7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics

Article abstract of DOI:10.1021/jm950894b

Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4- oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1- piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.

Full text of DOI:10.1021/jm950894b

2962
J . Med. Chem. 1996, 39, 2962-2970
7-[3-(1-P ip er id in yl)p r op oxy]ch r om en on es a s P oten tia l Atyp ica l An tip sych otics
J ordi Bolo´s,*,† Santiago Gubert,† Llu´ıs Anglada,† J osep M. Planas,‡ Carme Burgarolas,† J osep M. Castello´,
Aurelio Sacrista´n, and J ose´ A. Ortiz
Centro de Investigacio´n Grupo Ferrer, J uan de Sada, 32, 08028-Barcelona, Spain
Received December 7, 1995X
Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic in-
termediate identified as a potential atypical antipsychotic, was selected as the starting point
for pharmacological improvement. From 1, sequential structural variations were conducted
in order to improve its potency and oral bioavailability. These variations included a series of
piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some
orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity
in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further
optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chrome-
nones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher
than required for inhibition of climbing suggest an atypical antipsychotic profile, which is
assumed to predict a reduced induction of extrapyramidal side effects in humans.
Ch a r t 1. Some Atypical Antipsychotics
In tr od u ction
CH3
For many years, treatment of schizophrenia and
psychoses has relied on conventional neuroleptics, such
as chlorpromazine, fluphenazine, and haloperidol. How-
ever, their application is limited by the frequent ap-
pearance of adverse neurological effects,1 mainly invol-
untary movement disorders and extrapyramidal side
effects. For some time, these side effects have been
regarded as inherent to the same mechanism of action
of the antipsychotic drugs. Thus, the term neuroleptic
(that is a drug producing neurological side effects) was
considered a synonym of antipsychotic drug. Neverthe-
less, the efforts to discover more effective antipsychotic
medications introduced some compounds characterized
by minimal induction of extrapyramidal effects. Cloza-
pine2 (Chart 1) was the prototype of these new drugs,
which were classified as “atypical antipsychotics”. This
compound proved to be effective in the treatment of
psychoses without essentially any tendency to produce
extrapyramidal side effects. Unfortunately, clozapine
is not devoid of other severe undesirable effects,3 such
as agranulocytosis and seizures in a significant number
of cases. For this reason, its use has been restricted to
a small population of closely monitored patients, who
have been resistant to other drugs. In the recent years
several potential atypical antipsychotics have been
developed, among them, remoxipride4 and risperidone5
have been launched; however, remoxipride was with-
drawn from the market in 1993 due to some cases of
induction of aplastic anemia.6 Thus, the discovery of
novel atypical antipsychotics as safe substitutes for
clozapine still remains a primary goal in the research
for the therapy of schizophrenia.
N
N
O
C
C2H5
N
CH3O
N
H
Cl
NH
N
OCH3
H
Br
N
clozapine
remoxipride
CH3
N
N
O
N
F
O
risperidone
CH3
N
N
O
F
1
affinities for D2 receptors.8 On the other hand, the
extrapyramidal effects have been attributed to dopa-
mine antagonism at nigrostriatal regions.9 However,
at present, although several models have been proposed,
there is not a theory that satisfactorily explains the
atypical antipsychotic profile. Selective binding to
certain subtypes of dopaminergic receptors,10 preferen-
tial 5-HT2 in relation to D2 antagonism,11 σ receptor
blockade,12 and neurotensin agonism13 are among the
proposed theories to account for their mechanism of
action. In animal models, it is widely accepted that
atypical antipsychotics are identified by inhibition of
apomorphine-induced stereotyped behavior (character-
istic of dopamine antagonism at nigrostriatal system)
at doses significantly higher than those required for
inhibition of apomorphine-induced climbing response
(indicative of antagonism in the mesolimbic dopamine
system).14
The most accepted model to explain the biochemical
basis of schizophrenia postulates that dopaminergic
activity is increased in the mesolimbic system of the
brain.7 In accordance with this, the pharmacological
potencies of classical antipsychotics correlate with their
* Author to whom correspondence should be addressed.
† Department of Medicinal Chemistry.
‡ Department of Pharmacology.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
S0022-2623(95)00894-6 CCC: $12.00 © 1996 American Chemical Society

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2963
Ta ble 1. Physicochemical Data of Compounds 1-34
Y
CH3
Y
Y
CH3
N
N
CH3
N
X
N
X
N
X
R
R
R
F
F
I
II
III
Y
N
O
O
O
R
F
R′
IV
structure
type
compd
X
Y
R
R′
methoda yield, %
mp, °C (cryst solvent)
formulab
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
I
II
II
II
II
II
II
III
III
III
III
III
III
III
IV
III
III
III
IV
IV
IV
IV
IV
IV
IV
IV
IV
CdO
CHOH
CdO
CHOH
CdO
CHOH
CdO
CHOH
CdO
CHOH
CdO
CHOH
O
CH(4-FC6H4)
CO(4-FC6H4)
CH2
CH2
CH2
CH2
CdO
CdO
SO2
H
B
C
B
C
A
C
B
C
B
C
B
C
A
A
B
C
B
C
A
A
A
A
A
C
A
A
A
A
A
A
A
A
A
A
72
33
55
67
59
72
83
60
54
74
83
88
67
69
86
66
44
66
36
39
41
30
42
77
49
38
77
41
53
50
59
38
39
22
207-209 (iPrOH)
189-192 (iPrOH)
210-212 (EtOH)
205-207 (iPrOH)
131-133 (iPrOH)
C22H27FN2O‚2HCl
C22H29FN2O‚2HCl
C22H26F2N2O‚2HCl
C22H28F2N2O‚2HCl
H
F
F
F
F
CH3
CH3
H
H
F
F
F
F
H
H
F
F
F
F
F
C22H24F2N2O2‚HCl
153-156 (iPrOH-Et2O) C22H26F2N2O2‚HCl
148-149 (iPrOH-Et2O) C22H27FN2O3S‚HCl
SO2
141-143 (EtOH)
212-215 (iPrOH)
208-209 (iPrOH)
227-229 (EtOH)
219-222 (EtOH)
237-239 (EtOH)
204-206 (EtOH)
182-184 (EtOH-Et2O)
186-188 (EtOH-Et2O)
170-172 (EtOH-iPrOH) C22H25F2NO‚HCl
188-190 (EtOH-iPrOH) C22H27F2NO‚HCl
144-147 (EtOH-iPrOH) C21H25F2NO‚HCl
98-100 (iPrOH-Et2O) C28H30F3N‚HCl
192-194 (EtOH-Et2O)
78-80 (EtOH-Et2O)
190-192d (EtOH-Et2O)
116-117 (iPrOH-Et2O) C21H25F2NO2
109-111 (acet-Et2O)
236-238 (iPrOH)
251-253 (MeOH-Et2O) C25H26FNO4‚HCl
248-250 (MeOH-Et2O) C25H23F4NO4‚HCl
259-262 (MeOH-Et2O) C30H28FNO4‚HCl
224-227 (MeOH-Et2O) C25H26FNO4‚HCl
173-176 (MeOH-Et2O) C26H28FNO4‚HCl
217-218 (MeOH-Et2O) C25H26FNO5‚HCl
240-243 (MeOH-Et2O) C24H23ClFNO4‚HCl
234-237 (MeOH-Et2O) C24H23F2NO4‚HCl
C22H29FN2O3S‚HCl
C21H27FN2O‚2HCl
C21H29FN2O‚2HCl
C21H26F2N2O‚2HCl
C21H28F2N2O‚2HCl
C20H26F2N2O‚2HCl
C27H31F3N2‚2HCl
C22H26FNO‚HCl
CH2
CH2
CH2
CH2
CH2
CH2
CH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
CHOH(4FC6H4) CH2
CO(4-FC6H4) CH2
CHOH(4FC6H4) CH2
O(4-FC6H4)
CH(4-FC6H4)2
CH2-DOADc
C22H28FNO‚HCl
CH2
CH2
CH2
CH2
CdO
CHOH
CH(OCH3)
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
CdO
C25H35FN2O2‚HCl
C24H26FNO3‚HCl
H
F
F
F
H
O(4-FC6H4)
O(4-FC6H4)
O(4-FC6H4)
C22H27F2NO2‚HCl
24H24FNO4‚HCl
H
H
H
H
H
C
CH3
CF3
C6H5
H
H
H
CH3
CH2CH3
CH2OH
Cl
F
H
H
a
b
See the Experimental Section for details. All compounds gave satisfactory elemental analyses ((0.4%) for C, H, N, and Cl. c DOAD
) 7,9-dioxo-8-azaspiro[4.5]decan-8-yl. Lit.18 mp 186-188.5 (iPrOH).
d
Ch em istr y
As a part of a research program aimed at the
discovery of novel antipsychotic drugs, from a prelimi-
nary screening process, we had selected compound 1 as
a structural starting point. This compound, formerly
obtained as a synthetic intermediate in the preparation
of other antipsychotic entities,15 was found to possess a
potentially atypical antipsychotic profile, showing a
difference between doses for inhibition of apomorphine-
induced climbing and for inhibition of stereotypies.
