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)​- Cyclohexanecarboxami​de, 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

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

 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

 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

 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

 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

 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

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)

…………………..

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

Example 74

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

[0709] 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).