Hydrazonoyl halides as precursors for new fused heterocycles of 5α-reductase inhibitors

Article abstract of DOI:10.1002/ardp.201100212

A new series of benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidines 8a-l was synthesized via reaction of heterocyclic thione 4 or its methyl derivatives 10 with hydrazonoyl halides 5a-l. Also, reaction of compound 4 with a mixture of chloroacetic acid a

Full text of DOI:10.1002/ardp.201100212

Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
117
Full Paper
Hydrazonoyl Halides As Precursors For New Fused
Heterocycles of 5a-Reductase Inhibitors
Thoraya A. Farghaly1, Sobhi M. Gomha1, Eman M. H. Abbas2, and Mohamed M. Abdalla3
1 Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
2 Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo, Egypt
3 MAPCO Pharmaceuticals Ltd., Balteem, Egypt
A new series of benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidines 8a–l was synthesized via reaction
of heterocyclic thione 4 or its methyl derivatives 10 with hydrazonoyl halides 5a–l. Also, reaction of
compound 4 with a mixture of chloroacetic acid and aromatic aldehyde derivatives gave
benzo[6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidin-3-ones 12–14. The microanalyses and spectral
data of the synthesized compounds are in full agreement with their molecular structure. All the
newly synthesized products were screened against 5a-reductase and showed activities with good ED50
for all compounds.
Keywords: 5a-Reductase inhibitors / Benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidines /
Benzo[6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidin-3-ones / Hydrazonoyl halides
Received: June 20, 2011; Revised: August 26, 2011; Accepted: September 1, 2011
DOI 10.1002/ardp.201100212
Introduction
Results and discussion
Chemistry
In a previous work we reported that some of our newly
substituted heterocyclic compounds exhibited antitumor
[1–5], antimicrobial [3, 4], 5a-reductase inhibitor [6] and
anti-HCV [1, 2, 4] activities. Benzosuberone ring system and
its fused systems present interesting pharmacological and
biological activities as blood platelet aggregation inhibitors
[7], antidepressants [8], analgesic [9], anti-inflammatory [9],
antipyretic [10], and antirheumatic activities [11]. In addition,
the structure of anastrozole (a drug used to treat breast
cancer after surgery and for metastases in both pre- and
post-menopausal women) is 1-substituted-1,2-4-triazole. In
view of these reports and in continuation of our previous
works in synthesis of bioactive heterocyclic compounds [1–6],
we have herein been interested in synthesis of fused triazoles
with pyrimidine and benzosuberone moieties and investi-
gated their activity as 5a-reductase inhibitors compared with
anastrozole drug.
The required 4-(4-methoxyphenyl)-1,3,4,5,6,7-hexahydro-2-
thioxo-benzo[6,7]cyclohepta[1,2–d]pyrimidine (4) was pre-
pared as outlined in Scheme 1. Thus, reaction of thiourea
with 2-(4-methoxybenzylidene)-benzo[1,2]cycloheptan-1-one
(3) in absolute ethanol in presence of potassium hydroxide
led to formation of compound 4. The structure of compound
4 was confirmed by elemental analyses and spectral data
(see Experimental).
Refluxing equimolar quantities of each of hydrazonoyl
halides 5a–l with 4-(4-methoxyphenyl)-1,3,4,5,6,7-hexahy-
dro-2-thioxo-benzo[6,7]cyclohepta[1,2-d]pyrimidine (4) in
dioxane in presence of triethylamine gave in each case a
single product as indicated by TLC analysis of the crude
product. The structure of the product was identified as ben-
zo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidine 8 (Scheme 2)
based on its elemental analysis and spectral (IR, 1H NMR and
MS) data. The other possible isomeric structure, namely,
benzo[6,7]cyclohepta[2,1-e]triazolo[4,3-a]pyrimidine
9
was
1
discarded. For example, the H NMR spectra of the isolated
products showed in each case a singlet signal in the region
d 5.86–6.51 ppm, assigned to H-4 of the pyrimidine ring
residue in the products 8. This assignment is based on the
Correspondence: Dr. Thoraya A. Farghaly, Department of Chemistry,
Cairo University, El Gama street, Giza 12613, Egypt.
