WO 2016024224, New Patent, Trelagliptin, SUN PHARMA

WO 2016024224, New Patent, Trelagliptin, SUN PHARMA

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

BARMAN, Dhiren, Chandra; (IN).
NATH, Asok; (IN).
PRASAD, Mohan; (IN)

The present invention provides a process for the preparation of 4-fluoro-2- methylbenzonitrile of Formula (II), and its use for the preparation of trelagliptin or its salts. The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

Trelagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, chemically designated as 2- [[6-[(3i?)-3 -aminopiperidin- 1 -yl] -3 -methyl -2,4-dioxopyrimidin- 1 -yljmethyl] -4-fluorobenzonitrile, represented by Formula I.

Formula I

Trelagliptin is administered as a succinate salt of Formula la, chemically designated as 2-[[6-[(3i?)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxopyrimidin-l-yl]methyl]-4-fluorobenzonitrile butanedioic acid (1 : 1).

Formula la

U.S. Patent Nos. 7,795,428, 8,288,539, and 8,222,411 provide a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 2-bromo-5-fluorotoluene with copper (I) cyanide in N,N-dimethylformamide.

Chinese Patent No. CN 102964196 provides a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 4-fluoro-2-methylbenzyl alcohol with cuprous iodide in the presence of 2,2′-bipyridine and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) in an anhydrous ethanol.

Copper (I) cyanide is toxic to humans, and therefore its use in the manufacture of a drug substance is not advisable. In addition, 2-bromo-5-fluorotoluene is converted to 4-fluoro-2-methylbenzonitrile by refluxing in N,N-dimethylformamide at 152°C to 155°C for 24 hours. This leads to some charring, resulting in a tedious work-up process and low yield. Furthermore, the use of reagents like cuprous iodide, 2,2′-bipyridine, and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) is hazardous and/or environmentally-unfriendly, and therefore their use in the manufacture of a drug substance is not desirable.

The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

EXAMPLES

Example 1 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (1.38 g) was added to ethanol (10 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (2.76 g) and pyridine (1 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 3 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 2: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (5 g) was added to ethanol (37 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (10 g) and N,N-diisopropylethylamine (3.6 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 2 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 3 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (10 g) was added to ethanol (40 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (7.5 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 11.0 g

Example 4: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (70 g) and N,N-diisopropylethylamine (36 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 6 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 51.0 g

Example 5 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (20 g) was added to ethanol (200 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (18 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (60 mL) was charged into the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 20 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (50 mL) to afford the pure title compound. Yield: 21.0 g

Example 6: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methyl benzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (50 g) and N,N-diisopropylethylamine (46.4 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (150 mL) was charged to the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 50 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (200 mL) to afford the pure title compound. Yield: 53.5 g

Example 7: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3.1 g) and phosphorous pentoxide (1 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.1 g

Example 8: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3 g) and phosphorous pentoxide (2 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.0 g

Example 9: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (5 g) and concentrated sulphuric acid (2 mL) were added to toluene (100 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (50 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 3.24 g

Example 10: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (25 g) and concentrated sulphuric acid (35 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (250 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 20.5 g

Example 11 : Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (5 g) and sodium bisulphate monohydrate (3.1 g) were added to toluene (50 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C, then filtered, and then washed with toluene (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound. Yield: 3.0 g

Example 12: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (50 g) and sodium bisulphate monohydrate (31.6 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C using a Dean-Stark apparatus for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25 °C to 30°C, then filtered, and then washed with toluene (100 mL). The filtrate was concentrated under reduced pressure to afford a crude product. The crude product obtained was recrystallized in a mixture of toluene (200 mL) and hexane (500 mL) to afford the title compound.

Yield: 38.0 g

Sun Pharma managing director Dilip Shanghvi.

/////////////WO 2016024224, New Patent, Trelagliptin, SUN PHARMA

WO 2016024289, NILOTINIB, New Patent by SUN PHARMA

NILOTINIB

WO 2016024289, NILOTINIB, New Patent by SUN

SUN PHARMACEUTICAL INDUSTRIES LTD [IN/IN]; 17/B, Mahal Industrial Estate, Off Mahakali Caves Road, Andheri (east), Mumbai 400093 (IN)

THENNATI, Rajamannar; (IN).
KILARU, Srinivasu; (IN).
VALANCE SURENDRAKUMAR, Macwan; (IN).
SHRIPRAKASH DHAR, Dwivedi; (IN)

The present invention provides novel salts of nilotinib and polymorphs thereof. The acid addition salts of nilotinib with benzenesulfonic acid, butanedisulfonic acid, 1-5- naphthalenedisulfonic acid, naphthalene-1-sulfonic acid and 1-hydroxynaphthoic acid; hydrates and anhydrates thereof.

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.

WIPO publication 2014059518A1 discloses crystalline forms of nilotinib hydrochloride and methods of the preparation of various crystalline solvates of nilotinib hydrochloride including benzyl alcohol, acetic acid and propylene glycol.

WIPO publication 2011033307A1 discloses nilotinib dihydrochloride and its hydrates and method for their preparation.

WIPO publication 2011163222A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts of nilotinib disclosed are hydrochloride, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, p-toluenesulfonate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate and malonate.

WIPO publication number 2011086541A1 discloses a nilotinib monohydrochloride monohydrate salt and methods for preparing.

WIPO publication number 2010054056A2 describes several crystalline forms of nilotinib hydrochloride.

WIPO publication number 2007/015871A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts are mixtures of nilotinib and one acid wherein the acids are selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sul- fonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.

WIPO publication number 2007015870A2 discloses several nilotinib salts including amorphous and crystalline forms of nilotinib free base, nilotinib HC1 and nilotinib sulfate along with their hydrate and solvates.

EXAMPLES:

Example 1: Preparation of nilotinib benzenesulfonate crystalline Form I

Nilotinib base (1 g) was suspended in water (20 ml). A solution of benzenesulfonic acid (0.4 g) in water (3ml) was added and the content was heated at 60 °C for 2-3 h. The mixture was cooled to 25-30 °C, filtered, washed with water (3 x 5 ml) and dried under vacuum for 2 h at 50-55 °C.

1H NMR (500 MHz, DMSO-d6) δ 2.40 (s,3H), 2.42 (s,3H), 7.35-7.37 (m,3H), 7.51-7.66 (m,5H),7.83 (d,lH), 7.96 (s,lH),8.08 (s,lH),8.30 (s,lH) 8.39 (s,lH),8.54 (d,lH), 8.61 (d,lH), 8.64 (s,lH), 8.75 (d,lH), 9.25 (s,lH), 9.34 (d,lH), 9.61 (s,lH), 10.84 (s,lH).

The salt provides an XRPD pattern substantially same as set forth in FIG. 1.

Example 2: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (100 g) was dissolved in 20 % water in THF solution (2000 ml) at 60-65 °C and insoluble matter was filtered. The filtrate was concentrated under vacuum below 60 °C. Filtered water (1000 ml) was added to the reaction mixture and it was heated at 50-55 °C, followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution (28.6 ml) at same temperature. The content was stirred at 50-55 °C for 2-3h. Reaction mixture as cooled to 25-30 °C and product was filtered, washed with water (200 ml x 2) and dried in air oven at 50-55 °C (yield: 115 g).

Sun Pharma managing director Dilip Shanghvi.

Purity (by HPLC):99.76%

1H NMR (400 MHz,DMSO-d6) δ 1.63-1.66(m,2H), 2.40(d,3H),2.42(s,3H),2.43-2.47(m,2H), 7.51-7.62(m,3H),7.85(dd,lH),7.96(s,lH),8.08(s,lH),8.34(s,lH),8.38(d,lH),8.52-8.55(m,lH), 8.60-8.62 (m,2H), 8.75(d,lH), 9.25(S,1H),9.34(S,1H),9.59(S,1H),10.86(S,1H)

Water content: 7.95 %.

The salt has a XRPD pattern substantially same as set forth in FIG. 2.

Example 3: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (300 g) was suspended in methanol (3000 ml) and aqueous hydrochloric acid was added to get pH less than 2. Reaction contents were heated at reflux and was filtered and washed with methanol (100 ml). 5% (w/w) NaOH (1200 ml) solution was added at 40-45 °C within 15 min, reaction mixture was stirred for 2h. Product was filtered, washed with water

(300 ml x 3) and dried for lh. Wet material was suspended in water (3000 ml), heated at 50- 55 °C followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution. The reaction mixture was stirred at 50-55°C for 2hrs. Product was filtered at room temperature, washed with water (500 ml x 2) and dried in air oven at 50-55 °C (yield: 293 g).

Purity (by HPLC): 99.88 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.75-1.78(m,2H), 2.36(d,3H),2.38(s,3H),2.69- 2.72(m,2H),7.45(d,lH),7.68(d,lH),7.83(s,lH),7.88(dd,lH),7.97(s,lH),8.16-8.19(m,lH), 8.35

(s,2H), 8.63(d,lH),8.68(d,lH),9.04(d,lH),9.21(d,lH),9.53(br s,lH),9.69(d,lH)10.80 (s,lH)

Water content: 6.44 %

Example 4: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form III

Nilotinib butanedisulfonate (210g) was dissolved in acetic acid water mixture (50:50) (2520 ml) at 75-80 °C and was filtered to remove insoluble matter and washed with acetic acid water mixture (50:50) (210 ml). Water (3150ml) was added to the filtrate and stirred first at room temperature and then at 0-5 °C. Product was filtered and washed with water. Material was dried in air oven at 70-75 °C. Dried material was leached with methanol (3438 ml) at reflux temperature, filtered and dried in air oven 70-75°C (yield: 152.6 g)

Purity (by HPLC): 99.89 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.73-1.77(m,2H), 2.40(s,6H),2.67-2.70(m,2H), 7.50 (d,lH), 7.70(d,lH), 7.88-7.92(m,2H), 8.07(s,lH),8.23 (dd,lH), 8.34(s,2H), 8.67 (d,lH), 8.72 (d,lH), 9.09(d,lH), 9.23 (s,lH), 9.54(d,lH), 9.74(d,lH), 10.86(s,lH).

Water content: 0.61 %

The salt provides an XRPD pattern substantially same as set forth in FIG. 3.

Example 5: Preparation of crystalline form of nilotinib butanedisulfonate (2: 1)

Crystalline Nilotinib butanedisulfonate (1 g) of Example 2 was suspended in methanol (20 ml) and was stirred at reflux for 60 min. The mixture was cooled to room temperature. Solid was filtered, washed with methanol (2 ml x 3) and dried in air oven at 70-75°C (yield: 0.8 g)

Example 6: Preparation of nilotinib butanedisulfonate (1: 1) crystalline Form IV

Nilotinib base (20 g) was suspended in methanol (800 ml) and 1,4-butanedisulfonic acid -60

% aqueous solution (6 ml) was added at 50-55 °C, and was filtered to remove insoluble matter. Filtrate was stirred at room temperature for 2-3 h. Product formed was filtered, washed with methanol (20 ml x 2) and dried the product in air oven at 70-75 °C (yield: 18.4 g).

Purity (by HPLC):99.86 %

1H NMR (400 MHz,DMSO-d6) δ 1.64-1.68(m,4H), 2.47-2.5 l(m,4H), 2.41(s,3H), 2.42(d,3H), 7.52(d,lH), 7.83-7.89(m,2H), 7.99(s,lH), 8.15(s,lH), 8.36 (d,lH), 8.39(s,lH), 8.65-8.66(m,2H), 8.79(d,lH), 8.89(br s,lH), 9.36(s,lH), 9.41(br s,lH), 9.74(d,lH), 10.91(s,lH).

The salt has XRPD pattern substantially same as set forth in FIG. 4.

Example 7: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (2: 1) crystalline Form V

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.4 g; 0.6 eq.) in water (5ml) was added and the content was heated at 50-55 °C for lh. The mixture was cooled to 25-30 °C, filtered and washed with water (10 ml). The product was dried in air oven at 50-55°C (yield: 1.2 g).

1H NMR (400 MHz,DMSO-d6) δ 2.39 (s,3H), 2.42 (s,3H), 7.45-7.61 (m,4H),7.84 (d,lH), 7.97(s,2H),8.08 (m,lH),8.31 (s,lH) 8.38 (s,lH),8.55 (d,lH), 8.63 (s,2H), 8.75 (s,lH), 8.92 (d,lH), 9.26 (s, 1H), 9.34 (s,lH),9.62 (s,lH), 10.85 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 5.

Example 8: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (1: 1) crystalline Form VI

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.8 g; 1.2eq) in water (5 ml) was added and the content was heated at 50-55 °C for 1 h. The mixture was cooled to 25-30 °C, filtered, washed with water (10 ml) and dried in air oven at 50-55 °C (yield: 1.4g).

1H NMR(400 MHz,DMSO-d6) δ 2.40 (s,3H),2.41 (s,3H), 7.43-7.52 (m,3H),7.61 (d,lH), 7.85-7.99(m,5H),8.11 (s,lH),8.34 (s,2H), 8.64-8.67 (m,2H), 8.89-8.92 (m,4H),9.40(d,2H), 9.72 (s,lH), 10.87 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 6.

Example 9: Preparation of nilotinib napthalene-1- sulfonic acid salt crystalline Form VII Nilotinib base (1 g) was suspended in water (10 ml) and heated to 50-55 °C. A solution of napthelene-1 -sulfonic acid and methanol (10 ml) was added to it and heated at 70-75 °C for 30 min. The mixture was cooled to 25-30 °C and stirred for 10 min. The product was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1-2 h at 50-55 °C.

1H NMR (400 MHz,DMSO-d6) δ 2.41 (s,3H),2.42 (s,3H), 7.46-7.58 (m,5H), 7.70-8.00 (m,7H)8.11(s,lH)8.31(s,lH),8.37(s,lH),8.63-8.66 (m,3H), 8.81-8.89 (m,2H), 9.31 (s,lH), 9.37 (d,lH), 9.71 (d,lH), 10.86 (s,lH)

The salt has a XRPD pattern substantially same as set forth in FIG. 7.

Example 10: Preparation of nilotinib l-hydroxy-2-napthoic acid salt crystalline Form VIII Nilotinib base (1 g) was suspended in water (20 ml) and heated to 50-55 °C. l-Hydroxy-2-napthoic acid was added to it and the content was heated at 50-55 °C for 1 h. Methanol (5 ml) was added to the mixture and stirred for 30 min. The content was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1 h at 50-55 °C.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s,3H), 2.41 (s,3H), 7.40-7.92 (m,l lH), 8.23-8.73 (m,8H), 9.24 (s,lH), 9.34(s,lH), 10.70 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 8.

NILOTINIB

SYSTEMATIC (IUPAC) NAME
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
CLINICAL DATA
TRADE NAMES	Tasigna
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a608002
LICENCE DATA	EMA:Link, US FDA:link
PREGNANCY CATEGORY	AU: D US: D (Evidence of risk)
LEGAL STATUS	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
ROUTES OF ADMINISTRATION	Oral
PHARMACOKINETIC DATA
BIOAVAILABILITY	30%[1]
PROTEIN BINDING	98%[1]
METABOLISM	Hepatic (mostly CYP3A4-mediated)[1]
BIOLOGICAL HALF-LIFE	15-17 hours[1]
EXCRETION	Faeces (93%)[1]
IDENTIFIERS
CAS NUMBER	641571-10-0(base)
ATC CODE	L01XE08
PUBCHEM	CID 644241
IUPHAR/BPS	5697
DRUGBANK	DB04868
CHEMSPIDER	559260
UNII	F41401512X
KEGG	D08953
CHEBI	CHEBI:52172
CHEMBL	CHEMBL255863
PDB LIGAND ID	NIL (PDBe, RCSB PDB)
CHEMICAL DATA
FORMULA	C28H22F3N7O
MOLAR MASS	529.5245 g/mol

//////////////WO 2016024289, WO-2016024289, NILOTINIB, New Patent,  SUN

Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F

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