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Figure imgf000077_0001

GSK 2256294

GSK 2256294A

CAS  1142090-23-0

MF C21H24F3N7O
MW 447.46

Antiasthmatics, soluble epoxide hydrolase inhibitor

Chronic obstructive pulmonary disease COPD …PHASE 1

(1R,3S)- Cyclohexanecarboxamide, N-[[4-cyano-2-(trifluoromethyl)phenyl]methyl]-3-[[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino]-,

cis-N-[[4-Cyano-2-(trifluoromethyl)phenyl]methyl]-3-[[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]amino]cyclohexanecarboxamide

(1R,3S)-N-(4-cyano-2-(trifluoromethyl)benzyl)-3-(4-methyl-6-(methylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxamide

cis-N-((4-Cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide

Cyclohexanecarboxamide, N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)-, (1R,3S)-rel-

  • Originator GlaxoSmithKline
  • Class Antiasthmatics
  • Mechanism of Action Epoxide hydrolase inhibitors

GSK 2256294 is a soluble epoxide hydrolase inhibitor in phase I clinical trials at GlaxoSmithKline for the oral treatment of patients with chronic obstructive pulmonary disease (COPD).

GSK2256294A is a potent, reversible, tight binding inhibitor of isolated recombinant human sEH (IC50 value 27 pM), and displays potent inhibition against the rat (IC50 = 61 pM) and murine (IC50 = 189 pM) orthologs of sEH. GSK2256294A also displays potent cellular inhibition (IC50 = 0.66 nM) of sEH in a cell line transfected with the human sEH enzyme.The selectivity of the compound has been demonstrated by testing against a large panel of enzymes, receptors and ion channels, including the phosphatase activity of EPHX2.

  • 01 Jan 2015GlaxoSmithKline initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT02262689)
  • 09 Oct 2014GlaxoSmithKline plans a phase I trial in Healthy volunteers in USA (NCT02262689)
  • 01 May 2014GlaxoSmithKline completes a phase I pharmacokinetics trial for Chronic obstructive pulmonary disease (in the elderly, in volunteers) in USA (NCT02006537)

 

PATENT

http://www.google.com/patents/WO2009049157A1?cl=en

Step 1:

4- (bromomethyl) -3- (trifluoromethyl) benzonitrile

 

Figure CN101896065BD00313

 A mixture of 4-methyl-3- (trifluoromethyl) benzonitrile (10g, 54mmOl) was dissolved in 200mL of carbon tetrachloride, and acid imide with N- desert shot glass (10.5g, 59mmol) and peroxybenzoate (benzoyl peroxide) (1.3g, 0.54mmol) processing. The reaction mixture was heated to reflux temperature and stirred for one week. SOmL water was then added, and the layers separated. The aqueous layer with methylene chloride (2X50mL) and extracted. The organic layers were washed with water (2X50mL), dried over magnesium sulfate, and concentrated to give 4- (bromomethyl) -3- (trifluoromethyl) benzonitrile (14g, 53mm0l), as a yellow oil which was used without further purification for the subsequent steps.

Step 2:

4- (aminomethyl) -3- (trifluoromethyl) benzonitrile

 

Figure CN101896065BD00314

 4- (bromomethyl) -3- (trifluoromethyl) benzonitrile (14g) was dissolved in 500mL of 5M methanol solution of ammonia, and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo to give a yellow solid, which was dissolved in IM HCl and extracted with diethyl ether (3X30mL). Then, with IM NaOH and the aqueous layer was adjusted to pH 9-10 and extracted with dichloromethane (3X80mL). Thus obtained 4- (aminomethyl) -3- (trifluoromethyl) benzonitrile (4.7g, 23mm0l, 43%), as a yellow solid. MS (ES) m / e 201 [M + H] + “1H NMR (400MHz, DMS0-D6) δ 8.2 (s, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 3.9 (s, 2H).

Step 1:

4-chloro -N, 6- dimethyl-1,3,5-triazin-2-amine

 

Figure CN101896065BD00411

 Intermediate 13 (500mg, 3.07mmol) was added 25-30% methylamine (300uL, 3.07mmol) in aqueous CH3CN / H20 (15mL) in a solution. The mixture was cooled to (TC, with the pH adjusted to 9_10.pH IMNaOH maintained at 9-10 for 0.5 hours. The reaction progress was monitored by LCMS, the mixture was used in the subsequent step without any treatment.

Intermediate 19

 3 – {[methyl (methyl-amino) triazin-2-yl 4 -1,3,5_ -6-] amino} cyclohexanecarboxylic acid was prepared

 

Figure CN101896065BD00303

 To 2,4-dichloro-6-methyl-1,3,5-triazine (2.291g, 13.97mmol) and methylamine (6.98ml, 13.97mmol) was added dropwise IN NaOH, to maintain the pH of 10. The reaction mixture was stirred for 30 minutes. Subsequently, a solution of 3-amino-cyclohexane – carboxylic acid (2.0g, 13.97mmol), was added dropwise to maintain a pH of 10 INNaOH. The reaction mixture was heated to 70 ° C overnight. Cooling the reaction mixture was directly purified by preparative HPLC. MS (ES +): m / e266.2 [M + H] +. 1H NMR (400MHz, DMS0-D6) δ 9.0_8.5 (bm, 2Η), 3.9 (bs, 1Η), 2.9 (m, 2Η), 2.3 (s, 3Η), 2.2 (s, 3Η), 1.9- 1.7 (bm, 4Η), 1.4-1.1 (bm, 4Η).

