Synthesis and biological evaluation as AChE inhibitors of new indanones and thiaindanones related to donepezil

European Journal of Medicinal Chemistry 40 (2005) 1222–1245

www.elsevier.com/locate/ejmech

Original article

Synthesis and biological evaluation as AChE inhibitors of new indanones

and thiaindanones related to donepezil

Ziad Omran, Thomas Cailly, Elodie Lescot, Jana Sopkova-de Oliveira Santos,

Jean-Hugues Agondanou, Vincent Lisowski, Frédéric Fabis, Anne-Marie Godard,

Silvia Stiebing, Guillaume Le Flem, Michel Boulouard, François Dauphin,

Patrick Dallemagne *, Sylvain Rault

Centre d’études et de recherche sur le médicament de Normandie, département de pharmacochimie U.F.R. des sciences pharmaceutiques,

université de Caen Basse-Normandie, boulevard Becquerel, 14032 Caen cedex, France

Received 28 April 2005; received in revised form 17 June 2005; accepted 1 July 2005

Available online 30 August 2005

Abstract

Sixty-four new indanones and thiaindanones related to donepezil were synthesized and evaluated in vitro as potential AChE inhibitors.

Among them, 11 derivatives were found to inhibit the enzyme in the submicromolar range; the best compound revealed its inhibitory activity

with an IC₅₀in the same range (0.06 µM) than the reference compound, donepezil (IC₅₀= 0.02 µM).

Keywords: Alzheimer disease; Donepezil; Acetylcholinesterase; Cyclopentathiophene; Indanone; Thiaindanone

1. Introduction

2. Chemistry

The access to the aminocyclopentanone system fused on a

benzene or a thiophene ring was achieved as previously

described by our group from various benzene or thiophene

carboxaldehydes 76–79 (Scheme 1). The synthetic pathway

involved the b-aminoacids 80–83 obtained from the latter

according to the Rodionow–Johnson [10,11] reaction which

were then, eventually after halogenation, cyclized and ﬁnally

Alzheimer disease (AD) is characterized by reduced cor-

tical and hippocampal levels of acetylcholine (ACh). Agents

that restore the latter through the inhibition of acetylcholinest-

erase (AChE) constitute as of today the main palliative treat-

ment of this affection [1]. Among AChE inhibitors, done-

pezil (E2020; 1) [2], a dimethoxyindanone derivative, exhibits

a long and selective action and manageable adverse effects

that confer to it a lead position in this pharmacological series

in view to design analogues with potential interest in the treat-

ment of AD [3]. Taking our experience in the indanone ﬁeld

into account, we focused on the synthesis and the in vitro

biological evaluation as AChE inhibitors of new derivatives

2–65 related to donepezil, prepared from 5,6-dimethoxy-3-

aminoindan-1-one 66 and its thiophene isosters 67–75 (Fig. 1 )

[4–9].

* Corresponding author. Tel.: +33 2 31 56 59 10; fax: +33 2 31 93 34 73.

E-mail address: patrick.dallemagne@unicaen.fr (P. Dallemagne).

Fig. 1.

doi:10.1016/j.ejmech.2005.07.009

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1223

Scheme 1

.

hydrolyzed to yield the hydrochloric salts of the aminocyclo-

pentanones 66–75. The latter were treated in alkaline medium

to liberate the free bases which were then involved in a reac-

tion with bromoacetyl bromide yielding the bromoaceta-

mides 84–92, which were ﬁnally reacted with various

N-substituted piperazines to provide the title derivatives 2–58

(Scheme 2).

The commercially unavailable piperazinyl reagents in-

volved in this nucleophilic substitution were prepared from

substituted arylmethylhalides by reaction with an excess of

piperazine. The unknown N-(pyrrol-2-ylmethyl)- 99 and [(2,5-

dimethoxythien-3-yl)]methyl- 100 piperazines were issued

from the reductive amination of arylcarboxaldehydes 95, 96

by ethyl piperazine-carboxylate in the presence of sodium

cyanoborohydride and subsequent N-deprotection of the car-

boxylates 97, 98 in alkaline medium under microwave appli-

cation (Scheme 3).

The dibromocyclopenta[c]thiophene series, selected by the

biological evaluation, was particularly submitted to various

pharmacomodulations. For example, the oximes 59–61 were

selectively prepared under their E form starting from 13, 20

or 43, respectively, using hydroxylamine displaced from its

hydrochloride (Scheme 4).

On the other hand, in a similar manner as above and start-

ing from the corresponding bromoacetamide 91, the benzyl-

homopiperazinyl 62 and piperidinyl derivatives 63 were pre-

pared (Scheme 5).

Finally, the length of the linker chain between the piper-

azinyl and the thiaindanone moieties was declined through

the synthesis of the compounds 64 and 65 (Scheme 6). The

latter were prepared from the aminodibromocyclopen-

ta[c]thiophene derivative 74 whose the hydrochloric salt was

reacted with bromobutyryl- and bromopropionyl chloride,

respectively, to give the bromide 93 and the a,b-unsaturated

derivative 94. The latter was issued from a b-elimination

which took place in the presence of an excess of TEA, while

no traces of the corresponding halide were observed in this

case. Compounds 93 and 94 yielded 64 and 65, respectively,

under treatment with 2-chlorobenzylpiperazine.

3. Discussion

Compounds 2–65 were tested for in vitro inhibition of

AChE on the commercially available electric eel enzyme

according to the Ellman et al.’s [12] method. Taking into

account the SAR recently established by the structure eluci-

dation of AChE-donepezil co-crystal [13], we ﬁrst evaluated

a dimethoxyindanone derivative 2 substituted on the

3-position by a benzyl-piperazinylacetamide moiety likely to

reproduced the interactions between donepezil andAChE. The

result (Table 1 ), however, was quite disappointing since 2

inhibited AChE at a two hundred-fold higher concentration

than donepezil (IC₅₀= 4.00 µM versus 0.02 µM).

Substitution of the phenyl ring of 2 by various halogen

atoms or groups did not permit to recover the inhibitory activ-

ity at the noteworthy exception of the 2-chlorophenyl deriva-

tive 9 (IC₅₀= 0.65 µM). On the other hand, replacement of

the indanone moiety of 2 by an oxodibromocyclopen-

ta[c]thiophene one slightly improved the activity of com-

pound 12 (IC₅₀= 0.56 µM) and consequently the latter was

considered as a new lead for further pharmacomodulations.

So, replacement of the piperazine ring of 12 by piperidine

(63) or homopiperazine (62) resulted in a total loss of anti-

AChE activity in a similar manner as for the introduction of a

cyclohexylmethyl (56), a phenyl (57) or a phenethyl (58)

group in place of the benzyl one (Table 2 ). Substitution of the

latter was also examined. The results showed that introduc-

tion of a substituent in the 4- or 3-position resulted in a loss

of activity whatever its nature, except for a ﬂuorine atom

which however decreased it (22, IC₅₀= 1.40 µM and 21,

IC₅₀= 2.50 µM). In the mean time and in a similar manner

than for the indanone series, substitution of the 2-position of

the benzyl group by a chlorine (13, IC₅₀= 0.22 µM), ﬂuorine

(20, IC₅₀= 0.40 µM) or bromine atom (23, IC₅₀= 0.58 µM)

or a methyl group (26, IC₅₀= 0.75 µM) preserved or improved

the anti-AChE activity at the condition that the other phenyl

positions remain unsubstituted. It was not the case for the

derivatives bearing on this 2-position an iodine atom (24), a

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Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

Scheme 2

.

triﬂuoromethyl (25), a nitro (29), an amino (32), or a meth-

oxy group (34) which were almost devoid of activity. In a

similar manner, replacement of the phenyl ring of the benzyl

moiety by a naphthalene (38), a pyridine (39–41), a furane

(46, 47) or a pyrrole (48) ring dramatically resulted in

decreased activity. The latter was nevertheless preserved at a

lower level with a 2-thiophene ring (42, IC₅₀= 1.25 µM) and

even increased with a 3-thiophene one (43, IC₅₀= 0.18 µM).

Substitution of the thiophene ring of 42 and 43 by a chlorine

atom (44) or by two methoxy groups (45), respectively, how-

ever suppressed the activity.

On the other hand, compounds 64 and 65, the upper homo-

logues of 13, showed that the acetamido group between the

cyclopentane moiety and the piperazine one is critical for anti-

AChE activity since these compounds were almost devoid of

activity (Table 3 ).

Scheme 3

.

Scheme 4.

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1225

Scheme 5

.

The effect of the position of the sulfur atom of the

thiophene ring as well as the nature of the substituents of the

latter on the activity of 20 were then examined (Table 4). It

appeared that the cyclopentane ring must be fused on the

c-side of the thiophene since the cyclopenta[b] thiophene

derivatives 53–55 were inactive. The thiophene ring must be

further substituted on the 1- and 3-positions by two methyl

groups (51, IC₅₀= 0.57 µM), or halogen atoms since the

dibromo compound 20 remained three to four-fold more active

than its 1-monobromo derivative (49, IC₅₀= 1.10 µM) or than

its dichloro analog (52, IC₅₀= 1.50 µM) and the unsubsti-

tuted derivative 50 totally losing the activity.

Finally, the role of the cyclopentane carbonyl of the most

active compounds 13, 20 and 43 was studied through its con-

densation into an oxime group (Table 5). Compound 59

was totally devoid of the activity of 13, whereas 61

(IC₅₀= 0.14 µM) conserved those of 43. In the 2-ﬂuorobenzyl

series, the oxime (60, IC₅₀= 0.06 µM) signiﬁcantly improved

the inhibitory activity of the oxo derivative 20.

4. Molecular modeling

The crystal structure of AChE cocrystallized with done-

pezil 1 [13], showed that donepezil binds in the active-site

cleft principally by (i) stacking interaction of indanone with

Trp₂₇₉and (ii) stacking interaction of the benzyl ring with

Trp₈₄(Fig. 2 ). (iii) A p-cation interaction occurs between the

charged nitrogen of the piperidine ring and the phenyl ring of

Phe₃₃₀. No direct hydrogen bond between the enzyme and

donepezil could be detected in the structure; donepezil binds

to the enzyme via hydrogen bonds through water molecules

(iv).

A 3D model of the inhibitor molecules was built and posi-

tioned into the AChE cleft automatically by the program

Scheme 6

.

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Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

Table 1

Table 2

Anti-AchE activity of compounds 1–12

Anti-AchE activity of compounds 12–48, 56–58, 62, 63

Compd^a

R

IC₅₀SD (µM)^b

0.02 0.01 (N = 4)^c

4.00 (N = 1)

Inactive

1

2

3

4

5

6

7

8

–

Compd

12^a

13^a

14

Ar₂

IC₅₀SD (µM)^b

0.56 0.05 (N = 2)^c

0.22 0.01 (N = 2)

Inactive

–

4-OMe

4-Br

4-Cl

3-CF₃

3-Cl

3-CN

2-Cl

2-NO₂

2,6-diCl

–

2-Cl-C₆H₄

3-Cl-C₆H₄

4-Cl-C₆H₄

2,3-diCl-C₆H₃

2,4-diCl-C₆H₃

2,5-diCl-C₆H₃

2,6-diCl-C₆H₃

2-F-C₆H₄

Inactive

15

Inactive

16

Inactive

17^a

18^a

19

Inactive

9

0.65 0.05 (N = 2)

Inactive

10

11

12

20^a

21^a

22^a

23^a

24

0.40 0.07 (N = 3)

2.50 0.20 (N = 2)

1.40 0.20 (N = 2)

0.58 0.03 (N = 2)

Inactive

3-F-C₆H₄

0.56 0.05 (N = 2)

4-F-C₆H₄

^aThe value of the hydrochloride is shown.

2-Br-C₆H₄

2-I-C₆H₄

^bIC₅₀value was measured for enzyme activity < 20% at 10⁻⁵M.

^cN = number of duplicate independent experiments.

25^a

26^a

27^a

28^a

29

30^a

31^a

32^a

33^a

34^a

35

2-CF₃-C₆H₄

2-Me-C₆H₄

3-Me-C₆H₄

4-Me-C₆H₄

2-NO₂-C₆H₄

3-NO₂-C₆H₄

4-NO₂-C₆H₄

2-NH₂-C₆H₄

4-NH₂-C₆H₄

2-OMe-C₆H₄

3-OMe-C₆H₄

4-OMe-C₆H₄

3,4-diOMe-C₆H₃

Inactive

LigandFit (Cerius2) [14]. The position of 12 we found is very

similar to that of donepezil (Fig. 2). In the bottom part, the

interactions of donepezil are conserved: (i) the benzyl moi-

ety stacks against the indole ring of Trp₈₄and (ii) the charged

nitrogen of the piperazine ring is oriented in a position suit-

0.75 0.65 (N = 3)

Inactive

able for a p-cation interaction with the phenyl ring Phe₃₃₀

.

1.40 0.60 (N = 3)

Inactive

The differences are observed in upper part, the dibromocy-

clopenta [c]thiophene moiety takes different orientations with

respect to Trp₂₇₉. (iii) The p-stacking interaction between this

moiety and the indole is perturbed, and the bromine atom at

position 1 on the thiophene is oriented outside of the protein

cavity contrary to the brome at position 3, which is oriented

inside of the protein, in a hydrophobic environment.

Inactive

36^a

37^a

38

Inactive

In vitro tests showed that substitution of the ortho position

of the benzyl ring by a chlorine (compound 13) or ﬂuorine

atom (compound 20) increases the inhibitory activity. Mod-

eling studies on 20 showed that substitution of the benzyl at

the ortho position by a ﬂuorine atom modiﬁes the orientation

of the benzyl ring in a manner that its p-stacking with the

Trp₈₄is ampliﬁed.

We further observed that the presence of a hydrophobic

aromatic group on the place of a benzyl group is favorable

for a good afﬁnity. The best inhibition activity was observed

for the thiophene derivative 43. Sulfur is a hydrophobic atom

and its presence in the ring enhanced the hydrogen bond donor

capacity of two neighboring carbons (Fig. 3). Along to our

39^a

40^a

Inactive

›

41^a

42^a

43^a

Inactive

1.25 0.25 (N = 2)

0.18 0.01 (N = 2)

(continued on next page)

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1227

Table 2

Table 3

(continued)

Anti-AchE activity of compounds 13, 64, 65

Compd

Ar₂

IC₅₀SD (µM)^b

Compd^a

13

64

65

IC₅₀SD (µM)^b

0.22 0.01 (N = 2)^c

Inactive

44^a

Inactive

45^a

Inactive

^aThe value of the hydrochloride is shown.

^bIC₅₀value was measured for enzyme activity < 20% at 10⁻⁵M.

^cN = number of duplicate independent experiments.

46^a

47^a

Inactive

48^a

Inactive

Table 4

Anti-AchE activity of compounds 20, 49–55

56

–

Inactive

57^a

58

62^a

63

^aThe value of the hydrochloride is shown.

^bIC₅₀value was measured for enzyme activity < 20% at 10⁻⁵M.

^cN = number of duplicate independent experiments.

docking results the thiophene ring is situated in the way that

one of the neighboring carbons is opposite to the carbonyl of

glutamic acid at a distance favorable for the formation of a

weak hydrogen bond (d_C–H~3.5Å). Therefore, the thiophene

interacts through p–p stacking and in the same time through

weak hydrogen bond with AChE.

In vitro tests revealed furthermore that the oxime 60 cor-

responding to the orthoﬂuorobenzyl derivative 20 exerts an

inhibitory activity onAChE close to the donepezil one. Mod-

eling studies showed that the upper part is differently posi-

tioned differently between 60 and 20. For the latter, it takes a

position in which p–p stacking with the indole ring of Trp₂₇₉

is better preserved and in which the oxime group makes a

hydrogen bond with the carboxyl group of Ser₂₈₆(Fig. 4 ).

Compd^a

20

49

50

51

52

53

IC₅₀S.D. (µM)^b

0.40 0.07 (N = 3)^c

1.10 0.20 (N = 2)

Inactive

0.57 0.13 (N = 2)

1.50 0.30 (N = 2)

Inactive

54

Inactive

5. Conclusion

55

Inactive

^aThe value of the hydrochloride is shown.

^bIC₅₀value was measured for enzyme activity < 20% at 10⁻⁵M.

^cN = number of duplicate independent experiments.

We have synthesized and evaluated as potential AChE

inhibitors 64 new indanones and thiaindanones related to

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Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

Table 5

Anti-AchE activity of compounds 13, 20, 43, 59–61

Compd

13^a

20^a

43^a

59

IC₅₀S.D. (µM)^b

0.22 0.01 (N = 2)^c

0.40 0.07 (N = 3)

0.18 0.01 (N = 2)

Inactive

60

0.06 0.02 (N = 3)

61

0.14 0.07 (N = 2)

^aThe value of the hydrochloride is shown.

^bIC₅₀value was measured for enzyme activity < 20% at 10⁻⁵M.

^cN = number of independent experiments.

Fig. 3. The stick representation of the binding site ofAChE (green) and done-

pezil (purple) from X-ray structure, with the modeled position of compound

43 (gray).

donepezil. Among them, 11 derivatives were found to inhibit

the enzyme in the submicromolar range and one of them (60),

revealed its inhibitory activity with an IC₅₀(0.06 µM) in a

same order of magnitude than the reference compound, done-

pezil (1, IC₅₀= 0.02 µM). This result prompts us to now study

the in vivo biological comportment of these new inhibitors.

6. Experimental protocols

6.1. In vitro tests of AChE biological activity

Inhibitory capacity of compounds on AChE biological

activity were evaluated through the use of the spectrometric

method of Ellman et al. [12]. Lyophilized electric eel AChE

(Type III, electric eel, Sigma Chemical Co.) was dissolved in

0.2 M phosphate buffer pH 7.4 such as to have an enzyme

solution stock with 2.5 units.ml^–1AChE activity. Acetylthio-

choline iodide (Sigma Chemical Co.) was used as a substrate

of the enzymatic reaction and 5,5-dithiobis-(2-nitrobenzoic)

acid (DTNB, Sigma Chemical Co.) as label for the measure-

ment of cholinesterase activity. In the procedure, 1880 µL of

60 mg/500 ml DTNB dissolved in phosphate buffer pH

7.4 were mixed with 40 µl of test compound solution and

40 µl of enzyme stock solution were mixed. After 5 min of

preincubation, 40 µl of 10 mM acetylthio-choline iodide solu-

Fig. 2. The stick representation of the binding site ofAChE (green) and done-

pezil (gray) from X-ray structure, with the modeled position of compound

12 (purple).

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1229

6.3. Chemistry

Melting points were determined on a Koﬂer melting point

apparatus and are uncorrected. IR spectra were recorded on a

Genesis series FTIR spectrometer using KBr pellets. The ¹H

(400 MHz) and ¹³C (100 MHz) NMR spectra were obtained

on a Jeol Lambda 400 spectrometer using DMSO-d₆or

CDCl₃. The chemical shifts (d) are reported in ppm, and the

coupling constants are in Hertz. Electron impact mass spec-

tra were obtained using a Jeol JMS GCMate spectrometer

and with pfk as internal standard for high-resolution proce-

dure. Reactions were monitored by thin-layer chromatogra-

phy (TLC) using 0.2 mm Polygram Sil silica gel G/UV

254 precoated plates with visualization by irradiation with a

short-wavelength UV light. Silica gel ﬂash chromatography

was performed using 63–200 mM Kieselgel Merck 60 silica

gel.

6.4. General experimental procedure for the synthesis

of 2–58, 62–64

To a solution of one of the compounds 84–93 (1.5 mmol)

in methylene chloride (10 ml) was added the desired pipera-

zine, piperidine or homopiperazine derivative (3 mmol) and

potassium carbonate (0.426 g, 3 mmol). The reaction mix-

ture was stirred at room temperature for 12 h. Methylene chlo-

ride (50 ml) was then added and the mixture was washed sev-

eral times with water. The organic layer was dried over MgSO₄

and evaporated under reduced pressure. The product was puri-

ﬁed by ﬂash chromatography.

Fig. 4. The stick representation of the binding site ofAChE (green) and done-

pezil (gray) from X-ray structure, with the modeled position of compound

60 (cyan).

tion was added to the assay solution. The change in absor-

bance at 412 nm was recorded (AGILENT 8453 UV–VIS

Spectroscopy System) during 10 min First screening ofAChE

activity was carried out at a 10⁻⁵M concentration of com-

pounds under study. For the compounds with signiﬁcant inhi-

bition (≥ 80%) after 4 min of reaction, IC₅₀values were deter-

mined graphically from log concentration–inhibition curves,

using a range of 10⁻¹⁰–10⁻³M concentrations of the test com-

pounds.

6.4.1. 2-(4-Benzylpiperazin-1-yl)-N-(5,6-dimethoxy-3-oxo-

2,3-dihydro-1H-inden-1-yl)acetamide (2)

Yield: 89%. M.P. 190 °C. IR (KBr, cm⁻¹): 3309 (NH), 1690

(CO), 1659 (CO amide), 1503, 1452, 1302, 1213, 840, 735.

¹H-NMR (CDCl₃) d (ppm): 7.28 (m, 5H, H_phenyl), 7.18 (s,

3

1H, H-4), 6.95 (s, 1H, H-7), 6.77 (d, J_NH-H1c= 9.0 Hz,

1H,NH), 5.65 (m, 1H, H-3), 3.93 (s, 6H, 2OMe), 3.47 (s, 2H,

H

_benzyl), 3.20 (dd, ³J_H2b-H1c= 7.5 Hz, ²J_H2b-H2a= 18.9 Hz, 1H,

H-2b), 3.09 (s, 2H, COCH₂N), 2.42(m, 9H, H-2a and

H

_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 201.75 (C-3), 170.50

6.2. Computational methods

(NHCO), 156.06 (C-6), 150.82 (C-5), 149.30 (C-7a), 137.78

(C-1_phenyl), 129.72 (C-3a), 129.10 (C-2_phenyland C-6_phenyl),

128.28 (C-3_phenyland C-5_phenyl), 127.19 (C-4_phenyl), 106.53

(C-7), 103.57 (C-4), 64.43 (COCH₂N), 62.17 (C_benzyl), 56.57

(OMe), 56.24 (OMe), 53.58 (C-3_piperazineand C-5_piperazine),

52.90 (C-2_piperazineand C-6_piperazine), 46.45 (C-1), 44.92 (C-2).

HRMS: calculated (423.2158), found (423.2222).

6.2.1. Inhibitor structures

The 3D models of inhibitors were generated using the

Cerius2 software (Accelerys Co.). To derive a stable confor-

mation for the models, the full geometry optimization was

carried out by semiempirical AM1 method (MOPAC pro-

gram in Cerius2 software [15–17]).

6.4.2. 2-[4-(4-Methoxybenzyl)piperazin-1-yl]-N-(5,6-

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (3)

Yield: 15%. M.P. 195 °C. IR (KBr, cm⁻¹): 3310 (NH), 1705

(CO), 1660 (CO amide), 1594, 1461, 1332, 1051, 1010, 841.

6.2.2. Complex models

The crystal structure of complex AChE from Torpedo

Californica/Donepezil (E2020) (PDB ﬁle identiﬁcator 1EVE)

[13] was used as template to construct the complex models.

The studied compounds were placed automatically by dock-

ing procedure of LigandFit [14] in the active-site cleft of pro-

tein model.

3

¹H-NMR (CDCl₃) d (ppm): 7.40 (d, J_NH-H1c= 9.3 Hz,

1H,NH), 7.00 (m, 6H, H-4, H-7 and H_phenyl), 5.65 (m, 1H,

H-3), 3.93 (s, 6H, 2OMe), 3.79 (s, 3H, OMe), 3.45 (s, 2H,

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Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

H

_benzyl), 3.20 (dd, ³J_H2b-H1c= 7.5 Hz, ²J_H2b-H2a= 18.8 Hz, 1H,

H-2b), 3.08 (s, 2H, COCH₂N), 2.48 (m, 9H, H-2a and

_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 201.76 (C-3), 170.22

2H, COCH₂N), 2.48 (m, 9H, H-2a and H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 201.78 (C-3), 170.35 (NHCO), 156.05

(C-6), 150.81 (C-5), 149.28 (C-7a), 139.00 (C-1_phenyl), 132.25

(C-6_phenyl), 130.67 (q, ²J_C–F= 131.4 Hz, CF₃), 129.75 (C-3a),

129.72 (C-3_phenyl), 128.76 (C-5_phenyl), 125.55 (C-4_phenyl),

124.12 (C-2_phenyl), 106.31 (C-7), 103.53 (C-4), 62.45

(C_benzyl), 61.16 (COCH₂N), 56.47 (OMe), 56.24 (OMe), 53.46

(C-3_piperazineand C-5_piperazine), 52.90 (C-2_piperazineand

C-6_piperazine), 46.43 (C-1), 44.89 (C-2). HRMS: calculated

(491.2032), found (491.1996).

H

(NHCO), 160.00 (C-4_phenyl), 155.84 (C-6), 150.60 (C-5),

149.88 (C-7a), 129.49 (C-3a), 129.04 (C-1_phenyl), 121.21

(C-2_phenyland C-6_phenyl), 114.45 (C-3_phenyland C-5_phenyl),

106.31 (C-7), 103.53 (C-4), 62.45 (C_benzyl), 61.16 (COCH₂N),

56.24 (OMe), 56.00 (OMe), 54.98 (OMe), 53.22 (C-3_piperazine

and C-5_piperazine), 52.61 (C-2_piperazineand C-6_piperazine), 46.23

(C-1), 44.68 (C-2). MS (m/z): 453.2 (⁺M).

6.4.3. 2-[4-(4-Bromobenzyl)piperazin-1-yl]-N-(5,6-

6.4.6. 2-[4-(3-Chlorobenzyl)piperazin-1-yl]-N-(5,6-

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (4)

Yield: 95%. M.P. 222 °C. IR (KBr, cm⁻¹): 3338 (NH), 1706

(CO), 1640 (CO amide), 1593, 1505, 1462, 1309, 1266, 845.

¹H-NMR (CDCl₃) d (ppm): 7.10 (m, 6H,NH, H-4 and

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (7)

Yield: 46%. M.P. 145 °C. IR (KBr, cm⁻¹): 3348 (NH), 1705

(CO), 1650 (CO amide), 1594, 1503, 1461, 1303, 1211, 1011.

3

¹H-NMR (CDCl₃) d (ppm): 7.42 (d, J_NH-H1c= 8.7 Hz,

H

_phenyl), 6.95 (s, 1H, H-7), 5.66 (m, 1H, H-3), 3.93 (s, 6H,

1H,NH), 7.50 (m, 5H, H-4 and H_phenyl), 6.95 (s, 1H, H-7),

5.66 (m, 1H, H-3), 3.93 (s, 6H, 2OMe), 3.43 (s, 2H, H_benzyl),

3.21 (dd, ³J_H2b-H1c= 7.4 Hz, ²J_H2b-H2a= 18.9 Hz, 1H, H-2b),

3.09 (s, 2H, COCH₂N), 2.48 (m, 9H, H-2a and H_piperazine).

¹³C-NMR (CDCl₃) d (ppm): 201.75 (C-3), 170.04 (NHCO),

156.07 (C-6), 150.84 (C-5), 149.29 (C-7a), 140.10 (C-3_phenyl),

134.21 (C-1_phenyl), 129.74 (C-3a), 129.55 (C-5_phenyl), 128.95

(C-2_phenyl), 127.40 (C-6_phenyl), 127.07 (C-4_phenyl), 106.54

(C-7), 103.75 (C-4), 62.17 (COCH₂N), 61.41 (C_benzyl), 56.47

(OMe), 56.24 (OMe), 53.53 (C-3_piperazineand C-5_piperazine),

52.90 (C-2_piperazineand C-6_piperazine), 46.45 (C-1), 44.92 (C-2).

HRMS: calculated (457.1768), found (457.1742).

3

2OMe), 3.41 (s, 2H, H_benzyl), 3.20 (dd, J_H2b-H1c= 7.6 Hz,

²J_H2b-H2a= 18.8 Hz, 1H, H-2b), 3.09 (s, 2H, COCH₂N), 2.48

(m, 9H, H-2a and H_piperazine). ¹³C-NMR (CDCl₃) d (ppm):

201.68 (C-3), 170.37 (NHCO), 156.03 (C-6), 150.81 (C-5),

149.25 (C-7a), 136.86 (C-1_phenyl), 131.35 (C-3_phenyland

C-5_phenyl), 130.63 (C-2_phenyland C-6_phenyl), 129.69 (C-3a),

120.95 (C-4_phenyl), 106.52 (C-7), 103.73 (C-4), 62.01

(C_benzyl), 61.36 (COCH₂N), 56.42 (OMe), 56.20 (OMe), 53.48

(C-3_piperazineand C-5_piperazine), 52.82 (C-2_piperazineand

C-6_piperazine), 46.40 (C-1), 44.87 (C-2). HRMS: calculated

(501.1263), found (501.1246).

6.4.4. 2-[4-(4-Chlorobenzyl)piperazin-1-yl]-N-(5,6-

6.4.7. 2-[4-(3-Cyanobenzyl)piperazin-1-yl]-N-(5,6-

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (5)

Yield: 12%. M.P. 218 °C. IR (KBr, cm⁻¹): 3447 (NH), 1689

(CO), 1660 (CO amide), 1595, 1505, 1456, 1330, 1267, 986.

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (8)

Yield: 88%. M.P. 118 °C. IR (KBr, cm⁻¹): 3314 (NH), 1679

(CO), 1660 (CO amide), 1594, 1500, 1457, 1303, 1214, 861.

¹H-NMR (CDCl₃) d (ppm): 7.48 (m, 5H,NH and H_phenyl),

7.18 (s, 1H, H-4), 6.97 (s, 1H, H-7), 5.66 (m, 1H, H-3), 3.92

(s, 6H, 2OMe), 3.47 (s, 2H, H_benzyl), 3.19 (dd,

3

¹H-NMR (CDCl₃) d (ppm): 7.42 (d, J_NH-H1c= 8.7 Hz,

1H,NH), 7.20 (m, 5H, H-4 and H_phenyl), 6.95 (s, 1H, H-7),

5.66 (m, 1H, H-3), 3.93 (s, 6H, 2OMe), 3.43 (s, 2H, H_benzyl),

3.20 (dd, ³J_H2b-H1c= 7.5 Hz, ²J_H2b-H2a= 18.8 Hz, 1H, H-2b),

3.09 (s, 2H, COCH₂N), 2.48 (m, 9H, H-2a and H_piperazine).

¹³C-NMR (CDCl₃) d (ppm): 201.03 (C-3), 170.44 (NHCO),

156.05 (C-6), 150.81 (C-5), 149.29 (C-7a), 136.34 (C-1_phenyl),

132.89 (C-4_phenyl), 130.31 (C-2_phenyland C-6_phenyl), 129.70

(C-3a), 128.44 (C-3_phenyland C-5_phenyl), 106.53 (C-7), 103.71

(C-4), 62.00 (COCH₂N), 61.28 (C_benzyl), 56.47 (OMe), 56.24

(OMe), 53.51 (C-3_piperazineand C-5_piperazine), 52.48 (C-

2

³J_H2b-H1c= 8.2 Hz, J_H2b-H2a= 20.0 Hz, 1H, H-2b), 3.09 (s,

2H, COCH₂N), 2.43 (m, 9H, H-2a and H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 201.74 (C-3), 170.36 (NHCO), 156.09

(C-6), 150.86 (C-5), 149.30 (C-7a), 139.78 (C-1_phenyl), 133.23

(C-6_phenyl), 132.20 (C-4_phenyl), 130.95 (C-2_phenyl), 129.71

(C-3a), 129.13 (C-5_phenyl), 118.48 (CN), 112.48 (C-3_phenyl),

106.59 (C-7), 103.76 (C-4), 61.81 (COCH₂N), 61.38

(C_benzyl), 56.47 (OMe), 56.24 (OMe), 53.47 (C-3_piperazineand

C-5_piperazine), 52.91 (C-2_piperazineand C-6_piperazine), 46.46

(C-1), 44.87 (C-2). HRMS: calculated (448.2111), found

(448.2085).

2_piperazineand C-6_piperazine), 46.41 (C-1), 44.89 (C-2). HRMS:

calculated (457.1768), found (457.1719).

6.4.5. 2-[4-(3-Triﬂuoromethylbenzyl)piperazin-1-yl]-N-

(5,6-dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-

6.4.8. 2-[4-(2-Chlorobenzyl)piperazin-1-yl]-N-(5,6-

yl)acetamide (6)

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide (9)

Yield: 57%. M.P. 160 °C. IR (KBr, cm⁻¹): 3333 (NH), 1698

(CO), 1673 (CO amide), 1595, 1504, 1300, 1212, 1120, 865.

¹H-NMR (CDCl₃) d (ppm): 7.30 (m, 6H,NH, H-4 and

Yield: 16%. M.P. 130 °C. IR (KBr, cm⁻¹): 3446 (NH), 1689

(CO), 1660 (CO amide), 1595, 1505, 1456, 1330, 1121, 986.

¹H-NMR (CDCl₃) d (ppm): 7.50 (m, 5H,NH and H_phenyl),

7.18 (s, 1H, H-4), 6.95 (s, 1H, H-7), 5.66 (m, 1H, H-3), 3.93

(s, 6H, 2OMe), 3.51 (s, 2H, H_benzyl), 3.20 (dd,

H

_phenyl), 6.96 (s, 1H, H-7), 5.66 (m, 1H, H-3), 3.93 (s, 6H,

3

2OMe), 3.47 (s, 2H, H_benzyl), 3.21 (dd, J_H2b-H1c= 7.4 Hz,

³J_H2b-H1c= 7.4 Hz, J_H2b-H2a= 18.9 Hz, 1H, H-2b), 3.10 (s,

²J_H2b-H2a= 18.9 Hz, 1H, H-2b), 3.18 (s, 2H, COCH₂N), 2.43

2

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1231

3

(m, 9H, H-2a and H_piperazine). ¹³C-NMR (CDCl₃) d (ppm):

201.72 (C-3), 170.38 (NHCO), 156.06 (C-6), 150.83 (C-5),

149.21 (C-7a), 134.38 (C-1_phenyl), 131.60 (C-2_phenyl), 130.86

(C-6_phenyl), 129.75 (C-3a), 129.52 (C-3_phenyl), 128.411

(C-4_phenyl), 126.68 (C-5_phenyl), 106.50 (C-7), 103.76 (C-4),

61.37 (COCH₂N), 58.89 (C_benzyl), 56.47 (OMe), 56.24 (OMe),

53.46 (C-3_piperazineand C-5_piperazine), 52.81 (C-2_piperazineand

C-6_piperazine), 46.50 (C-1), 44.93 (C-2). HRMS: calculated

(457.1768), found (457.1749).

¹H-NMR (CDCl₃) d (ppm): 7.56 (d, J_NH-H4c= 8.2 Hz,

1H,NH), 7.28 (m, 5H, H_phenyl), 5.36 (dt, ³J_H4c-H5a= 3.8 Hz,

³J_H4c-H5b= J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.51 (m, 3H,

3

H_benzyland H-5b), 3.06 (s, 2H, COCH₂N), 2.82 (dd,

³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.55 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.35 (C-6),

170.23 (NHCO), 151.68 (C-6a), 141.95 (C-3a), 137.55

(C-1_phenyl), 129.31 (C-2_phenyland C-6_phenyl), 128.30 (C-3_phenyl

and C-5_phenyl), 127.22 (C-4_phenyl), 111.95 (C-1), 106.01 (C-3),

62.84 (C_benzyl), 61.33 (COCH₂N), 53.65 (C-3_piperazineand

C-5_piperazine), 52.94 (C-2_piperazineand C-6_piperazine), 52.15

(C-5), 43.04 (C-4). MS (m/z): 529.1 (⁺M+2), 527.1 (⁺M),

525.1 (⁺M–2). Anal. CHN C₂₀H₂₁Br₂N₃O₂S.

6.4.9. 2-[4-(2-Nitrobenzyl)piperazin-1-yl]-N-(5,6-

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl) acetamide

(10)

Yield: 70%. M.P. 126 °C. IR (KBr, cm⁻¹): 3311 (NH), 1697

(CO), 1666 (CO amide), 1594, 1500, 1303, 1266, 1123, 861.

6.4.12. 2-[4-(2-Chlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (13)

3

¹H-NMR (CDCl₃) d (ppm): 7.79 (d, J_NH-H1c= 7.8 Hz,

1H,NH), 7.45 (m, 4H, H_phenyl), 7.17 (s, 1H, H-4), 6.94 (s, 1H,

H-7), 5.66 (m, 1H, H-3), 3.93 (s, 6H, 2OMe), 3.75 (s, 2H,

Yield: 77%. M.P. 170 °C. IR (KBr, cm⁻¹): 3284 (NH), 1717

(CO), 1661 (CO amide), 2811, 1503, 1469, 1131, 1011, 753.

H

_benzyl), 3.20 (dd, ³J_H2b-H1c= 7.3 Hz, ²J_H2b-H2a= 18.9 Hz, 1H,

H-2b), 3.07 (s, 2H, COCH₂N), 2.43 (m, 9H, H-2a and

3

¹H-NMR (CDCl₃) d (ppm): 7.59 (d, J_NH-H4c= 8.1 Hz,

H

_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 201.72 (C-3), 170.33

1H,NH), 7.35 (d, ³J_{H3phenyl-H4phenyl}= 7.6 Hz, 1H, H-3_phenyl),

(NHCO), 156.06 (C-6), 150.82 (C-5), 149.85 (C-2_phenyl),

149.21 (C-7a), 133.34 (C-1_phenyl), 132.32 (C-5_phenyl), 130.91

(C-4_phenyl), 129.75 (C-3a), 127.13 (C-6_phenyl), 124.44 (C-

7.24 (d, ³J_{H6phenyl-H5phenyl}= 7.2 Hz, 1H, H-6_phenyl), 7.19 (m,

3

2H, H-4_phenyland H-5_phenyl), 5.27 (dt, J_H4c-H5a= 3.6 Hz,

³J_H4c-H5b= J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.52 (s, 2H,

3

3_phenyl), 106.50 (C-7), 103.74 (C-4), 61.31 (COCH₂N), 58.81

H

_benzyl), 3.28 (dd, ³J_H5b-H4c= 8.1 Hz, ²J_H5b-H5a= 20.0 Hz, 1H,

(C_benzyl), 56.47 (OMe), 56.24 (OMe), 53.06 (C-3_piperazineand

C-5_piperazine), 52.92 (C-2_piperazineand C-6_piperazine), 46.44

(C-1), 44.91 (C-2). HRMS: calculated (468.2008), found

(468.2022).

H-5b), 2.97 (s, 2H, COCH₂N), 2.73 (dd, ³J_H5a-H4c= 3.6 Hz,

²J_H5a-H5b= 20.0 Hz, 1H, H-5a), 2.45 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.26 (C-6), 170.14 (NHCO),

151.62 (C-6a), 141.88 (C-3a), 135.50 (C-1_phenyl), 134.20

(C-2_phenyl), 130.58 (C-6_phenyl), 129.39 (C-3_phenyl), 128.16

(C-4_phenyl), 126.57 (C-5_phenyl), 111.80 (C-1), 105.91 (C-3),

61.26 (COCH₂N), 58.92 (C_benzyl), 53.62 (C-3_piperazineand

C-5_piperazine), 52.93 (C-2_piperazineand C-6_piperazine), 52.05

(C-5), 42.99 (C-4). MS (m/z): 563.0 (⁺M+2), 561.0 (⁺M),

559.0 (⁺M–2). Anal. CHN C₂₀H₂₀Br₂ClN₃O₂S.

6.4.10. 2-[4-(2,6-Dichlorobenzyl)piperazin-1-yl]-N-(5,6-

dimethoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide

(11)

Yield: 40%. M.P. 198 °C. IR (KBr, cm⁻¹): 3325 (NH), 1700

(CO), 1641 (CO amide), 1595, 1499, 1303, 1267, 1121, 860.

3

¹H-NMR (CDCl₃) d (ppm): 7.46 (d, J_NH-H1c= 8.5 Hz,

3

1H,NH), 7.29 (d, J_{H3phenyl-H4phenyl}= ³J_{H5phenyl-H4phenyl}

=

6.4.13. 2-[4-(3-Chlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (14)

7.5 Hz, 2H, H-3_phenyland H-5_phenyl), 7.19 (s, 1H, H-4), 7.13

3

(t, J_{H4phenyl-H3phenyl}= J_{H4phenyl-H5phenyl}= 7.5 Hz, 1H,

H-4_phenyl), 6.96 (s, 1H, H-7), 5.65 (m, 1H, H-3), 3.95 (s, 3H,

OMe), 3.93 (s, 3H, OMe), 3.71 (s, 2H, H_benzyl), 3.22 (dd,

Yield: 66%. M.P. 195 °C. IR (KBr, cm⁻¹): 3374 (NH), 1718

(CO), 1662 (CO amide), 2890, 1509, 1476, 1129, 1008, 779.

2

³J_H2b-H1c= 7.5 Hz, J_H2b-H2a= 18.8 Hz, 1H, H-2b), 3.06 (s,

3

¹H-NMR (CDCl₃) d (ppm): 7.57 (d, J_NH-H4c= 8.0 Hz,

2H, COCH₂N), 2.43 (m, 9H, H-2a and H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 201.77 (C-3), 170.58 (NHCO), 156.09

(C-6), 150.86 (C-5), 149.26 (C-7a), 136.94 (C-2_phenyland

C-6_phenyl), 134.00 (C-1_phenyl), 129.79 (C-3a), 128.94 (C-

1H,NH), 7.23 (m, 4H, H_phenyl), 5.37 (dt, ³J_H4c-H5a= 3.7 Hz,

³J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H, H-4c), 3.52 (dd, J_H5b-

3

2

^H4c= 8.0 Hz, J_H5b-H5a= 19.2 Hz, 1H, H-5b), 3.45 (s, 2H,

H

_benzyl), 3.06 (s, 2H, COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.7 Hz,

4_phenyl), 128.39 (C-3_phenyland C-5_phenyl), 106.50 (C-7), 103.81

²J_H5a-H5b= 19.2 Hz, 1H, H-5a), 2.56 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.36 (C-6), 170.15 (NHCO),

151.66 (C-6a), 141.93 (C-3a), 140.00 (C-3_phenyl), 134.21

(C-1_phenyl), 129.55 (C-5_phenyl), 128.94 (C-2_phenyl), 127.36

(C-6_phenyl), 127.08 (C-4_phenyl), 111.92 (C-1), 105.99 (C-3),

62.17 (COCH₂N), 61.29 (C_benzyl), 53.59 (C-3_piperazineand

C-5_piperazine), 52.93 (C-2_piperazineand C-6_piperazine), 52.13

(C-5), 43.03 (C-4). MS (m/z): 563.0 (⁺M+2), 561.0 (⁺M),

559.0 (⁺M–2).

(C-4), 61.39 (COCH₂N), 56.61 (C_benzyl), 56.47 (OMe), 56.24

(OMe), 53.62 (C-3_piperazineand C-5_piperazine), 52.80 (C-

2_piperazineand C-6_piperazine), 46.51 (C-1), 45.01 (C-2). HRMS:

calculated (491.1378), found (491.1437).

6.4.11. 2-(4-Benzylpiperazin-1-yl)-N-(1,3-dibromo-6-oxo-

5,6-dihydro-4H-cyclopenta[c]thien-4-yl) acetamide (12)

Yield: 50%. M.P. 211 °C. IR (KBr, cm⁻¹): 3373 (NH), 1717

(CO), 1661 (CO amide), 2813, 1510, 1092, 1007, 699.

1232

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

6.4.14. 2-[4-(4-Chlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (15)

(C-6a), 141.94 (C-3a), 134.82 (C-1_phenyl), 134.27 (C-2_phenyl),

133.24 (C-4_phenyl), 131.91 (C-6_phenyl), 129.27 (C-3_phenyl),

126.98 (C-5_phenyl), 111.97 (C-1), 105.97 (C-3), 61.29

(COCH₂N), 58.40 (C_benzyl), 53.65 (C-3_piperazineand

C-5_piperazine), 52.95 (C-2_piperazineand C-6_piperazine), 52.14

(C-5), 43.07 (C-4). MS (m/z): 596.9 (⁺M+2), 594.9 (⁺M),

592.9 (⁺M–2).

Yield: 30%. M.P. 192 °C. IR (KBr, cm⁻¹): 3369 (NH), 1717

(CO), 1661 (CO amide), 2812, 1510, 1334, 1130, 1008, 807.

3

¹H-NMR (CDCl₃) d (ppm): 7.57 (d, J_NH-H4c= 8.0 Hz,

1H,NH), 7.27 (m, 4H, H_phenyl), 5.36 (dt, ³J_H4c-H5a= 3.7 Hz,

3

³J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H, H-4c), 3.50 (dd, J_H5b-

2

6.4.17. 2-[4-(2,5-Dichlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (18)

^H4c= 8.0 Hz, J_H5b-H5a= 19.4 Hz, 1H, H-5b), 3.46 (s, 2H,

H

_benzyl), 3.06 (s, 2H, COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.7 Hz,

²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.56 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.36 (C-6), 170.15 (NHCO),

151.66 (C-6a), 141.91 (C-3a), 136.39 (C-1_phenyl), 132.85

(C-4_phenyl), 130.31 (C-2_phenyland C-6_phenyl), 128.41 (C-3_phenyl

and C-5_phenyl), 111.89 (C-1), 105.98 (C-3), 61.99 (COCH₂N),

61.28 (C_benzyl), 53.60 (C-3_piperazineand C-5_piperazine), 52.87

(C-2_piperazineand C-6_piperazine), 52.10 (C-5), 43.00 (C-4). MS

(m/z): 563.0 (⁺M+2), 561.0 (⁺M), 559.0 (⁺M–2). Anal. CHN

C₂₀H₂₀Br₂ClN₃O₂S.

Yield: 50%. M.P. 195 °C. IR (KBr, cm⁻¹): 3341 (NH), 1728

(CO), 1670 (CO amide), 2817, 1507, 1472, 1132, 1012, 811.

3

¹H-NMR (CDCl₃) d (ppm): 7.51 (d, J_NH-H4c= 8.0 Hz,

1H,NH), 7.46 (d, ⁴J_{H6phenyl-H4phenyl}= 2.4 Hz, 1H, H-6_phenyl),

7.26 (d, ³J_{H3phenyl-H4phenyl}= 8.5 Hz, 1H, H-3_phenyl), 7.16 (dd,

3

⁴J_{H4phenyl-H6phenyl}= 2.4 Hz, J_{H4phenyl-H3phenyl}= 8.5 Hz, 1H,

3

H-4_phenyl), 5.36 (dt, J_H4c-H5a= 3.6 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.0 Hz, 1H, H-4c), 3.58 (s, 2H, H_benzyl), 3.51 (dd,

³J_H5b-H4c= 8.0 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.07 (s,

2

3

2

2H, COCH₂N), 2.84 (dd, J_H5a-H4c= 3.6 Hz, J_H5a-H5b

=

6.4.15. 2-[4-(2,3-Dichlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (16)

19.3 Hz, 1H, H-5a), 2.58 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.31 (C-6), 170.16 (NHCO), 151.66

(C-6a), 141.96 (C-3a), 137.59 (C-1_phenyl), 132.73 (C-5_phenyl),

132.29 (C-2_phenyl), 130.52 (C-3_phenyl), 130.18 (C-6_phenyl),

128.23 (C-4_phenyl), 111.97 (C-1), 105.99 (C-3), 61.30

(COCH₂N), 58.69 (C_benzyl), 53.66 (C-3_piperazineand

C-5_piperazine), 53.06 (C-2_piperazineand C-6_piperazine), 52.17

(C-5), 43.09 (C-4). MS (m/z): 515.9 (⁺M+1-Br), 513.9 (⁺M–

1-Br).

Yield: 60%. M.P. 181 °C. IR (KBr, cm⁻¹): 3437 (NH), 1721

(CO), 1667 (CO amide), 2818, 1508, 1132, 1011, 777.

3

¹H-NMR (CDCl₃) d (ppm): 7.59 (d, J_NH-H4c= 8.1 Hz,

1H,NH), 7.34 (d, ³J_{H4phenyl-H5phenyl}= 7.8 Hz, 1H, H-4_phenyl),

7.31 (d, ³J_{H6phenyl-H5phenyl}= Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz,

1H, H-4c), 3.58 (s, 2H, H_benzyl), 3.45 (dd, ³J_H5b-H4c= 8.1 Hz,

²J_H5b-H5a= 19.3 Hz,7.8 Hz, 1H, H-6_phenyl), 7.13 (t,

3

³J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}= 7.8 Hz, 1H,

6.4.18. 2-[4-(2,6-Dichlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (19)

3

H-5_phenyl), 5.32 (dt, J_H4c-H5a= 3.8 1H, H-5b), 3.02 (s, 2H,

COCH₂N), 2.79 (dd, ³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.3 Hz,

1H, H-5a), 2.56 (m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d

(ppm): 192.29 (C-6), 170.08 (NHCO), 151.59 (C-6a), 141.85

(C-3a), 138.05 (C-1_phenyl), 132.99 (C-3_phenyl), 132.21 (C-

Yield: 68%. M.P. 245 °C. IR (KBr, cm⁻¹): 3338 (NH), 1708

(CO), 1653 (CO amide), 2817, 1472, 1135, 1006, 762.

3

¹H-NMR (CDCl₃) d (ppm): 7.64 (d, J_NH-H4c= 8.0 Hz,

3

1H,NH), 7.29 (d, J_{H3phenyl-H4phenyl}= ³J_{H5phenyl-H4phenyl}

=

2

_phenyl), 128.91 (C-4_phenyl), 128.38 (C-6_phenyl), 126.96

(C-5_phenyl), 111.82 (C-1), 105.91(C-3), 61.24 (COCH₂N),

59.62 (C_benzyl), 53.60 (C-3_piperazineand C-5_piperazine), 52.98

(C-2_piperazineand C-6_piperazine), 52.03 (C-5), 42.97 (C-4). MS

(m/z): 596.9 (⁺M+2), 594.9 (⁺M), 592.9 (⁺M–2).

7.7 Hz, 2H, H-3_phenyland H-5_phenyl), 7.16 (t,

3

³J_{H4phenyl-H3phenyl}= J_{H4phenyl-H5phenyl}= 7.7 Hz, 1H,

H-4_phenyl), 5.36 (m, 1H, H-4c), 3.74 (s, 2H, H_benzyl), 3.44 (dd,

2

³J_H5b-H4c= 7.9 Hz, J_H5b-H5a= 18.9 Hz, 1H, H-5b), 3.00 (s,

3

2

2H, COCH₂N), 2.79 (dd, J_H5a-H4c= 3.6 Hz, J_H5a-

^H5b= 18.9 Hz, 1H, H-5a), 2.58 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.42 (C-6), 170.35 (NHCO),

151.66 (C-6a), 141.97 (C-3a), 136.93 (C-2_phenyland C-6_phenyl),

134.04 (C-1_phenyl), 128.94 (C-4_phenyl), 128.38 (C-3_phenyland

C-5_phenyl), 111.92 (C-1), 106.00 (C-3), 61.27 (COCH₂N),

56.25 (C_benzyl), 53.67 (C-3_piperazineand C-5_piperazine), 52.87

(C-2_piperazineand C-6_piperazine), 52.15 (C-5), 43.07 (C-4).). MS

(m/z): 596.5 (⁺M+2), 594.5 (⁺M), 592.5 (⁺M–2).

6.4.16. 2-[4-(2,4-Dichlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (17)

Yield: 25%. M.P. 195 °C. IR (KBr, cm⁻¹): 3425 (NH), 1721

(CO), 1659 (CO amide), 2925, 1468, 1199, 1195, 812.

3

¹H-NMR (CDCl₃) d (ppm): 7.51 (d, J_NH-H4c= 8.2 Hz,

1H,NH), 7.32 (d, ³J_{H5phenyl-H6phenyl}= 7.8 Hz, 1H, H-5_phenyl),

7.2 (s, 1H, H-3_phenyl), 7.13 (d, ³J_{H6phenyl-H5phenyl}= 7.8 Hz, 1H,

3

H-6_phenyl), 5.30 (dt, J_H4c-H5a= 3.6 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.50 (s, 2H, H_benzyl), 3.44 (dd,

6.4.19. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (20)

³J_H5b-H4c= 8.2 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.00 (s,

2

3

2

2H, COCH₂N), 2.79 (dd, J_H5a-H4c= 3.6 Hz, J_H5a-H5b

=

19.3 Hz, 1H, H-5a), 2.56 (m, 8H, H_piperazine). ¹³C-NMR

Yield: 50%. M.P. 185 °C. IR (KBr, cm⁻¹): 3370 (NH), 1718

(CO), 1660 (CO amide), 2935, 1510, 1216, 1192, 1044, 754.

(CDCl₃) d (ppm): 192.30 (C-6), 170.14 (NHCO), 151.64

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1233

3

4

¹H-NMR (CDCl₃) d (ppm): 7.55 (d, J_NH-H4c= 8.2 Hz,

151.72 (C-6a), 141.99 (C-3a), 133.60 (d, J_C–F= 3.3 Hz,

C-1_phenyl), 130.52 (d, ³J_C–F= 8.2 Hz, C-2_phenyland C-6_phenyl),

115.11 (d, ²J_C–F= 21.4 Hz, C-3_phenyland C-5_phenyl), 111.95

(C-1), 106.00 (C-3), 62.02 (C_benzyl), 61.34 (COCH₂N), 53.66

(C-3_piperazineand C-5_piperazine), 52.90 (C-2_piperazineand

C-6_piperazine), 52.18 (C-5), 43.09 (C-4). MS (m/z): 546.5

(⁺M+2), 544.5 (⁺M), 542.5 (⁺M–2).

4

1H,NH), 7.36 (dt, J_{H6phenyl-H4phenyl}= 1.7 Hz, J_H6phenyl-F

=

³J_{H6phenyl-H5phenyl}= 7.5 Hz, 1H, H-6_phenyl), 7.22 (m, 1H,

H-4_phenyl), 7.10 (t, J_{H5phenyl- H4phenyl}= ³J_{H5phenyl-H6phenyl}

=

3

7.5 Hz, 1H, H-5_phenyl), 7.02 (t, J_H3phenyl-

H4phenyl

3

³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.35 (dt, J_H4c-H5a

3.5 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.59 (s, 2H,

H

_benzyl), 3.50 (dd, ³J_H5b-H4c= 8.2 Hz, ²J_H5b-H5a= 19.4 Hz, 1H,

H-5b), 3.05 (s, 2H, COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.5 Hz,

²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.60 (m, 8H, H_piperazine). ¹³C-

NMR (DMSO-d6) d (ppm): 191.92 (C-6), 169.68 (NHCO),

160.84 (d, ¹J_C–F, = 246.2 Hz, C-2_phenyl), 151.27 (C-6a), 141.43

6.4.22. 2-[4-(2-Bromobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (23)

Yield: 79%. M.P. 176 °C. IR (KBr, cm⁻¹): 3333 (NH), 1722

(CO), 1666 (CO amide), 2813, 1502, 1132, 1011, 752.

3

(C-3a), 131.03 (d, J_C–F= 5.0 Hz, C-6_p₂_henyl), 128.40 (d,

³J_C–F= 8.3 Hz, C-4_phenyl), 123.73 (d, J_C–F= 14.8 Hz,

¹H-NMR (CDCl₃) d (ppm): 7.64 (d, J_NH-H4c= 8.1 Hz,

3

4

1H,NH), 7.52 (dd, ⁴J_{H3phenyl-H5phenyl}= 1.3 Hz,

³J_{H3phenyl-H4phenyl}= 7.3 Hz, 1H, H-3_phenyl), 7.44 (d,

³J_{H6phenyl-H5phenyl}= 7.3 Hz, 1H, H-6_phenyl), 7.27 (t,

C-1_phenyl), 123.42 (d, J_C–F= 3.3 Hz, C-5_phenyl), 114.76

(²J_C–F= 22.3 Hz,C-3_phenyl), 111.20 (C-1), 105.49 (C-3), 60.83

(COCH₂N), 54.49 (C_benzyl), 53.09 (C-3_piperazineand

C-5_piperazine), 52.13 (C-2_piperazineand C-6_piperazine), 51.50

(C-5), 42.46 (C-4). MS (m/z): 547.3 (⁺M+2), 545.3 (⁺M),

543.3 (⁺M–2). Anal. CHN C₂₀H₂₀Br₂FN₃O₂S.

³J_{H4phenyl-H5phenyl}= J_{H4phenyl-H3phenyl}= 7.3 Hz, 1H,

3

H-4_phenyl), 7.10 (dt, ⁴J_{H5phenyl-H3phenyl}= 1.3 Hz,

³J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}= 7.3 Hz, 1H,

3

H-5_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.53 (s, 2H, H_benzyl), 3.48 (dd,

6.4.20. 2-[4-(3-Fluorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (21)

³J_H5b-H4c= 8.1 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.06 (s,

2

2H, COCH₂N), 2.83 (dd, ³J_H5a-H4c= 3.7 Hz,

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.59 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.30 (C-6), 170.15 (NHCO),

151.68 (C-6a), 141.90 (C-3a), 137.20 (C-1_phenyl), 132.70

(C-3_phenyl), 130.63 (C-4_phenyl), 128.47 (H-6_phenyl), 127.22

(C-5_phenyl), 124.57 (C-2_phenyl), 111.74 (C-1), 105.93 (C-3),

61.48 (C_benzyl), 61.29 (COCH₂N), 53.64 (C-3_piperazineand

C-5_piperazine), 52.93 (C-2_piperazineand C-6_piperazine), 52.04

(C-5), 42.99 (C-4). MS (m/z): 608.3 (⁺M+3), 606.3 (⁺M+1),

604.3 (⁺M–1), 602.3 (⁺M-3). Anal. CHN C₂₀H₂₀Br₃N₃O₂S.

Yield: 71%. M.P. 192 °C. IR (KBr, cm⁻¹): 3376 (NH), 1716

(CO), 1661 (CO amide), 2816, 1510, 1478, 1255, 1092, 797.

3

¹H-NMR (CDCl₃) d (ppm): 7.54 (d, J_NH-H4c= 8.2 Hz,

3

1H,NH), 7.29-6.92 (m, 4H, H_phenyl), 5.36 (dt, J_H4c-H5a

=

3.7 Hz, J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.50 (m,

3H, H_benzyland H-5b), 3.06 (s, 2H, COCH₂N), 2.82 (dd,

³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.60 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.29 (C-6),

3

1

170.11 (NHCO), 162.99 (d, J_C–F= 245.3 Hz, C-3_phenyl),

151.69 (C-6a), 141.98 (C-3a), 140.59 (d, J_C–F= 6.6 Hz,

3

C-1_phenyl), 129.74 (d, J_C–F= 7.4 Hz, C-5_phenyl), 124.48 (d,

6.4.23. 2-[4-(2-Iodobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (24)

⁴J_C–F= 2.5 Hz, C-6_phenyl), 115.71 (d, J_C–F= 21.4 Hz,

2

C-4_phenyl), 114.13 (d, J_C–F= 20.7 Hz, C-2_phenyl), 111.96

Yield: 66%. M.P. 175 °C. IR (KBr, cm⁻¹): 3424 (NH), 1719

(C-1), 106.00 (C-3), 62.19 (C_benzyl), 61.31 (COCH₂N), 53.59

(C-3_piperazineand C-5_piperazine), 52.93 (C-2_piperazineand

C-6_piperazine), 52.16 (C-5), 43.09 (C-4). MS (m/z): 546.5

(⁺M+2), 544.5 (⁺M), 542.5 (⁺M–2).

(CO), 1655 (CO amide), 2818, 1511, 1127, 1006, 750.

¹H-NMR (CDCl₃) d (ppm): 7.83 (dd, J_{H3phenyl-H5phenyl}

=

4

3

1.0 Hz, J_{H3phenyl-H4phenyl}= 7.7 Hz, 1H, H-3_phenyl), 7.60 (d,

³J_NH-H4c= 8.2 Hz, 1H,NH), 7.38 (dd, J_{H6phenyl-H4phenyl}

1.7 Hz, ³J_{H6phenyl-H5phenyl}= 7.7 Hz, 1H, H-6_phenyl), 7.30 (dt,

⁴J_{H5phenyl-H3phenyl}= 1.0 ³J_{H5phenyl-H4phenyl}

Hz,

³J_{H5phenyl-H3phenyl}= 7.7 Hz, 1H, H-5_phenyl), 6.95 (dt,

⁴J_{H4phenyl-H6phenyl}= 1.7 ³J_{H4phenyl-H5phenyl}

Hz,

=

4

6.4.21. 2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (22)

=

Yield: 79%. M.P. 176 °C. IR (KBr, cm⁻¹): 3372 (NH), 1716

(CO), 1662 (CO amide), 2811, 1510, 1476, 1222, 1129, 822.

=

³J_{H4phenyl-H3phenyl}= 7.7 Hz, 1H, H-4_phenyl), 5.37 (dt,

³J_H4c-H5a= 3.7 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c),

3.53 (m, 3H, H_benzyland H-5b), 3.07 (s, 2H, COCH₂N), 2.84

(dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.45

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.36 (C-6),

170.21 (NHCO), 151.60 (C-6a), 141.90 (C-3a), 140.18

(C-1_phenyl), 139.49 (C-3_phenyl), 130.21 (C-5_phenyl), 128.78

(C-4_phenyl), 128.01 (C-6_phenyl), 111.92 (C-1), 106.00 (C-3),

100.55 (C-2_phenyl), 66.21 (C_benzyl), 61.28 (COCH₂N), 53.68

(C-3_piperazineand C-5_piperazine), 52.84 (C-2_piperazineand

3

¹H-NMR (CDCl₃) d (ppm): 7.54 (d, J_NH-H4c= 8.0 Hz,

1H,NH), 7.28 (m, 2H, H-2_phenyland H-6_phenyl), 6.98 (t,

³J_{H3phenyl-H2phenyl}

= = =

³J_{H5phenyl-H6phenyl}³J_H3phenyl-F

³J_H5phenyl-F= 8.6 Hz, 2H, H-3_phenyland H-5_phenyl), 5.36 (dt,

³J_H4c-H5a= 3.6 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H, H-4c),

3.51 (m, 3H, H_benzyland H-5b), 3.06 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.54

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.29 (C-6),

1

170.17 (NHCO), 162.10 (d, J_C–F= 244.6 Hz, C-4_phenyl),

1234

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

C-6_piperazine), 52.11 (C-5), 43.01 (C-4). MS (m/z): 573.9

(⁺M+1-Br), 571.9 (⁺M–1-Br).Anal. CHN C₂₀H₂₀Br₂IN₃O₂S.

7.4 Hz, 1H, H-5_phenyl), 7.11 (s, 1H, H-2_phenyl), 7.09 (d,

³J_{H6phenyl-H5phenyl}= 7.4 Hz, 1H, H-6_phenyl), 7.05 (d,

³J_{H4phenyl-H5phenyl}= 7.4 Hz, 1H, H-4_phenyl), 5.36 (dt,

³J_H4c-H5a= 3.8 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c),

3.47 (m, 3H, H_benzyland H-5b), 3.05 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55

(m, 8H, H_piperazine), 2.33 (s, 3H, Me). ¹³C-NMR (CDCl₃) d

(ppm): 192.30 (C-6), 170.19 (NHCO), 151.73 (C-6a), 141.94

(C-3a), 137.86 (C-1_phenyl), 137.60 (C-3_phenyl), 129.82 (C-

6.4.24. 2-[4-(2-Triﬂuorometheylbenzyl)piperazin-1-yl]-N-

(1,3-dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c]thien-4-

yl)acetamide (25)

Yield: 30%. M.P. 130 °C. IR (KBr, cm⁻¹): 3429 (NH), 1718

(CO), 1666 (CO amide), 2814, 1508, 1313, 1117, 770.

3

¹H-NMR (CDCl₃) d (ppm): 7.76 (d, J_NH-H4c= 7.6 Hz,

1H,NH), 7.64 (d, ³J_{H3phenyl-H4phenyl}= 7.5 Hz, 1H, H-3_phenyl),

2

_phenyl), 128.12 (C-5_phenyl), 127.92 (C-6_phenyl), 126.20

3

(C-4_phenyl), 111.77 (C-1), 105.97 (C-3), 62.82 (C_benzyl), 61.32

(COCH₂N), 53.61 (C-3_piperazineand C-5_piperazine), 52.93

(C-2_piperazineand C-6_piperazine), 52.06 (C-5), 43.02 (C-4), 21.37

(Me). MS (m/z): 542.5 (⁺M+2), 540.5 (⁺M), 538.5 (⁺M–2).

7.60 (d, J_{H6phenyl-H5phenyl}= 7.5 Hz, 1H, H-6_phenyl), 7.51 (t,

3

³J_{H4phenyl-H5phenyl}= J_{H4phenyl-H3phenyl}= 7.5 Hz, 1H,

3

H-4_phenyl), 7.33 (t, J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}

=

3

7.5 Hz, 1H, H-5_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz,

³J_H4c-H5b= J_H4c-NH= 7.6 Hz, 1H, H-4c), 3.66 (s, 2H,

3

_benzyl), 3.49 (dd, ³J_H5b-H4c= 7.6 Hz, ²J_H5b-H5a= 19.3 Hz, 1H,

6.4.27. 2-[4-(4-Methylbenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (28)

H

H-5b), 3.07 (s, 2H, COCH₂N), 2.84 (dd, ³J_H5a-H4c= 3.7 Hz,

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.59 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.22 (C-6), 170.02 (NHCO),

151.59 (C-6a), 141.82 (C-3a), 137.23 (C-1_phenyl), 131.68

Yield: 77%. M.P. 181 °C. IR (KBr, cm⁻¹): 3372 (NH), 1720

(CO), 1662 (CO amide), 2809, 1510, 1476, 1129, 1007, 838.

2

3

¹H-NMR (CDCl₃) d (ppm): 7.58 (d, J_NH-H4c= 8.1 Hz,

(C-5_phenyl), 130.16 (C-6_phenyl), 128.40 (q, J_C–F= 30.1 Hz,

3

1H,NH), 7.18 (d, J_{H3phenyl-H2phenyl}= ³J_{H5phenyl-H6phenyl}

=

C-2_phenyl), 126.77 (C-4_phenyl), 125.62 (C-3_phenyl), 124.18 (q,

¹J_C–F= 292.9 Hz, CF₃), 111.64 (C-1), 105.84 (C-3), 61.20

(COCH₂N), 57.82 (C_benzyl), 53.55 (C-3_piperazineand

C-5_piperazine), 52.93 (C-2_piperazineand C-6_piperazine), 51.91

(C-5), 42.92 (C-4). MS (m/z): 598.0 (⁺M+2), 596.0 (⁺M),

594.0 (⁺M–2). Anal. CHN C₂₁H₂₀Br₂F₃N₃O₂S.

8.0 Hz, 2H, H-3_phenyland H-5_phenyl), 7.11 (d,

³J_{H2phenyl-H3phenyl}= ³J_{H6phenyl-H5phenyl}= 8.0 Hz, 2H, H-2_phenyl

3

and H-6_phenyl), 5.35 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.47 (m, 3H, H_benzyland H-5b),

3.05 (s, 2H, COCH₂N), 2.82 (dd, J_H5a-H4c= 3.7 Hz,

3

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine), 2.33

(s, 3H, Me). ¹³C-NMR (CDCl₃) d (ppm): 192.31 (C-6), 170.19

(NHCO), 151.72 (C-6a), 141.95 (C-3a), 136.78 (C-1_phenyl),

134.64 (C-4_phenyl), 129.08 (C-3_phenyland C-5_phenyl), 128.94

(C-2_phenyland C-6_phenyl), 111.81 (C-1), 105.96 (C-3), 62.54

(C_benzyl), 61.33 (COCH₂N), 53.65 (C-3_piperazineand

C-5_piperazine), 52.86 (C-2_piperazineand C-6_piperazine), 52.09

(C-5), 43.02 (C-4), 21.09 (Me). MS (m/z): 543.2 (⁺M+2),

541.2 (⁺M), 539.2 (⁺M–2).

6.4.25. 2-[4-(2-Methylylbenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (26)

Yield: 65%. M.P. 175 °C. IR (KBr, cm⁻¹): 3372 (NH), 1720

(CO), 1658 (CO amide), 2813, 1511, 1130, 1007, 741.

3

¹H-NMR (CDCl₃) d (ppm): 7.62 (d, J_NH-H4c= 8.1 Hz,

1H,NH), 7.20 (m, 4H, H_phenyl), 5.36 (dt, ³J_H4c-H5a= 3.7 Hz,

3

³J_H4c-H5b= J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.50 (dd,

2

³J_H5b-H4c= 8.1 Hz, J_H5b-H5a= 19.4 Hz, 1H, H-5b), 3.45 (s,

2H,

H_benzyl), 3.04 (s, 2H, COCH₂N), 2.82 (dd,

6.4.28. 2-[4-(2-Nitrobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (29)

³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.55 (m,

8H, H_piperazine), 2.34 (s, 3H, Me). ¹³C-NMR (CDCl₃) d (ppm):

192.35 (C-6), 170.26 (NHCO), 151.71 (C-6a), 141.94 (C-3a),

137.53 (C-2_phenyl), 136.06 (C-1_phenyl), 130.30 (C-3_phenyl),

129.76 (H-6_phenyl), 127.15 (C-4_phenyl), 125.48 (C-5_phenyl),

111.85 (C-1), 105.98 (C-3), 61.32 (C_benzyl), 60.68 (COCH₂N),

53.77 (C-3_piperazineand C-5_piperazine), 53.03 (C-2_piperazineand

C-6_piperazine), 52.13 (C-5), 43.03 (C-4), 19.21 (Me). MS (m/z):

543.0 (⁺M+2), 541.0 (⁺M), 539.0 (⁺M–2). Anal. CHN

C₂₁H₂₃Br₂N₃O₂S.

Yield: 75%. M.P. 180 °C. IR (KBr, cm⁻¹): 3412 (NH), 1720

(CO), 1664 (CO amide), 1526, 1503, 1469, 1131, 753.

3

¹H-NMR (CDCl₃) d (ppm): 7.72 (d, J_NH-H4c= 8.1 Hz,

1H,NH), 7.49 (m, 3H, H-3_phenyl, H-5_phenyland H-6_phenyl), 7.32

3

(t, J_{H4phenyl-H3phenyl}= J_{H4phenyl-H5phenyl}= 7.7 Hz, 1H,

3

H-4_phenyl), 5.27 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.71 (s, 2H, H_benzyl), 3.41 (dd,

³J_H5b-H4c= 8.1 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 2.97 (s,

2

3

2

2H, COCH₂N), 2.75 (dd, J_H5a-H4c= 3.7 Hz, J_H5a-H5b

=

19.3 Hz, 1H, H-5a), 2.45 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.24 (C-6), 170.10 (NHCO), 151.60

(C-6a), 149.75 (C-2_phenyl), 141.86 (C-3a), 133.38 (C-1_phenyl),

132.32 (C-5_phenyl), 130.77 (C-4_phenyl), 127.98 (C-6_phenyl),

124.31 (C-3_phenyl), 111.78 (C-1), 105.87 (C-3), 61.16

(COCH₂N), 58.66 (C_benzyl), 53.52 (C-3_piperazineand

C-5_piperazine), 52.92 (C-2_piperazineand C-6_piperazine), 52.01

6.4.26. 2-[4-(3-Methylbenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (27)

Yield: 67%. M.P. 170 °C. IR (KBr, cm⁻¹): 3367 (NH), 1716

(CO), 1660 (CO amide), 2814, 1514, 1133, 1094, 1007, 773.

3

¹H-NMR (CDCl₃) d (ppm): 7.62 (d, J_NH-H4c= 8.2 Hz,

3

1H,NH), 7.19 (t, J_{H5phenyl-H4phenyl}= ³J_{H5phenyl-H6phenyl}

=

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1235

(C-5), 43.01 (C-4). MS (m/z): 574.5 (⁺M+2), 572.5 (⁺M),

570.5 (⁺M–2).

H_benzyland H-5b), 3.04 (s, 2H, COCH₂N), 2.81 (dd,

³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.51 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.36 (C-6),

170.14 (NHCO), 151.60 (C-6a), 146.87 (C-2_phenyl), 141.94

(C-3a), 130.51 (C-4_phenyl), 128.57 (C-6_phenyl), 121.83 (C-

6.4.29. 2-[4-(3-Nitrobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (30)

1

_phenyl), 117.65 (C-3_phenyl), 115.55 (C-5_phenyl), 112.01 (C-1),

Yield: 100%. M.P. 152 °C. IR (KBr, cm⁻¹): 3368 (NH),

1719 (CO), 1661 (CO amide), 2810, 1612, 1512, 1130, 1008,

842. ¹H-NMR (CDCl₃) d (ppm): 8.19 (s, 1H, H-2_phenyl), 8.11

106.01 (C-3), 61.81 (C_benzyl), 61.28 (COCH₂N), 53.83

(C-3_piperazineand C-5_piperazine), 52.64 (C-2_piperazineand

C-6_piperazine), 52.14 (C-5), 43.07 (C-4). MS (m/z): 545.0

(⁺M+2), 543.0 (⁺M), 541.0 (⁺M–2).

3

(d, J_{H4phenyl-H5phenyl}= 8.1 Hz, 1H, H-4_phenyl), 7.66 (d,

³J_{H6phenyl-H5phenyl}= 8.1 Hz, 1H, H-6_phenyl), 7.53 (d,

3

³J_NH-H4c= 8.1 Hz, 1H,NH), 7.49 (t, J_{H5phenyl-H4phenyl}

=

6.4.32. 2-[4-(4-Aminobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (33)

³J_{H5phenyl-H6phenyl}= 8.1 Hz, 1H, H-5_phenyl), 5.36 (dt,

³J_H4c-H5a= 3.7 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c),

3

3.59 (s, 2H, H_benzyl), 3.50 (dd, J_H5b-H4c= 8.1 Hz,

Yield: 53%. M.P. 130 °C. IR (KBr, cm⁻¹): 3350 (NH), 1720

(CO), 1666 (CO amide), 2811, 1516, 1262, 1131, 802.

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.08 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.45

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.32 (C-6),

170.07 (NHCO), 151.68 (C-6a), 148.43 (C-3_phenyl), 141.97

(C-3a), 140.47 (C-1_phenyl), 134.90 (C-6_phenyl), 129.27 (C-

3

¹H-NMR (CDCl₃) d (ppm): 7.59 (d, J_NH-H4c= 8.2 Hz,

3

1H,NH), 7.06 (d, J_{H2phenyl-H3phenyl}= ³J_{H6phenyl-H5phenyl}

=

8.3 Hz, 2H, H-2_phenyland H-6_phenyl), 6.63 (d,

³J_{H3phenyl-H2phenyl}= ³J_{H5phenyl-H6phenyl}= 8.3 Hz, 2H, H-3_phenyl

3

5

_phenyl), 123.66 (C-2_phenyl), 122.35 (C-4_phenyl), 111.99 (C-1),

and H-5_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.6 (large, 2H,NH₂), 3.48 (dd,

105.99 (C-3), 61.84 (C_benzyl), 61.29 (COCH₂N), 53.57

(C-3_piperazineand C-5_piperazine), 53.00 (C-2_piperazineand

C-6_piperazine), 52.16 (C-5), 43.09 (C-4). MS (m/z): 574.5

(⁺M+2), 572.5 (⁺M), 570.5 (⁺M–2).

³J_H5b-H4c= 8.2 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.41 (s,

2

2H,

H_benzyl), 3.04 (s, 2H, COCH₂N), 2.81 (dd,

³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.53 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.34 (C-6),

170.24 (NHCO), 151.71 (C-6a), 145.58 (C-4_phenyl), 141.94

(C-3a), 130.34 (C-2_phenyland C-6_phenyl), 127.26 (C-1_phenyl),

114.86 (C-3_phenyland C-5_phenyl), 111.82 (C-1), 105.97 (C-3),

62.33 (C_benzyl), 61.32 (COCH₂N), 53.62 (C-3_piperazineand

C-5_piperazine), 52.76 (C-2_piperazineand C-6_piperazine), 52.08

(C-5), 43.39 (C-4). MS (m/z): 545.1 (⁺M+2), 543.1 (⁺M),

541.1 (⁺M–2).

6.4.30. 2-[4-(4-Nitrobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (31)

Yield: 55%. M.P. 190 °C. IR (KBr, cm⁻¹): 3369 (NH), 1716

(CO), 1660 (CO amide), 2818, 1516, 1348, 1130, 1007, 741.

3

¹H-NMR (CDCl₃) d (ppm): 8.17 (d, J_{H3phenyl-H2phenyl}

=

³J_{H5phenyl-H6phenyl}= 8.8 Hz, 2H, H-3_phenyland H-5_phenyl), 7.55

(d, ³J_NH-H4c= 8.0 Hz, 1H,NH), 7.50 (d, ³J_{H2phenyl-H3phenyl}

=

³J_{H6phenyl-H5phenyl}= 8.8 Hz, 2H, H-2_phenyland H-6_phenyl), 5.37

6.4.33. 2-[4-(2-Methoxybenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (34)

(dt, J_H4c-H5a= 3.6 Hz, J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H,

3

H-4c), 3.60 (s, 2H, H_benzyl), 3.51 (dd, J_H5b-H4c= 8.0 Hz,

²J_H5b-H5a= 19.4 Hz, 1H, H-5b), 3.08 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.58

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.30 (C-6),

170.03 (NHCO), 151.68 (C-6a), 147.27 (C-4_phenyl), 146.00

(C-1_phenyl), 141.97 (C-3a), 129.40 (C-2_phenyland C-6_phenyl),

123.60 (C-3_phenyland C-5_phenyl), 111.98 (C-1), 105.98 (C-3),

61.93 (C_benzyl), 61.31 (COCH₂N), 53.60 (C-3_piperazineand

C-5_piperazine), 53.08 (C-2_piperazineand C-6_piperazine), 52.17

(C-5), 43.08 (C-4). MS (m/z): 574.0 (⁺M+2), 572.0 (⁺M),

570.0 (⁺M–2).

Yield: 60%. M.P. 110 °C. IR (KBr, cm⁻¹): 3430 (NH), 1721

(CO), 1666 (CO amide), 2935, 2815, 1469, 1241, 1132, 755.

3

¹H-NMR (CDCl₃) d (ppm): 7.60 (d, J_NH-H4c= 8.2 Hz,

1H,NH), 7.32 (dd, ⁴J_{H6phenyl-H4phenyl}= 1.5 Hz,

³J_{H6phenyl-H5phenyl}= 7.5 Hz, 1H, H-6_phenyl), 7.25 (dt, ⁴J_H4phenyl-

3

^H6phenyl= 1.5 Hz, J_{H4phenyl-H3phenyl}= ³J_{H4phenyl-H5phenyl}

=

7.5 Hz, 1H, H-4_phenyl), 6.93 (dt, ⁴J_{H5phenyl-H3phenyl}= 0.8 Hz,

³J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}= 7.5 Hz, 1H,

3

H-5_phenyl), 6.87 (dd, ⁴J_{H3phenyl-H5phenyl}= 0.8 Hz,

³J_{H3phenyl-H4phenyl}= 7.5 Hz, 1H, H-3_phenyl), 5.36 (dt,

³J_H4c-H5a= 3.7 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c),

3.82 (s, 3H, OMe), 3.58 (s, 2H, H_benzyl), 3.50 (dd,

6.4.31. 2-[4-(2-Aminobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (32)

2

³J_H5b-H4c= 8.2 Hz, J_H5b-H4c= 19.3 Hz, 1H, H-5b), 3.06 (s,

3

2

2H, COCH₂N), 2.82 (dd, J_H5a-H4c= 3.7 Hz, J_H5a-H5b

=

Yield: 75%. M.P. >240 °C. IR (KBr, cm⁻¹): 3369 (NH),

1720 (CO), 1657 (CO amide), 2804, 1510, 1476, 1135, 747.

19.3 Hz, 1H, H-5a), 2.60 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.35 (C-6), 170.29 (NHCO), 157.78

(C-2_phenyl), 151.65 (C-6a), 141.92 (C-3a), 130.49 (C-4_phenyl),

128.15 (C-6_phenyl), 125.74 (C-1_phenyl), 120.30 (C-5_phenyl),

111.86 (C-3_phenyl), 110.48 (C-1), 105.95 (C-3), 61.30

3

¹H-NMR (CDCl₃) d (ppm): 7.56 (d, J_NH-H4c= 8.2 Hz,

1H,NH), 6.90 (m, 4H, H_phenyl), 5.36 (dt, ³J_H4c-H5a= 3.8 Hz,

3

³J_H4c-H5b= J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.51 (m, 3H,

1236

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

3

(COCH₂N), 55.74 (C_benzyl), 55.41 (OMe), 53.68 (C-3_piperazine

and C-5_piperazine), 52.86 (C-2_piperazineand C-6_piperazine), 52.11

(C-5), 43.00 (C-4). MS (m/z): 559.7 (⁺M+2), 557.7 (⁺M),

555.7 (⁺M–2).

H-6_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.3 Hz, 1H, Hc), 3.88 (s, 3H, pOMe), 3.87 (s, 3H,

3

2

mOMe), 3.50 (dd, J_H5b-H4c= 8.3 Hz, J_H5b-H4c= 19.4 Hz,

1H, H-5b), 3.44 (s, 2H, H_benzyl), 3.06 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.4 Hz, 1H, H-5a), 2.54

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.34 (C-6),

170.24 (NHCO), 151.71 (C-6a), 148.94 (C-4_phenyl), 148.23

(C-3_phenyl), 141.96 (C-3a), 130.47 (C-1_phenyl), 121.22 (C-

6.4.34. 2-[4-(3-Methoxybenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (35)

Yield: 60%. M.P. 148 °C. IR (KBr, cm⁻¹): 3376 (NH), 1716

(CO), 1660 (CO amide), 2934, 2814, 1512, 1262, 1136, 780.

6

_phenyl), 112.16 (C-5_phenyl), 111.91 (C-1), 110.16 (C-2_phenyl),

105.99 (C-3), 62.58 (COCH₂N), 61.34 (C_benzyl), 55.92

(2OMe), 53.70 (C-3_piperazineand C-5_piperazine), 52.91 (C-

2_piperazineand C-6_piperazine), 52.14 (C-5), 43.05 (C-4). MS

(m/z): 589.0 (⁺M+2), 587.0 (⁺M), 585.0 (⁺M–2).

3

¹H-NMR (CDCl₃) d (ppm): 7.59 (d, J_NH-H4c= 8.2 Hz,

3

1H,NH), 7.23 (t, J_{H5phenyl-H4phenyl}= ³J_{H5phenyl-H6phenyl}

=

7.9 Hz, 1H, H-5_phenyl), 6.88 (m, 2H, H-2_phenyland H-4_phenyl),

4

3

6.80 (dd, J_{H6phenyl-H4phenyl}= 1.8 Hz, J_{H6phenyl-H5phenyl}

=

3

6.4.37. 2-[4-(1-Naphthylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (38)

7.9 Hz, 1H, H-6_phenyl), 5.37 (dt, J_H4c-H5a= 3.7 Hz,

³J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.80 (s, 3H, OMe),

3.50 (m, 3H, H-5b and H_benzyl), 3.06 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.56

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.21 (C-6),

170.03 (NHCO), 159.40 (C-3_phenyl), 151.48 (C-6a), 141.70

(C-3a), 139.29 (C-1_phenyl), 129.01 (C-5_phenyl), 121.16 (C-

Yield: 51%. M.P. 115 °C. IR (KBr, cm⁻¹): 3368 (NH), 1717

1

(CO), 1660 (CO amide), 2820, 1512, 1134, 750, 466. H-

NMR (CDCl₃) d (ppm): 8.17 (d, ³J_{H4naphthalene -H3naphthalene}

8.6 Hz, 1H, H-4_naphthalene), 7.75 (d, ³J_{H8naphthalene-H7naphthalene}

5.8 Hz, 1H, H-8_naphthalene), 7.69 (t, ³J_{H7naphthalene-H6naphthalene}

=

6

_phenyl), 114.36 (C-4_phenyl), 112.20 (C-2_phenyl), 111.68 (C-1),

³J_H7₃_{naphthalene -H8naphthalene}= 5.8 Hz, 1H, H-7_naphthalene), 7.55

105.78 (C-3), 62.52 (C_benzyl), 61.10 (COCH₂N), 54.99 (OMe),

53.44 (C-3_piperazineand C-5_piperazine), 52.71 (C-2_piperazineand

C-6_piperazine), 51.88 (C-5), 42.77 (C-4). MS (m/z): 559.3

(⁺M+2), 557.3 (⁺M), 555.3 (⁺M–2).

(d, J_NH-H4c= 8.1 Hz, 1H,NH), 7.41 (m, 4H, H-2_naphthalene

,

H-3_naphthaleneH-5_naphthalene,and H-6_naphthalene), 5.25 (dt,

³J_H4c-H5a= 3.6 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c),

3.81 (s, 2H,NCH₂naphthalene), 3.39 (dd, ³J_H5b-H4c= 8.1 Hz,

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 2.95 (s, 2H, COCH₂N), 2.73

(dd, ³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.50

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.31 (C-6),

170.19 (NHCO), 151.63 (C-6a), 141.85 (C-3a), 133.75

(C-1_naphthalene), 133.59 (C-4a_naphthalene), 132.40 (C-

8a_naphthalene), 128.33 (C-5_naphthalene), 128.02 (C-4_naphthalene),

127.32 (C2_naphthalene), 125.71 (C-7_naphthalene), 125.60 (C-

6.4.35. 2-[4-(4-Methoxybenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (36)

Yield: 44%. M.P. 167 °C. IR (KBr, cm⁻¹): 3330 (NH), 1714

(CO), 1658 (CO amide), 2824, 1526, 1351, 1135, 1010, 735.

3

¹H-NMR (CDCl₃): d (ppm) 7.57 (d, J_NH-H4c= 8.1 Hz,

3

1H,NH), 7.20 (d, J_{H2phenyl-H3phenyl}= ³J_{H6phenyl-H5phenyl}

=

8.2 Hz, 2H, H-2_phenyland H-6_phenyl), 6.84 (d,

3_naphthalene), 125.00 (C-6_naphthalene), 124.60 (C-8_naphthalene),

³J_{H3phenyl-H2phenyl}

=

³J_{H5phenyl-H6phenyl}= 8.2 Hz, 2H,

111.78 (C-1), 105.93 (C-3), 61.55 (NCH₂naphthalene), 60.90

(COCH₂N), 53.64 (C-2_piperazineand C-6_piperazine), 53.08

(C-3_piperazineand C-5_piperazine), 52.03 (C-5), 42.93 (C-4). MS

(m/z): 579.3 (⁺M+2), 577.3 (⁺M), 575.3 (⁺M–2).

3

H-3_phenyland H-5_phenyl), 5.35 (dt, J_H4c-H5a= 3.4 Hz,

³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.79 (s, 3H, OMe),

3.47 (m, 3H, H-5b and H_benzyl), 3.05 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.4 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.56

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.32 (C-6),

170.23 (NHCO), 158.83 (C-4_phenyl), 151.72 (C-6a), 141.96

(C-3a), 130.28 (C-2_phenyland C-6_phenyl), 129.80 (C-1_phenyl),

113.65 (C-3_phenyland C-5_phenyl), 111.86 (C-1), 105.99 (C-3),

62.21 (C_benzyl), 61.34 (COCH₂N), 55.25 (OMe), 53.68

(C-3_piperazineand C-5_piperazine), 52.83 (C-2_piperazineand

C-6_piperazine), 52.13 (C-5), 43.04 (C-4). MS (m/z): 559.7

(⁺M+2), 557.7 (⁺M), 555.7 (⁺M–2).

6.4.38. 2-[4-(Pyridin-2-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (39)

Yield: 40%. M.P. 211 °C. IR (KBr, cm⁻¹): 3372 (NH), 1718

1

(CO), 1662 (CO amide), 2809, 1508, 1092, 751, 547. H-

NMR (DMSO d-6) d (ppm): 8.46 (dd, ⁴J_{H6pyridine-H4pyridine}

=

3

1.8 Hz, J_{H6pyridine-H5pyridine}= 4.9 Hz, 1H, H-6_pyridine), 8.35

(d, ³J_NH-H4c= 8.8 Hz, 1H,NH), 7.74 (dt, ⁴J_{H4pyridine-H6pyridine}

=

1.8 Hz, ³J_{H4pyridine-H5pyridine}= ³J_{H4pyridine-H3pyridine}= 7.7 Hz,

3

6.4.36. 2-[4-(3,4-Dimethoxybenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclo-penta[c]thien-4-yl)-

acetamide (37)

1H_,H-4_pyridine), 7.40 (d, J_{H3pyridine-H4pyridine}= 7.7 Hz, 1H_,

3

H-3_pyridine), 7.23 (dd, J_{H5pyridine-H6pyridine}= 4.9 Hz,

³J_{H5pyridine-H4pyridine}= 7.7 Hz, 1H, H-5_pyridine), 5.36 (dt,

³J_H4c-H5a= 3.5 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.8 Hz, 1H, H-4c),

Yield: 55%. M.P. 128 °C. IR (KBr, cm⁻¹): 3325 (NH), 1721

(CO), 1669 (CO amide), 2816, 2933, 1514, 1263, 1134, 1027.

3

3.57 (s, 2H,NCH₂pyridine), 3.29 (dd, J_H5b-H4c= 8.8 Hz,

3

¹H-NMR (CDCl₃) d (ppm): 7.58 (d, J_NH-H4c= 8.3 Hz,

²J_H5b-H5a= 18.7 Hz, 1H, H-5b), 2.92 (s, 2H, COCH₂N), 2.82

1H,NH), 6.87 (s, 1H, H-2_phenyl), 6.80 (m, 2H, H-5_phenyland

(dd, ³J_H5a-H4c= 3.5 Hz, ²J_H5a-H5b= 18.7 Hz, 1H, H-5a), 2.55

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1237

(m, 8H, H_piperazine). ¹³C-NMR (DMSO d-6) d (ppm): 193.40

6.4.41. 2-[4-(Thien-2-ylmethyl)piperazin-1-yl]-N-(1,3-

(C-6), 168.89 (NHCO), 158.14 (C-2_pyridine), 153.50 (C-6a),

148.72 (C-6_pyridine), 142.57 (C-3a), 136.45 (C-4_pyridine),

122.73 (C-3_pyridine), 122.11 (C5_pyridine), 109.50 (C-1), 104.62

(C-3), 63.70 (NCH₂pyridine), 61.26 (COCH₂N), 52.95

(C-3_piperazineand C-5_piperazine), 52.43 (C-2_piperazineand

C-6_piperazine), 51.10 (C-5), 40.12 (C-4). MS (m/z): 530.2

(⁺M+2), 528.2 (⁺M), 526.2 (⁺M–2).

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (42)

Yield: 33%. M.P. 170 °C. IR (KBr, cm⁻¹): 3372 (NH), 1718

(CO), 1662 (CO amide), 2811, 1511, 1476, 1130, 1008, 702.

3

¹H-NMR (CDCl₃) d (ppm): 7.61 (d, J_NH-H4c= 8.2 Hz,

4

1H,NH), 7.23 (dd, J_{H5thiophene-H3thiophene}= 1.2 Hz,

³J_{H5thiophene-H4thiophene}= 4.9 Hz, 1H, H-5_thiophene), 6.94 (dd,

3

³J_{H4thiophene-H3thiophene}= 3.4 Hz, J_{H4thiophene-H5thiophene}

=

4

4.9 Hz, 1H, H-4_thiophene), 6.89 (dd, J_{H3thiophene-H5thiophene}

1.2 Hz, ³J_{H3thiophene-H4thiophene}= 3.4 Hz, 1H, H-3_thiophene), 5.35

6.4.39. 2-[4-(Pyridin-3-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (40)

3

(dt, J_H4c-H5a= 3.8 Hz, J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H,

3

H-4c), 3.71 (s, 2H,NCH₂thiophene), 3.47 (dd, J_H5b-H4c

=

2

Yield: 43%. M.P. 241 °C. IR (KBr, cm⁻¹): 3416 (NH), 1718

8.2 Hz, J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.06 (s, 2H,

COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.3 Hz,

1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d

(ppm): 192.30 (C-6), 170.15 (NHCO), 151.73 (C-6a), 141.93

(C-2_thiophene), 141.16 (C-3a), 126.44 (C-4_thiophene), 126.09

(C-5_thiophene), 125.09 (C-3_thiophene), 111.73 (C-1), 105.94

(C-3), 61.28 (COCH₂N), 56.59 (NCH₂thiophene), 53.57

(C-3_piperazineand C-5_piperazine), 52.58 (C-2_piperazineand

C-6_piperazine), 52.02 (C-5), 43.02 (C-4). MS (m/z): 453.1

(⁺M+1-Br), 451.1 (⁺M–1-Br).

1

(CO), 1651 (CO amide), 2807, 1508, 1133, 716, 576. H-

NMR (CDCl₃) d (ppm): 8.52 (s, 1H, H-2_pyridine), 8.05 (d,

³J_{H6pyridine-H5pyridine}= 4.7 Hz, 1H H-6_pyridine), 7.65 (d,

³J_{H4pyridine-H5pyridine}= 7.6 Hz, 1H_,H-4_pyridine), 7.54 (d,

³J_NH-H4c= 7.8 Hz, 1H,NH), 7.26 (dd, ³J_H5pyridine-

3

^H4pyridine= 7.6 Hz, J_{H53pyridine-H6pyridine}= 4.7 Hz, 1H_,

3

H-5_pyridine), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 7.8 Hz, 1H, H-4c), 3.57 (m, 3H, H-5b and

NCH₂pyridine), 3.06 (s, 2H, COCH₂N), 2.82 (dd,

³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.5 Hz, 1H, H-5a), 2.55 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.41 (C-6),

170.18 (NHCO), 151.76 (C-6a), 150.50 (C-2_pyridine), 148.72

(C-6_pyridine), 142.57 (C-3a), 136.45 (C-4_pyridine), 133.39

(C-3_pyridine), 123.50 (C5_pyridine), 112.10 (C-1), 106.10 (C-3),

61.40 (COCH₂N), 60.70 (NCH₂pyridine), 53.68 (C-3_piperazine

and C-5_piperazine), 53.02 (C-2_piperazineand C-6_piperazine), 52.25

(C-5), 43.16 (C-4). MS (m/z): 530.8 (⁺M+2), 528.8 (⁺M),

526.8 (⁺M–2).

6.4.42. 2-[4-(Thien-3-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (43)

Yield: 71%. M.P. 203 °C. IR (KBr, cm⁻¹): 3369 (NH), 1716

(CO), 1661 (CO amide), 2811, 1511, 1461, 1130, 1006, 769.

3

¹H-NMR (CDCl₃) d (ppm): 7.57 (d, J_NH-H4c= 8.1 Hz,

4

1H,NH), 7.27 (dd, J_{H4thiophene-H2thiophene}= 3.1 Hz,

³J_{H4thiophene-H5thiophene}= 4.9 Hz, 1H, H-4_thiophene), 7.10 (d,

⁴J_{H2thiophene-H4thiophene}= 3.1 Hz, 1H, H-2_thiophene), 7.04 (d,

³J_{H5thiophene-H4thiophene}= 4.9 Hz, 1H, H-5_thiophene), 5.36 (dt,

³J_H4c-H5a= 3.8 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c),

6.4.40. 2-(4-Pyridin-4-ylmethyl)piperazin-1-yl)-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (41)

3

3.54 (s, 2H,NCH₂thiophene), 3.49 (dd, J_H5b-H4c= 8.1 Hz,

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.06 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.8 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.33 (C-6),

170.19 (NHCO), 151.69 (C-6a), 141.88 (C-3a), 138.80

(C-3_thiophene), 128.46 (C-5_thiophene), 125.54 (C-4_thiophene),

122.86 (C-2_thiophene), 111.88 (C-1), 105.98 (C-3), 61.32

(COCH₂N), 57.42 (NCH₂thiophene), 53.67 (C-3_piperazineand

C-5_piperazine), 52.12 (C-2_piperazineand C-6_piperazine), 52.05

(C-5), 42.99 (C-4). HRMS: calculated (530.9287), found

(530.9282).

Yield: 43%. M.P. 241 °C. IR (KBr, cm⁻¹): 3368 (NH), 1717

1

(CO), 1660 (CO amide), 2820, 1512, 1134, 750, 466. H-

3

NMR (DMSO d-6) d (ppm): 8.48 (d, J_{H2pyridine-H3pyridine}

=

³J_{H6pyridine-H5pyridine}= 5.3 Hz, 2H, H-2_pyridine, H-6_pyridine), 8.34

(d, ³J_NH-H4c= 8.7 Hz, 1H,NH), 7.29 (d, ³J_{H3pyridine-H2pyridine}

=

³J_{H5pyridine-H6pyridine}= 5.3 Hz, 2H, H-3_pyridine, H-5_pyridine), 5.28

(dt, J_H4c-H5a= 3.5 Hz, J_H4c-H5b= ³J_H4c-NH= 8.7 Hz, 1H,

3

H-4c), 3.48 (s, 2H,NCH₂pyridine), 3.26 (dd, J_H5b-H4c

=

2

8.7 Hz, J_H5b-H5a= 18.7 Hz, 1H, H-5b), 2.92 (s, 2H,

COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.5 Hz, ²J_H5a-H5b= 18.7 Hz,

1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-NMR (DMSO d-6)

d (ppm): 193.35 (C-6), 168.91 (NHCO), 153.47 (C-6a),

149.48 (C-2_pyridineand C-6_pyridine), 147.31 (C-4_pyridine), 142.57

(C-3a), 123.75 (C-3_pyridineand C-5_pyridine), 109.58 (C-1),

104.67 (C-3), 61.22 (NCH₂pyridine), 60.60 (COCH₂N), 52.91

(C-3_piperazineand C-5_piperazine), 52.31 (C-2_piperazineand

C-6_piperazine), 51.08 (C-5), 42.31 (C-4). MS (m/z): 530.2

(⁺M+2), 528.2 (⁺M), 526.2 (⁺M–2).

6.4.43. 2-{4-[(5-Chlorothien-2-yl)methyl]piperazin-1-yl}-

N-(1,3-dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c]thien-

4-yl)acetamide (44)

Yield: 73%. M.P. 188 °C. IR (KBr, cm⁻¹): 3380 (NH), 1719

(CO), 1662 (CO amide), 2813, 1509, 1329, 1129, 1092, 784.

3

¹H-NMR (CDCl₃) d (ppm): 7.55 (d, J_NH-H4c= 8.2 Hz,

3

1H,NH), 6.73 (d, J_{H4thiophene-H3thiophene}= 3.6 Hz, 1H,

3

H-4_thiophene), 6.65 (d, J_H₃_{3thiophene-H4thiophene}= 3.6 Hz, 1H,

3

H-3_thiophene), 5.37 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

1238

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

³J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.61 (s, 2H,NCH₂thiophene),

6.4.46. 2-[4-(Fur-3-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (47)

3.50 (dd, ³J_H5b-H4c= 8.2 Hz, ²J_H5b-H5a= 19.3 Hz, 1H, H-5b),

3

2

3.06 (s, 2H, COCH₂N), 2.82 (dd, J_H5a-H4c= 3.7 Hz, J_H5a-

^H5b= 19.3 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 192.33 (C-6), 170.10 (NHCO),

151.68 (C-6a), 141.94 (C-2_thiophene), 140.74 (C-3a), 129.33

(C-5_thiophene), 125.41 (C-3_thiophene), 125.00 (C-4_thiophene),

111.91 (C-1), 105.98 (C-3), 61.25 (COCH₂N), 57.32

(NCH₂thiophene), 53.58 (C-3_piperazineand C-5_piperazine), 52.61

(C-2_piperazineand C-6_piperazine), 52.13 (C-5), 43.04 (C-4). MS

(m/z): 569.9 (⁺M+2), 567.9 (⁺M), 565.9 (⁺M–2).

Yield: 21%. M.P. 158 °C. IR (KBr, cm⁻¹): 3371 (NH), 1717

(CO), 1662 (CO amide), 2813, 1508, 1261, 1130, 1020, 801.

3

¹H-NMR (CDCl₃) d (ppm): 7.55 (d, J_NH-H4c= 8.1 Hz,

1H,NH), 7.38 (d, ³J_{H5furan-H4furan}= 1.5 Hz, 1H, H-5_furan), 7.33

3

(s, 1H, H-2_furan), 6.38 (d, J_{H4furan-H5furan}= 1.5 Hz, 1H,

3

H-4_furan), 5.37 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.49 (dd, J_H5b-H4c= 8.1 Hz,

3

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.40 (s, 2H,NCH₂furan), 3.06

3

(s, 2H, COCH₂N), 2.82 (dd, J_H5a-H4c= 3.7 Hz,

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 191.97 (C-6), 169.79 (NHCO),

151.34 (C-6a), 142.77 (C-5_furan), 141.60 (C-3a), 140.58

(C-2_furan), 120.64 (C-3_furan), 111.55 (C-1), 110.99 (C-4_furan),

105.63 (C-3), 60.92 (COCH₂N), 53.15 (NCH₂furan), 52.34

(C-3_piperazineand C-5_piperazine), 52.33 (C-5), 51.76 (C-2_piperazine

and C-6_piperazine), 42.70 (C-4). MS (m/z): 518.7 (⁺M+2), 516.7

(⁺M), 514.7 (⁺M–2).

6.4.44. 2-{4-[(2,5-Dimethoxythien-3-yl)methyl]piperazin-1-

yl}-N-(1,3-dibromo-6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)acetamide (45)

Yield: 71%. M.P. >240 °C. IR (KBr, cm⁻¹): 3419 (NH),

1716 (CO), 1640 (CO amide), 2926, 1455, 1261, 1233, 1016,

801. ¹H-NMR (CDCl₃) d (ppm): 7.57 (d, ³J_NH-H4c= 8.1 Hz,

1H,NH), 7.27 (s, 1H, H-4_thiophene), 5.36 (dt, ³J_H4c-H5a= 3.8 Hz,

³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.74 (s, 3H, OMe),

3.73 (s, 3H, OMe), 3.45 (s, 2H,NCH₂thiophene), 3.40 (dd,

6.4.47. 2-[4-(1H-Pyrrol-2-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclo-penta[c]thien-4-yl)-

acetamide (48)

2

³J_H5b-H4c= 8.1 Hz, J_H5b-H5a= 19.7 Hz, 1H, H-5b), 3.06 (s,

3

2

2H, COCH₂N), 2.76 (dd, J_H5a-H4c= 3.8 Hz, J_H5a-H5b

=

Yield: 73%. M.P. 209 °C. IR (KBr, cm⁻¹): 3344 (NH), 1720

(CO), 1643 (CO amide), 2820, 1514, 1134, 1002, 835, 725.

¹H-NMR (CDCl₃) d (ppm): 9.12 (s, 1H,NH_pyrrole), 7.46 (d,

19.7 Hz, 1H, H-5a), 2.68 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.43 (C-6), 169.68 (NHCO), 154.59

(C-5_thiophene), 151.73 (C-6a), 151.42 (C-2_thiophene), 141.91

(C-3a), 114.07 (C-3_thiophene), 111.84 (C-1), 106.02 (C-3),

102.90 (C-4_thiophene), 62.89 (OMe), 61.32 (COCH₂N), 60.16

(OMe), 57.42 (NCH₂thiophene), 53.67 (C-3_piperazineand

C-5_piperazine), 52.12 (C-2_piperazineand C-6_piperazine), 52.05

(C-5), 42.99 (C-4). HRMS: calculated (590.9495), found

(590,9497).

³J_NH-H4c= 8.2 Hz, 1H,NH_amide), 6.72 (dd, ⁴J_{H5pyrrole-H3pyrrole}

=

2.6 Hz, ³J_{H5pyrrole-H4pyrrole}= 4.0 Hz, 1H, H-5_pyrrole), 6.10 (m,

3

2H, H-3_pyrroleand H-4_pyrrole), 5.35 (dt, J_H4c-H5a= 3.7 Hz,

3

³J_H4c-H5b= J_H4c-NH= 8.2 Hz, 1H, H-4c), 3.71 (s,

3

2

2H,NCH₂pyrrole), 3.47 (dd, J_H5b-H4c= 8.2 Hz, J_H5b-H5a

=

19.3 Hz, 1H, H-5b), 3.06 (s, 2H, COCH₂N), 2.82 (dd,

³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55 (m,

8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.16 (C-6),

169.66 (NHCO), 151.85 (C-6a), 142.18 (C-3a), 125.04

(C-2_pyrrole), 118.98 (C-5_pyrrole), 112.06 (C-1), 109.39 (C-

6.4.45. 2-[4-(Fur-2-ylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (46)

4_pyrrole), 108.29 (C-3_pyrrole), 106.08 (C-3), 61.20 (COCH₂N),

54.92 (NCH₂pyrrole), 52.73 (C-3_piperazineand C-5_piperazine),

52.37 (C-2_piperazineand C-6_piperazine), 52.23 (C-5), 43.35 (C-4).

MS (m/z): 517.9 (⁺M+2), 515.9 (⁺M), 513.9 (⁺M–2).

Yield: 33%. M.P. 152 °C. IR (KBr, cm⁻¹): 3371 (NH), 1717

(CO), 1662 (CO amide), 817, 1509, 1474, 1262, 1093, 801.

3

¹H-NMR (CDCl₃) d (ppm): 7.54 (d, J_NH-H4c= 8.2 Hz,

1H,NH), 7.38 (d, ³J_{H5furan-H4furan}= 2.2 Hz, 1H, H-5_furan), 6.32

(dd, ³J_{H4furan-H5furan}= 2.2 Hz, ³J_{H4furan-H3furan}= 3.0 Hz, 1H,

H-4_f₃_uran), 6.20 (d, ³J_{H3furan-H4furan}= 3.0 Hz, 1H, H-3_furan), 5.36

6.4.48. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(3-bromo-

6-oxo-5,6-dihydro-4H-cyclopenta[c]thien-4-yl)acetamide

(49)

3

(dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b= ³J_H4c-NH= 8.2 Hz, 1H,

Yield: 57%. M.P. 136 °C. IR (KBr, cm⁻¹): 3329 (NH), 1716

(CO), 1668 (CO amide), 2820, 1506, 1467, 1183, 1133, 726.

H-4c), 3.54 (s, 2H,NCH₂furan), 3.50 (dd, ³J_H5b-H4c= 8.2 Hz,

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.06 (s, 2H, COCH₂N), 2.82

(dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.28 (C-6),

170.07 (NHCO), 151.63 (C-6a), 151.19 (C-2_furan), 142.26

(C-5_furan),141.88 (C-3a), 111.73 (C-1), 110.03 (C-4_furan),

108.91 (C-3_furan), 105.93 (C-3), 61.21 (COCH₂N), 54.58

(NCH₂furan), 53.41(C-3_piperazineand C-5_piperazine), 52.55

(C-2_piperazineand C-6_piperazine), 52.04 (C-5), 42.96 (C-4). MS

(m/z): 518.7 (⁺M+2), 516.7 (⁺M), 514.7 (⁺M–2).

¹H-NMR (CDCl₃) d (ppm): 7.80 (s, 1H, H-1), 7.59 (d,

4

³J_NH-H4c= 8.0 Hz, 1H,NH), 7.36 (dt, J_{H6phenyl-H4phenyl}

=

4

3

1.7 Hz, J_H6phenyl-F= J_{H6phenyl-H5phenyl}= 7.5 Hz, 1H,

H-6_phenyl), 7.23 (m, 1H, H-4_phenyl), 7.11 (dt,

⁴J_{H5phenyl-H3phenyl}= 1.1

Hz,

³J_{H5phenyl-H4phenyl}

=

³J_{H5phenyl-H6phenyl}= 7.5 Hz, 1H, H-5_phenyl), 7.02 (dt,

⁴J_{H3phenyl-H5phenyl}= 1.1

Hz,

³J_{H3phenyl-H4phenyl}

=

³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.42 (dt, J_H4c-H5a

3

3.9 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H, H-4c), 3.58 (s, 2H,

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1239

2

H

_benzyl), 3.52 (dd, ³J_H5b-H4c= 8.0 Hz, ²J_H5b-H5a= 19.3 Hz, 1H,

C-5_phenyl), 115.25 (d, J_C–F= 22.4 Hz, C-3_phenyl), 61.44

(COCH₂N), 55.00 (C_benzyl), 53.60 (C-3_piperazineand

C-5_piperazine), 52.65 (C-2_piperazineand C-6_piperazine), 52.51

(C-5), 42.48 (C-4), 13.389 (C1-Me), 12.48 (C3-Me). MS

(m/z): 415.7 (⁺M).

H-5b), 3.06 (s, 2H, COCH₂N), 2.83 (dd, ³J_H5a-H4c= 3.9 Hz,

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 193.58 (C-6), 170.28 (NHCO),

161.38 (d, ¹J_C–F= 245.2 Hz, C-2_phenyl), 151.31 (C-6a), 144.36

3

(C-3a), 131.49 (d, J_C–F= 4.1 Hz, C-6_phenyl), 128.89 (d,

³J_C–F= 8.2 Hz, C-4_phenyl), 125.76 (C-1), 124.37 (d,

²J_C–F= 14.8 Hz, C-1_phenyl), 123.92 (d, J_C–F= 3.3 Hz,

4

6.4.51. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(6-oxo-5,6-

dihydro-4H-cyclopenta[b]thien-4-yl) acetamide (52)

C-5_phenyl), 115.27 (²J_C–F= 21.4 Hz,C-3_phenyl), 106.74 (C-3),

61.37 (COCH₂N), 55.01 (C_benzyl), 53.61 (C-3_piperazineand

C-5_piperazine), 52.71 (C-2_piperazineand C-6_piperazine), 52.11

(C-5), 43.75 (C-4). MS (m/z): 466.9 (⁺M+1), 464.9 (⁺M–1).

Yield: 28%. M.P. 130 °C. IR (KBr, cm⁻¹): 3446 (NH), 1700

(CO), 1660 (CO amide), 2820, 1507, 1455, 1129, 1095, 760.

¹H-NMR (CDCl₃₃) d (ppm): 7.85 (d, J_H2-H3= 4.6 Hz, 1H,

3

H-2), 7.43 (d, J_NH-H4c= 7.6 Hz, 1H,NH), 7.27 (dt,

⁴J_{H6phenyl-H4phenyl}= 1.7 Hz, ⁴J_H6phenyl-F= ³J_{H6phenyl-H5phenyl}

=

6.4.49. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(6-oxo-5,6-

dihydro-4H-cyclopenta[c]thien-4-yl) acetamide (50)

Yield: 32%. M.P. 130 °C. IR (KBr, cm⁻¹): 3350 (NH), 1711

(CO), 1662 (CO amide), 2823, 1513, 1455, 1154, 1008, 758.

7.0 Hz, 1H, H-6_phenyl), 7.16 (m, 1H, H-4_phenyl), 7.02 (m, 2H,

4

H-5_phenyland H-3), 6.93 (dt, J_{H3phenyl-H5phenyl}= 1.0 Hz,

³J_{H3phenyl-H4phenyl}= ³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.51

¹H-NMR (CDCl₃) d (ppm): 7.85 (s, 1H, H-1), 7.54 (d,

3

(dt, J_H4c-H5a= 2.5 Hz, J_H4c-H5b= ³J_H4c-NH= 7.6 Hz, 1H,

³J_NH-H4c= 7.8 Hz, 1H,NH), 7.34 (t, J_H6phenyl-F

=

3

4

H-4c), 3.49 (s, 2H, H_benzyl), 3.37 (dd, J_H5b-H4c= 7.6 Hz,

³J_{H6phenyl-H5phenyl}= 7.1 Hz, 1H, H-6_phenyl), 7.27 (s, 1H, H-3),

²J_H5b-H5a= 18.6 Hz, 1H, H-5b), 2.98 (s, 2H, COCH₂N), 2.67

(dd, ³J_H5a-H4c= 2.5 Hz, ²J_H5a-H5b= 18.6 Hz, 1H, H-5a), 2.45

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 193.15 (C-6),

170.10 (NHCO), 167.24 (C-3a), 161.18 (d, ¹J_C–F= 244.4 Hz,

C-2_phenyl), 141.82 (C-6a), 141.25 (C-2), 131.37 (d,

4

7.23 (m, 1H, H-4_phenyl), 7.11 (t, J_H5phenyl-

=

H4phenyl

³J_{H5phenyl-H6phenyl}= 7.1 Hz, 1H, H-5_phenyl), 7.02 (t,

³J_{H3phenyl-H4phenyl}= ³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.35

(m, 1H, H-4c), 3.58 (s, 2H, H_benzyl), 3.50 (dd,

³J_H5b-H4c= 7.6 Hz, J_H5b-H5a= 19.0 Hz, 1H, H-5b), 3.06 (s,

2

³J_C–F= 5.0 Hz, C-6_phenyl), 128.77 (d, J_C–F= 8.2 Hz,

3

2

2H, COCH₂N), 2.78 (dd, J_H5a-H4c= 3.3 Hz, J_H5a-H5b

=

C-4_phenyl), 124.00 (d, ²J_C–F= 14.9 Hz, C-1_phenyl), 123.75 (d,

19.0 Hz, 1H, H-5a), 2.60 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 194.14 (C-6), 170.16 (NHCO), 161.23 (d,

¹J_C–F, = 246.8 Hz, C-2_phenyl), 154.15 (C-6a), 143.71 (C-3a),

131.40 (C-6_phenyl), 128.82 (C-4_phenyl), 124.64 (C-1), 124.00

⁴J_C–F= 3.3 Hz, C-5_phenyl), 123.20 (C-3), 115.08 (d, J_C–F

=

2

22.2 Hz, C-3_phenyl), 61.18 (COCH₂N), 54.78 (C_benzyl), 53.28

(C-3_piperazineand C-5_piperazine), 52.38 (C-2_piperazineand

C-6_piperazine), 49.21 (C-5), 44.58 (C-4). MS (m/z): 387.3 (⁺M).

2

(d, J_C–F= 14.8 Hz, C-1_phenyl), 123.79 (C-5_phenyl), 119.57

(C-3), 115.12 (d, J_C–F= 22.2 Hz, C-3_phenyl), 61.21

2

(COCH₂N), 54.84 (C_benzyl), 53.36 (C-3_piperazineand

C-5_piperazine), 52.48 (C-2_piperazineand C-6_piperazine), 51.45

(C-5), 43.49 (C-4). MS (m/z): 387.1 (⁺M).

6.4.52. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(2-bromo-

4-oxo-5,6-dihydro-4H-cyclopenta[b]thien-6-yl)acetamide

(53)

Yield: 50%. M.P. 155 °C. IR (KBr, cm⁻¹): 3439 (NH), 1707

(CO), 1663 (CO amide), 2813, 1505, 1390, 1155, 1010, 755.

6.4.50. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(1,3-dim-

ethyl-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (51)

3

¹H-NMR (CDCl₃) d (ppm): 7.53 (d, J_NH-H6c= 7.0 Hz,

1H,NH), 7.24 (t, ⁴J_H6phenyl-F= ³J_{H6phenyl-H5phenyl}= 7.3 Hz, 1H,

H-6_phenyl), 7.16 (m, 1H, H-4_phenyl), 7.00 (m, 2H, H-5_phenyland

Yield: 71%. M.P. 153 °C. IR (KBr, cm⁻¹): 3434 (NH), 1705

(CO), 1643 (CO amide), 2817, 1514, 1178, 1015, 838, 768.

3

H-3), 6.92 (t, J_{H3phenyl-H4phenyl}= ³J_H3phenyl-F= 9.2 Hz, 1H,

3

¹H-NMR (CDCl₃) d (ppm): 7.32 (d, J_NH-H4c= 8.3 Hz,

3

1H,NH), 7.27 (t, ⁴J_H6phenyl-F= ³J_{H6phenyl-H5phenyl}= 7.3 Hz, 1H,

H-3_phenyl), 5.42 (dt, J_H6c-H5a= 2.5 Hz, J_H6c-H5b

=

³J_H6c-NH= 7.0 Hz, 1H, H-6c), 3.49 (s, 2H, H_benzyl), 3.24 (dd,

H-6_phenyl), 7.15 (m, 1H, H-4_phenyl), 7.03 (t, ³J_{H5phenyl- H4phenyl}

=

³J_H5b-H6c= 7.0 Hz, J_H5b-H5a= 18.3 Hz, 1H, H-5b), 2.96 (s,

2

³J_{H5phenyl-H6phenyl}= 7.3 Hz, 1H, H-5_phenyl), 6.95 (t,

³J_{H3phenyl-H4phenyl}= ³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.36

3

2

2H, COCH₂N), 2.58 (dd, J_H5a-H6c= 2.5 Hz, J_H5a-H5b

=

18.3 Hz, 1H, H-5a), 2.45 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.79 (C-6), 170.78 (NHCO), 168.59

(C-6a), 161.12 (d, ¹J_C–F= 246.2 Hz, C-2_phenyl), 144.93 (C-3a),

3

(dt, J_H4c-H5a= 2.3 Hz, J_H4c-H5b= ³J_H4c-NH= 8.3 Hz, 1H,

3

H-4c), 3.50 (s, 2H, H_benzyl), 3.35 (dd, J_H5b-H4c= 8.3 Hz,

²J_H5b-H5a= 19.1 Hz, 1H, H-5b), 2.96 (s, 2H, COCH₂N), 2.64

(dd, ³J_H5a-H4c= 2.3 Hz, ²J_H5a-H5b= 19.1 Hz, 1H, H-5a), 2.45

(m, 14H, H_piperazineand C1-Me and C3-Me). ¹³C-NMR

(CDCl₃) d (ppm): 195.58 (C-6), 169.80 (NHCO), 161.40 (d,

¹J_C–F= 246.1 Hz, C-2_phenyl), 147.93(C-6a), 141.14 (C-1),

3

131.28 (d, J_C–F= 4.9 Hz, C-6_phenyl), 128.67 (d, J_C–F

8.3 Hz, C-4_phenyl), 124.04 (d, J_C–F= 14.9 Hz, C-1_phenyl),

123.64 (d, J_C–F= 3.3 Hz, C-5_phenyl), 121.33 (C-3), 119.81

(C-2), 115.02 (d, J_C–F= 22.3 Hz, C-3_phenyl), 60.96

=

2

4

2

3

(COCH₂N), 54.75 (C_benzyl), 53.31 (C-3_piperazineand

C-5_piperazine), 52.37 (C-2_piperazineand C-6_piperazine), 46.85

(C-5), 46.04 (C-4). MS (m/z): 467.0 (⁺M+1), 465.0 (⁺M–1).

139.31 (C-3), 131.48 (d, J_C–F= 5.1 Hz, C-6_phenyl), 130.28

3

(C-3a), 128.89 (d, J_C–F= 8.2 Hz, C-4_phenyl), 124.37 (d,

²J_C–F= 14.9 Hz, C-1_phenyl), 123.91 (d, J_C–F= 3.3 Hz,

4

1240

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

6.4.53. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(2,3-

dibromo-4-oxo-5,6-dihydro-4H-cyclopenta[b] thien-4-yl)-

acetamide (54)

8.0 Hz, 1H, H-4c), 3.43 (dd, ³J_H5b-H4c= 8.0 Hz, ²J_H5b-H4c

=

19.3 Hz, 1H, H-5b), 2.98 (s, 2H, COCH₂N), 2.82 (dd,

³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.48 (m,

8H, H_piperazine), 2.06 (m, 2H,NCH₂CH), 1.65 (m, 6H,

H-3_cyclohexyl, H-4_cyclohexyland H-5_cyclohexyl), 1.39 (m, 1H,

H-1_cyclohexyl), 1.15 (m, 4H, H-2_cyclohexyland H-6_cyclohexyl). ¹³C-

NMR (CDCl₃) d (ppm): 192.38 (C-6), 170.26 (NHCO),

151.63 (C-6a), 141.88 (C-3a), 111.83 (C-1), 105.94 (C-3),

65.39 (NCH₂CH), 61.29 (COCH₂N), 53.60 (C-3_piperazineand

C-5_piperazine), 53.50 (C-2_piperazineand C-6_piperazine), 52.08

(C-5), 42.97 (C-4), 34.89 (C-1_cyclohexyl), 31.78 (C-2_cyclohexyl

and C-6_cyclohexyl), 26.70 (C-4_cyclohexyl), 26.05 (C-3_cyclohexyland

C-5_cyclohexyl). MS (m/z): 535.6 (⁺M+2), 533.6 (⁺M), 531.6

(⁺M–2).

Yield: 58%. M.P. 85 °C. IR (KBr, cm⁻¹): 3340 (NH), 1716

(CO), 1661 (CO amide), 2931, 1492, 1456, 1261, 1106, 759.

3

¹H-NMR (CDCl₃) d (ppm): 7.47 (d, J_NH-H6c= 7.2 Hz,

1H,NH), 7.27 (t, ⁴J_H6phenyl-F= ³J_{H6phenyl-H5phenyl}= 7.3 Hz, 1H,

H-6_phenyl), 7.05 (m, 3H, H-3_phenyl, H-4_phenyland H-5_phenyl),

5.61 (m, 1H, H-6c), 3.53 (s, 2H, H_benzyl), 3.33 (dd,

2

³J_Hb-H6c= 7.0 Hz, J_H5b-H5a= 18.4 Hz, 1H, H-5b), 2.99 (s,

3

2

2H, COCH₂N), 2.65 (dd, J_H5a-H6c= 2.6 Hz, J_H5a-H5b

=

18.4 Hz, 1H, H-5a), 2.47 (m, 8H, H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 191.28 (C-4), 171.39 (NHCO), 168.16

(C-6a), 161.40 (d, ¹J_C–F= 245.1 Hz, C-2_phenyl), 141.69 (C-3a),

3

131.57 (d, J_C–F= 4.1 Hz, C-6_phenyl), 128.98 (d, J_C–F

=

7.4 Hz, C-4_phenyl), 123.91 (m, 2C, C-1_phenyland C-5_phenyl),

118.98 (C-2), 115.31 (d, ²J_C–F= 21.4 Hz, C-3_phenyl), 107.52

(C-3), 61.06 (COCH₂N), 55.00 (C_benzyl), 53.54 (C-3_piperazine

and C-5_piperazine), 52.59 (C-2_piperazineand C-6_piperazine), 47.25

(C-5), 45.75 (C-6). MS (m/z): 547.7 (⁺M+2), 545.7 (⁺M),

543.7 (⁺M–2).

6.4.56. 2-(4-Phenylpiperazin-1-yl)-N-(1,3-dibromo-6-oxo-

5,6-dihydro-4H-cyclopenta[c]thien-4-yl) acetamide (57)

Yield: 46%. M.P. 205 °C. IR (KBr, cm⁻¹): 3438 (NH), 1712

(CO), 1663 (CO amide), 2824, 1503, 1471, 1239, 758.

3

¹H-NMR (CDCl₃) d (ppm): 7.59 (d, J_NH-H4c= 8.1 Hz,

3

1H,NH), 7.26 (t, J_{H3phenyl-H2phenyl}= ³J_{H3phenyl-H4phenyl}

=

6.4.54. 2-[4-(2-Fluorobenzyl)piperazin-1-yl]-N-(1,3-

dichloro-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (55)

³J_{H5phenyl-H4phenyl}= ³J_{H5phenyl-H6phenyl}= 8.1 Hz, 2H, H-3_phenyl

and H-5_phenyl), 6.89 (m, 3H, H-2_phenyl, H-4_phenyland

3

H-6_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

Yield: 77%. M.P. 220 °C. IR (KBr, cm⁻¹): 3366 (NH), 1722

(CO), 1657 (CO amide), 2815, 1491, 1230, 1140, 752.

³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.53 (dd, J_H5b-H4c= 8.1 Hz,

3

²J_H5b-H5a= 19.3 Hz, 1H, H-5b), 3.18 (m, 6H, , COCH₂N,

3

¹H-NMR (CDCl₃) d (ppm): 7.57 (d, J_NH-H4c= 8.0 Hz,

3

H

_piperazine-3 and H_piperazine-5), 2.84 (dd, J_H5a-H4c= 3.7 Hz,

4

1H,NH), 7.35 (dt, J_{H6phenyl-H4phenyl}= 1.7 Hz, J_H6phenyl-F

=

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.71 (m, 4H, H_piperazine

-

³J_{H6phenyl-H5phenyl}= 7.4 Hz, 1H, H-6_phenyl), 7.24 (m, 1H,

H-4_phenyl), 7.11 (dt, ⁴J_{H5phenyl-H3phenyl}= 1.0 Hz,

³J_{H5phenyl-H4phenyl}= ³J_{H5phenyl-H6phenyl}= 7.4 Hz, 1H, H-5_phenyl),

2 and H_piperazine-6). ¹³C-NMR (CDCl₃) d (ppm): 192.23 (C-6),

169.96 (NHCO), 151.66 (C-6a), 150.97 (C-1_phenyl), 141.98

(C-3a), 129.18 (C-3_phenyland C-5_phenyl), 120.14 (C-4_phenyl),

116.23 (C-2_phenyland C-6_phenyl), 112.012 (C-1), 105.94 (C-3),

61.42 (COCH₂N), 53.68 (C-3_piperazineand C-5_piperazine), 52.17

(C-5), 49.29 (C-2_piperazineand C-6_piperazine), 43.19 (C-4).). MS

(m/z): 515.6 (⁺M+2), 513.6 (⁺M), 511.6 (⁺M–2).

4

3

7.03 (dt, J_{H3phenyl-H5phenyl}= 1.0 Hz, J_{H3phenyl-H4phenyl}

=

³J_H3phenyl-F= 9.2 Hz, 1H, H-3_phenyl), 5.42 (dt, J_H4c-H5a

3

3.9 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.59 (s, 2H,

H

_benzyl), 3.47 (dd, ³J_H5b-H4c= 8.1 Hz, ²J_H5b-H5a= 19.3 Hz, 1H,

H-5b), 3.05 (s, 2H, COCH₂N), 2.82 (dd, ³J_H5a-H4c= 3.9 Hz,

²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-

NMR (CDCl₃) d (ppm): 191.87 (C-6), 170.19 (NHCO),

161.45 (d, ¹J_C–F= 245.2 Hz, C-2_phenyl), 147.45 (C-6a), 138.59

6.4.57. 2-[4-(2-Phenylethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

acetamide (58)

3

(C-3a), 131.51 (d, J_C–F= 4.9 Hz, C-6_phenyl), 128.82 (d,

³J_C–F= 8.2 Hz, C-4_phenyl), 127.16 (C-1), 124.37 (d,

Yield: 50%. M.P. 198 °C. IR (KBr, cm⁻¹): 3364 (NH), 1716

(CO), 1660 (CO amide), 2811, 1514, 1130, 1007, 697.

²J_C–F= 14.8 Hz, C-1_phenyl), 123.92 (d, J_C–F= 3.3 Hz,

4

2

C-5_phenyl), 120.73 (C-3), 115.30 (d, J_C–F= 22.2 Hz,

3

¹H-NMR (CDCl₃) d (ppm): 7.54 (d, J_NH-H4c= 6.5 Hz,

C-3_phenyl), 61.31 (COCH₂N), 55.03 (C_benzyl), 53.60 (C-

3_piperazineand C-5_piperazine), 52.70 (C-2_piperazineand

C-6_piperazine), 51.92 (C-5), 42.84 (C-4). MS (m/z): 455.0

(⁺M+2), 457.0 (⁺M), 459.0 (⁺M–2).

1H,NH), 7.28 (m, 5H, H_phenyl), 5.36 (m, 1H, H-4c), 3.51 (dd,

2

³J_H5b-H4c= 6.7 Hz, J_H5b-H4c= 18.1 Hz, 1H, H-5b), 3.00 (s,

2H, COCH₂N), 2.62 (m, 13H, H-5a, NCH₂CH₂Ph and

8H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 192.33 (C-6),

170.07 (NHCO), 151.69 (C-6a), 141.92 (C-3a), 139.96

(C-1_phenyl), 128.62 (C-2_phenyland C-6_phenyl), 128.39 (C-3_phenyl

and C-5_phenyl), 126.11 (C-4_phenyl), 111.82 (C-1), 105.96 (C-3),

61.30 (COCH₂N), 60.18 (CH₂Ph), 53.53 (C-3_piperazineand

C-5_piperazine), 53.03 (C-2_piperazineand C-6_piperazine), 52.01

(C-5), 43.01 (C-4), 33.48 (CH₂CH₂Ph). MS (m/z): 544.0

(⁺M+2), 542.0 (⁺M), 540.0 (⁺M–2).

6.4.55. 2-[4-(Cyclohexylmethyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta [c]thien-4-yl)-

acetamide (56)

Yield: 30%. M.P. 177 °C. IR (KBr, cm⁻¹): 3377 (NH), 1720

(CO), 1662 (CO amide), 2922, 1509, 1128, 1014, 590.

3

¹H-NMR (CDCl₃) d (ppm): 7.55 (d, J_NH-H4c= 8.1 Hz,

1H,NH), 5.37 (dt, ³J_H4c-H5a= 3.6 Hz, ³J_H4c-H5b= ³J_H4c-NH

=

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1241

6.4.58. 2-(4-Benzyl-1,4-Diazepan-1-yl)-N-(1,3-dibromo-6-

oxo-5,6-dihydro-4H-cyclopenta[c]thien-4-yl)acetamide

(62)

³J_H4c-NH= 8.3 Hz, 1H, H-4c), 3.42 (m, 3H, H-5b H_benzyl),

2.35 (dd, ³J_H5a-H4c= 3.7 Hz, ²J_H5a-H5b= 19.4 Hz, 1H, H-5a),

2.45 (m, 14H, COCH₂CH₂CH₂N and H_piperazine). ¹³C-NMR

(CDCl₃) d (ppm): 192.64 (C-6), 172.60 (NHCO), 152.33

(C-6a), 141.99 (C-3a), 135.45 (C-1_phenyl), 134.38 (C-2_phenyl),

130.71 (C-6_phenyl), 129.46 (C-3_phenyl), 128.23 (C-4_phenyl),

126.52 (C-5_phenyl), 111.64 (C-1), 106.11 (C-3), 59.13

(C_benzyl), 58.40 (CH₂CH₂CH₂N), 53.14 (C-3_piperazineand

C-5_piperazine), 52.52 (C-2_piperazineand C-6_piperazine), 52.36

(C-5), 43.03 (C-4), 35.87 (CH₂CH₂CH₂N), 21.52

(CH₂CH₂CH₂N). MS (m/z): 591.6 (⁺M+2), 589.6 (⁺M), 587.6

(⁺M–2).

Yield: 76%. M.P. 209 °C. IR (KBr, cm⁻¹): 3427 (NH), 1717

(CO), 1660 (CO amide), 2809, 1501, 1467, 1131, 753.

3

¹H-NMR (CDCl₃) d (ppm): 7.81 (d, J_NH-H4c= 8.3 Hz,

3

1H,NH), 7.23-715 (m, 5H, H_phenyl), 5.31 (dt, J_H4c-H5a

=

3.8 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.3 Hz, 1H, H-4c), 3.57 (s, 2H,

_benzyl), 3.37 (dd, ³J_H5b-H4c= 8.3 Hz, ²J_H5b-H5a= 19.3 Hz, 1H,

H-5b), 3.13 (s, 2H, COCH₂N), 2.68 (m, 9H, H-5a, H-2_diazepane

H

,

H-3_diazepane, H-5_diazepane, H-7_diazepane), 1.71 (quintet,

3

³J_H6-H5= J_H6-H7= 6.0 Hz, 2H, H-6_diazepane). ¹³C-NMR

(CDCl₃) d (ppm): 192.23 (C-6), 170.74 (NHCO), 151.82

(C-6a), 141.77 (C-3a), 138.20 (C-1_phenyl), 128.72 (C-3_phenyl

and C-5_phenyl), 128.13 (C-2_phenyland C-6_phenyl), 127.04

(C-4_phenyl), 111.38 (C-1), 105.74 (C-3), 62.65 (C_benzyl), 61.25

(COCH₂N), 55.87 (C-3_diazepane), 54.95 (C-5_diazepane), 54.54

(C-2_diazepane), 54.03 (C-7_diazepane), 51.77 (C-5), 42.75 (C-4),

27.69 (C-6_diazepane). MS (m/z): 542.4 (⁺M+2), 540.4 (⁺M),

540.4 (⁺M–2).

6.5. General experimental procedure for the synthesis

of 59–61

To a solution of one of the compounds 13, 20 or 43

(1 mmol) in ethanol (10 ml) was added a solution of hydroxy-

lamine hydrochloride (256 mg, 4 mmol) and sodium acetate

(328 mg, 4 mmol) in water (3 ml). The reaction mixture was

reﬂuxed for 3 h. The solvent was evaporated under reduced

pressure and the residue was diluted with methylene chloride

(50 ml) and washed several times with water. The organic

layer was dried over MgSO₄, and evaporated under reduced

pressure. The product was puriﬁed by ﬂash chromatography.

6.4.59. 2-(4-Benzylpiperidin-1-yl)-N-(1,3-dibromo-6-oxo-

5,6-dihydro-4H-cyclopenta[c]thien-4-yl) acetamide (63)

Yield: 100%. M.P. 230 °C. IR (KBr, cm⁻¹): 3426 (NH),

1716 (CO), 1659 (CO amide), 2922, 1511, 1330, 1128, 699.

3

¹H-NMR (CDCl₃) d (ppm): 7.65 (d, J_NH-H4c= 7.3 Hz,

6.5.1. 2-[4-(2-Chlorobenzyl)piperazin-1-yl]-N-[(6E)-1,3-

dibromo-6-(hydroximino)-5,6-dihydro-4H-

3

1H,NH), 7.28 (t, J_{H3phenyl-H2phenyl}= ³J_{H3phenyl-H4phenyl}

=

³J_{H5phenyl-H4phenyl}= ³J_{H5phenyl-H6phenyl}= 7.1 Hz, 2H, H-3_phenyl

cyclopenta[c]thien-4-yl]acetamide (59)

Yield: 75%. M.P. >240 °C. IR (KBr, cm⁻¹): 3372 (NH),

2819 (OH), 1672 (CO), 1499, 1444, 1264, 1163, 1011, 754.

and H-5_phenyl), 7.19 (t, ³J_{H4phenyl-H3phenyl}= ³J_{H4phenyl-H5phenyl}

=

3

7.1 Hz, 1H, H-4_phenyl), 7.12 (d, J_{H2phenyl-H3phenyl}

¹H-NMR (DMSO-d6) d (ppm): 11.46 (s, 1H, OH), 8.37 (d,

³J_{H6phenyl-H5phenyl}= 7.1 Hz, 2H, H-2_phenyland H-6_phenyl), 5.36

4

³J_NH-H4c= 8.7 Hz, 1H,NH), 7.52 (dd, J_{H3phenyl-H5phenyl}

=

3

2

(m, 1H, H-4c), 3.51 (dd, J_H5b-H4c= 8.3 Hz, J_H5b-H5a

=

1.5 Hz, ³J_{H3phenyl-H4phenyl}= 7.3 Hz, 1H, H-3_phenyl), 7.46 (dd,

19.0 Hz, 1H, H-5b), 3.00 (s, 2H, COCH₂N), 2.05 (m, 13H,

H-5a, H_benzyland H_piperidine). ¹³C-NMR (CDCl₃) d (ppm):

191.99 (C-6), 171.00 (NHCO), 151.24 (C-6a), 141.47 (C-3a),

139.79 (C-1_phenyl), 128.59 (C-3_phenyland C-5_phenyl), 127.78

(C-2_phenyland C-6_phenyl), 125.48 (C-4_phenyl), 111.37 (C-1),

105.57 (C-3), 61.24 (COCH₂N), 54.00 (C-2_piperidineand

C-6_piperidine), 51.66 (C-5), 43.04 (C_benzyl), 42.53 (C-4), 36.66

(C-4_piperidine), 31.74 (C-3_piperidineand C-5_piperidine). MS (m/z):

528.0 (⁺M+2), 526.0 (⁺M), 524.0 (⁺M–2).

3

⁴J_{H6phenyl-H4phenyl}= 1.0 Hz, J_{H6phenyl-H5phenyl}= 7.3 Hz, 1H,

H-6_phenyl), 7.37 (dt, ⁴JH_{4phenyl-H6phenyl}= 1.0 Hz,

3

³J_{H4phenyl-H3phenyl}= J_{H4phenyl-H5phenyl}= 7.3 Hz, 1H,

H-4_phenyl), 7.32 (dt, ⁴J_{H5phenyl-H3phenyl}= 1.5 Hz,

3

³J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}= 7.3 Hz, 1H,

3

H-5_phenyl), 5.25 (dt, J_H4c-H5a= 4.1 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.7 Hz, 1H, H-4c), 3.60 (s, 2H, H_benzyl), 3.55 (dd,

³J_H5b-H4c= 8.7 Hz, J_H5b-H5a= 18.8 Hz, 1H, H-5b), 2.98 (s,

2

3

2

2H, COCH₂N), 2.89 (dd, J_H5a-H4c= 4.1 Hz, J_H5a-H5b

=

18.8 Hz, 1H, H-5a), 2.55 (m, 8H, H_piperazine). ¹³C-NMR

(DMSO-d6) d (ppm): 169.16 (NHCO), 152.84 (C-6), 150.69

(C-6a), 141.69 (C-3a), 136.00 (C-1_phenyl), 133.71 (C-2_phenyl),

131.31 (C-6_phenyl), 129.68 (C-3_phenyl), 129.03 (C-4_phenyl),

127.47 (C-5_phenyl), 104.19 (C-1), 101.76 (C-3), 61.64

(COCH₂N), 58.97 (C_benzyl), 53.36 (C-3_piperazineand

C-5_piperazine), 52.87 (C-2_piperazineand C-6_piperazine), 45.02

(C-5), 41.01 (C-4). MS (m/z): 578.5 (⁺M+2), 576.5 (⁺M),

574.5 (⁺M–2).

6.4.60. 2-[4-(2-Chlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

butanamide (64)

Yield: 77%. M.P. 203 °C. IR (KBr, cm⁻¹): 3300 (NH), 1722

(CO), 1650 (CO amide), 2935, 1471, 1259, 1129, 912, 742.

¹H-NMR (DMSO d-6) d (ppm): 8.55 (d, ³J_NH-H4c= 8.3 Hz,

1H,NH), 7.32 (dd, ⁴J_{H3phenyl-H5phenyl}= 1.9 Hz,

³J_{H3phenyl-H4phenyl}= 7.4 Hz, 1H, H-3_phenyl), 7.24 (dd,

3

⁴J_{H6phenyl-H4phenyl}= 1.7 Hz, J_{H6phenyl-H5phenyl}= 7.4 Hz, 1H,

H-6_phenyl), 7.15 (dt, ⁴J_{H4phenyl-H6phenyl}= 1.7 Hz,

6.5.2. 2-[4-(2-Fluororobenzyl)piperazin-1-yl]-N-[(6E)-1,3-

dibromo-6-(hydroxyimino)-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl]acetamide (60)

Yield: 75%. M.P. 150 °C. IR (KBr, cm-1): 3346 (NH), 2820

(OH), 1652 (CO), 1517, 1455, 1226, 1131, 1007, 758.

3

³J_{H4phenyl-H3phenyl}= J_{H4phenyl-H5phenyl}= 7.4 Hz, 1H,

H-4_phenyl), 7.10 (dt, ⁴J_{H5phenyl-H3phenyl}= 1.9 Hz,

3

³J_{H5phenyl-H4phenyl}= J_{H5phenyl-H6phenyl}= 7.4 Hz, 1H,

3

H-5_phenyl), 5.36 (dt, J_H4c-H5a= 3.7 Hz, J_H4c-H5b

=

1242

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1H-NMR (CDCl₃) d (ppm): 10.76 (s, 1H, OH), 7.56 (d,

chromatography. Yield: 43%. M.P. 152 °C. IR (KBr, cm⁻¹):

3421 (NH), 1714 (CO), 1670 (CO amide), 2926, 1508, 1446,

1090, 804. H-NMR (CDCl₃) d (ppm): 9.36 (d, J_NH-H4c=

4

³J_NH-H4c= 8.6 Hz, 1H,NH), 7.36 (dt, J_{H6phenyl-H4phenyl}

=

4

3

1

3

1.7 Hz, J_H6phenyl-F= J_{H6phenyl-H5phenyl}= 7.5 Hz, 1H,

H-6_phenyl), 7.22 (m, 1H, H-4_phenyl), 7.10 (dt,

8.0 Hz, 1H,NH), 7.46-7.17 (m, 4H, H_phenyl), 5.12 (dt,

⁴J_{H5phenyl-H3phenyl}

=

1.1 Hz, ³J_{H5phenyl-H4phenyl}

=

³J_H4c-H5a= 3.0 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.0 Hz, 1H, H-4c),

³J_{H5phenyl-H6phenyl}= 7.5 Hz, 1H, H-5_phenyl), 7.02 (ddd,

3.42 (s, 2H, H_benzyl), 3.37 (dd, J_H5b-H4c= 8.0 Hz,

3

⁴J_{H3phenyl-H5phenyl}= 1.1 Hz, J_{H3phenyl- H4phenyl}= 8.5 Hz,

²J_H5b-H5a= 18.6 Hz, 1H, H-5b), 2.72 (dd, ³J_H5a-H4c= 3.0 Hz,

²J_H5a-H5b= 18.6 Hz, 1H, H-5a), 2.62 (m, 12H, COCH₂CH₂N

and H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 191.38 (C-6),

171.93 (NHCO), 159.85 (C-6a), 151.43 (C-3a), 135.54

(C-1_phenyl), 134.46 (C-2_phenyl), 130.77 (C-6_phenyl), 129.60

(C-3_phenyl), 128.47 (C-4_phenyl), 126.68 (C-5_phenyl), 118.81

(C-1), 85.51 (C-3), 59.14 (C_benzyl), 53.41 (COCH₂CH₂), 52.61

(C-5), 52.09 (C-3_piperazineand C-5_piperazine), 51.62 (C-2_piperazine

and C-6_piperazine), 43.52 (C-4), 31.52 (COCH₂CH₂). MS (m/z):

576.4 (⁺M+2), 574.4 (⁺M), 572.4 (⁺M–2).

3

³J_H3phenyl-F= 9.8 Hz, 1H, H-3_phenyl), 5.38 (dt,

³J_H4c-H5a= 3.6 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.6 Hz, 1H, H-4c),

3.72 (dd, ³J_H5b-H4c= 8.6 Hz, ²J_H5b-H5a= 19.3 Hz, 1H, H-5b),

3.60 (s, 2H, H_benzyl), 3.07 (s, 2H, COCH₂N), 2.95 (dd,

³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.3 Hz, 1H, H-5a), 2.60 (m,

8H, H_piperazine). ¹³C-NMR (DMSO-d6) d (ppm): 168.74

1

(NHCO), 161.41 (d, J_C–F= 246.2 Hz, C-2_phenyl), 153.35

3

(C-6), 148.49 (C-6a), 139.89 (C-3a), 131.68 (d, J_C–F

=

3

4.1 Hz, C-6_phenyl), 129.09 (d, J_C–F= 7.4 Hz, C-4_phenyl),

2

4

124.11 (d, J_C–F= 14.8 Hz, C-1_phenyl), 123.97 (d, J_C–F

=

3.3 Hz, C-5_phenyl), 115.42 (²J_C–F= 22.3 Hz, C-3_phenyl), 106.04

(C-1), 103.59 (C-3), 62.12 (COCH₂N), 54.88 (C_benzyl), 53.54

(C-3_piperazineand C-5_piperazine), 52.17 (C-2_piperazineand

C-6_piperazine), 44.93 (C-5), 41.42 (C-4). HRMS: calculated

(557.9734), found (557,9822).

6.6. General experimental procedure for the synthesis

of 84–92

To a suspension of one of the compounds 66–75 (2 mmol)

in methylene chloride (15 ml) at room temperature was added

triethylamine (0.7 ml, 4.98 mmol). The resulting solution was

then cooled to 0 °C and bromoacetyl bromide (0.22 ml,

2.49 mmol) solved in methylene chloride (5 ml) was added

dropwise. The reaction mixture was stirred for 1 h at 0 °C

and for further 1 h at room temperature. The resulting mix-

ture was evaporated under reduced pressure to give an oil

which was then dissolved in methylene chloride and washed

several times with water. The combined organic layers were

dried over MgSO₄and evaporated under reduced pressure.

6.5.3. 2-[4-(Thien-3-ylmethyl)piperazin-1-yl]-N-[(6E)-1,3-

dibromo-6-(hydroxyimino)-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl]acetamide (61)

Yield: 70%. M.P. 185 °C. IR (KBr, cm⁻¹): 3305 (NH), 2820

(OH), 1661 (CO), 1506, 1456, 1261, 1130, 1008, 834.

¹H-NMR (CDCl₃) d (ppm): 10.66 (s, 1H, OH), 7.57 (d,

³J_NH-H4c= 8.8 Hz, 1H,NH), 7.20 (dd, ⁴J_{H4thiophene-H2thiophene}

=

2.9 Hz, ³J_{H4thiophene-H5thiophene}= 4.9 Hz, 1H, H-4_thiophene), 7.06

(d, ⁴J_{H2thiophene-H4thiophene}= 2.9 Hz, 1H, H-2_thiophene), 7.04 (d,

³J_{H5thiophene-H4thiophene}= 4.9 Hz, 1H, H-5_thiophene), 5.31 (dt,

³J_H4c-H5a= 3.2 Hz, ³J_H4c-H5b= ³J_H4c-NH= 8.8 Hz, 1H, H-4c),

3.62 (dd, ³J_H5b-H4c= 8.8 Hz, ²J_H5b-H5a= 18.8 Hz, 1H, H-5b),

3.49 (s, 2H,NCH₂thiophene), 3.05 (s, 2H, COCH₂N), 2.87

(dd, ³J_H5a-H4c= 3.2 Hz, ²J_H5a-H5b= 18.8 Hz, 1H, H-5a), 2.58

(m, 8H, H_piperazine). ¹³C-NMR (CDCl₃) d (ppm): 168.75

(NHCO), 153.28 (C-6), 148.49 (C-6a), 139.94 (C-3a), 138.30

(C-3_thiophene), 128.53 (C-5_thiophene), 125.61 (C-4_thiophene),

123.24 (C-2_thiophene), 106.03 (C-1), 103.51 (C-3), 62.11

(COCH₂N), 57.26 (NCH₂thiophene), 53.55 (C-3_piperazineand

C-5_piperazine), 52.38 (C-2_piperazineand C-6_piperazine), 44.92

(C-5), 41.43 (C-4). MS (m/z): 549.7 (⁺M+2), 547.7 (⁺M),

545.7 (⁺M–2).

6.6.1. 2-Bromo-N-(5,6-dimethoxy-3-oxo-2,3-dihydro-1H-

inden-1-yl)acetamide (84)

Yield: 65%. M.P. 208 °C. IR (KBr, cm⁻¹): 3273 (NH), 1697

(CO), 1655 (CO amide), 1592, 1502, 1469, 1044, 985, 861.

¹H-NMR (CDCl₃) d (ppm): 7.16 (s, 1H, H-4), 6.99 (s, 1H,

3

H-7), 6.77 (d, J_NH-H1c= 8.0 Hz, 1H,NH), 5.60 (ddd,

³J_H1c-H2a= 2.9 Hz, ³J_H1c-H2b= 7.4 Hz, ³J_H1c-NH= 8.0 Hz, 1H,

H-1c), 3.98 (s, 3H, OMe), 3.94 (s, 3H, OMe), 3.20 (dd,

³J_H2b-H1c= 7.4 Hz, ²J_H2b-H2a= 18.9 Hz, 1H, H-2b), 2.48 (dd,

2

³J_H2a-H1c= 2.9 Hz, J_H1a-H1b= 18.9 Hz, 1H, H-2a), 1.43 (s,

2H, COCH₂Br). ¹³C-NMR (CDCl₃) d (ppm): 201.58 (C-3),

166.19 (NHCO), 156.14 (C-6), 150.93 (C-5), 148.03 (C-7a),

129.72 (C-3a), 106.73 (C-7), 103.73 (C-4), 4656.57 (OMe),

56.25 (OMe), 46.20 (C-1), 44.45 (C-2), 28.92 (COCH₂Br).

MS (m/z): 329.0 (⁺M+1), 327.0 (⁺M–1).

6.5.4. 2-[4-(2-Chlorobenzyl)piperazin-1-yl]-N-(1,3-

dibromo-6-oxo-5,6-dihydro-4H-cyclopenta[c] thien-4-yl)-

propanamide (65)

To a solution of 94 (1.5 mmol) in acetonitrile (10 ml) was

added 1-(2-chlorobenzyl)-piperazine (3 mmol). The reaction

mixture was reﬂuxed for 4 h. The solvent was then removed

under reduced pressure to give an oil which was dissolved in

methylene chloride and washed several times with water. The

combined organic layers were dried over MgSO₄, evaporated

under reduced pressure and the product was puriﬁed by ﬂash

6.6.2. 2-Bromo-N-(1,3-dimethyl-6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)acetamide (85)

Yield: 77%. M.P. 203 °C. IR (KBr, cm⁻¹): 3420 (NH), 1701

(CO), 1645 (CO amide), 1559, 1436, 1218, 1070, 974.

¹H-NMR (DMSO d-6) d (ppm): 8.91 (d, ³J_NH-H4c= 8.4 Hz,

3

1H,NH), 5.19 (dt, J_H4c-H5a= 3.4 Hz, J_H4c-H5b

=

³J_H4c-NH= 8.4 Hz, 1H, H-4c), 3.85 (s, 2H, COCH₂Br), 3.38

(dd, ³J_H5b-H4c= 8.4 Hz, ²J_H5b-H5a= 18.8 Hz, 1H, H-5b), 2.70

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1243

(dd, ³J_H5a-H4c= 3.4 Hz, ²J_H5a-H5b= 18.8 Hz, 1H, H-5a), 2.49

(s, 3H, C1-Me), 2.46 (s, 3H, C3-Me). ¹³C-NMR (DMSO d-6)

d (ppm): 195.52 (C-6), 165.44 (NHCO), 148.53 (C-6a),

139.24 (C-1), 138.98 (C-3), 129.71 (C-3a), 50.98 (C-5), 42.60

(COCH₂Br), 42.57 (C-4), 12.84 (C1-Me), 12.01 (C3-Me). MS

(m/z): 302.9 (⁺M+1), 300.9 (⁺M–1).

1H, H-5a). ¹³C-NMR (CDCl₃) d (ppm): 193.08 (C-6), 168.01

(C-6a), 166.82 (NHCO), 145.36 (C-3a), 121.53 (C-3), 120.53

(C-2), 47.46 (C-5), 46.61 (C-6), 28.69 (COCH₂Br). MS (m/z):

355.9 (⁺M+2), 353.9 (⁺M), 351.9 (⁺M–2).

6.6.7. 2-Bromo-N-(2,3-dibromo-4-oxo-5,6-dihydro-4H-

cyclopenta[b]thien-6-yl)acetamide (90)

Yield: 62%. M.P. 102 °C. IR (KBr, cm⁻¹): 3305 (NH), 1714

(CO), 1659 (CO amide), 2926, 1530, 1390, 1108, 680. RMN

6.6.3. 2-Bromo-N-(6-oxo-5,6-dihydro-4H-

cyclopenta[b]thien-4-yl)acetamide (86)

Yield: 64%. Oil. IR (KBr, cm⁻¹): 3286 (NH), 1700 (CO),

¹H (CDCl₃) d (ppm): 7,35 (d, J_NH-H6c= 7,0 Hz, 1H,NH);

3

1

1660 (CO amide), 3077, 1538, 1430, 1290, 730. H-NMR

5,45 (dt, ³J_H6c-H5a= 2,7 Hz, ³J_H6c-H5b= ³J_H6c-NH= 7,0 Hz, 1H,

H-6c); 3,93 (s, 2H, COCH₂Br); 3,44 (dd, ³J_H5b-H6c= 7,0 Hz,

²J_H5b-H5a= 18,4 Hz, 1H, H-5b); 2,79 (dd, ³J_H5a-H6c= 2,7 Hz,

²J_H5a-H5b= 18,4 Hz, 1H, H-5a). RMN ¹³C (CDCl₃) d (ppm):

190,94 (C-4); 167,08 (NHCO); 166,62 (C-6a); 142,01 (C-3a);

119,38 (C-2); 107,55 (C-3); 46,93 (C-5); 46,90 (C-6); 28,16

(COCH₂Br). MS (m/z): 434.9 (⁺M+3), 432.9 (⁺M+1), 430.9

(⁺M–1), 428.9 (⁺M-3).

(CDCl₃) d (ppm): 7.95 (d, ³J_H2-H3= 4.6 Hz, 1H, H-2), 7.14

3

(d, J_H3-H2= 4.6 Hz, 1H, H-3), 7.10 (d, J_NH-H4c= 6.9 Hz,

1H,NH), 5.52 (dt, ³J_H4c-H5a= 2.5 Hz, ³J_H4c-H5b= ³J_H4c-NH

=

6.9 Hz, 1H, H-4c), 3.89 (s, 2H, COCH₂Br), 3.44 (dd,

³J_H5b-H4c= 6.9 Hz, ²J_H5b-H5a= 18.6 Hz, 1H, H-5b), 2.79 (dd,

2

³J_H5a-H4c= 2.5 Hz, J_H5a-H5b= 18.6 Hz, 1H, H-5a). ¹³C-

NMR (CDCl₃) d (ppm): 193.15 (C-6), 166.43 (NHCO),

165.89 (C-3a), 142.24 (C-6a), 141.70 (C-3), 123.56 (C-2),

48.99 (C-5), 45.97 (C-4), 28.61 (COCH₂Br). MS (m/z): 274.4

(⁺M+1), 272.4 (⁺M–1).

6.6.8. 2-Bromo-N-(1,3-dibromo-6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)acetamide (91)

Yield: 77%. M.P. 203 °C. IR (KBr, cm⁻¹): 3312 (NH), 1712

(CO), 1641 (CO amide), 2959, 1530, 1262, 1103, 800.

¹H-NMR (DMSO d-6) d (ppm): 8.91 (d, ³J_NH-H4c= 8.3 Hz,

6.6.4. 2-Bromo-N-(6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)acetamide (87)

Yield: 60%. M.P. 139 °C. IR (KBr, cm⁻¹): 3340 (NH), 1714

(CO), 1661 (CO amide), 2820, 1512, 1230, 1109, 760.¹H-

NMR (CDCl₃) d (ppm): 7.88 (s, 1H, H-1), 7.46 (s, 1H, H-3),

6.94 (d, ³J_NH-H4c= 8.3 Hz, 1H,NH), 5.19 (m, 1H, H-4c), 4.20

1H,NH), 5.19 (ddt, J_Hc-H2Br= 1.0 Hz, J_H4c-H5a= 3.5 Hz,

5

3

³J_H4c-H5b= ³J_H4c-NH= 8.3 Hz, 1H, H-4c), 3.86 (d, J_H2Br-

^Hc= 1.0 Hz, 2H, COCH₂Br), 3.08 (dd, J_H5b-H4c= 8.3 Hz,

5

3

²J_H5b-H5a= 18.0 Hz, 1H, H-5b), 2.70 (dd, ³J_H5a-H4c= 3.5 Hz,

²J_H5a-H5b= 18.0 Hz, 1H, H-5a). ¹³C-NMR (DMSO d-6) d

(ppm): 193.17 (C-6), 165.70 (NHCO), 152.91 (C-6a), 142.36

(C-3a), 110.39 (C-1), 105.67 (C-3), 51.17 (C-5), 45.94

(COCH₂Br), 43.50 (C-4). MS (m/z): 434.9 (⁺M+3), 432.9

(⁺M+1), 430.9 (⁺M–1), 428.9 (⁺M-3).

3

(s, 2H, COCH₂Br), 3.49 (dd, J_H5b-H4c= 8.0 Hz,

²J_H5b-H5a= 18.9 Hz, 1H, H-5b), 2.90 (dd, ³J_H5a-H4c= 3.3 Hz,

²J_H5a-H5b= 18.9 Hz, 1H, H-5a). MS (m/z): 274.4 (⁺M+1),

272.4 (⁺M–1).

6.6.5. 2-Bromo-N-(3-bromo-6-oxo-5,6-dihydro-4H-cyclo-

penta[c]thien-4-yl)acetamide (88)

6.6.9. 2-Bromo-N-(1,3-dichloro-6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)acetamide (92)

Yield: 80%. M.P. 190 °C. IR (KBr, cm⁻¹): 3258 (NH), 1708

(CO), 1652 (CO amide), 1548, 1470, 1183, 1030, 772.

¹H-NMR (CDCl₃) d (ppm): 7.80 (s, 1H, H-1), 6.93 (d,

Yield: 77%. M.P. 180 °C. IR (KBr, cm⁻¹): 3310 (NH), 1717

(CO), 1640 (CO amide), 1527, 1527, 1490, 1398, 1105.

¹H-NMR (DMSO d-6) d (ppm): 9.0 (large, 1H,NH), 5.26 (m,

1H, H-4c), 3.85 (s, 2H, COCH₂Br), 3.05 (m, 2H, H-5a and

H-5b). ¹³C-NMR (DMSO d-6) d (ppm): 192.40 (C-6), 165.57

(NHCO), 148.76 (C-6a), 138.96 (C-3a), 123.90 (C-1), 119.25

(C-3), 50.66 (C-5), 29.05 (COCH₂Br), 43.05 (C-4). MS (m/z):

343.8 (⁺M+1), 341.8 (⁺M–1).

3

³J_NH-H4c= 8.1 Hz, 1H,NH), 5.42 (dt, J_H4c-H5a= 3.6 Hz,

3

³J_H4c-H5b= J_H4c-NH= 8.1 Hz, 1H, H-4c), 3.94 (s, 2H,

COCH₂Br), 3.53 (dd, ³J_H5b-H4c= 8.1 Hz, ²J_H5b-H5a= 19.3 Hz,

1H, H-5b), 2.88 (dd, ³J_H5a-H4c= 3.6 Hz, ²J_H5a-H5b= 19.3 Hz,

1H, H-5a). ¹³C-NMR (CDCl₃) d (ppm): 192.99 (C-6), 165.37

(NHCO), 150.40 (C-6a), 144.12 (C-3a), 126.00 (C-1), 107.45

(C-3), 51.64 (C-5), 44.90 (C-4), 28.61 (COCH₂Br). MS (m/z):

354.8 (⁺M+2), 352.8 (⁺M), 350.8 (⁺M–2).

6.6.10. 4-Bromo-N-(1,3-dibromo-6-oxo-5,6-dihydro-4H-

cyclopenta[c]thien-4-yl)butanamide (93)

6.6.6. 2-Bromo-N-(2-bromo-4-oxo-5,6-dihydro-4H-cyclo-

penta[b]thien-6-yl)acetamide (89)

To a suspension of 6-amino-1,3-dibromo-5,6-dihydro-4H-

cyclopenta[c]thiophen-4-one hydrochloride 74 (2 mmol) in

methylene chloride (15 ml) at room temperature was added

triethylamine (0.7 ml, 4.98 mmol), the resulting solution was

then cooled to 0 °C and 4-bromobutyryl chloride (0,23 ml,

2.5 mmol) solved in methylene chloride (5 ml) was added

dropwise. The reaction mixture was stirred for 1 h at 0 °C

and for other 3 h at room temperature. The resulting mixture

was evaporated under reduced pressure to give an oil which

Yield: 64%. M.P. 90 °C. IR (KBr, cm⁻¹): 3366 (NH), 1720

(CO), 1656 (CO amide), 2815, 1514, 1492, 1390, 1099, 752.

3

¹H-NMR (CDCl₃) d (ppm): 7.40 (d, J_NH-H6c= 7.2 Hz,

3

1H,NH), 7.00 (s, 1H, H-3), 5.40 (dt, J_H6c-H5a= 2.5 Hz,

3

³J_H6c-H5b= J_H6c-NH= 7.2 Hz, 1H, H-4c), 3.49 (s, 2H,

COCH₂Br), 3.22 (dd, ³J_H5b-H6c= 7.2 Hz, ²J_H5b-H5a= 18.3 Hz,

1H, H-5b), 2.79 (dd, ³J_H5a-H6c= 2.5 Hz, ²J_H5a-H5b= 18.3 Hz,

1244

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

was then dissolved in methylene chloride and washed several

times with water. The combined organic layers were dried

over MgSO₄and evaporated under reduced pressure. Yield:

73%. M.P. 182 °C. IR (KBr, cm⁻¹): 3412 (NH), 1719 (CO),

6.7.1. Ethyl 4-(1H-pyrrol-2-ylmethyl)piperazine-1-

carboxylate (97)

Yield: 82%. Oil. IR (KBr, cm⁻¹): 1699 (CO), 2807, 1432,

1242, 1004, 679. ¹H-NMR (CDCl₃) d (ppm): 8.16 (s, 1H,NH),

4

3

1

6.73 (dd, J_{H5pyrrole-H3pyrrole}= 2.4 Hz, J_{H5pyrrole-H4pyrrole}

=

1638 (CO amide), 1547, 1472, 1132, 988, 692. H-NMR

5.0 Hz, 1H, H-5_pyrrole), 6.12 (dd, ³J_{H4pyrrole-H3pyrrole}= 2.9 Hz,

³J_{H4pyrrole-H5pyrrole}= 5.0 Hz, 1H, H-4_pyrrole), 6.0 (large, 1H,

H-3_pyrrole), 4.13 (q, ³J_H1-H2= 7.1 Hz, 2H, CH₂CH₃), 3.49 (s,

3

(DMSO-d6) d (ppm): 8.57 (d, J_NH-H4c= 7.8 Hz, 1H,NH),

5.16 (m, 1H, H-4c), 3,50 (t, ³J_H4′-H3′= 6.0 Hz, 2H, H-4′), 3.33

(dd, ³J_H5b-H4c= 8.1 Hz, ²J_H5b-H5a= 18.2 Hz, 1H, H-5b), 2.68

(d, ²J_H5a-H5b= 18.2 Hz, 1H, H-5a), 2.22 (t, ³J_H2′-H3′= 6.0 Hz,

2H,NCH₂pyrrole), 3.45 (t, J_H2-H3= ³J_H6-H5= 4.9 Hz, 4H,

3

H-2 and H-6), 2.38 (t, ³J_H3-H2= ³J_H5-H6= 4.9 Hz, 4H, H-3 and

3

2H, H-2′), 1.16 (q, J_H3′-H2′= ³J_H3′-H4′= 6.0 Hz, 2H, H-3).

H-5), 1.25 (t, J_H1-H2= 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR

3

¹³C-NMR (DMSO-d6) d (ppm): 193.14 (C-6), 170.52 (C-1′),

153.25 (C-6a), 142.08 (C-3a), 109.99 (C-1), 105.00 (C-3),

51.21 (C-5), 42.67 (C-4), 34.50 (C-4′), 32.24 (C-2′); 28.08

(C-3′). MS (m/z): 462.6 (⁺M+3), 460.6 (⁺M+1), 458.6 (⁺M–

1), 456.6 (⁺M-3).

(CDCl₃) d (ppm): 155.51 (CO), 127.96 (C-2_pyrrole), 117.55

(C-5_pyrrole), 108.00 (C-4_pyrrole), 107.83 (C-3_pyrrole), 61.35

(CH₂CH₃), 55.42 (NCH₂pyrrole), 52.67 (C-3 and C-5), 43.68

(C-2 and C-6), 14.70 (Me). MS (m/z): 237.2 (⁺M).

6.7.2. Ethyl 4-[(2,5-dimethoxythien-3-

yl)methyl]piperazine-1-carboxylate (98)

6.6.11. N-(1,3-Dibromo-6-oxo-5,6-dihydro-4H-cyclopen-

ta[c]thien-4-yl)acrylamide (94)

Yield: 71%. Oil. IR (KBr, cm⁻¹): 1699 (CO), 2818, 2932,

1432, 1242, 1123, 686. ¹H-NMR (CDCl₃) d (ppm): 5.78 (s,

3

To a suspension of 6-amino-1,3-dibromo-5,6-dihydro-4H-

cyclopenta[c]thiophen-4-one hydrochloride 74 (2 mmol) in

methylene chloride (15 ml) at room temperature was added

triethylamine (0.7 ml, 4.98 mmol), the resulting solution was

then cooled to 0 °C and 4-bromopropionyl chloride (0.25 ml,

2.5 mmol) solved in methylene chloride (5 ml) was added

dropwise. The reaction mixture was stirred for 1 h at 0 °C

and for another 1 h at room temperature. The resulting mix-

ture was evaporated under reduced pressure to give an oil

which was then dissolved in methylene chloride and washed

several times with water. The combined organic layers were

dried over MgSO₄and evaporated under reduced pressure.

Yield: 43%. M.P. 198 °C. IR (KBr, cm⁻¹): 3409 (NH), 1713

1H, H-4_thiophene), 4.09 (q, J_H1-H2= 7.1 Hz, 2H, CH₂CH₃),

3.76 (s, 3H, OMe), 3.74 (s, 3H, OMe), 3.49 (s,

2H,NCH₂thiophene), 3.43 (m, 8H, H_piperazine), 1.25 (t,

³J_H1-H2= 7.1 Hz, 3H, CH₂CH₃). ¹³C-NMR (CDCl₃) d (ppm):

155.49 (CO), 154.51 (C-5_thiophene), 149.96 (C-2_thiophene),

116.23 (C-3_thiophene), 102.89 (C-4_thiophene), 63.07 (OMe),

61.27 (CH₂CH₃), 60.05 (OMe), 57.52 (NCH₂thiophene),

52.62 (C-3 and C-5), 43.60 (C-2 and C-6), 14.68 (Me). MS

(m/z): 314.2 (⁺M).

6.8. General experimental procedure for the synthesis

of 99 and 100

Potassium hydroxide (5.61 g, 100 mmol) was slowly added

into the reaction vessel containing a solution of compound

97 or 98 (10 mmol), water (4 ml) and methanol (12 ml). The

reaction was heated under microwave irradiation to 100 °C

and monitored by thin-layer chromatography. After the start-

ing material had disappeared, the mixture was cooled, ﬁl-

tered and extracted with methylene chloride. The organic layer

was separated, dried and evaporated under reduced pressure.

1

(CO), 1657 (CO amide), 3266, 1550, 1133, 957. H-NMR

3

(DMSO-d6) d (ppm): 8.30 (d, J_NH-H4c= 8.4 Hz, 1H,NH),

3

6.13 (m, 2H, CH=CH₂), 5.63 (dd, J_H-Hcis= 3.9 Hz,

3

³J_H-Htrans= 8.9 Hz, 1H, CH=CH₂), 5.26 (dt, J_H4c-H5a

=

3

3.5 Hz, J_H4c-H5b= ³J_H4c-NH= 8.4 Hz, 1H, H-4c), 3.41 (dd,

³J_H5b-H4c= 8.4 Hz, ²J_H5b-H5a= 18.8 Hz, 1H, H-5b), 2.70 (dd,

2

³J_H5a-H4c= 3.5 Hz, J_H5a-H5b= 18.8 Hz, 1H, H-5a). ¹³C-

NMR (DMSO-d6) d (ppm): 193.16 (C-6), 164.05 (CONH),

153.06 (C-6a), 142.15 (C-3a), 131.14 (CH=CH₂), 126.02

(CH=CH₂), 110.39 (C-1), 105.39 (C-3), 51.39 (C-5); 42.82

(C-4). MS (m/z): 366.9 (⁺M–2), 364.9 (⁺M), 362.9 (⁺M–2).

6.8.1. 1-(1H-Pyrrol-2-ylmethyl)piperazine (99)

Yield: 100%. Oil, IR (KBr, cm⁻¹): 3370 (NH), 2826, 1540,

1419, 1271, 1113, 723. ¹H-NMR (CDCl₃) d (ppm): 8.84 (s,

1H,NH), 6.72 (d, ³J_{H5pyrrole-H4pyrrole}= 2.4 Hz, 1H, H-5_pyrrole),

6.10 (m, 2H, H-3_pyrroleand H-4_pyrrole), 3.48 (s,

6.7. General experimental procedure for the synthesis

of 97 and 98

3

2H,NCH₂pyrrole), 2.88 (t, J_H2-H3= ³J_H6-H5= 4.9 Hz, 4H,

H-2 and H-6), 2.42 (m, 5H,NH, H-3 and H-5). ¹³C-NMR

(CDCl₃) d (ppm): 127.42 (C-2_pyrrole), 117.52 (C-5_pyrrole),

107.92 (C-4_pyrrole), 107.44 (C-3_pyrrole), 55.69 (NCH₂pyrrole),

53.68 (C-2 and C-6), 45.41 (C-3 and C-5). MS (m/z): 165.4

(⁺M).

A solution of arylaldehyde 95 or 96 (20 mmol) and ethyl

N-piperazinecarboxylate (2.77 g, 20 mmol) in methanol

(40 ml) was added to sodium cyanoborohydride (2.36 g,

40 mmol). Acetic acid (1 ml) was added and the stirred mix-

ture was reﬂuxed for one night. The solution was then diluted

with ether (100 ml) and washed with an 1 N aqueous sodium

hydroxide solution. The organic layer was dried over MgSO₄

and evaporated under reduced pressure.

6.8.2. 1-[(2,5-Dimethoxythien-3-yl)methyl]piperazine

(100)

Yield: 60%. Oil, IR (KBr, cm⁻¹): 3390 (NH), 28281590,

1

1455, 1232, 999, 729. H-NMR (CDCl₃) d (ppm): 5.83 (s,

Z. Omran et al. / European Journal of Medicinal Chemistry 40 (2005) 1222–1245

1245

[6] P. Dallemagne, S. Rault, M. Cugnon de Sévricourt, K.M. Hassan,

M. Robba, Tetrahedron Lett. 27 (1986) 2607–2610.

[7] P. Dallemagne, S. Rault, M. Gordaliza, M. Robba, Heterocycles 26

(1987) 3233–3237.

1H, H-4_thiophene), 3.80 (s, 3H, OMe), 3.78 (s, 3H, OMe), 3.31

(s, 2H,NCH₂thiophene), 2.90 (t, ³J_H2-H3= ³J_H6-H5= 4.9 Hz,

4H, H-2 and H-6), 2.4 (large, 4H, H-3 and H-5). ¹³C-NMR

(CDCl₃) d (ppm): 154.43 (C-5_thiophene), 149.82 (C-2_thiophene),

116.63 (C-3_thiophene), 103.01 (C-4_thiophene), 63.13 (OMe),

60.05 (OMe), 57.70 (NCH₂thiophene), 53.67 (C-3 and C-5),

45.78 (C-2 and C-6). MS (m/z): 242.4 (⁺M).

[8] P. Dallemagne, A. Alsaïdi, M. Boulouard, S. Rault, M. Robba, Het-

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[9] O. Renault, P. Dallemagne, S. Rault, Pharm. Pharmacol. Commun. 4

(1998) 3–7.

[10] V.M. Rodionow, E.T. Malewinskaja, Chem. Ber. 59 (1926) 2952–

2958.

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Article Doi

Synthesis and biological evaluation as AChE inhibitors of new indanones and thiaindanones related to donepezil

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