DS-1040, Activated thrombin activatable fibrinolysis (TAFIa) inhibitor

DS-1040
Daiichi Sankyo Co Ltd
Ischemic stroke
(2S)-5-amino-2-[[1-(4-methylcyclohexyl)imidazol-4-yl]methyl]pentanoic acid
1H-​Imidazole-​4-​propanoic acid, α-​(3-​aminopropyl)​-​1-​(trans-​4-​methylcyclohexyl)​-​, (αS)​-
(2S)-5-amino-2-{[1-(trans-4-methylcyclohexyl)-1H-imidazol-4-yl]methyl}pentanoic acid
free form cas 1335138-62-9
1:1 TOSYLATE 1335138-89-0
1335138-90-3  1:1:1 TOSYLATE HYDRATE
phase 2, Ischemic stroke

Molecular Formula:	C16H27N3O2
Molecular Weight:	293.40448 g/mol

TAFIa inhibitors, useful for treating myocardial infarction, angina, pulmonary hypertension and deep vein thrombosis.
In March 2016, DS-1040 was reported to be in phase 2 C clinical development, and the study was expected to complete in June 2017.
https://clinicaltrials.gov/ct2/show/NCT02560688

• 01 Feb 2016Daiichi Sankyo initiates a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
• 09 Jan 2016Daiichi Sankyo plans a phase I trial in Healthy volunteers in United Kingdom (NCT02647307)
• 29 Sep 2015Daiichi Sankyo plans a drug-interaction phase I trial in Healthy volunteers in United Kingdom (IV) (NCT02560688)

SYNTHESIS

COMPLETE SYNTHESIS





Patent
WO201111506
PATENT
WO2013039202
PATENT
WO 2016043254

PATENT

WO2016043253
COMPLETE SYN..........

WO2016043253

The optical purity of the obtained compound was measured by the following HPLC analysis conditions.
(2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valeric acid (S)-2-amino 1-propanol salt (A1 step, A2 step, A3 step), (2S) -5 - [ (tert- butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazole 4-yl] methyl} optical purity measurement conditions valerate (A4 step):
column: CHIRAL AGP 4.6mmI. D. × 250mm (5μm),
mobile phase: methanol / 10mM phosphate buffer solution (pH7.0) = 95/5,
temperature: 40 ℃,
flow rate: 0.5mL / min,
detection method: UV at 220nm,
retention time: R body: 5.9 minutes, S body: 7.3 minutes.

(2S)-5-amino-2 - Optical purity measurement conditions {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step) :
column: CHIRLCEL OZ-H 4.6mmI. D. × 250mm (5μm),
mobile phase: hexane / ethanol / methanol / isopropanol / trifluoroacetic acid / triethylamine = 860/100/20/2/2
temperature: 30 ℃
flow rate: 1.0mL / min
detection method: UV at 220nm
retention time: R body: 16.1 minutes, S body: 13.0 minutes 　(example 　1) (1-1) 5 - [(Tert- butoxycarbonyl) amino] -2-methoxy-carbonyl) valeric acid morpholine salt

[Of 11]

　In methanol (400mL) solution of di -tert- butyl (100.0g) and 3-chloro-propylamine hydrochloride (71.5g), was added dropwise triethylamine (51.0g) at 0 ℃, at the same temperature It was stirred for 16 hours. To the reaction solution was added toluene (400 mL) and water (400 mL), then were separated, and the organic layer was washed with water. Toluene 400mL was added to the organic layer, was concentrated under reduced pressure to 300 mL, N, N-dimethylacetamide (210 mL) was added and concentrated in vacuo to 300 mL. Potassium carbonate solution (126.66g), tetrabutylammonium bromide (44.32g), was added dimethyl malonate (90.82g) and N, N-dimethylacetamide (100 mL), stirred for 20 hours at 55 ° C. did. Toluene (400 mL) and water (700 mL) was added to the reaction mixture, after separation, The organic layer was washed with water, with 1M aqueous sodium hydroxide and water, and concentrated under reduced pressure to 150 mL. This solution methanol (1870mL) and 1M sodium hydroxide solution (430.8mL) in addition to, and the mixture was stirred for 27.5 hours at 0 ℃. Concentrated hydrochloric acid to the reaction solution (2.5 mL) was added, the pH was adjusted to 7-9, and concentrated in vacuo to 375 mL. After addition of ethyl acetate (500mL) to the reaction solution, concentrated hydrochloric acid (35.1mL) was added, the pH was adjusted to 2.2-2.5, and the layers were separated. The aqueous layer was extracted with ethyl acetate (500 mL), after mixing the organic layer under reduced pressure, and prepared by dehydration condensation of ethyl acetate (250 mL) solution. The resulting solution of ethyl acetate (500 mL) and morpholine (37.5 g) was added to and stirred overnight. The precipitated crystals were filtered, washed with ethyl acetate, and dried under reduced pressure, to give the title compound (136.1g, 81.9% yield).

¹ H-NMR _{(DMSO-d- . 6} ) [delta]: 6.79 (1H, t, J = 5.5 Hz), 3.61 (4H, t, J = 4.9 Hz), 3.58 The (3H, s) , 3.14 (1H, t, J = 7.8Hz), 2.90-2.80 (6H, m), 1.74-1.59 (2H, m), 1.37 (9H, s) , 1.34-1.25 (2H, m).

(1-2) [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

[Of 12]

　N, and stirred for 4 h methanol (56 mL) solution at 5 ~ 10 ℃ of N- dimethylformamide dimethyl acetal (77.4 g) and ethyl isocyanoacetate (70.0g).The reaction solution was cooled to 0 ℃, water (5.3mL) and trans-4- methylcyclohexyl amine (105.1g) was added, and the mixture was stirred for 24 hours at 60 ~ 65 ℃. The reaction was cooled to room temperature, toluene (420 mL), supplemented with 10% brine (280 mL) and concentrated hydrochloric acid (68 mL), After separation, the organic layer was washed with 10% brine (140 mL). Organic layer to 10% sodium chloride solution (280mL) and concentrated hydrochloric acid were added for liquid separation after (78.4g), was added to separate liquid further 10% saline solution into the organic layer (210mL) and concentrated hydrochloric acid (31.3g). After dissolving sodium chloride (70.0 g) in aqueous layer, adding toluene (420 mL) and 50% aqueous sodium hydroxide (85 mL), after separation, toluene (350 mL) the organic layer was added, under reduced pressure, dehydration concentrated was prepared in toluene (420 mL) solution was. The solution was cooled to 0 ℃, dropped the hydrogenated bis (2-methoxyethoxy) aluminum sodium (70% toluene solution) (207.4g), and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C., was added dropwise 12.5% ​​aqueous sodium hydroxide solution (700 mL), stirred for 1 hour at room temperature. After the solution was separated and the organic layer was washed successively with 12.5% ​​aqueous solution of sodium hydroxide (700mL) and 20% sodium chloride solution (140mL), toluene in the organic layer (140mL), 1- butanol (14mL), water ( 280mL) and was added to aliquots of concentrated hydrochloric acid (48mL). It was further added to liquid separation with water (140 mL) and concentrated hydrochloric acid (2 mL) to the organic layer. Met The aqueous layer was stirred in for 1 hour activated carbon (10.5 g), activated charcoal was filtered off, the activated carbon was washed with water (210 mL). Matches the filtrate and washings, sodium chloride (140 g), toluene was added (980 mL) and 50% aqueous sodium hydroxide (42 mL), After separation, under reduced pressure and the organic layer was dried concentrated toluene (210 mL) It was prepared in solution. The solution was stirred 30 minutes at 50-55 ° C., cooled to room temperature, it was added dropwise heptane (560 mL), and stirred at the same temperature for 3 hours. The precipitated crystals were filtered to give after washing with toluene / heptane (1/4) mixture solution, the title compound was dried under reduced pressure (77.2 g, 64.2% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.49 (1H, s), 6.91 (1H, s), 4.58 (2H, s), 3.83 (1H, tt, J = 12.0 , 3.9Hz), 2.10-2.07 (2H, m), 1.87-1.84 (2H, m), 1.70-1.61 (2H, m), 1.48-1 .42 (1H, m), 1.15-1.06 (2H, m), 0.95 (3H, d, J = 6.5Hz).

(1-3) (2E) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1-trans-4- methylcyclohexyl]-lH-imidazol-4-yl} methylidene} methyl valerate

[Of 13]

　(1-2) The compound obtained in (50.0 g) in toluene (350 mL) and acetic acid (150 mL) was dissolved in a mixed solution, 2,2,6,6-tetramethylpiperidine -N- oxyl at 30 ° C. It was added (966mg) and ortho-periodic acid (16.9g), and the mixture was stirred for 1 hour at 30-35 ℃. The reaction mixture was added 10% aqueous sodium bisulfite solution (150 mL), after stirring for 30 minutes at room temperature, toluene was added (400 mL), and concentrated in vacuo to 300 mL. The solution further by the addition of toluene (400 mL), after concentration under reduced pressure again to 300 mL, was added toluene (500 mL), water (200 mL) and 50% aqueous sodium hydroxide (118 mL). Were separated, the organic layer was washed with 20% brine (150 mL), addition of toluene (200 mL), under reduced pressure and dehydrated concentrated prepared in toluene (400 mL) solution. The compound obtained in the solution (1-1) (116.5g), N, N- dimethylformamide (175 mL) and acetic acid (4.2 mL) was added, under reduced pressure, and dried for 8 hours under reflux. The reaction was cooled to room temperature, adding toluene (400 mL), washed once with 3 times with 5% aqueous sodium bicarbonate solution (400 mL) and 10% brine (250 mL), under reduced pressure and the organic layer was dried concentrated toluene It was prepared (900 mL) solution. This solution was added activated charcoal (15 g) at 35 ~ 40 ° C., after stirring for 30 minutes at the same temperature, filtered and the activated carbon was washed with toluene. Meet the filtrate and washings, after which was concentrated under reduced pressure until 250mL, it was added dropwise heptane (500mL) at room temperature. After stirring for 1.5 hours at the same temperature, then cooled to 0 ℃, and the mixture was stirred for 1 hour. The precipitated crystals were filtered to give after washing with toluene / heptane (1/2) mixture solution, the title compound was dried under reduced pressure (85.0 g, 81.5% yield).

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 7.47 (1H, s), 7.15 (1H, s), 7.08 (1H, brs), 3.92- 3.87 (1H, m), 3.78 (3H, s), 3.16-3.12 (2H, m), 2.96 (2H, t, J = 7.5Hz), 2.14- 2.11 (2H, m), 1.90-1.87 (2H, m), 1.77-1.65 (5H, m), 1.47 (9H, s), 1.17-1. 10 (2H, m), 0.96 (3H, d, J = 6.5Hz).

　(1-4) (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (S ) -2-amino-1-propanol salt (A1 process, A2 process, A3 process)

[Of 14]

　The compound obtained in (1-3) (40.0g), (R) -2,2'- bis (di-3,5-xylyl) -1,1'-binaphthyl (507.4Mg) and dichloro (p- cymene) ruthenium (II) (dimer) and (211.4mg), were dissolved in degassed 2,2,2 trifluoroethanol (400 mL), hydrogen under pressure (400-450kPa) , and the mixture was stirred for 24 hours at 60 ℃. The reaction was cooled to room temperature, after nitrogen substitution, and then concentrated under reduced pressure to 60 mL.Tetrahydrofuran (200 mL) was added, was concentrated under reduced pressure to 120 mL, of tetrahydrofuran was added (200 mL).

　To the resulting solution was added water (160mL), cooled to 0 ℃, was added a 50% aqueous solution of sodium hydroxide (24.0mL). After stirring the reaction mixture at room temperature for 26 hours, and the addition of 50% sodium hydroxide solution (8.00mL), and the mixture was stirred for a further 4 hours. The reaction mixture under ice-cooling was added dropwise concentrated hydrochloric acid (28 mL), activated carbon was added (2.0 g) was stirred at room temperature for 10 minutes. The active carbon was filtered off, washed with tetrahydrofuran / water (2/1) mixed solvent (180 mL), sodium chloride (40 g) was separated by adding and re-extract the aqueous layer with tetrahydrofuran (400 mL). The organic layer was matched, and concentrated in vacuo to 200 mL. After addition of toluene (400 mL) to this solution, under reduced pressure and dehydrated concentrated prepared in toluene (200 mL) solution.

　After adding tetrahydrofuran (400 mL) to the resulting solution was added (S) -2- amino-1-propanol (8.2 g) at room temperature and stirred for 3 hours. The solution was cooled to 0 ℃, and was filtered after stirring for 1.5 hours, it was precipitated crystals. The crystals were washed with tetrahydrofuran and dried under reduced pressure to give the title compound (45.4g, 98.2% yield, optical purity: ee 97.5%) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 7.57 (1H, s), 6.94 (1H, s), 3.98-3.85 (1H, yd), 3.69-3.64 ( 1H, m), 3.47-3.42 (1H , m), 3.29-3.23 (1H, m), 3.01 (2H, t, J = 6.5Hz), 2.84 ( 1H, dd, J = 14.6,8.4Hz) , 2.55 (1H, dd, J = 14.6,6.2Hz), 2.52-2.45 (1H, m), 2.03 (2H, d, J = 12.7Hz ), 1.83 (2H, d, J = 13.3Hz), 1.71 (2H, q, J = 12.5Hz), 1.60-1.44 ( 5H, m), 1.41 (9H , s), 1.23-1.20 (3H, m), 1.18-1.09 (2H, m), 0.94 (3H, d, J = 6.8Hz).

　(1-5) (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate (A4 process)

[Of 15]

　(1-4) The compound obtained in (40.0 g) in tetrahydrofuran (400 mL) and dissolved in a mixed solvent of water (160 mL), concentrated hydrochloric acid (7.3 mL) and added separation of sodium chloride (40 g) and washed 3 times with the organic layer 20% (w / w) brine (160 mL). The organic layer under reduced pressure, dehydrated concentrated prepared in toluene (320 mL) solution was dissolved after addition of tetrahydrofuran (80 mL) was warmed precipitated 83 ° C. crystal. After stirring overnight and cooled to room temperature, and stirred for a further 3 hours at 0 ℃, and filtered the precipitated crystals. After washing the crystals with toluene / tetrahydrofuran (4/1) mixed solution, and dried under reduced pressure to give the title compound (30.9g, 92.1% yield, optical purity: 97.4% ee) was obtained.

　¹ H-NMR (CDCl ₃ ) [delta]: 7.59 (1H, s), 6.73 (1H, s), 4.67 (1H, brs), 3.85-3.80 (1H, yd), 3.12-3.08 (2H, m), 2.88 (1H, dd, J = 15.2,8.8Hz), 2.79 (1H, dd, J = 15.2,3.6Hz) , 2.70-2.64 (1H, m), 2.13-2.06 (2H, m), 1.90-1.82 (2H, m), 1.79-1.52 (5H, m), 1.49-1.44 (2H, m ), 1.43 (9H, s), 1.15-1.05 (2H, m), 0.95 (3H, d, J = 6. 5Hz).

　(1-6) (2S) -5- amino -2 - {[1- (trans-4- methylcyclohexyl)-lH-imidazol-4-yl] methyl} valerate p- toluenesulfonate (A5 Step)

[Of 16]

　In tetrahydrofuran (100 mL), was dissolved the compound obtained in (1-5) (25.0 g) and p- toluenesulfonic acid monohydrate (13.3 g), activated charcoal (1 to this solution. 25 g) was added and stirred for 1 hour at 20 ~ 30 ℃. The charcoal was filtered and washed with tetrahydrofuran (50 mL).It matches the filtrate and washings, p- toluenesulfonic acid monohydrate (13.3 g) and water (7.5 mL) and the mixture was heated under reflux for 6 hours. The reaction was cooled to room temperature, it was added triethylamine (7.7 g), at room temperature and stirred overnight. To the reaction solution was added dropwise tetrahydrofuran (350 mL), after stirring for 3 hours at room temperature and filtered the precipitated crystal. After washing with tetrahydrofuran / water (50/1) mixed solution, and dried under reduced pressure to give the title compound (27.7g, 93.5% yield, optical purity: 98.4% ee) was obtained.

　¹ H-NMR _(CD 3 OD) [delta]: 8.18 (1H, s), 7.70 (2H, d-, J = 8.1 Hz), 7.22 (2H, d-, J = 7.5 Hz), 7.16 (1H, s), 4.06 (1H, tt, J = 12.0,3.9Hz), 2.94-2.86 (3H, m), 2.69 (1H, dd, J = 14.6,5.8Hz), 2.62-2.59 (1H, m), 2.36 (3H, s), 2.08-2.05 (2H, m), 1.86-1 .83 (2H, m), 1.76-1.46 (7H, m), 1.18-1.11 (2H, m), 0.94 (3H, d, J = 6.5Hz).

　(Example
2) (2-1) (2S) -5 - [(tert-butoxycarbonyl) amino] -2 - {[1- (trans -4- methylcyclohexyl)-lH-imidazol-4-yl] methyl } methyl valerate

[Of 17]

　It was asymmetrically reduced using a number of catalysts. The reaction conversion and the optical purity of the obtained title compound was determined by the following HPLC analysis conditions.

　Reaction conversion rate measurement:
Column: Waters XBridge C18 4.6mmI. D. × 150mm (3.5μm),
mobile phase: (A) 10mM aqueous ammonium acetate solution, (B)
acetonitrile, Gradient conditions: B: conc. ; 20% (0-5 minutes), 20-90% (5-20 minutes), 90% (20-24 minutes),
temperature: 40 ℃,
flow rate: 1.0mL / min,
detection method: UV at 215nm
retention time: raw material: 21.1 minutes, the product: 19.1 minutes,
(peak area of peak area + product of raw materials) peak area / of the reaction conversion rate = product.

　Optical purity measurement conditions:
column: CHIRALPAK IA 4.6mmI. D. × 250mm (5μm),
mobile phase: ethanol / hexane = 20/80
Temperature: 35 ℃,
flow rate: 1.0mL / min,
detection method: UV at 210nm,
retention time: R body: 6.8 minutes, S body: 7.8 minutes.

PATENT
Daiichi Sankyo Company,Limited, 第一三共株式会社
WO2011115064.....
http://www.google.co.in/patents/WO2011115064A1?cl=en
[Reference Example 1] 5 - [(tert- butoxycarbonyl) amino] -2- (diethoxyphosphoryl) valeric acid tert- butyl

Diethylphosphonoacetate tert- butyl (20.0g) was dissolved in tetrahydrofuran (500mL), sodium hydride (63%, 3.32g) was added at 0 ℃, 15 min at 0 ℃, and stirred for 1 hour at room temperature . (3-bromopropyl) tetrahydrofuran carbamic acid tert- butyl (20.0g) (20mL) was slowly at room temperature, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1/1-ethyl acetate) to give the title compound (26.6g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.31-1.36 (6H, m), 1.44 (9H, m), 1.48 (9H, m), 1.51-1.59 (2H, m), 1.78-2.00 (2H, m) , 2.83 (1H, ddd, J = 22.9, 10.7, 4.4 Hz), 3.06-3.18 (2H, m), 4.10-4.18 (4H, m), 4.58 (1H, br).
[Reference Example 2] 5 - [(tert- butoxycarbonyl) amino] -2- (1H- imidazol-4-ylmethyl) valeric acid tert- butyl

In acetonitrile (100mL) solution of the compound obtained in Reference Example 1 (8.35g), at room temperature 1,8-diazabicyclo [5.4.0] undec-7-ene (4.58mL) and lithium chloride (1 .30g) and we were added. The suspension was added with 1-trityl--1H- imidazole-4-carbaldehyde (6.90g) was stirred at room temperature overnight, under vacuum, and the solvent was evaporated. After the solution separated by adding ethyl acetate and 10% citric acid aqueous solution, an organic layer, saturated brine, and then washed with a saturated aqueous sodium bicarbonate solution and brine. Dried over anhydrous sodium sulfate, (2E) -5 - [(tert- butoxycarbonyl) amino] -2 - [(1-trityl--1H- imidazol-4-yl) methylene] valeric acid tert- butyl and (2Z) -5 - obtain [(1-trityl--1H- imidazol-4-yl) methylene] valeric acid tert- butyl mixture (11.3g) - [(tert- butoxycarbonyl) amino] -2. The mixture was suspended in methanol (500mL), 10% palladium-carbon catalyst (water content, 4g) was added and stirred for 3 days at room temperature under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. Silica gel chromatography gave (eluting solvent: methylene chloride / methanol = 9/1) the title compound (5.60g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.41 (9H, s), 1.44 (9H, s), 1.48-1.57 (3H, m), 1.57-1.66 (1H, m), 2.58-2.68 (1H, m) , 2.73 (1H, dd, J = 14.7, 5.3 Hz), 2.89 (1H, dd, J = 14.7, 8.4 Hz), 3.02-3.19 (2H, m), 4.67 (1H, br s), 6.79 (1H, s), 7.54 (1H, s).
[Reference Example 3] 5 - [(tert- butoxycarbonyl) amino] -2- (methoxycarbonyl) valeric acid

Sodium methoxide in dimethyl malonate (102mL) - methanol (28%, 90.4mL) was added at room temperature and stirred at 60 ℃ 30 minutes. After cooling the white suspension solution to room temperature, (3-bromopropyl) was added carbamic acid tert- butyl (106g) in one portion and stirred at room temperature for 12 hours. Water was added to the reaction solution and the organics extracted with diethyl ether. The organic layer was successively washed with 1 N sodium hydroxide aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was distilled off under reduced pressure {3 - [(tert- butoxycarbonyl) amino] propyl} malonic I got acid dimethyl of crude product. The resulting ester (94g) was dissolved in methanol (100mL), water lithium hydroxide monohydrate (13.6g) (300mL) - was added to methanol (300mL) solution at 0 ℃, 15 h stirring at room temperature It was. The methanol was distilled off under reduced pressure and the organics were extracted with ethyl acetate. 2N hydrochloric acid (160mL) was added to the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography: - is purified (eluent methylene chloride methylene chloride / methanol = 10/1) to give the title compound (69.1g).
¹ H-NMR (CDCl ₃₎ ^δ: 1.44 (9H, m), 1.50-1.60 (2H, m), 1.86-2.01 (2H, m), 3.07-3.20 (2H, m), 3.43 (1H, m) , 3.77 (3H, s), 4.64 (1H, br).
[Reference Example 4] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde [Step 1] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carboxylic acid ethyl

Was dissolved in 3- (dimethylamino) -2-isocyanoethyl ethyl acrylic acid (Liebigs Annalen der Chemie, 1979 years 1444 pages) (1.52g) and the trans-4- methyl cyclohexylamine (3.07g), 70 ℃ in it was stirred for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, the organic matter was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 2) to give the title compound (1.90g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.96 (3H, d, J = 6.6 Hz), 1.13 (2H, m), 1.39 (3H, d, J = 7.0 Hz), 1.47 (1H, m), 1.68 ( 2H, m), 1.88 (2H, m), 2.12 (2H, m), 3.91 (1H, tt, J = 12.1, 3.9 Hz), 4.36 (2H, q, J = 7.0 Hz), 7.54 (1H, s ), 7.66 (1H, s).
[Step 2] [1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methanol

Lithium aluminum hydride (92%, 0.31g) it was suspended in tetrahydrofuran (6mL). The compound obtained in Step 1 of this reference example (1.50g) was dissolved in tetrahydrofuran (6mL), it was slowly added dropwise to the suspension at 0 ℃.0 After stirring for 30 min at ℃, the reaction solution was diluted with diethyl ether, it was added a saturated aqueous solution of sodium sulfate. After stirring for 1 hour at room temperature, the resulting inorganic salt was removed by filtration through Celite. The filtrate to give the crude product was concentrated under reduced pressure. Mixed solvent of this from hexane and ethyl acetate: water (5 1), to give the title compound (1.09g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.95 (3H, d, J = 6.6 Hz), 1.04-1.17 (2H, m), 1.44 (1H, m), 1.59-1.73 (2H, m), 1.81-1.89 (2H, m), 2.04-2.13 (2H, m), 2.78 (1H, br), 3.84 (1H, tt, J = 12.1, 3.9 Hz), 4.59 (2H, s), 6.91 (1H, s), 7.49 (1H, s).
[Step 3] 1- (trans-4- methylcyclohexyl) -1H- imidazole-4-carbaldehyde

The compound obtained in Step 2 of this reference example (1.04g) was dissolved in toluene (10mL). Aqueous solution of sodium hydrogen carbonate (1.35g) (5mL), iodine (2.72g) and 2,2,6,6-tetramethyl-1-sequential piperidinyloxy (84mg) was added and stirred for 2 hours at room temperature It was. The reaction solution was added saturated aqueous sodium thiosulfate solution and the organics were extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered to give the solvent was distilled off under reduced pressure the crude product. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 1 / 1-1 / 2) to give the title compound (0.900g).
¹ H-NMR (CDCl ₃₎ ^δ: 0.97 (3H, d, J = 6.8 Hz), 1.09-1.19 (2H, m), 1.48 (1H, m), 1.65-1.75 (2H, m), 1.87-1.93 (2H, m), 2.11-2.18 (2H, m), 3.95 (1H, tt, J = 12.2, 3.9 Hz), 7.62 (1H, s), 7.68 (1H, s), 9.87 (1H, s).
[Example 15] (2R) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid and (2S) -5- amino-2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valeric acid [Step 1] 5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans 4-methylcyclohexyl) -1H- imidazole-4-yl] methyl} methyl valerate

The compound obtained in Reference Example 4 (300mg) and the compound obtained in Reference Example 3 (860mg) was suspended in cyclohexane (10mL). Piperidine (0.154mL) and cyclohexane propionic acid (0.116mL) and (10mL) solution was added, and the mixture was heated under reflux for 48 hours. After cooling, aqueous potassium carbonate solution was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was dissolved in ethanol (12mL), 10% palladium-carbon catalyst (water, 250mg) was added and atmospheric pressure hydrogen atmosphere at room temperature for 4 hours and stirred at 60 ℃ 2.5 hours. After Celite filtration, to give the crude product and the filtrate was concentrated under reduced pressure. This silica gel column chromatography and purified (eluent hexane / ethyl acetate = 2 / 1-1 / 3) to give the title compound (562mg).
¹ H-NMR (CDCl ₃₎ ^δ: 0.94 (3H, d, J = 6.6 Hz), 1.02-1.15 (2H, m), 1.34-1.69 (7H, m), 1.43 (9H, s), 1.80-1.87 (2H, m), 1.99-2.09 (2H, m), 2.69 (1H, dd, J = 13.7, 6.3 Hz), 2.79 (1H, m), 2.88 (1H, dd, J = 13.7, 7.4 Hz), 3.03-3.13 (2H, m), 3.63 (3H, s), 3.79 (1H, tt, J = 12.1, 3.9 Hz), 4.76 (1H, br), 6.67 (1H, s), 7.47 (1H, s) .
[Step 2] (2R) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate and ( 2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate

The compound obtained in Step 1 of this Example (40mg) was dissolved in hexane (1.5mL) and ethanol (0.5mL), using CHIRALPAK IA semi-preparative column (2.0cm × 25.0cm) It was optically resolved by high performance liquid chromatography. Flow rate: 15mL / min, elution solvent: hexane / ethanol = 75/25, detection wavelength: 220nm.
The solvent of the divided solution was evaporated under reduced pressure to give both enantiomers each (15mg). Both enantiomers were confirmed to be optically pure by analytical HPLC. Column: CHIRALPAK IA (0.46cm × 25.0cm), flow rate: 1mL / min, elution solvent: hexane / ethanol = 80/20 <v / v>, detection wavelength: 220nm, retention time: (2R) -5- [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (7.2 min), (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} methyl valerate (11.2 min).
[Step 3] (2R) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2R) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200. After the resin was washed with water and eluted with 4% aqueous ammonia. The eluate was concentrated, the crude product was washed with acetone to give the title compound (2.2mg).
[Step 4] (2S) -5- amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valerate

Obtained in Step 2 of this Example (2S) -5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl } the methyl valerate (15.0mg) was added to 5 N hydrochloric acid (2mL), and the mixture was heated under reflux for 4 hours. After cooling, the solvent it was evaporated under reduced pressure. The resulting crude hydrochloride salt was dissolved in methanol, was added DOWEX50WX8-200 (200mg). After the resin was washed with water, ammonia water (4%, 80mL) and eluted with. The eluate was concentrated, the crude product was washed with acetone to give the title compound (1.8mg).
[Example 16] 5-amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazole-4-yl] methyl} valeric acid benzyl hydrochloride [Step 1] 5 - [(tert- butoxycarbonyl) amino] -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate

The compound obtained in step 1 of Example 15 (7.00g) was dissolved in a mixed solvent consisting of tetrahydrofuran (70mL) and water (14mL), lithium hydroxide monohydrate and (1.26g) at room temperature The mixture was stirred overnight.The reaction solution 2 N hydrochloric acid (8.6mL) was added to neutralize, followed by distilling off the solvent under reduced pressure. The resulting residue was dried with anhydrous sodium sulfate added methylene chloride was to give the crude product was distilled off the solvent under reduced pressure the title compound. This it was used in the next reaction.
MS (ESI) m / z 394 [M ⁺ H] +.
[Example 40] (2S) -5- Amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate, anhydrous

The compound obtained in Step 4 of Example 15 (2.04g) was suspended stirring in tetrahydrofuran (15mL), p- toluenesulfonate monohydrate (1.32g) was added, at room temperature for 1 day the mixture was stirred. The precipitated crystals were collected by vacuum filtration to obtain dried in one day like the title compound (3.01g).
¹ H-NMR (CD ₃ OD) ^δ: 0.95 (3H, d, J = 6.5 Hz), 1.11-1.21 (2H, m), 1.43-1.79 (7H, m), 1.83-1.89 (2H, m), 2.05-2.10 (2H, m), 2.37 (3H, s), 2.57-2.64 (1H, m), 2.70 (1H, dd, J = 14.5, 5.5 Hz), 2.85-2.95 (3H, m), 4.07 ( 1H, tt, J = 11.7, 3.9 Hz), 7.18 (1H, s), 7.23 (2H, d, J = 7.8 Hz), 7.70 (2H, d, J = 8.2 Hz), 8.22 (1H, s).
Elemental _{analysis: C 16} H ₂₇ N _{3 O 2} · C 7 H ₈ O ₃ S,
Theoretical value: C; 59.33, H; 7.58, N; 9.02, O; 17.18, S; 6.89,
Measured value: C; 59.09, H; 7.53, N; 8.92, O; 17.22, S; 6.78.
----------------------------------.
[Example 41] (2S) -5- Amino -2 - {[1- (trans-4- methylcyclohexyl) -1H- imidazol-4-yl] methyl} valerate · p- toluenesulfonate & 1 Water hydrate

The obtained compound (101.6mg) in 6% water-containing tetrahydrofuran (600μL) was added in Example 40, was dissolved by heating at 60 ℃. Was allowed to stand at room temperature for 1 day, it was collected by filtration and the precipitated crystals were obtained by dried for one day wind the title compound (79.3mg).
Elemental _{analysis: C 16 H 27} N ₃ O ₂ · C 7 H 8 O ₃ S · _{1H 2} O,
Theoretical value: C; 57.12, H; 7.71, N; 8.69, O; 19.85, S; 6.63,
Measured value: C; 56.90, H; 7.69, N; 8.67, O; 19.81, S; 6.42.

References
Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke (NCT02586233
Phase I Study to Evaluate the Safety and Tolerability of DS-1040b Intravenous Infusion With Clopidogrel in Healthy Subjects (NCT02560688)
Study of the Effects of Ethnicity on the Pharmacokinetics, Pharmacodynamics and Safety of DS-1040b (NCT02647307)
Edo, N.; Noguchi, K.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Hemorrhagic risk assessment of DS-1040 in a cerebral ischemia/reperfusion model of rats with hypertension and hyperglycemia
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP283

Noguchi, K.; Edo, N.; Ito, Y.; Morishima, Y.; Yamaguchi, K.
Improvement of cerebral blood flow with DS-1040 in a rat thromboembolic stroke model
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst TP271
Lapchak, P.A.; Boitano, P.D.; Noguchi, K.
DS-1040 an inhibitor of the activated thrombin activatable fibrinolysis inhibitor improves behavior in embolized rabbits
41st Int Stroke Conf (February 17-19, Los Angeles) 2016, Abst WP282 
A first-in-human, single ascending dose study of DS-1040, an inhibitor of the activated form of thrombinactivatable fibrinolysis inhibitor (TAFIa), in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO621-MON
Dow, J.; Puri, A.; McPhillips, P.; Orihashi, Y.; Dishy, V.; Zhou, J.
A drug-drug interaction study of DS-1040 and aspirin in healthy subjects
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO603-TUE
Noguchi, K.; Edo, N.; Ito, Y.; Yamaguchi, K.
Effect of DS-1040 on endogenous fibrinolysis and impact on bleeding time in rats
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst AS145
Noguchi, K.; Edo, N.; Ito, Y.; Maejima, T.; Yamaguchi, K.
DS-1040: A novel selective inhibitor of activated form of thrombin-activatable fibrinolysis inhibitor
25th Congr Int Soc Thromb Haemost (ISTH) (June 20-25, Toronto) 2015, Abst PO203-MON
DS1040b/Aspirin Drug/Drug Interaction Study (NCT02071004)
ClinicalTrials.gov Web Site 2014, February 26

Patent ID	Date	Patent Title
US2014178349	2014-06-26	Cycloalkyl-Substituted Imidazole Derivative
US8609710	2013-12-17	Cycloalkyl-substituted imidazole derivative

//////DS-1040, DS 1040, phase 2, Daiichi Sankyo Co Ltd, Ischemic stroke
O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2
O=S(=O)(O)c1ccc(C)cc1.O=C(O)[C@@H](CCCN)Cc1cn(cn1)[C@@H]2CC[C@@H](C)CC2

LY 2922470

LY 2922470
as per WO2013025424A1

LY 2922470

Picture credit....Bethany Halford

(3S)-3-[4-[[5-[(8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]thiophen-2-yl]methoxy]phenyl]hex-4-ynoic acid
Benzenepropanoic acid, 4-​[[5-​[(3,​4-​dihydro-​8-​methoxy-​1(2H)​-​quinolinyl)​methyl]​-​2-​thienyl]​methoxy]​-​β-​1-​propyn-​1-​yl-​, (βS)​-
Glucose Lowering Agents, Signal Transduction Modulators

CAS	1423018-12-5
Molecular Formula:	C28H29NO4S

Molecular Weight:	475.59916 g/mol

https://clinicaltrials.gov/ct2/show/NCT01867216

• Phase I Type 2 diabetes mellitus

Eli Lilly
Eli Lilly And Company
Antihyperglycaemics

• 28 Jan 2014 Eli Lilly completes a phase I trial in Type-2 diabetes mellitus in USA (NCT01867216)
• 30 Jun 2013 Phase-I clinical trials in Type-2 diabetes mellitus in USA (PO)
• 14 Jun 2013 Eli Lilly plans a phase I trial for Type-2 diabetes mellitus in USA (NCT01867216)

PATENT
WO 2013025424
https://www.google.com/patents/US20130045990?cl=de

Also published as	CA2843474A1, CA2843474C, CN103687856A, CN103687856B, EP2744806A1, US8431706, WO2013025424A1, Less «
Inventors	Chafiq Hamdouchi
Original Assignee	Eli Lilly And Company

Preparation 18-Methoxyquinoline
Add potassium hydroxide (435 g, 7.76 mol) to a solution of 8-hydroxy quinoline (250 g, 1.724 mol) in THF (10 L) at ambient temperature and stir. Add methyl iodide (435 g, 2.58 mol) dropwise and stir overnight. Filter the reaction mixture and wash the solid with THF (2 L). Concentrate the solution to dryness; add water; extract with dichloromethane (2×3 L); combine the organic layers; and wash with brine. Collect the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a red oil, which solidifies on standing, to give the title compound (281 g, 102%), which can be used without further purification. ESI (m/z) 160(M+H).
Preparation 2
8-Methoxy-1,2,3,4-tetrahydroquinoline
Add sodium cyanoborohydride (505 g, 8.11 mol) in EtOH (1 L) to a solution of 8-methoxy quinoline (425 g, 2.673 mol) in EtOH (9 L), and stir. Cool the reaction mixture to an internal temperature of 0° C. and add HCl (35%, 1.12 L, 10.962 mol) dropwise over 60 min so that the internal temperature did not rise above 20° C. Allow the reaction mixture to warm to ambient temperature and then heat to reflux for 2.5 hours. Cool to ambient temperature and stir overnight. Add ammonium hydroxide (25%, 1 L); dilute with water (15 L); and extract the mixture with dichloromethane (3×10 L). Combine the organic layers and dry over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give a residue. Purify the residue by silica gel flash chromatography, eluting with ethyl acetate: hexane (1:10) to give the title compound (357 g, 82%). ESI (m/z) 164(M+H).
Preparation 3
Methyl-5-methylthiophene-2-carboxylate
Add thionyl chloride (153 ml, 2.1 mol) dropwise over 20 min to a solution of 5-methylthiophene-2-carboxylic acid (100 g, 0.703 mol) in MeOH (1 L) at 0° C. and stir. After the addition is complete, heat the reaction mixture to reflux for 3.5 hours. Cool and concentrate in vacuo to give a thick oil. Dilute the oil with EtOAc (500 ml) and sequentially wash with water (300 ml) then brine (300 ml). Dry the organic layer over sodium sulfate. Remove the solids by filtration. Collect the filtrate and concentrate under reduced pressure to give the title compound (106 g, 97%), which is used without further purification. ESI (m/z) 156(M+H).
Preparation 4
Methyl 5-(bromomethyl)thiophene-2-carboxylate
Add freshly recrystallised NBS (323.8 g, 1.81 mol) to a solution of methyl-5-methylthiophene-2-carboxylate (258 g, 1.65 mol) in chloroform (2.6 L) at room temperature, and stir. Add benzoyl peroxide (3.99 g, 0.016 mol) and heat the reaction mixture to reflux for 7 hours. Cool the reaction mixture to ambient temperature and filter through diatomaceous earth. Wash the filter cake with chloroform (250 ml). Collect the organic layers and remove the solvent to give the title compound (388 g, 100%), which is used without further purification. ESI (m/z) 236(M+H).
Preparation 5
Methyl-5-[8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]thiophene-2-carboxylate
Add methyl-5-(bromoethyl)thiophene-2-carboxylate (432.5 g, 1.84 mol) in EtOH (500 ml) to a solution of 8-methoxy-1,2,3,4-tetrahydroquinoline (300 g 1.84 mol) in EtOH (1 L) and stir. Add DIPEA (641 ml, 3.67 mol) dropwise and stir at room temperature overnight. After completion of the reaction, remove the EtOH in vacuo, and add water (5 L). Extract the aqueous with EtOAc (3×3 L); combine the organic layers; and dry over sodium sulfate. Filter the solution and concentrate under reduced pressure to give a residue. Purify the residue by silica gel flash chromatography eluting with ethyl acetate: hexane (6:94) to give the title compound (325 g, 56%). ESI (m/z) 318(M+H).
Preparation 6
[5-[(8-Methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methanol
Add DIBAL-H (1 M in toluene 2.7 L, 2.66 mol) slowly via a cannula over a period of 1.5 h to a stirred solution of methyl-5-(8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophene-2-carboxylate (281 g, 0.886 mol) in THF (4 L) at −70° C. Monitor the reaction via thin layer chromatography (TLC) for completion. After completion of the reaction, allow the reaction mixture to warm to 20° C. and add a saturated solution of ammonium chloride. Add a solution of sodium potassium tartrate (1.3 Kg in 5 L of water), and stir overnight. Separate the organic layer; extract the aqueous phase with EtOAc (2×5 L); then combine the organic layers; and dry the combined organic layers over sodium sulfate. Remove the solids by filtration. Remove the solvent from the filtrate under reduced pressure to give the title compound as a white solid (252 g, 98%). ESI (m/z) 290(M+H).
Preparation 7
Ethyl(3S)-3-[4-[[5-[(8-methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methoxy]phenyl]hex-4-ynoate
Add tributylphosphine (50% solution in EtOAc, 543 ml, 1.34 mol) to a solution of ADDP (282.5 g, 1.5 eq) in THF (3 L) and cool the mixture to an internal temperature of 0° C., then stir for 15 minutes. Add (S)-ethyl 3-(4-hydroxyphenyl)hex-4-ynoate (173.5 g, 0.747 mol) in THF (3 L) dropwise over 15 min; then add 5-((8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophene-2-yl)methanol (216 g, 0747 mol) in THF (5 L) dropwise. Allow the reaction mixture to warm to ambient temperature and stir overnight. Filter the reaction mixture through diatomaceous earth and wash the filter cake with ethyl acetate (2 L). Concentrate the organic filtrate to dryness. Add water (4 L); extract with ethyl acetate (3×5 L); combine the organic layers; and dry the combined organic layers over sodium sulfate. Remove the solids by filtration and concentrate under reduced pressure to give an oil. Purify the residue by silica gel flash chromatography by eluting with ethyl acetate: hexane (6:94) to give the title compound (167 g, 44%). ESI (m/z) 504(M+H).
Example 1
(3S)-3-[4-[[5-[(8-Methoxy-3,4-dihydro-2H-quinolin-1-yl)methyl]-2-thienyl]methoxy]phenyl]hex-4-ynoic acid

Add a solution of potassium hydroxide (49.76 g, 0.88 mol) in water (372 ml) to a solution of (S)-ethyl-3-(4-((5-8-methoxy-3,4-dihydroquinolin-1(2H)-yl)methyl)thiophen-2-yl)methoxy) phenyl)hex-4-ynoate (149 g, 0.296 mol) in EtOH (1.49 L) at room temperature and stir overnight. Concentrate the reaction mixture to dryness and add water (1.3 L). Extract the resulting solution with EtOAc (2×300 ml) and separate. Adjust the pH of the aqueous layer to pH=6 with 2 N HCl. Collect the resulting solids. Recrystallise the solids from hot MeOH (298 ml, 2 vol) to give the title compound (91 g, 65%). ESI (m/z) 476(M+H).
Abstract
GPR40 agonists for the treatment of type 2 diabetes: From the laboratory to the patient
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 260

Presenter

Chafiq Hamdouchi

Senior Research Advisor at Eli Lilly and Company

https://www.linkedin.com/in/chafiq-hamdouchi-4988126

Summary

Dr. Hamdouchi earned his bachelor’s degree and doctorate in organic chemistry from Louis Pasteur University, Strasbourg-France.
Following two postdoctoral fellowships, sponsored by the National Science Foundation-USA and Ministerio de Educación y Ciencia-Spain, he joined Eli Lilly and Company in 1995.
Throughout his 20 years of career at Lilly, he has contributed to a sustainable drug discovery portfolio from preclinical hypothesis to clinical proof-of-concept that spans the oncology, neuroscience and endocrinology therapeutic areas. He has led multidisciplinary (chemistry, pharmacology, ADMET, PK, medical) scientific teams in USA, Europe and Asia to deliver a number of compounds that achieved first human dose.
He is a co-inventor of six innovative molecules being pursued in clinical development for the treatment of Diabetes, Cancer and Neurodegenerative Diseases.
He has an extensive patent and publication record and deep experience in conducting drug discovery and development in Asia through effective partnership and mentorship.

SEE AT............ONE ORGANIC CHEMIST ONE DAY BLOG

LINK......http://oneorganichemistoneday.blogspot.in/2016/03/chafiq-hamdouchi-senior-research.html

Patent ID	Date	Patent Title
US8431706	2013-04-30	1,2,3,4-tetrahydroqinoline derivative useful for the treatment of diabetes

References
GPR40 agonists for the treatment of type 2 diabetes: From the laboratory to the patient
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 260
//////Phase 1, LY2922470, LY 2922470, Eli Lilly, Type 2 diabetes mellitus, 1423018-12-5, Chafiq Hamdouchi

CC#CC(CC(=O)O)C1=CC=C(C=C1)OCC2=CC=C(S2)CN3CCCC4=C3C(=CC=C4)OC
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

 

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

 amcrasto@gmail.com

P.S
THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.
I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

.
Picture credit....Bethany Halford

PF  06650833

MFC18H20FN3O4, MW361.37
1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide
6-​Isoquinolinecarboxam​ide, 1-​[[(2S,​3S,​4S)​-​3-​ethyl-​4-​fluoro-​5-​oxo-​2-​pyrrolidinyl]​methoxy]​-​7-​methoxy-
CAS 1817626-54-2
WO 2015150995
1st disclosures is @pfizer's  on inflammatory disease treatment targeting IRAK4
$PFE IRAK4 inhibitor
Phase I Lupus vulgaris

• 01 Feb 2016 Pfizer completes a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02609139)
• 01 Nov 2015 Pfizer initiates a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02609139)
• 01 Jun 2015 Pfizer completes a phase I trial for Lupus (In volunteers) in USA (PO) (NCT02224651)

Compounds useful for the treatment of autoimmune and inflammatory diseases associated with lnterleukin-1 Receptor Associated Kinase (IRAK) and more particularly compounds that modulate the function of IRAK4.
Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified in tyrosine and serine/threonine kinases. Inappropriate activity arising from dysregulation of certain kinases by a variety of mechanisms is believed to underlie the causes of many diseases, including but not limited to, cancer, cardiovascular diseases, allergies, asthma, respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases. As such, potent and selective inhibitors of kinases are sought as potential treatments for a variety of human diseases.
There is considerable interest in targeting the innate immune system in the treatment of autoimmune diseases and sterile inflammation. Receptors of the innate immune system provide the first line of defense against bacterial and viral insults. These receptors recognize bacterial and viral products as well as pro-inflammatory cytokines and thereby initiate a signaling cascade that ultimately results in the up-regulation of inflammatory cytokines such as TNFa, IL6, and interferons. Recently it has become apparent that self-generated ligands such as nucleic acids and products of inflammation such as high-mobility group protein B1 (HMGB1) and Advanced Glycated End-products (AGE) are ligands for Toll-like receptors (TLRs) which are key receptors of the innate immune system (O'Neill 2003, Kanzler et al 2007, Wagner 2006). This demonstrates the role of TLRs in the initiation and perpetuation of inflammation due to autoimmunity.
lnterleukin-1 receptor associated kinase 4 (I RAK4) is a ubiquitously expressed serine/threonine kinase involved in the regulation of innate immunity (Suzuki & Saito 2006). IRAK4 is responsible for initiating signaling from TLRs and members of the I L- 1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice were reported to cause reductions in TLR and IL-1 induced pro-inflammatory cytokines (Kawagoe et al 2007; Fraczek et al. 2008; Kim et al. 2007). IRAK4 kinase-dead knock-in mice have also been shown to be resistant to induced joint inflammation in the antigen-induced-arthritis (AIA) and serum transfer-induced (K/BxN) arthritis models (Koziczak-Holbro 2009). Likewise, humans deficient in IRAK4 also appear to display the inability to respond to challenge by Toll ligands and IL-1 (Hernandez & Bastian 2006). However, the immunodeficient phenotype of IRAK4-null individuals is narrowly restricted to challenge by gram positive bacteria, but not gram negative bacteria, viruses or fungi. This gram positive sensitivity also lessens with age, implying redundant or compensating mechanisms for innate immunity in the absence of IRAK4 (Lavine et al 2007).
These data indicate that inhibitors of IRAK4 kinase activity should have therapeutic value in treating cytokine driven autoimmune diseases while having minimal immunosuppressive side effects. Additional recent studies suggest that targeting IRAK4 may be useful in other inflammatory pathologies such as atherosclerosis and diffuse large B-cell lymphoma (Rekhter et al 2008; Ngo et al 2011). Therefore, inhibitors of IRAK4 kinase activity are potential therapeutics for a wide variety of diseases including but not limited to autoimmunity, inflammation, cardiovascular diseases, cancer, and metabolic diseases. See the following references for additional information: N. Suzuki and T. Saito, Trends in Immunology, 2006, 27, 566. T. Kawagoe, S. Sato, A. Jung, M. Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi and S. Akira, Journal of Experimental Medicine, 2007, 204, 1013. J. Fraczek, T. W. Kim, H. Xiao, J. Yao, Q. Wen, Y. Li, J.-L. Casanova, J. Pryjma and X. Li, Journal of Biological Chemistry, 2008, 283, 31697. T. W. Kim, K. Staschke, K. Bulek, J. Yao, K. Peters, K.-H. Oh, Y. Vandenburg, H. Xiao, W. Qian, T. Hamilton, B. Min, G. Sen, R. Gilmour and X. Li, Journal of Experimental Medicine, 2007, 204, 1025. M. Koziczak-Holbro, A. Littlewood- Evans,
B. Pollinger, J. Kovarik, J. Dawson, G. Zenke, C. Burkhart, M. Muller and H. Gram, Arthritis & Rheumatism, 2009, 60, 1661. M. Hernandez and J. F. Bastian, Current Allergy and Asthma Reports, 2006, 6, 468. E. Lavine, R. Somech, J. Y. Zhang, A. Puel, X. Bossuyt, C. Picard, J. L. Casanova and C. M. Roifman, Journal of Allergy and Clinical Immunology, 2007, 120, 948. M. Rekhter, K. Staschke, T. Estridge, P. Rutherford, N. Jackson, D. Gifford-Moore, P. Foxworthy,
C. Reidy, X.-d. Huang, M. Kalbfleisch, K. Hui, M.S. Kuo, R. Gilmour and C. J. Vlahos, Biochemical and Biophysical Research Communications, 2008, 367, 642. O'Neill, L. A. (2003). "Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases." Curr Opin Pharmacol 3(4): 396. Kanzler, H et al. (2007) "Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists." Nature Medicine 13:552. Wagner, H. (2006) "Endogenous TLR ligands and autoimmunity" /Advances in Immunol 91 : 159. Ngo, V. N. et al. (2011) "Oncogenically active MyD88 mutations in human lymphoma" Nature 470: 115.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015150995&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription
Preparation 1 : 1-chloro-7-methoxyisoquinoline-6-carbonitrile (P1) Step 1. Synthesis of methyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9. CD.
To a solution of 3-hydroxy-4-iodobenzoic acid (CAS 58123-77-6, C12) (10800 g, 40.9 moles) in DMF (65 L) was added K₂C0₃ (25398 g, 184 moles), followed by the slow addition of dimethyl sulfate (11352 g, 90 moles). This mixture was heated to about 50 °C for over night. The reaction mixture was cooled to about 25 °C, diluted with EtOAc (50 L) and filtered through a plug of Celite®. The solid was thoroughly washed with EtOAc (10 L X 3). The combined EtOAc filtrates were poured into water. After stirring for about 30 min, the EtOAc layer was separated and it was further washed sequentially with water, 1 M NaOH and brine. The EtOAc layer was separated, dried over Na₂S0₄, filtered and concentrated to provide the title compound C1. Yield: 11750 g (98%).
Step 2. Synthesis of (4-iodo-3-methoxyphenyl)methanol (CAS 244257-61-2, C2).
To a solution of compound C1 (11750 g, 40.2 moles) in THF (35 L) was added NaBH₄ (7645 g, 201.09 moles) and refluxed. While refluxing, MeOH (25 L) was slowly added into the reaction mixture at a rate of about 1 L per hour. After completion of the reaction, it was poured into a solution of cold dilute HCI. Once the excess of NaBH₄was quenched, the solution was filtered and extracted with EtOAc (2.5 L X 3). The combined EtOAc extracts were washed sequentially with water, brine and dried over Na₂S0₄. The solvent was evaporated under reduced pressure and the resulting crude material was treated with MTBE. The resulting solid was filtered and filtrate was washed with water, brine, dried over Na₂S0 , and filtered. The solvent was evaporated under reduced pressure to provide the title compound C2. Yield: 9900 g (93%).
Step 3. Synthesis of 4-iodo-3-methoxybenzaldehyde (CAS 121404-83-9, C3).
To a solution of compound C2 (9900 g, 34.5 moles) in CHCI₃ (186 L), was added manganese dioxide (18000 g, 207 moles) and the resulting mixture was refluxed for about 16 h. The mixture was cooled to about 25 °C and filtered through a Celite pad, which was then washed thoroughly with CHCI₃. The CHCI₃ was evaporated under reduced pressure to provide the title compound C3. Yield: 9330 g (95%). ¹ H NMR (400 MHz, CDCI₃): δ 9.95 (s, 1 H), 7.99 (d, 1 H), 7.14 (dd, 1 H), 3.95 (s, 3 H).
Step 3. Synthesis of 6-iodo-7-methoxyisoquinoline (CAS 244257-63-4. C4).
To a solution of compound C3 (9300 g, 35 moles) in toluene (60 L) was added amino acetaldehyde dimethyl acetal (5590 g, 53 moles) and the mixture was refluxed for about 4 h, while removing the liberated water by the use of a Dean - Stark water separator. The reaction mixture was cooled to about 0 °C, after which trifluoroacetic anhydride (22305 g, 106 moles) followed by BF₃-Et₂0 (15080 g, 106 moles) were added, keeping internal temperature below 5 °C. The reaction mixture was stirred at about 25 °C for about 16 h and quenched by pouring into a mixture of ice and ammonium hydroxide. The product was extracted with EtOAc (10 L X 3), and the combined EtOAc extracts were washed sequentially with water and brine. The combined EtOAc extracts were dried over Na₂S0₄, filtered, and concentrated to afford a dark tan colored residue. This was treated with a mixture of MTBE and hexane (1 :1 v/v, 30 L), followed by 6 M HCI (9 L), with stirring. The precipitated solid was filtered and washed with MTBE. The solid was suspended in EtOAc (5 L) and made alkaline with ammonium hydroxide. The EtOAc layer was separated, washed with brine, dried over Na₂S0₄, filtered, and concentrated to afford crude compound C4 as a brown solid. HPLC (230 nm) showed it to be about 83% pure.
The crude material (1000 g) was taken in AcOH (2.5 L) and stirred for about 90 min at about 25 °C. The solid was filtered and washed with AcOH (500 ml_). The filtrate was neutralized with saturated aqueous Na₂C0₃ solution. The resulting precipitated solid was filtered, washed with water (4 L), and oven dried at about 70 - 75 °C for about 5 h to afford about 780 g of pure C4. Similarly, the remaining crude C4 (4 kg) was purified to provide the title compound C4. Yield: 4300 g (42%). ¹H NMR (400 MHz, CDCI₃): δ 9.15 (s, 1 H), 8.45 (d, 1 H), 8.35 (s, 1 H), 7.45 (d, 1 H), 7.15 (s, 1 H) 4.00 (s, 3 H).
Step 4. Synthesis of 7-methoxyisoquinoline-6-carbonitrile (C5).
To a solution of compound C4 (4300 g , 15 moles) in DMSO (39 L) was added copper(l) cyanide (2954 g, 33 moles) and the mixture was heated to about 120 °C for about 3 h. The reaction mixture was quenched by pouring into a mixture of ice and ammonium hydroxide (40 L) and filtered. The filtrate was extracted with EtOAc (10 L X 2). While stirring, the solid residue was again treated with ammonium hydroxide solution (10 L) and EtOAc (10 L). After filtration, the precipitated material was repeatedly washed with a mixture of MeOH and CHCI₃ (1 :9, v/v) several times and the combined extracts were washed with brine. The extracts were dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The resulting crude material was triturated with hexane to provide the title compound C5. Yield: 2250 g (87%). ¹H NMR (400 MHz, CDCI₃): δ 9.25 (br. s, 1 H), 8.55 (br. s, 1 H), 8.15 (s, 1 H), 7.60 (d, 1 H), 7.30 (s, 1 H), 4.05 (s, 3 H).

A solution of a reactant such as 1-(((2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile (200 mg, 0.5 mmol) in concentrated H₂SO₄ (1.5 ml.) was warmed to about 55 °C for about two hours, then cooled to about 20 °C. The reaction mixture was added dropwise with vigorous stirring to 7.3 ml_ of ice cold concentrated ammonium hydroxide with cooling in ice. The precipitated solid was filtered and washed with water, heptane, ether, and dried under vacuum. The residue may be used directly for subsequent work, or it may be purified by chromatography or HPLC.
ABSTRACTS
251st Am Chem Soc (ACS) Natl Meet (March 13-17, San Diego) 2016, Abst MEDI 261




//////////PF  06650833, IRAK4 inhibitor, inflammatory disease treatment , PFIZER, 1817626-54-2
N1C([C@H](C([C@H]1COc3c2cc(c(cc2ccn3)C(=O)N)OC)CC)F)=O
NC(=O)c2cc3ccnc(OC[C@H]1NC(=O)[C@@H](F)[C@H]1CC)c3cc2OC
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

 

Join me on Linkedin

 

Join me on Facebook FACEBOOK

Join me on twitter

Join me on google plus Googleplus

 amcrasto@gmail.com

P.S
THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, amcrasto@gmail.com, +91 9323115463 India.
I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP