Synthesis of pyrimidine derivatives possessing an antioxidative property and their inhibitory effects on picryl chloride-induced contact hypersensitivity reaction

Article abstract of DOI:10.1248/cpb.51.1451

We conducted a preliminary structure-activity relationship (SAR) study of some barbituric acid and uracil derivatives against the picryl chloride-induced contact hypersensitivity reaction. The introduction of an antioxidative moiety to the side chain of the C(6)-position of uracil was effective against this model. The introduction of dimethoxyphenol (8b) or dimethylphenol (8c) instead of di-t-butylphenol (8a) as an antioxidative moiety gave diminished activities, so, the reactive oxygen would contribute to the inflammation of this model, and an antioxidative activity was required for exhibiting the inhibitory activity. The inhibitory activity was significantly affected by the substituent at the N(1)-phenyl moiety.

Full text of DOI:10.1248/cpb.51.1451

December 2003
Notes
Chem. Pharm. Bull. 51(12) 1451—1454 (2003)
1451
Synthesis of Pyrimidine Derivatives Possessing an Antioxidative Property
and Their Inhibitory Effects on Picryl Chloride-Induced Contact
Hypersensitivity Reaction
a
,b
*
Yoshiaki ISOBE and Kosaku HIROTA
a Pharmaceuticals and Biotechnology Laboratory, Japan Energy Corporation; Toda, Saitama 335–8502, Japan: and
b Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University; Mitahora-higashi, Gifu 502–8585, Japan.
Received August 12, 2003; accepted September 30, 2003
We conducted a preliminary structure–activity relationship (SAR) study of some barbituric acid and uracil
derivatives against the picryl chloride-induced contact hypersensitivity reaction. The introduction of an antiox-
idative moiety to the side chain of the C(6)-position of uracil was effective against this model. The introduction of
dimethoxyphenol (8b) or dimethylphenol (8c) instead of di-t-butylphenol (8a) as an antioxidative moiety gave di-
minished activities, so, the reactive oxygen would contribute to the inflammation of this model, and an antioxida-
tive activity was required for exhibiting the inhibitory activity. The inhibitory activity was significantly affected
by the substituent at the N(1)-phenyl moiety.
Key words uracil; barbituric acid; delayed type hypersensitivity (DTH); di-t-butylphenol; antioxidative activity
with an antioxidative activity.9) We describe herein the syn-
thesis and suppressive effects against picryl chloride (PC)-in-
duced CHR of novel pyrimidine derivatives, such as barbi-
turic acids and uracils, having a 2,6-di-t-butylphenol moiety
at the side chain of the C(5) or C(6)-position of the pyrimi-
dine ring.
Recently, patients suffering from allergic cutaneous disor-
ders such as atopic dermatitis and allergic contact dermatitis
have been increasing in number. T cell-mediated delayed
type hypersensitivity (DTH) reactions are thought to be in-
volved in these diseases.1) Many antiallergic drugs are clini-
cally used for treatment of these dermatitis, but they are not
very efficacious because these drugs are not effective against
DTH reactions. Glucocorticoids have a suppressive effect
against DTH reactions, and are widely used for the treatment
of these disorders. However, long-time use of glucocorticoids
is limited because of its many side effects, such as atrophia
cutis and infections. Therefore, development of non-steroidal
agents having inhibitory activity against DTH reactions and
low toxicity has been ardently desired.
