Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents

Article abstract of DOI:10.1002/ardp.200500982

A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti-convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyridino-imide derivative 3 was prepared by condensation of 1 wit

Full text of DOI:10.1002/ardp.200500982

Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
DOI 10.1002/ardp.200500982
433
Synthesis and Reactions of Some New Substituted
Pyridine and Pyrimidine Derivatives as Analgesic,
Anticonvulsant and Antiparkinsonian Agents
Abd El-Galil E. Amra, Hayam, H. Sayeda, Mohamed M. Abdullab
a National Research Center, Cairo, Egypt
b Research Unit, Egyptian Pharmacist Company, Cairo, Egypt
A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti-
convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyr-
idino-imide derivative 3 was prepared by condensation of 1 with tetrachlorophthalic anhydride and
compounds 4 and 5 were also obtained by reaction of compound 1 with 1,2,4,5-benzene-tetra-
carboxylic dianhydride and 1,4,5,8-naphthalenetetracarboxylic dianhydride, respectively. Similarly,
compound 2 was reacted with previous anhydrides to afford the corresponding imide 6 and bis-imide
derivatives 7 and 8, respectively. Bis-arylmethylene derivatives 9 were treated with hydrogen peroxide
to afford the corresponding bis-oxiranocycloalkanone derivatives 10, which condensed with thiourea
to give the corresponding thioxopyrimidine derivatives 11. Treatment of compound 11 with chlo-
roacetic acid in the presence of anhydrous sodium acetate afforded the corresponding thiazolopyrim-
idine derivative 12 which condensed with aromatic aldehydes in acetic acid/acetic anhydride to give
arylmethylene derivative 13. Also, compounds 13 could be prepared by reaction of compounds 11
with chloroacetic acid, aromatic aldehydes, and sodium acetate in a mixture of acetic acid and acetic
anhydride. The pharmacological screening showed that many of these obtained compounds have good
analgesic, anticonvulsant, and antiparkinsonian activities comparable to Valdecoxib, Carbamazepine,
and Benzatropine as reference drugs.
Keywords: Pyridine derivatives; Thiazolopyrimidine; Analgesic; Anticonvulsant; Antiparkinsonian
Received: February 14, 2005; Accepted: July 5, 2005
Introduction
Results and discussion
Chemistry
In previous work we have found that certain substituted
pyridine derivatives show antimicrobial, anti-inflammatory
[1Ϫ6], and antitumor activities [7Ϫ9]. In addition, the bio-
logical and analgesic activities of many heterocyclic com-
pounds containing a sulfur atom have been reviewed
[10Ϫ12]. On the other hand, thioxopyrimidine and thiazolo-
pyrimidine derivatives have promising biological activities,
e.g. anticancer properties [13Ϫ16]. Recently, some new
thienopyrimidinone derivatives have been synthesized and
tested for their analgesic, anticonvulsant, and antiparkin-
sonian activities [17]. In view of these observations and in
continuation of our previous work in pyridine and pyrim-
idine chemistry, we synthesized some new heterocyclic com-
pounds containing the pyridine or pyrimidine moiety and
tested their biological activities.
6-Amino-6Ј-chloro-2Ј-ethoxy-4-thien-2-yl-[2,4Ј]bipyridinyl-
5-carbonitrile (1) [6] and ethyl-2-amino-5,6,7,8-tetrahydro-
4H-cyclohepta[b]thiophene-3-carboxylate (2) were prepared
according to the published methods [18]. Condensation of
compound 1 with acid anhydrides, namely, 3,4,5,6-tetra-
chlorophthalic anhydride, 1,2,4,5-benzenetetracarboxylic
dianhydride, and 1,4,5,8-naphthalene tetracarboxylic dian-
hydride in refluxing acetic acid afforded the corresponding
6Ј-chloro-2Ј-ethoxy-6-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-
dihydroisoindol-2-yl)-4-thien-2-yl-[2,4Ј]bipyridinyl-5-carbo-
nitrile (3), 2,6-bis-[substituted-bipyridinyl]pyrrolo[3,4-f]iso-
indole-1,3,5,7-tetraone derivative (4), and 2,7-bis-[substi-
tuted-bipyridinyl]benzo[l,m,n][3,8]phenanthroline-1,3,6,8-
tetraone derivative (5), respectively (Scheme 1). The IR
spectra of compounds 3Ϫ5 showed the absence of ν (NH2)
at 3450Ϫ3310 cmϪ1 for compound 1, the presence of bands
at 1690Ϫ1685 cmϪ1 corresponding to n (CϭO, imide), and
bands at 2220Ϫ2210 cmϪ1 corresponding to ν (CϵN).
Correspondence: Abd El-Galil E. Amr, Applied Organic Chemistry
Department, National Research Center, Dokki, Cairo, Egypt.
Phone: ϩ20 2 337-1362, -1423, Fax: ϩ20 2 337-0931, e-mail:
aamr1963@yahoo.com
Similarly, condensation of ethyl-2-amino-5,6,7,8-tetrahydro-
4H-cyclohepta[b]thiophene-3-carboxylate (2) with the pre-
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434
Amr et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Scheme 1. Synthesis routes to compounds 3Ϫ5.
vious acid anhydride in refluxing acetic acid yielded the
corresponding 2-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thio-
phene-3-carboxylic acid ethyl ester (6), 2,6-bis-[substituted
cyclohepta[b]thien]pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone
derivative (7) and 2,7-bis-[substituted cyclohepta[b]thien]-
benzol-[l,m,n][3,8]phenanthroline-1,3,6,8-tetraone deriva-
tive (8), respectively (Scheme 2). The IR spectra of com-
pounds 6Ϫ8 showed the absence of n (NH2) at 3360Ϫ3300
cmϪ1 for compound 2 and the presence of bands at
1680Ϫ1675 cmϪ1 and 1725Ϫ1715 cmϪ1 corresponding to ν
(CϭO, imide) and n (CϭO, ester), respectively.
pounds 11aϪf showed bands at 3100Ϫ3250 cmϪ1 and at
3350Ϫ3400 cmϪ1 corresponding to ν (NH) and n (OH),
respectively, while bands corresponding to ν (CϭO) and ν
(NH2, thiourea) are not observed.
The thioxopyrimidine derivatives (11aϪf) synthesized by
the above procedure, were condensed with chloroacetic acid
in a mixture of acetic acid/acetic anhydride in the presence
of anhydrous sodium acetate to yield the corresponding
thiazolopyrimidine derivatives (12aϪf) (Scheme 3). The
IR spectra of compounds 12a؊f showed bands at
3310Ϫ3390 cmϪ1 and at 1683 cmϪ1 corresponding to ν
(OH) and
ν (CϭO), respectively, while, the bands
Bis-arylmethylene cycloalkanone derivatives (9a-f) [19] re-
quired for the synthesis of the corresponding bis-(aryl)-1,6-
dioxa-dispirodecane-4-one derivatives (10aϪf) were ob-
tained by treatment with hydrogen peroxide (30%) in the
presence of sodium hydroxide (Scheme 3). The IR (KBr)
of compounds 10aϪf showed bands at 1713Ϫ1729 cmϪ1
corresponding to ν (NH) and ν (CϭS) presented in the IR
spectra of 11 are not observed.
Condensation of 12aϪf with p-nitrobenzaldehyde in re-
fluxing acetic acid/acetic anhydride mixture afforded the
corresponding arylmethylene derivatives 13aϪf. However,
the arylmethylene derivatives 13a-f could also be prepared
directly from 11aϪf by reaction with chloroacetic acid, so-
dium acetate, and p-nitrobenzaldehyde in an acetic acid/
acetic anhydride mixture [15,21] (Scheme 3). The IR spectra
of compounds 13aϪf showed bands at 1700Ϫ1705 cmϪ1
and at 3300Ϫ3450 cmϪ1 corresponding to ν (CϭO) and ν
(OH), respectively, while bands corresponding to ν (NH)
are not observed.
corresponding to
ν (CϭO) and also, the bands at
1700Ϫ1703 cmϪ1 (CϭO in the α,β-unsaturated system) in
compounds 9aϪf are not observed.
Thioxopyrimidine derivatives (11aϪf) were obtained from
the reaction of the oxirane derivatives (10aϪf) with thiourea
in ethanolic potassium hydroxide according to a published
procedure [20, 21] (Scheme 3). The IR spectra of com-
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Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Substituted Pyridine and Pyrimidine Derivatives
435
Scheme 2. Synthesis routes to compounds 6Ϫ8.
Pharmacological Screening
The tested three pharmacological properties namely, anal-
gesic, anticonvulsant, and antiparkinsonian all have despite
of their different biological receptors a neurological basis.
Ten representative compounds (3, 4, 7, 10a, 10d, 11c, 11e,
12b, 12f, and 13a) were studied with respect on these proper-
ties.
Analgesic activity
All compounds tested exhibited analgesic activities in a hot
plate assay (Table 1). The most potent are compounds 12f
and 13a showing higher activities than that of Valdecoxib
by nearly 140Ϫ160% (compound 12f showed the most pro-
nounced effect). Also, the analgesic activities of 3, 4, 7, 10a,
10d, 11c, 11e, and 12b approached those of Valdecoxib, and
showed 61Ϫ83% activity as compared to Valdecoxib
(ϭ 100%) (Table 1).
Anticonvulsant activity
Antagonism against yohimbine-induced clonic seizures in
mice is considered to be a predictive model of potential anti-
convulsant and GABA-mimetic [22]. Compounds 7, 10a,
and 10e are devoid of anticonvulsant activity in the yohim-
bine-induced clonic seizures assay, in which they provide no
protection against yohimbine-induced clonic seizures. Com-
pounds 3, 11b showed interesting anticonvulsant activities.
Scheme 3. Synthesis routes to compounds 10Ϫ13.
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Amr et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Table 1. Analgesic activities of selected compounds in a hot plate assay.
Compound
Analgesic activity related to Valdecoxib after
10 min.