Step 2:

3 – {[4_-methyl-6- (methylamino) _1,3,5_ triazine _2_ yl] amino} cyclohexanecarboxylic acid

 

Figure CN101896065BD00412

 in (TC, 4-chloro -N, 6- dimethyl-1,3,5-triazin-2-amine mixture (485mg, 3.07mmol) was added 3-amino-cyclohexyl burning acid (527mg, 3.68mmol). The mixture was allowed to warm to room temperature .pH maintained between 9 to 10 for 3 hours. The mixture was concentrated and the product was purified by HPLC to afford 0.6g (2.26mmol, 74% yield) of the desired product, as a white solid .MS (ES +): m / e 266.2 [M + H] + “

 

 

Example 74

(cis)-N-{[4-cyano-2-(trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1 ,3,5- triazin-2-yl]amino}cyclohexanecarboxamide

Figure imgf000077_0001

To a solution of 3-{[4-methyl-6-(methylamino)-1 ,3,5-triazin-2- yl]amino}cyclohexanecarboxylic acid (0.100 g, 0.264 mmol) in N,N-Dimethylformamide (DMF) (4 ml) was added 4-(aminomethyl)-3-(trifluoromethyl)benzonitrile (0.053 g, 0.264 mmol) followed by diisopropylethylamine (0.101 ml, 0.580 mmol) and 1 H-1 ,2,3- benzotriazol-1-yloxy-tris(dirnethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.128 g, 0.290 mmol). The reaction was stirred at room temperature for 4 hours and then purified by preparative HPLC to provide (cis)-N-{[4-cyano-2- (trifluoromethyl)phenyl]methyl}-3-{[4-methyl-6-(methylamino)-1 ,3,5-triazin-2- yl]amino}cyclohexanecarboxamide (83 mg, 0.148 mmol, 56 %). MS (ES) m/e 448

[M+H]+. 1H NMR (400 MHz, DMSO-D6) D 7.8 (bs, 1 H), 7.3 (bs, 1 H), 7.2 (m, 1 H), 6.9 (m, 1 H), 3.8 (bs, 2H), 3.3 (bm, 1 H), 2.2 (bm, 4H), 1.8 – 1.5 (bm, 4H), 1.3 – 1.1 (bm, 4H), 0.8 – 0.5 (bm, 4H)

PATENT

http://www.google.com/patents/CN101896065B?cl=en

(cis) -N – {[4- cyano-2- (trifluoromethyl) phenyl] methyl} -3 – {[4_-methyl-6- (methylamino) _1,3, .5- triazin-2-yl] amino} cyclohexanecarboxamide

Figure CN101896065BC00051

 

Example 74

(cis) -N- {[4- cyano-2- (trifluoromethyl) phenyl] methyl} -3- {[4_ methyl _6_ (methylamino) -1,3 , 5-triazin-2-yl] amino} cyclohexanecarboxamide

 

Figure CN101896065BD00571

 To 3 – {[4_-methyl-6- (methylamino) -l, 3,5- triazin-2-yl] amino} cyclohexanecarboxylic acid (0.1OOg,

0.264mmol) in N, N- dimethylformamide (DMF) (4ml) was added 4- (aminomethyl) -3- (trifluoromethyl) benzonitrile (0.053g, 0.264mmol), followed by the addition of diisopropylethylamine (0.1Olml, 0.580mmol) and 1H-1,2,

3- benzotriazol-1-yloxy – tris (dimethylamino) _ scale hexafluorophosphate (Β0Ρ reagent, 0.128g, 0.290mmol). The reaction mixture was stirred at room temperature for 4 hours, and then purified by preparative HPLC to afford (cis) -N- {[4- cyano-2- (trifluoromethyl) phenyl] methyl} -3 – {[4_ methyl-6- (methylamino) -1,3,5_ triazin-2-yl] amino} cyclohexane carboxamide (83mg, 0.148mmol, 56%) “MS (ES) m / e 448 [ M + H] +. 1H NMR (400MHz, DMS0-D6) δ 7.8 (bs, 1H), 7.3 (bs, 1H), 7.2 (m, 1H), 6.9 (m, 1H), 3.8 (bs, 2H) , 3.3 (bm, 1H), 2.2 (bm, 4H),

1.8-1.5 (bm, 4H), 1.3-1.1 (bm, 4H), 0.8-0.5 (bm, 4H).

SMILES  Cc1nc(nc(n1)N[C@H]2CCC[C@H](C2)C(=O)NCc3ccc(cc3C(F)(F)F)C#N)NC

P.L. Podolin et al. In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. Prostaglandins Other Lipid Mediat. 2013, 104-105, 25-31.
L.A. Morgan et al. Soluble epoxide hydrolase inhibition does not prevent cardiac remodeling and dysfunction after aortic constriction in rats and mice. J. Cardiovasc. Pharmacol. 2013, 61, 291-301. 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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