In the pathogenesis of many inflammatory skin diseases,
there are both direct and indirect evidences implicating a re-
active oxygen species (ROS) such as superoxide and hydro-
gen peroxide.2) Overproduction of ROS has also been postu-
lated for immune-mediated skin diseases such as atopic der-
matitis, contact dermatitis, and psoriasis.3) Monocytes or
neutrophils of these patients show an increased capacity to
release ROS.4,5) Therefore, compounds having inhibitory ac-
tivity on the production and/or scavenging of ROS may be
effective against DTH reactions. For example, tocopherol
was reported to show a suppressive effect on chemical hap-
ten-induced contact hypersensitivity reaction (CHR), one of
the DTH models,6) and showed efficacy against atopic der-
matitis in clinic.7,8)
Results and Discussion
The synthetic methods of pyrimidine derivatives (3, 6)
possessing a 4-hydroxyphenyl group at the 5-position are de-
scribed in Chart 1. 6-Amino-5-(3,5-di-t-butyl-4-hydroxyben-
zyl)uracil (3) was synthesized by the reaction of 6-
aminouracil (2) with 3,5-di-t-butyl-4-hydroxybenzyl chloride
as previously reported.10) For the synthesis of 5-(3,5-di-t-
butyl-4-hydroxybenzyl)barbituric acids (6a—d), first, several
N-substituted barbituric acids (4a—d), which were easily
prepared10) by acid-hydrolysis of the corresponding 6-
aminouracils,11) were condensed12) with 3,5-di-t-butyl-4-hy-
droxybenzaldehyde to give the 5-benzylidenebarbituric acids
(5a—d) in moderate yields. The NMR analysis of an unsym-
metrical product (5a) possessing different substituents at the
1,3-N-positions indicates them to be a mixture of E- and Z-
isomers. The reduction of 5a—d with NaBH4 afforded the
desired 3,5-di-t-butyl-4-hydroxybenzylbarbituric acids (6a—
d).
The synthesis of uracil derivatives (8a—g, 10) possessing
an antioxidant moiety at the terminal of the side-chain of the
6-position is shown in Chart 2. Thus, 6-hydrazinouracils
(7a, d—g, 9) were obtained by chlorination13) of barbituric
acids (4a, d—g) with phosphorus oxychloride followed by
treatment with hydrazine or methylhydrazine as previously
reported.14—16) Chlorination of unsymmetrical 3-methyl-1-
phenylbarbituric acids (4a, f, g) proceeded regioselectively to
afford the corresponding 6-chloro-3-methyl-1-phenyluracils
as previously reported.17) The desired hydrazones (8a—g,
10) were prepared by the reaction of 6-hydrazinouracils
(7a, d—g, 9) with 3,5-disubstituted 4-hydroxybenzaldehydes
in good yields.
In a previous paper, we described antiallergic activities
against DTH reaction of various 5-acylamido-6-aminouracil
derivatives, which originated from the lead compound (1)
The antiallergic activities of the test compounds were eval-
uated by PC-induced CHR in mice at a dose of 10 mg/kg.
Fig. 1.
1
To whom correspondence should be addressed. e-mail: hirota@gifu-pu.ac.jp
© 2003 Pharmaceutical Society of Japan

1452
Vol. 51, No. 12
Reagents and conditions: i) 3,5-Di-t-butyl-4-hydroxybenzyl chloride, Et3N, i-PrOH, reflux; ii) 3,5-di-t-butyl-4-hydroxybenzaldehyde, EtOH, reflux; iii) NaBH4, EtOH, rt.
Chart 1
Reagents and conditions: i) POCl3, reflux; ii) NH2NH2, i-PrOH, reflux; iii) MeNHNH2, i-PrOH; iv) 3,5-disubstituted-4-hydroxybenzaldehyde, EtOH, 50 °C.
Chart 2
The antioxidative activities were measured by the inhibition (8b, c) possessing the dimethoxyphenol or the dimethylphe-
toward auto-oxidation using rat brain homogenate.
nol instead of the di-t-butylphenol at the 6-position were syn-
Compounds 3, 5, 6 did not show efficacy against this in thesized in order to evaluate the contribution of the reactive
vivo model by oral administration (Inhibition of these com- oxygen on this in vivo model. The inhibitory activities of 8b
pounds was less than 10%); however, compounds 1 and 5a and 8c were diminished, corresponding well with their results
showed moderate inhibitory activities against this model by of weak antioxidative activities. Accordingly, we thought that
topical administration. The percent of inhibition of com- the reactive oxygen contributed to the process of inflamma-
pounds 1 and 5a at a dose of 1 mg/ear was 55% and 46%, re- tion of this in vivo model. The 1-(4-fluorophenyl)uracil (8f)
spectively. Moreover, antioxidative activities of 1 and 5a in- showed 27% inhibition at this dose, which was nearly equiva-
dicated IC50 of 33 and 34 mM, respectively, suggesting that lent with that of 8a. On the other hand, compounds 8d, 8e,
compound 5a did not exhibit the activities against PC-in- and 10 did not exhibit inhibitory activity at this dose. From
duced CHR owing to its poor oral bioavailability. Therefore, these results, it was suggested that the phenyl group for R1
an amino group at the C(6) position and/or carboxamide as and the hydrogen atom for R3 were needed for exhibiting the
the linker between the uracil ring and the di-t-butylphenol inhibitory activities.
moiety as shown in the lead compound (1) would be needed
to exhibit the inhibitory activity by oral administration.
Next, we evaluated the dose-dependency of 8a and 8f on
this model. Compound 8a did not exhibit dose–dependent in-
The inhibitory activities of 6-substituted uracil derivatives hibition; the most potent inhibition was observed at a dose of
(8a—g, 10) are summarized in Table 1. Compound 8a 3 mg/kg (Fig. 2). The reason why the dose–response inhibi-
showed inhibitory activity against this model by oral admin- tion indicated a bell-shaped curve is not clear. Different from
istration, but the inhibitory potency of 8a was somewhat the result of 8a, compound 8f showed inhibition in a dose de-
weaker than that of 1 at a dose of 10 mg/kg. The uracils pendent manner against this model, suggesting modification

December 2003
1453
Table 1. Inhibitory Effects of 6-Benzylidenehydrazinouracils (8a—g, 10) on PC-Induced CHR and Lipid Peroxidation
PC-induced CHR
% of inhibition
(10 mg/kg)
Lipid peroxidation
Compound
R1
R2
R3
R4
IC50 (mM)
1
8a
8b
8c
8d
8e
8f
8g
10
54
32
Ϫ8
Ϫ9
4
33
27
Ͼ100
Ͼ100
22
Ph
Ph
Ph
Me
Me
Me
c-Hexyl
Me
Me
H
H
H
H
H
H
H
Me
t-Bu
OMe
Me
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
c-Hexyl
Me
4-F-Ph
4-MeO-Ph
Ph
16
27
32
29
nd
20
nd
nd
Me
Me
Ϫ21
10
Tranilast
Prednisolone
Ϫ10a)
67
nd: not determined. a) 200 mg/kg.
Acids (5a—d) A mixture of barbituric acids (4a—d) (1.0 mmol) and 3,5-
di-t-butyl-4-hydroxybenzaldehyde (1.0 mmol) in EtOH was refluxed for 1—
3 h. After cooling, the resulting precipitate was filtered and recrystallized
from an appropriate solvent to give 5a—d.
5-(3,5-Di-t-butyl-4-hydroxybenzylidene)-3-methyl-1-phenylbarbituric
Acid (5a) Yield 66% (a mixture of E and Z isomer); mp 156—158 °C; 1H-
NMR (CDCl3) d: 8.52, 8.61 (1H, s, Ar-CHϭ), 8.26, 8.32 (2H, s, ArH),
7.21—7.55 (5H, m, Ph), 6.02, 6.08 (1H, s, OH), 3.48 (3H, s, N-Me), 1.47
(18H, s, 2ϫt-Bu); MS (TOF): m/z 435 (MϩH)ϩ; Anal. Calcd for
C26H30N2O4·0.1H2O: C, 71.57; H, 6.98; N, 6.42. Found: C, 71.45; H, 7.12;
N, 6.35.
5-(3,5-Di-t-butyl-4-hydroxybenzylidene)-1-phenylbarbituric Acid (5b)
1
Yield 98%; mp 295—296 °C; H-NMR (DMSO-d6) d: 11.57 (1H, s, NH),
8.38 (1H, s, Ar-CHϭ), 8.33 (2H, s, ArH), 7.38—7.58 (5H, m, Ph), 1.48
(18H, s, 2ϫt-Bu); MS (TOF): m/z 421 (MϩH)ϩ; Anal. Calcd for
C25H28N2O4: C, 71.41; H, 6.71; N, 6.66. Found: C, 71.28; H, 6.84; N, 6.46.
1-Cyclohexyl-5-(3,5-di-t-butyl-4-hydroxybenzylidene)barbituric Acid
(5c) Yield 96%; mp 223 °C; 1H-NMR (DMSO-d6) d: 8.34 (1H, s, Ar-
CHϭ), 8.31 (2H, s, ArH), 4.63 (1H, t, Jϭ12.0 Hz, CH), 1.22—2.35 (10H,
m, c-Hex), 1.49 (18H, s, 2ϫt-Bu); MS (TOF): m/z 427 (MϩH)ϩ; Anal.
Fig. 2. Inhibitory Activities of 8a and 8f against PC-Induced CHR
of the N(1)-substituent at uracil would be possible to enhance
the inhibitory potency. In addition, diarrhea, which was ob- Calcd for C25H34N2O4: C, 70.39; H, 8.03; N, 6.57. Found: C, 70.47; H, 8.13;
N, 6.52.
served in mouse treated with 1, was not monitored in 8a or
1,3-Dicyclohexyl-5-(3,5-di-t-butyl-4-hydroxybenzylidene)barbituric
8f administered animals.
In conclusion, we have conducted a preliminary SAR
Acid (5d) Yield 71%; mp 215—216 °C; 1H-NMR (CDCl3) d: 8.39 (1H, s,
Ar-CHϭ), 8.14 (2H, s, ArH), 5.93 (1H, s, OH), 4.72 (2H, t, Jϭ12.0 Hz,
study of some pyrimidine derivatives against the PC-induced
CHR. In addition to the 5-substituted lead compound (1), the
introduction of an antioxidative moiety to the C(6)-position
of uracil was effective against this model. The inhibitory ac-
tivity against PC-induced CHR was dependent on antioxida-
tive activity and oral bioavailability.
2ϫCH), 1.24—2.42 (20H, m, 2ϫc-Hex), 1.47 (18H, s, 2ϫt-Bu); MS (TOF):
m/z 509 (MϩH)ϩ; Anal. Calcd for C31H44N2O4: C, 73.19; H, 8.72; N, 5.51.
Found: C, 73.24; H, 9.07; N, 5.32.
General Procedure for the Synthesis of 5-Benzylbarbituric Acids
(6a—d) To a suspension of 5-benzylidenebarbituric acids (5a—d) (1.0
mmol) in EtOH (10 ml) was added NaBH4 (1.0 mmol). The reaction mixture
was stirred at room temperature for 2 h, and was concentrated. Water (10 ml)
was added to the residue and neutralized to pH 7 with 1 N HCl. The resulting
precipitate was collected and washed with water to give 6a—d.
Experimental
General All reagents and solvents were obtained from commercial sup-
5-(3,5-Di-t-butyl-4-hydroxybenzyl)-3-methyl-1-phenylbarbituric Acid
1
pliers and were used without further purification. Melting points were mea- (6a) Yield 92%; mp 147—149 °C; H-NMR (CDCl3) d: 7.36—7.39 (3H,
sured with a BÜCHI 535 melting point apparatus and were uncorrected. m, Ph), 6.90 (2H, s, ArH), 6.76 (2H, m, Ph), 5.23 (1H, s, OH), 3.88—3.92
Proton NMR spectra were recorded on a JEOL GSX270 FT NMR spectro- (2H, m, CH2Ar), 3.50 (1H, Abq, Jϭ23.2, 4.9 Hz, H-5), 3.29 (3H, s, N-Me),
meter. Chemical shifts were given in parts per million (ppm) using tetra- 1.40 (18H, s, 2ϫt-Bu); MS (TOF): m/z 437 (MϩH)ϩ; Anal. Calcd for
methylsilane as the internal standard for spectra obtained in DMSO-d6 or C26H32N2O4: C, 71.53; H, 7.39; N, 6.42. Found: C, 71.48; H, 7.43; N, 6.40.
CDCl3. TOF MS (time-of-flight mass spectrometry) was recorded on a Com-
5-(3,5-Di-t-butyl-4-hydroxybenzyl)-1-phenylbarbituric Acid (6b)
pact MALDI 3 V4.0.0 spectrometer. High-resolution mass spectra were ob- Yield 65%; mp 162—164 °C; 1H-NMR (CDCl3) d: 8.27 (1H, s, NH), 7.36—
tained on a JEOL JMS-700 mass spectrometer. Elemental analyses were per- 7.39 (3H, m, Ph), 6.95 (2H, s, ArH), 6.74 (2H, m, Ph), 5.23 (1H, s, OH),
formed on Yanagimoto MT-3. Wakogel C-200 (Wako; 70—150 mm) was 3.87 (2H, m, CH2Ar), 3.46—3.55 (1H, m, H-5), 1.41 (18H, s, 2ϫt-Bu); MS
used for column chromatography. Monitoring of reactions was carried out (TOF): m/z 423 (MϩH)ϩ; Anal. Calcd for C25H30N2O4: C, 71.07; H, 7.16; N,
by using Merck 60 F254 silica gel, glass-supported TLC plates, and visualiza- 6.63. Found: C, 71.01; H, 7.22; N, 6.56.
tion with UV light (254, 365 nm).
1-Cyclohexyl-5-(3,5-di-t-butyl-4-hydroxybenzyl)barbituric Acid (6c)
1
General Procedure for the Synthesis of 5-Benzylidenebarbituric Yield 75%; mp 159—160 °C; H-NMR (CDCl3) d: 8.25 (1H, s, NH), 6.87

1454
Vol. 51, No. 12
(2H, s, ArH), 5.13 (1H, s, OH), 4.33 (1H, m, CH), 3.64—3.67 (2H, m,
CH2Ar), 3.41 (1H, Abq, Jϭ23.2, 4.9 Hz, H-5), 1.98—2.09 (2H, m, c-Hex),
11.67.
1-(4-Fluorophenyl)-3-methyl-6-(1-methylhydrazino)uracil (9) A so-
1.62—1.77 (2H, m, c-Hex), 1.11—1.60 (6H, m, c-Hex), 1.41 (18H, s, 2ϫt- lution of 6-chloro-1-(4-fluorophenyl)-3-methyluracil (1.02 g, 4 mmol) and
Bu); MS (TOF): m/z 429 (MϩH)ϩ; Anal. Calcd for C25H36N2O4: C, 70.06;
H, 8.47; N, 6.54. Found: C, 69.84; H, 8.69; N, 6.31.
methylhydrazine (5 ml) in 2-propanol (10 ml) was refluxed for 5 min. The re-
action mixture was concentrated to dryness and the residue was triturated
1,3-Dicyclohexyl-5-(3,5-di-t-butyl-4-hydroxybenzyl)barbituric Acid with water. The resulting precipitate was filtered to give 755 mg (72%) of 9.
Recrystallization from EtOH gave a pure sample, mp 192—193 °C. Anal.
(6d) Yield 85%; mp 148 °C; 1H-NMR (CDCl3) d: 6.85 (2H, s, ArH), 5.10
(1H, s, OH), 4.46 (2H, m, 2ϫCH), 3.60 (1H, m, H-5), 3.37—3.39 (2H, m, Calcd for C12H13FN4O4: C, 54.54; H, 4.96; N, 21.20. Found: C, 54.76; H,
CH2Ar), 2.10—2.20 (4H, m, c-Hex), 1.76—1.78 (4H, m, c-Hex), 1.18— 4.98; N, 21.31.
1.65 (12H, m, c-Hex), 1.41 (18H, s, 2ϫt-Bu); MS (TOF): m/z 511 (MϩH)ϩ;
Anal. Calcd for C31H46N2O4: C, 72.91; H, 9.08; N, 5.49. Found: C, 73.00; H,
9.38; N, 5.29.
6-[2-(3,5-Di-t-butyl-4-hydroxybenzylidene)-1-methylhydrazino]-1-(4-
fluorophenyl)-3-methyluracil (10) Yield 60%; mp 235—236 °C (recrys-
tallized from AcOEt/benzene); 1H-NMR (CDCl3) d: 7.26—7.36 (5H, s,
General Procedure for the Synthesis of 6-Benzylidenehydrazino- NϭCH, Ph), 7.01—7.07 (2H, m, ArH), 5.64 (1H, s, OH), 5.42 (1H, s, H-5),
uracils (8a—g) A mixture of barbituric acids (4a, d—g) in POCl3 was 3.38 (3H, s, N(3)-Me), 3.01 (3H, s, N-Me), 1.45 (18H, s, 2ϫt-Bu); MS
refluxed for 2 h and concentrated. The residue was poured into crashed ice (TOF) m/z 481 (MϩH)ϩ; Anal. Calcd for C27H33FN4O3: C, 67.48; H, 6.92;
and the resulting precipitate was collected to give 6-chlorouracil derivatives, N, 11.66. Found: C, 67.71; H, 6.93; N, 11.47.
which were used to next step. A solution of 6-chlorouracil derivatives and
Picryl-Chloride Induced Contact Hypersensitivity Reaction18) Male
hydrazine hydrate in 2-PrOH was refluxed for 30 min. The reaction mixture ICR mice were sensitized by applying 100 ml of 7% (w/v) PC solution in
was concentrated to half volume and stood at room temperature overnight. acetone to the shaved abdomen. Seven days later, the mice were challenged
The resulting precipitate was filtered and washed with water to give 6-hy- by applying 20 ml of 1% (w/v) PC solution in acetone to the left ear. The ear
drazinouracils (7a, d—g).14—16) A mixture of the 6-hydrazinouracils and 4- thickness was measured with a digital thickness gauge before and 24 h after
hydroxybenzaldehyde derivatives in EtOH was heated 50 °C for 15 min. the challenge, and the difference in thickness was calculated. Test com-
After cooling, the resulting precipitate was filtered and recrystallized from pounds were orally administered 1 h prior to the challenge, or dissolved in
an appropriate solvent to give the hydrazones (8a—g).
acetone and were administered 5 min after the challenge.
6-[2-(3,5-Di-t-butyl-4-hydroxybenzylidene)hydrazino]-3-methyl-1-
Lipid Peroxidation Rat brain was homogenated in 9 volumes of 0.1 M
phenyluracil (8a) Yield 96%; mp 258—260 °C (recrystallized from phosphate buffer (pH 7.4) at 4 °C with a Polytron homogenizer. After elimi-
1
MeOH); H-NMR (DMSO-d6) d: 9.13 (1H, s, NH), 8.20 (1H, s, NϭCH), nation of tissue debris by centrifugation at 120ϫg for 5 min, the supernatant
7.46—7.63 (5H, m, Ph), 7.44 (2H, s, ArH), 5.57 (1H, s, H-5), 3.22 (3H, s, was used for the assay. The test compound in DMSO was added to the ho-
N-Me), 1.45 (18H, s, 2ϫt-Bu); MS (TOF) m/z 449 (MϩH)ϩ; Anal. Calcd for mogenate on ice, and the mixture was incubated for 1 h at 37 °C. The detec-
C26H32N4O3: C, 69.62; H, 7.19; N, 12.49. Found: C, 69.35; H, 7.25; N, tion of lipid peroxidation products in the homogenate was performed by
12.41.
monitoring thiobarbituric acid-reactive substances according to the method
6-[2-(4-Hydroxy-3,5-dimethoxybenzylidene)hydrazine]-3-methyl-1- of Ohkawa et al.19) Sodium thiobarbituric acid solution (1.2%, v/v) was
phenyluracil (8b) Yield 92%; mp 266—268 °C (recrystallized from added to the mixture (final 2.0 ml), and the solution was heated for 1 h at
1
MeOH); H-NMR (DMSO-d6) d: 9.20 (1H, s, NH), 8.13 (1H, s, NϭCH), 95—97 °C. After cooling, 0.5 ml of distilled water and 2.5 ml of n-
7.47—7.65 (5H, m, Ph), 6.95 (2H, s, ArH), 5.68 (1H, s, H-5), 3.86 (6H, s, butanol/pyridine (15 : 1, v/v) were added to the solution, which was then
2ϫOMe), 3.23 (3H, s, N-Me); MS (TOF) m/z 429 (MϩH)ϩ; Anal. Calcd for mixed vigorously. The absorbance of the thiobarbituric acid-reactive sub-
C20H20N4O5: C, 60.60; H, 5.09; N, 14.14. Found: C, 60.70; H, 5.17; N, stances extracted in the organic layer was determined at 532 nm, and the
14.14.
6-[2-(4-Hydroxy-3,5-dimethylbenzylidene)hydrazino]-3-methyl-1- using an external malondialdehyde standard.
phenyluracil (8c) Yield 91%; mp 287—289 °C (recrystallized from DMF-
EtOH); 1H-NMR (DMSO-d6) d: 9.14 (1H, s, NH), 8.04 (1H, s, NϭCH), References
level of lipid peroxides was expressed as malondialdehyde concentration by
7.41—7.60 (5H, m, Ph), 7.23 (2H, s, ArH), 5.61 (1H, s, H-5), 3.18 (3H, s,
N-Me), 2.20 (6H, s, 2ϫMe); MS (TOF) m/z 397 (MϩH)ϩ; Anal. Calcd for
C20H20N4O3: C, 65.92; H, 5.53; N, 15.38. Found: C, 65.87; H, 5.72; N,
15.45.
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1,3-Dicyclohexyl-6-[2-(3,5-di-t-butyl-4-hydroxybenzylidene)hy-
1
drazino]uracil (8d) Yield 90%; mp 228—230 °C; H-NMR (DMSO-d6)
d: 10.23 (1H, s, NH), 8.35 (1H, s, NϭCH), 7.53 (2H, s, ArH), 5.45 (1H, s,
H-5), 4.71 (1H, m, CH), 4.08 (1H, m, CH), 2.38—2.59 (8H, m, c-Hex), 1.49
(18H, s, 2ϫt-Bu), 1.12—1.83 (12H, m, c-Hex); MS (TOF) m/z 523
(MϩH)ϩ; Anal. Calcd for C31H46N4O3: C, 71.23; H, 8.87; N, 10.72. Found:
C, 71.01; H, 8.95; N, 10.55.
6-[2-(3,5-Di-t-butyl-4-hydroxybenzylidene)hydrazino]-1,3-dimethyl-
uracil (8e) Yield 93%; mp 262—264 °C (recrystallized from MeOH); 1H-
NMR (DMSO-d6) d: 8.37 (1H, s, NϭCH), 7.53 (2H, s, ArH), 5.48 (1H, s,
H-5), 3.44 (3H, s, N(1)-Me), 3.22 (3H, s, N(3)-Me), 1.49 (18H, s, 2ϫt-Bu);
MS (TOF) m/z 387 (MϩH)ϩ; Anal. Calcd for C21H30N4O3: C, 65.26; H,
7.82; N, 14.50. Found: C, 65.48; H, 7.89; N, 14.58.
6-[2-(3,5-Di-t-butyl-4-hydroxybenzylidene)hydrazino]-1-(4-fluoro-
phenyl)-3-methyluracil (8f) Yield 98%; mp 250—251 °C (recrystallized 11) Papesch V., Schroeder E. F., J. Org. Chem., 16, 1879—1890 (1951).
from EtOH); 1H-NMR (DMSO-d6) d: 7.52 (1H, s, NϭCH), 7.43 (2H, s, 12) Tanaka K., Chen X., Kimura T., Yoneda F., Chem. Pharm. Bull., 36,
ArH), 7.26—7.40 (4H, m, 4-F-Ph), 6.81 (1H, br s, NH), 5.94 (1H, s, OH),
60—69 (1988).
5.54 (1H, s, H-5), 3.37 (3H, s, N-Me), 1.44 (18H, s, 2ϫt-Bu); MS (TOF) m/z 13) Strauss G., Justus Liebigs Ann. Chem., 638, 205—212 (1960).
467 (MϩH)ϩ; Anal. Calcd for C26H31FN4O3: C, 66.93; H, 6.70; N, 12.01. 14) Pfleiderer W., Schundehutte K. H., Justus Liebigs Ann. Chem., 612,
Found: C, 66.82; H, 6.77; N, 11.92.
158—163 (1958).
6-[2-(3,5-Di-t-butyl-4-hydroxybenzylidene)hydrazino]-1-(4-methoxy-
15) Senda S., Hirota K., Chem. Pharm. Bull., 22, 1459—1467 (1974).
phenyl)-3-methyluracil (8g) Yield 71%; mp 276—277 °C (recrystallized 16) Naka T., Furukawa Y., Chem. Pharm. Bull., 27, 1965—1972 (1979).
from EtOH); 1H-NMR (DMSO-d6) d: 9.14 (1H, s, NH), 8.24 (1H, s,
NϭCH), 7.44 (2H, s, ArH), 7.39 (2H, d, Jϭ8.8 Hz, Ph), 7.17 (2H, d,
17) Senda S., Hirota K., Asao T., Chem. Pharm. Bull., 22, 189—195
(1974).
Jϭ8.8 Hz, Ph), 5.55 (1H, s, H-5), 3.92 (3H, s, OMe), 3.22 (3H, s, N-Me), 18) Asherson G. L., Ptak W., Immunology, 15, 405—416 (1968).
1.46 (18H, s, 2ϫt-Bu); MS (TOF) m/z 479 (MϩH)ϩ; Anal. Calcd for 19) Ohkawa H., Ohishi N., Yagi K., Anal. Biochem., 95, 351—358 (1979).
C27H34N4O4: C, 67.76; H, 7.16; N, 11.71. Found: C, 67.59; H, 7.08; N,