E-mail: thoraya-f@hotmail.com
Fax: 00202-35727550
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

118
T. A. Farghaly et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
O
O
CHO
Alternatively, the formation of 8 from 2-methylthio deriva-
tive 10 (prepared from the reaction of thione 4 with methyl
iodide in acetone in presence of anhydrous potassium carbon-
ate) and hydrazonoyl halides 5 can be accomplished by cycli-
zation in situ of the non isolated intermediate amidrazone 11
with concurrent elimination of methanethiol (Scheme 3).
Finally, compound 4 reacted with chloroacetic acid in a
mixture of acetic acid and acetic anhydride and in presence
of fused sodium acetate to give 5-(4-methoxyphenyl)-2,5,6,7,8-
pentahydro-benzo[6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidin-
3-one (13). Treatment of the latter product 13 with benzal-
dehyde or 3,4,5-trimethoxybenzaldehyde in acetic acid and
in presence of fused sodium acetate afforded 5-(4-methoxy-
phenyl)-2-(phenylmethylene)-5,6,7,8-tetrahydro-benzo[6,7]
cyclohepta[2,1-d]thiazolo[3,2-a] pyrimidin-3-one (12) or 5-(4-
methoxyphenyl)-2-(3,4,5-trimethoxy-phenylmethylene)-5,6,7,
8-tetrahydro-benzo[6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidin-
3-one (14), respectively. Compound 12 was also prepared by
one step reaction via chloroacetic acid and benzaldehyde
under the same reaction conditions (Scheme 4). The structure
of compounds 12–14 was confirmed by elemental analyses
and spectral data (see Experimental).
OMe
KOH
+
3
1
OMe
2
NH2-CS-NH2
S
H
N
H
N
OMe
4
Scheme 1. Synthesis of compound 4.
fact that the H-4 in the pyrimidine ring is markedly affected
by the nature of the adjacent nitrogen (N3) (pyrrole type in
structure 8 and pyridine type in structure 9). The carbon
atom near N-pyrrole type is electron rich carbon and so
H-4 is expected to be more shielded than the carbon atom
near N-pyridine type. Typically the signal of H-4 in similar
compounds to 8 usually appears at d 5.6 – 6.3 [6, 12–14] whereas
that similar to compound 9 appears at d 3.95–4.15 [15].
R
S
N
H
NNHAr
N
S
H
N
H
Et3N/ Dioxane
N
R-C(X)=N-NH-Ar
5
+
6
OMe
4
OMe
Ar
N
N
Ar
N
N
N
R
NH
N
N
HS
-H2S
8
R
7
OMe
OMe
Ar = YC6H4
-H2S
X = Cl or Br
R
N
N
R/Y : a, CH3CO / H; b, CH3CO / 4-CH3; c, CH3CO / 4-Cl;
d, EtOCO / H; e, EtOCO / 4-CH3; f, EtOCO / 4-Cl;
N
Ar
g, PhNHCO / H; h, PhNHCO / 4-Cl; i, Ph / H;
j, PhCO / H; k, 2-naphthoyl / H; l, 2-thienyl / 4-NO2
N
9
Scheme 2. Synthesis of compound 8.
OMe
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Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
Hydrazonoyl Halides As Precursors
119
Table 1. Evaluation of ED50 and 5a-reductase inhibitor activities
relative to anastrozole
H
N
SMe
H
N
S
H
MeI
a
Compd.
No.
ED50
Potency relative
to anastrozole
N
N
(mg kgS1
)
K2CO3 / acetone
8k
8b
8e
8f
13
14
10
8c
8d
8l
8h
8j
8i
0.0123 ꢀ 000046
0.0156 ꢀ 000043
0.0188 ꢀ 000022
0.0196 ꢀ 000023
0.0256 ꢀ 000021
0.0278 ꢀ 000023
0.0311 ꢀ 000045
0.0411 ꢀ 000067
0.0512 ꢀ 000054
0.0678 ꢀ 000033
0.0689 ꢀ 000046
0.0714 ꢀ 000067
0.0723 ꢀ 000065
0.0744 ꢀ 000044
0.0754 ꢀ 000011
1.09
88.61789
69.87179
57.97872
556.1224
42.57813
39.20863
35.04823
26.52068
21.28906
16.0767
15.82003
15.26611
15.07607
14.65054
14.45623
1.00
10
4
OMe
OMe
R-C(X)=N-NH-Ar
Et3N/ Dioxane
5
SMe
NNHAr
N
Ar
N
N
N
N
N
R
R
8
-MeSH
4
12
11
OMe
Anastrozole
OMe
Ar = YC6H4
X = Cl or Br
R/Y : a, CH3CO / H; d, EtOCO / H; g, PhNHCO / H; i, Ph / H; j, PhCO / H
aED50: Dose caused 50% of pharmacological response in the test.
