6-(alkylamino)-9-alkylpurines. A new class of potential antipsychotic agents

Article abstract of DOI:10.1021/jm960662s

A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This model for identifying potential antipsychotic agents is based on the hypothesis that agents that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity of lead compound 1 (6-(dimethylamino)- 9-(3-phenylalaninamidobenzyl)-9H-purine) was improved 48-fold with 6- (cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H-purine (80) (po ED₅₀ of 2 mg/kg), which was obtained through an iterative sequence of structure-activity relationship studies that encompassed evaluation of the effects of structure variations at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed further due to undesirable effects on the stomach.

Full text of DOI:10.1021/jm960662s

J . Med. Chem. 1997, 40, 3207-3216
3207
6-(Alk yla m in o)-9-a lk ylp u r in es. A New Cla ss of P oten tia l An tip sych otic Agen ts
J ames L. Kelley,*,†,§ R. Morris Bullock,† Mark P. Krochmal,† Ed W. McLean,†,| J ames A. Linn,†,|
Micheal J . Durcan,‡, and Barrett R. Cooper‡,#
Division of Organic Chemistry and Division of Pharmacology, Burroughs Wellcome Co.,
Research Triangle Park, North Carolina 27709
Received September 23, 1996X
A series of 6-(alkylamino)-9-alkylpurines was synthesized and evaluated for the property of
antagonizing the behavioral effects in animals of the dopamine agonist apomorphine. This
model for identifying potential antipsychotic agents is based on the hypothesis that agents
that antagonize apomorphine-induced aggressive behavior in rats and apomorphine-induced
climbing in mice, but that do not block stereotyped behavior, could have an antipsychotic effect
in humans without producing extrapyramidal side effects. The antiaggressive-behavior activity
of lead compound 1 (6-(dimethylamino)-9-(3-phenylalaninamidobenzyl)-9H-purine) was im-
proved 48-fold with 6-(cyclopropylamino)-9-(cyclopropylmethyl)-2-(trifluoromethyl)-9H-purine
(80) (po ED50 of 2 mg/kg), which was obtained through an iterative sequence of structure-
activity relationship studies that encompassed evaluation of the effects of structure variations
at the purine 9-, 6-, and 2-positions. Potency was enhanced with a 9-cyclopropyl group, the
duration of action was improved with the 6-(cyclopropylamino) substituent, potency was further
enhanced with an N-formyl prodrug, and an agent with reduced cardiovascular effect emerged
with the 2-trifluoromethyl purine 80. This potential antipsychotic agent was not developed
further due to undesirable effects on the stomach.
Sch em e 1a
The introduction of chlorpromazine in the 1950s for
the treatment of schizophrenia initiated a therapeutic
revolution in the treatment of psychotic disorders.1
Although chlorpromazine and other conventional an-
tipsychotic agents are effective in alleviating the positive
symptoms of many psychoses, they produce a high
incidence of extrapyramidal side effects and tardive
dyskinesias in patients.2,3 The dopamine hypothesis of
manic psychosis and schizophrenia proposes that these
disorders arise from hyperactivity of dopaminergic
neurotransmission; antipsychotic agents exert their
effect through blockade of dopamine receptors.4,5 The
ability of compounds to antagonize the behavioral effects
in animals of apomorphine, a dopamine agonist, has
been used as a model for identifying potential antipsy-
chotic agents.6 However, agents that antagonize apo-
morphine-induced stereotyped behavior produce a high
incidence of extrapyramidal side effects and tardive
dyskinesias in humans.7,8 Apomorphine also causes
aggressive behavior in paired rats9 and elicits climbing
behavior in mice,10 both of which are antagonized by
neuroleptic agents. Apomorphine-induced climbing and
aggressive behavior are probably a reflection of the
stimulation of dopamine receptors in the limbic system,
while stereotyped behavior is associated with dopamine
receptor stimulation in the striatum.6,10 Since the
limbic system has been implicated in the etiology of
psychotic behavior,11 investigators proposed that an
agent that antagonized apomorphine-induced aggres-
sion in rats and apomorphine-induced climbing in mice,
a
Reagents: (i) BuOH, Et3N, RNH2; (ii) HC(OEt)3, EtSO3H; (iii)
DMSO, K2CO3, RCl; (iv) EtOH, R2NH.
but that did not block stereotyped behavior in either
species, could have an antipsychotic effect in humans
without producing extrapyramidal side effects.12 Rim-
cazole (BW 234U, cis-9-[3-(3,5-dimethyl-1-piperazinyl)-
propyl]carbazole dihydrochloride), a novel agent with
antipsychotic potential, emerged from a research pro-
gram based on this hypothesis.13 During the screening
of new compounds for central nervous system (CNS)
activity, the ability of 1 (Table 3) to block apomorphine-
induced aggressive behavior in rats was discovered.
Owing to the novelty of this structural lead, a synthesis
program was initiated to explore structure-activity
relationships with the objective of increasing potency
and specificity of action.
* Author to whom correspondence should be addressed.
† Division of Organic Chemistry.
‡ Division of Pharmacology.
§ Present address: Krenitsky Pharmaceuticals Inc., Four University
Place, 4611 University Drive, Durham, NC 27707.
| Present address: Division of Chemistry, Glaxo Wellcome Inc.,
Research Triangle Park, NC 27709.
Ch em istr y. Compounds 28-70 and 72 (Table 2)
were prepared from 5-amino-4,6-dichloropyrimidine (I)
or 6-chloropurine (IV) as outlined in Scheme 1. Ami-
nation of I with the appropriate amine by modification
of a general literature method14-16 gave the 4-substi-
tuted pyrimidines II in 59 to 95% yields (Table 1).
Present address: CNS Clinical Research, Glaxo Wellcome Inc.,
Research Triangle Park, NC 27709.
#
Present address: 5018 Dresden Drive, Durham, NC 27707.
X Abstract published in Advance ACS Abstracts, September 1, 1997.
S0022-2623(96)00662-0 CCC: $14.00 © 1997 American Chemical Society

3208 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20
Kelley et al.
Ta ble 1. Physical Properties of 4-Chloro-
5,6-diaminopyrimidines
The 2-aminopurine 81 was prepared in two steps from
2-amino-6-chloro-9H-purine (113). Alkylation of 113
with chloromethylcyclopropane gave 114 in 45% yield.
Amination of 114 with cyclopropylamine at 75 °C gave
81 in 64% yield. The structure of intermediate 114 was
substantiated by conversion to the 6-(dimethylamino)
analogue 115 with dimethylamine. The latter com-
pound had an UV spectrum very similar to that of the
9-benzyl analogue.22
yield,
no.
R
method
%
mp, °C
formulaa
89 CH2CH2CH3
90 (CH2)3CH3
91 (CH3)4CH3
92 CH(CH3)CH2CH3
93 CH2CH(CH3)2
94 CH2C3H5
95 CH2C4H7
96 C3H5
97 C4H7
98 C5H9
99 C6H11
100 C7H13
A
A
A
A
A
A
A
B
A
A
A
A
A
95
71
91
77
59
88
75f
94
93
77
82
77
113-114b C7H11ClN4
80-81c
84-85c
C8H13ClN4
C9H15ClN4
Biologica l Resu lts a n d Discu ssion
130-132d C8H13ClN4
120-121e C8H13ClN4
152-153f C8H11ClN4
155-156 C9H13ClN4
156-158f C7H9ClN4
139-140f C8H11ClN4
138-140e C9H13ClN4
137-138c C10H15ClN4
138-140c C11H17ClN4
The compounds in Tables 3-7 were tested, by the oral
and ip routes, for activity against apomorphine-induced
aggression (fighting behavior as defined by McKenzie9)
in rats.9,12 The paired animals were observed for the
presence or absence of stereotyped behavior during the
fighting observation period. Five pairs of animals were
used for each dose; approximate ED50 values were
estimated from experiments at two or three doses that
bracketed the ED50. Most of the compounds were tested
initially at 25 or 50 mg/kg ip; if activity was high, an
ED50 was determined. Oral ED50s were determined for
the most active compounds.
101 CH(CH3)C3H5
61e 125-126 C9H13ClN4
a
b
All compounds were analyzed for C, H, N. Recrystallized
from heptane. c Recrystallized from cyclohexane Recrystallized
d
from dichloromethane. e Recrystallized from ethyl acetate:cyclo-
hexane. f Recrystallized from toluene.
Condensation of II with triethyl orthoformate17 and
ethanesulfonic acid18 provided the 6-chloropurines III.
For preparation of 9-methylthiomethyl purine 67, 6-chlo-
ropurine (IV) was alkylated with chloromethyl methyl
sulfide to give intermediate chloropurine 105.19 The
6-chloro-9-substituted purines III were reacted with the
appropriate amines to give V (28-70 and 72) in 6 to
86% yields (Table 2).
Several 6-cyclopropyl amino purines VI (Scheme 2)
were converted to the N-formamido derivatives 73-76
and 78 (Table 2). Initial efforts to synthesize VI met
with difficulties; however, use of 4-(dimethylamino)-
pyridine and acetic formic anhydride20 in hot dichlo-
romethane gave the desired products in good yield.
Acetylation of 62 with acetic anhydride provided acet-
amide 77 in 72% yield. The N-ethyl analogue 71 was
prepared from 54 with sodium hydride and ethyl iodide
(Table 2).
The 2-substituted purines 79-88 (Table 2) were
prepared from 2,6-dichloropurine 109 or 6-chloro-2-
trifluoromethylpurine 110.21 Alkylation of 109 (Scheme
3) with chloromethylcyclopropane did not give the
desired product, due to facile hydrolysis of the 6-chloro
substituent. Therefore, 109 was aminated with cyclo-
propylamine to give 111, which reacted smoothly with
chloromethylcyclopropane to give 79 in high yield. The
2-(trifluoromethyl)purine 80 was prepared from 110 in
a similar manner via 112. The structures of 79 and 80
as 9-substituted purines were based on earlier work
showing that 6-(dimethylamino)-2-(trifluoromethyl)-9H-
purine alkylates cleanly to give only 9-substituted
purine.21
Compounds 82-88 were prepared from the common
intermediate 2-chloropurine 79. Amination of 79 with
the appropriate amine in ethanol at 80 °C provided 82-
84 in good yields. When 79 was heated at reflux in a
basic solution of the appropriate alcohol, compounds
85-87 were obtained in good yields. If the time of
reflux for preparation of 87 was extended to several
days, substantial N-6 dealkylation occurred. Reaction
of 79 with methyl mercaptan in ethanol containing
sodium ethanolate gave 88.
9-(Ben zyl)p u r in es. Compound 1, which has weak
antirhinovirus activity,23 was found to block apomor-
phine-induced aggressive behavior in rats with an ip
ED50 of 27 mg/kg and an oral ED50 of 96 mg/kg (Table
3). The behavioral profile (blocked apomorphine-
induced aggression but not stereotyped behavior) of 1
was similar to that of rimcazole,12 which suggested that
if 1 had antipsychotic activity in humans, it would not
cause extrapyramidal side effects. Consequently, we
initiated a synthesis program to explore structure-
activity relationships with the objective of increasing
potency and specificity of action.
Removal of the phenylalanine moiety of 1 gave the
amine 2, which was significantly more potent by the oral
route with an ED50 of 58 mg/kg. The unsubstituted
parent 9-benzylpurine 3 was about twice as potent as 1
after ip and po administration. Several para-substitut-
ed analogues were evaluated by the ip route of admin-
istration. Only the small fluoro (4) and hydrophilic
amino (11) substituents gave compounds with activity
comparable to 2 and 3 (Table 3). Among several meta-
substituted analogues, only the (3-cyanobenzyl)purine
17 was as potent as the unsubstituted parent 3 with
an ip ED50 of 13 mg/kg. Of several ortho-substituted
derivatives only the (2-fluorobenzyl)purine 19 was ac-
tive, although the ip ED50 was only 37 mg/kg. Thus,
the phenylalaninamide moiety of lead compound 1 was
not necessary for activity. The unsubstituted parent
9-benzylpurine 3 was most potent, with an oral ED50 of
52 mg/kg. Substitution on 3 with a variety of substit-
uents did not improve potency.
9-Alk yl-6-(d im eth yla m in o)p u r in es. Since the an-
tiaggression activity of 3 was not significantly improved
by introduction of aryl substituents, the effects of other
lipophilic purine 9-substituents were examined (Table
4). Reduction of the phenyl moiety gave (cyclohexyl-
methyl)purine 25, which was not active at 50 mg/kg.
However, the 9-methylpurine 26 reduced aggressive
behavior by 30% at 25 mg/kg. The 9-ethyl (27), 9-(1-
propyl) (28), and 9-(1-butyl) (29) analogues were as
potent as 3 by the ip route, but the 9-(1-pentyl) (30)
analogue lacked activity at 25 mg/kg.

6-(Alkylamino)-9-alkylpurines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20 3209
Ta ble 2. Physical Properties of Substituted Purines
no.
R2
R6
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
N(CH3)2
NHCH3
R9
method
yield, %
mp, °C
formulaa
C10H15N5
C11H17N5
C12H19N5
C10H15N5
C11H17N5
C11H17N5
C11H17N5
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CF3
NH2
CH2CH2CH3
(CH2)3CH3
(CH2)4CH3
CH(CH3)2
C(CH3)3
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2C3H5
CH2C4H7
C3H5
C,D
C,D
C,D
A,C,D
A,D,E
C,D
C, D
C,D
D,F
D,G
C,D
C,F
C,D
C,D
C,D
C,H
C,F
C,F
C,D
C,D
C,F
C,D
C,D
C,F
C,F
C,Dn
C,I
64
53-56b
36-38
59c
62b
28
44-46
66-67b,d
103-105e
68-71b
34
21
53
79-80c
73f
20g
60h
75b
33g
67i
67b
57j
67k
55l
66l
56g
40b
15g
35m
66m
50
68-70
C11H15N5
C12H17N5‚HCl
C10H13N5
185-189
120-121
91-92
C4H7
C5H9
C6H11
C7H13
C11H15N5
182-188
87-88
60-62
112-114
190-193
157-159t
173-176
161-164
81-83
C12H17N5‚HCl‚1/2H2O
C13H19N5
C14H21N5
C10H13N5
C9H11N5
C12H17N5‚HCl
C13H19N5‚HCl
C13H19N5‚HCl
C12H15N5
C14H19N5‚HCl
C11H15N5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C4H7
CH2C5H9
CH(CH3)C3H5
CH(CH3)C3H5(-)o
CH(CH3)C3H5(+)q
C3H5
NH2
N(CH3)CH2CH3
N(CH3)CH(CH3)2
N(CH2CH3)2
N(CH2)3
N(CH2)5
195-198
71-73
85-86
NHCH2CH3
NHCH2CH2CH3
NHC(CH3)3
NHCH2C3H5
NHC6H5
NHC3H5
N(CH3)C3H5
NHC4H7
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
C12H17N5
200-204
199-201
144-146
112-113
168-171
208-210
98-100
109-110
110-112
110-112
111-112
157-159
132-134
124-125
98-100
114-116
124-126
166-168
100-103
156-160
oil
C13H19N5‚HCl
C13H17N5‚HCl
C15H15N5
12g
81j
68m
51g
50g
36j
46j
49m
48m
51m
85j
26j
51j
30j
42j
6j
C12H15N5
C,J
C13H17N5‚HCl
C13H17N5‚HCl
C13H17N5
C14H19N5
C13H17N5
C13H17N5
C13H17N5
C11H11N5
C12H15N5
C13H17N5
C11H15N5
C11H15N5
C10H13N5S
C12H17N5‚HCl
C12H17N5
C,F
G,K
A,G,K
G,K
Ap,G,K
ArG,K
G,B
G,K
G,K
G,I
G,K
I,L
G,J
G,K
G,K
M
G,K
N
N
N
N
expl
N
expl
expl
expl
O
C4H7
C5H9
CH2CH2CH3
CH(CH3)2
CH2SCH3
(CH2)3CH3
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2C3H5
C3H5
CH2C3H5
CH(CH3)C3H5(-)s
CH2C4H7
C3H5
32g
42j
61j
97
NHC3H5
NHC3H5
C12H17N5
C14H19N5‚0.5H2O
C12H15N5
N(CH2CH3)C3H5
N(CH3)C3H5
N(C3H5)CHO
N(C3H5)CHO
N(C3H5)CHO
N(C3H5)CHO
N(C3H5)COCH3
N(C3H5)CHO
NHC3H5
NHC3H5
NHC3H5
NHC3H5
NHC3H5
27m
50l
71m
57m
66j
72l
65j
67
74-76
156-158
101-102
74-77
C13H15N5O
C14H17N5O
C14H17N5O
C12H13N5O
C13H15N5O
C13H15N5O
C12H14ClN5
C13H14F3N5
C12H16N6
C13H18N6
C14H20N6
C14H20N6
C13H17N5O
C14H19N5O
C15H21N5O
C13H17N5S
125-126
146-147
119-121
144-146j
101-103m
160-162
147-149
150-152l
133-135
122-124
97-99
C3H5
C4H7
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
CH2C3H5
66
64l
62l
82
NHCH3
NHCH2CH3
N(CH3)2
OCH3
OCH2CH3
O(CH2)2CH3
SCH3
O
O
P
NHC3H5
NHC3H5
NHC3H5
NHC3H5
76l
72j
48m
42m
P
Pt
87-89
120-122
NHC3H5
Pu
a
d
All compounds were analyzed for C, H, N. b Recrystallized from pentane. c Recrystallized from petroleum ether (35-60 °C). Dimorphic
form isolated from a separate reaction with mp 50-52 °C. e Recrystallized from methanol:water. f Recrystallized from pentane:cyclohexane.
g
h
j
Recrystallized from ethyl acetate:ethanol. Recrystallized from pentane:ethanol. Recrystallized from petroleum ether (35-60 °C):
ethanol. j Recrystallized from cyclohexane:ethyl acetate. Recrystallized from ethanol. Recrystallized from ethyl acetate. Recrystallized
k
l
m
from cyclohexane. Reaction was heated to reflux for 6 h. o [R]20D - 39.5° (c 1.0, EtOH) Prepared from 109. [R]20D +36.8° (c 1.0, EtOH)
n
p
q
Prepared from 108. [R]20 -36.0° (c 1.0, EtOH) Crude product was purified by column chromatography as in method D. Methyl
r
s
t
u
D
mercaptan was added to the sodium ethanolate solution before addition of 79.
Several branched 9-alkyl substituents were examined.
The 9-(2-propyl) analogue 31 had a low ip ED50 of 11
mg/kg, and its oral potency was excellent, with an ED50
of 15 mg/kg. This level of activity represented a 6-fold

3210 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20
Kelley et al.
Sch em e 2a
Ta ble 3. Antagonism of Apomorphine-Induced Aggression by
9-Benzylpurines
ED50, mg/kga
no.
R
ip
po
1b
2b
3-NHCOCH(NH2)CH2C6H5
3-NH2
H
4-F
4-Cl
4-CH3
4-OCH3
4-NO2
4-CN
4-OH
4-NH2
4-NHCOCH3
3-F
27
23
15
96
58
52
3c
4c
21
5c
(0)d
(0)d
58
6c
7c
8c
(0)d
(0)d
(0)e
17
9c
10c
11c
12f
13c
14c
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
a
Reagents: (i) CH2Cl2, DMAP, AcOCHO; (ii) DMSO, NaH, EtI;
(0)d
(6)e
50
(iii) Ac2O.
Sch em e 3a
3-Cl
3-CH3
3-OCH3
3-CN
3-OH
2-F
2-Cl
2-CH3
2-OMe
2-NO2
2-NH2
(12)d
(48)d
13
(33)e
37
(0)e
(0)e
(0)e
(0)d
(0)d
a
The compounds were tested for their ability to antagonize
apomorphine-induced aggression in male rats as described in refs
9 and 12. The ED50 was the dose needed to decrease the fighting
time by 50%. The compounds were administered as solutions or
fine dispersions in water or 0.5% methylcellulose. Values in
parentheses are percent inhibition at the footnoted dose. The ED50
values are screening numbers that do not have a standard error.
Five pairs of animals were used for each dose; approximate ED50
values were estimated from experiments at two or three doses that
bracketed the ED50. The ED50s for BW 234U were 12.5 ( 3.2 mg/
b
kg ip and 48 ( 6.9 mg/kg po.12 For synthesis, see ref 23. c For
d
synthesis, see ref 16. Percent inhibition at 50 mg/kg. e Percent
inhibition at 25 mg/kg.
a
Reagents: (i) EtOH, c-C3H5NH2; (ii) DMSO, K2CO3,
gression agents when tested individually (Table 5).
These data suggested that an analogue of 35 that could
not be readily dealkylated might be a more potent
antagonist of apomorphine-induced aggression.
c-C3H5CH2Cl; (iii) EtOH, H2O, c-C3H5NH2; (iv) EtOH, RRNH; (v)
ROH, NaH; (vi) EtOH, NaH, CH3SH.
improvement over the lead compound 1 and more than
a 3-fold improvement over 9-benzylpurine 3. Several
9-cycloalkyl-substituted purines (35-41) were evalu-
ated. The cyclopropylmethyl (35), cyclopropyl (37), and
cyclobutyl (38) analogues had good ip and oral antiag-
gression activity. However, 35 emerged as the most
attractive 6-(dimethylamino)purine with an oral ED50
of 17 mg/kg and an oral LD50 of 570 mg/kg, for a safety
ratio of 30. In addition to showing potent antagonism
of apomorphine-induced aggression, 35 did not affect the
performance of chewing and licking, or other compo-
nents of stereotyped behavior.
Metabolism studies with 35 showed that its half-life
was less than 10 min in mice after iv dosing.24 The
6-methylamino (42) and 6-amino (43) derivatives (Table
5) were the main metabolites present in mouse serum
with half-lives of 0.5 and 1 h, respectively. Since the
antiaggression test was not initiated until 1 h after
dosing, the concentration of 35 in the circulation was
very low. Both 42 and 43 were much weaker antiag-
9-(Cyclop r op ylm eth yl)p u r in es. Fifteen 6-substi-
tuted analogues of 35 were synthesized and tested for
antiaggression activity (see 42-56, Table 5). All were
less potent, except for the 6-cyclopropylamino purine 54,
which had ip and oral ED50s of 4 and 12 mg/kg,
respectively. In addition to excellent oral activity, 54
exhibited a long duration of action. When 54 was tested
at 2 times its ED50, fighting was blocked by 100% at 6
h. This marked improvement in the duration of action
compared with 35 is apparently derived from the greater
stability of the 6-(cyclopropylamino) substituent toward
metabolic dealkylation. However, 54 was substantially
more toxic than 35. It had an oral LD50 ) 160 mg/kg
for an acute safety ratio of only 13.
6-(Cyclop r op yla m in o)p u r in es. Although 54 dem-
onstrated good oral activity in antagonizing apomor-
phine-induced aggression in rats with a long duration
of action, the compound was too toxic for further
development. In an effort to identify a compound with

6-(Alkylamino)-9-alkylpurines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20 3211
Ta ble 4. Antagonism of Apomorphine-Induced Aggression by
9-alkyl-6-dimethylamino-9H-purines
Ta ble 6. Antagonism of Apomorphine-Induced Aggression by
6-(Cyclopropylamino)-9-substituted Purines
ED50, mg/kga
ED50, mg/kga
no.
R
ip
po
52
no.
R1
R2
CH2C3H5
CH2C4H7
CH2C5H9
CH(CH3)C3H5
CH(CH3)C3H5 (-)
CH(CH3)C3H5 (+)
C3H5
ip
po
3b
CH2C6H5
CH2C6H11
CH3
CH2CH3
CH2CH2CH3
(CH2)3CH3
(CH2)4CH3
CH(CH3)2
C(CH3)3
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2C3H5
CH2C4H7
C3H5
15
(0)c
(30)d
15
54
57
58
59
60
61
62
63
64
65
66
67
68
69
70
55
71
72
73
74
75
76
77
78
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4
10
15
12
44
25b
26b
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
4.5
25
9
>25
20
14
(15)d
(0)d
2
12.5
4.5
19
d
10
(0)d
11
15
C4H7
C5H9
(0)d
14
5
4.5
8
CH2CH2CH3
CH(CH3)2
CH2SCH3
(CH2)3CH3
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2C3H5
CH2C3H5
C3H5
CH2C3H5
CH(CH3)C3H5 (-)
CH2C4H7
C3H5
6
4
(0)b
30
22
17
(0)d
25
26
23
18
13.5
10
7.5
20
4.5
8
2.5
7
2.4
(22)b
20
9
11
C4H7
C5H9
C6H11
C7H13
(0)b
35
(27)d
(70)d
(0)d
CH3
CH2CH3
CH3
CHO
CHO
CHO
CHO
COCH3
CHO
12.5
30
7.5
See footnote a in Table 3. For synthesis see ref 16. c Percent
inhibition at 50 mg/kg. Percent inhibition at 25 mg/kg.
a
b
d
7.4 ( 0.9c
(0)b
Ta ble 5. Antagonism of Apomorphine-Induced Aggression by
6-Substituted 9-Cyclopropylmethylpurines
C3H5
C4H7
a
b
See footnote a in Table 3. Percent inhibition at 25 mg/kg.
c At twice the ED50, the duration of action was 14 h. Toxic at 25
d
mg/kg.
9-cyclopentyl 64 was toxic at 25 mg/kg, cyclobutyl 63
had fair activity, and cyclopropyl 62 was equipotent to
54 by the ip route of administration. However, the oral
ED50 of 62 was 20 mg/kg, and it was relatively toxic with
an LD50 of 130 mg/kg. Noncyclic aliphatic 9-substitu-
ents gave analogues with ip ED50s ranging from 4 mg/
kg for 2-propyl 66 to 23 mg/kg for methylthiomethyl 67,
but the oral potency of 66 was much less than that of
54.
Substitution on the 6-amino group of 54 with methyl
(55) (Table 5) or ethyl (71) led to less active agents.
However, N(6)-methylation of 62 gave 72, which was
equipotent with 54, but the LD50 was not improved.
With the intention of decreasing toxicity, the N-formyl
derivative of 54 (73) was evaluated. Indeed, the LD50
for 73, was much higher at 500 mg/kg, but the oral ED50
was also higher, giving a safety ratio of 16. The formyl
derivatives of 57, 60, 62, and 63 were also evaluated
(see 74-76, 78). Both 74 and 76 demonstrated excellent
activity with ip and oral ED50s of about 2.5 and 7.5 mg/
kg, respectively. The oral LD50 of 76 was 175 mg/kg,
for a safety ratio of 23.
Metabolism studies revealed that 76 is rapidly con-
verted to 62 in vitro.24 When 76 was administered to
mice po the plasma levels of 62 accounted for most of
the compound within 5 min and levels were sustained
over several hours. Although 76 is stable as a solid, in
water (pH 7) it is 25% deformylated to 62 in 24 h. Thus,
exposure to plasma considerably accelerates deformy-
lation to generate 62. Administration of 62 as the
prodrug 76 results in increased plasma levels of 62 and
ED50, mg/kga
no.
R
ip
po
35
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
N(CH3)2
4.5
17
NHCH3
NH2
12
20
(38)b
N(CH3)CH2CH3
N(CH3)CH(CH3)2
N(CH2CH3)2
N(CH2)3
12.5
(32)b
(0)b
(30)b
(28)b
22
(0)b
N(CH2)5
NHCH2CH3
NHCH2CH2CH3
NHC(CH3)3
NHCH2C3H5
NHC6H5
NHC3H5
N(CH3)C3H5
NHC4H9
(0)b
(0)b
(28)b
(0)b
4
12c
35
7.5
(0)b
a
b
See footnote a in Table 3. Percent inhibition at 25 mg/kg.
c At twice the oral ED50 fighting was inhibited by 100% at 6 h.
an improved overall profile, the 9-(cyclopropylmethyl)
substituent of 54 was systematically varied (Table 6).
The 9-(cyclobutylmethyl) (57) and 9-(cyclopentylmethyl)
(58) analogues were less potent than 54, but substitu-
tion of a methyl on the methylene of 54 gave racemic
59, which was equipotent to 54 by the ip route. The
individual enantiomers 60 and 61 were tested; the
levorotatory isomer 60 was 6-fold more potent than the
dextrorotatory isomer 61 with an ip ED50 ) 2 mg/kg
and an oral ED50 ) 9 mg/kg. Three compounds with
cyclic side chains had highly divergent activities: the

3212 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20
Kelley et al.
Ta ble 7. Antagonism of Apomorphine-Induced Aggression by
2-Substituted-6-(cyclopropylamino)-
9-cyclopropylmethylpurines
relevant to the potential antipsychotic activity. This
property was considered to be incompatible with further
development of 80 as a candidate antipsychotic agent.
Con clu sion
The synthesis and pharmacological evaluation of a
series of 6-(alkylamino)-9-substituted purines has led
to agents with potent activity in the apomorphine-
induced aggressive behavior test. The activity of com-
pound 1 was improved 48-fold with 2-(trifluoromethyl)-
purine 80 (oral ED50 ) 2 mg/kg) through an iterative
series of structure-activity relationship studies that
encompassed evaluation of the effect of structure varia-
tions at the purine 9-, 6-, and 2-positions. Potency was
enhanced with the 9-(cyclopropylmethyl) group of 35,
the duration of action was improved with the 6-(cyclo-
propylamino) substituent of 54, activity was further
enhanced with the N-formyl prodrug 76, and an agent
with less cardiovascular effects emerged with 2-(tri-
fluoromethyl)purine 80. The lack of any inhibition of
binding to either dopamine D1 and D2 receptors would
indicate that the behavioral effects in these compounds
are not caused by direct interaction with dopamine D1
or D2 receptors. Although the overall profile of 80 is
incompatible with clinical development, the 6-(alkyl-
amino)-9-alkylpurines represent a new class of candi-
date antipsychotic agents. These compounds may serve
as useful leads for further research.
ED50, mg/kga
no.
R
ip
po
54
79
80
81
82
83
84
85
86
87
88
H
Cl
CF3
NH2
4
12
2.5
0.9
9
3
9
4
2.0
(26)b
12.5
11
NHCH3
NHCH2CH3
N(CH3)2
OCH3
OCH2CH3
O(CH2)2CH3
SCH3
3.7
4
2.5
0.8
2.5
5
a
b
See footnote a in Table 3. Percent inhibition at 25 mg/kg.
in an apparent improved pharmacological profile. How-
ever, secondary pharmacological studies revealed that
76 had a pronounced effect on the cardiovascular
system. In unconscious dogs, iv administration of 76
resulted in tachycardia.25
2-Su bstitu ted -6-(cyclop r op yla m in o)p u r in es. To
find an analogue free of cardiovascular effects, we
examined a series of 2-substituted analogues of 54
(Table 7). The 2-chloro analogue 79 had improved
potency, and the 2-(trifluoromethyl) analogue 80 was
even more active with an ip ED50 of 0.9 mg/kg and an
oral ED50 of 2 mg/kg, some 6-fold more potent than
parent 54. Its oral LD50 was greater than 100 mg/kg,
for a safety ratio greater than 50, and the propensity
to cause tachycardia was substantially less than that
of 76. Other 2-substituents such as amino (81) and
alkylamino (81-84) gave analogues that were less
active. The alkoxy analogues (85-87) had excellent oral
activity, but they were too toxic to warrant further
study.
The compounds in Tables 3-7 were tested for their
ability to inhibit binding to dopamine D1 and D2
receptors. None of the compounds tested inhibited the
binding of [3H]SCH23390 to rat striatal dopamine D1
receptors or the binding of [3H]raclopride to rat striatal
dopamine D2 receptors by greater than 50% at a
concentration of 10-5 M.
(Trifluoromethyl)purine 80 appeared to be an excel-
lent candidate for development as an antipsychotic
agent. However, in acute oral toxicity studies in fasted
rats, the gross pathological findings revealed varying
degrees of damage of stomach mucosa.26 These findings
prompted further study of the effect of 80 and several
other analogues on stomach emptying. Compounds 35,
60, 76, and 80 were studied in rats in a semiquantitative
test for blockade of stomach emptying based on the
elimination of phenol red dye.27 Compounds were tested
at the oral ED50 dose for blockage of apomorphine-
induced aggression, and the degree of retardation of
stomach emptying during a 1-h period was determined.
Stomach emptying was retarded by 25-100% for 35
(100%), 60 (25%), 76 (100%), and 80 (45%) at oral doses
Exp er im en ta l Section
5-Amino-4,6-dichloropyrimidine was purchased from Pacific
Chemical Laboratories, and 100% formic acid was obtained
from Fluka. Melting points were taken in capillary tubes on
a Mel-Temp block or a Thomas-Hoover Unimelt and were
uncorrected. UV spectra were measured on a Unicam SP 800
or a Cary 118 UV-vis spectrophotometer. NMR data were
recorded on a Varian XL-100-15-FT, a Varian FT-80A, a
Varian T-60, or an Hitachi Perkin-Elmer R-24 spectrometer
with Me4Si as an internal standard. Each analytical sample
produced spectral data compatible with its assigned structure
and moved as a single spot on TLC. TLCs were developed on
Whatman 200 µm MK6F plates of silica gel with fluorescent
indicator. Preparative flash chromatography28 was performed
on silica gel 60 (40-63 µM, E. Merck, no. 9385). In Tables
1-6 cycloalkanes are designated as follows: C3H5 for cyclo-
propyl, C4H7 for cyclobutyl, C5H9 for cyclopentyl, C6H11 for
cyclohexyl, and C7H13 for cycloheptyl. All compounds were
analyzed for C, H, N and gave values within 0.4% of the
theoretical values. Elemental analyses were performed by
Atlantic Microlab, Inc.
Meth od A. 5-Am in o-4-ch lor o-6-(p r op yla m in o)p yr im i-
d in e (89). A mixture of 5-amino-4,6-dichloropyrimidine (10.0
g, 61.0 mmol), 1-propylamine (4.50 g, 76.2 mmol), 1-butanol
(120 mL), and triethylamine (7.1 g, 76.2 mmol) was refluxed
with stirring for 16 h. The resultant solution was spin
evaporated in vacuo. The residual oil was dissolved in
dichloromethane (125 mL) and washed with water (3 × 10
mL). The combined extracts were spin evaporated in vacuo,
redissolved in dichloromethane, and added to silica gel 60. This
mixture was spin evaporated, and the residual solids were
introduced on a column of silica gel 60 wetted with ethyl
acetate:cyclohexane 1:2. The column was eluted with the same
solvent using the flash chromatography technique. The frac-
tions were combined and spin evaporated to give 10.86 g (95%)
of 89, mp 113-114 °C, which was single spot on TLC (ethyl
acetate-cyclohexane 1:2). Recrystallization of 1.00 g of 89 from
cyclohexane gave 0.79 g of analytically pure material of
unchanged melting point: 1H NMR (DMSO-d6) 7.72 (s, 1H,
CH), 6.77 (br m, 1H, NH), 4.98 (br s, 2H, NH2), 3.35 (q, 2H,
NCH2), 1.57 (m, 2H, CH2CH3), 0.92 (t, 3H, CH3).

6-(Alkylamino)-9-alkylpurines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20 3213
44, mp 157-159 °C (with softening and resolidification at ∼134
Meth od B. 5-Am in o-4-ch lor o-6-(cyclop r op yla m in o)-
p yr im id in e (96). A mixture of 5-amino-4,6-dichloropyrimi-
dine (40.0 g, 244 mmol), 1-propanol (400 mL), and cyclopropyl
amine (69.0 g, 1.208 mol) was refluxed with stirring for 3 h
and then stirred at ambient temperature for 3 days. The
resultant solution was spin evaporated. The residual oil was
dissolved in dichloromethane (600 mL) and washed with water
(3 × 50 mL). The combined aqueous extracts were back-
washed with dichloromethane (4 × 50 mL). The combined
dichloromethane solutions were filtered through glass wool and
spin evaporated in vacuo. The yellow solid was stirred and
heated with cyclohexane (300 mL), cooled, collected, and dried
at 100 °C to give 42.40 g (94%) of 96, mp 153-156 °C.
Recrystallization of a sample from toluene gave the analytical
1
°C); H NMR (DMSO-d6) δ 11.26 (br s, 1H, HCl), 8.57 (s, 1H,
purine H), 8.43 (s, 1H, purine H), 4.2 (br m, 2H, NCH2CH3),
4.17 (d, 2H, J ) 8 Hz, NCH2CH), 3.37 (s, 3H, NCH3), 1.27 (t,
3H, J ) 7, CCH3), 1.2 (br m, 1H, CH), 0.53 (m, 4H, CH2CH2).
Meth od G. 6-Ch lor o-9-cyclop r op yl-9H-p u r in e (104). A
mixture of dry 96 (21.70 g, 117.5 mmol), triethyl orthoformate
(300 mL), and ethanesulfonic acid (0.25 mL) was stirred at
ambient temperature for 46 h. The reaction was spin evapo-
rated in vacuo. The brown residue was dissolved in dichlo-
romethane and added to silica gel 60. This mixture was spin
evaporated in vacuo and the residual solids were introduced
on a column of silica gel 60 wetted with ethyl acetate:
cyclohexane 2:1. The column was eluted with ethyl acetate:
cyclohexane 2:1 using the flash chromatography technique.
The appropriate fractions were pooled and spin evaporated to
give 18.40 g (80%) of 104, mp 114-117 °C. Recrystallization
of a sample from cyclohexane:ethyl acetate gave the analytical
sample: mp 118-119 °C; 1H NMR (CDCl3) δ 8.77 (s, 1H,
purine H), 8.13 (s, 1H, purine H), 3.53 (m, 1H, NCH), 1.2 (m,
4H, CH2CH2). Anal. (C8H7ClN4) C, H, N.
1
sample: mp 156-158 °C; H NMR (DMSO-d6) δ 7.78 (s, 1H,
NCHN), 6.92 (br s, 1H, NH), 4.95 (br s, 2H, NH2), 2.87 (m,
1H, NCHC), 0.85-0.40 (m, 4H, CH2CH2).
Meth od C. 6-Ch lor o-9-(cyclop r op ylm eth yl)-9H-p u r in e
(102). A mixture of dry 94 (11.86 g, 59.7 mmol), triethyl
orthoformate (75 mL), and ethanesulfonic acid (0.125 mL) was
stirred at ambient temperature for 68 h. The reaction was
spin evaporated in vacuo. The brown residue was dissolved
in dichloromethane (125 mL) and washed with 5% aqueous
sodium bicarbonate (15 mL) and water (15 mL). The solution
was filtered through glass wool and spin evaporated in vacuo
to give a quantitative yield of 102, which was essentially a
single spot on TLC. This material was used without further
purification in the next reaction: UV (0.1 N HCl plus 20%
EtOH): λmax 265 nm; UV (0.1 N NaOH plus 20% EtOH); λmax
Meth od H. 6-Am in o-9-(cyclop r op ylm eth yl)-9H-p u r in e
(43). A solution of 102 (5.00 g, 24.0 mmol) and methanol
saturated with ammonia (75 mL) was heated at 90 °C in a
stainless steel reaction vessel for 18 h. The vessel was cooled,
and the solids were collected to give 3.11 g (68%) of 43, mp
192-195 °C. The filtrates were evaporated, the residue was
dispersed in water, and the solids were collected to give 0.60
g of a second crop. The combined solids were recrystallized
1
266 nm; H NMR (DMSO-d6) δ 8.70 (s, 2H, purine Hs), 4.10
1
from ethanol to give 3.06 g (67%) of 43: mp 190-193 °C; H
(d, 2H, J ) 6 Hz, NCH2), 1.35 (m, 1H, CH), 0.45 (m, 4H, CH2-
CH2).
NMR (DMSO-d6) δ 8.20 (s, 2H, purine Hs), 7.22 (br s, 2H,
NH2), 4.02 (d, 2H, J ) 7 Hz, NCH2), 1.27 (m, 1H, CH), 0.50
(m, 4H, CH2CH2).
Meth od D. 9-(Cyclop r op ylm eth yl)-6-(d im eth yla m in o)-
9H-p u r in e (35). A solution of 102 (10.2 g, 49.0 mmol), ethanol
(50 mL), and 40% aqueous dimethylamine (25 mL) was stirred
at ambient temperature for 18 h. The reaction was spin
evaporated to remove the volatiles. The residue was dissolved
in dichloromethane (200 mL) and washed with water (2 × 50
mL). The combined extracts were spin evaporated in vacuo,
redissolved in dichloromethane, and added to silica gel 60. This
mixture was spin evaporated, and the residual solids were
introduced on a 5-cm-diameter column of silica gel 60 wetted
with ethyl acetate. The column was eluted with ethyl acetate
using the flash chromatography technique. The appropriate
fractions were combined and spin evaporated to give a
homogeneous residue, which was recrystallized from pentane:
Meth od I. 9-Cyclop r op yl-6-(cyclop r op yla m in o)-9H-
p u r in e (62). A solution of 104 (27.20 g, 140.0 mmol),
cyclopropylamine (30 mL), triethylamine (40 mL), and ethanol
(200 mL) was stirred at ambient temperature for 15 h. The
reaction was spin evaporated to remove the volatiles. The
residue was dissolved in dichloromethane (500 mL) and
washed with water (2 × 50 mL). The solution was filtered
through glass wool and spin evaporated in vacuo. The yellow
residue was digested with hot cyclohexane (200 mL), cooled,
collected, and dried at 80 °C to give 25.77 g (85%) of 62, mp
156-158 °C, which was a single spot on TLC (ethyl acetate:
ethanol 10:1). Recrystallization of 4.00 g of 62 from cyclohex-
ane:ethyl acetate (charcoal) gave 2.80 g of analytically pure
62: mp 157-159 °C; 1H NMR (DMSO-d6) δ 8.30 (s, 1H, purine
H), 8.13 (s, 1H, purine H), 7.82 (br d, 1H, NH), 3.50 (m, 1H,
NCH), 3.13 (m, 1H, HNCH), 1.10 (m, 4H, CH2CH2), 0.73 (m,
4H, HNCH(CH2)2).
1
cyclohexane to give 7.86 g (73%) of 35: mp 68-70°; H NMR
(DMSO-d6) δ 8.23 (s, 1H, purine H), 8.20 (s, 1H, purine H),
4.03 (d, 2H, J ) 7 Hz, NCH2), 3.47 (s, 6H, N(CH3)2), 1.30 (m,
1H, CH), 0.50 (m, 4H, CH2CH2).
Meth od E. 9-ter t-Bu tyl-6-ch lor o-9H-p u r in e (103).
A
Meth od J . 9-Bu tyl-6-(cyclop r op yla m in o)-9H-p u r in e
Hyd r och lor id e (68). A solution of 9-butyl-6-chloro-9H-purine
(9.50 g, 45.1 mmol), cyclopropylamine (15 mL), triethylamine
(10 mL), and ethanol (100 mL) was stirred at ambient
temperature for 72 h. The reaction was spin evaporated to
remove the volatiles. The residue was dissolved in dichlo-
romethane (200 mL) and washed with water (2 × 50 mL). The
combined extracts were spin evaporated in vacuo, redissolved
in dichloromethane, and added to silica gel 60. This mixture
was spin evaporated, and the residual solids were introduced
on a 5-cm-diameter column of silica gel 60 wetted with ethyl
acetate. The column was eluted with 2% ethanol in ethyl
acetate using the flash chromatography technique. The ap-
propriate fractions were combined and spin evaporated to give
9.00 g (86%) of 68 as a homogeneous oil. The oil was dissolved
in ethanol (100 mL), diluted with 12 N hydrochloric acid (5
mL), and spin evaporated in vacuo to remove the volatiles.
The residue was recrystallized from ethyl acetate:ethanol to
give 1.49 g (12%) of 68‚HCl, mp 166-168 °C. The volume of
the mother liquors was condensed to give an additional 2.42 g
solution of 5-amino-4-(tert-butylamino)-6-chloropyrimidine (4.53
g, 22.6 mmol), triethyl orthoformate (50 mL), and ethane-
sulfonic acid (0.1 mL) was refluxed with stirring for 5 days.
The reaction was spin evaporated in vacuo. The residue was
dissolved in ethyl acetate (100 mL) and washed with 5%
aqueous sodium bicarbonate (2 × 25 mL) and water (25 mL).
The volatiles were removed by spin evaporation to give an oil
that was crystallized from methanol to give 2.93 g of 103, mp
144-146 °C. The mother liquors were processed to give an
additional 0.52 g of crystals, mp 140-143.5 °C. A second
recrystallization of the combined crops from heptane gave 3.06
1
g (64%) of 103: mp 144-146 °C; H NMR (DMSO-d6) δ 8.75
(s, 1H, purine H), 8.67 (s, 1H, purine H), 1.78 (s, 9H, (CH3)3).
Anal. (C9H11ClN4) C, H, N.
Meth od F. 9-(Cyclop r op ylm eth yl)-(N-m eth yleth yla m i-
n o)-9H-p u r in e Hyd r och lor id e (44). A solution of 102 (3.0
g, 14.4 mmol), ethanol (30 mL), ethylmethylamine hydrochlo-
ride (4.11 g, 42.9 mmol), triethylamine (5 mL), and water (15
mL) was stirred at ambient temperature for 66 h. The reaction
was spin evaporated in vacuo to remove the volatiles. The
residue was dissolved in dichloromethane (100 mL) and
washed with water (2 × 25 mL). The combined extracts were
spin evaporated in vacuo, dissolved in ether, and diluted with
hydrogen chloride saturated ether. The solids were collected
and recrystallized from ethyl acetate to give 2.15 g (55%) of
1
(32% total) of 68‚HCl: mp 167-170 °C; H NMR (DMSO-d6)
δ 12.2 (br, 1H, HCl), 10.07 (br, 1H, NH), 8.67 (s, 1H, purine
H), 8.53 (s, 1H, purine H), 4.33 (t, 2H, J ) 7 Hz, NCH2), 3.13
(br, 1H, NCH), 1.88 (m, 2H, NCH2CH2), 1.5-0.67 (m, 9H, CH2-
CH3, NCH(CH2)2).

3214 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20
Kelley et al.
Meth od K. 9-(1-(2-Meth yl)p r op yl)-6-(cyclop r op yla m i-
n o)-9H-p u r in e (70). A solution of 6-chloro-9-(1-(2-methyl)-
propyl)-9H-purine (9.50 g, 45.1 mmol), cyclopropylamine (14
mL), triethylamine (10 mL), and ethanol (100 mL0 was stirred
at ambient temperature for 72 h. The reaction was spin
evaporated to remove the volatiles. The residue was dissolved
in dichloromethane (200 mL) and washed with water (2 × 50
mL). The combined extracts were spin evaporated in vacuo,
redissolved in dichloromethane, and added to silica gel 60. This
mixture was spin evaporated, and the residual solids were
introduced on a 5-cm-diameter column of silica gel 60 wetted
with ethyl acetate. The column was eluted with 2% ethanol
in ethyl acetate using the flash chromatography technique.
The appropriate fractions were combined and spin evaporated
to give a solid that was recrystallized from cyclohexane: ethyl
25 mL), with water (25 mL), and then filtered through glass
wool. The solution was spin evaporated in vacuo. The residue
was dissolved in dichloromethane and added to silica gel 60
wetted with ethyl acetate:cyclohexane 2:1. The column was
eluted with ethyl acetate:cyclohexane 2:1 using the flash
chromatography technique. The fractions containing the
highest Rf (major spot) were combined and spin evaporated
in vacuo to give 14.20 g (66%) of 76, mp 122-124 °C, which
was a single spot on TLC (ethyl acetate). Recrystallization
from cyclohexane:ethyl acetate gave the analytical sample: mp
1
125-126 °C; H NMR (DMSO-d6) δ 9.75 (s, 1H, HCO), 8.77
(s, 1H, purine H), 8.53 (s, 1H, purine H), 3.60 (m, 1H, NCH),
3.00 (m, 1H, OCNCH), 1.33-0.43 (m, 8H, 2 CH2CH2).
Met h od O. 6-(Cyclop r op yla m in o)-9-(cyclop r op yl-
m eth yl)-2-(m eth yla m in o)-9H-p u r in e (82). A mixture of 79
(5.25 g, 19.90 mmol), ethanol (50 mL), and 40% aqueous
methylamine (20 mL) was heated at 80 °C in a stainless steel
reaction vessel for 60 h. The vessel was cooled, and the
contents were spin evaporated in vacuo. The residue was
purified by the flash chromatography technique as described
in method D to give 5.00 g (97%) of 82, which was a single
spot on TLC (ethyl acetate). Recrystallization from ethyl
acetate gave 3.20 g (62%) of 82: mp 147-149 °C; NMR
(DMSO-d6) δ 7.72 (s, 1H, H-8), 7.21 (d, 1H, J ) 4.8 Hz, NHCH),
6.20 (q, 1H, J ) 4.8, NHCH3), 3.82 (d, 2H, J ) 7.0 Hz, NCH2),
3.0 (m, 1H, NCH), 2.79 (d, 2H, J ) 4.8, CH3), 1.2 (m, 1H,
NCH2CH), 0.70-0.39 (m, 8H, 2 CH2CH2).
1
acetate to give 6.39 g (61%) of 70: mp 156-160 °C; H NMR
(DMSO-d6) δ 8.28 (s, 1H, purine H), 8.15 (s, 1H, purine H),
7.81 (br d, 2H, NH), 4.00 (d, 1H, I ) 7 Hz, NCH2), 3.13 (m,
1H, HNCH), 2.27 (m, 1H, CH(CH3)2) 0.83 (d, 6H, J ) 6 Hz,
(CH3)2), 0.67 (m, 4H, CH2CH2).
Met h od L. 6-Ch lor o-9-[(m et h ylt h io)m et h yl]-9H -p u -
r in e (105). A mixture of 6-chloropurine (7.00 g, 45.3 mmol),
dimethyl sulfoxide (100 mL), anhydrous potassium carbonate
(8.00 g, 58.0 mmol), and chloromethyl methyl sulfide (3.90 g,
40.4 mmol) was stirred at ambient temperature for 6 days.
The reaction was poured into ice water (400 mL) and extracted
with dichloromethane (4 × 100 mL). The combined extracts
were washed with water (6 × 50 mL), filtered through glass
wool, and spin evaporated in vacuo. The residue was dissolved
in dichloromethane and added to silica gel 60. This mixture
was spin evaporated in vacuo, and the residual solids were
introduced on a 4-cm-diameter column of silica gel 60 wetted
with ethyl acetate:cyclohexane 1:1. The column was eluted
with the same solvent using the flash chromatography tech-
nique. The fractions containing the higher Rf (major spot)
were combined and spin evaporated to give 1.20 g (10%) of
105, which was a single spot on TLC (ethyl acetate:cyclohexane
1:1): UV (0.1 N HCl) λmax 265.5 nm; UV (0.1 N NaOH) λmax
265.5 nm.
Met h od P .
6-(Cyclop r op yla m in o)-9-(cyclop r op yl-
m eth yl)-2-eth oxy-9H-p u r in e (86). Ethanol (100 mL) was
added dropwise to sodium hydride (60.2% in mineral oil) (2.00
g, 50.0 mmol) under a nitrogen atmosphere with ice-bath
cooling. Compound 79 (3.56 g, 13.5 mmol) was added to the
solution of sodium ethoxide, and the reaction was refluxed with
stirring for 20 h. The cooled solution was spin evaporated to
dryness, and the residue was dissolved in dichloromethane
(350 mL). The solution was washed with water (200 mL),
filtered through glass wool, and spin evaporated in vacuo. The
solid was recrystallized from cyclohexane to give 1.79 g (48%)
of 86: mp 97-99 °C; NMR (DMSO-d6
) δ 7.96 (s, 1H, 8-H), 7.85
(d, 1H, J ) 7.0 Hz, NH), 4.30 (q, 2H, J ) 7.0, OCH2), 3.90 (d,
2H, J ) 7.1, NCH2), 3.0 (m, 1H, NCH), 1.31 (t, 3H, J ) 7.0,
CH3), 1.2 (m, 1H, NCH2CH), 0.73-0.38 (m, 8H, 2 CH2CH2).
9-Cyclop r op yl-6-(N -cyclop r op yla ce t a m id o)-9H -p u -
r in e (77). A solution of 62 (2.00 g, 9.29 mmol) and acetic
anhydride (10 mL) was refluxed with stirring for 15 min. The
solution was spin evaporated in vacuo, diluted with ethyl
acetate, and re-evaporated to remove the volatiles. The
residue was recrystallized from ethyl acetate to give 1.74 g
(72%) of 77: mp 146-147 °C;
Meth od M. 9-(Cyclop r op ylm eth yl)-6-(eth ylcyclop r o-
p yla m in o)-9H-p u r in e (71). To a magnetically stirred dis-
persion of cyclohexane-washed sodium hydride (60.2% in
mineral oil) (2.60 g, 65.2 mmol) in dimethyl sulfoxide (75 mL)
was added 54 (8.00 g, 34.8 mmol) in portions. After 1 h, when
dissolution was complete, ethyl iodide (8 mL) was added, and
the reaction was stirred for 2 h. The reaction was diluted with
ethanol (10 mL) and then poured over ice water (300 mL). The
mixture was acidified to pH 5-6 with acetic acid (5 mL) and
extracted with dichloromethane (4 × 75 mL). The combined
extracts were back-washed with water (5 × 50 mL) to remove
residual dimethyl sulfoxide, filtered through glass wool, and
spin evaporated in vacuo. The residual oil was dissolved in
dichloromethane and applied to a 4-cm-diameter column of
silica gel 60. The column was eluted with ethyl acetate:
cyclohexane 1:1 using the flash chromatography technique.
The appropriate fractions were pooled and spin evaporated to
give 8.72 g (97%) of 71 as an oil, which was a single spot on
TLC (ethyl acetate:cyclohexane 1:1): 1H NMR (DMSO-d6) δ
8.28 (s, 1H, purine H), 8.20 (s, 1H, purine H), 4.07 (q, 2H, CH2-
CH3), 4.02 (d, 2H, CH2CH), 3.17 (m, 1H, NCH), 1.17 (t, 3H,
CH3), 1.5-0.33 (m, 9H, CH(CH2)2, CH2CH2).
Meth od N. 6-(N-Cyclop r op ylfor m a m id o)-9-cyclop r o-
p yl-9H-p u r in e (76). To a stirred, ice-bath-cooled solution of
62 (18.82 g, 87.5 mmol), 4-dimethyl-aminopyridine (11.00 g,
90.0 mmol), and dry dichloromethane (200 mL) was added the
acetic formic anhydride prepared from acetic anhydride (100
mL) and 100% formic acid (50 mL).20 The solution was
refluxed with stirring for 1.5 h, cooled on ice, and recharged
with the acetic formic anhydride prepared from acetic anhy-
dride (50 mL) and 100% formic acid (25 mL). The solution
was refluxed with stirring for 1.5 h and then stirred at ambient
temperature for 15 h. The reaction was spin evaporated to
remove the volatiles. The residue was dissolved in ethyl
acetate (200 mL), cooled, and spin evaporated. The residual
solid was dissolved in dichloromethane (400 mL), washed with
water (3 × 25 mL), with 5% aqueous sodium bicarbonate (3 ×
1H NMR (DMSO-d6) δ 8.83 (s,
1H, purine H), 8.54 (s, 1H, purine H), 3.6 (m, 1H, NCH), 3.2
(m, 1H, OCNCH), 2.11 (s, 3H, CH3), 1.2-0.3 (m, 8H, 2 CH2-
CH2).
2-Ch lor o-6-(cyclop r op yla m in o)-9-(cyclop r op ylm eth yl)-
9H-p u r in e (79). This compound was prepared from 111 (22.5
g, 107.4 mmol) and chloromethylcyclopropane (17.0 g, 188.0
mmol) by method L, except that the reaction was heated at
60 °C for 8 h and stirred at ambient temperature for 2 days.
The chromatography solution was spin evaporated in vacuo
to give 19.0 g (67%) of 79, mp 139-142 °C. The analytical
sample was recrystallized from cyclohexane:ethyl acetate: mp
144-146 °C; UV (0.1 N HCl) λmax 281 nm; UV (0.1 N NaOH)
1
λmax 274 nm; H NMR (DMSO-d6) δ 8.36 (d, 1H, NH), 8.20 (s,
1H, H-8), 3.96 (d, 2H, J ) 7.1 Hz, NCH2), 3.0 (br, 1H, NCH),
1.3 (m, 1H, NCH2CH), 0.7-0.4 (m, 8H, 2 CH2CH2); 13CNMR
(DMSO-d6) δ 156.17 (C-6), 152.93 (C-2), 140.87 (C-8), 118.04
(C-5).
6-Cyclop r op yla m in o)-9-(cyclop r op ylm eth yl)-2-(tr iflu o-
r om eth yl)-9H-p u r in e (80). This compound was prepared
from 112 (1.61 g, 6.63 mmol) and chloromethylcyclopropane
(1.10 g, 12.1 mmol) by method L, except that the reaction was
heated at 60 °C for 5 h and stirred at ambient temperature
for 2 days. The chromatography solution was spin evaporated
in vacuo to give 1.30 g (66%) of 80, which was one spot on
TLC. The analytical sample was recrystallized from cyclo-
hexane: mp 101-103 °C; UV (0.1 N HCl) λmax 281 nm; UV
(0.1 N NaOH) λmax 271 nm; NMR (DMSO-d6) δ 8.42 (d, 1H,

6-(Alkylamino)-9-alkylpurines
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20 3215
NH), 8.39 (s, 1H H-8), 4.06 (d, 2H, J ) 7.2 Hz, NCH2), 3.2 (br,
1H, NCH), 1.3 (m, 1H, NCH2CH), 0.8-0.4 (m, 8H, 2 CH2CH2).
2-Am in o-6-(cyclop r op yla m in o)-9-(cyclop r op ylm eth yl)-
9H-p u r in e (81). A solution of 114 (2.50 g, 11.18 mmol),
ethanol (50 mL), cyclopropylamine (10 mL), and water (5 mL)
was heated at 75 °C in a stainless steel reaction vessel for 48
h. The vessel was cooled, and the contents were spin evapo-
rated in vacuo. The residue was dispersed in water (50 mL),
and the solid was collected and washed with water. Recrys-
tallization from ethyl acetate gave 1.75 g (64%) of 81: mp 160-
162 °C; UV (0.1 N HCl) λmax 297, 257 nm; UV (0.1 N NaOH)
λmax 284, 262 (sh) nm; NMR (DMSO-d6) δ 7.74 (s, 1H, H-8)
7.24 (d, 1H, J ) 4.5 Hz, NH), 5.81 (s, 2H, NH2), 3.80 (d, 2H, J
) 7.0 Hz, NCH2), 3.05 (m, 1H, NCH2CH), 1.25 (m, 1H, NCH),
0.69-0.34 (m, 8H, 2 CH2CH2).
resultant crystals were collected, washed with cold water (25
mL), and dried. The crude product was recrystallized eight
times from ethanol:water to a constant melting point to give
15.08 g (45%) of the L-tartaric acid salt of 108b: mp 163-
164.5 °C. An additional recrystallization of a portion gave the
analytical sample of unchanged melting point. Anal. (C9H17
-
NO6) C, H, N. Fourteen grams of the tartrate was cautiously
added to a cold, saturated solution of potassium carbonate (100
g) in water (200 mL). The resultant mixture was extracted
with diethyl ether (6 × 100 mL), and the combined extracts
were dried over anhydrous potassium carbonate. The mixture
was filtered, and the ether was removed by fractional distil-
lation through a 30-cm Vigreux column on a hot-water bath
at 50-60 °C. The residual amine (6.41 g), which contained
some diethyl ether, was used without further purification in
the next step. From a separate preparation, 8.70 g of 108b
was converted to the hydrochloride as described for 108a to
give 4.82 g of the hydrochloride of 108b: mp 195-196.5 °C;
(Cyclop en tylm eth yl)a m in e Hyd r och lor id e (106).
A
solution of 1 M borane in tetrahydrofuran (527 mL, 527 mmol)
was added dropwise over 2 h to a stirred solution of cyclopen-
tanecarbonitrile (45.6 g, 479 mmol) in dry tetrahydrofuran (50
mL). The resultant solution was refluxed with stirring for 18
h. The reaction was cooled to ambient temperature and
cautiously diluted in small portions with methanol (670 mL).
The solution was cooled on an ice bath, and hydrogen chloride
gas was bubbled through the solution for 0.5 h. The reaction
was refluxed for 1.5 h, and the volatiles were removed by spin
evaporation in vacuo. Methanol (500 mL) was added to the
residue, and the mixture was spin evaporated in vacuo. This
methanol addition procedure was repeated twice to give a
white solid, which was recrystallized from ethanol:ethyl
acetate to give 36.2 g (56%) of (cyclopentylmethyl)amine
hydrochloride, mp 226-230 °C (dec). Recrystallization from
ethanol:tert-butyl methyl ether gave the analytical sample, mp
227.5-230 °C (dec) (lit.29). Anal. (C6H13N‚HCl) C, H, N.
(r a c)-1-Cyclop r op yleth yla m in e Hyd r och lor id e (107).
To ammonium acetate (230 g, 2.98 mol), which had been
repeatedly diluted with 2-propanol and spin evaporated until
a dry granular solid was obtained, were added dry methanol
(500 mL), cyclopropyl methyl ketone (25.0 g, 282 mmol), and
sodium cyanoborohydride (20.0 g, 318 mmol). The reaction
was stirred under a calcium chloride tube at ambient temper-
ature for 120 h. The reaction solution was cooled on an ice
bath and cautiously acidified in an efficient hood to pH 1 with
12 M hydrochloric acid (225 mL). The resultant mixture was
spin evaporated in vacuo, and the white residue was dissolved
in water (800 mL). The solution was washed with three
portions of diethyl ether (3 × 500 mL). The aqueous solution
was cooled on an ice bath and basified to pH 11 with solid
potassium hydroxide (120 g). This solution was extracted with
diethyl ether (5 × 600 mL), and the combined extracts were
dried with magnesium sulfate. The mixture was filtered, and
the ether was removed by fractional distillation through a 30-
cm Vigreux column on a hot-water bath at 50-60 °C. The
residual amine was distilled through a 10-cm Vigreux column
to give 32.3 g of crude 1-cyclopropylethylamine, bp 82-91 °C
(lit.30 bp 91-94 °C (740 mm)). This material was dissolved in
ethanol (250 mL), diluted with 12 M hydrochloric acid (30 mL),
and spin evaporated in vacuo. The residue was recrystallized
from ethanol to give 10.16 g (29%) of 107 hydrochloride, mp
180-181 °C. The mother liquors were condensed to give an
additional 6.57 g (48%) of product: mp 180-182 °C; 1H NMR
(DMSO-d6) δ 8.75 (br s, 3H, NH3Cl), 3.00 (m, 1H, NCH), 1.74
(d, 3H, J ) 6 Hz, CH3), 1.50 (m, 1H, CH(CH2)2), 1.00 (m, 4H,
CH2CH2). Anal. (C5H11N‚HCl) C, H, N.
[R]20 +3.3° (c 1.0, H2O).
D
2-Ch lor o-6-(cyclopr opylam in o)-9H-pu r in e (111). A mix-
ture of 2,6-dichloropurine (109) (5.00 g, 26.5 mmol), ethanol
(25 mL), and cyclopropylamine (5 mL) was stirred at ambient
temperature for 24 h. The solid was collected by suction
filtration and then dispersed in water (25 mL) with manual
stirring. The white solid was collected and dried to give 4.52
g (81%) of 111, mp 260-264 °C, which was one spot on TLC
(silica gel, EtOH:EtOAc 1:10). Recrystallization of a portion
from ethanol:water gave the analytical sample: mp 249-251
°C; NMR (DMSO-d6) δ 8.23 (d, 1H, HNC3H5), 8.12 (s, 1H, H-8),
3.1 (br m, 1H, HNCH), 0.70 (m, 4H, CH2CH2). Anal. (C8H8-
ClN5) C, H, N.
6-(Cyclop r op yla m in o)-2-(t r iflu or om et h yl)-9H -p u r in e
(112). This compound was prepared from 11021 (2.00 g, 8.98
mmol) as described for 111 to give 1.16 g (53%) of 112, mp
270-274 °C, which was one spot on TLC (silica gel, EtOH:
EtOAC 1:10). Recrystallization of a portion from ethyl acetate
gave the analytical sample: mp 276-278 °C; NMR (DMSO-
d6) δ 8.32 (br s, 2H, H-8 and HNC3H5), 3.2 (br m, 1H, HNCH),
0.70 (m, 4H, CH2CH2). Anal. (C9H8F3N5) C, H, N.
2-Am in o-6-ch lor o-9-(cyclop r op ylm et h yl)-9H -p u r in e
(114). This compound was prepared from 113 (10.00 g, 58.97
mmol) and chloromethylcyclopropane (7.00 g, 77.31 mmol) by
method L, except that the reaction was heated at 50 °C for 5
h and stirred at ambient temperature for 24 h. The chroma-
tography solution was spin evaporated in vacuo to give 6.00 g
(45%) of 114 mp 143-145 °C. The analytical sample was
recrystallized from cyclohexane:ethyl acetate: mp 143-145 °C;
NMR (DMSO-d6) δ 8.18 (s, 1H, H-8), 6.89 (s, 2H, NH2), 4.00
(d, 2H, J ) 7.1 Hz, NCH2), 1.3 (m, 1H, CH) 0.56-0.37 (m, 4H,
CH2CH2). Anal. (C9H10N5Cl) C, H, N.
2-Am in o-9-(cyclopr opylm eth yl)-6-(dim eth ylam in o)-9H-
p u r in e (115). This compound was prepared from 114 (3.00
g, 13.41 mmol) and 40% aqueous dimethylamine (25 mL) as
for the preparation of 81. Recrystallization from ethyl acetate
gave 2.15 g (69%) of 115: mp 175-178 °C; UV (0.1 N HCl)
λ
max 292, 257 nm; UV (0.1 N NaOH) λmax 285, sh 265 nm; NMR
(DMSO-d6) δ 7.76 (s, 1H, H-8), 5.78 (s, 2H, NH2), 3.82 (d, 2H,
J ) 7.0 Hz, NCH2), 3.36 (s, 6H, N(CH3)2), 1.2 (m, 1H, CH),
0.53-0.33 (m, 4H, CH2CH2). Anal. (C11H16N6) C, H, N.
Dop a m in e Recep tor Assa ys. Inhibition of binding to the
dopamine D1 receptor was assessed using a method adapted
from Porceddu et al.31 The test compounds were incubated at
10-5 M, with 0.2 nM [3H]-SCH23390 and rat striatal mem-
branes (10-15 µg protein per tube) for 15 min at 37 °C in a
total volume of 0.5 mL. Nonspecific binding was determined
using 0.1 µM SCH23390. Inhibition of binding to the dopam-
ine D2 receptor was assessed using a method adapted from
Dewar, et al.32 The test compounds were incubated at 10-5
M with 1.0 nM [3H]-raclopride and rat striatal membrane
preparation (60-65 µg protein per tube) for 30 min at room
temperature in a total volume of 0.5 mL. Nonspecific binding
was determined using 1 µM halperidol. Bound and free
radioligand were separated by rapid filtration through What-
man GF/B filters using a Brandel M-24 cell harvester. Filters
were washed once with 3 mL of ice-cold assay buffer, placed
(+)-1-Cyclop r op yleth yla m in e (108a ). This compound
was prepared by the method of Vogel and Roberts.30 For
characterization, a 5-g sample of liquid 108a was dissolved in
100 mL of ethanol, diluted with 5 mL of concentrated hydro-
chloric acid, and spin evaporated in vacuo. The residue was
covered with ethanol and re-evaporated. The residue was
covered with diethyl ether, which induced crystallization, and
the solids were collected and dried to give 2.55 g of the hydro-
chloride: mp 197-198 °C; [R]2D0 -3.6° (c 1.0, H2O).
(-)-1-(Cyclop r op yl)eth yla m in e (108b). To an ice-bath-
cooled solution of L-tartaric acid (42.30 g, 281.8 mmol) in water
(31 mL) was added a cold solution of racemic 1-cyclopropyl-
ethylamine (107) (23.93 g, 281.2 mmol) in water (25 mL). The

3216 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 20
Kelley et al.
(12) Ferris, R. M.; Harfenist, M.; MacKenzie, G. M.; Cooper, B.;
Soroko, F. E.; Maxwell, R. A. BW 234U, (cis-9-[3-(3,5-dimethyl-
1-piperazinyl)propyl]carbazole dihydrochloride): A novel anti-
psychotic agent. J . Pharm. Pharmacol. 1982, 34, 388-390.
(13) Davidson, J .; Miller, R.; Wingfield, M.; Zung, W.; Dren, A. T.
The first clinical study of BW 234U in schizophrenia. Psycho-
pharmacol. Bull. 1982, 18, 173-176.
(14) Montgomery, J . A.; Temple, C., J r. Synthesis of Potential
Anticancer Agents. XII. 9-Alkyl-6-substituted-purines. J . Am.
Chem. Soc. 1958, 80, 409-411.
(15) Greenberg, S. M.; Ross, L. O.; Robins, R. K. Potential Purine
Antagonists XXI. Preparation of Some 9-Phenyl-6-substituted
Purines. J . Org. Chem. 1959, 24, 1314-1317.
(16) Kelley, J . L.; Krochmal, M. P.; Linn, J . A.; McLean, E. W.;
Soroko, F. E. 6-(Alkylamino)-9-benzyl-9H-purines. A new class
of anticonvulsant agents. J . Med. Chem. 1988, 31, 606-612.
(17) Temple, C., J r.; Kussner, C. L.; Montgomery, J . A. Synthesis of
Potential Antineoplastic Agents. XXXI. 9-Alkyl-9H-Purines. J .
Med. Pharm. Chem. 1962, 5, 866-870.
(18) Schaeffer, H. J .; Vince, R. Enzyme inhibitors. XIX. The
synthesis of some 1-hydroxy-2-hydroxymethyl-4-(6-substituted-
9-purinyl)cyclohexanes as nucleoside analogs. J . Med. Chem.
1968, 11, 15-20.
(19) Montgomery, J . A.; Temple, C., J r. Synthesis of Potential
Anticancer Agents. XXVI.The Alkylation of 6-Chloropurine. J .
Am. Chem. Soc. 1961, 83, 630-635.
(20) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley:
New York, 1967; Vol. 1, p 4.
in vials containing 10 mL scintillation fluid, and the radioac-
tivity was measured using a liquid scintillation counter.
Reta r d a tion of Stom a ch Em p tyin g. Stomach emptying
was determined using a phenol red method.27 Each rat was
fasted overnight and treated by the oral route with the test
compound or saline. One control group remained untreated.
Fifteen minutes after the drug or saline administration, each
animal received a 2 mL oral gavage of 0.05% phenol red in
1.5% carboxycellulose. The total stomach contents of phenol
red were determined 5 min after gavage for the untreated
control group and compared to values determined 1 h after
gavage to calculate the extent of stomach emptying induced
by the drug or saline treatments.
Ack n ow led gm en t. The excellent technical assis-
tance of A. Melton is acknowledged. We thank Dr. B.
S. Hulbert and his staff for some of the NMR spectra.
The aggressive behavior experiments were performed
by K. Viik. We thank D.T. Staton for the artwork, the
Burroughs Wellcome Co. Research Document Center for
assistance in preparation of the manuscript, and L.
Cotterman for proofreading the final draft. We thank
Dr. A. Mackars for the LD50 values, A. Zeman for the
toxicology work on 80, Dr. R. Welch for metabolic
studies on several compounds, and Dr. W. Wastila for
the cardiovascular studies.
(21) Kelley, J . L.; Linn, J . A.; Selway, J . W. T. Synthesis and
Antirhinovirus Activity of 6-(Dimethylamino)-2-(trifluoromethyl)-
9-(substituted benzyl)-9H-purines; J . Med. Chem. 1989, 32,
1757-1763.
(22) Kelley, J . L.; Linn, J . A.; Selway, J . W. T. Synthesis and
Structure-Activity Relationships of 2-Substituted-6-(dimethyl-
amino)-9-(4-methylbenzyl)-9H-purines with Antirhinovirus Ac-
tivity. J . Med. Chem. 1989, 32, 218-224.
(23) Kelley, J . L.; Miller, C. A.; Selway, J . W. T., Schaeffer, H. J .
Synthesis and anti-viral activity of 6-amino- and 6-dimethyl-
amino-9-(aminoacylamidobenzyl)purines. Eur. J . Med. Chem.
1988, 23; 319-323.
(24) Unpublished observations of Dr. R. Welch.
(25) Unpublished observations of Dr. W. Wastila.
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