α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters as prodrugs of carboxylic acid containing drugs

Article abstract of DOI:10.1016/j.tetlet.2007.04.121

Synthesis of α-(1H-imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters have been reported in 2-3 simple steps. α-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters were found to be chemically labile and thus serve as novel prodrugs of carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2007.04.121

Tetrahedron Letters 48 (2007) 4609–4611
a-(1H-Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters as
prodrugs of carboxylic acid containing drugs
Susruta Majumdar, Maren Mueller Spaeth, Sashikala Sivendran, Juha Juntunen,
Joshua D. Thomas and K. B. Sloan*
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA
Received 26 February 2007; revised 11 April 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—Synthesis of a-(1H-imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters have been reported in 2–3 simple steps. a-(1H-
Imidazol-1-yl)alkyl (IMIDA) carboxylic acid esters were found to be chemically labile and thus serve as novel prodrugs of carb-
oxylic acids.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The ionization and poor lipid solubility of carboxylic
acid containing drugs compromises their permeability
across biological membranes like skin. Prodrugs, which
are biologically inactive derivatives of a drug and which
hydrolyze in vivo to the pharmacologically active drug
molecule, are useful in breaching biological barriers.
Various prodrug ester based approaches utilizing a sim-
ple alkyl group in the ester promoiety have been used in
the past to improve the lipid solubility and hence theo-
retically the permeability of carboxylic acids across the
skin.1,2 However it is now clear that water solubility is
also important in increasing permeability.2–7 On the
other hand, it is not always possible to improve the
water solubility of carboxylic acids without introducing
an ionized dialkylamino(CH2)n group (pKa 8–10)8–10 or
polar group3,4 in the ester promoiety, which may de-
crease the lipid solubility of the derivative compared
to a simple alkyl ester. In order to explore the possibility
of incorporating lower pKa amines, which would be less
highly ionized but still polar and more water soluble
than a simple alkyl ester,11 into the ester promoiety,
we have synthesized a-(1H-imidazol-1-yl)alkyl (IMIDA)
carboxylic acid esters and measured their hydrolysis in
aqueous buffers and in vitro hairless mouse skins.
and N1 in imidazole, is –CH2 or –CHCH3. The synthesis
of a-(1H-imidazol-1-yl)methyl (A = –CH2) carboxylic
acid esters was achieved in two steps. Imidazole was first
converted to 1-hydroxymethylimidazole then coupled to
the parent carboxylic acid in the next step. 1-Hydroxy-
methylimidazole was synthesized by heating parafor-
maldehyde, imidazole and catalytic amounts of
triethylamine at 80 ꢁC with constant stirring for 5 min
till all the solid residue had completely melted to a col-
orless viscous liquid. The contents in the flask were then
allowed to cool to room temperature. 1-Hydroxymethyl-
imidazole was isolated as a low melting white solid in
excellent yields.12 Previous reports on the synthesis of
1-hydroxymethylimidazole have used the reaction of
formaldehyde with imidazole at 120–130 ꢁC in a sealed
tube for 15 h to give a crude mixture of products which
included 1,2-(dihydroxymethyl)imidazole, 2,4,5-(trihydr-
oxymethyl)imidazole, and 1-hydroxymethylimidazole.
1-Hydroxymethylimidazole was isolated as its picrate
salt from those crude reaction mixtures in poor yields.13
On the other hand, the present simple and regioselective
route gives 1-hydroxymethylimidazole in high yields.
The parent carboxylic acid was then reacted with car-
bonyldiimidazole (CDI) in methylene chloride (DCM)
for 4 h at room temperature and the intermediate was
coupled to 1-hydroxymethylimidazole. The reaction
was allowed to run overnight and the product (Table
1, 1–7) isolated by either crystallization or column chro-
matography in good yields (Scheme 1).14 Reaction of
salicyclic acid with CDI and 1-hydroxymethylimidazole
gave several products and poor yield of the desired
We have synthesized two types of IMIDA ester pro-
drugs where A, the alkyl spacer between Drug-CO2
Keywords: Prodrugs; IMIDA; Permeability; Carboxylic acids.
*
Corresponding author. Tel.: +1 352 846 1957; fax: +1 352 392
9455; e-mail: sloan@cop.ufl.edu
Contributed equally.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.121

4610
S. Majumdar et al. / Tetrahedron Letters 48 (2007) 4609–4611
Table 1. Compounds synthesized with their respective rates of
hydrolysis in pH 7.1 buffer at 39 ꢁC
azole which catalyzed the hydrolysis of the phenolic es-
ter moiety.
O
R
Synthesis of a-(1H-imidazol-1-yl)ethyl (A = –CHCH3)
carboxylic acid esters (8 and 9) was carried out in three
steps. The parent carboxylic acid was first converted to
the acid chloride by reacting it with thionyl chloride.
The corresponding acid chloride was next converted to
a-(acyloxy)ethyl iodide by reacting it with paraldehyde,
AlCl3, NaI in dry methylene chloride.15,16 The desired
alkylating agent was used in the next step without any
purification. Alkylation of imidazole with a-(acyloxy)-
ethyl iodide in the presence of K2CO3 and in acetone
gave the desired product in moderate yields (Scheme
2).15
DRUG
O
N
N
Compd Drug
R
Yield Logk17 t1/2
(%)
(sꢀ1
)
(min)
1
2
3
4
5
6
7
8
9
Naproxen
Indomethacin
Salicyclic acid
Ibuprofen
H
H
H
H
H
H
H
94
66
33
66
20
80
74
ꢀ4.35
ꢀ4.29
257.79
224.22
a
a
—
—
a
a
—
—
Nalidixic acid
—
>24 h
220.08
310.87
72.59
p-Nitrobenzoic acid
Niflumic acid
Naproxen
ꢀ4.28
ꢀ4.43
ꢀ3.79
CH3 22
CH3 50
a
a
Ibuprofen
—
—
To exhibit pharmacological activity these prodrugs must
hydrolyze to the parent molecule. Hydrolysis studies17
were carried out in pH 7.1 buffers at 39 ꢁC for 1, 2
and 5–8. The prodrugs hydrolyzed to the parent drug
exhibiting pseudo unimolecular first order kinetics and
t1/2 values ranged from 72 min to greater than 24 h.
The topical delivery of 1 and 7 was also investigated in
in vitro diffusion cell experiments from hairless mouse
skin.18 Compound 1 hydrolyzed completely to naproxen
and about 37% of 7 hydrolyzed to niflumic acid on pas-
sage of the prodrug through mouse skin.
a Not determined.
(CH2O)n
TEA
N
N
OH
N
NH
O
1. CDI, DCM, 4 h
N
N
O
R
RCOOH
N
N
OH
2.
,18 h
R = Drug Compounds 1-7
Scheme 1.
In conclusion, a novel synthesis of 1-hydroxymethyl-
imidazole and of IMIDA (A = –CH2 and –CHCH3)
carboxylic acid esters has been reported. IMIDA esters
of carboxylic acids represent novel class of carboxylic
acid prodrugs which hydrolyze chemically to yield the
parent carboxylic acid. Since this type of delivery system
does not rely on enzymes to generate the active princi-
product. Reaction of 2-acetoxybenzoic acid (aspirin)
with CDI and 1-hydroxymethylimidazole gave cleaner
reaction mixtures and the desired product (3) was ob-
tained by simple crystallization. Apparently the acetate
group was deprotected in situ by the generation of imid-
Representative prodrug structures
O
N
N
O
N
N
O
R
O
R
H3CO
4, R = H, Ibuprofen prodrug
9, R = Me, Ibuprofen prodrug
1, R = H, Naproxen prodrug
8, R = Me, Naproxen prodrug
H3CO
O
N
N
O
N
O
O
N
O
N
N
N
O
Cl
5, Nalidixic acid prodrug
2, Indomethacin prodrug
O
CF3
N
O
N
N
NH
OH
3, Salicylic acid prodrug
N
O
N
O
7, Niflumic acid prodrug

S. Majumdar et al. / Tetrahedron Letters 48 (2007) 4609–4611
4611
O
N
NH
O
NaI, AlCl3, DCM
O
SOCl2
RCOOH
RCOCl
R
O
N
N
R
O
I
K2CO3, Acetone
O
O
R = Drug Compounds 8-9
Scheme 2.
quickly with 5 ml of cold 0.05 N HCl and then with 5 ml
of brine. The organic layer was dried over Na2SO4 and
concentrated to give a solid/oily residue depending on the
drug being used. The crude mixture was purified by
recrystallization or column chromatography. The charac-
terization of 1 follows: recrystallization using methylene
chloride–petroleum ether, yield = 94%, mp = 119–121 ꢁC.
1H NMR (CDCl3): d 7.66 (q, 3H), 7.53 (s, 1H), 7.27 (s,
1H), 7.15 (d, 1H), 7.13 (d, 1H), 7.1 (d, 1H), 7.02 (d, 1H),
5.89–5.75 (2d, 2H), 3.9 (s, 3H), 3.84 (q, 1H), 1.54 (d, 3H).
Anal. Calcd for C18H18N2O3: C, 69.33; H, 5.85; N, 9.03.
Found: C, 69.19; H, 5.87; N, 8.85.
ple, they are not prone to biological variability in tissues
and cells which affects the therapeutic efficiency of
enzyme dependent prodrugs. We are currently investi-
gating the mechanism of hydrolysis and topical delivery
of these prodrugs.
Acknowledgment
The authors would like to acknowledge Professor Wil-
liam Dolbier of Department of Chemistry, University
of Florida, Gainesville, USA for his valuable sugges-
tions in designing these prodrugs.
15. Protocol for synthesis of 8: This compound was made in
three steps. Naproxen was first converted to its acid
chloride by reacting 2 g naproxen (1 equiv) with 2.5 ml
thionyl chloride (3.5 equiv) in 10 ml benzene under reflux
conditions at 80 ꢁC for 2 h. The reaction mixture was
concentrated under vacuum to give a yellow solid.
Yield = 97%, 1H NMR (CDCl3): d 7.75 (m, 3H), 7.34–
7.36 (2d, 1H), 7.18–7.12 (3d, 2H), 4.22 (q, 1H), 3.9 (s, 3H),
1.7 (d, 3H). Naproxoyl chloride was next converted to the
a-(acyloxy)ethyl iodide. NaI (1.2 equiv) and paraldehyde
(3.36 equiv) were stirred at 0 ꢁC under N2 in dry DCM
(25 ml) covered with an Al foil to which naproxoyl chloride
(1 equiv), AlCl3 (0.03 equiv), and I2 (0.007 equiv) were then
added. The dark orange colored reaction mixture was
stirred overnight at room temperature. The suspension was
filtered and the residue thoroughly washed with 50 ml
DCM. The filtrate was subsequently washed with 10%
sodium thiosulfate solution (10 ml) and water (3 · 5 ml).
The CH2Cl2 solution was dried over Na2SO4 for an hour
and filtered. The a-(acyloxy)ethyl iodide solution was
concentrated using a rotavapor under vacuum at 40 ꢁC to
References and notes
1. Bundgard, H. In Design and Application of Prodrugs. In a
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2. Sloan, K. B. In Topical and Ocular Drug Delivery; Sloan,
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1
give an oil. Crude yield = 50%. H NMR (CDCl3): d 7.75
7. Sloan, K. B. Adv. Drug Delivery Rev. 1989, 3, 67–101.
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(m, 3H), 7.34–7.36 (2d, 1H), 7.18–7.12 (3d, 2H), 6.8 (qq,
1H), 4.22 (q, 1H), 2.15 (2d, 3H), 3.9 (s,3H), 1.7 (d, 3H).
Alkylation of imidazole with the a-(acyloxy)ethyl iodide
gave 8. Imidazole (1 equiv), K2CO3 (1 equiv), and alkylat-
ing agent (1 equiv) in dry acetone (25 ml) were stirred at
room temperature overnight. The suspension was filtered
and the filtrate was concentrated to an oil. The filtrate was
washed with water (3 · 5 ml). The CH2Cl2 solution was
dried over Na2SO4 for an hour and filtered. The solution
was concentrated using a rotavapor under vacuum at 40 ꢁC
to give 8 as an oil. The resulting material was purified by
column chromatography using 20% ethyl acetate–hexane
11. Klixbull, U.; Bundgaard, H. Arch. Pharm. Chem., Sci. Ed.
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12. 1-Hydroxymethylimidazole: Imidazole (3 g, 44 mmol),
paraformaldehyde (1.46 g, 49 mmol), and 2–3 drops of
triethylamine were heated with stirring in an oil bath at
80 ꢁC till the solid completely melted to give a viscous
residue. The contents were then cooled to room temper-
1
as the eluent to an oil. Yield = 50%. H NMR (CDCl3):
d 7.9 (2d, 1H), 7.3–7.6 (m, 5H), 7–6.8 (m, 3H), 6.67 (qq,
1H), 3.99 (2s, 3H), 3.9 (2q, 1H), 1.7–1.8 (2d, 3H), 1.65 (d,
3H).
ature and allowed to solidify to
a white solid.
Yield = 85%, mp = 36–38 ꢁC. 1H NMR (CDCl3): d 7.37
(s, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 5.4 (s, 2H).
16. Thomas, J. D.; Sloan, K. B. Tetrahedron Lett. 2006, 47,
8785–8787.
13. Alley, P. W. J. Org. Chem. 1975, 40, 1837–1838.
14. Protocol for esterification: To 4 mmol of carboxylic acid
drug was added CDI (1,10-carbonyldiimidazole)
(1.1 equiv) in 20 ml dry DCM and the contents were
stirred for 4 h. 1-Hydroxymethylimidazole (1.1 equiv) was
then added and contents were stirred overnight at room
temperature. The reaction was worked up by diluting the
reaction mixture to 200 ml with DCM and washing
17. The rates of hydrolysis in aqueous buffers were determined
by UV spectroscopy. An aliquot (100 ll) of a stock solution
of compound dissolved in acetonitrile was added to 2.9 ml
of buffer in a cuvette such that the final concentration was
about 10ꢀ5 M. Half-lives were calculated from the plot of
log(A1 ꢀ At) or log(ꢀ(A1 ꢀ At)) versus time.
18. Wasdo, S.; Sloan, K. B. Pharm. Res. 2004, 21, 940–946,
and references cited therein.