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Structure-Activity Relationship Studies of CNS Agents Part 31[1]Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment В Э New 5-HT1A Receptor Ligands.

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45 1
New ~ - H T I Receptor
A
Ligands
Structure-ActivityRelationship Studies of CNS Agents, Part 31"':
Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the
Heteroaromatic Fragment - New ~ - H T Receptor
~A
Ligands
Maria H. Paluchowska*, Anna Deren-Wesolek, Jerzy L. Mokrosz (deceased), Sijka Charakchieva-Minol, and
Ewa Chojnacka-W6jcik
Institute of Pharmacology, Polish Academy of Sciences, 12 Smqtna St., 31-343 Krakbw, Poland
Key Words: 1-(2-methoxyphenyl)piperazines;~ - H T receptor
~A
ligands; a1-adrenergic receptor ligands;
~-HTIA
receptor partial agonist; ~ - H T receptor
~A
antagonist
Summary
Two series of new M P 3022 analogs, i.e. l-(o-methoxyphenyl)-4n-propylpiperazines (3,4a, 4b,6-9, and 1213) and 2-(n-propyl)1,2,3,4-tetrahydroisoquinolines(5a,5b,lla, and llb) containing
a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their ~ - H T ~ A / ~ - H
and
T ~a1A
receptor affinity was assayed. The majority of investigated
1: M P 3 0 2 2 , R = H
2a:R = 5-C1
piperazines may be classified as non-selective S-HTIA/~-HT~A/CII
2b:R 6-C1
receptor ligands. Compounds 3,4a, 4b, 7-9a with the highest
Chart 1
affinity for S-HTIAreceptors (fi = 4 - 54 nM) were tested in vivo.
Their functional activity was differentiated; while 3, 8, and 9a
behaved like weak antagonists of postsynaptic S-HTIAreceptors,
To evaluate chemical features of 4-substituted 1-aryl4b and 7 may be classified as potential partial ~ - H T I receptor
A
piperazines that modulate their affinity and intrinsic activity
agonists. Isomer 4a has characteristic features of a potential weak
for S - H T ~ Areceptors, we synthesized two series of new
postsynaptic ~-HTIA
receptor agonist.
MP 3022 analogs (Chart 2), i.e. compounds 3, 4a, 4b, 6-9,
and 12-13 with a different number of nitrogen atoms at the
terminal heteroaromatic ring system, and derivatives 5a, 5b,
Introduction
l l a , and l l b in which the 1-(2-methoxyphenyl)piperazine
fragment was replaced by a 1,2,3,4-tetrahydroisoquinoline
The arylpiperazine class of ~ - H T I A
receptor li ands has (THIQ) moiety.
been still the subject of intensive inve~tigationf~-~'.
We
previously described new, full, potent antagonists of S - H T ~ A
Results and Discussion
receptors, MP 3022 (I)"] and its 5-chloro analog (2a), with
the same pharmacological profile[91 (Chart 1). In fact,
Simple, one- or two-step methods of alkylation used for the
MP 3022 and compound 2a bind with high affinity for 5- synthesis of the desired compounds are illustrated in
HT~A
receptors and in several functional studies they have Scheme 1.
Compounds 4a, 4b, 5a, 5b, 6-8, 9a, 9b, 10a, lob, 12a4,
been shown to be potent antagonists of pre- and postsynaptic
~ - H T ~receptors.
A
They antagonized the responses induced 13a, and 13b were obtained by a modified method described
by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), earlier[']. Alkylation of benzotriazole, indazole, 4-azawell known ~ - H T ~receptor
A
agonist, i.e. hypothermia in benzimidazole, 7-azabenzotriazole, and purine in acetonitrile
mice, the lower lip retraction in rats, and the behavioral in the presence of the KF/Al2O3 catalyst["] led to a mixture
syndrome in reserpinized
Moreover, 1 significantly of two or three isomeric products which were separated by a
attenuated the 8-OH-DPAT-induced decrease in the popula- column chromatography.
The structure of isomers 4a and 4b, 9a and 9b, 1 2 a 4, 13a,
tion spike evoked in the CA1 cell layer of the hippocampal
and 13b was defined on the basis of 'H NMR spectra and
slice preparation, the 8-OH-DPAT-mediated decrease in the one-dimensional nuclear Overhauser enhancement (1D
5-HT turnover in the hippocampus, and the 8-OH-DPAT- NOE) measurements. Irradiation of the resonance of a
evoked increase in the corticosterone concentration in the methylene group adjacent to the heteroaromatic ring caused
serum in rats"01. In the same time, both compounds were enhancement of appropriate neighboring proton signals (Tadevoid of agonist properties ['-lo] . On the other hand, the ble 1). The structure of 1 2 a 4 was additionally confirmed by
isomeric 6-chloro analog (2b) as well as the 5,6-dimethyl
13C NMR spectra. Isomers 5a, 5b, and l l a , l l b were identiderivative of 1'91behaved like partial agonists at ~ - H T I A fied on the basis of 'H NMR spectra. The 'H NMR spectra
receptors.
clearly differentiated between 1- and 2-benzotriazole deriva-
Arch. Pharm. Pharm. Med. Chem.
0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996
0365-6233/96/1010-0451$5.00 + .25/0
452
Mokrosz and co-workers
rn
tives. The proton signals of the 2-benzotriazolyl fragment
formed a diagnostic symmetrical pattern in the spectrum of
l l a . In the case of 5a and 5b different chemical shifts for H-3
and H-4 protons were observed, similarly to those for 4a and
4b.