SE
20 min
SE
30 min
SE
45 min
SE
60 min
SE
90 min
SE
120 min
SE
Valdecoxib
1.0
0.01
1.0
0.01
1.0
0.01
1.0
0.01
1.0
0.01
1.0
0.01
1.0
0.01
3
0.88 0.011
0.66 0.012
0.77 0.012
0.61 0.013
0.82 0.014
0.61 0.013
0.91 0.011
0.63 0.010
1.29 0.18
0.97 0.013
0.89 0.011
0.63 0.012
0.85 0.014
0.73 0.012
0.91 0.015
0.65 0.011
0.92 0.009
0.64 0.017
1.45 0.16
0.98 0.015
0.89 0.011
0.88 0.012
0.84 0.012
0.79 0.001
0.93 0.017
0.74 0.012
0.93 0.016
0.73 0.013
1.45 0.13
1.40 0.14
0.91 .017
0.88 0.016
0.87 0.015
0.81 0.015
0.95 0.021
0.75 0.018
0.88 0.019
0.73 0.018
1.44 0.20
1.55 0.21
0.92 0.016
0.88 0.021
0.88 0.018
0.84 0.016
0.95 0.032
0.77 0.011
0.83 0.021
0.74 0.019
1.41 0.32
1.56 0.35
0.93 0.015
0.89 0.017
0.84 0.012
0.84 0.016
0.94 0.018
0.77 0.011
0.79 0.016
0.75 0.016
1.41 0.29
1.61 0.34
0.91 0.017
0.89 0.018
0.83 0.019
0.84 0.035
0.94 0.026
0.77 0.013
0.65 0.012
0.78 0.013
1.39 0.28
1.42 0.45
4
7
10a
10d
11c
11e
12b
12f
13a
Compounds 11a, 11d, 12b, and 12f showed nearly no anti-
parkinsonian activities. While compounds 8, 10c, and 10d
showed moderate antiparkinsonian activities (relative po-
tencies to Benzatropine (ϭ 1.0) are 0.64, 0.60 and 0.40).
Compounds 10b, 13a, and 13d are the most potent antipar-
kinsonian agents (0.80 relative potencies) (Table 3).
Table 2. Anticonvulsant activities of selected compounds (as
ED50 values) needed to antagonize yohimbine-induced clonic
seizure and compared to the anticonvulsant activity of
Carbamazepine.
Compound
ED50
[mg/kg]/ SE
Relative potency compared
to Carbamazepine
SE
Experimental
Control
Carbamazepine
0
0
Chemistry
29 0.31
1.0
0.01
3
53 0.41
30 0.32
No protection
No protection
No protection
34 0.34
0.67
0.008
Melting points were determined on open glass capillaries using an
Electrothermal IA 9000 SERIES digital melting point apparatus
(Electrothermal, Essex, U.K.) and are uncorrected. Elemental
analyses were performed with all final compounds on Elementar,
Vario EL, Microanalytical Unit, National Research Centre, Cairo
Egypt and were found within 4% of the theoretical values. Infra-
red (IR) spectra were recorded on a Pye Unicam SP-1000 spectro-
photometer (Pye Unicam. Ltd., Papakura, New Zealand) using the
KBr disc technique. 1H-NMR spectra were recorded on Varian EM-
360-270 MHz spectrometer (DMSO-d6 or CDCl3) (Varian, Palo
Alto, CA, USA) and the chemical shifts are given in δ (ppm) down-
field from tetramethylsilane (TMS) as an internal standard. Split-
ting patterns were designated as follows: s singlet; d doublet; t trip-
let; m multiplet. The mass spectra (MS) were measured using VG
2AM-3F mass spectrometer (Thermo electron corporation, Madi-
son, WI, USA). Follow up of the reactions and checking the purity
of the compounds were made by TLC on silica gel-precoated alumi-
num sheets (Type 60 F254, Merck, Darmstadt, Germany) and the
spots were detected by exposure to UV lamp at λ 254 nm for few
seconds.
5
0.954 0.0091
No protection
No protection
No protection
0.74
2.31
2.53
2.01
1.83
7
10a
10e
11b
11f
12d
13a
13c
0.0068
0.019
0.021
0.023
0.0178
12 0.11
11 0.112
14 0.117
16 0.123
Their relative potencies to Carbamazepine (1.0) are 0.67
and 0.74, respectively. Compounds 11f, 12d, 13a, and 13c
are more potent than Carbamazepine where their relative
potencies are 2.31, 2.53, 2.01, and 1.83, respectively (Table
2). ED50 was estimated via determining the dose, which pro-
tected 5% of the tested animals against the convulsant in-
duced by yohimbine.
Synthesis of 6-Amino-6Ј-chloro-2Ј-ethoxy-4-thien-2-yl-[2,4Ј]bipyridi-
nyl-5-carbonitrile (1)
Antiparkinsonian activity
The muscarinic agonists Tremorine and Oxotremorine in-
duce parkinsonian signs such as tremor, ataxia, spasticity,
salivation, lacrimation, and hypothermia. Antiparkinsonian
agents antagonize these signs. The antiparkinsonian activity
measured by the ability of compounds to protect animals
against the parkinsonian like signs induced by agonists.
A mixture of 2-chloro-6-ethoxy-4-acetylpyridine (0.2g, 1 mmol),
2-thiophencarbaldehyde (0.1g, 1 mmol), malononitrile (0.066g,
1 mmol) and ammonium acetate (0.6 g, 8 mmol) in absolute ethanol
(25 mL) was heated under reflux for 3 h. The reaction mixture was
cooled, the formed solid was then filtered off, washed with and
crystallized from ethanol to give compound 1: mp. 184Ϫ186°C (Lit.
mp. 186Ϫ188°C [6]).
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Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Substituted Pyridine and Pyrimidine Derivatives
437
Table 3. Antiparkinsonian activities of selected compounds compared to that of Benzatropine.
Compound
Salivation and
lacrimation
score
Tremors
score
Decrease of
Oxotremerine
rectal temperature [%]
SE
Relative potency
compared to
Benzatropine mesilate
SE
Control
0
0
0
0
Benzatropine
1
1
1
2
2
3
3
3
3
1
1
1
1
1
2
2
3
3
3
3
1
1
25 0.41
16 0.31
20 0.38
15 0.28
10 0.11
4.0 0.01
3.0 0.012
4.0 0.013
3.0 0.016
20.0 0.51
20.0 481
1.00 0.09
0.64 0.07
0.80 0.075
0.60 0.059
0.40 0.031
0.16 0.014
0.12 0.013
0.16 0.012
0.12 0.011
0.80 0.06
0.80 0.071
8
10b
10c
10d
11a
11d
12b
12f
13a
13d
Table 4. Physico-chemical data of newly synthesized compounds.
Comp.
Ar
n
Yield
[%]
Mp.
[°C]
Color and
Mol. Formula*
(Mol. wt)
solvent for
crystallization
3
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
1
60
72
75
80
82
65
80
75
80
65
70
75
60
65
70
60
63
68
240Ϫ2
225Ϫ7
232Ϫ4
189Ϫ91
196Ϫ8
210Ϫ2
148Ϫ49
178Ϫ9
155Ϫ6
135Ϫ6
185Ϫ6
142Ϫ3
173Ϫ4
200Ϫ2
192Ϫ3
188Ϫ9
236Ϫ7
207Ϫ8
white
DMF/H2O (2:1)
White
AcOH/H2O (2:1)
Yellow
DMF/H2O (2:1)
White
EtOH
White
AcOH
White
AcOH
Yellow
EtOH
Orange
EtOH
Pale yellow
MeOH
brown
MeOH/H2O (2:1)
Orange
MeOH
Yellow
EtOH
White
MEOH
White
Dioxane
Yellow
MeOH
White
Dioxane
Brown
Dioxane
Orange
C25H11Cl5N4O3S
(624.71)
C44H24Cl2N8O6S2
(895.75)
C48H26Cl2N8O6S2
(945.80)
C20H15Cl4NO4S
(507.20)
C34H32N2O8S2
(660.70)
C38H34N2O8S2
(710.80)
C20H18O3
(306.30)
C22H22O5
(366.04)
C20H16Cl2O3
(375.20)
C21H20O3
(320.40)
C23H24O5
(380.40)
C21H18Cl2O3
(389.30)
C21H22N2OS
(366.50)
C23H26N2O4S
(426.50)
C21H20Cl2N2O2S
(435.40)
C22H24N2O2S
(380.50)
C24H28N2O4S
(440.50)
C22H22Cl2N2O2S
(449.40)
4
Ϫ
5
Ϫ
6
Ϫ
7
Ϫ
8
Ϫ
10a
10b
10c
10d
10e
10f
11a
11b
11c
11d
11e
11f
C6H5
C6H4-p-CH3
C6H4-p-Cl
C6H5
1
1
2
C6H4-p-OCH3
C6H4-p-Cl
C6H5
2
2
1
C6H4-p-OCH3
C6H4-p-Cl
C6H5
1
1
2
C6H4-p-OCH3
C6H4-p-Cl
2
2
Dioxane
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Amr et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Table 4. (continued).
Comp.
Ar
n
Yield
[%]
Mp.
[°C]
Color and
solvent for
crystallization
Mol. Formula*
(Mol. wt)
12a
12b
12c
12d
12e
12f
13a
13b
13c
13d
13e
13f
C6H5
1
1
1
2
2
2
1
1
1
2
2
2
55
58
62
50
54
60
62
65
70
57
63
70
148Ϫ50
172Ϫ3
164Ϫ5
157Ϫ8
189Ϫ90
178Ϫ9
196Ϫ8
227Ϫ8
209Ϫ10
231Ϫ2
268Ϫ9
253Ϫ4
Yellow
MeOH
Red
MeOH
Pale yellow
EtOH
C23H22N2O3S
(406.50)
C25H26N2O5S
(466.50)
C23H20Cl2N2O3S
(475.40)
C24H24N2O3S
(420.50)
C26H28N2O5S
(480.60)
C24H22Cl2N2O3S
(489.40)
C30H25N3O5S
(539.60)
C32H29N3O7S
(599.60)
C30H23Cl2N3O5S
(608.50)
C31H27N3O5S
(553.60)
C33H31N3O7S
(613.70)
C31H25Cl2N3O5S
(622.50)
C6H4-p-OCH3
C6H4-p-Cl
C6H5
White
MeOH
Orange
MeOH
Brown
Dioxane
White
Benzene
Yellow
MeOH
Orange
EtOH
Yellow
Dioxane
White
Dioxane
Yellow
Dioxane
C6H4-p-OCH3
C6H4-p-Cl
C6H5
C6H4-p-OCH3
C6H4-p-Cl
C6H5
C6H4-p-OCH3
C6H4-p-Cl
* Confirmed by elemental analysis showing values within 0.4% of the theoretical values unless otherwise stated.
