Aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines as potential antipsychotic agents: Synthesis and structure-activity relationships

Article abstract of DOI:10.1021/jm950721m

A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6- tetrahydropyridines with dopaminergic activity is described. The structure- activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D₂ receptor and inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and aryl groups were varied. Compounds having a 4-phenyl- 1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to have exceptional in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological activity including binding affinities for other DA receptor subtypes as well as effects on brain DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.

Full text of DOI:10.1021/jm950721m

J . Med. Chem. 1996, 39, 3179-3187
3179
Ar yl 1-Bu t-3-yn yl-4-p h en yl-1,2,3,6-tetr a h yd r op yr id in es a s P oten tia l
An tip sych otic Agen ts: Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s
Shelly A. Glase,* Hyacinth C. Akunne, Thomas G. Heffner, J uan C. J aen, Robert G. MacKenzie,
Leonard T. Meltzer, Thomas A. Pugsley, Sarah J . Smith, and Lawrence D. Wise
Departments of Chemistry and Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company,
Ann Arbor, Michigan 48105
Received September 29, 1995X
A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic
activity is described. The structure-activity relationships of this series were studied by
synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and
inhibition of locomotor activity (LMA) in rodents. The basic amine, alkyne chain length, and
aryl groups were varied. Compounds having a 4-phenyl-1,2,3,6-tetrahydropyridine and an aryl
group with hydrogen-bonding substituents separated by a butynyl chain were found to have
the most potent dopaminergic activity. Several compounds that were found to have exceptional
in vivo activity in LMA inhibition in rodents were evaluated for additional pharmacological
activity including binding affinities for other DA receptor subtypes as well as effects on brain
DA synthesis, DA neuronal firing, and conditioned avoidance responding in squirrel monkeys.
In tr od u ction
Schizophrenia is generally believed to involve mani-
festations of an excessive dopaminergic neurotransmis-
sion in the brain.1 Blockade of postsynaptic dopamine
(DA) D2 receptors is a characteristic common to all
effective antipsychotics in clinical use today. Serious
side effects of extrapyramidal syndrome, tardive dys-
kinesia, and hyperprolactinemia, which are associated
with this class of drugs, have also been linked to their
postsynaptic DA receptor blockade.2 An alternative to
the use of DA receptor antagonists would be to regulate
DA neuronal function by activation of presynaptic DA
receptors (DA autoreceptors). Their stimulation inhibits
DA neuronal firing, synthesis, and release.3 In order
to be a viable antipsychotic agent, the DA agonist must
selectively activate presynaptic DA receptors, since
postsynaptic stimulation would tend to exacerbate
psychotic symptoms.4
Traditional DA autoreceptor agonists can be classified
as compounds derived from dopamine or the ergot
skeleton. Notable examples are (-)-3-PPP (1)5 and
terguride (2)6 which incorporate a dopaminergic phar-
macophore into rigid structures. There are many more
D2 agonists that are linear, flexible compounds that do
not easily fit the conventional models of the D2 receptor.
Some examples of this class are roxindole (3)7 and the
(aminoalkoxy)aniline 4.8 The flexibility of roxindole
allows it to be superimposed over apomorphine with the
indolic NH group acting as the m-hydroxy group of
dopamine.9 It is therefore reasonable to believe that
the agonist activity of 4 could be explained in a similar
isosteres and a basic amine functional group separated
manner.
by an alkynyl carbon chain (Figure 1). To understand
Interestingly, the more rigid, linear compound PD
the structure-activity relationship (SAR) of this new
class of compounds, three structural features were
investigated as follows: the aryl group, the alkyne chain
length, and the basic amine ending.
135385 (5)10 was found to be a selective DA D2 agonist.
It is unlikely that the activity of this compound can be
explained using the apomorphine backbone model. To
determine whether other rigid, linear analogs would be
equally potent and selective DA autoreceptor agonists,
we prepared a series of compounds containing phenolic
Ch em istr y
The compounds found in Tables 1-3 were synthesized
in one of four ways as shown in Scheme 1. Method A
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
S0022-2623(95)00721-7 CCC: $12.00 © 1996 American Chemical Society

3180 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Glase et al.
Since arylpiperazines and 4-aryl-1,2,3,6-tetrahydro-
pyridines are common amine endings found in DA
autoreceptor agonists (3-5),7,8,10 the SAR of the butynyl
series was explored further by substitution of a number
of these amines (Table 2). Of the amine endings that
were examined, the aryltetrahydropyridines 10 and 12
had the best dopaminergic activity. Compound 12 had
only moderate binding affinity (Ki ) 255 nM) but still
possessed potent inhibition of LMA in mice with an ED50
value of 0.86 mg/kg ip. Of the arylpiperazines that were
examined, 13 and 14 had weak binding affinity for the
DA D2 receptor (Ki ) 1673 and 5388 nM) but retained
significant inhibition of mouse LMA (ED50 values of 4.7
and 2.2 mg/kg ip). These results may be explained in a
number of ways including activation of other receptors
or formation of active metabolites. The pyrimidinylpip-
erazine 15 was inactive in DA D2 binding and rodent
LMA tests. Because of the high D2 affinity and LMA
potency of compound 10, 4-phenyl-1,2,3,6-tetrahydro-
pyridine was selected as the best amine ending to use
in subsequent SAR studies.
F igu r e 1.
provided a convenient means to vary the amine ending.
An aryl halide was coupled to an alkynyl alcohol in 40-
70% yield with bis(triphenylphosphine)palladium(II)
chloride and copper iodide in refluxing dichloromethane
with triethylamine.11 The resulting arylalkynyl alcohol
was converted to the mesylate under standard condi-
tions followed by displacement with the desired amine
in DMF in the presence of a base such as triethylamine
or sodium bicarbonate. When n ) 1 and 3, the yield
from the alcohol to the final product was typically 40%,
but when n ) 2, elimination of the mesylate to the enyne
was prevalent resulting in yields less than 20%.
The majority of the compounds were prepared by
coupling 6 to an aryl halide with a palladium catalyst
(method B). The butynylamine 6 was obtained by
reacting 3-butynyl p-toluenesulfonate with 4-phenyl-
1,2,3,6-tetrahydropyridine in DMF at 70 °C in the
presence of sodium bicarbonate. The catalyst used in
method B was palladium(II) acetate with triphenylphos-
phine in piperidine at 100 °C.12
Two additional palladium-coupling procedures are
shown in methods C and D. In method C, 6 is reacted
with an aryl halide in the presence of bis(triphenylphos-
phine)palladium(II) chloride with copper iodide in dichlo-
romethane or acetonitrile. Method D uses tetrakis-
(triphenylphosphine)palladium(0) in refluxing butylamine
to effect the coupling of 6 to the aryl halide.13 The rate
and yields of the various palladium-coupling reactions
ranged from 25% to 81% depending on the functionality
on the aryl halide. This reaction is facilitated by
electron-withdrawing groups ortho or para to the ha-
lide.14
The 4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-bu-
tyne (6), having the optimal combination of alkyne chain
length and amine ending, was used to prepare a variety
of analogs (Table 3). The simple phenyl analog 16 had
moderate DA D2 affinity (Ki ) 284 nM) and was weak
in inhibiting LMA (ED50 ) 9.5 mg/kg, mouse ip). Since
classical dopamine agonist pharmacophores contain a
hydrogen-bonding moiety like a catechol or phenol,
compound 17 was prepared. The binding affinity for
the DA D2 receptor and the inhibition of LMA improved
considerably (Ki ) 54 nM and ED50 ) 1.5 mg/kg, mouse
ip) from the unsubstituted phenyl. As expected, 17 was
not active orally (ED50 > 30 mg/kg, rat LMA po) since
phenols are known to have poor oral bioavailability.17
The phenol was replaced by an indole, which is a
common bioisosteric replacement for phenol and cat-
echol.18 Even though compound 18 had only moderate
DA D2 binding affinity compared to the phenol analog
17 (Ki ) 193 nM compared to 53 nM), 18 had equivalent
activity to 17 in mouse LMA ip and oral activity in rat
LMA with an ED50 value of 5.2 mg/kg po. Several
additional nitrogen-containing heterocycles were pre-
pared. The 4- and 3-pyridyl analogs 19 and 10 had very
similar profiles, with DA D2 affinities of 32 and 37 nM
and ED50 values of 0.1 and 0.07 mg/kg in mouse LMA
ip. It is interesting to note that the activity for the
2-pyridyl analog 20 dropped significantly. While the DA
D2 binding affinity for the quinoline 8 was essentially
the same as for the corresponding pyridine 10 (Ki ) 30
versus 37 nM), the binding affinity for the isoquinoline
21 was weaker (Ki ) 73 nM). The three aniline analogs
22-24 show the same trends in dopaminergic activity
as the pyridine series. The para- and meta-substituted
compounds 22 and 23 had higher DA D2 binding affinity
(Ki ) 48 and 87 nM versus 183 nM) and inhibition of
rodent LMA than the ortho 24 (ED50 values of 0.36 and
0.68 mg/kg versus 1.6 mg/kg in mice ip). One might
conclude from this, and the similar results for the
pyridine series, that there is an important hydrogen-
bonding interaction that can only be satisfied by sub-
stitution in the meta and para positions. The in vitro
and in vivo activities of the two aminopyridine analogs
25 and 26 were also comparable to their pyridine (19
and 10) and aniline (22 and 23) counterparts. Ad-
Resu lts a n d Discu ssion
The first three tables summarize the results of the
SAR studies including variation of the alkyne chain
length (Table 1), basic amine ending (Table 2), and aryl
group (Table 3). The compounds in these tables were
evaluated for their affinity for the DA D2 receptor in
rat striatal membrane with the antagonist ligand [3H]-
spiperone15 and for their ability to inhibit spontaneous
locomotor activity (LMA) in mice (ip) and rats (po).16
Several compounds that were particularly potent in
these tests were then subjected to additional receptor
binding and secondary pharmacological tests to deter-
mine their level of agonist activity and efficacy in a
primate antipsychotic model (Tables 4 and 5).