N-R(R1)
R
4a
5a
3
I
4b
5b
R
Rl
aN>
Rl
R
A
7
6
K
QQ
N
R
I
Table 1. Results of proton-proton 1D NOE experiments in heteroaromatic
fragments of selected compounds
Compound NOE observed (96)
8
ON>
R
4a*
3-H(2.3), 4- and 7-H(1.2), 6-H(0.7)
4b
3-H(1.0), 4-H(0.9), 5-H( 1.2j, 6-H(1,2), 7-H(2.7)
9a
2-H(1.7), 4-H(0.5),5-H(0.2), 6-H(0.3)
9b
2-H(2.9), 5-H(1 .0), 6-H( I .3), 7-H(2.4)
12a
5-H( 1.0), 6-H( 1.4),7-H( 1.2)
N
9a
Ila
9b
Ilb
a>N
\
A
12a
12b
A
12c
5-H(0.7), 6-H(0.7), 7-H( I .7)
13a
2-H(l.1), 6-H( l.2j, 8-H(3.1)
13b
2-H(0.6), 6-H(2.2), 8-H(2.6)
12c
*signal of 5-H is overlapped by signal of aromatic protons
R
I
r&)
Receptor binding data on ~ - H T ~and
A~-HT~
asAwell as
al-adrenergic receptors for compounds 3-9 and 11-13 are
displayed in Table 2, along with those for 1[*].In general, the
investigated arylpiperazines showed a lower ~ - H T ~than
A
13a
13b
~ - H T receptor
~A
affinity, and the most significant 5-HT2~/5HT~A
receptor selectivity ratio was found for compounds 3,
4b, and 6. Moreover, the majority of the tested compounds
where R = --(CH~)%-N
RI = -(cyj,RN
revealed submicromolar affinity for a1 -adrenergic receptors.
U
Searching for the structural requirements for a high ~ - H T ~ A
receptor affinity, we investigated compounds with a different
Chart 2
number of nitrogen atoms in the heteroaromatic ring system
in comparison with 1 (Table 2). Replacement of the benzotriazole
Het-H
+ CI-(CH2),-N * N P
4a, b; 6 - 8; 9a, b;
W
fragment by the 1-indazolyl group
12a - c; 13a, b
OCHJ
afforded 4b which showed the
highest affinity for ~ - H T ~
recepA
tors (El= 4 nM). Compound 3 with
the 1-indolyl group showed almost
E
N
+ CI-(CH~)J-N
5a, b
the same 5-HT1A receptor affinity
H
(Kj = 23 nM) as the model compound 1 (K; = 15 nM). Introduction
of a nitrogen atom into position 3 of
the 5-membered ring considerable
decreased the ~ - H T ~
receptor
A
afii
a : N
+ Br-(CHZ)3-Br +
~ ~ : N - ( C H ~ ) J - B +~
finity (6 vs. 3), while the 2-methyl
N'
analog of 6 was insignificantly less
H
I
(CH2)3-Br
potent than 3 (Kl = 41 nM). On the
other hand, introduction of a nitro1Oa
10b
gen atom into position 2 of the 5iii
iii
membered ring of 3 increased the
5-HTl~receptor
affinity (3 vs. 4b).
lla
llb
We
also
found
that
introduction of
Scheme 1. Reagents and conditions: (ij - KOH, DMSO, room temp; (ii) - KF/A1201, CH3CN, 1-6 h reflux;
a nitrogen atom into the benzene
(iii) - THIQ, K2CO3, n-BuOH, 5 h reflux.
ring of the heteroaromatic moiety in
QK) R
n~5 rn
9
K3
mi+
EN
'
1
1
Arch. Phurm.Phum. Med. Chem. 329,451456 (19%)
453
New ~ - H T Receptor
~A
Ligands
Table 2. The ~ - H T I A~-HTzA,
,
and ai binding data and the S-HT~A/~-HTIAand 9a significantly antagonized the flat body posture and
ratio of investigated compounds
forepaw treading induced by 8-OH-DPAT after the highest
Ki f SEM [nMI
Cmpd
~-HTIA
S-HT~A
~-HTzA/
S-HTIA
selectivity
a
1*
15f2
1040 f 30
69f11
69
3
23f6
693 f 47
I1 f 1
30
4a
29f4
421 f 19
65 f I
14
4b
4f1
172 50
14 f 2
43
5a
1218f344
4520 f 433
NT
5b
457f87
262 f 30
NT
6
84fll
4290 f 260
12f2
51
7
41f6
603 f 140
41f10
15
8
41f3
157 f 17
22f3
4
4
0.6
9a
54+ 1
140 f 16
23f4
3
9b
129f17
1440 f 145
22 f 1
11
lla
1079f192
2144 f 355
496
llb
372f58
2337 485
173
12a
119f28
2190 f 670
2
6
69f13
18
12b
88f3
734fll
6 6 f 16
8
12e
140f 17
2650 f 415
124f21
19
13a
135f I7
1140 f 35
13b
1013f I96
4288 f 607
* from reference '81. NT -not
78f7
215
+ 34
8
4
tested
position 4 or 7 was an unfavorable structure modification,
since the observed ~ - H T receptor
~A
affinities of 8, 9a, 9b,
12b, and 12c were relatively lower than those for their 4- or
7-deazaanalogs (3, 7, and 1). Introduction of two nitrogen
atoms into the 6-membered ring of 6 led to the equipotent
isomer 13a and lowered the affinity in the case of isomer 13b.
Substitution of the 1-(2-methoxyphenyl)piperazine fragment by the 1,2,3,4-tetrahydroisoquinoline
group was also
not beneficial. Derivatives 5a, Sb, l l a , and l l b were found
to bind to ~ - H T receptor
~A
with a substantially lower affinity
than their arylpiperazine analogs 4a, 4b, 1, and the 2-benzotriazolyl isomer of I['], respectively. In contrast, replacement
of the 1-(2-pyrimidinyl)piperazine fragment in buspirone by
the 1,2,3,4-tetrahydroisoquinoline
ring system did not significantly affect either the observed 5-HT1 receptor affinity or
the functional profile at those receptorsh2]. Our results demonstrate that the (2-methoxypheny1)piperazine fragment is
the pivotal feature for the binding of this class of compounds
to ~ - H T I receptors.
A
Compounds which exhibited the highest affinity for 5HT~A
receptors (Kj = 4 - 54 nM) were selected for in vivo
experiments. The functional activity of compounds 3,4a, 4b,
7,8, and 9a at presynaptic and postsynaptic ~ - H T receptors
~A
was demonstrated in several commonly used in vivo models.
