Synthesis and cyclic AMP phosphodiesterase 4 isoenzyme inhibitory activity of heterocycle condensed purines.

Article abstract of DOI:10.1248/cpb.50.1163

To reverse the adverse reactions of alkylxanthines and to develop novel inhibitors of cyclic AMP phosphodiesterase 4 (PDE4), a series of heterocycle [a]-, [b]-, [c,d]-, and [i]-condensed purines were designed and synthesized. Although all compounds did no

Full text of DOI:10.1248/cpb.50.1163

September 2002
Chem. Pharm. Bull. 50(9) 1163—1168 (2002)
1163
Synthesis and Cyclic AMP Phosphodiesterase 4 Isoenzyme Inhibitory
Activity of Heterocycle Condensed Purines
Hirokazu SUZUKI, ,a Manabu YAMAMOTO,d Susumu SHIMURA,d Ken-ichi MIYAMOTO,c
*
a
Kenji YAMAMOTO,b and Hiroyuki SAWANISHI
a Department of Synthetic Chemistry, Hokuriku University; and b Department of Chemistry, Faculty of Pharmaceutical
Sciences, Hokuriku University; Ho-3 Kanagawa-machi, Kanazawa 920–1181, Japan: c Department of Hospital Pharmacy,
School of Medicine; Kanazawa University; 13–1 Takara-machi, Kanazawa 920–8641, Japan: and d Central Laboratory,
Lotte Co., Ltd.; 3–1–1 Numakage, Saitama 336–8601, Japan. Received January 31, 2002; accepted April 18, 2002
To reverse the adverse reactions of alkylxanthines and to develop novel inhibitors of cyclic AMP phosphodi-
esterase 4 (PDE4), a series of heterocycle [a]-, [b]-, [c,d]-, and [i]-condensed purines were designed and synthe-
sized. Although all compounds did not display PDE1 and PDE3 inhibitory activities, several heterocycle [i]-con-
densed purines strongly inhibited PDE4. Especially, dl-3,4-dipropyl-8-methyl-4,5,7,8-tetrahydro-1H-imidazo[2,1-
i]purin-5-one (dl-7c) exhibited comparable PDE4 inhibitory activity (IC50؍1.9 mM) to rolipram and denbufylline
(DBF).
Key words PDE4 inhibitor; heterocycle condensed purine; tetrahydro-imidazo[2,1-i]purine
cAMP-phosphodiesterase 4 (PDE4) inhibitors have relax- ment of 18 with aminoalcohols and subsequent ring closure
ation effects on bronchochial smooth muscle and anti-inflam- of 19a, b with thionyl chloride, the corresponding [b]-con-
matory activities, and have attracted attention as a remedy for densed purines (20a, b) were obtained. Debenzylation of 20
asthmatic patients.1,2) Our investigations on the structure–ac- by catalytic hydrogenation afforded the desired 5a, b, which
tivity relationships of alkylxanthines as PDE4 inhibitors have were alkylated with n-propyl bromide in the presence of
shown that 1-, 3- and 7-substituents on the xanthine nucleus potassium carbonate to give 5c, d (Chart 4).
are important for PDE4 inhibitory activity.3—5) Although
[c,d]-Condensed purines (6) were prepared according to
denbufylline (DBF) and XT-44, among compounds prepared the method of Simo et al.17) Catalytic hydrogenation of ni-
by us, were effective against osteoporosis animal models,6,7) tropyrimidines (21a, b)18) gave diamines (22a, b), which were
two compounds caused emesis as an undesirable side effect, treated with ethyl orthoformate without purification to give
comparable to several prototype PDE4 inhibitors such as the [c,d]-condensed purines (6a, b), respectively. N-propyla-
rolipram and its analogs.8)
tion of 6a, b with n-propyl bromide in the presence of potas-
Previous work in this series has shown that heterocycle sium carbonate yielded 6c, d (Chart 5).
condensed purines, namely tetrahydro- imidazo[2,1-i]purine
Substituted [i]-condensed purines (7, 8) were prepared ac-
(1)9) and (2),10) were effective for reducing the side effects of cording to our reported method.9) 6-(Hydroxyethylamino)-
xanthines, and it became desirable to determine the effect of purines (dl-24, dl-25, dl-27 and dl-28) were obtained respec-
other condensed purines on PDE4 inhibitory activity.
As a continuation of studies on [g,h]-condensed purines
(3),11) we have designed and synthesized a series of heterocy-
cles [a]- (4), [b]- (5), [c,d]- (6), and [i]-condensed purines
(7, 8) fixing the propyl group12) as a substituent on the imida-
zole N atom, and examined their in vitro effects on PDE
isoenzymes.
Chart 1
Chemistry
[a]-Condensed purines (4) were prepared according to the
method of Nagamatsu et al.13) Treatment of 9 with propanal
and sodium cyanoborohydride gave 5-(propylamino)imida-
zole (10), which was treated with benzoylisothiocyanate to
give 11. Cyclization of 11 in aq. NaOH yielded 12. Succes-
sive S-methylation of 12, treatment of 13 with aminoalcohol,
and ring closure of 14 with thionyl chloride gave the [a]-con-
densed purines (4a, b). N-Propylation of 4a, b afforded 4c
and 4d, respectivery (Chart 3).
[b]-Condensed purines (5) were prepared according to the
method of Ahn et al.14) 7-Benzyl-1-propylxanthine (17),
which was obtained from regioselective benzylation15) of 5,6-
diamino-3-propyluracil (15)16) and ring closure of 16 with di-
ethoxymethyl acetate, was treated with excess phosphorus
Chart 2
oxychloride to give 7-benzyl-2-chloropurine (18). By treat-
To whom correspondence should be addressed. e-mail: h-suzuki@hokuriku-u.ac.jp
© 2002 Pharmaceutical Society of Japan

1164
Vol. 50, No. 9
Chart 3
Chart 4
Chart 5
Chart 6

September 2002
1165
Table 1. PDE Inhibitory Activities of Heterocycle Condensed Purines
(4—8)
tively from reaction between 6-chloro-3,7-dipropylxanthine
(23) or 3-propyl-6-(1,2,4-triazol-4-yl)purine (26) with each
of dl-1-amino-2-propanol and dl-2-amino-1-propanol. dl-24,
dl-25, dl-27 and dl-28 were reacted with methanesulfonyl
chloride in the presence of triethylamine to give dl-7a, dl-8a,
dl-7b and dl-8b, respectively. N-Propylation of dl-7b and dl-
8b with n-propyl bromide in the presence potassium carbon-
ate afforded dl-7c and dl-8c, respectively (Chart 6).
IC50 (mM)
Compd.
No.
PDE1
PDE3
PDE4
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
dl-7a
dl-7b
dl-7c
dl-8a
dl-8b
dl-8c
1
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
92
41
Ͼ100
35
77
Ͼ100
98
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
94
Ͼ100
92
Ͼ100
Ͼ100
Ͼ100
53
Ͼ100
Ͼ100
24
70
Ͼ100
Ͼ100
30
Results and Discussion
The inhibitory activities of the heterocycle condensed
purines (4—8) against PDE1 and PDE4 isoenzymes from
guinea-pig brain and PDE3 from guinea-pig heart were mea-
sured according to the published methods.9) The results are
shown in Table 1 together with the PDE inhibitory activities
of 1, 2, 3, XT-44, DBF and rolipram, reported already.19)
All newly prepared condensed purines showed no or only
weak inhibitory activities against PDE1 and PDE3 isoen-
zymes. Against the PDE4 isoenzyme, the conclusions shown
below were drawn.
1. The PDE4 inhibitory activities of heterocycle [a]- (4),
[b]- (5), [c,d]- (6) and [g,h]-condensed purines (3) were
weak. Compounds 4a, 4c, 5a and 5b inhibited selectively
PDE4, but were weak compared with the [i]-condensed
purines (1, 2, 7, 8).
2. All of the heterocycle fused purines (4, 5, 7, 8), except
6, substituted with a propyl group at the N-position of the im-
idazole ring inhibited PDE4 more strongly than the corre-
sponding unsubstituted compounds. 4c, 4d vs. 4a, 4b; 5c, 5d
vs. 5a, 5b; dl-7a, dl-7c vs. dl-7b; dl-8a, dl-8c vs. dl-8b.
3. N-propyl substituted [i]-condensed purines (dl-7a, c
and dl-8a, c) having a methyl group at the 7- or 8-position,
although they caused a decline in selectivity, exert more in-
fluence on the PDE4 inhibitory activities than 1 and 2.
In conclusion, dl-3,4-dipropyl-8-methyl-4,5,7,8-dihydro-
1H-imidazo[2,1-i]purine-5-one (dl-7c) exhibited comparable
PDE4 inhibitory activity to the known PDE4 inhibitors,
rolipram and DBF. An earlier paper9) has shown that the in-
tramolecular interaction between the alkyl group at the 1-po-
sition and the carbonyl group at the 6-position of the xan-
thine skeleton may be important to elicit selectivity. This ob-
58
Ͼ100
Ͼ100
Ͼ100
Ͼ100
4.7
88
1.9
19
Ͼ100
15
7.0
5.7
Ͼ100
Ͼ100
5.7
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
78
2
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
Ͼ100
3a (nϭ1)
3b (nϭ2)
XT-44
DBF
Rolipram
1.5
2.9
Ͼ100
Data are mean of three experiments.
give 10 (0.66 g, 64%)), which was recrystallized from CHCl3–MeOH. mp
155—156 °C. 1H-NMR (DMSO-d6) d: 0.88 (3H, t, Jϭ7.1 Hz), 1.49 (2H,
sext., Jϭ7.1 Hz), 3.14 (2H, t, Jϭ7.1 Hz), 6.00 (1H, br s), 6.64 (2H, br s),
7.20 (1H, s), 11.57 (1H, br s). IR (KBr) nmax: 3413, 3351, 3302, 1651,
1631 cmϪ1. Anal. Calcd for C7H12N4O: C, 49.99; H, 7.19; N, 33.31. Found:
C, 50.13; H, 7.40; N, 33.47.
5-[N-(Benzoylthiocarbamoyl)-N-propylamino]imidazole-4-carboxam-
ide (11) To a suspension of 10 (0.66 g, 3.9 mmol) in CH2Cl2 (15 ml) was
added dropwise benzoylisothiocyanate (0.77 g, 4.7 mmol), the reaction mix-
ture was stirred for 6 h at rt. The precipitate was filtered and recrystallized
1
from MeOH to give 11 (0.88 g, 68%). mp 185—186 °C. H-NMR (DMSO-
d6) d: 0.82 (3H, t, Jϭ7.2 Hz), 1.59 (2H, sext., Jϭ7.2 Hz), 3.16 (2H, t, Jϭ7.2
Hz), 6.00 (1H, br s), 6.64 (2H, br s), 7.52—8.00 (8H, m), 11.13 (1H, br s). IR
(KBr) nmax: 3344, 3284, 3234, 1658 cmϪ1. Anal. Calcd for C15H17N5O2S: C,
servation also suggests that the dihydroimidazole ring moiety 54.37; H, 5.17; N, 21.13. Found: C, 54.33; H, 5.40; N, 20.97.
3-Propyl-2-thioxanthine (12) A solution of 11 (2.7 g, 8.2 mmol) in 1 M
of [i]-condensed purine may be important for PDE4 in-
hibitory activity. Currently, we are investigating the synthesis
and PDE4 inhibitory activity of enantiomers of racemic hete-
rocycle [i]-condensed purines (dl-7a, c).
NaOH (30 ml) was heated to reflux for 3 h. The reaction mixture was neu-
tralized with hydrochloric acid and the precipitate was collected by filtration
and recrystallized from MeOH to give 12 (1.4 g, 79%). mp Ͼ290 °C. 1H-
NMR (DMSO-d6) d: 0.91 (3H, t, Jϭ7.2 Hz), 1.78 (2H, sext., Jϭ7.2 Hz),
4.42 (2H, t, Jϭ7.2 Hz), 8.16 (1H, s), 12.37 (1H, br s). IR (KBr) nmax: 3471,
1654, 1620 cmϪ1. Anal. Calcd for C8H10N4OS: C, 45.70; H, 4.79; N, 26.65.
Experimental
Melting points were measured on a Yanagimoto micro melting point hot Found: C, 45.88; H, 4.98; N, 26.69.
stage apparatus and are uncorrected. Infrared spectra (IR) were determined
2-Methylthio-3-propylpurin-6-one (13) To a solution of 12 (0.64 g, 3.1
with a Horiba FT-720 spectrometer or a Hitachi 270-30 spectrometer. Mass mmol) in 2 M NaOH (15 ml) was added dimethyl sulfate (0.46 g, 3.7 mmol),
spectra (MS) were measured with JEOL-DX300 instrument. Nuclear mag- and the reaction mixture was stirred for 1 h at rt, then neutralized with acetic
netic resonance spectra (1H-NMR) were recorded on a JEOL EX 90A spec- acid. The precipitate was collected by filtration and recrystallized from
trometer. Chemical shifts are quoted in parts per million (ppm) with tetra- AcOEt–MeOH to give 13 (0.41 g, 60%). mp 257—258 °C. 1H-NMR
methyl silane as an internal standard. Microanalyses were performed in the (DMSO-d6) d: 0.92 (3H, t, Jϭ7.2 Hz), 1.80 (2H, sext., Jϭ7.2 Hz), 2.56 (3H,
Micro Analytical Laboratory of this faculty. Yield and physicochemical data s), 4.18 (2H, t, Jϭ7.2 Hz), 8.10 (1H, s), 13.50 (1H, br s). IR (KBr) nmax
:
for the heterocycles [a]- (4), [b]- (5), [c,d]- (6) and [i]-condensed purines (7,
8) are summarized in Tables 2 and 3, respectively.
3467, 1630, 1618 cmϪ1. Anal. Calcd for C9H12N4OS: C, 48.20; H, 5.39; N,
24.98. Found: C, 48.31; H, 5.18; N, 24.83.
5-Propylaminoimidazole-4-carboxamide (10) To
aminoimidazole-4-carboxamide hydrochloride 9 (1.0 g, 6.2 mmol) in MeOH
(10 ml) was added sodium cyanoborohydride (0.31 g, 4.9 mmol) and propi-
a
solution of 5-
2-(Hydroxyethylamino)-3-propylpurin-6-one (14a) and 2-(Hydroxy-
propylamino)-3-propylpurin-6-one (14b) A mixture of 13 (0.41 g, 1.8
mmol) and aminoalcohol (5 ml) in pyridine (10 ml) was heated at reflux
onal (0.43 g, 7.4 mmol), the reaction mixture was stirred for 24 h at room overnight and then concentrated in vacuo. The residue was recrystallized
temperature (rt), then filtered, and evaporated in vacuo. The residue was from AcOEt–MeOH to give 14.
1
chromatographed on silica gel using CHCl3–MeOH (6 : 1) as an eluent to
14a: Yield: 83%. mp 253—254 °C. H-NMR (DMSO-d6) d: 0.88 (3H, t,

1166
Vol. 50, No. 9
Table 2. Physicochemical Data for Heterocycle Condensed Purines (4— 8)
Analysis (%)
Calcd (Found)
Compd. No.
n
Yielda) (%)
mp ( °C)
Recryst. solv.
Formula
C
H
N
4a
4b
2
3
70
66
63
62
87
72
63
30
51
56
45
51
83
71
85
74
77
83
256—257
280—281
108—109
105—106
242—243
261—262
60—61
AcOEt–MeOH
AcOEt–MeOH
Pet. Ether
Pet. Ether
AcOEt–MeOH
AcOEt–MeOH
Pet. Ether
—
C10H13N5O
C11H15N5O
C13H19N5O
C14H21N5O
C10H13N5O
C11H15N5O
C13H19N5O
C14H21N5O
C8H8N4O2
C9H10N4O2
C11H14N4O2
C12H16N4O2
C14H21N5O
C11H15N5O
C14H21N5O
C14H21N5O
C11H15N5O
C14H21N5O
54.78
(54.99)
56.64
(56.91)
59.75
(59.90)
61.07
(61.21)
54.78
(54.53)
56.64
(56.45)
59.75
5.98
(6.05)
6.48
(6.59)
7.33
(7.31)
7.69
(7.78)
5.98
(6.04)
6.48
(6.47)
7.33
(7.32)
275.1746
257.1752b)
4.20
(4.18)
4.89
(4.95)
6.02
(5.95)
6.50
(6.34)
7.69
(7.72)
6.48
(6.51)
7.69
(7.84)
275.1746
275.1744b)
6.48
(6.66)
275.1746
275.1749b)
31.94
(31.97)
30.02
(30.56)
26.8
(26.89)
25.43
(25.53)
31.94
(31.77)
30.02
(29.97)
26.80
4c
2
4d
3
5a
2
5b
3
5c
2
(57.91)
(25.85)
5d
3
Oil
6a
3
Ͼ290
EtOH
50.00
(49.81)
52.42
(52.33)
56.40
(56.30)
58.08
(57.92)
61.07
(61.33)
56.64
(56.57)
61.07
29.15
(28.99)
27.17
(26.95)
23.92
(23.88)
22.57
(22.56)
25.43
(25.38)
30.02
(29.97)
25.43
6b
4
Ͼ290
EtOH
6c
3
248—249
204—205
128—129
248—249
111—112
Oil
AcOEt–MeOH
AcOEt–MeOH
Pet. Ether
AcOEt–MeOH
Pet. Ether
—
6d
4
dl-7a
dl-7b
dl-7c
dl-8a
dl-8b
dl-8c
—
—
—
—
—
—
(61.33)
(25.50)
272—273
Oil
AcOEt–MeOH
—
56.64
(56.71)
30.02
(29.94)
a) Yield of final step and for purified product. b) High resolution MS spectra data.
(2.0 g) in 1 M NaOH (100 ml) at 3 atom for 12 h. After removal of catalyst
and concentration the filtrate, then adjusting the pH to 6 with acetic acid, the
crude product was recrystallized from EtOH to give 16 (4.10 g, 75%). mp
210—211 °C. 1H-NMR (DMSO-d6) d: 0.81 (3H, t, Jϭ7.3 Hz), 1.48 (2H,
sext., Jϭ7.3 Hz), 3.65 (2H, t, Jϭ7.3 Hz), 3.82 (2H, s), 5.73 (1H, br s),
7.20—7.38 (7H, s), 10.19 (1H, br s). IR (KBr) nmax: 3332, 3268, 3196, 1698,
1662 cmϪ1. Anal. Calcd for C14H18N4O2: C, 61.30; H, 6.61; N, 20.42. Found:
C, 61.46; H, 6.60; N, 20.26.
7-Benzyl-1-propylxanthine (17) A mixture of 16 (2.7 g, 9.9 mmol) and
diethoxymethyl acetate (6.4 g, 39 mmol) in DMF (15 ml) was stirred for 5 h
at 80 °C. The reaction mixture was concentrated in vacuo and the residue
was recrystallized from MeOH to give 17 (1.7 g, 61%). mp 177—178 °C.
1H-NMR (DMSO-d6) d: 0.84 (3H, t, Jϭ7.3 Hz), 1.52 (2H, sext., Jϭ7.3 Hz),
3.76 (2H, t, Jϭ7.3 Hz), 5.45 (2H, s), 7.33 (5H, s), 8.15 (1H, s), 11.86 (1H,
br s). IR (KBr) nmax: 3504, 1709, 1657 cmϪ1. Anal. Calcd for C15H16N4O2: C,
63.37; H, 5.67; N, 19.71. Found: C, 63.41; H, 5.77; N, 19.67.
Jϭ7.2 Hz), 1.70 (2H, sext., Jϭ7.2 Hz), 3.38—3.62 (4H, m), 4.05 (2H, t,
Jϭ7.2 Hz), 4.90 (1H, br s), 6.97 (1H, br s), 7.84 (1H, s), 12.98 (1H, br s). IR
(KBr) nmax
: . Anal. Calcd for
3448, 3288, 3164, 1630, 1606 cmϪ1
C10H15N5O2: C, 50.62; H, 6.37; N, 29.52. Found: C, 50.43; H, 6.40; N,
29.67.
1
14b: Yield: 71%. mp 194—195 °C. H-NMR (DMSO-d6) d: 0.88 (3H, t,
Jϭ7.2 Hz), 1.45—1.83 (4H, m), 4.04 (2H, t, Jϭ7.3 Hz), 4.68 (1H, br s), 6.97
(1H, br s), 7.84 (1H, s), 12.69 (1H, br s). IR (KBr) nmax: 3421, 3282, 3337,
1681 cmϪ1. Anal. Calcd for C11H17N5O2: C, 52.58; H, 6.82; N, 27.87. Found:
C, 52.73; H, 6.70; N, 27.77.
4-Propyl-4,5,6,7-tetrahydro-1H-imidazo[1,2-a]purin-9-one (4a) and 4-
Propyl-4,5,6,7-tetrahydro-1H-pyrimido[1,2-a]purin-10-one (4b) A mix-
ture of 14 (0.63 mmol) and SOCl2 (0.23 g, 1.9 mmol) in CH2Cl2 (30 ml) was
stirred for 24 h at rt. The reaction mixture was evaporated in vacuo, and the
residue was chromatographed on silica gel using CHCl3–MeOH (3 : 1) as an
eluent to give 4, which was recrystallized from AcOEt–MeOH.
7-Benzyl-2-chloro-1-propylxanthine (18) A mixture of 17 (1.0 g, 3.7
mmol) and POCl3 (20 ml) was refluxed for 5 h. The reaction mixture was
concentrated in vacuo and the residue was partitioned between CHCl3 and
sat. NaHCO3 solution and the organic layer was washed with brine, dried
and concentrated. The crude product was chromatographed on silica gel
using CHCl3–MeOH (20 : 1) as an eluent to give 18 (0.44 g, 40%), which
1,4-Dipropyl-4,5,6,7-tetrahydro-1H-imidazo[1,2-a]purin-9-one (4c)
and 1,4-Dipropyl-4,5,6,7-tetrahydro-1H-pyrimido[1,2-a]purin-10-one
(4d) To a mixture of 4a or 4b (2.0 mmol) and anhydrous K2CO3 (0.41 g,
2.9 mmol) in N,N-dimethylformamide (DMF, 10 ml) was added propyl bro-
mide (0.37 g, 3.0 mmol), and the mixture was stirred at rt for 10 h then con-
centrated in vacuo. The residue was chromatographed on silica gel using
CHCl3–MeOH (20 : 1) as an eluent to give 4c and 4d, which was recrystal-
lized from petroleum ether.
