4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention

38

J. Med. Chem. 2005, 48, 38-55

4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and

Related 2-Aminoethylbenzofuran H₃Receptor Antagonists Potently Enhance

Cognition and Attention

Marlon Cowart,*^,†Ramin Faghih,^†Michael P. Curtis,^†Gregory A. Gfesser,^†Youssef L. Bennani,^#

Lawrence A. Black,^†Liping Pan,^§Kennan C. Marsh,^§James P. Sullivan,^†Timothy A. Esbenshade,^†

Gerard B. Fox,^†and Arthur A. Hancock^†

Department of Neuroscience Research and Department of Drug Metabolism and Pharmacokinetics, Abbott Laboratories,

Abbott Park, Illinois 60064-6123

Received June 21, 2004

H₃receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered,

which are potent in vitro at human and rat H₃receptors, with K_ivalues of 0.1-5.8 nM.

Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing

properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-

yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H₃receptor

antagonism and excellent pharmacokinetic and metabolic properties across species, with full

efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat

pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg.

Furthermore, this compound did not stimulate locomotor activity and showed high selectivity

for the induction of behavioral efficacy versus central nervous system based side effects. The

potency and selectivity of this compound and of analogues from this class support the potential

of H₃receptor antagonists for the treatment of cognitive dysfunction.

Introduction

and hormones, including acetylcholine, glutamate, and

dopamine,^1,2and by blockade of these receptors, H₃

receptor antagonists can enhance the release of these

neurotransmitters. H₃receptors have been found in, and

cloned from, several animal species,⁹and the pharma-

cology of these diverse receptors has been character-

ized.¹⁰In native cells and in cells expressing cloned H₃

receptors, a high degree of intrinsic activity is present.^11,12

In some systems, as much as 25% of the human H₃

receptor pool may be activated in the absence of endog-

enous agonist.¹¹This has led to the suggestion that

“inverse agonists” that block this intrinsic receptor

activity may be able to play a special role in disease

treatment, possibly even distinct from “antagonists”.^11a

As generally used, the term “inverse agonist” constitutes

a special category of receptor antagonists, able not only

to counteract the actions of exogenous agonists but to

reduce the intrinsic activity of the receptor. While the

more general term “antagonist” is used in this report,

it is with the understanding that many H₃receptor

antagonists have varying degrees of inverse ago-

nism.^11,12

In animal models, H₃receptor antagonists have been

shown to enhance attentive and cognitive behaviors,⁵

to enhance wakefulness, and when coadministered with

H₁antagonists to act as nasal decongestants.¹³The

molecular mechanisms whereby H₃antagonists induce

these effects are indirect and probably mediated by the

enhanced release of neurotransmitters such as hista-

mine, acetylcholine, dopamine, and others. The dem-

onstrations of in vivo activity have heightened interest

in finding H₃receptor antagonists with optimal druglike

properties for potential clinical use. Some of the first

potent H₃receptor antagonists were analogues of the

Histamine receptors play well recognized and impor-

tant roles in human disease, and drugs acting at these

receptors are clinically important.^1-3Peripheral-selec-

tive H₁antagonists are used in the treatment of allergic

asthma and allergies, and H₂antagonists offer treat-

ment for gastric distress due to hyperacidity. The safety

and efficacy of H₁and H₂antagonists have enabled the

use of some of these drugs as “over the counter nonpre-

scription medications. A third type of histamine recep-

tor, the H₃receptor, is a pharmacologically distinct

histamine receptor located predominantly on presyn-

aptic nerve terminals, where it modulates the release

of histamine and other neurotransmitters.⁴The H₃

receptor has recently gained attention for its potential

role in modulating cognitive, psychiatric, appetitive,

allergic, and other physiological processes,⁵and there

is much recent interest in finding potent and efficacious

H₃receptor antagonists to treat these diseases.⁶

On presynaptic histaminergic nerve terminals, the H₃

receptor acts as an autoreceptor through an inhibitory

feedback loop, suppressing the neuronal release of

histamine.^4,7,8H₃receptor antagonists block this auto-

inhibitory feedback and thereby induce elevations of the

neurotransmitter histamine, which then stimulates

postsynaptic H₁and H₂receptors. H₃receptors are also

located on heterotopic nerve terminals, exerting nega-

tive control over the release of other neurotransmitters

* To whom correspondence should be addressed. Phone: (847) 938-

8170. Fax: (847) 937-9195. E-mail: marlon.d.cowart@abbott.com.

^†Department of Neuroscience Research, Abbott Laboratories.

^#Present address: Vertex Pharmaceuticals, 130 Waverly St.,

Cambridge, MA 01239.

^§Department of Drug Metabolism and Pharmacokinetics, Abbott

Laboratories.

Published on Web 12/13/2004

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 39

Figure 1. Structures of histamine (1), imidazole-based H₃antagonists 2-6, and non-imidazole H₃antagonists 7-13.

endogenous ligand histamine (1) and therefore contain

an imidazole moiety. Examples of compounds in this

class include thioperamide (2), ciproxifan¹⁴(3), and

FUB-181¹⁵(4), seen in Figure 1. These compounds have

robust effects in vitro and in vivo and constitute

reference standards against which newer antagonists

are often compared. Two newer imidazole-based com-

pounds, GT-2331¹⁶(5) and SCH-79876^13b(6), have also

been described in the literature as potent H₃receptor

antagonists. Compound 6, in combination with an H₁

antagonist, was active as a nasal decongestant in a

feline model at 3-10 mg/kg.^13a

As potential candidates for a drug targeted for the

treatment of central nervous system (CNS) symptoms,

two potential liabilities have been reported for imida-

zole-based H₃receptor antagonists.¹⁷One is the associa-

tion of imidazole-based analogues with poor CNS pen-

etration. For example, 6, which is targeted for a

peripheral indication (allergic rhinitis), had a brain/

plasma ratio of 0.02 in rats at 10 mg/kg.^13aWhile low

CNS penetration may be a desirable property in a drug

targeted to the treatment of peripheral diseases, it is

likely a liability in drugs targeted to the treatment of

CNS diseases.

The other property associated with imidazole-based

structures is their propensity to potently inhibit cyto-

chromes P₄₅₀(CYP).¹⁸In this way, such drugs can

perpetrate drug-drug interactions against coadminis-

tered drugs by inhibiting hepatic clearance.¹⁹A well-

known historical example of this phenomenon is the

potentially fatal interaction of orally administered ke-

toconazole (an imidazole-containing antifungal) with

terfenadine. Additionally, drugs that inhibit CYP en-

zymes have the potential to alter the endogenous

metabolism of important circulating hormones, as re-

ported for the H₃receptor antagonist thioperamide^18a

(2). Because of these liabilities, much of the recent

interest in the field has been directed toward the design

of potent non-imidazole H₃receptor antagonists.

There are many examples of non-imidazole H₃recep-

tor antagonists, many of which share certain structural

features.⁶Potent compounds all possess a basic tertiary

amine as an imidazole replacement, connected through

a flexible linker chain to a lipophilic moiety. The

requirement for the basic amine as the imidazole

replacement probably reflects a requirement to main-

tain a key ionic interaction between the positively

charged ammonium group of the drug and an aspartate

(D114) residue present in H₃receptor isoforms from all

species.²⁰Many other G-protein-coupled receptors

(GPCRs) also have a negatively charged aspartate at

positions analogous to the aspartate (D114) in the H₃

receptor, and the aspartate likely plays a critical role

in the binding of endogenous ligands in those GPCRs

as well. A prominent subset of potent H₃receptor

antagonists is built on a common pharmacophore: a

tertiary basic amine or imidazole connected through an

alkyloxy (often propyloxy) chain connected to a lipophilic

moiety⁶(usually an aromatic ring). This structural motif

is present in several reported H₃receptor antagonists,

for example, UCL-1972²¹(7), the natural product

aplysamine 8, 9, 10,²²11,²³12,²³and 13.²⁴Pharma-

cophore 14 may therefore constitute a “privileged struc-

ture”, a structural class likely to be a rich source of H₃

receptor antagonists.

2-Aminoethylbenzofurans (15) constitute a new struc-

tural class of H₃receptor antagonists, of which the

discovery and potent human and rat H₃receptor binding

of the first members of the series, including ABT-239

(20), have been described.²⁵As illustrated in Figure 2,

the benzofurans can be considered rigidified versions

of the aforementioned aminepropyloxyphenyl pharma-

cophore (14), but with structure 15 having two fewer

rotatable bonds. Rigidification has been empirically

associated with improved absorption and druglikeness²⁶

40 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

tion of 18 (95%). We have observed that the presence of

a basic nitrogen on the homopropargylamine 23 often

leads to lower yields of benzofurans compared to the

yields of benzofurans produced using homopropargyl

alcohol as the acetylenic coupling partner.

Figure 2. Protypical H₃antagonist 14 has five freely rotatable

bonds linking the basic amine and the lipophilic moiety. The

benzofuran antagonists 15 are similar, but more rigid, with

three freely rotatable bonds.

A different synthetic route was used to make the

target benzophenone analogues 33a-i, with 32 envi-

sioned to allow efficient synthesis of a large number of

analogues through reaction of this penultimate inter-

mediate with Grignard reagents. To make 32, the

carboxylic acid 27 was treated with oxalyl chloride to

give 28 (99%), which was converted to the Weinreb³⁰

amide 29 (95%). The benzyl group of 29 was removed

by Pd-catalyzed hydrogenolysis, and the product 30 was

monoiodinated with I₂and NH₄OH as base to give 31

in 67% yield. The iodophenol 31 was converted to the

N-methoxy-N-methylbenzamide 32 in 21% yield as

described above, which was then reacted with aryl

Grignard reagents to produce the target benzophenones

33a-i in 12-68% yields.

and may in part underlie the high in vivo potency of

the benzofurans.^25cAspects of the SAR between the

basic amine moiety of 15 and in vitro H₃receptor

binding have been described, but this report describes

the in vitro pharmacological profiles of new analogues

with variant R substituents at the 5-position of the

benzofuran ring of 15, as well as the potent behavioral

activity of the series in animal models of cognition and

attention.

Materials

Synthesis. The preparation of the target benzofuran

H₃receptor antagonists 15 required several distinct

synthetic routes, which are depicted in Schemes 1 and

2. The new target analogues (Table 1) incorporate

aromatic and benzoyl substituents at the 5-position of

the benzofuran ring, and except for 21, all the com-

pounds bear (R)-2-methylpyrrolidine as the amine. The

synthesis of 20 (Scheme 1) required as a first step the

selective iodination of 4′-hydroxybiphenyl-4-carbonitrile

(16). By judicious choice of conditions, using NaOCl,

NaOH, and NaI in aqueous methanol,²⁷monoiodide 17

could be selectively formed in good yield (53%) with

minimal formation of the diiodide side product. The

cyclization of 17 to 18 in 95% yield was effected by the

Pd(Ph₃P)₂Cl₂/CuI catalyzed reaction of 17 with ho-

mopropargyl alcohol in the presence of base. Though

this reaction may proceed by a two-step process, with a

Pd-catalyzed coupling of the 2-iodophenol 36 with

homopropargyl alcohol to give an acetylene intermediate

followed by cyclization to give 18, we never observed

any intermediate acetylenes, only the benzofuran prod-

ucts. The alcohol 18 was activated for displacement by

conversion to a mesylate (19, 89%), followed by treat-

ment with (R)-2-methylpyrrolidine²⁸in CH₃CN, which

proceeds at room temperature over several hours or

days to give 20 (34%). The displacement reaction can

be accelerated by elevated temperatures, but this in-

creases the formation of the styrene side product,

formed through base-catalyzed elimination. In a similar

fashion, 21, the S-enantiomer of 20, was formed in 63%

yield by the reaction of 19 with (S)-2-methylpyrroli-

dine.²⁹

The goal of making additional analogues of 20, for

instance, the target benzophenone analogues 26a-c,

motivated development of a synthesis that is more

efficient than that described for 20 and 21. (R)-2-

Methylpyrrolidine was alkylated with the tosylate ester

of homopropargyl alcohol to give the acetylene 23, use

of which was envisioned to eliminate the need to form

and displace mesylate intermediates. As an alternative

to the method used to monoiodinate 16, the monoiodi-

nation of 24a-c was effected with I₂and NH₄OH as

base. The Pd-catalyzed reaction of 23 with iodophenols

25a-c did give the target benzophenones 26a-c but

in much lower yield (18%) than the yield in the forma-

For the preparation of targets 37-39 (Scheme 2),

4-iodophenol (34) was converted to 35 in 97% yield

through a Suzuki reaction, after which monoiodination

of 35 gave 36 (21%). Reaction of 36 with 23 under Pd

catalysis gave ketone 37 in 30% yield. The ketone 37

could be reacted with MeMgBr to give 38 (27%) or with

NaBH₄to give 39 in 37% yield. To prepare 44-46,

4-iodophenol (34) was converted to 40 in 71% yield

through a Suzuki reaction and 40 was transformed into

the iodophenol 41 (37%) with I₂and NH₄OH as base.

Compound 41 reacted with 23 under Pd catalysis to give

a benzofuran ethyl ester intermediate which was hy-

drolyzed with NaOH to give the aminocarboxylic acid

42. This acid was treated with oxalyl chloride to give

the acid chloride, which was treated with O,N-dimeth-

ylhydroxylamine hydrochloride to give the Weinreb

amide 43. The carboxylic acid 42 reacted with BH₃to

give 44 (70%), 43 with EtMgBr to give 45 (65%), and

with cyclopropylmagnesium bromide gave 46 (69%).

When 4-bromophenol (47) was treated with NaOCl,

NaI, and NaOH in aqueous CH₃OH, the monoiodophe-

nol 48 was produced in 89% yield. This material was

treated with 23 to give the 5-bromobenzofuran 49 in

26% yield, which was subjected to the Suzuki reaction

to give 50 in 66% yield. The 2-iodophenol 48 was

converted to the benzofuran 51 (8%) by a copper-

catalyzed reaction with homo-propargyl alcohol, after

which 51 was subjected to the Suzuki reaction with

3-cyanophenylboronic acid to give 52 in 82% yield. In a

two-step process, 52 was mesylated and then treated

with (R)-2-methylpyrrolidine as described for 20 to give

53 in 28% yield. In one case, target compound 20 could

itself be directly transformed into a new target com-

pound; in this case, reaction of 20 with cyclopropylmag-

nesium bromide under CuI catalysis gave the cyclopro-

pyl ketone 54 in 44% yield.

Results and Discussion

Pharmacological Properties. The compounds de-

scribed here were selected from a larger group of related

analogues as being particularly potent at H₃receptors,

as assessed in in vitro binding assays^23bin membranes

isolated from cells transfected with either cloned rat H₃

receptors or human H₃receptors.

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 41

Scheme 1^a

^a(a) NaI, NaOCl, NaOH; (b) 3-butyn-1-ol, (Ph₃P)₂PdCl₂, CuI, Et₃N, DMF; (c) CH₃SO₂Cl, Et₃N; (d) 22, Na₂CO₃, CH₃CN; (e) (S)-2-

methylpyrrolidine, Na₂CO₃, CH₃CN; (f) 3-butynyl 4-toluenesulfonate, K₂CO₃, CH₃CN, 50 °C; (g) I₂, NaI, NH₄OH; (h) 23, Pd(OAc) ₂, (p-

tol)₃P, IPr₂NH, CuI, CH₃CN; (i) oxalyl chloride, DMF, CH₂Cl₂; (j) HN(OCH₃)CH₃, Et₃N; (k) H₂, Pd(C), CH₃OH; (l) RMgX, 0 °C f 33a-

33i.