Scheme 3. Alternative synthesis of compound 8.
synthesized compounds were tested for their 5a-reductase
inhibitor activity in vivo; the ED50 data that indicate efficacy
were determined and are given in Table 1. (We determined
ED50 not IC50 according to the adopted procedure where we
measure ED50 mg/kg not the IC50 that involve molar
measurements.)
H
N
S
N
CHO
H
+
AcOH / AcONa
+
Cl-CH2-COOH
4
Some selected derivatives were screened for their 5a-reduc-
atase inhibitor activities and it is worth to mention that all
are more active than the reference drug anstrozole and they
arranged as follow in descending order of potency 8k, 8b, 8e,
8f, 13, 14, 10, 8c, 8d, 8I, 8h, 8j, 8i, 4, 12.
OMe
Cl-CH2-COOH
AcOH / AcONa
N
S
CHO
N
O
N
S
N
Experimental
12
AcOH / AcONa
CHO
O
OMe
13
All melting points were determined on an electrothermal
Gallenkamp apparatus. Solvents were distilled and dried by
standard literature procedures prior to use. The IR spectra were
measured on a Pye-Unicam SP300 instrument in potassium bro-
mide discs. The 1H NMR and 13C NMR spectra were recorded on a
Varian Mercury (300 MHz for 1H-NMR and 75 MHz for 13C NMR)
and the chemical shifts were related to that of the solvent
DMSO-d6. The mass spectra were recorded on GCMS-Q1000-EX
Shimadzu and GCMS 5988-A HP spectrometers, the ionizing
voltage was 70 eV. Elemental analyses were carried out by
the Microanalytical Center of Cairo University, Giza, Egypt.
Hydrazonoyl halides 5a–l were prepared following literature
methods [16].
OMe
MeO
OMe
OMe
N
OMe
S
N
OMe
OMe
O
OMe
14
Scheme 4. Synthesis of compounds 12 and 14.
Preparation of 4-(4-methoxyphenyl)-1,3,4,5,6,7-
hexahydro-2-thioxo-benzo[6,7]cyclohepta[1,2-d]-
pyrimidine (4)
To a boiling mixture of compound 3 (2.78 g, 0.01 mol) in ethanol
(100 mL) containing potassium hydroxide (1 g) in water (0.5 mL)
was added thiourea (0.76 g, 0.01 mol) and the reaction mixture
Pharmacological screening
Circulating testosterone and dihydrotestosterone hormone
levels or tissue concentrations were measured after admin-
istration of 5a-reductase inhibitor radioimmuno assays. All
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T. A. Farghaly et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
was refluxed for 3h, allowed to cool and the solid formed was
filtered off, dissolved in water and precipitated by HCl. The solid
formed was filtered off and crystallized from ethanol to afford
compound 4 as yellow crystals. Yield (96%) mp 2108C. IR (KBr,
cmꢁ1) 3298, 3201 (2NH), 1H NMR (DMSO-d6) at d ¼ 1.40–2.42
(m, 6H, 3CH2), 3.76 (s, 3H, OCH3), 4.87 (s, 1H, pyrimidine–H),
6.95 (d, J ¼ 8 Hz, 2H, Ar-H), 7.20–7.26 (m, 4H, ArH), 7.28
(d, J ¼ 8 Hz, 2H, Ar-H), 8.83 (s, 1H, NH, exchangeable with
D2O), 9.66 (s, 1H, NH, exchangeable with D2O), MS m/z (%) 336
(Mþ, 100), 335 (77), 334 (34), 307 (66), 275 (24), 229 (92), 214 (11),
154 (18), 128 (20), 115 (46), 91 (14), 77 (23), Anal. Calcd.
for C20H20N2OS (336.46): C, 71.40; H, 5.99; N, 8.33. Found C,
71.21; H, 5.82; N, 8.15%.
