Methylxanthine Analogues
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 14 2533
report7 that showed that 1-propargyl-3,7-dimethylxan-
thine and 1-propyl-3,7-dimethylxanthine were more
potent than caffeine in releasing Ca2+ from PC12 cells.
These findings provide novel tools for basic research
and suggest possibilities to improve both the potency
and the efficacy of caffeine. In the future, it is possible
to envisage that parent compounds developed through
the use of this information could be used for the
treatment of disorders where it is known that intra-
cellular Ca2+ homeostasis is altered. Further work is
needed to dissect potent and efficacious molecules that
possess Ca2+-releasing activity but are devoid of activity
on adenosine receptors and phosphodiesterases.
H2O was added to the residue, and it was extracted with Et2O,
dried over Na2SO4, and evaporated to give the esters 24d -e
(95-98% yield) that were used without further purification.
P r ep a r a tion of th e Keta ls 25a -e. The carbonylic groups
were protected by refluxing in a Dean-Stark apparatus 24a -e
(10-20 mmol) in dry benzene (50 mL) with an excess of dry
ethylene glycol (3 mL) and a catalytic amount of p-toluene-
sulfonic acid for 2 h. Then Et2O was added, and the mixture
was neutralized and extracted with Et2O. The organic layer
was dried over Na2SO4 and then evaporated to give the ketals
25a -e (90-95% yield), which were used without further
purification.
P r ep a r a t ion of t h e Alcoh ols 26a ,b ,d ,e. The esters
25a ,b,d ,e (8-18 mmol) in dry THF (3-6 mL) were added to a
solution of 3 equiv of LiAlH4 in dry THF (30-40 mL), stirring
the mixture at room temperature for 2-4 h. Then Et2O/HCl 1
N was added to the mixture and it was filtered over Celite;
the organic layer was evaporated to give crude products.
6-Hyd r oxy-2-h exa n on e Eth ylen e Aceta l, 26c. Ketal 25c
was hydroborated (10.6 mmol) in dry THF (15 mL), and 0.33
equiv of BH3 was added dropwise under nitrogen atmosphere
at 0 °C. To the mixture, after stirring at room temperature
for 2 h, was added dropwise a solution of 2.25 equiv of NaOH
3 M and 0.1 mL of H2O2 40% for each mmol of 25c. Then the
temperature was brought 50 °C for 2-6 h. Et2O was added,
and the mixture was neutralized by adding 0.1 N HCl and
extracted with Et2O. The organic layer was dried over Na2-
SO4 and evaporated to give the crude product, which was
purified by chromatography on a silica gel column eluted with
CHCl3/MeOH 95:5 to provide the alcohol 26c as an oil.
P r ep a r a tion of th e Tosyld er iva tives 27a -e, 42, 43.
Compounds 26a -e, 40, and 41 (4-8 mmol) were tosylated in
pyridine (2-5 mL), 1.4 equiv of p-TsCl was added, and the
mixture was stirred at room temperature for 18 h. Then H2O
was added and, after 10 min, Et2O was added to the mixture.
The organic layer was separated and washed several times
with H2O/HCl 1 N, dried over Na2SO4, and evaporated to give
the crude product. Compounds 27a -e, 42, 43 were obtained
in 50-60% yields and used without further purification.
1,3-Dim eth yl-7-(9-oxod ecyl)xa n th in e, 47, a n d 3-Meth -
yl-7-(7-oxooctyl)xa n th in e, 65. Compounds 45 and 64 (0.5
mmol) were hydrated with H2SO4 35% (4 mL) at 50 °C for 2
h, under nitrogen atmosphere. The mixtures were then cooled
in the refrigerator, neutralized with NaOH 5 N, extracted with
CHCl3, dried over Na2SO4, and evaporated to give the corre-
ponding secondary alcohols in quantitative yields. The crude
products, used without further purification, were treated with
PCC (0.8 mmol) in dry CH2Cl2 (5 mL) at room temperature
for 3 h. Then the mixtures were filtered over SiO2 and
evaporated.
Exp er im en ta l Section
Ch em istr y. Meltings points were determined using a
Reichert Thermovar apparatus and are uncorrected. NMR
spectra were recorded on a Varian Gemini 200 MHz; the
chemical shifts are expressed in δ values (parts per million)
relative to tetramethylsilane as internal standard. Thin-layer
chromatography (TLC) was performed on silica gel 60F-254
glass-supported plates with 0.25 mm thickness (Macherey-
Nagel Reagents). Spots were visualized by either ultraviolet
light, exposure to iodine, or spraying with an acid solution of
dinitrophenylhydrazine (DNF) in ethanol. Preparative thin-
layer chromatography was performed on silica gel 60F-254
glass-supported plates with 2 mm thickness (Macherey-Nagel
Reagents). Merck silica gel 60 (70-230 mesh) was used for
column chromatography. All the reactions were monitored by
TLC. The physical-chemical data and purification methods
of the compounds are available as Supporting Information.
1,3-Dim eth yl-7-(2-oxop r op yl)xa n th in e, 6. Xanthine 6
was synthesized in two steps. The first step was performed
refluxing theophylline 1 (2.5 mmol) in a mixture of H2O (15
mL), EtOH (25 mL), and NaOH (2.5 mmol) for 25 min. The
mixture was evaporated and the residue dried in a vacuum at
80 °C for 2 h. To the resulting sodium salt in DMF (15 mL) a
5-fold excess of ClCH2COCH3 was added, and the reaction
mixture was heated for 24 h at 60 °C. Solvent was removed in
a vacuum, and then the residue was dissolved in saturated
NaHCO3, extracted with CHCl3, dried over Na2SO4, and
evaporated.
Gen er a l Alk yla tion P r oced u r e for Dia lk ylxa n th in es.
A stirred suspension of dialkylxanthine (2 mmol) and anhy-
drous K2CO3 (2 mmol) in dry DMF was brought to 120 °C (for
xanthines 8-14 and 16 the reaction temperature was 40-75
°C) for 1 h; then the appropriate alkyl halide or tosyl derivative
(2.2 mmol) was added dropwise, and the mixture was stirred
for 1-18 h. The reaction mixture was cooled at room temper-
ature, H2O was added, and it was neutralized by adding 0.1
N HCl. The mixture was extracted with CHCl3; after drying
over Na2SO4, the organic layer was evaporated in vacuo to give
crude products. The alkylation with tosyl derivatives was
followed by deprotection of the correspondig ketals stirring in
MeOH/HCl 1 N 9:1 at room temperature for 3-14 h. Com-
pounds 7-16, 28-35, 44, 45, 55-57, 61-63, and 66 were
obtained.
Gen er a l P r oced u r e for Red u ction of Oxoa lk yld im eth -
ylxa n th in es. Compounds 6, 7, 15, 30, 31, 33, and 34 (0.2-
0.65 mmol) were reduced in a mixture of MeOH/Et2O 1:1 (3-6
mL) by adding 10 mg of NaBH4, each time monitoring the
reaction by TLC (CHCl3/MeOH 9:1) until it was completed.
Then the mixture was neutralized by adding 0.1 N HCl,
extracted with CHCl3, dried over Na2SO4, and evaporated to
give crude products.
Gen er a l P r oced u r e for Ester s Hyd r olysis. The esters
13, 14, and 16 (0.6 mmol) were heated to boiling with 1 N HCl
(5 mL) for 1 h. The mixtures were then allowed to cool,
producing microneedles of desired products 20, 21, and 22 as
white solids.
Select ive Mon oa lk yla t ion of 3-Met h ylxa n t h in e 5.
3-Methylxanthine 5 was alkylated as described above using
equimolar amounts of alkylating agent at 70 °C for 2 h.
Compounds 60 and 64 were obtained.
P r ep a r a tion of 8-Br om oocta n oyl Ch lor id e, 49. 8-Bro-
mooctanoyl chloride was prepared by adding SOCl2 (10.5
mmol) to 8-bromooctanoic acid (10.3 mmol) in CCl4 (10 mL)
and some drops of DMF, stirring at 100 °C overnight. The
solvent was evaporated to provide 49 in quantitative yield, and
it was used without further purification.
Dia lk yla tion of 3-Meth ylxa n th in e 5. 3-Methylxanthine
5 (1 mmol) was dialkylated as described above, using 2 equiv
of alkylating agent and K2CO3. The alkylation with tosyl
derivative was followed by deprotection of the corresponding
ketal stirring in MeOH/HCl 1 N 9:1 at room temperature for
3-14 h. Compounds 58-59 were obtained.
P r ep a r a tion of th e Ester s 24d -e. Compounds 24d and
24e were synthesized by refluxing the acids 23d -e (20 mmol)
in MeOH (20 mL) with some drops of concentrated H2SO4 for
1.5 h. The reaction mixture was cooled and neutralized by
adding saturated NaHCO3, and MeOH was evaporated. Then
P r ep a r a tion of Alk yl Ha lid es 52-54. A mixture of the
aromatic starting material 50 or 51 (benzene or anisolo, 10
mmol), dry CH2Cl2 (20 mL), and AlCl3 (6 mmol) was stirred
at -10 °C under nitrogen atmosphere. Then the appropriate
acylhalide (6-bromohexanoyl chloride or 49, 7.8 mmol) in dry