AZD 9291 Third-generation, oral, irreversible, selective epidermal growth factor receptor (EGFR) inhibitor for Non-small cell lung cancer (NSCLC)

AZD 9291

2-Propenamide, N-[2-[[2-(dimethylamino)ethyl]methylamino]-4-methoxy-5-[[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]amino]phenyl]-

 N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide. 
cas :1421373-65-0, 1421373-66-1(mesylate salt)
Phase II Clinical Trials

ASTRAZENECA

Astrazeneca Ab, Astrazeneca Uk Limited
Mechanism of Action: Third-generation, oral, irreversible, selective  epidermal growth factor receptor (EGFR) inhibitor
Non-small cell lung cancer (NSCLC)

AZD-9291 M. Wt: 499.61 
AZD-9291 Formula: C28H33N7O2 

AZD9291, a third-generation orally irreversible epidermal growth factor receptor (EGFR) inhibitor, is under development by British drug maker AstraZeneca for the treatment of patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC).
Lung cancer is the major cause of cancer death in the world while non small cell lung cancer (NSCLC) accounts approx. 85% of all lung cancer diagnosis. Approximately 50% of non–small cell lung cancer (NSCLC) patients who develop resistance to inhibitors of the epidermal growth factor receptor (EGFR) have acquired a second mutation, T790M. There are currently no approved treatments for patients who develop a T790 mutation.

AZD-9291 is a third-generation EGFR inhibitor, showed promise in preclinical studies and provides hope for patients with advanced lung cancers that have become resistant to existing EGFR inhibitors. AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines

Synthesis of AZD9291,

WO 2013014448 

http://www.google.com/patents/WO2013014448A1?cl=en

Example 27: V-f5-{[5-Cvano-4-flH-indol-3-yl)pyrimidin-2-yllamino}-4-methoxy-2-{4- methylpiperazin-l-yl}phenyl)prop-2-enamide

Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2- {[5-amino-2-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl] amino} -4-(lH-indol-3- yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at -10°C over a period of 2 minutes under N₂.The mixture was then stirred at 0°C for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to -10°C and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0°C for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH₂C1₂ (2 mL). This solution was washed with sat. NaHC0₃ (1 mL), dried (MgS0₄) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH₂C1₂ gave a residue that was washed with CH₃OH (0.1 mL) and dried in air to give the title compound (1 lmg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES⁺ MH⁺ 509. Example 28: V-f2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-fl- methylindol-3-yl)pyrimidin-2-yllamino}phenyl)prop-2-enamide

A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH₂C1₂ (1 mL) was added dropwise to a stirred mixture of N^;-(2-dimethylaminoethyl)-5-methoxy-N^;-methyl-N^¥-[4- (l-methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH₂C1₂ (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5h and then diluted with CH₂C1₂ (25 mL) and washed with sat.NaHCOs (50 mL). The aqueous washes were extracted with CH₂C1₂ (2 x 25 mL). The combined organic solutions were dried (MgSC^) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH₂C1₂ gave the title compound (75 mg, 39%) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES⁺ MH⁺ 500.42.

Example 28 (Alternative synthesis 1): V-f2-{2-Dimethylaminoethyl-methylamino}-4- methoxy-5-{[4-(l-methylindol-3-yl)pyrimidin-2-yllamino}phenyl)prop-2-enamide

To a stirred solution of 3-chloro-N-[2-[2-dimethylaminoethyl(methyl)amino]-4-methoxy- 5-[[4-(l-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide (Intermediate 174, 31.5 g, 58.76 mmol) in acetonitrile (310 mL) was added triethylamine (17.84 g, 176.28 mmol) at r.t. The resulting mixture was heated to 80°C for 6h then cooled to r.t.. Water (130 mL) was then added and the mixture stirred for 12h. The mixture was then filtered, washed with a mixture of water and acetonitrile (160 mL, 1 : 1) and dried at 50°C for overnight to give the title compound (19.2 g, 94%) as a solid form identified herein as polymorphic form D. 1H NMR: 2.69 (3H, s), 2.83 (6H, d), 3.35 (4H, s), 3.84 (3H, s), 3.91 (3H, s), 5.75 (IH, d), 6.28 (IH, d), 6.67 (IH, dd), 7.05-7.23 (2H, m), 7.29 (IH, t), 7.43 (IH, d), 7.56 (IH, d), 8.21 (2H, s), 8.81 (IH, s), 9.47 (IH, s), 9.52 (IH, s), m/z: ES⁺ MH⁺ 500.26.

Example 28 (Alternative synthesis 2): V-f2-{2-Dimethylaminoethyl-methylamino}-4- methoxy-5-{[4-(l-methylindol-3-yl)pyrimidin-2-yllamino}phenyl)prop-2-enamide

To a stirred solution of N¹-(2-dimethylaminoethyl)-5-methoxy-N¹-methyl-N⁴-[4-(l- methylindol-3-yl)pyrimidin-2-yl]benzene-l,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0°C was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65°C for lOh. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50°C for 12h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D.¹H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (IH, d) 6.28 (IH, d) 6.67 (IH, dd) 7.05-7.23 (2H, m) 7.29 (IH, t) 7.43 (IH, d) 7.56 (IH, d) 8.21 (2H, s) 8.81 (IH, s) 9.47 (IH, s) 9.52 (IH, s) ES⁺ MH⁺ 500.26.

Example 28A: V-f2-{2-Dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-fl- methylindol-3-yl)pyrimidin-2-yll amino}phenyl)prop-2-enamide mesylate salt

Procedure 1: To a stirred solution of N-[2-[2-dimethylaminoethyl(methyl)amino]-4- methoxy-5 – [[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl] amino]phenyl]prop-2-enamide

(Example 28, 20 g, 36.63 mmol) in ethanol (120 mL) and EtOAc (80 mL) at 70°C was added methane sulfonic acid (3.59 g, 36.63 mmol) as a solution in EtOAc (40 mL). The resulting mixture was stirred for 1.5h. The resulting solid was collected by filtration and dried at 80°C under vacuum overnight to give the title salt (20.5 g, 94%) in a solid form defined herein as polymorphic Form B for this salt.

Procedure 2: To a stirred solution of N-[2-[2-dimethylaminoethyl(methyl)amino]-4- methoxy-5 – [[4-( 1 -methylindol-3 -yl)pyrimidin-2-yl] amino]phenyl]prop-2-enamide

(Example 28, 5 g, 9.11 mmol) in acetone (45.5 mL) and water (4.55 mL) at 50°C was added methane sulfonic acid (0.893 g, 9.11 mmol) as a solution in acetone (4.55 mL). The resulting mixture was stirred for 1.5h. The resulting solid was collected by filtration and dried at 80°C under vacuum overnight to give the title salt (4.9 g, 94%) in a solid form defined herein as polymorphic Form B for this salt; ^ΧΗ NMR (acetone-ii⁶): 2.72 (3H, s), 2.96 (3H, s), 3.01 (6H, s), 3.58 (3H, t), 3.87-3.90 (7H, m), 5.76 (1H, dd), 6.38-6.53 (2H, m), 7.12 (1H, t), 7.20 (1H, t), 7.29 (1H, s), 7.40 (2H, t), 8.07-8.16 (3H, m), 8.56 (1H, s), 9.30 (1H, s), 9.60 (1H, s), 9.66 (1H, s ); m/z: ES⁺ MH⁺ 500.26.

Procedure 3: Polymorphic Form A of N-(2-{2-dimethylaminoethyl-methylamino}-4- methoxy-5 – { [4-( 1 -methylindol-3 -yl)pyrimidin-2-yl] amino } phenyl)prop-2-enamide mesylate salt was prepared in a similar manner as described above on a ~50 mg scale, except that acetonitrile was used as the solvent. Specifically, ~9.6mg methanesulfonic acid was dissolved into a minimum volumn of acetonitrile. ~50 mg N-(2- {2-dimethylamino- ethyl-methylamino } -4-methoxy-5 – { [4-( 1 -methylindol-3 -yl)pyrimidin-2-yl] amino } phenyl)- prop-2-enamide was also dissolved into a minimum volume of acetonitrile and then the resulting solution was added to the methanesulfonic acid solution. Formation of a solid resulted upon addition. This solid was collected by filtration and was air-dried and then analysed. The particular solid form produced in this experiment was designated as

Polymorphic Form A for this salt.