(S)-(-)-4-[4-[2-(isochroman-1-yl)ethyl]-piperazin-1- yl]benzenesulfonamide, a selective dopamine D4 antagonist

Full text of DOI:10.1021/jm960084f

© Copyright 1996 by the American Chemical Society
Volume 39, Number 13
J une 21, 1996
Communications to the Editor
At the same time, clozapine's affinity for the D4 receptor
may play a part in its atypical nature.
(S)-(-)-4-[4-[2-(Isoch r om a n -1-yl)eth yl]-
p ip er a zin -1-yl]ben zen esu lfon a m id e, a
Selective Dop a m in e D4 An ta gon ist
Ruth E. TenBrink,*,† Carol L. Bergh,†
J . Neil Duncan,‡ Douglas W. Harris,§ R. M. Huff,
Robert A. Lahti,| Charles F. Lawson,#
Barry S. Lutzke,# Iain J . Martin,‡ Susan A. Rees,‡
Siusaidh K. Schlachter,# J ohn C. Sih,∇ and
Martin W. Smith#
Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49001
Received J anuary 26, 1996
Schizophrenia affects about 1% of the population
worldwide.1 The onset of symptoms is generally in the
late teens to early twenties. There is no cure for the
disease, and current therapies have numerous, debili-
tating side effects. The combination of early onset of
chronic disease and problematic therapies results in
high costs for the patient, his or her family, and society
at large.2 While the etiology of schizophrenia remains
unknown, several lines of research point to the dopam-
inergic system,3 and, in particular, the dopamine D4
receptor, as important in schizophrenia and psychotic-
type diseases in general.4
Classical antipsychotics such as haloperidol, though
effective in treating certain schizophrenic states, cause
extrapyramidal side effects and tardive dyskinesias.
These side effects have been linked to the blockade of
dopamine receptors in the striatum.5 Clozapine (1), an
“atypical” antipsychotic, is relatively free of extrapyram-
idal side effects, but causes tachycardia (25%), sialor-
rhea (30%), dizziness (20%), drowsiness and sedation
(40%), and agranulocytosis (1-3%). Many of these side
effects can be attributed to clozapine's high affinity for
a number of central nervous system (CNS) receptors.6
Some years ago, we prepared a series of dimethoxy-
isochromans, typified by 2, as antihypertensives work-
ing through the R-adrenergic receptors.7 More recently,
the in vitro examination of these compounds against a
panel of CNS receptors revealed them to have high
affinity for the D4 (hD4.2) receptor (vide infra) and,
importantly, some preference for the D4 vs the D2
receptor.8 We then set out to prepare analogs with high
affinity and selectivity for the D4 receptor with the
expectation that side effects would be reduced with
minimal binding at other receptors.
Sch em e 1
† Structural, Analytical, and Medicinal Chemistry, Kalamazoo, MI.
‡ Metabolism and Pharmacokinetics, Crawley, U.K.
§ Cardiovascular Pharmacology, Kalamazoo, MI.
CNS Diseases Research, Kalamazoo, MI.
| Current address: Maryland Psychiatric Research Center, Balti-
more, MD.
#
Chemical and Biological Screening, Kalamazoo, MI.
∇ Chemical Process R&D, Kalamazoo, MI.
S0022-2623(96)00084-2 CCC: $12.00 © 1996 American Chemical Society

2436 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13
Communications to the Editor
Ta ble 1. Binding Affinities (Ki, nM) of Isochromans at Various CNS Receptorsa
compd
D1
D2
D3
D4
5-HT1A
5-HT2
2.1
R1
R2
(75%)
2
26
400
nt
24
93
(100%)
(24-29)
410
(280-560)
160
(72-120)
120
(1.9-2.3)
5.8
7a
240
3.0
38
140
(310-540)
>2400
(140-180)
1100
(800-1500)
790
(590-1100)
>1800
(220-270)
(2.8-3.3)
(100-130)
1100
(860-1340)
490
(400-600)
>1600
(5.7-5.9)
76
(69-84)
28
(27-29)
30
(28-32)
>1800
(36-40)
(120-170)
7b
1200
1.4
1280
1800
(950-1500)
1300
(930-1700)
220
(170-290)
5800
(3900-8600)
2900
(1.3-1.6)
2.2
(2.0-2.5)
25
(23-28)
7.2
(6.6-7.8)
100
(900-1800)
(20%)
(1200-2700)
(9%)
S-(-)-7b
R-(+)-7b
S-(-)-15
R-(+)-15
1
>2400
>2400
(20%)
(17%)
(36%)
>4900
(41%)
(0%)
>4300
>3700
>2600
(15%)
5600
2400
(1600-3800)
150
(4%)
(3600-8800)
(1900-4300)
280
(90-110)
32
170
(140-200)
55
3.8
(3.4-4.2)
(46-65)b
138c
(230-350)b
(30-35)b
9c
(140-160)
82d
29d
3
398
530
21
94
a
The numbers in parentheses represent 95% confidence intervals associated with the Ki values. Membranes prepared from cloned
mammalian receptors expressed in cultured cells or from rat whole brain (adrenergic receptors) were used as the source of binding sites.