6-Amino-5-(benzylamino)-3-propyluracil (16) A mixture of 15 (3.7 g,
20 mmol) and benzaldehyde (3.2 g, 30 mmol) in H2O (150 ml) was stirred
for 2 h at rt. The solution was cooled and the benzylidene was separated
from the solution. The benzylidene was then hydrogenated over Raney-Ni
1
was recrystallized from MeOH. mp 142—143 °C. H-NMR (DMSO-d6) d:
1.01 (3H, t, Jϭ7.5 Hz), 1.80 (2H, sext., Jϭ 7.5 Hz), 4.24 (2H, t, Jϭ7.5 Hz),
5.61 (2H, s), 7.59 (5H, s), 7.84 (1H, s). IR (KBr) nmax: 1707 cmϪ1. MS m/z:
302 (Mϩ), 304 (Mϩϩ2). Anal. Calcd for C15H15N4OCl: C, 59.51; H, 4.99; N,
18.51. Found: C, 59.52; H, 5.07; N, 18.53.
7-Benzyl-2-(hydroxyethylamino)-1-propylpurin-6-one (19a) and 7-

September 2002
1167
Table 3. 1H-NMR Data of Heterocycle Condensed Purines (4—8)
Compd. No.
IR (KBr) cmϪ1
1H-NMR
4aa)
4ba)
3458, 1722, 1639
3471, 1716, 1597
0.95 (3H, t, Jϭ7.2 Hz), 1.77 (2H, sext., Jϭ7.2 Hz), 3.82—4.36 (6H, m), 8.24 (1H, s), 12.19 (1H, br s)
0.93 (3H, t, Jϭ7.2 Hz), 1.45 (2H, sext., Jϭ7.2 Hz), 1.96 (2H, quint., Jϭ5.6 Hz), 3.47 (2H, t, Jϭ5.6 Hz),
3.95 (2H, t, Jϭ5.6 Hz), 4.18 (2H, t, Jϭ7.2 Hz), 8.13 (1H, s), 12.03 (1H, br s)
0.94 (3H, t, Jϭ7.3 Hz), 0.98 (3H, t, Jϭ7.3 Hz), 1.64—2.12 (4H, m), 3.86—4.25 (8H, m), 7.39 (1H, s)
0.94 (3H, t, Jϭ7.3 Hz), 0.96 (3H, t, Jϭ7.3 Hz), 1.49—2.01 (6H, m), 3.53 (2H, t, Jϭ5.8 Hz), 3.84—4.25
(6H, m), 7.39 (1H, s)
4cb)
4db)
1682, 1637
1676, 1633
5aa)
5ba)
5cb)
5db)
3471, 1685, 1631
3496, 1676, 1635
1670, 1623
0.98 (3H, t, Jϭ7.5 Hz), 1.85 (2H, sext., Jϭ7.5 Hz), 3.97 (2H, t, Jϭ7.5 Hz), 4.08 (2H, t, Jϭ5.3 Hz), 4.10
(2H, t, Jϭ5.3 Hz), 7.64 (1H, s)
0.95 (3H, t, Jϭ7.3 Hz), 1.69 (2H, sext., Jϭ7.3 Hz), 1.94 (2H, quint., Jϭ5.7 Hz), 3.60 (2H, t, Jϭ5.7 Hz),
4.01 (2H, t, Jϭ5.7 Hz), 4.03 (2H, t, Jϭ7.3 Hz), 7.62 (1H, s)
0.93 (3H, t, Jϭ7.5 Hz), 0.96 (3H, t, Jϭ7.5 Hz), 1.71 (2H, sext., Jϭ7.5 Hz), 1.71 (2H, sext., Jϭ7.5 Hz),
3.75—4.26 (8H, m), 7.38 (1H, s)
0.94 (6H, t, Jϭ7.3 Hz), 1.46—1.85 (4H, m), 3.58 (2H, t, Jϭ5.7 Hz), 3.93 (2H, t, Jϭ5.7 Hz), 4.04 (2H, t,
Jϭ7.3 Hz), 4.20 (2H, t, Jϭ7.3 Hz), 7.37 (1H, s)
2.15 (2H, quint., Jϭ5.7 Hz), 3.78 (2H, t, Jϭ5.7 Hz), 4.01 (2H, t, Jϭ5.7 Hz), 7.72 (1H, s), 10.80 (1H, br s)
1.89—2.16 (4H, m), 4.16 (2H, t, Jϭ5.3Hz), 4.30 (2H, t, Jϭ5.3Hz), 7.63 (1H, s), 10.93 (1H, br s)
0.95 (3H, t, Jϭ7.3 Hz), 1.67 (2H, sext., Jϭ7.3 Hz), 2.34 (2H, quint., Jϭ5.9 Hz), 3.97 (2H, t, Jϭ7.3 Hz),
4.01 (2H, t, Jϭ5.9 Hz), 4.18 (2H, t, Jϭ5.9 Hz), 7.46 (1H, s)
0.95 (3H, t, Jϭ7.3 Hz), 1.69 (2H, sext., Jϭ7.3 Hz), 2.04—2.27 (4H, m), 3.99 (2H, t, Jϭ7.3 Hz), 4.25
(2H, t, Jϭ5.4 Hz), 4.32 (2H, t, Jϭ5.4 Hz), 7.36 (1H, s), 10.93 (1H, br s)
0.96 (3H, t, Jϭ7.2 Hz), 0.97 (3H, t, Jϭ7.2 Hz), 1.34 (3H, d, Jϭ6.4 Hz), 1.52—2.04 (4H, m), 3.45
(1H, dd, Jϭ7.1, 9.1 Hz), 3.86—4.42 (6H, m), 7.43 (1H, s)
0.87 (3H, t, Jϭ7.3 Hz), 1.30 (3H, d, Jϭ5.9 Hz), 1.68 (2H, sext., Jϭ7.3 Hz), 3.92 (2H, t, Jϭ7.3 Hz),
4.05—4.34 (1H, m), 7.60 (1H, s), 12.40 (1H, br s)
0.94 (3H, t, Jϭ7.3 Hz), 0.97 (3H, t, Jϭ7.2 Hz), 1.34 (3H, d, Jϭ6.4 Hz), 1.60—2.04 (4H, m), 3.45
(1H, dd, Jϭ6.8, 10.4 Hz), 3.89—4.49 (6H, m), 7.52 (1H, s)
0.96 (6H, t, Jϭ7.4 Hz), 1.44 (3H, d, Jϭ5.9 Hz), 1.64—2.05 (4H, m), 3.64 (1H, dd, Jϭ4.6, 13.7 Hz),
3.88—4.48 (6H, m), 7.45 (1H, s)
0.87 (3H, t, Jϭ7.3 Hz), 1.38 (3H, d, Jϭ6.1 Hz), 1.68 (2H, sext., Jϭ7.3 Hz), 4.02 (2H, t, Jϭ7.3 Hz),
4.47—4.66 (1H, m), 7.69 (1H, s), 12.65 (1H, br s)
0.95 (3H, t, Jϭ7.3 Hz), 0.97 (3H, t, Jϭ7.2 Hz), 1.42 (3H, d, Jϭ6.1 Hz), 1.50—2.12 (4H, m), 3.59
(1H, dd, Jϭ4.4, 13.7 Hz), 3.82—4.56 (6H, m), 7.42 (1H, s)
1687, 1633
6aa)
6ba)
6cb)
3448, 1694, 1634
3423, 1682
1693, 1664
6db)
1697, 1654
1693, 1651
dl-7ab)
dl-7ba)
dl-7cbb)
dl-8ab)
dl-8ba)
dl-8cb)
3423, 1708, 1664
1685, 1653
1691, 1658
1710, 1654
1689, 1658
1H-NMR spectra were recorded in a) DMSO-d6 or b) CDCl3.
Benzyl-2-(hydroxyproylamino)-1-propylpurin-6-one (19b) A mixture of ture of 20 (0.81 mmol) and 20% palladium hydroxide on carbon (0.25 g) in
18 (0.44 g, 1.5 mmol), aminoalcohol (1 ml) and CH3CN (20 ml) were re- MeOH (30 ml) was shaken under hydrogen (3 atom) for 24 h. The catalyst
fluxed overnight. The reaction mixture was concentrated in vacuo and the was removed and the filtrate was concentrated in vacuo, and the residue was
residue was purified by recrystallization from AcOEt–MeOH to give 19.
recrystallized from AcOEt–MeOH to yield 5.
1
19a: Yield: 52%. mp 214—215 °C. H-NMR (DMSO-d6) d: 0.87 (3H, t,
3,5-Dipropyl-5,6,7,8-tetrahydro-3H-imidazo[2,1-b]purine-4-one (5c)
and 3,5-Dipropyl-5,6,7,8-tetrahydro-3H-pyrimido[2,1-b]purine-4-one
(5d) To a mixture of 5a or 5b (1.7 mmol) and anhydrous K2CO3 (0.35 g,
Jϭ7.3 Hz), 1.55 (2H, sext., Jϭ7.3 Hz), 3.48 (2H, t, Jϭ5.1 Hz), 3.90 (2H, t,
Jϭ7.3 Hz), 4.74 (2H, t, Jϭ5.1 Hz), 5.44 (2H, s), 6.78 (1H, br s), 7.30 (5H,
s), 8.10 (1H, s). IR (KBr) nmax: 3340, 1692 cmϪ1. Anal. Calcd for 2.5 mmol) in DMF (10 ml) was added propyl bromide (0.31 g, 2.5 mmol)
C17H21N5O2: C, 62.37; H, 6.47; N, 21.39. Found: C, 62.27; H, 6.65; N,
21.53.
and the mixture was stirred at rt for 10 h, then concentrated in vacuo. The
residue was chromatographed on silica gel using CHCl3–MeOH (20 : 1) as
19b: Yield: 57%. Oil. 1H-NMR (CDCl3) d: 0.92 (3H, t, Jϭ7.3 Hz), an eluent to give 5c or 5d, which was recrystallized from petrolum ether.
1.48—2.04 (4H, m), 3.57—4.01 (6H, m), 5.48 (2H, s), 6.00 (1H, br s), 7.30
(5H, s), 7.62 (1H, s). IR (KBr) nmax: 3356, 1681 cmϪ1. HR-MS m/z: hydro-10H-diazepino[1,2,3-c,d]purine-9,11-dione (6b) A suspension of
341.1854 (Calcd for C18H23N5O2: 341.1852). 21 (4.6 mmol) in H2O (100 ml) was hydrogenated over 10% palladium on
4,5-Dihydro-9H-pyrimido[1,2,3-c,d]purine-8,10-dione (6a) and 4,5-Di-
3-Benzyl-5-propyl-5,6,7,8-tetrahydro-3H-imidazo[2,1-b]purine-4-one carbon (0.15 g) at 3 atom for 15 h. The catalyst was removed and the filtrate
(20a) and 3-Benzyl-5-propyl-5,6,7,8-tetrahydro-3H-pyrimido[2,1-b]- was concentrated in vacuo. A mixture of the residue, DMF (20 ml), triethyl
purine-4-one (20b) To a solution of 19 (0.47 mmol) in CH2Cl2 (5 ml) was orthoformate (1.1 g, 7.5 mmol) and p-toluenesulfonic acid (0.050 g) was
added SOCl2 (0.17 g, 1.4 mmol) at 0 °C and stirred for 12 h at rt. The reac- stirred overnight at 100 °C. The reaction mixture was then concentrated in
tion mixture was adjusted to pH 7—8 with 4 M NaOH. The CH2Cl2 layer was
vacuo and the residue was chromatographed on silica gel using CHCl3–
washed with brine, dried and concentrated. The residue was chromato- MeOH (3 : 1) as an eluent to give 6, which was recrystallized from EtOH.
graphed on silica gel using CHCl3–MeOH (10 : 1) as an eluent to give 20,
9-Propyl-4,5-dihydro-9H-pyrimido[1,2,3-c,d]purine-8,10-dione (6c)
and 10-Propyl-4,5-dihydro-10H-diazepino[1,2,3-c,d]purine-9,11-dione
which was recrystallized from iso-propylether.
1
20a: Yield: 67%. mp 133—134 °C. H-NMR (CDCl3) d: 0.96 (3H, t, Jϭ (6d) A mixture of 6a or 6b (6.0 mmol) and anhydrous K2CO3 (1.5 g, 12
7.5 Hz), 1.72 (2H, sext., Jϭ7.5 Hz), 3.75—4.16 (6H, m), 5.44 (2H, s), 7.34 mmol) and propyl bromide (1.6 g, 12 mmol) in DMF (20 ml) was stirred
(5H, s), 7.40 (1H, s). IR (KBr) nmax: 1686, 1642 cmϪ1. Anal. Calcd for overnight at 60 °C. The reaction mixture was concentrated in vacuo and the
C17H19N5O: C, 66.00; H, 6.19; N, 22.64. Found: C, 65.95; H, 6.27; N, 22.58.
residue was chromatographed on silica gel using CHCl3–MeOH (10 : 1) as
20b: Yield: 72%. mp 160—161 °C. 1H-NMR (CDCl3) d: 0.92 (3H, t, an eluent to give 6c or 6d, which was recrystallized from AcOEt–MeOH.
Jϭ7.3 Hz), 1.74 (2H, sext., Jϭ7.3 Hz), 1.91 (2H, quint., Jϭ5.7 Hz), 3.56
(2H, t, Jϭ5.7 Hz), 3.95 (2H, t, Jϭ7.3 Hz), 3.97 (2H, t, Jϭ5.7 Hz), 5.46 (2H,
dl-6-[(2-Hydroxy-1-methyl)ethylamino]-3,7-dipropylpurin-2-one (dl-
24) To 23 (0.51 g, 2.0 mmol) in pyridine (10 ml) was added dl-2-amino-1-
s), 7.33 (5H, s), 7.39 (1H, s). IR (KBr) nmax: 1684, 1634 cmϪ1. Anal. Calcd propanol (4 ml) and the mixture was refluxed overnight. The reaction mix-
for C18H21N5O: C, 66.85; H, 6.55; N, 21.66. Found: C, 66.70; H, 6.64; N, ture was evaporated in vacuo and the residue was chromatographed on silica
21.48.
gel using CHCl3–MeOH (3 : 1) as an eluent to give dl-24 (0.39 g, 83%). 1H-
Propyl-5,6,7,8-tetrahydro-3H-imidazo[2,1-b]purine-4-one (5a) and 5- NMR (CDCl3) d: 0.95 (3H, t, Jϭ7.3 Hz), 0.98 (3H, t, Jϭ7.3 Hz), 1.27 (3H,
Propyl-5,6,7,8-tetrahydro-3H-pyrimido[2,1-b]purine-4-one (5b) A mix- d, Jϭ6.6 Hz), 1.64—2.03 (4H, m), 2.45 (1H, br s), 3.50—4.28 (7H, m), 4.49

1168
Vol. 50, No. 9
(1H, br s), 7.47 (1H, s). IR (KBr) nmax: 3390, 1633 cmϪ1. HR-MS m/z:
293.1857 (Calcd for C14H23N5O2: 293.1852).
N., J. Med. Chem., 37, 1696—1703 (1994).
2) Raeburn D., Souness J. E., Tomkinson A., Karlsson J.-A., Prog. Drug.
Res., 40, 9—32 (1993).
3) Miyamoto K., Sakai R., Kurita M., Ohmae S., Sanae F., Sawanishi H.,
Hasegawa T., Takagi K., Biol. Pharm. Bull., 18, 431—434 (1995).
4) Miyamoto K., Kurita M., Ohmae S., Sanae F., Takagi K., Eur. J. Phar-
macol. (Mol. Pharmacol. Soc.), 267, 317—322 (1994).
5) Sakai R., Konno K., Yamamoto Y., Sanae F., Takagi K., Hasegawa T.,
Iwasaki N., Kakiuchi, M., Kato H., Miyamoto K., J. Med. Chem., 35,
4039—4044 (1992).
Compounds dl-25, dl-027 and dl-28 were prepared by a similar procedure
to that described above from 23 or 26.9)
dl-6-[(2-Hydroxy-2-methyl)ethylamino]-3,7-dipropylpurin-2-one (dl-25):
Yield: 72%. 1H-NMR (CDCl3) d: 0.95 (6H, t, Jϭ7.1 Hz), 1.18 (3H, d, Jϭ6.2
Hz), 1.64—2.03 (4H, m), 2.70 (1H, br s), 3.20—3.48 (2H, m), 3.73—4.31
(5H, m), 6.07 (1H, br s), 7.48 (1H, s). IR (KBr) nmax: 3323, 1628,
1610 cmϪ1. HR-MS m/z: 293.1856 (Calcd for C14H23N5O2: 293.1852).
dl-6-[(2-Hydroxy-1-methyl)ethylamino]-3-propylpurin-2-one (dl-27):
1
Yield: 85%. mp 296—297 °C. H-NMR (DMSO-d6) d: 0.94 (3H, t, Jϭ7.3
6) Waki Y., Horita T., Miyamoto K., Ohya K., Kasugai S., Jpn. J. Phar-
macol., 79, 477—483 (1999).
Hz), 1.17 (3H, d, Jϭ6.8 Hz), 1.62 (2H, sext., Jϭ7.3 Hz), 3.88 (2H, t, Jϭ7.3
Hz), 4.23 (1H, br s), 4.95 (1H, br s), 7.23 (1H, br s) 7.88 (1H, s). IR (KBr)
7) Miyamoto K., Waki Y., Horita T., Kasugai S., Biochem. Pharamcol.,
54, 613—617 (1997).
8) Burnouf C., Pruniaux M.-P., Szilagy C. M., Annu. Rep. Med. Chem.,
33, 91—109 (1998).
9) Sawanishi H., Suzuki H., Yamamoto S., Waki Y., Kasugai S., Ohya K.,
Suzuki N., Miyamoto K., Takagi K., J. Med. Chem., 40, 2—9 (1997).
10) Suzuki H., Sawanishi H., Yamamoto K., Yokogawa K., Miyamoto K.,
Chem. Pharm. Bull., 49, 188—191 (2001).
11) Suzuki H., Sawanishi H., Yamamoto K., Miyamoto K., Chem. Pharm.
Bull., 47, 1322—1325 (1999).
12) Our investigation of the structure–activity relationships has shown that
elongation of the alkyl group from ethyl to propyl at the 1-position of
the xanthine skeleton markedly increased PDE4 inhibitory activity.3—5)
For this reasons, the propyl group as a substituent for the imidazole N
atom of the condensed purine was chosen.
n
max: 3325, 1635, 1612 cmϪ1. Anal. Calcd for C11H17N5O2: C, 52.58; H,
6.82; N, 27.87. Found: C, 57.92; H, 6.34; N, 22.56.
dl-6-[(2-Hydroxy-2-methyl)ethylamino]-3-propylpurin-2-one (dl-28):
1
Yield: 81%. mp 288—289 °C. H-NMR (DMSO-d6) d: 0.85 (3H, t, Jϭ7.3
Hz), 1.10 (3H, d, Jϭ6.2 Hz), 1.62 (2H, sext., Jϭ7.3 Hz), 3.87 (2H, t, Jϭ7.3
Hz), 5.10 (1H, br s), 7.60 (1H, br s) 7.88 (1H, s). IR (KBr) nmax: 3448, 3309,
3238, 1643, 1614 cmϪ1. Anal. Calcd for C11H17N5O2: C, 52.58; H, 6.82; N,
27.87. Found: C, 57.92; H, 6.34; N, 22.56.
dl-1,4-Dipropyl-8-methyl-4,5,7,8-tetrahydro-3H-imidazo[2,1-i]purin-
5-one (dl-7a), dl-1,4-Dipropyl-7-methyl-4,5,7,8-tetrahydro-3H-imidazo-
[2,1-i]purin-5-one (dl-8a), dl-4-Propyl-8-methyl-4,5,7,8-tetrahydro-3H-
imidazo[2,1-i]purin-5-one (dl-7b), and dl-4-Propyl-7-methyl-4,5,7,8-
tetrahydro-3H-imidazo[2,1-i]purin-5-one (dl-8b) To a mixture of dl-24,
dl-25, dl-27 or dl-28 (1.3 mmol) and triethylamine (0.16 g, 1.6 mmol) was
added methanesulfonyl chloride (0.18 g, 1.6 mmol) at 0 °C. The reaction
mixture was stirred for 6 h at rt, and then concentrated in vacuo. The residue
was chromatographed on silica gel using CHCl3–MeOH (6 : 1) as an eluent
to give dl-7a, dl-8a, dl-7b or dl-8b, which was recrystallized from AcOEt or
petroleum ether.
13) Nagamatsu T., Yamasaki H., J. Chem. Soc., Chem. Commun., 1995,
2041—2043 (1995).
14) Ahn H.-S., Bercovici A., Boykow G., Bronnenkant A., Chackalaman-
nil S., Chow J., Cleven R., Cook J., Czarniecki M., Domalski C.,
Fawzi A., Green M., Gundes A., Ho G., Laudicina M., Lindo N., Ma
K., Mckittrick B., Mirzai B., Nechuta T., Neustadt T., Puchalski C.,
Pula K., Silverman L., Smith E., Stamfood A., Tedesco R. P., Tsai H.,
Tulshian D., Vaccaro H., Watkins R. W., Weng X., Witkowski J. T., Xia
Y., Zhang H., J. Med. Chem., 40, 2196—2210 (1997).
dl-3,4-Dipropyl-8-methyl-4,5,7,8-tetrahydro-3H-imidazo[2,1-i]purin-
5-one (dl-7c) and dl-3,4-Dipropyl-7-methyl-4,5,7,8-tetrahydro-3H-imi-
dazo[2,1-i]purin-5-one (dl-8c) Compounds dl-7c and dl-8c were prepared
from dl-7b and dl-8b, respectively as described above for 4c.
15) Fenn M. D., Lister J. H., Aust. J. Chem., 33, 1611—1617 (1980).
16) Muller C. E., Synthesis, 125—128 (1993).
Acknowledgements This study was partly supported by the Special Re-
search Fund of Hokuriku University.
17) Simo O., Rybar A., Alfoldi J., Synthesis, 835—840 (1995).
18) Uhlmann E., Prleiderer W., Heterocycles, 15, 437—453 (1981).
19) Catherine B., Marie P. P., Corinne M. S., Ann. Rep. Med. Chem., 33,
91—109 (1998).
References and Notes
1) Ashton M. J., Cook D. C., Fenton G., Karlsson J.-A., Palfreyman M.
N., Raeburn D., Ratcliffe A. J., Souness J. E., Thurairatnam S., Vicker