3-Acetyl-1,5,6,7,8-pentahydro-1-(4-methylphenyl)-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[2,1-d]-
triazolo[4,3-a]pyrimidine (8b)
Dark orange solid, yield (90%), mp 82–848C (ethanol), IR (KBr,
cmꢁ1) 1693 (CO). 1H NMR (DMSO-d6) d ¼ 1.25–2.0 (m, 6H, 3CH2),
2.35 (s, 3H, CH3), 2.51 (s, 3H, COCH3), 3.81 (s, 3H, OCH3), 6.28
(s, 1H, pyrimidine-H), 6.88 (d, J ¼ 8 Hz, 2H, Ar-H), 7.13–7.59
(m, 8H, Ar-H), 8.14 (d, J ¼ 8 Hz, 2H, Ar-H). MS m/z (%) 477
(Mþþ1, 17), 476 (Mþ , 66), 368 (100), 336 (37), 242 (49), 202
(34), 178 (57), 154 (69), 127 (63), 104 (37), 92 (49), 77 (97). Anal.
Calcd. for C30H28N4O2 (476.58): C, 75.61; H, 5.92; N, 11.76. Found
C, 75.88; H, 5.83; N, 11.54%.
3-Acetyl-1,5,6,7,8-pentahydro-1-(4-chlorophenyl)-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8c)
Preparation of 4-(4-methoxyphenyl)-3,4,5,6,7-pentahydro-
2-methylthio-benzo[6,7]cyclohepta[1,2-d]pyrimidine (10)
To a stirred solution of compound 4 (1.68 g, 5 mmol) in acetone
(20 mL) was added anhydrous potassium carbonate (0.70 g,
5 mmol) and methyl iodide (0.71 g, 5 mmol). The reaction mix-
ture was stirred overnight at room temperature, then the solvent
was evaporated. The solid formed was filtered off, washed with
water, dried and crystallized from ethanol to give compound 10
as yellow solid. Yield (81%) mp 2008C. IR (KBr, cmꢁ1) 3245 (NH). 1H
NMR (DMSO-d6) at d ¼ 1.23–2.42 (m, 6H, 3CH2), 2.67 (s, 3H, SCH3),
3.77 (s, 3H, OCH3), 4.73 (s, 1H, pyrimidine–H), 6.95 (d, J ¼ 9 Hz,
2H, Ar-H), 7.19–7.29 (m, 4H, ArH), 7.31 (d, J ¼ 9 Hz, 2H, Ar-H), 9.41
(s, 1H, NH, exchangeable with D2O). MS m/z (%) 350 (Mþ, 21), 348
(44), 320 (13), 241 (100), 168 (11), 128 (28), 115 (30), 91 (24), 77 (41).
Anal. Calcd. for C21H22N2OS (350.49): C, 71.97; H, 6.33; N, 7.99.
Found C, 71.76; H, 6.25; N, 7.84%.
Orange crystal, yield (81%), mp 1208C (ethanol), IR (KBr, cmꢁ1
)
1
1697 (CO). H NMR (DMSO-d6) d ¼ 1.15–2.46 (m, 6H, 3CH2), 2.58
(s, 3H, COCH3), 3.76 (s, 3H, OCH3), 6.26 (s, 1H, pyrimidine–H),
6.88–7.61 (m, 12H, ArH). MS m/z (%) 498 (Mþþ2, 15), 497 (Mþþ1,
41), 496 (Mþ, 66), 389 (100), 336 (95), 229 (59), 190 (46), 168 (39),
153 (42), 121 (75), 115 (46), 111 (22), 91 (53), 76 (19). Anal. Calcd.
for C29H25ClN4O2 (497.0): C, 70.09; H, 5.07; N, 7.13. Found C,
70.10; H, 5.32; N, 7.09%.
3-Ethoxycarbonyl-1,5,6,7,8-pentahydro-1-phenyl-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8d)
Yellow solid, yield (79%), mp 146–1488C (ethanol), IR (KBr, cmꢁ1
)
1724 (CO).1H NMR (CDCl3) d ¼ 1.27 (t, J ¼ 7 Hz, 3H, CH3),
1.73–2.55 (m, 6H, 3CH2), 3.80 (s, 3H, OCH3), 4.34 (q, J ¼ 7 Hz,
2H, CH2), 6.32 (s, 1H, pyrimidine–H), 6.84 (d, J ¼ 8 Hz, 2H, Ar-H),
6.98–7.77 (m, 9H, ArH), 8.27 (d, J ¼ 8 Hz, 2H, Ar-H). MS m/z (%) 493
(Mþþ1, 7), 492 (Mþ, 29), 385 (48), 307 (17), 278 (20), 135 (33), 121
(31), 115 (30), 105 (22), 103 (29), 91 (96), 77 (100). Anal. Calcd. for
C30H28N4O3 (492.58): C, 73.15; H, 5.73; N, 11.37. Found C, 73.34;
H, 5.54; N, 11.49%.
Preparation of benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-
a]pyrimidines (8a–l)
Method A: To a mixture of equimolar amounts of 4 and the
appropriate hydrazonoyl halides 5a–l (2.5 mmol of each) in
dioxane (20 mL) was added triethylamine (0.35 mL, 2.5 mmol).
The reaction mixture was refluxed till all of the starting
materials have disappeared and hydrogen sulfide gas ceased to
evolve (10 h monitored by TLC). The solvent was evaporated and
the residue was treated with methanol. The solid that formed
was filtered off and crystallized from the appropriate solvent to
give compounds 8a–l.
Method B: To a mixture of equimolar amounts of 10 and the
appropriate hydrazonoyl halides 5a,d,g,I,h (2.5 mmol of each) in
dioxane (20 mL) was added triethylamine (0.35 mL, 2.5 mmol).
The reaction mixture was refluxed till all methanethiol gas
ceased to evolve (20 h, monitored by TLC). The solvent was
evaporated and the residue was treated with methanol. The solid
that formed was filtered off and crystallized from the appropri-
ate solvent to give products identical in all respects (mp, mixed
mp and IR) with that formed by Method A.
3-Ethoxycarbonyl-1,5,6,7,8-pentahydro-1-
(4-methylphenyl)-5-(4-methoxyphenyl)-benzo[6,7]-
cyclohepta[1,2-d]triazolo[4,3-a]pyrimidine (8e)
Yellow solid, yield (78%), mp 1608C (ethanol/dioxane), IR (KBr,
cmꢁ1) 1724 (CO).1H NMR (CDCl3) d ¼ 1.23 (t, J ¼ 7 Hz, 3H, CH3),
1.60–2.0 and 2.39–2.49 (m, 6H, 3CH2), 2.33 (s, 3H, CH3), 3.73 (s, 3H,
OCH3), 4.27 (q, J ¼ 7 Hz, 2H, CH2), 6.25 (s, 1H, pyrimidine–H), 6.90
(d, J ¼ 9 Hz, 2H, Ar-H), 7.15–7.32 (m, 4H, ArH), 7.35 (d, J ¼ 8 Hz,
2H, Ar-H), 7.57 (d, J ¼ 8 Hz, 2H, Ar-H), 8.08 (d, J ¼ 9 Hz, 2H, Ar-H).
MS m/z (%) 507 (Mþþ1, 27), 506 (Mþ, 71), 399 (99), 327 (36), 121
(56), 115 (28), 104 (42), 91 (100), 77 (54). Anal. Calcd. for
C31H30N4O3 (506.61): C, 73.50; H, 5.97; N, 11.06. Found C,
73.38; H, 5.82; N, 11.00%.