Synthesis of Ethyl 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thio-
2-(4,5,6,7-Tetrachloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5,6,7,8-
phene-3-carboxylate (2)
tetrahydro-4H-cyclohepta[b]-thiophene-3-carboxylic acid ethyl ester
(6)
A mixture of cycloheptanone (1.12 g, 10 mmol), ethyl cyanoacetate
(1.13 g, 10 mmol) and sulfur (0.48 g, 15 mmol) in 50 mL of absolute
ethanol was stirred and a few drops of pyridine were added. The
reaction mixture was stirred at room temperature for 12 hr. The
excess ethanol was evaporated under reduced pressure, the residue
was triturated with diethyl ether and n-hexane (1:1, ratio) to give
compound 2: 1.2 g, 50% yield, mp. 117Ϫ118°C (Lit. mp.
118Ϫ119°C [18]).
IR (KBr, cmϪ1): 1725 (CϭO, ester), 1680 (CϭO, imide). 1H-NMR
(CDCl3) δ: 1.25Ϫ2.00 (m, 10H, 5 ϫ CH2, cycloheptyl-H), 2.10 (t,
3H, CH3), 4.10 (q, 2H, 2 ϫ CH2). MS m/z (%): 507 (Mϩ, 100, base
peak) corresponding to the molecular formula C20H15Cl4NO4S.
Synthesis of Bis-[substituted bipyridinyl or cyclohepta[b]thien]pyr-
roloisoindolyl derivatives 4 and 7
Synthesis of tetrachlorodioxo-isoindolyl derivatives 3 and 6
A mixture of compound 1 or 2 (2 mmol) and benzene tetracar-
boxylic dianhydride (0.218 g, 1 mmol) in glacial acetic acid (50 mL)
was heated under reflux for 6 h. The residue formed was filtered off
and crystallized from AcOH/H2O (2:1) and AcOH, respectively, to
yield the corresponding compounds 4 and 7 (Table 4).
A mixture of compound 1 or 2, respectively (1 mmol) and 1,2,3,4-
tetrachlorophthalic anhydride (0.285 g, 1 mmol) in glacial acetic
acid (50 mL) was refluxed for 6 h. The solvent was evaporated under
reduced pressure and the obtained residue solidified with dry ether,
the crude product was collected by filtration and purified by recrys-
tallization from DMF/H2O and EtOH, respectively, to yield the cor-
responding compounds 3 and 6, respectively (Table 4).
2,6-Bis-[2Ј-chloro-6Ј-ethoxy-4-thien-2-yl-[2,4Ј]bipyridinyl-5-carbo-
nitril-6-yl]pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone (4)
6Ј-Chloro-2Ј-ethoxy-6-(4,5,6,7-tetrachloro-1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-4-thien-2-yl-[2,4Ј]bipyridinyl-5-carbonitrile (3)
IR (KBr, cmϪ1): 2210 (CϵN), 1688, 1665 (two CϭO), 1632
(CϭN). 1H-NMR (DMSO-d6) δ: 1.90 (t, 6H, 2 ϫ CH3), 3.75 (q,
4H, 2 ϫ CH2), 7.25Ϫ7.75 (m, 6H, 2 ϫ thiophene-H), 7.80 (s, 2H,
Ar-H), 8.25Ϫ8.35 (m, 6H, pyridyl-H). MS m/z (%): 895 (Mϩ, 8.5)
corresponding to the molecular formula C44H24Cl2N8O6S2 and at
296 (100, as base peak).
IR (KBr, cmϪ1): 2220 (CϵN), 1690 (CϭO, imide), 1640 (CϭN).
1H-NMR (DMSO-d6) δ: 1.85 (t, 3H, CH3), 3.80 (q, 2H, CH2),
6.90Ϫ7.50 (m, 3H, thiophene-H), 8.25Ϫ8.40 (m, 3H, pyridyl-H).
MS m/z (%): 625 (Mϩ, 18) corresponding to the molecular formula
C25H11Cl5N4O3S and at 296 (100, base peak).
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Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Substituted Pyridine and Pyrimidine Derivatives
439
2,6-Bis-[3Ј-ethyl-5Ј,6Ј,7Ј,8Ј-tetrahydro-4ЈH-cyclohepta[b]thien-car-
boxylate-2Ј-yl]pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone (7)
refluxed for 3 h. The solvent was evaporated under reduced pres-
sure, the residue was dissolved in water and neutralized with 1N
hydrochloric acid. The solid formed was collected by filtration and
crystallized from the proper solvent to give the corresponding thiox-
opyrimidines 11aϪf, respectively (Table 4).
IR (KBr, cmϪ1): 1723 (CϭO, ester), 1677 (CϭO, imide). 1H-NMR
(DMSO-d6) δ: 1.30-1.95 (m, 20H, 10 ϫ CH2, cycloheptyl ring), 2.05
(t, 6H, 2 ϫ CH3), 4.25 (q, 4H, 2 ϫ CH2), 7.90 (s, 2H, Ar-H). MS
m/z (%): 660 (Mϩ, 35) corresponding to the molecular formula
C34H32N2O8S2 and at 514 (100, base peak).
4a-Hydroxy-8-[hydroxyl-(4-methoxyphenyl)methyl]-4-(4-methoxy-
phenyl)-3,4,4a,5,6,7-hexahydro-1H-quinazolin-2-thione (11b)
Synthesis of 2,7-Bis-[substituted bipyridinyl or cyclohepta[b]thien]-
benzo[l,m,n][3,8]phen-anthroline Derivatives 5 and 8
IR (KBr, cmϪ1): 3400Ϫ3100 (OH, NH), 1195 (CϭS). 1H-NMR
(DMSO-d6) δ: 0.95Ϫ2.15 (m, 6H, 3 ϫ CH2), 3.70 (s, 1H, CH-Ar),
3.85 (s, 6H, 2 ϫ OCH3), 4.46 (bs, 1H, OH, which is exchangeable
with D2O), 5.40 (s, 1H, CH-pyrimidine), 7.10Ϫ7.65 (m, 8H, Ar-H),
7.85 (bs, 1H, NH which is exchangeable with D2O), 10.10 (bs, 1H,
OH, which is exchangeable with D2O), 10.20 (br, 1H, NH). MS
(m/z,%): 426 (Mϩ, 28) corresponding to the molecular formula
A mixture of compound 1 or 2 (2 mmol) and naphthalene tetracar-
boxylic dianhydride (0.268 g, 1 mmol) in glacial acetic acid (50 mL)
was heated under reflux for 6 h. The obtained solid was filtered off,
washed with acetic acid, and crystallized from DMF/H2O (2:1) and
AcOH, respectively, to afford the corresponding derivatives 5 and 8
(Table 4).
C
23H26N2O4S and at 319 (100, base peak).
2,7-Bis-[2ЈЈ-chloro-6ЈЈ-ethoxy-4Ј-thien-2Ј-yl-[2Ј,4ЈЈ]bipyridinyl-5Ј-
carbonitril-6Ј-yl]benzo[l,m,n]phenanthroline-1,3,6,8-tetraone (5)
4a-Hydroxy-9-[hydroxyl-(4-methoxyphenyl)methyl]-4-(4-methoxy-
phenyl)-1,3,4,4a,5,6,7,8-octa-hydrocycloheptapyrimidine-2-thione
(11e)
IR (KBr, cmϪ1): 2215 (CϵN), 1685 (two CϭO), 1636 (CϭN). MS
m/z (%): 945 (Mϩ 15) corresponding to the molecular formula
IR (KBr, cmϪ1): 3380Ϫ3200 (OH, NH), 1198 (CϭS). 1H-NMR
(CDCl3) δ: 1.20-2.10 (m, 8H, 4 ϫ CH2), 3.50 (s, 1H, CH-Ar), 3.90
(s, 6H, 2 ϫ OCH3), 4.30 (bs, 1H, OH, which is exchangeable with
D2O), 5.20 (s, 1H, CH-pyrimidine), 6.80Ϫ7.30 (m, 8H, Ar-H), 7.80
(bs, 1H, NH which is exchangeable with D2O), 9.80 (bs, 1H, OH,
which exchangeable with D2O), 10.50 (br, 1H, NH). MS m/z (%):
440 (Mϩ, 18) corresponding to the molecular formula C24H28N2O4S
and at 318 (100, base peak).
,
C48H26Cl2N8O6S2 and at 296 (100, base peak).
2,7-Bis-[3Ј-ethyl-5Ј,6Ј,7Ј,8Ј-tetrahydro-4ЈH-cyclohepta[b]thien-car-
boxylat-2Ј-yl]benzo[l,m,n][3,8]phenanthroline-1,3,6,8-tetraone (8)
IR (KBr, cmϪ1): 1715 (CϭO, ester), 1675 (CϭO, imide). 1H-NMR
(DMSO-d6) δ: 1.25Ϫ1.85 (m, 20H, 10 ϫ CH2, cycloheptyl ring),
2.15 (t, 6H, 2 ϫ CH3), 4.05 (q, 4H, 2 ϫ CH2), 7.85 (d, 4H, Ar-H).
MS m/z (%): 710 (Mϩ, 100) corresponding to the molecular formula
C38H34N2O8S2 and also as base peak.
Synthesis of Thiazolopyrimidine Derivatives 12aϪf
A mixture of compounds 11aϪf (10 mmol), chlororacetic acid
(0.95 g, 10 mmol) and anhydrous sodium acetate (1.72 g, 20 mmol)
in glacial acetic acid (30 mL) and acetic anhydride (10 mL) was
refluxed for 3 h. The reaction mixture was poured into water, the
formed solid was filtered off and crystallized from the proper sol-
vent to give the corresponding thiazolopyrimidine derivatives
12aϪf, respectively (Table 4).
