Synthesis of a new series of imidazo-[1,5-a]pyrido[2,3-e]pyrazines as potential ligands for the GABA receptor complex

Article abstract of DOI:10.1007/s007060200037

Starting from 2-chloro-3-nitropyridine, 2-isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-2(3H),3-dione was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to afford an intermediate dihydropyrido[2,3-b]pyrazin-2-y

Full text of DOI:10.1007/s007060200037

Monatshefte f uÈ r Chemie 133, 653±659 ꢀ2002)
Synthesis of a New Series of Imidazo-
[1,5-a]pyrido[2,3-e]pyrazines as Potential
Ligands for the GABA Receptor Complex
Manuela Weber, Herbert Bartsch, and Thomas ErkerÃ
Institute of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria
Summary. Starting from 2-chloro-3-nitropyridine, 2-isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-
ꢀ3H),3-dione was synthesized. This compound was reacted with potassium tert-butoxide and
2
diethyl chlorophosphate to afford an intermediate dihydropyrido[2,3-b]pyrazin-2-ylphosphate de-
rivative which in turn furnished the desired 1,2,4-oxadiazolylimidazo[1,5-a]pyrido[2,3-e]pyrazine
derivatives with 5-alkyl-3-isocyanomethyl-1,2,4-oxadiazoles in the presence of additional tert-
butoxide. The title compounds are potential ligands for the ꢀ-aminobutyric acid A=benzodiazepine re-
ceptor complex.
Keywords. Annelation; GABA receptor complex; Heterocycles; Imidazo[1,5-a]pyrido[2,3-e]pyr-
azines.
Introduction
Associated with the GABA ion channel are a varietyof recognition sites for small
A
molecules [1] which can directlyin¯uence the abilityof this channel to transport
chloride ions across neuronal membranes. When ꢀ-aminobutyric acid ꢀGABA),
the major inhibitoryneurotransmitter in the central nervous s ys tem, binds to the
receptor, the ¯ow of chloride ions through the channel is increased, and the
excitabilityof the neuron is reduced. Of the manycompounds in¯uencing this
GABA-induced chloride ¯ux, the benzoediazepines have been the most widely
studied. In general, all species which bind to this receptor complex mayhave a
continuum of intrinsic activity, ranging from full agonists through antagonists to
inverse agonists [2, 3]. Full agonists potentiate the GABA-induced chloride ¯ux to
further decrease the excitabilityof the neuron and have found wide-spread use as
anxiolytic, hypnotic, and anticonvulsant agents. In contrast, inverse agonists which
decrease the ¯ow of chloride ion are proconvulsant and anxiogenic in nature.
Antagonists which have minimal or no effect on the chloride ¯ux have neutral
ef®cacy.
In particular, the partial agonists mayhave reduced benzodiazepine-mediated
side effects such as sedation, physical dependence, amnesia, muscle relaxation,
à Corresponding author. E-mail: thomas.erker@univie.ac.at

6
54
M. Weber et al.
Scheme 1
and ethanol potentiation. The current interest in 1,2,4-oxadiazolylimidazo[1,5-a]
pyrido[2,3-e]pyrazines originates from their potential usefulness as partial agonists
for the treatment of anxietyand sleep disorders. One of the compounds that are
reported to be partial agonist at the benzodiazepine receptor is panadiplon [4].
Unfortunately, this imidazo[1,5-a]quinoxaline derivative contains a 5-cyclopropyl-
1,2,4-oxadiazole group at position 3, which is metabolized to release cyclopro-
panecarboxylic acid, leading to an increase in serum triglycerides [5, 6]. Therefore,
we attempted to synthesize the pyrido analogues to achive an improved pharma-
cological pro®le; the target compounds are shown in Scheme 1. In an effort to
®nd further replacement candidates for the partial agonist panadiplon, another ana-
log with a 1,4-thiazin instead of a 1,4-diazin subunit was also a goal of this
investigation.
Results and Discussion
The synthesis of the starting pyrido[2,3-b]pyrazine-2,3-dione was carried out as
shown in Scheme 2. Reaction of 1 with isopropylamine provided the substitution
product 2 ꢀ92%), which was acylated with ethyl oxalyl chloride in the presence of
triethylamine to yield amide 3 ꢀ78%). To accomplish the necessarylactam linkage,
the nitro group of 3 was reduced bytreatment with iron powder in glacial acetic
ꢀ
acid at 70 C for 30 min to afford 4 ꢀ60%).
The desired 1,2,4-oxadiazolylimidazo[1,5-a]pyrido[2,3-e]pyrazines were syn-
thesized according to Scheme 3. Reaction of 4 with potassium tert-butoxide and
diethyl chlorophosphate provided the enol phosphate ester 5. This intermediate,
which was not isolated, was reacted with isocyanides in the presence of additional

Imidazo[1,5-a]pyrido[2,3-e]pyrazines
655
Scheme 2
Scheme 3
potassium tert-butoxide to provide compounds 6±12 ꢀ74±93% with respect to 4).
The oxadiazole isocyanide reagents themselves were synthesized following the
general procedure of Watjen [7].

6
56
M. Weber et al.
Experimental
1
Melting ranges were determined on a Ko¯er hot-stage apparatus and are uncorrected. H and
13
C
NMR spectra were recorded on a Varian UnityPlus 300 spectrometer ꢀTMS as internal reference, ꢁ
values in ppm). Mass spectra were obtained byShimadzu QP 5000 or Hewlett Packard 5970
spectrometers. Analytical TLC was performed on silica gel F254 plates, preparative layer chro-
matographyon silica gel F254s plates. Column chromatographywas done on Merck silica gel 60,
0
.063±0.200 mm. Evaporation refers to evaporation under reduced pressure, drying of solutions
refers to the use of anhydrous Na SO . The results of elemental analyses agreed with the calculated
2
4
values within experimental error.
2
-Isopropylamino-3-nitropyridine ꢀ2; C H N O )
8 11 3 2
3
A solution of 1 ꢀ10 mmol) and isopropylamine ꢀ30 mmol) in 20 cm dry DMF was heated at 40 C
ꢀ
for 6 h. The reaction mixture was diluted with H O and extracted with ethyl acetate. The combined
2
organic layers were dried, and the solvent was evaporated. The residue was puri®ed via column
chromatographyon silica gel ꢀeluent: toluene:eth yl acetate ˆ 6:4) to give 1.66 g ꢀ92%) of 2 as an
oil.
1
H NMR ꢀCDCl , ꢁ, 300 MHz): 1.33 ꢀd, J ˆ 6.6 Hz, 6H, 2 CH ), 4.51 ꢀsept, J ˆ 6.6 Hz, 1H, CH),
3
3
6
.61 ꢀdd, J ˆ 8.2 Hz, J ˆ 4.6 Hz, 1H, pyridine-H), 8.12 ꢀs, br, 1H, NH), 8.35±8.45 ꢀm, 2H, pyridine-
1
H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz): 22.6, 42.6, 111.1, 127.5, 135.1, 151.9, 155.7 ppm; MS:
3
3
‡
m=z ꢀ%) ˆ 181 ꢀM , 30), 166 ꢀ100), 133 ꢀ48), 119 ꢀ78), 93 ꢀ50).
Ethyl 2-#isopropyl-#3-nitro-2-pyridyl)-amino)-2-oxoacetate ꢀ3; C H N O )
12 15 3 5
3
To a solution of compound 2 ꢀ10 mmol) dissolved in 50 cm of dry toluene under Ar, ethyl oxalyl
chloride ꢀ12 mmol) and triethylamine ꢀ15 mmol) were added dropwise. The mixture was stirred
under re¯ux for 24 h. The reaction mixture was diluted with H O and extracted with ethyl acetate.
2
The combined organic layers were dried, and the solvent was evaporated. The residue was puri®ed
via column chromatographyon silica gel ꢀeluent: toluene:ethyl acetate ˆ 8:2) to give 2.11 g ꢀ54%) of
3
as an oil.
1
H NMR ꢀCDCl , ꢁ, 300 MHz): 1.19±1.34 ꢀm, 9H, 3 CH ), 4.09 ꢀq, J ˆ 7.1 Hz, 2H, CH ), 4.71
3
3
2
ꢀ
sept, J ˆ 6.4 Hz, 1H, CH), 7.58 ꢀdd, J ˆ 7.8 Hz, J ˆ 4.8 Hz, 1H, pyridine-H), 8.39 ꢀd, J ˆ 7.8 Hz, 1H,
1
3
pyridine-H), 8.79 ꢀd, J ˆ 4.8 Hz, 1H, pyridine-H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz): 13.6, 19.9,
3
‡
5
1.8, 62.4, 124.1, 134.2, 143.3, 146.0, 152.4, 158.2, 160.4 ppm; MS: m=z ꢀ%) ˆ 282 ꢀM , 0.2), 160
ꢀ
100), 150 ꢀ38), 120 ꢀ27), 79 ꢀ28).
2
-Isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-2#3H),3-dione ꢀ4; C H N O )
10 11 3 2
3
A mixture of compound 3 ꢀ10 mmol), 80 cm glacial acetic acid, and 5 cm H O was heated to 70 C.
3
ꢀ
2
Iron powder ꢀ0.1 mol) was added in small portions, and the mixture was stirred for 10 min. Then the
iron powder was ®ltered off and washed with hot H O. The ®ltrate was cooled, neutralized with 5%
2
NaHCO solution, and extracted with ethyl acetate. The combined organic layers were dried, and the
3
solvent was evaporated. The residue was recrystallized from toluene to give 1.23 g ꢀ60%) of 4 as
white needles.
ꢀ
1
M.p.: 250 C; H NMR ꢀCDCl =DMSO-d , ꢁ, 300 MHz): 1.58 ꢀd, J ˆ 7.1 Hz, 6H, 2 CH ), 5.75
3
6
3
ꢀ
sept, J ˆ 7.1 Hz, 1H, CH), 7.15 ꢀdd, J ˆ 7.9 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 7.55 ꢀd, J ˆ 7.9 Hz,
1
3
1
H, pyridine-H), 8.17 ꢀd, J ˆ 4.7 Hz, 1H, pyridine-H), 12.18 ꢀs, br, 1H, NH) ppm; C NMR
ꢀ
CDCl =DMSO-d , ꢁ, 75 MHz): 17.2, 44.3, 117.4, 120.4, 121.5, 137.1, 139.7, 152.2, 154.1 ppm; MS:
3 6
‡
m=z ꢀ%) ˆ 205 ꢀM , 10), 163 ꢀ26), 135 ꢀ100), 107 ꢀ35), 91 ꢀ26).

Imidazo[1,5-a]pyrido[2,3-e]pyrazines
657
General procedure for the synthesis of compounds 6±10
3
ꢀ
A solution of the lactam 4 ꢀ2 mmol) in 30 cm THF was cooled to À40 C, and potassium tert-butoxide
ꢀ
1.0 M in THF, 2.2 mmol) was added dropwise over 5 min. The mixture was allowed to warm to room
ꢀ
temperature over 30 min and then cooled to À50 C. Diethyl chlorophosphate ꢀ2.6 mmol) was added
ꢀ
ꢀ
dropwise over 5 min, and the mixture was allowed to warm from À50 C to À30 C over 1 h and then to
ꢀ
room temperature over 30 min. The solution was cooled to À78 C, and the corresponding isocyanide
ꢀ
2.4 mmol) was added. Potassium tert-butoxide ꢀ1.0 M in THF, 2.4 mmol) was added dropwise over
1
0 min. The mixture was allowed to warm slowlyto room temperature and stirred overnight. The
mixture was diluted with H O and extracted with ethyl acetate. The combined organic layers were
2
dried, and the solvent was evaporated.
Ethyl 5-isopropyl-4-oxo-4,5-dihydroimidazo[1,5-a]pyrido[2,3-e]pyrazine-
3
-carboxylate ꢀ6; C H N O )
15 16 4 3
The residue was recrystallized from petroleum ether to give 429 mg ꢀ72%) of 6 as light-brown
crystals.
ꢀ
1
M.p.: 152 ± 153 C; H NMR ꢀCDCl =DMSO-d , ꢁ, 300 MHz): 1.45 ꢀt, J ˆ 7.2 Hz, 3H, CH ), 1.66
3
6
3
ꢀ
d, J ˆ 7.1 Hz, 6H, 2 CH ), 4.50 ꢀq, J ˆ 7.2 Hz, 2H, CH ), 5.89 ꢀsept, J ˆ 7.1 Hz, 1H, CH), 7.27 ꢀdd,
3
2
J ˆ 7.9 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 8.22 ꢀd, J ˆ 7.9 Hz, 1H, pyridine-H), 8.50 ꢀd, J ˆ 4.7 Hz, 1H,
1
3
pyridine-H), 8.53 ꢀs, 1H, imidazole-H) ppm; C NMR ꢀCDCl =DMSO-d , ꢁ, 75 MHz): 14.2, 19.5,
3
6
4
6.4, 61.6, 116.6, 118.2, 122.3, 123.2, 135.5, 142.2, 146.6, 153.4, 161.6 ppm; MS: m=z ꢀ%) ˆ 300
‡
ꢀM , 37), 254 ꢀ42), 135 ꢀ100).
3
4
-#5-Ethyl-1,2,4-oxadiazol-3-yl)-5-isopropylimidazo[1,5-a]pyrido[2,3-e]pyrazine-
#5H)-one ꢀ7; C H N O )
6 16 6 2
1
The residue was recrystallized from petroleum ether=toluene to give 603 mg ꢀ93%) of 7 as white
crystals.
ꢀ
1
M.p.: 203±205 C; H NMR ꢀCDCl , ꢁ, 300 MHz): 1.45 ꢀt, J ˆ 7.5 Hz, 3H, CH ), 1.67 ꢀd,
3
3
J ˆ 6.8 Hz, 6H, 2 CH ), 3.04 ꢀq, J ˆ 7.5 Hz, 2H, CH ), 5.91 ꢀsept, J ˆ 6.8 Hz, 1H, CH), 7.26 ꢀdd,
3
2
J ˆ 7.9 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 8.17 ꢀd, J ˆ 7.9 Hz, 1H, pyridine-H), 8.50 ꢀd, J ˆ 4.7 Hz, 1H,
1
3
pyridine-H), 8.58 ꢀs, 1H, imidazole-H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz): 10.8, 19.6, 20.3, 46.3,
3
‡
1
17.0, 118.2, 120.8, 122.9, 131.8, 142.4, 146.4, 154.2, 163.6, 180.7 ppm; MS: m=z ꢀ%) ˆ 324 ꢀM ,
8
), 282 ꢀ21), 227 ꢀ28), 57 ꢀ100).
5-Isopropyl-3-#5-isopropyl-1,2,4-oxadiazol-3-yl)imidazo[1,5-a]pyrido[2,3-e]pyrazine-
4
#5H)-one ꢀ8; C H N O )
7 18 6 2
1
The residue was recrystallized from petroleum ether=toluene to give 513 mg ꢀ76%) of 8 as white
crystals.
ꢀ
1
M.p.: 195 C; H NMR ꢀCDCl , ꢁ, 300 MHz): 1.49 ꢀd, J ˆ 7.1 Hz, 6H, 2 CH ), 1.67 ꢀd, J ˆ 6.9 Hz,
3
3
6
H, 2 CH ), 3.36 ꢀsept, J ˆ 7.1 Hz, 1H, CH), 5.91 ꢀsept, J ˆ 6.9 Hz, 1H, CH), 7.26 ꢀdd, J ˆ 8.0 Hz,
3
J ˆ 4.7 Hz, 1H, pyridine-H), 8.21 ꢀdd, J ˆ 8.0 Hz, J ˆ 1.5 Hz, 1H, pyridine-H), 8.50 ꢀdd, J ˆ 4.7
1
3
Hz, J ˆ 1.5 Hz, 1H, pyridine-H), 8.62 ꢀs, 1H, imidazole-H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz):
3
1
9.5, 20.1, 27.4, 46.2, 116.9, 118.1, 120.7, 123.0, 131.8, 142.3, 146.4, 154.1, 163.3, 183.7 ppm; MS:
‡
m=z ꢀ%) ˆ 338 ꢀM , 7), 296 ꢀ13), 227 ꢀ19), 69 ꢀ100).
3
4
-#5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-5-isopropylimidazo[1,5-a]pyrido[2,3-e]pyrazine-
#5H)-one ꢀ9; C H N O )
17 16 6 2
The residue was recrystallized from petroleum ether=toluene to give 499 mg ꢀ74%) of 9 as white
crystals.

6
58
M. Weber et al.
ꢀ
1
M.p.: 203±205 C; H NMR ꢀCDCl , ꢁ, 300 MHz): 1.20±1.43 ꢀm, 4H, 2 CH ), 1.66 ꢀd,
3
2
J ˆ 7.1 Hz, 6H, 2 CH ), 2.27±2.39 ꢀm, 1H, CH), 5.90 ꢀsept, J ˆ 7.1 Hz, 1H, CH), 7.26 ꢀdd,
3
J ˆ 7.9 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 8.21 ꢀd, J ˆ 7.9 Hz, 1H, pyridine-H), 8.49 ꢀd, J ˆ 4.7 Hz,
1
3
H, pyridine-H), 8.59 ꢀs, 1H, imidazole-H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz): 7.7, 10.1, 19.5,
1
4
3
6.2, 116.9, 118.2, 120.6, 123.0, 131.7, 142.3, 146.4, 154.1, 163.4, 181.4 ppm; MS: m=z ꢀ%) ˆ 336
‡
ꢀ
M , 5), 294 ꢀ11), 227 ꢀ15), 69 ꢀ100).
3
4
-#5-tert-Butyl-1,2,4-oxadiazol-3-yl)-5-isopropylimidazo[1,5-a]pyrido[2,3-e]pyrazine-
#5H)-one ꢀ10; C H N O )
8 20 6 2
1
The residue was recrystallized from petroleum ether=toluene to give 565 mg ꢀ80%) of 10 as white
crystals.
ꢀ
1
M.p.: 227±228 C; H NMR ꢀCDCl , ꢁ, 300 MHz): 1.53 ꢀs, 9H, 3 CH ), 1.67 ꢀd, J ˆ 6.8 Hz, 6H, 2
3
3
CH ), 5.91 ꢀsept, J ˆ 6.8 Hz, 1H, CH), 7.26 ꢀdd, J ˆ 7.9 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 8.17 ꢀd,
3
J ˆ 7.9 Hz, 1H, pyridine-H), 8.50 ꢀd, J ˆ 4.7 Hz, 1H, pyridine-H), 8.58 ꢀs, 1H, imidazole-H) ppm;
1
3
C NMR ꢀCDCl , ꢁ, 75 MHz): 19.5, 28.4, 33.6, 46.3, 116.9, 118.1, 120.7, 123.0, 131.9, 142.5,
3
‡
1
46.4, 154.2, 163.2, 186.1 ppm; MS: m=z ꢀ%) ˆ 352 ꢀM , 4), 310 ꢀ10), 295 ꢀ9), 57 ꢀ100).
3
4
-#5-Cyclohexyl-1,2,4-oxadiazol-3-yl)-5-isopropylimidazo[1,5-a]pyrido[2,3-e]pyrazine-
#5H)-one ꢀ11; C H N O )
20 22 6 2
The residue was recrystallized from petroleum ether=toluene to give 576 mg ꢀ76%) of 11 as yellow
crystals.
ꢀ
1
M.p.: 220±222 C; H NMR ꢀCDCl , ꢁ, 300 MHz): 1.24±1.51 ꢀm, 3H, cyclohexyl-H), 1.66 ꢀd,
3
J ˆ 6.8 Hz, 6H, 2 CH ), 1.70±1.93 ꢀm, 5H, cyclohexyl-H), 2.10±2.24 ꢀm, 2H, cyclohexyl-H), 3.00±
3
3
.14 ꢀm, 1H, cyclohexyl-H), 5.90 ꢀsept, J ˆ 6.8 Hz, 1H, CH), 7.26 ꢀdd, J ˆ 8.1 Hz, J ˆ 4.7 Hz, 1H,
pyridine-H), 8.20 ꢀdd, J ˆ 8.1 Hz, J ˆ 1.3 Hz, 1H, pyridine-H), 8.49 ꢀdd, J ˆ 4.7 Hz, J ˆ 1.3 Hz,
1
H, pyridine-H), 8.61 ꢀs, 1H, imidazole-H) ppm; C NMR ꢀCDCl , ꢁ, 75 MHz): 19.5, 25.3, 25.4,
3
1
3
3
0.1, 36.3, 46.2, 116.9, 118.1, 120.6, 123.0, 131.9, 142.3, 146.4, 154.2, 163.3, 182.8 ppm; MS:
‡
m=z ꢀ%) ˆ 378 ꢀM , 7), 336 ꢀ10), 227 ꢀ21), 55 ꢀ100).
5
4
-Isopropyl-3-#5-phenyl-1,2,4-oxadiazol-3-yl)-imidazo[1,5-a]pyrido[2,3-e]pyrazine-
#5H)-one ꢀ12; C H N O )
20 16 6 2
The residue was recrystallized from petroleum ether=toluene to give 575 mg ꢀ77%) of 12 as brown
crystals.
ꢀ
1
M.p.: 212±214 C; H NMR ꢀCDCl =DMSO-d , ꢁ, 300 MHz): 1.65 ꢀd, J ˆ 6.8 Hz, 6H, 2 CH ),
3
6
3
5
.88 ꢀsept, J ˆ 6.8 Hz, 1H, CH), 7.44 ꢀdd, J ˆ 8.1 Hz, J ˆ 4.7 Hz, 1H, pyridine-H), 7.65±7.81 ꢀm, 3H,
phenyl-H), 8.25 ꢀd, J ˆ 6.8 Hz, 2H, phenyl-H), 8.55 ꢀdd, J ˆ 4.7 Hz, J ˆ 1.5 Hz, 1H, pyridine-H),
1
3
8
.81 ꢀdd, J ˆ 8.1 Hz, J ˆ 1.5 Hz, 1H, pyridine-H), 9.36 ꢀs, 1H, imidazole-H) ppm; C NMR
ꢀ
CDCl =DMSO-d , ꢁ, 75 MHz): 19.2, 45.0, 117.1, 118.4, 120.6, 123.4, 124.5, 127.6, 129.2, 129.8,
3
6
‡
1
32.8, 141.5, 146.8, 153.6, 164.1, 174.7 ppm; MS: m=z ꢀ%) ˆ 372 ꢀM , 9), 371 ꢀ16), 105 ꢀ100),
7
7 ꢀ76).
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Imidazo[1,5-a]pyrido[2,3-e]pyrazines
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Received November 26, 2001. Accepted December 3, 2001