It is commonly accepted that the 8-OH-DPAT-induced flat
body posture and forepaw treading in reserpinized rats['31 and
the lower lip retraction (LLR) in normal rats[I4,l5]are mediated by postsynaptic ~ - H T receptors.
~A
Compounds 3, 7, 8,
Arch. P h a m Pham. Med. Chem. 329,451456 (19%)
doses used (16 and 32 mgkg). Compound 4b reduced the
forepaw treading but failed to inhibit the flat body posture
evoked by 8-OH-DPAT; its isomer 4a, given in doses up to
16 mgkg, was ineffectivein that model (Table 3). At the same
time, neither of the six compounds (3,4a, 4b, 7,8, and 9a),
injected in doses of 2-16 mgkg to reserpinized rats, yielded
any component of the 8-OH-DPAT-induced syndrome (data
not shown). Compound 8, used in the highest dose of 32
mgkg, inhibited the 8-OH-DPAT-induced LLR by 34%,
whereas 3, 4a, 4b, 7, and 9a were inactive in that model
(Table 3). Compounds 4a, 4b, and 7, given alone in doses of
4 - 16 mgkg, induced the LLR in rats in a dose-dependent
manner, the maximum score being 53%, 60%, and 40%,
respectively, after the highest dose used, whereas derivatives
3, 8, and 9a, given alone in doses up to 32 mgkg, had no
activity in that test (Table 3).
The results presented above indicate that compounds 3, 8,
and 9a behave like weak antagonists of postsynaptic S-HT~A
receptors; however, the ~ - H T I antagonistic
A
activity of 3 and
9a was observed only towards the 8-OH-DPAT-induced behavioral syndrome, but not in relation to the 8-OH-DPAT-induced LLR. Compounds 4b and 7 may be classified as
potential partial ~ - H T ~receptor
A
agonists but the further
investigations are needed to confirm this statement. On the
other hand, only isomer 4a has characteristic features of a
weak postsynaptic ~ - H T receptor
~A
agonist.
In conclusion, compounds with the indazole (4a, 4b),
benzimidazole (7), azaindole (S), and azabenzimidazole (9a)
fragments, as well as MP 3022 (l),2a, and 2b'8,91show high
affinity for ~ - H T receptors.
~A
However, their functional profiles are neither so unequivocal nor so clear as those of 1,2a,
or 2b[8-'01.
Acknowledgement
This study was supported by the Polish State Committee for Scientific
Research (KBN), grant no. 6-P206-024-07(1994-1996).
Experimental Part
Melting points: Boetius apparatus (uncorrected).- Elemental analyses:
Within 0.4% of theoretical values. Perkin Elmer 240 analyser (Institute of
Organic Chemistry, Warszawa). - 'H NMR spectra (CDC13): Bruker AC
200F (200 MHz) or Varian EM-360 L (60 MHz) spectrometers, TMS int.
standard.- I3C NMR spectra (CDC13): Bruker AMX 500 (125 MHz).Commercially available reagent grade solvents and reagents were used
without further purification. 4-(3-Chloropropyl)-1-(2-methoxyphenyl)piperazine was obtained according to Mokrosz et al."'.
4-[3-(I-Indolyl)propyl]-I-(2-methoxyphenyl)piperazine(3)
A mixture of indole (1.17 g, 10 mmol) and powdered 87% KOH (1.68 g)
in DMSO (30 ml) was stirred at room temp. for 1 h. Reaction mixture was
cooled in ice-water bath to 0 "C and 4-(3-chloropropyl)-l-(2-methoxypheny1)piperazine (2.7 g, 10 mmol) in DMSO (10 ml) was added dropwise.
The stirring was continued at room temp. for 2 h. After addition of water
(50 ml) and extraction with EtzO, the organic layer was washed with water
and dried over anhydrous Na2S04. The solvent was evaporated and the oily
residue was purified by CC (Si02, AcOEth-hexane - 1/2) to give 3 (1.14 g,
33%) as an oil. Rf0.29 (SiOz, AcOEtln-hexane - 111). The fumarate was
obtained in acetone from equimolar amounts of free base and fumaric acid.
M.p. 167-168 "C (acetone).- 'H NMR (base, 60 MHz): 6 = 1.8-2.8 (cluster,
8H, 4 CH:), 2.8-3.3 (m, 4H, 2 CHz), 3.8 (s, 3H, OCH3), 4.2 (t, J = 7 Hz, 2H,
454
Mokrosz and co-workers
Table 3.The effect of compounds 3,4a,4b,7,8,and 9a on the 8-OH-DPAT-inducedbehavioral syndrome in reserpine-pretreated
rats') (A) and on the 8-OH-DPAT-induced lower lip retraction (LLR)b' (B) and induction of LLR by the investigated compounds in ratsc).
-
Dose
mg/kg
A
MeanSEM behavioral score
Flat body posture
Forepaw treading
B
C
vehicle
-
3
8
16
32
12.6 f 0.4
10.8 i 0.5
8.5 f 1.0
3.5 f 2.4d'
12.2 f 0.8
11.5 f 0.8
3.5 f 0 . 9 C '
0.0 f O.Oe'
2.7 f 0.3
NT
2.8 f 0.2
2.3 f 0.1
0.1 f 0. I
NT
0. I f 0.2
0.2 i 0.2
13.2 f 0.5
12.3 f 0.7
NT
2.4 f 0.3
I .9 f 0.5
NT
0. I k 0. I
0.4 i 0.2
I .3 i 0.3
1.6 f 0.3e'
Treatment
vehicle
-
4a
4
8
16
behicle
-
4b
2
4
8
16
NT
NT
NT
13.2 i 0.8
11.0 f 0.8
NT
13.2 f 0.8
12.8 f 0.7
l 0 . 7 i 1.8
13.4 f 0.2
10.7 f 0.8
2.4 f 0.3
2.6 k 0.1
2.3 f 0.2
0.1 f 0 . 1
NT
1.6f 0.4e'
1.8 k 0.2?'
11.0f1.5
10.5 f 0.9
vehicle
-
13.2 f 0.5
7
2
4
8
NT
16
vehicle
-
8
8
16
32
vehicle
-
9a
8
16
32
MeanSEM LLR \core
10.7 f 0.5
5.7 i 1 .se'
4.5
* 0.9e'
NT
0.3 f 0.1
1.0 f 0.3*'
0.1 f O . l
12.3 f 0.7
NT
9.7 f 0.9
9.3 O.gd'
3.6 f 1 .Oc'
2.4 i 0.3
3.0 0.0
2.6 f 0. I
NT
13.2 f 0.5
13.0 L 0.6
13.6 f 0.5
2.3 f 0.3"'
12.3 f 0.7
2.4 i 0.3
NT
0.1 f 0 . l
2.3 f 0.3
0.2 f 0.2
0.1 * 0 , l
12.6 f 0.4
10.2 f 0.8
6.5 f 0.8"'
12.2 f I .2
11 .0 f 0.8
1 1.8 f 0.7
10.0 f 0.4d'
6.2 f 0.1")
3.7
* 1 .7c'
*
10.9 f 0.7
7.8 f 0 9 '
I .2 f 0.2C'
5.3 i 0.9"'
1.3 f O.ge)
NT
I .6 f 0.3d'
2.7 f 0.3
NT
2.3 f 0.2
2.0 f 0.3
0.5 f 0.2
0.9 f 0.Y)
1 .o f 0Sd'
1.2 f 0.3e)
NT
0.1 f 0.1
NT
0. I f 0.1
0.6 f 0.2
Reserpine (1 mg/kg, A,(..) and the investigated compounds (ip)
were administered 18 h and 45 min. respectively, before
8-OH-DPAT ( 5 mgkg, i.p.). h)Theinvestigated compounds were given i.p. 30 min before 8-OH-DPAT (1 mgkg, i.p.).
"The investigated compounds were injected i.p. 15 min before the test. d'p<0.05 vs. vehicle. e)p<O.O1v s . vehicle. NT = not tested
a'
indole-CHz), 6.5 (d, .I= 3 Hz, IH, indole 3-H), 6.7-7.6 (m. 8H, aromatic H),
7.6-7.8 (m.IH, indole 4-H).- Anal. (C22H27N10 C4H404).
Generul procedure jor prepurution 01 compounds 4a,4b, 5a, 5b, M,9a,
9b. 10a, 10b. 12a-c, 13a, mid 13b
Equiinolar ainounts (3 inmol) of appropriate heterocyclic compound and
4-(3-chloropropyl)-1 -(2-methoxyphenyl)piperazine or 1,3-dibrnmopropane
(for 10a and lob) or 2-(3-chloropropyl)- 1.2,3,4-tetrahydroisoquinoline1"
(for 5a and 5b) were refluxed in MeCN (30 ml) in the presence of the
KF/AI?Oj catalyst (3 g) for 1-6 h. The catalyst was filtered off and washed
with benzene ( I 0 ml). The filtrate was evaporated and the residue containing
product or a mixture of isomeric products was separated by CC as follows:
4a and 4b, 8 - Si02, AcOEt; 6 - Si02, CHC13; 7,9a and 9b, 13a and 13b SiOz, C H C I I M ~ O H( I Y I ) ; 10a and 10b - Si02, CHCls/n-hexane (l/2):
12a-c - neutral A1203, AcOEtln-hexane (1/2). Free bases were converted
into the hydrochloride or oxalate salts in acetone by treatment with excess of
Et2O satd. with gaseous HCI or with two-fold excess of oxalic acid, respectively.
4-[3-~2-ln~uiolyl)pr0pyl]-l-(2-metlio.~~phenyl)piperu,-ine
(4a)
Yield 24%. Pale yellow oil. Reaction time 3 h. Rr0.13 (Si02, AcOEt).' H NMR (200 MHz): = 2.1-2.3 (m, 2H, CH2CHzCH2), 2.4-2.5 (m. 2H,
CHz-piperazinc). 2.6-2.7 (m, 4H, piperazine 2 CH2), 3.1-3.2 (m, 4H,
p i p e r a h e 2 CHz), 3.84 (s, 3H, OCH3), 4.5 (t, J = 6.8 H L , 2H, CH2-indazole).
6.8-7.1 (m, SH, aromatic H), 7.2-7.3 (m, IH, indarole 6-H), 7.6-7.7 (in,2H,
indazole 4-H and 7-H), 7.93 (5, 1H. indazole 3-H).- 4a (HCI salt): M.p.
159-161 "C (acetonc/ethanol - W).- Anal. (C21Hz6N30 3 HCI).
'
4-[3-(I - I i ~ d a i o l ~ l ) p r u p1y-(2-methoxyphenyl)[email protected]
l~(4b)
Yield 49%. M.p. 82-84 "C (AcOEtln-hexane
-
l/4). Reaction time 3 h.
Rf 0.32 (SiOr, AcOEt).- IH NMR (200 MHz): 6 = 2.1-2.3 (m. 2H,
CH~CH~CHZ
2.3-2.4
),
(m, 2H, CH~-piperazine),2.6-2.7 (m, 4H, piperazine
2 CH2), 3.0-3.2 (ni, 4H, piperazine 2 CHz), 4.5 (t, J = 6.6 Hz, 2H, CHz-indazole),6.8-7.0(m,4H,aromaticH),7.14(ddd,J=8.1,6.8,and
1.0Hz, IH,
indazole 5-H), 7.37 (ddd, J = 8.4, 6.8, and 1.1 Hz, IH, indazole 6-H), 7.52
(dd, J = 8.4 and 0.9 Hz, 1H, indazole 7-H), 7.73 (ddd, J = 8. I , 1.0,and 0.8
Hz, I H, indazole 4-H), 8.02 (d, J = 0.8 Hz, 1H, indazole 3-H).- 4b(HCI salt):
O
M.p. 138-141 "C (acetone/ethanol- ?/I).- Anal. ( C ~ I H Z ~ N J3HC1).
Arch. Phurm. Phurm. Med Chem. 329,451456 (1996)
455
New ~ - H T Receptor
~A
Ligands
2-[3-(2-I~iduzolyl)propyl]-1,2,3,4-teiruhydroisoquin~line
(5a)
3-(2-Benzotriuzolyl)propylbromide (10a)
Yield 20%. Pale yellow oil. Reaction time 3 h. Rr 0.34 (Si02,
CHC13/MeOH - 19/1).- 'H NMR (60 MHz): 6 = 2.0-3.0 (cluster, 8H,
4 CHz), 3.5 (s, 2H, THIQ 2-H), 4.4 (t, J = 7 Hz, 2H, CHz-indazole), 6.8-7.4
(m, 6H, aromatic H), 7.5-7.9 (m, 3H, aromatic H).- 5a (HCI salt): M.p.
181-183 "C (acetone/ethanol - 3/l),- Anal. (C19HziN3. 2HC1).
Yield 18%. Yellow oil. Reaction time 4 h. Rf 0.76 (Si02, CHC13).- 'H
3.45 (t, J = 7 Hz, 2H,
NMR (60 MHz): 6 = 2.4-2.9 (m, 2H, CH~CHZCHZ),
CHzBr), 4.9 (t, J = 7 Hz, 2H, CHz-N), 7.3-7.6 (m, 2H, benzotriazole 5-H and
6-H), 7.8-8.1 (m, 2H, benzotriazole 4- and 7-H).
3-(I -Benzotriazolyl)propyopylbromide (lob)
2-[3-(I-lnduzolyl)propyl]-I,2,3,4-terruhydroisoyuinzoline
(5b)
Yield 52%. Yellow oil. Reaction time 3 h. Rr0.57 (SiOz, CHC13/MeOH
19/1).- 'H NMR (60 MHz): 6 = 1.9-3.0 (cluster, 8H, 4 CHz), 3.5 (s, 2H,
THIQ 2-H), 4.4 (t, J = 7 Hz, 2H, CHz-indazole), 6.9-7.5 (m, 7H, aromatic
H), 7.6-7.8 (m, IH, indazole4-H), 8.0 (s, IH, indazole 3-H).-5b (HCI salt):
M.p. 171-173 "C (acetone).- Anal. (Ci9HziN3 . 2 HCI).
-
4-[3-(
I -Benzimiduzolyl)propyl]-1-(2-metl~r~~phenyllpipiperuzine
(6)
Yield 78%. Pale yellow oil. Reaction time 1 h. Kf 0.39 (SiOz,
CHCh/MeOH - 19/1).- 'H NMR (60 MHz): 6 = 1.8-2.8 (cluster, 8H,
4 CHz), 2.9-3.3 (m, 4H, piperazine 2 CH2), 3.85 (s, 3H, OCH3), 4.2 (t, J =
7 Hz, 2H, CHz-benzimidazole), 6.95 (s, 4H, aromatic H), 7.1-7.5 (m, 3H,
aromatic H), 7.7-7.9 (m, 1H, henzimidazole 4-H), 8.0 (s, I H, benzimidazole
2-H).- 6 (oxalate): M.p. 170-172 "C (ethanol).- Anal.
(CziH26N40 ' 2 CzH204).
4-[3-(2-Methylbenzimiduz~lI -yl)propyl]-l-(2-methoxyphenyl)piperuzine
(7)
Yield 78%. Yellow oil. Reaction time 6 h. Rf0.32 (Si02, CHCWMeOH 19/l).- 'H NMR (60 MHz): 6 = 1.8-2.7 (cluster, 8H, 4 CHz), 2.65 ( 8 , 3H,
CH3), 2.9-3.3 (m, 4H, piperazine 2 CHz), 3.85 (s, 3H, OCH?), 4.2 (t, J = 7
Hz, 2H, CHz-benzimidazole), 7.0 (s, 4H, aromatic H), 7.1-7.5 (m, 3H,
aromatic H), 7.67.8 (m, 1H, benzimidazole 4-H).- 7 (HC1 salt): M.p.
162-164 "C (acetone/ethanol - 2/1).- Anal. (C22H28N40 . 3HCl Hz0).
Yield43%. Yellow oil. Reaction time4 h. Rr0.4 (SiOz, CHC13).- 'HNMR
(60 MHz): 6 = 2.3-2.9 (m, 2H, CHzCHzCHz), 3.4 (t. J = 7 Hz, 2H, CHzBr),
4.8 (t. J = 7 Hz, 2H, CHz-N), 7.2-7.7 (m, 3H, benzotriazole 5-, 6-, and 7-H),
7.9-8.2 (m, lH, benzotriazole 4-H).
4-[3-(4-Azubenzotriuzol-2-yl)prop~l]-l-(2-methoxyphenyl)piperuzine
(12a)
Yield 33%. M.p. 89-90 "C (AcOEdn-hexane - UI). Reaction time 3 h.
Rf0.53 (A1203, AcOEtln-hexane- l/l).- 'H NMR (200 MHz): = 2.25-2.45
(m, 2H, CHzCHzCHz), 2.45-2.60 (m, 2H, CHz-piperazine), 2.60-2.75 (m,
4H, piperazine 2 CH2), 3.0-3.15 (m, 4H, piperazine 2 CHz), 3.85 (s, 3H,
OCH?), 4.88 (t. J = 6.9 Hz, 2H, CHz-azabenzotriazole), 6.8-7.1 (m, 4H,
aromatic H), 7.33 (dd, J = 8.6 and 4.2 Hz, IH, heteroaromatic 6-H), 8.23 (dd,
J = 8.6 and 1.6 Hz, IH, heteroaromatic 7-H), 8.80 (dd, J = 4.2 and 1.6 Hz,
IH, heteroaromatic 5-H).- 13C NMR (125 MHz): 6 = 27.14 (chain C-2),
50.55 (piperazine C-3 and C-5), 53.29 (piperazine C-2 and C-6), 55.1 1 (chain
C-I), 55.28 (OCH3), 55.66 (chain C-3), 111.12 (aromatic C-6), 118.12
(aromatic C-3), 120.90 (aromatic C-4), 121.86 (heteroaromatic C-6), 122.81
(aromatic C-S), 126.89 (heteroaromatic C-7), 136.35 (heteroaromatic C-7a),
141.24 (aromatic C-l), 1.51.55 (heteroaromatic C-5), 152.20 (aromatic C-2),
155.78 (heteroaromatic C-3a).- 12a (HCI salt): M.p. 190-192 "C (acetone/ethanol - 3/1).- Anal. (C19Hz4N60 . 2HC1 . 2.5H20).
4-/3-(7-Azaherzzotriazol-I-yl)propyl]-l-(2-methoqphenyl)piperuzine(12b)
Yield 59%. Yellow oil. Reaction time 4 h. Rf0.55 (SiOz, CHCI3/MeOH 9/l).- 'H NMR (60 MHL): 6 = 1.9-2.8 (cluster, 8H, 4 CH2), 2.8-3.2 (m, 4H,
piperazine 2 CH2), 3.85 (s, 3H, OCH3), 4.4 (t, J = 7 Hz, 2H, CHz-azaindole),
6.45 (d, J = 4 Hz, IH, heteroaromatic 3-H), 6.8-7.2 (m, SH, aromatic H and
heteroaromatic 5-H), 7.35 (d, J = 4 Hz. 1 H, heteroaromatic 2-H), 7.95 (dd, J
= 8 and 2 Hz, IH, heteroaromatic 4-H), 8.35 (dd, J = 5 and 2 Ha, 1H,
heteroaromatic 6-H).- 8 (HCI salt): M.p. 146-148 "C (ethanol).- Anal.
(CziHz6N40 ' 3HC1' 0.5HzO).
Yield 33%. Pale yellow oil. Reaction time 3 h. Rf0.67 (A1z03, AcOEtlnhexane- l/l).-'HNMR (60MHz): 6=2.1-2.8(cluster, 8H,4CHz),2.9-3.2
(m, 4H, piperazine 2 CHz), 3.85 (s, 3H, OCH3), 4.9 (t, J = 7 Hz, 2H,
CHz-azabenzotriazole), 6.95 (s, 4H, aromatic H), 7.35 (dd, J = 8.0 and
4.0 Hz, 1 H, heteroaromatic 5-H), 8.45 (dd, J = 8.0 and 4.0 Hz, 1H, heteroaromatic 4-H), 8.7 (dd, J = 4.0 and 2.0 Hz, IH, heteroaromatic 6-H).- I3C NMR
(125 MHz): = 26.71 (chain C-2), 45.37 (chain C-3), 50.51 (piperazine C-3
and C-5),53.26 (piperazine C-2 and C-6), 55.27 (OCH3), 55.43 (chain C-3),
111.12 (aromatic C-6), 118.11 (aromatic C-3), 119.61 (heteroaromatic C-5),
120.9 (aromatic C-4), 122.8 (aromatic C-5), 128.48 (heteroaromatic C-4),
136.97 (heteroaromatic C-3a), 141.26 (aromatic C-l), 145.88 (heteroaromatic C-7a), 149.96 (heteroaromatic C-6), 152.19 (aromatic C-2).- 12b (HCI
salt): M.p. 210-212 "C (acetonelethanol - 2/1).- Anal.
(C19Hz4N60 ' 2 HCl).
4-[3-(7-Azubenzimiduzol-I-yl)propyl]- 1-(2-methoxyphenyl)piperuzine(9a)
4-[3-(4-Azabenzotriuzol1-yl)propyl]-l-(2-methoxyphenyl)piperuzine
(12c)
4-[3-(7-Azuindol-I
-yl)propyl]-l-(2-methoxyphenyl)piperuzine(8)
Yield 61%. Yellow oil. Reaction time 3 h. Rf0.62 (SiOz, CHCWMeOH 9/1).- 'H NMR (200 MHz): 6 = 2.05-2.25 (m, 2H, CHZCH~CHZ),
2.35-2.45
(m, 2H, CH2-piperazine), 2.6-2.7 (m, 4H, piperazine 2 CH2), 3.0-3.15 (m,
4H, piperazine 2 CHz), 3.85 (s, 3H, OCH3), 4.42 (t, J = 6.7 Hz, 2H, CH2azabenzimidazole), 6.8-7.0(m,4H, aromaticH),7.24(dd,J= 8.0and4.8 Hz,
IH, heteroaromatic 5-H), 8.08 (dd, J = 8.0 and 1.4 Hz, 1H, heteroaromatic
4-H), 8.12 (s, IH, heteroaromatic 2-H), 8.41 (dd, J = 4.8 and 1.4 Hz, 1H,
heteroaromatic 6-H).- 9a (HCI salt): M.p. 163-165 "C (acetone/ethanol
l/l).- Anal. (CzoHzsNsO~3HC1 . 1.5H20).
-
4-[3-(4-Azubenzimiduzol-l
-yl)prop)~l]-l-(2-methoxyphenyl)piperuzine
(9b)
Yield 24%. Yellow oil. Reaction time 3 h. Rf0.47 (SiOz, CHCI?/MeOH 9/l).- 'H NMR (200 MHz): 6 = 2.0-2.15 (m, 2H, CH~CH~CHZ),
2.25-2.4
(m, 2H, CHz-piperazine), 2.55-2.65 (m, 4H, piperazine 2 CH2), 3.0-3.15 (m,
4H, piperazine 2 CH2), 3.86 (s, 3H, OCH3), 4.34 (t, J = 6.5 Hz, 2H, CHzazabenzimidazole), 6.85-7.05 (m, 4H, aromatic H), 7.22 (dd, J = 8.1 and 4.8
Hz, lH, heteroaromatic6-H),7.81 (dd,J= 8.1 and 1.4Hz, IH, heteroaromatic
7-H), 8.18 (s, 1H, heteroaromatic 2-H), 8.56 (dd, J = 4.7 and 1.4 Hz, IH,
heteroaromatic 5-H).- 9b (HCI salt): M.p. 230-232 "C (acetone/ethanol
1/1).- Anal. (CzoHz5N50 . 3HC1 0.5Hz0).
-
Arch Phuim. Phunn. Med. Chem.329,451456(1996)
Yield 18%. M.p. 103-105 "C (AcOEdn-hexane- U I ) . Reaction time 3 h.
Rf0.27 (AlzO?, AcOEt/n-hexane- l/l).-'HNMR (200MHz): 6=2.15-2.45
(cluster, 4H, 2 CHz), 2.5-2.65 (m, 4H, piperazine 2 CHz), 2.95-3. I (m, 4H,
piperazine 2 CHz), 3.85 (s, 3H, OCH3), 4.79 (t, J = 6.6 Hz, 2H, CHz-azabenzotriazole), 6.8-7.0 (m, 4H, aromatic H), 7.43 (dd, J = 8.3 and 4.4 Hz, 1H,
heteroaromatic 6-H), 8.07 (d, J = 8.4, 1H, heteroaromatic 7-H), 8.75 (dd, J
= 4.3 and 1.2 Hz, 1H, heteroaromatic 5-H).- 13CNMR (125 MHz): 6 = 26.73
(chain C-2), 46.34 (chain C-3), 50.53 (piperazine C-3 and C-5), 53.17
(piperazineC-2andC-6),54.38 (chainC-l),55.31 (OCH3), 11 1.20(aromatic
C-6), 118.06 (aromatic C-3), 118.66 (heteroaromatic C-6), 120.92 (aromatic
C-4), 121.73 (heteroaromatic C -7), 122.95 (aromatic C-S), 125.58 (heteroaromatic C-7a), 141.09 (aromatic C-I), 148.07 (heteroaromatic C-5),
152.19 (aromatic C-2), 157.41 (heteroaromatic C-3a).- 12c (HCI salt): M.p.
216-218 "C (acetone/ethanol - 2/l).- Anal. (C19Hz4N60'2HCl . 0.5HzO).
4-/3-(9-Purinyl)prupyll-I
-(2-methoqphenyl)piperazine(13a)
Yield 60%. Yellow oil. Reaction time 4 h. Rf0.48 (SiO2, CHC13/MeOH l9/l).- 'H NMR(200 Hz): 6 = 2.1-2.25 (m, 2H, CHKHzCHz), 2.35-2.45
(m, 2H, CH2-piperazine), 2.55-2.70 (m, 4H, piperazine 2 CHz), 3.0-3.15 (m,
4H, piperazine 2 CHz), 3.86 (s, 3H, OCH3), 4.43 (t, J = 6.6 Hz, 2H,
CHz-purine), 6.8-7.1 (m, 4H, aromatic H), 8.18 (s, IH, purine 8-H), 9.0 (s,
456
IH, purine 2-H), 9.15 (8, IH, purine 6-H).- 13a (HCI salt): M.p. 227-229 "C
(acetone/methanol - 2/1).- Anal. (C19H24N60. 3HCl . H20).
Mokrosz and co-workers
periods, amounted to 15 for each symptom/animal"21. Reserpine (1 mgkg,
s.c.) and the investigated compounds (ip)were administered at 18 h and 45
min before 8-OH-DPAT, respectively.
4-(3-(7-PurinylJprop~l]I - ( 2 - m e t h ~ ~ ~ ~ ~ ) h e n y l J p i ~(13b
~ e r n) r i n e
Yield 30%. Pale yellow oil. Reaction time 4 h. Rr 0.34 (SiOz,
CHCWMeOH - 9/1).- 'H NMR (200 MHr): 6 = 2.05-2.2 (m. 2H,
CH2CHCH2), 2.3-2.4 (m, 2H, CH2-piperazine), 2.5-2.7 (m, 4H, piperazine
2 CH2), 3.0-3.2 (m, 4H, piperahe 2 CH2), 3.86 (s, 3H, OCH3), 4.44 (t.
J = 6.4 Hz, 2H, CH2-purine), 6.8-7.1(m, 4H, aromatic H), 8.3 1 (s, 1H, purine
8-H), 9.05 (s, IH, purine 6-H), 9.15 (s, 1H, purine 2-H).- 13b (HCI salt):
M.p. 218-219 "C (acetone/methanol - 2/1).- Anal. (C19H24N60.3HC1).
General Procedure,fiw Preparcition ojCumpounds l l a and l l b
The mixture ofequimolar amount5 (3 mmol) of 1,2,3,4-tetrahydroisoquinoline and appropriate benzotriazolylpropyl bromide (10a or lob) with twofold excess of anhydrous K2CO3 in 30 ml of n-butanol was refluxed for 5 h
and left overnight at room temp. The inorganic precipitate was filtered off
and the filtrate was evaporated under reduced pressure. The residue was
purified by CC: l l a - Si02, CHCls; I l b -neutral A1203, AcOEt/n-hexane
- 1/2. Free bases were converted into hydrochloride salts (see above).
2-[3-(2-B~~nzotriaiolyl)propyl]1,2,3,4-tetrahydroisoquinoline
(1 1 a)
Yield 49%. Yellow oil. Rr 0.34 (SiOz, CHC13MeOH - 49/1).- 'H NMR
(60 MHz): 6 = 2.1-3.0 (cluster, SH, 4 CH2), 3.6 (s, 2H, THIQ 2-H), 4.8 (t, J
= 7Hz, 2H, CHr-benzotriazole). 7.05 (s, 4H, aromatic H), 7.2-7.5 (m, 2H,
benzotriazole 5- and 6-H). 7.8-8.05 (m, 2H, benzotriazole 4- and 7-H).- l l a
(HCI salt): M.p. 186-188 "C (acetone).- Anal. (CixHzoN4 HC1)
2 - ( 3 - ( l - B e n z o t r i a ~ o l y l ) ~ ~ r1,2,3,4-tetruh~droisoquinoline
~~p~l](1lbJ
Yield43F. Yellow oil. Rf0.74 (A1203, AcOEt/n-hexaue- 1/2),- 'H NMR
(60 MHz): 6 = 2.1-3.0 (cluster, 8H, 4 CHz), 3.55 (s, 2H, THIQ 2-H), 4.7 (t,
J = 7Hz, 2H. CHz-benzotriazole), 7.0-7.7 (cluster, 7H, aromatic H and
benzotriazole 5-, 6-, and 7-H), 7.9-8.2 (m, IH, benzotriazole 4-H).- l l b
(HC1 salt): M.p. 179-181 "C (acetone).- Anal. (CixHzoN4. HCI)
Radidigand Binding Studies
Lower Lip Retraction (LLR)
The LLR was assessed according to the method described by Berendsen
et al."41The rats were individually placed in cages (30 x 25 x 25 cm), having
been scored three times (at 15,30, and 45 min after 8-OH-DPAT administration) as follows: 0 = lower incisors not visible, 0.5 = partly visible, 1 =
completely visible. The maximum score, summed, amounted to 3 for each
rat. The investigated compounds were administered i.p. 30 min before
8-OH-DPAT (1 mgkg, i.p.). The induction of LLR by the studiedcompounds
given alone was tested in a separate experiment, and animals were scored 15,
30, and 45 min after the treatment.
References
Part 30: J. L. Mokrosz, M. J. MokrosL, B. Duszynska, A. DerenWesolek, A. Klodzinska, P. Kowalski, S. Charakchieva-Minol, E. Tatarczynska, T. Kowalska, 2. Majka, E. Chojnacka-Wbjcik, S. Misztal,
Phurmazie, in press.
R. Perrone, F. Berardi, M. Leopoldo, V. Tortorella, I / Farmaco 1995,
50,505-5 10.
A. Orjales, L. Alonso-Cires, L. Labeaga, R. Corcostegui, J. Med. Chem.
1995,38, 1273-1277.
W. Kuipers, I. van Wijngaarden, C. G. Kruse, M. ter Horst-van Amstel,
M. Th. M. Tulp, A. P. IJzerman, J. Med. Chem. 1995,38, 1942-1954.
B. J. van Steen, 1. van Wijngaarden, M. Th. M. Tulp, W. Soudijn,
J. Med. Chem. 1995,38,4303-4308.
P. Gaillard, P.-A. Carrupt, B. Testa, P. Schambel, J. Med. Chem. 1996,
39, 126-134.
J, L. Mokrosz, M. H. Paluchowska, A. Klodzinska, S. CharakcbievaMinol, E.Chojnacka-Wbjcik, Arch. Pharm. (Weinheim) 1995, 328,
770-774.
J. L. Mokrosz, M. H. Paluchowska, E. Chojnacka-Wbjcik, M. Filip,
S. Charakchieva-Minol, A. Deren-Wesolek, M. J. Mokrosz, J. Med.
Chem. 1994,37, 2754-2760.
The affinity of investigated compounds for 5-HTIA,S-HT~A,and CLI
receptors in vitro was assessed on the basis of their ability to displace
['H]-8-OH-DPA.T, l3H]-ketanserin, and [3H]-prazosin, respectively. Radioligand binding experiments were carried out in the rat brain using the tissues
from hippocampus for S-HTIAreceptors and cortex for both ~ - H T and
~A
cxi receptors according to the published procedure^"^"^'. Ki values were
determined from at least three competition binding experiments in which
10-14 drug concentrations, mn in triplicate, were used. Cheng and Prusuff
' 'I equation was used for Ki calculation.
M. H. Paluchowska, A. Deren-Wesolek, S. Charakchieva-Minol,
E. Chojnacka-Wbjcik, J. L. Mokrosz, Med. Chem. Res. 1995, 5, 479486.
In Vii~oStudies
J. Yamawaki, T. Ando, T. Hanafusa, Chem. Lett. 1981, 1143-1145.
The experiments were carried out on male Wistar rats (260-300 g). The
animals were kept at an ambient temperature of 20 k 1 "C during the experiment, and had free access to food (standard laboratory pellets, LSM) and tap
water. All experiments were performed in the light phase on a natural
light-dark cycle (from September to February) between 9 a.m. and 2 p.m.
8 Hydroxy-2-(di-n-propylamino)tetralinhydrobromide (8-OH-DPAT, Rcsearch Biochemicals, Inc.) and the investigated salts of 3, 4a, 4b, 7, 8, and
9a were used in the form of freshly prepared aqueous solutions and were
administered in a volume of 2 ml/kg. The obtained data were analyzed by
Dunnett's test.
J. L. Mokrosz, A. Deren-Wesolek, E. Tatarczynska, B. Duszynska,
A. J. Bojarski, M. J. Mokrosz, E. Chojnacka-Wbjcik, J. Med. Chem.
1996,39, 1125-1 129.
Behavioral Syndrome in Reserpinized Rats
The rats were individually placed in cages (30 x 25 x 25 cm) 5 min before
the injection of 8-OH-DPAT ( 5 mg/kg, i.p.). Observation sessions, lasting
45 5 each, began 3 min after 8-OH-DPAT administration and were repeated
every 3 min. Reciprocal forepaw treading and flat body posture were scored
using a ranked intensity scale, where 0 = absent, 1 =equivocal, 2 =present,
and 3 = intcnsc. The maximum score, summed up over five observation
E. Przegalinski, M. Filip, M. Bijak, K. Wgdzony, B. Budziszewska,
K. Tokarski, M. Mackowiak, K. Fijak, Pol. J. Pharmacol. 1996, 48,
13-22.
M. D. Tricklebank, C. Forler, J. R. Fozard, Eur. J. Pharmucol. 1985,
106, 271-282.
H. M. G. Berendsen, C. L. E. Broekkamp, A. M. L. Van Delft, Eur. J.
Pharmacol. 1990, 1x7, 97-103.
P. Cassutti, A. Carugo, R. A. McArthur, Phurmacol. Rex 1995, 32
Suppl. 269.
A. J. Bojarski, M. T. Cegh, S. Charakchieva-Minol, M. J. Mokrosz,
M. Mackowiak, S. Misztal, J. L. Mokrosz, Pharmarie 1993, 48, 289295.
J. Ma;, V. Klimek, G. Nowak, Eur. J. Pharmacol. 1985,119,113-116.
Y.-C. Cheng, W. H. Prusoff, Biochem. Pharmacol. 1973,22,3099.
Received: August 12, 1996 [FP144]
Arch. P h u m P h u m Med. Chem. 329,451456 (1996)
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cns, ht1a, different, fragmenty, relationships, analogi, new, ligand, structure, part, heteroaromatic, atom, nitrogen, agenti, activity, number, 3022, receptov, studies
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