Synthesis, characterization, and DGAT1 inhibition of new 5-piperazinethiazole and 5-piperidinethiazole analogs

Article abstract of DOI:10.1002/jhet.2194

In this study, a novel series of 5-piperazinethiazole 2,2-dimethylbutanoic acid and 5-piperidinethiazole 2,2-dimethylbutanoic acid derivatives have been synthesized. Structures of the newly synthesized compounds have been elucidated using ¹H-NMR, ¹³C-NMR, high-resolution mass spectroscopy, and high-performance liquid chromatographic analysis. The synthesized derivatives have been evaluated in vitro for their ability to inhibit the enzyme diacylglycerol acyltransferase 1 responsible for triglyceride biosynthesis.

Full text of DOI:10.1002/jhet.2194

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New
5-Piperazinethiazole and 5-Piperidinethiazole Analogs
a
b
c
a
a
*
Kishorkumar S. Kadam, Thirumanavelan Gandhi, M. Maheshkumar Reddy, Amol Gupte, and Rajiv Sharma
aDepartment of Medicinal Chemistry, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai
400063, India
bMaterial Chemistry Division, School of Advanced Sciences, VIT University, Vellore, 632014, Tamil Nadu, India
cDepartment of Pharmacology, Piramal Enterprises Limited, 1-Nirlon Complex, Goregaon (E), Mumbai 400063, India
*
E-mail: amol.gupte@piramal.com
Received September 2, 2013
DOI 10.1002/jhet.2194
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
In this study, a novel series of 5-piperazinethiazole 2,2-dimethylbutanoic acid and 5-piperidinethiazole
2,2-dimethylbutanoic acid derivatives have been synthesized. Structures of the newly synthesized
compounds have been elucidated using 1H-NMR, 13C-NMR, high-resolution mass spectroscopy, and
high-performance liquid chromatographic analysis. The synthesized derivatives have been evaluated in vitro
for their ability to inhibit the enzyme diacylglycerol acyltransferase 1 responsible for triglyceride biosynthesis.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
Diacylglycerol acyltransferase 1 (DGAT1) is an enzyme
involved in the final committed step of triglyceride biosyn-
thesis [1]. Inhibitors of DGAT1 can find potential applica-
tion as anti-obesity agents [2] and in conditions that require
reduction in triglycerides. Several DGAT1 inhibitors have
been reported (Fig. 1). A recent publication [3] highlights
a series of carboxylic acid derivatives, exemplified by com-
pound 1, as DGAT1 inhibitors. Of late, we have reported
[4] a substituted 5-phenyl thiazole scaffold, exemplified
by compound 2, for its DGAT1 inhibition. We further
identified that combining a carboxylic acid such as 2,2-
dimethylbutanoic acid along with 5-phenylthiazole, as
shown in compound 3, also exhibited promising DGAT1
A common intermediate, CBZ-glycine (7), required
for the synthesis of the desired 5-piperazinethiazole
and 5-piperidinethiazole scaffolds, was synthesized by
incorporating a benzyl carbamate protection (CBZ) on
the amine functionality of glycine (6) using benzyl
chloroformate (Scheme 1) as reported in literature [6].
Another important intermediate, 5-methoxy-4,4-dimethyl-
5-oxopentanoic acid (10), was also synthesized (Scheme 2)
using literature mentioned procedure [7] starting from
2,2-dimethyl glutaric anhydride (8).
The synthesis of 5-piperazinethiazole 2,2-dimethylbutanoic
acid derivatives (19–27) was initiated (Scheme 3) by the BOC
(tert-Butyloxy carbamate) protection of 1-benzylpiperazine
(11) with BOC anhydride [8] to 1-BOC-4-benzylpiperazine
(12). Compound 12 was subjected to debenzylation using
10% Pd/C and ammonium formate [9] to yield the
corresponding tert-butyl piperazine-1-carboxylate (13).
Compound 13 was then coupled along with compound 7
using HATU [10] to afford the amide, tert-butyl 4-(2-
(((benzyloxy)carbonyl)amino)acetyl)piperazine-1-carbox-
ylate (14). Deprotection of the CBZ [11] group on 14 by
hydrogenation in the presence of 10% Pd/C afforded the
free amine, tert-butyl 4-(2-aminoacetyl)piperazine-1-
carboxylate (15). Compound 15 was further coupled with
compound 10 in the presence of HATU as the coupling
reagent to give tert-butyl 4-(2-(5-methoxy-4,4-dimethyl-
5-oxopentanamido)acetyl)piperazine-1-carboxylate (16).
Cyclization of 16 using Lawesson’s reagent [12] resulted
in the formation of BOC protected 5-piperazinethiazole
inhibition and resulted in
a 5-phenylthiazole 2,2-
dimethylbutanoic acid scaffold [5]. In our efforts to
identify novel heterocyclic scaffolds for DGAT1
inhibition, we envisaged replacing the phenyl ring of our
5-phenylthiazole 2,2-dimethylbutanoic acid scaffold with
non-aromatic saturated heterocycles such as piperazine
and piperidine (Fig. 2). This modification resulted in
5-piperazinethiazole 2,2-dimethylbutanoic acid (4) and
5-piperidinethiazole 2,2-dimethylbutanoic acid (5) scaf-
folds. Diversifications at both these scaffolds were under-
taken by attaching substituted phenyl or cyclohexyl
groups to the 5-piperazinethiazole or 5-piperidinethiazole
cores through a variety of linkers. The synthesis, cha-
racterization, and in vitro DGAT1 activity of these novel
5-piperazinethiazole and 5-piperidinethiazole derivatives
is discussed.
© 2014 HeteroCorporation

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
Figure 1. Structures of some diacylglycerol acyltransferase 1 inhibitors.
Figure 2. 5-Piperazinethiazole and 5-piperidinethiazole scaffolds.
Scheme 1. Synthesis of CBZ-glycine (7)
Scheme 2. Synthesis of 5-methoxy-4,4-dimethyl-5-oxopentanoic acid (10).
2,2-dimethylbutanoate methyl ester (17). Deprotection of
BOC [13] protecting functionality in 17 under acidic condi-
tions resulted in the key intermediate, methyl 2,2-dimethyl-
4-(5-(piperazin-1-yl)thiazol-2-yl)butanoate hydrochloride
(18), which was subsequently used for further diversification.
The use of two different amine protecting groups, BOC and
CBZ, in this synthetic route provides for orthogonal protec-
tion of the two amine functionalities allowing for successful
implementation of this synthetic strategy. However, revers-
ing this protecting strategy by incorporating CBZ protection
on the benzyl piperazine and BOC protection on the glycine
proved ineffective as the eventual deprotection of the CBZ
group to yield compound 18 was unsuccessful.
various isocyanates in the presence of triethylamine
followed by alkaline hydrolysis using lithium hydroxide
afforded the corresponding urea compounds (19–21).
Similarly coupling with acid chlorides yielded the corre-
sponding amide analogs (22–24) and using sulfonyl
chlorides in place of isocyanates yielded the corre-
sponding sulfonamide derivatives (25–27). Replacing
1-benzylpiperazine (11) with 1-benzylpiperidin-4-amine
(28) and following a similar sequence as in the case
of 5-piperazinethiazole scaffold yielded the key amino
piperidine intermediate methyl 4-(5-(4-aminopiperidin-
1-yl)thiazol-2-yl)-2,2-dimethylbutanoate hydrochloride (35).
Urea (36–40), amide (41), and sulfonamide (42 and 43)
derivatives were synthesized from compound 35 following
treatment with corresponding isocyanates, acid chloride, and
sulfonyl chlorides respectively (Scheme 4).
Diversification of compound 18 at the piperazine –
NH was subsequently undertaken to yield the desired
5-piperazinethiazole derivatives. Treatment of 18 with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
Scheme 3. Synthesis of 5-piperazinethiazole 2,2-dimethylbutanoic acid derivatives (19–27).
The structures of these newly synthesized 5-piperazine
thiazole and 5-piperidine thiazole analogs were confirmed
using 1H-NMR, 13C-NMR, and high-resolution mass
spectroscopic (HRMS) analysis. In addition, high-performance
liquid chromatographic (HPLC) purities of these final
compounds (19–27 and 36–43) were also determined. The
1H-NMR of 5-piperazinethiazole analogs (19–27) recorded
in DMSO-d6 exhibits a singlet representing the thiazole –
CH proton around 6.8 ppm. All piperazine –CH2 protons
appear between 2.9–3.1 and 3.2–3.6 as multiplets. The
two –CH3 protons of dimethyl butanoic acid side chain
appear as a sharp singlet around 1.1 ppm. The –CH2
protons present on a carbon adjacent to the thiazole ring
appear between 2.7 and 2.8 ppm whereas the methylene
protons adjacent to dimethyl carbon appear between 1.7
and 1.8 ppm as multiplets. Aromatic protons of the phenyl
substituents appear between 7.0 and 8.3 ppm. Protons of
the cyclohexyl substituent appear as multiplets between
1.1 and 1.8 ppm. In case of 5-piperidine thiazole analogs
(36–43), the 1H-NMR signal due to thiazole –CH appears
around 6.7 ppm as a singlet. The 4-position –CH proton of
the piperidine ring appears as a multiplet between 3.6 and
3.7 ppm. All other piperidine –CH2 protons are scattered
as multiplets between 1.3–3.3 ppm. The acid head protons
of the dimethyl butanoic acid side chain appear as multi-
plets around 1.7–1.8 ppm and 2.7–2.8 ppm. The –NH of
the 4-amino piperidine appears around 6.7 ppm as a
doublet. Aromatic protons of the phenyl substituent
appear between 6.6 and 8.0 ppm. Protons of the cyclohexyl
substituent appear as multiplets between 1.1 and
1.8 ppm. These signals appear to be consistent with the
structures of the final compounds (19–27 and 36–43).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
Scheme 4. Synthesis of 5-piperidinethiazole 2,2-dimethylbutanoic acid derivatives (36–43).
