AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Novartis, Torrent drug for diabetes, NVP-LBX192, LBX-192

 Uncategorized  Comments Off on Novartis, Torrent drug for diabetes, NVP-LBX192, LBX-192
Jun 192016
 

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Figure US07750020-20100706-C00023

 

CHEMBL573983.png

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

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R(−) 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

R(−)17c BELOW

Abstract Image
Inventors Gregory Raymond Bebernitz, Ramesh Chandra Gupta, Vikrant Vijaykumar Jagtap, Appaji Baburao Mandhare, Davinder Tuli,
Original Assignee Novartis Ag

 

Molecular Formula: C26H33N5O4S2
Molecular Weight: 543.70132 g/mol

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LBX192, also known as NVP-LBX192, is a Liver Targeted Glucokinase Activator. LBX192 activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice. A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.

SYNTHESIS BY WORLDDRUGTRACKER

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54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM
Nathan Hale North (Hilton Third Floor)
Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA
Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching clinical evaluation.  A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.  We will describe our efforts to generate liver selective GK activators which culminated in the discovery of NVP-LBX192 (3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide).  This compound activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice.

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes

2009 52 (19) 6142 – 6152
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Journal of Medicinal Chemistry
Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao JP, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang JS, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, Denny IS, Taslimi PM, Vash B, Caplan SL

2010 240th (August 22) Medi-198
Glucokinase activators with improved physicochemicalproperties and off target effects
American Chemical Society National Meeting and Exposition
Kirman LC, Schuster HF, Grondine MS et al

2010 240th (August 22) Medi-197
Investigation of functionally liver selective glucokinase activators
American Chemical Society National Meeting and Exposition
Schuster HF, Kirman LC, Bebernitz GC et al

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]+.

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]+.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]+.

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]+.

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

The title G compound, 3-cyclopentyl-2-(4-methyl piperazinyl sulfonyl)phenyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)propionamide (2.8 g, 0.0051 mol) is added to a cooled solution of 10% hydrochloric acid in isopropanol (3.75 mL). The reaction mixture is stirred at 0° C. for 1 h and then at RT for 2 h. The solid is separated, triturated with 10 mL of isopropanol and collected by vacuum filtration and washed with 50 mL of hexane. The solid is dried at 70° C. for 48 h to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride as an off white solid.

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139
Torrent Research Centre, Village Bhat, Gujarat, India
J. Med. Chem., 2009, 52 (19), pp 6142–6152
DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αKa = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

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PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2
Patent ID Date Patent Title
US2015218151 2015-08-06 NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020 2010-07-06 Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

 

 

 PAPER

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139
Torrent Research Centre, Village Bhat, Gujarat, India
J. Med. Chem., 2009, 52 (19), pp 6142–6152
DOI: 10.1021/jm900839k
Publication Date (Web): September 11, 2009
Copyright © 2009 American Chemical Society
*To whom correspondence should be addressed. Phone: (617) 871 7302. Fax: (617) 871 7042. E-mail: greg.bebernitz@novartis.com.

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αKa = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

str1

https://www.google.com/patents/US7750020

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

 

Patent ID Date Patent Title
US2015218151 2015-08-06 NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020 2010-07-06 Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

Torrent Research Centre, Village Bhat, Gujarat, India

Mr. Samir Mehta, 52, is the Vice Chairman of the USD 2.75 billion Torrent Group and Chairman of Torrent Pharma

 

Mr. Sudhir Mehta - Executive Chairman

 

 

 

 

 

 

 

 

 

Shri Sudhir Mehta – Chairman Emeritus ::

 

Dr. Chaitanya Dutt – Director (Research & Development) ::
Dr. Chaitanya Dutt - Director (R&D)Born in the year 1950, Dr. Chaitanya Dutt holds an MD in Medicine. He practiced as a consulting physician before joining the company in 1982. Since then he has been associated with the Company. His rich experience spans in the areas of Pharma R&D, clinical research, manufacturing, quality assurance, etc. He is one of the key professionals in the top management team of the Company. He has been instrumental in setting up the Torrent Research Centre (TRC), the research wing of the Company. Under his prudent guidance and leadership, TRC has achieved tremendous progress in the areas of discovery research as well as development work on formulations. He does not hold any directorship in any other company.

 

///NOVARTIS, DIABETES, Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes, 866772-52-3, Novartis Molecule, functionally liver selective glucokinase activators, treatment of type 2 diabetes , NVP-LBX192, LBX-192

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

 

 

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Novartis Molecule for functionally liver selective glucokinase activators for the treatment of type 2 diabetes

 Uncategorized  Comments Off on Novartis Molecule for functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Apr 052016
 

STR3

Figure US07750020-20100706-C00023

2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

(3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide)

cas 866772-52-3

Novartis Ag

NVP-LBX192

LBX-192

54 Discovery and Evaluation of NVP-LBX192, a Liver Targeted Glucokinase Activator

Thursday, October 8, 2009: 10:30 AM
Nathan Hale North (Hilton Third Floor)
Gregory R. Bebernitz, PhD , Global Discovery Chemistry, Novartis Institute for Biomedical Research, Cambridge, MA
Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching clinical evaluation.  A GK activator has the promise of potentially affecting both the beta-cell of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post prandial glucose uptake and storage as glycogen.  We will describe our efforts to generate liver selective GK activators which culminated in the discovery of NVP-LBX192 (3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide).  This compound activated the GK enzyme in vitro at low nM concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal as well as diabetic mice.

https://acs.confex.com/acs/nerm09/webprogram/Paper75087.html

Molecular Formula: C26H33N5O4S2
Molecular Weight: 543.70132 g/mol

Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes

2009 52 (19) 6142 – 6152
Investigation of functionally liver selective glucokinase activators for the treatment of type 2 diabetes
Journal of Medicinal Chemistry
Bebernitz GR, Beaulieu V, Dale BA, Deacon R, Duttaroy A, Gao JP, Grondine MS, Gupta RC, Kakmak M, Kavana M, Kirman LC, Liang JS, Maniara WM, Munshi S, Nadkarni SS, Schuster HF, Stams T, Denny IS, Taslimi PM, Vash B, Caplan SL

2010 240th (August 22) Medi-198
Glucokinase activators with improved physicochemicalproperties and off target effects
American Chemical Society National Meeting and Exposition
Kirman LC, Schuster HF, Grondine MS et al

2010 240th (August 22) Medi-197
Investigation of functionally liver selective glucokinase activators
American Chemical Society National Meeting and Exposition
Schuster HF, Kirman LC, Bebernitz GC et al

PATENT

http://www.google.com/patents/US7750020

EXAMPLE 1 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) is treated with catalytic amount of sulfuric acid (4 mL). The reaction mixture is refluxed for 4 h. The reaction is then concentrated in vacuo. The residue is dissolved in diethyl ether (300 mL) and washed with saturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100 mL). The organic layer dried over sodium sulfate filtered and concentrated in vacuo to give phenylacetic acid ethyl ester as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.2 (t, J=7.2, 3H), 3.6 (s, 2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]+.

B. (4-Chlorosulfonyl-phenyl)-acetic acid ethyl ester

To a cooled chlorosulfonic acid (83.83 g, 48 mL, 0.71 mol) under nitrogen is added the title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol) over a period of 1 h. Reaction temperature is brought to RT (28° C.), then heated to 70° C., maintaining it at this temperature for 1 h while stirring. Reaction is cooled to RT and poured over saturated aqueous sodium chloride solution (200 mL) followed by extraction with DCM (2×200 mL). The organic layer is washed with water (5×100 mL), followed by saturated aqueous sodium chloride solution (1×150 mL). The organic layer dried over sodium sulfate, filtered and concentrated in vacuo to give crude (4-chlorosulfonyl-phenyl)acetic acid ethyl ester. Further column chromatography over silica gel (60-120 mesh), using 100% hexane afforded pure (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester as a colorless oil.

C. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester

A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester

A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]+.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid

A solution of the title D compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester (14 g, 0.034 mol) in methanol:water (30 mL:10 mL) and sodium hydroxide (4.11 g, 0.10 mol) is stirred at 60° C. for 8 h in an oil bath. The methanol is then removed in vacuo at 45-50° C. The residue is diluted with water (25 mL) and extracted with ether (1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueous hydrochloric acid solution. The precipitated solid is collected by vacuum filtration, washed with water (20 mL), followed by isopropyl alcohol (20 mL). Finally, solid cake is washed with 100 mL of hexane and dried under vacuum at 40° C. for 6 h to give 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 1.1-2.0 (m, 11H), 2.4 (s, 3H), 2.7 (br s, 4H), 3.1 (br s, 4H), 3.6 (m, 1H), 7.5 (d, J=8.3, 2H), 7.6 (d, J=8.3, 2H); MS 381 [M+l]+.

