GEMIGLIPTIN
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.
A 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  |
| 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-8, DPP-9, elastase,trypsin, urokinase 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 HbA1c, FPG 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.
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WO 2006104356
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]
[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)
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WO 2012030106
Reaction Scheme 1
PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
- 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.2008.10.013. PMID 19014837.
- 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:10.5772/23604. ISBN 978-953-307-657-7.
- 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/s00535-013-0783-4. PMID 23475323.
- 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.2014.50. PMID 24687121.
- 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/cp201568. PMID 22192641. |
- Rhee EJ, Lee WY, Yoon KH, Yoo SJ, Lee IK, Baik SH, Kim YK, Lee MK, Park KS, Park JY, Cha BS, Lee HW, Min KW, Bae HY, Kim MJ, Kim JA, Kim DK, Kim SW (December 2010). "A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes". Diabetes Obes Metab.12 (12): 1113–1119. doi:10.1111/j.1463-1326.2010.01303.x. PMID 20977584.
- Lim KS, Cho JY, Kim BH, Kim JR, Kim HS, Kim DK, Kim SH, Yim HJ, Lee SH, Shin SG, Jang IJ, Yu KS (December 2009). "Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers". Br J Clin Pharmacol. 68 (6): 883–890. doi:10.1111/j.1365-2125.2009.03376.x. PMC 2810799.PMID 20002082.
- Dal-Mi Hwang, Sung-Ho Kim, Min-Kyung Yoon, O Hwan Kwon, Ki Dong Koo, Changhee Min, Sung-Hack Lee, Jaeick Lee, Chang-Seok Lee, Hyeon Joo Yim (June 2008). "LC15-0444 is a novel, potent, selective, and orally active dipeptidyl peptidase IV inhibitor" (PDF). American Diabetes Association 68th Scientific Sessions.
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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Gastric inhibitory polypeptide (GIP) is an important metabolic hormone in animals. It has a special molecular structure and plays an important physiological role in animal organisms. Gastric Inhibitory Polypeptide
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