In the 13C-NMR of 5-piperazine thiazole analogs (19–27)
recorded in DMSO-d6, the carboxylic acid carbon appears con-
sistently around 178.8 ppm. The prominent signals correspond-
ing to the carbons of thiazole ring in all compounds were
observed nearly at 122.4, 154.1, and 158.5 ppm. In case of urea
derivatives, carbonyl carbon appears around 155.4 ppm,
whereas amide carbonyl appears around 169.6 ppm. The piper-
azine –CH2 carbons appear around 52.3 ppm. The carbon on
the 2,2 dimethyl carboxylic acid side chain that is attached di-
rectly to the thiazole ring appears around 29.4 ppm and the
one next to it appears around 41.6 ppm. The quartenary carbon
adjacent to the carboxylic acid and the dimethyl carbons on it
appear around 43.6 and 25.3 ppm, respectively. In case of the
13C-NMR of 5-piperidine thiazole analogs (36–43) the –CH2
carbons next to the ring nitrogen appear around 51.1 ppm ,
the –CH2 carbons next to these appear around 31.4 ppm, and
the piperidine –CH also appears around 51.1 ppm . The
carbon assignments are a further proof of evidence
towards these compound structures. The HRMS were
also found to be in agreement with molecular formulae
of the synthesized compounds. The HRMS spectra of
all final compounds with an error range of less than 5.0
ppm along with their HPLC chromatograms provide
substantial proof of purity for these compounds. Thus
all synthesized compounds exhibited spectral data con-
sistent with their structures.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
Diacylglycerol acyltransferase 1 inhibition. The synthesized
heterocyclic analogs were studied in vitro for their DGAT1
inhibition using (Tables 1 and 2) an enzymatic assay that
measured a triolein output from diolein and radiolabeled
oleoyl-CoA [14]. These DGAT1 assays were performed
using 2.5 μg of the protein from a post nuclear supernatant
preincubated with 100 μL of the assay buffer [100 mM Tris-
HCl (pH 7.5), 250 mM sucrose, and 1.25 mg/mL fatty acid
Table 1
Diacylglycerol acyltransferase 1 inhibition of 5-piperazinethiazole analogs.
Compound no.
19
Linker
R
DGAT 1% inhibition [1 μM]
31
20
22
21
22
30
33
23
34
24
25
42
34
26
27
49
30
84
2 (Standard)
—
—
DGAT1, diacylglycerol acyltransferase 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
Table 2
Diacylglycerol acyltransferase 1 inhibition of 5-piperidinethiazole analogs.
Compound no.
36
Linker
R
DGAT 1% inhibition [1 μM]
NA
NA
15
37
38
39
07
40
41
42
NA
20
16
43
NA
84
2 (Standard)
—
—
DGAT1, diacylglycerol acyltransferase 1; NA, not active.
free BSA] containing a known concentration of the inhibitor
and supplemented using 2047.5 μM of 1,2-dioleoylglycerol.
The DGAT1 reaction was initiated following an addition of
16.8 nci of [14C]-oleoyl CoA. The reaction was terminated
after 10 min of incubation at 37°C using 300 μL alkaline
ethanol stop solution mix [12.5% of 100% non-
denatured ethanol, 10% deionized water, 2.5% NaOH,
and 75% stop solution (78.4% isopropanol, 19.6%
n-heptane, and 2% deionized water)]. The 14C
triglyceride formed in this reaction was extracted using
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
using a Waters Alliances 2695 system implementing either
method A or method B.
High-performance liquid chromatography solvents.
A: Acetonitrile
B: 0.01 M NH4OAc + 0.5% TEA, pH 5.0 with AcOH
High-performance liquid chromatography columns.
Column 1: Poroshell 120 C18, (50 × 4.6 mm I.D.),2.7 μm
operated at 1 mL/min, detection at 239 nm
Column 2: Ascentis TM Express (50 × 4.6 mm I.D.), 2.7 μm
operated at 1 mL/min, detection at 288 nm
High-performance liquid chromatography methods.
Method A: Elution with 20–80% linear gradient of A in 6 min
followed by 20–80% linear gradient of B in 1 min that is
continued using a isocratic elution with 80% B for 3 min using
Column 1.
Method B: Elution with 20–80% linear gradient of A in 6 min
followed by 20–80% linear gradient of B in 1 min that is
continued using an isocratic elution with 80% B for 3 min using
600 μL of heptane. A total of 250 μL of this extracted
heptane was added to scintillation fluid and subjected to
radioactivity measurement. The screening of DGAT1
inhibitors was carried out at 1.0 μM concentration.
Compound 2 (DGAT1 inhibition = 84% [1 μM]) [4] that
has been developed in-house was used as a standard during
the assay. Compounds possessing the 5-piperazinethiazole
2,2-dimethylbutanoic acid scaffold (Table 1, 19–27) exhibited
moderate DGAT1 inhibition ranging from 22–49%. Com-
pounds 19–21 possessing the urea linker exhibited
DGAT1 inhibition ranging from 22% to 32%, compounds
22–24 possessing the amide linker ranged between 30%
and 35% while compounds 25–27 possessing the
sulfonamide linker ranged between 30% and 49%. On
the other hand, compounds possessing the 5-
piperidinethiazole 2,2-dimethylbutanoic acid scaffold
(Table 2, 36–43) exhibited low DGAT1 inhibition at
1 μM concentration. While the urea analogs (36–40) in
this scaffold ranged in between 0–16%, the amide
analog 41 exhibited 20% DGAT1 inhibition, and the
sulfonamide analogs 42 and 43 exhibited 16% and 0%
DGAT1 inhibition, respectively. The 5-piperazinethiazole
2,2-dimethylbutanoic acid scaffold thus appears better than
the 5-piperidinethiazole 2,2-dimethylbutanoic acid scaffold.
Column 2.
2-(((Benzyloxy)carbonyl)amino)acetic acid (7). A mixture
of compound 6 (10 g, 133 mmol, 1.0 equiv) and 2.0 N aqueous
sodium hydroxide solution (253 mL, 506 mmol, 3.9 equiv) were
cooled in an ice bath to 0°C. Under vigorous stirring benzyl
chloroformate (19 mL, 133 mmol, 1.0 equiv) and 2.0 N aqueous
sodium hydroxide solution (280 mL, 560 mmol, 4.2 equiv) were
added simultaneously over a period of 2 min. The resulting
mixture was stirred for 20 min at RT and extracted with diethyl
ether (4 × 150 mL). The aqueous layer was separated and
acidified using concentrated HCl to a pH of 2.0. The resulting
emulsion was extracted with ethyl acetate (3 × 200 mL). The
organic phases were combined, washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure to
afford the title compound as light brown needles (11 g, 40%);
1H-NMR (300 MHz, DMSO-d6): δ 12.56 (bs, 1H, –COOH),
7.56 (t, J = 6.0 Hz ,1H, amide–NH), 7.33–7.32 (m, 5H, PhH),
5.02 (s, 2H, –OCH2), 3.66 (d, J = 6.0 Hz , 2H, –C(O)CH2); mp:
CONCLUSIONS
In summary, we have described the synthesis of two novel
scaffolds, 5-piperidinethiazole 2,2-dimethylbutanoic acid
and 5-piperazinethiazole 2,2-dimethylbutanoic acid. The
1
synthesized compounds were characterized using H-NMR,
118–120°C; MS (ESIÀ): m/z 210.1 [M + H]+
13C-NMR, HRMS, and HPLC analysis. The synthesized
derivatives were evaluated for their DGAT1 enzymatic assay
wherein the 5-piperazinethiazole 2,2-dimethylbutanoic acid
derivatives exhibited moderate DGAT1 inhibition and
the 5-piperidinethiazole 2,2-dimethylbutanoic acid ana-
logs exhibited low DGAT1 inhibition.
Dimethyl 2,2-dimethylpentanedioate (9). To a solution of
3,3-dimethyldihydro-2H-pyran-2,6-(3H)-dione (30 g, 211 mmol,
1.0 equiv) in MeOH (300 mL) was added catalytic amount of
H2SO4 (0.2 mL, 4.2 mmol, 0.02 equiv) under nitrogen and
heated to 55°C for 24 h. The reaction mass was cooled and
solvent was removed under reduced pressure to obtain pale
brown oil. The oil was purified by silica gel column
chromatography using 2:8 EtOAc:petroleum ether to obtain title
1
compound as an oil (33 g, 83%); H-NMR (300 MHz, CDCl3):
EXPERIMENTAL
δ 3.68 (s, 6H, –OCH3), 2.32–2.27 (m, 2H, –C(O)–CH2), 1.92–
1.86 (m, 2H, –CH2–C–), 1.20 (s, 6H, –C(CH3)2); MS (ESI+):
Unless mentioned otherwise, all reactions were performed un-
der atmosphere. Unless otherwise specified all reagents were
obtained from Aldrich and solvents were obtained from Thomas
Baker and used without further purification. 1H-NMR (either
300 or 500 MHz) and 13C-NMR (either 75 or 125 MHz) spectra
were recorded on a Bruker spectrometer using either CDCl3 or
DMSO-d6 as the solvent. Chemical shifts, δ, are reported in
ppm relative to the solvent peak. Multiplicities are indicated by
s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet),
and m (multiplet). Coupling constants, J, are reported in Hertz.