Compound 7 (Table 1), where n ) 1, had no significant
affinity for the DA D2 receptor and was inactive in
mouse LMA. The butynyl analogs 8 and 10, however,
demonstrated very good dopaminergic activity with Ki
values of 30 and 37 nM for the DA D2 receptor. Both
compounds were quite potent in vivo. Compound 8
inhibited LMA with an ED50 value of 1.1 mg/kg in both
mouse (ip) and rat (po), while 10 inhibited LMA in
mouse and rat with ED50 values of 0.07 mg/kg ip and
1.4 mg/kg po. The pentynyl analogs 9 and 11 had
slightly lower binding affinity and in vivo activity than
their butynyl counterparts. Butyne was determined to
be the optimal chain length and was used in subsequent
SAR studies.

Aryl Tetrahydropyridines as Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3181
Sch em e 1a
a
Method A: (a) (PPh3)2PdCl2, CuI, Et3N, CH2Cl2; (b) MsCl, iPr2NH, CH2Cl2; (c) NaHCO3 or Et3N, DMF. Method B: (a) NaHCO3,
DMF; (b) Pd(OAc)2, PPh3, piperidine. Method C: (a) NaHCO3, DMF; (b) (PPh3)2PdCl2, CuI, Et3N, CH2Cl2 or CH3CN. Method D: (a)
NaHCO3, DMF; (b) Pd(PPh3)4, BuNH2.
Ta ble 1. Variation of Alkyne Chain Length
a
[3H]Spiperone in rat striatum; Ki values were obtained from four to six concentrations, run in triplicate, by a nonlinear regression
analysis. LMA ) locomotor activity; ED50 values generated from three to six doses, n ) 6-18 animals/dose. c Not tested.
b
ditional oxygen-containing analogs 27-29 were also
prepared but showed no improvement over the phenol
17. The best aryl groups (Ar1) were those containing
nitrogen in the meta or para position. Because of their
good DA D2 binding affinity and high potency in
inhibiting LMA in rodents, several of these aniline and
pyridine analogs were selected to undergo additional
receptor binding and pharmacological testing (Tables 4
and 5).
Table 4 summarizes the results of additional dopam-
inergic, serotonergic, and adrenergic binding for several
of the best compounds selected from Table 3. None of
the compounds had significant binding affinity for DA
D1 receptors19 and very little binding affinity for DA D4
receptors.20 The binding to DA D2 high-affinity sites
was determined with the use of the DA agonist ligand
[3H]-n-propylnorapomorphine ([3H]NPA).21 These com-
pounds, as expected of DA agonists, exhibited a greater
affinity for DA agonist-labeled receptors than for DA
antagonist-labeled sites (Table 3). They were also found
to have high affinity for the DA D3 receptor (0.36-24
nM), which may contribute to the observed inhibition
of LMA22 and decreased dopamine synthesis.23 Only
compound 26 showed even moderate affinity (69 nM)
for 5-HT1a receptors.24 All of the compounds in Table
4, except 23, had moderate (14.1-57.5 nM) affinity for
R1 receptors.25
The results of tests to determine autoreceptor agonist
efficacy are shown in Table 5. In vitro, DA D2 receptor
activation stimulates [3H]thymidine uptake in CHO p-5
cells.20,26 When compared to the 100% maximal stimu-
lation of mitogenesis by the full DA agonist quinpirole,
the compounds described appear to be partial agonists
with maximal stimulation of 49-85% and EC50 values
of 0.5-1.7 nM. In vivo, DA autoreceptor agonist activity
was evaluated by the ability of a compound to reverse
the γ-butyrolactone (GBL)-induced increase in DA syn-
thesis in rats, as measured by the rate of DOPA
formation in rat striatum following decarboxylase in-
hibition.27 The percent decrease of DOPA synthesis
ranged from 42% to 79% at 10 mg/kg ip, suggestive of
partial agonist activity at terminal DA autoreceptors.

3182 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Ta ble 2. Variation of Amine Ending
Glase et al.
Ta ble 3. Variation of Aryl Group
a-c See footnotes for Table 1.
Autoreceptor agonist activity was also determined elec-
trophysiologically by measuring the inhibition of DA
neuronal firing in the substantia nigra of anesthetized
rats.28 In this test, all of the compounds listed in Table
5, except 25, caused complete inhibition of DA neuronal
firing at 2.5 mg/kg ip. Stimulation of LMA at higher
doses (30 mg/kg ip in mice and 100 mg/kg po in rats),
which is indicative of postsynaptic receptor activation,
was not observed for the compounds described here. The
apparent selectivity of some DA agonists for the au-
toreceptor may be due to the much larger receptor
reserve of presynaptic versus postsynaptic DA D2 recep-
tors.29,30 Consideration of the present results leads us
to conclude that these compounds are partial DA
agonists.
The compounds in Table 5 were also evaluated in the
Sidman conditioned avoidance test in squirrel mon-
keys,31 a primate test which has been correlated with
antipsychotic efficacy in humans.32 Compounds 22 and
25 had good activity at 2.8 and 3.8 mg/kg po; 26 was
especially potent with an ED50 value of 0.43 mg/kg.
A comparison of roxindole (3) to 26 (Table 6) shows
that 26 has weaker binding affinity for the D2 family of
receptors. Both compounds were equally effective in
mouse LMA ip, but roxindole was less active orally in
rats (12.8 mg/kg), suggesting differences in bioavail-
ability. No stimulation of LMA was observed at high
doses for either compound, indicating lack of significant
postsynaptic stimulation. In tests to determine intrinsic
activity (receptor mitogenesis, DOPA synthesis, and DA
neuronal firing), 26 and roxindole appear to have
similar agonist profiles. While 26 inhibited conditioned
avoidance in the squirrel monkey at 0.43 mg/kg, roxin-
dole was inactive. In clinical trials, roxindole was found
to be ineffective and even exacerbated psychotic symp-
toms in some schizophrenic patients.33
a,b
See footnotes for Table 1.
through a 1-butynyl chain. A number of compounds in
this series bind selectively to DA D2 and D3 receptors
and have excellent in vivo activity in rodent LMA.