Synthesis of 2,7-Bis-(aryl)-1,6-dioxa-dispirodecane-4-one Deriva-
tives 10aϪf
To a mixture of bis-arylmethylene derivatives (9aϪf) [19] (100
mmol) in acetone/dioxane (50 mL, 3:2 ratio) and sodium hydroxide
(2 g) in few drops of water, hydrogen peroxide (6 mL, 30%) was
added dropwise with stirring for 15 min. The reaction mixture was
stirred for further 8 h at room temperature, then left overnight at
Ϫ5°C. The solid formed was collected by filtration and crystallized
from proper solvent to give the corresponding bis-spiro compounds
10aϪf, respectively (Table 4).
5a-Hydroxy-9-[hydroxyl-4-(4-methoxyphenyl)methyl]-5-(4-meth-
oxyphenyl)-5a,6,7,8-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one
(12b)
IR (KBr, cmϪ1): 3390Ϫ3310 (OH), 1683 (CϭO). MS m/z (%): 466
2,6-Bis-(4-methoxyphenyl)-1,6-dioxadispiro[2.1.2.3]decan-4-one
(10b)
(Mϩ 100, base peak) corresponding to the molecular formula
,
C25H26N2O5S.
IR (KBr, cmϪ1): 1729 (CϭO). 1H-NMR (DMSO-d6) δ: 1.15Ϫ2.10
(m, 6H, 3 ϫ CH2), 3.65 (s, 2H, 2 ϫ CH-Ar), 3.95 (s, 6H, 2 ϫ
OCH3), 7.35Ϫ7.75 (m, 8H, 2 ϫ Ar-H). MS m/z (%): 366 (Mϩ, 100),
as base peak and corresponds to the molecular formula C22H22O5.
4a-Hydroxy-9-[hydroxyl-4-(4-methoxyphenyl)methyl]-5-(4-meth-
oxyphenyl)-4,4a,5,6,7,8-hexa-hydro-1-thia-3a,10-diaza-cyclohepta-
[f]inden-3-one (12e)
IR (KBr, cmϪ1): 3375Ϫ3290 (OH), 1680 (CϭO). MS m/z (%): 480
2,7-Bis-(4-methoxyphenyl)-1,6-dioxadispiro[2.1.2.4]undecan-4-one
(10e)
(Mϩ 100, base peak) corresponding to the molecular formula
,
C
26H28N2O5S.
IR (KBr, cmϪ1): 1713 (CϭO). 1H-NMR (DMSO-d6) δ: 1.10Ϫ2.20
(m, 8H, 4 ϫ CH2), 3.60 (s, 2H, 2 ϫ CH-Ar), 3.90 (s, 6H, 2 ϫ
OCH3), 7.20Ϫ7.80 (m, 8H, 2 ϫ Ar-H). MS m/z (%): 380 (Mϩ, 16)
corresponding to the molecular formula C23H24O5 and at 348 (100,
base peak).
Synthesis of thiazoloarylarylmethylene derivatives 13aϪf
Method A: To a mixture of compounds 11a-f (10 mmol), chlo-
roacetic acid (0.95 g, 10 mmol) and anhydrous sodium acetate (1.72
g, 20 mmol) in glacial acetic acid (30 mL)/acetic anhydride (10 mL)
and p-nitrobenzaldehyde (1.51 g, 10 mmol) was added. The reaction
mixture was heated under reflux for 3 h, then cooled and poured
into water. The solid formed was collected by filtration and crys-
Synthesis of Thioxopyrimidine Derivatives 11aϪf
A mixture of compounds 10aϪf (10 mmol), thiourea (1.34 g,
20 mmol) and potassium hydroxide (1 g) in ethanol (50 mL) was
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440
Amr et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 433−440
Antiparkinsonian activity
tallized from the proper solvent to yield the corresponding thi-
azoloarylmethylene derivatives 13aϪf, respectively (Table 4).
Groups of eight male mice (18Ϫ20 g) were used. They were dosed
orally with the tested compounds (5 mg/kg) or the standard (Benz-
atropine, 5 mg/kg) [26] one hour prior to the administration of
0.5 mg/kg of Oxotremorine s.c. Rectal temperature was measured
before administration of the compounds and one hour after Oxo-
tremorine application. The score for the recorded signs are zero
(absent), one (slight), two (mediums), and three (highs) (Table 3).
Method B: A mixture of compounds 12aϪf (10 mmol) and p-nitro-
benzaldehyde (1.51 g, 10 mmol) in glacial acetic acid/acetic anhy-
dride (40 mL, 3:1) was refluxed for 3 h, allowed to cool down, and
then poured into water. The solid formed was collected by filtration
and crystallized from the proper solvent to give compounds 13aϪf,
respectively. The crystallized products were identified by mp., mixed
mp. and TLC in comparison with authentic samples from Method
A. It should be notified that Method A generally resulted in higher
yields than Method B.
References
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5a-Hydroxy-9-[hydroxyl-4-(4-methoxyphenyl)-2-(4-nitrobenzyl-
idene)-5a,6,7,8-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3-one (13b)
[2] A. E. Amr, A. M. Mohamed, A. A. Ibrahim, Z. Naturforsch.
2003, 58b, 861Ϫ868.
[3] M. H. Abo-Ghalia, A. E. Amr, M. M. Abdulla, Z. Naturforsch.
2003, 58b, 903Ϫ910.
IR (KBr, cmϪ1): 3450Ϫ3360 (OH), 1700 (CϭO). 1H-NMR (CDCl3)
δ: 1.30Ϫ1.80 (m, 6H, 3 ϫ CH2), 3.50 (s, 1H, CH-Ar), 3.80 (s, 6H,
2 ϫ OCH3), 4.60 (bs, 1H, OH, which is exchangeable with D2O),
5.50 (s, 1H, CH-pyrimidine), 6.80Ϫ7.90 (m, 12H, Ar-H), 8.10 (s,
1H, benzylic proton), 9.30 (s, 1H, OH, which is exchangeable with
D2O). MS m/z (%): 599 (Mϩ, 13) corresponding to molecular for-
mula C32H29N3O7S and at 467 (100, base peak).
[4] H. H. Sayed, Indian J. Chem., Sec B, 1998, 37B, 1054Ϫ1058.
[5] A. Attia, O. I. Abdel-Salam, A. E. Amr, I. Stibor, M. Budesin-
sky, Egypt. J. Chem. 2000, 43(2), 187Ϫ201.
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4a-Hydroxy-9-[hydroxyl-4-(4-methoxyphenyl)methyl]-4-(4-nitro-
benzylidene)-4,4a,5,6,7,8-hexahydro-1-thia-3a,10-diaza-cyclohepta-
[f]indin-3-one (13e)
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IR (KBr, cmϪ1): 3400Ϫ3350 (OH), 1705 (CϭO). 1H-NMR (CDCl3)
δ: 1.25-1.95 (m, 8H, 4 ϫ CH2), 3.60 (s, 1H, CH-Ar), 3.90 (s, 6H,
2 ϫ OCH3), 4.65 (bs, 1H, OH, which is exchangeable with D2O),
5.70 (s, 1H, CH-pyrimidine), 7.10Ϫ7.90 (m, 12H, Ar-H), 8.25 (s,
1H, benzylic proton), 9.45 (s, 1H, OH, which is exchangeable with
[10] A. G. Hammam, A. F. Fahmy, A. E. Amr, A. M. Mohamed,
Indian J. Chem., Sec B,. 2003, 42B, 1985Ϫ1993.
D2O). MS m/z (%): 613 (Mϩ 100) corresponding the molecular
[11] A. G. Hammam, A. S. Mohie, A. A. Naglaa, Indian J. Chem.,
Sec B, 2001, 40B, 213Ϫ221.
,
formula C33H31N3O7S and also as base peak.
[12] A. G. Hammam, S. M. Hussain, I. R. Kotob, Phosphorus Sul-
fur and Silicon, 1990, 47, 47Ϫ51.
Pharmacological screening
[13] A. E. Amr, M. M. Abdulla, Indian J. Heterocycl. Chem. 2002,
12, 129Ϫ134.
Analgesic activity
[14] A. G. Hammam, A. A. Naglaa, M. H. Wanda, M. Marian, Z.
Naturforsch. 2000, 55b, 417Ϫ424.
Sixty Webster mice of both sexes weighting from 20Ϫ25 g were
divided into 10 groups. (All animals were obtained from the Animal
House Colony, Research Institute of Ophthalmology, Giza, Egypt)
One group was kept as control (received saline), the second group
received vehicle (Gum acacia), and the third one received Valde-
coxib as a reference drug, whereas the other groups received tested
compounds (SC administration). Mice were dropped gently in a dry
glass beaker of one-liter capacity maintained at 55Ϫ55.5°C. Nor-
mal reaction time in seconds for all animals was 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 jump out of the beaker (dose 5 mg/kg) [23],
relative potencies to that of Valdecoxib were determined (Table 1).
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352Ϫ353.
[16] S. Wawzonek, J. Org. Chem. 1976, 41, 3149Ϫ3151.
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99Ϫ113.
Anticonvulsant activity
Male Webster mice (20-30 g) were individually placed in clear
plastic cylinder and the tested compounds were administrated intra-
peritoneally (5 mg/kg), 30 min prior to a dose of 45 mg/kg of yohim-
bine-HCl. The animals were observed for onset and number of
clonic seizures [24] (Table 2). Evaluation of ED50 values for com-
pounds with 95% confidence limits were calculated for the antago-
nism of yohimbine-induced clonic seizure according to Austen et
al. [25].
[23] A. Tgolsen, G. H. Rofland, O. G. Berge, K. Hole, J. Pharmacol.
Exp. Ther. 1991, 25, 241Ϫ250.
[24] R. Dunm, S. Fielding, Drug Dev. Res. 1987, 10, 177Ϫ188.
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521Ϫ524.
[26] M. D. Tyahr, The Basal Ganglion, Raven Press, New York,
1976, p. 293.
 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim