Synthesis of new pyrroles of potential anti-inflammatory activity

Article abstract of DOI:10.1002/ardp.201100056

We herein disclose a series of novel pyrrole derivatives 1-4 and pyrrolo[2,3-d]pyrimidine derivatives 6-11 as novel potent anti-inflammatory compounds. The structures were confirmed by IR, ¹H-NMR, and MS. Some newly synthesized compounds were e

Full text of DOI:10.1002/ardp.201100056

830
Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Full Paper
Synthesis of New Pyrroles of Potential Anti-Inflammatory
Activity
Mosaad S. Mohamed1, Rehab Kamel2, and Samar S. Fathallah1
1 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Ein Helwan,
Cairo, Egypt
2 Toxicology and Pharmacology Department, Faculty of Pharmacy, Helwan University, Ein Helwan, Cairo,
Egypt
We herein disclose a series of novel pyrrole derivatives 1–4 and pyrrolo[2,3-d]pyrimidine derivatives
1
6–11 as novel potent anti-inflammatory compounds. The structures were confirmed by IR, H-NMR,
and MS. Some newly synthesized compounds were examined for their in-vivo anti-inflammatory
activity. Several derivatives showed
a promising anti-inflammatory activity compared to
ibuprofen. In this paper, we examine and discuss the structure–activity relationships and anti-
inflammatory activities of these compounds.
Keywords: Anti-inflammatory activity / Pyrrole / Pyrrolo[2,3-d]pyrimidine / Structure–activity-relationship
Received: February 14, 2011; Revised: June 8, 2011; Accepted: June 20, 2011
DOI 10.1002/ardp.201100056
Introduction
Recently, other pyrrole compounds have been reported
[9–12] as potent selective COX-2 inhibitors. PNU-142731A [13]
(Fig. 1) is a potent and efficient pyrrolopyrimidine inhibitor of
eosinophilic lung inflammation that is currently in Phase II
clinical evaluation for the potential treatment of asthma.
Motivated by these aforementioned findings, and in con-
tinuance of our research efforts [14–17], we decided to pre-
pare certain novel pyrrole and pyrrolopyrimidine derivatives
and evaluate them for anti-inflammatory activity.
In the past decade, efforts aimed at the discovery of thera-
peutically useful inhibitors of cyclooxygenase-2 (COX-2) have
intensified. These efforts have resulted [1, 2] in the identifi-
cation of a variety of templates, which depend on the nature
of the attached substituent that provides a selective inhibition.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most
widely prescribed and effective therapy for decreasing pain
and inflammation, whereas, one of its privileged scaffolds is
the pyrrole nucleus, which has served [3] as the core template Results and discussion
for a variety of potential selective COX-2 inhibitors.
The favorable presence of pyrrole derivatives provoked an
interest in the search for new active NSAIDs in generalized
classes: analogs of effective COX-2 inhibitors [4–7]. Pyrrole
compounds are a promising starting point in drug research
in view of their various pharmacological activities [8].
Derivatives of pyrrolylacetic acid proved as NSAIDs are:
tolmetin (CAS 64490-92-2), ketorolac (CAS 74103-06-3), indo-
methacin (CAS 53-86-1), and zomepirac (CAS 64092-48-4)
(Fig. 1).
Chemistry
Compound 1 was prepared as reported in [14–17, 23]. This
compound was utilized for the preparation of pyrrole deriva-
tives 2 and 3 using appropriate reagents and reaction con-
ditions. Diazotization of the 2-amino-pyrrole was reported
[18] many times in the literature. This reaction is considered
as the key route to prepare a series of 2-triazenopyrroles,
deaza analogues of dacarbazine, a famous anti-tumor drug.
Diazotization [19] of 1 using a mixture of sodium nitrite and
HCl (without acetic acid) at 0–58C, without separation, add-
ing an active methylene compounds, namely malononitrile
in ethanol in the presence of sodium acetate afforded the
corresponding hydrazono derivatives 2. This reaction could
be explained via formation of the diazonium chlorides at
Correspondence: Samar S. Fathallah, Faculty of Pharmacy, Helwan
University, Ein-Helwan, Helwan, Egypt.
E-mail: ssfathallah@yahoo.com, samarradwan1@yahoo.com
Fax: þ202-2554-1601
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Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity
831
O
O
-
O
+OOCH2C
Na
COOH
N
COOH
N
N
CH3
H3C
Zomepirac
Tolmetin
Ketorolac
N
N
Cl
CH2COOH
CH3O
N
O
N
N
N
O
N
Cl
PNU-142731A
Indomethacine
Figure 1. Anti-inflammatory drugs (NSAIDs).
first, which in addition to malononitrile afforded 2. Biological results and discussion
Cyclization of hydrazono derivatives 2 using hydrazine
hydrate in boiling ethanol leads to the formation of the
corresponding pyrazolin-5-one derivatives 3.
Synthesized compounds were assessed for their anti-inflam-
matory activity. Compounds 2c, 3a, 4a, 6a, 6b, 7a, and 9c
induced significant anti-inflammatory activity, comparable
with that of ibuprofen (Fig. 2).
On the other hand, diazotization [20] of 1 using sodium
nitrite in a mixture of acetic acid and HCl (2:1) at 0–58C
afforded compound 4 the carboxamide derivatives. The
spectral data of compounds 4a,b assigned their structure
(cf. Experimental). Many reports [18, 20–22] stated that
diazotization of compounds analogous to 1 gave the corre-
sponding triazine derivatives; however, our attempts to
cyclize compound 1 to 5 by stirring with nitrous acid gave
the unexpected carboxamide derivatives 4. The formation of
compounds 4 was explained by the hydrolysis of cyano
group on acidic medium to amide group without formation
of the unstable diazonium salt on the amino group. In
addition, this could be established chemically through
hydrolysis of compound 1c, same compound 4c was
obtained; 4c prepared by this method gave the same data
as reported [23].