3-Acetyl-1,5,6,7,8-pentahydro-1-phenyl-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8a)
3-Ethoxycarbonyl-1,5,6,7,8-pentahydro-1-
(4-chlorophenyl)-5-(4-methoxyphenyl)-benzo[6,7]-
cyclohepta[1,2-d]triazolo[4,3-a]pyrimidine (8f)
Yellow solid, yield (85%), mp 100–1028C (ethanol/dioxane), IR
(KBr, cmꢁ1) 1728 (CO).1H NMR (CDCl3) d ¼ 1.24 (t, J ¼ 7 Hz,
3H, CH3), 1.60–2.40 (m, 6H, 3CH2), 3.73 (s, 3H, OCH3), 4.28
(q, J ¼ 7 Hz, 2H, CH2), 6.26 (s, 1H, pyrimidine–H), 6.90
Yellow solid, yield (80%) mp 120–1228C (ethanol), IR (KBr, cmꢁ1
)
1
1692 (CO), H NMR (DMSO-d6) d ¼ 1.20–2.43 (m, 6H, 3CH2), 2.51
(s, 3H, COCH3), 3.79 (s, 3H, OCH3), 6.46 (s, 1H, pyrimidine-H),
7.01–8.03 (m, 13H, Ar-H). MS m/z (%) 462 (Mþ, 10), 109 (35), 91 (80),
77 (100), Anal. Calcd. for C29H26N4O2 (462.56): C, 75.30; H, 5.67;
N, 12.11. Found C, 75.21; H, 5.48; N, 12.05%.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
Hydrazonoyl Halides As Precursors
121
(d, J ¼ 9 Hz, 2H, Ar-H), 7.18–7.32 (m, 4H, ArH), 7.36 (d, J ¼ 9 Hz,
2H, Ar-H), 7.56 (d, J ¼ 9 Hz, 2H, Ar-H), 8.26 (d, J ¼ 9 Hz, 2H, Ar-H).
MS m/z (%) 528 (Mþþ2, 6), 527 (Mþþ1, 17), 526 (Mþ, 49), 419 (70),
126 (79), 125 (87), 111 (100), 90 (72), 77 (45). Anal. Calcd. for
C30H27ClN4O3 (527.03) C, 68.37; H, 5.16; N, 10.63. Found C, 68.21;
H, 5.09; N, 10.58%.
(d, J ¼ 8 Hz, 1H, naphthyl-H), 8.32 (d, J ¼ 9 Hz, 2H, Ar-H).
MS m/z (%) 575 (Mþþ1, 11), 574 (Mþ, 36), 467 (32), 452 (30),
279 (23), 155 (100), 129 (27), 127 (93), 126 (59), 121 (48), 115
(39), 92 (30), 77 (86). Anal. Calcd. for C38H30N4O2(574.68): C, 79.42;
H, 5.26; N, 9.75. Found: C, 79.52; H, 5.43; N, 9.59%.
3-(2-Thienyl)-1,5,6,7,8-pentahydro-1-(4-nitrophenyl)-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8l)
Yellow solid, yield (74%), mp. 1388C (ethanol/dioxane); MS m/z (%)
548 (Mþþ1, 26), 547 (Mþ, 57), 437 (61), 228 (30), 217 (61), 167 (44),
131 (65), 127 (57), 121 (91), 115 (100), 111 (22), 106 (70), 91 (78), 77
(61), 76 (91)105 (46), 91 (100). Anal. Calcd. for C31H25N5O3S
(547.64): C, 67.99; H, 4.60; N, 12.79. Found: C, 67.86; H, 4.65;
N, 12.58%.
3-Phenylcarbamoyl-1,5,6,7,8-pentahydro-1-phenyl-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8g)
Dark red solid, yield (70%), mp 1308C (ethanol), IR (KBr, cmꢁ1
)
3421 (NH), 1693 (CO), MS m/z (%) 540 (Mþþ1, 20), 539 (Mþ, 42), 432
(43), 418 (37), 280 (31), 170 (31), 159 (43), 119 (51), 105 (17), 91 (86),
77 (100). Anal. Calcd. for C34H29N5O2 (539.64): C, 75.68; H, 5.42; N,
12.98. Found C, 75.92; H, 5.27; N, 12.78%.
Preparation of 5-(4-methoxyphenyl)-2,5,6,7,8-pentahydro-
benzo[6,7]cyclohepta [1,2-d]thiazolo[3,2-a]pyrimidine-3-
one (13)
3-Phenylcarbamoyl-1,5,6,7,8-pentahydro-1-
(4-chlorophenyl)-5-(4-methoxy-phenyl)-benzo[6,7]-
cyclohepta[1,2-d]triazolo[4,3-a]pyrimidine (8h)
A mixture of compound 4, chloroacetic acid (0.005 mol each),
and fused sodium acetate (3 g) in glacial acetic acid (15 mL) and
acetic anhydride (5 mL) was refluxed for 3h, left to cool, then
poured gradually with stirring onto cold water. The solid formed
was filtered off, washed with water and crystallized from ethanol
to give compound 13 as rose solid, yield (71%), mp. 200–2028C
(ethanol), IR (KBr, cmꢁ1) 1695 (CO). 1H NMR (DMSO-d6) at
d ¼ 1.37–2.25 (m, 6H, 3CH2), 3.75 (s, 3H, OCH3), 5.69 (s, 2H,
CH2), 6.93–7.46 (m, 9H, ArH þ pyrimidinyl-H). MS m/z (%) 376
(Mþ,12), 346 (26), 332 (100), 121 (48), 104 (16), 84 (25), 77 (31).
Anal. Calcd. for C22H20N2O2S (376.48): C, 70.19; H, 5.35; N, 7.44.
Found: C, 70.22; H, 5.25; N, 7.29%.
Yellow solid, yield (73%), mp. 858C (ethanol/dioxane), IR (KBr,
cmꢁ1) 3305 (NH), 1685 (CO).1H-NMR (CDCl3) d ¼ 1.27–2.63
(m, 6H, 3CH2), 3.77 (s, 3H, OCH3), 6.51 (s, 1H, pyrimidine–H),
6.83–8.24 (m, 17H, ArH), 11.42 (s, 1H, NH, exchangeable with
D2O). MS m/z (%) 576 (Mþþ2, 14), 574 (Mþ, 42), 468 (51), 466 (100),
426 (54), 316 (51), 225 (30), 151 (74), 147 (42), 121 (58), 111 (28),
105 (35), 91 (91), 77 (95). Anal. Calcd. for C34H28ClN5O2 (574.09): C,
71.14; H, 4.92; N, 12.20. Found C, 71.32; H, 5.04; N, 12.25%.
1,3-Diphenyl-1,5,6,7,8-pentahydro-5-(4-methoxyphenyl)-
benzo[6,7]cyclohepta[1,2-d]triazolo[4,3-a]pyrimidine (8i)
Yellow solid, yield (79%), mp. 1008C (ethanol), 1H-NMR (DMSO-d6)
d ¼ 1.39–2.62 (m, 6H, 3CH2), 3.72 (s, 3H, OCH3), 5.86 (s, 1H,
pyrimidine–H), 6.62–8.40 (m, 18H, ArH). MS m/z (%) 496
(Mþ, 39), 495 (13), 392 (28), 389 (41), 140 (20), 121 (47), 115
(25), 105 (17), 103 (31), 91 (93), 77 (100). Anal. Calcd. for
C33H28N4O(496.62): C, 79.81; H, 5.68; N, 11.28. Found C, 79.73;
H, 5.43; N, 11.20%.
Preparation of 2-arylidine-benzo[6,7]cyclohepta[1,2-d]-
thiazolo[3,2-a]pyrimidine-3-one (12 and 14)
Method A: A mixture of compound 4 (0.34 g, 0.001 mol), chloro-
acetic acid (0.10 g, 0.001 mol) and fused sodium acetate (0.6 g) in
glacial acetic acid (10 mL), acetic anhydride (5 mL) and the
appropriate aromatic aldehyde (0.001 mole) was refluxed for
3h. The reaction mixture was cooled, poured onto cold water
and the solid formed was collected and crystallized from ethanol
to give compound 12 or 14.
Method B: A mixture of compound 13 (0.38 g, 0.001 mol), and
fused sodium acetate (0.6 g) in glacial acetic acid (10 mL), acetic
anhydride (5 mL) and benzaldehyde (0.11 g, 0.001 mole) was
refluxed for 3h. The reaction mixture was cooled, poured onto
cold water and the solid formed was collected and crystallized
from ethanol to give compound 12.
5-(4-Methoxyphenyl)-2-(phenylmethylene)-5,6,7,8-tetrahydro-benzo[6,7]cy-
clohepta [1,2-d]thiazolo[3,2-a]pyrimidine-3-one (12) as yellow solid, yield
(65%), mp. 1558C (EtOH). MS m/z (%) 465 (Mþþ1, 19), 464 (Mþ, 48),
343 (51), 329 (30), 232 (16), 134 (74), 133 (46), 121 (26), 92 (17), 76
(14). Anal. Calcd. for C29H24N2O2S (464.59): C, 74.97; H, 5.21; N,
6.03. Found: C, 74.85; H, 5.19; N, 6.27%.
3-Benzoyl-1,5,6,7,8-pentahydro-1-phenyl-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8j)
Red solid, yield (76%), mp. 1588C (ethanol/dioxane), IR (KBr, cmꢁ1
)
1
1680 (CO), H-NMR (DMSO-d6) d ¼ 1.20–2.43 (m, 6H, 2CH2), 3.66
(s, 3H, OCH3), 6.42 (s, 1H, pyrimidine–H), 6.83 (d, J ¼ 9 Hz, 2H,
Ar-H), 7.17–8.02 (m, 14H, ArH), 8.25 (d, J ¼ 9 Hz, 2H, Ar-H). MS m/z
(%) 524 (Mþ, 6), 394 (18), 393 (23), 392 (36), 336 (24), 339 (15), 141
(21), 130 (18), 117 (18), 115 (33), 105 (68), 91 (44), 89 (19), 77 (100).
Anal. Calcd. for C34H28N4O2 (524.63): C, 77.84; H, 5.38; N, 10.68.
Found C, 77.82; H, 5.43; N, 10.48%.
3-(2-Naphthoyl)-1,5,6,7,8-pentahydro-1-phenyl-5-
(4-methoxyphenyl)-benzo[6,7]cyclohepta[1,2-d]-
triazolo[4,3-a]pyrimidine (8k)
5-(4-Methoxyphenyl)-2-(3,4,5-trimethoxyphenylmethylene)-5,6,7,8-tetra-
hydro-benzo [6,7]cyclohepta[1,2-d]thiazolo[3,2-a]pyrimidine-3-one (14) as
yellow solid, yield (62%), mp. 1798C (EtOH). 1H-NMR (DMSO-d6)
at d ¼ 1.25–2.41 (m, 6H, 2CH2), 3.72, 3.80, 3.83, 3.87 (4s, 12H,
4OCH3), 5.79 (s, 1H, pyrimidine–H), 6.94 (d, J ¼ 9 Hz, 2H, Ar-H),
7.11–7.34 (m, 6H, ArH), þ7.37 (d, J ¼ 9 Hz, 2H, ArH), 7.67 (s, 1H,
Orange solid, yield (82%), mp. 1308C (ethanol/dioxane), IR
(KBr, cmꢁ1
)
1693 (CO). 1H-NMR (DMSO-d6) d ¼ 1.20–2.41
(m, 6H, 2CH2), 3.72 (s, 3H, OCH3), 6.27 (s, 1H, pyrimidine–H),
6.88 (d, J ¼ 9 Hz, 2H, Ar-H), 7.16–7.28 (m, 13H, ArH), 7.37
(d, J ¼ 8 Hz, 2H, naphthyl-H), 7.45 (s, 1H, naphthyl-H), 7.59
–
–
CH). MS m/z (%) 554 (M , 36), 553 (20), 448 (31), 447 (100), 446
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

122
T. A. Farghaly et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 117–122
(45), 433 (28), 224 (17), 209 (30), 120 (15), 77 (8). Anal. Calcd.
for C32H30N2O5S (554.67): C, 69.29; H, 5.45; N, 5.05. Found: C,
69.35; H, 5.28; N, 5.27%.
Determination of acute toxicity
ED50 was determined by using male albino rats and injecting
them with different increasing doses of agents. Doses that killed
50% of the tested animals, was calculated according to Austen
et al. [19] (Table 1).
Pharmacology
Biological assay
The authors have declared no conflict of interest.
Treatment of animals
Animals were obtained from the animal house colony of the
National Research Center, Cairo, Egypt. All animals were allowed
free access to water and were kept on a constant standard diet.
Twenty three groups, each of 12 male Sprague-Dawley rats in the
postnatal third days, were treated subcutaneously with the 5a-
reductase inhibitor (tested compound or reference standard).
The tested compounds were dissolved in 5% Tween 80 in water.
The solvent was used for both standard and negative control
group, beginning on the postnatal third day until the age of
seven weeks.
Twenty-one groups were used to test the activities, of which
one was used as the positive control for anastrozole and another
served as the negative control group. After scarifying, blood was
withdrawn for testosterone and dihydrotestosterone (DHT) deter-
mination [17]. Moreover, intraprostatic concentrations of testos-
terone and DHT were determined [18].
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com