Synthesis and binding affinity of new pyrazole and isoxazole derivatives as potential atypical antipsychotics

Article abstract of DOI:10.1016/j.bmcl.2007.06.045

We describe the synthesis and binding affinities on D₂, 5-HT_2A and 5-HT_2C receptors of 6-aminomethyl-6,7-dihydro-1H-indazol-4(5H)-ones and 6-aminomethyl-6,7-dihydro-3-methyl-benzo[d]isoxazol-4(5H)-ones, as conformationally

Full text of DOI:10.1016/j.bmcl.2007.06.045

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4873–4877
Synthesis and binding affinity of new pyrazole
and isoxazole derivatives as potential atypical antipsychoticsq
a
a
a,
b
*
´
´
´
Marıa Barcelo, Enrique Ravina, Christian F. Masaguer, Eduardo Domınguez,
˜
b
b
b
´
´
Filipe Miguel Areias, Jose Brea and Marıa I. Loza
aDepartamento de Quı´mica Orga´nica, Laboratorio de Quı´mica Farmace´utica, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
bDepartamento de Farmacologı´a, Facultad de Farmacia, Universidad de Santiago de Compostela,
E-15782 Santiago de Compostela, Spain
Received 22 May 2007; revised 11 June 2007; accepted 12 June 2007
Available online 14 June 2007
Abstract—We describe the synthesis and binding affinities on D2, 5-HT2A and 5-HT2C receptors of 6-aminomethyl-6,7-dihydro-1
H-indazol-4(5H)-ones and 6-aminomethyl-6,7-dihydro-3-methyl-benzo[d]isoxazol-4(5H)-ones, as conformationally constrained
butyrophenone analogues. One of the new compounds showed good in vitro binding features, and a Meltzer’s ratio characteristic
of an atypical antipsychotic profile.
Ó 2007 Elsevier Ltd. All rights reserved.
CH3
Schizophrenia is a complex disorder affecting ca. 1% of
the population.1 The use of classical (typical) neurolep-
tics such as haloperidol (Fig. 1) for the treatment of this
disease is associated with severe mechanism-related side
effects, including induction of acute extrapyramidal
symptoms (EPS).2 Also, these compounds are ineffective
against the negative symptoms of schizophrenia. The
clinical efficacy of classical antipsychotics in the treat-
ment of schizophrenia and other psychotic disorders is
directly related to their ability to block dopamine D2
receptors in the brain.3 However, it has been reported
that the blockage of the dopamine receptor in the stria-
tum is closely associated with extrapyramidal side
effects.4
N
OH
N
O
N
Cl
N
Cl
N
H
F
Clozapine
Haloperidol
O
N
O
N
F
N
N
CH3
Risperidone
The introduction of clozapine (Fig. 1) for treatment-
resistant schizophrenia gave rise to a new group of atyp-
ical or nonclassical antipsychotics that have no EPS at
the doses frequently used in therapy, and are effective
also against the negative symptoms.5 Clozapine exhibits
Figure 1. Structures of some antipsychotics.
potent affinities at multiple receptors,6 its action at 5-HT
receptors is now thought to mediate its beneficial effects
on cognition, negative symptoms and the low incidence
of EPS,7 but it also displays affinity for dopamine recep-
tors, related to its efficacy on positive symptoms, as well
as a-adrenergic, muscarinic and histaminergic (H1)
receptors. Meltzer et al.8 related the special clinical pro-
file of clozapine and other atypical antipsychotics with
an empirical ratio, the so-called Meltzer Index, between
D2 and 5-HT2A receptors.9 They proposed that this ratio
Keywords: Pyrazole; Isoxazole; Butyrophenones; Antipsychotics;
Dopamine; Serotonin.
q
This is the 36th paper in the series ‘Synthesis and CNS Activity of
Conformationally Restricted Butyrophenones’; for preceding paper,
see Ref. 21.
*
Corresponding author. Tel.: +34 981 594 628; fax: +34 981 594
912; e-mail: qojcfm@usc.es
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.045

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M. Barcelo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4873–4877
4874
may be used to discriminate atypical antipsychotics
(ratio >1.12) from classical antipsychotics (<1.09).
Experimental and clinical studies seem to confirm the
major role of the 5-HT2A receptor for the atypical pro-
file of the antipsychotics.10 Additionally, many of the
hexane-1,3-dione 1 (Scheme 1) as a starting material,
which was prepared from the commercial 3,5-dime-
thoxy- (or 3,4,5-trimethoxy-) benzoic acid in a four-step
procedure, as previously described by our research
laboratory.18
atypical antipsychotic agents block not only 5-HT2A
but also other serotonin receptors, particularly 5-
,
The synthon 1 was condensed with N,N-dimethylform-
amide dimethylacetal (DMFDMA) to give amino
ketone 2 in 95% yield. On the other hand, 1 was con-
verted into 2-acetyl derivative 3 by treatment with acetic
anhydride and triethylamine in the presence of 4-(dim-
ethylamino)-pyridine (DMAP) in 69% yield. By a Mi-
chael addition–elimination/cyclodehydration process,
using hydrazine dihydrochloride and NaOH at reflux,
2 was transformed into pyrazole 4 in 70% yield, and
methylhydrazine at reflux afforded 5 as a single regio-
isomer, also in 70% yield. In the same way, condensation
of 3 with hydroxylamine hydrochloride in the presence
of KOH yielded 6 in 71%. Methyl ethers of 4 and 5 were
cleaved with BBr3 in CH2Cl2 at ꢀ40 °C ! rt, affording
the corresponding alcohols 7 and 8 in 81% and 40%
yield, respectively. Forcing these conditions (2 mol equiv
BBr3, higher temperatures, or longer reaction times) or
using other reagents, such as trimethylsilane iodide, gave
complex mixtures of products.
HT2C.
11 It has also been suggested that 5-HT2C receptor
blockade is responsible for reducing EPS.12 These find-
ings have made the 5-HT2C receptor a potential target
in the treatment of psychotic illnesses.13
Four decades after its introduction into the clinic, cloza-
pine remains the prototype of atypical antipsychotic
drugs, and no currently available agents appear to have
the spectrum of efficacy of this drug. However, treat-
ment with clozapine is associated with an increased risk
of agranulocytosis,14 which strongly limits its therapeu-
tic use. Hence, the discovery of a more-effective, side-ef-
fects free therapy for the treatment of schizophrenia
remains a challenging research goal.
Over the last few years, we have been working on the
modulation of the butyrophenone system, with the aim
of combining the antagonism at the 5-HT2 family and
the D2 receptors in a single molecule.15 We have
reported the synthesis, pharmacology and molecular
modelling of the ‘aminobutyrophenones’ (substructure
marked bold) called QF0408B, QF0409B, QF1003B
and QF1004B (Fig. 2), which show high affinity for
the 5-HT2A receptor subtype, with pKi values of 8.06,
8.37, 7.29 and 7.97, respectively.16 As part of our ongo-
ing work on the development of strategies for the prep-
aration of new atypical antipsychotics, we explored the
possibility of synthesizing analogues of the above-men-
tioned aminobutyrophenones, in which the furan or pyr-
role ring of these compounds was replaced by pyrazole
and isoxazole, to form a tetrahydro-indazolone or -ben-
zisoxazolone system, respectively, considering that the
substitution of –CH@ by –N@ in aromatic rings has
been one of the most-successful applications of classical
isosterism.17 In this paper, we report the synthesis of two
new series of conformationally constrained aminobutyr-
ophenones, and the evaluation of their affinity on sev-
eral dopamine and serotonin receptors.
Similarly, methylether cleavage of benzisoxazolone 6
with BBr3 led to alcohol 9 in a modest 30% yield. The
addition of 15-crown-5 to BBr3 allowed us to improve
the yield up to 56%.
Tosylation of 7 was complicated due to the reaction
between the unprotected nitrogen of the pyrazole ring
and the tosyl chloride: first attempts for tosylation of
the hydroxyl group led to a mixture of chloride 10,
monotosylate 11 and ditosylate 12. Then, we decided
to increase the number of equivalents of tosyl chloride
to force the formation of ditosyl derivative 12, to further
deprotect the pyrazole ring; under these conditions,
ditosylate 12 was obtained in 50% yield as the only
product. Tosylation of alcohols 8 and 9 under standard
conditions furnished the corresponding sulfonates 13
and 14 in 71% and 61% yield, respectively. Tosylates
12–14 were converted into the required amines 15–17
by nucleophilic displacement of the tosyl group by the
corresponding substituted piperidines a or b (Scheme
1). Yields and conditions of the synthesized piperidine
derivatives are collected in Table 1.19 Nucleophilic
substitution reaction of ditosylate 12 by piperazines pro-
ceeded with simultaneous attack at the electron-deficient
sulfur atom of the N-tosylpyrazole, which resulted in
deprotection of the pyrazole ring, affording the desired
amines 15a and 15b in a single step. Deprotection of
N-tosylpyrazoles with hydrazine has been reported,20
but this is, to our knowledge, the first example of this
cleavage with a secondary amine.
For the synthesis of the indazolones 15 and 16, and ben-
zisoxazolones 17 we have used 5-(methoxymethyl)cyclo-
O
O
O
N
O
N
N
N
N
F
F
H
H
QF0409B
QF0408B
pKi = 8.37 (5-HT2A), 7.04 (D2)
pKi = 8.06 (5-HT2A), 6.20 (D2)
O
O
O
N
O
The affinity of the compounds 15–17 for cloned human
D2, 5-HT2A and 5-HT2C receptors was evaluated in
in vitro binding assays using the radioligands [3H]spipe-
rone, [3H]ketanserin and [3H]mesulergine, respectively,
according to our previously described procedures.21 Ki
values (expressed as pKi) were calculated according to
N
N
O
O
F
F
QF1004B
pKi = 7.97 (5-HT2A), 8.02 (D2)
QF1003B
pKi = 7.29 (5-HT2A), 7.02 (D2)
Figure 2. Structures of some heterocyclic aminobutyrophenones.

´
M. Barcelo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4873–4877
4875
O
O
O
O
c)
a)
h)
N
N
f)
N
H3CO
H3CO
RO
R
N
H
N
O
O
R1
1
2
4: R = CH3
7: R = H
10: R1 = Ts, R = Cl
11: R1 = H, R = OTs
12: R1 = Ts, R = OTs
c)
b)
O
O
i)
O
O
i)
N
RO
H3CO
O
N
N
O
RRN
CH3
N
3
N
CH3
5: R = CH3
8: R = H
RRN
N
16a-b
f)
H
d)
h)
15a-b
13: R = Ts
O
CH3
N
NRR
O
CH3
N
i)
RO
O
O
N
O
RRN
6: R = CH3
9: R = H
O
g)
h)
N
N
F
F
17a-b
a
b
14: R = Ts
Scheme 1. Reagents and conditions: (a) DMFDMA, THF, 80 °C, 3 h, 95%; (b) Ac2O, Et3N, DMAP, CHCl3, rt, 24 h, 69%; (c) NH2NH2Æ2HCl,
NaOH, MeOH, 80 °C, 4 h, 70%; (d) NH2NHCH3, MeOH, 80 °C, 2.5 h, 70%; (e) NH2OHÆHCl, KOH, MeOH, C6H6, rt, 48 h, 71%; (f) BBr3, CH2Cl2,
ꢀ40 °C ! rt, 24 h, 40–81%; (g) BBr3, 15-crown-5, CH2Cl2, ꢀ30 °C, 4 h, 56%; (h) TsCl, Py, rt, 24 h, 50–71%; (i) HNRR, solvent, reflux (see Table 1).
Table 1. Conditions and yields of synthesized compounds 15–17
Compound
Solvent
Time (h)
Yielda (%)
Microanalysis
Mp (°C)
15a
15b
16a
16b
17a
17b
CH3CN
CH3CN
CH3CN
C6H6
24
72
96
19
31
24
24
44
27
47
50
50
C20H22FN3O2Æ2HClÆ0.5H2O
C20H21FN4O2Æ2HClÆ2.9H2O
C21H24FN3O2
220–223
204–207
169–170
220–221
129–130
212–215
C21H23FN4O2ÆHCl
C21H23FN2O3Æ0.1H2O
C21H22FN3O3ÆHClÆ0.35H2O
CH3CN
CH3CN
a Yields after purification by column chromatography.
Table 2. Binding affinities for compounds 15a,b–17a,b (see Scheme 1) and reference antipsychotics
Compound
pKia
pKi ratio
5-HT2A
5-HT2C
D2
5-HT2A/D2
15a (QF4104B)
15b (QF4108B)
16a (QF4124B)
16b (QF4128B)
17a (QF4214B)
17b (QF4218B)
QF0409Bb
7.37 0.22
8.67 0.19
7.52 0.16
7.76 0.44
7.39 0.12
7.76 0.32
8.37 0.80
7.97 0.03
6.78 0.25
8.04 0.31
9.30 0.25
<5
6.40 0.15
6.95 0.06
<5
1.15
1.25
—
6.91 0.16
6.96 0.18
6.15 0.30
<5
<5
<5
—
—
6.13 0.27
6.42 0.02
6.47 0.26
5.14 0.18
7.98 0.11
8.13 0.16
6.92 0.30
7.04 0.07
8.02 0.11
9.22 0.12
6.65 0.17
8.21c
1.12
1.19
0.99
0.73
1.21
1.13
QF1004Bb
Haloperidol
Clozapine
Risperidone
a Values are means of two separate experiments.
b Data from Ref. 16.
c Value taken from Ref. 23.
the Cheng–Prusoff equation,22 and the in vitro receptor
binding data are summarized in Table 2.
(15a) and 8.67 (15b)] than for the serotonin 5-HT2C or
dopamine D2 receptors. Also, those compounds bearing
a 6-fluorobenzisoxazolylpiperidine moiety (amine b)
showed higher affinities for the 5-HT2A receptor than
All compounds displayed higher affinity for the seroto-
nin 5-HT2A receptor [pKi values ranging between 7.37
those with
a
4-fluorobenzoylpiperidine fragment

´
M. Barcelo et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4873–4877
4876
(amine a). Compounds 15a, 15b and 17b expressed a
modest affinity for the dopamine D2 receptors compared
to haloperidol or risperidone, but similar to that of clo-
zapine. Compounds 16a, 16b and 17a are not considered
as potential antipsychotics because of their low affinity
to D2 receptors, although 17a could have an interesting
profile as selective 5-HT2A compound (pKi = 7.39,
Ki = 40.7 nM). At the 5-HT2C receptor, compounds
15b, 16a, 16b and 17b showed pKi values ranging be-
tween 6.13 and 6.96, whereas compounds 15a and 17a
were inactive. The highest affinity compound was 15b
(QF4108B), with high affinity at the 5-HT2A receptors
(pKi = 8.67, Ki = 2.1 nM), and moderate affinity for
5-HT2C and D2 receptors (both pKis’ values around
6.9). This behaviour could be attributed to the presence
of an NH group in compound 15b (and not in com-
pounds 16 or 17), which could establish an additional
interaction with an acceptor group in the D2 receptor
binding site. On the basis of the 5-HT2A/D2 antagonism
hypothesis, it is also worth mentioning the indazolone
15b as a potential atypical antipsychotic, with a Melt-
zer’s ratio of 1.25, higher than 1.12, the value from
which Meltzer predicts an atypical profile for
antipsychotics.8
pound should be below a certain limit. Two differing
limits have been proposed: van de Waterbeemd et al.24
2
suggest a limit of 90 A , whereas Kelder et al. have a
25
˚
2
lower limit of 60–70 A . The value of polar surface area
˚
2
(75.2 A ) indicates that compound 15b could penetrate
˚
the BBB. Lipophilicity (ClogP) correlates positively
with BBB penetration, and the mean value for ClogP
for the marketed CNS drugs is 2.5,26 which is in good
agreement with the range found by Hansch et al.27
The ClogP value of indazolone 15b was calculated as
2.49, which also indicates that this compound has poten-
tial to penetrate the BBB. With regard to molecular vol-
ume, for compound 15b there are no significant
differences with those of haloperidol, risperidone or
clozapine.
Several computational methods have been employed for
the prediction of BBB-penetrating and nonpenetrating
compounds with overall accuracies from 75% to
97%.28 QSAR models for brain permeation are based
on the log of the blood–brain barrier coefficient
(logBB). To assess whether our compounds are likely
to permeate BBB, we calculated the logBB value for
compound 15b using a software program based on topo-
logical descriptors29 and compared it to the values
obtained for the selection of antipsychotics (see Table
3). Experimental values of logBB published cover the
range from about ꢀ2.00 to +1.04. Within this range,
compounds with logBB > 0.30 cross the BBB readily,
while compounds with a logBB < ꢀ1.00 are poorly dis-
tributed to the brain.30 For compound 15b, the
logBB = ꢀ0.22, not too far from that of risperidone
(logBB = ꢀ0.13), seems to indicate a medium BBB
penetration.
In comparison with its benzisoxazolylpiperidine ana-
logues QF0409B and QF1004B (Fig. 2), aminobutyr-
ophenone compound 15b exhibits similar affinities for
the 5-HT2A, 5-HT2C and D2 receptors to those of indo-
lone derivative QF0409B, but a lower affinity for the D2
receptors compared to QF1004B (one order of magni-
tude), which causes a more favourable 5-HT2A/D2 pKi
ratio in 15b. Again, a favourable interaction between
N–H (in the pyrrole or the pyrazole ring) and the recep-
tors could be the cause of the similar binding profile of
15b and QF0409B.
In summary, new conformationally constrained butyro-
phenone analogues in the pyrazole and isoxazole series
have been synthesized, and their binding affinities were
determined. From these data compound 15b has
emerged, which showed the higher affinities for D2,
5-HT2A and 5-HT2C receptors between the new
compounds, and a Meltzer’s ratio characteristic of an
atypical antipsychotic profile. Moreover, different
For antipsychotics, like the great majority of drugs
aimed at CNS targets, the blood–brain barrier (BBB)
must be crossed for a therapeutic effect to be exerted.
The most important molecular descriptors used to pre-
dict BBB penetration are polar surface area (PSA), logP
and the molecular volume. Therefore, we calculated
PSA, ClogP and molecular volume values for com-
pound 15b using different software programs and com-
pared them to the values obtained for reference
antipsychotics (see Table 3).
molecular descriptors and
a prediction program
suggested that this compound has the potential to
penetrate the blood–brain barrier.
For good brain permeation, the PSA—a measure of a
molecule’s hydrogen-bonding capacity—of the com-
Acknowledgment
This work was supported by Spanish Ministerio de
´
and SAF2005-08025-C03) and Xunta de Galicia (Grants
PGIDIT06PXIC203104PN and PGIDIT06 PXIC
203051PN). A Ph.D. fellowship (FPU) has been granted
Educacion
y
Ciencia (Grants SAF2005-08025-C01
Table 3. Calculated polar surface areas (PSA), ClogP values and
volumes for compound 15b and reference antipsychotics
2
3
˚
˚
Compound
PSAa (A ) ClogPb Volumea (A ) logBBc
´ ´
to M. Barcelo by the Ministerio de Educacion y Ciencia.
15b
75.02
2.49
4.63
3.37
3.21
323.968
336.979
374.488
292.303
ꢀ0.22
0.31
Haloperidol 40.54
Risperidone 64.17
ꢀ0.13
0.21
Clozapine
35.16
References and notes
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19. Data for selected compounds: Compound 15a: IR: 1667.
1H NMR (CDCl3, 300 MHz): d 7.98 (s, 1H); 7.97 (dd,
J = 8.9, 5.4 Hz, 2H); 7.14 (t, J = 17.2, 8.6 Hz, 2H); 3.20–
3.11 (m, 2H); 2.99–2.85 (m, 2H); 2.68–2.54 (m, 3H); 2.46–
2.04 (m, 5H); 1.87–1.78 (m, 4H). MS (EI): m/z 355 (M+).
Compound 15b: IR: 1665, 1616. 1H NMR (CDCl3,
300 MHz): d 8.00 (s, 1H); 7.68 (dd, J = 8.7, 5.1 Hz, 1H);
7.23 (dd, J = 8.5, 2.1 Hz, 1H); 7.06 (dt, J = 8.8, 2.0 Hz,
1H); 3.18–2.94 (m, 5H); 2.73–2.11 (m, 7H); 2.09–2.02 (m,
4H). MS (EI): m/z 368 (M+).
Compound 16a: IR: 1666. 1H NMR (CDCl3, 300 MHz): d
7.97 (dd, J = 8.8, 5.4 Hz, 2H); 7.84 (s, 1H); 7.14 (t,
J = 8.6 Hz, 2H); 3.83 (s, 3H); 3.22–3.10 (m, 2H); 3.06–2.97
(m, 2H); 2.89–2.86 (m, 1H); 2.63–2.35 (m, 4H); 2.28–2.04
(m, 1H); 1.89–1.80 (m, 2H). MS (CI): m/z 370 (100).
Compound 16b: IR: 1662, 1613. 1H NMR (CDCl3,
300 MHz): d 7.85 (s, 1H); 7.67 (dd, J = 8.7, 5.1 Hz, 1H);
7.25–7.22 (m, 1H); 7.06 (dt, J = 8.8, 2.1 Hz, 1H); 3.84 (s,
3H); 3.09–2.93 (m, 5H); 2.65–2.40 (m, 3H); 2.30–2.22 (m,
4H); 2.18–2.06 (m, 4H). MS (EI): m/z 382 (M+).
Compound 17a: IR: 1682. 1H NMR (CDCl3, 300 MHz): d
7.96 (dd, J = 8.8, 5.5 Hz, 2H); 7.14 (t, J = 8.5 Hz, 2H);
3.25–3.15 (m, 2H); 2.96–2.85 (m, 2H); 2.76–2.61 (m, 3H);
2.46 (s, 3H); 2.40 (d, J = 6.6 Hz, 1H); 2.33–2.06 (m, 4H);
1.85–1.83 (m, 4H). MS (EI): m/z 370 (M+).
Compound 17b: IR: 1683, 1610. 1H NMR (CDCl3,
300 MHz): d 7.67 (dd, J = 8.7, 5.1 Hz, 1H); 7.23 (dd,
J = 8.5, 2.1 Hz, 1H); 7.05 (dt, J = 8.8, 2.1 Hz, 1H); 3.20
(dd, J = 17.3, 4.6 Hz, 1H); 3.08–2.92 (m, 3H); 2.77–2.61
(m, 3H); 2.45 (s, 3H); 2.45–2.42 (m, 1H); 2.34–2.13 (m,
4H); 2.09–2.00 (m, 4H). MS (EI): m/z 383 (M+).
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