Polycyclic N-heterocyclic compounds, part 67: Reaction of 6,7-substituted N-(quinazolin-4-yl)amidine derivatives with hydroxylamine hydrochloride: Formation of in vitro inhibitors of pentosidine

Article abstract of DOI:10.1002/jhet.695

Reactions of N-(quinazolin-4-yl)amidines and their amide oximes with hydroxylamine hydrochloride gave cyclization products that were formed by an initial ring cleavage of the pyrimidine component followed by a ring closure formation of 1,2,4-oxadiazole to

Full text of DOI:10.1002/jhet.695

November 2011
Polycyclic N-Heterocyclic Compounds, Part 67: Reaction of 6,7-
Substituted N-(Quinazolin-4-yl)amidine Derivatives with
Hydroxylamine Hydrochloride: Formation of in Vitro
Inhibitors of Pentosidine
1407
Kensuke Okuda,a* Hideki Muroyama,b and Takashi Hirotab
aLaboratory of Medicinal and Pharmaceutical Chemistry, Gifu Pharmaceutical University,
Gifu 501-1196, Japan
bLaboratory of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University, Kita-ku, Okayama 700-8530, Japan
*E-mail: okuda@gifu-pu.ac.jp
Received June 14, 2010
DOI 10.1002/jhet.695
Published online 19 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
Reactions of N-(quinazolin-4-yl)amidines and their amide oximes with hydroxylamine hydrochloride
gave cyclization products that were formed by an initial ring cleavage of the pyrimidine component fol-
lowed by a ring closure formation of 1,2,4-oxadiazole to give N-[2-([1,2,4]oxadiazol-5-yl)phenyl]forma-
mide oximes. All isolated products were evaluated for in vitro inhibitory activity on the formation of
pentosidine, which is one of representative advanced glycation end products. Some products exhibited
significant inhibitory activity against pentosidine formation.
J. Heterocyclic Chem., 48, 1407 (2011).
ery and development of inhibitors of AGEs formation
represents a new approach for treatment of diabetic or
other pathogenic complications [3,4]. Pimagedine (ami-
noguanidine hydrochloride) was the first AGEs inhibitor
explored in clinical trials and initially appeared to be
promising for treatment of overt nephropathy of type 1
diabetics [5]. However, clinical trial results in overt ne-
phropathy of type 2 diabetics were vague and the drug
ultimately was not approved for commercial production.
In our own approach to developing AGEs inhibitors
we have initiated development and random screening of
compound libraries.
INTRODUCTION
Hyperglycemia plays a major role in the complicated
pathogenesis of diabetes by increasing protein glycation
through nonenzymatic reaction of amino groups (partic-
ularly the lysine residue) with reducing sugars (Maillard
reaction) [1]. This glycation then leads to the formation
of Amadori products via reversible Schiff-base adducts.
Through subsequent oxidation and dehydration steps, a
broad range of heterogeneous fluorescent and brown
products form that are termed advanced glycation end
products (AGEs) [2]. The gradual accumulation of
AGEs in body tissues is a physiological phenomenon
associated with normal aging. However, they are formed
at an accelerated rates in diabetes as a result of the asso-
ciated hyperglycemia and oxidative stress. In addition to
diabetes, AGEs are also important causative factors in
the pathogenesis of neurological diseases such as Alz-
heimer’s disease and they also play a major role in vas-
cular stiffening, atherosclerosis, osteoarthritis, inflamma-
tory arthritis and cataracts [3]. Accordingly, the discov-
Recently, we have reported that reaction of N-(quina-
zolin-4-yl)formamidines (1) with hydroxylamine hydro-
chloride results in a pyrimidine ring opening reaction
accompanied by formation of the 1,2,4-oxadiazole ring
to give N-[2-([1,2,4]oxadiazol-5-yl)phenyl]formamide
oximes (2) (Fig. 1) [6]. This reaction is applicable to
several substituted quinazoline derivatives for the syn-
thesis of potential pharmaceutics and we found some of
the products showed some inhibitory effects on the
C
V
2011 HeteroCorporation

1408
K. Okuda, H. Muroyama, and T. Hirota
Vol 48
2.4 equivalents of hydroxylamine hydrochloride at room
temperature for 4 h was necessary to yield amide oxime 5e
(74%). Reflux conditions were required for the reaction of
5e with hydroxylamine hydrochloride (3.6 equivalents) to
form 6e. In contrast, in the reactions of 4a, 4b, and 4d with
1.2 equivalents hydroxylamine hydrochloride at room tem-
perature, we were unable isolate amide oxime 5. In those
cases, thin layer chromatography (TLC) analysis indicated
that amide oxime 5 and 1,2,4-oxadiazole derivative 6 were
present in the reaction mixture, even though two equivalent
of hydroxylamine hydrochloride was necessary to give the
1,2,4-oxadiazole derivatives [7]. Therefore we added 4–6
equivalents of hydroxylamine hydrochloride for the reac-
tions of 4a, 4b, and 4d at room temperature and obtained
6a, 6b, and 6d, respectively, without isolation of intermedi-
ate oximes. The reason that 5e was quite resistant to reaction
with hydroxylamine hydrochloride and needed reflux condi-
tion compared to 5c could be explained as follows. Com-
pound 5e has two methoxy groups, which are strong electron
donating groups. As we have already discussed [6], LUMO
energy level of amide oxime 5 govern the reactivity of these
intermediates. The calculated LUMO energy of 5e is
–1.3181 eV, whilst that of 5c is –1.7516 [8]. Therefore, it is
reasonable that 5e would be more resistant to nucleophilic
attack of amide oxime than 5c.
Figure 1. Substrates (1) and their rearranged products (2).
formation of pentosidine, which is one of representative
AGEs. Here we report these results in detail.
RESULTS AND DISCUSSION
First, we studied reactions of the formamidines (4).