Mass spectral (MS) data were obtained on a Bruker Daltonics
spectrometer using an electrospray ionization-quadrupole-time
of flight analyzer. All melting points have been determined on a
manually operated Veego (VMP-1) melting point apparatus and
are reported uncorrected. HPLC purities have been determined
m/z 189.1 [M + H]+.
5-Methoxy-4,4-dimethyl-5-oxopentanoic acid (10). To a
solution of dimethyl 2,2-dimethylpentanedioate (30g, 159 mmol,
1.0 equiv) in MeOH (300mL) and THF (198 mL) was added
K2CO3 (44.1 g, 319mmol, 2.0 equiv) followed by Water
(198 mL) and stirred at RT for 24 h. The organic solvent was
removed at reduced pressure to obtain residue which was poured
onto water and extracted with ethyl acetate (2 × 100mL). The
aqueous layer was acidified with 3.0 N HCl and extracted with
ethyl acetate (3 × 250mL). Then combined organic layer was
washed with brine solution, dried over sodium sulfate, and
evaporated to obtain the title compound as an oil (22g, 79%);
1H-NMR (300 MHz, DMSO-d6): δ 12.10 (bs, 1H, –COOH),
3.59 (s, 3H, –OCH3), 2.16–2.10 (m, 2H, –C(O)CH2), 1.75–1.70
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
(m, 2H, –CH2–C–), 1.10 (s, 6H, –C(CH3)2); MS (ESIÀ): m/z
173 [M–H]À.
tert-Butyl 4-(2-(5-methoxy-4,4-dimethyl-5-oxopentanamido)
acetyl)piperazine-1-carboxylate (16). To solution of
a
tert-Butyl 4-benzylpiperazine-1-carboxylate (12). To
a
compound 10 (6.6g, 41.1mmol, 1.0 equiv) in DMF (200mL)
were added HATU (18.7g, 49.3mmol, 1.2 equiv), compound 15
(10 g, 41.1 mmol, 1.0 equiv), and TEA (11.5mL, 82mmol, 2.0
equiv). The reaction mixture was stirred at RT for 4 h following
which it was concentrated under vacuum to obtain a pale brown
residue. This was further purified by silica gel column
chromatography using 1:9 MeOH:CHCl3 to get a pale green solid.
The solid was crystallized in chloroform/petroleum ether to obtain
the title compound as a white solid (15.1 g, 92%); 1H-NMR
(300 MHz, DMSO-d6): δ 7.93 (t, 1H, J = 5.4 Hz, amide–NH),
4.05–3.90 (d, J = 5.4 Hz, 2H, –C(O)–CH2–N–), 3.57 (s, 3H, –
OCH3), 3.38 (m, 4H, 2 × piperazine–CH2), 3.23 (m, 4H,
2 × piperazine–CH2), 2.08–2.03 (m, 2H, –C(O)CH2), 1.71–1.66
(m, 2H, –CH2–C–), 1.46 (s, 9H, –C(CH3)3), 1.18 (s, 6H, –C(CH3)2);
cooled solution of BOC anhydride (43.5 mL, 187 mmol, 1.1
equiv) and sodium bicarbonate (22.6 g, 213 mmol, 1.2 equiv) in
1,4-dioxane (300 mL) and water (300 mL) was added compound
11 (30 g, 170 mmol, 1.0 equiv) over 10 min. The resulting
suspension was stirred at 5–10°C for 1 h, allowed to warm to
RT, and then stirred for 24 h. The reaction mixture was diluted
with water and extracted with chloroform (3 × 800 mL). The
organic layer was dried over sodium sulfate and evaporated to
obtain an off-white solid. The solid was crystallized in EtOAc/
petroleum ether to yield the desired compound as a white solid
(46.5 g, 99%); 1H-NMR (300 MHz, CDCl3): δ 7.32–7.28
(m, 5H, PhH), 3.50 (s, 2H, –CH2–Ph), 3.43–3.40 (m, 4H,
2 × piperazine–CH2), 2.39–2.36 (m, 4H, 2 × piperazine–
CH2), 1.44 (s, 9H, –C(CH3)3); mp: 70–72°C; MS (ESI+):
m/z 277.2 [M + H]+.
mp: 106–108°C; MS (ESI+): m/z 400 [M + H]+.
tert-Butyl 4-(2-(4-methoxy-3,3-dimethyl-4-oxobutyl)thiazol-
5-yl)piperazine-1-carboxylate (17). To a solution of compound
16 (13g, 32.5 mmol, 1.0 equiv) in 1,4-dioxane (130 mL) was
added Lawesson’s Reagent (13.2 g, 32.5 mmol, 1.0 equiv) and
heated to reflux for 1.5 h. The reaction mixture was subsequently
cooled, diluted with water, and neutralized using a saturated
solution of sodium carbonate. The product was separated from the
aqueous mixture using EtOAc. The organic layer was dried over
sodium sulfate, filtered, and concentrated under reduced pressure
to give a dark brown residue. The residue was subjected to
column chromatography using 3:7 EtOAc:CHCl3 to get a dark
yellow colored solid that was crystallized in chloroform/petroleum
ether to yield the desired product as an off-white solid (3.6g,
tert-Butyl piperazine-1-carboxylate (13).
To a solution of
compound 12 (46 g, 166 mmol, 1.0 equiv) in MeOH
(460 mL) was added 10% palladium on carbon (4.6 g, 10%
w/w) and ammonium formate (31.5 g, 499 mmol, 3.0
equiv) and refluxed at 65°C for 2 h. The reaction mixture
was filtered through celite and the filtrate was concentrated
under reduced pressure to obtain a pale brown solid. To
this water was added and the resulting mixture was
extracted with EtOAc. The organic layer was washed with
brine, dried over sodium sulfate, and the solvent was
removed under reduced pressure to obtain an off-white
solid. The solid was crystallized in chloroform/petroleum
ether to obtain the title compound as a white solid (26 g,
84%); 1H-NMR (300 MHz, CDCl3): δ 3.39–3.36 (m, 4H,
2 × piperazine–CH2), 2.81–2.77 (m, 4H, 2 × piperazine–CH2),
1.73–1.72 (m, 1H, piperazine–NH), 1.45 (s, 9H, –C(CH3)3); mp:
1
28%); H-NMR (300 MHz, DMSO-d6): δ 6.82 (s, 1H, thiazole–
H), 3.58 (s, 3H, –OCH3), 3.43–3.40 (m, 4H, 2 × piperazine–CH2),
2.96–2.93 (m, 4H, 2 × piperazine–CH2), 2.72–2.66 (m, 2H,
thiazole–CH2), 1.87–1.81 (m, 2H, –CH2–C), 1.39 (s, 9H, –C
(CH3)3), 1.14 (s, 6H, –C(CH3)2); mp: 72–74°C; MS (ESI+): m/z
44–46°C; MS (ESI+): m/z 187.1 [M + H]+.
tert-Butyl 4-(2-(((benzyloxy)carbonyl)amino)acetyl)piperazine-
398.2 [M+ H]+.
1-carboxylate (14).
To a solution of compound 7 (15.7 g,
Methyl 2,2-dimethyl-4-(5-(piperazin-1-yl)thiazol-2-yl)butanoate
75mmol, 1.0 equiv) in DMF (280mL) were added HATU
(34.3 g, 90mmol, 1.2 equiv), compound 13 (14g, 75mmol, 1.0
equiv), and TEA (20.9 mL, 150 mmol, 2.0 equiv). The reaction
mixture was stirred at RT for 4 h followed by the removal of
organic solvent to obtain a pale brown residue. This was then
purified by silica gel column chromatography using 1:9
CH3OH:CHCl3 to obtain a pale green solid. The solid was
crystallized in chloroform/petroleum ether to obtain the title
compound as a white solid (27 g, 95%); 1H-NMR (300 MHz,
DMSO-d6): δ 7.34–7.27 (m, 5H, Ar–H), 5.01 (s, 2H, –
OCH2), 3.86 (d, J = 6.0 Hz , 2H, –C(O)–CH2), 3.38 (m, 4H,
2 × piperazine–CH2), 3.26 (m, 4H, 2 × piperazine–CH2), 1.38 (s,
hydrochloride (18).
To compound 17 (3.5 g, 8.80 mmol, 1.0
equiv) was added 5.0 N HCl in isopropanol (25.2 mL, 176 mmol,
20.0 equiv) the mixture was stirred overnight at RT. Subsequently,
the solvent was removed under reduced pressure to obtain a
solid which was stirred in diethyl ether, filtered, and dried
to obtain the desired product as an off-white solid (2.7 g,
91%); 1H-NMR (300 MHz, DMSO-d6): δ 9.33 (bs, 2H, –
NH2), 6.98 (s, 1H, thiazole–H), 3.58 (s, 3H, –OCH3), 3.25
(m, 4H, 2 × piperazine–CH2), 3.19 (m, 4H, 2 × piperazine–
CH2), 2.79–2.73 (m, 2H, thiazole–CH2), 1.89–1.83 (m, 2H,
–CH2–C–), 1.14 (s, 6H, –C(CH3)2); mp: >250°C; MS (ESI+):
m/z 298.2 [M + H]+.
