The Lasmiditan hydrochloride obtained according to the preparation method of Example 8 in CN100352817 is a white amorphous substance which also has the disadvantages of unstable crystalline form, high hygroscopicity and poor topography.
The synthesis of Lasmiditan hemisuccinate intermediate, including Lasmiditan and Lasmiditan hydrochloride, is reported in Example 2 of U.S. Patent No. 8,697,876 B2. The inventor’s study found that Lasmiditan prepared according to US8697876B2 is also a pale brown oily amorphous substance and Lasmiditan hydrochloride is also a white amorphous substance.
In view of the deficiencies in the prior art, there is still a need in the art for the development of crystalline polymorphic Lasmiditan solid forms with more improved properties to meet the rigorous requirements of pharmaceutical formulations for physico-chemical properties such as morphology, stability and the like of active materials.
Preparation 1 Preparation of Lasmiditan (Prior Art)
Lasmiditan was prepared as described in Example 21 of CN100352817C by the following procedure: Triethylamine (10.67 mL, 76.70 mmol, 2.4 equiv) was added to a solution of 2-amino- (6- (1-methylpiperidine -4-yl) -carbonyl) -pyridine (7 g, 31.96 mmol, 1 eq) in dry THF (100 mL). 2,4,6-Trifluorobenzoyl chloride (7.46 g, 5 mL, 38.35 mmol, 1.20 equiv.) Was added dropwise at room temperature. After 2 hours, an additional 2,4,6-trifluorobenzoyl chloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) were added to the reaction mixture and the mixture was stirred for a further 3 h. The reaction was quenched with distilled water (10 mL) and 30% NaOH (15 mL). The resulting two-phase system was stirred for 1 hour, then the two phases were separated. By addition of H 2 to extract the organic portion O (75mL) and acetic acid (12mL), followed by addition of cyclohexane (70mL). The organic portion was washed with water (50 mL) containing acetic acid (1 mL). All aqueous phases were combined, washed and neutralized with 30% NaOH (15 mL). Extract with methyl tert-butyl ether (MTBE) (3 x 50 mL). The organic phases were combined, dried MgS04 . 4 dried, filtered, and concentrated under reduced pressure and dried in vacuo at room temperature to give the title compound as a pale brown solid (11.031g, 91% yield).
The 1 H-NMR (CDCl 3 ) data of the product are as follows:
1 H NMR (400 MHz, CHLOROFORM-D) ppm 1.54 (m, 2H) 2.02 (m, 2H) 2.13 (t, J = 18.37 Hz, 2H) 2.29 (s, 3.56 (d, J = 12.59 Hz, 1H) 6.17 (d, J = 13.6 Hz, 1H) 6.75 (m, 2H) 7.45 (t, J = 12.59 Hz, 1H) 7.53 (m, 1H ) 7.95 (s, 1H).
The isothermal adsorption curve shown in Figure 5, in the 0% to 80% relative humidity range of 9.5% weight change.
The above characterization results show that Lasmiditan obtained by the preparation method of Example 21 according to CN100352817C is amorphous.
Preparation 2 Preparation of Lasmiditan hydrochloride (Prior Art)
The Lasmiditan hydrochloride was prepared as described in Example 8 of CN100352817C by the following procedure: A mixture of 2-amino-6- (1-methylpiperidin-4-yloxy) pyridine Trifluorobenzoyl chloride (3.57 g, 18.4 mmol) and 1,4-dioxane (100 mL) were combined and heated to reflux with heating. After 3 hours, cool the reaction mixture to room temperature, reduce pressure and concentrate. The concentrated mixture was loaded onto a SCX column (10 g), washed with methanol and eluted with 2M ammonia in methanol. The eluate was concentrated to give the title compound as an oily free base (3.65 g (> 100%)). The oil was dissolved in methanol (50 mL) and treated with ammonium chloride (0.5 g, 9.2 mmol). The mixture was concentrated and dried in vacuo to give a white amorphous.
IC characterization showed that Lasmiditan hydrochloride salt formed by Lasmiditan and hydrochloric acid in a molar ratio of 1: 1.
The XRPD pattern shown in Figure 19, no diffraction peaks, no amorphous.
The PLM pattern is shown in Figure 20 as an irregular, unpolarized solid.
The isotherm adsorption curve is shown in FIG. 21, with a weight change of 8.1% in a relative humidity range of 0% to 80%.
The above characterization results show that: Lasmiditan hydrochloride obtained by the preparation method of Example 8 with reference to CN100352817C is amorphous.
Example 1
Take 500mg of Lasmiditan of Preparation 1, add 1mL methanol solution containing 5% water to clarify, evaporate the crystals at room temperature and evaporate dry after 1 day to obtain 487mg Lasmiditan Form 1 in 95% yield.

References

  1.  “Molecule of the Month July 2010: Lasmiditan hydrochloride”Prous Science. Retrieved 2011-08-03.
  2.  Dahlöf, CG; Mathew, N (1998). “Cardiovascular safety of 5HT1B/1D agonists–is there a cause for concern?”. Cephalalgia : an international journal of headache18 (8): 539–45. doi:10.1046/j.1468-2982.1998.1808539.xPMID 9827245.
  3.  Mutschler, Ernst; Geisslinger, Gerd; Kroemer, Heyo K.; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 265. ISBN 978-3-8047-1763-3OCLC 47700647.
  4.  http://www.fiercebiotech.com/biotech/lilly-buys-migraine-biotech-colucid-for-960m-and-drug-it-out-licensed
  5.  http://adisinsight.springer.com/drugs/800028519
  6.  Clinical trial number NCT00384774 for “A Placebo-Controlled Adaptive Treatment Assignment Study of Intravenous COL-144 in the Acute Treatment of Migraine” at ClinicalTrials.gov
  7.  Clinical trial number NCT00883051 for “Dose-ranging Study of Oral COL-144 in Acute Migraine Treatment” at ClinicalTrials.gov
  8. Clinical trial number NCT02605174 for “Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute Treatment of Migraine (SPARTAN)” at ClinicalTrials.gov
  9.  Clinical trial number NCT02565186 for “An Open-label, Long-term, Safety Study of Lasmiditan for the Acute Treatment of Migraine (GLADIATOR)” at ClinicalTrials.gov
  10.  https://investor.lilly.com/releasedetail.cfm?ReleaseID=1036101
Lasmiditan
Lasmiditan skeletal.svg
Clinical data
Routes of
administration
By mouthintravenous
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H18F3N3O2
Molar mass 377.36 g/mol
3D model (JSmol)

/////////////LASMIDITAN, phase III, LILY, COL-144 , LY-573144, CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.C(CC(=O)O)C(=O)O

ELAGOLIX


Elagolix.svgChemSpider 2D Image | Elagolix | C32H30F5N3O5Elagolix.png

ELAGOLIX

  • Molecular FormulaC32H30F5N3O5
  • Average mass631.590 Da
NBI56418, ABT 620
UNII:5B2546MB5Z
4-({(1R)-2-[5-(2-Fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phenylethyl}amino)butanoic acid
834153-87-6 FREE ACID
SODIUM SALT  832720-36-2
Acide 4-({(1R)-2-[5-(2-fluoro-3-méthoxyphényl)-3-[2-fluoro-6-(trifluorométhyl)benzyl]-4-méthyl-2,6-dioxo-3,6-dihydro-1(2H)-pyrimidinyl]-1-phényléthyl}amino)butanoïque
Butanoic acid, 4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-

GNRH antagonist, Endometriosis

Endometriosis PREREGISTERED

Phase III Uterine leiomyoma

WO2001055119A2,

Inventors Yun-Fei ZhuChen ChenFabio C. TucciZhiqiang GuoTimothy D. GrossMartin RowbottomR. Scott Struthers,
Applicant Neurocrine Biosciences, Inc.

WO 2005007165 PDT PATENT

Image result for Neurocrine Biosciences, Inc.

Inventors Zhiqiang GuoYongsheng ChenDongpei WuChen ChenWarren WadeWesley J. DwightCharles Q. HuangFabio C. Tucci
Applicant Neurocrine Biosciences, Inc.
  • Originator Icahn School of Medicine at Mount Sinai
  • Developer AbbVie; Neurocrine Biosciences
  • Class Antineoplastics; Fluorinated hydrocarbons; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Highest Development Phases
  • Preregistration Endometriosis
  • Phase III Uterine leiomyoma
  • Discontinued Benign prostatic hyperplasia; Prostate cancer
  • Most Recent Events
  • 23 Nov 2017 AbbVie plans a phase III trial for Endometriosis (Monotherapy, Combination therapy) in USA in November 2017 (NCT03343067)
  • 01 Nov 2017 Updated efficacy and adverse events data from two phase III extension trials in Endometriosis released by AbbVie
  • 27 Oct 2017 Elagolix receives priority review status for Endometriosis in USA

 

SYN

Elagolix is a specific highly potent non-peptide, orally active antagonist of the GnRH receptor. This compound inhibits pituitary luteinizing hormone (LH) secretion directly, potentially preventing the several week delay and flare associated with peptide agonist therapy.

Image result for Neurocrine Biosciences, Inc.

In 2010, elagolix sodium was licensed to Abbott by Neurocrine Biosciences for worldwide development and commercialization for the treatment of endometriosis. In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie.

AbbVie , following its spin-out from Abbott in January 2013, under license from Neurocrine , is developing elagolix, the lead from a series of non-peptide gonadotropin-releasing hormone antagonists, for treating hormone-dependent diseases, primarily endometriosis and uterine fibroids.

Elagolix sodium is an oral gonadotropin releasing hormone (GnRH) antagonist in development at Neurocrine Biosciences and Abbvie (previously Abbott). In 2017, Abbvie submitted a New Drug Application (NDA) in the U.S. for the management of endometriosis with associated pain. The candidate is being evaluated in phase III trials for the treatment of uterine fibroids.

Elagolix (INNUSAN) (former developmental code names NBI-56418ABT-620) is a highly potent, selective, orally-active, short-duration, non-peptide antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (KD = 54 pM) which is under development for clinical use by Neurocrine Biosciences and AbbVie.[2][3] As of 2017, it is in pre-registration for the treatment of endometriosis and phase III clinical trials for the treatment of uterine leiomyoma.[1][4] The drug was also under investigation for the treatment of prostate cancer and benign prostatic hyperplasia, but development for these indications was ultimately not pursued.[4] Elagolix is the first of a new class of GnRH inhibitors that have been denoted as “second-generation”, due to their non-peptide nature and oral bioavailability.[1]

Because of the relatively short elimination half-life of elagolix, the actions of gonadotropin-releasing hormone (GnRH) are not fully blocked throughout the day.[1][5] For this reason, gonadotropin and sex hormone levels are only partially suppressed, and the degree of suppression can be dose-dependently adjusted as desired.[1][5] In addition, if elagolix is discontinued, its effects are rapidly reversible.[1][5] Due to the suppression of estrogen levels by elagolix being incomplete, effects on bone mineral density are minimal, which is in contrast to first-generation GnRH inhibitors.[6][7] Moreover, the incidence and severity of menopausal side effects such as hot flashes are also reduced relative to first-generation GnRH inhibitors.[1][5]

Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl] -4-methyl-2,6-dioxopyrimidin- 1 -yl] -1 -phenylethyl] amino] butanoate as below.

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-IH.

The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

The US patent number 7056927 B2 discloses a process for preparation of elagolix sodium salt in Example -1 as given in below scheme -I.

Scheme -I

The US patent number 8765948 B2 describes a process for preparation of elagolix sodium in example- 1 and 4 as given below scheme-II:

(1c) (1e) (4a)

Scheme-II

Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (le) as mentioned below scheme-Ill.

Scheme -III

PATENT

WO2001055119A2 * Jan 25, 2001 Aug 2, 2001 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto

PATENT

WO 2005007165

https://encrypted.google.com/patents/WO2005007165A1?cl=en

EXAMPLE 1

3-[2(R)-{HYD OXYCARBONYLPROPYL-AMINθ} -2-PHENYLETHYL]-5-(2-FLUORO-3- METHOXYPHENYL)-l-[2-FLUORO-6-(TRIFLUOROMETHYL)BENZYL]-6-METHYL- PYRIMIDINE-2,4(lH,3H)-DIONE

Figure imgf000027_0001

Step IA: Preparation of 2-fluoro-6-(trifluoromethyl)benzylamine la To 2-fluoro-6-(trifluoromethyl)benzonitrile (45 g, 0.238 mmol) in 60 mL of TΗF was added 1 M BΗ3:TΗF slowly at 60 °C and the resulting solution was refluxed overnight. The reaction mixture was cooled to ambient temperature. Methanol (420 mL) was added slowly and stirred well. The solvents were then evaporated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4. Evaporation gave la as a yellow oil (46 g, 0.238 mmol). MS (C\) m/z 194.0 (MH+).

Step IB: Preparation of N-|2-fluoro-6-(trifluoromethyl)benzyl|urea lb To 2-fluoro-6-(trifluoromethyl)benzylamine la (51.5 g, 0.267 mmol) in a flask, urea (64 g, 1.07 mmol), HC1 (cone, 30.9 mmol, 0.374 mmol) and water (111 mL) were added. The mixture was refluxed for 6 hours. The mixture was cooled to ambient temperature, further cooled with ice and filtered to give a yellow solid. Recrystallization with 400 mL of EtOAc gave lb as a white solid (46.2 g, 0J96 mmol). MS (CI) m/z 237.0 (MH+).

Step 1C: Preparation of l-[2-fluoro-6-(trifluoromethyl)benzyl]-6- methylpyrimidine-2.4(lH.3H)-dione lc Nal (43.9 g, 293 mmol) was added to N-[2-fluoro-6- (trifluoromethyl)benzyl]urea lb (46.2 g, 19.6 mmol) in 365 mL of acetonitrile. The resulting mixture was cooled in an ice-water bath. Diketene (22.5 mL, 293 mmol) was added slowly via dropping funnel followed by addition of TMSCl (37.2 mL, 293 mmol) in the same manner. The resulting yellow suspension was allowed to warm to room temperature slowly and was stirred for 20 hours. LC-MS showed the disappearance of starting material. To the yellow mixture 525 mL of water was added and stirred overnight. After another 20 hours stirring, the precipitate was filtered via Buchnner funnel and the yellow solid was washed with water and EtOAc to give lc as a white solid (48.5 g, 16 mmol). 1H ΝMR (CDC13) δ 2.15 (s, 3Η), 5.37 (s, 2H), 5.60 (s, 1H), 7.23-7.56 (m, 3H), 9.02 (s, 1H); MS (CI) m/z 303.0 (MH+).

Step ID: Preparation of 5-bromo-l -[2-fluoro-6-(trifluoromethyl)benzyl|-6- methylpyrimidine-2.4(lH.3H)-dione Id Bromine (16.5 mL, 0.32 mmol) was added to l-[2-fluoro-6-

(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(lHJH)-dione lc (48.5 g, 0J6 mol) in 145 mL of acetic acid. The resulting mixture became clear then formed precipitate within an hour. After 2 hours stirring, the yellow solid was filtered and washed with cold EtOAc to an almost white solid. The filtrate was washed with sat. ΝaΗCO3 and dried over Na2SO4. Evaporation gave a yellow solid which was washed with EtOAC to give a light yellow solid. The two solids were combined to give 59.4 g of Id (0J56 mol) total. Η NMR (CDC13) δ 2.4 (s, 3H), 5.48 (s, 2H), 7.25-7.58 (m, 3H), 8.61 (s, 1H); MS (CI) m/z 380.9 (MH+). 5-Bromo-l-[2, 6-difluorobenzyl]-6-methylpyrimidine-2,4(lHJH)-dione ld.l was made using the same procedure.

Step IE: Preparation of 5-bromo-l -r2-fluoro-6-(trifluoromethyl)benzyll-6- methyl-3-[2(R)-tert-butoxycarbonylamino-2-phenylethyll-pyrimidine-2.4(lHJH)-dione le To 5-bromo- 1 -[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine- 2,4(lHJH)-dione Id (15 g, 39.4 mmol) in 225 mL of TΗF were added N-t-Boc-D- phenylglycinol (11.7 g, 49.2 mmol) and triphenylphosphine (15.5 g, 59J mmol), followed by addition of di-tert-butyl azodicarboxylate (13.6 g, 59J mmol). The resulting yellow solution was stirred overnight. The volatiles were evaporated and the residue was purified by silica gel with 3:7 EtOAc Ηexane to give le as a white solid (23.6 g, 39.4 mmol). MS (CI) m/z 500.0 (MΗ+-Boc).

Step IF: Preparation of 3-[2(R)-amino-2-phenylethyll-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyll-6-methyl-pyrimidine- 2.4(lH.3H)-dione If To 5-bromo-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-3-[2(R)- tert-butoxycarbonylamino-2-phenylethyl]-pyrimidine-2,4(lH,3H)-dione le (15 g, 25 mmol) in 30 mL/90 mL of Η2O/dioxane in a pressure tube were added 2-fluoro-3- methoxyphenylboronic acid (4.25 g, 25 mmol) and sodium carbonate (15.75 g, 150 mmol). N2 gas was bubbled through for 10 min.

Tetrakis(triphenylphosphine)palladium (2.9 g, 2.5 mmol) was added, the tube was sealed and the resulting mixture was heated with stirring at 90 °C overnight. After cooling to ambient temperature, the precipitate was removed by filtration. The volatiles were removed by evaporation and the residue was partitioned between EtOAc/sat. NaHCO3. The organic solvent was evaporated and the residue was chromatographed with 2:3 EtOAc/Hexane to give 13.4 g (20.8 mmol, 83 %) yellow solid. This yellow solid (6.9 g, 10.7 mmol) was dissolved in 20 mL/20 mL CH2C12/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave If as a yellow oil (4.3 g, 7.9 mmol, 74%). Η NMR (CDC13) δ 2.03 (s, 3H), 3.72-4.59 (m, 6H), 5.32-5.61 (m, 2H), 6.74-7.56 (m, 11H); MS (CI) m/z 546.0 (MH+). 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-l-[2,6- difluorobenzyl]-6-methyl-pyrimidine-2,4(lH,3H)-dione lf.l was made using the same procedure described in this example.

Step 1G: Preparation of 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyll-5-

(2-fluoro-3 -methoxyphenyl)- 1 -[2-fluoro-6-(trifluoromethyl)benzyl|-6-methyl- pyrimidine-2,4(lHJH)-dione lg To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3- methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione If (5 g, 9.4 mmol) in 100 mL of acetonitrile were added ethyl 4- bromobutyrate (4 mL, 28.2 mmol) and Ηunig’s base (1.6 mL, 9.4 mmol). After reflux at 95 °C overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10: 1 EtOAc/Ηexane/Et3N to give lg as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).

Step 1H: Preparation of 3-[2(R)- {hydroxycarbonylpropyl-amino} -2-phenylethyl]- 5-(2-fluoro-3-methoxyphenyl)-l- 2-fluoro-6-(trifluoromethyl)benzyl1-6-methyl- pyrimidine-2,4(lHJH)-dione 1-1 Compound 3-[2(R)- {ethoxycarbonylpropyl-amino} -2-phenylethyl]-5-(2- fluoro-3-methoxyphenyl)-l-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine- 2,4(lH,3H)-dione lg (2.6 g, 4.0 mmol) was dissolved in 30 mL/30 mL of TΗF/water. Solid NaOΗ (1.6 g, 40 mmol) was added and the resulting mixture was heated at 50 °C overnight. The mixture was cooled to ambient temperature and the volatiles were evaporated. Citric acid was added to the aqueous solution until pΗ = 3. Extraction with EtOAc followed by evaporation of solvent gave 1.96 g of a white gel. The gel was passed through a Dowex MSC-1 macroporous strong cation-exchange column to convert to sodium salt. Lyopholization gave white solid 1-1 as the sodium salt (1.58 g, 2.47 mmol). Η NMR (CD3OD) δ 1.69-1.77 (m, 2H), 2.09 (s, 3H), 2.09-2.19 (t, J = 7.35 Hz, 2H), 2.49-2.53 (t, J = 735 H, 2H), 3.88 (s, 3H), 4.15-4.32 (m, 3H), 5.36-5.52 (m, 2H), 6.60-7.63 (m, 1 IH); HPLC-MS (CI) m/z 632.2 (MH+), tR = 26.45, (method 5)

PATENT

WO 2017221144

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017221144&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Process for the preparation of elagolix sodium and its polymorph forms and intermediates is claimed. Represents first filing from Dr. Reddy’s Laboratories Limited and the inventors on this API.

n a seventh aspect, the present invention provides a process for preparation of compound of formula (VII)

(VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like,

comprising;

a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above

b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula

(VII)

(VI) (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

The seventh aspect of the present invention is depicted below scheme-IV.

Scheme-IV

The eighth aspect of the present invention is depicted below scheme-IV.

R=alkyl

Scheme-IV

Example 11: Preparation of ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (Ilia; R is ethyl)

R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with IN HC1 (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). ¾ NMR (400 MHz, DMSO-d6): δ 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH )

Example 12: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l-phenylethyl) amino)butanoate (III; R is ethyl)

Ethyl (R)-4-((2-hydroxy-l-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5 °C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5 °C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). ¾ NMR (400 MHz, CDC13): δ 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH )

Example 13: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl)

Ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-l -phenyl ethyl) amino)butanoate (III; R is ethyl) (1.0 g), 5-bromo-l-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) withl5-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); l NMR (DMSO-d6) δ 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+

Example 14: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl)

Ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethylacetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethylacetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.

Example 15: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VII; R is ethyl)

Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoro methyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl)-l-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5 °C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5 °C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). ‘H NMR (400 MHz, DMSO-d6): δ 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH )

PAPER

Discovery of sodium R-(+)-4-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl-)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl)-1-phenylethamino)butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2008, 51(23): 7478

Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor

Department of Medicinal Chemistry, Department of Endocrinology, and Department of Preclinical Development, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130
J. Med. Chem.200851 (23), pp 7478–7485
DOI: 10.1021/jm8006454

* To whom correspondence should be addressed. Phone: 1-858-617-7600. Fax: 1-858-617-7925. E-mail: cchen@neurocrine.comsstruthers@neurocrine.com., †

Department of Medicinal Chemistry., ‡ Department of Endocrinology., § Department of Preclinical Development.

Abstract

Abstract Image

The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.

NA SALT

(R)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric Acid Sodium Salt

sodium salt as a white solid (1.58 g, 2.47 mmol, 62%). HPLC purity: 100% (220 and 254 nm). 1H NMR (CD3OD): 1.72 (m, 2H), 2.08 (s, 3H), 2.16 (t, J = 6.9 Hz, 2H), 2.50 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 4.24 (m, 3H), 5.40 (d, J = 9.0 Hz, 1H), 5.46 (d, J = 9.0 Hz, 1H), 6.62 and 6.78 (m, 1H), 7.12 (m, 2H), 7.34 (m, 5H), 7.41 (m, 1H), 7.56 (m, 1H), 7.61 (d, J = 8.0 Hz, 1H). MS: 632 (M − Na + 2H+). Anal. (C32H29F5N3O5Na·0.75H2O): C, H, N, Na.

PATENT

CN 105218389

PATENT

WO2014143669A1

“Elagolix” refers to 4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2- fluoro-6 rifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-l-yl]-l- phenyl-ethylamino)-butyric acid or a pharmaceutically acceptable salt thereof. Elagolix is an orally active, non-peptide GnRH antagonist and is unlike other GnRH agonists and injectable (peptide) GnRH antagonists. Elagolix produces a dose dependent suppression of pituitary and ovarian hormones in women. Methods of making Elagolix and a pharmaceutically acceptable salt thereof are described in WO 2005/007165, the contents of which are herein incorporated by reference.

References

  1. Jump up to:a b c d e f g Ezzati, Mohammad; Carr, Bruce R (2015). “Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain”. Women’s Health11(1): 19–28. doi:10.2217/whe.14.68ISSN 1745-5057.
  2. Jump up^ Chen C, Wu D, Guo Z, Xie Q, Reinhart GJ, Madan A, Wen J, Chen T, Huang CQ, Chen M, Chen Y, Tucci FC, Rowbottom M, Pontillo J, Zhu YF, Wade W, Saunders J, Bozigian H, Struthers RS (2008). “Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem51 (23): 7478–85. doi:10.1021/jm8006454PMID 19006286.
  3. Jump up^ Thomas L. Lemke; David A. Williams (24 January 2012). Foye’s Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1411–. ISBN 978-1-60913-345-0.
  4. Jump up to:a b AdisInsight: Elagolix.
  5. Jump up to:a b c d Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513Freely accessiblePMID 19033369.
  6. Jump up^ Diamond MP, Carr B, Dmowski WP, Koltun W, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study”. Reprod Sci21 (3): 363–71. doi:10.1177/1933719113497292PMID 23885105.
  7. Jump up^ Carr B, Dmowski WP, O’Brien C, Jiang P, Burke J, Jimenez R, Garner E, Chwalisz K (2014). “Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density”Reprod Sci21 (11): 1341–51. doi:10.1177/1933719114549848PMC 4212335Freely accessiblePMID 25249568.

External links

Citing Patent Filing date Publication date Applicant Title
WO2014143669A1 Mar 14, 2014 Sep 18, 2014 AbbVie Inc . Compositions for use in treating heavy menstrual bleeding and uterine fibroids
EP2881391A1 Dec 5, 2013 Jun 10, 2015 Bayer Pharma Aktiengesellschaft Spiroindoline carbocycle derivatives and pharmaceutical compositions thereof
US8084614 Apr 4, 2008 Dec 27, 2011 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588 Apr 4, 2008 Sep 11, 2012 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738 Nov 10, 2011 Jul 9, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8507536 Aug 10, 2012 Aug 13, 2013 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8952161 Jun 5, 2013 Feb 10, 2015 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9034850 Nov 19, 2010 May 19, 2015 Sk Chemicals Co., Ltd. Gonadotropin releasing hormone receptor antagonist, preparation method thereof and pharmaceutical composition comprising the same
US9422310 Jan 8, 2015 Aug 23, 2016 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
Patent ID

Patent Title

Submitted Date

Granted Date

US9382214 Processes for the preparation of uracil derivatives
2014-06-19
2016-07-05
US2014288031 METHODS OF TREATING HEAVY MENSTRUAL BLEEDING
2014-03-14
2014-09-25
Patent ID

Patent Title

Submitted Date

Granted Date

US2010190692 METHODS FOR REDUCING GNRH-POSITIVE TUMOR CELL PROLIFERATION
2010-02-05
2010-07-29
US8273716 USE OF LHRH ANTAGONISTS FOR INTERMITTENT TREATMENTS
2009-09-03
US8765948 PROCESSES FOR THE PREPARATION OF URACIL DERIVATIVES
2011-04-28
US2010092463 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
2009-11-20
2010-04-15
US2010061976 Method for treating or preventing osteoporosis by reducing follicle stimulating hormone to cyclic physiological levels in a mammalian subject
2009-07-27
2010-03-11
Patent ID

Patent Title

Submitted Date

Granted Date

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
US7419983 Gonadotropin-releasing hormone receptor antagonists and methods related thereto
2007-08-16
2008-09-02
US7176211 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2006-06-08
2007-02-13
US7056927 Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
2005-02-17
2006-06-06
Elagolix
Elagolix.svg
Clinical data
Synonyms NBI-56418; ABT-620
Routes of
administration
By mouth
Drug class GnRH analogueGnRH antagonistantigonadotropin
Pharmacokinetic data
Biological half-life 2.4–6.3 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C32H30F5N3O5
Molar mass 631.590 g/mol
3D model (JSmol)

///////////////ELAGOLIX, NBI 56418, UNII:5B2546MB5Z, ABT 620, priority review status, PHASE 3, AbbVie, Neurocrine Biosciences, Endometriosis

CC1=C(C(=O)N(C(=O)N1CC2=C(C=CC=C2F)C(F)(F)F)CC(C3=CC=CC=C3)NCCCC(=O)O)C4=C(C(=CC=C4)OC)F

%d bloggers like this: