Daprodustat, GSK1278863

Daprodustat, GSK1278863

960539-70-2

GSK1278863; GSK 1278863; GSK-1278863; Daprodustat

C19H27N3O6
Exact Mass: 393.18999

(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine

N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine

2-(1,3-dicyclohexyl-2,4,6-triohexahydropyrimidine-5-carboxamide acetic acid
Mechanism of Action: HIF-prolyl hydroxylase inhibitor
Indication: anemia, diabetic wounds, and reduction of ischemic complications
Development Stage: Phase II
Developer:GlaxoSmithKline

UNII:JVR38ZM64B

Daprodustat , also known as GSK1278863, is a novel HIF-prolyl hydroxylase inhibitor. Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease

• OriginatorGlaxoSmithKline
• ClassAntianaemics; Pyrimidines; Small molecules
• Mechanism of ActionErythropoiesis stimulants; Prolyl hydroxylase inhibitors

• Phase II Anaemia; Perioperative ischaemia
• Phase I Diabetic foot ulcer; Tendon injuries
• DiscontinuedPeripheral arterial disorders

Most Recent Events

• 27 Jul 2015No recent reports of development identified – Phase-II for Anaemia in India and New Zealand (PO)
• 27 Jul 2015Daprodustat is still in phase II trials for Anaemia in the USA, Australia, Canada, Czech Republic, Denmark, France, Germany, Hungary, Japan, Poland, Russia, Spain, South Korea, and United Kingdom
• 01 Jun 2015GlaxoSmithKline completes a phase I trial in Tendon injuries (In volunteers) in USA (PO) (NCT02231190)

WO 2007150011

https://www.google.com.ar/patents/WO2007150011A2

Illustrated Methods of preparation

Scheme 1

a) 1. NaH, THF, rt 2. R¹NCO, 60 ⁰C; b) 1. NaH, THF or dioxane, rt 2. R⁴NCX, heat; c) H₂NCH₂CO₂H, DBU, EtOH, 160⁰C, microwave.

Scheme 2

a) R¹NH₂, CH₂Cl₂ or R¹NH₂-HCl, base, CH₂Cl₂; b) CH₂(C(O)Cl)₂, CH₂Cl₂, reflux or CH₂(CO₂Et)₂, NaOEt, MeO(CH₂)₂OH, reflux or 1. EtO₂CCH₂COCl, CHCl₃, 70 ⁰C 2.

DBU, CHCl₃, 70 ⁰C; c) 1. YCNCH₂CO₂Et,, EtPr’₂N, CHCl₃ or CH₂Cl₂ 2. aq NaOH, EtOH, rt. Scheme 3 (for R¹ = R⁴)

a) CDI,

DMF, 70 ⁰C or , EtOAc, rt

Scheme 4

a) OCNCH₂CO₂Et, EtPr’₂N, CHCl₃ or CH₂Cl₂; b) 1. R¹HaI, Na/K₂CO₃, DMF or DMA, 100 ⁰C or R¹HaI, pol-BEMP, DMF, 120 ⁰C, microwave 2. aq NaOH, MeOH or EtOH, rt.

Scheme 5

a) 1. CH₂(CO₂H)₂, THF, O ⁰C – rt 2. EtOH, reflux; b) 1. OCNCH₂CO₂Et, EtPr’₂N, CH₂Cl₂ 2. aq NaOH, EtOH, rt.

Scheme 6

a) 1. Phthalimide, DIAD, PPh₃, THF 2. (NH₂)₂, EtOH, reflux.

Scheme 7

a) Ac₂O, AcOH, 130 ⁰C.

Example 18

N-T(1 ,3-Dicvclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahvdro-5-pyrimidinyl)carbonyl1grycine Method 1

18.1a) h3-Dicvclohexyl-2A6(lH,3H,5H)-pyrimidinetrione. Dicyclohexylurea (3.0 g, 13.39 mmoles) was stirred in chloroform (80 mL) and treated with a solution of malonyl dichloride (1.3 mL, 13.39 mmoles) in chloroform (20 mL), added dropwise under argon. The mixture was heated at 50⁰C for 4 hours, wasahed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (10-30% ethyl acetate in hexane) to give the title compound (2.13 g, 55%). 1Η NMR (400 MHz, OMSO-d₆) δ ppm 4.46 (tt, J=12.13, 3.54 Hz, 2 H), 3.69 (s, 2 H), 2.15 (qd, J=12.46, 3.28 Hz, 4 H), 1.77 (d, J=13.14 Hz, 4 H), 1.59 (t, J=12.76 Hz, 6 H), 1.26 (q, J=12.97 Hz, 4 H), 1.04 – 1.16 (m, 2 H)

18.1b) N-r(1.3-Dicvclohexyl-6-hvdroxy-2.4-dioxo-1.2.3.4-tetrahvdro-5- pyrimidinvDcarbonyll glycine. Ethyl isocyanatoacetate (802 uL, 7.15 mmoles) was added to a mixture of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (2.1 g, 7.15 mmoles) and diisopropylethylamine (2.47 mL, 14.3 mmoles) in dichloromethane (100 mL) and stirred overnight. The reaction mixture was washed with 1 molar hydrochloric acid (x2) and evaporated. The residue was dissolved in ethanol (10 mL) and treated with 1.0 molar sodium hydroxide (5 mL). The mixture was stirred for 72 hours, acidified and extracted into ethyl acetate. Some ester remained, therefore the solution was evaporated and ther residue was dissolved in 1 molar soldium hydroxide solution with warming and strred for 2 hours. The mixture was acidified with IM HCl and extracted with ethyl acetate (x2). The combined extracts were washed with 1 molar hydrochloric acid , dried and evaporated to a solid which was slurried in a mixture of diethyl ether and hexane, collected, washed with the same solvent mixture and dried to give the title compound (1.86 g, 66%). IH NMR (400 MHz, DMSO-^₆) δ ppm 13.07 (br. s., 1 H), 10.19 (t, J=5.31 Hz, 1 H), 4.63 (t, J=10.99 Hz, 2 H), 4.12 (d, J=5.56 Hz, 2 H), 2.27 (q, J=I 1.71 Hz, 4 H), 1.79 (d, J=12.88 Hz, 4 H), 1.50 – 1.69 (m, 6 H), 1.28 (q, J=12.97 Hz, 4 H), 1.12 (q, J=12.72 Hz, 2 H)

Method 2

18.2a) 1.3-Dicvclohexyl-2.4.6πH.3H.5H)-pyrimidinetrione. A solution of N₅N- dicyclohexylcarbodiimide (254 g; 1.23 mol.) in anhydrous TΗF (700 mL) was added dropwise to a cold (0 ⁰C) solution of malonic acid (64.1 g; 0.616 mol.) in anhydrous TΗF (300 mL) over a period of- 30 minutes. The mixture was stirred and allowed to warm to room temperature over 2 h. (After 1 h, the mixture became very thick with precipitate so further anhydrous TΗF (500 mL) was added to facilitate agitation.). The mixture was filtered and the filtrate evaporated to afford a yellow solid which was immediately slurried in ethanol (1 L) and heated to reflux temperature. The mixture was then allowed to cool to room temperature then filtered and the solid washed with cold ethanol (250 mL) to afford the title compound (129.4 g; 72%) as a colorless solid. 1Η NMR (400 MHz, DMSO-(Z₆) δ ppm 1.03 – 1.18 (m, 2 H) 1.18 – 1.34 (m, 4 H) 1.59 (t, J=13.14 Hz, 6 H) 1.76 (d, J=12.88 Hz, 4 H) 2.04 – 2.24 (m, 4 H) 3.69 (s, 2 H) 4.35 – 4.54 (m, 2 H).

18.2b) Ethyl N-[(l .3-dicvclohexyl-6-hvdroxy-2.4-dioxo- 1.2.3.4-tetrahydro-5- pyrimidinyPcarbonyll glycinate. A solution of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (120.0 g; 0.41 mol.) and diisopropylethylamine (105.8 g; 0.82 mol.) in dichloromethane (1 L) was stirred and treated dropwise with a solution of ethyl isocyanatoacetate (53.0 g; 0.41 mol.) in dichloromethane (500 mL) and the mixture was then stirred at room temperature overnight. The mixture was then treated dropwise with 6M aq. hydrochloric acid (500 mL) and the separated organic layer was dried and evaporated. The resulting solid was slurried in hexanes (500 mL) and heated to reflux temperature. The mixture was then allowed to cool and filtered to afford ethyl N- [(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.1 g; 92%) as a cream powder. IH NMR (400 MHz, CHLOROFORM-,/) δ ppm 1.24 (s, 2 H) 1.37 (s, 7 H) 1.52 – 1.76 (m, 6 H) 1.78 – 1.94 (m, 4 H) 2.25 – 2.48 (m, 4 H) 4.17 (d, J=5.81 Hz, 2 H) 4.28 (q, J=7.24 Hz, 2 H) 4.74 (s, 2 H) 10.37 (t, J=4.67 Hz, 1 H). 18.2c)

N-rπ^-Dicyclohexyl-ό-hydroxy^^-dioxo-l^J^-tetralivdro-S- pyrimidinyDcarbonyll glycine. A stirred suspension of ethyl Ν-[(l,3-dicyclohexyl-6-hydroxy-2,4- dioxo-l,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.0 g; 0.377 mol.) in ethanol (1.5 L) was treated dropwise with 6M aq. Sodium hydroxide (250 mL) and stirred at room temperature for 3 h. The solution was then acidified by the dropwise addition of 6M aq. hydrochloric acid (300 mL), diluted with water (IL) and then filtered. The crude solid was slurried in water (2 L) then stirred vigorously and heated at 35 ⁰C for 1 h and filtered and dried. The solid material (~ 138 g) was then crystallized from glacial acetic acid (1.5 L) (with hot filtration to remove a small amount of insoluble material). The solid, which crystallized upon cooling, was collected and washed with cold glacial acetic acid (3 x 100 mL) to afford N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine (116.2 g; 78%) as a colorless solid.

IH NMR (400 MHz, DMSO-(Z₆) δ ppm 1.11 (d, J=12.88 Hz, 2 H) 1.27 (q, J=12.80 Hz, 4 H) 1.62 (s, 6 H) 1.70 – 1.90 (m, J=12.88 Hz, 4 H) 2.11 – 2.44 (m, 4 H) 4.11 (d, J=5.81 Hz, 2 H) 4.45 – 4.77 (m, 2 H) 10.19 (t, J=5.81 Hz, 1 H) 13.08 (s, 1 H).

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SEE

http://www.google.com/patents/WO2014132100A1?cl=en

///////////////Daprodustat, GSK1278863, GlaxoSmithKline , PHASE 2