A wide variety of amines have been found in potent

H₃receptor antagonists from different chemical

series.^{6,15b,17,21,24}It was previously determined²⁵that

benzofurans bearing cyclic amines such as pyrrolidine

and piperidine have high binding potency. In that SAR

study, the dependence of potency on the structure of the

amine moiety in the benzofuran series of analogues 15

(Figure 2) was more sharply defined than with homolo-

gous alkoxyphenyl analogues 14.^25bIn particular, it was

found that for the benzofurans 15, 2-alkyl cyclic amines

such as (R)-2-methylpyrrolidine imparted high in vitro

potency at human and rat H₃receptors. For this reason

and to allow a clear comparison of the potency of

compounds with a variety of substituents at the 5-posi-

tion of the benzofuran ring, the compounds in this report

bear (R)-2-methylpyrrolidine as the amine. Some of the

5-substituents chosen for incorporation into the ana-

logues 15 were similar to substituents found in dispar-

ate H₃receptor antagonist series reported previously.

For example, the cyclopropyl ketone in 46 and 54 is

found in the imidazole-based H₃receptor antagonist

ciproxifan¹⁴3 and in the non-imidazoles 11 and 12.²³

Also, imidazole-based benzophenones have been de-

scribed³¹with some structural similarity to 26c, and the

4-cyanophenyl moiety found in 20 has been described

in two series of non-imidazole H₃receptor antago-

nists.^21,32

determining which compounds to advance to behavioral

testing because compounds were ultimately to be tested

in rat behavioral models; on this point, the target

compounds all showed potent binding to the rat H₃

receptor, with K_ivalues ranging from 0.52 to 5.75 nM.

It is noted that other 2-substituted cyclic amines such

as (S)-2-methylpyrrolidine were able to support potent

binding in benzofuran analogues,^25aas illustrated by the

S-enantiomer 21 (human H₃K_i) 0.69 nm; rat H₃K_i)

2.57 nM). Thus, the compounds of the series have

potencies at rat H₃receptors comparable to the poten-

cies of reference H₃receptor antagonists such as thio-

peramide (2), ciproxifan (3), 11, and 12. However, in

comparison to the reference H₃receptor antagonists, the

new benzofuran analogues have 100-1000 times greater

potency at the human H₃receptor in binding assays.

The benzofuran analogues in Table 1 were competi-

tive antagonists of the H₃receptor in a variety of assays;

they completely blocked H₃receptor activation by the

agonist R-R-methyl histamine in a Ca²⁺flux assay in

whole cells, as assessed using assays based on FLIPR

(fluorometric imaging plate reader) technology.^23bThe

benzofuran analogues were also found to be potent

inverse agonists at H₃receptors; at low nanomolar drug

concentrations, these new compounds reduced basal

GTP-γ-S binding in H₃receptor transfected cells.^11b,23b

Compounds were also assessed for the ability to bind

to native H₃receptor preparations from rat or human

cortex. The potencies found in these native preparations

closely paralleled those shown in Table 1. For example,

20 had a K_iof 3.22 nM at membranes isolated from

native rat cortex and had a K_iof 4.60 nM in native

human cortical membranes.

All of the target benzofuran analogues (Table 1) were

highly potent in in vitro binding assays, with K_ivalues

at the human receptor ranging from 0.1 to 0.69 nM, as

assessed by competitive displacement of the H₃receptor

specific ligand [³H]-N-R-methylhistamine. Potent bind-

ing to the rat H₃receptor was most important for

42 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

Scheme 2^a

^a(a) 3-Acetyl-PhB(OH)₂, Pd(OAc)₂, Na₂CO₃; (b) I₂, NaI, NH₄OH; (c) 23, Pd(OAc) ₂, Biphenyl-2-yl-dicyclohexyl-phosphane, CuI, IPr₂NH,

CH₃CN; (d) CH₃MgBr; (e) NaBH₄; (f) 3-EthoxycarbonylPhB(OH)₂, Pd(OAc)₂, Na₂CO₃; (g) Aq. NaOH; (h) Oxalyl Chloride, DMF, CH₂Cl₂;

HN(OCH₃)CH₃, Et₃N; (i) BH₃; (j) RMgX; (k) NaI, NaOCl, NaOH; (l) 23, Pd(OAc)₂, CuI, IPr₂NH, CH₃CN; (m) 4-HydroxymethylPhB(OH)₂,

PdCl₂(Ph₃P)₂, Na₂CO₃; (n) 3-butyn-1-ol, Cu₂O, pyridine, NMP; (o) 3-CN-PhB(OH)₂, Pd(Ph₃P)₄, Na₂CO₃; (p) CH₃SO₂Cl, Et₃N; 22, Cs₂CO₃,

CH₃CN; (q) cyclopropyl-MgBr, CuI.

The analogues were tested for their selectivity for H₃

receptors by screening for binding at a variety of other

receptors. When tested at histamine H₁, H₂, and H₄

receptors, all compounds had K_i> 1000 nM and were

therefore more than 4000× selective for H₃. When tested

for binding at dopamine (D_4.2, D_2S, D₁) and serotonin

(5-HT₁, 5-HT₂, 5-HT₃) receptors or at neurotransmitter

transporters for norepinephrine, dopamine, or serotonin,

compounds were >100× selective for the human H₃

receptor. When tested against a battery of adrenergic

and muscarinic receptors, selectivity was similarly high

for 20. However, one exception to such high selectivity

was found with compound 21, which was only 30×

selective for the R_2Cadrenergic receptors and 75×

selective for R_1Badrenergic receptors. After H₃, the

receptor next most likely to demonstrate measurable

receptor antagonists have previously demonstrated

activity in animal models of attention,³⁴the high

selectivity of 26c for H₃receptors argues for an H₃-

specific mechanism for the behavioral activity. Simi-

larly, other benzofurans show potent behavioral activity

but minimal binding at the M₂receptor (20, K_i) 582

nM; 53, K_i) 573 nM), supporting an H₃-specific mode

of action for these compounds, a finding which also

applies to GT-2227, a selective H₃receptor antagonist

from a different chemical series with potent activity in

a behavioral model.³⁵Because the H₃receptor is the only

receptor bound by all of the analogues with potent

behavioral activity (Table 2) and because these ana-

logues were highly potent and selective for H₃receptors,

the cognitive and attention-enhancing activity of these

analogues is likely solely due to H₃receptor antagonism.

Because the compounds were selected as candidates

for testing in rodent cognitive models, the pharmaco-

kinetic profiles were assessed to determine the suit-

ability of compounds for administration to rats (Table

1). Clearance rates and volumes of distribution for the

compounds varied, as did compound half-lives after iv

administration. While all of the compounds (except for

50; t_1/2) 20 min) possessed pharmacokinetic properties

that would allow assessment of behavioral activity

following iv administration, the ultimate goal was to

find agents suitable for treatment of human disease. For

the purposes of comparison, agents with low oral bio-

availability in rats were less favored, since this route

would be precluded for in vivo testing. Also, such

compounds may be more likely to have poor oral

affinity for most analogues was the adrenergic (R_2C

)

receptor. After that, for three compounds, weak binding

to muscarinic (M₂) receptors (26c, K_i) 41 nM; 33a, K_i

) 119 nM; 33e, K_i) 68 nM) was demonstrated. It has

been reported that the R_2Cadrenergic agonists clonidine

and guanfacine enhance cognitive performance in some

animal behavioral models, whereas the antagonist yo-

himbine impairs memory.³³It was not determined

whether these compounds were agonists or antagonists

at adrenergic (R_2C) or M₂receptors, but the selectivity

of the new compounds for H₃receptors was in all cases

very high, greater than 50-fold versus other receptors.

Furthermore, the analogue with the greatest potency

at the M₂receptor (26c) is still 150-fold more potent at

human H₃receptors than M₂. Therefore, although M₂

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 43

Table 1. Pharmacological Profiles of Target Compounds in in Vitro Binding Assays and Important Pharmacokinetic (PK( Properties

human H₃

binding^a

rat H₃

human H₃

antagonism

Ca²⁺flux^b

binding^a

PK parameters^c

CNS penetration^d

R substituent

on benzofuran 15

K_i

t_1/2(h)

iv

Vâ CLb oral bioavl brain brain/plasma

compd (nM) pK_i( SEM (nM) pK_i( SEM pK_b( SEM

iv

F (%)

concn

ratio

Ph (4-CN)

20

0.45 9.35 ( 0.04 1.35 8.87 ( 0.04 7.87 ( 0.15 5.3 rat

11.6 1.5

9.3 0.78

53

74

89

73

32

26

1.4

10

57

5

14

62

46

20

3082

36-52×

8.3 dog

29.2 mky 12.7 0.3

Ph (4-CN)

COPh (2-F)

COPh (3-F)

21

26a

26b

0.69 9.16 ( 0.09 2.57 8.59 ( 0.09 7.87 ( 0.11 17.7 rat 12.4 0.48

0.51 9.29 ( 0.08 1.96 8.71 ( 0.08 8.02 ( 0.13 2.6 rat

11.5 3.08

12.1 1.73

18.9 1.61

8.9 1.62

12.2 1.77

11.3 1.21

0.10 10.0 ( 0.13 0.57 9.24 ( 0.09 8.42 ( 0.09 4.9 rat

1322

1997

12×

21×

8.1 dog

3.7 mky

0.27 9.57 ( 0.16 1.00 9.00 ( 0.08 8.09 ( 0.06 4.8 rat

6.4 dog

COPh (4-F)

26c

9.8 mky 13.3 0.9

0.19 8.75 ( 0.12 0.77 9.11 ( 0.12 7.84 ( 0.11 12.4 rat 12.3 0.68

COPh (4-Cl)

33a

33b

33c

33d

33e

33f

33g

33h

33i

37

1776

848

22×

11×

COPh (4-CH₃)

COPh (4-OCH₃)

COPh (4-N(CH₃) ₂)

COPh (3-CH₃, 4-F)

COPh (3-CH₃, 4-Cl)

COPh (3-Cl)

0.21 9.67 ( 0.07 1.73 8.76 ( 0.10 7.93 ( 0.06 3.3 rat

0.52 9.28 ( 0.14 2.69 8.57 ( 0.10 8.09 ( 0.03 2.5 rat

0.52 9.28 ( 0.14 4.57 8.34 ( 0.08

0.21 9.69 ( 0.08 5.75 8.24 ( 0.24 7.49 ( 0.06 3.3 rat

0.35 9.45 ( 0.07 1.05 8.98 ( 0.14 7.42 ( 0.03 7.6 rat

0.19 9.71 ( 0.08 0.65 9.19 ( 0.10 7.92 ( 0.16 5.2 rat

0.09 10.07 ( 0.14 0.54 9.27 ( 0.06 8.30 ( 0.07 7.8 rat

0.22 9.66 ( 0.23 0.52 9.28 ( 0.34 7.98 ( 0.14 3.6 rat

0.08 10.08 ( 0.11 0.41 9.39 ( 0.07 8.09 ( 0.15 3.0 rat

6.5 dog

13.1 2.68

11.6 3.05

26.8 5.78

24.1 2.18

10.5 2.82

14.3 1.25

14.6 2.84

27.1 8.48

37.2 3.89

9

46

49

68

24

6

27

72

69

55

3

COPh (3,5-di-F)

COPh

Ph (3-COCH₃)

649

44×

5.4 mky 13.2 1.70

0.25 9.61 ( 0.09 2.04 8.69 ( 0.08 8.12 ( 0.09 2.8 rat

Ph (3-(CH₃)₂OH)

Ph (3-CH(CH₃)OH)

Ph (3-CH₂OH)

Ph (3-COCH₂CH₃)

Ph (3-CO cyclopropyl)

Ph (4-CH₂OH)

Ph (3-CN)

38

39

44

45

46

50

53

54

5.0 1.23

23.0 2.09

13.6 3.1

0.44 9.36 ( 0.13 1.40 8.85 ( 0.06 8.25 ( 0.15 7.6 rat

0.49 9.31 ( 0.11 2.31 9.64 ( 0.02 8.42 ( 0.13 3.0 rat

0.23 9.64 ( 0.19 1.00 9.00 ( 0.10 7.91 ( 0.07

0.21 9.69 ( 0.11 0.72 9.14 ( 0.06 7.83 ( 0.13 5.0 rat

0.88 9.06 ( 0.09 3.34 8.48 ( 0.03 8.49 ( 0.06 0.3 rat

0.27 9.57 ( 0.12 0.91 9.04 ( 0.07 7.72 ( 0.13 4.3 rat

0.26 9.58 ( 0.07 1.36 8.87 ( 0.06 7.28 ( 0.15 9.3 rat

6.2 0.86

8.0 18.1

7.5 1.2

8.2 0.61

70

0

38

48

2477

3548

27×

61×

Ph (4-CO cyclopropyl)

reference H₃antagonists

thioperamide

2

72

63

7.14 ( 0.06 3.63 8.44 ( 0.07 6.82 ( 0.06

48

0.24×

3.6×

ciproxifan

3

7.20 ( 0.05 0.51 9.29 ( 0.09 6.84 ( 0.08 1.7 rat

2.5 0.89

51

500^e

GT-2331

5

2.15 8.67 ( 0.05 0.08 10.1 ( 0.14

A-304121

11

12

13

760

93

6.12 ( 0.08 2.50 8.60 ( 0.07 5.95 ( 0.10 4.4 rat

7.03 ( 0.04 0.71 9.15 ( 0.08 7.26 ( 0.14 0.7 rat

17.8 2.7

2.3 2.3

6.3 3.2

2.3 0.6

7.5 1.0

83

32

121

33

78

13^e

5^e

0.9×

0.08×

0.6×

A-317920

A-349821

0.41 9.39 ( 0.08 1.66 8.78 ( 0.12 8.27 ( 0.12 1.3 rat

75^e

2.6 dog

5.3 mky

^aAssessed by displacement of ³H-N-R-methyl histamine from cell membranes isolated from C6 cells expressing cloned rat and human

H₃receptors. K_ivalues are listed for reader convenience, where pK_i) -log(K_i). Three or more independent K_ideterminations for all

compounds. ^bDetermined by FLIPR. ^cPK properties were determined after administration of 1-5 mg/kg of drug; n ) 3 animals; Vâ

(volume of distribution, L/h); CLb (clearance, L h^-1kg^-1); F (oral bioavailability, %). ^dBrain concentrations were normalized for the amount

of compound administered and expressed as tissue concentration of compound in ng (g of tissue)^-1(mg of compound)^-1, administered iv

to rats, measured 1 h after dosing. ^eAdministered po.

bioavailability in humans. Not surprisingly, the com-

pounds with the lowest oral bioavailability in rats, for

example, 33c (F ) 20%), 33e (F ) 9%), 50 (F ) 0%), 37

(F ) 6%), and 44 (F ) 3%), tended to also have the

highest clearance rates (CL). Although the routes of

metabolism were not determined, the rapid clearance

for compound 50 might have been due to the presence

of a primary alcohol, which might be a target for

metabolic conjugation or oxidation. The benzofuran

analogues also had high volumes of distribution relative

to the reference H₃receptor antagonists. This is very

likely a reflection of the high lipophilicity of the benzo-

furans; the CLogP values of the new compounds range

from 4.7 (for 44) to 5.73 (for 54). It has been found that

higher lipophilicity is strongly correlated with higher

volumes of distribution in rats and humans.³⁶The two

benzophenones (26b and 26c) had poorer oral bioavail-

ability in dog and monkey than in rat, while the

acetophenone 37 had improved pharmacokinetic prop-

erties in these other species. Overall, 20 had the most

promising pharmacokinetic profile, with high oral bio-

availability and low clearance across different species

(Figure 3).

For agents targeted for treatment of CNS diseases,

high brain levels are likely a positive attribute, as is

efficient CNS penetration, expressed as the brain/blood

concentration ratio. The rationale is that high brain

levels should maximize exposure of drug to the H₃

receptors in the CNS that mediate the pharmacological

effects compared to receptors in the periphery, which

should thereby allow lower doses for efficacy. Also,

where behavioral efficacy can be achieved with low-

circulating drug levels, the risk of side effects due to

interaction with peripheral H₃receptors or other sites

can be minimized. The previously disclosed compounds

2, 11, 12, and 13 have low brain/blood ratios (0.24×,

0.9×, 0.08×, and 0.6×, respectively) and do not achieve

high brain concentrations (Table 1). In contrast, com-

pounds 20, 26b, 26c, 33a, 37, 53, 54 all have high brain/

blood ratios (11×-61×) and achieve high brain concen-

trations (649-3548 ng g^-1mg^-1dosed), probably as a

consequence of their high lipophilicity (CLogP g 5.1).

This high lipophilicity contrasts with that of many

known reference H₃receptor antagonists (CLogP: 2, 2.3;

3, 3.0, 5, 3.3; 11, 2.4; 12, 3.1; 13, 4.6). We believe this

achievement of higher CNS drug concentrations best

44 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

Table 2. Activity of H₃Receptor Antagonists in Two Behavioral Models: Inhibitory Avoidance Acquisition in Rat Pups and Social

Memory in Adult Rats^a

therapeutic index

inhibitory avoidance social memory^c,d

lowest dose to CNS

vs inhibitory

therapeutic index

compd

acquisition^b(mg/kg)

(mg/kg)

side effects^d(mg/kg) avoidance acquisition vs social memory

20

0.1

0.01

28

280×

325×

330×

97×

2800×

325×

21

0.1^e

0.3

26a

0.3

98

26b

0.3^e

0.3

98

29

>97

100

26c

0.003-0.03

1

0.3

9700×

97×

33b

1

97×

33h

0.3^e

1

330×

37

46

0.1^f

0.03-0.3

31

9

310×

30×

53

0.1

90×

reference H₃antagonists

2

10

15

0.3

82

30

18

280

118

8×

6×

3

1

10×

90×

5

18×

11

12

13

10

3^f-10

1^f-3^f

28×

93×

3^f-10

42×

1^f-10

12-118×

^aThe lowest dose to induce CNS side effects is shown, along with the therapeutic index. ^bUnless otherwise noted, p < 0.05 versus

saline and fully efficacious, effects were equal to the reference standard ciproxifan at 3 mg/kg. All drugs dosed sc. ^cUnless otherwise

noted, p < 0.05 versus saline and fully efficacious, effects were equal to reference at 1 mg/kg. ^dDrugs dosed ip. ^ePartially effective, p >

0.05, 60-80% effect compared to ciproxifan. ^fPartially effective, p < 0.05, 60-80% effect compared to ciproxifan.

Figure 3. (A) Mean ((SEM, n ) 3) blood concentrations of 20 after a 1 mg/kg intravenous, subcutaneous, or oral dose in rat. (B)

Mean ((SEM) blood concentrations of 20 after a 1 mg/kg intravenous or oral dose in monkey.

explains the increased potency of the new analogues in

behavioral models (Table 2). At the same time, it is

important to consider that drug lipophilicity introduces

additional factors that can temper a portion of the

beneficial effect of high CNS drug concentrations.

Although lipophilicity may increase CNS penetration

and drug levels, it also likely increases binding of the

drug to tissue lipids and proteins. This may result in

lower concentrations of “free unbound” drug available

to bind the target receptor. Possibly as a reflection of

its lipophilic character, 20 was found to have relatively

high binding to plasma proteins across species, with

94.1% bound to plasma proteins in rats, 91.2% in dogs,

93.6% in monkeys, and 97.3% in humans.

Activity in Animal Models of Cognition and

Attention. H₃receptor antagonists from a variety of

structural classes have shown positive effects in animal

models of wakefulness, cognition, attention, and mem-

ory.⁵Meguro found that thioperamide (2) at 15 mg/kg

increased acquisition of avoidance behavior in a strain

of senescence-accelerated mice in a 5-day, 5-trial passive

avoidance (PAR) paradigm.³⁷Similarly, Orsetti found

that intracranial administration of 2 improved place-

recognition memory in rats.³⁸Miyazaki also found that

2 improved memory in scopolamine-treated mice in an

elevated plus maze model, but the effect was small and

seen at the high dose of 20 mg/kg, ip.³⁹In the same

model, Onodera found that the more lipophilic FUB-

181 (4) at 2.5-5 mg/kg ip reversed the scopolamine-

induced deficit.^15c

In addition to memory, the inhibitory avoidance

acquisition paradigm is thought to model aspects of

impulsive behavior. Consistent with this, drugs that

suppress impulsiveness in humans are active in this

model. Methylphenidate is used in the clinic to treat

attention deficit hyperactivity disorder and is fully

effective in a 5-trial version of this model at 1-3 mg/

kg, as described by Fox,⁴⁰and by Yates³⁵in a related

10-trial version. In this model, an imidazole-based H₃

receptor antagonist, GT-2227, was active in rat pups at

1-3 mg/kg.³⁵Ciproxifan (3) significantly improved

performance in a five-choice task in rats at 3 mg/kg, ip.¹⁴

Fox has reported the activity of thioperamide (2),

ciproxifan (3), and 5 in the 5-trial inhibitory avoidance

model used in this report and used ciproxifan as a

positive control to gauge activity of new H₃receptor

antagonists in animal models, seen in Table 2.^40,41In

previous reports by our group, non-imidazole H₃recep-

tor antagonists 11⁴²(A-304121), 12⁴²(A-317920), and

13^24,43(A-349821) were also shown to significantly

improve performance in this assay (Table 2).

Activity in the 5-Trial Inhibitory Avoidance

Acquisition Model. H₃receptor antagonists were

tested for their ability to enhance learning in the 5-trial

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 45

Figure 4. Effect of H₃antagonists in the 5-trial inhibitory avoidance acquisition model. As depicted in parts a and b, the transfer

latency tracks learning, with latency increasing over successive trials to a maximum of 180 s per trial as animals acquire the

avoidance behavior. The H₃antagonists 26c (a), 53 (b), and ciproxifan (CPX, 3 mg/kg) increase the rate of acquisition compared

to vehicle-treated controls. Drugs were administered sc 30 min prior to testing in animals, with separate positive and negative

controls for each compound; SEM was omitted for clarity. In parts c (compound 26c) and d (compound 53), after the training trial

(T1), the summed latency shows the improvement in acquisition for the next four trials (T2-T5) compared to vehicle-treated

controls. Error bars depict SEM; (/) P < 0.05, Mann-Whitney test; n ) 27 animals for 26c; n ) 12 for 53.

inhibitory avoidance acquisition model.⁴⁰In the model,

rat pups (spontaneously hypertensive strain) are placed

in a brightly lit half of a bipartite chamber, whereupon

their inherent preference for the dark leads them to

escape (transfer) into the darkened half. Pairing this

transference with a mild aversive stimulus motivates

the animals to learn to remain in the brightly lit

chamber, which is assessed over the course of four more

trials conducted under the same conditions. Agents that

are thought to enhance attention or learning, such as

methylphenidate or nicotinic agonists, enhance the rate

at which this avoidance behavior is acquired.⁴⁰The new

benzofuran-based compounds are also active in this

model, with full efficacy being attained at doses of less

than 1 mg/kg. For example, as seen in Figure 4a and

4b, learning of the avoidance behavior increased with

successive trials, as assessed by transfer latency, and

was dose-dependently increased after administration of

26c and 53, compared to vehicle-treated control ani-

mals. To better analyze the dose dependence of the

learning, the transfer latencies from the training trials

2-5 were added together and analyzed for statistical

significance versus vehicle-treated controls, as seen in

Figure 4c and 4d. It is clear that both 26c (at 0.3 mg/

kg) and 53 (at 0.03 mg/kg) induce a significant increase

in learning compared to control animals, as efficacious

as the reference standard ciproxifan at 3 mg/kg. Besides

26c and 53, other compounds such as 20, 26a, 33b, and

37 were found to be similarly efficacious (Table 2).

Activity in the Social Recognition Memory

Model. Another behavioral model used to assess the

memory-enhancing ability of compounds is a social

recognition memory test, which measures the ability of

agents to improve the retention of encounters between

animals. Prast has demonstrated the importance of

histamine in general, and H₃receptors in particular,

in a model of social memory in adult rats, where

intracerebroventricular administration of histamine, the

histamine precursor L-histidine, and thioperamide (2)

all potently enhanced retention of encounters with

juvenile rats.⁴⁴As used in this report, adult rats are

observed for the amount of time they spend investigat-

ing a novel juvenile rat, with the adult typically sniffing

and closely following the juvenile.^42aAfter the adult rats

gain familiarity with the juvenile, this duration of

investigation is reduced, and on retesting, the duration

drops to about 60% of that of the initial encounter. The

investigation duration remains reduced as long as the

memory of the social encounter is retained through at

least 30 min in adult rats. However, as more time

passes, 2 h or more, the memory of the social encounter

is lost and the adult reverts to reinvestigating the

juvenile for the same duration as in the initial encoun-

ter. Several previously reported H₃receptor antagonists

are able to delay⁴²this time-dependent memory loss at

doses of 0.3-15 mg/kg (Table 2). Figure 5 depicts the

ability of 33b to improve retention of the social encoun-

ter, where, at a dose of 1 mg/kg, 33b significantly

46 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

general behavioral screen by dosing animals with suc-

cessively higher doses of compounds and then noting

any unusual behavioral or physiological effects (Table

2).^42aAt doses higher than those effective in enhancing

cognition, it has previously been reported that some H₃

receptor antagonists can induce hypothermia, piloerec-

tion, loss of righting reflexes, hypoactivity, ptosis,

tremors, or even seizures.^42aThe lowest dose found to

induce a significant incidence of any of these side effects

is noted in Table 2. The therapeutic index (TI) was

defined as this dose divided by the dose found effective

in the avoidance acquisition or social memory model. A

goal was to find compounds with a high TI (∼300×) in

both models. Only partial efficacy in cognitive tests was

noted for compounds 21, 26b, 33h, and 46 at an initial

screening dose, and testing at higher doses was not

attempted because the TI would have been inadequate,

even if greater efficacy could have been attained. The

high potency of 20 in the cognition models contributed

to its high TI in the acquisition avoidance model (280×)

and social recognition memory model (2800×). The

favorable profile of 20 in behavioral models and in vitro

assays, coupled with favorable pharmacokinetic proper-

ties in several species, motivated an examination of this

compound in more detail.

Figure 5. Effect of 33b on the social memory test in adult

rats. After 120 min, adults forget an initial encounter with a

juvenile rat and reinvestigate the juvenile for the same amount

of time as the initial encounter (ratio of second/first contact )

0.9-1). With increasing doses of 33b or the reference H₃

antagonist ciproxifan (CPX), recall of the encounter is im-

proved, with a reduction in the time spent reinvestigating the

juvenile (ratio of second/first contact ) 0.6): (/) P < 0.0001,

Fisher’s post hoc test; n ) 12 animals, dosed ip.

The propensity of an agent to stimulate locomotor

behavior and stereotypy in rodents may be a predictor

of stimulant properties in humans. Both amphetamine⁴⁵

and methylphenidate^41,42astimulate locomotion and

stereotypy in rodents, which can under some conditions

become sensitized to the locomotor effects, and cross-

sensitized.⁴⁶As seen in Figure 7a, methylphenidate

(MPH) was efficacious in the 5-trial inhibitory acquisi-

tion avoidance model at 1-3 mg/kg, as measured by an

increase in latency, but at comparable doses (3-10 mg/

kg), it also stimulated spontaneous locomotor behavior,

as measured by the distance travelled. In contrast, the

H₃receptor antagonist 20 was active in the inhibitory

avoidance model at 0.1 mg/kg (Figure 7b) and in the

social recognition memory model at 0.01 mg/kg but did

not stimulate spontaneous locomotor behavior at (10-

100)× higher doses (tested to 1 mg/kg). These results

are consistent with previous reports that the H₃receptor

antagonists thioperamide,⁴¹GT-2227,³⁵ciproxifan,⁴³and

A-349821⁴³do not stimulate locomotor activity at be-

haviorally active doses. Together, the animal data

suggest that H₃receptor antagonists in general are able

to enhance cognition and suppress impulsiveness with-

out inducing CNS stimulation.

Figure 6. Effect of ABT-239 (20) on the social memory test

in aged rats. Adults recall their encounter with a juvenile after

30 min and through this period will reduce the amount of time

they spend reinvestigating the juvenile (ratio of second/first

contact ) 0.6). In contrast, even after 30 min, aged rats do

not recall their encounter with the juvenile and reinvestigate

juveniles for the same time as on first exposure (ratio of second/

first contact ) 1). However, after oral dosing with ABT-239

(0.3-3 mg/kg), the aged animals recall the juvenile as well as

the adults: (/) P < 0.05, Fisher’s post hoc test.

reduced the reinvestigation duration and did so with

an efficacy equivalent to that of ciproxifan dosed at 1

mg/kg. In this model, 20, at 0.01 mg/kg, also produced

a fully efficacious response equivalent to ciproxifan.^42b

Other benzofuran analogues such as 26a, 26c, 33b, 33h,

and 53 were also fully effective in this model at low

doses.

Next, a group of aged rats were tested in the social

memory model instead of adult rats but with only a 30

min interval before reintroduction of the juvenile be-

cause aged rats do not retain the memory of the juvenile

for 30 min. As seen in Figure 6, after administration of

20 at doses as low as 0.3 mg/kg, the aged rats retain

the memory of the first encounter and, in retesting after

30 min, perform as well as nonaged adults.

Lack of CYP Inhibition. As has been discussed in

the literature, it is highly desirable that the potential

for drug-drug interactions of candidate compounds be

minimized; compounds should not alter the metabolism

of, or have their metabolism altered by, coadministered

compounds.¹⁹An important tenet motivating efforts to

find non-imidazole H₃receptor antagonist drug candi-

dates is the hypothesis that such agents will not inhibit

17

hepatic cytochromes P₄₅₀and therefore will have

minimal liability to inhibit the metabolism of coadmin-

istered drugs. This allows greater safety in the clinic

and negates concerns when interpreting pharmacologi-

cal results with coadministered agents. This goal was

realized with 20. When incubated with human liver

microsomes at 2 µM, 20 showed no inhibition of the

CNS Therapeutic Index. The propensity of com-

pounds to induce CNS side effects was assessed in a

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 47

small amount of inhibition seen at 20 µM may be due

to competition as substrate; 20 was found to be a

substrate for human CYPs 3A4, 1A2, and 2D6, as well

as flavin monooxygenases FMO-1 and FMO-3, where

turnover was seen in c-DNA expressed enzyme prepara-

tions (L. Pan, unpublished results).

Concluding Summary

New benzofuran-based H₃receptor antagonists have

been synthesized. The new compounds have balanced

nanomolar potency at rat and human H₃receptors and

very high selectivity over other receptors. Many of the

compounds had excellent pharmacokinetic profiles in

rats; as a consequence of their highly lipophilic nature,

the new compounds achieve high CNS concentrations

and have large brain/plasma ratios. When tested in two

rodent models of cognition and attention, six benzofuran

analogues showed robust efficacy and were highly

potent, with full efficacy achieved at doses ranging from

0.003 to 1 mg/kg.

One compound, 20, combined high potency (0.1 mg/

kg) in an inhibitory avoidance acquisition model of

learning/impulsiveness, high potency (0.01 mg/kg) in a

social memory model, and excellent pharmacokinetic

properties across different species.⁴⁷Furthermore, 20

did not inhibit hepatic cytochromes P₄₅₀, consistent with

a hypothesis that non-imidazole H₃receptor antagonists

would be free of this liability. Additionally, 20 displayed

a high CNS therapeutic index for cognitive enhance-

ment (it did not stimulate locomotor behavior or induce

stereotypy), a profile that suggests that H₃receptor

antagonists will be free of CNS stimulant liability. The

overall profile of these compounds, and of 20 in par-

ticular, supports the potential utility of H₃receptor

antagonists in the treatment of cognitive dysfunction

in such human diseases as attention deficit hyperactiv-

ity disorder, schizophrenia, mild cognitive impairment,

and Alzheimer’s dementia.

Figure 7. Methylphenidate (MPH) enhanced acquisition of

inhibitory avoidance response at 1-3 mg/kg (a), as measured

by an increase in latency but also increased locomotion at 3-10

mg/kg.^41,42aThe H₃antagonist 20 enhanced acquisition^25cat

0.1 mg/kg (b) without effects on locomotion (0.03-1 mg/kg).

Latency ) summed improvement in inhibitory avoidance

acquisiton over four trials (sum: T2-T5) compared to vehicle-

treated controls: (/) P < 0.05, Mann-Whitney test. Doses were

administered sc 30 min prior to testing. Spontaneous locomotor

activity was measured as distance travelled: (/) P < 0.05, post

hoc Tukey’s test.

Experimental Section

Chemistry Methods. Unless otherwise noted, all solvents,

chemicals, and reagents were obtained commercially and used

without purification and reactions were conducted under N₂

1

atmosphere at 23 °C. The H NMR spectra were obtained at

300 MHz on a Nicolet/GE QE300 spectrometer, with chemical

shifts (δ, ppm) reported relative to TMS or TSP as in internal

standard. Mass spectra were obtained on a Kratos MS-50

instrument, and unless otherwise indicated, all MS instru-

ments were operated in the +APCI or +DCI mode to detect

positively charged ions. Elemental analyses were performed

by Robertson Microlit Laboratories, Inc., Madison, NJ. Flash

chromatography was carried out using silica gel 60 (E. Merck,

230-400 mesh) or with prepacked 40 mm silica gel columns

from BioTage. Thin-layer chromatography was performed on

250 µM silica-coated glass plates from EM Science. Samples

were analyzed by HPLC-MS-ELSD on a Finnigan Navigator/

Agilent 1100/Sedere Sedex 75 system using a Phenomenex

metabolism of the CYP-specific substrates listed in

Table 3. At 20 µM, only weak inhibition of CYPs 2D6

and 2C9 was noted. Because these concentrations are

much higher than the blood levels necessary for efficacy

in the cognition models, which ranged from 0.22 to 4.7

ng/mL (0.7-14 nM), it is likely that 20 and perhaps

similar non-imidazole H₃receptor antagonists will have

low liability to perpetrate drug-drug interactions. The

Table 3. At 2 and 20 µM, the Non-Imidazole H₃Receptor Antagonist 20 Shows Little or No Inhibition of CYPs, As Assessed by

Effect of 20 on the Rate of Oxidation of CYP-Specific Substrates

enzyme isoform:

substrate:

CYP 1A2

CYP 2C9

CYP 3A4

CYP 2C19

CYP 2D6

CYP 2E1

CYP 2A6

coumarin

phenacetin

tolbutamide terfenadine S-mephenytoin dextromethorphan chlorzoxazone

metabolic process: O-deethylation hydroxylation hydroxylation 4′-hydroxylation O-demethylation 6-hydroxylation 7-hydroxylation

% enzyme inhib

by 20 (2 µM)

% enzyme inhib

by 20 at (20 µM)

0

3.1

2.2

0

4.0

2.4

21.9

3.2

4.8

23.6

1.6

3.0

48 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

Luna C8 column (5 µm, 2.1 mm × 50 mm). The elution system

used was a gradient of either 10-100% CH₃CN/0.1% aqueous

CF₃CO₂H, or CH₃CN/10 mM aqueous NH₄OAc over 4.5 min

at 1.5 mL/min. Purification by preparative HPLC was carried

out on a Waters Symmetry C8 column (40 mm × 100 mm, 7

µm particle size), eluting with a gradient (12 min) of either

CH₃CN:/0.1% aqueous CF₃CO₂H, or CH₃CN/10 mM aqueous

NH₄OAc. Melting points were determined on a Buchi 510

melting point apparatus and are uncorrected. NH₄OH refers

to a saturated aqueous solution of NH₃, and brine refers to a

saturated aqueous solution of NaCl. Calculations of CLogP

were made using ChemDraw Ultra, from CambridgeSoft Corp.

4′-Hydroxy-3′-iodo[1,1′-biphenyl]-4-carbonitrile (17).

To a solution of 6.00 g (30.8 mmol) of 4-hydroxy-4′-cyanobi-

phenyl (16), 4.61 g (30.8 mmol) of NaI, and 1.23 g (30.8 mmol)

of NaOH in CH₃OH (90 mL) at 0 °C was added an aqueous

solution of 5.25% NaOCl (47 mL of Clorox, 2.29 g, 30.8 mmol)

over 45 min. The mixture was stirred at 0 °C for 1 h, warmed

to 23 °C, and diluted with saturated aqueous sodium thiosul-

fate (10 mL), H₂O (80 mL), then adjusted to pH 7 by addition

of saturated aqueous NaH₂PO₄. The mixture was extracted

with CH₂Cl₂(2 × 90 mL). The combined organic extracts were

dried (Na₂SO₄), filtered, and concentrated under vacuum to

give a white powder. The solid was purified by flash chroma-

tography, eluting with CH₂Cl₂to give 40 (5.19 g, 53%). ¹H

NMR (DMSO-d₆) δ 10.70 (s, 1H), 8.08 (d, 1H, J ) 1.2 Hz), 7.85

(d, 2H, J ) 8.3 Hz), 7.78 (d, 2H, J ) 8.3 Hz), 7.76 (dd, 1H, J

) 7.5, 1.2 Hz), 7.02 (d, 2H, J ) 7.5 Hz); MS (DCI) m/z 339 (M

+ NH₄)⁺.

mL of CH₂Cl₂. The reaction mixture was allowed to warm to

23 °C over the course of 2 h and then poured into CH₂Cl₂,

whereupon the organic phase was washed with saturated

NaHCO₃, dried over Na₂SO₄, and concentrated under vacuum.

Residual CH₂Cl₂was removed by addition of toluene, then

concentrated under vacuum. The mesylate ester thus obtained

was dissolved in 8 mL of CH₃CN, and 4 g of 4 Å molecular

sieves was added, together with 0.95 g (9.0 mmol) of Na₂CO₃

and 0.50 g of (R)-2-methylpyrrolidine hydrobromide. The

mixture was heated at 70 °C for 4 days, diluted with CH₃OH,

and filtered through Celite. The filtrate was added to 200 mL

of Et₂O, washed with 700 mL of 0.5 M Na₂CO₃, concentrated

under vacuum, and purified by flash chromatography, eluting

with 5% CH₃OH/0.1% NH₄OH in CH₂Cl₂to give 0.52 g (53%)

of 20 as a glass. The l-tartrate salt of 20 crystallized from water

as white crystals. Anal. (C₂₂H₂₂N₂O‚C₄H₄O₆‚H₂O) C, H, N. The

phosphate salt was obtained as a white powder after recrys-

tallization from methanol, mp 203-204 °C. Anal. (C₂₂H₂₂N₂O‚

H₃PO₄) C, H, N. The phosphate salt is more soluble in water

(10 mg/mL) than the ^L-tartrate salt (3 mg/mL).

4-(2-(2-[2(S)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-

5-yl)benzonitrile (21). To a suspension of 0.682 g (2.00 mmol)

of19 in 3 mL of CH₃CN was added a solution of 6.0 mmol of

(S)-2-methylpyrrolidine in 3 mL of toluene (prepared by

treating 1.41 g of (S)-2-methylpyrrolidine tartrate with 6 mL

of 25% aqueous NaOH, then extracting the mixture with 3

mL of toluene). The reaction mixture was stirred at 23 °C for

4 days, poured into 80 mL of H₂O containing 1 mL of saturated

aqueous NH₄OH, and extracted with 40 mL of CH₂Cl₂. After

concentration of the CH₂Cl₂extract under vacuum, the residue

was purified by flash chromatography, eluting with 2% CH₃OH

and 0.1% NH₄OH in CH₂Cl₂to give 0.418 g (63%) of 21. This

was dissolved in 3 mL of i-PrOH, and 0.183 g of ^D-tartaric acid

was added. Upon slow evaporation of the solvent, white

crystals were deposited, which were recrystallized from an-

hydrous EtOH to give 0.49 g of 21 as the ^D-tartrate salt, mp

151-152 °C. ¹H NMR (DMSO-d₆) δ 7.96 (m, 1H), 7.90 (m, 4H),

7.62 (m, 2H), 6.78 (s, 1H), 3.35 (m, 1H), 3.10 (m, 3 H), 2.80

(m, 3H), 2.00 (m, 1H), 1.78 (m, 2H), 1.40 (m, 1H), 1.18 (d, J )

7 Hz, 3H); MS (DCI) m/z 331 (MH)⁺. Anal. (C₂₂H₂₂N₂O‚C₄H₄O₆)

C, H, N.

1-(3-Butynyl)-2(R)-methylpyrrolidine (23). (R)-2-Meth-

ylpyrrolidine tartrate (22) (1.65 g, 7.00 mmol) and powdered

K₂CO₃(2.03 g, 14.7 mmol) in CH₃CN (60 mL) were heated at

50 °C in a sealed bottle for 24 h. The mixture was allowed to

cool to 23 °C and treated with 3-butynyl 4-toluenesulfonate

(1.24 mL, 7.0 mmol). The mixture was stirred for 1 h at 23 °C

and then heated at 50 °C for 24 h. The mixture was allowed

to cool to 23 °C and filtered, and the filter cake was washed

with CH₃CN. The filtrate was diluted to a total volume of 70

mL with CH₃CN and used as a 0.1 M solution of 23 in

subsequent steps without purification.

(3-Fluorophenyl)(4-hydroxyphenyl)methanone (24b).

To a well-stirred solution of 1.0 g (4.34 mmol) of 3-fluorophen-

yl(4-methoxyphenyl)methanone in 50 mL of CH₂Cl₂at -78 °C

was added 13.03 mL of (13.03 mmol) of 1 M BBr₃dropwise

over 20 min. The mixture was allowed to warm to 25 °C and

stirred for 18 h. The mixture was cautiously treated with H₂O

(1 mL) and stirred for 5 min, followed by additional H₂O (2

mL). After the mixture was stirred for 10 min, 50 mL of H₂O

was added, and after 20 min, the mixture was then extracted

with CH₂Cl₂(2 × 50 mL). The organic layers were combined,

dried over Na₂SO₄, and filtered, and the filtrate was concen-

trated under vacuum. The residue was purified by flash

chromatography, eluting with 5% CH₃OH/CH₂Cl₂to provide

24b (0.69 g, 74% yield). ¹HNMR (300 MHz, CD₃OD) δ 7.79 (d,

2H, J ) 8.9 Hz), 7.50 (m, 3H), 7.26 (m, 1H), 6.92 (d, 2H, J )

8.9 Hz); MS (DCI) m/z 217 (MH)⁺, 234 (M + NH₄)⁺.

4-[2-(2-Hydroxyethyl)-1-benzofuran-5-yl]benzoni-

trile (18). To a solution of 17 (5.19 g, 16.2 mmol), Et₃N (5.60

mL, 40.4 mmol), and 3-butyn-1-ol (1.90 g, 27.2 mmol) in 13

mL of DMF at 20 °C was added CuI (0.46 g, 2.4 mmol) and

(Ph₃P)₂PdCl₂(0.56 g, 0.80 mmol). The mixture was stirred at

65 °C for 12 h, cooled, and diluted with CH₂Cl₂(20 mL) and

hexane (100 mL). Celite (5 g) was added with stirring, and

the solids were removed by filtration. The filtrate was washed

with H₂O (600 mL), the organic layer separated and saved,

and the aqueous layer was extracted with dichloromethane

(3 × 100 mL). The combined organic extracts were dried

(Na₂SO₄), filtered, and concentrated under vacuum to give a

tan solid. The solid was purified by flash chromatography,

1

eluting with 3% CH₃OH/CH₂Cl₂to give 18 (4.02 g, 95%). H

NMR (CD₃OD) δ 7.80 (m, 5H), 7.52 (m, 2H), 6.62 (s, 1H), 3.93

(t, 2H, J ) 6.9 Hz), 3.03 (t, 2H, J ) 6.9 Hz); MS (DCI) m/z 281

(M + NH₄)⁺.

2-[5-(4-Cyanophenyl)-1-benzofuran-2-yl]ethyl Meth-

anesulfonate (19). To a solution of 18 (0.57 g, 2.2 mmol) and

Et₃N (0.9 mL, 6.5 mmol) in CH₂Cl₂(10 mL) at 20 °C was added

CH₃SO₂Cl (0.79 g, 4.5 mmol). The mixture was stirred for 30

min, diluted with CH₂Cl₂, washed with water, dried over

Na₂SO₄, filtered, and concentrated under vacuum. The residue

was purified by flash chromatography, eluting with CH₂Cl₂

to give 19 (0.66 g, 89%). ¹H NMR (CDCl₃) δ 7.73 (m, 5H), 7.51

(d, 1H, J ) 8.1 Hz), 7.46 (dd, 1H, J ) 8.1, 1.8 Hz), 4.60 (t, 2H,

J ) 6.3 Hz), 3.29 (t, 2H, J ) 6.3 Hz), 2.97 (s, 3H); MS (DCI)

m/z 359 (MH)⁺.

4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-

5-yl)benzonitrile (20). A suspension of 0.19 g (0.55 mmol)

of 19, 0.17 g (1.0 mmol) of (R)-2-methylpyrrolidine hydro-

bromide^28a(22), and Na₂CO₃(0.23 g, 2.2 mmol) in CH₃CN (0.4

mL) was heated with stirring at 50 °C for 48 h. The reaction

mixture was cooled to 23 °C and diluted with CH₃CN, and the

solids were removed by centrifugation. The supernatant was

concentrated under vacuum and the residue was purified by

preparative HPLC, eluting with aqueous CH₃CN/0.1% aqueous

1

CF₃CO₂H to give 20 (0.065 g, 34%). H NMR (CD₃OD) δ 7.88

(m, 1H), 7.71 (m, 4H), 7.50 (m, 2H), 6.82 (s, 1H), 3.72-3.9 (m,

2H), 3.58 (m, 1H), 3.25-3.5 (m, 4H), 2.48 (m, 1H), 2.05-2.2

(m, 2H), 1.75 (m, 1H), 1.50 (d, J ) 6 Hz, 3H); MS (DCI) m/z

331 (MH)⁺.

(2-Fluorophenyl)(4-hydroxy-3-iodophenyl)metha-

none (25a). A solution of 2.0 g (9.25 mmol) of 24a in 120 mL

of NH₄OH was stirred at 25 °C for 15 min, then treated with

a solution of KI (7.48 g, 45.1 mmol) and I₂(2.35 g, 9.25 mmol)

in 240 mL of H₂O. The reaction mixture was adjusted to pH

7, extracted with EtOAc, washed with H₂O and brine, dried,

As an alternative route, powdered methane sulfonic anhy-

dride (1.57 g, 9.0 mmol) was added to a (-10 °C) solution of

2.25 g (8.57 mmol) of 18 and 1.73 g (17 mmol) of Et₃N in 20

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 49

and filtered, and the filtrate was concentrated under vacuum.

The residue was purified by flash chromatography, eluting

with 95% CH₂Cl₂/5% MeOH to give 25a (2.41 g, 76%). MS

(DCI) m/z 343 (MH)⁺, 360 (M + NH₄)⁺.

(3-Fluorophenyl)(4-hydroxy-3-iodophenyl)metha-

none (25b). Compound 24b (2.0 g, 9.25 mmol) was iodinated

by the method used to prepare 25a, using an aqueous solution

(20 mL) of KI (7.48 g, 45.05 mmol) and I₂(2.35 g, 9.25 mmol)

in NH₄OH (100 mL) to give 25b (2.30 g, 73%) after purification

by flash chromatography (95% CH₂Cl₂, 5% MeOH). ¹HNMR

(300 MHz, CD₃OD) δ 8.18 (s, 1H), 7.67 (d, 1H, J ) 8.9 Hz),

7.45 (m, 4H), 6.92 (d, 1H, J ) 8.9 Hz); MS (DCI) m/z 343

(MH)⁺, 360 (M + NH₄)⁺. Anal. (C₂₂H₂₂FNO₂‚1.3 C₄H₆O₆‚0.5

H₂O) C, H, N.

(4-Fluorophenyl)(4-hydroxy-3-iodophenyl)metha-

none (25c). A solution of 20.0 g (92.5 mmol) of 24c in 770 mL

of NH₄OH was stirred at 25 °C for 15 min, then treated with

a solution of KI (74.79 g, 450.5 mmol) and I₂(23.48 g, 92.5

mmol) in 185 mL of H₂O. The reaction mixture was stirred at

25 °C for 18 h and then filtered. The precipitate was dissolved

in ethyl acetate, washed with H₂O and brine, dried, and

filtered and the filtrate was concentrated under vacuum to

provide 25c as a pale-green solid (23.4 g, 74% yield). ¹H NMR

(300 MHz, CD₃OD) δ 8.17 (s, 1H), 7.78 (m, 2H), 7.64 (dd, 1H,

J ) 8.9, 2.1 Hz), 7.26 (t, 2H, J ) 8.9 Hz), 6.91 (d, 1H, J ) 8.9

Hz); MS (DCI) m/z 342.9 (MH)⁺, 360 (M + NH₄)⁺.

purified on silica gel, eluting with 90% CH₂Cl₂/9.9% MeOH/

0.1% NH₄OH to provide 26c (1.21 g, 18.0% yield). ¹HNMR (300

MHz, CD₃OD) δ 7.97 (s, 1H), 7.86 (m, 2H), 7.71 (dd, 1H, J )

8.9, 2.1 Hz), 7.58 (d, 1H, J ) 8.9 Hz), 7.27 (t, 2H, J ) 8.9 Hz),

6.68 (s, 1H), 3.28 (m, 2H), 3.06 (m, 2H), 2.49 (m, 2H), 2.02-

2.28 (m, 2H), 1.81 (m, 2H), 1.46 (m, 1H), 1.09 (d, 3H, J ) 6.1

Hz); MS (ESI) m/z 352 (MH)⁺. Anal. (C₂₂H₂₂FNO₂) C, H, N.

The tartrate salt was formed by addition of ^L-tartaric acid in

aqueous CH₃OH, followed by concentration under vacuum to

give a glass. Anal. (C₂₂H₂₂FNO₂‚C₄H₆O₆‚H₂O) C, H, N.

4-(Benzyloxy)benzoyl Chloride (28). To a solution of 15.0

g (65.72 mmol) of 27 (4-benzyloxybenzoic acid) and 0.75 mL

of DMF in 150 mL of CH₂Cl₂at 0 °C was added oxalyl chloride

(11.5 mL, 131.44 mmol) dropwise over 25 min. The resulting

mixture was stirred at 23 °C for 2 h, followed by concentration

under vacuum to give 28 as a light-yellow solid (16.1 g, 99%

yield). ¹H NMR (300 MHz, CDCl₃) δ 8.07 (d, 2H, J ) 8.9 Hz),

7.33 (m, 5H), 7.03 (d, 2H, J ) 8.9 Hz).

4-(Benzyloxy)-N-methoxy-N-methylbenzamide (29). To

a solution of 19.7 g (80.26 mmol) of 4-(benzyloxy)benzoyl

chloride (28) in CH₂Cl₂was added powdered N,O-dimethyl-

hydroxylamine hydrochloride (7.83 g, 80.26 mmol). The reac-

tion mixture was cooled to 0 °C and after 30 min was treated

with Et₃N (25.47 mL, 182.41 mmol). The reaction mixture was

allowed to warm to 25 °C, stirred for 16 h, diluted with CH₂Cl₂

(150 mL), and washed with saturated aqueous NaHCO₃,

saturated aqueous NaCl, and H₂O. The organic phase was

dried over Na₂SO₄and filtered, and the filtrate was concen-

trated under vacuum to provide 29 as a pale-yellow solid (18.65

(2-Fluorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (26a). To 2.0 g (5.85

mmol) of 25a was added 70.2 mL (7.02 mmol) of a 0.1 M

solution of 23 in CH₃CN, followed by Pd(OAc)₂(0.039 g, 0.175

mmol), tris(4-methylphenyl)phosphine (0.107 g, 0.351 mmol),

and CuI (0.167 g, 0.877 mmol). After the mixture was stirred

at 25 °C for 10 min, the reaction mixture was treated with

i-Pr₂NH (8.4 mL, 59 mmol) and then heated at 60 °C under

N₂for 16 h. The reaction mixture was allowed to cool and

filtered through Celite, and the filtrate was concentrated under

reduced pressure. The residue was purified by flash chroma-

tography, eluting with 95% CH₂Cl₂/4.5% MeOH/0.5% NH₄OH

1

g, 95% yield). H NMR (300 MHz, CDCl₃) δ 7.76 (d, 2H, J )

8.9 Hz), 7.40 (m, 5H), 6.98 (d, 2H, J ) 8.9 Hz), 3.56 (s, 3H),

3.36 (s, 3H); MS (ESI) m/z 272 (MH)⁺.

4-Hydroxy-N-methoxy-N-methylbenzamide (30). To a

suspension of 10% Pd(C) (4.5 g) in 10 mL of CH₃OH was added

a solution of 18.60 g (68.55 mmol) of 29 (4-(benzyloxy)-N-

methoxy-N-methylbenzamide) in 150 mL of CH₃OH. The

mixture was shaken under an atmosphere of H₂at 67 psi until

TLC indicated complete consumption of 29, then filtered. The

filtrate was concentrated under vacuum and purified by flash

chromatography, eluting with 90% CH₂Cl₂/10% CH₃OH to

provide 30 (10.3 g, 83% yield). ¹H NMR (300 MHz, CD₃OD) δ

7.59 (d, 2H, J ) 8.9 Hz), 6.81 (d, 2H, J ) 8.9 Hz), 3.58 (s, 3H),

3.32 (s, 3H); MS (DCI) m/z 182 (MH)⁺, 199 (M + NH₄)⁺.

1

to give 26a (0.38 g, 19%). HNMR (300 MHz, CD₃OD) δ 7.99

(s, 1H), 7.79 (d, 1H, J ) 8.9 Hz), 7-50-7.67 (m, 3H), 7.30 (m,

2H), 6.76 (s, 1H), 3.45 (m, 2H), 3.18 (m, 2H), 2.93 (m, 2H),

2.10-2.78 (m, 2H), 1.93 (m, 2H), 1.59 (m, 1H), 1.28 (d, 3H, J

) 6.1 Hz); MS (ESI) m/z 352.1 (MH)⁺. The tartrate salt was

formed by addition of l-tartaric acid in aqueous methanol,

followed by evaporation to give a glass. Anal. (C₂₂H₂₂FNO₂‚

C₄H₆O₆‚H₂O) C, H, N.

4-Hydroxy-3-iodo-N-methoxy-N-methylbenzamide (31).

A suspension of 10.3 g (56.84 mmol) of 4-hydroxy-N-methoxy-

N-methylbenzamide (30) in NH₄OH (400 mL) was stirred at

25 °C for 15 min, then treated with KI (45.96 g, 276.83 mmol)

and I₂(14.43 g, 56.84 mmol) in 65 mL of H₂O. After the

mixture was stirred for 16 h, the solvent was removed under

vacuum, and the residue was redissolved in CH₂Cl₂(500 mL)

and washed with H₂O (2 × 350 mL). The organic phase was

dried over Na₂SO₄and filtered, and the filtrate was concen-

trated under vacuum. The residue was purified by flash

chromatography, eluting with 90% CH₂Cl₂/10% CH₃OH, to

(3-Fluorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (26b). A mixture of 2.0

g (5.85 mmol) of 25b, 70.2 mL (7.02 mmol) of a 0.1 M solution

of 23 in CH₃CN, Pd(OAc)₂(0.039 g, 0.175 mmol), tris(4-

methylphenyl)phosphine (0.107 g, 0.351 mmol), and CuI (0.167

g, 0.877 mmol) was heated at 60 °C for 16 h. The reaction

mixture was allowed to cool and filtered through Celite, and

the filtrate was concentrated under vacuum and purified by

flash chromatography, eluting with 95% CH₂Cl₂/4.5% MeOH/

0.5% NH₄OH to provide 26b (0.37 g, 18%). ¹HNMR (300 MHz,

CD₃OD) δ 7.98 (s, 1H), 7.76 (d, 1H, J ) 8.9 Hz), 7.48 (m, 5H),

6.76 (s, 1H), 3.42 (m, 2H), 3.18 (m, 2H), 2.87 (m, 2H), 2.36 (m,

2H), 1.91 (m, 2H), 1.57 (m, 1H), 1.26 (d, 3H, J ) 6.1 Hz); MS

(ESI) m/z 352.1 (MH) ⁺. The tartrate salt was formed by

addition of ^L-tartaric acid in aqueous methanol, followed by

evaporation to give a glass. Anal. (C₂₂H₂₂FNO₂‚1.3C₄H₆O₆‚0.5

H₂O) C, H, N.

(4-Fluorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (26c). To 6.5 g (18.5

mmol) of 25c was added 230 mL (23.0 mmol) of a 0.1 M

solution of 1-(3-butynyl)-2(R)-methylpyrrolidine (23) in CH₃CN,

followed by Pd(OAc)₂(0.127 g, 0.566 mmol), tris(4-methylphen-

yl)phosphine (0.344 g, 1.130 mmol), and CuI (1.08 g, 95.72

mmol). After being stirred at 25 °C for 10 min, the reaction

mixture was treated with i-Pr₂NH (26.6 mL, 189 mmol) and

then heated at 60 °C under N₂for 16 h. The reaction mixture

was allowed to cool and filtered through Celite, and the filtrate

was concentrated under reduced pressure. The residue was

1

provide 31 as a white solid (11.6 g, 67% yield). H NMR (300

MHz, CD₃OD) δ 8.06 (s, 1H), 7.58 (d, 1H, J ) 8.9 Hz), 6.83 (d,

1H, J ) 8.9 Hz), 3.59 (s, 3H), 3.32 (s, 3H); MS (DCI) m/z 308

(MH)⁺, 325 (M + NH₄)⁺.

N-Methoxy-N-methyl-2-(2-[2(R)-methyl-1-pyrrolidinyl]-

ethyl)-1-benzofuran-5-carboxamide (32). To a solution of

11.6 g (37.77 mmol) of 4-hydroxy-3-iodo-N-methoxy-N-meth-

ylbenzamide (31) in CH₃CN (50 mL) was added in sequential

fashion 378 mL (45.33 mmol) of a 0.12 M solution of 1-(3-

butynyl)-2(R)-methylpyrrolidine (23) in CH₃CN, Pd(OAc)₂

(0.254 g, 1.13 mmol), tris(4-methylphenyl)phosphine (0.518 g,

1.699 mmol), and i-Pr₂NH (39.7 mL, 283.3 mmol). After being

stirred at 25 °C for 10 min, the mixture was treated with CuI

(2.16 g, 11.33 mmol) and heated at 50 °C under N₂for 18 h.

The reaction mixture was cooled to 23 °C and filtered through

Celite, and the filtrate was concentrated under reduced

pressure. The residue was purified by flash chromatography,

eluting with 95% DCM/9.9% MeOH/0.1% NH₄OH to provide

32 (1.22 g) with a recovery of 6 g of iodophenol, which was

resubjected to the reaction conditions (adjusting for scale) to

50 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

give an additional 1.10 g of 32 for a total yield of 2.32 g (21%)

of 32. Note that the Pd-catalyzed cyclization appeared some-

what dependent on the scale, with reactions starting with 1,

5, and 6 g of iodophenol giving yields of 32 of 42%, 47%, and

44%, respectively. ¹H NMR (300 MHz, CD₃OD) δ 7.84 (s, 1H),

7.51 (q, 2H, J ) 10.5 Hz), 6.63 (s, 1H), 3.59 (s, 3H), 3.38 (s,

3H), 3.26 (m, 2H), 3.06 (m, 2H), 2.50 (m, 2H), 2.12 (m, 2H),

1.78 (m, 2H), 1.47 (m, 1H), 1.18 (d, 3H, J ) 6.1 Hz); MS (ESI)

m/z 317.2 (MH)⁺. Anal. (C₁₈H₂₄N₂O₃‚0.85CH₃OH) C, H, N.

(4-Chlorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (33a). A solution of 0.250

g (0.79 mmol) of 32 in 20 mL of THF at 0 °C was treated with

4-chlorophenylmagnesium bromide (1.58 mL of a 1.0 M THF

solution, 1.58 mmol). The mixture was allowed to warm slowly

to 25 °C and stirred for 18 h. The reaction mixture was

quenched with saturated aqueous NH₄Cl and extracted with

CH₂Cl₂(2 × 50 mL). The organic phases were combined, dried

over Na₂SO₄, and filtered, and the filtrate was evaporated

under vacuum. The residue was purified by flash chromatog-

raphy, eluting with 95% CH₂Cl₂/4.5% MeOH/0.5% NH₄OH to

provide 33a (0.061 g, 21% yield). ¹H NMR (300 MHz, CD₃OD)

δ 7.97 (s, 1H), 7.78 (m, 3H), 7.57 (m, 3H), 6.67 (s, 1H), 3.23

(m, 2H), 3.03 (m, 2H), 2.50 (m, 2H), 2.01-2.36 (m, 2H), 1.78

(m, 2H), 1.46 (m, 1H), 1.18 (d, 3H, J ) 6.1 Hz); MS (ESI) m/z

368.1 (MH)⁺. The tartrate salt was formed by addition of

L-tartaric acid in aqueous methanol, followed by evaporation

to give a glass. Anal. (C₂₂H₂₂ClNO₂‚1.2C₄H₆O₆) C, H, N.

mide (0.30 mL of a 1 M solution in THF, 0.30 mmol) was

reacted to provide 33e (0.016 g, 13% yield) after purification

by flash chromatography (95% CH₂Cl₂/4.5% MeOH/ 0.5% NH₄-

1

OH). H NMR (300 MHz, CD₃OD) δ 7.95 (d, 1H, J ) 2.1 Hz),

7.70 (dd, 2H, J ) 8.9, 2.1 Hz), 7.63 (m, 1H), 7.57 (d, 1H, J )

8.9 Hz), 7.19 (t, 1H, J ) 8.9 Hz), 6.65 (s, 1H), 3.25 (m, 2H),

3.05 (m, 2H), 2.50 (m, 2H), 2.30 (m, 4H), 2.0 (m, 1H), 1.80 (m,

2H), 1.45 (m, 1H), 1.17 (d, 3H, J ) 6.1 Hz); MS (ESI) m/z 366

(MH)⁺. The tartrate salt was formed by addition of L-tartaric

acid in aqueous methanol, followed by evaporation to give a

glass. Anal. (C₂₃H₂₄FNO₂‚C₄H₆O₆‚0.5H₂O) C, H, N.

(4-Chloro-3-methylphenyl)(2-(2-[2(R)-methyl-1-pyrro-

lidinyl]ethyl)-1-benzofuran-5-yl)methanone (33f). By the

method used to prepare 33a, a solution of 32 (0.35 g, 1.11

mmol) in THF and 4-chloro-3-methylphenylmagnesium bro-

mide (11.1 mL of a 0.5 M solution in THF, 5.53 mmol) was

reacted to provide 33f (0.290 g, 68% yield) after purification

by flash chromatography (95% CH₂Cl₂, 4.5% MeOH, 0.5%

1

NH₄OH). H NMR (300 MHz, CD₃OD) δ 8.01 (d, 1H, J ) 2.1

Hz), 7.79 (dd, 1H, J ) 8.9, 2.1 Hz), 7.7 (bs, 1H), 7.50 (m, 3H),

6.85 (s, 1H), 3.80 (m, 2H), 3.55 (m, 1H), 3.50 (m, 2H), 2.44 (s,

3H), 2.38 (m, 1H), 2.10 (m, 2H), 1.80 (m, 2H), 1.75 (m, 1H),

1.47 (d, 3H, J ) 6.1 Hz); MS (ESI) m/z 382 (MH)⁺. The tartrate

salt was formed by addition of ^L-tartaric acid in aqueous

methanol, followed by evaporation to give a glass. Anal.

(C₂₃H₂₄ClNO₂‚1.0C₄H₆O₆‚0.5H₂O) C, H, N.

(3-Chlorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (33g). A solution of 0.400

g (1.26 mmol) N-methoxy-N-methyl-2-(2-[(2R)-2-methyl-1-pyr-

rolidinyl]ethyl)-1-benzofuran-5-carboxamide (32) in 20 mL of

THF at 0 °C was treated with 3-chlorophenylmagnesium

bromide (12.6 mL of a 0.5 M THF solution, 6.32 mmol). The

mixture was allowed to warm slowly to 25 °C and stirred for

18 h. The reaction mixture was quenched with saturated

aqueous NH₄Cl and extracted with CH₂Cl₂(2 × 50 mL). The

organic phases were combined, dried over Na₂SO₄, and filtered,

and the filtrate was evaporated under vacuum. The residue

was purified by flash chromatography, eluting with 95% DCM/

4.5% MeOH/0.5% NH₄OH to provide 33g (0.18 g, 39% yield).

¹H NMR (300 MHz, CD₃OD) δ 8.02 (d, 1H, J ) 1.2 Hz), 7.65

(m, 6H), 6.90 (s, 1H), 3.80 (m, 2H), 3.55 (m, 1H), 3.30 (m, 4H),

2.35 (m, 1H), 2.10 (m, 2H), 1.72 (m, 1H), 1.50 (d, 3H, J ) 6.1

Hz); MS (ESI) m/z 368 (MH)⁺. The tartrate salt was formed

by addition of ^L-tartaric acid in aqueous methanol, followed

by evaporation to give a glass. Anal. (C₂₂H₂₂ClNO₂‚C₄H₆O₆)

C, H, N.

(3,5-Difluorophenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]-

ethyl)-1-benzofuran-5-yl)methanone (33h). By the method

used to prepare 33a, a solution of 32 (0.40 g, 1.26 mmol) and

3,5-difluorophenylmagnesium bromide (12.6 mL of a 0.5 M

THF solution, 6.32 mmol) was reacted to provide 33h (0.115

g, 25% yield) after purification by flash chromatography,

eluting with 95% CH₂Cl₂/4.5% MeOH/0.5% NH₄OH. ¹H NMR

(300 MHz, CD₃OD) δ 8.05 (d, 1H, J ) 2.1 Hz), 7.80 (dd, 1H, J

) 8.9, 2.1 Hz), 7.63 (d, 1H, J ) 8.9 Hz), 7.30 (m, 3H), 6.88 (s,

1H), 3.82 (m, 2H), 3.56 (m, 1H), 3.30 (m, 4H), 2.35 (m, 1H),

2.13 (m, 2H), 1.75 (m, 1H), 1.45 (d, 3H, J ) 6.1 Hz); MS (ESI)

m/z 370 (MH)⁺. The tartrate salt was formed by addition of

L-tartaric acid in aqueous methanol, followed by evaporation

to give a glass. Anal. (C₂₂H₂₁F₂NO₂‚1.25C₄H₆O₆) C, H, N.

(4-Methylphenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]eth-

yl)-1-benzofuran-5-yl)methanone (33b). By the method

used to prepare 33a, a solution of 32 (0.20 g, 0.63 mmol) and

4-methylphenylmagnesium bromide (3.16 mL of a 1 M solution

in THF, 3.16 mmol) was reacted to provide 33b (0.118 g, 54%

yield) after purification by flash chromatography, eluting with

1

95% CH₂Cl₂/4.5% MeOH/0.5% NH₄OH). H NMR (300 MHz,

CD₃OD) δ 8.0 (d, 1H, J ) 2.1 Hz), 7.75 (dd, 1H, J ) 8.9, 2.1

Hz), 7.70 (d, 2H, J ) 8.9 Hz), 7.60 (d, 1H, J ) 8.9 Hz), 7.38 (d,

2H, J ) 8.9 Hz), 6.85 (s, 1H), 3.80 (m, 2H), 3.57 (m, 1H), 3.30

(m, 4H), 2.45 (s, 3H), 2.38 (m, 1H), 2.1 (m, 2H), 1.75 (m, 1H),

1.48 (d, 3H, J ) 6.1 Hz); MS (ESI) m/z 348 (MH)⁺. The tartrate

salt was formed by addition of ^L-tartaric acid in aqueous

methanol, followed by evaporation to give a glass. Anal.

(C₂₃H₂₅NO₂‚2.0C₄H₆O₆) C, H, N.

(4-Methoxyphenyl)(2-(2-[2(R)-methyl-1-pyrrolidinyl]-

ethyl)-1-benzofuran-5-yl)methanone (33c). By the method

used to prepare 33a, a solution of 32 (0.080 g, 0.253 mmol) in

THF and 4-methoxyphenylmagnesium bromide (0.61 mL of a

0.5 M solution in THF, 0.30 mmol) was reacted to provide 33c

(0.014 g, 12% yield) after purification by flash chromatography

(95% CH₂Cl₂/ 4.5% MeOH/0.5% NH₄OH). ¹H NMR (CD₃OD) δ

7.92 (s, 1H), 7.80 (d, 2H, J ) 8.9 Hz), 7.68 (d, 1H, J ) 8.9 Hz),

7.54 (d, 1H, J ) 8.9 Hz), 7.05 (d, 2H, J ) 8.9 Hz), 6.67 (s, 1H),

3.88 (s, 3H), 3.24 (m 2H), 3.06 (m, 2H), 2.50 (m, 2H), 2.26 (m,

1H), 2.07 (m, 1H), 1.78 (m, 2H), 1.46 (m, 1H), 1.18 (d, 3H, J )

6.1 Hz); MS (ESI) m/z 364 (MH)⁺. The tartrate salt was formed

by addition of ^L-tartaric acid in aqueous methanol, followed

by evaporation to give a glass. Anal. (C₂₃H₂₅NO₃‚C₄H₆O₆‚H₂O)

C, H, N.

[4-(Dimethylamino)phenyl](2-(2-[2(R)-methyl-1-pyrro-

lidinyl]ethyl)-1-benzofuran-5-yl)methanone (33d). By the

method used to prepare 33a, a solution of 32 (0.05 g, 1.26

mmol) and 4-(dimethylamino)phenylmagnesium bromide (1.58

mL of a 0.5 M solution in THF, 0.79 mmol) was reacted to

provide 33d (0.016 g, 27% yield) after purification by prepara-

tive HPLC. ¹H NMR (300 MHz, CD₃OD) δ 7.95 (d, 1H, J )

2.1 Hz), 7.75 (d, 2H, J ) 8.9 Hz), 7.65 (dd, 1H, J ) 8.9, 2.1

Hz), 7.56 (d, 1H, J ) 8.9 Hz), 6.85 (s, 1H), 6.80 (d, 2H, J ) 8.9

Hz), 3.80 (m, 2H), 3.55 (m, 1H), 3.50 (m, 2H), 3.18 (s, 6H),

2.35 (m, 1H), 2.15 (m, 2H), 1.80 (m, 2H), 1.73 (m, 1H), 1.44 (d,

3H, J ) 6.1 Hz); MS (ESI) m/z 377 (MH)⁺. Anal. (C₂₄H₂₈N₂O₂‚

1.5CF₃CO₂H) C, H, N.

(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-

5-yl)(phenyl)methanone (33i). By the method used to

prepare 33a, a solution of 32 (0.40 g, 1.26 mmol) and PhMgBr

(12.6 mL of a 0.5 M THF solution, 6.32 mmol) was reacted to

provide 33i (0.161 g, 38% yield) after purification by flash

chromatography, eluting with 95% CH₂Cl₂/4.5% MeOH/0.5%

1

NH₄OH. H NMR (300 MHz, CD₃OD) δ 7.98 (d, 1H, J ) 2.1

Hz), 7.80 (m, 3H), 7.65 (m, 1H), 7.55 (m, 3H), 6.63 (s, 1H),

3.30 (m, 4H), 2.50 (m, 2H), 2.30 (m, 1H), 2.00 (m, 1H), 1.80

(m, 2H), 1.45 (m, 1H), 1.15 (d, 3H, J ) 6.1 Hz); MS (ESI) m/z

334 (MH)⁺. The tartrate salt was formed by addition of

L-tartaric acid in aqueous methanol, followed by evaporation

to give a glass. Anal. (C₂₂H₂₃NO₂‚C₄H₆O₆) C, H, N.

(4-Fluoro-3-methylphenyl)(2-(2-[2(R)-methyl-1-pyrro-

lidinyl]ethyl)-1-benzofuran-5-yl)methanone (33e). By the

method used to prepare 33a, a solution of 32 (0.080 g, 0.253

mmol) in THF and (4-fluoro-3-methyl)phenylmagnesium bro-

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 51

1-(4′-Hydroxy-1,1′-biphenyl-3-yl)ethanone (35). A mix-

ture of 4-iodophenol (34, 5.39 g, 24.5 mmol) and 3-acetylphen-

ylboronic acid (4.42 g, 26.95 mmol) in 15 mL of DMF and 75

mL of 1 M aqueous Na₂CO₃was treated with 110 mg (0.49

mmol) of Pd(OAc)₂, heated at 55 °C for 1 h, and then cooled,

diluted with 100 mL of CH₂Cl₂, and filtered. The aqueous

filtrate was extracted with CH₂Cl₂, and the combined organic

phases were washed consecutively with potassium phosphate

buffer (pH 7) and brine, dried over Na₂SO₄, and concentrated

under vacuum. The residue was purified by flash chromatog-

raphy, eluting with a 33-100% gradient of CH₂Cl₂/hexane,

then 0-3% EtOAc/CH₂Cl₂, to provide an oil that crystallized

[3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]ethanol (39). A solution of 256 mg (0.73

mmol) of 37 in 2 mL of EtOH and 0.5 mL of THF was treated

with 38 mg (1.0 mmol) of NaBH₄. After 2.5 h the mixture was

treated with 3 M aqueous HCl (8 mL), stirred for 10 min, and

adjusted to pH 7 by addition of aqueous K₃PO₄. The mixture

was extracted with EtOAc, and the organic phase was dried

over Na₂SO₄and concentrated under vacuum. The residue was

purified by flash chromatography, eluting with 2-8% CH₃OH

in 1:1 EtOAc/CH₂Cl₂followed by 8-20% CH₃OH/CH₂Cl₂to

provide 39 (0.197 g, 77%). ¹H NMR (300 MHz, CD₃OD) δ 7.71

(m, 1 H), 7.62 (m, 1 H), 7.50 (m, 1 H), 7.46-7.49 (m, 2 H),

7.39 (dd, 1 H, J ) 7.8, 7.8 Hz), 7.32 (m, 1 H), 6.62 (s, 1 H),

4.90 (q, 1 H, J ) 6.4 Hz), 3.23-3.42 (m, 2 H), 2.97-3.18 (m, 2

H), 2.55-2.65 (m, 2 H), 2.35-2.50 (m, 1 H), 1.99-2.13 (m, 1

H), 1.78-1.90 (m, 2 H), 1.49 (d, 3 H, J ) 6.4 Hz), 1.42-1.57

(m, 1 H), 1.17 (d, 3 H, J ) 6.1 Hz); MS (ESI) m/z 350 (MH)⁺.

The tartrate salt was formed by addition of ^L-tartaric acid in

methanol, followed by evaporation to give a glass. Anal. C₂₃H₂₇-

NO₂‚1.2C₄H₆O₆‚0.3 CH₃OH) C, H, N.

Ethyl 4′-Hydroxy-1,1′-biphenyl-3-carboxylate (40). A

mixture of 34 (9.90 g, 45 mmol) and 3-ethoxycarbonylphenyl-

boronic acid (9.70 g, 50.0 mmol) in 15 mL of DMF and 135

mL of 1 M aqueous Na₂CO₃was treated with 224 mg (1.0

mmol) of Pd(OAc)₂and stirred at 23 °C for 16 h, then cooled,

diluted with 50 mL of CH₂Cl₂, acidified with 140 mL of 1 M

HCl, and filtered. The aqueous filtrate was extracted with

CH₂Cl₂, and the combined organic phases were washed

consecutively with potassium phosphate buffer (pH 6) and

brine, dried over Na₂SO₄, and concentrated under vacuum. The

residue was purified by flash chromatography, eluting first

with 50% CH₂Cl₂/hexanes and then with a gradient of 0-1%

MeOH/CH₂Cl₂to give 40 as a white powder (7.73 g, 71% yield).

MS (ESI APCI negative ion mode) m/z 241 (M - H)^-; ¹H NMR

(400 MHz, DMSO-d₆) δ 9.62 (s, 1 H), 8.11 (m, 1 H), 7.83-7.89

(m, 2 H), 7.50-7.59 (m, 3 H), 6.89 (d, 2 H, J ) 8.9 Hz), 4.34

(q, 2 H, J ) 7.1 Hz), 1.34 (t, 3 H, J ) 7.1 Hz).

1

to a white solid on standing (35, 6.3 g, 97% yield). H NMR

(400 MHz, CDCl₃) δ 8.13 (dd, 1 H, J ) 1.7, 1.7 Hz), 7.88 (m, 1

H), 7.74 (m, 1 H), 7.47-7.53 (m, 3 H), 6.97 (d, 2 H, J ) 9.1

Hz), 2.65 (s, 3 H); MS (ESI APCI negative ion mode) m/z 211

(M - H)^-.

1-(4′-Hydroxy-3′-iodo-1,1′-biphenyl-3-yl)ethanone (36).

A mixture of 35 (5.76 g, 27 mmol) in 400 mL of NH₄OH was

treated with a solution of KI (23.3 g, 140 mmol) and I₂(7.24

g, 28.5 mmol) in 100 mL of H₂O. After 1 h, additional KI (15.8

g, 95 mmol) and I₂(4.83 g, 19 mmol) in 50 mL of H₂O were

added, and after an hour, the reaction mixture was concen-

trated under vacuum to remove NH₄OH. The resulting residue

was extracted with EtOAc, washed consecutively with potas-

sium phosphate buffer (pH 7) and brine, dried over Na₂SO₄,

concentrated under vacuum, and purified by flash chromatog-

raphy, eluting with 0-5% EtOAc/CH₂Cl₂/1% CH₃CO₂H to give

1

36 as a beige powder (1.97 g, 21% yield). H NMR (300 MHz,

CDCl₃) δ 8.09 (dd, 1 H, J ) 1.4 Hz), 7.88-7.93 (m, 2 H), 7.71

(m, 1 H), 7.48-7.55 (m, 2 H), 7.08 (d, 1 H, J ) 5.9 Hz), 5.37

(bs, 1 H), 2.65 (s, 3 H). MS (ESI APCI negative ion mode) m/z

337 (M - H)^-.

1-[3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]ethanone (37). To a suspension of 36 (1.15

g, 3.40 mmol), Pd(OAc)₂(38 mg, 0.17 mmol), biphen-2-yl-

dicyclohexylphosphine (119 mg, 0.34 mmol), and CuI (76 mg,

0.40 mmol) in i-Pr₂NH (4.8 mL, 34 mmol) and 10 mL of DMF

was added 4.0 mmol of 23 in 45 mL of CH₃CN. The mixture

was heated at 45 °C for 12 h, cooled, and poured into a mixture

of 100 mL of CH₂Cl₂and 100 mL of 5% aqueous NH₄OH (100

mL). After filtration to remove solids, the organic phase was

washed consecutively with water and brine, dried over Na₂SO₄,

and concentrated under vacuum. The residue was purified by

flash chromatography, eluting with 0-4% CH₃OH/CH₂Cl₂,

then again by flash chromatography, eluting with 0-5% CH₃-

OH/CH₂Cl₂to give 37 (0.35 g, 30% yield). ¹H NMR (300 MHz,

CD₃OD) δ 8.22 (m, 1 H), 7.96 (ddd, 1 H, J ) 7.9, 1.7, 1.7 Hz),

7.88 (ddd, 1 H, J ) 7.9, 2.0, 2.0 Hz), 7.78 (m, 1 H), 7.57 (dd, 1

H, J ) 7.8, 7.8 Hz), 7.49-7.52 (m, 2 H), 6.62 (s, 1 H), 3.19-

3.32 (m, 2 H), 2.95-3.14 (m, 2 H), 2.67 (s, 3 H), 2.40-2.58 (m,

2 H), 2.23-2.34 (m, 1 H), 1.94-2.07 (m, 1 H), 1.73-1.86 (m, 2

H), 1.38-1.52 (m, 1 H), 1.17 (d, 3 H, J ) 6.0 Hz); MS (APCI)

m/z 348 (MH)⁺. The tartrate salt was formed by addition of

L-tartaric acid in methanol, followed by evaporation to give a

glass. Anal. (C₂₃H₂₅NO₂‚1.2C₄H₆O₆) C, H, N.

2-[3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]-2-propanol (38). A solution of 87 mg (0.25

mmol) of 37 in 5 mL of THF was treated with 0.3 mL (0.9

mmol) of a 3 M solution of CH₃MgBr in Et₂O. The reaction

mixture was stirred for 12 h, treated with 0.5 M aqueous

K₂HPO₄, and then diluted with EtOAc and CH₂Cl₂. The

aqueous phase was separated and reextracted with EtOAc. The

combined organic phases were washed consecutively with 0.5

M aqueous K₂HPO₄and brine, dried over Na₂SO₄, concen-

trated under vacuum, and purified by flash chromatography,

eluting with 2-20% CH₃CN/CH₂Cl₂followed by 10% CH₃OH/

CH₂Cl₂to provide 38 (0.025 g, 27% yield). ¹H NMR (300 MHz,

CD₃OD) δ 1.20 (d, 3 H), 1.42-1.58 (m, 1 H), 1.58 (s, 6 H), 1.76-

1.90 (m, 2 H), 1.96-2.12 (m, 1 H), 2.3-2.7 (m, 3 H), 2.97-

3.13 (m, 2 H), 3.22-3.4 (m, 2 H), 6.62 (s, 1 H), 7.38 (dd, 1 H),

7.40-7.46 (m, 2 H), 7.46-7.48 (m, 2 H), 7.72 (dd, 1 H), 7.76

(dd, 1 H); MS (ESI) m/z 364 (M + H)⁺. Anal. (C₂₄H₂₉NO₂‚

C₄H₆O₆‚1.5CH₃OH) C, H, N.

Ethyl 4′-Hydroxy-3′-iodo-1,1′-biphenyl-3-carboxylate

(41). A solution of 7.71 g (31.8 mmol) of 40 in 30 mL of DMF

and 320 mL of NH₄OH was treated with a solution of KI (27.72

g, 167 mmol) and I₂(8.48 g, 33.4 mmol) in 100 mL of H₂O.

The mixture was stirred for 1 h, then concentrated under

vacuum. The residual solution was adjusted to pH 7 with

aqueous HCl and extracted with EtOAc (200 mL). The aqueous

phase was reextracted with EtOAc, and the organic phases

were combined and washed consecutively with water and

brine, dried over Na₂SO₄, concentrated under vacuum, and

purified by flash chromatography, eluting with a 33-100%

gradient of CH₂Cl₂/hexane to give 41 as a white solid (4.36 g,

1

37% yield). H NMR (400 MHz, DMSO-d₆) δ 10.55 (bs, 1 H),

8.08 (m, 1 H), 7.97 (d, 1 H, J ) 2.1 Hz), 7.90 (m, 1 H), 7.86 (m,

1 H), 7.53-7.60 (m, 2 H), 7.00 (d, 1 H, J ) 8.3 Hz), 4.35 (q, 2

H, J ) 7.1 Hz), 1.35 (t, 3 H, J ) 7.1 Hz).

3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-

5-yl)benzoic Acid (42). To 1.47 g (4.0 mmol) of 41, 45 mg

(0.20 mmol) of Pd(OAc)₂, 105 mg (0.30 mmol) of biphen-2-

yldicyclohexylphosphine, and 38 mg (0.20 mmol) of CuI under

nitrogen was added a mixture of 5.6 mL (40 mmol) of Et₃N

and 50 mL (5.0 mmol) of 23 in CH₃CN. The reaction mixture

was heated at 65 °C for 15 h, then cooled, and poured into a

mixture of 70 mL of CH₂Cl₂and 40 mL of 5% aqueous NH₄OH

(40 mL). The layers were separated, and the aqueous phase

was reextracted with 70 mL of CH₂Cl₂. The organic phase was

washed consecutively with water and brine, dried over Na₂-

SO₄, and concentrated under vacuum to give 0.79 g (52%) of

crude ethyl 3-(2-(2-[(2R)-2-methyl-1-pyrrolidinyl]ethyl)-1-ben-

zofuran-5-yl)benzoate, which was used without further puri-

fication. MS (ESI APCI) m/z 378 (MH)⁺. The ethyl ester was

dissolved in EtOH (20 mL) and treated with 2 M aqueous

NaOH (2 mL). The mixture was heated at 55 °C for 40 min,

cooled, concentrated under vacuum, and poured into 20 mL

of i-PrOH and a mixture of 2 mL of 1 M aqueous KH₂PO₄and

2 mL of saturated aqueous NaCl. A biphasic mixture was

formed from which the organic phase was separated. The

52 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1

Cowart et al.

aqueous phase was reextracted three times with 2 mL of

i-PrOH, and the organic phases were combined and washed

with a mixture of 0.5 mL of pH 7 potassium phosphate and 2

mL of brine. The aqueous phase was separated and extracted

with 2-propanol (3 × 2 mL), and the combined organic phases

were washed with saturated aqueous NaCl. Again, the aqueous

phase was separated and extracted with 2-propanol (3 × 2

mL), and the combined organic phases were diluted with

EtOAc and filtered. The filtrate was dried (Na₂SO₄) and

concentrated. The resulting amino acid was purified by flash

chromatography, eluting with 50% EtOAc/CH₂Cl₂, then 10%

MeOH/45% EtOAc/CH₂Cl₂, then with 30% MeOH/CH₂Cl₂.

Product-containing fractions were concentrated under vacuum

to give a solid, which was triturated with EtOAc/CH₂Cl₂to

7.6 Hz), 7.28-7.34 (m, 1 H), 6.60 (s, 1 H), 4.68 (s, 2 H), 3.19-

3.34 (m, 2 H), 2.94-3.14 (m, 2 H), 2.41-2.60 (m, 2 H), 2.24-

2.36 (m, 1 H), 1.94-2.08 (m, 1 H), 1.73-1.87 (m, 2 H), 1.38-

1.53 (m, 1 H), 1.18 (d, 3 H, J ) 6.1 Hz). MS (ESI APCI) m/z

336 (MH)⁺. The tartrate salt was formed by addition of

L-tartaric acid in methanol, followed by evaporation to give a

glass. Anal. C₂₂H₂₅NO₂‚1.1C₄H₆O₆) C, H, N.

1-[3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]-1-propanone (45). A solution of 245 mg

(0.62 mmol) of 43 in 10 mL of THF was cooled to 0 °C and

treated with 1.5 mL (1.5 mmol) of a 1.0 M solution of EtMgBr

in THF. The reaction mixture was stirred at 23 °C for 12 h,

then treated with more EtMgBr (0.75 mL, 0.75 mmol). After

4.5 h, 2 mL of saturated aqueous NH₄Cl was added to the

reaction mixture and then the mixture was made basic and

extracted with 10 mL of EtOAc. The combined organic extract

was washed consecutively with 0.5 M aqueous K₂HPO₄and

brine, concentrated under vacuum, and purified by preparative

HPLC to give 45 (147 mg, 65% yield). ¹H NMR (300 MHz, CD₃-

OD) δ 8.22 (dd, 1 H, J ) 1.7, 1.7 Hz), 7.96 (m, 1 H), 7.87 (m,

1 H), 7.78 (m, 1 H), 7.58 (dd, 1 H, J ) 7.7, 7.7 Hz), 7.50-7.52

(m, 2 H), 6.63 (s, 1 H), 3.20-3.35 (m, 2 H), 2.94-3.18 (m, 4

H), 2.42-2.61 (m, 2 H), 2.24-2.37 (m, 1 H), 1.95-2.09 (m, 1

H), 1.74-1.87 (m, 2 H), 1.39-1.53 (m, 1 H), 1.21 (t, 3 H, J )

7.1 Hz), 1.18 (d, 3 H, J ) 6.1 Hz). MS (ESI APCI) m/z 362

(MH)⁺. The tartrate salt was formed by addition of L-tartaric

acid in methanol, followed by evaporation to give a glass. Anal.

C₂₄H₂₇NO₂‚1.1C₄H₆O₆) C, H, N.

Cyclopropyl[3-(2-(2-[2(R)-methyl-1-pyrrolidinyl]ethyl)-

1-benzofuran-5-yl)phenyl]methanone (46). By the method

used to prepare 45, a solution of 245 mg (0.62 mmol) of 43 in

10 mL of THF was reacted with 2.2 mL (1.5 mmol) of 0.6 M

cyclopropylmagnesium bromide in THF. The reaction mixture

was worked up as described for 45 and purified by flash

chromatograhy, eluting with 1-6% CH₃OH/CH₂Cl₂, then re-

purified by flash chromatography, eluting with 0-4% CH₃OH

in 1:1 EtOAc/CH₂Cl₂to give 46 (161 mg, 69% yield). ¹H NMR

(300 MHz, CD₃OD) δ 8.25 (dd, 1 H, J ) 1.7, 1.7 Hz), 8.02 (m,

1 H), 7.89 (m, 1 H), 7.80 (m, 1 H), 7.60 (dd, 1 H, J ) 7.8, 7.8

Hz), 7.48-7.55 (m, 2 H), 6.63 (s, 1 H), 3.19-3.35 (m, 2 H),

2.87-3.15 (m, 3 H), 2.41-2.60 (m, 2 H), 2.23-2.35 (m, 1 H),

1.95-2.08 (m, 1 H), 1.73-1.86 (m, 2 H), 1.39-1.53 (m, 1 H),

1.08-1.22 (m, 7 H). MS (ESI APCI) m/z 374 (M + H)⁺. The

tartrate salt was formed by addition of ^L-tartaric acid in

methanol, followed by evaporation to give a glass. Anal.

(C₂₅H₂₇NO₂‚0.4CH₃OH) C, H, N.

1

provide 42 as a white powder. H NMR (300 MHz, CD₃OD) δ

8.23 (s, 1 H), 7.92 (d, 1 H, J ) 7.8 Hz), 7.79 (s, 1 H), 7.69 (d,

1 H, J ) 7.1 Hz), 7.39-7.59 (m, 3 H), 6.70 (s, 1 H), 3.50-3.71

(m, 2 H), 3.08-3.3 (m, 4 H), 2.89-3.04 (m, 1 H), 2.16-2.31

(m, 1 H), 1.91-2.10 (m, 2 H), 1.58-1.76 (m, 1 H), 1.39 (d, 3 H,

J ) 6.4 Hz). MS (ESI APCI) m/z 350 (M + H)⁺.

N-Methoxy-N-methyl-3-(2-(2-[2(R)-methyl-1-pyrrolidin-

yl]ethyl)-1-benzofuran-5-yl)benzamide (43). The amino

acid 42 was suspended in CH₂Cl₂(25 mL) and treated with

3.0 mL (6.0 mmol) of 2 M oxalyl chloride in CH₂Cl₂. After the

gas evolution subsided, 0.3 mL of DMF was added over 15 min,

and after 60 min, more DMF (0.1 mL) was added. The mixture

was concentrated under vacuum after 30 min, and the residue

was poured into 5 mL of CH₂Cl₂and treated with N,O-

dimethylhydroxylamine hydrochloride (0.488 g, 5.0 mmol) and

pyridine (1 mL). After being stirred for 12 h, the reaction

mixture was concentrated under vacuum, diluted with 1,2-

dichloroethane (5 mL), and heated at 85 °C for 4 h, then cooled

and poured into a mixture of CH₂Cl_2,H₂O, and saturated

aqueous NaHCO₃. The organic phase was separated, the

aqueous phase was reextracted with CH₂Cl₂, and the combined

organic extracts were washed consecutively with H₂O and

brine, dried over Na₂SO₄, and concentrated under vacuum. The

residue was purified by flash chromatography, eluting with

0-4% CH₃OH/CH₂Cl₂to give 43 as a syrup (0.495 g, 60%

yield). ¹H NMR (300 MHz, CD₃OD) δ 7.86 (m, 1 H), 7.73-7.81

(m, 2 H), 7.46-7.83 (m, 4 H), 6.62 (s, 1 H), 3.63 (s, 3 H), 3.39

(s, 3 H), 3.20-3.3 (m, 2 H), 2.95-3.17 (m, 2 H), 2.45-2.64 (m,

2 H), 2.27-2.39 (m, 1 H), 1.95-2.09 (m, 1 H), 1.73-1.88 (m, 2

H), 1.37-1.54 (m, 1 H), 1.19 (d, 3 H, J ) 6.1 Hz); MS (ESI

APCI) m/z 393 (MH)⁺.

[3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]methanol (44). A solution of 167 mg (0.48

mmol) of 42 in 2 mL (2 mmol) of 1 M BH₃in THF was stirred

at 23 °C for 12 h, then poured into 0.5 M aqueous K₂HPO₄,

and diluted with EtOAc. The organic phase was separated and

washed consecutively with 0.5 M aqueous K₂HPO₄and brine,

dried over Na₂SO₄, and concentrated under vacuum. The

residue was purified by flash chromatography, eluting with

0-5% CH₃OH/CH₂Cl₂, and again by flash chromatography,

eluting with 0-5% CH₃CN/CH₂Cl₂. Product-containing resi-

dues were combined and freed of residual borate adducts by

dissolving in 1.5 mL of CH₃OH and 0.3 mL of 0.1 M aqueous

HCl and heating the mixture at 60 °C for 4 h. After concentra-

tion under vacuum, the residue was purified by flash chro-

matography, eluting with 2-10% 2 M NH₃in MeOH/CH₂Cl₂

to provide 44 as a white powder (21 mg, 13% yield). Compound

44 was also prepared by an alternative procedure in which a

suspension of 247 mg (0.80 mmol) of 49, 182 mg (1.20 mmol)

of 3-(hydroxymethyl)phenylboronic acid, and 28 mg (0.040

mmol) of PdCl₂(PPh₃)₂in 4 mL of i-PrOH and 1.2 mL of 2.0 M

aqueous Na₂CO₃was heated at 80 °C for 12 h. The reaction

mixture was cooled to 23 °C and partitioned between 15 mL

of CH₂Cl₂and 2 mL of 2 M aqueous NaOH. The aqueous phase

was separated and extracted with CH₂Cl₂, and the combined

organic phases were filtered through Celite, concentrated

under vacuum, and purified by flash chromatography, eluting

with 2-8% MeOH/CH₂Cl₂to give 44 (190 mg, 70%). ¹H NMR

(300 MHz, CD₃OD) δ 7.73 (dd, 1 H, J ) 1.4, 1.4 Hz), 7.62 (s,

1 H), 7.52 (m, 1 H), 7.46-7.49 (m, 2 H), 7.40 (dd, 1 H, J ) 7.6,

4-Bromo-2-iodophenol (48). To a solution of 4-bromophe-

nol (47, 34.60 g, 200 mmol), 29.98 g (200 mmol) of NaI, and

8.00 g (200 mmol) of NaOH in CH₃OH (400 mL) at 0 °C was

added an aqueous solution of 5.25% NaOCl (283 g, 200 mmol)

over 45 min. The mixture was stirred at 0 °C for 1 h, warmed

to 23 °C, and diluted with saturated aqueous sodium thiosul-

fate (50 mL) and H₂O (500 mL), then adjusted to a pH of 7 by

addition of saturated aqueous NaH₂PO₄. Saturated aqueous

NaCl (50 mL) was added, and the mixture was extracted with

250 mL of 80% EtOAc/hexanes (250 mL). The aqueous phase

was reextracted, and the combined organic phases were

washed with saturated aqueous NaCl, dried over Na₂SO₄, and

concentrated under vacuum to provide 48 (89% yield). A

portion was purified by chromatography on silica, eluting with

25-80% CH₂Cl₂/hexanes. ¹H NMR (300 MHz, DMSO-d₆) δ

10.59 (s, 1H), 7.79 (d, 1H, J ) 2.4 Hz), 7.36 (dd, 1H, J ) 8.4,

2.4 Hz), 6.83 (d, 1H, J ) 8.4 Hz).

1-[2-(5-Bromo-1-benzofuran-2-yl)ethyl]-2(R)-methylpyr-

rolidine (49). 4-Bromo-2-iodophenol (48, 32.99 g, 90% pure,

9 mmol), Pd(OAc)₂(112 mg, 0.50 mmol), Ph₃P (262 mg, 1.0

mmol), CuI (571 mg, 3.0 mmol), and i-Pr₂NH (14 mL, 100

mmol) were added to 120 mL of CH₃CN containing (10.8 mmol)

of 1-but-3-ynyl-2(R)-methylpyrrolidine (23) and stirred at 23

°C for 3 days, then heated at 80 °C for 12 h. The reaction

mixture was cooled, concentrated under vacuum, and purified

by flash chromatography, eluting with 2:1 hexanes/CH₂Cl₂

followed by a 0-1% gradient of CH₃OH/CH₂Cl₂. Product-

containing fractions were concentrated, partitioned between

Enhancers of Cognition and Attention

Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 53

CH₂Cl₂and 1 M aqueous Na₂CO₃, dried (Na₂SO₄), and

concentrated under vacuum to give 49 as dark-red syrup (717

mg, 26% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.75 (d, 1 H,

J ) 2.4 Hz), 7.48 (d, 1 H, J ) 8.9 Hz), 7.35 (dd, 1 H, J ) 8.9,

2.4 Hz), 6.65 (s, 1 H), 3.18-2.84 (m, 4 H), 2.25-2.45 (m, 2 H),

2.06-2.15 (m, 1 H), 1.80-1.93 (m, 1 H), 1.57-1.68 (m, 2 H),

1.20-1.34 (m, 1 H), 1.02 (d, 3 H, J ) 6.0 Hz); MS (ESI APCI)

m/z 308, 310 (MH)⁺.

furan-2-yl]ethyl methanesulfonate, which was used without

purification in the next step.

The 2-[5-(3-cyanophenyl)-1-benzofuran-2-yl]ethyl methane-

sulfonate, 306 mg (1.3 mmol) of (R)-2-methylpyrrolidine ^L-

tartrate, and Cs₂CO₃(652 mg, 2.0 mmol) were suspended in 3

mL of CH₃CN and heated at 40 °C for 12 h. More Cs₂CO₃(326

mg, 1.0 mmol) and CH₃CN (0.5 mL) were added, and the

reaction mixture was stirred at 40 °C for 4 days before being

cooled to 23 °C, diluted with CH₂Cl₂, filtered, and concentrated

under vacuum. The residue was purified twice by flash

chromatography, eluting with a 0-5% MeOH/CH₂Cl₂to give

53 as an orange-tan gum (0.12 g, 28% yield). ¹H NMR (300

MHz, CD₃OD) δ 7.98 (m, 1 H), 7.95 (m, 1 H), 7.78 (m, 1 H),

7.67 (m, 1 H), 7.62 (dd, 1 H, J ) 7.8, 7.8), 7.49-7.52 (m, 2 H),

6.63 (s, 1 H), 3.20-3.35 (m, 2 H), 2.95-3.15 (m, 2 H), 2.46-

2.63 (m, 2 H), 2.27-2.39 (m, 1 H), 1.96-2.09 (m, 1 H), 1.75-

1.87 (m, 2 H), 1.39-1.54 (m, 1 H), 1.18 (d, 3 H, J ) 6.0 Hz);

MS (DCI) m/z 331 (MH)⁺. Anal. (C₂₂H₂₂N₂O‚HCl) C, H, N.

Cyclopropyl[4-(2-(2-[2(R)-methyl-1-pyrrolidinyl]ethyl)-

1-benzofuran-5-yl)phenyl]methanone (54). To a solution

of 10 mg of CuI and 330 mg (1.0 mmol) of 20 in 1 mL of THF

was added 2 mL (1.4 mmol) of a 0.7 M solution of cyclopropyl-

magnesium bromide in THF. The reaction mixture was heated

at 45 °C for 24 h, at 60 °C for 48 h, then cooled and poured

into a stirred mixture of EtOAc and 0.4 M aqueous HCl. After

the solids dissolved, the mixture was made basic with 0.5 M

aqueous K₂HPO₄and brine, and the organic phase was

separated and washed consecutively with 0.5 M aqueous

K₂HPO₄and brine, dried over Na₂SO₄, and concentrated under

vacuum. The residue was purified by preparative HPLC to give

[4-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofu-

ran-5-yl)phenyl]methanol (50). A suspension of 247 mg

(0.80 mmol) of 49, 182 mg (1.2 mmol) of 4-(hydroxymethyl)-

phenylboronic acid, 28 mg (0.04 mmol) of PdCl₂(PPh₃)₂in 4

mL of i-PrOH, and 1.2 mL of 2 M aqueous Na₂CO₃was heated

at 80 °C for 12 h. The reaction mixture was cooled to 23 °C

and partitioned between 15 mL of CH₂Cl₂and 2 mL of 2 M

aqueous NaOH. The aqueous phase was separated and ex-

tracted with CH₂Cl₂, and the combined organic phases were

filtered through Celite, concentrated under vacuum, and

purified by flash chromatography, eluting with a gradient of

2-8% MeOH/CH₂Cl₂to provide 50 as a thick orange syrup

(177 mg, 66%). ¹H NMR (300 MHz, CD₃OD) δ 7.72 (dd, 1 H, J

) 1.4, 1.4 Hz), 7.60 (d, 2 H, J ) 8.2 Hz), 7.45-7.48 (m, 2 H),

7.42 (d, 2 H, J ) 8.2 Hz), 6.61 (s, 1 H), 4.64 (s, 2 H), 3.2-3.4

(m, 2 H), 2.97-3.18 (m, 2 H), 2.35-2.77 (m, 3 H), 1.99-2.13

(m, 1 H), 1.77-1.91 (m, 2 H), 1.42-1.58 (m, 1 H), 1.21 (d, 3 H,

J ) 6.1 Hz). MS (ESI APCI) m/z 336 (MH)⁺. The tartrate salt

was formed by addition of ^L-tartaric acid in methanol, followed

by concentration under vacuum to give a glass. Anal. C₂₂H₂₅-

NO₂‚1.1C₄H₆O₆) C, H, N.

2-(5-Bromo-1-benzofuran-2-yl)ethanol (51). A mixture

of 4-bromo-2-iodophenol (48) (26.9 g, 80 mmol), 3-butyn-1-ol

(6.05 mL, 79.9 mmol), and Cu₂O (7.15 g, 50.0 mmol) in a

mixture of 40 mL of pyridine and 160 mL of NMP was heated

at 70 °C overnight, then heated further at 100 °C for 3.5 h.

The mixture was cooled to 23 °C, diluted with Et₂O, and

filtered to remove solids. The filtrate was diluted with Et₂O

and washed consecutively with 5% aqueous NH₄OH, 0.5 M

aqueous NaOH, and saturated aqueous NaCl, then dried over

Na₂SO₄, and concentrated under vacuum. The syrupy residue

was diluted with 2:1 hexanes/CH₂Cl₂and cooled to -78 °C.

When the mixture was warmed to 23 °C, the product (51)

crystallized and was collected by filtration and washed with

1

54 (166 mg, 44% yield). H NMR (300 MHz, CD₃OD) δ 8.12

(d, 2 H, J ) 8.6 Hz), 7.82 (d, 1 H, J ) 2.0 Hz), 7.79 (d, 2 H, J

) 8.6 Hz), 7.56 (dd, 1 H, J ) 8.7, 2.0 Hz), 7.51 (d, 1 H, J ) 8.7

Hz), 6.62 (s, 1 H), 3.19-3.34 (m, 2 H), 2.83-3.15 (m, 3 H),

2.40-2.59 (m, 2 H), 2.23-2.34 (m, 1 H), 1.94-2.08 (m, 1 H),

1.73-1.86 (m, 2 H), 1.38-1.53 (m, 1 H), 1.06-1.21 (m, 7 H);

MS (ESI APCI) m/z 374 (MH)⁺. The tartrate salt was formed

by addition of ^L-tartaric acid in methanol, followed by evapora-

tion to give a glass. Anal. C₂₅H₂₇NO₂‚0.5 CH₃OH) C, H, N.

Acknowledgment. We thank the following scien-

tists for their contributions: Yu-Ming Pu, Yiyin Ku,

Jonathan Pease, John Pratt, and Andrew Stewart for

(R)-2-methylpyrrolidine; Timothy Grieme for large-scale

synthesis of 53; Kathleen M. Krueger, Thomas R. Miller,

David Witte, Tracy Carr, John Baranowski, Rahul

Sharma, and Betty B. Yao for receptor binding and

FLIPR assays; Ellen Roberts, for assessment of CYP

inhibition of 20; Antony Borre and Hugh Nellans for

determination of plasma protein binding of 20; Jill M.

Wetter for determination of compound pharmacokinet-

ics; Jia Bao Pan, Mike Buckley, and Vicky Komater for

animal behavioral assays; and Kaitlin Browman for

assistance in summarizing behavioral data.

1

4:1 hexane/CH₂Cl₂to give a solid (1.55 g, 8% yield). H NMR

(300 MHz, DMSO-d₆) δ 7.75 (d, 1H, J ) 2.3 Hz), 7.48 (d, 1H,

J ) 8.7 Hz), 7.35 (dd, 1H, J ) 8.7, 2.3 Hz), 6.63 (t, 1H, J ) 0.7

Hz), 4.82 (t, 1H, J ) 5.4 Hz), 3.75 (dt, 2H, J ) 6.4, 5.4 Hz),

2.92 (td, 2H, J ) 6.4, 0.7 Hz).

3-[2-(2-Hydroxyethyl)-1-benzofuran-5-yl]benzoni-

trile (52). A suspension of 193 mg (0.80 mmol) of 51,

3-cyanophenylboronic acid (147 mg, 1.00 mmol), and Pd(PPh₃)₄

(35 mg, 0.03 mmol) in a mixture of 3 mL of dioxane and 2.1

mL (2.1 mmol) of 1.0 M aqueous Na₂CO₃was heated at 90 °C

for 3.5 h, then cooled to 23 °C, then partitioned between EtOAc

and H₂O, dried over Na₂SO₄, and concentrated under vacuum.

The residue was purified by flash chromatography, eluting

with 0-2% EtOAc/CH₂Cl₂to provide 52 as a syrup (0.174 g,

82% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (dd, 1H, J )

1.6, 1.6 Hz), 8.04 (ddd, 1H, J ) 7.8, 1.6, 1.6 Hz), 7.91 (dd, 1H,

J ) 1.6, 1.6 Hz), 7.80 (ddd, 1H, J ) 7.8, 1.6, 1.6 Hz), 7.66 (dd,

1H, J ) 7.8, 7.8 Hz), 7.57-7.63 (m, 2H), 6.70 (s, 1H), 4.83 (t,

1H, J ) 5.5 Hz), 3.78 (dt, 2H, J ) 6.6, 5.5 Hz), 2.95 (t, 2H, J

) 6.6 Hz); MS (DCI) m/z 263 (M)⁺.

3-(2-(2-[2(R)-Methyl-1-pyrrolidinyl]ethyl)-1-benzofuran-

5-yl)benzonitrile (53). A solution of 52 (170 mg, 0.65 mmol)

and Et₃N (0.1 mL, 0.72 mmol) in 3 mL of CH₂Cl₂at 0 °C was

treated with CH₃SO₂Cl (55 µL, 0.71 mmol), and after 10 min

the mixture was allowed to warm to 23 °C. More CH₃SO₂Cl

(10 µL, 0.13 mmol) and Et₃N (10 µL, 0.072 mmol) were added,

and the mixture was stirred until all starting alcohol 52 was

consumed, as assessed by TLC. The reaction mixture was

diluted with CH₂Cl₂, washed consecutively with water and

saturated aqueous NaCl, dried over Na₂SO₄, and concentrated

under vacuum to give a glass, 2-[5-(3-cyanophenyl)-1-benzo-

Supporting Information Available: Results from com-

busion analysis. This material is available free of charge via

the Internet at http://pubs.acs.org.

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JM040118G

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4-(2-[2-(2(R)-Methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention

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