SYNTHESIS OF ARYL- AND HETEROARYLPIPERAZINYL

SYNTHESIS OF ARYL- AND HETEROARYLPIPERAZINYL

SYNTHESIS OF ARYL- AND HETEROARYLPIPERAZINYL
DERIVATIVES OF AZATRICYCLOUNDECANE SYSTEM AS
POTENTIAL 5-HT RECEPTOR LIGANDS
J. Kossakowski, M. Krawiecka, B. Kuran
Department of Medical Chemistry, Medical University, 3 Oczki St.,
02-007 Warsaw, Poland
Introduction
Well-know anxiolytics e.g buspirone, gepirone, tandospirone display high affinity for
the 5-HT1A and D2 receptor types and therefore are widely used in the treatment of
psychotic and neurotic disorders. These drugs posses 4-aryl(heteroaryl)-1piperazinealkyl group linked with the imide nitrogen [1-4]. Many analogs have been
synthesized and have demonstrated anxiolytic and/or antidepressive activity in the
pharmacological tests [5-10].
This work is a continuation of our previous studies in search for compounds with
anxiolytic and antidepressant activity among a group of long-chain arylpiperazine
ligands. Thus the design of the present compound was inspired in the structures of the
anxiolytic compounds of new generation and results of our earlier works [10-19].
Results and discussion
The starting imides I and III were obtained in Diels-Alder’s reaction between ethyl 2methyl-4-oxocyclohex-2-ene-1-carboxylate and ethyl 3-ethyl-2-methyl-4-oxocyclohex2-ene-1-carboxylate (appropriate) and maleimide, in isopropenyl acetate with catalytic
amount of p-toluenesulphonic acid (p-TSA).
The next step was hydrolysis of compound I, using anhydrous ethanol with 25%
NH3 (aq.). The compound II was obtained as a result of conducted reaction (Scheme 1).
O
+
CH3
p-TSA
H5C2OOC
O
C 2H 5
+
CH3
COOC2H5
25% NH3
NH
MeOH
NH
O
O
O
isopropenyl acetate
COOC2H5
O
O
AcO
O
CH3
O
H5C2OOC
I
O
II
NH
NH
O
CH3
O
AcO
isopropenyl acetate
p-TSA
NH
H 5C 2
H5C2OOC
CH3
O
III
Scheme 1
The imides II and III were reacted in acetonitrile in the presence of anhydrous K2CO3
and KI with the 1-bromo-4-chlorobutane or 1,4-dibromobutane to give derivatives IV
and V, respectively. Finally, the resulting N-substituted imides were condensed with
appropriate amines in acetone, again in the presence of anhydrous K2CO3 and KI to give
derivatives VI-XIX (Scheme 2). All new piperazinyl derivatives were converted into
their corresponding hydrochlorides. The structures of the all compounds obtained were
confirmed by 1H-NMR spectra and elemental analysis.
Conclusion
In continuation of our research on cyclic imides with potential anxiolytic and
antidepressive activity we have obtained fourteen new compounds belonging to the
long-chain arylpiperazine ligand class. From the chemical and pharmacological point of
view, these compounds are the basis for further research in the field of the potential
drugs derived from cyclic imides.
O
O
AcO
O
NH
NH
H5C2
H5C2OOC
CH3
O
H5C2OOC
II
III
Br(CH2)4Cl
Br(CH2)4Br
O
O
AcO
O
N (CH2)4Br
N (CH2)4Cl
H5C2
H5C2OOC
O
CH3
H5C2OOC
IV
+
N
HN
R
O
N
N (CH2)4 N
V
+
O
N (CH2)4 N
R
H5C2
O
CH3
O
CH3
AcO
O
H5C2OOC
O
CH3
H5C2OOC
VI-XII
CH3
N
R
O
XIII-XIX
R:
OCH 3
F
OCH 3
N
OCH 3
N
N
OCH 3
VI
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
Scheme 2.
Experimental
Melting points were determined in a capillary on an Electrothermal 9100 apparatus and
are given uncorrected. 1H-NMR spectra were recorded in DMSO-d6 or CDCl3 on a
Bruker AVANCE DMX400 spectrometer operating at 400 MHz. The chemical shift
values are expressed in ppm (parts per million) relatively to tetramethylsilane used as an
internal standard and coupling constants J are given in Hz. Column chromatography
was done using 0.05-0.2 mm Kieselgel (70-325 mesh ASTM, Merck). Reactions were
monitored by TLC on 0.2 mm thick Kieselgel G plates with 254 nm fluorescent
indicator (Merck), eluted with 9.8:0.2 or 9.5:0.5 chloroform-methanol.
Synthesis of ethyl 10-(acetoxy)-7-methyl-3,5-dioxo-4-azatricyclo [5.2.2.02,6]undec10-ene-8-carboxylate (I) and ethyl 10-(acetoxy)-11-ethyl-7-methyl-3,5-dioxo-4azatricyclo[5.2.2.02,6]undec-10-ene-8-carboxylate (III)
A mixture of ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate or ethyl 3-ethyl-2methyl-4-oxocyclohex-2-ene-1-carboxylate (0.01 mol), maleimide (0.01 mol) and a
catalytic amount of p-toluenesulphonic acid (p-TSA) was refluxed for 2h in isopropenyl
acetate (30 mL). The boiling mixture was filtered and the solvent was evaporated. The
residue was crystallized from ethyl acetate.
ethyl
10-(acetoxy)-7-methyl-3,5-dioxo-4-azatricyclo
[5.2.2.02,6]undec-10-ene-8carboxylate (I) m.p. 196-197 °C, 1H NMR 400MHz, DMSO δ (ppm):11.14 (s, 1H,
NH), 5.39 (s, 1H, C11-H), 4.01 (m, 2H, O-CH2-CH3), 3.33 (s, 1H, C6-H), 2.94 (m, 1H,
C2-H), 2.88 (m, 1H, C1-H), 2.71 (d, 3J = 8.0Hz, 1H, C8-H), 2.10 (s, 3H, C10-OAc),
2.06-1.99 (m, 1H, C9-H),1.81-1.77 (m, 1H, C9-H), 1.44 (s, 3H, C7-CH3), 1.15 (t, 3J =
7.2Hz, 3J = 6.8Hz, 3H, O-CH2-CH3); Anal. Calc. for C16H19NO6: 60.02 % C, 6.00 % H,
4.33 % N; found: 59.76 % C, 6.09 % H, 4.94 % N.
ethyl 10-(acetoxy)-11-ethyl-7-methyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-10-ene-8carboxylate (III) m.p 190-191 °C ; 1H NMR, 400MHz, CDCl3 δ (ppm):8.96 (s, 1H,
NH), 4.12-4.04 (m, 2H, O-CH2-CH3), 3.06 (d, 3J = 2.8Hz, 1H, C8-H), 2.86 (dd, 3J =
2.8Hz, 3J = 8.4Hz, 1H, C2-H), 2.60 (d, 3J = 8.4Hz, 1H, C6-H), 2.45 (m, 1H, C7-H), 2.14
(m, 4H, C10-OAc, C9-H), 2.05-1.87 (m, 3H, C11-CH2-CH3, C9-H ), 1.62 (s, 3H, C7CH3),1.23 (t, 3J = 7.2Hz, 3H, O-CH2-CH3), 0.87 (t, 3J = 7.6Hz, 3H, C11-CH2-CH3);
Anal. Calc. for C18H23NO6: 61.89 % C, 6.59 % H, 4.01% N; found: 61.95 % C, 6.66 %
H, 3.977 % N.
Synthesis of ethyl 7-methyl-3,5,10-trioxo-4-azatricyclo[5.2.2.02,6]undecane-8carboxylate (II)
The imide I (0,01mol) was dissolved in methanol (30mL) and the 25% solution NH3
(7mL) was added. The mixture was refluxed for 4h. The boiling mixture was filtered
and the solvent was evaporated. The residue was crystallized from ethyl acetate.
ethyl 7-methyl-3,5,10-trioxo-4-azatricyclo[5.2.2.02,6]undecane-8-carboxylate (II) m.p.
215-216 °C; 1H NMR 400MHz, DMSO δ (ppm): 11.41 (s, 1H, NH), 4.10 (m, 2H, OCH2-CH3), 3.25 (dd, 3J = 3.2Hz, 3J=9.2Hz, 1H, C2-H), 2.90 (d, J3 = 9.2Hz, 1H, C6-H),
2.67 (dd, 3J = 6.8Hz, 3J = 10.4Hz, 1H, C1-H), 2.62-2.50 (m, 2H, C8-H, C11-H), 2.23
(m, 1H, C9-H), 1.89-1.78 (m, 2H, C8-H, C9-H), 1.15 (m, 6H, C7-CH3, O-CH2-CH3);
Anal. Calc. for C14H17NO5: 60.02 % C, 6.09 % H, 5.02 % N; found: 60.12 % C, 6.17 %
H, 5.04 % N.
General synthesis of N- butyl derivatives of the imides (IV, V)
The appropriate imide (II or III) (0.01 mol) was dissolved in acetone (30 mL), then
anhydrous K2CO3 (0.01 mol) and 1-bromo-4-chlorobutane or 1,4-dibromobutane (0.02
mol) (respectively)- were added. The mixture was refluxed for 12h. When the reaction
was complete, as indicated by TLC, the mixture was filtered and the solvent was
evaporated. The residue was purified by flash chromatography (eluent: chloroformmethanol 100:0.2).
ethyl
4-(4-chlorobutyl)-7-methyl-3,5,10-trioxo-4-azatricyclo[5.2.2.02,6]undecane-8carboxylate (IV) oil; 1H NMR 400MHz, CDCl3 δ (ppm): 4.25-4.13 (m, 2H, O-CH2-
CH3), 3.54 (t, 3J = 6.0Hz, 2H, C1’-H), 3.50 (t, 3J = 6.4Hz, 2H, C4’-H), 3.12 (dd, 3J =
3.2Hz, 3J = 9.3Hz, 1H, C2-H), 2.92 (m, 1H, C1-H), 2.85 (d, 3J = 2.0Hz, 1H, C6-H), 2.72
(dd, 3J = 9.3Hz, 4J = 2.0Hz, 1H, C11-H), 2.64-2.59 (m, 1H, C8-H), 2.22-2.19 (m, 2H,
C9-H), 1.93-1.87 (m, 1H, C11-H), 1.70 (m, 4H, C2’-H, C3’-H), 1.40 (s, 3H, C7-CH3),
1.29 (t, 3J = 7.2Hz, 3H, O-CH2-CH3); Anal. Calc. for C18H24ClNO5: 58.46 % C, 6.54 %
H, 3.79 % N; found: 58.12 % C, 6.54 % H, 3.80 % N.
ethyl
4-(4-bromobutyl)-10-(acetoxy)-11-ethyl-7-methyl-3,5-dioxo-4-azatricyclo
[5.2.2.02,6]undec-10-ene-8-carboxylate (V) oil; 1H NMR, 400MHz, CDCl3 δ (ppm):
4.14-4.05 (m, 2H, O-CH2-CH3), 3.51-3.38 (m, 4H, C1’-H, C4’-H), 3.08 (m, 1H, C1-H),
2.80 (dd, 3J = 2.4Hz, 3J = 8.0Hz, 1H, C2-H), 2.54 (d, 3J = 8.0Hz, 1H, C6-H), 2.46 (m,
1H, C8-H), 2.17-1.89 (m, 7H, C10-OAc, C11-CH2-CH3, C9-H), 1.82 (m, 2H, C2’-H),
1.64 (m, 5H, C1-CH3, C3’-H),1.24 (t, 3J = 7.2Hz, 3H, O-CH2-CH3), 0.85 (t, 3J = 7.6Hz,
3H, C11-CH2-CH3); Anal. Calc. for C22H30BrNO6: 54.55 % C, 6.24 % H, 2.89 % N;
found: 54.24 % C, 6.16 % H, 2.94 % N.
General synthesis of aryl- and heteroarylpiperazinyl dervatives of ethyl 4-(4chlorobutyl)-7-methyl-3,5,10-trioxo-4-azatricyclo[5.2.2.02,6]undecane-8-carboxylate
(VI-XII) and ethyl 4-(4-bromobutyl)-10-(acetoxy)-11-ethyl-7-methyl-3,5-dioxo-4azatricyclo[5.2.2.02,6]undec-10-ene-8-carboxylate (XIII-XIX)
The appropriate pipperazine (0.02 mol) was added to a mixture of N-butylimide (0.01
mol), powdered anhydrous K2CO3 (0.01 mol), and a catalytic amount of KI in acetone
(30 mL). The reaction mixture was refluxed for 24 h. After the reaction completion the
inorganic residue was filtered off and the solvent was evaporated. The crude compound
obtained was purified by flash chromatography (eluents: chloroform or chloroformmethanol 100:0.2). All new derivatives were converted into their corresponding
hydrochlorides with ethereal HCl and recrystallized from methanol.
The results of elemental analysis (C, H, N) of compounds VI-XIX were within ± 0.5%
of theoretical values. The values of 1H NMR chemical shifts of these compounds
support the reported structures and are available on request.
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