9H, –C(CH3)3); mp: 80–82°C; MS (ESI+): m/z 400.2 [M+ Na]+.
tert-Butyl 4-(2-aminoacetyl)piperazine-1-carboxylate (15). To
tert-Butyl (1-benzylpiperidin-4-yl)carbamate (29).
To a
cooled solution of BOC anhydride (40.3 mL, 173 mmol, 1.1
equiv) and sodium bicarbonate (20.9 g, 197 mmol, 1.2 equiv) in
1,4-dioxane (300 mL) and water (300 mL) was added compound
28 (32.2 mL, 158 mmol, 1.0 equiv) over 10 min. The resulting
suspension was stirred at 5–10°C for 1 h, and the reaction
mixture was allowed to warm up to RT stirred for an additional
24 h. The reaction mixture was diluted with water and extracted
with chloroform (3 × 800 mL). The organic layer was dried over
sodium sulfate and evaporated to obtain an off-white solid. The
solid was crystallized in EtOAc/petroleum ether to yield the
desired compound as a white solid (41.5 g, 91%); 1H-NMR
a solution of compound 14 (27 g, 71.5 mmol, 1.0 equiv) in MeOH
(270 mL) and THF (270 mL) was added 10% palladim on carbon
(2.7 g, 25.4 mmol, 10% w/w). The mixture was hydrogenated in a
Parr shaker at 60–65 psi of H2 pressure for 2 h. The reaction
mixture was filtered through celite, and the filtrate was concentrated
under reduced pressure to obtain an off-white solid. The obtained
solid was crystallized in chloroform/petroleum ether to yield the
title compound as a white solid (16.7 g, 96%); 1H-NMR (300 MHz,
CDCl3): δ 3.60–3.59 (m, 2H, piperazine–CH2), 3.46 (s, 2H, –C
(O)–CH2), 3.43–3.42 (m, 4H, 2 × piperazine–CH2), 3.35–3.34
(m, 2H, piperazine–CH2), 1.46 (s, 9H, –C(CH3)3); mp: 96–98°C;
MS (ESI+): m/z 244.2 [M + H]+.
(300 MHz, DMSO-d6):
(d, J = 7.8 Hz, 1H, –C(O)–NH–), 3.39 (s, 2H, –CH2–Ph), 3.18
δ 7.31–7.21 (m, 5H, PhH), 6.75
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
(m, 1H, piperidine–CH), 2.72–2.68 (m, 2H, piperidine–CH2),
1.93–1.86 (m, 2H, piperidine–CH2), 1.65–1.61 (m, 2H,
piperidine–CH2), 1.34 (s, 9H, –C(CH3)3), 1.32–1.28 (m, 2H,
piperidine–CH2); mp: 123–125°C; MS (ESI+): m/z 291.2
light green solid. The solid was crystallized in chloroform/
petroleum ether to obtain the title compound as a white solid
(10.8 g, 84%); 1H-NMR (300 MHz, DMSO-d6):
δ 7.91
(t, J = 5.4 Hz, 1H, –C–NH–C(O)–), 6.89 (d, J = 7.5 Hz, 1H, –C
(O)–NH–piperidine), 4.17–4.13 (m, 1H, piperidine–CH), 3.89–
3.84 (m, 2H, –C(O)–CH2–N–), 3.57 (s, 3H, –OCH3), 3.43 (bs,
1H, piperidine–CH), 3.04–2.96 (m, 1H, piperidine–CH), 2.66
(m, 2H, –C(O)–CH2), 2.10–2.02 (m, 2H, piperidine–CH2),
1.71–1.65 (m, 4H, –CH2–C– and piperidine–CH2), 1.36 (s, 9H,
–C(CH3)3), 1.31–1.16 (m, 2H, piperidine–CH2), 1.08 (s, 6H, –C
[M + H]+.
tert-Butyl piperidin-4-ylcarbamate (30). To a solution of 29
(41 g, 141 mmol, 1.0 equiv) in MeOH (820 mL) was added 10%
palladium on carbon (4.1 g, 10% w/w), and the reaction mixture
was hydrogenated in a Parr shaker at 60–65 psi H2 pressure for
5 h. The reaction mixture was filtered through celite, and the
filtrate was concentrated under reduced pressure to obtain an
off-white solid, which was crystallized in CHCl3/petroleum
ether to obtain the title compound as a white solid (24 g, 85%);
1H-NMR (300 MHz, DMSO-d6): δ 6.73 (d, J = 7.5 Hz, 1H, C
(O)–NH–), 3.21 (m, 1H, piperidine–CH), 2.86–2.82 (m, 2H,
piperidine–CH2), 2.40–2.32 (m, 2H, piperidine–CH2), 1.83 (bs,
1H, piperidine–NH), 1.61–1.57 (m, 2H, piperidine–CH2), 1.35
(s, 9H, –C(CH3)3), 1.23–1.09 (m, 2H, piperidine–CH2); mp:
(CH3)2); mp: 81–83°C; MS (ESI+): m/z 414.2 [M + H]+.
Methyl 4-(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)
thiazol-2-yl)-2,2-dimethylbutanoate (34).
To a solution of
compound 33 (10.6 g, 25.6 mmol, 1.0 equiv) in 1,4-dioxane
(106 mL) was added Lawesson’s reagent (10.4 g, 25.6 mmol,
1.0 equiv) and heated to reflux for 1 h. The reaction mixture
was subsequently cooled, added to water, and neutralized
with a saturated solution of sodium carbonate. The product
was separated from the aqueous mixture using EtOAc. The
organic layer was dried over sodium sulfate, filtered, and
concentrated under reduced pressure to get a dark brown residue.
The residue was subjected to column chromatography using 3:7
EtOAc:CHCl3 to get a dark yellow colored solid that was
crystallized in CHCl3/petroleum ether to yield the desired product
161–163°C; MS (ESI+): m/z 201.1[M + H]+.
[1-(2-Benzyloxycarbonylamino-acetyl)-piperidin-4-yl]-carbamic
acid terthyphen;butyl ester (31). To a solution of compound 7
(20.9 g, 100 mmol, 1.0 equiv) in DMF (380 mL) were added
HATU (45.6 g, 120 mmol, 1.2 equiv), compound 30 (20 g,
100 mmol, 1.0 equiv), and TEA (27.8 mL, 200 mmol, 2.0 equiv).
The mixture was stirred at RT for 4 h following which the organic
solvent was removed to obtain a pale brown residue. This was
purified by silica gel column chromatography using 1:9 CH3OH:
CHCl3 to get a light green colored solid. The solid was crystallized
in chloroform/petroleum ether to obtain the title compound as a
1
as an off-white solid (3.2 g, 30%); H-NMR (300 MHz, DMSO-
d6): δ 6.88 (d, J = 7.8 Hz, 1H, –C(O)–NH–piperidine), 6.73 (s,
1H, thiazole–H), 3.58 (s, 3H, –OCH3), 3.26 (bs, 1H, piperidine–
CH), 2.80–2.70 (m, 2H, piperidine–CH2), 2.69–2.64 (m, 2H,
thiazole–CH2), 1.86–1.80 (m, 2H, –CH2–C–), 1.78–1.73
(m, 2H, piperidine–CH2), 1.52–1.45 (m, 4H, 2 × piperidine–CH2),
1.36 (s, 9H, –C(CH3)3), 1.13 (s, 6H, –C(CH3)2); mp: 103–105°C;
1
white solid (26 g, 66%); H-NMR (300 MHz, DMSO-d6): δ 7.33
(bs, 5H, PhH), 7.23 (t, J= 5.7 Hz, 1H, –C(O)–NH–piperidine), 6.88
(d, J= 7.5 Hz, 1H, –C–NH–C(O)–), 5.01 (s, 2H, –OCH2), 4.17–
4.13 (m, 1H, piperidine–CH), 3.81 (t, J= 5.1 Hz, 2H, –C(O)–CH2),
3.73–3.68 (m, 1H, piperidine–CH), 3.43 (bs, 1H, piperidine–CH),
3.05–2.95 (m, 1H, piperidine–CH), 2.73–2.63 (m, 1H, piperidine–
CH), 1.70 (bs, 2H, piperidine–CH2), 1.36 (s, 9H, –C(CH3)3),
1.27–1.11 (m, 2H, piperidine–CH2); mp: 156–158°C; MS (ESI+):
MS (ESI+): m/z 412.2 [M + H]+.
Methyl 4-(5-(4-aminopiperidin-1-yl)thiazol-2-yl)-2,2-dimethyl-
butanoate hydrochloride (35).
To compound 34 (3.1 g,
7.53 mmol, 1.0 equiv) was added 5.0 N HCl in isopropanol
(21.5 mL, 151 mmol, 20.0 equiv) and the mixture was stirred for
16 h at RT. Solvent was removed under reduced pressure to
obtain an off-white solid, which was stirred in diethyl ether,
filtered, and dried to obtain the title compound as an off-white
solid (2g, 76%); 1H-NMR (300 MHz, DMSO-d6): δ 8.17 (bs,
2H, –NH2), 6.89 (s, 1H, thiazole–H), 3.58 (s, 3H, –OCH3),
3.46–3.33 (m, 2H, piperidine–CH2), 3.16 (bs, 1H, piperidine–
CH), 2.87–2.80 (m, 2H, piperidine–CH2), 2.77–2.72 (m, 2H,
thiazole–CH2), 1.95–1.91 (m, 2H, piperidine–CH2), 1.87–1.81 (m,
2H, –CH2–C–), 1.71–1.59 (m, 2H, piperidine–CH2), 1.14 (s, 6H,
C(CH3)2); mp: >250°C ; MS (ESI+): m/z 312.2 [M+ H]+.