The radioligands used were [3H]SCH23390 (D1), [3H]U-86170 (D2),12 [3H]spiperone (D3 and D4),13 [3H]-8-OH-DPAT (5-HT1A), [3H]ketanserin
(5-HT2), [3H]prazosin (R1-adrenergic), and [3H]clonidine (R2-adrenergic). Binding data are given either as binding constant (Ki) in nM (
b
SEM or as % inhibition when tested at 1 µM concentration (n ) 3). Reference 14. c Reference 4a. The ligand is [3H]spiperone for both
d
D2 and D4. Reference 8. The ligand is [3H]YM-09151-2 for both D2 and D4.
Resu lts a n d Discu ssion . Removal of the dimethoxy
groups of 2 led to 7a , which exhibited an increased
preference for the D4 over the D2 receptor. However,
7a retained significant binding at other CNS receptors
(Table 1). Additional racemic, desmethoxyisochromans
were synthesized by the method shown in Scheme 1.
Mixed acetal 5, prepared from 4, was isolated and
carried on to the chloromethyl intermediate 6, using
AlCl3 as the Lewis acid. Displacement of the chloro
group with aryl piperazines gave final products 7a and
7b. Compound 7b was found to have a 400-fold prefer-
ence for the D4 vs D2 receptors.
Sch em e 2
Further analog work required an improved synthesis
of the isochroman system, as well as a handle for
resolution at the chiral center. The route shown in
Scheme 2, using TiCl4 as the Lewis acid and ethyl 3,3-
diethoxypropionate (8) as the acetal, gave ester 9 in
excellent yield. Originally, the enantiomers of 7b were
obtained through fractional crystallization of racemic
acid 10 with (R)-(+)-R-methylbenzylamine and (S)-(-)-
R-methylbenzylamine, followed by borane reduction of
11 and 12 to give alcohols 13 and 14, respectively.
HPLC using a Daicel OJ column indicated >99% ee for
13 by this method. Another method of resolution
involved the Amano PS-30 lipase-mediated hydrolysis
of ester 9 to give 11 (Scheme 3). Acid 11 was then
reduced to the alcohol 13 with borane-methyl sulfide.
HPLC analysis (Daicel OJ or OD column) of the alcohol
indicated >99% ee. Mesylation of the alcohol, followed
by displacement of the mesylate with 4-(piperazin-1-yl)-
benzenesulfonamide, gave (S)-(-)-15 (U-101387), whose
absolute configuration was determined by X-ray crystal-
lography.9 Chiral chromatography using a Chiralpak
AD column immersed in an ice bath (40% 2-propanol +
0.1% trifluoroacetic acid in hexane as eluant) gave
nearly baseline separation (R ) 1.33) of (S)-(-)-15 and
(R)-(+)-15, but tailing precluded an accurate estimation
of % ee; the chiral purity of alcohol 13 was taken as
indicative of the % ee of the final product, (S)-(-)-15.
Table 1 details the binding affinities of selected
isochromans and also, for comparison, clozapine and J L
18 (3), a clozapine analog reported to have increased
dopamine D4 selectivity over that of clozapine.10 The
first analog in the isochroman series to show a reason-
able degree of selectivity was 7b. When the individual
enantiomers were prepared, (S)-(-)-7b was shown to
have a higher affinity for the dopamine D4 receptor
when compared to (R)-(+)-7b, while binding at the D2
receptor remained the same. Unfortunately, metabo-
lism and bioavailability studies indicated (S)-(-)-7b was
rapidly metabolized, principally through an O-demethy-

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 13 2437
Sch em e 3
search Preparations, Pharmacia & Upjohn, for scale-
up of the lipase-mediated hydrolysis of 9; and Lester A.
Dolak, Chemical and Biological Screening, Pharmacia
& Upjohn, for chiral HPLC of (S)-(-)-15.
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for compounds in this paper (8 pages). Ordering information
is given on any current masthead page.
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(9) The structure of S-(-)-15 (as its methanesulfonate salt), which
crystallized in the monclinic space group P21 with Z ) 4, was
confirmed by x-ray using graphite monochromatized Cu KR
radiation. The absolute configuration was determined to be S
by the method of Bijvoet (Endeavour 1955, 14, 7) by comparison
of accurate measurements of 18 reflections which were very
strongly influenced by anomalous dispersion (36 Friedel pairs).
All 36-comparisons indicated unequivocally that the enantiomer
shown is the correct one. The final agreement index R was 0.052
for 4072 reflections.
(10) Lie´geois, J .-F; Bruhwyler, J .; Damas, J .; Rogister, F.; Masereel,
B.; Geczy, J .; Delarge, J . Modulation of the clozapine structure
increases its selectivity for the dopamine D4 receptor. Eur. J .
Pharmacol. 1995, 273, R1-R3.
(11) Drug levels were determined after an i.v. injection of 23
micromoles of (S)-(-)-15 into the mouse tail vein. Brain (nmol/
g) and plasma (nmol/mL) concentrations were measured at 5
and 60 min.
(12) Ennis, M. D.; Baze, M. E.; Smith, M. W.; Lawson, C. F.; McCall,
R. B.; Lahti, R. A.; Piercey, M. F. Novel indolodioxanes with
antihypertensive effects: potent ligands for the 5-HT1A receptor.
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303-307.
F igu r e 1. Antagonism of quinpirole-induced mitogenesis in
CHO cells expressing the human D4 receptor.15 Quinpirole
(300 nM) was added to cells, along with the test compound
(1µ M) or sterile water, 16-18 h prior to the addition of [3H]-
thymidine (1 µCi/well). After 2 h of incubation, the cells were
harvested onto filter mats and counted.
lation (as indicated by monkey and human microsome
studies). Further analog work led to benzenesulfon-
amide (S)-(-)-15; this compound exhibits remarkable
selectivity for the D4 receptor (Table 1) vs both the
receptors shown in Table 1 and a panel of some 50
receptors as assayed by Novascreen (Oceanix Bio-
sciences, Inc.). As with 7b, the (S)-(-)-15 has higher
affinity at the D4 receptor when compared to the (R)-
(+)-enantiomer.
A comparison of (S)-(-)-7b and (S)-(-)-15 (as the
maleate salt) indicated a 15% oral bioavailability in the
rat for S-(-)-7b, vs a 66% oral bioavailability for the
sulfonamide analog (S)-(-)-15. Indeed, (S)-(-)-15 was
found to be a potent D4 antagonist (Figure 1) with a
monkey oral bioavailability of 76% and a half-life of 13.6
h. Penetration into the brain (mouse parenchyma) is
rapid, and brain vs plasma concentration is high.11 In
summary, the high affinity and specificity of (S)-(-)-15
for the dopamine D4 receptor make this compound a
unique tool for the study of the role of the D4 receptor
in normal and pathological states. (S)-(-)-15 has been
entered into phase II clinical trials for the treatment of
schizophrenia.
(15) Chio, C. L.; Drong, R. F.; Riley, D. T.; Gill, G. S.; Slighthom, J .
L.; Huff, R. M. D4 dopamine receptor-mediated signaling events
determined in transfected Chinese hamster ovary cells. J . Biol.
Chem. 1994, 269, 11813-11819.
Ack n ow led gm en t. We would like to thank Con-
stance G. Chidester, Structural, Analytical, and Me-
dicinal Chemistry, Pharmacia & Upjohn, for the X-ray
determination of (S)-(-)-15; Allen Scott, Chemical Re-
J M960084F