F. 5-Methoxy-thiazolo[5,4-b]pyridin-2-ylamine

A solution of 6-methoxy-pyridin-3-ylamine (5.0 g, 0.0403 mol) in 10 mL of acetic acid is added slowly to a solution of potassium thiocyanate (20 g, 0.205 mol) in 100 mL of acetic acid at 0° C. followed by a solution of bromine (2.5 mL, 0.0488 mol) in 5 mL of acetic acid. The reaction is stirred for 2 h at 0° C. and then allowed to warm to RT. The resulting solid is collected by filtration and washed with acetic acid, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The insoluble material is removed by filtration and the organic layer is evaporated and dried to afford 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine as a tan solid.

G. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]+.

H. 3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride

The title G compound, 3-cyclopentyl-2-(4-methyl piperazinyl sulfonyl)phenyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)propionamide (2.8 g, 0.0051 mol) is added to a cooled solution of 10% hydrochloric acid in isopropanol (3.75 mL). The reaction mixture is stirred at 0° C. for 1 h and then at RT for 2 h. The solid is separated, triturated with 10 mL of isopropanol and collected by vacuum filtration and washed with 50 mL of hexane. The solid is dried at 70° C. for 48 h to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide dihydrochloride as an off white solid.

EXAMPLE 2 (R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100° C. for 1 h. The clear reaction solution is cooled to RT (27° C.) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(−)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4° C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250×20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min/% B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

EXAMPLE 3 (S)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

The title compound is prepared analogously to Example 2.

J MED CHEM 2009, 52, 6142-52

Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, Massachusetts 02139
Torrent Research Centre, Village Bhat, Gujarat, India
J. Med. Chem., 2009, 52 (19), pp 6142–6152
DOI: 10.1021/jm900839k

http://pubs.acs.org/doi/abs/10.1021/jm900839k

Abstract Image

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10−15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the β-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (αKa = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

STR3

STR3

PATENT

EP-1735322-B1

Example 2(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide

Image loading...

The title compound is obtained analogously to Example 1 by employing the following additional resolution step:

The racemic title E compound of Example 1, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (10 g, 0.026 mol) in 1,4-dioxane (500 mL) is treated in a three necked 1 liter flask, equipped with heating mantle, water condenser, calcium chloride guard tube and mechanical stirrer with 3.18 g (0.026 mol) of (R)-(+)-1-phenylethylamine. This reaction mixture is then refluxed at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized salt is collected by filtration under vacuum, washed with 5 mL of hexane and dried under vacuum to afford salt A.

The salt A is dissolved in 1,4-dioxane (500 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 50 mL of hexane, and dried under vacuum to afford salt B.

The salt B is dissolved in 1,4-dioxane (290 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30 mL of hexane, and dried under vacuum to afford salt C.

The salt C is dissolved in 1,4-dioxane (100 mL) and heated at 100°C for 1 h. The clear reaction solution is cooled to RT (27°C) and stirred for 10 h. The crystallized product is collected by filtration under vacuum, washed with 30ml of hexane, and dried under vacuum to afford salt D.

The salt D is treated with aqueous hydrochloric acid solution (20 mL, 1 mL of concentrated hydrochloric acid diluted with 100 mL of water) and stirred for 5 min. The white solid precipitates out and is collected by vacuum filtration, washed with 10 mL of cold water, 5 mL of isopropanol and 20 mL of hexane, and dried under vacuum to yield the hydrochloride salt of (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid, salt E.

The salt E is neutralized by stirring with aqueous sodium bicarbonate solution (10 mL, 1 g of sodium bicarbonate dissolved in 120 mL of water) for 5 min. The precipitated solid is collected by filtration, washed with 10 mL of cold water, 100 mL of hexane, and dried to afford (R)-(-)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid: m.p. 202.2-203.4°C.

Alternatively, the title compound may be obtained by the resolution of the racemic title compound of Example 1 using the following preparative chiral HPLC method:

  • Column: Chiralcel OD-R (250 x 20 mm) Diacel make, Japan;
  • Solvent A: water:methanol:acetonitrile (10:80:10 v/v/v);
  • Solvent B: water:methanol:acetonitrile (05:90:05 v/v/v);
  • Using gradient elution: gradient program (time, min / %B): 0/0, 20/0, 50/100, 55/0, 70/0;
  • Flow rate: 6.0 mL/min; and
  • Detection: by UV at 305 nm.

REFERENCES

US 7750020

WO-2005095418-A1

US-20080103167-A1

1 to 2 of 2
Patent ID Date Patent Title
US2015218151 2015-08-06 NOVEL PHENYLACETAMIDE COMPOUND AND PHARMACEUTICAL CONTAINING SAME
US7750020 2010-07-06 Sulfonamide-Thiazolpyridine Derivatives As Glucokinase Activators Useful The Treatment Of Type 2 Diabetes

///NOVARTIS, DIABETES, Sulfonamide-Thiazolpyridine Derivatives,  Glucokinase Activators, Treatment Of Type 2 Diabetes, 866772-52-3, Novartis Molecule, functionally liver selective glucokinase activators, treatment of type 2 diabetes , NVP-LBX192, LBX-192

c1(sc2nc(ccc2n1)OC)NC(C(c3ccc(cc3)S(=O)(=O)N4CCN(CC4)C)CC5CCCC5)=O

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What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem

 diabetes, Uncategorized  Comments Off on What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem
Jul 152015
 

A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218,  from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”

This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司

Applicant Tfchem

 

Figure imgf000110_0001

List above as in http://www.google.com/patents/WO2012160218A1?cl=en

FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW

COMPD 16 as in/WO2012160218

 

 

COMPD 16

COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-​myo-​Inositol, 1-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​1,​2,​3-​trideoxy-​2,​2-​difluoro-​3-​(hydroxymethyl)​-

Just scrolling through the patent gave me more insight

MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows

Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF2 moiety.

 

Figure imgf000091_0001

This assay has been carried out at a dose of 3 mg/ kg.

The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.

• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF2 in place of the CH-OH moiet .

 

Figure imgf000092_0001
NOTE=COMPD 9 OF WO 2009/1076550 has  CAS 1161430-16-5, D-​scyllo– ​Inositol, 1-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​1,​3-​dideoxy-​3- ​(hydroxymethyl)​-  and  is very similar to the compd under discussion

 

Company Sirona Biochem Corp.
Description Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Molecular Target Sodium-glucose cotransporter 2 (SGLT2)
Mechanism of Action Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Preclinical
Standard Indication Diabetes
Indication Details Treat Type II diabetes
Regulatory Designation
Partner Shanghai Fosun Pharmaceutical Group Co. Ltd.

SBM-TFC-039

PATENT

WO 2012160218

http://www.google.com/patents/WO2012160218A1?cl=en

Examples within this first subclass include but are not limited to:

 

Figure imgf000019_0001

Synthesis of compound 8

C35H34O5 M = 534.64 g.mol

Mass: (ESI ): 535.00 (M + H); 552.00 (M + H20); 785.87; 1086.67 (2M + H20)

Figure imgf000053_0001

A.

 

Figure imgf000053_0002

Procedure A:

To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl3 (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et20 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et20 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9

C15H12BrC102 M = 339.61 g.moF1

Mass: (GC-MS): 338-340

 

Figure imgf000054_0001

The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10

C15H14B1CIO M = 325.63 g.mof1

 

Figure imgf000054_0002

10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.

Synthesis of compound 11

C50H49CIO6 M = 781.37 g.moF1

Mass: ESI+): 798.20 (M + H20)

 

Figure imgf000054_0003

Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et20, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).

Synthesis of compound 12

C5oH49C105 M = 765.37 g.mol“1

+): 782.13 (M + H20)

 

Figure imgf000055_0001

Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF3, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH2C12 (10mLx3) and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).

Synthesis of compound 13

C5oH5tC106 M = 783.39g.moF1

Mass: (ESI+): 800 (M + H20); 1581 (2M + H20)

Figure imgf000056_0001

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H20, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H20, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.

Synthesis of compound 14

C50H49CIO6 M = 781.37g.mol“1

Mass: (ESI+): 798 (M + H20); 1471; 1579 (2M + H20)

 

Figure imgf000056_0002

13 14

Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15

C5oH49ClF206 M = 803.37g.moF1

19 F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).

Mass: (ESI+): 820.00 (M+H20)

 

Figure imgf000057_0001

14 15

A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC03. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).

Synthesis of compound 16

C22H25CIF2O5 M = 442.88g.mor1

19 F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,

Jl=254Hz, J2=28Hz, IF, CFF).

Mass: (ESI+): 465.3 (M+Na)

 

Figure imgf000057_0002

o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).

 …………………….
CN 103649033

Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

Vancouver, British Columbia – December 7, 2012 – Sirona Biochem Corp. (TSX-V: SBM), announced its sodium glucose transporter (SGLT) inhibitor for Type 2 diabetes reduced blood glucose more effectively than Johnson and Johnson’s canagliflozin, an advanced SGLT inhibitor being considered for market approval in Europe and the U.S.  Studies compared Sirona Biochem’s SGLT Inhibitor, SBM-TFC-039, with canagliflozin and were conducted on Zucker Diabetic Fatty (ZDF) rats.

In the study, SBM-TFC-039 significantly and rapidly reduced blood glucose levels at a dose of 1.0 mg/kg.  Six (6) hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to canagliflozin at 26%.  SBM-TFC-039 also had a longer duration of effect than canagliflozin.  At 36 and 48 hours after treatment, SBM-TFC-039, at a dose of 1.0 mg/kg, was still effective at reducing blood glucose, whereas canagliflozin lost its effect after 36 hours.  Studies were conducted at the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ) by Principal Investigator Dr. Denis Richard, Research Chair on Obesity and Professor, Faculty of Medicine, Department of Anatomy & Physiology at Laval University.

“SGLT Inhibitors are a ground-breaking new treatment for Type 2 diabetes and these results demonstrate that SBM-TFC-039 will be a significant competitor for other SGLT Inhibitors,” said Neil Belenkie, Chief Executive Officer of Sirona Biochem. “The first SGLT Inhibitor,Forxiga™, was approved last month by the European Commission.  We believe there is tremendous market potential worldwide for SGLT Inhibitors in the treatment of diabetes.”

SBM-TFC-039 is a sodium glucose transporter (SGLT) inhibitor.  SGLT inhibitors are a new class of drug candidates for the treatment of diabetes. In the kidneys, SGLT inhibitors reduce the reabsorption of glucose into the bloodstream by eliminating excess glucose into the urine.

About Sirona Biochem Corp.
Sirona Biochem is a biotechnology company developing diabetes therapeutics, skin depigmenting and anti-aging agents for cosmetic use, biological ingredients and cancer vaccine antigens.  The company utilizes a proprietary chemistry technique to improve pharmaceutical properties of carbohydrate-based molecules. For more information visit www.sironabiochem.com.

Laboratory – France
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Pharma Parc II
Chaussée du Vexin
27100 Val de Reuil
France

Phone:
+33(0)2.32.09.01.16
Fax:+33(0)2.32.25.07.64


 

……………………………………………………………………………….

Shanghai Fosun Pharmaceutical Group Co. Ltd.

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GEMIGLIPTIN

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Jul 062015
 

Structure of gemigliptin (LC15-0444).svg

 

GEMIGLIPTIN

1-[2(S)-Amino-4-[2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]-4-oxobutyl]-5,5-difluoropiperidin-2-one

PHASE 3, DPP-IV inhibitor, Lg Life Sciences Ltd.

CAS 911637-19-9

Mol. Formula:   C18H19F8N5O2

Mol. Weight:489.36

Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey.

Gemigliptin, a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor, is currently undergoing phase III clinical trials at LG Life Sciences as an oral treatment for type II diabetes. The company is also testing the compound in phase II/III clinical studies for the treatment of patients with cisplatin-induced acute kidney injury.

DPP IV inhibitors have glucose-lowering effects mediated by GLP-1 incretin hormone which is inactivated by DPP IV. In 2010, gemigliptin was licensed to Beijing Double-Crane Pharmaceutical by LG Life Sciences for distribution and supply in China for the treatment of type 2 diabetes.

New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed.

…………

Efficient synthesis of gemigliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus, has been developed. Gemigliptin were prepared from two key API starting materials, DP18 and DP57, in 75~80% yield and >99% purity over three steps under the GMP control: coupling, deprotection of N-Boc group, and final crystallization with L-tartaric acid. All steps were conducted in the same solvent system and the intermediates were isolated by simple filtration without distillation of solvent. The established process was validated obviously through the three consecutive batches for a commercial production.

………..

 

 

 

(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one
Clinical data
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 94% (rat), 73% (dog), 26% (monkey)
Biological half-life 3.6 h (rat), 5.2 h (dog), 5.4 h (monkey)
Identifiers
CAS Registry Number 911637-19-9 
ATC code A10BH06
PubChem CID: 11953153
ChemSpider 10127461 Yes
UNII 5DHU18M5D6 
Synonyms LC15-0444
Chemical data
Formula C18H19F8N5O2
Molecular mass 489.36 g/mol

……………….

History

The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world.

Mechanism of action

DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.[2]

Preclinical studies

Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8DPP-9elastase,trypsinurokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

Studies on animals suggest its positive effect on hepatic and renal fibrosis .[3][4] Data on human patients are still inconclusive .[5]

 

Clinical studies

The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA1c from baseline compared to the placebo group without a significant difference between the doses.

Subjects with a higher baseline HbA1c (≥8.5%) had a greater reduction in HbA1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment.

The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group.

The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA1cFPG level, oral glucose tolerance testresults, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes.

Results of Phase 3 clinical trials which have been finished recently will be updated near future.

 

…………..

WO 2006104356

 http://www.google.co.in/patents/WO2006104356A1?cl=en

EXAMPLE 83: Synthesis of l-(f2SV2-amino-4-r2.4-bisftrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7f6H)

-yl1-4-oxobutyll-5.5-difluoropiperidin-2-one [1960]

 

Figure imgf000147_0001

[1961] 21 mg of the title compound was obtained in a yield of 56% at the same manner as in EXAMPLE 1, except that 42 mg (0.071 mmol) of t-butyl

{(lS)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-l-[(5,5

-difluoro-2-oxpiperidin-l-yl)methyl]-3-oxpropyl}carbamate obtained in

PREPARATION 143 was used. [1962] 1K NMR (CD3OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m),

3.70-3.59 (2H, m), 3.54-3.48 (IH, m), 3.36-3.33 (2H, m), 3.24 (IH, bra), 3.14 (IH, bra), 2.83-2.76 (IH, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H, m) [1963] Mass (m/e) 490 (M+l)

[1964]

[1965] PREPARATION 144: Synthesis of t-butyl

(riSV3-r2.4-bisrtrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7r6HVyl]-l-(rr2 S)-2-methyl-5-oxomorpholin-4-yl1methyl 1 -3-oxpropyl 1 carbamate

[1966] 14 mg of the title compound was obtained in a yield of 17% at the same manner as in PREPARATION 45, except that 43.7 mg (0.138 mmol) of (3S)-3-[(t-butoxycarbonyl)amino]-4-[2(S)-2-methyl-5-oxomoφholin-4-yl]-butanoic acid obtained in PREPARATION 55 and 42.5 mg (0.138 mmol) of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloric acid salt (product of PREPARATION 127) were used.

[1967] 1K NMR (CDCl3) δ 5.85-5.83 (IH, m), 5.09-4.92 (IH, m), 4.95-4.78 (IH, m),

4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (IH, m), 3.46-3.38 (IH, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (IH, m), 2.61-2.50 (IH, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1968] Mass (m/e) 470 (M+l-Boc)

…………..

WO 2012030106

https://www.google.com/patents/WO2012030106A2?cl=en

Reaction Scheme 1

 

Figure PCTKR2011006260-appb-I000001

PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate

 

Figure PCTKR2011006260-appb-I000014

To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50℃, TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH4Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.

1H NMR (400 MHz, CDCl3) δ 1.26 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H).

 

PREPARATION 2: Synthesis of ethyl 4,4-difluoro-5-hydroxypentanoate

 

Figure PCTKR2011006260-appb-I000015

14.8 g of the compound obtained from the above Preparation 1 was diluted with ethanol (20.4 g) and tetrahydrofuran (69.1 g) and then cooled to 0℃. To this solution was slowly added sodium borohydride (NaBH4, 3.5 g) stepwise while keeping the internal temperature below 30℃. After confirming completion of the reaction by 1H NMR, the reaction solution was cooled to the temperature of 10℃ and 10% aqueous ammonium chloride solution (77.7 g) was slowly added. The remaining boron compound was filtered through celite, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. Then, ethyl acetate (105.2 g) was added to separate the layers, and the organic layer was distilled under reduced pressure to obtain 10.8 g of the title compound.

1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=7.2 Hz, 3H), 2.15-2.29 (m, 2H), 2.49 (t, J=7.2 Hz, 2H), 3.69 (t, J=12.0 Hz, 2H), 4.12 (q, J=4.0 Hz, 2H).

 

EXAMPLE 1: Synthesis of ethyl 4,4-difluoro-5-{[(trifluoromethyl)sulfonyl]oxy}- pentanoate

 

Figure PCTKR2011006260-appb-I000016

To the solution of 10.8 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (100.2 g) was added pyridine (7.0 g), and then the mixture was cooled to -5.0℃. After completion of cooling, trifluoromethane sulfonic acid anhydride (20.1 g) was slowly added dropwise while keeping the reaction temperature below 6.3℃. After stirring the reaction solution for 30 minutes, 1.5 N hydrochloric acid solution was added dropwise at 0℃ to separate the layers. The aqueous layer as separated was back-extracted twice with dichloromethane (33.4 g), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 19.7 g of the title compound as a yellow oil.

1H NMR (500 MHz, CDCl3) δ 1.27 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.55 (t, J=11.6 Hz, 2H).

 

EXAMPLE 2-1: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

 

Figure PCTKR2011006260-appb-I000017

To the solution of 100.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (300.0 ml) was added pyridine (65.7 g), and the mixture was then cooled to -10.0℃. After completion of cooling, nonafluorobutanesulfonic anhydride (477.4 g) was slowly added dropwise. After stirring the reaction solution for 3 hours, 1.0 N hydrochloric acid solution (300.0 ml) was added dropwise to separate the layers. The aqueous layer as separated was back extracted once with dichloromethane (500.0 ml), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 177.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.26 (t, 3H, J=7.3 Hz), 2.30-2.36 (m, 2H), 2.58 (t, 2H, J=7.4 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.57 (t, 2H, J=11 Hz).

 

EXAMPLE 2-2: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 500.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (1000.0 ml) was added triethylamine (389.0 g), and the mixture was then cooled to 0℃. After completion of cooling, perfluorobutanesulfonyl chloride (948.80 g) was slowly added dropwise. The reaction solution was stirred for 3 hours at room temperature, distilled under reduced pressure, dissolved in methyl t-butyl ether (MTBE, 3000.0 ml) and then washed three times with water. The organic layer thus obtained was dehydrated with magnesium sulfate, filtered through a celite and then distilled under reduced pressure to obtain 960.0 g of the title compound.

 

EXAMPLE 3: Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxo- pentanoate

 

Figure PCTKR2011006260-appb-I000018

To 25.0 g of the starting material, (3S)-3-[(t-butoxycarbonyl)amino]-4-oxo- pentanoic acid, was added t-butanol (96.9 g) followed by the addition of Boc2O (25.4 g) and dimethylaminopyridine (DMAP, 62.0 g, 0.5 mol%) at room temperature, and the reaction mixture was then stirred for 23 hours at 40℃. Upon completion of the reaction, ethylene dichloride (62.3 g) in t-butanol was added, and the mixture was then distilled under reduced pressure to obtain 30.7 g of the title compound.

1H NMR (400 MHz, CDCl3) δ 1.45 (s, 9H), 1.47 (s, 9H), 2.71 (dd, J=4.8, 16.4 Hz, 1H), 2.88 (dd, J=4.4, 16.4 Hz, 1H), 3.75 (s, 3H), 4.53 (m, 1H), 5.44 (br d, J=8.0 Hz, 1H).

 

EXAMPLE 4: Synthesis of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy- butanoate

 

Figure PCTKR2011006260-appb-I000019

30.7 g of the compound obtained from the above Example 3 was dissolved in ethanol (112.3 g) and, after lowering the internal temperature to 10.5℃ sodium borohydride (NaBH4, 5.7 g) was slowly added dropwise. This reaction solution was stirred while maintaining the temperature below 22℃. After confirming completion of the reaction by 1H NMR and TLC, to the reaction solution was slowly added 3.0 N hydrochloric acid solution (30.7 g) dropwise at the internal temperature of 10℃ followed by addition of diluted 0.2% hydrochloric acid solution (100.0 g). The reaction solution was adjusted to pH 3~4 with addition of 9.0% aqueous hydrochloric acid solution, and then back-extracted twice with ethyl acetate (100.0 g) and toluene (44.0 g). The organic layer thus obtained was distilled under reduced pressure to obtain 25.1 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.48-2.57 (m, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.97 (m, 1H), 5.22 (bs, 1H).

 

EXAMPLE 5: tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]- butanoate

 

Figure PCTKR2011006260-appb-I000020

To 25.1 g of the compound obtained from the above Example 4 was added dichloromethane (133.0 g) and triethylamine (148.0 g), and the mixture was then cooled to 0℃. To this reaction solution was slowly added methanesulfonyl chloride (11.8 g) diluted with dichloromethane (39.9 g) dropwise for 50 minutes while maintaining the internal temperature below 12℃. After completion of the reaction, the reaction solution was washed with 0.5 N aqueous hydrochloric acid solution (120.0 g) and water (100.4 g), and then distilled under reduced pressure to obtain 31.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.46 (s, 9H), 2.62 (d, J=6.0 Hz, 2H), 3.04 (s, 3H), 4.21 (m, 1H), 4.30 (d, J=5.2 Hz, 2H), 5.16 (br d, J=7.2 Hz, 1H).

 

EXAMPLE 6: Synthesis of tert-butyl (3S)-4-azido-3-[(tert-butoxycarbonyl)amino]- butanoate

 

Figure PCTKR2011006260-appb-I000021

Sodium azide (NaN3, 11.6 g) was diluted with dimethylacetamide (DMAc, 260.0 g). After elevating the internal temperature to 80℃, a solution of 31.5 g of the compound, as obtained from the above Example 5, diluted with dimethylacetamide (DMAc, 45.0 g) was added thereto. The reaction proceeded at 80℃ for 2 hours. To the reaction solution were added toluene (251.0 g) and water (320.0 g) to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 24.0 g of the title compound.

1H NMR (500 MHz, CDCl3) δ 1.47 (s, 9H), 1.49 (s, 9H), 2.49 (d, J=6.0 Hz, 2H), 3.44-3.55 (m, 2H), 4.09 (br s, 1H), 5.14 (br s, 1H).

 

EXAMPLE 7: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

 

Figure PCTKR2011006260-appb-I000022

To 21.0 g of the compound obtained from the above Example 6 was added tetrahydrofuran (93.3 g) followed by the addition of triphenylphosphine (PPh3, 21.0 g) at 40℃, the mixture was stirred for 2 hours at the same temperature, and water (3.8 g) was then added thereto. The reaction solution was distilled under reduced pressure, and the resulting triphenylphosphine oxide solid was diluted with toluene (26.0 g) and n-hexane (41.0 g), and then filtered off. The filtrate was adjusted to pH 2~3 with 1.0 N aqueous hydrochloric acid solution (110.0 g) and then subjected to separation of the layers. To remove any residual triphenylphosphine oxide solid, the aqueous layer obtained above was washed with dichloromethane (100.0 g) and then adjusted to pH 8~9 with 28% aqueous ammonia solution (7.6 g). The aqueous solution thus obtained was extracted with dichloromethane (100.0 g) and distilled under reduced pressure to obtain 8.5 g of the title compound as a white solid.

1H NMR (500 MHz, CDCl3) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

 

EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester

 

Figure PCTKR2011006260-appb-I000023

N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).

1H NMR (400 MHz, CDCl3) δ: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).

Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).

 

EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester

 

Figure PCTKR2011006260-appb-I000024

L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).

1H NMR (400 MHz, CDCl3) δ: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).

Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).

 

EXAMPLE 10: Synthesis of N,N-dibenzyl-4-amino-3(S)-N(Boc)-aminobutanoic acid 4-tert-butyl ester

 

Figure PCTKR2011006260-appb-I000025

10.0 g of the compound obtained from the above Example 8, Ru3(CO)12 (136 mg, 1mol%), and diphenylsilane (19.7 ml, 106.7 mmol) were added to tetrahydrofuran (50 ml), and the reaction solution was stirred under reflux for over 40 hours. The reaction solution was extracted with ethyl acetate (200 ml) and concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (4.7 g, 10.5 mmol).

1H NMR (400 MHz, CDCl3) δ: 7.31-7.20 (m, 10H), 5.12 (bs, 1H), 3.90 (bs, 1H), 3.63 (d, J=12.0 Hz, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.24 (m, 1H), 3.16 (bs, 1H), 2.42 (m, 2H), 1.81 (m, 1H), 1.59 (m, 9H), 1.46 (s, 9H), 1.06 (s, 9H).

Mass (ESI, m/z): 455 (M+H), 441 (M-13).

 

EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate

 

Figure PCTKR2011006260-appb-I000026

360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc2O (353.0 g) and ammonium bicarbonate (NH4HCO3, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.

 

EXAMPLE 12: Synthesis of (S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate

 

Figure PCTKR2011006260-appb-I000027

To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25℃. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

 

EXAMPLE 13: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

 

Figure PCTKR2011006260-appb-I000028

To 212.1 g of the compound obtained from the above Example 12 was added acetic acid (4000 ml) followed by addition of 20 wt% Pd(OH)2 (1.1 g) at 40℃. The mixture was stirred for 8 hours while keeping the internal temperature below 45℃ and 3 atmospheric pressure of hydrogen. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, diluted with toluene (640 L) and then filtered through a celite. To the filtrate was added 0.25 N aqueous hydrochloric acid solution (1060 ml) to separate the layers. The aqueous layer thus obtained was basified with aqueous ammonia solution (543.1 g) and then extracted with methyl t-butyl ether (MTBE, 1000 ml). The organic layer thus obtained was distilled under reduced pressure to obtain 185.0 g of the title compound.

 

EXAMPLE 14: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid t-butyl ester

 

Figure PCTKR2011006260-appb-I000029

Triethylamine (13.2 g) was added to 16.0 g of the compound obtained from the above Example 1 or 2-1 or 2-2, and 14.1 g of the compound obtained from the above Example 7 or 13, and the mixture was then stirred for 21 hours at 40℃. Then, dichloromethane (154.8 g) and acetic acid (18.3 g) were added, and the mixture was stirred for 5 hours at room temperature. To the resulting reaction solution was added 0.5 N aqueous hydrochloric acid solution (116.8 g) and then, the mixture was stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 23.6 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.42 (s, 9H), 1.46 (s, 9H), 2.27 (m, 2H), 2.40-2.64 (m, 4H), 3.20 (dd, J=4.3, 13.5 Hz, 1H), 3.56-3.70 (m, 2H), 3.76-3.91 (m, 2H), 4.16 (m, 1H), 5.20 (d, J=8.6 Hz, 1H).

 

EXAMPLE 15: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid

 

Figure PCTKR2011006260-appb-I000030

23.6 g of the compound obtained from the above Example 14 was added to dichloromethane (20.0 g) followed by addition of H3PO4 (30.0 g), and the mixture was stirred for 16 hours at room temperature. After confirming the detachment of all of t-butyl group and t-butyloxycarbonyl group, the reaction solution was adjusted to pH 7.0~8.0 with 10 N aqueous hydrogen peroxide, and Boc2O (16.0 g) was added thereto. After completion of the addition, 10 N aqueous hydrogen peroxide was used to maintain the pH of the reaction solution at 8.0~9.0. After stirring for 3 hours, the resulting sodium phosphate was filtered off, and the filtrate was then adjusted to pH 2.0~3.0 with 3.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and dried under nitrogen to obtain 14.5 g of the title compound.

1H NMR (500 MHz, CDCl3) δ: 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H), 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

 

For the title compound resulting from the above, its enantiomeric isomers―i.e. S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess of the enantiomeric isomers (S vs. R form) (enantiomeric excess; ee) was then calculated as being ee > 99%. On the other hand, in case of the Comparative Example prepared according to the prior method based on WO 06/104356, as described below, the excess (ee) of enantiomeric isomers (S vs. R form) was 80%. From this, it can be identified that the compound of formula (2) having an optically high purity could be obtained according to the method of the present invention.

 

COMPARATIVE EXAMPLE 1: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

 

COMPARATIVE EXAMPLE 1-1: Synthesis of methyl 5-amino-4,4-difluoro- pentanoate HCl

 

Figure PCTKR2011006260-appb-I000031

To 10.0 g of the compound obtained from Example 1 was added 40 ml of anhydrous ammonia solution (7 M solution in methanol), and the mixture was stirred for 3 hours. The reaction solution was distilled and 30 ml of hydrochloric acid solution saturated with methanol was added dropwise thereto. The reaction mixture was stirred at room temperature and then distilled to obtain 7.2 g of the title compound as a white solid.

1H NMR (500 MHz, CD3OD) δ: 2.35 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 3.49 (t, J=15.3 Hz, 2H), 3.68 (s, 3H).

 

COMPARATIVE EXAMPLE 1-2: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

To the solution of the compound (1.93 g), as obtained from the above Example 4, dissolved in dichloromethane (20.0 g) and H2O (4.0 g) were added NaBr (0.8 g) and TEMPO (11 mg, 1 mol%). To this reaction solution was slowly added a solution of 5% NaOCl (11.5 g) and NaHCO3 (1.7 g) dissolved in H2O (12.0 g) dropwise for about 2 hours while maintaining the temperature below 5℃. Upon completion of dropwise addition, the reaction solution was stirred for 30 minutes to separate the layers. To the organic layer thus obtained was added the compound (1.6 g) obtained from the above Comparative Example 1-1. After stirring for 15 minutes at room temperature, NaBH(OAc)3 (2.23 g) was added to the reaction solution. After stirring for about 19 hours, 10% aqueous NaHCO3 solution (20.0 g) and 0.5 N aqueous hydrochloric acid solution (20.0 g) were added dropwise to the reaction solution to separate the layers. The organic layer thus obtained was dehydrated under anhydrous MgSO4 to obtain 2.0 g (yield 73%) of the same title compound as Example 14, as a yellow solid. For the title compound resulting from the above, its enantiomeric isomers―i.e., S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess (ee) of the enantiomeric isomers (S vs. R form) was then calculated as being ee = 80%.

WO2006104356A1 Mar 30, 2006 Oct 5, 2006 Seong Cheol Bu Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
EP0279435A2 * Feb 18, 1988 Aug 24, 1988 BASF Aktiengesellschaft Process for the reduction of mono- and dicarboxylic acids
US5556982 * Jul 12, 1993 Sep 17, 1996 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US20080039517 * Aug 7, 2007 Feb 14, 2008 Washburn David G Pyrrolidinone anilines as progesterone receptor modulators

Footnotes

  1. Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ (October 2008). “Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study”. Clin Ther 30 (10): 1817–30. doi:10.1016/j.clinthera.2008.10.013PMID 19014837.
  2.  Ábel T. “A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors”. In Rigobelo EC. Hypoglycemia – Causes and Occurrences. Croatia: InTech. pp. 3–52. doi:10.5772/23604ISBN 978-953-307-657-7.
  3.  Kaji K (Mar 2014). “Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.”J Gastroenterol.. 49 (3): 481–91.doi:10.1007/s00535-013-0783-4PMID 23475323.
  4.  Min HS (Jun 2014). “Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.”Lab Invest. 94 (5): 598–607.doi:10.1038/labinvest.2014.50PMID 24687121.
  5.  Gouni-Berthold I (2014). “The role of oral antidiabetic agents and incretin mimetics in type 2 diabetic patients with non-alcoholic Fatty liver disease.”Curr Pharm Des. 20 (5): 3705–15.PMID 24040873.

Further reading

 Kim SE, Yi S, Shin KH, Kim TE, Kim MJ, Kim YH, Yoon SH, Cho JY, Shin SG, Jang IJ, Yu KS (January 2012). “Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15-0444and pioglitazone in healthy volunteers”Int J Clin Pharmacol Ther. 50 (1): 17–23. doi:10.5414/cp201568PMID 22192641.

External links

 

DAVID G. WASHBURN ET AL.: ‘Discovery or orally active, pyrrolidinone-based progesterone receptor partial agonist‘ BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 19, no. 16, 2009, pages 4664 – 4667, XP026419052
2 * MONICA LOPEZ-GARCIA ET AL.: ‘Synthesis of (R)-3,4- diaminobutanoic acid by desymmetrization of dimethyl 3-(benzylamino)-glutarate through enzymatic ammonolysis‘ JOURNAL OF ORGANIC CHEMISTRY vol. 68, no. 2, 2003, pages 648 – 651, XP055105976

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Sitagliptin

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Jul 052015
 

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

A practical and economical approach to synthesize sitagliptin

Volume 43, Issue 24, 2013

DOI:
10.1080/00397911.2013.773353

Kuaile Lina, Zhengyan Caia & Weicheng Zhoua*

pages 3281-3286

1Kuaile Lin, Zhengyan Cai, Weicheng Zhou*
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of
Anti-Infectives,
Shanghai Institute of Pharmaceutical Industry, State Institute
ofPharmaceutical Industry, Shanghai 200437, China
* Corresponding author: Weicheng Zhou, profzhouwc@yahoo.com.cn, Tel./fax: +8621 35052484
Economic syntheses of sitagliptin phosphate monohydrate, acknowledged as the first dipeptidyl peptidase 4 (DPP-4) inhibitor, have been achieved in an overall yield of 42.4% in four steps from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione. The key stereoselective reduction of this process was carried out by NaBH4/HCOOH instead of expensive and toxic catalysts or ligands.
 LOOK FOR SUPPLEMENTARY INFO IN ABOVE PAPER 
 

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NMR
SEE AN ONLINE NMR BELOW




 

NMR…………http://file.selleckchem.com/downloads/nmr/S400205-Sitagliptin-phosphate-monohydrate-HNMR-Selleck.pdf





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PAPER





Graphical abstract: Quantitative analysis of sitagliptin using the 19F-NMR method: a universal technique for fluorinated compound detection

 

http://pubs.rsc.org/en/content/articlelanding/2014/an/c4an01681e#!divAbstract

Quantitative analysis of sitagliptin using the 19F-NMR method: a universal technique for fluorinated compound detection

*
Corresponding authors
a
State Key Laboratory of
Natural Medicines, Department of Pharmaceutical Analysis, China
Pharmaceutical University, Nanjing 210009, China E-mail:
ayanju@163.com
b
Shanghai Institute for Food and Drug Control, Shanghai 201203, China
c
Department of Chemistry
and Chemical Engineering, Royal Military College of Canada, Kingston,
Canada
d
Pharmaceutical Research
Institute, China Pharmaceutical University, Nanjing 210009, China E-mail:
cpunmrswb@163.com
Analyst, 2015,140, 280-286


DOI:
10.1039/C4AN01681E

 


Vishva Shah, Royal Military College of Canada


 

CHECK OUT PREDICTIONS
UNDERSTAND THE SIGNALS
PREDICTIONS 1H NMR

Sitagliptin phosphate monohydrate NMR spectra analysis, Chemical CAS NO. 654671-77-9 NMR spectral analysis, Sitagliptin phosphate monohydrate H-NMR spectrum

PREDICTIONS 13 C NMR
LOOK FOR DELTA VALUES OF GROUPS
Sitagliptin phosphate monohydrate NMR spectra analysis, Chemical CAS NO. 654671-77-9 NMR spectral analysis, Sitagliptin phosphate monohydrate C-NMR spectrum
COSY NMR PREDICTION

BELOW PAPENT DESCIBES THIS DRUG WELL IS RANDOMLY CHOSEN


http://www.google.com/patents/EP2491040A2?cl=en

The present invention relates to a novel method of preparing sitagliptin, and intermediates used therein. BACKGROUND OF THE INVENTION
Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved in October 2006 by the US Food and Drug Administration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes and it is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent).
Various methods for preparing sitagliptin and sitagliptin phosphate have been developed. For example, International Patent Publication WO 2003/004498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert Homologation using t-butoxylcarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid as a sitagliptin intermediate, as shown in Reaction Scheme 1.
Reaction Scheme 1
Figure imgf000003_0001
Wherein,
Boc is tert-butoxycarbonyl, TEA is trimethylamine, HOBt is 1- hydroxybenzotriazole, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, and DIPEA is N,N-diisopropylethylamine.
International Patent Publication WO 2004/087650 discloses a method for preparing sitagliptin phosphate comprising the steps of: subjecting (2,4,5- trifluorophenyl)acetic acid to two-step reactions to obtain methyl 4-(2,4,5- trifluorophenyl)-3-oxophenylbutylate; conducting a stereoselective reduction of the resulting compound in the presence of (S)-BrNAP-RuCl2-Et3N under a high hydrogen pressure; hydrolyzing the reduced product to obtain (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid, a key sitagliptin intermediate; and subjecting (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid to seven-step processes to obtain sitagliptin phosphate, as shown in Reaction Scheme 2.
Reaction Scheme 2
Figure imgf000004_0001
Wherein,
BINAP is 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, Bn is benzyl, DIAD is diisopropyl azodicarboxylate, NMM is N-methylmorpholine, and ACN is acetonitrile.
Further, International Patent Publication WO 2004/085661 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a platinum catalyst, PtO2, as shown in Reaction Scheme 3. Reaction Scheme 3
Figure imgf000005_0001

Further, WO 2005/097733 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine employing a rhodium-based catalyst, [Rh(cod)Cl]2 having a chiral diphosphine ligand, as shown in Reaction Scheme 4.

Figure imgf000005_0002
The document [J. Am. Chem. Soc, 2009, 131, p.l 1316-11317] discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a ruthenium-based catalyst, Ru(OAc)2 having a chiral diphosphine ligand, and International Patent Publication WO 2009/064476 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using Ru(OAc)2and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent (e.g., NaBH4).
Reaction Scheme 5
Figure imgf000009_0001
Example 1: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)- oxirane
Figure imgf000013_0001
Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol
Magnesium (Mg) (1.26 g) was suspended in tetrahydrofuran (THF) (10 ml), and a drop of 1,2-dibromoethane was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (0.55 g) was added dropwise slowly and then stirred for 30 min. 2,4,5-trifluorobenzene bromide (9.0 g) dissolved in THF (50 ml) was added slowly dropwise to the resulting mixture for 30 min and then stirred at room temperature for 1 hour. Cul (0.72 g) was added to the resulting mixture and the reaction temperature was cooled to 0°C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added dropwise to the resulting mixture slowly over 30 min, heated to room temperature, and stirred for 2 hours. Satuated NH4CI (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane
(2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml), and NaOH (2.3 g) was added dropwise thereto. The resulting mixture was stirred for 1 hour and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (6.8 g; yield: 80%).
1H-NMR(300MHz, CDC13): 6 7.17-7.05 (2H, m), 6.96-6.88 (2H, m), 3.16-3.13 (1H, m) 3.14 (1H, dd, J=4.68, 14.7), 2.82-2.77 (2H, m), 2.54-2.47 (1H, m). Preparation Example 2: Preparation of (2S)-2-(2,4,5-trifIuorobenzyl)- oxirane
Figure imgf000014_0001
Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol
2N -PrMgCl (26 ml) suspended in THF was added dripwise to the 2,4,5-trifluorobenzene bromide (9.55 g) dissolved in THF (30 ml) at -15 °C for 60 min. Cul (0.72 g) was added thereto at -15 °C , and heated to -10 °C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added slowly to the resulting mixture, and stirred at 0 °C for 1 hour. Satuated NH4C1 (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in 50 ml of methanol, and NaOH (2.3 g) was added dropwise thereto. A mixture was stirred for 1 hour, and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added thereto, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.6 g; yield: 85%). Example 1: Preparation of Sitagliptin
Step 1: Preparation of (2R)-l-(2,4,5-trifluorophenyl -4-pentene-2-ol
Figure imgf000015_0001
CuBr(CH3)2 (3.3 g) was added to a reactor under the nitrogen atmosphere and cooled to -78 °C . Vinylmagnesium bromide (240 ml) was added slowly to the reactor and stirred for 20 min. (2S)-2-(2,4,5- trifluorobenzyl)-oxirane (30 g) dissolved in THF (90 ml) was added dropwise slowly over 30 min, stirred at -78 °C for 30 min, and heated to 0 °C . 2N aqueous HC1 (300 ml) was added slowly to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (34.5 g; yield: 100%).
1H-NMR(300MHz, CDC13): δ 7.15-7.06 (1H, m), 6.94-6.86 (1H, m), 5.85-5.79 (1H, m), 5.20-5.14 (2H, m), 3.90-3.85 (1H, m), 3.82 (1H, dd, J=4.6, 18.5), 2.69 (1H, dd, J=7.9, 14.0), 2.37-2.32 (1H, m), 2.24-2.17 (1H, m), 1.86(1H, Br). Step 2: Preparation of (2S)-l-(2-azido-4-pentenyl)-2A5-trifluorobenezene
Figure imgf000016_0001
Dichloromethane (300 ml) was added to the (2R)-1 -(2,4,5- trifluorophenyl)-4-pentene-2-ol obtained in step 1, and cooled to 0°C . Triethylamine (20.4 ml) and 4-dimethylaminopyridine (DMAP) (1.57 g) were added successively to the mixture, and methansulfonyl chloride (1 1.2 ml) was added dropwise thereto for 30 min. The resulting mixture was stirred for 1 hour, water (150 ml) was added, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure. The residue thus obtained was dissolved in DMF (300 ml), and NaN3 (9.91 g) was added thereto. The resulting mixture was heated to 70 °C , stirred for 2 hours, and cooled to room temperature. And then water (150 ml) and ethyl acetate (150 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The organic layer was washed twice with 150 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (31.5 g; yield: 94%).
1H-NMR(300MHz, CDC13): δ 7.11-7.02 (1H, m), 7.97-6.87 (1H, m), 5.89-5.80 (1H, m), 5.23-5.17 (1H, m), 3.63-3.59 (1H, m), 2.87 (1H, dd, J=4.7, 18.7), 2.68 (1H, dd, J=7.9, 13.7), 2.38-2.17 (2H, m). Step 3: Preparation of (3R)-3-azido-4-(2A5-trifluorophenyl)-butyric acid
Figure imgf000017_0001
Acetonitril (300 ml) and water (300 ml) were added to the (2S)-l-(2- azido-4-pentenyl)-2,4,5-trifluorobenezene obtained in step 2, and cooled to 0°C . RuCl3 (0.5 g) and NaIO4 (93 g) were added to the mixture successively, and stirred for 5 hours. Ethyl acetate (90 ml) was added to the resulting mixture, filtered and the organic layer formed thereafter was separated. The separated organic layer was washed with IN HC1 (300 ml), satuated aqueous Na2S2O3 (300 ml) and satuated saline (300 ml), successively, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (32.2 g; yield: 100%). 1H-NMR(300MHz, CDC13): 5 10.5 (1H, br), 7.17-7.05 (1H, m), 7.02-
6.87 (1H, m), 4.14-4.03 (1H, m), 2.94-2.78 (2H, m), 2.65-2.51 (2H, m).
Step 4: Preparation of (3R)-3-azido-l-(3-trifluoromethyl-5,6-dihydro-8H- [ 1 ,2,41triazolor4,3-alpyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan- 1 -one
Figure imgf000017_0002
(3R)-3-azido-4-(2,4,5-trifluorophenyl)-buryric acid (5 g) obtained in step 3 and triazole derivative of formula (VI) (5.3 g) were added to DMF (40 ml) and water (20 ml), stirred for 15 min, and cooled to 10°C . N- methylmorpholine (2.4 ml) was added to the mixture, stirred for 10 min, and cooled to 0 °C . EDC (5.6 g) was added to the resulting mixture, and stirred for 1 hour. Ethyl acetate (50 ml) and water (25 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed four times with 50 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.8 g; yield: 93%).
1H-NMR(300MHz, CDC13): δ 7.20-7.11 (1H, m), 6.99-6.90 (1H, m), 5.20-4.96 (2H, m), 4.28-4.05 (5H, m), 2.98-2.67 (4H, m).
Step 5: Preparation of sitagliptin
Figure imgf000018_0001
(3R)-3-azido- 1 -(3-trifluoromethyl-5,6-dihydro-8H-[ 1 ,2,4]triazolo[4,3- a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan-l-one (6.4 g) obtained in step 4 and triphenylphosphin (4.3 g) were dissolved in THF (74 ml), heated to 50 °C , and stirred for 2 hours. An aqueous NH4OH (37 ml) was added to the resulting mixture and stirred for 10 hours. THF was removed from the resulting mixture under a reduced pressure, HCl (30 ml) and ethyl acetate (60 ml) were added threreto, and stirred. The water layer separated from the mixture was washed twice with 30 ml of n-hexane, satuated sodium bicarbonate was added to the water layer, and extracted three times with 60 ml of ethyl acetate. The resulting extracts were dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (5.2 g; yield: 86%).
1H-NMR(300MHz, CDC13): δ 7.14-7.06 (1H, m), 7.00-6.88 (1H, m), 5.13-4.88 (2H, m), 4.24-3.80 (4H, m), 3.58 (1H, m), 2.85-2.66 (2H, m), 2.61-2.46 (2H, m), 2.11 (3H, br).
ABOVE IS ONLY ONE EXAMPLE LEADING TO SITAGLIPTIN



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(S)-Sitagliptin……….Synfacts by Thieme

 

For description see at synfacts

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

Contributor: Philip Kocienski

Philip Kocienski, Professor of Organic Chemistry.

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

 

Bao H, Bayeh L, Tambar UK * The University of Texas Southwestern Medical Center at Dallas, USA
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

Synlett 2013;
24: 2459-2463

 

 

P. J. Kocienski
School of Chemistry
University of Leeds
Leeds LS2 9JT, UK
p.kocienski@chem.leeds.ac.uk
http://www.chem.leeds.ac.uk

Philip J. Kocienski was born in Troy, New York, in 1946. His love for organic chemsitry, amply stimulated by Alfred Viola whilst an undergraduate at Northeastern University, was further developed at Brown University, where he obtained his PhD degree in 1971 under Joseph Ciabattoni. Postdoctoral study with George Büchi at MIT and later with Basil Lythgoe at Leeds University, England, confirmed his interest in the synthesis of natural products. He was appointed Brotherton Research lecturer at Leeds in 1979 and Professor of Chemistry at Southampton University in 1985. In 1990 he was appointed Glaxo Professor of Chemistry at Southampton University. He moved to the University of Glasgow in 1997, where he was Regius Professor of Chemistry and now he is a Professor of Chemistry at Leeds University.

In addition to Prof. Kocienski’s work as an author he is also a member of the SYNTHESIS Editorial Board and contributes greatly to the development of Thieme Chemistry’s journals

Furthermore, Prof. Kocienski has also contributed to the Science of Synthesis project where he was an author for Volume 4, Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds.

Prof. Kocienski is also responsible for compiling a database called Synthesis Reviews. This resource is free and contains 16,257 English review articles (from journals and books) of interest to synthetic organic chemists. It covers literature from 1970 to 2002.

SITAGLIPTIN……………..

GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine.

MERCK was selected for the award in the greener synthetic pathways category for revising the synthesis for sitagliptin, a chiral β-amino acid derivative that is the active ingredient in Januvia, the company’s pending new treatment for type 2 diabetes. The breakthrough leading to the new synthesis was the discovery that the amino group of the key enamine intermediate doesn’t need to be protected prior to enantioselective catalytic hydrogenation of the double bond.

This development has solved a long-standing problem in the synthesis of β-amino acid derivatives, which are known for their pharmacological properties and are commonly used as chiral building blocks, noted Karl B. Hansen, a Merck process chemist involved with the synthetic effort. The outcome has been to slash the number of reaction steps in the sitagliptin synthesis from eight to three, leading to an equally dramatic reduction in the amount of chemicals and solvent needed and the amount of waste generated.

Merck’s first-generation synthesis of sitagliptin involved preparing a β-hydroxy carboxylic acid, which was converted to a protected β-lactam and then coupled to a triazole building block. Deprotecting the resulting intermediate provided the β-amino acid moiety, and sitagliptin was isolated as a phosphoric acid salt.

This synthesis involved a roundabout route involving four steps to introduce the pivotal chiral amino group of sitagliptin. The synthesis worked well to prepare more than 100 kg of the compound for clinical trials, and with modifications it was deemed to be a viable though not very green manufacturing process, Hansen pointed out. For example, the original synthesis required a number of distillations and aqueous extractions to isolate intermediates, leading to a large volume of waste to treat.

“Being environmentally friendly and economically savvy can, and does, go hand-in-hand.”

Merck process chemists recognized that a much more efficient process was possible by synthesizing the β-amino acid portion of the molecule directly from an enamine. But the protection-deprotection of the amine nitrogen with an acyl group during the hydrogenation is difficult on a large scale, and unprotected reactions generally result in lower yields and lower enantiomeric excesses, Hansen said.

Undaunted, the Merck scientists working on the revised synthesis discovered that the amino group could be efficiently introduced by an unprotected hydrogenation using a rhodium catalyst with a ferrocenyl phosphine ligand named Josiphos (C&EN, Sept. 5, 2005, page 40). Merck turned to Solvias, a Swiss company with experience in asymmetric hydrogenations that manufactures Josiphos, as a partner to help speed up the process development.

The new synthesis involves first coupling trifluorophenyl acetic acid and triazole building blocks to form a diketoamide, which in turn is converted to the enamine. This sequence is carried out without isolating intermediates. The enamine is then hydrogenated, sitagliptin is isolated and recrystallized as the phosphoric acid salt, and the rhodium Josiphos catalyst is recovered.

In sum, the revised synthesis increases the overall yield of sitagliptin by nearly 50% and reduces the amount of waste by more than 80%. A key difference is that the original synthesis produced more than 60 L of aqueous waste per kg of product, while the new synthesis completely eliminates aqueous waste. When tallied up, Merck expects these savings will prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia. Industry analysts speculate that regulatory approval of the drug will come by early next year and that it’s destined to become a top-selling drug.

The novel enamine hydrogenation “is arguably the most efficient means to prepare β-amino acid derivatives,” noted R. P. (Skip) Volante, Merck’s vice president of process research. The company currently is using the procedure to make several other exploratory drug candidates, he added. Overall, the redesigned synthesis of sitagliptin “is a green chemistry solution to the preparation of a challenging synthetic target and is an excellent example of a scientific innovation resulting in benefits to the environment,” Volante said.

First generation route to sitagliptin. BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride; DIAD = di-isopropyl azodicarboxylate; NMM = N-methylmorpholine……..http://www.technology.matthey.com/article/55/2/135-139/

http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc11592h#!divAbstract

http://www.nature.com/nature/journal/v485/n7397/fig_tab/nature11117_F4.html

 

 

PAPER


SITAGLIPTIN……………..

First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin

Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Org. Process Res. Dev., 2005, 9 (5), pp 634–639
DOI: 10.1021/op0500786
Abstract Image

A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.

Figure

Figure

Figure

The synthesis of 1 was completed using a four-step through-process (Scheme 4). Lactam 5 or ester 13 was hydrolyzed to amino acid 2bwith LiOH18 in THF/water by either stirring at room temperature or, in the case of 13, heating to 40 °C. While the benzyloxy group of 2b could be cleaved by hydrogenation and then protected with Boc2O to prevent side reactions during the coupling to triazole 3, the benzyloxy group of 2b was found to sufficiently protect the amino group to allow the desired amide to be formed. Thus, triazole 3 was coupled to2b at 0 °C using EDC−HCl and N-methylmorpholine (NMM) as base to afford 14in >99% assay yield. Following an aqueous workup, the organic extracts were distilled into ethanol and the solution was subjected to hydrogenation with 10% Pd on carbon. The presence of water in the hydrogenation was found to be crucial to the reaction success; anhydrous solutions of 14 hydrogenated with dry Pd on carbon proceeded only to low levels of conversion to 1, and addition of water to these reductions resulted in restored performance of the catalyst. Following hydrogenation, the catalyst was removed by filtration to provide an ethanol solution of 1. Sitagliptin was isolated in >99.5% purity as its anhydrous phosphoric acid salt by crystallizing from aqueous ethanol.

PATENT

http://www.google.co.in/patents/WO2003004498A1?cl=en

Scott D Edmondson, Michael H Fisher,Dooseop Kim, Malcolm Maccoss, Emma R Parmee, Ann E Weber, Jinyou Xu

MORE INFO………

Sitagliptin phosphate monohydrate, a dipeptidyl-peptidase IV inhibitor, is marketed by Merck & Co. for the once-daily oral treatment of type 2 diabetes. The product was first launched in Mexico followed by commercialization in the U.S. The compound has also been filed for approval in the U.S. as adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain. In 2009, sitagliptin phosphate monohydrate was approved and launched in Japan. The product is also available in Japan for the treatment of type 2 diabetes in combination with alpha-glucosidase inhibitors and in combination therapy with insulin. In 2012, the company filed for approval in Japan for the treatment of type 2 diabetes in patients with severe renal dysfunction, and in 2013 obtained the approval.

Sitagliptin phosphate monohydrate boasts a much lower risk of hypoglycemia than currently available insulin-inducing products due to its novel mechanism of action. MSD KK (formed in 2010 following the merger of Banyu and Schering-Plough KK) and Ono are developing the drug candidate in Japan. In 2008, the compound was licensed to Almirall by Merck Sharp & Dohme for comarketing in Spain for the treatment of type 2 diabetes. In 2010, FAES obtained a comarketing and commercialization license from Merck Sharp & Dohme in Spain for the treatment of type 2 diabetes.

Januvia (sitagliptin phosphate) is an antihyperglycaemic drug containing an orally active inhibitor of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Developed by Merck Sharp & Dohme (MSD), a UK subsidiary of Merck & Co, sitagliptin is used for treating type 2 diabetes mellitus. The drug has proved effective in lowering blood sugar levels of diabetes patients when taken alone or in combination with other oral diabetes medications such as metformin and thiazolidinedione.

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006 and is marketed under the brand name Januvia in the US. Sitagliptin in combination with metformin was approved by the FDA in March 2007 and is marketed as Janumet in the US. In the EU, Januvia was approved in April 2007 and Janumet was approved in July 2008.

Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV, which was discovered by
Merck. It is a potent (IC50= 18 nM) and highly selective over DPP-8 (48000 nM), DPP-9
(>100000 nM) and other isozymes.[16] It enhances the pancreatic β-cell functions, fasting and
post-prandial glycemic control in type 2 diabetic patients. In the crystal structure with DPP-IV,
unlike other substrate-based DPP-IV inhibitors, the binding orientation of the amide carbonyl of
sitagliptin is reversed, i.e. the aromatic trifluorophenyl moiety occupies S1 pocket and the β-
amino amide moiety fits into S2 pockets. The amino group forms a salt bridge and hydrogen
bonding interactions with Glu205 and Glu206, and Tyr662, respectively.The triazolopiperazinemoiety occupies the S2 extended pocket and stacks against Phe357. The exhibited binding
interactions of the trifluoromethyl group with the Arg358 and Ser209 are responsible for its high
selectivity profile. The presence of the trifluoromethyl group in the triazole ring also improves
the oral bioavailability in animal models. Sitagliptin inhibited the plasma DPP-IV up to 80% and
47% at 2 and 24 h, respectively, after a single dose of 25.0 mg in a dose-dependent manner. In a
24-week study, sitagliptin significantly decreased fasting glucose levels and HbA1c levels
(0.8%) at doses of 100 mg q.d. Thus, sitagliptin is well tolerated and body weight neutral. It is
the first DPP-IV inhibitor in the class approved by USFDA in 2006 and is used as either a
monotherapy or in combination with metformin

S2

 

 

 

S1

S3

 

In the first synthetic approach, the synthesis of sitagliptin was started with the reaction of a Schollkopf reagent 6 with 2,4,5-trifluorobenzyl bromide to afford the compound 7, which was converted to compound 9 via hydrolysis of ester 8. The resulting Boc-protected amino acid 9 was converted to diazoketone 11 through mix anhydride protocol by using diazomethane. The intermediate 11 was converted to desired β-amino acid 12 by sonication in the presence of silver benzoate.[21] The sitagliptin (14) was synthesized by coupling of β-amino acid 12 with triazolopiperazine intermediate 5 followed by Boc deprotection of amino group of 13, and its corresponding hemi fumarate salt was then prepared (Scheme 1).[16]

SYN1

 

The second approach for synthesis of sitagliptinwas started from asymmetric reduction of β-ketoester 15 using the (S)-BinapRuCl2 complex with a catalytic amount of HBr in methanol followed by hydrolysis afforded the β-hydroxy acid 16. Lactam 17 was synthesized by coupling of 16 with BnONH2 •HCl using N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC), followed by cyclization reaction with diisopropyl azodicarboxylate (DIAD) and PPh3 . [22] Treatment of a catalytic amount of 0.1% NaOH with lactam 17 hydrolyzed and directly afforded the β-amino acid 18. This wascoupled withtriazolopiperazine 5 using EDC•HCl and N-methylmorpholine to provide the N-benzyloxy protected compound 19, which after hydrogenation using Pd/C and by consequent treatment with phosphoric acid provided the phosphate salt of sitagliptin (14) (Scheme 2).

 

SYN2

The third approach towards the synthesis of sitagliptin is outlined in scheme 3. Meldrum adduct 22 (Hunig’s base salt) was synthesized from trifluorophenylacetic acid 20 by the formation of a mixed anhydride with pivaloyl chloride in the presence of Meldrum’s acid 21, DIPEA and catalytic amount of dimethylamino pyridine (DMAP) in acetonitrile. Treatment of 22 with TFA resulted compound 23. β-keto amide 24 was formed on reaction of 23 with triazolopiperazine 5. β-keto amide 24 on treatment with ammonium acetate in methanol formed a key intermediate, dehydrositagliptin 25 (enamine amide). This intermediate contains the entire structure of sitagliptin 14 except two hydrogen atoms. Thus, sitagliptin 14 was synthesized by enantioselective hydrogenation of dehydrositagliptin 25 in the presence of [Rh(COD)2 OTf] 12,13 and t Bu JOSIPHOS in excellent yield with 95% ee.[23,24]

SYN3

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

 

 

 

 REF

 

http://www.apiindia.org/medicine_update_2013/chap88.pdf

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

 

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MELOGLIPTIN

 diabetes, phase 2, Uncategorized  Comments Off on MELOGLIPTIN
Jul 032015
 

 

GRC 8200; 868771-57-7, EMD-675992

4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile

4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile

GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America for the treatment of type 2 diabetes, however, these rights were reaquired by Glenmark in 2008.