These compounds stimulated mitogenesis in CHO p-5
cells transfected with the human D2L receptor, reversed
GBL-stimulated brain DA synthesis, and inhibited DA
neuronal firing in rats, effects consistent with DA
autoreceptor activation. In addition, compounds 22, 25,
and 26 have good oral activity in a primate model of
antipsychotic activity. This indicates that building
rigidity into this type of chemical system does not
diminish dopaminergic activity.
Con clu sion
This study has identified a novel series of aryl 1-but-
3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with DA
receptor activity. Optimal activity is obtained when
an aryl group, with meta or para H-bonding substitu-
ents, is attached to 4-phenyl-1,2,3,6-tetrahydropyridine

Aryl Tetrahydropyridines as Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3183
Ta ble 4. Evaluation of Selected Compounds in Receptor
Binding
The above alcohol (4.0 g, 20 mmol) was reacted with
4-phenyl-1,2,3,6-tetrahydropyridine (6.45 g, 40 mmol) as de-
scribed in the second step of the synthesis of 7. Purification
by MPLC on silica gel eluting with 2% MeOH/CH2Cl2 gave 8
(0.78 g, 11%) as a yellow solid: mp 94-96 °C; IR (KBr) 3450,
receptor binding Ki (nM)
a
b
c
c
d
e
compd no.
D1
D2
hD3
hD4
5-HT1a
R1
1
2939, 1670, 1646, 741 cm-1; H NMR (CDCl3) δ 2.62 (m, 2H),
10
19
22
23
25
26
5004
3.3
4.1
0.67 24
20
6.5
681
570
228
555
593
>10 000
14.1
25.8
34.5
2.72-2.90 (m, 6H), 2.27-3.30 (m, 2H), 6.08 (m, 1H), 7.21-
7.42 (m, 5H), 7.54 (t, 1H, J ) 7.2 Hz), 7.65-7.76 (m, 2H), 8.07
(d, 1H, J ) 8.4 Hz), 8.17 (s, 1H), 8.88 (s, 1H); MS (EI) m/z 338
(9.2), 172 (100). Anal. (C24H22N2‚0.09H2O) C, H, N, H2O.
>10 000
18
0.36
7.0
2.6
1547 107
632
69
>10 000 19
>10 000 1.9
278
371
55.8
57.5
3-[5-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-pen tyn yl]-
qu in olin e (9). 3-Bromoquinoline (13.6 mL, 0.10 mol) was
coupled to 4-pentyn-1-ol (11.1 mL, 0.12 mol) as described in
the first step of the synthesis of 7. Purification by MPLC on
silica gel eluting with 2% MeOH/CH2Cl2 gave 5-(3-quinolinyl)-
4-pentyn-1-ol (16.3 g, 78%) as a yellow solid: mp 55-56 °C;
a
b
[3H]SCH 23390. [3H]NPA. c [3H]Spiperone, human DA D3
and D4 receptors expressed in CHO K1 cells. [3H]-8-OH-DPAT.
d
e [3H]Prazosin.
Exp er im en ta l Section
IR (CHCl3 solution) 3437, 2928, 1805, 1490, 1466, 1025 cm-1
;
Melting points were determined on a Gallenkamp capillary
melting point apparatus and are uncorrected. 1H NMR were
determined for CDCl3 or DMSO-d6 solutions on Varian Gemini-
200, XL-300, or 400 and Bruker AM 250 spectrometers. The
peaks are described in ppm downfield from TMS (internal
standard). IR spectra were recorded on a Nicolet MX-1 FT
spectrophotometer. Mass spectra were obtained on a Finnigan
4500 or a VG analytical 7070E/HF mass spectrometer. Rela-
tive intensity values are listed in parentheses. Elemental
analyses were performed by the Analytical Research Section
at Parke-Davis, Ann Arbor, MI. TLC was performed on 0.25
mm silica gel F254 (E. Merck) glass plates. Medium pressure
liquid chromatography (MPLC) was performed on silica gel
(E. Merck grade 60, 230-400 mesh, 60 Å).
1H NMR (DMSO-d6) δ 1.72-1.83 (m, 2H), 2.59 (t, 2H, J ) 7.2
Hz), 3.57-3.63 (m, 2H), 4.65 (t, 1H, J ) 5.4 Hz), 7.62-7.68
(m, 1H), 7.76-7.82 (m, 1H), 7.96-8.06 (m, 2H), 8.45 (s, 1H),
8.87 (s, 1H); MS (EI) m/z 211 (100), 192 (48), 182 (46), 167
(56), 155 (45), 139 (31). Anal. (C14H13NO) C, H, N.
The above alcohol (2.0 g, 9 mmol), triphenylphosphine (2.98
g, 11 mmol), and imidazole (0.6 g, 9 mmol) were combined in
CCl4 (10 mL) and CH3CN (10 mL), and the reaction mixture
was stirred for 2 h at 20 °C. The reaction mixture was
concentrated in vacuo and filtered through silica gel eluting
with 50% EtOAc/hexanes. The chloride (1.7 g, 86%) was
obtained as a yellow oil: IR (CHCl3 solution) 3400, 3055, 2218,
1610, 1590, 1560 cm-1; 1H NMR (CDCl3) δ 2.04-2.16 (m, 2H),
2.69 (t, 2H, J ) 6.8 Hz), 3.75 (t, 2H, J ) 6.4 Hz), 7.50-7.56
(m, 1H), 7.66-7.76 (m, 2H), 8.07 (d, 1H, J ) 8.3 Hz), 8.17 (s,
1H), 8.86 (s, 1H); MS (EI) m/z 229 (43), 194 (100), 166 (70),
139 (47); TLC (50% EtOAc/hexane) Rf ) 0.35.
Meth od A. 3-[3-(3,6-Dih yd r o-4-p h en yl-1(2H)-p yr id i-
n yl)-1-p r op yn yl]qu in olin e (7). To a degassed (N2) solution
of propargyl alcohol (17.5 mL, 0.30 mol), 3-bromoquinoline
(27.1 mL, 0.20 mol), and triethylamine (83.6 mL, 0.60 mol) in
CH2Cl2 (160 mL) were added copper(I) iodide (0.26 g, 1.4 mmol)
and bis(triphenylphosphine)palladium(II) chloride (1.4 g, 2.0
mmol). The reaction mixture was heated at reflux under N2
for 5 h, cooled, diluted with CH2Cl2 (200 mL), and washed with
water (4 × 200 mL). The organic phase was dried over Na2-
SO4, filtered, and concentrated in vacuo. Purification by
MPLC on silica gel eluting with 2% MeOH/CH2Cl2 gave 3-(3-
quinolinyl)-2-propyn-1-ol (19.3 g, 53%) as a white solid: mp
This chloride (1.5 g, 6.5 mmol), 4-phenyl-1,2,3,6-tetrahy-
dropyridine hydrochloride (1.53 g, 7.8 mmol), NaHCO3 (1.65
g, 19.6 mmol), and NaI (0.05 g, 0.3 mmol) were combined in
DMF (50 mL). The reaction mixture was stirred overnight at
80 °C, concentrated in vacuo, diluted with CH2Cl2 (100 mL),
and washed with water (100 mL). The organic phase was
dried over MgSO4, filtered, and concentrated in vacuo to
give 9 (0.95 g, 41%) as a yellow oil. This oil was purified by
MPLC on silica gel eluting with 1% MeOH/CH2Cl2 and
converted to the HCl salt: mp 191-192 °C; IR (KBr) 3455,
1
121-122 °C; H NMR (CDCl3) δ 4.40 (br s, 1H), 4.58 (s, 2H),
7.56 (t, 1H, J ) 6.9 Hz), 7.69-7.79 (m, 2H), 8.09 (d, 1H, J )
8.2 Hz), 8.22 (s, 1H), 9.04 (s, 1H); MS (EI) m/z 183 (100), 154
(85), 129 (40). Anal. (C12H9NO‚0.13H2O) C, H, N, H2O.
2574, 1566, 1488, 1446, 749 cm-1 1H NMR (DMSO-d6) δ
;
2.15 (m, 2H), 2.67-2.79 (m, 3H), 2.82-3.15 (m, 1H), 3.24-
3.40 (m, 3H), 3.65-3.90 (m, 2H), 4.01-4.15 (m, 1H), 6.21
(m, 1H), 7.21-7.50 (m, 5H), 7.72 (t, 1H, J ) 7.3 Hz), 7.86 (t,
1H, J ) 7.3 Hz), 8.02-8.12 (m, 2H), 8.85 (s, 1H), 9.02 (s, 1H);
MS (EI) m/z 351 (55), 184 (71), 128 (85), 115 (100). Anal.
(C25H24N2‚1.5HCl‚0.2H2O) C, H, N, Cl, H2O.
Methanesulfonyl chloride (1.9 mL, 25 mmol) was added
dropwise to a cold (0 °C) solution of the above alcohol (3.5 g,
19 mmol) and diisopropylethylamine (6.7 mL, 38 mmol) in CH2-
Cl2 (70 mL), and the mixture was stirred for 1 h. The solvent
was concentrated in vacuo without heating, and the resulting
residue was taken up in DMF (40 mL). To this solution was
added 4-phenyl-1,2,3,6-tetrahydropyridine (6.1 g, 38 mmol)
and triethylamine (13.2 mL, 95 mmol). The reaction mixture
was stirred overnight at 20 °C, concentrated in vacuo, diluted
with CH2Cl2 (100 mL), and washed with water (100 mL). The
organic phase was dried over MgSO4, filtered, and concen-
trated in vacuo to give 5 g of a dark yellow solid. This solid
was recrystallized from heptane to give 7 (2.5 g, 40%) as a
pale yellow solid: mp 100-101 °C; IR (KBr) 3413, 2904, 1489,
1324, 754, 741 cm-1; 1H NMR (CDCl3) δ 2.68 (m, 2H), 2.94 (t,
2H, J ) 5.7 Hz), 3.41 (m, 2H), 3.75 (s, 2H), 6.12 (m, 1H), 7.21-
7.43 (m, 5H), 7.55, (t, 1H, J ) 7.2 Hz), 7.67-7.78 (m, 2H), 8.08
(d, 1H, J ) 8.4 Hz), 8.33, (s, 1H), 8.92, (s, 1H); MS (EI) m/z
324 (62), 166 (100). Anal. (C23H20N2) C, H, N.
3-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
qu in olin e (8). 3-Bromoquinoline (20.4 mL, 0.15 mol) was
coupled to 3-butyn-1-ol (17.0 mL, 0.225 mol) as described in
the first step of the synthesis of 7 to give 4-(3-quinolinyl)-3-
butyn-1-ol (13 g, 44%) as a light brown solid: mp 96-97 °C;
IR (KBr) 3246, 2914, 2225, 1493, 1049, 785, 752 cm-1; 1H NMR
(CDCl3) δ 2.70-2.79 (m, 3H), 3.90 (m, 2H), 7.51-7.57 (m, 1H),
7.66-7.74 (m, 2H), 8.06-8.14 (m, 2H), 8.88 (s, 1H); MS (EI)
m/z 197 (90), 166 (100), 139 (41). Anal. (C13H11NO) C, H, N.
3-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
p yr id in e (10). 3-Bromopyridine (9.6 mL, 0.10 mol) was
coupled to 3-butyn-1-ol (9.0 mL, 0.12 mol) as described in the
first step of the synthesis of 7. Purification by MPLC on silica
gel eluting with 2% MeOH/CH2Cl2 gave the alcohol (7.36 g,
50%) as a gold oil: IR (CHCl3 solution) 3373, 2955, 2205, 1566
cm-1; 1H NMR (CDCl3) δ 2.71 (t, 2H, J ) 6.2 Hz), 3.01 (t, 1H,
J ) 5.8 Hz), 3.80-3.88 (m, 2H), 7.19-7.24 (m, 1H), 7.67 (m,
1H), 8.48 (d, 1H, J ) 4.9 Hz), 8.62 (s, 1H); MS (EI) m/z 147
(61), 117 (100), 89 (36), 63 (25); TLC (10% MeOH/CH2Cl2) Rf
) 0.28.
The above alcohol (4.0 g, 27 mmol) was reacted with
4-phenyl-1,2,3,6-tetrahydropyridine (6.45 g, 40 mmol) as de-
scribed in the second step of the synthesis of 7. Purification
by MPLC on silica gel eluting with 2% MeOH/CH2Cl2 gave 10
(1.34 g, 17%) as a dark yellow solid: mp 74-75 °C; IR (KBr)
3288, 2932, 2359, 1565, 1494, 1477, 1151 cm-1 1H NMR
;
(CDCl3) δ 2.54 (m, 2H), 2.60-2.67 (m, 2H), 2.72-2.79 (m, 4H),
3.18-3.21 (m, 2H), 6.01 (m, 1H), 7.11-7.34 (m, 6H), 7.61 (d,
1H, J ) 7.9 Hz), 8.41 (d, 1H, J ) 4.9 Hz), 8.57 (s, 1H); MS
(EI) m/z 288 (6), 172 (100). Anal. (C20H20N2) C, H, N.
3-[5-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-pen tyn yl]-
p yr id in e (11). 3-Bromopyridine (9.6 mL, 0.10 mol) was

3184 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Glase et al.
Ta ble 5. Evaluation of Selected Compounds in Secondary in Vivo Tests
DA D2 receptor mitogenesisa
decrease (%) of DOPA
decrease (%) of DA neuronal
firing (2.5 mg/kg, ip)e
inhibtn of conditioned
compd no. maximal effect (%)b
EC50 (nM)c
synthesis (10 mg/kg, ip)d
avoidance ED50 (mg/kg, po)f
10
19
22
23
25
26
64
77
49
75
54
85
1.7 (0.54-5.6)
1.0 (0.45-2.6)
0.5 (0.24-1.2)
9.8 (2.7-35)
0.5 (0.13-1.9)
1.3 (0.32-5.3)
79 ( 3.1
79 ( 6.6
51 ( 5
42 ( 4.4
65 ( 6.7
59 ( 4.2
100 ( 0
93 ( 7
10.1 (6.8-13.4)
11.9 (8.8-16.0)
3.8 (2.4-6.0)
81 ( 19
98 ( 2.5
63 ( 6
9.3 (4.3-20.1)
2.8 (2.3-3.4)
100 ( 0
0.43 (0.25-0.73)
a
b
Measurement of [3H]thymidine incorporation in CHO p-5 cells expressing human D2L receptors. Percent maximal effect compared
to that of the full DA agonist quinpirole (100%). c EC50 values (95% confidence intervals) were generated from 10 concentrations, n ) 4.
Percent reversal of the increase on DOPA levels in the striatum of GBL-treated rats, n ) 4. e Percent decrease of the firing rate of rat
d
substantia nigra DA neurons, n ) 2. f ED50 values (95% confidence intervals) were generated from three doses, 4 squirrel monkeys/dose.
Ta ble 6. Comparison of Pharmacological Profiles
1-(4-F lu or op h en yl)-4-[4-(3-p yr id in yl)-3-bu tyn yl]p ip er -
a zin e (13). 4-Pyridin-3-ylbut-3-yn-1-ol (4.0 g, 27 mmol) from
the synthesis of 10 was reacted with 1-(p-fluorophenyl)-
piperazine (9.8 g, 54 mmol) as described in the second step of
the synthesis of 7. Purification by MPLC on silica gel eluting
with 25% EtOAc/hexane gave 13 (2.26 g, 27%) as a white
solid: mp 97 °C; IR (KBr) 3433, 2822, 1512, 810, 828 cm-1; 1H
NMR (CDCl3) δ 2.62-2.79 (m, 8H), 3.06-3.16 (m, 4H), 6.85-
7.01 (m, 4H), 7.18-7.27 (m, 1H), 7.64-7.69 (m, 1H), 8.49 (d,
1H, J ) 4.9 Hz), 8.63 (s, 1H); MS (EI) m/z 309 (24), 193 (100),
150 (85), 122 (87). Anal. (C19H20N3F) C, H, N.
test
26
roxindole (3)
dopamine receptor binding (Ki, nM)a
rat D1 ([3H]SCH 23390)
rat D2 ([3H]spiperone)
rat D2 ([3H]NPA)
>10 000
>10 000
9.1
85
1.9
2.8
371
human D3 ([3H]spiperone)
human D4 ([3H]spiperone)
inhibition of LMA (ED50, mg/kg)b
in mouse ip
0.4
24
0.15
1.7
0.2
12.8
in rat po
DA D2 receptor mitogenesisc
maximal effect (%)
1-(2-P yr id in yl)-4-[4-(3-p yr id in yl)-3-b u t yn yl]p ip e r a -
zin e (14). 4-Pyridin-3-ylbut-3-yn-1-ol (1.0 g, 6.8 mmol) from
the synthesis of 10 was reacted with 1-(2-pyridyl)piperazine
(1.66 g, 10 mmol) as described in the second step of the
synthesis of 7. Purification by MPLC on silica gel eluting with
2.5% MeOH/CH2Cl2 gave 14 (0.40 g, 25%) as a yellow solid:
mp 105-106 °C; IR (KBr) 3452, 2946, 1593, 1480, 1431, 774
85
97
EC50 (nM)
1.3 (0.32-5.3)
0.37 (0.10-1.2)
decrease (%) of DOPA synthesis
in ratd (10 mg/kg, ip)
59 ( 4.2
100 ( 0
64 ( 2.2
100 ( 0
decrease (%) of DA neuronal firing
in rate (2.5 mg/kg, ip)
inhibition of conditioned avoidance
in squirrel monkeyf ED50
(mg/kg, po)
cm-1 1H NMR (CDCl3) δ 2.64-2.78 (m, 8H), 3.56-3.60 (m,
;
0.43 (0.25-0.73) >10
4H), 6.61-6.68 (m, 2H), 7.20-7.28 (m, 1H), 7.45-7.52 (m, 1H),
7.66-7.70 (m, 1H), 8.20 (d, 1H, J ) 4.8 Hz), 8.50 (d, 1H, J )
4.9 Hz), 8.64 (s, 1H); MS (EI) m/z 292 (19), 198 (49), 176 (100),
121 (44). Anal. (C18H20N4‚0.08H2O) C, H, N, H2O.
a,b
See footnotes a and b in Table 1. c See footnotes a-c in Table
5. d-f See footnotes d-f in Table 5.
2-[4-[4-(3-P yr id in yl)-3-bu tyn yl]-1-p ip er a zin yl]p yr im i-
d in e (15). 4-Pyridin-3-ylbut-3-yn-1-ol (4.0 g, 27 mmol) from
the synthesis of 10 was reacted with 4-(2-pyrimidyl)piperazine
(8.9 g, 54 mmol) as described in the second step of the synthesis
of 7. Purification by MPLC on silica gel eluting with 2.5%
MeOH/CH2Cl2 gave 15 (1.51 g, 19%) as a pale yellow solid:
mp 96-97 °C; IR (KBr) 3412, 2942, 1583, 1559, 1480, 1451,
coupled to 4-pentyn-1-ol (13.9 mL, 0.15 mol) as described in
the first step of the synthesis of 7. Purification by MPLC on
silica gel eluting with 2% MeOH/CH2Cl2 gave the alcohol (8.3
g, 52%) as a gold oil: IR (CHCl3 solution) 3404, 2936, 2228,
1565, 1477, 1408, 1061, 807, 705 cm-1 1H NMR (CDCl3) δ
;
1.82-1.92 (m, 2H), 2.57 (t, 2H, J ) 7.0 Hz), 2.66 (br s, 1H),
3.79-3.84 (m, 2H), 7.19-7.24 (m, 1H), 7.64-7.69 (m, 1H), 8.47
(d, 1H, J ) 4.9 Hz), 8.60 (s, 1H); MS (EI) m/z 161 (76), 142
(100), 132 (94), 117 (90); TLC (10% MeOH/CH2Cl2) Rf ) 0.46.
The above alcohol (5.0 g, 31 mmol), carbon tetrabromide
(20.5 g, 62 mmol), and triphenylphosphine (16.3 g, 62 mmol)
were combined with Et2O (300 mL), and the reaction mixture
was stirred at 20 °C for 1.5 h. The reaction mixture was
concentrated in vacuo and filtered through silica gel eluting
with 50% EtOAc/hexane. The bromide (4.5 g, 65%) was
obtained as a yellow oil (2.2 g, 9.7 mmol) and was reacted with
4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (2.28 g, 11.7
mmol) as described in the synthesis of 9. Purification by
MPLC on silica gel eluting with 2% MeOH/CH2Cl2 gave 11 as
a pale yellow solid: mp 63-64 °C; IR (KBr) 3463, 2931, 2897,
800 cm-1 1H NMR (CDCl3) δ 2.57-2.86 (m, 8H), 3.41-3.88
;
(m, 4H), 6.48 (t, 1H, J ) 4.8 Hz), 7.18-7.30 (m, 1H), 7.67 (d,
1H, J ) 7.9 Hz), 8.30 (d, 2H, J ) 4.8 Hz), 8.48 (d, 1H, J ) 4.8
Hz), 8.63 (s, 1H); MS (EI) m/z 293 (3), 177 (100), 148 (83), 122
(46). Anal. (C17H19N5‚0.05H2O) C, H, N, H2O.
4-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
isoq u in olin e (21). 4-Bromoisoquinoline (31.2 g, 0.15 mol)
was coupled to 3-butyn-1-ol (22.7 mL, 0.30 mol) as described
in the first step of the synthesis of 7 to give 4-isoquinolin-4-
ylbut-3-yn-1-ol (21.2 g, 72%) as a white solid: mp 65 °C; IR
1
(KBr) 3252, 2275, 1620 cm-1; H NMR (CDCl3) δ 2.38 (br s,
1H), 2.86 (t, 2H, J ) 6.2 Hz), 3.95 (t, 2H, J ) 6.3 Hz), 7.54-
7.60 (m, 1H), 7.68-7.74 (m, 2H), 7.87 (d, 1H, J ) 8.2 Hz), 8.16
(d, 2H, J ) 8.3 Hz), 8.59 (s, 1H), 9.08 (s, 1H); MS (EI) m/z 197
(70), 166 (100), 139 (44). Anal. (C13H11NO) C, H, N.
1
1477, 1405, 749, 704 cm-1; H NMR (CDCl3) δ 1.83-1.94 (m,
2H), 2.49-2.64 (m, 6H), 2.71-2.75 (m, 2H), 3.18 (m, 2H), 6.07
(m, 1H), 7.17-7.41 (m, 6H), 7.64-7.69 (m, 1H), 8.46-8.49 (m,
1H), 8.63 (s, 1H); MS (EI) m/z 302 (89), 301 (100), 273 (98),
225 (89). Anal. (C21H22N2‚0.05H2O) C, H, N, H2O.
The above alcohol (4.0 g, 20 mmol) was reacted with
4-phenyl-1,2,3,6-tetrahydropyridine (6.45 g, 40 mmol) as de-
scribed in the second step of the synthesis of 7. Purification
by MPLC on silica gel eluting with 25% EtOAc/hexane gave
21 (1.04 g, 15%) as a yellow solid: mp 58-59 °C; IR (KBr)
3427, 2911, 1618, 1447, 753 cm-1; 1H NMR (CDCl3) δ 2.64 (m,
2H), 2.82-2.97 (m, 6H), 3.30-3.34 (m, 2H), 6.09-6.12 (m, 1H),
7.21-7.43 (m, 5H), 7.62 (t, 1H, J ) 7.4 Hz), 7.74 (t, 1H, J )
8.1 Hz), 7.96 (d, 1H, J ) 8.1 Hz), 8.27 (d, 1H, J ) 8.3 Hz),
8.64 (s, 1H), 9.15 (s, 1H); MS (EI) m/z 338 (7), 172 (100), 166
(20). Anal. (C24H22N2‚0.09H2O) C, H, N, H2O.
Meth od B. 4-(3,6-Dih yd r o-4-p h en yl-1(2H)-p yr id in yl)-
1-bu tyn e (6). 3-Butynyl p-toluenesulfonate (25 g, 0.11 mol),
4-phenyl-1,2,3,6-tetrahydropyridine (16.1 g, 0.10 mol), and
NaHCO3 (9.3 g, 0.11 mol) in DMF (150 mL) were heated to 70
°C for 5 h. The reaction mixture was concentrated in vacuo
3-[4-[3,6-Dih yd r o-4-(2-th ien yl)-1(2H)-p yr id in yl]-1-bu ty-
n yl]p yr id in e (12). 4-Pyridin-3-ylbut-3-yn-1-ol (3.3 g, 22
mmol) from the synthesis of 10 was reacted with 4-(2-thienyl)-
1,2,3,6-tetrahydropyridine (15.5 mL, 0.11 mol) as described in
the second step of the synthesis of 7. Purification by MPLC
on silica gel eluting with 2.5% MeOH/CH2Cl2 gave 12 (0.67 g,
10%) as a yellow solid: mp 77-78 °C; IR (KBr) 3417, 2951,
1407, 809, 709, 691 cm-1; 1H NMR (CDCl3) 2.60-2.84 (m, 8H),
3.24-3.25 (m, 2H), 6.09 (m, 1H), 6.96 (m, 2H), 7.11-7.14 (m,
1H), 7.21-7.28 (m, 1H), 7.68 (d, 1H, J ) 8.0 Hz), 8.49 (d, 1H,
J ) 4.9 Hz), 8.63 (s, 1H); MS (EI) m/z 293 (8), 178 (100), 149
(17). Anal. (C18H18N2S‚0.04H2O) H, N; C: calcd, 73.25; found,
72.27.

Aryl Tetrahydropyridines as Antipsychotic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3185
and the resulting residue partitioned between CH2Cl2 (200 mL)
and H2O (200 mL). The organic phase was dried over Na2-
SO4, filtered, and concentrated in vacuo to give a brown oil.
Purification by MPLC on silica gel eluting with 2% MeOH/
CH2Cl2 gave 6 (16 g, 76%) as a light yellow solid: mp 27 °C;
IR (KBr) 3250, 2804, 748, 690 cm-1; 1H NMR (CDCl3) δ 2.0 (t,
1H, J ) 2.7 Hz), 2.43-250 (m, 2H), 2.57-2.59 (m, 2H), 2.65-
2.78 (m, 4H), 3.19-3.23 (m, 2H), 6.03-6.06 (m, 1H), 7.20-
7.40 (m, 5H); MS (EI) m/z 211 (22), 172 (100). Anal. (C15H17N)
C, H, N.
butynyl]-4-phenylpyridine (5.76 g, 87%) as a yellow solid: mp
93-95 °C; IR (KBr) 2970, 2375, 1534, 1347 cm-1 1H NMR
;
(CDCl3) δ 2.61 (m, 2H), 2.70-2.77 (m, 2H), 2.80-2.87 (m, 4H),
3.28 (m, 2H), 6.08 (m, 1H), 7.21-7.51 (m, 6H), 7.73 (d, 1H, J
) 8.9 Hz), 8.15 (d, 1H, J ) 9.0 Hz), 8.25 (s, 1H); MS (EI) m/z
332 (11), 172 (100). Anal. (C21H20N2O2) C, H, N.
The nitro intermediate was reduced as described in 22.
Purification by MPLC on silica gel eluting with 1% MeOH/
CH2Cl2 gave 23 (1.62 g, 40%) as a pale yellow solid: mp 117-
118 °C; IR (KBr) 3476, 2918, 1614, 1597, 1578, 1490, 752, 699
1,2,3,6-Tetr a h yd r o-4-p h en yl-1-(4-p h en yl-3-bu tyn yl)p y-
r id in e (16). To a degassed (N2) solution of 6 (3.0 g, 14 mmol)
and iodobenzene (1.9 mL, 17 mmol) in piperidine (10 mL) were
added palladium(II) acetate (31 mg, 0.14 mmol) and triph-
enylphosphine (74 mg, 0.28 mmol). The reaction mixture was
heated to 80 °C under N2 for 2 h, filtered, and concentrated in
vacuo to give a brown oil. Purification by MPLC on silica gel
eluting with 25% EtOAc/hexane gave 16 (1.0 g, 25%) as a white
solid: mp 102-103 °C; IR (KBr) 2899, 1491, 1442, 1374, 833,
813, 700 cm-1; 1H NMR (CDCl3) δ 2.61-2.81 (m, 8H), 3.27 (m,
2H), 6.07 (m, 1H), 7.23-7.43 (m, 10H); MS (EI) m/z 287 (9),
172 (100), 128 (17), 115 (19). Anal. (C21H21N) C, H, N.
1,2,3,6-Tetr a h yd r o-4-p h en yl-1-[4-(2-p yr id in yl)-3-bu ty-
n yl]p yr id in e (20). 2-Bromopyridine (0.99 mL, 10 mmol) was
coupled to 6 (2.0 g, 9.5 mmol) as described in the synthesis of
16. Purification by MPLC on silica gel eluting with 1% MeOH/
CH2Cl2 gave 20 (1.06 g, 39%) as a yellow solid: mp 88-89 °C;
IR (KBr) 3433, 2954, 2223, 1581, 1465, 1427, 784, 752, 698
cm-1 1H NMR (CDCl3) δ 2.62-2.73 (m, 4H), 2.80-2.91 (m,
;
4H), 3.28-3.32 (m, 2H), 3.57 (br s, 2H), 6.06 (m, 1H), 6.60 (d,
1H, J ) 7.9 Hz), 6.73 (s, 1H), 6.81 (d, 1H, J ) 7.7 Hz), 7.07 (t,
1H, J ) 7.8 Hz), 7.21-7.41 (m, 5H); MS (CI) m/e 303 (MH+,
4), 172 (100). Anal. (C21H22N2) C, H, N.
2-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
ben zen a m in e (24). 1-Bromo-2-nitrobenzene (4.06 g, 20
mmol) was coupled to 6 (4.24 g, 20 mmol) as described in the
synthesis of 19. Purification by MPLC on silica gel eluting
with 10% EtOAc/hexane gave 1,2,3,6-tetrahydro-1-[4-(2-nitro-
phenyl)-3-butynyl]-4-phenylpyridine (2.43 g, 36%) as a gold
solid: mp 187-188 °C; IR (KBr) 1524, 1342, 743 cm-1; 1H NMR
(CDCl3) δ 2.61 (m, 2H), 2.70-2.90 (m, 6H), 3.28 (m, 2H), 6.08
(m, 1H), 7.21-7.44 (m, 6H), 7.53-7.63 (m, 2H), 7.96 (d, 1H, J
) 9.0 Hz); MS (CI) m/e 333 (MH+, 23), 172 (100). Anal.
(C21H20N2O2‚0.90HCl‚0.11H2O) H, N; C: calcd, 68.69; found,
67.72.
The nitro intermediate was reduced as described in 22.
Purification by MPLC on silica gel eluting with 25% EtOAc/
hexane gave 24 (1.5 g, 68%) as a light brown solid: mp 133-
cm-1 1H NMR (CDCl3) δ 2.60 (m, 2H), 2.69-2.90 (m, 6H),
;
3.24-3.28 (m, 2H), 6.06 (t, 1H, J ) 1.7 Hz), 7.16-7.41 (m, 7H),
7.58-7.65 (m, 1H), 8.54 (d, 1H, J ) 4.9 Hz); MS (EI) m/z 288
(9), 172 (100). Anal. (C20H20N2) C, H, N.
1
134 °C; IR (KBr) 3428, 2923, 1637, 1493, 750, 694 cm-1; H
NMR (CDCl3) δ 2.61-2.71 (m, 2H), 2.75-2.84 (m, 6H), 3.26-
3.29 (m, 2H), 4.37 (br s, 2H), 6.08 (m, 1H), 6.60 (m, 2H), 7.03-
7.09 (m, 1H), 7.19-7.39 (m, 6H); MS (CI) m/e 303 (MH+, 25),
172 (100). Anal. (C21H22N2‚0.05H2O) C, H, N, H2O.
Meth od C. 4-[4-(3,6-Dih yd r o-4-p h en yl-1(2H)-p yr id i-
n yl)-1-bu tyn yl]p yr id in e (19). To a degassed (N2) solution
of 6 (3.0 g, 14 mmol), 4-bromopyridine hydrochloride (2.7 g,
14 mmol), and triethylamine (5.9 mL, 42 mmol) in CH2Cl2 (50
mL) were added copper(I) iodide (18 mg, 0.096 mmol) and bis-
(triphenylphosphine)palladium(II) chloride (0.10 g, 0.14 mmol).
The reaction mixture was heated at reflux under N2 overnight,
cooled, diluted with CH2Cl2 (20 mL), and washed with water
(4 × 20 mL). The organic phase was dried over Na2SO4,
filtered, and concentrated in vacuo to give a brown solid.
Purification by MPLC on silica gel eluting with 2% MeOH/
CH2Cl2 gave 19 (1.79 g, 45%) as a tan solid: mp 112-113 °C;
6-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
3-p yr id in a m in e (26). 2-Bromo-5-nitropyridine (4.23 g, 21
mmol) was coupled to 6 (4.0 g, 19 mmol) as described in the
synthesis of 19. Purification by MPLC on silica gel eluting
with 0.5% MeOH/CH2Cl2 gave 5-nitro-2-[4-(4-phenyl-3,6-di-
hydro-2H-pyridin-1-yl)but-1-ynyl]pyridine (3.3 g, 52%) as a
gold solid: mp 133-134 °C; IR (KBr) 3437, 2924, 2222, 1589,
1
1571, 1516, 1370, 856, 765 cm-1; H NMR (CDCl3) δ 2.61 (m,
2H), 2.75-2.92 (m, 6H), 3.25-3.28 (m, 2H), 6.07 (m, 1H), 7.21-
7.56 (m, 6H), 8.42 (d, 1H, J ) 8.6 Hz), 9.37 (s, 1H); MS (EI)
m/z 333 (5), 172 (100). Anal. (C20H19N3O2‚0.1H2O) C, H, N,
H2O.
IR (KBr) 3415, 2922, 1592, 821, 756, 546 cm-1 1H NMR
;
(CDCl3) δ 2.60-2.86 (m, 8H), 3.25-3.28 (m, 2H), 6.06-6.09
(m, 1H), 7.18-7.38 (m, 7H), 8.53 (d, 2H, J ) 5.6 Hz); MS (EI)
m/z 288 (8), 172 (100). Anal. (C20H20N2) C, H, N.
The nitro intermediate was reduced as described in 22.
Purification by MPLC on silica gel eluting with 5% MeOH/
CH2Cl2 gave 26 (1.34 g, 74%) as a gold solid: mp 136-137 °C;
4-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
ben zen a m in e (22). 1-Bromo-4-nitrobenzene (2.1 g, 10.4
mmol) was coupled to 6 (2.0 g, 9.46 mmol) as described in the
synthesis of 19. Purification by MPLC on silica gel eluting
with 1% MeOH/CH2Cl2 gave 1,2,3,6-tetrahydro-1-[4-(4-nitro-
phenyl)-3-butynyl]-4-phenylpyridine (2.0 g, 66%) as a gold
solid: mp 148-149 °C; IR (KBr) 3443, 2813, 1591, 1511, 1338,
854, 752 cm-1; 1H NMR (CDCl3) δ 2.61 (m, 2H), 2.70-2.87 (m,
6H), 3.26 (m, 2H), 6.08 (m, 1H), 7.21-7.41 (m, 5H), 7.53 (d,
2H, J ) 8.9 Hz), 8.15 (d, 2H, J ) 9.0 Hz); MS (EI) m/z 332 (5),
172 (100). Anal. (C21H20N2O2) C, H, N.
IR (KBr) 3382, 2924, 1633, 1589, 1561, 1476, 748, 695 cm-1
;
1H NMR (CDCl3) δ 2.59-2.86 (m, 8H), 3.25 (m, 2H), 3.78 (br
s, 2H), 6.06 (m, 1H), 6.88 (d, 1H, J ) 8.5 Hz), 7.16-7.40 (m,
6H), 8.02 (s, 1H); MS (CI) m/e 303 (MH+, 4), 172 (100). Anal.
(C20H21N3‚0.05H2O) C, H, N, H2O.
Meth od D. 4-[4-(3,6-Dih yd r o-4-p h en yl-1(2H)-p yr id i-
n yl)-1-bu tyn yl]p h en ol (17). To a degassed (N2) solution of
6 (0.50 g, 2.4 mmol), 4-iodophenol (0.52 mL, 2.4 mmol), and
butylamine (20 mL) was added tetrakis(triphenylphosphine)-
palladium(0) (0.17 mg, 0.15 mmol). The reaction mixture was
heated to reflux under N2 overnight, cooled, and concentrated
in vacuo. The residue was dissolved in CH2Cl2 (20 mL) and
washed with water (10 mL). The organic phase was dried over
Na2SO4, filtered, and concentrated to give a brown solid.
Purification by MPLC on silica gel eluting with 25% EtOAc/
hexane gave 17 (0.16 g, 22%) as a tan solid: mp 135-136 °C;
IR (KBr) 3400, 2930, 1606, 1510, 1267, 832, 751 cm-1; 1H NMR
(CDCl3) δ 2.62-2.71 (m, 4H), 2.81-2.87 (m, 4H), 3.30-3.31
(m, 2H), 6.07 (m, 1H), 6.76 (d, 2H, J ) 8.5 Hz), 7.21-7.42 (m,
7H); MS (EI) m/z 303 (11), 172 (100). Anal. (C21H21NO) C,
H, N.
The above nitro compound (1.6 g, 4.8 mmol) was suspended
in 95% EtOH (25 mL) and heated to 80 °C. To this suspension
were added concentrated HCl (0.08 mL) and reduced iron (2.5
g). The reaction mixture was stirred at 80 °C for 0.5 h, filtered
through Celite, and concentrated in vacuo to give 1.52 g of a
gold solid. Purification by MPLC on silica gel eluting with
1% MeOH/CH2Cl2 gave 22 (1.0 g, 70%) as a gold solid: mp
88-89 °C; IR (KBr) 3372, 2906, 1625, 1606, 1514, 828, 748
cm-1 1H NMR (CDCl3) δ 2.60-2.70 (m, 4H), 2.77-2.83 (m,
;
4H), 3.24-3.26 (m, 2H), 3.74 (br s, 2H), 6.07 (m, 1H), 6.58 (d,
2H, J ) 8.4 Hz), 7.19-7.41 (m, 7H); MS (EI) m/z 302 (19), 172
(100), 130 (28). Anal. (C21H22N2‚0.08H2O) C, H, N, H2O.
3-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
ben zen a m in e (23). 1-Iodo-3-nitrobenzene (5.0 g, 20 mmol)
was coupled to 6 (4.24 g, 20 mmol) as described in the synthesis
of 19. Purification by MPLC on silica gel eluting with 1%
MeOH/CH2Cl2 gave 1,2,3,6-tetrahydro-1-[4-(3-nitrophenyl)-3-
5-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
1H-in d ole (18). 5-Bromoindole (0.93 g, 4.7 mmol) was coupled
to 6 (1.0 g, 4.7 mmol) as described in the synthesis of 17.
Purification by MPLC on silica gel eluting with 1% MeOH/
CH2Cl2 gave 18 (0.42 g, 28%) as a yellow solid: mp 173-174

3186 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Glase et al.
1
°C; IR (KBr) 2917, 2818, 1495, 1446, 809, 744, 730 cm-1; H
and an ED50 was calculated from increasing doses by regres-
sion analysis.
NMR (CDCl3) δ 2.53 (m, 2H), 2.59-2.65 (m, 2H), 2.72-2.81
(m, 4H), 3.21 (m, 2H), 6.01 (m, 1H), 6.37 (m, 1H), 7.09-7.34
(m, 8H), 7.61 (s, 1H), 9.98 (br s, 1H); MS (EI) m/z 326 (15),
172 (100). Anal. (C23H22N2‚0.05H2O) C, H, N, H2O.
Mit ogen esis Assa y.20 The effects of test compounds on
[3H]thymidine uptake were carried out essentially as described
by Chio et al.26 CHO p-5 cells transfected with human D2L
cDNA were seeded into 96-well plates at a density of about
5000 cells/well and grown at 37 °C in a minimum essential
medium (RMEM; Gibco) with 10% calf serum for 2 days. The
wells were then rinsed three times with serum-free media.
Fresh media (90 µL) were added along with 10 µL of test
compound in water or vehicle alone. Eight wells of each plate
received 100 µL of RMEM with 10% fetal calf serum. After
culture for 16-17 h, [3H]thymidine (1 µCi/well) was added for
4 h. The cells were trypsinized and harvested onto filter mats
with a 96-well Brandel cell harvester. The filters were counted
in a Beta-Plate scintillation counter.
5-[4-(3,6-Dih ydr o-4-ph en yl-1(2H)-pyr idin yl)-1-bu tyn yl]-
2-p yr id in a m in e (25). 2-Amino-5-bromopyridine (1.0 g, 5.8
mmol) was coupled to 6 (0.50 g, 2.4 mmol) as described in the
synthesis of 17. Purification by MPLC on silica gel eluting
with 1% MeOH/CH2Cl2 gave 25 (0.58 g, 33%) as a yellow
solid: mp 180-181 °C; IR (KBr) 3411, 2924, 1611, 1497, 1389,
1
825, 695 cm-1; H NMR (CDCl3) δ 2.60-2.70 (m, 4H), 2.78-
2.83 (m, 4H), 3.25 (d, 2H, J ) 3.2 Hz), 4.53 (br s, 2H), 6.07 (m,
1H), 6.41 (d, 1H, J ) 8.5 Hz), 7.21-7.46 (m, 6H), 8.14 (s, 1H);
MS (EI) m/z 303 (11), 172 (100). Anal. (C20H21N3‚0.10H2O)
C, H, N, H2O.
In h ibition of GBL-Stim u la ted DA Syn th esis.27 Com-
pounds were administered to male Long-Evans rats (Blue
Spruce Farms, Altamont, NY) 1 h and GBL (750 mg/kg ip)
and NSD 1015 (100 mg/kg ip) 30 min before sacrifice. Brain
striatal levels of DOPA were analyzed by HPLC with electro-
chemical detection.35 DOPA concentrations were 1.03 ( 0.04
and 3.76 ( 0.28 mg/g ( SEM for control and GBL-treated
animals, respectively (n ) 10).
E ffect s on t h e F ir in g R a t e of Su bst a n t ia Nigr a DA
Neu r on s.28 The action potential of zona compacta DA cells
was recorded in chloral-anesthetized rats by using standard
extracellular recording techniques. DA cells were identified
by wave form and firing pattern, and recording sites were
verified histologically. Drugs were administered intraperito-
neally via an indwelling catheter. Base-line firing rate was
calculated by averaging the rate over 2 min prior to drug
injection. Drug effects were determined by averaging the
response during the 1 min period of maximal inhibition. Drug-
induced inhibition of firing was reversed with the DA antago-
nist haloperidol to confirm a DA agonist mechanism.
Con d ition ed Avoid a n ce in Squ ir r el Mon k eys. This
procedure was carried out according to methods described
previously.31 Inhibition of conditioned avoidance was mea-
sured for 6 h after oral administration of compound. Drug
effects were expressed as percentage inhibition of avoidance
responding relative to control performance during the 4 h of
peak effect.
1,2,3,6-Tetr a h yd r o-1-[4-(4-m eth oxyp h en yl)-3-bu tyn yl]-
4-p h en ylp yr id in e (27). p-Iodoanisole (1.1 g, 4.7 mmol) was
coupled to 6 (1.0 g, 4.7 mmol) as described in the synthesis of
17. Purification by MPLC on silica gel eluting with 25%
EtOAc/hexane gave 27 (0.54 g, 36%) as a white solid: mp 148-
1
149 °C; IR (KBr) 2934, 1605, 1508, 1376, 837, 748 cm-1; H
NMR (CDCl3) δ 2.61-2.72 (m, 4H), 2.80-2.86 (m, 4H), 3.26-
3.30 (m, 2H), 3.79 (s, 3H), 6.07 (m, 1H), 6.81 (d, 2H, J ) 8.8
Hz), 7.20-7.41 (m, 7H); MS (EI) m/z 317 (12), 172 (100). Anal.
(C22H23NO‚0.05H2O) C, H, N, H2O.
1-[4-(2,3-Dih yd r ob en zo[1,4]d ioxin -6-yl)b u t -3-yn yl]-4-
ph en yl-1,2,3,6-tetr ah ydr opyr idin e (28). 3,4-(Ethylenedioxy)-
bromobenzene (1.02 g, 4.7 mmol) was coupled to 6 (1.0 g, 4.7
mmol) as described in the synthesis of 17. Purification by
MPLC on silica gel eluting with 25% EtOAc/hexane gave 28
(0.68 g, 42%) as a yellow solid: mp 105-107 °C; IR (KBr) 2958,
1573, 1499, 896, 809, 752 cm-1; 1H NMR (CDCl3) δ 2.59-2.75
(m, 4H), 2.77-2.82 (m, 4H), 3.24-3.26 (m, 2H), 4.23 (s, 4H),
6.06 (m, 1H), 6.76 (d, 1H, J ) 8.0 Hz), 6.86-6.92 (m, 2H),
7.22-7.40 (m, 5H); MS (CI) m/e 346 (MH+, 49), 216 (52), 172
(100). Anal. (C23H23NO2) C, H, N.
1-[4-(5-Ben zofu r a n yl)-3-bu tyn yl]-1,2,3,6-tetr a h yd r o-4-
p h en ylp yr id in e (29). 5-Bromobenzofuran34 (1.00 g, 5.1
mmol) was coupled to 6 (1.25 g, 5.1 mmol) as described in the
synthesis of 17. Purification by MPLC on silica gel eluting
with 25% EtOAc/hexane gave 29 (0.43 g, 26%) as a yellow
solid: mp 127-130 °C; IR (KBr) 3429, 2897, 2822, 2771, 2361,
1
1464 cm-1; H NMR (CDCl3) δ 2.60-2.64 (m, 2H), 2.70-2.73
Ack n ow led gm en t. We would like to thank C. L.
Christoffersen, A. E. Corbin, S. DeMattos, L. Georgic,
D. J . J ohnston, F. W. Ninteman, K. A. Serpa, Y.-H. Shih,
S. Z. Whetzel, J . Wiley, and K. Zoski for biological
testing.
(m, 2H), 2.83-2.89 (m, 4H), 3.29 (m, 2H), 6.07 (m, 1H), 6.72
(m, 1H), 7.21-7.42 (m, 7H), 7.61 (s, 1H), 7.66 (s, 1H); MS (EI)
m/z 327 (11), 198 (26), 172 (100). Anal. (C23H21NO‚0.05H2O)
C, H, N, H2O.
P h a r m a cologica l Meth od s. Cell Cu ltu r es. CHO K1
cells (donated by Dr. J . Granneman, Wayne State University,
Detroit, MI) expressing either human D3, human D2L, or
human D4.2 receptors20 were grown in F-12 medium (GIBCO
Laboratories, Grand Island, NY) supplemented with 10% fetal
bovine serum (Hyclone Laboratories, Logan, UT) in T-150
culture flasks in a humidified atmosphere of 5% CO2 and 95%
air.
Recep tor Bin d in g Assa ys. The inhibition of binding of
[3H]ligand to each receptor (final concentration), brain area,
nonspecific agent (final concentration), and method were
carried out as follows: DA D2, [3H]spiperone (0.2 nM), rat
striatum, and (+)-butaclamol (1.0 µM) according to the method
of Grigoriadis and Seeman;15 human D3, [3H]spiperone (0.5
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