Reaction of 7-(2-mesyloxy-2-phenylethyl)theophylline with amines: Synthesis of 1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine derivatives

Article abstract of DOI:10.1016/S0040-4020(00)00683-9

Theophylline was converted to 7-(2-phenyl-2-methanesulfonyloxy)ethyl congener and the product was treated with ammonia or primary amines in a mixture solution of water and organic solvents. Two products were proven to be the styrene analogue and 7-(2-amino-2-phenylethyl)theophylline. The structure of the third product was elucidated as the 1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine derivatives by spectroscopic analysis including HMBC correlation and X-ray crystallography. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00683-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7685±7690
Reaction of 7-(2-Mesyloxy-2-phenylethyl)theophylline with
Amines: Synthesis of 1,2,3,6-Tetrahydro-6-imino-
2-oxo-7H-purine Derivatives
*
Shigetada Kozai, Kyoko Ogimoto and Tokumi Maruyama
Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 21 June 2000; accepted 2 August 2000
AbstractÐTheophylline was converted to 7-(2-phenyl-2-methanesulfonyloxy)ethyl congener and the product was treated with ammonia or
primary amines in a mixture solution of water and organic solvents. Two products were proven to be the styrene analogue and 7-(2-amino-2-
phenylethyl)theophylline. The structure of the third product was elucidated as the 1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine derivatives
by spectroscopic analysis including HMBC correlation and X-ray crystallography. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
amidines are important as precursors of the drug,6 several
methods to prepare these compounds from amide have been
developed. For instance, imidate salt was prepared by treat-
ment of amide with triethyloxonium tetra¯uoroborate and
converted into amidines.6a,7 Also 1-methyl-2-pyrrolidone
was reacted with chlorosulfonyl isocyanate followed by
hydrolysis with aqueous sodium hydroxide to give
2-imino-1-methylazacarbocycles.8 We report here a new
method for the synthesis of the 7-substituted-1,2,3,6-tetra-
hydro-6-imino-2-oxo-7H-purine from theophylline.
Theophylline, a xanthine derivative, has been used for the
treatment of the bronchi. Many derivatives of xanthine have
been reported to exert interesting biological activity such as
inhibition of phosphodiesterases (PDEs),1 adenosine
receptor antagonists2 and calcitonin-inducing activities.3
Recently, the iminooxopurines, amidine analogues of
xanthine, have emerged as strong inhibitors of PDEs.
Sawanishi et al.4 reported that 1,6-cycloalkyl-1,2,3,6-tetra-
hydro-6-imino-2-oxo-9H-purine (A) is a strong PDE IV
inhibitor and shows tracheal-relaxant activity (Fig. 1).
Also tetracyclic guanines (B) which possess 1,2,3,6-tetra-
hydro-2-imino-6-oxo-7H-purine structure have been shown
to be potent and selective inhibitors of the cGMP-hydroliz-
ing enzyme PDE1 and PDE5.5
Results and Discussion
We attempted the conversion of caffeine to amidine
congener. For instance, caffeine (1) was successively treated
with triethyloxonium tetra¯uoroborate and ammonia.6a,7
However, the ring-opening product (2) was obtained in a
low yield. It is speculated that the initial attack of the
reagent at oxygen is dif®cult since much more electron-
rich nitrogen receives a preferential attack of the electro-
phile (Chart 1). Another trial using chlorosulfonyl iso-
cyanate and alkali as reagents recovered caffeine.8 The
authors postulated that the carbocation at the side-chain is
favored to attack the exocyclic oxygen without affecting
ring nitrogen of caffeine. Thus, the 2-hydroxy-2-phenyl-
ethyl derivative (4a) was prepared from theophylline (3a)
in 2 steps and converted to the mesylate (4b) by the conven-
tional manner (Chart 2). Then 4b was treated with 28%
ammnia in the mixture of dioxane and MeOH. After
work-up of the reaction mixture, the products were sepa-
rated by silica gel chromatography. From the ®rst fraction,
the styrene analogue (5), which shows absorption maximum
at 308 nm on UV spectrum, was obtained. The most polar
substance from the third fraction was proven as the
However, synthesis of these compounds was achieved by
ring construction, and conversion of commercially available
caffeine or theophylline to iminooxopurine, an amidine
analogue of xanthine, has not been examined. Since
Figure 1. Phosphodiesterase inhibitors.
Keywords: amidines; X-ray crystallography; xanthates.
* Corresponding author. Tel: 181-886-22-9611; fax: 181-886-55-3051;
e-mail: maruyama@ph.bunri-u.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00683-9

7686
S. Kozai et al. / Tetrahedron 56 (2000) 7685±7690
Chart 1.
Table 1. Yields of the products obtained by the reaction of the mesylate
(4b) with amines
2-amino-2-phenylethyl compound (6a). The second fraction
was evaporated to produce the new compound (7a) as white
crystals. The UV spectrum of 7a was different from the
caffeine analogue such as 1, 3b and 4a,b and showed an
absorption maximum at 297.5 nm in an acidic condition.
The bathochromic effect in the acidic condition suggests a
modi®cation of the chromophore. Reaction of 4b with
primary amines also gave 7b,c (Table 1). The imino-
oxopurine structure was con®rmed by HMBC spectrum of
the N6-ethyl derivative (7c) which shows a C±H correlation
between methylene protons of ethyl group and C6 (Fig. 2).
The presence of the ethyl group near C6 strongly suggests
that a nucleophilic attack of amines at C6 occurred during
the reaction. Podona et al. reported that neighboring
group participation of the side-chain was observed in the
reaction of N-(2-bromoethyl)glutarimide with primary
amine to afford N-(2-hydroxyethyl)imino-glutarimide.9
Consequently the new products were estimated as imino-
oxopurines (7a±c). The structure of 7a was ®nally
determined by the X-ray diffraction method (Fig. 3). The
mechanism to form 7a±c could be explained as the follow-
ing: At ®rst the carbocation (S-1) was formed from starting
5 (%)
6a±c (%)
7a±c (%)
a series; RˆH
31
3.2
4.3
3.3
43
7.6
40
23
45
b series; RˆCH3
c series; RˆC2H5
Figure 2. HMBC correlations of 7c in CDCl3.
Figure 3. Ortep drawing of compound 7a.

S. Kozai et al. / Tetrahedron 56 (2000) 7685±7690
7687
Chart 2. (i) PhCOCH2Cl, K2CO3, acetone-DMF, (ii) NaBH4, MeOH±iPrOH, (iii) MsCl, pyridine (iv) R±NH2 in 1,4-dioxane.
material, then intramolecular electrophilic attack of the
cation to the O6 formed the ammonium of the ring structure
(S-2). Nucleophilic substitution of ammines at C6 and the
subsequent elimination of proton formed 7a±c (Chart 2).
The ratio of the amidine derivatives (7) to the substitution
product (6) is changeable by the amines. The reason is under
investigation.
mesh) was employed for column chromatography. X-ray
re¯ection data were collected with a Mac Science MXC18
diffractometer using MoKa radiation (lˆ0.71073 A).
Ê
Reaction of caffeine (1) with alkylating agent and
ammonia. To a suspension of caffeine (1, 970 mg,
5 mmol) in dry CH2Cl2 (10 mL) was added 1 M triethyl-
oxonium tetra¯uoroborate in CH2Cl2 (5 mL, 5 mmol) and
stirred at room temperature overnight. The solution was
concentrated to dryness, to which anhydrous ether
(10 mL) was added. The insolubles were collected by ®ltra-
tion to give a solid. The product was dissolved in saturated
ammonia solution in MeOH (10 mL) and stirred at room
temperature for 3 days. Then, the solution was ®ltered to
remove insoluble materials. The ®ltrate was evaporated and
chromatographed over a column of silica gel (2£32 cm)
using 0±12% EtOH in CHCl3 (2 L) to give 6-ethylamino-
5-[(N-formyl-N-methyl)amino]-1,3-dimethyluracil (2) as
white crystals (83 mg, 7%): mp 137.5±138.58C; UV lmax
(MeOH) nm: 272 (log eˆ4.22); UV lmax (0.05 M HCl) nm:
272 (log eˆ4.24); MS m/z: 240 (M1); the structure of the
product was determined by X-ray diffraction method as
shown in Fig. 4.
Although nitrogen of caffeine is facilitated to the electro-
philic attack, the carbocation at the side-chain of N7 is able
to attack regio-speci®cally at exocyclic oxygen (O6) of
theophylline derivative. Nucleophilic substitution of the
intermediate with ammonia or primary amines afforded
1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purines 7a±c. This is
the ®rst report that describes the conversion of the 1-alkyl-6-
oxopurine to the amidine analogue.
Experimental
Melting points (mp) were determined using a Yanagimoto
micro-melting point apparatus (hot stage type) and are
uncorrected. UV spectra were recorded with a Shimadzu
UV-190 digital spectrometer. Low resolution mass spectra
were obtained on a Shimadzu-LKB 9000B mass spectro-
meter in the direct-inlet mode. High resolution mass spectra
were obtained on a JMS AX-500 spectrometer in the direct-
inlet mode. 1H NMR spectra were recorded on either Varian
UNITY 200 (200 MHz) or Varian UNITY 600 (600 MHz)
in CDCl3 with tetramethylsilane as an internal standard.
Merck Art 5554 plates precoated with silica gel 60 contain-
ing ¯uorescent indicator F254 were used for thin-layer
chromatography and silica gel 60 (Merck 7734, 60±200
7-Phenacyltheophylline (3b). To a solution of theophylline
(3a, 5.4 g, 30 mmol) in a mixture of DMF (120 mL) and
acetone (120 mL) was added potassium carbonate (4.98 g,
36 mmol) and 2-chloroacetophenone (6.96 g, 45 mmol) and
the mixture was stirred at room temperature for 2 h. The
solution was neutralized by addition of acetic acid
(4.2 mL) and evaporated to a small volume, then the residue
was partitioned between CHCl3 (500 mL) and water
(500 mL). The organic layer was evaporated to give a

7688
S. Kozai et al. / Tetrahedron 56 (2000) 7685±7690
Figure 4. Ortep drawing of compound 2.
residue, which was recrystallized from MeOH to afford 3b
as white crystals (8.3 g, 93%): mp 188.5±1898C; H NMR
toluene to afford 4b as white crystals (3.28 g, 70%); 146±
1478C. H NMR (CDCl3) d: 7.61 (1H, s, H-8), 7.43±7.53
1
1
(CDCl3) d: 7.50±8.06 (6H, m, Ph, H-8), 5.82 (2H, m, CH2),
3.63 (3H, s, CH3), 3.35 (3H, s, CH3); UV lmax (MeOH) nm:
273 (log eˆ4.04); MS m/z: 298 (M1); Anal. Calcd for
C15H14N4O3: C, 60.39; H, 4.73; N, 18.78. Found: C,
60.21; H, 4.71; N, 18.77.
(5H, m, Ph), 5.99 (1H, dd, Jˆ2.9, 9.2 Hz, CH±Ph), 4.77
(1H, dd, Jˆ3.1, 14.5 Hz, one of CH2), 4.39±4.51 (1H, m,
one of CH2), 3.61 (3H, s, CH3), 3.44 (3H, s, CH3), 2.72 (3H,
s, CH3). UV lmax (MeOH) nm: 273 (log eˆ3.93); MS m/z:
378 (M1). Anal. Calcd for C16H18N4O5S: C, 50.78; H, 4.79;
N, 14.80. Found: C, 51.22; H, 5.01; N, 14.82.
7-[(2-Hydroxy-2-phenyl)ethyl]theophylline (4a). To a
solution of 3b (4.4 g, 14.8 mmol) in a mixture of MeOH
(60 mL) and i-PrOH (60 mL) was added NaBH4 (1.25 g,
33 mmol) and the mixture was re¯uxed for 1 h. Then, the
solution was concentrated to a small volume and the residue
was partitioned between CHCl3 (200 mL) and water
(200 mL). The organic layer was dried over MgSO4, evapo-
rated and the solid was crystallized from EtOH to give 4a as
white crystals (4.2 g, 94%): mp 155±1568C; 1H NMR
(CDCl3) d: 7.31±7.41 (6H, m, Ph, H-8), 5.10±5.17 (1H,
m, CH±Ph), 4.69 (1H, dd, Jˆ3.1, 13.9 Hz, one of CH2),
4.17±4.28 (1H, m, one of CH2), 3.62 (1H, d, Jˆ3.5 Hz,
OH), 3.56 (3H, s, CH3), 3.40 (3H, s, CH3); UV lmax
(MeOH) nm: 273 (log eˆ3.93); MS m/z: 300 (M1); Anal.
Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.65. Found:
C, 59.60; H, 5.53; N, 18.41.
Reaction of 4b with ammonia. To a solution of 4b
(500 mg, 1.32 mmol) in 1,4-dioxane (30 mL) was added
25% ammonia (1 mL, 15 mmol) and heated in a steel tube
at 1008C overnight. After cooling, the solution was concen-
trated to a small volume, and chromatographed over a
column of silica gel (2.6£18 cm) using 0±25% MeOH in
AcOEt. From the ®rst fraction 7-(2-phenylvinyl)theophyl-
line (5) was obtained as a white solid (116 mg, 31%): mp
185.5±187.58C; 1H NMR (CDCl3) d: 8.04 (1H, s, H-8), 8.01
(1H, d, Jˆ14.7 Hz, CH), 7.32±7.50 (5H, m, Ph), 6.98 (1H,
d, Jˆ15.0 Hz, CH), 3.63 (3H, s, CH3), 3.59 (3H, s, CH3);
UV lmax (MeOH) nm (log e): 269 (4.21), 308 (4.24); MS
m/z: 282 (M1); Anal. Calcd for C15H14N4O2: C, 63.82; H,
5.00; N, 19.85. Found: C, 63.59; H, 4.47 N, 19.70. The third
fraction was evaporated and the residue was crystallized
from MeOH to give 7-(2-hydroxy-2-phenylethyl)-1,3-
dimethyl-1,2,3,6-tetrahydro-6-imino-2-oxo-7H-purine (7a)
as white crystals (157 mg, 40%): mp 148±148.58C; 1H
NMR (CDCl3) d: 7.29±7.39 (5H, m, Ph), 7.01 (1H, s,
H-8), 5.14(1H, dd, Jˆ2.9, 5.8 Hz, CH±Ph), 4.86 (1H, dd,
Jˆ2.9, 14.3 Hz, one of CH2), 4.39 (1H, dd, Jˆ6.2, 14.3 Hz,
one of CH2), 3.53 (3H, s, CH3), 3.42 (3H, s, CH3); UV lmax
(MeOH) nm: 277 (log eˆ3.99), lmax (0.05 M HCl) nm:
297.5 (log eˆ4.04); MS m/z: 299 (M1); Anal. Calcd for
C15H17N5O2´0.1H2O: C, 59.82; H, 5.76; N, 23.26. Found:
7-[(2-Methanesulfonyloxy-2-phenyl)ethyl]theophylline
(4b). To a solution of 4a (3.7 g, 12.3 mmol) in pyridine
(37 mL) was added methanesulfonyl chloride (4.36 mL,
55 mmol) and the mixture was stirred at room temperature
for 1 h. Then, water (6.2 mL) was added to the solution. The
mixture was concentrated to a small volume and the residue
was partitioned between CHCl3 (250 mL) and water
(250 mL). The organic layer was dried over MgSO4 and
evaporated to give a residue, which was crystallized from

S. Kozai et al. / Tetrahedron 56 (2000) 7685±7690
7689
C, 59.86; H, 5.70 N, 23.30. Evaporation of the fourth frac-
tion gave 7-(2-amino-2-phenylethyl)theophylline (6a) as a
white solid (13 mg, 3.3%): mp 152.5±1548C. 1H NMR
(CDCl3) d: 7.29±7.37 (5H, m, Ph), 7.29 (1H, s, H-8),
4.35±4.54 (2H, m, CH±Ph and one of CH2), 4.27±4.35
(1H, m, one of CH2), 3.59 (3H, s, CH3), 3.45 (3H, s,
CH3); UV lmax (MeOH) nm: 274.0 (log eˆ3.92), UV
lmax (0.05 M HCl) nm: 274 (log eˆ3.96); MS m/z: 299
(M1); Anal. Calcd for C15H17N5O2: C, 60.19; H, 5.72; N,
23.40. Found: C, 60.15; H, 5.71 N, 23.31. Also 4a was
obtained from the second fraction in 3.2% yield.
dimethyl-6-ethylimino-1,2,3,6-tetrahydro-2-oxo-7H-purine
(7c) as white crystals (195 mg, 45%): mp 157±1588C; H
1
NMR (CDCl3) d: 7.23±7.37 (5H, m, Ph), 6.95 (1H, s, H-8),
5.09 (1H, dd, Jˆ3.0, 6.6 Hz, CH±Ph), 4.71 (1H, dd, Jˆ3.0,
14.3 Hz, one of CH2), 4.35 (1H, dd, Jˆ6.6, 14.3 Hz, one of
CH2), 3.77 (2H, dq, Jˆ1.9, 7.1 Hz, CH2CH3), 3.55 (3H, s,
CH3), 3.52 (3H, s, CH3), 1.39 (3H, t, Jˆ7.1 Hz, CH2CH3);
13C NMR (150 MHz, CDCl3) d: 152.9 (C2), 144.4 (C4),
142.8 (C6), 141.7 (Ph), 139.9 (C8), 128.5 (Ph), 127.9
(Ph), 125.7 (Ph), 109.6 (C5), 74.0 (CH2±CH(OH)±), 53.4
(CH2±CH(OH)±), 43.9 (N6±CH2CH3), 36.1 (N1±CH3), 29.6
(N3±CH3), 17.9 (N6±CH2CH3); UV lmax (MeOH) nm: 283.5
(log eˆ4.02), lmax (HCl) nm: 312 (log eˆ4.12); MS m/z:
327 (M1); Anal. Calcd for C17H21N5O2: C, 62.37; H, 6.47;
N, 21.39. Found: C, 62.57; H, 6.39; N, 21.51. The fourth
fraction was evaporated to give 7-(2-ethylamino-2-phenyl-
Reaction of 4b with methylamine. To a solution of 4b
(500 mg, 1.32 mmol) in 1,4-dioxane (30 mL) was added
40% methylamine (1 mL, 12.9 mmol) and heated in a
steel tube at 808C overnight. A similar work-up of the solu-
tion as described in the section of 7a and separation by a
column of silica gel (2.6£24 cm) using 0±12.5% MeOH in
AcOEt gave three products. From the third fraction, 7-[(2-
hydroxy-2-phenyl)ethyl]-1,3-dimethyl-1,2,3,6-tetrahydro-
6-methylimino-2-oxo-7H-purine (7b) was obtained as white
crystals (96 mg, 23%): mp 153±154.58C; 1H NMR (CDCl3)
d: 7.28±7.37 (5H, m, Ph), 6.90 (1H, s, H-8), 5.08 (1H, dd,
Jˆ3.0, 6.3 Hz, CH±Ph), 4.70 (1H, dd, Jˆ3.0, 14.6 Hz, one
of CH2), 4.30 (1H, dd, Jˆ6.3, 14.3 Hz, one of CH2), 3.57
(3H, s, CH3), 3.48 (3H, s, CH3), 3.47 (3H, s, CH3); UV lmax
(MeOH) nm: 282.5 (log eˆ4.00), UV lmax (0.05 M HCl)
nm: 310 (log eˆ4.09); MS m/z: 313 (M1); Anal. Calcd for
C16H19N5O2: C, 61.33; H, 6.11; N, 22.35. Found: C, 61.45;
H, 6.17; N, 22.38. The fourth fraction was evaporated to
give 7-[(2-methylamino-2-phenyl)ethyl]theophylline (6b)
as white crystals (180 mg, 43%): mp 160±1618C; 1H
NMR (CDCl3) d: 7.28±7.36 (5H, m, Ph), 7.10 (1H, s,
H-8), 4.44 (2H, dd, Jˆ0.8, 6.9 Hz, CH2), 4.03 (1H, t,
Jˆ6.3 Hz, CH±Ph), 3.57 (3H, s, CH3), 3.44 (3H, s, CH3),
2.32 (3H, s, NCH3); UV lmax (MeOH) nm: 274
(log eˆ3.93), UV lmax (0.05 M HCl) nm: 274
(log eˆ3.96); MS m/z: 313 (M1); Anal. Calcd for
C16H19N5O2: C, 61.33; H, 6.11; N, 22.35. Found: C,
61.20; H, 6.10; N, 22.34. Compound 5 was obtained from
the ®rst fraction as white crystals in 3.2% yield. Also start-
ing material was recovered from the second fraction in 19%
yield.
1
ethyl)theophylline (6c) as a caramel (33 mg, 7.6%): H
NMR (CDCl3) d: 7.22±7.37 (5H, m, Ph), 7.12 (1H, s,
H-8), 4.42 (2H, dd, Jˆ0.7, 6.6 Hz, CH2), 4.03 (1H, t,
Jˆ6.6 Hz, CH±Ph), 3.58 (3H, s, CH3), 3.44 (3H, s, CH3),
2.59 (2H, q, Jˆ7.3 Hz, CH2CH3), 1.05 (3H, t, Jˆ7.3 Hz,
CH2CH3); UV lmax (MeOH) nm: 274, UV lmax (0.05 M
HCl) nm: 275; MS m/z: 327 (M1).
Crystal data
Crystal data of 2: Recrystallized from ethanol; Monoclinic,
Ê
Ê
space group P21/c, aˆ7.888(0) A, bˆ9.757 (0) A,
Ê
Ê 3
cˆ15.305 (0) A, bˆ97.473 (0)8, Vˆ1167.900(0) A , Zˆ4.
Program using to solve structure: maXus SIR92. Program
using to re®ne structure: maXus. The structure re®ned by
full matrix least-squares; Re®nement on F, Rˆ0.052,
wRˆ0.090, Sˆ1.966.
Crystal data of 7a: Recrystallized from ethanol; Mono-
Ê
clinic, space group P21/c, aˆ11.078 (4) A, bˆ14.248
Ê
Ê
Ê 3
(4) A, cˆ18.696 (6) A, bˆ90.20 (3)8, Vˆ2950.930(2) A ,
Zˆ8. Program using to solve structure: maXus SIR92.
Program using to re®ne structure: maXus. The structure
re®ned by full matrix least-squares; Re®nement on F,
Rˆ0.047, wRˆ0.056, Sˆ1.944.
References
Reaction of 4b with ethylamine. To a solution of 4b
(500 mg, 1.32 mmol) in 1,4-dioxane (30 mL) and water
(1 mL) was added 2.0 M ethylamine solution in MeOH
(4 mL, 8 mmol) and the solution was heated in a steel
tube at 1008C overnight. A similar work-up of the solution
as described in the section of 7a and separation by a column
of silica gel (2.6£24 cm) using 0±12.5% MeOH in AcOEt
gave four products. From the ®rst fraction 5 was obtained as
a caramel in 4.3% yield. Second fraction was evapoarted to
give 7-(2-methoxy-2-phenylethyl)theophylline as a white
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1
solid (26 mg, 6.4%): mp 145±146.58C; H NMR (CDCl3)
d: 7.58 (1H, s, H-8), 7.32±7.42 (5H, m, Ph), 4.54±4.67 (2H,
m, CH±Ph and one of CH2), 4.13±4.27 (1H, m, one of CH2),
3.62 (3H, s, CH3), 3.44 (3H, s, CH3), 3.21 (3H, s, OCH3);
UV lmax (MeOH) nm: 273 (log eˆ3.95), UV lmax (0.05 M
HCl) nm: 273 (log eˆ3.97); MS m/z: 314 (M1); Anal.
Calcd for C16H18N4O3´H2O: C, 57.82; H, 6.06; N, 16.86.
Found: C, 57.91; H, 5.49; N, 16.66. Evaporation of the
third fraction gave 7-(2-hydroxy-2-phenylethyl)-1,3-
4. Sawanishi, H.; Suzuki, H.; Yamamoto, S.; Waki, Y.; Kasugai,
S.; Ohya, K.; Suzuki, N.; Miyamoto, K.; Takagi, K. J. Med. Chem.
1997, 40, 3248±3253.
5. Ahn, H.-S.; Bercovici, A.; Boykow, G.; Bronnenkant, A.;
Chackalamannil, S.; Chow, J.; Cleven, R.; Cook, J.; Czarniecki,
M.; Domalski, C.; Fawzi, A.; Green, M.; Gundes, A.; Ho, G.;
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