Unfortunately, it displayed only moderate intraperito-
neal activity and was not active on oral administration.
This fact encouraged us to explore several structural
variants of 1 that could give rise to novel therapeutically
useful antipsychotics. We report here the results in our
efforts in the chemical improvement of this structure,
which have led to the discovery of new potent and orally
active atypical antipsychotic compounds.
The target compounds 1-34 (see Table 1) were
prepared by alkylation of the corresponding secondary
amines (piperazines, piperidines or ethanediamines)
with the appropriate chlorides in the presence of potas-
sium iodide (method A), as indicated in Scheme 1.
Similarly, introduction of the butyrophenone moiety was
accomplished by alkylation with the protected chlo-
roketal, followed by acidic hydrolysis of the crude
product (method B). The corresponding phenylbutanols
were prepared by sodium borohydride reduction of
butyrophenones (method C).
The required N-benzylpiperazine precursors 35 and
36 (Scheme 2) were obtained by selective monoalkyla-
tion of 2-methylpiperazine at the less hindered position
in a variant of the method reported for 1-benzyl-3-
methylpiperazine (35).16 Similarly, N,N′-dimethyl-

2964 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Bolo´s et al.
Sch em e 4.a Synthesis of Piperidine Precursors
Sch em e 1.a Synthesis of Target Compounds
Method A
O
C
O
C
i
R
R
F
N
CH3
F
CH2
N H
i
N
H + Cl
X
N
X
41
R′
ii
R′
Method B
R
O
C
O
O
i
F
N
H
N
H + Cl
R′
42
F
iii
R
O
O
O
R
O
C
O
R
ii
N
N
iv
F
N
COO
t
Bu
R′
F
CH
N R′
R′
F
F
43
44: R = H; R′ = COO-t-Bu
v
iii
Method C
R
45: R = CH3; R′ = COO-t-Bu
46: R = CH3; R′ = H
vi
OH
N
a
R′
Reagents: (i) (1) NH2NH2, EtOH; (2) NaOH, diglyme; (ii) 6 M
HCl; (iii) (t-BuOCO)2O, Et3N, THF; (iv) NaBH4, EtOH; (v) (1) CH3I,
NaH, THF; (2) 4 M HCl, EtOH.
F
a
Reagents and conditions: (i) K2CO3, CH3CN, reflux; (ii) 6 M
HCl, 70 °C; (iii) NaBH4, EtOH, room temperature.
Piperidines were either commercial or easily synthe-
sized from the common intermediate N-acetyl-4-(4-
fluorobenzoyl)piperidine18 (see Scheme 4). Simulta-
neous amide hydrolysis and ketone reduction under
Wolff-Kishner conditions afforded 4-(4-fluorobenzyl)-
piperidine (41).19 On the other hand, amide hydrolysis
under acidic conditions provided 4-(4-fluorobenzoyl)-
piperidine (42).18 Alternatively, compound 42 was
protected as the N-tert-butoxycarbonyl derivative (43),
reduced to alcohol 44, O-alkylated with methyl iodide,
and deprotected to yield the 4-(methoxymethyl)piperi-
dine 46. The smoothly removable tert-butoxycarbonyl
protecting group avoided methanol elimination during
hydrolysis.
Sch em e 2.a Synthesis of Piperazine Precursors
CH3
CH3
i
+
HN
NH
HN
N
Y
R
Cl
Y
R
35: Y = CH2; R = H
36: Y = CH2; R = F
39: Y = CO; R = F
40: Y = SO2; R = CH3
a
Reagents: (i) NaHCO3, EtOH or H2O-acetone.
Sch em e 3.a Synthesis of Ethanediamine Precursors
NH
CH3
i
+
CH3 NH
Cl
CH2
R
Most alkylating reagents were commercially avail-
able. The (3-chloropropoxy)chromenones (see Table 2)
were prepared from the adequate 2,4-dihydroxyphenyl
ketones through two different sequences, as shown in
Scheme 5.
CH3
N
CH3 NH
CH2
R
37: R = H
38: R = F
Conversion of 2,4-dihydroxyphenyl ketones into the
corresponding 7-hydroxychromenones was effected ac-
cording to published procedures for some of the simpler
analogues. Thus, 7-hydroxy-2-(trifluoromethyl)chromen-
4-one (47) was prepared by the Kostanecki-Robinson
procedure, by heating 2′,4′-dihydroxyacetophenone with
trifluoroacetic anhydride and sodium trifluoroacetate
a
Reagents: NaHCO3, EtOH.
ethanediamine was monoalkylated with the appropriate
benzyl chlorides to afford 3717 and 38 (Scheme 3). In a
related procedure, monoacylation of 2-methylpiperazine
with the corresponding acid chlorides afforded benza-
mide 39 and sulfonamide 40.
Ta ble 2. Physicochemical Data for Novel Chromen-4-ones
compd
R
R′
R′′
method
yield, %
mp, °C
formulaa
47
50
51
54
55
56
57
58
59
60
61
62
63
CF3
H
H
H
H
H
H
D
E
E
c
F
F
F
F
F
G
G
c
68
88
23
70
85
69
96
63
86
67
66
51
40
208-10
231-34b
179-81
76-8d
113-15
77-9
C10H5F3O3
CH3
C2H5
H
H
H
C11H10O3
H
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
(CH2)3Cl
CH3
CF3
C6H5
H
H
H
H
H
H
C13H13ClO3
C13H10ClF3O3
C18H15ClO3
C13H13ClO3
H
119-21
83-5
CH3
C2H5
Cl
oil
101-3
89-91
105-8
102-4
C12H10Cl2O3
C12H10ClFO3
C13H11ClO4
C13H13ClO4
F
CHO
CH2OH
c
a
b
Compounds were analyzed for C, H, and, where present, for Cl, and were within (0.4% of theoretical values. Lit.23 mp 222-224 °C.
c See the Experimental Section for details. Lit.22 mp 70-74 °C.
d

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2965
Sch em e 5.a Synthetic Routes to 7-(3-Chloropropoxy)chromenones
O
O
O
R′
CH2 R′
i (Method D)
or
iii (Method F)
HO
OH
HO
R
ii (Method E)
47–51
O
O
O
iii
R′
NMe2
v (Method G)
Cl
O
R
O
Cl
O
OH
O
54–63
53
62
iv
vi
CH3
OH
vii
Cl
O
CHO
52
Cl
O
O
a
Reagents: (i) (RCO)2O, RCOONa; (ii) HC(OEt)3, HClO4; (iii) Cl(CH2)3Br, K2CO3, acetone; (iv) Me2NCH(OMe)2; (v) t-BuOCl or 1-F-
2,4,6-Me3Pyr; (vi) POCl3, DMF; (vii) NaBH4, MeOH, CH2Cl2.
(method D) in a procedure related to that reported for
the 2-methyl (48)20 and the 2-phenyl (49)21 derivatives.
Some of the 2-unsubstituted chromenones were pre-
pared from the appropriate ketones by reaction with
triethyl orthoformate in the presence of perchloric acid
following a procedure similar to that described for
7-hydroxychromen-4-one22 (method E). Further, the
hydroxychromenones obtained by one of these methods
were in turn O-alkylated with 1-bromo-3-chloropropane
(method F). Alternatively, some (3-chloropropoxy)-
chromenones could be obtained from 1-[4-(3-chloropro-
poxy)-2-hydroxyphenyl]ethanone (52) on formation of a
pyran ring by means of formylating reagents. Thus,
reaction with dimethylformamide dimethyl acetal af-
forded keto enamine 53. Acidic cyclization of this
compound provided an alternative access to unsubsti-
tuted chromenone 54,22 whereas treatment with ap-
propriate halogenating reagents afforded in a one-pot
procedure the 3-halochromenones 60 and 61 (method
G). If formylation was effected with dimethylform-
amide-phosphoryl chloride reagent, the corresponding
3-formylchromenone 62 was obtained, which was con-
verted into the 3-hydroxymethyl derivative 63 by so-
dium borohydride reduction. The chromenones pre-
pared are summarized in Table 2.
Biologica l Resu lts a n d Discu ssion
Structural optimization of the compounds was con-
ducted on the basis of pharmacological profiles in animal
models, instead of a definite binding pattern to selected
receptors. Efforts were focused upon compounds pos-
sessing a pharmacological profile suggestive of high oral
antipsychotic activity and minimal induction of extra-
pyramidal side effects. The antipsychotic potential of
compounds was evaluated by testing their ability to
antagonize climbing behavior25 and hyperactivity26 in
apomorphine-dosed mice. Propensity to cause extrapyr-
amidal side effects was assessed by the ability to
antagonize stereotypy27 produced by subcutaneous ad-
ministration of apomorphine in rats, and for some
compounds, also by the induction of catalepsy.28
Our initial approaches to structural variants of com-
pound 1 were started with modifications of the benzyl
moiety. Thus, a series of substituted piperazines (1-
8) was synthesized and tested. The results are shown
in Table 3. Benzyl derivatives 1 and 4 were moderately
active on intraperitoneal administration, although all
compounds lacked appreciable oral activity. Benzoyl
and arylsulfonyl amides were essentially inactive.
In an attempt to improve oral bioavailability of our
compounds, we turned our attention to the modification
Ta ble 3. Biological Activity of Piperazine (1-8) and Ethanediamine (9-14) Derivatives
climbinga hyperactivityb
compd
ip
28.2 (22.0-35.1)
>50
>50
po
ip
po
stereotypyc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
30
35
45
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
30
16
19
48
22
0
30.0 (23.4-40.1)
50
>50
>50
>200
>200
>50
>50
>200
>200
50
8
0
38.2 (25.9-56.3)
>50
33
NTd
35
38
NT
NT
>50
15.2 (10.3-22.8)
48.4 (33.6-69.7)
15.2 (10.5-21.8)
33.6 (24.7-45.7)
40.0 (28.8-56.8)
35.0 (25.9-47.2)
>200
>200
>200
32
>200
>200
>200
25.0 (17.3-31.8)
>50
30
a
Inhibition of apomorphine-induced climbing behavior in mice. Results are expressed as ED50 values in mg/kg; 95% confidence limits
b
are shown in parentheses. Inhibition of apomorphine-induced hyperactivity in mice. Results are expressed as ED50 values in mg/kg.
c Inhibition of apomorphine-induced stereotypy in rats. Results are expressed in percent inhibition at 50 mg/kg ip dose. NT ) not
d
tested.

2966 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Bolo´s et al.
Ta ble 4. Biological Activity of Piperidine Derivatives
climbinga
hyperactivityb
compd
ip
po
ip
po
stereotypyc
15
16
17
18
19
20
21
22
23
24
25
26
2.85 (0.9-8.3)
20.0 (12.0-33.2)
6.6 (4.5-9.6)
8.0 (4.6-13.8)
12.7 (8.7-18.4)
45.3 (36.2-54.1)
>50
>50
1.82 (0.7-4.4)
11.3 (7.6-16.6)
11.6 (7.2-18.6)
3.6 (2.4-5.4)
7.7 (5.1-11.6)
5.2 (2.9-9.1)
0.21 (0.07-0.60)
0.20 (0.09-0.40)
15.2 (7.2-21.2)
12.3 (6.8-22.2)
12.6 (7.3-21.6)
4.7 (2.3-6.8)
5.5 (2.3-13.6)
7.6 (5.7-9.9)
8.6 (5.7-13.5)
12.5 (9.3-16.7)
NT
1.15 (0.6-1.9)
12.9 (9.1-18.3)
11.1 (8.0-15.1)
1.65 (1.4-1.9)
7.8 (2.5-23.6)
4.2 (2.0-8.6)
0.20 (0.08-0.40)
0.14 (0.09-2.30)
NTe
>200
46
48
25
20
45
>200
23.0 (4.6-113.8)
15.6 (11.7-20.8)
35.9 (26.5-48.7)
13.7 (6.1-30.8)
15.6 (12.3-19.7)
13.1 (4.0-42.5)
12.0 (11.7-12.2)
>100
>200
>200
23.0d (17.0-30.7)
43.1d (30.3-61.2)
0
>200
>200
4.9 (2.2-8.4)
4.3 (2.0-9.1)
12.4d (10.8-14.1)
48
15
16.8 (10.7-26.4)
34.6 (27.9-42.9)
6.4 (4.4-9.2)
21.3 (12.3-36.8)
25.7 (18.7-35.4)
2.9 (2.7-3.1)
11.0 (8.2-14.5)
11.1 (7.4-16.3)
0.56 (0.5-0.6)
0.26 (0.16-0.40)
18.6d (15.5-22.3)
85.3d (68.0-106.0)
48.7d (37.0-64.2)
1.95d (1.6-2.2)
3.80d (3.1-4.5)
clozapine
14.5 (9.8-21.3)
16.0 (9.0-28.3)
1.6 (0.8-3.1)
remoxipride
haloperidol
risperidone
0.74 (0.5-1.2)
a
Inhibition of apomorphine-induced climbing behavior in mice. Results are expressed as ED50 values in mg/kg; 95% confidence limits
b
are shown in parentheses. Inhibition of apomorphine-induced hyperactivity in mice. Results are expressed as ED50 values in mg/kg;
95% confidence limits are shown in parentheses. c Inhibition of apomorphine-induced stereotypy in rats. Results are expressed in percent
inhibition at 50 mg/kg ip dose, unless where noted. Stereotypy ED50 in mg/kg ip. e NT ) not tested.
d
Ta ble 5. Biological Activity of (Piperidinylpropoxy)chromenones
climbinga
(ED50, po)
hyperactivityb
(ED50, po)
stereotypyc
(ED50, po)
catalepsyd
(ED50, po)
compd
26
27
28
29
30
31
32
33
34
6.4 (4.4-9.2)
2.9 (2.7-3.1)
4.6 (3.5-5.8)
63.4 (22.0-179.0)
35.2 (28.0-44.3)
94.8 (65.0-137.7)
28.0 (13.7-59.3)
60.0 (31.1-115.8)
>100
10.9 (5.0-23.7)
48.4 (35.8-65.3)
1.65 (1.3-2.0)
6.9 (3.2-19.4)
1.32 (0.6-4.1)
7.0 (2.6-18.5)
20.0 (6.4-65.7)
11.0 (8.2-14.5)
11.1 (7.4-16.3)
0.56 (0.5-0.6)
0.26 (0.16-0.40)
>100
>100
>100
>100
>100
5.7 (4.4-7.3)
11.3 (7.9-15.9)
3.2 (2.4-4.1)
77.3 (49.0-120.0)
37.5 (30.7-45.7)
NT
NTe
35.9 (10.0-126.0)
14.0 (11.2-17.3)
21.2 (15.6-29.7)
18.0 (6.0-53.5)
107.3 (88.6-129.8)
64.3 (36.1-114.4)
2.5 (2.2-2.8)
11.2 (9.1-13.9)
23.5 (4.6-117.7)
14.5 (9.8-21.3)
16.0 (9.0-28.3)
1.6 (0.8-3.1)
>100
NT
clozapine
85.3 (68.0-106.0)
48.7 (37.0-64.2)
1.95 (1.6-2.2)
3.8 (3.1-4.5)
remoxipride
haloperidol
risperidone
0.74 (0.5-1.2)
5.0 (4.8-5.3)
a
Inhibition of apomorphine-induced climbing behavior in mice. Results are expressed as ED50 values in mg/kg po; 95% confidence
b
limits are shown in parentheses. Inhibition of apomorphine-induced hyperactivity in mice. Results are expressed as ED50 values in
mg/kg po; 95% confidence limits are shown in parentheses. c Inhibition of apomorphine-induced stereotypy in rats. Results are expressed
d
as ED50 values in mg/kg po. Induction of catalepsy. Results are expressed as dose required to produce a 50% of maximum catalepsy
score in mg/kg, po; 95% confidence limits are shown in parentheses. e NT ) not tested.
of the piperazine nucleus, while maintaining the benzyl
moiety. Thus, a series of benzylethanediamines and a
series of benzylpiperidines were designed. The results
for the ethanediamine compounds (9-14) are shown in
Table 3. The most active compounds on intraperitoneal
administration were ketone 11 and ether 13, but only
11 showed appreciable oral activity. This compound,
at doses required for inhibition of climbing and hyper-
activity, retained a small inhibition of stereotypies. Our
next efforts were then focused on the substitution of the
piperazine by a piperidine ring. In the 4-benzylpiperi-
dine series (15-22), a number of compounds displayed
good oral activity in the climbing and hyperactivity tests
(Table 4). For most compounds, it was not possible to
calculate the ED50 for the inhibition of stereotypies due
to poor activity in this assay, and thus, results are
expressed as percent inhibition at the maximum prac-
ticable dose of 50 mg/kg ip. This difference is in
agreement with the suggested potentially atypical an-
tipsychotic profile of these compounds. Particularly,
compounds 17 and 18, with a ketone or an alcohol
function, showed a high potency in the climbing and
hyperactivity tests and an appreciable difference with
doses required for inhibition of stereotypies. Unfortu-
nately, they displayed other important side effects, such
as motor incoordination, hypothermia, and tremors in
the Irwin test,24 even at doses lower than the ED50 in
the climbing assay. With a similar oral potency, ether
19 possessed a broader margin for the above side effects.
Thus, the structural framework of [(aryloxy)propyl]-
piperidine was selected as the target for further im-
provement.
On the basis of the structure of compound 19, we
devised again the introduction of some modifications on
the benzyl group. Thus, the corresponding derivatives
hydroxy-, methoxy-, and keto-substituted at the benzyl
position were synthesized. Alcohol 24 and ketone 23
can be regarded as the “reversed piperidine” analogues
of phenylbutanol 18 and butyrophenone 17. For these
compounds, the climbing and hyperactivity potencies
were similar to those of their analogues; however, the
reversed derivatives showed lesser motor incoordination
and hypothermia side effects. The greater potency
corresponded to compound 23, with a ketone function.
An additional improvement was achieved by substitu-
tion of the p-fluorophenyl group for a chromenone ring
(26), which afforded a similarly potent compound, but
with a somewhat broader margin for inhibition of
stereotypies and devoid of motor incoordination, hypo-
thermia, and tremors. All analogues in the piperidine

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2967
(dd, J ) 9 and 6 Hz, 2H, Ph-2H and -6H), 8.25 (d, J ) 6.3 Hz,
1H, 2-H); 13C NMR (DMSO-d6) δ 22.93 (OCH2CH2), 25.46
(piper-3C and -5C), 40.03 (piper-4C), 50.85 (piper-2C and -6C),
53.18 (NCH2), 65.77 (OCH2), 101.77 (8-C), 111.91 (3-C), 114.62
(6-C), 115.65 (d, J ) 21.7 Hz, Ph-3C and -5C), 117.90 (4a-C),
126.13 (5-C), 131.04 (d, J ) 9.2 Hz, Ph-2C and -6C), 131.52
(d, J ) 3.5 Hz, Ph-1C), 156.16 (2-C), 157.34 (8a-C), 162.31 (7-
C), 164.78 (d, J ) 250.4 Hz, Ph-4C), 175.25 (4-C), 199.09
(PhCdO). Anal. (C24H24FNO4.HCl) C, H, N, Cl.
series displayed appreciable oral activities, as shown in
Table 4. Also, the corresponding data for some repre-
sentative standard antipsychotics are included for com-
parison.
Finally, we explored the chemical modification of the
chromenone ring of compound 26 with the introduction
of some substituents at positions 2 and 3. The biological
results for the substituted chromene derivatives are
indicated in Table 5. Evaluation of stereotypies was
effected on oral administration, due to high oral potency
of most of these compounds. Assessment of potential
induction of extrapyramidal effects is complemented
with the catalepsy assay. All of the 2-substituted
derivatives prepared were less active in the climbing
and hyperactivity tests, but some of the 3-substituted
analogues showed a higher potency than the parent
compound 26. Thus, the 3-(hydroxymethyl)chromenone
32 is the most active compound, whereas the 3-methyl
derivative 30 shows the broader margin for induction
of catalepsy and stereotypy in the conditions of the test.
As a conclusion, compounds 26, 30, and 32 stand for
the most potent members of this interesting family of
7-[3-(1-piperidinyl)propoxy]chromenones. They possess
in vivo pharmacological profiles predictive of possible
atypical antipsychotic activity, with high potency on oral
administration. On the basis of these pharmacological
profiles, an oral potency for these compounds higher
than that of clozapine or remoxipride and a lesser
induction of extrapyramidal effects than haloperidol and
at least similar to that of risperidone can be suggested.
Compounds 26, 30, and 32 have been selected as
candidates for further studies in order to evaluate their
therapeutic potential as antipsychotic drugs.
Meth od B: 4-(p-F lu or oben zyl)-1-[4-(p-flu or op h en yl)-
4-oxobu tyl]-2-m eth ylp ip er a zin e (3). A mixture of 75 g
(0.36 mol) of 1-(p-fluorobenzyl)-3-methylpiperazine (36), 90 g
(0.36 mol) of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3-dioxo-
lane, 175 g (1.27 mol) of anhydrous potassium carbonate, and
3 g of potassium iodide in 500 mL of acetonitrile was stirred
at reflux for 24 h. The insoluble residue was removed by
filtration, and the solution was concentrated to give 42 g (30%)
of crude 4-(p -flu or ob en zyl)-1-[4,4-(et h ylen ed ioxy)-4-(p -
flu or op h en yl)bu tyl]-2-m eth ylp ip er a zin e as an oil, which
was used in the next step without further purification: IR
1
(film) 1600, 1520, 1240 cm-1; H NMR (CDCl3) δ 1.50 (d, 3H,
CH3), 2.20 (m, 4H, NCH2CH2CH2), 3.10 (m, 2H, NCH2), 3.50-
4.00 (m, 7H, piperazine), 4.00-4.20 (2 m, 4H, OCH2CH2O),
4.50 (s, 2H, CH2Ar), 7.00 (t, J ) 9 Hz, 4H, Ar-H), 7.60 (m, 4H,
Ar-H).
The crude ketal was dissolved in 300 mL of ethanol and 100
mL of aqueous 6 M HCl, and the resulting solution was heated
at 70 °C for 2 h. Then, the solvent was evaporated under
vacuum, and the residue was crystallized from absolute
ethanol to afford 25.6 g (55%) of 3: mp 210-212 °C; IR (KBr)
1
2560, 2480, 1680, 1600, 1230 cm-1; H NMR (CD3OD) δ 1.67
(d, 3H, CH3), 2.25 (m, 2H, NCH2CH2), 3.40 (m, 4H, NCH2 and
CH2CdO), 3.50-4.00 (m, 7H, piperazine), 4.55 (s, 2 H, CH2-
Ph), 7.20 (t, J ) 9 Hz, 4H, Ar-H), 7.70 (dd, J ) 9 and 5 Hz,
2H, benzyl-2H and -6H), 8.10 (dd, J ) 9 and 5 Hz, 2H, benzoyl-
2H and -6H). Anal. (C22H26F2N2O‚2HCl) C, H, N, Cl.
Meth od C: 1-[4-(p-F lu or op h en yl)-4-h yd r oxybu tyl]-4-
(p-flu or oben zyl)-2-m eth ylp ip er a zin e (4). Sodium borohy-
dride (3.2 g, 85 mmol) was added portionwise to a solution of
11.5 g (27 mmol) of ketone 3 in 1 L of absolute EtOH, and the
mixture was stirred at room temperature for 24 h. Then, the
solution was acidified with 6 M HCl and concentrated. The
residue was dissolved in CH2Cl2, washed with diluted NaOH
solution and with water, and evaporated. The resulting oil
was dissolved in 2-propanol and precipitated by dropwise
addition of an isopropanolic solution of HCl. The solid was
collected and recrystallized from isopropanol to afford 7.7 g
(67%) of 4: mp 204-207 °C; IR (KBr) 3390, 2440, 1510, 1220
Exp er im en ta l Section
Ch em istr y. Gen er a l Meth od s. Melting points were
determined in open capillary tubes on a Bu¨chi apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded on a
Varian Gemini 300 spectrometer. Chemical shifts are ex-
pressed in parts per million downfield from TMS as internal
standard. IR spectra were registered with a Perkin-Elmer
1710 apparatus. Microanalyses were obtained using a Perkin-
Elmer 2400 elemental analyzer. Where analyses are indicated
with the symbols of the elements, the results are within (0.4%
of the theoretical values. Column chromatography separations
were carried out using Merck silica gel 60 (70-230 mesh
ASTM). Prior to concentration, under reduced pressure, all
organic extracts were dried over anhydrous Na2SO4 powder.
The general methods of synthesis exemplified are illustra-
tive of those of the analogous compounds.
cm-1 1H NMR (CD3OD) δ 1.55 (d, 3H, CH3), 1.90 (m, 4H,
;
NCH2CH2CH2), 3.45 (m, 2H, NCH2), 3.55-4.00 (m, 7H, pip-
erazine), 4.52 (s, 2H, CH2Ph), 4.70 (m, 1H, CHOH), 7.08 (t, J
) 9 Hz, 2H, Ph-3H and -5H), 7.20 (t, J ) 9 Hz, 2H, Ph′-3H
and -5H), 7.44 (dd, J ) 9 and 5 Hz, 2H, Ph-2H and 6-H), 7.70
(dd, J ) 9 and 5 Hz, 2H, Ph′-2H and 6-H). Anal. (C22H28
F2N2O‚2HCl) C, H, N, Cl.
-
1-(4-F lu or oben zyl)-3-m eth ylp ip er a zin e (36). A mixture
of 60 g (0.6 mol) of 2-methylpiperazine, 87 g (0.6 mol) of
4-fluorobenzyl chloride, and 150 g (1.8 mol) of NaHCO3 in 500
mL of EtOH was heated to reflux for 24 h. The cooled solution
was filtered and evaporated under vacuum. The residue was
dissolved in 500 mL of 1 M HCl and washed with CH2Cl2. The
aqueous solution was then basified to pH 13 with NaOH and
extracted with CH2Cl2. Evaporation gave 80 g (64%) of crude
36. A sample was purified by distillation at 75-77 °C/0.1
Meth od A: 7-[3-[4-(p-F lu or oben zoyl)-1-p ip er id in yl]-
p r op oxy]ch r om en -4-on e (26). A mixture of 3.9 g (18.8
mmol) of 4-(p-fluorobenzoyl)piperidine (42), 4.5 g (18.8 mmol)
of 7-(3-chloropropoxy)chromen-4-one (54), 2.7 g (18.8 mmol)
of anhydrous potassium carbonate, and a trace of potassium
iodide in 250 mL of acetonitrile was heated to reflux for 24 h.
The resulting suspension was filtered, and the filtrates were
evaporated, then redissolved in CH2Cl2, washed with brine,
and concentrated. The residue was dissolved in 2-propanol
and precipitated by addition of an isopropanolic solution of
hydrogen chloride. The solid was collected and recrystallized
from methanol-ether to afford 2.2 g (26%) of 26: mp 235-
238 °C; IR (KBr) 3200-3600, 2300-2800, 1680, 1650, 1630
1
mmHg: IR (neat) 1610, 1510, 1230 cm-1; H NMR (CDCl3) δ
1.08 (d, J ) 6 Hz, 3H, CH3), 1.49 (s, 1H, NH), 1.70 (t, J ) 10.5
Hz, 1H, 3-Hax), 2.02 (dt, J ) 11 and 7 Hz, 1H, 5-Hax), 2.60-
3.00 (m, 5H, piperazine), 3.49 (s, 2H, PhCH2), 7.00 (t, J ) 9
Hz, 2H, Ph-3H and -5H), 7.30 (dd, J ) 9 and 6.5 Hz, 2H, Ph-
2H and -6H). Anal. (C12H17FN2) C, H, N.
1
cm-1; H NMR (DMSO-d6) δ 2.01 (m, 4H, piper-3H and -5H),
2.30 (m, 2H, OCH2CH2), 3.13 (m, 2H, piper-2Hax and -6Hax),
3.24 (br t, J ) 6 Hz, 2H, NCH2), 3.61 (br d, J ) 10.2 Hz, 2H,
piper-2Heq and -6Heq), 3.75 (m, 1H, piper-4H), 4.25 (br t, J )
6 Hz, 2H, OCH2), 6.29 (d, J ) 6.3 Hz, 1H, 3-H), 7.08 (dd, J )
9 and 2 Hz, 1 H, 6-H), 7.16 (d, J ) 2 Hz, 1H, 8-H), 7.40 (t, J
) 9 Hz, 2H, Ph-3H and -5H), 7.96 (d, J ) 9 Hz, 1H, 5-H), 8.11
N-(4-F lu or oben zyl)-N,N′-d im eth yleth a n ed ia m in e (38).
Operating as above, from 50 g (0.57 mol) of N,N′-dimethyl-
ethanediamine and 72 g (0.57 mol) of 4-fluorobenzyl chloride
was obtained the title compound, which was purified by
distillation at 65-67 °C/ 0.01 mmHg to afford 47 g (42%) of
pure 38: IR (neat) 1610, 1510, 1220 cm-1; 1H NMR (CDCl3) δ

2968 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Bolo´s et al.
1.45 (s, 1H, NH), 2.11 (s, 3H, NCH3), 2.27 (s, 3H, NCH3), 2.41
(t, J ) 6 Hz, 2H, NCH2), 2.57 (t, J ) 6 Hz, 2H, NCH2), 3.44 (s,
2H, PhCH2), 7.12 (t, J ) 9 Hz, 2H, Ph-3H and -5H), 7.32 (dd,
J ) 9 and 6.5 Hz, 2H, Ph-2H and -6H). Anal. (C11H17FN2) C,
H, N.
CHOCH3), 3.95-4.15 (m, 2H, 2-Heq and 6-Heq), 7.03 (t, J ) 9
Hz, 2H, Ph-3H and -5H), 7.20 (dd, J ) 9 and 6.5 Hz, 2H, Ph-
2H and -6H).
A solution of 45 (5 g, 15 mmol) in 35 mL of ethanol and 35
mL of 4 M HCl was stirred at room temperature for 1 h, and
the ethanol was removed in vacuo. The aqueous solution was
washed with benzene and then was basified to pH 14 by
addition of NaOH and extracted with chloroform. The chlo-
roform extracts were dried and evaporated to give 2.4 g (69%)
of 4-[1-(4-flu or op h en yl)-1-m eth oxym eth yl]p ip er id in e (46)
as an oil which solidified on standing: mp 73-76 °C; IR (KBr)
1-(4-F lu or oben zoyl)-3-m eth ylp ip er a zin e (39). A solu-
tion of 40 g (0.4 mol) of 2-methylpiperazine and 150 g (1.79
mol) of NaHCO3 in 500 mL of H2O was diluted with 300 mL
of acetone and cooled in an ice bath. Then, a solution of 70.5
g (0.44 mol) of 4-fluorobenzoyl chloride in 200 mL of acetone
was added dropwise at a temperature lower than 10 °C, and
the mixture was allowed to warm to room temperature and
stirred for further 1.5 h. The reaction mixture was concen-
trated under vacuum to a volume of 500 mL and was extracted
with three portions of CH2Cl2. The crude product was purified
on column chromatography (1:9 MeOH-CHCl3) to give 46 g
(48%) of 39 as an oil: IR (neat) 3100-3500, 1630, 1510, 1440,
1
3270, 1610, 1510, 1230, 1090 cm-1; H NMR (CDCl3) δ 1.00-
1.30 (m, 3H, 3-Hax, 5-Hax, and 4-H), 1.62 (m, 1H, 3-Heq), 2.00
(br d, J ) 11 Hz, 1H, 5-Heq), 2.18 (br s, 1H, NH), 2.40-2.60 (2
overlapped t, 2H, 2-Hax and 6-Hax), 2.98 (br d, J ) 12 Hz, 1 H,
2-Heq), 3.10 (br d, J ) 12 Hz, 1H, 6-Heq), 3.16 (s, 3H, OCH3),
3.78 (d, J ) 6 Hz, 1H, CHOCH3), 7.02 (t, J ) 9 Hz, 2H, Ph-3H
1
1280, 1220 cm-1; H NMR (CDCl3) δ 1.10 (d, J ) 6 Hz, 3H,
and -5H), 7.20 (dd, J ) 9 and 6.5 Hz, 2H, Ph-2H and -6H); 13
C
CH3), 2.10 (s, 1H, NH), 2.50-3.10 (m, 5H, piperazine), 3.60
(m, 1H, 6-Heq), 4.55 (m, 1H, 2-Heq), 7.11 (t, J ) 9 Hz, 2H, Ph-
3H and -5H), 7.41 (dd, J ) 9 and 6.5 Hz, 2H, Ph-2H and -6H).
Anal. (C12H15FN2O) C, H, N.
NMR (CDCl3) δ 29.36 and 30.06 (3-C and 5-C), 43.02 (4-C),
46.29 and 46.36 (2-C and 6-C), 56.70 (OCH3), 87.78 (CHOCH3),
114.84 (d, J ) 22 Hz, Ph-3C and -5C), 128.65 (Ph-2C and -6C),
135.90 (Ph-1C), 161.93 (d, J ) 260 Hz, Ph-4C). Anal. (C13H18
-
FNO) C, H, N.
1-[(4-Meth ylp h en yl)su lfon yl]-3-m eth ylp ip er a zin e (40).
Operating as above, from 22.6 g (0.22 mol) of 2-methylpipera-
zine and 50 g (0.26 mol) of p-toluenesulfonyl chloride was
obtained 35 g (57%) of 40 as a solid of mp 112-114 °C: IR
Meth od D: 7-Hyd r oxy-2-(tr iflu or om eth yl)ch r om en -4-
on e (47). A mixture of 1-(2,4-dihydroxyphenyl)ethanone (10
g, 66 mmol), sodium trifluoroacetate (16.6 g, 122 mmol), and
trifluoroacetic anhydride (39 mL, 277 mmol) was heated in
an oil bath, allowing excess trifluoroacetic anhydride to distill
off until the internal temperature was about 125 °C, and then
stirred at this temperature for 40 h. The cooled solution was
treated with 100 mL of 3 M HCl, and the resulting suspension
was stirred for 2 h at room temperature. The solid was
collected, suspended in H2O, warmed at 40 °C, and dissolved
by addition of a solution of NaOH to pH 9. The solution was
filtered and then precipitated by dropwise addition of HCl. The
solid was collected by filtration, washed with water, and
vacuum-dried to afford pure 47 (10.3 g, 68%): mp 208-210
°C; IR (KBr) 3400-3600, 1665, 1560, 1250 cm-1; 1H NMR (CD3-
COCD3) δ 3.60 (br, 1H, OH), 6.75 (s, 1H, 3-H), 7.03 (d, J ) 2.3
Hz, 1H, 8-H), 7.10 (dd, J ) 8.8 and 2.3 Hz, 1H, 6-H), 8.01 (d,
J ) 8.8 Hz, 1H, 5-H); 13C NMR (CD3COCD3) δ 103.33 (8-C),
111.11 (3-C), 116.65 (6-C), 117.58 (4a-C), 119.61 (q, J ) 271
Hz, CF3), 127.87 (5-C), 151.68 (q, J ) 37.5 Hz, 2-C), 158.06
(8a-C), 164.26 (7-C), 175.64 (4-C). Anal. (C10H5F3O3) C, H.
Meth od E: 7-Hyd r oxy-3-m eth ylch r om en -4-on e (50).
To an ice bath cooled suspension of 1-(2,4-dihydroxyphenyl)-
1-propanone (75 g, 0.45 mol) in 750 mL (4.5 mol) of triethyl
orthoformate was added dropwise over a 30 min period 66 mL
of 70% perchloric acid (0.77 mol). The mixture was heated
for 5 h at 50 °C, and then the resulting solution was
concentrated to a volume of 500 mL and poured dropwise on
2500 mL of ice-water. The suspension that resulted was
stirred while allowing to warm to room temperature, and the
solid was collected by filtration, washed with water, and
vacuum-dried to afford 77 g (97%) of pure 50. A sample was
crystallized from EtOH-H2O: mp 231-234 °C (lit.23 mp 222-
24 °C).
1
(KBr) 1620, 1470, 1340, 1170 cm-1; H NMR (CDCl3) δ 1.02
(d, J ) 6 Hz, 3H, piper-CH3), 1.42 (s, 1H, NH), 1.88 (t, J )
10.6 Hz, 1H, 3-Hax), 2.25 (td, J ) 11 and 4 Hz, 1 H, 5-Hax),
2.43 (s, 3H, PhCH3), 2.84-3.04 (m, 3H, piperazine), 3.60 (br
d, J ) 11 Hz, 2H, piper), 7.35 (d, J ) 8 Hz, 2H, Ph-3H and
-5H), 7.62 (d, J ) 8 Hz, 2H, Ph-2H and -6H). Anal.
(C12H18N2O2S) C, H, N, S.
4-[1-(4-Flu or oph en yl)-1-m eth oxym eth yl]piper idin e (46).
A mixture of 4-(4-fluorobenzoyl)piperidine (42) (10 g, 48 mmol),
di-tert-butyl dicarbonate (10.5 g, 48 mmol), and triethylamine
(10 mL) in tetrahydrofuran (50 mL) was stirred overnight at
room temperature. Then, the solvent was evaporated and the
residue was dissolved in benzene, washed with diluted HCl
and water, and evaporated to afford 12 g (83%) of 1-(ter t-
bu toxyca r bon yl)-4-(4-flu or oben zoyl)p ip er id in e (43) as a
colorless oil: 1H NMR (CDCl3) δ 1.47 (s, 9H, t-Bu), 1.60-1.80
(m, 2H, 3-Hax and 5-Hax), 1.80-1.90 (m, 2H, 3-Heq and 5-Heq),
2.88 (br t, J ) 11 Hz, 2H, 2-Hax and 6-Hax), 3.39 (tt, J ) 11
and 3 Hz, 1H, 4-H), 4.18 (br d, J ) 11 Hz, 2H, 2-Heq and 6-Heq),
7.15 (t, J ) 9 Hz, 2H, Ph-3H and -5H), 7.98 (dd, J ) 9 and 6.5
Hz, 2H, Ph-2H and -6H).
To a solution of 43 (10 g, 33 mmol) in 100 mL of ethanol
was added 2 g of sodium borohydride, and the mixture was
stirred for 2 h at room temperature. The solution was
evaporated, and the residue was redissolved in benzene,
poured onto ice water, and acidified with HCl to pH 5-6. The
organic extract was washed with water and evaporated to give
5.9 g (59%) of 1-(ter t-bu toxyca r bon yl)-4-[1-(4-flu or op h en -
yl)-1-h yd r oxym eth yl]p ip er id in e (44) as an oil which was
used without further purification: 1H NMR (CDCl3) δ 1.00-
1.20 (m, 1H, 4-H), 1.20-1.30 (m, 2H, 3-Hax and 5-Hax), 1.43
(s, 9H, t-Bu), 1.70 (m, 1H, 3-Heq), 1.92 (br d, J ) 11 Hz, 1H,
5-Heq), 2.50-2.70 (m, 2H, 2-Hax and 6-Hax), 4.00-4.20 (m, 2H,
2-Heq and 6-Heq), 4.36 (d, J ) 6 Hz, 1H, CHOH), 7.02 (t, J )
9 Hz, 2H, Ph-3H and -5H), 7.26 (dd, J ) 9 and 6.5 Hz, 2H,
Ph-2H and -6H).
Meth od F : 7-(3-Ch lor op r op oxy)-3-m eth ylch r om en -4-
on e (58). A mixture of 30 g (0.17 mol) of 7-hydroxy-3-
methylchromen-4-one (51), 25 mL (0.25 mol) of 1-bromo-3-
chloropropane, and 35 g (0.25 mol) of anhydrous potassium
carbonate in 200 mL of acetone was stirred at reflux for 24 h.
After removal of the insoluble solids by filtration, the solution
was evaporated under vacuum. The residue was stirred with
diethyl ether, and the resulting solid was filtered and vacuum-
dried to afford 27 g (63%) of 58.
Sodium hydride (0.8 g of 80% dispersion in paraffin),
previously washed with hexane, was suspended in 25 mL of
anhydrous tetrahydrofuran, and 5 g (16 mmol) of 44 was
added. The mixture was stirred for 30 min at room temper-
ature, and then 2 mL (32 mmol) of iodomethane was added.
After further stirring for 16 h, the solvent was evaporated,
and the residue was dissolved in chloroform. The solution was
poured into ice-water and neutralized by addition of HCl.
Evaporation of the organic extract afforded 5 g (96%) of crude
1-(ter t-bu toxyca r bon yl)-4-[1-(4-flu or op h en yl)-1-m eth oxy-
A sample was recrystallized from Et2O: mp 83-85 °C. IR
1
(KBr) 1640, 1600, 1240 cm-1; H NMR (CDCl3) δ 2.00 (s, 3H,
CH3), 2.28 (quint, J ) 6 Hz, 2H, OCH2CH2), 3.76 (t, J ) 6 Hz,
2H , CH2Cl), 4.19 (t, J ) 6 Hz, 2H, OCH2), 6.80 (d, J ) 2.3 Hz,
1H, 8-H), 6.93 (dd, J ) 9 and 2.3 Hz, 1H, 6-H), 7.71 (d, J )
0.9 Hz, 1H, 2-H), 8.12 (d, J ) 9 Hz, 1H, 5-H); 13C NMR (CDCl3)
δ 11.08 (CH3), 31.81 (OCH2CH2), 41.12 (CH2Cl), 64.69 (OCH2),
100.48 (8-C), 114.32 (6-C), 117.55 (4a-C), 120.34 (3-C), 127.00
(5-C), 151.12 (2-C), 158.11 (8a-C), 162.58 (7-C), 177.42 (4-C).
Anal. (C13H13ClO3) C, H, Cl.
1
m eth yl]p ip er id in e (45): H NMR (CDCl3) δ 1.00-1.30 (m,
3H, 3-Hax, 5-Hax, and 4-H), 1.44 (s, 9H, t-Bu), 1.70 (m, 1H,
3-Heq), 1.92 (br d, J ) 11 Hz, 1H, 5-Heq), 2.45-2.65 (m, 2H,
2-Hax and 6-Hax), 3.16 (s, 3H, OCH3), 3.78 (d, J ) 6 Hz, 1H,

Potential Atypical Antipsychotics
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15 2969
1-[4-(3-Ch lor op r op oxy)-2-h yd r oxyp h e n yl]-1-e t h a n -
on e (52). A mixture of 50 g (0.33 mol) of 2′,4′-dihydroxyac-
etophenone, 50 mL (0.50 mol) of 1-bromo-3-chloropropane, and
65 g (0.47 mol) of anhydrous potassium carbonate in 700 mL
of acetone was heated at reflux for 16 h. The cooled solution
was filtered to remove the insoluble solids, and the solvent
was evaporated under vacuum. The residue was suspended
in MeOH, filtered, and vacuum-dried to afford 52 g (69%) of
52 as a white solid. A sample was recrystallized from EtOAc-
hexane (1:2): mp 73-74 °C; IR (KBr) 3200-3600, 1650, 1590,
cooled solution (0 °C) of 52 (20 g, 87 mmol) in 80 mL of N,N-
dimethylformamide. The solution was stirred at 0 °C for 30
min, and for 16 h at room temperature. Then, it was poured
onto ice, extracted with CHCl3, washed with water, and
evaporated to give crude 62, which was purified by column
chromatography (CHCl3) to afford the title compound (12 g,
51%) as an oil which solidified on standing: mp 105-108 °C
dec; IR (KBr) 1695, 1650, 1620 cm-1 1H NMR (CDCl3) δ 2.31
.
(quint, J ) 6 Hz, 2H, OCH2CH2), 3.78 (t, J ) 6 Hz, 2H, CH2-
Cl), 4.25 (t, J ) 6 Hz, 2H, OCH2), 6.94 (d, J ) 2 Hz, 1H, 8-H),
7.04 (dd, J ) 9 and 2 Hz, 1 H, 6-H), 8.18 (d, J ) 9 Hz, 1H,
5-H), 8.47 (s, 1H, 2-H), 10.35 (s, 1H, CHO); 13C NMR (CDCl3)
δ 31.73 (OCH2CH2), 41.02 (CH2Cl), 65.07 (OCH2), 101.55 (8-
C), 115.53 (6-C), 118.72 (4a-C), 120.01 (3-C), 127.31 (5-C),
157.58 (8a-C), 160.01 (2-C), 163.64 (7-C), 174.88 (4-C), 188.45
(CHO). Anal. (C13H11ClO4) C, H, Cl.
1285, 1160 cm-1
;
1H NMR (CDCl3) δ 2.25 (quint, J ) 6 Hz,
2H, OCH2CH2), 2.56 (s, 3H, CH3), 3.73 (t, J ) 6 Hz, 2H, CH2-
Cl), 4.15 (t, J ) 6 Hz, 2H, OCH2), 6.42 (m, 2H, 3-H and 5-H),
7.63 (d, J ) 8.1 Hz, 1H, 6-H), 12.73 (s, 1H, OH). Anal. (C11H13
ClO3) C, H, Cl.
-
(E )-1-[4-(3-Ch lor op r op oxy)-2-h yd r oxyp h e n yl]-3-(d i-
m eth yla m in o)-1-p r op en on e (53). A mixture of 52 (6 g, 26
mmol) and 5.2 mL (39 mmol) of dimethylformamide dimethyl
acetal was heated at reflux for 3.5 h. The resulting solution
was evaporated under vacuum, and the residue was suspended
in 40 mL of ether. The solid that formed was filtered and dried
to afford 5.6 g (75%) of 53: mp 119-121 °C; IR (KBr) 3200-
7-(3-Ch lor op r op oxy)-3-(h yd r oxym et h yl)ch r om en -4-
on e (63). To an ice-salt bath cooled solution of 2.5 g (9.4
mmol) of 62 in 15 mL of CHCl3 and 15 mL of absolute EtOH
was added portionwise 0.2 g (5.3 mmol) of sodium borohydride.
The solution was stirred for 15 min at -10 °C and for a further
1 h at 0 °C, poured on ice-water, neutralized with HCl, and
extracted with CHCl3. The crude product was purified by
column chromatography (MeOH-CHCl3, 2:98) to afford 1 g
(40%) of the title compound: mp (Et2O) 102-104 °C; IR (KBr)
1
3600, 1620, 1530, 1350, 1235, 1100 cm-1; H NMR (CDCl3) δ
2.24 (quint, J ) 6 Hz, 2H, OCH2CH2), 2.96 (br s, 3H, NCH3),
3.18 (br s, 3H, NCH3), 3.73 (t, J ) 6 Hz, 2H, CH2Cl), 4.13 (t,
J ) 6 Hz, 2H, OCH2), 5.68 (d, J ) 12 Hz, 1H, dCH-N), 6.38
(d, J ) 8.6 Hz, 1H, Ph-5H), 6.41 (s, 1H, Ph-3H), 7.61 (d, J )
8.6 Hz, 1H, Ph-6H), 7.84 (d, J ) 12 Hz, 1H, dCH-CO); 13C
NMR (CDCl3) δ 31.96 (OCH2CH2), 37.28 (NCH3), 41.25 (CH2-
Cl), 45.20 (NCH3), 64.15 (OCH2), 89.59 (dCHN), 101.48 (Ph-
3C), 106.31 (Ph-5C), 113.81 (Ph-1C), 129.45 (Ph-6C), 153.73
(CO-CHd), 163.04 (Ph-2C), 165.13 (Ph-4C), 190.17 (CdO).
Anal. (C14H18ClNO3) C, H, Cl, N.
1
3330, 1638, 1625, 1590, 1445, 1270 cm-1; H NMR (CDCl3) δ
2.30 (quint, J ) 6 Hz, 2H, OCH2CH2), 3.24 (t, J ) 6.4 Hz, 1H,
OH), 3.77 (t, J ) 6 Hz, 2H, CH2Cl), 4.22 (t, J ) 6 Hz, 2H,
OCH2), 4.56 (d, J ) 6.4 Hz, 2H, CH2OH), 6.85 (d, J ) 2.4 Hz,
1H, 8-H), 6.98 (dd, J ) 9 and 2.4 Hz, 1H, 6-H), 7.87 (s, 1H,
2-H), 8.11 (d, J ) 9 Hz, 1H, 5-H); 13C NMR (CDCl3) δ 31.77
(OCH2CH2), 41.02 (CH2Cl), 58.55 (CH2OH), 64.17 (OCH2),
100.65 (8-C), 114.75 (6-C), 117.60 (4a-C), 122.81 (3-C), 126.75
(5-C), 151.94 (2-C), 158.01 (8a-C), 162.98 (7-C), 177.42 (4-C).
Anal. (C13H13ClO4) C, H, Cl.
7-(3-Ch lor op r op oxy)ch r om en -4-on e (54). To a cooled
solution of 3 g (11 mmol) of 53 in 60 mL of chloroform were
added 2 mL of a 5.6 M solution of HCl in ethanol, and the
mixture was stirred at room temperature for 15 min. The
chloroformic solution was washed with water and with a
saturated solution of NaHCO3. Evaporation of the dried
extracts gave a solid, which was suspended in ether, filtered,
and dried to afford 2 g (70%) of 54: mp 76-78 °C (lit.22 mp
70-74 °C).
P h a r m a cologica l Meth od s. Gen er a l. Subjects were
either male Swiss Albino mice (20-24 g) or male Sprague-
Dawley rats (180-200 g), and 8-12 individuals were used per
dose group. Animals were placed in cages and allowed for
adaptation two hours before each assay. Test compounds were
administered as suspensions in 0.25% agar in water, and
dosing volume was 1 mL/100 g of body weight.
In h ibition of Ap om or p h in e-In d u ced Clim bin g Beh a v-
ior in Mice. A modification of the method of Protais et al.25
was used. Mice received either the test drug or the vehicle
alone 30 min (for ip administration) or 60 min (for po
administration) prior to apomorphine challenge (1 mg/kg, sc)
and were individually placed in transparent vertical poly-
methacrylate boxes (11 × 7.5 × 4.5 cm) with one of the broad
lateral walls formed by a wire reticle of 3 mm mesh. Animals
were then observed for climbing behavior at 10, 20, and 30
min. Climbing was scored as follows: all four feet on the floor
cage, 0; three feet on the floor, 1; two feet on the floor, 2; one
foot on the floor, 3; and all four feet off the cage floor, 4.
Percent inhibition of apomorphine was calculated by the
difference from total score of treated subjects to total score of
control animals, and referring it to total score of control group
set to 100%. ED50 values, with 95% confidence limits, were
calculated by linear regression analysis.
In h ibition of Ap om or p h in e-In d u ced Hyp er a ctivity in
Mice.26 Animals were either dosed with vehicle or with test
compounds, and after 30 min (for ip administration) or 60 min
(for po administration), mice were challenged with 1 mg/kg
(sc) of apomorphine. Then, animals were placed in groups of
three per cage on a Panlab Actisystem D. A. S. 16 v. 1 activity
meter, and the motility was recorded through a 90 min period.
The percent inhibition of treated groups was recorded with
respect to control group.
In h ib it ion of Ap om or p h in e-In d u ced St er eot yp y in
Ra ts. The procedure is a modification of Puech et al.27 Rats
were dosed with vehicle or with test compounds 30 min prior
to apomorphine (1.5 mg/kg, sc) and were placed individually
in transparent observation cages. At 10, 20, and 30 min,
animals were observed for the presence of stereotyped behav-
ior, which was scored as follows: any abnormal movement, 0;
Met h od G: 3-Ch lor o-7-(3-ch lor op r op oxy)ch r om en -4-
on e (60). To a solution of 4.5 g (16 mmol) of 53 in 60 mL of
chloroform was added at 0-5 °C a solution of 1.9 g (16 mmol)
of tert-butyl hypochlorite in 40 mL of chloroform. Then, the
mixture was stirred for 4 h at room temperature and evapo-
rated. The residue was washed with diisopropyl ether to afford
2.9 g (67%) of 60: mp 101-103 °C; IR (KBr) 1635, 1610, 1255,
1220 cm-1 1H NMR (CDCl3) δ 2.30 (quint, J ) 6 Hz, 2H,
;
OCH2CH2), 3.77 (t, J ) 6 Hz, 2H, CH2Cl), 4.23 (t, J ) 6 Hz,
2H, OCH2), 6.87 (d, J ) 2.4 Hz, 1H, 8-H), 7.02 (dd, J ) 9 and
2.4 Hz, 1H, 6-H), 8.10 (s, 1H, 2-H), 8.16 (d, J ) 9 Hz, 1H, 5-H);
13C NMR (CDCl3) δ 31.81 (OCH2CH2), 41.08 (CH2Cl), 65.00
(OCH2), 100.72 (8-C), 115.38 (6-C), 117.20 (4a-C), 120.61 (3-
C), 127.50 (5-C), 151.53 (2-C), 157.58 (8a-C), 163.25 (7-C),
171.51 (4-C). Anal. (C12H10Cl2O3) C, H, Cl.
7-(3-Ch lor op r op oxy)-3-flu or och r om en -4-on e (61).
A
solution of 1 g (3.5 mmol) of 53 and 1.2 g (3.5 mmol) of 85%
1-fluoro-2,4,6-trimethylpyridinium triflate in 10 mL of dichlo-
romethane and 10 mL of acetonitrile was heated at reflux for
1 h. After cooling to room temperature, an additional 0.5 g
(1.5 mmol) of fluoropyridinium triflate was added, and the
solution was stirred for 2 h at room temperature. Then, the
solution was poured onto diluted hydrochloric acid and was
stirred for 15 min. The organic extract was washed with
diluted HCl and evaporated to give 1 g of crude 61, which was
purified on column chromatography (3:1 C6H6-Et2O) to afford
0.6 g (66%) of title compound: mp 89-91 °C; 1H NMR (CDCl3)
δ 2.30 (quint, J ) 6 Hz, 2H, OCH2CH2), 3.77 (t, J ) 6 Hz, 2H,
CH2Cl), 4.22 (t, J ) 6 Hz, 2H, OCH2), 6.88 (d, J ) 2.4 Hz, 1H,
8-H), 7.00 (dd, J ) 9 and 2.4 Hz, 1H, 6-H), 8.08 (d, J ) 3.6 Hz,
1H, 2-H), 8.16 (d, J ) 9 Hz, 1H, 5-H). Anal. (C12H10ClFO3)
C, H, Cl.
7-(3-Ch lor opr opoxy)-3-for m ylch r om en -4-on e (62). Phos-
phoryl chloride (30 mL, 214 mmol) was added dropwise to a

2970 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 15
Bolo´s et al.
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slight head rotation movements and intermittent sniffing, 1;
intense head movements, mild licking, and continuous sniffing,
2; and intense sniffing, licking, and gnawing, 3. Results are
expressed as percent inhibition of treated groups with respect
to controls.
Ca ta lep sy in Ra ts.28 Rats were dosed with vehicle or with
test compounds. At 30, 60, 90, 120, 180, and 300 min after
dosing, each rat’s forepaws were elevated by placing them on
a wooden bar 9 cm high, and then, on a bar 3 cm high. It was
scored 1 for each forepaw that remained on the 9 cm bar for
10 s and 0.5 for each forepaw on the 3 cm bar. Additionally,
a homolateral leg crossing was effected, and was scored 1 if
position was maintained for 10 s. For each dosage group,
scores were totaled, and results are expressed as percent with
respect to maximum possible score (4 for each animal).
Ack n ow led gm en t. We thank Mr. J oan Nieto and
Mr. Miguel Gonza´lez for accurate synthetic work. Many
thanks are also due to Mrs. Marta Pr´ıncep and to Miss
Marta Sans for performing pharmacological tests and
to Mr. J osep M. Ferna´ndez for analytical determina-
tions.
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