K. Lange et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3141–3144
3143
Table 1 demonstrates that the vasodilator potencies of
PETN, GTN, and their metabolites correlate with the
number of nitrate groups. But the decrease of potency
is more than a stoichiometric one and previous investi-
gations have shown that not only the number of nitrate
groups; but also the ‘nitrate carriers’ structure signifi-
retention factors: 22.3 min PETN; 13.5 min PETriN;
7
Performance RP-18 100 to 4.6 mm (5 lm); eluent: meth-
anol/water 30:70; flow: 0.3 mL/min (isocratic); detection:
UV, 215 nm; retention factors: 11.7 min 1,3-GDN;
ꢂ
.6 min PEDN; 5.8 min PEMN. (B) column: Chromolith
1
6.8 min 1,2-GDN.
4. Pentaerythrityl tetranitrate (PETN): Pentaerythritol
0.50 g, 3.67 mmol) was dissolved dropwise under stirring
1
2
cantly influences the vasorelaxant activity. Here too,
(
acetylation of the mononitrate 2-GMN to the mononi-
trate 3 enhances the vasodilator potency dramatically.
Furthermore, quite significant differences in vasodilator
potency were found between the isomeric 1,3-GDN and
in 2 mL of concentrated nitric acid (100%) at À5 to
À10 ꢁC. After 2–3 h 1 mL of water was added and the
mixture maintained for 2 more hours. The voluminous
white precipitate was filtered off, washed carefully with
water, dissolved in 20 mL of acetone, and filtered again.
The filtrate was diluted with 20 mL of water and the
acetone cautiously evaporated. The white precipitate was
separated and dried in a desiccator under reduced
1
,2-GDN and between 1-GMN and 2-GMN, respec-
tively. In general, a terminal location of the nitrate
group (1,3-GDN, 1-GMN vs 1,2-GDN, 2-GMN) in-
creases the vasoactivity. We conclude that these differ-
ences in vasorelaxant potency are due to different
affinities and reactivities toward the nitrate bioactivating
enzymes. After all it should be mentioned that the
in vitro results given in Table 1 are not simply transmit-
table to the in vivo situation due to very different bioav-
ailabilities of the compounds. For example, the clinical
dosages of PETN have to be ꢀ80-fold higher than those
pressure. Yield 0.51 g (44%), white solid, mp 142.2 ꢁC
9
(
5. Pentaerythrityl trinitrate (PETriN): Similarly to Hess
lit. 142 ꢁC). Anal. (C H N O ) C, H, N.
5
8
4
12
12
1
pentaerythrityl tetranitrate (2.25 g, 7.12 mmol) was dis-
solved under stirring in a boiling mixture of 50 mL of
dioxane and 50 mL of ethanol. Hydrazine hydrate (0.72 g,
14.4 mmol) in 30 mL of water was added dropwise to the
stirred solution over 1 h. The mixture was refluxed for 2 h
and cooled to room temperature. The progress of the
reaction was monitored with HPLC-method A. The
solution was diluted with 100 mL of water and extracted
with 6· 50 mL of dichloromethane. The combined organic
of GTN, although PETN is superior to GTN in vitro
3
(
Table 1).
phases were dried (MgSO ) and evaporated. The crude oil
4
Supplementary data
Spectral data of the synthesized compounds ( H NMR,
C NMR, and IR). Supplementary data associated with
was purified by column chromatography on silica gel using
hexane/ethylacetate (40:60) as eluent and obtained as a
light yellow oil. Yield 0.98 g (51%), light yellow oil. Anal.
1
1
3
(C
H N O10) C, H, N.
5 9 3
1
2
1
6. Pentaerythrityl dinitrate (PEDN): Similarly to Hess
pentaerythrityl tetranitrate (2.43 g, 7.69 mmol) was dis-
solved under stirring in a boiling mixture of 50 mL of
dioxane and 50 mL of ethanol. Hydrazine hydrate (3.09 g,
6
1.7 mmol) in 30 mL of water was added dropwise under
References and notes
stirring for over 1.5 h. The mixture was refluxed for
further 5 h and then cooled to room temperature. The
progress of the reaction was monitored with HPLC-
method A. The solution was diluted with 100 mL of water
and extracted with 6· 50 mL of ethylacetate. The
1
2
3
. Konter, J.; Moellmann, U.; Lehmann, J. Bioorg. Med.
Chem. 2008, 16, 8294.
. Koenig, A.; Roegler, C.; Lange, K.; Daiber, A.; Glusa, E.;
Lehmann, J. Bioorg. Med. Chem. Lett. 2007, 17, 5881.
. Koenig, A.; Lange, K.; Konter, J.; Daiber, A.; Stalleicken,
D.; Glusa, E.; Lehmann, J. J. Cardiovasc. Pharmacol.
combined organic phases were dried (MgSO ) and evap-
4
orated, and the resulting oil was purified by column
chromatography on silica gel using hexane/ethylacetate
(40:60) as eluent. Yield 0.75 g (43%), light yellow oil, later
2
007, 5, 68.
1
5
4
5
6
. Weber, W.; Michaelis, K.; Luckow, V.; Kuntze, U.;
Stalleicken, D. Arzneim.-Forsch. 1995, 45, 781.
. Boschan, R.; Merrow, R. T.; Van Dolah, R. W. Chem.
Rev. 1955, 55, 485.
crystallizing to a light yellow solid. Anal. (C H N O ·
5
10
2
8
ethylacetate) C, H, N.
17. Pentaerythrityl mononitrate (PEMN): A solution of 2-
bromomethyl-2-hydroxymethyl-1,3-propandiol (6.61 g,
. Berthmann, A.; Ratz, H.. In Houben-Weyl – Methoden
Houben-Weyl—Methoden der Organischen Chemie; Bayer,
E., Berthmann, A., Hausweiler, A., Eds.; Stuttgart:
Thieme, 1963; 6, p 329.
. Merrow, R. T. J. Am. Chem. Soc. 1956, 78, 1297.
. Capellos, C.; Fisco, W. J.; Ribaudo, C.; Hogan, V. D.;
Campisi, J.; Murphy, F. X.; Castorina, T. C. Int. J. Chem.
Kinet. 1982, 14, 903.
33.2 mmol) and silver nitrate (12.41 g, 73.0 mmol) in
50 mL of dry acetonitrile was heated at 50 ꢁC under
stirring and protection from light. The precipitated
silver bromide was filtered off repeatedly. After 8 days
the mixture was cooled to room temperature and
saturated sodium chloride solution was added. The
filtrate of this mixture was extracted with 10 · 100 mL
of ethylacetate. The combined organic phases were
7
8
9
. Brandstaetter-Kuhnert, M.; Kuhnert, G. Sci. Pharm.
1
dried (MgSO ) and evaporated. One hundred microli-
4
ters of water was added and the mixture extracted with
960, 28, 287.
1
0. Korolev, A. M.; Eremenko, L. T.; Meshikhina, L. V. Russ.
Chem. Bull. 2002, 51, 2306, (Translation of Izv. Akad.
Nauk, Ser. Khim. 2002, 51, 2141).
3· 100 mL of n-hexane, 4· 100 mL of diethylether, 4·
100 mL of dichloromethane, and 6· 100 mL of
ethylacetate. The n-hexane, diethylether and dichloro-
methane phases were discarded and the ethylacetate
phases were analyzed for byproducts by HPLC. The
pure ethylacetate phases were combined, dried
11. Bentley, P. H.; McCrae, W. J. Org. Chem. 1970, 35, 2082.
12. Hess, U. U.S. Patent 6180664, 1997, 10.
13. HPLC-methods: (A) column: Chromolith Performance
ꢂ
RP-18 100 to 4.6 mm (5 lm); eluent: methanol/water 1:1;
flow: 0.3 mL/min (isocratic); detection: UV, 215 nm;
(MgSO ), and evaporated. The remaining precipitated
4
white solid was recrystallized from diethylether. Yield
Lange, Kathrin
