N-tosylcarbamide derivatives of 2-pyridinium and 2-pyrimidinium - A new class of inhibitors of metabolically excitable potassium channels in cells of the myocardium [2]

Full text of DOI:10.1007/s10593-007-0075-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 4, 2007
N-TOSYLCARBAMIDE DERIVATIVES OF 2-PYRIDINIUM AND 2-PYRIMIDINIUM –
A NEW CLASS OF INHIBITORS OF METABOLICALLY EXCITABLE POTASSIUM
CHANNELS IN CELLS OF THE MYOCARDIUM
A. P. Stankevicius, L. N. Janusene, V. I. Gendviliene,
G. A. Gurskaite, and D. P. Zablockaite
Keywords: N-tosylcarbamide derivatives of 2-pyridinium and 2-pyrimidinium, inhibitors of
metabolically excited potassium channels of myocardium cells.
Inhibitors are the most important among modulators of the potassium channels of cells – derivatives of
sulfonylureas or thioureas [1]. While compounds of similar type, for example glibenclamide, have been used
with success in the treatment of diabetes, the search for agents for correction of the potassium current in cells of
the heart is still continuing, since they are very important for heart failure, arrhythmia, etc. The majority of
derivatives of sulfonylureas inhibit potassium channels of the ventricles of the heart and have almost no effect on
the atria. Imitating the structure of acetylcholine (or muscarine), we have succeeded in preparing the
N-tosylcarbamide derivatives of 2-pyridinium 1a,b and 2-pyrimidinium 2a,b which strongly inhibit the
potassium acetycholinic channels (KAch) of the atria of the porpoise. The effectiveness of the compounds
synthesized was determined by a previously described method [2]. We note that derivatives containing a
heterocyclic nitrogen quaternized with a methyl or 4-nitrobenzyl group, exceptionally strongly the contractibility
of the myocardium and the duration of the potential effect.
The 2-pyridinium N-tosylcarbamides 1a,b were prepared as follows:
OCNSO2C6H4Me-4
NH2
N
NHCONHSO2C6H4Me-4
N
1
RX
+
N
NHCONHSO2C6H4Me-4
X
R
1a,b
1 a R = CH2C6H4NO2-4, b R = Me, a X = Br, b X = I
__________________________________________________________________________________________
Institute of Cardiology, Kaunas Medical University, Kaunas 50009, Lithuania; e-mail:
carsynt@med.kmu.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 611-613, April, 2007.
Original article submitted December 14, 2007
0009-3122/07/4304-0505©2007 Springer Science+Business Media, Inc.
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The 2-pyrimidinium salts 2a,b were prepared analogously.
OCNSO2C6H4Me-4
N
N
N
N
NH2
NHCONHSO2C6H4Me-4
2
RX
X
+
N
N
R
NHCONHSO2C6H4Me-4
2a,b
2 a R = CH2C6H4NO2-4, b R = Me, a X = Br, b X = I
1H NMR spectra of DMSO-d6 solutions with HMDS as internal standard were recorded with Bruker AC
250-P (250 MHz) instrument. The course of reactions and the purity of the products were monitored by TLC on
Silufol UV-254 strips with 8:4:1:3 butan-1-ol–ethanol–acetic acid–water as eluant and revelation of the spots
with iodine vapor.
1-[4-(Methylphenyl)sulfonyl]-3-pyridin-2-yl)urea (1), mp 154-155°C, and 1-[4-(Methyl-
phenyl)sulfonyl]-3-(pyrimidin-2-yl)urea (2), mp >250°C, were prepared by method [3].
2-[(4-Methylphenyl)sulfonylcarbamido]-1-(4-nitrobenzyl)pyridinium Bromide (1a). 4-Nitrobenzyl
bromide (2.16 g 10 mmol) was added to a solution of compound 1 (2.91 g, 10 mmol) in 2-butanone (15 ml) and
the mixture was heated at 90°C for 3 h, cooled, the precipitate was separated, washed with 2-butanone and
1
recrystallized from ethanol; mp > 250°C (dec.), Rf 0.52. H NMR spectrum, δ, ppm (J, Hz): 8.51-8.52 (2H, s,
2NH); 8.30-8.26 (2H, m, ArH); 8.18 (2H, d, J = 8.7, ArH); 8.99 (1H, dt, J = 1.5, J = 6.9, ArH); 7.49 (2H, d,
J = 8.7, ArH); 7.23 (1H, dt, J = 1.5, J = 6.9); 5.72 (2H, s CH2), 3.38 (3H, s, CH3). Found, %: C 47.07; H 3.49;
Br 15.52; N 10.81; S 6.09. C20H19BrN4O5S. Calculated, %: C 47.30; H 3.74; Br 15.77; N 11.04; S 6.31.
1-Methyl-2-[(4-methylphenyl)sulfonylcarbamido]pyridinium Iodide (1b) was prepared analogously
to 1a from compound 1 (2.91 g, 10 mmol) in 2-butanone and methyl iodide (1.42 g, 10 mmol) after heating at
70°C for 1.5 h and cooling, the crystal substance was filtered off and washed with 2-butanone to give 1b (1.3 g,
30%); mp 138°C (dec.), Rf = 0.68. Found, %: C 38.51; H 3.47; I 29.18; N 9.45; S 7.44. C14H16IN3O3S.
Calculated, %: C 38.77; H 3.69; I 29.31; N 9.69; S 3.79.
2-[(4-Methylphenyl)sulfonylcarbamido]-1-(4-nitrobenzyl)pyrimidinium Bromide (2a). 4-Nitrobenzyl
bromide (2.16 g, 10 mmol) was added to a solution of compound 2 (2.92 g, 10 mmol) in DMF (10 ml).. The
mixture was heated at 90°C for 3 h, cooled and ethyl acetate (150 ml) was added. The mass which separated
solidified after intense stirring. Compound 2a was isolated as a crystalline powder (2.3 g, 45%) after
1
crystallization from a 1 : 1 mixture of ethanol and 2-propanol; mp 24-243°C, Rf = 0.51. H NMR spectrum, δ,
ppm (J, Hz): 9.68-9.37 (1H, br. s, NH); 8.98 (1H, dd, J = 2.1, J = 4.2, ArH); 8.77 (1H, dd, J = 2.1, J = 6.6, ArH);
8.28 (2H, dd, J = 4.2, J = 8.8, ArH); 7.60 (2H, d, J = 8.8, ArH); 7.24 (1H, dd, J = 4.2, J = 6.6, ArH); 5.68 (2H, s,
CH2); 3.40 (3H, s, CH3). Found, %: C 44.58; H 3.29; Br 15.69; N 13.47; S 6.07. C19H18BrN5O5S. Calculated, %:
C 44.86; H 3.54; Br 15.74; N 13.77; S 6.29.
1-methyl-2-[(4-Methylphenyl)sulfonylcarbamido]pyrimidinium Iodide (2b). Methyl iodide (1.42 g,
10 mmol) was added to a solution of compound 2 (2.92 g, 10 mmol) in 2-butanone (10 ml). After heating at 70°C
for 2h, cooling and adding ethyl acetate (20 ml), compound 2b crystallized after several hours. The crystals were
506

filtered off and washed with ethyl acetate to give 2b (1.5 g, 34%); mp 183°C, Rf = 0.72. Found, %: C 33.67; H 3.21;
N 12.63; I 29.01; S 7.19. C13H15IN4O3S. Calculated, %: C 33.93; H 3.45; N 12.90; I 29.25; S 7.37.
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