General procedure I. Synthesis of 5-piperazinethiazole
analogs (19–21) and 5-piperidinethiazole analogs (36–40)
possessing the urea linker. To a suspension of compound 18
(0.3 mmol, 1.0 equiv) in DCM (2 mL) was added TEA
(0.7 mmol, 2.5 equiv) followed by the appropriately substituted
isocyanate (0.3 mmol, 1.1 equiv) and the mixture was stirred for
24 h at RT. The reaction mixture was then concentrated and
purified using flash column chromatography (1:1 EtOAc-
petroleum ether) to afford the desired methyl ester. Replacing
compound 18 with compound 35 resulted in synthesis of the
corresponding 5-piperidinethiazole analogs (36–40).
m/z 392.2 [M+ H]+.
tert-Butyl (1-(2-aminoacetyl)piperidin-4-yl)carbamate (32). To
a solution of compound 31 (27.5 g, 70.2 mmol, 1.0 equiv) in
MeOH (275 mL) and THF (275mL) was added 10% palladium
on carbon (2.7g, 10% w/w). The reaction mixture was
hydrogenated in a Parr shaker at 60–65psi H2 pressure for 2 h.
The reaction mixture was filtered through celite and the filtrate
concentrated under reduced pressure to obtain an off-white solid.
This solid was crystallized in CHCl3/petroleum ether to afford the
title compound as a white solid (17.1 g, 95%); NMR (300 MHz,
DMSO-d6): δ 6.86 (d, J = 7.5 Hz, 1H, –C(O)–NH), 4.23–4.18
(m, 1H, piperidine–CH), 3.67–3.62 (m, 1H, piperidine–CH),
3.43 (m, 2H, –NH2), 3.27 (m, 3H, –C(O)–CH2 and piperidine–
CH), 2.98–2.90 (m, 1H, piperidine–CH), 2.71–2.63 (m, 1H,
piperidine–CH), 1.68 (bs, 2H, piperidine–CH2), 1.36 (s, 9H, –C
(CH3)3), 1.28–1.09 (m, 2H, piperidine–CH2); mp: 86–88°C;
MS (ESI+): m/z 258 [M + H]+.
Methyl 5-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-
2-oxoethyl)amino)-2,2-dimethyl-5-oxopentanoate (33). To
a
solution of compound 10 (5.4 g, 31.1 mmol, 1.0 equiv) in DMF
(160 mL) were added HATU (14.2 g, 37.3 mmol, 1.2 equiv),
compound 34 (8 g, 31.1 mmol, 1.0 equiv) and TEA (8.7 mL,
62.2 mmol, 2.0 equiv). The mixture was stirred at RT for 4 h
following which the solvent was removed under vacuum to
obtain a pale brown residue. This was purified by silica gel
column chromatography using 1:9 CH3OH:CHCl3 to obtain a
General procedure II. Synthesis of 5-piperazinethiazole
analogs (22–24) and 5-piperidinethiazole analog (41)
possessing the amide linker.
To a suspension of compound
18 (0.3 mmol, 1.0 equiv) in DCM (2 mL) was added TEA
(0.7 mmol, 2.5 equiv) followed by the appropriately substituted
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
acid chloride (0.3 mmol, 1.1 equiv), and the mixture was stirred
for 24 h at RT. The reaction mixture was then concentrated and
purified using flash column chromatography (4:6 EtOAc:
petroleum ether) to afford the desired methyl ester. Replacing
compound 18 with compound 35 resulted in synthesis of the
corresponding 5-piperidinethiazole analog (41).
General procedure III. Synthesis of 5-piperazinethiazole
analogs (25–27) and 5-piperidinethiazole analogs (42 and 43)
(41.2 mg, 0.3 mmol, 1.1 equiv) as the isocyanate and subsequently
deprotected by following general procedure IV to afford the title
compound (76mg, 62%) as an off-white solid; 1H-NMR
(300 MHz, DMSO-d6): δ 12.23 (bs, 1H, –COOH), 6.82 (s, 1H,
thiazole–H), 6.28 (d, J = 7.5 Hz, 1H, cyclohexyl–NH), 3.37
(m, 4H, 2 × piperazine–CH2), 2.94 (m, 4H, 2 × piperazine–CH2),
2.74–2.69 (m, 2H, thiazole–CH2), 1.84–1.78 (m, 2H, –CH2–C–),
1.74–1.64 (m, 4H, 2 × cyclohexyl–CH2), 1.56–1.53 (m, 1H,
cyclohexyl–CH), 1.21–1.15 (m, 6H, 3 × cyclohexyl–CH2), 1.11
(s, 6H, –C(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ 178.83,
158.23, 157.13, 154.27, 122.15, 52.31 (4C), 49.65, 43.32, 41.60,
33.56 (2C), 29.39, 25.83, 25.54 (2C), 25.29 (2C); mp: 178–180°C;
HRMS (ESIÀ) calcd for C20H32N4O3S [M–H]À 407.2122,
found 407.2123 (error 0.24 ppm); HPLC: retention time 3.16 min,
possessing the sulfonamide linker.
To a suspension of
compound 18 (0.3 mmol, 1.0 equiv) in DCM (2 mL) was added
TEA (0.7 mmol, 2.5 equiv) followed by the appropriately
substituted sulfonyl chloride (0.3 mmol, 1.1 equiv), and the
mixture was stirred for 24 h at RT. The reaction mixture was
then concentrated and purified using flash column chromatography
(4:6 EtOAc-petroleum ether) to afford the desired methyl ester.
Replacing compound 18 with compound 35 resulted in synthesis of
the corresponding 5-piperidinethiazole analog (42 and 43).
purity 98.48% (Method A).
4-(5-(4-(2-Chlorobenzoyl)piperazin-1-yl)thiazol-2-yl)-2,2-
dimethylbutanoic acid (22). The methyl ester was synthesized
by general procedure II using 2-chlorobenzoyl chloride (57.7mg,
0.3 mmol, 1.1 equiv) as the substituted acid chloride and
subsequently deprotected by following general procedure IV to
afford the title compound (19mg, 15%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.21 (bs, 1H, –COOH),
7.56–7.50 (m, 1H, Ar–H), 7.48–7.44 (m, 1H, Ar–H), 7.42–7.39
(m, 2H, 2 × Ar–H), 6.83 (s, 1H, thiazole–H), 3.77 (t, J = 5.1 Hz,
2H, piperazine–CH2), 3.24 (t, J = 5.1 Hz, 2H, piperazine–CH2),
3.12–3.08 (q, J = 5.1 Hz, 2H, piperazine–CH2), 2.97 (t, J = 5.1 Hz,
2H, piperazine–CH2), 2.75–2.69 (m, 2H, thiazole–CH2), 1.83–
1.78 (m, 2H, –CH2–C–), 1.11 (s, 6H, –C(CH3)2); 13C-NMR
(75 MHz, DMSO-d6): δ 178.79, 166.00, 158.79, 153.76, 135.87,
131.11, 129.91, 129.58, 128.47 , 128.12 , 122.72 , 52.36 (4C),
45.92, 41.59, 29.39, 25.28 (2C); mp: 172–174°C; HRMS (ESI+)
calcd for C20H24ClN3O3S [M+ H]+ 422.1300, found 422.1270
(error 7.10ppm); HPLC: retention time 3.19min, purity 96.73%
General procedure IV. Deprotection of esters.
To a
solution of the methyl ester (1 equiv), synthesized either using
general procedure I, II, or III in THF and MeOH was added
1.0 M solution of LiOH in water (4 equiv) and stirred for 20 h at
RT. The solvent was removed, the obtained residue was diluted
with water and acidified to pH 2 using 2.0 M HCl. The solid
thus obtained was filtered and dried to yield the desired acid.
4-(5-(4-((2-Chlorophenyl)carbamoyl)piperazin-1-yl)thiazol-
2-yl)-2,2-dimethylbutanoic acid (19). The methyl ester was
synthesized by general procedure I using 2-chlorophenyl
isocyanate (50.6 mg, 0.3 mmol, 1.1 equiv) as the substituted
isocyanate and subsequently deprotected by following general
procedure IV to afford the title compound (51 mg, 38%) as an
off-white solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.16
(bs, 1H, –COOH), 8.34 (s, 1H, Ar–NH–C(O)–), 7.45
(t, J = 7.8 Hz, 2H, 2 × Ar–H), 7.27 (t, J = 7.8 Hz, 1H, Ar–H),
7.13 (t, J = 7.8 Hz, 1H, Ar–H), 6.86 (s, 1H, thiazole–H), 3.57
(m, 4H, 2 × piperazine–CH2), 3.04 (m, 4H, 2 × piperazine–
CH2), 2.76–2.70 (m, 2H, thiazole–CH2), 1.85–1.79 (m, 2H, –
CH2–C–), 1.12 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz,
DMSO-d6): δ 178.83, 158.41, 155.44, 154.14, 136.97, 129.74,
128.94, 127.69 (2C), 126.27, 122.36, 52.32 (4C), 43.74,
41.61, 29.41, 25.30 (2C); mp: 172–174°C; HRMS (ESIÀ)
calcd for C20H25ClN4O3S [M–H]À 435.1263, found
435.1268 (error 1.15 ppm); HPLC: retention time 3.35 min,
(Method A).