The requisite 4-aminoquinazolines (3) were prepared
from 2-aminobenzonitriles and formamidine acetate. The
amidines 4 then were prepared by the reaction of 3 with
N,N-dimethylformamide dimethyl acetal in refluxing tolu-
ene (Scheme 1). The reactions of 4 with hydroxylamine
hydrochloride in dry methanol were then investigated. In
the case of 4c, the reaction with 1.4 equivalents of hydrox-
ylamine hydrochloride at room temperature gave amide
oxime 5c (53%). Reaction of 5c with 4 equivalents of hy-
droxylamine hydrochloride at room temperature for 4h pro-
duced the 1,2,4-oxadiazole derivative 6c. In the case of 4e,
Next, we examined reactions of the acetamidines (7).
The amidines 7 were prepared by the reaction of 3 with
Scheme 1. Synthesis of 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Reaction of 6,7-Substituted N-(Quinazolin-4-yl)amidine
Derivatives with Hydroxylamine Hydrochloride
1409
Scheme 2. Synthesis of 8.
1
sium bromide and frequencies are expressed in cmꢀ1. The H
NMR spectra were recorded on a Varian VXR-200 instrument
operating at 200 MHz with tetramethylsilane as an internal stand-
ard. Chemical shifts are given in ppm (d) and J values in Hz, and
the signals are designated as follows: s, singlet; d, doublet; dd,
double doublet; t, triplet; q, quartet; br, broad; m, multiplet. TLC
was carried out on Kieselgel 60F254 (Merck).
N,N-dimethylacetamide dimethyl acetal in refluxing tol-
uene (Scheme 2). In all attempts, the reaction of 7 with
1.2 equivalents of hydroxylamine hydrochloride at room
temperature did not completely consume 7 as evidenced
by TLC analysis. Reaction of 7 with the 4–4.5 equiva-
lents of hydroxylamine hydrochloride gave the oxadia-
zoles 8 directly (70–78%) instead of amide oximes.
Finally, all isolated products in the present study as
well as parent compounds (2a and 2b) [6] were evaluated
for their ability to inhibit the formation of pentosidine
(Table 1). Aminoguanidine hydrochloride [3,9] was used
as a positive control. Amidine derivatives (4 and 7) did
not show any significant inhibitory activity (<20%, data
not shown). In contrast, some formamide oximes (2, 5, 6,
and 8) showed significant inhibitory activity. Among
them, 2a exhibited the most potent inhibitory activity
against pentosidine formation. Compound 6b, 6c, and 6d
also showed some significant inhibitory activity. We are
currently exploring their structure-activity relationships
for further elucidation of anti-AGEs compounds.
4-Amino-6-chloroquinazoline (3a). To a solution of 2-
amino-5-chlorobenzonitrile (2.00 g, 13.1 mmol) in dry 2-ethoxye-
thanol (20 mL) was added formamidine acetate (7.00 g, 67.2
mmol) and the reaction mixture was refluxed for 4 h. After cool-
ing to room temperature, water was added. The precipitate was
filtered, washed with 10% aqueous sodium chloride solution,
water, and then recrystallized from DMF to give 3a (2.00 g,
85%) as colorless feathers, mp >300ꢁC (lit [10] >310ꢁC); IR (po-
tassium bromide): 3270, 3350 (NH2) cmꢀ1 1H NMR (DMSO-
;
d6): d 7.66 (d, 1H, J ¼ 9.0 Hz, H8), 7.78 (dd, 1H, J ¼ 9.0, 2.2
Hz, H7), 7.88 (br s, 2H, deuterium oxide exchangeable, NH2),
8.37 (d, 1H, J ¼ 2.2 Hz, H5), 8.40 (s, 1H, H2); FAB-ms: m/z
180 (MHþ), 182 (MHþþ2).
4-Amino-6-nitroquinazoline (3b). To
a solution of 2-
amino-5-nitrobenzonitrile (2.00 g, 12.3 mmol) in dry 2-ethox-
yethanol (20 mL) was added formamidine acetate (9.60 g, 92.2
mmol) and the reaction mixture was refluxed for 5 h. After
cooling to room temperature, water was added. The precipitate
was filtered, washed with 10% aqueous sodium chloride solu-
tion, water, and then recrystallized from DMF to give 3b (1.73
g, 74%) as colorless feathers, mp >300ꢁC (lit [11] 320–
EXPERIMENTAL
All melting points were determined on a Yanagimoto micro-
melting point apparatus, and are uncorrected. Elemental analyses
were performed on a Yanagimoto MT-5 CHN Corder elemental
analyzer. The fast atom bombardment (FAB) mass spectra were
obtained on a VG 70 mass spectrometer and m-nitrobenzyl alco-
hol was used as the matrix. The IR spectra were recorded on a
Japan Spectroscopic FT/IR-200 spectrophotometer with potas-
320.5ꢁC); IR (potassium bromide): 3340, 3440 (NH2) cmꢀ1
;
1H NMR (DMSO-d6): d 7.81 (d, 1H, J ¼ 9.2 Hz, H8), 8.40
(br s, 2H, deuterium oxide exchangeable, NH2), 8.48 (1H, dd,
J ¼ 9.2, 2.5 Hz, H7), 8.52 (s, 1H, H2), 9.33 (d, 1H, J ¼ 2.5
Hz, H5); FAB-ms: m/z 191 (MHþ).
Table 1
Effects of 2, 5, 6, and 8 on pentosidine formation in vitro.
Compd.
% inhibition
Compd
% inhibition
Compd.
% inhibition
2a
6a
6b
6c
6d
6e
72.0
21.2
2b
8a
8b
8c
8d
8e
11.1
ꢀ0.4
3.6
3.6
5.9
5c
5e
28.9
ꢀ11.5
46.0
41.5
51.7
Aminoguanidine
44.8
ꢀ22.8
ꢀ23.7
Data represent % inhibition of the vehicle control group.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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K. Okuda, H. Muroyama, and T. Hirota
Vol 48
9.02 (s, 1H, N¼¼CHNMe2), 9.20 (d, 1H, J ¼ 2.7 Hz, H5); FAB-ms:
m/z 246 (MHþ). Anal. Calcd. for C11H11N5O2: C, 53.87; H, 4.52;
N, 28.56. Found: C, 53.53; H, 4.67; N, 28.49.
4-Amino-7-chloroquinazoline (3c). To a solution of 2-
amino-4-chlorobenzonitrile (1.80 g, 11.8 mmol) in dry 2-
ethoxyethanol (20 mL) was added formamidine acetate (6.40
g, 61.5 mmol) and the reaction mixture was refluxed for 6 h.
After cooling to room temperature, water was added. The pre-
cipitate was filtered, washed with 10% aqueous sodium chlo-
ride solution, water, and then recrystallized from methanol to
give 3c (1.60 g, 76%) as colorless feathers, mp >300ꢁC (lit
[12] 305–310ꢁC); IR (potassium bromide): 3270, 3370 (NH2)
N1,N1-Dimethyl-N2-(7-chloroquinazolin-4-yl)formamidine
(4c). To a suspension of 3c (500 mg, 2.78 mmol) in dry tolu-
ene (50 mL) was added N,N-dimethylformamide dimethyl
acetal (550 mg, 4.62 mmol), and the mixture was refluxed for
3.5 h. After evaporation of solvent in vacuo, the residue was
recrystallized from cyclohexane to give 4c (476 mg, 73%) as
colorless needles, mp 133–135ꢁC. 1H NMR (DMSO-d6): d
3.23 and 3.26 (each s, each 3H, 2 x NMe), 7.57 (dd, 1H, J ¼
8.8, 2.2 Hz, H6), 7.80 (d, 1H, J ¼ 2.2 Hz, H8), 8.45 (d, 1H,
J ¼ 8.8 Hz, H5), 8.70 (s, 1H, H2), 8.95 (s, 1H, N¼¼CHNMe2);
FAB-ms: m/z 235 (MHþ), 237 (MHþþ2). Anal. Calcd. for
C11H11ClN4: C, 56.30; H, 4.72; N, 23.87. Found: C, 56.45; H,
4.58; N, 23.91.
N1,N1-Dimethyl-N2-(7-methylquinazolin-4-yl)formamidine
(4d). To a suspension of 3d (100 mg, 0.628 mmol) in dry tol-
uene (10 mL) was added N,N-dimethylformamide dimethyl
acetal (105 mg, 0.881 mmol), and the mixture was refluxed for
1 h. After evaporation of solvent in vacuo, the residue was
recrystallized from cyclohexane to give 4d (112 mg, 83%) as
a white powder, mp 92–93ꢁC. 1H NMR (DMSO-d6): d 2.50
(s, 3H, 7-Me), 3.21 and 3.24 (each s, each 3H, 2 x NMe), 7.38
(d, 1H, J ¼ 8.4 Hz, H6), 7.55 (s, 1H, H8), 8.33 (d, 1H, J ¼
8.4 Hz, H5), 8.64 (s, 1H, H2), 8.90 (s, 1H, N¼¼CHNMe2);
FAB-ms: m/z 215 (MHþ). Anal. Calcd. for C12H14N4: C,
67.27; H, 6.59; N, 26.15. Found: C, 66.95; H, 6.65; N, 26.27.
N1,N1-Dimethyl-N2-(6,7-dimethoxyquinazolin-4-yl)form-
amidine (4e). To a suspension of 3e (500 mg, 2.44 mmol) in
dry toluene (50 mL) was added N,N-dimethylformamide di-
methyl acetal (378 mg, 3.17 mmol) and then the mixture was
refluxed for 2 h. After evaporation of solvent in vacuo, the res-
idue was recrystallized from toluene to give 4e (537 mg, 85%)
as a white powder, mp 159–161ꢁC. 1H NMR (DMSO-d6): d
3.21 and 3.22 (each s, each 3H, 2 x NMe), 3.90 and 3.93
(each s, each 3H, 2 x OMe), 7.16 (s, 1H, H8), 7.69 (s, 1H,
H5), 8.55 (s, 1H, H2), 8.86 (s, 1H, N¼¼CHNMe2); FAB-ms:
m/z 261 (MHþ). Anal. Calcd. for C13H16N4O2: C, 59.99; H,
6.20; N, 21.52. Found: C, 60.03; H, 6.07; N, 21.62.
1
cmꢀ1; H NMR (DMSO-d6): d 7.54 (dd, 1H, J ¼ 8.8, 2.0 Hz,
H6), 7.71 (d, 1H, J ¼ 2.0 Hz, H8), 7.94 (br s, 2H, deuterium
oxide exchangeable, NH2), 8.25 (d, 1H, J ¼ 8.8 Hz, H5), 8.40
(s, 1H, H2); FAB-ms: m/z 180 (MHþ), 182 (MHþþ2).
4-Amino-7-methylquinazoline (3d). To
a
solution of
2-amino-4-methylbenzonitrile (500 mg, 3.78 mmol) in dry
2-ethoxyethanol (5.0 mL) was added formamidine acetate
(2.00 g, 19.2 mmol) and the reaction mixture was refluxed for
1 h. After cooling to room temperature, water was added. The
precipitate was filtered, washed with 10% aqueous sodium
chloride solution, water, and then recrystallized from methanol
to give 3d (473 mg, 79%) as colorless feathers, mp 288–
289ꢁC (lit [13] 286–289ꢁC); IR (potassium bromide): 3240,
3330 (NH2) cmꢀ1 1H NMR (DMSO-d6): d 2.46 (s, 3H,
;
7-Me), 7.32 (d, 1H, J ¼ 8.4 Hz, H6), 7.46 (s, 1H, H8), 7.65
(br s, 2H, deuterium oxide exchangeable, NH2), 8.09 (d, 1H,
J ¼ 8.4 Hz, H5), 8.34 (s, 1H, H2); FAB-ms: m/z 160 (MHþ).
4-Amino-6,7-dimethoxyquinazoline (3e). To a solution of
2-amino-4,5-dimethoxybenzonitrile (500 mg, 2.81 mmol) in
dry 2-ethoxyethanol (5.0 mL) was added formamidine acetate
(1.40 g, 13.4 mmol) and the reaction mixture was refluxed for
2 h. After cooling to room temperature, water was added. The
precipitate was filtered, washed with 10% aqueous sodium
chloride solution, water, and then recrystallized from ethanol
to give 3e (435 mg, 76%) as colorless feathers, mp 208–210ꢁC
(lit [14] 204–206ꢁC); IR (potassium bromide): 3320, 3390
(NH2) cmꢀ1 1H NMR (DMSO-d6): d 3.87 and 3.89 (each s,
;
each 3H, 2 x OMe), 7.06 (s, 1H, H8), 7.40 (br s, 2H, deute-
rium oxide exchangeable, NH2), 7.56 (s, 1H, H5), 8.25 (s, 1H,
H2); FAB-ms: m/z 206 (MHþ).
N1,N1-Dimethyl-N2-(6-chloroquinazolin-4-yl)formamidine
(4a). To a suspension of 3a (300 mg, 1.67 mmol) in dry tolu-
ene (30 mL) was added N,N-dimethylformamide dimethyl ace-
tal (275 mg, 2.31 mmol), and the mixture was refluxed for
3 h. After evaporation of solvent in vacuo, the residue was
recrystallized from cyclohexane to give 4a (300 mg, 77%) as a
pale yellow powder, mp 128–130ꢁC; 1H NMR (DMSO-d6): d
3.24 and 3.26 (each s, each 3H, 2 x NMe), 7.77 (d, 1H, J ¼
9.0 Hz, H8), 7.84 (dd, 1H, J ¼ 9.0, 2.4 Hz, H7), 8.40 (d, 1H,
J ¼ 2.4 Hz, H5), 8.69 (s, 1H, H2), 8.94 (s, 1H, N¼¼CHNMe2);
FAB-ms: m/z 235 (MHþ), 237 (MHþþ2). Anal. Calcd. for
C11H11ClN4: C, 56.30; H, 4.72; N, 23.87. Found: C, 56.03; H,
4.79; N, 24.11.
N-(7-Chloroquinazolin-4-yl)formamide oxime (5c). To a
solution of 4c (200 mg, 0.852 mmol) in dry methanol (20 mL)
was added hydroxylamine hydrochloride (80.0 mg, 1.15 mmol),
and the reaction mixture was stirred at room temperature for
4 h. Water was added, and then the solution was made basic
with saturated aqueous sodium bicarbonate solution. The pre-
cipitate was filtered, washed with water and then recrystallized
from methanol to give 5c (100 mg, 53%) as a white powder,
mp 155–157ꢁC (dec); IR (potassium bromide): 3070, 3370
(NH and OH) cmꢀ1 1H NMR (DMSO-d6): d 7.64 (dd, 1H,
;
J ¼ 9.0, 2.2 Hz, H6), 7.89 (d, 1H, J ¼ 2.2 Hz, H8), 8.14 (br s,
1H, changed to sharp singlet after addition of deuterium oxide,
NCH¼¼NOH), 8.70 (d, 1H, J ¼ 9.0 Hz, H5), 8.73 (s, 1H, H2),
9.98 (br, 1H, deuterium oxide exchangeable, NH), 10.90 (br s,
1H, deuterium oxide exchangeable, OH); FAB-ms: m/z 223
(MHþ), 225 (MHþ þ 2). Anal. Calcd. for C9H7ClN4O: C,
48.55; H, 3.17; N, 25.17. Found: C, 48.19; H, 3.55; N, 25.28.
N1,N1-Dimethyl-N2-(6-nitroquinazolin-4-yl)formamidine (4b).
To a suspension of 3b (500 mg, 2.63 mmol) in dry toluene
(50 mL) was added N,N-dimethylformamide dimethyl acetal
(440 mg, 3.47 mmol), and the mixture was refluxed for 2 h.
After evaporation of solvent in vacuo, the residue was recrystal-
lized from benzene-cyclohexane to give 4b (536 mg, 83%) as yel-
N-(6,7-Dimethoxyquinazolin-4-yl)formamide oxime (5e). To
a solution of 4e (100 mg, 0.384 mmol) in dry methanol
(10 mL) was added hydroxylamine hydrochloride (64.0 mg,
0.921 mmol), and the reaction mixture was stirred at room
1
low needles, mp 174–176ꢁC (lit [15] 153ꢁC). H NMR (DMSO-
d6): d 3.23 and 3.26 (each s, each 3H, 2 x NMe), 7.89 (d, 1H, J ¼
9.2 Hz, H8), 8.50 (dd, 1H, J ¼ 9.2, 2.7 Hz, H7), 8.78 (s, 1H, H2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Reaction of 6,7-Substituted N-(Quinazolin-4-yl)amidine
Derivatives with Hydroxylamine Hydrochloride
1411
temperature for 4 h. Water was added, and then the solution
was made basic with saturated aqueous sodium bicarbonate so-
lution. The precipitate was filtered, washed with water and then
recrystallized from DMF-ethanol to give 5e (71.0 mg, 74%) as
a white powder, mp 217–219ꢁC (dec); IR (potassium bromide):
189ꢁC; IR (potassium bromide): 3120, 3240 (NH and OH)
1
cmꢀ1; H NMR (DMSO-d6): d 7.64 (dd, 1H, J ¼ 9.0, 2.2 Hz,
H5), 7.70 (d, 1H, J ¼ 9.0 Hz, H6), 7.93 (d, 1H, J ¼ 10.0 Hz,
changed to singlet after addition of deuterium oxide,
NCH¼¼NOH), 8.05 (d, 1H, J ¼ 2.2 Hz, H3), 9.53 (s, 1H, H3’),
10.54 (s, 1H, deuterium oxide exchangeable, OH), 10.55
(d, 1H, J ¼ 10.0 Hz, deuterium oxide exchangeable, NH);
FAB-ms: m/z 239 (MHþ), 241 (MHþ þ 2). Anal. Calcd. for
C9H7ClN4O2: C, 45.30; H, 2.96; N, 23.48. Found: C, 45.15;
H, 3.30; N, 23.60.
1
3080, 3410 (NH and OH) cmꢀ1; H NMR (DMSO-d6): d 3.94
and 3.96 (each s, each 3H, 2 x OMe), 7.22 (s, 1H, H8), 7.91 (s,
1H, H5), 8.12 (d, 1H, J ¼ 9.0 Hz, changed to singlet after addi-
tion of deuterium oxide, NCH¼¼NOH), 8.56 (s, 1H, H2), 9.81
(d, 1H, J ¼ 9.0 Hz, deuterium oxide exchangeable, NH), 10.72
(br s, 1H, deuterium oxide exchangeable, OH); FAB-ms: m/z
249 (MHþ). Anal. Calcd. for C11H12N4O3: C, 53.22; H, 4.87;
N, 22.57. Found: C, 53.16; H, 5.04; N, 22.48.
N-[4-Nitro-2-([1,2,4]oxadiazol-5-yl)phenyl]formamide oxime
(6b). Compound 4b (100 mg, 0.408 mmol) was allowed to
react with hydroxylamine hydrochloride (120 mg, 1.73 mmol)
in dry methanol (10 mL) for 5 h. Compound 6b (66.0 mg,
65%) was obtained as yellow feathers, mp 195–197ꢁC; IR (po-
N-[5-Chloro-2-([1,2,4]oxadiazol-5-yl)phenyl]formamide oxime
(6c). To a solution of 5c (50.0 mg, 0.225 mmol) in dry methanol
(5.0 mL) was added hydroxylamine hydrochloride (63.0 mg,
0.907 mmol), and the reaction mixture was stirred at room
temperature for 4 h. Water was added, and then the solution
was made basic with saturated aqueous sodium bicarbonate so-
lution. The precipitate was filtered, washed with water then
recrystallized from methanol to give 6c (37.0 mg, 69%) as col-
orless feathers, mp 190–192ꢁC; IR (potassium bromide): 3130,
tassium bromide): 3110, 3230 (NH and OH) cmꢀ1 1H NMR
;
(DMSO-d6): d 7.86 (d, 1H, J ¼ 9.6 Hz, H6), 8.11 (d, 1H, J ¼
9.6 Hz, changed to singlet after addition of deuterium oxide,
NCH¼¼NOH), 8.38 (dd, 1H, J ¼ 9.6, 2.6 Hz, H5), 8.82 (d, 1H,
J ¼ 2.6 Hz, H3), 9.39 (s, 1H, H3’), 10.95 (s, 1H, deuterium
oxide exchangeable, OH), 11.10 (d, 1H, J ¼ 9.6 Hz, deuterium
oxide exchangeable, NH). FAB-ms: m/z 250 (MHþ). Anal.
Calcd. for C9H7N5O4: C, 43.38; H, 2.83; N, 28.11. Found: C,
43.16; H, 3.15; N, 28.10.
3240 (NH and OH) cmꢀ1 1H NMR (DMSO-d6): d 7.12 (dd,
;
1H, J ¼ 8.6, 1.9 Hz, H4), 7.81 (d, 1H, J ¼ 1.9 Hz, H6), 8.00
(d, 1H, J ¼ 10.0 Hz, changed to singlet after addition of deute-
rium oxide, NCH¼¼NOH), 8.07 (d, 1H, J ¼ 8.6 Hz, H3), 9.30
(s, 1H, H3’), 10.56 (s, 1H, deuterium oxide exchangeable,
OH), 10.65 (d, 1H, J ¼ 10.0 Hz, deuterium oxide exchange-
able, NH); FAB-ms: m/z 239 (MHþ), 241 (MHþ þ 2). Anal.
Calcd. for C9H7ClN4O2: C, 45.30; H, 2.96; N, 23.48. Found:
C, 45.10; H, 3.35; N, 23.58.
N-[5-Methyl-2-([1,2,4]oxadiazol-5-yl)phenyl]formamide
oxime (6d). Compound 4d (100 mg, 0.467 mmol) was
allowed to react with hydroxylamine hydrochloride (130 mg,
1.87 mmol) in dry methanol (10 mL) for 4 h. Compound 6d
(59.0 mg, 58%) was obtained as colorless feathers, mp 177–
179ꢁC; IR (potassium bromide): 3120, 3260 (NH and OH)
1
cmꢀ1; H NMR (DMSO-d6): d 2.38 (s, 3H, Me), 6.91 (d, 1H,
N-[4,5-Dimethoxy-2-([1,2,4]oxadiazol-5-yl)phenyl]formamide
oxime (6e). To a solution of 5e (50.0 mg, 0.201 mmol) in dry
methanol (5.0 mL) was added hydroxylamine hydrochloride
(50.0 mg, 0.720 mmol), and the reaction mixture was refluxed
for 4 h. After cooling, water was added, and then the solution
was made basic with saturated aqueous sodium bicarbonate so-
lution. The precipitate was filtered, washed with water then
recrystallized from DMF-ethanol to give 6e (37.0 mg, 70%) as
colorless feathers, mp 197–200ꢁC; IR (potassium bromide):
J ¼ 8.0 Hz, H4), 7.50 (s, 1H, H6), 7.91 (d, 1H, J ¼ 10.2 Hz,
changed to singlet after addition of deuterium oxide,
NCH¼¼NOH), 7.94 (d, 1H, J ¼ 8.0 Hz, H3), 9.24 (s, 1H, H3’),
10.41 (1H, s, deuterium oxide exchangeable, OH), 10.49
(d, 1H, J ¼ 10.2 Hz, deuterium oxide exchangeable, NH).
FAB-ms: m/z 219 (MHþ). Anal. Calcd. for C10H10N4O2: C,
55.04; H, 4.62; N, 25.68. Found: C, 54.73; H, 4.54; N, 25.97.
N1,N1-Dimethyl-N2-(6-chloroquinazolin-4-yl)acetamidine
(7a). To a suspension of 3a (200 mg, 1.11 mmol) in dry tolu-
ene (20 mL) was added N,N-dimethylacetamide dimethyl ace-
tal (247 mg, 1.85 mmol), and the mixture was refluxed for 5 h.
After evaporation of solvent in vacuo, the residue was recrystal-
lized from cyclohexane to give 7a (192 mg, 69%) as a pale yel-
1
3110, 3210 (NH and OH) cmꢀ1; H NMR (DMSO-d6): d 3.81
and 3.92 (each s, each 3H, 2 x OMe), 7.13 (s, 1H, H6), 7.43
(s, 1H, H3), 8.00 (d, 1H, J ¼ 10.0 Hz, changed to singlet after
addition of deuterium oxide, NCH¼¼NOH), 9.18 (s, 1H, H3’),
10.33 (s, 1H, deuterium oxide exchangeable, OH), 10.46
(d, 1H, J ¼ 10.0 Hz, deuterium oxide exchangeable, NH);
FAB-ms: m/z 265 (MHþ). Anal. Calcd. for C11H12N4O2: C,
50.00; H, 4.58; N, 21.20. Found: C, 49.89; H, 4.75; N, 21.23.
1
low powder, mp 93–95ꢁC. H NMR (DMSO-d6): d 2.30 (s, 3H,
Me), 3.21 and 3.27 (each s, each 3H, 2 x NMe), 7.67 (dd, 1H,
J ¼ 8.8, 2.4 Hz, H7), 7.81 (d, 1H, J ¼ 8.8 Hz, H8), 8.20
(d, 1H, J ¼ 2.4 Hz, H5), 8.80 (s, 1H, H2); FAB-ms: m/z 249
(MHþ), 251 (MHþþ2). Anal. Calcd. for C12H13ClN4: C, 57.95;
H, 5.27; N, 22.53. Found: C, 57.97; H, 5.17; N, 22.35.
General procedure for the reaction of 4a, 4b, and 4d
with hydroxylamine hydrochloride to give 6. To a solution
of amidine 4a, 4b, and 4d in dry methanol was added hydrox-
ylamine hydrochloride, and the reaction mixture was stirred at
room temperature. Water was added, and then the solution was
made basic with saturated aqueous sodium bicarbonate solu-
tion. The precipitate was filtered, washed with water then
recrystallized from methanol to give 6a, 6b, and 6d.
N1,N1-Dimethyl-N2-(6-nitroquinazolin-4-yl)acetamidine
(7b). To a suspension of 3b (500 mg, 2.63 mmol) in dry tolu-
ene (50 mL) was added N,N-dimethylacetamide dimethyl ace-
tal (800 mg, 6.01 mmol), and the mixture was refluxed for
3 h. After evaporation of solvent in vacuo, the residue was
recrystallized from benzene-cyclohexane to give 7b (440 mg,
65%) as yellow needles, mp 173–174ꢁC. 1H NMR (DMSO-
d6): d 2.38 (s, 3H, Me), 3.25 and 3.28 (each s, each 3H, 2 x
NMe), 7.88 (d, 1H, J ¼ 9.2 Hz, H8), 8.48 (dd, 1H, J ¼ 9.2,
2.8 Hz, H7), 8.75 (s, 1H, H2), 9.23 (d, 1H, J ¼ 2.8 Hz, H5);
N-[4-Chloro-2-([1,2,4]oxadiazol-5-yl)phenyl]formamide
oxime (6a). Compound 4a (200 mg, 0.852 mmol) was
allowed to react with hydroxylamine hydrochloride (354 mg,
5.09 mmol) in dry methanol (20 mL) for 7 h. Compound 6a
(133 mg, 65%) was isolated as pale yellow feathers, mp 187–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1412
K. Okuda, H. Muroyama, and T. Hirota
Vol 48
FAB-ms: m/z 260 (MHþ). Anal. Calcd. for C12H13N5O2: C,
55.59; H, 5.05; N, 27.01. Found: C, 55.49; H, 5.01; N, 26.86.
N-[4-Nitro-2-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]forma-
mide oxime (8b). Compound 7b (100 mg, 0.386 mmol) was
allowed to react with hydroxylamine hydrochloride (120 mg,
1.73 mmol) in dry methanol (10 mL) for 4 h. Compound 8b
(71.0 mg, 70%) was obtained as yellow feathers, mp 200–
201ꢁC. IR (potassium bromide): 3160, 3220 (NH and OH)
N1,N1-Dimethyl-N2-(7-chloroquinazolin-4-yl)acetamidine
(7c). To a suspension of 3c (500 mg, 2.78 mmol) in dry tolu-
ene (50 mL) was added N,N-dimethylacetamide dimethyl ace-
tal (880 mg, 6.61 mmol), and the mixture was refluxed for 8
h. After evaporation of solvent in vacuo, the residue was
recrystallized from cyclohexane to give 7c (520 mg, 75%) as
pale brown needles, mp 138–140ꢁC; 1H NMR (DMSO-d6): d
2.28 (s, 3H, Me), 3.20 (s, 6H, NMe2), 7.52 (dd, 1H, J ¼ 8.7,
2.2 Hz, H6), 7.78 (d, 1H, J ¼ 2.2 Hz, H8), 8.22 (d, 1H, J ¼
8.7 Hz, H5), 8.68 (s, 1H, H2); FAB-ms: m/z 249 (MHþ), 251
(MHþþ2). Anal. Calcd. for C12H13ClN4: C, 57.95; H, 5.27; N,
22.53. Found: C, 57.74; H, 5.25; N, 22.22.
1
cmꢀ1; H NMR (DMSO-d6): d 2.48 (s, 3H, Me), 7.84 (d, 1H,
J ¼ 9.6 Hz, H6), 8.12 (d, 1H, J ¼ 9.6 Hz, changed to singlet
after addition of deuterium oxide, NCH¼¼NOH), 8.37 (dd, 1H,
J ¼ 9.6, 2.8 Hz, H5), 8.76 (d, 1H, J ¼ 2.8 Hz, H3), 10.93 (s,
1H, deuterium oxide exchangeable, OH), 11.10 (d, 1H, J ¼ 9.6
Hz, deuterium oxide exchangeable, NH). FAB-ms: m/z 264
(MHþ). Anal. Calcd. for C10H9N5O4: C, 45.63; H, 3.45; N,
26.61. Found: C, 45.38; H, 3.70; N, 26.59.
N1,N1-Dimethyl-N2-(7-methylquinazolin-4-yl)acetamidine
(7d). To a suspension of 3d (200 mg, 1.26 mmol) in dry tolu-
ene (20 mL) was added N,N-dimethylacetamide dimethyl acetal
(282 mg, 2.12 mmol), and the mixture was refluxed for 1 h. Af-
ter evaporation of solvent in vacuo, the residue was recrystal-
lized from cyclohexane/n-hexane to give 7d (192 mg, 67%) as
N-[5-Chloro-2-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]for-
mamide oxime (8c). Compound 7c (200 mg, 0.804 mmol)
was allowed to react with hydroxylamine hydrochloride
(222 mg, 3.20 mmol) in dry methanol (20 mL) for 3 h. Com-
pound 8c (148 mg, 73%) was obtained as colorless feathers,
mp 195–197ꢁC; IR (potassium bromide): 3050, 3190 (NH and
OH) cmꢀ1 1H NMR (DMSO-d6): d 2.44 (s, 3H, Me), 7.01
;
1
pale brown needles, mp 89–91ꢁC; H NMR (DMSO-d6): d 2.21
(dd, 1H, J ¼ 8.6, 1.8 Hz, H4), 7.79 (d, 1H, J ¼ 1.8 Hz, H6),
7.97 (d, 1H, J ¼ 10.0 Hz, changed to singlet after addition of
deuterium oxide, NCH¼¼NOH), 8.15 (d, 1H, J ¼ 8.6 Hz, H3),
10.50 (1H, s, deuterium oxide exchangeable, OH), 10.60 (d,
1H, J ¼ 10.0 Hz, deuterium oxide exchangeable, NH); FAB-
ms: m/z 253 (MHþ), 255 (MHþ þ 2). Anal. Calcd. for
C10H9ClN4O2: C, 47.54; H, 3.59; N, 22.18. Found: C, 47.24;
H, 3.85; N, 22.31.
(s, 3H, Me), 2.49 (s, 3H, Me), 3.17 (s, 6H, NMe2), 7.34 (d, 1H,
J ¼ 8.4 Hz, H6), 7.54 (s, 1H, H8), 8.06 (d, 1H, J ¼ 8.4 Hz,
H5), 8.64 (s, 1H, H2); FAB-ms: m/z 229 (MHþ). Anal. Calcd.
for C13H16N4: C, 68.39; H, 7.06; N, 24.54. Found: C, 68.03; H,
7.08; N, 24.41.
N1,N1-Dimethyl-N2-(6,7-dimethoxyquinazolin-4-yl)acetami-
dine (7e). To a suspension of 3e (300 mg, 1.46 mmol) in dry
toluene (50 mL) was added N,N-dimethylacetamide dimethyl
acetal (331 mg, 2.49 mmol) and then the mixture was refluxed
for 3 h. After evaporation of solvent in vacuo, the residue was
chromatographed on silica gel. The eluate of ethyl acetate was
evaporated and the residue was recrystallized from toluene-
cyclohexane to give 7e (290 mg, 72%) as a white powder, mp
N-[5-Methyl-2-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]for-
mamide oxime (8d). Compound 7d (144 mg, 0.631 mmol)
was allowed to react with hydroxylamine hydrochloride (178
mg, 2.56 mmol) in dry methanol (15 mL) for 1 h. Compound
8d (110 mg, 75%) was obtained as a white powder, mp 221–
224ꢁC; IR (potassium bromide): 3100, 3190 (NH and OH)
1
125–127ꢁC; H NMR (DMSO-d6): d 2.20 (s, 3H, Me), 3.17 (s,
1
cmꢀ1; H NMR (DMSO-d6): d 2.37 (s, 3H, Me), 2.43 (s, 3H,
6H, NMe2), 3.86 and 3.92 (each s, each 3H, 2 x OMe), 7.15
(s, 1H, H8), 7.42 (s, 1H, H5), 8.56 (s, 1H, H2); FAB-ms: m/z
275 (MHþ). Anal. Calcd. for C14H18N4O2: C, 61.30; H, 6.61;
N, 20.42. Found: C, 61.34; H, 6.57; N, 20.56.
Me), 6.89 (d, 1H, J ¼ 8.2 Hz, H4), 7.47 (s, 1H, H6), 7.88
(d, 1H, J ¼ 10.2 Hz, changed to singlet after addition of deute-
rium oxide, NCH¼¼NOH), 7.89 (d, 1H, J ¼ 8.2 Hz, H3), 10.35
(s, 1H, deuterium oxide exchangeable, OH), 10.48 (d, 1H, J ¼
10.2 Hz, deuterium oxide exchangeable, NH); FAB-ms: m/z
233 (MHþ). Anal. Calcd. for C11H12N4O2: C, 56.89; H, 5.21;
N, 24.12. Found: C, 56.89; H, 5.37; N, 24.12.
General procedure for the reaction of 7 with hydroxyla-
mine hydrochloride to give 8. To a solution of amidine 7 in
dry methanol was added hydroxylamine hydrochloride, and the
reaction mixture was stirred at room temperature. Water was
added, and then the solution was made basic with saturated
aqueous sodium bicarbonate solution. The precipitate was fil-
tered, washed with water and then recrystallized from metha-
nol (except 8e) to give 8.
N-[4,5-Dimethoxy-2-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]-
formamide oxime (8e). Compound 7e (100 mg, 0.365 mmol)
was allowed to react with hydroxylamine hydrochloride (101
mg, 1.45 mmol) in dry methanol (10 mL) for 2 h. Compound
8e (79.0 mg, 78%) was obtained as colorless feathers from
DMF-ethanol, mp 235–237ꢁC; IR (potassium bromide):
N-[4-Chloro-2-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl]for-
mamide oxime (8a). Compound 7a (100 mg, 0.402 mmol)
was allowed to react with hydroxylamine hydrochloride (111
mg, 1.60 mmol) in dry methanol (10 mL) for 3 h. Compound
8a (75.0 mg, 74%) was obtained as colorless feathers, mp 210–
212ꢁC; IR (potassium bromide): 3150, 3210 (NH and OH)
1
3150, 3290 (NH and OH) cmꢀ1; H NMR (DMSO-d6): d 2.41
(s, 3H, C-Me), 3.80 and 3.91 (each s, each 3H, 2 x OMe),
7.11 (s, 1H, H6), 7.38 (s, 1H, H3), 7.97 (d, 1H, J ¼ 10.2 Hz,
changed to singlet after addition of deuterium oxide,
NCH¼¼NOH), 10.27 (s, 1H, deuterium oxide exchangeable,
OH), 10.43 (d, 1H, J ¼ 10.2 Hz, deuterium oxide exchange-
able, NH); FAB-ms: m/z 279 (MHþ). Anal. Calcd. for
C12H14N4O2: C, 51.80; H, 5.07; N, 20.13. Found: C, 51.89; H,
5.16; N, 20.03.
1
cmꢀ1; H NMR (DMSO-d6): d 2.46 (s, 3H, Me), 7.62 (dd, 1H,
J ¼ 9.1, 2.2 Hz, H5), 7.68 (d, 1H, J ¼ 9.1 Hz, H6), 7.91 (d,
1H, J ¼ 10.0 Hz, changed to singlet after addition of deuterium
oxide, NCH¼¼NOH), 7.99 (d, 1H, J ¼ 2.2 Hz, H3), 10.49 (s,
1H, deuterium oxide exchangeable, OH), 10.54 (d, 1H, J ¼
10.0 Hz, deuterium oxide exchangeable, NH); FAB-ms: m/z 253
(MHþ), 255 (MHþ þ 2). Anal. Calcd. for C10H9ClN4O2: C,
47.54; H, 3.59; N, 22.18. Found: C, 47.20; H, 3.78; N, 21.95.
Determination of pentosidine formation in vitro. Test
compound stock solutions were prepared at 100 mM concen-
tration except for 5c, 5e, and 6e (50 mM) in DMSO and
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
Reaction of 6,7-Substituted N-(Quinazolin-4-yl)amidine
Derivatives with Hydroxylamine Hydrochloride
1413
[3] Reddy, V. P.; Beyaz, A. Drug Discov Today 2006, 11, 646.
[4] Sasaki, N. A.; Garcia-Alvarez, M. C.; Wang, Q.; Ermo-
lenko, L.; Franck, G.; Nhiri, N.; Martin, M.-T.; Audic, N.; Potier, P.
Bioorg Med Chem 2009, 17, 2310.
diluted to 100 mM sodium phosphate buffer (pH 7.4) to be 2.0
mM final concentration. The assay was performed based on a
modified method of Vinson and Howard III [16]. In brief, the
reaction mixture (total volume 100 lL) consisting of 30 mg/
mL bovine serum albumin, 10 mM L-(þ)-arabinose, and 2.0
mM test compounds in 100 mM sodium phosphate buffer (pH
7.4) was incubated at 37ꢁC for 14 d. Then 10% trichloroacetic
acid (100 lL) was added to precipitate proteins. After collect-
ing the precipitate by centrifugation and drying under vacuum,
hydrolysis was performed at 110ꢁC for 16 h in 6N hydrochlo-
ric acid. After neutralization by 5N aqueous sodium hydroxide
solution and filtration by ‘‘Millipore DIMEX" membrane (pore
size 0.22 lm), liberated pentosidine was analyzed by HPLC
(1.0 mL/min, Waters, Puresil C18 column (4.6 x 250 mm).
The fluorescence (excitation: 335 nm, emission: 385 nm) was
monitored for detection with the gradient from water contain-
ing 0.1% trifluoroacetic acid (0 min) to 80% acetonitrile 20%
water 0.1% trifluoroacetic acid (30 min). The inhibitory activ-
[5] Bolton, W. K.; Cattran, D. C.; Williams, M. E.; Adler, S.
G.; Appel, G. B.; Cartwright, K.; Foiles, P. G.; Freedman, B. I.; Ras-
kin, P.; Ratner, R. E.; Spinowitz, B. S.; Whittier, F. C.; Wuerth, J.-P.
Am J Nephrol 2004, 24, 32.
[6] Okuda, K.; Zhang, Y.-X.; Ohtomo, H.; Hirota, T.; Sasaki,
K. Chem Pharm Bull 2010, 58, 369.
[7] Sasaki, K.; Zhang, Y.-X.; Yamamoto, H.; Kashino, S.; Hir-
ota, T. J Chem Res Synop 1999, 92.
[8] Data were calculated with B3LYP/6-31G* by Gaussian03W,
Revision D.01; Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,Jr.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Bar-
one, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jara-
millo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Pis-
korz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M.
A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; John-
son, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc.:
Wallingford CT, 2004.
ity was calculated using the equation:
%
inhibition
¼
[1ꢀ{pentosidine formation (pmol/mL) with test compound/
pentosidine formation (pmol/mL) without test compound
(DMSO blank)}] x 100. Aminoguanidine hydrochloride was
used as a reference compound.
Acknowledgments. The authors are grateful to the SC-NMR
Laboratory of Okayama University for 200 MHz 1H NMR experi-
ments. They thank Dr. Ying-Xue Zhang (Laboratory of Pharma-
ceutical Chemistry, Faculty of Pharmaceutical Sciences,
Okayama University) for her preliminary experimental results
and Dr. K. L. Kirk (NIDDK, NIH) for helpful comments on the
manuscript.
[9] Thomas, M. C.; Baynes, J. W.; Thorpe, S. R.; Cooper, M.
E. Curr Drug Targets 2005, 6, 453.
[10] Foster, C. H.; Elam, E. U. J Org Chem 1976, 41, 2646.
[11] Morley, J. S.; Simpson, J. C. E. J Chem Soc 1948, 360.
[12] Rosowsky, A.; Papathanasopoulos, N. J Heterocycl Chem
1972, 9, 1235.
[13] Geward, K.; Schafer, H.; Mauersberger, K. Zeit Chem
1977, 17, 223.
REFRENCES AND NOTES
[14] Ueda, I.; Kato, M.; Nagano, M. Eur Pat Appl 0,030,156 (1981).
[15] Warren, J. D.; Lang, S. A., Jr.; Chan, P. S.; Marsico, J. W.
J Pharm Sci 1978, 67, 1479.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet