Synthesis and Reactions of Some Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives with a Thiophene Ring as Analgesic, Anticonvulsant, and Antiparkinsonian Agents

Article abstract of DOI:10.1007/s00706-003-0051-z

A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimidinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition, they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the corresponding Schiff's base and imide derivatives. Diazotization of amides gave thienotriazinone derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone derivatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding thioethyl- or thioglycolic acid pyrimidinone derivatives. The pharmacological screening showed that many of these obtained compounds have good analgesic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene, Carbamazepine, and Benzotropene as reference drugs.

Full text of DOI:10.1007/s00706-003-0051-z

Monatshefte f€ur Chemie 134, 1395–1409 (2003)
DOI 10.1007/s00706-003-0051-z
Synthesis and Reactions of Some Fused
Oxazinone, Pyrimidinone, Thiopyrimidinone,
and Triazinone Derivatives with a Thiophene
Ring as Analgesic, Anticonvulsant,
and Antiparkinsonian Agents
Abdel-Galil E. Amr1;ꢀ, Mohamed I. Hegab1,
Alhusain A. Ibrahiem1, and Mohamed M. Abdulla2
1
Organic Chemistry Dept., National Research Center, Cairo, Egypt
2
Medicinal Chemistry Dept., Faculty of Pharmacy, Minia University, Egypt
Received January 23, 2003; accepted (revised) March 17, 2003
Published online September 15, 2003 # Springer-Verlag 2003
Summary. A series of 2,6-disubstituted pyridine ester derivatives and the corresponding amides were
prepared. The esters were hydrolysed to the sodium salts, which were treated with acetic anhydride to
afford oxazinone derivatives. These were treated with ammonium acetate to afford 2-methylpyrimi-
dinone derivatives, which were methylated to yield 2,3-dimethylpyrimidinone derivatives. In addition,
they were reacted with aniline or hydrazine hydrate to give 3-phenyl- or 3-aminopyrimidinone
derivatives. The latter reacted with 2-thiophenecarbaldehyde or phthalic anhydride to afford the
corresponding Schiff’s base and imide derivatives. Diazotization of amides gave thienotriazinone
derivatives, which were treated with ethyl iodide to afford the corresponding 3-ethyltriazinone deri-
vatives. Also, they were reacted with phenyl isothiocyanate to give the corresponding thiopyrimidinone
derivatives, which were alkylated with ethyl iodide or chloroacetic acid to afford the corresponding
thioethyl- or thioglycolic acid pyrimidinone derivatives.
The pharmacological screening showed that many of these obtained compounds have good analge-
sic, anticonvulsant, and antiparkinsonian activities comparable to Voltarene+, Carbamazepine+, and
Benzotropene+ as reference drugs.
Keywords. 2,6-Disubstituted pyridine; Oxazinone; Pyrimidinone; Analgesic; Anticonvulsant;
Antiparkinsonian.
Introduction
In previous work we have found that certain substituted pyridine and their amide
derivatives show antimicrobial [1–4] and antitumor activities [5–7]. In addition,
ꢀ
Corresponding author. E-mail: aamr1963@yahoo.com

1396
A. E. Amr et al.
the biological and antianalgesic activities of many heterocyclic compounds con-
taining a sulfur atom have been reviewed [8–10]. On the other hand, thienopy-
rimidine and thioxopyrimidine derivatives have promising biological [11, 12] and
anticancer activity [13, 14]. Recently, some new thienopyrimidinone derivatives
have been synthesized [15]. In view of these observations and in continuation of
our previous work in pyridine chemistry, we synthesized some new heterocyclic
compounds containing the thieno[2,3-b]pyridine moiety fused with a pyridine,
oxazinone, pyrimidinone, or triazinone nucleus and tested their biological
activity.
Results and Discussion
Synthesis
The 2,6-di(4-aryl-3-cyano-2-oxopyridin-6-yl)pyridine derivatives 1a and 1b were
prepared according to literature [1]. Thionation of 1a and 1b to the corresponding
thione derivatives 2a and 2b were achieved by the action of P2S5 in dry pyridine.
Scheme 1

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1397
Condensation of 2a and 2b with ethyl chloroacetate in the presence of anhydrous
K2CO3 gave 3a and 3b, which were cyclized by sodium methoxide in methanol
to give the amino ester derivatives 4a and 4b (method A). The latter compounds
were also obtained from 2a and 2b with ethyl chloroacetate and sodium meth-
oxide in methanol (method B). Aminolysis of 4a and 4b by ammonia gave 5a
and 5b (Scheme 1). The IR spectra of 4a and 4b showed the absence of
ꢀꢀ(CꢁN) at 2219, 2220 cmꢂ 1 for 3a and 3b and the presence of broad bands
at 3439 ꢂ 3310 cmꢂ 1 corresponding to ꢀꢀ(NH2). Correspondingly, the IR spectra
of 5a and 5b showed the absence of ꢀꢀ(C¼O, ester) at 1738, 1732 cmꢂ 1 of 4a and
4b and the presence of bands at ꢀꢀ¼ 1680, 1675 cmꢂ 1 corresponding to ꢀꢀ(C¼O,
amide).
Compounds 4a and 4b were hydrolyzed by refluxing with ethanolic NaOH
solution to their sodium salts, which were treated with acetic anhydride to give
the oxazinone derivatives 6a and 6b. Reaction of 6a and 6b with ammonium
acetate in acetic acid afforded the corresponding pyrimidinone derivatives 7a
Scheme 2

1398
A. E. Amr et al.
and 7b, which were reacted with methyl iodide in N,N-dimethylformamide in the
presence of anhydrous K2CO3 to yield the 3-methylpyrimidinone derivatives 8a
and 8b (Scheme 2).
Similarly, reaction of oxazinone derivatives 6a and 6b with aniline in acetic
acid or hydrazinehydrate in ethanol under reflux afforded 9a and 9b and 10a and
10b. Condensation of 10a and 10b with 2-thiophenecarbaldehyde in refluxing
ethanol containing a few drops of piperidine yielded the corresponding Schiff’s
bases 11a and 11b. Also, the reaction of 10a and 10b with phthalic anhydride in
refluxing acetic acid gave the corresponding 3-imido-pyrimidinone derivatives 12a
and 12b (Scheme 3).
Scheme 3

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1399
Scheme 4

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A. E. Amr et al.
Diazotization of 5a and 5b gave the corresponding triazinone derivatives 13a
and 13b, which were treated with ethyl iodide in the presence of K2CO3 to give the
corresponding 3-ethyltriazinone derivatives 14a and 14b (Scheme 4). Moreover,
the reaction of 5a and 5b with phenyl isothiocyanate in refluxing dioxane gave the
3-phenyl-2-thioxopyrimidin-4-one derivatives 15a and 15b, which were reacted
with ethyl iodide in ethanolic sodium hydroxide to give the corresponding 2-
thioethylpyrimidinone derivatives 16a and 16b. Similarly, reaction of 15a and
15b with chloroacetic acid in refluxing ethanolic NaOH gave the corresponding
2-thioglycolic acids 17a and 17b (Scheme 4).
Pharmacological Screening
The tested three pharmacological activities namely, analgesic, anticonvulsant, and
antiparkinsonism despite of their different biological receptors yet all of a neu-
rological. Seven representative compounds 2a, 4b, 6a, 8a, 10a, 10b, and 13a
were studied with respect to analgesic, anticonvulsant, and antiparkinsonian
activities.
Analgesic Activity
All tested compounds exhibited analgesic activities (Table 1). The most potent one
is 13a that showed the same activity as Voltarene+ after 45 min and it had even
higher activity than Voltarene+ after 60, 90, and 120 min. Also the analgesic activ-
ities of 4b and 8a approached those of Voltarene+, and 10b had 31–47% activity as
compared with Voltarene+ (Table 1).
Anticonvulsant Activity
Compounds 4b and 6b are devoid of any anticonvulsant activity where they pro-
vide no protection against yohinobine-induced clonic seizures. Compounds 2a, 8a,
and 10a showed interesting anticonvulsant activities, their relative potencies to
Carbamazebene+ are 0.58, 0.94, and 0.7. Compounds 10b and 13a are even more
potent than Carbamazebene+ (1.93 and 2.23, relative potency).
Table 1. Analgesic activity of the new compounds as compared with Voltarene+ in mice
Comp. no.
Analgesic activity after
10 min
20 min
30 min
45 min
60 min
90 min
120 min
Voltarene+
1
1
1
1
1
1
1
2a
0.59
0.79
0.54
0.81
0.61
0.31
0.97
0.61
0.83
0.56
0.89
0.63
0.40
0.98
0.69
0.87
0.58
0.88
0.71
0.40
0.99
0.71
0.88
0.55
0.91
0.73
0.42
1.07
0.77
0.88
0.51
0.93
0.74
0.45
1.12
0.81
0.88
0.49
0.94
0.74
0.43
1.21
0.80
0.91
0.47
0.94
0.74
0.47
1.41
4b
6b
8a
10a
10b
13a

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1401
Table 2. Anticonvulsant activity of the new compounds and Carbamazepine+ via ED50 needed to
antagonize yohimbine seizure
Comp. no.
ED50 value=mg=kg
Relative potency
to Carbamazepine+
Control
Carbamazepine+
0
0
29
1
2a
50
0.58
–
4b
6b
No protection
No protection
–
8a
31
35
15
13
0.935
0.70
1.933
2.23
10a
10b
13a
Table 3. Antiparkinsonian activity of the new compounds as compared with Benzotropene+
Comp. no.
Salivation &
lacrimation
score
Tremors
score
% decrease from
Oxotremerine+
rectal temp.
Relative
potency to
Benzotropene+
Control
0
1
2
3
3
2
2
1
1
0
1
2
3
3
2
2
1
1
0
25
10
3
0
Benzotropene
1
2a
0.4
0.12
0.16
0.44
0.6
0.8
0.8
4b
6b
4
8a
11
15
20
20
10a
10b
13a
Antiparkinsonian Activity
Compounds 2a, 8a, and 10a showed moderate activity (relative potencies to
Benzotropene+ 0.40, 0.44, and 0.6). Compounds 10b and 13a are the most potent
antiparkinsonic agents (0.8 relative potency) (Table 3).
Experimental
Melting points are uncorrected and were recorded on an Electrothermal IA 9000 SERIES Digital
Melting Point Apparatus. Analytical data were obtained from the Microanalytical unit, National
Research Center, Cairo, Egypt. Their results were found to be in good agreement with the calculated
values. The IR spectra (KBr) were recorded on a FT IR-8201 PC Spectro-photometer (Shimadzu).
1
The H NMR spectra were measured with Jeol 270MHz in DMSO-d6 and the chemical shifts were
recorded in ppm relative to TMS. The Mass spectra were run at 70 eV with a Finnigan SSQ GC=MS
spectrometer using EI. The reactions were followed by TLC (Silica gel, aluminum sheets 60 F254,
Merck). Starting materials 1a and 1b were prepared according to published procedures [1].

1402
A. E. Amr et al.
Synthesis of 2a and 2b
A mixture of 1 mmol of 1a or 1b and 4.45g of P2S5 (20 mmol) in 50 cm3 of dry pyridine was heated
under reflux for 6 h with stirring. The reaction mixture was cooled, then poured into ice-water, the
separated solid was collected by filtration, washed with water, dried, and crystallized.
2,6-Bis(3-cyano-4-phenyl-2-thioxopyridin-6-yl)pyridine (2a, C29H17N5S2)
Mp 228–230ꢃC (dioxane); IR (film): ꢀꢀ¼ 3330 (NH), 2210 (CꢁN) cmꢂ 1; 1H NMR (270MHz, DMSO-
d6): ꢁ ¼ 6.90–7.50 (m, 10 Ar-H), 8.10–8.20 (m, 3pyridine-H), 8.55 (s, 2C-50-H), 10.68 (s, 2NH,
exchangeable with D2O); MS (EI, 70eV): m=z ¼ 499 [Mþ ].
2,6-Bis(3-cyano-4-(2-thienyl)-2-thioxopyridin-6-yl)pyridine (2b, C25H13N5S4)
Mp 235–237ꢃC (dioxane); IR (film): ꢀꢀ¼ 3324 (NH), 2216 (CꢁN) cmꢂ 1; 1H NMR (270MHz, DMSO-
d6): ꢁ ¼ 6.80–7.15 (m, 6thiophene-H), 8.00–8.25 (m, 3pyridine-H), 8.35 (s, 2C-50-H), 10.55 (s, 2NH,
exchangeable with D2O); MS (EI, 70eV): m=z ¼ 511 [Mþ ].
Synthesis of 3a and 3b
A mixture of 1 mmol of 2a or 2b and 0.27 g of anhydrous K2CO3 (2mmol) in 25cm3 of N,N-
dimethylformamide was stirred at room temperature for 1=2 h, then 2.16 g of ethyl chloroacetate
(2mmol) were added with stirring. The reaction mixture was heated at 60ꢃC for 2 h and after cooling
poured into ice. The solid formed was collected by filtration and crystallized.
2,6-Bis(3-cyano-2-ethylthioglycolate-4-phenylpyridin-6-yl)pyridine (3a, C37H29N5O4S2)
1
Mp 175–177ꢃC (EtOH); IR (film): ꢀꢀ¼ 2220 (CꢁN), 1735 (C¼O, ester) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 1.20 (t, 2CH2CH3), 3.85 (q, 2CH2CH3), 4.90 (s, 2S–CH2), 6.95–7.65 (m, 10phenyl-H),
8.10–8.25 (m, 3pyridine-H), 8.55 (s, 2C-50-H); MS (EI, 70eV): m=z ¼ 671 [Mþ ].
2,6-Bis(3-cyano-2-ethylthioglycolate-4-(2-thienyl)pyridin-6-yl)pyridine (3b, C33H25N5O4S4)
1
Mp 182–184ꢃC (EtOH); IR (film): ꢀꢀ¼ 2219 (CꢁN), 1728 (C¼O, ester) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 1.15 (t, 2CH2CH3), 3.70 (q, 2CH2CH3), 4.75 (s, 2S-CH2), 6.80–7.35 (m, 6thiophene-
H), 7.95–8.15 (m, 3pyridine-H), 8.40 (s, 2C-50-H); MS (EI, 70eV): m=z ¼ 683 [Mþ ].
Synthesis of 4a and 4b
Method A: A mixture of 1 mmol of 3a or 3bin 20cm3 ofa sodium ethoxide solution(2%) was refluxedfor
1 h on a water bath at 70ꢃC with stirring. The reaction mixturewas evaporated under reduced pressure, the
obtained residue was dissolved in CH2Cl2, washed with H2O, 10cm3 1N HCl and then H2O. The solvent
was dried over anhydrous CaCl2, evaporated under reduced pressure, and the product was crystallized.
Method B: Compounds 4a and 4b were also prepared from compounds 2a and 2b according to the
literature method [19] in yields 55 and 65%, respectively. The obtained products were identified by mp
and TLC in comparison with authentic samples from Method A.
2,6-Bis(3-amino-2-carbethoxy-4-phenylthieno[2,3-b]pyridin-6-yl)pyridine
(4a, C37H29N5O4S2)
1
Mp 208–210ꢃC (EtOH); IR (film): ꢀꢀ¼ 3419 ꢂ 3360 (NH2), 1732 (C¼O, ester) cmꢂ 1; H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 0.95 (t, 2CH2CH3), 4.10 (q, 2CH2CH3), 4.65 (brs, 2NH2, exchangeable

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1403
with D2O), 7.00–7.55 (m, 10phenyl-H), 8.15–8.30 (m, 3pyridine-H), 8.60 (s, 2C-50-H); MS (EI,
70eV): m=z ¼ 671 [Mþ ].
2,6-Bis(3-amino-2-carbethoxy-4-(2-thienyl)thieno[2,3-b]pyridin-6-yl)-pyridine
(4b, C33H25N5O4S4)
Mp 198–200ꢃC (EtOH); IR (film): ꢀꢀ¼ 3439–3310 (NH2), 1738 (C¼O, ester) cmꢂ 1
;
1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 0.90 (t, 2CH3), 3.90 (q, 2CH2), 4.60 (brs, 2NH2, exchangeable with
D2O), 6.90–7.25 (m, 6thiophene-H), 8.10–8.35 (m, 3pyridine-H), 8.50 (s, 2C-50-H); MS (EI,
70eV): m=z ¼ 683 [Mþ ].
Synthesis of 5a and 5b
Compounds 4a or 4b (1mmol) were suspended in 100 cm3 of ethanol, then a current of NH3 was
passed through at 0ꢃC till saturation, the reaction mixture was left overnight at ꢂ4ꢃC, evaporated under
reduced pressure, and the residue obtained was triturated with n-hexane, the formed solid was filtered
off, washed with H2O, and crystallized.
2,6-Bis(3-amino-2-carboxamido-4-phenylthieno[2,3-b]pyridin-6-yl)pyridine
(5a, C33H23N7O2S2)
Mp 214–216ꢃC (AcOH); IR (film): ꢀꢀ¼ 3415–3309 (NH2), 1680 (C¼O, amide) cmꢂ 1; MS (EI,
70eV): m=z ¼ 613 [Mþ ].
2,6-Bis(3-amino-2-carboxamido-4-(2-thienyl)thieno[2,3-b]pyridin-6-yl)pyridine
(5b, C29H19N7O2S4)
Mp 224–226ꢃC (dioxane); IR (film): ꢀꢀ¼ 3460–3380 (NH2), 1675 (C¼O, amide) cmꢂ 1; MS (EI,
70eV): m=z ¼ 625 [Mþ ].
Synthesis of 6a and 6b
A mixture of 1 mmol of 4a or 4b in 100 cm3 of ethanolic NaOH (5%) was heated under reflux for 4 h.
The corresponding sodium salt precipitated and was filtered off and dried. It was dissolved in 100cm3
of acetic anhydride and refluxed for 6 h. The reaction mixture was concentrated and allowed to cool.
The obtained solid was collected and crystallized.
2,6-Bis(2-methyl-4-oxo-9-phenylpyrido[30,20:4,5]thieno[3,2-d]oxazin-7-yl)pyridine
(6a, C37H21N5O4S2)
1
Mp 186–188ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1750 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.09 (s, 2CH3), 7.20–7.60 (m, 10phenyl-H), 7.95–8.10 (m, 3pyridine-H), 8.45 (s, 2C-50-H); MS
(EI, 70 eV): m=z ¼ 663 [Mþ ].
2,6-Bis(2-methyl-4-oxo-9-(2-thienyl)pyrido[30,20:4,5]thieno[3,2-d]oxazin-7-yl)pyridine
(6b, C33H17N5O4S4)
1
Mp 212–214ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1745 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 1.85 (s, 2CH3), 6.75–7.25 (m, 6thiophene-H), 8.10–8.25 (m, 3pyridine-H), 8.35 (s, 2C-50-H); MS
(EI, 70 eV): m=z ¼ 675 [Mþ ].

1404
A. E. Amr et al.
Synthesis of 7a and 7b
A mixture of 1 mmol of 6a or 6b and 0.6 g of ammonium acetate (4mmol) in 100 cm3 of glacial acetic
acid was refluxed for 6 h. The reaction mixture was concentrated under reduced pressure, then poured
into H2O, and the solid formed was collected by filtration and crystallized.
2,6-Bis(2-methyl-4-oxo-9-phenyl-3,4-dihydropyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-7-yl)-pyridine (7a, C37H23N7O2S2)
1
Mp 245–247ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3420 (NH), 1650 (C¼O) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 2.30 (s, 2CH3), 7.10–7.70 (m, 10phenyl-H), 8.0–8.20 (m, 3pyridine-H), 8.50 (s,
2C-50-H), 9.20 (s, 2NH, exchangeable with D2O); MS (EI, 70 eV): m=z ¼ 661 [Mþ ].
2,6-Bis(2-methyl-4-oxo-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno[3,2-d]
pyrimidin-7-yl)pyridine (7b, C33H19N7O2S4)
1
Mp 234–236ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3400 (NH), 1660 (C¼O) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 2.10 (s, 2CH3), 7.50–7.80 (m, 6thiophene-H), 8.15–8.30 (m, 3pyridine-H), 8.65 (s,
2C-50-H), 8.85 (s, 2NH exchangeable with D2O); MS (EI, 70 eV): m=z ¼ 673 [Mþ ].
Synthesis of 8a and 8b
A solution of 1 mmol of 7a or 7b in 20 cm3 of DMF was stirred with 0.55g of anhydrous K2CO3
(4mmol) for 10 min at room temperature, then 0.56g of methyl iodide (4mmol) in 5 cm3 of DMF were
added. The reaction mixture was heated at 60ꢃC for 4 h, after cooling poured into H2O, and the
precipitate was filtered off and crystallized.
2,6-Bis(2,3-dimethyl-4-oxo-9-phenyl-3,4-dihydropyrido[30,2:4,5]thieno[3,2-d]
pyrimidin-7-yl)pyridine (8a, C39H27N7O2S2)
1
Mp 210–212ꢃC (AcOH=H2O); IR (film): ꢀꢀ¼ 1665 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.20 (s, 2CH3), 3.45 (s, 2N-CH3), 6.80–7.40 (m, 10phenyl-H), 8.00–8.20 (m, 3pyridine-H), 8.55
(s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 689 [Mþ ].
2,6-Bis(2,3-dimethyl-4-oxo-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)pyridine (8b, C35H23N7O2S4)
1
Mp 205–207ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1658 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.00 (s, 2CH3), 3.25 (s, 2N-CH3), 6.55–7.10 (m, 6thiophene-H), 8.10–8.25 (m, 3pyridine-H), 8.40
(s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 701 [Mþ ].
Synthesis of 9a and 9b
A mixture of 1 mmol of 6a or 6b and 0.4 cm3 of aniline (4mmol) in 50cm3 of glacial acetic acid was
heated under reflux for 6 h. The reaction mixture was concentrated, poured onto ice, and the formed
solid was filtered off and crystallized.
2,6-Bis(2-methyl-4-oxo-3,9-diphenyl-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)pyridine (9a, C49H31N7O2S2)
1
Mp 264–266ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1665 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.0 (s, 2CH3), 6.75–7.50 (m, 20phenyl-H), 8.05–8.20 (m, 3pyridine-H), 8.35 (s, 2H, 2C-50-H); MS
(EI, 70 eV): m=z ¼ 813 [Mþ ].

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1405
2,6-Bis(2-methyl-4-oxo-3-phenyl-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-pyrimidin-7-yl)pyridine (9b, C45H27N7O2S4)
1
Mp 254–256ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1680 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 1.95 (s, 2CH3), 6.90–7.60 (m, 16phenyl-H þ thiophene-H), 8.10–8.25 (m, 3pyridine-H), 8.40
(s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 825 [Mþ ].
Synthesis of 10a and 10b
A mixture of 1 mmol of 6a or 6b and 0.8cm3 of hydrazine hydrate (16 mmol) in 100 cm3 of absolute
ethanol was refluxed for 4 h. After cooling the solid formed was collected and crystallized.
2,6-Bis(3-amino-2-methyl-4-oxo-9-phenyl-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)pyridine (10a, C37H25N9O2S2)
Mp 244–246ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3340–3280 (NH2), 1658 (C¼O) cmꢂ 1
;
1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 2.10 (s, 2CH3), 4.75 (s, 2NH2, exchangeable with D2O), 6.90–7.35 (m,
10phenyl-H), 8.15–8.30 (m, 3pyridine-H), 8.45 (s, 2C-50-H); MS (EI, 70eV): m=z ¼ 691 [Mþ ].
2,6-Bis(3-amino-2-methyl-4-oxo-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-pyrimidin-7-yl)pyridine (10b, C33H21N9O2S4)
Mp 238–240ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3365–3300 (NH2), 1670 (C¼O) cmꢂ 1
;
1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 2.30 (s, 2CH3), 4.80 (s, 2NH2, exchangeable with D2O), 7.10–7.55
(m, 6thiophene-H), 8.10–8.25 (m, 3pyridine-H), 8.60 (s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 703 [Mþ ].
Synthesis of 11a and 11b
A mixture of 1 mmol of 10a or 10b and 0.22 g of 2-thiophenecarbaldehyde (2mmol) in 25cm3 of
absolute ethanol was refluxed for 6 h (a solid was formed after 1 h). The obtained solid was filtered off,
washed with ethanol, and crystallized.
2,6-Bis(2-methyl-4-oxo-3-(2-thienylmethylidene)amino)-9-phenyl-3,4-dihydropyrido
[30,20:4,5]-thieno[3,2-d]pyrimidin-7-yl)pyridine (11a, C47H29N9O2S4)
Mp >300ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1670 (C¼O) cmꢂ 1
;
1H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.35 (s, 2CH3), 6.75–7.10 (m, 10phenyl-H), 7.30–7.60 (m, 6thiophene-H), 7.95–8.10 (m, 3pyr-
idine-H), 8.45 (s, 2C-50-H), 9.20 (s, 2CH¼N); MS (EI, 70eV): m=z ¼ 880 [Mþ ].
2,6-Bis(2-methyl-4-oxo-3-(2-thienylmethylidene)amino)-9-(2-thienyl)-3,4-dihydropyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-7-yl)pyridine (11b, C43H25N9O2S6)
Mp 285–287ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 1678 (C¼O) cmꢂ 1; 1H NMR (270 MHz, DMSO-d6): 2.20
(s, 2CH3), 7.10–7.65 (m, 12thiophene-H), 8.00–8.20 (m, 3pyridine-H), 8.35 (s, 2C-50-H), 8.95 (s,
2CH¼N); MS (EI, 70eV): m=z ¼ 892 [Mþ ].
Synthesis of 12a and 12b
A mixture of 1 mmol of 10a or 10b and 0.29 g of phthalic anhydride (2mmol) was refluxed in 50cm3
of glacial acetic acid for 6 h. The reaction mixture was cooled, the obtained product was collected by
filtration, dried, and crystallized.

1406
A. E. Amr et al.
2,6-Bis(2-methyl-4-oxo-3-(phthalimido)-9-phenyl-3,4-dihydropyrido
[30,20:4,5]thieno[3,2-d]-pyrimidin-7-yl)pyridine (12a, C53H29N9O6S2)
1
Mp >300ꢃC (DMF=EtOH); IR (film): ꢀꢀ¼ 1680 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.35 (s, 2CH3), 6.80–7.60 (m, 18Ar-H), 8.00–8.20 (m, 3pyridine-H), 8.4 (s, 2C-50-H); MS (EI,
70eV): m=z ¼ 951 [Mþ ].
2,6-Bis(2-methyl-4-oxo-3-(phthalimido)-9-(2-thienyl)-3,4-dihydropyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-7-yl)pyridine (12b, C49H25N9O6S4)
1
Mp >300ꢃC (DMF=EtOH); IR (film): ꢀꢀ¼ 1680 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 2.20 (s, 2CH3), 6.75–7.10 (m, 8Ar-H), 7.25–7.75 (m, 6thiophene-H), 8.05–8.25 (m, 3pyridine-
H), 8.45 (s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 964 [Mþ ].
Synthesis of 13a and 13b
A mixture of 1 mmol of 5a or 5b, 10cm3 of conc. H2SO4, and 20cm3 of glacial acetic acid
was stirred for 15min at ꢂ5ꢃC. Then 0.2 g of NaNO2 (3mmol) in 10cm3 of H2O were added
dropwise with constant stirring during 10 min. The reaction mixture was stirred for 1 h at 0ꢃC
and then diluted with H2O. The obtained product was filtered off, washed with water, and
crystallized.
2,6-Bis(4-oxo-9-phenyl-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-[1,2,3]-triazin-7-yl)-pyridine (13a, C33H17N9O2S2)
1
Mp 215–217ꢃC (AcOH); IR (film): ꢀꢀ¼ 3300–2600 (NH), 1660 (C¼O) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 6.80–7.40 (m, 10phenyl-H), 7.90–8.10 (m, 3pyridine-H), 8.50 (s, 2C-50-H), 8.90
(s, 2NH, exchangeable with D2O); MS (EI, 70eV): m=z ¼ 635 [Mþ ].
2,6-Bis(4-oxo-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-[1,2,3]-triazin-7-yl)-pyridine (13b, C29H13N9O2S4)
1
Mp 196–198ꢃC (AcOH); IR (film): ꢀꢀ¼ 3380–2300 (NH), 1680 (C¼O) cmꢂ 1; H NMR (270 MHz,
DMSO-d6): ꢁ ¼ 7.20–7.60 (m, 6thiophene-H), 8.10–8.30 (m, 3pyridine-H), 8.55 (s, 2C-50-H), 9.10
(s, 2NH, exchangeable with D2O); MS (EI, 70eV): m=z ¼ 647 [Mþ ].
Synthesis of 14a and 14b
A solution of 1 mmol of 13a or 13b in 20cm3 of DMF was stirred with 0.55 g of anhydrous K2CO3
(4mmol) for 10 min at room temperature. Then 0.62g of ethyl iodide (4mmol) were added. The
reaction mixture was heated at 60ꢃC for 4 h. After cooling the mixture was poured into H2O. The
formed solid was filtered off and crystallized.
2,6-Bis(3-ethyl-4-oxo-9-phenyl-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-1,2,3-triazin-7-yl)-pyridine (14a, C37H25N9O2S2)
1
Mp 223–225ꢃC (DMF=EtOH); IR (film): ꢀꢀ¼ 1670 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 1.60 (t, 2CH3), 4.6 (q, 2CH2), 6.85–7.35 (m, 10phenyl-H), 8.00–8.20 (m, 3pyridine-H), 8.45 (s,
2C-50-H); MS (EI, 70 eV): m=z ¼ 691 [Mþ ].

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
1407
2,6-Bis(3-ethyl-4-oxo-9-(2-thienyl)-3,4-dihydropyrido[30,20:4,5]thieno
[3,2-d]-1,2,3-triazin-7-yl)pyridine (14b, C33H21N9O2S4)
1
Mp 218–220ꢃC (DMF=EtOH); IR (film): ꢀꢀ¼ 1665 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 1.50 (t, 2CH3), 4.35 (q, 2CH2), 7.10–7.60 (m, 6thiophene-H), 8.10–8.35 (m, 3pyridine-H), 8.55
(s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 703 [Mþ ].
Synthesis of 15a and 15b
A mixture of 1 mmol of 5a or 5b and 2.7 g of phenyl isothiocyanate (2mmol) in 25cm3 of dioxane was
refluxed for 6 h. The reaction mixture was evaporated under reduced pressure, the obtained residue was
solidified with n-hexane, filtered off and crystallized.
2,6-Bis(4-oxo-3,9-diphenyl-1,2,3,4-tetrahydro-2-thioxopyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)-pyridine (15a, C47H27N7O2S4)
Mp 242–244ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3320 (NH), 1680 (C¼O), 1200 (C¼S) cmꢂ 1; MS (EI,
70eV): m=z ¼ 850 [Mþ ].
2,6-Bis(4-oxo-3-phenyl-9-(2-thienyl)-1,2,3,4-tetrahydro-2-thioxopyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)pyridine (15b, C43H23N7O2S6)
Mp 236–238ꢃC (DMF=EtOH); IR (film): ꢀꢀ¼ 3345 (NH), 1680 (C¼O), 1195 (C¼S) cmꢂ 1; 1H NMR
(270 MHz, DMSO-d6): ꢁ ¼ 6.90–7.30 (m, 10phenyl-H), 7.40–7.60 (m, 6thiophene-H), 7.90 (s, 2NH, ex-
changeablewithD2O), 8.00–8.25 (m, 3pyridine-H), 8.60 (s, 2C-50-H); MS (EI, 70eV): m=z ¼ 862 [Mþ ].
Synthesis of 16a and 16b
To a solution of 1 mmol of 15a or 15b in 100 cm3 of alcoholic NaOH (5%) 0.62g of ethyl iodide
(4mmol) were added with stirring. The reaction mixture was refluxed for 8 h, then the excess solvent
was evaporated under reduced pressure, and the residue was poured onto H2O. The obtained solid was
collected by filtration and crystallized.
2,6-Bis(4-oxo-3,9-diphenyl-3,4-dihydro-2-(ethylthio)pyrido[30,20:4,5]thieno
[3,2-d]pyrimidin-7-yl)pyridine (16a, C51H35N7O2S4)
1
Mp 186–188ꢃC (AcOH=H2O); IR (film): ꢀꢀ¼ 1668 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 1.10–1.20 (t, 2CH3), 2.4–2.60 (q, 2CH2), 7.10–7.65 (m, 20phenyl-H), 8.10–8.25 (m, 3pyridine-H),
8.55 (s, 2C-50-H); MS (EI, 70 eV): m=z ¼ 906 [Mþ ].
2,6-Bis-(2-(ethylthio)-4-oxo-3-phenyl-9-(2-thienyl)-3,4-dihydropyrido
[30,20:4,5]thieno[3,2-d]-pyrimidin-7-yl)pyridine (16b, C47H31N7O2S6)
1
Mp 210–212ꢃC (AcOH=H2O); IR (film): ꢀꢀ¼ 1675 (C¼O) cmꢂ 1; H NMR (270MHz, DMSO-d6):
ꢁ ¼ 0.95–1.20 (t, 2CH3), 2.60–2.85 (q, 2CH2), 6.65–7.60 (m, 16phenyl-H þ thiophene-H), 8.00–8.25
(m, 3pyridine-H), 8.60 (s, 2C-50-H); MS (EI, 70eV): m=z ¼ 918 [Mþ ].
Synthesis of 17a and 17b
Method A: A solution of 1 mmol of 15a or 15b in 100 cm3 of ethanolic NaOH (20%) was stirred at
room temperature for 1 h and 0.19g of chloroacetic acid (2mmol) were added. The reaction mixture

1408
A. E. Amr et al.
was refluxed for 12 h, concentrated, and then poured onto ice. The formed solid was collected by
filtration and crystallized.
Method B: A mixture of 1 mmol of 15a or 15b, 0.19 g of chloroacetic acid (2mmol), and 0.25g of
anhydrous sodium acetate (3mmol) in 40 cm3 of glacial acetic acid=acetic anhydride (3=1, v=v) was
refluxed for 6 h, then allowed to cool, and poured gradually with stirring into cold H2O. The formed
solid was filtered off and crystallized.
2,6-Bis(2-ethylthioglycolole-4-oxo-3,9-diphenyl-3,4-dihydropyrido
[30,20:4,5]thieno[3,2,-d]pyrimidin-7-yl)pyridine (17a, C51H31N7O6S4)
Mp >300ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3560–3440 (br, OH), 1723 (C¼O, acid), 1675 (C¼O)
1
cmꢂ 1; H NMR (270 MHz, DMSO-d6): ꢁ ¼ 4.20 (s, 2CH2), 7.20–7.60 (m, 20phenyl-H), 8.05–8.30
(m, 3pyridine-), 8.60 (s, 2C-50-H), 10.60 (s, 2OH, exchangeable with D2O); MS (EI, 70eV): m=z ¼ 966
[Mþ ].
2,6-Bis(2-ethylthioglycolole-4-oxo-3-phenyl-9-(2-thienyl)-3,4-dihydropyrido
[30,20:4,5]thieno[3,2-d]pyrimidin-7-yl)pyridine (17b, C47H27N7O6S6)
Mp >300ꢃC (DMF=H2O); IR (film): ꢀꢀ¼ 3520–3435 (br, OH), 1726 (C¼O, acid), 1680 (C¼O)
1
cmꢂ 1; H NMR (270 MHz, DMSO-d6): 3.95 (s, 2CH2), 6.85–7.10 (m, 10phenyl-H), 7.20–7.65 (m,
6thiophene-H), 8.15–8.35 (m, 3pyridine-H), 8.55 (s, 2C-50-H), 10.75 (s, 2OH, exchangeable with
D2O); MS (EI, 70eV): m=z ¼ 978 [Mþ ].
Pharmacology
Analgesic Activity
Sixty mice of both sexes weighting from 20–25g were divided into 10 groups. One group was kept as
control (received saline), the second group received vehicle (Gumacaccia), and the third one received
Voltarene+ as a reference drug, whereas the other groups received 2a, 4b, 6a, 8a, 10a, 10b, and 13a
(SC administration). Mice were dropped gently in a dry glass beaker of one liter capacity maintained at
55–55.5ꢃC, Normal reaction time in seconds for all animals were determined at time intervals of 10,
20, 30, 45, 60, 90, and 120 min. This is the interval extending from the instant the mouse reaches the
hot beaker till the animals licks its feet or jamb out of the beaker (dose 5 mg=kg). Relative potencies to
Voltarene+ were determined (Table 1).
Anticonvulsant Activity
Purpose and Rationale
Antagonism against yohimbine-induced seizures in mice is considered to be a predictive model of
potential anxiolytic and GABA-mimetic [16].
Procedure
Male Webster mice (20–30g) were individually placed in clear plastic cylinder and the tested com-
pounds were administered intrapretonial (5mg=kg), 30min prior to a dose of 45mg=kg of yohimbi-
neꢄ HCl. The animals were observed for onset and number of clonic seizures. Evaluation ED50 values
of compounds with 95% confidence limit were calculated for the antagonism of yohimbine-induced
clonic seizures by means of the Lichtfield-Wilcoxon procedure [17] (Table 2).

Fused Oxazinone, Pyrimidinone, Thiopyrimidinone, and Triazinone Derivatives
Antiparkinsonian Activity
1409
Purpose and Rationale
The muscarinic agonists Tremorine+ and Oxotremorine+ induce parkinisonisin-like signs such as
tremor, attaxia, spasticity, salivation, lacrimation, and hypothermia. These signs are antagonized by
antiparkinsonian agents.
Procedure
Groups of eight mail mice (18–20g) were used. They were dosed orally with the tested compounds
(5mg=kg) or the standard (Benzotropene+ mesilate, 5 mg=kg) [18] 1 h prior the administration of
0.5 mg=kg of Oxotremerine+ S.C. Rectal temperature was measured before administration of the
compounds and one hour after Oxotremerine+ dosage. The scores for the recorded signs are zero
(absent), one (slight), two (medium), and three (high) (Table 3).
References
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[2] Attia A, Abdel-Salam OI, Amr EA (197) Egypt J Chem 40(4): 317
[3] Attia A, Abdel-Salam OI, Amr AE, Stibor I, Budesinsky M (2000) Egypt J Chem 43(2): 187
[4] Attia A, Abdel-Salam OI, Abou-Galia MH, Amr AE (1995) Egypt J Chem 38(5): 543
[5] Amr AE, Abdel-Salam OI, Attia A, Stibor I (1999) Collect Czech Commun 64: 288
[6] Attia A, Abdel-Salam OI, Amr AE (2000) Egypt J Chem 43(4): 297
[7] Brana MF, Castellano JM, Moran M, Perez de Vega MJ, Qian XD, Romerdahl CA, Keihauer G
(1995) Eur J Med Chem 30: 235
[8] Chakrabarti JK, Horsman L, Hotten TM, Pullar IA, Tupper DE, Wright FC (1980) J Med Chem
23: 878
[9] Ram VJ, Pandey HK, Vlietinck AJ (1981) J Heterocycl Chem 18: 1277
[10] Fahmy HH, El-Eraqy W (2001) Arch Pharm Res 24(3): 171
[11] DeClercq E (1986) Anticancer Res 6: 549
[12] DeClercq E (1986) J Med Chem 29: 156
[13] Hammam AG, Sharaf M, Abdel-Hafez NA (2001) Ind J Chem 40B: 213
[14] Hammam AG, Fahmy AFM, Amr AE, Mohamed AM (2002) Ind J Chem Sec B (accepted
Oct 2002)
[15] El-Gazzar ABA, Hegab MI, Swelam SA, Aly AS (2002) Phosphorus, sulfur and silicon 177: 123
[16] Litchfield J, Wilcoxon F (1949) J Pharmacol Exp Ther 96: 99
[17] Dunm R, Fielding S (1987) Drug Rev Res 10: 117
[18] Tyahr MD (1976) The basal ganginia, Raven Press New York, p 293
[19] Vieweg H, Leistner S, Wagner G (1988) Pharmazie 43: 358