2,2-Dimethyl-4-(5-(4-(4-methylbenzoyl)piperazin-1-yl)thiazol-
2-yl)butanoic acid (23). The methyl ester was synthesized by
general procedure II using 4-methylbenzoyl chloride (50.9 mg,
0.3 mmol, 1.1 equiv) as the substituted acid chloride and
subsequently deprotected by following general procedure IV to
afford the title compound (19 mg, 16%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.26 (bs, 1H, –COOH), 7.30
(d, J = 8.1 Hz, 2H, 2 × Ar–H), 7.23 (d, J = 8.1 Hz, 2H, 2 × Ar–H),
6.83 (s, 1H, thiazole–H), 3.55 (m, 4H, 2 × piperazine–CH2), 3.03
(m, 4H, 2 × piperazine–CH2), 2.74–2.69 (m, 2H, thiazole–CH2),
2.32 (s, 3H, tolyl–CH3), 1.83–1.78 (m, 2H, –CH2–C–), 1.11
(s, 6H, –C(CH3)2); 13C-NMR (75 MHz, DMSO-d6): δ 178.80,
169.69, 158.61, 153.91, 139.83, 133.10, 129.38 (2C), 127.58
(2C), 122.53, 52.41 (4C), 41.59 (2C), 29.39, 25.28 (2C), 21.37;
mp: 150–152°C; HRMS (ESIÀ) calcd for C21H27N3O3S
[M–H]À 400.1700, found 400.1719 (error 4.75 ppm); HPLC:
purity 98.83% (Method A).
2,2-Dimethyl-4-(5-(4-(p-tolylcarbamoyl)piperazin-1-yl)thiazol-
2-yl)butanoic acid (20). The methyl ester was synthesized by
general procedure I using 1-isocyanato-4-methylbenzene (43.9 mg,
0.3 mmol, 1.1 equiv) as the substituted isocyanate and subsequently
deprotected by following general procedure IV to afford the title
compound (72 mg, 59%) as an off-white solid; 1H-NMR
(300 MHz, DMSO-d6): δ 12.23 (bs, 1H, –COOH), 8.52 (s, 1H,
A–NH), 7.31 (d, J= 8.4 Hz, 2H, 2 × Ar–H), 7.01 (d, J= 8.4 Hz, 2H,
2×Ar–H), 6.85 (s, 1H, thiazole–H), 3.55 (m, 4H, 2 × piperazine–
CH2), 3.02 (m, 4H, 2 × piperazine–CH2), 2.76–2.70 (m, 2H,
thiazole–CH2), 2.21 (s, 3H, tolyl–CH3), 1.85–1.79 (m, 2H, –CH2–
C–), 1.12 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ
178.86, 158.38, 155.47, 154.16, 138.21, 131.11, 129.18 (2C),
122.32, 120.28 (2C), 52.38 (4C), 43.57, 41.61, 29.41, 25.31 (2C),
20.81; mp: 186–188°C; HRMS (ESI+) calcd for C21H28N4O3S
[M + H]+ 417.1955, found 417.1948 (error 1.68 ppm); HPLC:
retention time 3.38 min, purity 96.83% (Method A).
retention time 3.30 min, purity 96.42% (Method A).
4-(5-(4-(Cyclohexanecarbonyl)piperazin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (24).
The methyl ester was
synthesized by general procedure II using cyclohexanecarbonyl
chloride (48.2 mg, 0.3 mmol, 1.1 equiv) as the substituted acid
chloride and subsequently deprotected by following general
procedure IV to afford the title compound (73 mg, 62%) as an
off-white solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.18 (bs, 1H,
–COOH), 6.83 (s, 1H, thiazole–H), 3.57 (m, 4H, 2 × piperazine–
CH2), 2.96 (m, 4H, 2 × piperazine–CH2), 2.75–2.69 (m, 2H,
thiazole–CH2), 2.58 (m, 1H, cyclohexyl–CH), 1.84–1.78 (m, 2H,
–CH2–C–), 1.68–1.61 (m, 4H, 2 × cyclohexyl–CH2), 1.32–1.22
4-(5-(4-(Cyclohexylcarbamoyl)piperazin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (21).
The methyl ester was
synthesized by general procedure I using cyclohexyl isocyanate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
(m, 6H, 3 × cyclohexyl–CH2), 1.11 (s, 6H, –C(CH3)2); 13C-NMR
(125MHz, DMSO-d6): δ 178.83, 173.98, 158.55, 153.98, 122.42,
52.96 (2C), 52.47 (2C), 44.51, 41.60, 40.69, 29.58 (2C), 29.41,
26.03, 25.60 (2C), 25.30 (2C); mp: 152–154°C; HRMS (ESI+)
calcd for C20H31N3O3S [M + H]+ 394.2159, found 394.2150
(error 2.28 ppm); HPLC: retention time 3.43min, purity 97.55%
procedure IV to afford the title compound (103 mg, 58%) as an
off-white solid; 1H-NMR (500 MHz, DMSO-d6): δ 12.28 (bs, 1H,
–COOH), 8.17 (d, J = 8.5 Hz, 1H, Ar–H), 7.97 (s, 1H, Ar–NH–C
(O)–), 7.39 (d, J = 7.5 Hz, 1H, Ar–H), 7.23 (t, J = 7.5 Hz, 1H,
Ar–H), 7.14 (d, J = 7.2Hz, 1H, –C(O)–NH–piperidine), 6.94
(t, J = 7.5 Hz, 1H, Ar–H), 6.80 (s, 1H, thiazole–H), 3.66 (bs, 1H,
piperidine–CH), 3.31–3.28 (m, 2H, piperidine–CH2), 2.91
(t, J = 10.0Hz, 2H, piperidine–CH2), 2.75–2.71 (m, 2H, thiazole–
CH2), 1.92 (d, J = 10.0Hz, 2H, piperidine–CH2), 1.85–1.81
(m, 2H, –CH2–C–), 1.56–1.50 (q, J= 10.0 Hz, 2H, piperidine–CH2),
1.13 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ 178.83,
157.65, 154.44, 137.14, 129.52, 127.91 (2C), 122.79, 121.56,
121.37, 120.92, 51.21 (2C), 45.70, 41.61, 31.44 (2C), 29.32, 25.30
(3C); mp: 187–189°C; HRMS (ESI+) calcd for C21H27ClN4O3S
[M + H]+ 451.1565, found 451.1555 (error 2.22 ppm); HPLC:
(Method A).
4-(5-(4-((2-Chlorophenyl)sulfonyl)piperazin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (25). The methyl ester was synthesized
by general procedure III using 2-chlorobenzenesulfonyl chloride
(69.5 mg, 0.329 mmol, 1.1 equiv) as the substituted sulfonyl
chloride and subsequently deprotected by following general
procedure IV to afford the title compound (71 mg, 52%) as an
1
off-white solid; H-NMR (500 MHz, DMSO-d6): δ 12.22 (bs, 1H,
–COOH), 8.01 (d, J= 7.5 Hz, 1H, Ar–H), 7.74–7.69 (m, 2H,
2×Ar–H), 7.59 (t, J= 7.5 Hz, 1H, Ar–H), 6.84 (s, 1H, thiazole–H),
3.31 (m, 4H, 2 × piperazine–CH2), 3.08 (m, 4H, 2 × piperazine–
CH2), 2.74–2.71 (m, 2H, thiazole–CH2), 1.83–1.80 (m, 2H, –CH2–
C–), 1.12 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ
178.80, 159.02, 153.53, 135.56, 135.24, 132.88, 132.14, 131.43,
128.42, 122.97, 52.22 (4C), 45.17, 41.59, 29.39, 25.28 (2C); mp:
165–167°C; HRMS (ESI+) calcd for C19H24ClN3O4S2 [M + H]+
458.0970, found 458.0973 (error 0.65 ppm); HPLC: retention time
retention time 3.60 min, purity 99.88% (Method A).
4-(5-(4-(3-(2-Fluorophenyl)ureido)piperidin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (37). The methyl ester was synthesized
by general procedure I using 2-fluorophenyl isocyanate (59.2mg,
0.4 mmol, 1.1 equiv) as the substituted isocyanate and
subsequently deprotected by following general procedure IV to
afford the title compound (128 mg, 75%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.22 (bs, 1H, –COOH), 8.19
(bs, 1H, Ar–NH–C(O)–), 8.11 (t, J = 8.1 Hz, 1H, Ar–H), 7.18–
7.11 (dd, J = 8.4 Hz, 1H, Ar–H), 7.05 (t, J = 7.8 Hz, 1H, Ar–H),
6.92–6.88 (m, 1H, Ar–H), 6.78 (s, 1H, thiazole–H), 6.74 (d,
J = 7.8Hz, 1H, –C(O)–NH–piperidine), 3.63 (bs, 1H, piperidine–
CH), 3.28–3.24 (m, 2H, piperidine–CH2), 2.89 (t, J = 9.9 Hz, 2H,
piperidine–CH2), 2.74–2.68 (m, 2H, thiazole–CH2), 1.91–1.78 (m,
4H, piperidine–CH2 and –CH2–C–), 1.55–1.48 (q, J = 9.9 Hz, 2H,
piperidine–CH2), 1.11 (s, 6H, –C(CH3)2); 13C-NMR (125MHz,
DMSO-d6): δ 178.84, 157.63, 154.58, 154.45, 152.93, 151.01,
128.74, 124.83, 121.73, 120.39, 115.21, 51.19 (2C), 45.56, 41.61,
31.47 (2C), 29.36 (2C), 25.30 (2C); mp: 194–196°C; HRMS (ESI
+) calcd for C21H27FN4O3S [M+ H]+ 435.1861, found
435.1855 (error 1.38ppm); HPLC: retention time 3.25min, purity
3.95 min, purity 99.03% (Method B).
2,2-Dimethyl-4-(5-(4-tosylpiperazin-1-yl)thiazol-2-yl)butanoic
acid (26).
The methyl ester was synthesized by general
procedure III using 4-methylbenzene-1-sulfonyl chloride (62.8 mg,
0.3 mmol, 1.1 equiv) as the substituted sulfonyl chloride and
subsequently deprotected by following general procedure IV to
afford the title compound (69 mg, 52%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.22 (bs, 1H, –COOH), 7.62
(d, J= 8.4 Hz, 2H, 2 × Ar–H), 7.45 (d, J= 8.4 Hz, 2H, 2 × Ar–H),
6.78 (s, 1H, thiazole–H), 3.06 (m, 4H, 2 × piperazine–CH2), 2.97
(m, 4H, 2 × piperazine–CH2), 2.72–2.66 (m, 2H, thiazole–CH2),
2.39 (s, 3H, tolyl–CH3), 1.80–1.75 (m, 2H, –CH2–C–), 1.09 (s, 6H,
–C(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ 178.79, 158.96,
153.38, 144.40, 132.22, 130.42 (2C), 128.10 (2C), 122.88, 51.68
(4C), 45.62, 41.58, 29.37, 25.27 (2C), 21.50; mp: 201–203°C;
HRMS (ESIÀ) calcd for C20H27N3O4S2 [M–H]À 436.1370,
found 436.1378 (error 1.83 ppm); HPLC: retention time 4.03 min,
99.48% (Method A).
4-(5-(4-(3-(2,4-Difluorophenyl)ureido)piperidin-1-yl)thiazol-
2-yl)-2,2-dimethylbutanoic acid (38).
The methyl ester was
synthesized by general procedure
I
using 2,4-difluoro-
purity 97.39% (Method A).
4-(5-(4-(Cyclohexylsulfonyl)piperazin-1-yl)thiazol-2-yl)-2,2-
1-isocyanatobenzene (67.0 mg, 0.4 mmol, 1.1 equiv) as the
substituted isocyanate and subsequently deprotected by
following general procedure IV to afford the title compound
(116 mg, 65%) as an off-white solid; 1H-NMR (500 MHz,
DMSO-d6): δ 12.25 (bs, 1H, –COOH), 8.18 (s, 1H, Ar–NH–C
(O)–), 8.08–8.05 (m, 1H, Ar–H), 7.26–7.22 (m, 1H, Ar–H),
6.98 (t, J = 8.5 Hz, 1H, Ar–H), 6.79 (s, 1H, thiazole–H), 6.69
(d, J = 8.5 Hz, 1H, –C(O)–NH–piperidine), 3.64 (bs, 1H,
piperidine–CH), 3.29–3.26 (m, 2H, piperidine–CH2), 2.90
(t, J = 10.0 Hz, 2H, piperidine–CH2), 2.74–2.71 (m, 2H,
thiazole–CH2), 1.92–1.89 (m, 2H, piperidine–CH2), 1.84–1.81
(m, 2H, –CH2–C–), 1.56–1.49 (q, J = 10.0 Hz, 2H, piperidine–
CH2), 1.13 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz, DMSO-
d6): δ 178.84, 157.63, 154.66, 154.43, 125.32, 121.57 (2C),
121.50, 111.36, 111.29, 104.00, 51.21 (2C), 45.63, 41.60,
31.47 (2C), 29.35, 25. 29 (3C); mp: 185–187°C; HRMS
(ESIÀ) calcd for C21H26F2N4O3S [M–H]À 451.1621, found
451.1602 (error 4.21 ppm); HPLC: retention time 3.32 min,
dimethylbutanoic acid (27). The methyl ester was synthesized
by general procedure III using cyclohexanesulfonyl chloride
(60.2 mg, 0.3mmol, 1.1 equiv) as the substituted sulfonyl chloride
and subsequently deprotected by following general procedure IV
to afford the title compound (45 mg, 35%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.22 (bs, 1H, –COOH), 6.83
(s, 1H, thiazole–H), 3.40 (m, 1H, cyclohexyl–CH), 3.03 (m, 4H,
2 × piperazine–CH2), 2.75–2.68 (m, 2H, thiazole–CH2), 1.99–1.96
(m, 2H, cyclohexyl–CH2), 1.84–1.73 (m, 4H, –CH2–C– and
cyclohexyl–CH2), 1.61–1.23 (m, 6H, 3 × cyclohexyl–CH2), 1.11
(s, 6H, –C(CH3)2); 13C-NMR (75 MHz, DMSO-d6): δ 178.81,
158.73, 153.79, 122.63, 59.94, 52.73 (4C), 45.26, 41.59, 29.38,
28.46, 26.60 (2C), 25.29 (2C), 24.92 (2C); mp: 190–192°C;
HRMS (ESIÀ) calcd for C19H31N3O4S2 [M–H]À 428.1683,
found 428.1664 (error 4.44 ppm); HPLC: retention time 3.88min,
purity 97.09% (Method A).
4-(5-(4-(3-(2-Chlorophenyl)ureido)piperidin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (36).
synthesized by general procedure
The methyl ester was
using 2-chlorophenyl
purity 99.67% (Method A).
2,2-Dimethyl-4-(5-(4-(3-(2,4,5-trifluorophenyl)ureido)piperidin-
I
1-yl)thiazol-2-yl)butanoic acid (39).
synthesized by general procedure
The methyl ester was
using 1,2,4-trifluoro-5-
isocyanate (66.4mg, 0.4 mmol, 1.1 equiv) as the substituted
isocyanate and subsequently deprotected by following general
I
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. S. Kadam, T. Gandhi, M. M. Reddy, A. Gupte, and R. Sharma
Vol 000
isocyanatobenzene (74.8 mg, 0.432 mmol, 1.1 equiv) as the
substituted isocyanate and subsequently deprotected by following
general procedure IV to afford the title compound (132 mg, 71%)
as an off-white solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.22
(bs, 1H, –COOH), 8.38 (bs, 1H, Ar–NH–C(O)–), 8.21–8.11
(m, 1H, Ar–H), 7.59–7.49 (m, 1H, Ar–H), 6.78–6.75 (m, 2H,
Ar–H, –C(O)–NH–piperidine), 3.61 (bs, 1H, piperidine–CH),
3.27–3.23 (m, 2H, piperidine–CH2), 2.89 (t, J=9.9Hz, 2H,
piperidine–CH2), 2.73–2.68 (m, 2H, thiazole–CH2), 1.90–1.78
(m, 4H, piperidine–CH2, –CH2–C–), 1.55–1.45 (m, 2H,
piperidine–CH2), 1.11 (s, 6H, –C(CH3)2); 13C-NMR (125 MHz,
DMSO-d6): δ 178.82, 157.70, 154.37, 147.70, 145.87, 144.07,
142.02, 125.77, 121.65, 108.00, 105.74, 51.14 (2C), 45.64,
41.60, 31.36 (2C), 29.33, 25.29 (3C); mp: 192–194°C; HRMS
(ESI+) calcd for C21H25F3N4O3S [M + H]+ 471.1672, found
471.1665 (error 1.48 ppm); HPLC: retention time 3.80 min,
2,2-Dimethyl-4-(5-(4-(4-(trifluoromethyl)phenylsulfonamido)
piperidin-1-yl)thiazol-2-yl)butanoic acid (42). The methyl
ester was synthesized by general procedure III using
4-(trifluoromethyl)benzene-1-sulfonyl chloride (105.7 mg,
0.4 mmol, 1.1 equiv) as the substituted sulfonyl chloride
and subsequently deprotected by following general
procedure IV to afford the title compound (82 mg, 40%) as
an off-white solid; 1H-NMR (300 MHz, DMSO-d6): δ 12.22
(bs, 1H, –COOH), 8.09 (d, J = 7.2 Hz, 1H, –S(O)2–NH–),
8.03 (d, J = 8.4 Hz, 2H, 2 × Ar–H), 7.97 (d, J = 8.4 Hz, 2H,
2 × Ar–H), 6.69 (s, 1H, thiazole–H), 3.23–3.19 (m, 3H,
piperidine–CH and piperidine–CH2), 2.77–2.65 (m, 4H,
piperidine–CH2 and thiazole–CH2), 1.80–1.75 (m, 2H, –
CH2–C–), 1.62–1.59 (m, 2H, piperidine–CH2), 1.53–1.41
(m, 2H, piperidine–CH2), 1.09 (s, 6H, –C(CH3)2); 13C-NMR
(125 MHz, DMSO-d6): δ 178.81, 157.65, 154.07, 146.45, 127.70
(3C), 127.01 (2C), 121.79 (2C), 51.16 (2C), 50.07, 41.58, 31.75
(2C), 29.32, 25.27 (3C); mp: 216–218°C; HRMS (ESIÀ) calcd
for C21H26F3N3O4S2 [M–H]À 504.1244, found 504.1241 (error
0.59ppm); HPLC: retention time 4.15 min, purity 99.60%
purity 99.52% (Method A).
4-(5-(4-(3-Cyclohexylureido)piperidine-1-yl)thiazol-2-yl)-2,2-
dimethylbutanoic acid (40). The methyl ester was synthesized
by general procedure I using cyclohexyl isocyanate (54.1 mg,
0.4 mmol, 1.1 equiv) as the substituted isocyanate and
subsequently deprotected by following general procedure IV to
afford the title compound (102 mg, 69%) as an off-white solid;
1H-NMR (300 MHz, DMSO-d6): δ 12.24 (bs, 1H, –COOH),
6.76 (s, 1H, thiazole–H), 5.76 (d, J = 7.8 Hz, 1H, Ar–NH–C
(O)–), 5.64 (d, J = 7.8 Hz, 1H, –C(O)–NH–piperidine), 3.52 (bs,
1H, piperidine–CH), 3.28–3.24 (m, 2H, piperidine–CH2), 2.84
(t, J = 9.9 Hz, 2H, piperidine–CH2), 2.74–2.68 (m, 2H, thiazole–
CH2), 1.85–1.79 (m, 4H, piperidine–CH2 and –CH2–C–), 1.74
(m, 2H, cyclohexyl–CH2), 1.61 (m, 2H, piperidine–CH2),
1.48–1.33 (m, 4H, 2 × cyclohexyl–CH2), 1.23 (m, 3H,
cyclohexyl–CH and cyclohexyl –CH2), 1.13 (s, 6H, –C(CH3)2),
1.07–1.04 (m, 2H, cyclohexyl–CH2); 13C-NMR (125 MHz,
DMSO-d6): δ 178.83, 173.98, 158.55, 153.98, 122.42, 52.96
(2C), 52.47 (2C), 44.51, 41.60, 29.58 (3C), 29.41, 26.03, 25.60
(3C), 25.33 (2C); mp: 176–178°C; HRMS (ESI+) calcd for
C21H34N4O3S [M + H]+ 423.2424, found 423.2413 (error
2.60 ppm); HPLC: retention time 3.17 min, purity 99.63%
(Method A).
4-(5-(4-(3,4-Dimethoxyphenylsulfonamido)piperidin-1-yl)
thiazol-2-yl)-2,2-dimethylbutanoic acid (43). The methyl ester
was synthesized by general procedure III using 3,4-
dimethoxybenzene-1-sulfonyl chloride (102.2 mg, 0.4 mmol, 1.1
equiv) as the substituted sulfonyl chloride and subsequently
deprotected by following general procedure IV to afford the title
compound (62 mg, 31%) as an off-white solid; 1H-NMR
(300 MHz, DMSO-d6): δ 12.22 (bs, 1H, –COOH), 7.62 (d,
J = 6.9 Hz, 1H, –S(O)2–NH–), 7.40–7.33 (m, 2H, 2 × Ar–H),
7.11 (d, J = 8.1 Hz, 1H, Ar–H), 6.70 (s, 1H, thiazole–H), 3.81
(s, 6H, 2 × –OCH3), 3.23–3.19 (m, 2H, piperidine–CH2), 3.07
(bs, 1H, piperidine–CH), 2.71–2.69 (m, 4H, piperidine–CH2,
thiazole–CH2), 1.82–1.75 (m, 2H, –CH2–C–), 1.58 (m, 2H,
piperidine–CH2), 1.47 (m, 2H, piperidine–CH2), 1.10 (s, 6H, –C
(CH3)2); 13C-NMR (125 MHz, DMSO-d6): δ 178.82, 157.57,
154.16, 152.19, 149.10, 133.93, 121.70, 120.37, 111.56, 109.66,
56.24 (2C), 51.17 (2C), 49.84, 41.59, 31.66 (2C), 29.32, 25.28
(3C); mp: 184–186°C; HRMS (ESIÀ) calcd for
C22H31N3O6S2 [M–H]À 496.1582, found 496.1583 (error
À0.20 ppm); HPLC: retention time 3.08 min, purity 98.18%
(Method A).
(Method A).
4-(5-(4-(Cyclohexanecarboxamido)piperidin-1-yl)thiazol-2-yl)-
2,2-dimethylbutanoic acid (41).
The methyl ester was
synthesized by general procedure II using cyclohexanecarbonyl
chloride (63.3 mg, 0.4 mmol, 1.1 equiv) as the substituted
acid chloride and subsequently deprotected by following
general procedure IV to afford the title compound (19 mg,
12%) as an off-white solid; 1H-NMR (500 MHz, DMSO-d6):
δ 12.25 (bs, 1H, –COOH), 7.66 (d, J = 8.0 Hz, 1H, –C(O)–
NH–piperidine), 6.76 (s, 1H, thiazole–H), 3.65 (bs, 1H,
piperidine–CH), 3.30 (m, 1H, cyclohexyl–CH), 2.82
(t, J = 11.5 Hz, 2H, piperidine–CH2), 2.73–2.70 (m, 2H,
thiazole–CH2), 2.06 (t, J = 11.5 Hz, 1H, piperidine–CH), 1.83–
1.80 (m, 2H, –CH2–C–), 1.76–1.74 (m, 2H, piperidine–CH2),
1.70–1.59 (m, 5H, cyclohexyl–CH and 2 × Cyclohexyl–CH2),
1.52–1.46 (q, J = 10.5 Hz, 2H, piperidine–CH2), 1.34–1.27
(q, J = 11.5 Hz, 2H, cyclohexyl–CH2), 1.23–1.16 (m, 3H,
2 × cyclohexyl–CH2 and cyclohexyl–CH), 1.13 (s, 6H, –C
(CH3)2); 13C-NMR (75 MHz, DMSO-d6): δ 178.83, 175.01,
157.42, 154.38, 121.52, 51.56 (3C), 45.12, 44.42, 41.59, 30.95
(2C), 29.68 (2C), 29.32, 25.91, 25.74 (2C), 25.29 (2C); mp:
190–192°C; HRMS (ESI+) calcd for C21H33N3O3S [M + H]+
408.2315, found 408.2308 (error 1.71 ppm); HPLC: retention
time 3.09 min, purity 96.85% (Method A).
REFERENCES AND NOTES
[1] Yen, C. L.; Stone, S. J.; Koliwad, S.; Harris, C.; Farese, Jr. R.
V. J Lipid Res 2008, 49, 2283.
[2] Subauste, A.; Burant, C. F. Curr Drug Targets Immune Endocr
Metabol Disord 2003, 3, 263.
[3] Bali, U.; Barba, O.; Dawson, G.; Gattrell, W. T.; Horswill, J. G.;
Pan, D. A.; Procter, M. J.; Rasamison, C. M.; Sambrook Smith, C. P.;
Taylor-Warne, A.; Wong-Kai-In, P. Bioorg Med Chem Lett 2012,
22, 824.
[4] Kadam, K. S.; Jadhav, R. D.; Kandre, S.; Guha, T.; Reddy, M.
M. K.; Brahma, M. K.; Deshmukh, N. J.; Dixit, A.; Doshi, L.; Srinivasan,
S.; Devle, J.; Damre, A.; Nemmani, K. V. S.; Gupte, A.; Sharma, R. Eur J
of Med Chem 2013, 65, 337.
[5] Sharma, R.; Kadam, K. S.; Jadhav, R. D.; Kandre, S. S.;
Gupte, A. WO2012029032, 2012.
[6] Schmuck, C.; Rehm, T.; Geiger, L.; Schafer, M. J Org Chem
2007, 72, 6162.
[7] Hutchinson, J. H.; Riendeau, D.; Brideau, C.; Chan, C.; Delorme, D.;
Denis, D.; Falgueyret, J. P.; Fortin, R.; Guay, J. J Med Chem 1993, 36, 2771.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and DGAT1 Inhibition of New 5-Piperazinethiazole
and 5-Piperidinethiazole Analogs
[8] Dolak, T. M.; Martin, T. A. 1985 US4495194.
[12] Kondo, T.; Nekado, T.; Sugimoto, I.; Ochi, K.; Takai, S.;
Kinoshita, A.; Hatayama, A.; Yamamoto, S.; Kishikawa, K.; Nakai, H.;
Toda, M. Bioorg Med Chem 2008, 16, 1613.
[13] Marc, N.; Melanie, E.; David, W. W.; Hans, M.; Ritter, K.;
Urmann, M.; Bauer, A.; Schreuder, H.; Czech, J.; Lorenz, M.; Laux, V.;
Wehner, V. Bioorg Med Chem Lett 2004, 14, 4197.
[9] Ram, S.; Spicer, L. D. Tetrahedron Lett 1987, 28, 515.
[10] Giannini, G.; Marzi, M.; Pezzi, R.; Brunetti, T.; Battistuzzi, G.;
Di Marzo, M.; Cabri, W.; Vesci, L.; Pisano, C. Bioorg Med Chem Lett
2009, 19, 2346.
[11] Gaeta, A.; Kong, X. L.; Salvage, S.; Fakih, S.; Hider, R. C.;
Francis, P. T.; Molina-Holgado, F.; Williams, R. J Bioorg Med Chem
2011, 19, 1285.
[14] Ramharack, R. R.; Spahr, M. A. Diacylglycerol acyltransferase
(DGAT) assay, US20020127627, 2002.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet