(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)
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, CDCl
3) 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, CDCl
3)
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, CDCl
3)
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, CDCl
3) 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, CDCl
3) 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
Gregory R. Bebernitz*†, Valerie Beaulieu†, Bethany A. Dale†, Richard Deacon†, Alokesh Duttaroy†, Jiaping Gao†, Melissa S. Grondine†, Ramesh C. Gupta‡, Mesut Kakmak†, Michael Kavana†, Louise C. Kirman†, Jinsheng Liang†, Wieslawa M. Maniara†, Siralee Munshi‡, Sunil S. Nadkarni‡, Herbert F. Schuster†, Travis Stams†, Irene St. Denny†, Paul M. Taslimi†, Brian Vash† and Shari L. Caplan†
† 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
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 (αK
a = 39 nM)
in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
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
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
| 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
