TOFOGLIFLOZIN

托格列净

CSG-452, R-7201, RG-7201

CAS..1201913-82-7 monohydrate

903565-83-3 (anhydrous)

(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)

PMDA Pharmaceuticals and Medical Devices Agency, Japan Approved mar24, 2014

THERAPEUTIC CLAIM Treatment of diabetes mellitus
CHEMICAL NAMES
1. Spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol, 6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-, hydrate (1:1), (1S,3’R,4’S,5’S,6’R)-
2. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol monohydrate
3. (1S,3’R,4’S,5’S,6’R)-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-6′-(hydroxymethyl)-
spiro[isobenzofuran-1(3H),2′-[2H]pyran]-3′,4′,5′-triol monohydrate

(3S,3’R,4’S,5’S,6’R)-5-[(4-ethylphenyl)methyl]-6′-(hydroxymethyl)spiro[1H-2-benzofuran-3,2′-oxane]-3′,4′,5′-triol;hydrate

MW404.5, MF C22H26O6

INNOVATOR  Chugai Pharmaceuticals

Sanofi, kowa

Deberza^{®………..KOWA}/Apleway®……………SANOFI

CODE DESIGNATION CSG 452

Tofogliflozin (USAN, codenamed CSG452) is an experimental drug for the treatment of diabetes mellitus and is being developed byChugai Pharma in collaboration with Kowa and Sanofi.^[1] It is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney. As of September 2012, the drug is in Phase III clinical trials.^[2][3]

Tofogliflozin is an SGLT-2 inhibitor first launched in 2014 in Japan by Sanofi and Kowa for the oral treatment of type II diabetes.

The product was discovered by Chugai and was licensed to Roche in 2007. In 2011, this license agreement was terminated. In 2012, the product was licensed to Kowa and Sanofi by Chugai Pharmaceutical in Japan for the treatment of diabetes type 2. In 2015, the license between Kowa and Chugai was expanded for developments and marketing of the agent in the U.S. and the E.U.

Chemistry

The active moiety or anhydrous form (ChemSpider ID: 28530778, CHEMBL2110731) has the chemical formula C₂₂H₂₆O₆ and amolecular mass of 386.44 g/mol.

The United States Adopted Name tofogliflozin applies to the monohydrate, which is the form used as a drug.^[4] The International Nonproprietary Name tofogliflozin applies to the anhydrous compound^[5] and the drug form is referred to as tofogliflozin hydrate.

Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin.

Tofogliflozin has recently demonstrated safety and efficacy as monotherapy or add-on treatment . This is very important, granted our expectations of SGLT-2 inhibitors as useful alternative oral hypoglycaemic agents. Although important questions remain to be answered, the results of the new trial add to the importance of SGLT-2 inhibitors as a useful new class of oral hypoglycaemic agents.

CLIP

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).

To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;

[α]D 26 +24.2° (c 1.02, MeOH);

1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);

13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;

MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

^{SGLT2 inhibitors inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes. Glucopyranosyl-substituted benzene derivative are described in the prior art as SGLT2 inhibitors, for example in}

^{WO 01/27128, WO 03/099836, WO 2005/092877, WO 2006/034489,}

^{WO 2006/064033, WO 2006/117359, WO 2006/117360,}

^{WO 2007/025943, WO 2007/028814, WO 2007/031548,}

^{WO 2007/093610, WO 2007/128749, WO 2008/049923, WO 2008/055870, WO 2008/055940.}

PATENTS

WO 2006080421

WO2009154276A1

WO 2011074675

WO 2012115249

Papers

Chinese Chemical Letters, 2013 ,  vol. 24,  2  pg. 131 – 133

Journal of Medicinal Chemistry, 2012 ,  vol. 55,  17  pg. 7828 – 7840

NMR

WO 2011074675

¹ H-NMR _(CD 3 OD) ^δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS ^(ESI +): 387 [M ^+1] +.

Second set

http://pubs.acs.org/doi/full/10.1021/jm300884k

J. Med. Chem., 2012, 55 (17), pp 7828–7840

¹H NMR (400 MHz, CD₃OD) δ: 1.20 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42–3.47 (1H, m), 3.63–3.67 (1H, m), 3.75–3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.3 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07–7.14 (4H, m), 7.17–7.23 (3H, m).

¹³C NMR (100 MHz, CD₃OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2.

MS (ESI): 387 [M + H]⁺. HRMS (ESI), m/z calcd for C₂₂H₂₇O₆ [M + H]⁺ 387.1802, found 387.1801.

THIRD SET

(1S,3′R,4′S,5′S,6′R)-6-[(4-Ethylphenyl)methyl]-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′- pyran]-3′,4′,5′-triol (1, tofogliflozin).

To a solution of 17b (89.9 g, 145 mmol) in DME (653 mL) and MeOH (73.0 mL), 2 N NaOH aq. solution (726 mL, 1.45 mol) was added dropwise for 1 h at waterbath temperature. After stirring at rt for 1 h, 2 N H2SO4 aq. solution (436 mL) was added slowly to the mixture. Water (700 mL) was added to the mixture, and the resultant mixture was extracted with AcOEt (500 mL × 2). The resultant organic layer was washed with brine (1.00 L) and then dried over anhydrous Na2SO4 (250 g). The mixture was concentrated in vacuo to obtain 1 (57.3 g, quant) as a colorless amorphous solid;

[α]D 26 +24.2° (c 1.02, MeOH);

1 H NMR (400 MHz, CD3OD) δ: 1.19 (3H, t, J = 7.6 Hz), 2.58 (2H, q, J = 7.6 Hz), 3.42−3.47 (1H, m), 3.63−3.67 (1H, m), 3.75−3.88 (4H, m), 3.95 (2H, s), 5.06 (1H, d, J = 12.5 Hz), 5.12 (1H, d, J = 12.5 Hz), 7.07−7.14 (4H, m), 7.17−7.23 (3H, m);

13C NMR (100 MHz, CD3OD) δ: 16.3, 29.4, 42.3, 62.8, 71.9, 73.4, 74.9, 76.2, 76.4, 111.6, 121.8, 123.6, 128.9, 129.9, 131.1, 139.7, 139.9, 140.2, 142.6, 143.2;

MS (ESI) m/z: 387 [M + H]+ ; HRMS (ESI) calcd for C22H27O6 [M + H]+ 387.1802, found 387.1801

DOI: 10.1021/acs.joc.5b02734 J. Org. Chem. 2016, 81, 2148−2153

Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.; Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S.-H.; Ahn, K.-H.; Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.; Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828−7840

PATENT

Prepn

WO 2011074675

[Example 1] (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro- -6′-(hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] -3 ‘, 4′, one of the preparation step [compound of formula (IX)] 5’-triol Preparation of methanol (2 – hydroxymethyl-phenyl – bromo-4)

To the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.1kg) in – bromoterephthalic was added at below 30 ℃ solution (7.5kg, 30.6mol) of the acid, and the mixture was stirred for 1 hour at 25 ℃. Then cooled to 19 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). In addition to methanol (15.0kg) in the mixture was kept for a while.

Again, to the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.0kg) in – was added at below 30 ℃ solution (7.5kg, 30.6mol) of bromo terephthalic acid, and the reaction was carried out for 1 hour at 25 ℃. Then cooled to 18 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). After addition of methanol (15.0kg) in the mixture is combined with the reaction mixture obtained in the previous reaction, and then the solvent was distilled off under reduced pressure. After addition of methanol (36kg) residue was obtained, and the solvent was evaporated under reduced pressure. Furthermore, (54 ℃ dissolved upon confirmation) which was dissolved by warming was added to methanol (36kg) to the residue. After cooling to room temperature the solution was stirred for 30 minutes added water (60kg). After addition of water (165kg) In addition to this mixture was cooled to 0 ℃, and the mixture was stirred for one hour. Centrifuge the obtained crystals were washed twice with water (45kg), and dried for 2 hours under reduced pressure to give (11.8kg, 54.4mol, 89% yield) of the title compound.

¹ H-NMR _{(DMSO-d 6)} ^δ: 4.49 (4H, t, J = 5.8Hz), 5.27 (1H, t, J = 5.8Hz), 5.38 (1H, t, J = 5.8Hz), 7.31 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 7.5Hz), 7.50 (1H, s).

Preparation of benzene (ethoxy methyl – methyl – – methoxy-1 1) – bromo-1 ,4 – 2:2 process bis

(- Bromo-4 – 2-hydroxyethyl methyl phenyl) in tetrahydrofuran (57kg) in the solution (8.0kg, 36.9mol) of methanol, I added (185.12g, 0.74mol) of pyridinium p-toluenesulfonate. After cooling to -15 ℃ below the mixture, 2 – was added at -15 ℃ or less (7.70kg, 106.8mol) methoxy propene, and the mixture was stirred 1 h at -15 ~ 0 ℃. Was added aqueous potassium carbonate (25 wt%, 40kg) and the reaction mixture was warmed to room temperature and separate the organic layer was added toluene (35kg). After washing with water (40kg) The organic layer was evaporated under reduced pressure. Was dissolved in toluene (28kg) and the residue obtained was obtained as a toluene solution of the title compound.

¹ H-NMR (CDCl ₃₎ ^δ: 1.42 (6H, s), 1.45 (6H, s), 3.24 (3H, s), 3.25 (3H, s), 4.45 ( 2H, s), 4.53 (2H, s), 7.28 (1H, dd, J = 1.5,8.0 Hz), 7.50 (1H, d, J = 8.0Hz), 7. 54 (1H, d, J = 1.5Hz).
MS ^(ESI +): 362 [M ^+2] +.

Preparation of on – (3R, 4S, 5R, 6R) -3,4,5 – tris (trimethylsilyloxy)-6 – trimethylsilyloxy methyl – tetrahydropyran-2: Step 3

Glucono -1,5 – – D-(+) in tetrahydrofuran (70kg) in the solution (35.8kg, 353.9mol) of N-methylmorpholine (7.88kg, 44.23mol) and lactone, chlorotrimethylsilane ( was added at 40 ℃ less 29.1kg, and 267.9mol), and the mixture was stirred for 2 hours at 30 ~ 40 ℃ resulting mixture. Was cooled to 0 ℃ the reaction mixture was added toluene (34kg) water (39kg), and the organic layer was separated. Twice sodium dihydrogen phosphate aqueous solution (5 wt%, 39.56kg) in, washed once with water (39kg) the organic layer the solvent was evaporated under reduced pressure. Was dissolved in toluene (34.6kg) and the residue obtained was obtained as a toluene solution of the title compound.

¹ H-NMR (CDCl ₃₎ ^δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74- 3.83 (3H, m), 3.90 (1H, t, J = 8.0Hz), 3.99 (1H, d, J = 8.0Hz), 4.17 (1H, dt, J = 2 .5,8.0 Hz).

Step 4: (1S, 3’R, 4’S, 5’S, 6’R) -3 ‘, 4’, 5 ‘, 6′-tetrahydro -6,6′ – bis (hydroxymethyl) – spiro [ (3H), 2’-[2H] pyran] -3 ‘, 4′, 5’-Preparation of triol isobenzofuran-1

(Methyl – – – methoxy 1-ethoxy-methyl) – bromo-1 ,4 – 2 prepared in step 2 bis cooled to below -10 ℃ toluene solution of benzene, hexane solution to (15 wt% n-butyl lithium , was added at below 0 ℃ 18.2kg, and 42.61mol), and the mixture was stirred 1.5 h at 5 ℃ resulting mixture. (10.5kg, 40.7mol), was added tetrahydrofuran (33.4kg) then magnesium bromide diethyl ether complex in the mixture, and the mixture was stirred for 1 hour at 25 ℃. Was added at below -10 ℃ toluene solution of the on – tris (trimethylsilyloxy) -6 – – 3,4,5 cooled to -15 ℃ below the mixture prepared in step 3 trimethylsilyloxy methyl – tetrahydropyran-2 was. After stirring 0.5 h at -15 ℃ or less, poured into 20% aqueous ammonium chloride solution to (80kg) of this solution, and the organic layer was separated. After washing with water (80kg) and the organic layer obtained, and the solvent was evaporated under reduced pressure. I was dissolved in methanol (43kg) residue was obtained. Was stirred for 1 hour at 20 ℃ was added (1.4kg, 7.4mol) and p-toluenesulfonic acid monohydrate in the mixture. Thereafter, it was stirred for another hour and cooled to 0 ℃, centrifuged crystals obtained was washed with methanol (25kg), and dried for 8 hours at reduced pressure under 40 ℃, (5.47kg, yield the title compound I got 50%) rate.

¹ H-NMR _{(DMSO-d 6)} ^δ :3.20-3 .25 (1H, m) ,3.41-3 .45 (1H, m) ,3.51-3 .62 (4H, m) , 4.39 (1H, t, J = 6.0Hz) ,4.52-4 .54 (3H, m), 4.86 (1H, d, J = 4.5Hz), 4.93 (1H, d, J = 5.5Hz), 4.99 (1H, d, J = 12.5Hz), 5.03 (1H, d, J = 12.5Hz), 5.23 (1H, t, J = 5 .8 Hz) ,7.24-7 .25 (2H, m), 7.29 (1H, dd, J = 1.5,8.0 Hz).

Step 5: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’ , 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2’-[2H] pyran isobenzofuran] spiro

(1S, 3’R, 4’S, 5’S, 6’R) – tetrahydro -6,6 ‘- bis (hydroxymethyl) – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran ] -3 ‘, 4′, 5’-triol 4 (5.3kg, 17.8mol) and – dissolved in acetonitrile (35kg) (13.7kg, 112.1mol) a chloroformate, in the solution of dimethylaminopyridine I was added at 12 ℃ or less (10.01kg, 105.9mol) methyl. Heated to 20 ℃, After stirring for 1 h, was added ethyl acetate (40kg) and water (45kg), and the organic layer was separated and the mixture. Once (45.4kg) aqueous solution consisting of (9.01kg) sodium chloride and potassium hydrogen sulfate (1.35kg), sodium chloride aqueous solution (weight 10%, 44.5kg), sodium chloride aqueous solution (the organic layer was washed successively 20% by weight, in 45.0kg), and the solvent was evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (18kg) and the residue obtained was then evaporated under reduced pressure. Was dissolved in ethylene glycol dimethyl ether (13.2kg) again and the residue obtained was obtained as ethylene glycol dimethyl ether solution of the title compound. I was used as it was in the six step.

¹ H-NMR (CDCl ₃₎ ^δ: 3.54 (3H, s), 3.77 (6H, s), 3.811 (3H, s), 3.812 (3H, s), 4.23 ( 1H, dd, J = 2.8,11.9 Hz), 4.32 (1H, dd, J = 4.0,11.9 Hz) ,4.36-4 .40 (1H, m), 5.11 -5.24 (5H, m), 5.41 (1H, d, J = 9.8Hz), 5.51 (1H, t, J = 9.8Hz), 7.25 (1H, d, J = 7.5Hz), 7.42 (1H, d, J = 7.5Hz), 7.44 (1H, s).
MS ^{(ESI +):} 589 [M ^{+1] +,} 606 [M +18] ^+.

Step 6: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-3 ‘4’, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – Preparation of [(3H), 2′-[2H] pyran isobenzofuran] spiro

[(Methoxycarbonyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro – (1S, 3’R, 4’S, 5’S, 6’R) -6 which had been prepared in Step 5 – 3 ‘, 4′, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – spiro [isobenzofuran -1 (3H), 2’-[2H] pyran] Ethylene glycol dimethyl ether in solution, 2 – (2.46kg, 17.8mol), 4 butanol (25kg), anhydrous potassium carbonate – – methyl-2 were sequentially added (3.73kg, 24.9mol) ethyl phenyl boronic acid, in the reaction vessel was replaced with argon atmosphere, was bubbled with argon mixture. To the mixture – after the addition (0.72kg, 0.88mol) and palladium (II) chloride dichloromethane adduct [1,1 ‘-bis (diphenylphosphino) ferrocene], it was replaced with argon again inside of the vessel, one at 80 ℃ I was stirring time. After cooling, I added sequentially (0.859kg, 5.3mol) of ethylene glycol dimethyl ether (9.85kg), ethyl acetate (19kg), N-acetyl-L-cysteine in the mixture. After stirring for 2.5 h the mixture was filtered and added Celite (5.22kg), and washed with ethyl acetate (78kg) and the filter residue. The combined washings and filtrate, and the solvent is evaporated off under reduced pressure, and in addition (0.58kg, 3.6mol) and ethanol (74kg), N-acetyl-L-cysteine residue was obtained, which is heated to 70 ℃ or I was dissolved residue is then. After addition of water (9.4kg) in the solution, cooled to 60 ℃, and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more The mixture was stirred for 1 hour or more at 5 ℃ less. Centrifuge the resulting solid was washed twice with a mixture of water (35kg) and ethanol (55kg). Was dissolved at 70 ℃ ethanol (77kg) again, wet powder was obtained (10.21kg), cooled to 60 ℃ added water (9.7kg), and the mixture was stirred for 1 h. After confirming solid precipitated, cooled to 0 ℃ from 60 ℃ over 2.5 hours or more, and the mixture was stirred for 1 hour or more at 5 ℃ less. (9.45kg, dry powder rate 8.47kg, 13.7mol which was centrifuged obtained crystals were washed with a mixture of water (32kg) and ethanol (51kg), was obtained as a moist powder the title compound, 77% overall yield from the previous step).

¹ H-NMR (CDCl ₃₎ ^δ: 1.20 (3H, t, J = 7.5Hz), 2.60 (2H, q, J = 7.5Hz), 3.50 (3H, s), ₃ .76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J = 2.8,11 .9 Hz), 4.33 (1H, dd, J = 4.5,11.9 Hz) ,4.36-4 .40 (1H, m) ,5.11-5 .20 (3H, m), 5 .41 (1H, d, J = 10.0Hz), 5.51 (1H, t, J = 10.0Hz) ,7.07-7 .11 (4H, m), 7.14 (1H, d, J = 7.8Hz), 7.19 (1H, dd, J = 1.5,7.8 Hz), 7.31 (1H, d, J = 1.5Hz).
MS (ESI ^+): 619 [M ^{+1] +,} 636 [M +18] ^+.

Step 7: (1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6’-tetrahydro-6 , 4 ‘, 5′-Preparation of triol’ – -3 [(3H), 2′-[2H] pyran isobenzofuran] spiro – (hydroxymethyl) ‘

(1S, 3’R, 4’S, 5’S, 6’R) -6 – [(4 – ethyl-phenyl) methyl] -3 ‘, 4’, 5 ‘, 6′-tetrahydro-3’, 4 ‘, 5′-tris (methoxycarbonyl) oxy-6′-[(methoxycarbonyl) methyl] – wet powder spiro [(3H), 2’-[2H] pyran isobenzofuran -1] (8.92kg, In addition at 20 ℃ (4mol / L, 30.02kg, the 104.2mol) aqueous solution of sodium hydroxide, 1 hour the reaction mixture to a solution of (28kg) ethylene glycol dimethyl ether dry end conversion 8.00kg, of 12.9mol) the mixture was stirred. And the organic layer was separated by addition of water (8.0kg) in the mixture. The ethyl acetate aqueous sodium chloride solution (25 wt%, 40kg) and a (36kg) in the organic layer and the aqueous layer was removed after washing. The washed again aqueous sodium chloride solution (25 wt%, 40kg) in the organic layer was evaporated under reduced pressure. Were added and acetone (32.0kg) water (0.8kg) residue was obtained. After the solvent was evaporated under reduced pressure, dissolved in acetone (11.7kg) in water (15.8kg) and the residue obtained was cooled to below 5 ℃. Was added below 10 ℃ water (64kg) to the mixture, and the mixture was stirred for 1 hour at below 10 ℃. Centrifuge the resulting crystals were washed with a mixture of water (8.0kg) and (1.3kg) acetone. For 8 hours through-flow drying 13 ~ 16 ℃ temperature ventilation, under the conditions of 24-33% relative humidity the wet powder, the monohydrate crystal (3.94kg, 9.7mol, 75% yield) of the title compound I was obtained as: (4.502 wt% water content).

Method of measuring the amount of water:
Analysis: coulometric KF titration analyzer: trace moisture measurement device manufactured by Mitsubishi Chemical Corporation Model KF-100
Anolyte: Aqua micron AX (manufactured by Mitsubishi Chemical Corporation)
Catholyte: Aqua micron CXU (manufactured by Mitsubishi Chemical Corporation)

¹ H-NMR _(CD 3 OD) ^δ: 1.19 (3H, t, J = 7.5Hz), 2.59 (2H, q, J = 7.5Hz) ,3.42-3 .46 (1H , m), 3.65 (1H, dd, J = 5.5,12.0 Hz) ,3.74-3 .82 (4H, m), 3.96 (2H, s), 5.07 (1H , d, J = 12.8Hz), 5.13 (1H, d, J = 12.8Hz) ,7.08-7 .12 (4H, m) ,7.18-7 .23 (3H, m) .
MS ^(ESI +): 387 [M ^+1] +.

PATENT

US20110306778

Example 1 Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose Step 1: Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

To a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) was added trimethylsilyl chloride (29.1 kg) at 40° C. or below, and then the mixture was stirred at a temperature from 30° C. to 40° C. for 2 hours. After the mixture was cooled to 0° C., toluene (34 kg) and water (39 kg) were added thereto. The organic layer was separated and washed with an aqueous solution of 5% sodium dihydrogen phosphate (39.56 kg×2) and water (39 kg×1). The solvent was evaporated under reduced pressure to give the titled compound as an oil. The product was used in the next step without further purification.

¹H-NMR (CDCl₃) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74-3.83 (3H, m), 3.90 (1H, t, J=8.0 Hz), 3.99 (1H, d, J=8.0 Hz), 4.17 (1H, dt, J=2.5, 8.0 Hz).

Step 2: Synthesis of 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene

Under a nitrogen atmosphere, to a solution of 2,4-dibromobenzyl alcohol (40 g, 0.15 mol) in tetrahydrofuran (300 ml) was added 2-methoxypropene (144 ml, 1.5 mol) at room temperature, and then the mixture was cooled to 0° C. At the same temperature, pyridinium p-toluenesulfonic acid (75 mg, 0.30 mmol) was added and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate cooled to 0° C., and extracted with toluene. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the titled compound as an oil in quantitative yield. The product was used in the next step without further purification.

¹H-NMR (CDCl₃) δ: 1.44 (6H, s), 3.22 (3H, 4.48 (2H, s), 7.42 (1H, d, J=8.0 Hz), 7.44 (1H, dd, J=1.5, 8.0 Hz), 7.68 (1H, d, J=1.5 Hz).

Step 3: Synthesis of 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran

Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (70 g, 207 mmol), which was obtained in the previous step, was dissolved in toluene (700 mL) and t-butylmethyl ether (70 ml), and n-butyllithium in hexane (1.65 M, 138 ml, 227 mmol) was added dropwise at 0° C. over 30 minutes. After the mixture was stirred for 1.5 hours at 0° C., the mixture was added dropwise to a solution of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one (Example 1, 108 g, 217 mol) in tetrahydrofuran (507 ml) at −78° C., and the reaction mixture was stirred for 2 hours at the same temperature. Triethylamine (5.8 ml, 41 mmol) and trimethylsilyl chloride (29.6 ml, 232 mmol) were added thereto, and the mixture was warmed to 0° C. and stirred for 1 hour to give a solution containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-bromo-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran.

The resulting solution was cooled to −78° C., and n-butyllithium in hexane (1.65 M, 263 ml, 434 mmol) was added dropwise thereto at the same temperature. After the mixture was stirred at −78° C. for 30 minutes, 4-ethylbenzaldehyde (62 ml, 455 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the organic layer was separated, and washed with water. The solvent was evaporated under reduced pressure to give a product containing the titled compound as an oil (238 g). The product was used in the next step without further purification.

A portion of the oil was purified by HPLC (column: Inertsil ODS-3, 20 mm I.D.×250 mm; acetonitrile, 30 mL/min) to give four diastereomers of the titled compound (two mixtures each containing two diastereomers).

Mixture of Diastereomers 1 and 2:

¹H-NMR (500 MHz, CDCl₃) δ: −0.47 (4.8H, s), −0.40 (4.2H, s), −0.003-0.004 (5H, m), 0.07-0.08 (1314, m), 0.15-0.17 (18H, m), 1.200 and 1.202 (3H, each t, J=8.0 Hz), 1.393 and 1.399 (3H, each s), 1.44 (3H, s), 2.61 (2H, q, J=8.0 Hz), 3.221 and 3.223 (3H, each s), 3.43 (1H, t, J=8.5 Hz), 3.54 (1H, dd, J=8.5, 3.0 Hz), 3.61-3.66 (1H, m), 3.80-3.85 (3H, m), 4.56 and 4.58 (1H, each d, J=12.4 Hz), 4.92 and 4.93 (1H, each d, J=12.4 Hz), 5.80 and 5.82 (1H, each d, J=3.0 Hz), 7.14 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.50-7.57 (2H, m).

MS (ESI⁺): 875 [M+Na]⁺.

Mixture of Diastereomers 3 and 4:

¹H-NMR (500 MHz, toluene-d₈, 80° C.) δ: −0.25 (4H, s), −0.22 (5H, s), 0.13 (5H, s), 0.16 (4H, s), 0.211 and 0.214 (9H, each s), 0.25 (9H, s), 0.29 (9H, s), 1.21 (3H, t, J=7.5 Hz), 1.43 (3H, s), 1.45 (3H, s), 2.49 (2H, q, J=7.5 Hz), 3.192 and 3.194 (3H, each s), 3.91-4.04 (4H, m), 4.33-4.39 (2H, m), 4.93 (1H, d, J=14.5 Hz), 5.10-5.17 (1H, m), 5.64 and 5.66 (1H, each s), 7.03 (2H, d, J=8.0 Hz), 7.28-7.35 (3H, m), 7.59-7.64 (1H, m), 7.87-7.89 (1H, m).

MS (ESI⁺): 875 [M+Na]⁺.

Step 4: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose

Under a nitrogen atmosphere, the oil containing 2,3,4,5-tetrakis(trimethylsilyloxy)-6-trimethylsilyloxymethyl-2-(5-(4-ethylphenyl)hydroxymethyl-2-(1-methoxy-1-methylethoxymethyl)phenyl)tetrahydropyran (238 g), which was obtained in the previous step, was dissolved in acetonitrile (693 ml). Water (37 ml) and 1N HCl aq (2.0 ml) were added and the mixture was stirred at room temperature for 5.5 hours. Water (693 ml) and n-heptane (693 ml) were added to the reaction mixture and the aqueous layer was separated. The aqueous layer was washed with n-heptane (693 ml×2), and water was evaporated under reduced pressure to give a product containing water and the titled compound (a diastereomer mixture) as an oil (187 g). The product was used in the next step without further purification.

¹H-NMR (500 MHz, CD₃OD) δ: 1.200 (3H, t, J=7.7 Hz), 1.201 (3H, t, J=7.7 Hz), 2.61 (2H, q, J=7.7 Hz), 3.44-3.48 (1H, m), 3.63-3.68 (111, m), 3.76-3.84 (4H, m), 5.09 (1H, d, J=12.8 Hz), 5.15 (1H, d, J=12.8 Hz), 5.79 (1H, s), 7.15 (2H, d, J=7.7 Hz), 7.24 and 7.25 (1H, each d, J=8.4 Hz), 7.28 (2H, d, J=7.7 Hz), 7.36 (1H, dd, J=8.4, 1.5 Hz), 7.40-7.42 (114, m).

MS (ESI⁺): 425 [M+Na]⁺.

Step 5: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (crude product)

To a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)hydroxymethyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (187 g), which was obtained in the previous step, in 1,2-dimethoxyethane (693 ml) was added 5% Pd/C (26 g, 6.2 mmol, water content ratio: 53%), and the mixture was stirred in the atmosphere of hydrogen gas at room temperature for 4 hours. After filtration, the filtrate was evaporated under reduced pressure to give an oil containing the titled compound (59 g). The purity of the resulting product was 85.7%, which was calculated based on the area ratio measured by HPLC. The product was used in the next step without further purification.

¹H-NMR (CD₃OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (3H, m).

MS (ESI⁺): 387 [M+1]⁺.

Measurement Condition of HPLC:

Column: Cadenza CD-C18 50 mm P/NCD032

Mobile phase: Eluent A: H₂O, Eluent B: MeCN

Gradient operation: Eluent B: 5% to 100% (6 min), 100% (2 min)

Flow rate: 1.0 mL/min

Temperature: 35.0° C.

Detection wavelength: 210 nm

Step 6: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose

Under a nitrogen atmosphere, to a solution of the oil containing 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose (59 g) and 4-(dimethylamino)pyridine (175 g, 1436 mmol) in acetonitrile (1040 ml) was added dropwose methyl chloroformate (95 ml, 1231 mmol) at 0° C. The mixture was allowed to warm to room temperature while stirred for 3 hours. After addition of water, the mixture was extracted with isopropyl acetate. The organic layer was washed with an aqueous solution of 3% potassium hydrogensulfate and 20% sodium chloride (three times) and an aqueous solution of 20% sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the resulting residue was added ethanol (943 mL) and the mixture was heated to 75° C. to dissolve the residue. The mixture was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (472 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound (94 g). To the product (91 g) was added ethanol (1092 ml), and the product was dissolved by heating to 75° C. The solution was cooled to 60° C. and a seed crystal of the titled compound was added thereto. The mixture was cooled to room temperature and stirred for 1 hour. After precipitation of solid was observed, water (360 ml) was added thereto, and the mixture was stirred at room temperature for 2 hours. The resulting crystal was collected by filtration, washed with a mixture of water and ethanol (1:1), and dried under reduced pressure to give the titled compound [83 g, total yield from 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene used in Step 3: 68%].

¹H-NMR (CDCl₃) δ: 1.20 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 3.50 (3H, s), 3.76 (3H, s), 3.77 (3H, s), 3.81 (3H, s), 3.96 (2H, s), 4.23 (1H, dd, J=2.5, 11.8 Hz), 4.33 (1H, dd, J=4.5, 12.0 Hz), 4.36-4.40 (1H, m), 5.11-5.20 (3H, m), 5.41 (1H, d, J=10.0 Hz), 5.51 (1H, t, J=10.0 Hz), 7.07-7.11 (4H, m), 7.14 (1H, d, J=7.5 Hz), 7.19 (1H, dd, J=1.5, 7.8 Hz), 7.31 (1H, d, J=1.5 Hz).

MS (ESI⁺): 619 [M+1]⁺, 636 [M+18]⁺.

Another preparation was carried out in the same manner as Step 6, except that a seed crystal was not used, to give the titled compound as a crystal.

Step 7: Synthesis of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-β-D-glucopyranose

To a solution of 1,1-anhydro-1-C-[5-(4-ethylphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-methoxycarbonyl-β-D-glucopyranose (8.92 kg as wet powder, corresponding to 8.00 kg of dry powder) in 1,2-dimethoxyethane (28 kg) was added a solution of sodium hydroxide (4 mol/L, 30.02 kg) at 20° C., and the mixture was stirred for 1 hour. Water (8.0 kg) was added to the mixture and the layers were separated. To the organic layer were added an aqueous solution of 25% sodium chloride (40 kg) and ethyl acetate (36 kg). The organic layer was separated, washed with an aqueous solution of 25% sodium chloride (40 kg), and the solvent was evaporated under reduced pressure. The purity of the resulting residue was 98.7%, which was calculated based on the area ratio measured by HPLC. To the resulting residue were added acetone (32.0 kg) and water (0.8 kg), and the solvent was evaporated under reduced pressure. To the resulting residue were added acetone (11.7 kg) and water (15.8 kg), and the solution was cooled to 5° C. or below. Water (64 kg) was added to the solution at 10° C. or below, and the mixture was stirred at the same temperature for 1 hour. The resulting crystal was collected by centrifugation, and washed with a mixture of acetone (1.3 kg) and water (8.0 kg). The resulting wet powder was dried by ventilation drying under a condition at air temperature of 13 to 16° C. and relative humidity of 24% to 33% for 8 hours, to give a monohydrate crystal (water content: 4.502%) of the titled compound (3.94 kg). The purity of the resulting compound was 99.1%, which was calculated based on the area ratio measured by HPLC.

¹H-NMR (CD₃OD) δ: 1.19 (3H, t, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.42-3.46 (1H, m), 3.65 (1H, dd, J=5.5, 12.0 Hz), 3.74-3.82 (4H, m), 3.96 (2H, s), 5.07 (1H, d, J=12.8 Hz), 5.13 (1H, d, J=12.8 Hz), 7.08-7.12 (4H, m), 7.18-7.23 (311, m).

MS (ESI⁺): 387 [M+1]⁺.

Measurement Condition of HPLC:

Column: Capcell pack ODS UG-120 (4.6 mm I.D.×150 mm, 3 μm, manufactured by Shiseido Co., Ltd.)

Mobile phase: Eluent A: H₂O, Eluent B: MeCN

Mobile phase sending: Concentration gradient was controlled by mixing Eluent A and Eluent B as indicated in the following table.

Flow rate: 1.0 mL/min

Temperature: 25.0° C.

Detection wavelength: 220 nm

Method for Measurement of Water Content:

Analysis method: coulometric titration method

KF analysis apparatus: Type KF-100 (trace moisture measuring apparatus manufactured by Mitsubishi Chemical Corporation)

Anode solution: Aquamicron AX (manufactured by Mitsubishi Chemical Corporation)

Cathode solution: Aquamicron CXU (manufactured by Mitsubishi Chemical Corporation)

PATENT

US20090030006

The compound of the present invention can be synthesized as shown in Scheme 1:

wherein R¹¹ and R¹² have the same meaning as defined above for substituents on Ar¹, A is as defined above, and P represents a protecting group for a hydroxyl group.

CLIP

Tofogliflozin hydrate (Deberza)
Tofogliflozin hydrate, which is a sodium-glucose co-transporter 2 inhibitor, was approved in Japan for the treatment of type 2 diabetes
at the same time as luseogliflozin hydrate (XIX). The drug was discovered by Chugai Pharmaceutical and jointly developed
with Sanofi-Aventis and Kowa.263

Tofogliflozin hydrate reduces glucose levels by inhibiting the reuptake of glucose by selectively
inhibiting SGLT2, and plays a key role in the reuptake of glucose in the proximal tubule of the kidneys.264–266 The synthetic
approach described in Scheme 48 represents the largest scale reported to date in a patent application.263,266–268

Reduction of commercially available 2-bromoterephtalic acid (268, Scheme 48) through the use of trimethoxyborane and borane-THF proceeded in 89% yield to afford diol 269.

Subjection of this compound to 2-methoxypropene (270) under acidic conditions generated bis-acetonide 271. This bromide then underwent lithium–halogen exchange followed by exposure to magnesium bromide and treatment with lactone 272 (which was prepared by persilylation of commercially available (3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl)tetrahydro-2Hpyran-2-one (277, Scheme 49).

This mixture was worked up with aqueous ammonium chloride and upon treatment with p-TsOH in methanol resulted in spiroacetal 273. Next, global protection of all alcohol functionalities within 273 was affected by reaction with methylchloroformate and DMAP in acetonitrile.

The benzyl carbonate within 274 was selectively exchanged via Suzuki coupling with 4-ethylphenylboronic acid (275) to afford methylene dibenzyl system 276. Subsequent treatment with aqueous sodium hydroxide in methanol followed by crystallization from 1:6 acetone and water furnished the desired product tofogliflozin hydrate (XXXIV) in 75% yield.

263 Takamitsu, K.; Tsutomu, S.; Masahiro, N. WO Patent 2006080421A1, 2006.
264. http://www.info.pmda.go.jp/shinyaku/P201400036/index.html.
265. Pafili, K.; Papanas, N. Expert Opin. Pharmacother. 2014, 15, 1197.

266. Ohtake, Y.; Sato, T.; Kobayashi, T.; Nishimoto, M.; Taka, N.; Takano, K.;Yamamoto, K.; Ohmori, M.; Yamaguchi, M.; Takami, K.; Yeu, S. Y.; Ahn, K. H.;Matsuoka, H.; Morikawa, K.; Suzuki, M.; Hagita, H.; Ozawa, K.; Yamaguchi, K.;Kato, M.; Ikeda, S. J. Med. Chem. 2012, 55, 7828.
267. Murakata, M.; Ikeda, T.; Kawase, A.; Nagase, M.; Kimura, N.; Takeda, S.;Yamamoto, K.; Takano, K.; Nishimoto, M.; Ohtake, Y.; Emura, T.; Kito, Y. WOPatent 2011074675A1, 2011.
268. Murakata, M.; Takuma, I.; Nobuaki, K.; Masahiro, N.; Kawase, A.; Nagase, M.;Yamamoto, K.; Takata, N.; Yoshizaki, S. WO Patent 2009154276A1, 2009.

References

Tofogliflozin monohydrate

Systematic (IUPAC) name
(1S,3′R,4′S,5′S,6′R)-6-(4-Ethylbenzyl)-6′-(hydroxymethyl)-3′,4′,5′,6′-tetrahydro-3H-spiro[2-benzofuran-1,2′-pyran]-3′,4′,5′-triol hydrate (1:1)
Legal status
Legal status	Investigational
Identifiers
CAS Number	1201913-82-7 903565-83-3 (anhydrous)
ATC code	None
PubChem	CID 46908928
ChemSpider	28527871
KEGG	D09978
ChEMBL	CHEMBL2105711
Synonyms	CSG452
Chemical data
Formula	C22H28O7
Molar mass	404.45 g/mol

//////////TOFOGLIFLOZIN, 托格列净 , CSG-452, R-7201, RG-7201, 1201913-82-7  , 903565-83-3, oral hypoglycaemic agents, SGLT-2 inhibitors, type 2 diabetes mellitus, Deberza

CCc1ccc(cc1)Cc2ccc3c(c2)[C@]4([C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O)OC3.O

^{The glucopyranosyl-substituted benzene derivatives are proposed as inducers of urinary sugar excretion and as medicaments in the treatment of diabetes.}

The term “canagliflozin” as employed herein refers to canagliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

The compound and methods of its synthesis are described in WO 2005/012326 and WO 2009/035969 for example. Preferred hydrates, solvates and crystalline forms are described in the patent applications WO 2008/069327 for example.

atigliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

The compound and methods of its synthesis are described in WO 2004/007517 for example.

ipragliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

The compound and methods of its synthesis are described in WO 2004/080990, WO 2005/012326 and WO 2007/114475 for example.

tofogliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

The compound and methods of its synthesis are described in WO 2007/140191 and WO 2008/013280 for example.

remogliflozin and prodrugs of remogliflozin, in particular remogliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods of its synthesis are described in the patent applications EP 1213296 and EP 1354888 for example.

sergliflozin and prodrugs of sergliflozin, in particular sergliflozin etabonate, including hydrates and solvates thereof, and crystalline forms thereof. Methods for its manufacture are described in the patent applications EP 1344780 and EP 1489089 for example.

luseoghflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

ertugliflozin, including hydrates and solvates thereof, and crystalline forms thereof and has the following structure:

and is described for example in WO 2010/023594.

The compound of the formula

is described for example in WO 2008/042688 or WO 2009/014970.

Dapagliflozin

The compound is described for example in WO 03/099836. Crystalline forms are described for example in WO 2008/002824.

Remogliflozin and Remogliflozin Etabonate

The compound is described for example in EP 1354888 A1.

Sergliflozin and Sergliflozin Etabonate

The compounds are described in EP 1 329 456 A1 and a crystalline form ofSergliflozin etabonate is described in EP 1 489 089 A1.

1-Chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethyl-benzyl)-benzene

The compound is described in WO 2006/034489.

(1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2-hydroxyphenyl]-D-glucitol

The compound (4-(Azulen-2-ylmethyl)-2-(β-D-glucopyranos-1-yl)-1-hydroxy-benzene) is described in WO 2004/013118 and WO 2006/006496. The crystalline choline salt thereof is described in WO 2007/007628.

(1S)-1,5-anhydro-1-[3-(1-benzothien-2-ylmethyl)-4-fluorophenyl]-D-glucitol

The compound is described in WO 2004/080990 and WO 2005/012326. A cocrystal with L-proline is described in WO 2007/114475.

Thiophen Derivatives of the Formula (7-1)

wherein R denotes methoxy or trifluoromethoxy. Such compounds and their method of production are described in WO 2004/007517, DE 102004063099 and WO 2006/072334.

1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene

The compound is described in WO 2005/012326. A crystalline hemihydrate is described in WO 2008/069327.

Spiroketal Derivatives of the Formula (9-1)

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl or tert. butyl. Such compounds are described in WO 2007/140191 and WO 2008/013280.

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.^[3]

Chong Kun Dang

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie^® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie^® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC₅₀:  0.02 μM, PPARγ EC₅₀:  0.018 μM, rosiglitazone; PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.02 μM, pioglitazone PPARα EC₅₀:  >10 μM, PPARγ EC₅₀:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKA^y mice than rosiglitazone and pioglitazone.¹⁷ Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.^[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.^[4][5]

SYNTHESIS

Chong Kun Dang’s Modcol Flu Dry Syrup is released in four different versions: All-Day, Night, Nose and Cough. [CHONG KUN DANG]

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

http://pubs.acs.org/doi/abs/10.1021/op060087u

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

Silica gel TLC R_f = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH₂Cl₂/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm^-1;

¹H NMR (400 MHz, CDCl₃) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH);

¹³C NMR (100 MHz, CDCl₃) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5;

MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C₂₄H₂₆N₄O₉S₂:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

Clip
Lobeglitazone sulfate (Duvie) Lobeglitazone sulfate, an oral peroxisome proliferator-activated receptor (PPARa/c) dual agonist with IC50 = 20 and 18 nM respectively, was developed by Chong Kun Dang Pharmaceutical in Korea for the treatment of diabetes.135 This drug is differentiated from two other PPAR agonists available—pioglitazone and rosiglitazone —which lack PPARa activity.135 The most likely processscale preparation of lobeglitazone sulfate follows the route described in a process communication from Chong Kun Dang Pharmaceutical.136

Commercially available 4,6-dichloropyrimidine (152) was treated with a stoichiometric equivalent of p-methoxyphenol (153) in the presence of KF in warm DMF (Scheme 24). Upon completion of this reaction, 2-methylaminoethanol was added to the mixture to provide pyrimidine 154 in high yield.137

Next, alcohol 154 underwent a substitution reaction with p-fluorobenzaldehyde (155) under basic conditions to provide alkoxy benzaldehyde 156 which was converted to the benzylidene thiazolidindione 158 upon subjection to Knoevenagel conditions with 2,4-thiazolidinedione (157) in 90% yield.

Finally, reduction of olefin 158 was facilitated by treatment with the Hantzsch ester (159) in the presence of silica gel followed by treatment with methanolic sulfuric acid (96%) at low temperature to ultimately furnish lobeglitazone sulfate in 90% yield.

135. Jin, S. M.; Park, C. Y.; Cho, Y. M.; Ku, B. J.; Ahn, C. W.; Cha, B.-S.; Min, K. W.;Sung, Y. A.; Baik, S. H.; Lee, K. W.; Yoon, K.-H.; Lee, M.-K.; Park, S. W. Diab.Obes. Metab. 2015, 17, 599.
136. Lee, H. W.; Ahn, J. B.; Kang, S. K.; Ahn, S. K.; Ha, D.-C. Org. Process Res. Dev.2007, 11, 190.
137. Lee, H. W.; Kim, B. Y.; Ahn, J. B.; Kang, S. K.; Lee, J. H.; Shin, J. S.; Ahn, S. K.; Lee,S. J.; Yoon, S. S. Eur. J. Med. Chem. 2005, 40, 862.

References

Lobeglitazone

Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names	Duvie
Routes of administration	Oral
Legal status
Legal status	Rx-only in South Korea
Pharmacokinetic data
Protein binding	>99%[1]
Metabolism	liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life	7.8–9.8 hours[2]
Identifiers
CAS Number	607723-33-1
PubChem	CID 9826451
DrugBank	DB09198
ChemSpider	8002194
Synonyms	CKD-501
Chemical data
Formula	C24H24N4O5S
Molar mass	480.53616 g/mol
SMILES CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC

Identifications:

Experimental: ¹H NMR (400 MHz, CDCl₃) δ 3.12 (m, 4H), 3.45 (m, 1H), 3.83 (s, 3H), 4.00 (m, 2H), 4.16 (m, 2H), 4.50 (m, 1H), 5.84 (bs, 1H), 6.83 (m, 2H), 7.06 (m, 2H), 7.15 (m, 2H), 8.31 (s, 1H), 8.89 (bs, NH).

///Lobeglitazone Sulfate, CKD-501, Duvie^®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes, CKD 501, 763108-62-9, 607723-33-1, IDR-105

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

AZD3514; AZD 3514; AZD-3514.

CAS 1240299-33-5
Chemical Formula: C25H32F3N7O2
Exact Mass: 519.25696

1-(4-(2-(4-(1-(3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethyl)piperazin-1-yl)ethanone

Ethanone, 1-[4-[2-[4-[1-[7,8-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-4-piperidinyl]phenoxy]ethyl]-1-piperazinyl]

6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine

6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine

• 1-[4-[2-[4-[1-[7,8-Dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-4-piperidinyl]phenoxy]ethyl]-1-piperazinyl]ethanone

• Originator AstraZeneca
• Class Antineoplastics
• Mechanism of Action Androgen receptor antagonists

AZD-3514 is a potent androgen receptor downregulator with potential anticancer cancer activity. AZD3514 is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

AZD3514 is currently in Phase I trail. This trial is looking at a new drug called AZD3514 for men who have prostate cancer that has spread to other parts of the body and is no longer responding to hormone therapy.  Doctors often use hormone therapy to treat prostate cancer. This may keep it under control for long periods of time. But researchers are looking for treatments that will help men who have prostate cancer that stops responding to hormone therapy.  Prostate cancer needs the hormone testosterone to grow. The testosterone locks into receptors on the cancer cells. AZD3514 works by breaking down these receptors so that testosterone canÂ’t tell the prostate cancer cells to grow.

6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-ihydro[1,2,4]triazolo[4,3-b]pyridazine 

as a white, free flowing solid.

¹H NMR (400 MHz, CDCl3): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d);

m/z = 520 [M+H]⁺. RT = 0.87: 99% purity.

HRMS found 520.26373,

Prostate cancer is the second leading cause of death from cancer among men in developed countries, and was projected to account for 25% of newly-diagnosed cases and 9% of deaths due to cancer in the USA in 2010. The androgen receptor (AR), a ligand binding transcription factor in the nuclear hormone receptor super family, is a key molecular target in the etiology and progression of prostate cancer.Binding of the endogenous AR ligand dihydrotestosterone stabilizes and protects the AR from rapid proteolytic degradation. The early stages of prostate cancer tumor growth are androgen dependent and respond well to androgen ablation,  either via surgical castration or by chemical castration with a luteinizing hormone releasing hormone agonist in combination with an AR antagonist, such as bicalutamide.

Although introduction of androgen deprivation therapy represented a major advance in prostate cancer treatment, recurrence within 1–2 years typically marks transition to the so-called castrate-resistant state, in which the tumor continues to grow in the presence of low circulating endogenous ligand and is no longer responsive to classical AR antagonists. Castrate-resistant prostate cancer (CRPC) is a largely unmet medical need with a 5-year survival rate of less than 15%. Antimitotic agents docetaxel and cabazitaxel, testosterone biosynthesis inhibitor abiraterone acetate and second generation AR antagonist enzalutamide (MDV3100) are the currently approved small-molecule drugs that have been shown to provide survival benefit.

Recent evidence from both pre-clinical and clinical studies is consistent with the importance of re-activation of AR signaling in a majority of castrate-resistant prostate tumors. It is also well established that the functional AR in castrate-resistant tumors is frequently mutated or amplified, and that over-expression can convert hormone-responsive cell lines to hormone refractory. Recent second-generation AR antagonists have been designed that retain antagonism in over-expressing cell lines, and among these agents enzalutamide has recently successfully met efficacy criteria in a large Phase III clinical trial.

By analogy with fulvestrant, an estrogen receptor (ER) downregulator approved by the FDA in 2002 for treatment of advanced breast cancer and initially characterized as a pure ER antagonist, a ligand which downregulates the AR represents one of a number of potential approaches to treatment of CRPC via a sustained reduction in tumor AR content. We recently described derivation from a novel 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine ligand of AR inhibitor 1 The compound also causes AR downregulation¹⁵ and high plasma levels following oral administration in pre-clinical models compensate for moderate cellular potency

Figure 1.

Structures of lead AR downregulator 1 and chemotype 2.

Scheme 3.

Synthesis of compounds 10, 11a–b, 12. Reagents and conditions: (a) 2-(1-Methyl-1H-pyrazol-5-yl)ethanol,²⁷ Ph₃P, diisopropyl azodicarboxylate, THF, 20 °C; (b) 2-(4-acetylpiperazine-1-yl)ethanol,²⁸ Ph₃P, diisopropyl azodicarboxylate, THF, 20 °C; (c) H₂, 10% Pd-C, MeOH, 50 °C.

PATENT

WO 2010092371

Preparation of 6-f4-{4-[2-f4-acetylpiperazin-l-yl)ethoxylphenyl}piperidin-l-yl)-3-

( trifluoromethyr)-7,8-dihvdro [ 1 ,2,41 triazolo [4,3-bl pyridazine

A solution of acetyl chloride (0.027 mL, 0.38 mmol) in DCM (0.5 mL) was added dropwise to 6-[4- [4- [2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl] -3 -(trifluoromethyl)- 7,8-dihydro-[l,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.31 mmol) and triethylamine (0.088 mL, 0.63 mmol) in DCM (1 mL) cooled to 0⁰C under nitrogen. The resulting solution was stirred at 0⁰C for 5 minutes then allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was diluted with water (2 mL), passed through a phase separating cartridge and then the organic layer was evaporated to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep Cl 8 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(4-{4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3- b]pyridazine (80 mg, 49%) as a gum.

IH NMR (399.9 MHz, CDC13) δ 1.69 (2H, m), 1.95 (2H, m), 2.08 (3H, s), 2.56 (4H, m), 2.71 – 2.84 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.48 (2H, m), 3.63 (2H, m), 4.10 (2H, t), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(piperazin- 1 -yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)-7,8- dihydro-[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of tert-butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate DIAD (12.60 mL, 64.00 mmol) was added dropwise to benzyl 4-(4-hydroxyphenyl)-5,6- dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (16.5 g, 53.34 mmol), tert-butyl 4-(2-hydroxyethyl)piperazine-l- carboxylate (CAS 77279-24-4) (14.74 g, 64.00 mmol) and triphenylphosphine (16.79 g, 64.00 mmol) in THF (150 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated to dryness then the residue was stirred in ether (200 mL) for 10 minutes at room temperature. The resulting precipitate was removed by filtration and discarded. The ether filtrate was washed with water (100 mL) followed by saturated brine (100 mL), then dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness to afford tert-butyl 4-[2-[4-(l- (benzyloxycarbonyl)- 1,2,3, 6-tetrahydropyridin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (34.6 g, 82%) as a gum which was contaminated with 34% by weight triphenylphosphine oxide.

IH NMR (399.9 MHz, DMSO-d6) δ 1.40 (9H, s), 2.42 – 2.47 (6H, m), 2.71 (2H, m), 3.32 (4H, m), 3.62 (2H, m), 4.03 – 4.10 (4H, m), 5.12 (2H, s), 6.06 (IH, m), 6.92 (2H, d), 7.31 – 7.40 (7H, m); m/z = 522 [M+H]+.

Preparation of tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate tert-Butyl 4-[2-[4-(l-(benzyloxycarbonyl)-l,2,3,6-tetrahydropyridin-4- yl)phenoxy]ethyl]piperazine-l-carboxylate (66% pure by weight) (34.62 g, 43.80 mmol) and 5% palladium on carbon (50% wet) (4.47 g, 1.05 mmol) in MeOH (250 mL) were stirred under an atmosphere of hydrogen at 5 bar and 60⁰C for 4 hours. The catalyst was removed by filtration and the solvents evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with 60% EtOAc in isohexane then 15% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l-carboxylate (15.42 g, 90%) as a solid. IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.62 (2H, m), 1.81 (2H, m), 2.50 – 2.59 (5H, m), 2.73 (2H, m), 2.80 (2H, t), 3.18 (2H, m), 3.44 (4H, m), 4.09 (2H, t), 6.85 (2H, d), 7.13 (2H, d); m/z = 390 [M+H]+.

Preparation of tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)-[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate

DIPEA (2.348 mL, 13.48 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (2 g, 8.99 mmol) and tert-butyl 4-[2-[4-(piperidin-4-yl)phenoxy]ethyl]piperazine-l- carboxylate (3.68 g, 9.44 mmol) in DMF (30 mL). The resulting solution was stirred at 80⁰C for 2 hours. The reaction mixture was cooled to room temperature and the solvents evaporated to dryness. The resulting solid was triturated with water then collected by filtration, washed with ether and dried to afford tert-butyl 4-[2-[4-[l-(3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazine-l -carboxylate (5.02 g, 97%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.76 (2H, m), 2.00 (2H, m), 2.54 (4H, m), 2.75 – 2.86 (3H, m), 3.11 (2H, m), 3.46 (4H, m), 4.11 (2H, m), 4.37 (2H, m), 6.87 (2H, d), 7.13 (3H, m), 7.92 (IH, d); m/z = 576 [M+H]+.

Preparation of tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro-

[1 ,2,4] triazolo [4,3-b] pyridazin-6-yl)piperidin-4-yl] phenoxy] ethyl] piperazine- 1- carboxylate

10% Palladium on carbon (0.924 g, 0.87 mmol) was added to tert-butyl 4-[2-[4-[l-(3- (trifluoromethyl)-[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl]phenoxy]ethyl]piperazine-l -carboxylate (2.5 g, 4.34 mmol) and ammonium formate (2.74 g, 43.43 mmol) in ethanol (100 mL). The resulting mixture was stirred at 78°C, with further portions of ammonium formate being added every 5 hours until the reaction was complete. The reaction mixture was cooled to room temperature and the catalyst was removed by filtration. The filtrate was evaporated to dryness, redissolved in DCM (100 mL) and the solution was washed with water (100 mL) followed by brine (50 mL), then the solvents were evaporated to afford tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02O g, 81%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.46 (9H, s), 1.69 (2H, m), 1.95 (2H, m), 2.52 (4H, m), 2.71 – 2.82 (5H, m), 3.00 (2H, m), 3.22 (2H, t), 3.45 (4H, m), 4.09 (2H, m), 4.31 (2H, m), 6.86 (2H, d), 7.12 (2H, d); m/z = 578 [M+H]+.

Preparation of 6- [4-[4- [2-(piperazin-l-yl)ethoxy] phenyl] piperidin-1-yl] -3- (trifluor omethyl)-7,8-dihydr o- [ 1 ,2,4] triazolo [4,3-b] pyridazine

TFA (10 mL) was added to tert-butyl 4-[2-[4-[l-[3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyπdazin-6-yl)pipeπdin-4-yl]phenoxy]ethyl]piperazine-l-carboxylate (2.02 g, 3.50 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia/MeOH and the solvents were evaporated to afford 6-[4-[4- [2-(piperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)-7,8-dihydro- [l,2,4]triazolo[4,3-b]pyridazine (1.660 g, 99%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.68 (2H, m), 1.95 (2H, m), 2.55 (4H, m), 2.70 – 2.80 (5H, m), 2.91 (4H, m), 3.00 (2H, m), 3.22 (2H, t), 4.09 (2H, t), 4.30 (2H, m), 6.87 (2H, d), 7.11 (2H, d); m/z = 478 [M+H]+.

Example 5.2

Larger scale preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-dihvdro [ 1 ,2,41 triazolo [4,3- blpyridazine

Ammonium formate (99 g, 1568.94 mmol) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazine (81.2 g, 156.89 mmol) and 10% palladium on carbon (8.35 g, 7.84 mmol) in EtOH (810 mL) under nitrogen. The resulting mixture was stirred at 70⁰C for 6 hours, then ammonium formate (50 g) was added. The mixture was stirred at 70⁰C for 2 hours then further portions of 10% palladium on carbon (8.35 g, 7.84 mmol) and ammonium formate (50 g) were added and stirring continued at 70⁰C for a further 10 hours. Ammonium formate (50 g) was added and the reaction mixture was stirred at 70⁰C for 24 hours then cooled to room temperature. The catalyst was removed by filtration and the reaction charged with further 10% palladium on carbon (8.35 g, 7.84 mmol) and stirred at 70⁰C for 16 hours. Further ammonium formate (50 g) was added and the stirring continued for 5 hours. The reaction mixture was cooled to room temperature and a further portion of 10% palladium on carbon (8.35 g, 7.84 mmol) was added. The mixture was heated to 70⁰C for a 30 hours, cooled to room temperature and the catalyst removed by filtration and washed with EtOH. The solvent was evaporated and the residue dissolved in DCM (500 mL) and the solution washed with water (500 mL). The aqueous layer was re-extracted with DCM (500 mL), then EtOAc (500 mL x 2). The combined extracts were dried over MgSO4, filtered and evaporated to give crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford a gum, which was slurried with ether (300 mL) and re-evaporated. Methyl tert-butyl ether (250 mL) was added and the mixture was stirred vigorously for 3 days. The solid was collected by filtration and dried to afford 6-(4-{4-[2-(4- acetylpiperazin- 1 -yl)ethoxy]phenyl}piperidin- 1 -yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine (60.8 g, 75%) as a solid.

IH NMR (399.9 MHz, CDC13) δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3-

(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of 4-(piperidin-4-yl)phenol Benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-l(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (37.7 g, 121.86 mmol) and 5% palladium on carbon (7.6 g, 3.57 mmol) in methanol (380 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25°C for 2 hours. The catalyst was removed by filtration, washed with MeOH and the solvents evaporated. The crude material was triturated with diethyl ether, then the desired product collected by filtration and dried under vacuum to afford 4-(piperidin-4-yl)phenol (20.36 g, 94%) as a solid. IH NMR (399.9 MHz, DMSO-d6) δ 1.46 (2H, m), 1.65 (2H, m), 2.45 (IH, m), 2.58 (2H, m), 3.02 (2H, m), 6.68 (2H, d), 7.00 (2H, d), 9.15 (IH, s); m/z = 178 [M+H]+.

Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol

DIPEA (48.2 mL, 276.86 mmol) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (24.65 g, 110.74 mmol) and 4-(piperidin-4-yl)phenol (20.61 g, 116.28 mmol) in DMF (200 mL). The resulting solution was stirred at 80⁰C for 1 hour. The reaction mixture was cooled to room temperature, then evaporated to dryness and re-dissolved in DCM (1 L) and washed with water (2 x 1 L). The organic layer was washed with saturated brine (500 mL), then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was triturated with ether to afford 4-{l-[3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (36.6 g, 91%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.

Preparation of 2-(4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6- yl]piperidin-4-yl}phenoxy)ethanol

A solution of ethylene carbonate (121 g, 1376.13 mmol) in DMF (200 mL) was added dropwise to a stirred suspension of 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3- b]pyridazin-6-yl]piperidin-4-yl}phenol (100 g, 275.23 mmol) and potassium carbonate (76 g, 550.45 mmol) in DMF (200 mL) at 80⁰C over a period of 15 minutes under nitrogen.

The resulting mixture was stirred at 80⁰C for 20 hours. The reaction mixture was cooled to room temperature, then concentrated and diluted with DCM (2 L), and washed sequentially with water (1 L) and saturated brine (500 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with EtOAc (150 mL). The resulting solid was washed with further EtOAc (50 mL) and ether then dried to give 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol. The filtrate was evaporated and further purified by flash silica chromatography, elution gradient 70 to 100% EtOAc in isohexane. Fractions containing the desired product were evaporated to dryness then triturated with ether, dried and combined with the material previously collected to afford 2-(4- { 1 -[3-

(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethanol (89 g, 79%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.66 (2H, m), 1.88 (2H, m), 2.80 (IH, m), 3.10 (2H, m), 3.70 (2H, m), 3.95 (2H, t), 4.41 (2H, m), 4.85 (IH, t), 6.87 (2H, d), 7.18 (2H, d), 7.67 (IH, d), 8.25 (IH, d); m/z = 408 [M+H]+.

Preparation of 2-(4-{ 1- [3-(trifluoromethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazin-6- yl] piperidin-4-yl}phenoxy)ethyl methanesulfonate

A solution of methanesulfonyl chloride (20.37 mL, 262.16 mmol) in DCM (300 mL) was added to 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethanol (89 g, 218.46 mmol) and triethylamine (60.9 mL, 436.93 mmol) in DCM (900 mL) at 0⁰C over a period of 30 minutes under nitrogen. The resulting solution was stirred at 0⁰C for 1 hour. The reaction mixture was diluted with DCM (1 L), and washed with water (2 L). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(4- { 1 -[3-(trifluoromethyl)[ 1 ,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4- yl}phenoxy)ethyl methanesulfonate (104 g, 98%) as a solid.

IH NMR (399.9 MHz, DMSO-d6) δ 1.67 (2H, m), 1.89 (2H, m), 2.83 (IH, m), 3.11 (2H, m), 3.23 (3H, s), 4.23 (2H, t), 4.41 (2H, m), 4.52 (2H, t), 6.91 (2H, d), 7.21 (2H, d), 7.66 (IH, d), 8.24 (IH, d); m/z = 486 [M+H]+. Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{l-[3-

(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 110⁰C for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basifϊed to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (IL), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid. IH NMR (399.9 MHz, DMS0-d6) δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.

Example 5.5

Alternative route for the preparation of 6-(4-{4-[2-(4-acetylpiperazin-l- vDethoxyl phenyllpiperidin- l-vD-3-f trifluoromethyl)-7.,8-(iihv(iro [ 1 ,2,41 triazolo [4,3- blpyridazine Form A

Methanol (375.0 mL) was added to 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin-l-yl]-3-(trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine (25.0 g, 48 m mol) in a 2.0 L autoclave reactor and to this was added 10% Pd/C (12.5 g, 50% w/w) paste at 22-25°C under nitrogen gas atmosphere. The reaction was performed under hydrogen pressure (5.0 bar) at 50⁰C temperature for 10.0 h. The reaction mass was cooled to room temperature and the catalyst removed by filtration. Filtered cake was washed with methanol. The solvent was evaporated and the residue was azeotropically distilled by ethylacetate (2 x 125.0 mL) at 40⁰C under reduced pressure to 3.0 rel vol (75.0 mL). Drop wise addition of tert-butylmethylether (MTBE, 375.0 mL) to the reaction mass resulted in solid material, which was collected by filtration and washed with MTBE (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50⁰C to afford the desired product 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo [4,3-b]pyridazine (22.3 g, 88%) as a white color free flowing solid. The isolated material was confirmed by XRPD as Form A. IH NMR (400.13 MHz, CDC13): δ 1.62 (2H, m), 1.88 (2H, m), 2.02 (3H, s), 2.49 (4H, m), 2.65 – 2.78 (5H, m), 2.94 (2H, m), 3.15 (2H, t), 3.42 (2H, m), 3.57 (2H, m), 4.03 (2H, t), 4.24 (2H, m), 6.80 (2H, d), 7.06 (2H, d); m/z = 520 [M+H]+.

The 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluoromethyl)[ 1,2,4] triazolo[4,3-b]pyridazine used as starting material was prepared as follows :-

Preparation of 4- { 1- [3-(trifluor omethyl) [1 ,2,4] triazolo [4,3-b] pyridazin-6-yl] piperidin- 4-yl}phenol: Dimethylacetamide (250.0 mL) was added to 6-chloro-3-(trifluoromethyl)- [l,2,4]triazolo[4,3-b]pyridazine [CAS: 40971-95-7] (50.0 g, 225 m mol) at 22-25°C in a suitable round bottom flask followed by 4-(piperidin-4-yl)phenol [CAS: 62614-84-0] (60.9 g, 236 m mol) at 22-25°C. The reaction mass was stirred to obtain a clear solution. Triethylamine (79.1 mL, 561 m mol) was slowly added to the reaction mass by drop wise addition over a period of 60 min at 25-30⁰C. Temperature was raised to 40⁰C and the reaction mass stirred for 1.0 h. After completion of reaction, water (500.0 mL) was added to the reaction mass by drop wise addition over a period of 30 min at 40-43⁰C. The slurry mass was stirred for 30 min at 40⁰C and then filtered under reduced pressure. The wet material was slurry washed using water (500.0 mL) for 30 min at 40⁰C. The solid was collected by filtration and the material washed with water (125.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50⁰C to afford the desired product 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (75.1 g, 89.9%) as a free flowing solid. IH NMR (400.13 MHz, DMSO-d6): δ 1.64 (2H, m), 1.87 (2H, m), 2.75 (IH, m), 3.09 (2H, m), 4.40 (2H, m), 6.69 (2H, d), 7.05 (2H, d), 7.65 (IH, d), 8.24 (IH, d), 9.15 (IH, s); m/z = 364 [M+H]+.

Preparation of 6-[4-[4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl]piperidin-l-yl]-3- (trifluor omethyl) [ 1 ,2,4] triazolo [4,3-b] pyridazine:

Dichloromethane (225.0 mL) and 4-{l-[3-(trifluoromethyl)[l,2,4]triazolo[4,3-b]pyridazin- 6-yl]piperidin-4-yl} phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25°C. Triphenylphosphine (72.2 g, 275 m mol) and l-[4-(2-hydroxy- ethyl)piperazin-l-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25°C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30⁰C over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30⁰C to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25°C and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25°C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dired under reduced pressure with nitrogen gas bleed at 50⁰C to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-l- yl)ethoxy]phenyl]piperidin- 1 -yl]-3-(trifluoromethyl)[ 1 ,2,4] triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.

IH NMR (400.13 MHz, DMSO-d6): δ 1.59-1.73 (2H, m), 1.87 (2H, d), 1.99 (3H, s), 2.42 (2H, t), 2.71 (2H, t), 2.76-2.86 (IH, t), 3.08 (2H, t), 3.38-3.47 (4H, m), 4.08 (2H, t), 4.41 (2H, d), 6.88 (2H, d), 7.18 (2H, d), 7.62 (IH, d), 8.26 (IH, d); m/z = 518 [M+H]+.

Example 5.8

Preparation of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluor omethyl)-7,8-dihydr 0 [1 ,2,4] triazolo [4,3-b] pyridazine maleate

A clear solution of maleic acid (0.445 g, 3.84 m mol) in methanol (1.0 mL) was added to a clear solution of 6-(4-{4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3- (trifluoromethyl)-7,8-dihydro[l,2,4]triazolo[4,3-b]pyridazine, obtained as described in Example 5.5, (2.0 g, 3.84 m mol) in methanol (2.0 mL) at 22-25°C and the resulting clear solution heated to 50⁰C for 30 min. The reaction mass was cooled to 22-25°C and ethylacetate (16.0 mL) added drop wise to the reaction mass at 22-25°C. The reaction mass was then stirred for 60 min at 22-25°C. The resulting white color material was collected by filtration and washed with ethylacetate (5.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50⁰C to afford the desired product 6-(4- {4-[2-(4-acetylpiperazin-l-yl)ethoxy]phenyl}piperidin-l-yl)-3-(trifluoromethyl)-7,8- dihydro[l,2,4]triazolo[4,3-b]pyridazine maleate (2.21 g, 90.0%) as free flowing white color material.

IH NMR (400.13 MHz, DMSO-d₆): δ 1.62 (2H, m), 1.77 (2H, m), 2.02 (3H, s), 2.75 (IH, m), 2.77 (2H, m), 2.80 (2H, m), 2.95 (4H, m), 3.16 (2H, t), 3.36 (6H, m), 4.22 (4H, m), 6.08 (2H, s), 6.91 (2H, d), 7.17 (2H, d).

PAPER

Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8

Bioorganic & Medicinal Chemistry Letters

Volume 23, Issue 7, 1 April 2013, Pages 1945–1948

Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.

http://www.sciencedirect.com/science/article/pii/S0960894X13002321

SYNTHESIS

AZD 3514

6-(4-{4-[2-(4-Acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine AZD 3514

SYNTHETIC ROUTE 2ND GENERATION

SYNTHETIC ROUTE 4TH GENERATION

REFERENCES

1: Bradbury RH, Acton DG, Broadbent NL, Brooks AN, Carr GR, Hatter G, Hayter BR,  Hill KJ, Howe NJ, Jones RD, Jude D, Lamont SG, Loddick SA, McFarland HL, Parveen  Z, Rabow AA, Sharma-Singh G, Stratton NC, Thomason AG, Trueman D, Walker GE, Wells SL, Wilson J, Wood JM. Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer. Bioorg Med Chem Lett. 2013 Apr 1;23(7):1945-8. doi: 10.1016/j.bmcl.2013.02.056. Epub 2013 Feb 21. PubMed PMID: 23466225.

///////////////AZD 3514 MALEATE, AZD 3514 , AZD-3514, Prostate cancer, Androgen receptor downregulator, AZD3514, 1240299-33-5

1H-Indole-1-acetic acid, 4-(acetylamino)-3-[(4-chlorophenyl)thio]-2-methyl-

• 2-[4-acetamido-3-(4-chlorophenyl)sulfanyl-2-methylindol-1-yl]acetic acid
• Originator AstraZeneca
• Developer AstraZeneca; Johns Hopkins University
• Class Antiasthmatics
• Mechanism of Action Prostaglandin D2 receptor antagonists
• • Phase II Urticaria
  • Discontinued Asthma; Chronic obstructive pulmonary disease

  Most Recent Events

  • 09 Mar 2016 AZD 1981 is still in phase II trials for Urticaria in USA (PO)
  • 07 Mar 2016 Johns Hopkins University in collaboration with AstraZeneca completes a phase II trial in Urticaria in USA (PO) (NCT02031679)
  • 04 Mar 2016 Efficacy and safety data from a phase II trial in Urticaria presented at the Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)

https://ncats.nih.gov/files/AZD1981.pdf

SEE

NMR

HPLC

AZD1981 is a potent, selective CRTh2 (DP2) receptor antagonist with IC50 of 4 nM, showing >1000-fold selectivity over more than 340 other enzymes and receptors, including DP1. Phase 2.

118 patients were randomised to treatment (AZD1981 n = 61; placebo n = 57); 83% of patients were male and the mean age was 63 years (range 43-83). There were no significant differences in the mean difference in change from baseline to end of treatment between AZD1981 and placebo for the co-primary endpoints of pre-bronchodilator FEV1 (AZD1981-placebo: -0.015, 95% CI: -0.10 to 0.070; p = 0.72) and CCQ total score (difference: 0.042, 95% CI: -0.21 to 0.30; p = 0.75). Similarly, no differences were observed between treatments for the other outcomes of lung function, COPD symptom score, 6-MWT, BODE index, and use of reliever medication. AZD1981 was well tolerated.

CONCLUSION:

There was no beneficial clinical effect of AZD1981, at a dose of 1000 mg twice daily for 4 weeks, in patients with moderate to severe COPD. AZD1981 was well tolerated and no safety concerns were identified.

Biological Activity

Protocol(Only for Reference)

Kinase Assay: ^[2]

Animal Study: ^[1]

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

References

[1] Luker T, et al. Bioorg Med Chem Lett. 2011, 21(21), 6288-6292.

[2] Schmidt JA, et al. Br J Pharmacol. 2013, 168(7), 1626-1638.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-09)

///////////

CC1=C(C2=C(N1CC(=O)O)C=CC=C2NC(=O)C)SC3=CC=C(C=C3)Cl

Pidotimod

H-Pyr-Thz-OH

(4R)-3-[(2S)-5-oxopyrrolidine-2-carbonyl]-1,3-thiazolidine-4-carboxylic acid

CAS 121808-62-6

Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod

(4R)-3-(5-oxo-L-prolyl)-l ,3-thiazolidine-4-carboxylic acid,  ITI 231723.

3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid

• 4-Thiazolidinecarboxylic acid, 3-[(5-oxo-2-pyrrolidinyl)carbonyl]-, [R-(R*,S*)]-
• (4R)-3-[[(2S)-5-Oxo-2-pyrrolidinyl]carbonyl]-4-thiazolidinecarboxylic acid
• Adimod
• Axil (pharmaceutical)
• Pigitil

Stefano Poli, Corona Lucio Del

POLI INDUSTRIA CHIMICA S.p.A.

Pidotimod is an immunostimulant.^[1]

Pidotimod, whose chemical name is (4R)-3-(5-oxo-L-prolyl)-l ,3-thiazolidine-4-carboxylic acid, was first disclosed in ITI 231723. It is a synthetic peptide-like molecule provided with an in vitro and in vivo immunomodulating action (Giagulli et al., International Immunopharmacology, 9, 2009, 1366-1373). The immune system assists in maintaining a homeostatic balance between the human body and all foreign substances. An abnormality in this balance may cause a defective or aberrant response towards non-self substances, as well as loss of tolerance toward self-antigens, in such cases, the immune system imbalance exhibits clinically as signs of disease.

Pidotimod has been shown to induce dendritic cell maturation and up-regulate the expression of HLA-DR and co-stimulatory molecules CD83 and CD86, which are integral to communication with adaptive immunity cells. Pidotimod has also been shown to stimulate dendritic cells to release pro-inflammatory molecules such as MCP-1 and TNF-a cytokines, and to inhibit thymocyte apoptosis caused by a variety of apoptosis-inducing molecules. Pidotimod exerts a protective action against infectious processes, although not through direct antimicrobial or antiviral action. Rather, pidotimod stimulates both innate and acquired immunity by enhancing humoral and cell-mediated immunity mechanisms.

Pidotimod, which may be administered as solid or liquid forms, for example, via an oral route, has been shown to increase natural resistance to viral or bacterial infections in animal models. Efficacy demonstrated in patients includes respiratory, urinary and genital infections, in particular recurrent respiratory infections in pediatric patients, respiratory infections in asthmatic patients and chronic obstructive pulmonary disease in adults and elderly patients.

Besides exhibiting activity to illnesses characterized by immune defects, pidotimod has been reported to be of benefit in to patients with other kinds of diseases, not directly related to immune defects, including gastroenterology diseases such as ulcerative colitis and irritable bowel syndrome, and dermatological diseases such as psoriasis and atopic dermatitis where symptoms relating to these diseases have been attenuated. In gastroenterology diseases pidotimod may be administered either by oral or by rectal route. Oral route or topical application, for example in creams or gels containing pidotimod, may be used to treat dermal conditions.

Further use of pidotimod includes treatment of inflammatory diseases, in particular those characterized by an aberrant activation of the non-canonical NF-kB pathway. Diseases implicated by such activation include allergic diseases, autoimmune diseases, and numerous other inflammatory diseases. Allergic diseases include allergic rhinitis, allergic conjunctivitis, contact dermatitis, eczema and allergic vasculitis.

Autoimmune diseases include alopecia areata, ankylosing spondylitis, autoimmune cardiomyopathy, autoimmune connective tissue diseases, autoimmune enteropathy, autoimmune hepatitis, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, celiac disease, chronic fatigue syndrome, cystic fibrosis, hashimoto’s thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IGA nephropathy, juvenile idiopathic arthritis for juvenile rheumatoid arthritis, or Still’s disease) Kawasaki’s disease, lichen planus, lupus erythematosus, rheumatoid arthritis, rheumatic fever, Sj5gren’s syndrome, spondyloarthropathy, temporal arteritis (or giant cell arteritis), urticarial vasculitis, and vitiligo.

Other inflammatory diseases include Alzheimer’s disease, atherosclerosis, chronic liver diseases, chronic nephropathy, gastritis, glomerulonephritis, hydradenitis suppurativa, hypogammaglobulinemia, interstitial cystitis, lichen sclerosus, liver steatosis, metabolic syndrome, obesity, Parkinson’s disease, pemphigus vulgaris, post-ischemic inflammation, raynaud phenomenon, restless leg syndrome, retroperitoneal fibrosis, and thrombocytopenia.

PATENT

CN 104926922

Synthesis pidotimod

A method for producing pidotimod, characterized in that: comprising the steps of: a) L- thiazolidine-4-carboxylic acid: L- cysteine formaldehyde solution was added dropwise, stirred at room temperature, filtered to give L- thiazolidine-4-carboxylic acid; (2) metal ion load type cation exchange resin preparation: strongly acidic with hydrochloric acid cation exchange resin is converted to the hydrogen form, the hydrogen form strong acid cation exchange resin was added a solution of a metal ion compound In, 40 ~ 80 ° C for 1 to 6 hours, cooled to room temperature, and dried to obtain a supported metal ion cation exchange resin; (3) Synthesis of pidotimod: the step (1) of L- thiazolidine – 4- carboxylic acid, in step (2) of the load as a catalyst metal ion type cation exchange resin, L- pyroglutamic acid and N, N- dimethylformamide mixed, 40 ~ 80 ° C for 1 to 4 hours, filtered to give a white solid, the white solid was acidified with hydrochloric acid, to give the finished pidotimod.

In four flask IOg L- thiazolidine-4-carboxylic acid, 11. 3g g L- pyroglutamic acid, 320mL N, N- dimethylformamide, 12g modified resin, 70 ° C the reaction 2 hours. Filtration, the reaction mixture by rotary evaporation, after removal of part of the solvent, placed in an ice bath to cool, the precipitated solid was suction filtered to give a white solid, this white solid was acidified with 37% hydrochloric acid, was allowed to stand at KTC, crystallization, filtration, a white product 14. 4g, a yield of 78.3%. Measured melting point 192 ~ 194 ° C, [a] 25D = – 150 ° (literature values mp: 192 ~ 194 ° C, [a] 25D = – 150 °).The whole preparation reaction pidotimod total yield of 64%. By HPLC, pidotimod content of 98.5%.

PAPER

Zhang, Yi; Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(24), PG 2566-2570

http://europepmc.org/abstract/med/19604731

10.1016/j.jchromb.2009.06.038

PATENT

WO2016113242,

Example 14 – Preparation of Pidotimod

Pidotimod was prepared following Example 1 of EP0422566 Al .

PATENT

WO2015036009,

https://www.google.com/patents/WO2015036009A1?cl=en

PATENT

EP276752,

PATENT

http://google.com/patents/EP0422566B1?cl=en

EXAMPLE 1

A solution of 16.78 g (0.084 mole) of ethyl L-thiazolidine-4-carboxylate hydrochloride in 33 ml of water is treated with 16.78 g of potassium carbonate and extracted with 40 ml of ethyl acetate. The organic phase is dried over sodium sulfate, filtered and diluted to 85 ml with ethyl acetate. The solution is stirred and cooled to 0-5°C, then 19.2 g (0.093 mole) of dicyclohexylcarbodiimide dissolved in 20 ml of ethyl acetate and 12 g (0.093 mole) of L-pyroglutamic acid are added thereto. The reaction mixture is stirred for 1 hour at 0-5°C, then 12 hours at room temperature, dicyclohexylurea is filtered, the filtrate is evaporated under vacuum and the oily residue, consisting in ethyl 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylate is taken up into 25 ml of water. 3.73 g of sodium hydroxide dissolved in 13.3 ml of water are dropped into the resulting solution. After 30 minutes, the reaction mixture is acidified with concentrated hydrochloric acid at 0-5°C, kept for 2 hours at 5°C, then filtered washing with little cool water and dried to obtain 17.8 g (87.6%) of 3-(L-pyroglutamyl)-L-thiazolidine-4-carboxylic acid, m.p. 193-194°C.

EXAMPLE 2

23 g (0.1 mol) of L-N-t-butoxycarbonylpyroglutamic acid (E. Schröder and E. Klinger, Ann. Chem., 673, 1964, 202) and 16.1 g (0.1 mol) of ethyl L-thiazolidine-4-carboxylate are dissolved in 150 ml of THF, to the solution stirred at 0-5°C, 21 g (0.105 mol) of dicyclohexylcarbodiimide are added and the slurry is stirred for 15 hours at room temperature. The dicyclohexylurea is filtered, the wear filtrate is evaporated u.v. and the oily residue is kept in 40 ml of water. In the solution 6.6 g of potassium hydroxyde in a little water are dropped in 30′ at 15-20°C, the pH is adjusted to 2 with hydrochloric acid at 0-5°C and after 2 hours the precipitated L-pyroglutamyl-L-thiazolidine-4-carboxylic acid is filtered and dried, giving 88%, mp. 193-4°.

CLIP

Drugs Fut 1991,16(12),1096

Liebigs Ann Chem 1964,673

The synthesis of pidotimod has been carried out using N-tert-butoxycarbonyl-L-pyroglutamic acid as starting material, in order to avoid the formation of diketopiperazine derivatives. L-Glutamic acid (I) was condensed with di-tert-butyl dicarbonate by means of triethylamine in DMF to give N-(tert-butoxycarbonyl)-L-glutamic acid (II), which is dissolved in THF and treated with dicyclohexylcarbodiimide (DCC) to obtain N-(tert-butoxycarbonyl)-L-glutamic anhydride (III). The treatment of anhydride (III) with dicyclohexylamine in THF-ethyl ether affords the dicyclohexylamine salt of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (IV), which by acidification with aqueous citric acid yields the corresponding free acid (V). The condensation of equimolecular amounts of N-(tert-butoxycarbonyl)-L-pyroglutamic acid (V) with L-thiazolidine-4-carboxylic acid ethyl ester (VIII) by means of DCC in methylene chloride gives the coupled ester (IX), which is hydrolyzed with aqueous NaOH, and the corresponding sodium salt acidified to yield the N-tert-butoxycarbonyl derivative (X). Finally, this compound is deprotected with trifluoroacetic acid to obtain crystalline pidotimod (XI). The intermediate thiazolidine (VIII) has been obtained as follows: Esterification of L-thiazolidine-4-carboxylic acid (VI) with ethanol by means of SOCl2 gives the corresponding ethyl ester hydrochloride (VII), which by treatment with K2CO3 in water yields the free ester (VIII).

CLIP

Arzneim-Forsch Drug Res 1994,44(12a),1402

Two new related routes for the synthesis of pidotimod have been reported: 1) The condensation of L-pyroglutamic acid (I) with L-thiazolidine-4-carboxylic acid ethyl ester (II) by means of dicyclohexylcarbodiimide (DCC) in methylene chloride gives the corresponding dipeptide ethyl ester (III), which is saponified with aqueous 1N NaOH. 2) By condensation of the activated ester L-pyroglutamic acid pentachlorophenyl ester (IV) with L-thiazolidine-4-carboxylic acid (V) by means of triethylamine in DMF.

PATENT

WO-2016112977

Novel crystalline, amorphous and solid forms of di-pidotimod benzathine (designated as Forms M and H), their hydrates, processes for their preparation and compositions comprising them are claimed. Also claimed is their use for treating viral or bacterial infections, respiratory, urinary and/or genital infections, ulcerative colitis, irritable bowel syndrome, psoriasis and atopic dermatitis

Example 14 – Preparation of Pidotimod

Pidotimod was prepared following Example 1 of EP0422566 Al .

NMR

Figure 17 is a Ή solution-state NMR spectrum of Form H

SEE

CN 104447947

Indian Pat. Appl. (2014), IN 2013MU00181 A

WO 2014111957

CN 103897025

References

Pidotimod

Systematic (IUPAC) name
(4R)-3-(5-oxo-L-prolyl)-1,3-thiazolidine-4-carboxylic acid
Clinical data
AHFS/Drugs.com	International Drug Names
Identifiers
ATC code	L03AX05 (WHO)
PubChem	CID 65944
ChemSpider	59348
UNII	785363R681
KEGG	D07261
ChEMBL	CHEMBL1488165
Synonyms	(4R)-3-[(2S)-5-oxopyrrolidine-2-carbonyl]-1,3-thiazolidine-4-carboxylic acid
Chemical data
Formula	C9H12N2O4S
Molar mass	244.26758 g/mol

//////////////Pidotimod, Thymodolic acid, Pidotimod, Timodolic acid, PGT/1A, Axil, Onaka, Pigitil, Polimod, H-Pyr-Thz-OH,  121808-62-6, ITI 231723, peptide, QA-7522, SMR000466390, Thymodolic acid, Timodolic acid, UNII:785363R681, 匹多莫德 , пидотимод ,  بيدوتيمود ,

O=C(O)[C@H]2N(C(=O)[C@H]1NC(=O)CC1)CSC2

Delamanid

デラマニド

MKT as Deltyba^® by Otsuka Pharmaceutical

http://www.ama-assn.org/resources/doc/usan/delamanid.pdf

(2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole

2(R)-Methyl-6-nitro-2-[4-[4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl]phenoxymethyl]-2,3-dihydroimidazo[2,1-b]oxazole

(R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

Imidazo[2,1-b]oxazole, 2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]phenoxy]methyl]-, (2R)-

(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

681492-22-8 CAS

Delamanid

C₂₅H₂₅F₃N₄O₆ : 534.48
[681492-22-8]

Delamanid (USAN, INN) is a drug for the treatment of multi-drug-resistant tuberculosis. It works by blocking the synthesis of mycolic acids in Mycobacterium tuberculosis, the organism which causes tuberculosis, thus destabilising its cell wall.^[2][3][4] The drug is approved in the EU under the trade name Deltyba (made by Otsuka Pharmaceutical).

It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basichealth system.^[5]

Adverse effects

Delamanid prolongs QT interval.^[6]

Interactions

Delamanid is metabolised by the liver enzyme CYP3A4, wherefore strong inducers of this enzyme can reduce its effectiveness.^[6]

History

In phase II clinical trials, the drug was used in combination with standard treatments, such as four or five of the drugsethambutol, isoniazid, pyrazinamide, rifampicin, aminoglycoside antibiotics, and quinolones. Healing rates (measured as sputum culture conversion) were significantly better in patients who additionally took delamanid.^[4][7]

The European Medicines Agency (EMA) recommended conditional marketing authorization for delamanid in adults with multidrug-resistant pulmonary tuberculosis without other treatment options because of resistance or tolerability. The EMA considered the data show that the benefits of delamanid outweigh the risks, but that additional studies were needed on the long-term effectiveness.^[8]

Delamanid was first approved by European Medicine Agency (EMA) on Apr 28, 2014, then approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on July 4, 2014. It was developed and marketed as Deltyba^® by Otsuka Pharmaceutical.

Delamanid is a novel bactericidal agent that interferes with the metabolism of the mycobacterium tuberculosis (MTB) cell walls. It is indicated for the treatment of pulmonary multi-drugresistant tuberculosis (MDR-TB) in adult patients.

Deltyba^® is available as tablets for oral use, containing 50 mg of free Delamanid, and the recommended dose is 100 mg twice daily for 24 weeks.

Delamanid, an antibiotic active against Mycobacterium tuberculosis strains, has been filed for approval in the E.U. and by Otsuka for the treatment of multidrug-resistant tuberculosis. In 2013, a positive opinion was received in the E.U. for this indication. Phase III trials for treatment of multidrug-resistant tuberculosis are under way in the U.S. Phase II study for the pediatric use is undergone in the Europe.

The drug candidate’s antimycobacterial mechanism of action is via specific inhibition of the synthesis pathway of mycolic acid, which is a cell wall component unique to M. tuberculosis.

In 2008, orphan drug designation was received in Japan for the treatment of pulmonary tuberculosis.

Tuberculosis (TB), an airborne lung infection, still remains a major public health problem worldwide. It is estimated that about 32% of the world population is infected with TB bacillus, and of those, approximately 8.9 million people develop active TB and 1.7 million die as a result annually according to 2004 figures. Human immunodeficiency virus (HIV) infection has been a major contributing factor in the current resurgence of TB. HIV-associated TB is widespread, especially in sub-Saharan Africa, and such an infectious process may further accelerate the resurgence of TB.

Moreover, the recent emergence of multidrug-resistant (MDR) strains ofMycobacterium tuberculosis that are resistant to two major effective drugs, isonicotinic acid hydrazide (INH) and rifampicin (RFP), has further complicated the world situation.

The World Health Organization (WHO) has estimated that if the present conditions remain unchanged, more than 30 million lives will be claimed by TB between 2000 and 2020. As for subsequent drug development, not a single new effective compound has been launched as an antituberculosis agent since the introduction of RFP in 1965, despite the great advances that have been made in drug development technologies.

Although many effective vaccine candidates have been developed, more potent vaccines will not become immediately available. The current therapy consists of an intensive phase with four drugs, INH, RFP, pyrazinamide (PZA), and streptomycin (SM) or ethambutol (EB), administered for 2 months followed by a continuous phase with INH and RFP for 4 months. Thus, there exists an urgent need for the development of potent new antituberculosis agents with low-toxicity profiles that are effective against both drug-susceptible and drug-resistant strains of M. tuberculosis and that are capable of shortening the current duration of therapy.

PATENT

US20060094767

(R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol

ARE THE INTERMEDIATES

Example 1884

Production of (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg, 1.96 mmol) was dissolved in N,N′-dimethylformamide (3 ml), and sodium hydride (86 mg, 2.16 mmol) was added while cooling on ice followed by stirring at 70-75° C. for 20 minutes. The mixture was cooled on ice. To the solution, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg, 2.75 mmol) in N,N′-dimethylformamide (3 ml) was added followed by stirring at 70-75° C. for 20 minutes. The reaction mixture was allowed to return to room temperature, ice water (25 ml) was added, and the resultant solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washed with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1). Recrystallization from ethyl acetate/isopropyl ether gave (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, 33%) as a light yellow powder.

PATENT

WO 2010021409 AND http://worldwide.espacenet.com/publicationDetails/biblio?CC=IN&NR=203704A1&KC=A1&FT=D

FOR 2, 4 DINITROIMIDAZOLE

PATENT

WO2011093529A1

These patent literatures disclose Reaction Schemes A and B below as the processes for producing the aforementioned 2, 3-dihydroimidazo [2, 1-b] oxazole compound.

Reaction Scheme A:

wherein R¹ is a hydrogen atom or lower-alkyl group; R² is a substituted pxperidyl group or a substituted piperazinyl group; and X¹ is a halogen atom or a nitro group.

Reaction Scheme B:

wherein X² is a halogen or a group causing a substitution reaction similar to that of a halogen; n is an integer from 1 to 6; and R¹, R² and X¹ are the same as in Reaction Scheme A.

An oxazole com ound represented by Formula (la) :

, i.e., 2-methyl-6-nitro-2-{4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl }-2, 3- dihydroimidazo [2, 1-b] oxazole (hereunder, this compound may be simply referred to as “Compound la”) is produced, for example, by the method shown in the Reaction Scheme C below (Patent

Literature 3) . In this specification, the term “oxazole compound’ means an oxazole derivative that encompasses compounds that contain an oxazole ring or an oxazoline ring (dihydrooxazole ring) in the molecule.

Reaction Scheme C:

However, the aforementioned methods are unsatisfactory in terms of the yield of the objective compound. For example, the method of Reaction Scheme C allows the objective oxazole Compound (la) to be obtained from Compound (2a) at a yield as low as 35.9%. Therefore, alternative methods for producing the compound in an industrially advantageous manner are desired. Citation List

Patent Literature

PTL 1: WO2004/033463

PTL 2: WO2004/035547

PTL 3: WO2008/140090

Example 9

Production of (R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

{R) -1- [ – {2 , 3-epoxy-2-methylpropoxy ) phenyl] -4- [4- ( trifluoromethoxy ) phenoxy ] piperidine (10.0 g, 23.6 mmol, optical purity of 94.3%ee), 2-chloro-4-nitroimidazole (4.0 g, 27.2 mmol), sodium acetate (0.4 g, 4.9 mmol), and t- butyl acetate (10 ml) were mixed and stirred at 100°C for 3.5 hours. Methanol (70 ml) was added to the reaction mixture, and then a 25% sodium hydroxide aqueous solution (6.3 g, 39.4 mmol) was added thereto dropwise while cooling with ice. The resulting mixture was stirred at 0°C for 1.5 hours, and further stirred at approximately room

temperature for 40 minutes. Water (15 ml) and ethyl acetate (5 ml) were added thereto, and the mixture was stirred at 45 to 55°C for 1 hour. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml) . Methanol (100 ml) was added to the resulting

crystals, followed by stirring under reflux for 30 minutes. The mixture was cooled to room temperature. The crystals were then collected by filtration and washed with methanol (30 ml) . The resulting crystals were dried under reduced pressure, obtaining 9.3 g of the objective product (yield: 73%) .

Optical purity: 99.4%ee.

PATENT

Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles
J Med Chem 2006, 49(26): 7854

http://pubs.acs.org/doi/abs/10.1021/jm060957y

(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (19,  DELAMANID).

To a mixture of 27 (127.56 g, 586.56 mmol) and 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28g) (165.70 g, 468.95 mmol) in N,N-dimethylformamide (1600 mL) was added 60% sodium hydride (22.51 g, 562.74 mmol) at 0 °C portionwise. After the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, the reaction mixture was cooled in an ice bath and carefully quenched with ethyl acetate (230 mL) and ice water (50 mL). The thus-obtained mixture was poured into water (3000 mL) and stirred for 30 min. The resulting precipitates were collected by filtration, washed with water, and dried at 60 °C overnight. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture (5/1) as solvent. The appropriate fractions were combined and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (1300 mL)−isopropyl alcohol (150 mL) to afford 19 (119.11 g, 48%) as a pale yellow crystalline powder.

Mp 195−196 °C.

¹H NMR (CDCl₃) δ 1.77 (3H, s), 1.87−2.16 (4H, m), 2.95−3.05 (2H, m), 3.32−3.41 (2H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.2 Hz), 4.18 (1H, J = 10.2 Hz), 4.36−4.45 (1H, m), 4.49 (1H, d, J = 10.2 Hz), 6.76 (2H, d, J = 6.7 Hz), 6.87−6.94 (4H, m), 7.14 (2H, d, J = 8.6 Hz), 7.55 (1H, s).

[α  −9.9° (c 1.01, CHCl₃).

MS (DI) m/z 535 (M⁺ + 1). Anal. (C₂₅H₂₅F₃N₄O₆) C, H, N.

http://pubs.acs.org/doi/suppl/10.1021/jm060957y/suppl_file/jm060957ysi20061113_095044.pdf

CLIPS

Delamanid (Deltyba)
Marketed by Otsuka, delamanid was approved in both the European Union and Japan in 2014 as part of combination therapies for
multi-drug resistant tuberculosis (TB). Because delamanid exhibited no adverse drug–drug interactions, it has found utility as a
combination therapy with standard antiretroviral drugs indicated for TB. Delamanid blocks mycolic acid biosynthesis in ycobacterium
tuberculosis, which allows its cell wall to be penetrated by small molecule antivirals.92

Although delamanid possesses a rather linear structure capable of a variety of retrosynthetic disconnections, the most likely scale
synthesis is a convergent approach involving two key synthons—diol 82 and piperidine 81, as is outlined in Scheme 13.93–95
Preparation of 82 proceeded through a Sharpless Asymmetric Epoxidation of commercial alcohol 86, followed by a diastereoselective
epoxide ring opening with 4-bromophenol to afford key diol 82 in 76% for the two step sequence (Scheme 14).93–96
Piperidine 81 was concurrently prepared by first generating biaryl ether 79, which arose from a substitution reaction between
pyridine N-oxide 77 and phenol 78 that proceeded in 86% yield. Next, removal of the N-oxide functionality by means of catalytic
hydrogenation under mild pressure and neutral conditions afforded diaryl ether 80 in excellent yield. Reduction of the pyridine
to the corresponding piperidine (81) was affected through the use of catalytic hydrogenation as well, this time under acidic
conditions and elevated pressures relative to the N-oxide reduction.95,97 At this juncture, subjection of piperidine 81 to Buchwald–
Hartwig conditions in the presence of diol subunit 82

(preparation described in Scheme 14) delivered diol 83. A two-step elimination to deliver enantiopure epoxide 84 set the stage for an
interesting cascade reaction to arrive at delamanid (XI) directly— the initial alkylation of the epoxide by imidazole 85 proceeded
under basic conditions with sodium acetate which then underwent an intramolecular nucleophilic substitution reaction by the liberated alcohol on the pendant imidazole chloride in the presence of sodium hydroxide. The reaction sequence proceeded in 73%
yield to provide delamanid (XI) as a free base.96

92. Blair, H. A.; Scott, L. J. Drugs 2015, 75, 91.
93. Tsubouchi, H.; Sasaki, H.; Kuroda, H.; Itotani, M.; Hasegawa, T.; Haraguchi, Y.;Kuroda, T.; Matsuzaki, T. US Patent 2006094767A1, 2006.
94. Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige,T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem.2006, 49, 7854.
95. Goto, F.; Takemura, N.; Otani, T.; Hasegawa, T.; Tsubouchi, H.; Utsumi, N.; Fujita, S.; Kuroda, H.; Shitsuta, T.; Sasaki, H. US2012130082A1, 2012.
96. Yamamoto, A.; Shinhama, K.; Fujita, N.; Aki, S.; Ogasawara, S.; Utsumi, N. WOPatent 2011093529A1, 2011.

References

17181168	12-28-2006	Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.	Journal of medicinal chemistry
17132069	11-1-2006	OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.	PLoS medicine

18691051

1-1-2008

New anti-tuberculosis drugs with novel mechanisms of action.

Current medicinal chemistry

21069962

11-11-2010

Synthesis and Structure-Activity Relationships of Aza- and Diazabiphenyl Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

Journal of medicinal chemistry

22421275	5-1-2012	Tuberculosis: the drug development pipeline at a glance.	European journal of medicinal chemistry
22148391	1-12-2012	Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).	Journal of medicinal chemistry

US2009227630	9-11-2009	Pharmaceutical Composition Achieving Excellent Absorbency of Pharmacologically Active Substance
US2009018169	1-16-2009	Sulfonamide Derivatives for the Treatment of Bacterial Infections

WO2004033463A1	Oct 10, 2003	Apr 22, 2004	Otsuka Pharma Co Ltd	2,3-DIHYDRO-6-NITROIMIDAZO[2,1-b]OXAZOLES
WO2004035547A1	Oct 14, 2003	Apr 29, 2004	Otsuka Pharma Co Ltd	1-substituted 4-nitroimidazole compound and process for producing the same
WO2008140090A1	May 7, 2008	Nov 20, 2008	Otsuka Pharma Co Ltd	Epoxy compound and method for manufacturing the same
JP2009269859A *	Title not available

Delamanid

Systematic (IUPAC) name
(2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole
Clinical data
Trade names	Deltyba
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral (film-coated tablets)
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Protein binding	≥99.5%
Metabolism	in plasma by albumin, in liver by CYP3A4 (to a lesser extent)
Biological half-life	30–38 hours
Excretion	not excreted in urine[1]
Identifiers
CAS Number	681492-22-8
ATC code	J04AK06 (WHO)
PubChem	CID 6480466
ChemSpider	4981055
ChEMBL	CHEMBL218650
Synonyms	OPC-67683
Chemical data
Formula	C25H25F3N4O6
Molar mass	534.48 g/mol

//////////////////////////681492-22-8 , Delamanid, Deltyba, Otsuka Pharmaceutical

FC(F)(F)Oc5ccc(OC4CCN(c3ccc(OC[C@@]2(Oc1nc(cn1C2)[N+]([O-])=O)C)cc3)CC4)cc5

Prucalopride (Resolor)

Drug Name：Prucalopride Succinate

Trade Name：Resolor^®, MOA：Serotonin (5-HT4) receptor agonist, Indication：Chronic constipation

Company：Shire (Originator) , Johnson & Johnson

APPROVED EU 2009-10-15

CHINA 2014-01-21

COA  NMR  HPLC CLICK

Prucalopride (brand name Resolor, developed by Johnson & Johnson and licensed to Movetis) is a drug acting as a selective, high affinity 5-HT₄ receptor agonist^[1] which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements.^{[2][3][4][5][6][7]} Prucalopride was approved for use in Europe in 2009,^[8] in Canada (named Resotran) on December 7, 2011^[9] and in Israel in 2014^[10] but it has not been approved by the Food and Drug Administration for use in the United States. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.^[11][12]

Mechanism of action

Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT₄) receptor agonist with enterokinetic activities.^[13] Prucalopride alters colonic motility patterns via serotonin 5-HT₄ receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.

The observed effects are exerted via highly selective action on 5-HT₄ receptors:^[13] prucalopride has >150-fold higher affinity for 5-HT₄ receptors than for other receptors.^[1][14] Prucalopride differs from other 5-HT₄ agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT_1B/D and the cardiac human ether-a-go-go K⁺ or hERG channelrespectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs.^[14] Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.^[13]

Pharmacokinetics

Prucalopride is rapidly absorbed (C_max attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in feces).Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,^[15] and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.^[13]

In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.^[13]

Efficacy

The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.^[7][16][17] Further measures are improvements in PAC-QOL^[18] (a quality of life measure) and PAC-SYM^[19] (a range of stool,abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.^{[20][21][22][23][24]}

In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo.^[7][16][17] There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).^[7][16][17] The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.^[25][26]

Side effects

Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache andgastrointestinal symptoms (abdominal pain, nausea or diarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.^[13]

Approval

In the European Economic Area, prucalopride was originally approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.^[13] Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication.^[27]

Contraindications

Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation orobstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn’s disease, and ulcerative colitis and toxic megacolon/megarectum.^[13]

CLIP

Prucalopride succinate, a first-in-class dihydrobenzofurancarboxamide, is a selective serotonin (5-HT4) receptor agonist.86–94 The drug, marketed under the brand name Resolor, possesses enterokinetic activity and was developed by the Belgian-based pharmaceutical firm Movetis. Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation, triggering the central propulsive force for defecation.95–97 The preparation of prucalopride succinate begins with the commercially available salicylic aniline 124 (Scheme 18). Acidic esterification, acetylation of the aniline nitrogen atom, and ambient-temperature chlorination via sulfuryl chloride (SO2Cl2) converted aminophenol 124 to acetamidoester 125 in 83% yield over the course of three steps.98–102 An unique set of conditions involving sodium tosylchloramide (chloramine T) trihydrate and sodium iodide were then employed to convert 125 to o-phenolic iodide 126, which then underwent sequential Sonogashira/cyclization reaction utilizing TMS-acetylene with tetramethylguanidine (TMG) in the presence of silica gel to furnish the benzofuran progenitor of 127.103 Hydrogenation of this intermediate benzofuranyl Sonagashira product saturated the 2,3-benzofuranyl bond while leaving the chlorine atom intact, ultimately delivering dihydrobenzofuran 127 in excellent yield for the two step sequence. Base-induced saponification and acetamide removal gave rise to acid 128. This acid was activated as the corresponding mixed anhydride and treated with commercial piperidine 129 to construct prucalopride which was stirred at room temperature for 24 h in ethanolic succinic acid to provide prucalopride succinate (XI). The yield for the formation of the salt was not provided.

86. Briejer, M. R.; Bosmans, J. P.; Van Daele, P.; Jurzak, M.; Heylen, L.; Leysen, J. E.;Prins, N. H.; Schuurkes, J. A. J. Eur. J. Pharmacol. 2001, 423, 71.
87. Briejer, M. R.; Prins, N. H.; Schuurkes, J. A. J. Neurogastroenterol. Motil. 2001, 13,465.
88. Coggrave, M.; Wiesel, P. H.; Norton, C. Cochrane Database Syst. Rev. 2006.CD002115.
89. Coremans, G.; Kerstens, R.; De Pauw, M.; Stevens, M. Digestion 2003, 67, 82.
90. De Winter, B. Y.; Boeckxstaens, G. E.; De Man, J. G.; Moreels, T. G.; Schuurkes, J.A. J.; Peeters, T. L.; Herman, A. G.; Pelckmans, P. A. Gut 1999, 45, 713.
91. Emmanuel, A. V.; Roy, A. J.; Nicholls, T. J.; Kamm, M. A. Aliment. Pharmacol.Ther. 2002, 16, 1347.
92. Frampton, J. E. Drugs 2009, 69, 2463.
93. Krogh, K.; Bach Jensen, M.; Gandrup, P.; Laurberg, S.; Nilsson, J.; Kerstens, R.;De Pauw, M. Scand. J. Gastroenterol. 2002, 37, 431.
94. Pau, D.; Workman, A. J.; Kane, K. A.; Rankin, A. C. J. Pharmacol. Exp. Ther. 2005,313, 146.
95. De Maeyer, J. H.; Schuurkes, J. A. J.; Lefebvre, R. A. Br. J. Pharmacol. 2009, 156,362.
96. Irving, H. R.; Tochon-Danguy, N.; Chinkwo, K. A.; Li, J. G.; Grabbe, C.; Shapiro,M.; Pouton, C. W.; Coupar, I. M. Pharmacology 2010, 85, 224.
97. Ray, A. M.; Kelsell, R. E.; Houp, J. A.; Kelly, F. M.; Medhurst, A. D.; Cox, H. M.;Calver, A. R. Eur. J. Pharmacol. 2009, 604, 1.
98. Baba, Y.; Usui, T.; Iwata, N. EP 640602 A1, 1995.
99. Fancelli, D.; Caccia, C.; Severino, D.; Vaghi, F.; Varasi, M. WO 9633186 A1,1996.
100. Hirokawa, Y.; Fujiwara, I.; Suzuki, K.; Harada, H.; Yoshikawa, T.; Yoshida, N.;Kato, S. J. Med. Chem. 2003, 46, 702.
101. Kakigami, T.; Usui, T.; Tsukamoto, K.; Kataoka, T. Chem. Pharm. Bull. 1998, 46,42.
102. Van Daele, G. H. P.; Bosmans, J.-P. R. M. A.; Schuurkes, J. A. J. WO 9616060 A1,1996.
103. Candiani, I.; DeBernadinis, S.; Cabri, W.; Marchi, M.; Bedeschi, A.; Penco, S.Synlett 1993, 269.

PAPER

Synlett 1993, 269

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-1993-22663

PAPER

Chem. Pharm. Bull. 1998, 46,42.

https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_article

https://www.jstage.jst.go.jp/article/cpb1958/46/1/46_1_42/_pdf

PATENT

US5948794

http://www.google.co.in/patents/US5948794

EXAMPLE 1

In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl₃. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).

US5854260

http://www.google.co.in/patents/US5854260

EXPERIMENTAL PART EXAMPLE 1

In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ±5° C. N,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10° C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10° C. The resulting mixture was added dropwise over a 20-min period to a solution of 1-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCl₃. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml)+ a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50° C.), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-N- 1-(3-methoxypropyl)-4-piperidinyl!-7-benzofurancarboxamide monohydrochloride (comp. 1).

PATENT

WO199616060A1

http://www.google.co.in/patents/WO1996016060A1?cl=en

EP-0,389,037-A, published on September 26, 1990, N-(3-hydroxy-4-piperidin- yl) (dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives are disclosed as having gastrointestinal motility stimulating properties. In our EP-0,445,862-A, published on September 11, 1991, N-(4-piperidinyl) (dihydrobenzo¬ furan or dihydro-2H-benzopyran)carboxamide derivatives are disclosed also having gastrointestinal motility stimulating properties.

The compound subject to the present application differs therefrom by showing superior enterokinetic properties.

The present invention concerns a compound of formula

and the pharmaceutically acceptable acid addition salts thereof.

The chemical name of the compound of formula (I) is 4-amino-5-chloro-2,3-dihydro-N- [l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide.

Example 1

In trichloromethane (135 ml) 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid (0.05 mol) (the preparation of which was described in EP-0,389,037-A) was suspended and cooled to ± 5 °C. H,N-diethylethanamine (0.05 mol) was added dropwise at a temperature below 10 °C. Ethyl chloroformate (0.05 mol) was added dropwise and the reaction mixture was stirred for 40 min. while keeping the temperature below 10°C. The resulting mixture was added dropwise over a 20-min period to a solution of l-(3-methoxypropyl)-4-piperidinamine (0.05 mol) in trichloromethane (35 ml). The cooling bath was removed and the reaction mixture was stirred for 150 min. Said mixture was washed with water (50 ml). The precipitate was filtered off over a glass filter and washed with water and CHCI3. The filtrate was separated in it’s layers. The separated organic layer was washed with water (50 ml) + a 50% NaOH solution (1 ml), dried, filtered and the solvent was evaporated. The residue was stirred in 2-propanol (100 ml). This mixture was acidified with HCl/2-propanol (7.2 ml; 5.29 N). The mixture was stirred for 16 hours at room temperature and the resulting precipitate was filtered off, washed with 2-propanol (15 ml) and dried (vacuum; 50 °C), yielding 12.6 g (62%) of 4-amino-5-chloro-2,3-dihydro-M-[ 1 -(3-methoxypropyl)-4-piperidinyl]-7- benzofurancarboxamide monohydrochloride (comp. 1).

Example 2

A mixture of 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzofuran- carboxamide(O.Olmol), l-chloro-3-methoxypropane (0.012mol), M,M-diethyl- ethanamine (2Jml) and KI (catalytic amount) in N,M-dimethylformamide (75ml) was stirred overnight at 50°C. The reaction mixture was cooled. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3/(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried (vacuum; 80°C), yielding 1.40g (35%) of 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxypropyl)- 4-piperidinyl]-7-benzofurancarboxamide monohydrochloride (comp. 1).

PAPER

Chinese Journal of Pharmaceuticals 2012, 43, 5-8.

CLIP

Chinese Patent CN 103012337 A report is as follows:

PAPER

Pharmaceutical & Clinical Research 2011, 19, 306-307.

CLIP

US5374637 (CN1045781, EP389037) and J. Het Chem, 1980,17 (6): 1333-5 reported synthetic route, as follows:

CLIP

Chinese Patent CN 104016949 A synthetic route reported as follows:

PATENT

CN104529960A

https://www.google.com/patents/CN104529960A?cl=zh

.

Example 1

1. Preparation of Compound II

Compound I (167. lg, Imol), triethylamine (111. lg, I. Imol) and methylene chloride (KMOg) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added dropwise trifluoroacetic anhydride (220. 5g, 1.05mol) / methylene chloride (150g) solution, maintaining the temperature throughout 5~15 ° C, dropping was completed, the reaction after 3 hours at room temperature, TLC (DCM = MeOH = 25: 1) The reaction was monitored to complete the reaction; the reaction mixture was slowly poured into ice water (560g) and stirred for 20 minutes, standing layer, the aqueous phase was separated, the organic phase was washed with saturated aqueous sodium bicarbonate (IOOg) wash sash; IM hydrochloric acid (IlOg) wash sash, then with saturated brine (200g) washed sash, magnesium sulfate (40g) dried, filtered and concentrated to give compound II (250. Ig), yield: 952%.

[0066] 2. Preparation of Compound III

[0067] Chloroacetyl chloride (101. 7g, 0. 9mol), nitrobenzene (20g) and dichloroethane (580 g) added to the reaction flask, nitrogen cooled to 5 ° C, was slowly added anhydrous trichloro aluminum powder (359. 2g, 2. 7mol), to keep the whole temperature 5~20 ° C, plus complete, insulation 15~25 ° C for 30 minutes to obtain a mixture A.

[0068] Compound II (. 236. 7g, 0 9mol) and dichloroethane (500g) added to the reaction flask, nitrogen cooled to 15 ° C; the mixture was added Compound II A quick solution, plus complete, rapid heating 65~75 ° C, 1 hours later once every 15 minutes in the control, monitoring TLC (DCM = MeOH = 50: 1) to complete the reaction; the reaction mixture was immediately poured into ice water (800g) and stirred for 30 minutes, controlling the temperature between 15~25 ° C, the organic phase was separated, the organic phase washed with water (180g) was washed with saturated brine (240g), dried over magnesium sulfate (45g) was dried, filtered and concentrated to give crude compound III (303 . 2g).

[0069] Take the crude compound III (291. 3g) / ethanol 1 dichloromethane: 1 solution (1500ml) was dissolved, and then adding activated carbon (14. 5g) was refluxed for one hour, cooled to room temperature filtered and the filtrate concentrated at room temperature to 600~ 650g, stop and concentrated down to 5~10 ° C, filtered to give a yellow solid (204. 7g); the resulting yellow solid (207. 6g) in tetrahydrofuran (510g) was purified, reduced to 10~15 ° C, filtered, The filter cake was washed with tetrahydrofuran (90g) dip, dried under vacuum to give compound III (181. 3g), yield: 61.7% billion

[0070] 3. Preparation of Compound IV

[0071] Compound 111 (! 169.68,0.5 11〇1), methanol (5,801,111) and sodium acetate (123.38,1.5111〇1) was added to the reaction flask. After 6 hours of reaction, began TLC (DCM: MeOH = 30: 1 ) the reaction was monitored to completion of the reaction; the reaction mixture was cooled to room temperature, concentrated, and the residue with ethyl acetate (500g) and water (200g) was dissolved, the organic phase was separated, the organic phase was washed with 2M sodium hydrogen carbonate (120g) was washed, then with saturated brine (IOOg), dried over magnesium sulfate (50g) was dried, filtered and concentrated to 250~280g, cooled to room temperature with stirring was added cyclohexane (200 g of), after stirring for 1 hour and then filtered and dried to obtain compound IV (126. 7g), yield: 83.4% billion

[0072] 4. Preparation of Compound V

[0073] Compound IV (12L 2g, 0. 4mol), methanol (380g) and Raney-Ni (12. 5g) added to the autoclave, purged with nitrogen, hydrogen is introduced (3. Ompa), the reaction was heated to 45 ° C after 8 hours, TLC (DCM = MeOH = 30: 1) to monitor the reaction, to complete the reaction, cooled to room temperature and pressure, and then purged with nitrogen, the reaction solution was filtered and concentrated to give crude compound V (103. 7g), taking compound V crude product (103g) was refluxed with ethyl acetate (420g) (1 hour) was purified, cooled to room temperature and stirred for 30 minutes and filtered to give a yellow solid was dried in vacuo to give compound V (76 8g.), yield: 663 %.

[0074] 5. Preparation of Compound VI

[0075] Compound ¥ (57.88,0.2111〇1), 1 ^ dimethylformamide (4.58) and acetonitrile (30 (^) was added to the reaction flask and heated 74~76 ° C; solution of N- chlorosuccinimide imide (. 26. 7g, 0 2mol) and acetonitrile (45g) was added dropwise over 30 minutes and maintaining the temperature finished 76~82 ° C, dropping was completed, the reaction was kept, after one hour the reaction started TLC (DCM: MeOH = 30: 1) to monitor the reaction, the reaction is complete the reaction solution cooled to 5~8 ° C, the filter cake was washed with water (210g) washed stirred, filtered, and dried in vacuo to give compound VI (57. 6g), yield. rate of 89.1%.

6. Preparation of Compound VII

Compound VI (48. 5g, 0. 15mol) and methanol (80g) added to the reaction flask, stirring at room temperature was added dropwise 4M aqueous sodium hydroxide (HOg), dropwise complete, for the reaction, 25 ° C~35 after 4 hours of reaction ° C, samples of about 7:00 adjust PH TLC (DCM = MeOH = 30: 1) to monitor the reaction, until the reaction was complete, down to 5~10 ° C, with 6M hydrochloric acid solution PH ~ 7. 5, half the solution was concentrated, then 2M hydrochloric acid solution PH ~ 7, reduced to 15~20 ° C was stirred for 30 minutes, filtered, the filter cake with methyl tert-butyl ether (70g) beating, filtration, and dried in vacuo to give compound VII (28. 7g), yield: 903%.

PAPER

Chem Pharm Bull 46 (1), 42-52 (1998) and Pharmaceutical and clinical study based on 2011 (4) 306-307 reported synthetic route is as follows:

Biological Activity

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

1

References

[1] Briejer MR, et al. Eur J Pharmacol, 2001, 423(1), 71-83.

[2] Priem E, et al. Neuropharmacology, 2012, 62(5-6), 2126-2135.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-23)

References

External links

• Resolor (prucalopride)- Movetis

Prucalopride

Systematic (IUPAC) name
4-Amino-5-chloro-N-[1-(3-methoxypropyl)piperidin-4-yl]-2,3-dihydro-1-benzofuran-7-carboxamide
Clinical data
Trade names	Resolor, Resotran
AHFS/Drugs.com	International Drug Names
License data	EU EMA: Resolor
Pregnancy category	AU: B1 Not recommended
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) ℞ (Prescription only)
Identifiers
CAS Number	179474-81-8
ATC code	A06AX05 (WHO)
PubChem	CID 3052762
IUPHAR/BPS	243
ChemSpider	2314539
UNII	0A09IUW5TP
Chemical data
Formula	C18H26ClN3O3
Molar mass	367.870 g/mol

//////////Prucalopride succinate, Resolor, R-093877, R-108512, Resolor®, Resolor, Resotran, UNII:0A09IUW5TP, 179474-81-8 , R-093877,  R-108512, Shire , Johnson & Johnson, 179474-85-2, UNII-4V2G75E1CK, SHIRE,  2010,  LAUNCHED, JANNSEN , PHASE 3,  IRRITABLE BOWL SYNDROME

COCCCN1CCC(CC1)NC(=O)C2=CC(=C(C3=C2OCC3)N)Cl

Varenicline (Chantix™)

Varenicline

• MF C₁₃H₁₃N₃
• MW 211.26

Varenicline (trade name Chantix and Champix usually in the form of varenicline tartrate), is a prescription medication used to treatnicotine addiction. Varenicline is a nicotinic receptor partial agonist—it stimulates nicotine receptors more weakly than nicotine itself does. In this respect it is similar to cytisine and different from the nicotinic antagonist, bupropion, and nicotine replacement therapies(NRTs) like nicotine patches and nicotine gum. As a partial agonist it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products. Through these mechanisms it can assist some patients to quit smoking.

バレニクリン酒石酸塩
Varenicline Tartrate

C₁₃H₁₃N₃C₄H₆O₆ : 361.35
[375815-87-5]

Medical uses

Varenicline is used for smoking cessation. In a 2009 meta-analysis varenicline was found to be more effective than bupropion (odds ratio 1.40) and NRTs (odds ratio 1.56).^[1]

A 2013 Cochrane overview and network meta-analysis concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.^[2][3]

The United States’ Food and Drug Administration (US FDA) has approved the use of varenicline for up to twelve weeks. If smoking cessation has been achieved it may be continued for another twelve weeks.^[4]

Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups. Varenicline is considered a class C pregnancy drug, as animal studies have shown no increased risk of congenital anomalies, however, no data from human studies is available.^[5] An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet.^[6] An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine.^[7]

Varenicline L-tartrate (Compound I) is the international commonly accepted name for 7,8,9,10- tetrahydro-6, 10-methano-6i7-pyrazino [2, 3- h] [3 ] benzazepme, (2R, 3R) -2 , 3-dihydroxybutanedioate (1:1) (which is also known as 5,8,14- tπazatetracyclo [10.3.1. O²‘¹¹. O⁴‘⁹] -hexadeca-2 (11) , 3, 5, 7, 9-pentaene, (2R, 3R)-2,3- dihydroxybutanedioate (1:1)) and has an empirical formula of C13H13N3 ^• C4H6O6 and a molecular weight of 361.35. Varenicline L-tartrate is a commercially marketed pharmaceutically active substance known to be useful for the treatment of smoking addiction.

(D

Varenicline L-tartrate is a partial agonist selective for (X₄β₂ nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the name Chantix™ for the treatment of smoking cessation. Varenicline base and its pharmaceutically acceptable acid addition salts are described in U.S. Patent No. 6,410,550. In particular, Example 26 of U.S. Patent No. 6,410,550 describes the preparation of varenicline hydrochloride salt using 1- (4 , 5-dinitro-10- aza-tπcyclo [6.3.1.O²‘⁷] dodeca-2, 4, 6-trien-10-yl) -2,2,2- tπfluoroethanone (compound of formula (III)) as starting compound. On the other hand, Example HA) of U.S. Patent No. 6,410,550 illustrates the preparation of compound of formula (III) via nitration of compound of formula (II) using an excess of nitronium triflate (>4 equiv) as a nitrating agent. The process disclosed in U.S. Patent No. 6,410,550 is depicted in Scheme 1.

VareniclineΗCl

Scheme 1

However, Coe et al., J. Med. Chem., 48, 3474 (2005), describes the same process and examples as U.S. Patent No. 6,410,550, and it also reveals that this process affords intermediate ortho-4 , 5-dinitrocompound of formula (III) together with the meta-3, 5-dinitro- isomer (i.e. the meta-dinitrocompound) in a ratio 9:1. The presence of the meta-dinitrocompound may affect not only the purity of the intermediate compound of formula III but it may also have an effect on the purity of the final varenicline tartrate, given that it can be carried along the synthetic pathway and/or it can also give rise to other derivative impurities. Thereby, as well as in U.S. Patent No. 6,410,550, in order to isolate pure compound of formula (III) , the raw product is triturated with ethyl acetate/hexane to afford compound of formula (III) with 77% yield. Additionally, the mother liquor is purified by chromatography on silica gel to improve the yield to a total of 82.8%. However, this process is not desirable for industrial implementation since it requires extensive and complicated purification procedures, i.e. trituration of the solid product along with column chromatography purification of the mother liquor, which is not very efficient or suitable for industrial scale-up.

Several improved processes for the synthesis of varenicline or its salts have been reported in the literature (e.g. WO2006/090236) . However, none of these processes tackle the optimization of the purification step of compound of formula (III).

There is therefore the need for providing an improved process for the preparation of varenicline L- tartrate which involves simple experimental procedures well suited to industrial production, which avoids the use of column chromatography purifications, and which affords high pure varenicline L-tartrate which hence can be used directly as a starting product for the preparation of the marketed pharmaceutical speciality.

Additionally, it has been observed that varenicline L-tartrate is usually obtained as a yellow solid under – A –

standard synthetic conditions. In this regard, colour must be attributed to the presence of some specific impurities that may or may not be detectable by conventional methods such as HPLC. The presence of impurities may adversely affect the safety and shelf life of formulations. In this connection, International application No. WO2006/090236 describes the isolation of vareniclme L- tartrate as a white solid. However, in order to remove coloured impurities, the varenicline L-tartrate obtained in WO2006/090236 is treated with a particular activated carbon having a specific grade (i.e. Darco KB-B™) . In fact, Example 5 of WO2006/090236 describes a large reprocessing step which comprises: dissolving varenicline L-tartrate in water, adding toluene, basifying with NaOH aqueous solution, collecting the toluene phase containing varenicline free base, distilling, adding methanol, azeotropically distilling the mixture, and adding more methanol to obtain a methanolic solution containing varenicline free base, adding Darco KB-B™ (10% w/w) , stirring for one hour, filtering through a pad of celite, and treating with L-tartaric acid to give varenicline L- tartrate salt as a white solid. Further, WO2006/090236 provides the absorbance at 430 nm of a varenicline L- tartrate salt solution, either in dichloromethane or in toluene, with or without using Darco KB-B™ activated carbon. However, this measure cannot be used to corroborate the whiteness of the solid varenicline L- tartrate. In addition, Example 3 of International application No. WO2002/092089, also disclose the preparation of varenicline L-tartrate polymorphic form C (i.e. a hydrate polymorph) as a white precipitate. Therefore, there is also a need for a simple and efficient method for preparing varenicline L-tartrate with enhanced whiteness and having a high purity.

SYNTHESIS

Synthesis of Intermediate VIII

Paper

J. Med. Chem. 48, 3474 (2005).

http://pubs.acs.org/doi/pdf/10.1021/jm050069n

PATENT

https://www.google.com/patents/WO2001062736A1?cl=en

CLIP

Profiles of Drug Substances, Excipients and Related Methodology, Volume 37

edited by Harry G. Brittain

SYNTHESIS

CLIP

Scheme (I) compound patent US6410550B1 is provided adjacent difluorobromobenzene as raw materials by DA reaction, oxidation, cyclization, debenzylation get varenicline intermediate (II). The synthesis route is as follows:

Patent CN101693712A mainly given varenicline intermediate (II) The preparation process is different from the compound patented. After the five-step method patents cited compounds. The entire route is longer, while using a large number of precious metal catalysts and reaction conditions need very strict control, inappropriate EVAL industry production.

PATENT

CN 102827079

A varenicline intermediate 2,3, 4, 5-tetrahydro-1,5-methylene bridge synthesis -1H-3- benzazepine hydrochloride, which comprises the following Step: (1) 2-indanone of formula 3 and the compound and paraformaldehyde under alkaline or acidic conditions Mannich reaction, as shown in general formula 2 intermediate; (2) the step (I) obtained through reaction of Formula 2 intermediate under basic or acidic conditions by reducing the role of the carbonyl group is reduced to a methylene group, and get varenicline intermediate (II) by debenzylation, the reaction is:

Wherein, R groups are selected from _H, _Me, _Et, _iPr> _t_Bu.

Figure 2;

Wherein, R group is -H, -Me, -Et, -iPr or -t_Bu.

(2) Step (I) obtained by the reaction intermediates of formula under basic or acidic conditions by reducing the role of the carbonyl group is reduced 2 methylene, and get by debenzylation cutting Lenk Lin intermediate (II);

CLIP

Varenicline, a nicotinic 􀀁4􀀂2 partial agonist, was approved in the US for the treatment of smoking cessation in May of 2006. It was developed and marketed by Pfizer as a treatment for cigarette smokers who want to quit. Varenicline partially activates the nicotinic receptors and thus reduces the craving for cigarette that smokers feel when they try to quit smoking. By mitigating this craving and antagonizing nicotine activity without other symptoms, this novel drug helps quitting this dangerous addiction easier on the patients [6,52]. Several modifications [54,55] to the original synthesis [53,56] have been reported in the literature, including an improved process scale synthesis of the last few steps (Scheme 15) [57]. The Grignard reaction was initiated on a small scale by addition of 2-bromo fluorobenzene 113 to a slurry of Magnesium turnings and catalytic 1,2-dibromoethane in THF and heating the mixture until refluxing in maintained. To this refluxing mixture was added a mixture of the 2-bromo fluorobenzene 113 and cyclopentadiene 114 over a period of 1.5 h. After complete addition, the reaction was allowed to reflux for additional 1.5 h to give the Diels- Alder product 115 in 64% yield. Dihydroxylation of the olefin 115 by reacting with catalytic osmium tetraoxide in the presence of N-methylmorpholine N-oxide (NMO) in acetone: water mixture at room temperature provided the diol 116 in 89% yield. Oxidative cleavage of diol 116 with sodium periodate in biphasic mixture of water: DCE at 10ºC provided di-aldehyde 117 which was immediately reacted with benzyl amine in the presence of sodium acetoxyborohydride to give benzyl amine 118 in 85.7% yield. The removal of the benzyl group was effected by hydrogenation of the HCl salt in 40-50 psi hydrogen pressure with 20% Pd(OH)2 in methanol to give amine hydrochloride 119 in 88% yield. Treatment of amine 119 with trifluoroacetic anhydride and pyridine in dichloromethane at 0ºC gave trifluoroacetamide 120 in 94% yield. Dinitro compound 121 was prepared by addition of trifluoroacetamide 120 to a mixture of trifluoromethane sulfonic acid and nitric acid, which was premixed, in dichloromethane at 0ºC. Reduction of the dinitro compound 121 by hydrogenation at 40-50 psi hydrogen in the presence of catalytic 5%Pd/C in isopropanol:water mixture provided the diamine intermediate 122 which was quickly reacted with glyoxal in water at room temperature for 18h to give compound 123 in 85% overall yield. The trifluoroacetamide 123 was then hydrolyzed with 2 M sodium hydroxide in toluene at 37-40ºC for 2-3h followed by preparation of tartrate salt in methanol to furnish varenicline tartrate (XV).

[52]Keating, G.; Siddiqui, M. A. A. CNSdrugs, 2006, 11, 946.
[53] Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Wirtz, M. C.; Arnold,E. P. ; Huang, J.; Sands, S. B.; Davis, T. I.; Lebel, L. A.; Fox, C.
B.; Shrikhande, A.; Heym, J. H.; Schaeffer, E.; Rollema, H.; Lu,Y.; Mansbach, R. S.; Chambers, L. K.; Rovetti, C. C.; Schulz, D.
W.; Tingley, III, F. D.; O’Neill, B. T. J. Med. Chem., 2005, 48,3474.
[54] Brooks, P. R.; Caron, S.; Coe, J. W.; Ng, K. K.; Singer, R. A.;Vazquez, E.; Vetelino, M. G.; Watson, Jr. H. H.; Whritenour, D.
C.; Wirtz, M. C. Synthesis, 2004, 11, 1755.
[55] Singer, R. A.; McKinley, J. D.; Barbe, G.; Farlow, R. A. Org. Lett.,2004, 6, 2357.
[56] Coe, J. W.; Brooks, P. R. P. US-6410550 B1, 2002.
[57] Busch, F. R.; Hawkins, J. M.; Mustakis, L. G.; Sinay, T. G., Jr.;Watson, T. J. N.; Withbroe, G. J. WO-2006090236 A1, 2006.

PATENT

WO 2002085843

https://google.com/patents/WO2002085843A2?cl=en

PATENT

https://www.google.com/patents/EP2204369A1?cl=en

Varenicline (a compound I of formula I) is the international commonly accepted non-proprietary name for 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (which is also known as 5,8,14-triazatetracyclo[10.3.1.0^2,11.0^4,9]-hexadeca-2(11),3,5,7,9-pentaene), and has an empirical formula of C₁₃H₁₃N₃ and a molecular weight of 211.26.

The L-tartrate salt of varenicline is known to be therapeutically useful and is commercially marketed for the treatment of smoking addiction. Varenicline L-tartrate is a partial agonist selective for α₄β₂ nicotinic acetylcholine receptor subtypes. In the United States, varenicline L-tartrate is marketed under the trade mark Chantix and is indicated as an aid to smoking cessation treatment.

Varenicline base and its pharmaceutically acceptable acid addition salts are described in U.S. Patent No. 6,410,550 . In particular, the preparation of varenicline provided in this reference makes use of 10-aza-tricyclo[6.3.1.0^2,7]-dodeca-2(7),3,5-triene (a compound of Formula VI), as a key intermediate compound (see Scheme 1 below). Specifically, Example 1 of U.S. Patent No. 6,410,550 describes the synthetic preparation of key intermediate compound of Formula VI as depicted in Scheme 1.

1,2,3,4-tetrahydro-1,4-methano-naphthalene-cis-2,3-diol (a compound of Formula III), and / or indane-1,3-dicarbaldehyde (a compound of Formula IV).

Example 1: Preparation of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-cis-2,3-diol (a compound of Formula III)

A 10mL round bottom flask was charged with a compound of formula II (142mg, 1mmol), N-methylmorpholine-N-oxide (120mg, 1.03mmol), tert-butanol (3mL) and water (1mL). FibreCat^™ 3003 (OsO₄ anchored onto a polymeric support) (11.6mg, 0.0025mmol) was added to this solution and the mixture was heated to reflux. Complete conversion to a compound of formula III was detected by GC, method A, after 48h.

Example 2: Preparation of 1,2,3,4-tetrahydro-1,4-methano-naphthalene-cis-2,3-diol (a compound of Formula III)Step A) Preparation of hexadecyl-trimethylammoniumpermanganate (HTAP):

HTAP was prepared from ion exchange reaction between hexadecyltrimethylammoniumbromide and potassium permanganate.

Potassium permanganate (17.38g, 0.11mol, 1equiv.) was dissolved in 500mL water. A solution of hexadecyltrimethylammoniumbromide (40.10g, 0.11mol, 1equiv) in 500mL water was added drop-wise over 45 min at 20-22°C, and the mixture stirred for 30 minutes at this temperature. The precipitated solid was collected by filtration, washed with water (3 x 100mL) and dried under vacuum at 35°C for 24 hours to give 34.38g of HTAP as a light purple solid.

Step B) Preparation of a compound of formula III:

Compound II (3.52g, 24.8mmol, 1equiv.) was dissolved in anhydrous tetrahydrofuran (80mL) and a solution of HTAP (10g, 24.8mmol, 1.0equiv.) in anhydrous tetrahydrofuran (125mL) was added drop-wise at 23-30°C over 45min. The reaction was monitored by TLC (hexane-ethyl acetate = 1:1). After complete reaction the mixture was cooled to below 10°C, and methyl tert-butyl ether (50mL) and 5% aqueous NaOH solution (50mL) were added and the mixture stirred for 30min. The solid was removed by filtration, and washed with methyl tert-butyl ether (2 x 30mL). The combined layers of the filtrate were separated and the aqueous phase extracted with methyl tert-butyl ether (2 x 30mL). The organic layers were combined and washed with 5% aqueous NaOH solution (50mL), water (2 x 50mL), dried over MgSO₄, filtered and concentrated to obtain a dark green solid. This residue was suspended in acetone (15mL) and collected by filtration, washing with additional acetone (3 x 5mL). The product was dried under vacuum at 40°C to give 2.215g (50.7% yield) as a white crystalline solid.

Analytical data: m.p. = 178.8-179.3°C; ¹H-NMR: See Figure 1; ¹³C-NMR: See Figure 2.

Example 3: Preparation of indane-1,3-dicarbaldehyde (a compound of Formula IV)

A 25 mL round bottom flask was charged with a compound of formula I (142mg, 1mmol), Ruthenium (III) chloride hydrate (Aldrich, Reagent Plus^™) (7.2mg, 0.035mmol), acetonitrile (8.5mL) and water (1.1mL). The solution was heated to 45°C and sodium periodate (449mg, 2.1mmol) was added portionwise over 25 minutes. After 1h, the reaction was cooled to ambient temperature and filtered. The solids were washed with ethyl acetate (3 x 2mL) and water (3mL). The filtrate was concentrated under vacuum and 5mL of water were added to the obtained residue. The mixture was extracted with ethyl acetate (2 x 5mL) and the combination of the organic layers was washed with water (3 x 5mL), dried with MgSO₄ and concentrated under vacuum to obtain a compound of formula IV (118mg) in 68% yield, 70.9% purity (analyzed by GC, method A).

PATENT

WO 199935131, WO 2002092089, US 2013030179

PATENT

https://www.google.com/patents/WO2009065872A2?cl=en

Example 1: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3] benzazepine L-tartrate (i.e. varenicline L-tartrate)

A) Preparation of compound of formula (III)

This example is based on U.S. Patent No. 6,410,550.

A 250 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O²‘⁷] dodeca-2, 4, 6- triene para-toluene sulfonic acid salt (12.4g, 37.5 mmol) and 44 mL of CH₂Cl₂. Triethylamine (8.3 g, 82.5 mmol) was added to the slurry and the resulting solution was cooled to 0-5 ⁰C. The addition funnel was charged with a solution of (CF₃CO)₂O (8.1q, 41.25 mmol) in 19 mL of CH₂Cl₂. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 ⁰C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 * 40 mL) and brine (40 mL) . The organic phase was used in the next step without further purification.

On the other hand, a 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF₃SO₃H (25.9 g, 172.5 mmol), CH₂Cl₂ (110 mL) and cooled to 0-5 ⁰C. At this temperature, fuming nitric acid (5.4 g, 86.25 mmol) was added slowly. To the resulting slurry at 0-5 ⁰C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 ⁰C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (60 mL) an ice (80 g) and stirred. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (3 x 50 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO₃, dried over Na₂SO₄ and volatiles evaporated under vacuum to obtain 11.9 g of a solid that was suspended and stirred for 2 hours in AcOEt (12 mL) and hexanes (24 mL) . The solid was filtered and washed with hexanes to obtain the compound of formula (III), 9.1g with a purity of 88.9% by GC (9.8% of meta-dimtrocompound impurity) .

B) Preparation of compound of formula (IV)

This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol), damp 5% Pd/C 50% and 180 mL of a 2- propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (40 mL) . To this solution, K₂HPO₄(458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop- wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 ⁰C to obtain the compound of formula (IV), 6.78 g.

C) Preparation of vareniclme L-tartrate (compound of formula (I) )

This example is based on International Patent No. WO/2006/090236.

A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with compound of formula (IV) (6.78 g, 22 mmol) and toluene

(47 mL) . To this solution was added a solution of NaOH (2.7 g, 68.2 mmol) in water (34 mL) . The mixture was heated to 40⁰C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (68 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (30 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (90 mL) and evaporated again. The final residue was dissolved in 156 mL of MeOH. 1.3 g of activated carbon “Darco G-60 100 mesh” were added and the mixture was stirred for 30 min and filtered through Celite to obtain an intense yellow solution. The process with activated carbon was repeated without any improvement in the colour. This solution was added drop-wise over a solution of L- tartaric acid (3.63 g, 24.2 mmol) in MeOH (47 mL) . The slurry was stirred for 72 hours at room temperature, filtered, washed with MeOH and dried in an oven at 50 ⁰C for 8 hours, to obtain 5.05 g of varenicline L-tartrate as a yellow solid with a 95.5% purity by HPLC (4.4% of unknown impurity A). Colour L: 92.75, a*: -7.19, b*:43.08.

Comparative Example 2: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazmo [2, 3-h] [3 ] benzazepine L-tartrate (i.e. varenicline L-tartrate) A) Preparation of compound of formula (IV)

This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) prepared according to Comparative Example 1.A) (4.1 g) , 123 mg of damp 5% Pd/C 50% and 81 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 24 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered through Celite and washed with 2-propanol (16 mL) . To this solution, K₂HPO₄ (207 mg, 1.19 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 1.84 g of 40% aqueous glyoxal diluted with water (6.6 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 30 mL and water (56 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water and dried in a oven at 50 ⁰C to obtain 3.15 g of compound of formula (IV) .

B) Preparation of vareniclme L-tartrate (compound of formula (I) )

This example is based on International application No. WO/2006/090236. A 100 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with

7, 8, 9, 10-tetrahydro-8- (tπfluoroacetyl) -6, 10-methano-6H- pyrazino [2 , 3-h] [3] benzazepine, i.e. compound of formula

(IV) (3.14 g, 10.2 mmol) and toluene (22 mL) . To this solution was added a solution of NaOH (1.3 g, 31.6 mmol) in water (16 mL) . The mixture was heated to 40 ⁰C and stirred for 2.5 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (30 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (15 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (45 mL) and evaporated again. The final residue was dissolved m 70 mL of MeOH. 314 mg of activated carbon “Darco G-60 100 mesh” were added and the mixture was stirred for 30 mm and filtered through Celite to obtain a yellow solution. This solution was added drop-wise over a solution of L- tartaπc acid (1.68 g, 11.22 mmol) m MeOH (22 mL) . The slurry was stirred for 1 hour at room temperature, filtered, washed with MeOH (2 x 5 mL) and dried under vacuum, to obtain vareniclme L-tartrate (2.48 g) as a yellow solid with a 95.6% purity by HPLC (4.4% of unknown impurity A). Colour L: 99.50, a*: -4.98, b*:43.02

Comparative Example 3: Preparation of 7,8,9,10- tetrahydro-6, 10-methano-6H-pyrazino [2, 3-h] [3 ] benzazepine L-tartrate (i.e. vareniclme L-tartrate)

This example is based on International application No. WO/2002/092089.

2 g of vareniclme L-tartrate as obtained from Comparative Example 1 were dissolved in 3 mL of water.

To this solution, 100 mL of CH₃CN were added, and the resulting slurry was stirred for 10 mm and filtered.

After drying the product was analysed to be a 98.2% purity by HPLC (1.7% of unknown impurity A) . Colour L: 91.44, a*: -3.24, b* : 33.47

Example 1: Preparation of 7, 8, 9, lO-tetrahydro-6, 10- methano-6H-pyrazmo [2, 3-h] [3] benzazepine L-tartrate

(i.e. vareniclme L-tartrate)

A) Preparation of compound of formula (III) This example is based on U.S. Patent No. 6,410,550, except for the purification step, which is the object of the present invention (i.e. crystallization in toluene) .

A 500 mL round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with 10-aza-tricyclo [ 6.3.1. O²‘⁷] dodeca-2, 4, 6- tπene para-toluene sulfonic acid salt (32.5g, 98.2 mmol) and 115 mL of CH₂Cl₂. Triethylamine (21.8 g, 216 mmol) was added to the slurry and the resulting solution was cooled to 0-5 ⁰C. The addition funnel was charged with a solution of (CF₃CO)₂O (22.7 g, 108 mmol) in 50 mL of CH₂Cl₂. This solution was slowly added to the reaction mixture, maintaining the temperature < 15 ⁰C. The resulting mixture was stirred for 1 hour, and the complete conversion was monitored by GC. The crude reaction mixture was washed with water (2 x 100 mL) and brine (100 mL) . The organic phase was used in the next step without further purification.

A l L round bottom flask with thermometer, condenser, addition funnel and magnetic stirring was charged with CF₃SO₃H (67.8 g, 452 mmol), CH₂Cl₂ (280 mL) and cooled to 0-5 ⁰C. At this temperature, fuming nitric acid (14.2 g, 226 mmol) was slowly added. To the resulting slurry at 0-5 ⁰C, the solution obtained in the previous step was slowly added, maintaining the temperature < 15 ⁰C. After the addition, the reaction mixture was stirred overnight. The complete dinitration was confirmed by GC. The crude reaction mixture was poured into water (150 mL) an ice (200 g) and stirred. The phases were separated and the aqueous phase was extracted with CH₂Cl₂ (100 mL) . The mixture of the organic phases was washed with aqueous saturated NaHCO₃ (2×100 mL) , water (100 mL) , dried over Na₂SO₄ and volatiles evaporated under vacuum to obtain 30.5 g of a solid with a 83.6% purity by GC (12.5% of meta- dinitrocompound impurity) . 20 g of this solid were crystallized in toluene (100 mL) to obtain the compound of formula (III), 15 g of a pale brown solid with a 98.5 % purity by GC (meta-dinitrocompound impurity not detected) .

B) Preparation of compound of formula (IV) This example is based on International Patent No. WO/2006/090236.

A 200 mL autoclave was charged with (III) (9.1 g, 26.3 mmol, crystals from toluene), damp 5% Pd/C 50% and 180 mL of a 2-propanol/water (80/20 wt/wt) . The reaction was stirred under 50 psi of hydrogen for 18 hours. The complete hydrogenation was confirmed by GC analysis. The reaction was filtered over Celite and washed with 2- propanol (40 mL) . To this solution, K₂HPO₄ (458 mg, 2.63 mmol) was added. The mixture was cooled at 0-5 ⁰C and a solution of 4.07 g of 40% aqueous glyoxal diluted with water (14.5 mL) was added slowly. The resulting solution was stirred 2 hours at this temperature and overnight at room temperature. The complete conversion was confirmed by GC analysis. The reaction was concentrated under vacuum to a volume of 68 mL and water (128 mL) was added drop-wise. The resulting suspension was stirred for 2 hours at room temperature, 1 hour in a ice/water bath, filtered, washed with water (20 mL) and dried m a oven at 50 ⁰C to obtain the product, 7.16 g of compound of formula (IV) with a 99.9% purity by HPLC. C) Preparation of varenicline L-tartrate (compound of formula ( I) )

Thrs example rs based on International Patent No. WO/2006/090236. A 250 mL round bottom flask with thermometer, condenser, and magnetic stirring was charged with a solution of NaOH (2.89 g, 72.23 mmol) in water (36 mL) , compound of formula (IV) (7.15 g, 23.3 mmol) and toluene (50 mL) . The mixture was heated to 40 ⁰C and stirred for 4 hours. The complete hydrolysis was confirmed by GC analysis. Toluene (71 mL) was added and the reaction was cooled. The phases were separated and the aqueous phase was extracted with toluene (36 mL) . The organic phases were evaporated under vacuum. The residue was dissolved in MeOH (110 mL) and evaporated again. The final residue was dissolved in 164 mL of MeOH. 750 mg of activated carbon “Darco G-60 100 mesh” were added and the mixture was stirred for 30 min and filtered through Celite to obtain a yellow solution. This solution was added drop- wise over a solution of L-tartaric acid (3.84 g, 25.6 mmol) in MeOH (50 mL) . The slurry was stirred for 14 hours at room temperature, filtered, washed with MeOH and dried under vacuum, to obtain varenicline L-tartrate

(7.04 g) as an off-white solid with a >99.9% purity by HPLC (unknown impurity A not detected) . Colour L: 94.39, a*: 2.27, b*:9.02.

Post-marketing surveillance

No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy has been found in one post-marketing surveillance study.^[23]

Mechanism of action

Varenicline displays full agonism on α₇ nicotinic acetylcholine receptors.^[24][25] And it is a partial agonist on the α₄β₂, α₃β₄, and α₆β₂ subtypes.^[26] In addition, it is a weak agonist on the α₃β₂ containing receptors.

Varenicline’s partial agonism on the α₄β₂ receptors rather than nicotine’s full agonism produces less effect of dopamine release than nicotine’s. This α₄β₂ competitive binding, reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system – similar to the method of action of buprenorphine in the treatment of opioid addiction.^[3]

Pharmacokinetics

Most of the active compound is excreted by the kidneys (92–93%). A small proportion is glucuronidated, oxidised, N-formylated or conjugated to a hexose.^[27] The elimination half-life is about 24 hours.

History

Use of Cytisus plant as a smoking substitute during World War II^[28] led to use as a cessation aid in eastern Europe and extraction of cytisine.^[29] Cytisine analogs led to varenicline at Pfizer.^[30][31][32]

Varenicline received a “priority review” by the US FDA in February 2006, shortening the usual 10-month review period to 6 months because of its demonstrated effectiveness inclinical trials and perceived lack of safety issues.^[33] The agency’s approval of the drug came on May 11, 2006.^[4] On August 1, 2006, varenicline was made available for sale in the United States and on September 29, 2006, was approved for sale in the European Union.^[34]

SEE

Varenicline standards and impurity controls. www.freepatentsonline.com/EP2004186.html.

Satheesh B, Kumarpulluru S, Raghavan V, Saravanan D. UHPLC Separation and Quantification of Related Substances of Varenicline Tartrate Tablet. Acta Chromatogr. 2010;22:207–218.http://dx.doi.org/10.1556/AChrom.22.2010.2.4.

References

External links

Manufacturer’s website USA

• Manufacturer’s website UK
• FDA Alert
• Package insert

Varenicline

Systematic (IUPAC) name
7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h] [3]benzazepine
Clinical data
Trade names	Chantix
AHFS/Drugs.com	Monograph
MedlinePlus	a606024
License data	EU EMA: Champix US FDA: Varenicline
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	<20%
Metabolism	Limited (<10%)
Biological half-life	24 hours
Excretion	Renal (81–92%)
Identifiers
CAS Number	249296-44-4  375815-87-5
ATC code	N07BA03 (WHO)
PubChem	CID 5310966
IUPHAR/BPS	5459
DrugBank	DB01273
ChemSpider	4470510
UNII	W6HS99O8ZO
KEGG	D08669
ChEBI	CHEBI:84500
ChEMBL	CHEMBL1076903
Chemical data
Formula	C13H13N3
Molar mass	211.267 g/mol

////////////Varenicline, Chantix™, FDA 2006, 249296-44-4, 375815-87-5,  Champix , Pfizer, バレニクリン酒石酸塩

n1c2cc3c(cc2ncc1)[C@@H]4CNC[C@H]3C4

as  CH3COOH salt

CD 101

Biafungin™; CD 101 IV; CD 101 Topical; CD101; SP 3025, Biafungin acetate

UNII-G013B5478J FRE FORM,

CAS 1396640-59-7 FREE FORM

MF, C63-H85-N8-O17, MW, 1226.4035

Biafungin acetate

CAS 1631754-41-0 ACETATE, Molecular Formula, C63-H85-N8-O17.C2-H3-O2, Molecular Weight, 1285.4472,

UNII: W1U1TMN677

CD101 – A novel echinocandin antifungal C. albicans (n=351) MIC90 = 0.06 µg/mL C. glabrata (n=200) MIC90 = 0.06 µg/mL  Echinocandins have potent fungicidal activity against Candida species

• Originator Seachaid Pharmaceuticals
• Developer Cidara Therapeutics
• Class Antifungals; Echinocandins; Small molecules
• Mechanism of Action Glucan synthase inhibitors

• Orphan Drug Status Yes – Candidiasis
• On Fast track Candidiasis; Vulvovaginal candidiasis
• Phase II Candidiasis; Vulvovaginal candidiasis

• Most Recent Events

  • 01 Jun 2016 Phase-II clinical trials in Vulvovaginal candidiasis in USA (Topical) (9197627; NCT02733432)
  • 31 May 2016 CD 101 receives Qualified Infectious Disease Product status for Vulvovaginal candidiasis in USA
  • 31 May 2016 CD 101 receives Fast Track designation for Vulvovaginal candidiasis [Topical] in USA
  Restricted Access
  POSTER……

  https://www.jmilabs.com/data/posters/ICAAC2014/M-1082.PDF

  http://www.cidara.com/wp-content/uploads/2014/12/A-694.-Biafungin-CD101-a-Novel-Echinocandin-Displays-a-Long-Half-life-in-the-Chimpanzee-Suggesting-a-Once-Weekly-IV-Dosing-Option.pdf

  CLIPPED IMAGE FROM FILE ABOVE

BIAFUNGIN, CD 101

Watch this space as I add more info…………….

U.S. – Fast Track (Treat candidemia);
U.S. – Fast Track (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat and prevent invasive fungal infections)

Fungal infections have emerged as major causes of human disease, especially among the immunocompromised patients and those hospitalized with serious underlying disease. As a consequence, the frequency of use of systemic antifungal agents has increased significantly and there is a growing concern about a shortage of effective antifungal agents. Although resistance rates to the clinically available antifungal agents remains low, reports of breakthrough infections and the increasing prevalence of uncommon fungal species that display elevated MIC values for existing agents is worrisome. Biafungin (CD101, previously SP 3025) is a novel echinocandin that displays chemical stability and long-acting pharmacokinetics that is being developed for once-weekly or other intermittent administration (see posters #A-693 and A- 694 for further information). In this study, we test biafungin and comparator agents against a collection of common Candida and Aspergillus species, including isolates resistant to azoles and echinocandins.

The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2 ) of the approved echinocandins.

Background  Vulvovaginal candidiasis (VVC) is a highly prevalent mucosal infection  VVC is caused by Candida albicans (~85%) and non-albicans (~15%)  5-8% of women have recurrent VVC (RVVC) which is associated with a negative impact on work/social life  Oral fluconazole prescribed despite relapse, potential DDIs and increased risk to pregnant women  No FDA-approved therapy for RVVC and no novel agent in >20 years

Cidara Therapeutics 6310 Nancy Ridge Drive, Suite 101 San Diego, CA 92121

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains ofCandida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.

Echinocandins are a new class of antifungal drugs^[1] that inhibit the synthesis of glucan in the cell wall, via noncompetitive inhibition of the enzyme 1,3-β glucan synthase^[2][3] and are thus called “penicillin of antifungals”^[4] (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi. Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is peptidoglycan). Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.^[5]

List of echinocandins:^[17]

• Pneumocandins (cyclic hexapeptides linked to a long-chain fatty acid)
• Echinocandin B not clinically used, risk of hemolysis
• Cilofungin withdrawn from trials due to solvent toxicity
• Caspofungin (trade name Cancidas, by Merck)
• Micafungin (FK463) (trade name Mycamine, by Astellas Pharma.)
• Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer)

History

or

 

Anidulafungin

Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were liposaccharide – i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase – and had action only on Candida spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against Candida spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

CIDARA THERAPEUTICS DOSES FIRST PATIENT IN PHASE 2 TRIAL OF CD101 TOPICAL TO TREAT VULVOVAGINAL CANDIDIASIS

SAN DIEGO–(BUSINESS WIRE)–Jun. 9, 2016– Cidara Therapeutics, Inc. (Nasdaq:CDTX), a biotechnology company developing novel anti-infectives and immunotherapies to treat fungal and other infections, today announced that the first patient has been dosed in RADIANT, a Phase 2 clinical trial comparing the safety and tolerability of the novel echinocandin, CD101, to standard-of-care fluconazole for the treatment of acute vulvovaginal candidiasis (VVC). RADIANT will evaluate two topical formulations of CD101, which is Cidara’s lead antifungal drug candidate.

“There have been no novel VVC therapies introduced for more than two decades, so advancing CD101 topical into Phase 2 is a critical step for women with VVC and for Cidara,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “Because of their excellent safety record and potency against Candida, echinocandin antifungals are recommended as first line therapy to fight systemic Candida infections. CD101 topical will be the first echinocandin tested clinically in VVC and we expect to demonstrate safe and improved eradication of Candida with rapid symptom relief for women seeking a better option over the existing azole class of antifungals.”

RADIANT is a Phase 2, multicenter, randomized, open-label, active-controlled, dose-ranging trial designed to evaluate the safety and tolerability of CD101 in women with moderate to severe episodes of VVC. The study will enroll up to 125 patients who will be randomized into three treatment cohorts. The first cohort will involve the treatment of 50 patients with CD101 Ointment while a second cohort of 50 patients will receive CD101 Gel. The third cohort will include 25 patients who will be treated with oral fluconazole.

The primary endpoints of RADIANT will be the safety and tolerability of a single dose of CD101 Ointment and multiple doses of CD101 Gel in patients with acute VVC. Secondary endpoints include therapeutic efficacy in acute VVC patients treated with CD101. Treatment evaluations and assessments will occur on trial days 7, 14 and 28.

The RADIANT trial will be conducted at clinical trial centers across the United States. More information about the trial is available at www.clinicaltrials.gov, identifier NCT02733432.

About VVC and RVVC

Seventy-five percent of women worldwide suffer from VVC in their lifetime, and four to five million women in the United Statesalone have the recurrent form of the infection, which is caused by Candida. Many women will experience recurrence after the completion of treatment with existing therapies. Most VVC occurs in women of childbearing potential (the infection is common in pregnant women), but it affects women of all ages. In a recent safety communication, the U.S. Food and Drug Administration(FDA) advised caution in the prescribing of oral fluconazole for yeast infections during pregnancy based on a published study concluding there is an increased risk of miscarriage. The Centers for Disease Control and Prevention (CDC) guidelines recommend using only topical antifungal products to treat pregnant women with vulvovaginal yeast infections. Vaginal infections are associated with a substantial negative impact on day-to-day functioning and adverse pregnancy outcomes including preterm delivery, low birth weight, and increased infant mortality in addition to predisposition to HIV/AIDS. According to the CDC, certain species of Candida are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents.

About CD101 Topical

CD101 topical is the first topical agent in the echinocandin class of antifungals and exhibits a broad spectrum of fungicidal activity against Candida species. In May 2016, the FDA granted Qualified Infectious Disease Product (QIDP) and Fast Track Designation to CD101 topical for the treatment of VVC and the prevention of RVVC.

About Cidara Therapeutics

Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment of diseases that are inadequately addressed by current standard-of-care therapies. Cidara’s initial product portfolio comprises two formulations of the company’s novel echinocandin, CD101. CD101 IV is being developed as a once-weekly, high-exposure therapy for the treatment and prevention of serious, invasive fungal infections. CD101 topical is being developed for the treatment of vulvovaginal candidiasis (VVC) and the prevention of recurrent VVC (RVVC), a prevalent mucosal infection. In addition, Cidara has developed a proprietary immunotherapy platform, Cloudbreak™, designed to create compounds that direct a patient’s immune cells to attack and eliminate pathogens that cause infectious disease. Cidara is headquartered inSan Diego, California. For more information, please visit www.cidara.com.

REF http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474

CLIP

CLIP

Biafungin is a potent and broad-spectrum antifungal agent with excellent activity against wild-type and troublesome azole- and echinocandin-resistant strains of Candida spp. The activity of biafungin is comparable to anidulafungin. • Biafungin was active against both wild-type and itraconazole-resistant strains of Aspergillus spp. from four different species. • In vitro susceptibility testing of biafungin against isolates of Candida and Aspergillus may be accomplished by either CLSI or EUCAST broth microdilution methods each providing comparable results. • The use of long-acting intravenous antifungal agents that could safely be given once a week to select patients is desirable and might decrease costs with long-term hospitalizations. Background: A novel echinocandin, biafungin, displaying long-acting pharmacokinetics and chemical stability is being developed for once-weekly administration. The activities of biafungin and comparator agents were tested against 173 fungal isolates of the most clinically common species. Methods: 106 CAN and 67 ASP were tested using CLSI and EUCAST reference broth microdilution methods against biafungin (50% inhibition) and comparators. Isolates included 27 echinocandin-resistant CAN (4 species) with identified fks hotspot (HS) mutations and 20 azole nonsusceptible ASP (4 species). Results: Against C. albicans, C. glabrata and C. tropicalis, the activity of biafungin (MIC50, 0.06, 0.12 and 0.03 μg/ml, respectively by CLSI method) was comparable to anidulafungin (AND; MIC50, 0.03, 0.12 and 0.03 μg/ml, respectively) and caspofungin (CSP; MIC50, 0.12, 0.25 and 0.12 μg/ml, respectively; Table). C. krusei strains were very susceptible to biafungin, showing MIC90 values of 0.06 μg/ml by both methods. Biafungin (MIC50/90, 1/2 μg/ml) was comparable to AND and less potent than CSP against C. parapsilosis using CLSI methodology. CLSI and EUCAST methods displayed similar results for most species, but biafungin (MIC50, 0.06 μg/ml) was eight-fold more active than CSP (MIC50, 0.5 μg/ml) against C. glabrata using the EUCAST method. Overall, biafungin was two- to four-fold more active against fks HS mutants than CSP and results were comparable to AND. Biafungin was active against A. fumigatus (MEC50/90, ≤0.008/0.015 μg/ml), A. terreus (MEC50/90, 0.015/0.015 μg/ml), A. niger (MEC50/90, ≤0.008/0.03 μg/ml) and A. flavus (MEC50/90, ≤0.008/≤0.008 μg/ml) using CLSI method. EUCAST results for ASP were also low for all echinocandins and comparable to CLSI results. Conclusions: Biafungin displayed comparable in vitro activity with other echinocandins against common wild-type CAN and ASP and resistant subsets that in combination with the long-acting profile warrants further development of this compound. 1. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW (2013). Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16: 81-95. 2. Castanheira M, Woosley LN, Messer SA, Diekema DJ, Jones RN, Pfaller MA (2014). Frequency of fks mutations among Candida glabrata isolates from a 10-year global collection of bloodstream infection isolates. Antimicrob Agents Chemother 58: 577-580. 3. Clinical and Laboratory Standards Institute (2008). M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: third edition. Wayne, PA: CLSI. 4. Clinical and Laboratory Standards Institute (2008). M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Second Edition. Wayne, PA: CLSI. 5. Clinical and Laboratory Standards Institute (2012). M27-S4. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4th Informational Supplement. Wayne, PA: CLSI. 6. European Committee on Antimicrobial Susceptibility Testing (2014). Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed January 1, 2014. 7. Pfaller MA, Diekema DJ (2010). Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1-53. 8. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011). Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. ABSTRACT Activity of a Novel Echinocandin Biafungin (CD101) Tested against Most Common Candida and Aspergillus Species, Including Echinocandin- and Azole-resistant Strains M CASTANHEIRA, SA MESSER, PR RHOMBERG, RN JONES, MA PFALLER JMI Laboratories, North Liberty, Iowa, USA C

REFERENCES

1. Denning, DW (June 2002). “Echinocandins: a new class of antifungal.”. The Journal of antimicrobial chemotherapy 49 (6): 889–91. doi:10.1093/jac/dkf045. PMID 12039879.
2.  Morris MI, Villmann M (September 2006). “Echinocandins in the management of invasive fungal infections, part 1”. Am J Health Syst Pharm 63 (18): 1693–703.doi:10.2146/ajhp050464.p1. PMID 16960253.
3. Morris MI, Villmann M (October 2006). “Echinocandins in the management of invasive fungal infections, Part 2”. Am J Health Syst Pharm 63 (19): 1813–20.doi:10.2146/ajhp050464.p2. PMID 16990627.
4. ^ Jump up to:^{a b} “Pharmacotherapy Update – New Antifungal Agents: Additions to the Existing Armamentarium (Part 1)”.
5.  Debono, M; Gordee, RS (1994). “Antibiotics that inhibit fungal cell wall development”.Annu Rev Microbiol 48: 471–497. doi:10.1146/annurev.mi.48.100194.002351.

17 Eschenauer, G; Depestel, DD; Carver, PL (March 2007). “Comparison of echinocandin antifungals.”. Therapeutics and clinical risk management 3 (1): 71–97. PMC 1936290.PMID 18360617.

///////////Biafungin™,  CD 101 IV,  CD 101 Topical,  CD101,  SP 3025, PHASE 2, CIDARA, Orphan Drug, Fast Track Designation, Seachaid Pharmaceuticals,  Qualified Infectious Disease Product, QIDP, UNII-G013B5478J, 1396640-59-7, 1631754-41-0, Vulvovaginal candidiasis,

FREE FORM

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)C(NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C

AND OF ACETATE

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C.CC(=O)[O-]

OR

Anidulafungin

V-Echinocandin

N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0^9,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide

• LY-307853
• LY-329960
• LY-333006
• LY303366
• VEC
• VER-002

¹H NMR (700 MHz, d₆-DMSO) δ 0.91 (t, 3H), 1.12 (d, 3H), 1.36 (m, 2H), 1.41 (m, 2H), 1.74 (p, 2H), 1.88 and 1.97 (overlapped, 2H), 3.85 (overlapped, 1H), 4.01 (t, 2H), 4.35 (overlapped, 1H), 4.44 (m, 1H), 4.76 (m, 1H), 4.80 (m, 1H), 5.02 (m, 1H), 5.07 (d, 1H), 5.52 (d, 1H), 7.04 (d, 1H), 7.66 (d, 1H), 7.74 (d, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.14 (broad s, 1H), 8.60 (d, 1H). IR (cm⁻¹)

KBr ν_max; 3450 (O−H), 2932 (C−H), 2871 (C−H), 1632 (C═O), 1517 (Ar), 1488 (Ar), 1248 (C−O), 821 (C−H out-of-plane bending Ar 2 adj H’s).

Anidulafungin (brand names: Eraxis (in U.S. and Russia), Ecalta (in Europe)) is a semisynthetic echinocandin used as anantifungal drug. Anidulafungin was originally manufactured and submitted for FDA approval by Vicuron Pharmaceuticals.^[1] Pfizeracquired the drug upon its acquisition of Vicuron in the fall of 2005.^[2] Pfizer gained approval by the Food and Drug Administration(FDA) on February 21, 2006;^[3] it was previously known as LY303366. Preliminary evidence indicates it has a similar safety profile tocaspofungin. Anidulafungin has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive Candidainfection;^[4][5][6] it may also have application in treating invasive Aspergillus infection. It is a member of the class of antifungal drugs known as the echinocandins; its mechanism of action is by inhibition of (1→3)-β-D-glucan synthase, an enzyme important to the synthesis of the fungal cell wall.

Pharmacodynamics and pharmacokinetics

Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body pH and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.^[7]

Distribution: 30–50 L. Protein binding: 84%.

Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. Thirty percent is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.^[8][9][10]

Mechanism of action

Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-D-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.^[11]

Semisynthesis

Anidulafungin is manufactured via semisynthesis. The starting material is echinocandin B (a lipopeptide fermentation product ofAspergillus nidulans or the closely related species, A. rugulosus), which undergoes deacylation (cleavage of the linoleoyl side chain) by the action of a deacylase enzyme from the bacterium Actinoplanes utahensis;^[12] in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin^[11][13] is synthesized.

Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-β-D-glucan, an essential component of fungal cell walls.

ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-dihydroxy-N -[[4“-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:

50 mg/vial – fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

100 mg/vial – fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.

The empirical formula of anidulafungin is C₅₈H₇₃N₇O₁₇ and the formula weight is 1140.3. The structural formula is

Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% DextroseInjection, USP or 0.9% Sodium Chloride Injection, USP (normal saline).

SYNTHESIS

J MED CHEM 1995, 38 3271-3281

Semisynthetic Chemical Modification of the Antifungal Lipopeptide …

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide “nucleus” as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.

PATENT

US 5965525

http://www.google.co.in/patents/US5965525

PATENT

US 4293482

http://www.google.co.in/patents/US4293482

Paper

Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/d-Fructose (Eraxis)

Many years ago anidulafungin 1 was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and d-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN·HCl) and the active ester 1-({[4′′-(pentyloxy)-1,1′:4′,1′′-terphenyl-4-yl]carbonyl}oxy)-1H-1,2,3-benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.

References

Anidulafungin

Systematic (IUPAC) name
N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S,2R)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-bis[(1R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide
Clinical data
Trade names	Eraxis
AHFS/Drugs.com	Monograph
Pharmacokinetic data
Protein binding	84 %
Biological half-life	40–50 hours
Identifiers
CAS Number	166663-25-8
ATC code	J02AX06 (WHO)
PubChem	CID 166548
DrugBank	DB00362
ChemSpider	21106258
UNII	9HLM53094I
KEGG	D03211
ChEBI	CHEBI:55346
ChEMBL	CHEMBL1630215
Chemical data
Formula	C58H73N7O17
Molar mass	1140.24 g/mol

//////////FUNGIN, ANIDULAFUNGIN, Eraxis , Ecalta,  semisynthetic echinocandin, anantifungal drug, FDA 2006, PFIZER, LY-307853, LY-329960, LY-333006, LY303366, VEC, VER-002, 166663-25-8, Eli Lilly and Company Inc.

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]6C[C@@H](O)[C@@H](O)NC(=O)C4[C@@H](O)[C@@H](C)CN4C(=O)C(NC(=O)C(NC(=O)C5C[C@@H](O)CN5C(=O)C(NC6=O)[C@@H](C)O)[C@@H](O)[C@H](O)c7ccc(O)cc7)[C@@H](C)O

Supporting Info

GSK-2041706A

[2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine]

2-[((1S)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

Potent GPR119 Receptor Agonists

CAS 1032824-43-3

G protein-coupled receptor 119 (GPR119) is a G protein-coupled receptor expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment of type 2 diabetes, with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706 [2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine], a GPR119 agonist, and metformin as monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30 mg/kg b.i.d.) or metformin at 30 and 100 mg/kg b.i.d. alone caused a 7.4%, 3.5%, and 4.4% (all P < 0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30 or 100 mg/kg resulted in a 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100 mg/kg caused a significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100 mg/kg, respectively. The combination of GSK2041706 with metformin caused greater reductions in cumulative food intake (22.2% at 30 mg/kg and 37.5% at 100 mg/kg) and higher fed plasma glucagon-like peptide 1 and peptide tyrosine tyrosine levels and decreased plasma insulin and glucose-dependent insulinotropic polypeptide levels compared with their monotherapy groups. In addition, we characterized the effect of GSK2041706 and metformin as monotherapy or in combination on neuronal activation in the appetite regulating centers in fasted DIO mice. In conclusion, our data demonstrate the beneficial effects of combining a GPR119 agonist with metformin in the regulation of body weight in DIO mice.

Diabetes mellitus is an ever-increasing threat to human health. For example, in the United States current estimates maintain that about 16 million people suffer from diabetes mellitus.

Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic β-cells, and necessitates regular administration of exogenous insulin. Without insulin, cells cannot absorb sugar (glucose), which they need to produce energy. Symptoms of Type I diabetes usually start in childhood or young adulthood. People often seek medical help because they are seriously ill from sudden symptoms of high blood sugar (hyperglycemia).

Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. Type II diabetes may be characterized by a defect in insulin secretion or by insulin resistance, namely those that suffer from Type II diabetes have too little insulin or cannot use insulin effectively. Insulin resistance refers to the inability of body tissues to respond properly to endogenous insulin. Insulin resistance develops because of multiple factors, including genetics, obesity, increasing age, and having high blood sugar over long periods of time. Type II diabetes, sometimes called mature or adult onset diabetes, can develop at any age, but most commonly becomes apparent during adulthood. The incidence of Type II diabetes in children, however, is rising

In diabetics, glucose levels build up in the blood and urine causing excessive urination, thirst, hunger, and problems with fat and protein metabolism. If left untreated, diabetes mellitus may cause life-threatening complications, including blindness, kidney failure, and heart disease.

Type II diabetes accounts for approximately 90-95% of diabetes cases, killing about 193,000 U.S. residents each year. Type II diabetes is the seventh leading cause of all deaths. In Western societies, Type II diabetes currently affects 6% of the adult population with world-wide frequency expected to grow by 6% per annum.

Although there are certain inheritable traits that may predispose particular individuals to developing Type II diabetes, the driving force behind the current increase in incidence of the disease is the increased sedentary lifestyle, diet, and obesity now prevalent in developed countries. About 80% of diabetics with Type II diabetes are significantly overweight. As noted above, an increasing number of young people are developing the disease. Type II diabetes is now internationally recognized as one of the major threats to human health in the 21^stcentury.

Type II diabetes currently is treated at several levels. A first level of therapy is through the use of diet and/or exercise, either alone or in combination with therapeutic agents. Such agents may include insulin or pharmaceuticals that lower blood glucose levels. About 49% of individuals with Type II diabetes require oral medication(s), about 40% of individuals require insulin injections or a combination of insulin injections and oral medication(s), and about 10% of individuals may use diet and exercise alone.

Current therapies for diabetes mellitus include: insulin; insulin secretagogues, such as sulphonylureas, which increase insulin production from pancreatic-cells; glucose-lowering effectors, such as metformin which reduce glucose production from the liver; activators of the peroxisome proliferator-activated receptor—(PPAR-), such as the thiazolidinediones, which enhances insulin action; and α-glucosidase inhibitors which interfere with gut glucose production. There are, however, deficiencies associated with currently available treatments, including hypoglycemic episodes, weight gain, loss in responsiveness to therapy over time, gastrointestinal problems, and edema.

There are several areas at which research is being targeted in order to bring new, more effective, therapies to the marketplace. For example, on-going research includes exploring a reduction in excessive hepatic glucose production, enhancing the pathway by which insulin transmits its signal to the cells such that they take up glucose, enhancing glucose-stimulated insulin secretion from the pancreatic-cells, and targeting obesity and associated problems with fat metabolism and accumulation.

One particular target is GPR119. GPR119 is a member of the rhodopsin family of G-protein-coupled receptors. In addition to the “GPR119” identifier, several other identifiers exist, including but not limited to RUP 3, Snorf 25, 19 AJ, GPR 116 (believed to be erroneous), AXOR 20, and PS1. GPR119 is expressed in human gastrointestinal regions and in human islets. Activation of GPR119 has been demonstrated to stimulate intracellular cAMP and lead to glucose-dependent GLP-1 and insulin secretion. See, T. Soga et al., Biochemical and Biophysical Research Communications 326 (2005) 744-751, herein incorporated by reference with regard to a background understanding of GPR119.

In type 2 diabetes the action of GLP-1 on the β-cell is maintained, although GLP-1 secretion, itself, is reduced. More recently, therefore, much research has been focused on GLP-1. Studies show glucose-lowering effects in addition to GLP-1’s ability to stimulate glucose-dependent insulin secretion including, but not limited to, an inhibition of the release of the hormone glucagon following meals, a reduction in the rate at which nutrients are absorbed into the bloodstream, and a reduction of food intake. Studies demonstrate that treatments to increase GLP-1, therefore, may be used for a variety of conditions and disorders including but not limited to metabolic disorders, gastrointestinal disorders, inflammatory diseases, psychosomatic, depressive, and neuropsychiatric disease including but not limited to diabetes mellitus (Type 1 and Type 2), metabolic syndrome, obesity, appetite control and satiety, weight loss, stress, inflammation, myocardial ischemia/reperfusion injury, Alzheimer’s Disease, and other diseases of the central nervous system.

The use of exogenous GLP-1 in clinical treatment is severely limited, however, due to its rapid degradation by the protease DPP-IV. There are multiple GLP-1 mimetics in development for type 2 diabetes that are reported in the literature, all are modified peptides, which display longer half-lives than endogenous GLP-1. For example, the product sold under the tradename BYETTA® is the first FDA-approved agent of this new class of medications. These mimetics, however, require injection. An oral medication that is able to elevate GLP-1 secretion is desirable. Orally available inhibitors of DPP-IV, which result in elevation in intact GLP-1, are now available, such as sitagliptin, marketed under the brand name JANUVIA®. Nevertheless, a molecule which may stimulate GLP-1 secretion would provide a therapeutic benefit. A molecule which could stimulate both GLP-1 secretion and insulin secretion through effects on the L-cell and direct effects on the β-cell would hold much promise for type 2 diabetes therapy.

The present invention identifies agonists of GPR119 which increase glucose-disposal in part through elevation of GIP, GLP-1, and insulin. Moreover, studies demonstrate that GPR119 agonists such as the compounds of the present invention can stimulate incretins independently of glucose. GIP and GLP-1 are peptides, known as incretins, secreted from enteroendocrine K and L cells, respectively, in response to ingestion of nutrients, and have a wide variety of physiological effects that have been described in numerous publications over the past two decades. See, for example, Bojanowska, E. et al.,Med. Sci. Monit., 2005, August 11(8): RA271-8; Perry, T. et al., Curr. Alzheimer Res., 2005, July 2(3): 377-85; and Meier, J. J. et al.,Diabetes Metab. Res. Rev., 2005, March-April; 21(2); 91-117 (each herein incorporated by reference with regard to a background understanding of incretins). Moreover, although the mechanisms regulating GLP-1 secretion remain unclear, the initial rapid rise in GLP-1 following a meal may be a result of hormonal stimulation of neuronal afferents involving GIP. See, for example, J. N. Roberge and P. L. Brubaker, Endocrinology 133 (1993), pp. 233-240 (herein incorporated by reference with regard to such teaching). Furthermore, later increases in GLP-1 may involve direct activation of L-cells by nutrients in the distal small-intestine and the colon. GIP and GLP-1 are potent stimulators of the body’s ability to produce insulin in response to elevated levels of blood sugar. In Type 2 diabetes, patients display a decreased responsiveness to GIP but not GLP-1, with respect to its ability to stimulate insulin secretion. The mechanism behind the decreased responsiveness to GIP remains unclear since type 2 diabetics retain sensitivity to a bolus administration of GIP but not to a continuous infusion (Meier et al. 2004 Diabetes 53 S220-S224). Moreover recent studies with a long-acting fatty-acid derivative of GIP showed beneficial effects on glucose homeostasis in ob/ob mice following 14 days of treatment (Irwin N. et al. (2006) J. Med. Chem. 49, 1047-1054.)

Agonists to GPR119 may be of therapeutic value for diabetes and associated conditions, particularly type II diabetes, obesity, glucose intolerance, insulin resistance, metabolic syndrome X, hyperlipidemia, hypercholesterolemia, and atherosclerosis.

NMR

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (bs, 1H), 8.40 (bs, 1 H), 8.28 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 8.5 Hz, 2H), 5.17–5.09 (m, 1H), 4.09–3.95 (m, 2H), 3.27 (s, 3H), 3.16–2.99 (m, 2H), 2.80 (q, J = 6.9 Hz, 1H), 1.98–1.85 (m, 2H), 1.83–1.70 (m, 1H), 1.47–1.33 (m, 2H), 1.31 (d, J = 6.3 Hz, 3H), 1.17 (d, J = 6.8 Hz, 6H).

¹³C NMR (100.6 MHz, DMSO-d₆) 175.3, 170.9, 159.8, 142.6, 141.2, 141.0, 139.1, 135.7, 128.1, 126.9, 75.7, 46.0, 45.9, 44.0, 40.2, 27.1, 27.0, 26.7, 20.7, 16.9.

HRMS calcd for C₂₃H₃₀N₅O₄S (M + H)⁺ 472.2013, found, 472.2009.

PATENT

Jing Fang, Jun Tang, Andrew J. Carpenter,Gregory Peckham, Christopher R. Conlee,Kien S. Du, Subba Reddy Katamreddy,

http://www.google.co.ug/patents/US20120077812

Example 156(±)-2-[(1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

Step 1: A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (prepared as in Example 158, Alternative synthesis, Step 3, 179 g, 0.78 mol) in MeOH (300 mL) was treated with 4-piperidinemethanol (108 g, 0.94 mol) and stirred and heated at 50° C. overnight. The solvent was removed and the residue was purified by flash chromatography on a silica gel column to give {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (60 g, 34%) as a pale yellow oil.

Step 2: A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (1.50 g, 6.66 mmol) in CH₂Cl₂ (50 mL) at 0° C. was treated with Dess-Martin periodinane (2.91 g, 6.66 mmol). The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction was quenched with aqueous 20% Na₂S₂O₃(100 mL) and aqueous saturated NaHCO₃ (100 mL) and then stirred for 10 minutes. The CH₂Cl₂ layer was separated and washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated to give the crude product as a cloudy colorless oil. The crude product was dissolved in 100 mL of 1:1 EtOAc/hexanes, filtered through a pad of silica gel, washed with 200 mL of 1:1 EtOAc/hexanes. The filtrate was concentrated to give 1.07 g (72%) of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde as a clear colorless oil, which was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 9.68 (s, 1H), 4.15-4.00 (m, 2H), 3.30-3.20 (m, 2H), 2.86 (septet, 1H, J=7.0 Hz), 2.55-2.45 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 2H), 1.26 (d, 6H, J=6.8 Hz).

Step 3: (±)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 49%) was prepared as a light brown oil from 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde (1.07 g, 4.79 mmol) and methylmagnesium bromide (3M in Et₂O, 3.51 mL, 10.54 mmol) then methanesulfonyl chloride (0.22 mL, 2.81 mmol) and Et₃N (0.66 mL, 4.68 mmol) in a manner similar to Example 139, Steps 1-2. The crude product was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 4.70-4.60 (m, 1H), 4.30-4.15 (m, 2H), 3.10-2.95 (m, 5H), 2.87 (septet, 1H, J=7.0 Hz), 1.95-1.70 (m, 3H), 1.55-1.35 (m, 5H), 1.26 (d, 6H, J=6.8 Hz).

Step 4: The title compound (0.212 g, 26%) was prepared as a white foam from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 0.43 g, 1.72 mmol), (±)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (0.74 g, 2.32 mmol) and K₂CO₃ (0.48 g, 3.44 mmol) in DMF (15 mL) in a manner similar to Example 152, Steps 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 25% EtOAc/CH₂Cl₂, followed by chromatography on a silica gel column eluted with 50% EtOAc/hexanes to give (±)-2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethypoxy]-5-[4-(methylsulfonyl)phenyl]pyrazine as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 8.25 (s, 1H), 8.10 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.1 Hz), 1.28 (d, 6H, J=7.1 Hz); LRMS (ESI), m/z 472 (M+H).

Example 1572-[((1R)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazin

The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO₂: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 23.42 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.

Example 158

2-[((1S)-1-{1-[3-(1-Methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine

The racemic 2-[(1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (prepared as in Example 156) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 70% CO₂: 30% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as an off-white solid with Tr of 25.83 min (second eluting peak). The (S) absolute stereochemistry was assigned by Ab initio VCD analysis. Alternative preparation from enantiomerically enriched material:

Step 1: Triethylamine (315 mL, 2.26 mol) was added dropwise to formic acid (150 mL, 3.91 mol) with overhead stirring while maintaining the internal temperature below 60° C. with ice-bath cooling. Neat 4-acetylpyridine (100 mL, 0.904 mol) was then added rapidly while maintaining the temperature below 50° C. Following this addition, the reaction was allowed to cool to 28° C. and the chiral ruthenium catalyst [N-[(1R,2R)-2-(amino-N)-1,2-diphenylethyl]-2,4,6-trimethylbenzenesulfonamidato-N]chloro[(1,2,3,4,5,6-n)-1-methyl-4-(1-methylethyl)benzene]ruthenium (CAS#177552-91-9; for catalyst preparation, see: Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R.; J. Am. Chem. Soc. 1996, 118, 4916-4917) (3 g, 4.46 mmol) was added. The mixture was stirred under house vacuum for 4 h and then overnight under an atmosphere of nitrogen. The reaction mixture was added dropwise to a stirred solution of 10% Na₂CO₃ (4 L) and then extracted with EtOAc (3×1 L). The combined EtOAc layers were washed once with brine (1 L), treated with MgSO₄ and Darco G-60 decolorizing charcoal and filtered through a 100 g plug of silica gel washing with 10% MeOH/EtOAc (1 L). The filtrate was concentrated to provide a dark oil that crystallized upon standing. The solid was dissolved in warm t-butyl methyl ether (250 mL) and the warm solution was filtered to remove a small amount of insoluble material. The filtrate was allowed to stir with cooling to room temperature and then to −15° C. The solids were collected by filtration, washing with cold t-butyl methyl ether and heptane, and then dried under high vacuum to yield (1R)-1-(4-pyridinyl)ethanol as a dark beige solid (62 g, 52.9% yield). This solid material was 96% ee based on chiral HPLC(HPLC conditions: AS-H column, 5% MeOH/CO₂, 40° C., 140 bar, 2 mL/min). The filtrate was combined with the insoluble solid from the crystallization and concentrated in vacuo to yield additional (1R)-1-(4-pyridinyl)ethanol as a dark oil (37.5 g, 32% yield). This oily material was 78% ee based on chiral HPLC (see HPLC conditions above). ¹H NMR (400 MHz, DMSO-d₆): δ 8.47-8.43 (m, 2H), 7.32-7.28 (m, 2H), 5.37 (d, 1H, J=4.4 Hz), 4.72-4.64 (m, 1H), 1.44 (d, 3H, J=6.6 Hz).

Step 2: A solution of (1R)-1-(4-pyridinyl)ethanol (37 g, 0.3 mol, 78% ee) in MeOH (2 L) was charged with PtO₂ (5 g) under nitrogen atmosphere followed by acetic acid (19 mL). The mixture was evacuated and purged with hydrogen several times and then stirred under an atmosphere of hydrogen for 2 d at room temperature. The mixture was filtered to remove catalyst and the filtrate was concentrated in vacuo and triturated with EtOAc to yield a cream-colored solid which was collected by filtration. The filter cake was dissolved in MeOH (500 mL) and 50% NaOH (15.8 g) was added. The resulting solution was stirred at 25° C. for 30 min and concentrated. The resulting solid was triturated with Et₂O (700 mL) and stirred at 25° C. for 30 min, the solids were removed by filtration and the filtrate was dried over MgSO₄ and filtered again. The final filtrate was concentrated to yield (1R)-1-(4-piperidinyl)ethanol (22 g, 57% yield) as a light beige solid. ¹H NMR (400 MHz, CDCl₃): δ 3.50 (quint, 1H, J=6.3 Hz), 3.13-3.01 (m, 2H), 2.61-2.47 (m, 2H), 1.88 (br, 2H), 1.84-1.73 (m, 1H), 1.63-1.52 (m, 1H), 1.41-1.27 (m, 1H), 1.23-1.05 (m, 2H), 1.13 (d, 3H, J=6.2 Hz).

Step 3: A stirred solution of N-hydroxy-2-methylpropanimidamide (16.33 g, 160 mmol) in pyridine (16.81 mL, 208 mmol) and dichloromethane (165 mL) at −15° C. was treated with trichloroacetyl chloride (19.63 mL, 176 mmol) over 40 min. The reaction was allowed to warm to ambient temperature and stirred for 42 h. Water (100 mL) was added and the reaction was stirred for 30 min. The dichloromethane was removed and the residue was diluted with water (50 mL) and extracted with ether (300 mL). The ether layer was washed with water, dried over MgSO₄ and concentrated to afford 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (28.0 g, 76% yield) as an orange liquid.¹H NMR (400 MHz, CDCl₃): δ 3.13 (septet, 1H, J=7.0 Hz), 1.36 (d, 6H, J=7.0 Hz).

Step 4: A solution of 3-(1-methylethyl)-5-(trichloromethyl)-1,2,4-oxadiazole (25.8 g, 112 mmol) and (1R)-1-(4-piperidinyl)ethanol (13.4 g, 104 mmol) in MeOH (15 mL) was stirred at ambient temperature under a stream of nitrogen for 7 days. The reaction was diluted with MeOH (40 mL), cooled in an ice bath and 1N NaOH (25 mL) was added. The mixture was allowed to warm to ambient temperature and stir for 1 h. The reaction was partitioned in EtOAc (300 mL)/1N NaOH (75 mL) and the layers were separated. The aqueous layer was saturated with NaCl and extracted with EtOAc (200 mL). The combined EtOAc layers were dried over MgSO₄, concentrated and placed under high vacuum for 18 h to afford (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (16.75 g, 68%) as an orange oil. ¹H NMR (400 MHz, CDCl₃): δ 4.14 (m, 2H), 3.57 (quint, 1H, J=6.3 Hz), 2.98 (m, 2H), 2.83 (septet, 1H, J=7.0 Hz), 1.90 (m, 1H), 1.86 (br, 1H), 1.67 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.23 (d, 6H, J=7.0 Hz), 1.16 (d, 3H, J=6.3 Hz); LRMS (ESI), m/z 240 (M+H).

Step 5: A solution of (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethanol (1.68 g, 7.0 mmol) in dichloromethane (100 mL) at 0° C. was treated with Et₃N (1.98 mL, 14.0 mmol) followed by methanesulfonyl chloride (0.66 mL, 8.4 mmol). The mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with 1M NaH₂PO₄ (75 mL×2) and brine, and dried over Na₂SO₄ and concentrated to give (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 100% yield) as a brown oil, which was used without further purification.

Step 6: A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Step 2, 1.3 g, 5.19 mmol), (1R)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl methanesulfonate (2.23 g, 7.0 mmol, 70% ee) and K₂CO₃ (1.45 g, 10.4 mmol) in DMF (35 mL) was stirred at 100° C. in a preheated oil bath overnight. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (75 mL×2). The combined organic extracts were washed with water, brine and dried over Na₂SO₄, filtered, and the filtrate was concentrated to a brown oil, which was by chromatography on a silica gel column eluted with 50% EtOAc/hexanes followed by chromatography on an ISCO silica gel column using 0 to 60% EtOAc/hexanes to give 2-[((1S)-1-{1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}ethyl)oxy]-5-[4-(methylsulfonyl)phenyl]pyrazine (0.73 g, 70% ee, 30%) as a white solid. The solid was subjected to chiral separation (similar to conditions used above for Example 158) to yield 0.30 g of the title compound as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (d, 1H, J=1.3 Hz), 8.25 (d, 1H, J=1.3 Hz), 8.10 (d, 2H, J=8.3 Hz), 8.02 (d, 2H, J=8.5 Hz), 5.20-5.10 (m, 1H), 4.35-4.20 (m, 2H), 3.15-3.00 (m, 5H), 2.90 (septet, 1H, J=7.0 Hz), 2.00-1.80 (m, 3H), 1.60-1.40 (m, 2H), 1.34 (d, 3H, J=6.3 Hz), 1.28 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 472 (M+H).

Paper

Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

Richard T. Matsuoka^*†, Eric E. Boros#, Andrew D. Brown†, Kae M. Bullock†, Will L. Canoy‡, Andrew J. Carpenter#, Jeremy D. Cobb†, Shannon E. Condon†, Nicole M. Deschamps†, Vassil I. Elitzin†, Greg Erickson†,Jing M. Fang#, David H. Igo§, Biren K. Joshi‡, Istvan W. Kaldor#, Mark B. Mitchell†, Gregory E. Peckham#, Daniel W. Reynolds‡, Matthew C. Salmon†, Matthew J. Sharp†, Elie A. Tabet#, Jennifer F. Toczko†, Lianming Michael Wu‡, and Xiao-ming M. Zhou†

Abstract

Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an S_NAr synthetic strategy.

/////////////GSK2041706A, GSK 2041706A, GSK-2041706A, GSK2041706, GSK 2041706, GSK-2041706

• Supporting Info

O=S(c4ccc(c3cnc(OC(C2CCN(c1nc(C(C)C)no1)CC2)C)cn3)cc4)(C)=O

Gemfibrozil

5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic Acid

IR (KBr, cm^–1): 2959.03, 2919.78, 2877.65, 1709.42, 1613.44, 1586.60, 1511.07, 1473.81, 1414.01, 1387.89, 1317.61, 1286.34, 1271.91, 1214.39, 1159.26, 1048.83, 996.57, 803.75;

¹H NMR (DMSO, 500 MHz, δ ppm): 1.12 (s, 6H), 1.60 and 1.67 (m, 4H), 2.08 (s, 3H), 2.24 (s, 3H), 3.90 (t, 2H), 6.62 (d, 1H), 6.70 (s, 1H), 6.97 (d, 1H);

¹³C NMR and DEPT (DMSO, 500 MHz, δ ppm): 15.39 (CH₃), 20.94 (CH₃), 24.67 (CH₂), 24.87 (CH_3, CH₃), 36.43 (CH₂), 40.91 (C), 67.57 (CH₂), 112.07 (CH), 120.45 (CH), 122.44 (C), 129.96 (CH), 135.93 (C), 156.43 (C), 178.56 (C);

MS M/_Z (ESI): 251.16 [(MH)⁺].

Solvent:CDCl3Instrument Type:JEOLNucleus:1HFrequency:400 MHzChemical Shift Reference:TMS

¹H NMR spectrum of C₁₅H₂₂O₃ in CDCL3 at 400 MHz

Gemfibrozil is the generic name for an oral drug used to lower lipid levels. It belongs to a group of drugs known as fibrates. It is most commonly sold as the brand name, Lopid. Other brand names include Jezil and Gen-Fibro.

Gemfibrozil was selected from a series of related compounds synthesized in the laboratories of the American company Parke Davisin the late 1970s. It came from research for compounds that lower plasma lipid levels in humans and in animals.^[1]

Actions

• Is an activator of peroxisome proliferator-activated receptor-alpha (PPARα), a nuclear receptor that is involved in metabolism ofcarbohydrates and fats, as well as adipose tissue differentiation. This increase in the synthesis of lipoprotein lipase thereby increases the clearance of triglycerides.^{[citation needed]}

Therapeutic effects

• Reduce triglyceride levels ^[2]
• Reduce very low density lipoprotein (VLDL) levels
• Modest reduction of low density lipoprotein (LDL) levels
• Moderate increase in high density lipoprotein (HDL) levels

Nontherapeutic effects and toxicities

• GI distress
• Musculoskeletal pain
• Increased incidence of gallstone
• Hypokalemia (low blood potassium)
• Increased risk of cancer

Indications

• Hyperlipidemia (Type III): Gemfibrozil is the drug of choice for therapy.
• Hypertriglyceridemia (Type IV): Gemfibrozil, though not as effective as niacin, is better tolerated.^{[citation needed]}

Contraindications and precautions

• Gemfibrozil should not be given to these patients:
  • Hepatic dysfunction
• Gemfibrozil should be used with caution in these higher risk categories:
  • Biliary tract disease
  • Renal dysfunction
  • Pregnant women
  • Obese patients

Drug interactions

• Anticoagulants: Gemfibrozil potentiates the action of warfarin and indanedione anticoagulants.^{[citation needed]}
• Statin drugs: Concomitant administration of fibrates (including gemfibrozil) with statin drugs increases the risk of muscle cramping, myopathy, andrhabdomyolysis.
• Gemfibrozil inhibits the activation of the liver’s Cytochrome P450 system, reducing hepatic metabolism of many drugs, and prolonging their half lives and duration of action.
  • Drugs metabolized by the Cytochrome P450 system include:
    • Many antidepressants
    • Many antipsychotics
    • Many antiepileptics
    • Theophylline and other methylxanthine drugs
    • Several anesthetic agents
    • Oral contraceptive pills
    • Statins
    • Warfarin

Environmental data

Gemfibrozil has been detected in biosolids (the solids remaining after wastewater treatment) at concentrations up to 2650 ng/g wet weight.^[3] This indicates that it survives the wastewater treatment process.

SYNTHESIS

The sodium isobutyrate (I) is metallated with lithium diisopropylamide, and the resulting compound is alkylated with 3- (2,5-dimethylphenoxy) propyl bromide.

PATENT

Paul, L. C. 2,2-Dimethyl-ω-aryloxy alkanoic acids and salts and ester thereof. U.S. 3,674,836, 1972.

http://www.google.co.in/patents/US3674836

CLIP

Production of Gemfibrozil
(1)2,5-Dimethylphenol and 1-Bromo-3-chloropropane reaction of 1-(2,5-dimethylphenoxy)-3-chloropropane. The reaction is carried out in toluene, adding new clean off reflux 5h. Just as follows:

(2)N/A can be used to manufacture Gemfibrozil.

PAPER

Improved Process for Preparation of Gemfibrozil, an Antihypolipidemic

An improved process for the preparation of gemfibrozil, an antihypolipodimic drug substance, with an overall yield of 80% and ∼99.9% purity (including three chemical reactions) is reported. Formation and control of possible impurities are also described. Finally, gemfibrozil is isolated from water without any additional solvent purification.

Literature References:

Serum lipid regulating agent. Prepn: P. L. Creger, DE 1925423; eidem, US 3674836 (1969, 1972, both to Parke, Davis).

Production: O. P. Goel, US 4126637 (1978 to Warner-Lambert).

Pharmacology: A. H. Kissebach et al.,Atherosclerosis 24, 199 (1976); M. T. Kahonen et al., ibid. 32, 47 (1979).

Series of articles on metabolism, clinical pharmacology, kinetics and toxicology: Proc. R. Soc. Med. 69, Suppl 2, 1-120 (1976).

Toxicity data: S. M. Kurtz et al., ibid. 15.

Clinical trial in hyperlipidemia: J. E. Lewis et al., Pract. Cardiol. 9, 99 (1983).

Clinical reduction of cardiovascular risk in patients with low HDL levels: H. B. Rubins et al., N. Engl. J. Med. 341, 410 (1999).

References

External links

• DrugBank Gemfibrozil
• NIH Gemfibrozil Drug Info
• Lopid International Study
• Author (2004). “Safety of Statins”. Circulation. 109: III–50–III–57. doi:10.1161/01.cir.0000131519.15067.1f.
• http://www.ihs.gov/nptc/documents/NPTC%20Lipid%20Review.pdf