In addition, compounds 1c, 4c, 8a and 11a exerted mod-
erate activities compared to ibuprofen at the 3rd and 4th
h
post-carrageenan. Their activity profile was the same as ibu-
profen (response increasing by time).
Compounds 2c, 3a, 6a and 7a showed a stronger anti-
inflammatory effect than ibuprofen, from 1st to 4th h post-
carrageenan. Yet, compound 4a showed the opposite profile
compared to ibuprofen: It showed 79.6% inhibition at 1-h
post-carrageenan and 68.5% inhibition at 2-h post-carra-
geenan and then decreased to 66% inhibition at 3-h and
4-h post-carrageenan.
Compound 6b exerted a stronger anti-inflammatory effect
than ibuprofen (95% and 96% inhibition at 2-h and 3-h inter-
val post-carrageenan). Likewise, compounds 8b showed a
significant higher inhibitory action at the 3-h interval;
95% inhibition.
The pyrrole derivatives 4 were converted to the correspond-
ing pyrrolo[2,3-d]pyrimidine-2-thione 6 via refluxing [24] with
thiourea in ethanol. Alkylation [25–27] of pyrrolopyrimidin-
2-thiones 6 with halo compounds gave the corresponding
S-alkylated pyrimidine derivatives 7. The reaction [28, 29] of
S-alkylated compounds 7 with hydrazine hydrate yielded the
2-hydrazine derivative 8. The reaction [27–30] of compound 8
with acetyl acetone in ethanol containing catalytic amount
of glacial acetic acid yielded the corresponding pyrazolyl
derivatives 9 in good yield. Refluxing [27] 4 with ethyl
acetoacetate in sodium ethoxide solution afforded the
pyrazolone derivatives 10. Reactions of 4-hydrazinopyrimi-
dines with one carbon donor moiety produce the respective
isomeric triazolopyrimidines [21, 22, 31]. Compound 8 was
used to prepare some pyrrolotriazolo[4,3-a]pyrimidines 11
acetic anhydride/acetic anhydride (Scheme 1).
Compound 9c showed no activity at 1st and 2nd h intervals
post-carrageenan injection. Yet, they exerted significantly
higher activity compared to ibuprofen at the 3rd and 4th
h
post-carrageenan; (63.5% at 3rd h and 79% at 4th h post-
carrageenan).
Compounds 1c, 4c, 8a and 11a exerted markedly but not
significantly higher activity compared to ibuprofen at the
4th h post-carrageenan. Compound 1c showed 68% inhi-
bition, 4c showed 62% inhibition, 8a showed 70% inhibition
and 11a showed 66% inhibition.
Compounds 1a and 1b showed weak activities 4 h after
carrageenan injection.
To analyze structure–activity relationships, three struc-
tural components were considered: The nature of the hetero-
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M. S. Mohamed et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Scheme 1. Synthesis of compounds 1–11.
group in 1c presented only 68% inhibition at 4th h post-
carrageenan injection.
Also, hydrolysis of cyano group in 1a to carboxamide group
in 4a increased the activity during all time intervals: While
amide 4a showed 79–66% inhibition at 1st h to 4th h post-
carrageenan, the cyano 1a exerted 7% inhibition at 1st h then
increased to 50% inhibition at 4th h.
Alkylation of thione group at compound 7a decreased
the activity at 1st to 3rd h, yet increased at 4th h than
the free thione in compound 6a. While 6a showed 66–
78.1% inhibition at 1st
h h post-carrageenan
to 3rd
and decreased to 77% inhibition at 4th h, 7a exerted 8–74%
inhibition at 1st h to 3rd h then increased to 79.5% inhibition
at 4th h.
Figure 2. Anti-inflammatory effect (% inhibition) of tested com-
pounds compared to the drug (Ibuprofen).
cycle nucleus, the type of the side chain, and the position of
the side chain.
Replacing the antipyrine moity in compound 4c with
benzyl group in compound 4a confers significantly higher
activity during all time intervals than antipyrine moiety at
4c; while 4a showed 79–66% inhibition at 1st h to 4th h post-
carrageenan, 4c exerted 19% inhibition at 1st h then
increased to 62% inhibition at 4th h.
First, the influence of the nature of the aromatic hetero-
cyclic system; pyrrolopyrimidine 6a, 6b, 7a, 8a and 8b con-
densed ring showed the highest activity over pyrrole 1c and
pyrrolotriazolopyrimidine 11a.
Regarding the side chain type, adding bulky group (as
hydrazonoyl dicyanide and pyrazolyl) in compounds 2c
and 3a confers greater activity over the net amino groups
in compound 1c: While compound 2c (hydrazonoyl dicya-
nide) showed 72.3% inhibition at 4th h post-carrageenan
injection, increased to 89% inhibition at 4th h post-
carrageenan injection in compound 3a (pyrazolyl), the amino
Regarding the side chain position, addition of bulky group
on position 2 decreased the activity; compounds 8b and 9c
over free thione in 6a and 6b. Also, triazolo ring as fused ring
with pyrrolopyrimidine at position 2 in compounds 11a
decreased the activity (6.5% and 66% inhibition) at 3rd
h
and 4th h post-carrageenan injection over pyrrolopyrimidine
system.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity
833
37Cl, 12.2%), 409 (Mþþ4, 2 (37Cl), 2.1%). 1H-NMR (DMSO-d6,
300 MHz) d (ppm): 6.9 (s, 1H, NH, hydrazone), 7.0 (s, 1H, C6-H),
7.2–7.8 (m, 8H, Ar–H). Anal. calcd. for C20H10Cl2N6 (405.24):
C, 59.28; H, 2.49; Cl, 17.50; N, 20.74. Found: C, 59.41; H, 2.62;
Cl, 17.65; N, 20.86.
Conclusion
We have synthesized and evaluated a series of heterocyclic
compounds as potential anti-inflammatory agents. Based on
their structure, we conclude that the best aromatic nucleus
is the pyrrole with an N-benzyl substituent and a pyrazolyl
subunit on the C-2 such as in compound 3a. In the pyrrolopyr-
imidine derivatives, the anti-inflammatory activity also depends
on the nature of the side group on the C-2 at the heterocyclic
system (compound 6a,b is more active than 8a,b or 11a).
(3-Cyano-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)-4,5-diphenyl-1H-pyrrol-2-yl)-
carbonohydrazonoyl dicyanide (2c)
Yield 48 %, m.p. 153–1578C. IR (KBr) n (cmꢁ1): 3290þ(NH), 2320
–
–
–
(C N), 1695 (C O), 1585 (C N). MS (EI) m/z (%): 522 (M , 18%), 523
–
1
(Mþþ1, 8.5%), 524 (Mþþ2, 0.8%). H-NMR (DMSO-d6, 300 MHz) d
–
(ppm): 2.2 (s, 2H, CH –C O), 2.33 (s, 3H, CH ), 3.12 (s, 3H, N–CH ),
3
–
2
3
Experimental
6.9 (s, 1H, NH, hydrazone), 7.3–7.9 (m, 15H, Ar–H). Anal. calcd.
for C31H22N8O (522.559): C, 71.25; H, 4.24; N, 21.44; O, 3.06.
Found: C, 71.48; H, 4.62; N, 21.55; O, 3.17.
General methods
All melting points were uncorrected and measured using Electro-
thermal IA 9100 apparatus (Shimadzu, Japan). IR spectra were
recorded as potassium bromide pellets on a Perkin-Elmer 1650
spectrophotometer (USA), Faculty of Science, Cairo University,
Cairo, Egypt. 1H-NMR spectra were determined on a Varian
Mercury (300 MHz) spectrometer (Varian, UK) and chemical shifts
were expressed as ppm against TMS as internal reference (Faculty
of Science, Cairo University, Cairo, Egypt). Mass spectra were
recorded on 70 eV EI Ms-QP 1000 EX (Shimadzu, Japan), Faculty
of Science, Cairo University, Cairo, Egypt. Microanalyses were
operated using Vario, Elmentar apparatus (Shimadzu, Japan),
Organic Microanalysis Unit, Faculty of Science, Cairo University,
Cairo, Egypt. Column chromatography was performed on (Merck)
Silica gel 60 (particle size 0.06–0.20 mm). Compounds 1a–c and 4c
were prepared as reported in [14–17, 23]. All new compounds
yielded spectral data consistent with the proposed structure and
microanalysis within ꢀ0.4% of the theoretical values.
General procedure for the preparation of compound 3
A mixture of compound 2 (0.01 mol) and hydrazine hydrate
(0.64 mL, 0.02 mol) in ethanol (30 mL) was heated under reflux
for 8 h controlled by TLC. The solvent was concentrated and the
reaction product was allowed to cool then poured on acidified
ice/H2O. The product was filtered off, washed with water, dried
and recrystallized from ethanol to give 3.
1-Benzyl-2-(2-(3,5-diamino-4H-pyrazol-4-ylidene)-
hydrazinyl)-4,5-diphenyl-1H-pyrrole-3-carbonitrile (3a)
Yield 60%, m.p. 112–1178C. IR (KBr) n (cmꢁ1): 3340–3290 (broad
þ
–
NH and NH ), 1560 (C N). MS (EI) m/z (%): 458 (M , 21%), 459
1
–
2
(Mþþ1, 6.5%), 460 (Mþþ2, 1.3%). H-NMR (DMSO-d6, 300 MHz) d
(ppm): 5.62 (s, 2H, CH2), 6.5 (s, 4H, 2 NH2), 6.8 (s, 1H, NH,
hydrazone), 7.2–7.9 (m, 15H, Ar-H). Anal. calcd. for C27H22N8
(458.517): C, 70.73; H, 4.84; N, 24.44. Found: C, 70.54; H, 4.91;
N, 24.65.
General procedure for the preparation of compound 2
A mixture of 1 (0.01 mol) in concentrated HCl (10 mL) was cooled
with stirring to 0–58C under ice, and cooled sodium nitrite
solution (2.5 g in 10 mL of water) added to it dropwise during
30 min. The reaction mixture was then stirred for 30 min.
Without separation an ice-cold mixture of malononitrile
(0.015 mol) and sodium acetate (4.10 g; 0.05 mol) in ethanol
(50 mL) was added dropwise with stirring over 15 min. The
stirring was continued for 30 min under ice and the reaction
mixture then left for 12 h at room temperature. The precipitate
was filtered off, recrystallized from ethanol/H2O to give 2.
2-(2-(3,5-Diamino-4H-pyrazol-4-ylidene)hydrazinyl)-1-
(3,4-dichloro phenyl)-4-phenyl-1H-pyrrole-3-carbonitrile
(3b)
Yield 51%, m.p. 178–1818C. IR (KBr) n (cmꢁ1): 3330–3270 (broad
þ
NH and NH ), 1580 (C N). MS (EI) m/z (%): 436 (M , 35Cl, 20%), 438
–
–
2
(Mþþ2, 37Cl, 13.5%), 440 (Mþþ4, 2 (37Cl), 2.5%). 1H-NMR (DMSO-d6,
300 MHz) d (ppm): 6.6 (s, 4H, 2 NH2), 6.9 (s, 1H, NH, hydrazone),
7.0 (s, 1H, C6-H), 7.3–7.8 (m, 8H, Ar–H). Anal. calcd.
for C20H14Cl2N8 (437.285): C, 54.93; H, 3.23; Cl, 16.22; N, 25.62.
Found: C, 54.69; H, 3.42; Cl, 16.51; N, 25.47.
(1-Benzyl-3-cyano-4,5-diphenyl-1H-pyrrol-2-yl)-
carbonohydrazonoyl dicyanide (2a)
Yield 58 %, m.p. 115–1208C. IR (KBr) n (cmþꢁ1): 3280 (NH), 2330
2-(2-(3,5-Diamino-4H-pyrazol-4-ylidene)hydrazinyl)-1-
(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-
4,5-diphenyl-1H-pyrrole-3-carbonitrile (3c)
þ
–
(C N), 1585 (C N). MS (EI) m/z (%): 426 (M , 18%), 427 (M þ1,
–
5.5%), 428 (Mþþ2, 1.5%). 1H-NMR (DMSO-d6, 300 MHz) d (ppm):
5.62 (s, 2H, CH2), 6.9 (s, 1H, NH, hydrazone), 7.2–7.8 (m, 15H,
Ar-H). Anal. calcd. for C27H18N6 (426.47): C, 76.04; H, 4.25;
N, 19.71. Found: C, 76.25; H, 4.41; N, 19.86.
Yield 48%, m.p. 178–1818C. IR (KBr) n (cmꢁ1): 3340–3290 (broad
–
–
NH and NH ), 1690 (C O), 1565 (C N). MS (EI) m/z (%): 554
–
–
2
(Mþ, 22%), 555 (Mþþ1, 9.1%), 556 (Mþþ2, 2.1%). 1H-NMR
–
(DMSO-d , 300 MHz) d (ppm): 2.2 (s, 2H, CH –C O), 2.3 (s, 3H,
6
–
2
(3-Cyano-1-(3,4-dichlorophenyl)-4-phenyl-1H-pyrrol-2-yl)-
carbono hydrazonoyl dicyanide (2b)
CH3), 3.14 (s, 3H, N–CH3), 6.58 (s, 4H, 2 NH2), 6.9 (s, 1H, NH,
hydrazone), 7.3–7.9 (m, 15H, Ar–H). Anal. calcd. for
C31H26N10O (554.605): C, 67.13; H, 4.73; N, 25.26; O, 2.88.
Found: C, 67.36; H, 4.95; N, 25.48; O, 2.96.
Yield 45 %, m.p. 218–2228C. IR (KBr) n (cmꢁ1): 3300 (NH), 2310
þ
(C N), 1565 (C N). MS (EI) m/z (%): 405 (M , 35Cl, 19%), 407 (Mþþ2,
–
–
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M. S. Mohamed et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
2-Amino-1-(aryl)-4-phenyl-5-substituted -1H-pyrrole-3-
carboxamide (4)
7-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-5,6-diphenyl-2-thioxo-2,3-dihydro-1H-pyrrolo[2,3-
d]pyrimidin-4(7H)-one (6c)
To a suspended solution of compound 1 (0.01 mol) in a mixture
of hydrochloric acid (5 mL, 34%) and glacial acetic acid (10 mL) at
0–58C, a solution of sodium nitrite (4 g in 10 mL water) was
added dropwise with continuous stirring over 30 min. After 8 h
of stirring at room temperature the foamy mixture was diluted
with water, neutralized with ammonia, filtered off, and recrys-
tallized from (EtOH/H2O) to give compound 4. Compound 4c
prepared with this method is identical in all respects (physical
and spectral data) as reported.
Yield 74%, m.p. 132–1378C. IR (KBr) n (cmꢁ1): 3390 (NH), 1690
þ
þ
–
–
–
–
(C O), 1630 (C S). MS (EI) m/z (%): 505 (M , 70.0%), 506 (M þ1,
22.17%), 507 (Mþþ2, 3.73%). 1H-NMR (DMSO-d6, 300 MHz)
d (ppm): 2.43 (s, 3H, CH3), 3.12 (s, 3H, N–CH3), 7.2–7.8 (m, 15H,
Ar–H), 12.32 (s, 1H, NH), 13.14 (s, 1H, NH). Anal. calcd.
for C29H23N5O2S (505.590): C, 68.89; H, 4.59; N, 13.85; O, 6.33;
S, 6.34. Found: C, 68.89; H, 4.59; N, 13.85; O, 6.33; S, 6.34.
7-Aryl-5,6-disubstituted-2-(ethylthio)-3H-pyrrolo[2,3-d]-
pyrimidin-4(7H)-one (7)
2-Amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carboxamide
(4a)
To a warmed sodium ethoxide solution (prepared by dissolving
0.56 g, 0.01 mol of sodium in 50 mL of ethanol) compound 6
(0.01 mol) was added, and heating was continued for 20 min.
The mixture was allowed to cool to r.t., and alkyl halide
(0.02 mol) was added dropwise with continuous stirring over
30 min. The mixture was stirred under reflux for 5 h con-
trolled by TLC, allowed to cool to r.t., and finally poured into
cold water. The solid product was filtered off and washed with
water; residue was dried and recrystallized from methanol to
give 7.
Yield 60%, m.p. 98–1028C. IR (KBþr) n (cmꢁ1): 3350–3300 (NH2),
þ
–
1680 (C O). MS (EI) m/z (%): 367 (M , 27%), 368 (M þ1, 8.5%), 369
–
(Mþþ2, 1.3%). H-NMR (DMSO-d6, 300 MHz) d (ppm): 5.62 (s, 2H,
1
CH2), 6.5 (s, 2H, NH2), 7.2–8 (m, 15H, Ar–H and 2H, CONH2). Anal.
calcd. for C24H21N3O (367.443): C, 78.45; H, 5.76; N, 11.44; O, 4.35.
Found: C, 78.26; H, 5.59; N, 11.32; O, 4.61.
2-Amino-1-(3,4-dichlorophenyl)-4-phenyl-1H-pyrrole-3-
carboxamide (4b)
Yield 58%, m.p. 178–1818C. IR (KBr) n (cmꢁ1): 3330–3280 (NH2),
þ
1670 (C O). MS (EI) m/z (%): 346 (M , 35Cl, 32%), 348 (Mþþ2, 37Cl,
–
–
19%), 350 (Mþþ4, 2ꢂ(37Cl), 5.6%). 1H NMR (DMSO-d6, 300 MHz)
d (ppm): 6.6 (s, 2H, NH2), 7.0 (s, 1H, C6-H), 7.3–8 (m, 8H, Ar–H and
2H, CONH2). Anal. calcd. for C17H13Cl2N3O (346.211): C, 58.98;
H, 3.78; Cl, 20.48; N, 12.14; O, 4.62. Found: C, 59.04; H, 3.96; Cl,
20.71; N, 12.47; O, 4.85.
7-Benzyl-2-(ethylthio)-5,6-diphenyl-3H-pyrrolo[2,3-
d]pyrimidin-4(7H)-one (7a)
Yield 80%, m.p. 84–868C. IR (KBr) n (cmꢁ1): 3330 (NH), 1680 (C O).
–
–
MS (EI) m/z (%): 437 (Mþ, 34%), 438 (Mþþ1, 10.28%), 439 (Mþþ2,
1.4%). 1H-NMR (DMSO-d6, 300 MHz)
d (ppm): 1.32 (t, 3H,
J ¼ 7.2 Hz, CH3), 3.53 (q, 2H, J ¼ 7.2 Hz, CH2), 5.98 (s, 2H,
CH2), 7.1–7.8 (m, 15H, Ar–H), 12.59 (s, 1H, NH). Anal. calcd.
for C27H23N3OS (437.556): C, 74.11; H, 5.30; N, 9.60; O, 3.66;
S, 7.33. Found: C, 74.41; H, 5.63; N, 9.80; O, 3.79; S, 7.56.
7-Aryl-5,6-disubstituted-2-thioxo-2,3-dihydro-1H-
pyrrolo[2,3-d] pyrimidin-4(7H)-one (6)
A mixture of compound 4 (0.01 mol) and thiourea (1.2 g,
0.02 mol) was refluxed in dry ethanol (20 mL) for 10 h. The
reaction mixture was evaporated under reduced pressure and
the residues were recrystallized from methanol to give 6.
7-(3,4-Dichlorophenyl)-2-(ethylthio)-5-phenyl-3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (7b)
Yield 76%, m.p. 125–1288C. IR (KBr) n (cmꢁ1): 3410 (NH), 1680
þ
(C O). MS (EI) m/z (%): 416 (M , 35Cl, 43.2%), 418 (Mþþ2, 37Cl,
–
–
7-Benzyl-5,6-diphenyl-2-thioxo-2,3-dihydro-1H-
pyrrolo[2,3-d] pyrimidin-4(7H)-one (6a)
8.9%), 420 (Mþþ4, 2 (37Cl), 2.1%). 1H-NMR (DMSO-d6, 300 MHz)
d (ppm): 1.43 (t, 3H, J ¼ 6.8 Hz, CH3), 3.23 (q, 3H, J ¼ 6.8 Hz, CH3),
6.9 (s, 1H, C6-H), 7.2–7.8 (m, 8H, Ar–H), 12.61 (s, 1H, NH). Anal.
calcd. for C20H15Cl2N3OS (416.324): C, 57.70; H, 3.63; Cl, 17.03;
N, 10.09; O, 3.84; S, 7.70. Found: C, 57.93; H, 3.89; Cl, 17.26;
N, 10.18; O, 3.96; S, 7.75.
Yield: 80%, m.p. 92–948C. IR (KBr) n (cmꢁ1): 3350 (NH), 1680 (C O),
–
–
þ
þ
–
1615 (C S). MS (EI) m/z (%): 409 (M , 45%), 410 (M þ1, 13.5%), 411
–
(Mþþ2, 1.1%). H-NMR (DMSO-d6, 300 MHz) d (ppm): 5.56 (s, 2H,
1
CH2), 7.1–7.8 (m, 15H, Ar-H), 12.20 (s, 1H, NH), 13.30 (s, 1H, NH).
Anal. calcd. for C25H19N3OS (409.503): C, 73.32; H, 4.68; N, 10.26;
O, 3.91; S, 7.83. Found: C, 73.49; H, 4.90; N, 10.42; O, 3.63; S, 7.86.
7-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-2-(ethylthio)-5,6-diphenyl-3H-pyrrolo[2,3-d]pyrimidin-
4(7H)-one (7b)
7-(3,4-Dichlorophenyl)-5-phenyl-2-thioxo-2,3-dihydro-1H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (6b)
Yield 75%, m.p. 138–1408C. IR (KBr) nþ(cmꢁ1): 3360 (NH), 1690
Yield 64%, m.p. 145–1478C. IR (KBr) n (cþmꢁ1): 3450 (NH), 1700
þ
(C O), 1605 (C S). MS (EI) m/z: 387 (M , 35Cl, 20%), 389 (Mþþ2,
(C O), 1675 (C O). MS (EI) m/z (%): 533 (M , 31.15%), 534 (M þ1,
–
–
–
–
–
–
–
–
1
37Cl, 8.3%), 391 (Mþþ4, 2 (37Cl), 7.5%). 1H-NMR (DMSO-d6,
300 MHz) d (ppm): 7.0 (s, 1H, C6-H), 7.3–8 (m, 8H, Ar–H),
12.20 (s, 1H, NH), 13.30 (s, 1H, NH). Anal. calcd. for
C18H11Cl2N3OS (388.270): C, 55.68; H, 2.86; Cl, 18.26; N, 10.82;
O, 4.12; S, 8.26. Found: C, 55.89; H, 2.97; Cl, 18.58; N, 10.99; O,
4.23; S, 8.49.
11.2%), 535 (Mþþ2, 2.3%). H-NMR (DMSO-d6, 300 MHz) d (ppm):
1H-NMR (DMSO, 300 MHz) d (ppm): 1.46 (t, 3H, J ¼ 7.5 Hz, CH3),
2.43 (s, 3H, CH3), 3.01 (q, 3H, J ¼ 7.5 Hz, CH3), 3.21 (s, 3H, N–CH3),
7.0–7.8 (m, 15H, Ar–H), 12.49 (s, 1H, NH). Anal. calcd.
for C31H27N5O2S (533.643): C, 69.77; H, 5.10; N, 13.12; O, 6.00;
S, 6.01. Found: C, 70.01; H, 5.38; N, 16.01; O, 6.25; S, 6.35.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity
835
7-Aryl-5,6-disubstituted-2-(hydrazinyl)-3H-pyrrolo[2,3-d]-
pyrimidin-4(7H)-one (8)
A mixture of 7 (0.01 mol) and hydrazine hydrate (99%, 0.03 mol)
in absolute ethanol (20 mL) was refluxed for 10 h. The reaction
mixture was poured onto ice. The solid product was filtered off
and washed with water; residue was dried and recrystallized
from methanol to give 8.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)-7-(1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-yl)-5,6-diphenyl-3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (9b)
Yield 58%, m.p. 125–1278C. IR (þKBr) n (cmꢁ1): 1695 (C O), 1680
–
–
þ
–
(C O). MS (EI) m/z (%): 551 (M , 65%), 552 (M þ1, 21%), 553
–
(Mþþ2, 3.1%). 1H-NMR (DMSO-d6, 300 MHz) d (ppm): 2.2 (s, 3H,
CH3), 2.33 (s, 3H, CH3), 2.48 (s, 3H, CH3), 3.12 (s, 3H, N–CH3), 6.8
(s, 1H, pyrazole), 7.2–7.7 (m, 15H, Ar–H), 10.6 (s, 1H, NH, pyrimi-
dine). Anal. calcd. for C34H29N7O2 (567.640): C, 71.94; H, 5.15; N,
17.27; O, 5.64. Found: C, 72.05; H, 5.39; N, 17.51; O, 5.74.
7-Benzyl-2-hydrazinyl-5,6-diphenyl-3H-pyrrolo[2,3-d]-
pyrimidin-4(7H)-one (8a)
Yield 60%, m.p. 100–1028C. IR (KBr) n (cmꢁ1): 3460–3380 (NH2),
þ
þ
7-(Aryl)-2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-
5,6-disubstituted-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one
(10)
A mixture of compound 8b,c (0.01 mol) and ethylacetoacetate
(0.05 mol) in sodium ethoxide solution (prepared by dissolving
0.23 g of sodium metal in absolute ethanol (30 mL)) was heated
under reflux with stirring for 10 h. The reaction mixture was
allowed to cool, poured into cold water and neutralized by HCl.
The solid product was filtered off and recrystallized from ethanol
to give 10a,b.
–
3350 (NH), 1680 (C O). MS (EI) m/z (%): 407 (M , 20%), 408 (M þ1,
–
8.2%), 409 (Mþþ2, 1.3%). 1H-NMR (DMSO-d6, 300 MHz) d (ppm): 5.92
(s, 2H, CH2), 6.70 (s, 2H, NH2), 7.1–7.8 (m, 15H, Ar–H), 8.1 (s, 1H,
NH, D2O exchangeable), 8.2 (s, 1H, NHNH2), 11.21 (s, 1H, NH). Anal.
calcd. for C25H21N5O (407.467): C, 73.69; H, 5.19; N, 17.19; O, 3.93.
Found: C, 73.47; H, 5.28; N, 17.42; O, 3.65.
7-(3,4-Dichlorophenyl)-2-hydrazinyl-5-phenyl-3H-
pyrrolo[2,3-d]pyrimidin-4(7H)-one (8b)
Yield 68%, m.p. 142–1468C. IR (KBr) n (cmꢁ1): 348þ0–3400 (NH2),
3380 (NH), 1670 (C O). MS (EI) m/z (%): 386 (M , 35Cl, 29%),
–
–
7-(3,4-Dichlorophenyl)-2-(5-methyl-3-oxo-2,3-dihydro-1H-
pyrazol-1-yl)-5-phenyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-
one (10a)
388 (Mþþ2, 37Cl, 12.5%), 390 (Mþþ4, 2(37Cl), 1.7%). 1H-NMR
(DMSO-d6, 300 MHz) d (ppm): 6.48 (s, 2H, NH2), 6.9 (s, 1H, C6-H),
7.1–7.8 (m, 8H, Ar–H), 8.23 (s, 1H, NHNH2), 11.21 (s, 1H, NH).
Anal. calcd. for C18H13Cl2N5O (386.235): C, 55.97; H, 3.39;
Cl, 18.36; N, 18.13; O, 4.14. Found: C, 56.09; H, 3.64; Cl, 18.57;
N, 18.41; O, 4.28.
Yield 45%, m.p. 132–1358C. IRþ(KBr) n (cmꢁ1): 1695 (C O), 1680
–
–
(C O). MS (EI) m/z (%): 452 (M , 35Cl, 32.1%), 454 (Mþþ2, 37Cl,
–
–
9.2%), 456 (Mþþ4, 2 (37Cl), 3.1%). H-NMR (DMSO-d6, 300 MHz) d
1
(ppm): 2.5 (s, 3H, CH3), 6.42 (s, 1H, pyrazole), 6.8 (s, 1H, C6-H), 7.0–
7.9 (m, 8H, Ar–H), 9.05 (s, 1H, NH, pyrazole), 10.8 (s, 1H, NH,
pyrimidine). Anal. calcd. for C22H15Cl2N5O2 (452.293): C, 58.42; H,
3.34; Cl, 15.68; N, 15.48; O, 7.07. Found: C, 58.42; H, 3.34; Cl,
15.68; N, 15.48; O, 7.27.
7-(1,5-Dimethyl-3-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-3-
yl)-2-hydrazinyl-5,6-diphenyl-3H-pyrrolo[2,3-d]pyrimidin-
4(7H)-one (8c)
Yield 56%, m.p. 153–1588C. IR (KBr) n (cmꢁ1): 3420, 3390 (NH2),
þ
–
–
3340 (NH), 1710 (C O), 1640 (C C). MS (EI) m/z (%): 502 (M , 65%),
–
–
7-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-
yl)-2-(5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5,6-
diphenyl-3H-pyrrolo [2,3-d]pyrimidin-4(7H)-one (10b)
503 (Mþþ1, 20.1%), 1H-NMR (DMSO, 300 MHz) d (ppm): 2.42 (s, 3H,
CH3), 3.23 (s, 3H, N–CH3), 6.62 (s, 2H, NH2), 7.2–7.9 (m, 15H, Ar–H),
8.30 (s, 1H, NH NH2). Anal. calcd. for C29H25N7O2 (503.555): C,
69.17; H, 5.00; N, 19.47; O, 6.35. Found: C, 69.04; H, 5.13; N, 19.24;
O, 6.61.
Yield 49%, m.p. 118–1208C. IRþ(KBr) n (cmꢁ1): 1695 (C O), 1680
–
–
þ
–
–
(C O). MS (EI) m/z (%): 569 (M , 16.2%), 570 (M þ1, 2.6%), 571
1
(Mþþ2, 1.2%). H-NMR (DMSO-d6, 300 MHz) d (ppm): 2.32 (s, 3H,
CH3), 2.51 (s, 3H, CH3), 3.15 (s, 3H, N–CH3), 6.58 (s, 1H, pyrazole),
7.2–7.8 (m, 15H, Ar–H), 9.15 (s, 1H, NH, pyrazole), 10.58 (s, 1H,
NH, pyrimidine). Anal. calcd. for C33H27N7O3 (569.613): C, 69.58;
H, 4.78; N, 17.21; O, 8.43. Found: C, 69.73; H, 4.92; N, 17.42;
O, 8.65.
7-(Aryl)-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5,6-
disubstituted-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (9)
A mixture of compound 8a,c (0.01 mol) and acetylacetone
(0.02 mol) in absolute ethanol (30 mL, containing a catalytic
amount of glacial acetic acid (2mL)) was heated under reflux
for 10 h. The precipitate was filtered while hot, washed with
water several times and recrystallized from ethanol to give 9a,b.
8-(Aryl)-3-methyl-6,7-disubstituted-1H-pyrrolo[2,3-
d][1,2,4]triazolo [4,3-a]pyrimidin-5(8H)-one (11)
A mixture of compound 8a,b (0.01 mol), acetic anhydride
(20 mL), and acetic acid (10 mL) was refluxed for 8 h. The reac-
tion mixture was cooled, poured onto ice-water, filtered, dried,
and recrystallized from ethanol to afford 11a,b.
7-Benzyl-2-(3,5-dimethyl-1H-pyrazol-1-yl)-5,6-diphenyl-
3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (9a)
Yield 55%, m.p. 162–1648C. IR (KBr) n (cmꢁ1): 1680 (C O), 1640
–
–
þ
þ
–
(C N). MS (EI) m/z (%): 471 (M , 15%), 472 (M þ1, 3.6%), 473
–
(Mþþ2, 1.1%). 1H-NMR (DMSO-d6, 300 MHz) d (ppm): 2.0 (s, 3H,
CH3), 2.58 (s, 3H, CH3), 5.31 (s, 2H, CH2), 6.8 (s, 1H, pyrazole), 7.3–
7.8 (m, 15H, Ar-H), 10.3 (s, 1H, NH, pyrimidine). Anal. calcd.
for C30H25N5O (471.552): C, 76.41; H, 5.34; N, 14.85; O, 3.39.
Found: C, 76.25; H, 5.62; N, 14.53; O, 3.21.
8-Benzyl-3-methyl-6,7-diphenyl-1H-pyrrolo[2,3-d]-
[1,2,4]triazolo[4,3-a]pyrimidin-5(8H)-one (11a)
Yield 53%, m.p. 110–1128C. IR (KBr) n (cmꢁ1): 1670 (C O), 1590
–
–
–
þ
þ
–
(C N). MS (EI) m/z (%): 431 (M , 18%), 432 (M þ1, 6.2%), 433
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

836
M. S. Mohamed et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Table 1. In vivo anti-inflammatory activity.
Edema induced by carrageenan (% edema inhibition relative to control)
Compounds
1 h
Swel W SE
2 h
Swel W SE
3 h
Swel W SE
4 h
Swel W SE
% inh.
% inh.
% inh.
% inh.
Ph
CN
NH2
1a
0.21 W 0.025
0.71
0.18 W 0.063
0.20 W 0.032
0.165 W 0.048
0.118 W 0.055
31
0.35 W 0.056
0.384 W 0.044
0.18 W 0.04a
0.19 W 0.042a
37
0.32 W 0.032a
0.33 W 0.031a
0.2 W 0.076a
50
Ph
N
Benzyl
Ph
CN
NH2
0.212 W 0.078 6.19
0.212 W 0.034 6.2
0.138 W 0.058 39
21.5
36.35
54.6
30
48.1
H
N
1b
Ar
Ph
CN
66.7
68
NH2
Ph
Ph
N
1c
Anti
CN
65.3
0.177 W 0.065a 72.3
NH
N=C(CN)
Ph
N
Anti
2c
Ph
N
Ph
N
CN
Benzyl
0.082 W 0.032 63.7
0.092 W 0.032
64.6
0.17 W 0.029a
69
0.07 W 0.03a
89
HN
3a
H2N
NH
N
N
Ph
CONH2
0.046 W 0.004 79.6
0.082 W 0.007
68.4
0.184 W 0.003a
66.41
0.218 W 0.02
66
NH2
Ph
N
4a
Benzyl
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Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Table 1. (continued )
Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity
837
Edema induced by carrageenan (% edema inhibition relative to control)
Compounds
1 h
Swel W SE
2 h
Swel W SE
3 h
Swel W SE
4 h
Swel W SE
% inh.
% inh.
% inh.
% inh.
Ph
CONH2
0.182 W 0.044 19.13
0.192 W 0.0403 26.15
0.28 W 0.08
47.8
0.23 W 0.062a
62.55
NH2
Ph
N
4c
Anti
O
Ph
NH
0.13 W 0.043
66.37
0.038 W 0.01a
85.4
0.12 W 0.035a
78.1
0.142 W 0.025a 77.8
Ph
H
S
N
H
N
6a
Benzyl
O
Ph
NH
0.212 W 0.09
6.19
0.012 W 0.002a
95.3
0.022 W 0.0058a 96
0.148 W 0.046a 76.87
S
N
N
Ar
H
6b
O
Ph
NH
0.206 W 0.021 8.8
0.101 W 0.023
61
0.142 W 0.006a
74
0.132 W 0.004a 79.3
Ph
SEt
N
N
7a
Benzyl
O
Ph
NH
0.212 W 0.048 6.2
0.228 W 0.025
0.182 W 0.018
0.26 W 0.024
12.3
30
0
0.326 W 0.032
40.5
0.19 W 0.039a
70.3
Ph
NHN
N
N
Benzyl
8a
O
Ph
NH
0.19 W 0.052
13.2
0.028 W 0.0048a 95
0.202 W 0.02a
68.4
H
NHNH
N
N
Ar
8b
O
Ph
NH
0.23 W 0.031
0
0.2 W 0.047a
63.5
0.134 W 0.027a 79
N
Ph
N
N
N
Anti
9c
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838
M. S. Mohamed et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Table 1. (continued )
Edema induced by carrageenan (% edema inhibition relative to control)
Compounds
1 h
Swel W SE
2 h
Swel W SE
3 h
Swel W SE
4 h
Swel W SE
% inh.
% inh.
% inh.
% inh.
O
Ph
N
NH
N
0.229 W 0.018
0
0.244 W 0.08
6.1
0.238 W 0.028
6.5
0.218 W 0.082a 66
Ph
N
N
11a
Benzyl
Ibuprofen
Control
0.216 W 0.034
0.23 W 0.033
6.08
0.1425 W 0.031
0.26 W 0.049
45
0.214 W 0.024a
0.544 W 0.081
60.66
0.192 W 0.012a
0.63 W 0.037
69.52
Swel ¼ mean difference in rat paw volume between right and left paw W S.E. % inhibition ¼ (1 – rt/rc) T 100; [rt ¼ swel. of tested
group; rc ¼ swel. of control group] a: Significantly different from control at the same time interval at p < 0.05 Swel ¼ swelling,
SE ¼ standard error, %inh. ¼ % inhibition, benzyl ¼ CH2Ph, Ar ¼ 3,4-Cl2C6H3, Anti ¼ antipyrine
(Mþþ2, 2.51%). 1H-NMR (DMSO-d6, 300 MHz) d (ppm): 2.83 (s, 3H,
plantar injection of 0.1 ml of 1% carrageenan (Sigma-Aldrich,
CH3), 5.68 (s, 2H, CH2), 7.3–7.8 (m, 15H, Ar–H), 9.3 (s, 1H, NH,
pyrazole). Anal. calcd. for C27H21N5O (431.489): C, 75.16; H, 4.91;
N, 16.23; O, 3.71. Found: C, 75.38; H, 4.98; N, 16.42; O, 3.65.
St. Louis, USA) into the right hind paw. Paw volume was
measured using a water plethysmometer (Basile, Comerio,
Italy). The difference between the right and left paw volume
was measured at 1, 2, 3 and 4 h after induction of inflam-
8-(3,4-Dichlorophenyl)-3-methyl-6-phenyl-1H-pyrrolo[2,3-d]-
[1,2,4] triazolo[4,3-a]pyrimidin-5(8H)-one (11b)
mation. Control group (five rats per group) received DMSO
subcutaneously and carrageenan in subplantar region.
Yield 42%, m.p. 170–1738C. IR (KBr) n (cmꢁ1): 1675 (C O). MS (EI)
–
–
m/z (%): 410 (Mþ, 35Cl, 20%), 412 (Mþþ2, 37Cl, 8.2%), 414 (Mþþ4,
Results were expressed as percentage inhibition of inflam-
1
2 (37Cl), 2.1%). H-NMR (DMSO-d6, 300 MHz) d (ppm): 2.56 (s, 3H,
mation. Ibuprofen (70 mg/kg) was used as the reference
CH3), 6.8 (s, 1H, C6-H), 7.1–7.9 (m, 8H, Ar-H), 9.15 (s, 1H, NH,
pyrazole), 10.8 (s, 1H, NH, pyrimidine). Anal. calcd.
for C20H13Cl2N5O (410.256): C, 58.55; H, 3.19; Cl, 17.28; N,
17.07; O, 3.90. Found: C, 58.82; H, 3.51; Cl, 17.06; N, 17.39; O, 3.75.
drug [33].
Statistical analysis
Results are expressed as the mean ꢀ SEM, and different
groups were compared using one way analysis of variance
(ANOVA) followed by Tukey-Kramer test for multiple com-
parisons, using GraphPad Instant (version 3.05) as the stat-
istical software to calculate the statistics (Table 1).
Biological assay
Anti-inflammatory activity
Animals
70 adult male Sprague-Dawley rats (5 rats per group), weigh-
ing 150–170 g, were housed in cages in a temperature-con-
trolled (25 ꢀ 18C) environment and provided free access to
pelleted food and purified drinking water ad libitum. The
animal experiments described below comply with the ethical
principles and guidelines for the care and use of laboratory
animals adopted by the National Egyptian Community.
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www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 830–839
Synthesis of New Pyrroles of Potential Anti-Inflammatory Activity
839
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