Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. Part II

4002

J. Med. Chem. 2008, 51, 4002–4020

Discovery of a Novel Series of Biphenyl Benzoic Acid Derivatives as Highly Potent and Selective

Human ꢀ3 Adrenergic Receptor Agonists with Good Oral Bioavailability. Part II

Masashi Imanishi,^†Shinji Itou,^†Kenichi Washizuka,^†Hitoshi Hamashima,^†Yutaka Nakajima,^†Takanobu Araki,^†

Yasuyo Tomishima, Minoru Sakurai,^†Shigeo Matsui,^‡Emiko Imamura,^‡Koji Ueshima,^§Takao Yamamoto,^‡

Nobuhiro Yamamoto,^‡Hirofumi Ishikawa, Keiko Nakano,^‡Naoko Unami,^‡Kaori Hamada,^‡Yasuhiro Matsumura,^|

Fujiko Takamura,^|and Kouji Hattori*^,†

Chemistry Research Laboratories, Pharmacological Research Laboratories, Applied Pharmacology Research Laboratories, and Analysis &

Pharmacokinetic Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan

ReceiVed January 15, 2008

The left-hand side (LHS) and central part of our ﬁrst generation biphenyl (FGB) series was modiﬁed to

improve in vitro and in vivo ꢀ3-AR potency without loss of oral bioavailability. First, in this study, we

focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl

ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this

series and discovered that introduction of a methyl group into the R-position of the phenethylamine moiety

greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker

of the central part with an ethoxy-based linker provided improved potency and PK proﬁles. As a result of

these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identiﬁed that

displayed an excellent balance of very higher human ꢀ3-AR potency compared to the FGB compounds,

high selectivity, and good pharmacokinetic proﬁles. Furthermore, these several compounds showed high in

vivo efﬁcacy in an overactive bladder (OAB) model. These ﬁndings suggest that our selected second

generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for

the treatment of OAB.

Introduction

availability and a long plasma half-life.⁷The structure-activity

relationship (SAR) studies at the R position of the terminal

phenyl ring on the RHS indicated that introduction of more

lipophilic substitution increased ꢀ3-AR activity (O-cyclohexyl,

8c > O-iso-pr, 8b > O-Me, 8a) but decreased oral bioavail-

ability (8a > 8b > 8c) (see Figure 2). On the basis of these

results, we selected lead candidate 8b with a good balance of

potency, selectivity, and pharmacokinetic proﬁle. We extended

optimization of the FGB series to further improve ꢀ3-AR

activity without loss of the good oral bioavailability.

Our designed second generation biphenyl (SGB) series

(9-11) is shown in Figure 3. First of all, we focused our efforts

on replacement of the 3-chlorophenyl moiety in the left-hand

side (LHS) with several identiﬁed partial structures such as

present in compounds 1,⁸2,⁹3,¹⁰and 4¹¹(see Figure 1). Second,

we investigated the replacement of the central part of this series,

through introduction of a methyl groups adjacent to the

secondary amino group, such as in compounds 5¹²and 6.¹³

Finally, we modiﬁed the two carbon linker region, such as in

compounds 4 and 7¹⁴(see Figure 1).

In this paper, we describe synthesis and SAR studies in which

we have varied the LHS and central part of the SGB series and

simultaneously evaluated the pharmacokinetic proﬁle by cassette

dosing assay in dogs, as previously described. These studies

have led to the successful discovery of several clinical drug

candidates with an excellent balance of very high potency,

selectivity and good pharmacokinetic proﬁle.

Chemistry. As shown in the ﬁrst and second reactions of

Scheme 1, in general, the requisite left and center part

intermediate Boc amine derivatives (17-19) were synthesized

by coupling of amino ethanol derivatives (12,¹⁵13, 14) with

carboxylic acid derivatives (15, 16) to afford the corresponding

amide intermediate, followed by selective reduction of the amide

moiety with BH₃·SMe₂to unmask the amino ethanol, followed

The ꢀ3-adrenergic receptor (ꢀ3-AR)^ahas been shown to

mediate various pharmacological and physiological effects such

as lipolysis, thermogenesis,¹intestinal smooth muscle relax-

ation,²and urinary bladder detrusor muscle relaxation.^3,4Thus,

the activation of the human ꢀ3-AR has attracted much attention

as a potential approach toward the treatment of obesity,

noninsulin-dependent diabetes mellitus (NIDDM), irritable

bowel syndrome, and overactive bladder, and the ꢀ3-AR is

therefore recognized as an attractive target for drug discovery.⁵

Recently, on the other hand, ꢀ3-AR selectivity over ꢀ1-AR and

ꢀ2-AR is also important because stimulation of ꢀ1-AR and ꢀ2-

AR may induce severe side effects such as enhancement of heart

rate and tracheal relaxation, respectively. In the past decade,

drug discovery efforts have shifted toward the design of selective

agonists for the ꢀ3-AR. Furthermore, several groups have

reported a number of potent and selective human ꢀ3-AR

chemotypes (see Figure 1), but these are still not sufﬁcient in

terms of the pharmacokinetic properties.^5b,6

Previous work in our laboratory has described the discovery

of a series of ﬁrst generation biphenyl (FGB) analogues

containing a benzoic acid moiety on the right-hand side (RHS),

represented by 8 (Figure 2), which exhibited good oral bio-

* To whom correspondence should be addressed. Phone: 81-29-863-7179.

Fax: 81-29-852-5387. E-mail: kouji.hattori@jp.astellas.com.

†

Chemistry Research Laboratories.

Pharmacological Research Laboratories.

Applied Pharmacology Research Laboratories.

Analysis & Pharmacokinetic Research Laboratories.

‡

§

|

^aAbbreviations: ꢀ-AR, ꢀ-adrenergic receptors; OAB, overactive bladder;

FGB, ﬁrst generation biphenyl; SGB, second generation biphenyl; LHS,

left-hand side; RHS, right-hand side; cAMP, cyclic adenosine monophos-

phate; ISP, isoproterenol; CHO, Chinese hamster ovary; IVP, intravesical

pressure; PAMPA, parallel artiﬁcial membrane permeation assay; PB,

protein binding.

10.1021/jm8000345 CCC: $40.75

2008 American Chemical Society

Published on Web 06/14/2008

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4003

Figure 1. Structures of some ꢀ-3 AR agonists

Figure 2. First generation biphenyl (FGB) series.

by protection of the amine with a Boc group. In a similar way,

the requisite intermediate 4-iodophenyl derivatives (24-26)

were synthesized by coupling of commercially available man-

delic acid derivatives 20 or 21 with amines 22, 23, which were

synthesized as outlined in Scheme 2.

The requisite intermediate Boc amine derivatives 28-32

containing a phenyl ethanol moiety were prepared as shown in

the third and fourth reactions of Scheme 1. Coupling of optically

active epoxides,^16,17in the presence of BSU with 4-bromophenyl

ethylamine 27, followed by protection of the amine with a Boc

group, gave the corresponding Boc amine derivatives 28-32.

In a similar manner, the requisite intermediate 4-iodophenyl

derivatives (38-41) were synthesized by reaction of optically

active epoxides 33 or 34, which are commercially available, or

2-chloro-5-[(2R)-2-oxiranyl]pyridine 35 prepared through known

synthetic procedures, and with the chiral amines 36 or 37, and

subsequently protection with a Boc group, respectively. As

shown in Scheme 2, the optically active amine intermediate 36

containing a chiral methyl group was prepared in ﬁve steps

starting from commercially available (2S)-2-amino-3-phenyl-

4004 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

Figure 3. Second generation biphenyl (SGB) series.

1-propanol 47. The optically active amino propanol intermediate

37 was prepared by reduction of commercially available (2S)-

2-amino-3-(4-iodophenyl)propanoic acid with NaBH₄in the

presence of H₂SO₄.

nitro derivative 55, followed by coupling with Ms-Cl. The nitro

derivative 55 was prepared from chiral oxirane 54, which has

been previously described¹⁹similar to procedures described for

the third and fourth reactions of Scheme 1 using Cbz-Cl instead

of Boc₂O. The target 9g was obtained through a Suzuki coupling

of Cbz derivative 56 and boronic ester 58, which was prepared

from bromide 57 followed by deprotection of the Cbz group

by catalytic hydrogenation.

As shown in Scheme 6, the target 10j with a dimethyl group

was synthesized from 61, similar to the preparation of 10d. The

requisite intermediate 61 was prepared by protection of the

amino group of commercially available 59 with triﬂuoro-acetyl,

followed by para-selective iodination.

As shown in the ﬁfth and sixth reactions of Scheme 1, the

intermediate Boc amine derivatives 43 and 44 containing an

amino-pyridine moiety in the left part were prepared. Coupling

of tosylate 42, which was prepared through known synthetic

procedures,¹⁸with 4-bromophenyl ethylamine 27 or 4-iodophe-

noxyethylamine 22 afforded a secondary amine, which was

protected by protected with Boc to give the corresponding Boc

amine derivatives 43 and 44. 4-Hydroxyphenyl intermediate 46

was prepared by coupling of commercially available (aS,bR)-

4-hydroxynorephedrine 45 with 4-bromophenylethylbromide,

followed by protection with a Boc group.

Results and Discussion

The general synthetic route to biphenyl targets (9a,b,h,j,k,

10a-i,g-k, 11a-k) is shown in Scheme 3. Suzuki cross-

coupling of Boc amine intermediates with boronic acids

(53a-h), the syntheses of which have been previously de-

scribed,⁷followed by alkaline hydrolysis of the methyl ester,

and deprotection of the Boc group with 4 N HCl provided the

target compounds as hydrochloride salts. In a similar manner,

pyridine analogues (10p-s) were obtained from 40, in an

additional step, through dechlorination by catalytic hydrogena-

tion in the presence of HCO₂NH₄. The amino pyridine analogues

(9i,l,m, 11l) were prepared by coupling of 43 or 44 with boronic

acids (53b,e,f) in the presence of a catalytic amount of

PdCl₂(dppf) · CHCl₃, followed by alkaline hydrolysis, and

subsequent deprotection of the Boc amine silyl ether using 4 N

HCl.

The preparation methods for the ﬁnal targets 9c-f are shown

in Scheme 4. The phenol analogue 9c was obtained through a

Suzuki coupling of Boc amine derivative 30 and boronic acid

53b, followed by deprotection of the benzyl group by catalytic

hydrogenation, followed by using the same methods as described

for 9a. In a similar manner, the aniline analogues 9e,f were

obtained from 31 and 32, through an additional step of reduction

of the nitro group with iron powder in the presence of NH₄Cl.

The methane sulfonamide analogue 9d was obtained from 31,

in an additional step, through acylation of the NH₂group with

Ms-Cl.

All compounds were evaluated for the ability to produce

cAMP in Chinese hamster ovary (CHO) cell lines expressing

cloned human ꢀ3 and ꢀ1-ARs. Selected compounds were also

evaluated for human ꢀ2 activity using a similar method, as

previously described.^7,20The results for reference compound,

isoproterenol (ISP, nonselective ꢀ-AR agonist) are shown for

comparison in Table 1. In addition, pharmacokinetic properties

of selected compounds were evaluated by cassette dosing assay

in dogs.^7,21

As shown in Figure 2 and Table 1, in a previous article, we

reported that our leading candidate 8b showed potent ꢀ3-AR

activity (EC₅₀) 1.1 nM), good selectivity relative to ꢀ1 and

ꢀ2 activity, and good pharmacokinetics in all three species

examined (rat, dog, and monkey). The O-cyclohexyl analogue

(8c) with enhanced lipophilicity, resulted in a further improve-

ment in ꢀ3-AR potency (EC₅₀) 0.46 nM) but poor bioavail-

ability. We also investigated the removal of the chloro atom on

the LHS phenyl ring. More lipophilic isobutyl (8e) and O-c-

hex (8f) analogues, relative to the O-iso-pr derivative (8d),

showed improved ꢀ3-AR activity and selectivity compared to

8d. However, in the cassette dosing assay, both analogues

displayed decreased C_maxlevels. (These compounds showed high

passive permeability in PAMPA.) These results indicated SAR

trends as for the 3-chlorophenyl analogues that we have

previously reported.⁷

The preparation of the ﬁnal target 9g is shown in Scheme 5.

The requisite intermediate 56 containing the methane sulfona-

mide moiety was obtained by reduction of the corresponding

First of all, to improve the ꢀ3-AR activity of 8b, we focused

on replacement of the LHS 3-chlorophenyl moiety with several

substituted phenyl groups. Shift of the chloro group to the

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4005

Scheme 1. Preparation of Left and Center Part Intermediates^a

^aFor ﬁrst and second reactions: (a) HOBt, WSCD, DMF; (b) BH₃·SMe₂, THF, DMI, then c. HCl; (c) (Boc)₂O, THF, aq NaOH (pH ) 7-8). For third

and fourth reactions: (a) BSU, DMSO, 65 °C, then (Boc)₂O, THF, H₂O; (b) EtOH, reﬂux; (c) (Boc)₂O, THF, H₂O, 1 N NaOH aq. For ﬁfth and sixth

reactions: (a) i-Pr₂NEt, DMSO or DMF, 80 °C; (b) (Boc)₂O, THF.

4-position (9a) and the ﬂuoro analogue (9b) resulted in slightly

decreased ꢀ3-AR activity relative to 8b. We investigated

replacement of the chloro group with a hydroxy group at the

3-position, such as in compounds 1 or 6 (Figure 1). As a result,

the phenol analogue (9c) resulted in 18-fold increased potency

(EC₅₀) 0.062 nM) for ꢀ3 relative to 8b and high selectivity

for ꢀ1. However, 9c showed lower C_maxlevels relative to 8b in

the cassette dosing assay. On the basis of this result, our efforts

were focused on improving the PK properties of 9c by replacing

the phenol part with isosteric functionalities. The methylsul-

4006 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

Scheme 2. Preparation of Alkyl Amine of Center Part Intermediates^a

^a(a) PPh₃, 40% DEAD in toluene, 4 °C-room temp, then 4 N HCl/AcOEt; (b) HOBt, WSCD, DMF, then 4 N HCl/AcOEt; (c) CF₃CO₂Et, MeOH; (d)

MsCl, Et₃N, THF; (e) Zn(powder), NaI, AcOH, DME, reﬂux; (f) I₂, HIO₄·2H₂O, AcOH, H₂SO₄, H₂O, 80 °C; (g) 1 N NaOH aq, dioxane, 50 °C; (h) NaBH₄,

THF, H₂SO₄, Et₂O.

Scheme 3. General Synthesis Route to Targets 9, 10, 11^a

^a(a) Pd(PPh₃)₄, aq NaHCO₃, DME, 70 °C; (b) 1 N NaOH aq, EtOH, THF, then 4 N HCl/AcOEt; (c) PdCl₂(dppf) CH₂Cl₂, dppf, aq Na₂CO₃, toluene,

EtOH, 75 °C (d) 1 N NaOH aq, EtOH, THF, then HCO₂NH₄, 10% Pd/C, MeOH, H₂O, reﬂux, then 4 N HCl/dioxane; (e) PdCl₂(dppf) CH₂Cl₂, dppf, aq

Na₂CO₃, DMF, 80 °C; (f) 1 N NaOH aq, EtOH, 100 °C, then 4 N HCl/dioxane, MeOH.

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4007

Scheme 4. Synthesis Route to Targets 9c-f^a

^a(a) Pd(PPh₃)₄, aq NaHCO₃, DME, 70 °C; (b) H₂(gas), 10% Pd/C, MeOH; (c) 1 N NaOH aq, EtOH, THF, then 4 N HCl/AcOEt (d) Fe (powder), NH₄Cl,

EtOH, reﬂux, (e) MsCl, pyridine.

Scheme 5. Synthesis Route to Targets 9g^a

^a(a) BSU, DMSO, 65 °C, then Cbz-Cl, THF, H₂O; (b) Fe (powder), NH₄Cl, EtOH, reﬂux, then MsCl, pyridine;(c) KOAc, pinacol diborane, PdCl₂

(dppf)-CHCl₃, dioxane, 90 °C; (d) Pd(PPh₃)₄, aq NaHCO₃, DME, 70 °C; (e) H₂(gas), 10% Pd/C, MeOH, then 4 N HCl/AcOEt.

Scheme 6. Synthesis Route to Targets 10j^a

^a(a) (CF₃CO)₂O, Et₃N, THF; (b) I₂, HIO₄·2H₂O, AcOH, H₂SO₄, H₂O, 80 °C; (c) 1 N NaOH aq, dioxane, 50 °C, then 34, EtOH, reﬂux; (d) (Boc)₂O,

THF, H₂O, 1 N NaOHaq (pH ) 8-8.5); (e) 53b, Pd(PPh₃)₄, aq NaHCO₃, DME, 70 °C; (f) 1 N NaOH aq, EtOH, THF, then 4 N HCl/AcOEt.

fonamide analogue 9d resulted in a substantial loss of potency

(EC₅₀) 30 nM) for ꢀ3 relative to 9c, and the C_maxlevel was

not improved. The 3-aniline analogue 9e showed signiﬁcantly

decreased potency for ꢀ3 (EC₅₀) 8.1 nM). The 4-aniline

analogue 9f resulted in slightly decreased ꢀ₃-AR activity (EC₅₀

) 2.6 nM) relative to 8b, but 9f had an improved C_maxlevel

relative to the phenol analogue 9c. 4-Hydroxy-3-methylsulfona-

mide analogue 9g displayed stronger ꢀ3-AR activity but lower

C_maxlevels relative to 8b.

We next investigated the replacement of LHS the 3-chloro-

phenyl ring with pyridine derivatives. The pyridine analogue

9h resulted in similar ꢀ3-AR activity (EC₅₀) 1.5 nM) relative

to 8b and 8d. Next, an amino-pyridine derivative was prepared

and examined. As a result, compound 9i had greatly increased

ꢀ3-AR activity (EC₅₀) 0.19 nM) relative to the corresponding

pyridine analogue 9h and phenyl analogues 8b and 8d,

respectively. In addition, the pyridine analogue 9h and the

amino-pyridine analogue 9i showed acceptable C_maxlevels

relative to 8b and 8d in the cassette dosing assay.

pyridine analogue 9i had reduced lipophilicity (9h, C log P )

1.09; 9i, C log P ) 0.79) relative to chloro-phenyl 8b and phenyl

8d analogues (8b, C log P ) 3.30; 8d, Clog P ) 2.58). By

analogy to the phenyl ring analogues (8e,f), the 3-pyridine

derivatives with R²) isobutyl (9j) and O-c-hex (9k) were

prepared, respectively. As predicted, the isobutyl analogue 9j

(EC₅₀) 0.26 nM) and the O-c-hex analogue 9k (EC₅₀) 0.26

nM) exhibited higher potent ꢀ3-AR activity and selectivity

relative to the O-iso-pr analogue 9h. Furthermore, compounds

9j and 9k were evaluated in the cassette dosing assay. It is

noteworthy that these more lipophilic compounds (9j,9k)

displayed acceptable C_maxlevels relative to the O-iso-pr

analogue 9h. In particular, the O-c-hex analogue (9k) showed

a remarkable improvement of C_maxlevel relative to the same

O-c-hex group analogues 8c and 8f. In consideration of the

superior PK proﬁle of 9k (9k, C log P ) 2.28) compared with

8c or 8f (8c, C log P ) 4.49; 8f, C log P ) 3.73), adjusting the

lipophilicity by incorporation of the pyridine ring to the LHS

may result in the improved PK proﬁle. Therefore, the pyridine

analogue 9k provided the best combination of high potency and

C_maxlevel.

On the basis of these ﬁndings, we attempted further optimiza-

tion of the R²substituent of pyridine and amino-pyridine

analogues. Both the pyridine analogue 9h and the amino-

4008 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Table 1. Effect of Conversion of Left-Hand Side of SGB Analogues

Imanishi et al.

c

human ꢀ₃EC₅₀,

human ꢀ₁EC₅₀,

human ꢀ₂EC₅₀,

cassette (po)

C_maxratio ^d

C log

a

compd

R¹

X

R²

nM (IA^b)

nM

ꢀ₁/ꢀ₃

nM

ꢀ₂/ꢀ₃

P^e

8b

8c

8d

8e

8f

3-Cl

H

CH O-iso-Pr 1.1 ( 0.1 (0.98)

CH O-c-Hex 0.46 ( 0.1 (1.0)

CH O-iso-Pr 2.0 ( 0.06 (0.97)

720 ( 106

55 ( 5

654

120

>500

>1667 >10000

867

>10000

NT

>10000

>9090

NT

>5000

>16670 0.25

NT

1.0

0.0

0.90

3.30

4.49

2.58

3.09

3.73

>1000

CH iso-Bu

0.60 ( 0.12 (0.99)

>1000

260 ( 45

CH O-c-Hex 0.30 ( 0.02 (1.0)

NT

0.0

9a

9b

9c

9d

9e

9f

9g

9h

9i

4-Cl

3-F

3-OH

3-NHMs

3-NH₂

4-NH₂

CH O-iso-Pr 2.4 ( 0.03 (0.96)

CH O-iso-Pr 2.1 ( 0.2 (0.99)

CH O-iso-Pr 0.062 ( 0.04 (0.99)

CH O-iso-Pr 30 (0.74)

CH O-iso-Pr 8.1 ( 0.6 (0.99)

CH O-iso-Pr 2.6 ( 0.3 (0.98)

500 ( 40

320 ( 38

440 ( 26

>1000

208

152

NT

>6667

>58800 0.49

NT

>38400 0.48

48480

31420

NT

3.30

2.73

1.92

1.39

1.36

0.73

1.09

0.76

1.71

2.28

1.27

1.95

0.61

0.10

0.15

NT

0.35

0.06

0.65

7100

>33

>123

>380

577

>667

760

>3846 NT

>1000

150 ( 8.8

>1000

130 ( 11

>1000

480 ( 52

3-NHMs 4-OH CH O-iso-Pr 0.26 ( 0.03 (1.0)

H

4-NH₂

H

N

O-iso-Pr 1.5 ( 0.1 (0.97)

O-iso-Pr 0.19 ( 0.02 (1.0)

>10000

9j

9k

9l

iso-Bu

O-c-Hex 0.26 ( 0.02 (1.0)

iso-Bu

0.26 ( 0.01 (0.99)

0.36

1769

2300

1114

>10000

3200

1100

4-NH₂

0.066 ( 0.004 (0.97) 150 ( 5

0.36

0.09

9m

O-c-Hex 0.035 ( 0.005 (0.99) 39 ( 0.5

f

ISP

0.97 ( 0.14 (1.0) 0.084 ( 0.02

0.087

2.0 ( 0.9

2.1

NT

^aThe results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. ^bThe intrinsic activity (IA) was deﬁned as the ratio

between the maximal effect of test compound and the maximal effect produced by isoproterenol. ^cDose 0.1 mg/kg po (n ) 2-3). See References section

for further details. ^dThe ratio was deﬁned between the C_maxof test compounds and the C_maxof 1b. The ratio value of 1b was presented as 1.0. ^eBiobyte

C log P version 4.3. ^fIsoproterenol. NT: not tested.

On the other hand, the amino-pyridine derivatives with R²

) isobutyl (9l) and O-c-hex (9m) had greatly increased ꢀ3-AR

activity (9l, EC₅₀) 0.066 nM; 9m, EC₅₀) 0.035 nM) relative

to the parent pyridine analogues (9j,9k), respectively. In

addition, the isobutyl analogue 9l maintained C_maxlevels relative

to the pyridine analogues and the corresponding O-iso-pr

analogue 9i. Compound 9l showed the best proﬁle of potency,

selectivity, and C _maxlevel in Table 1. Unfortunately, the most

potent amino-pyridine analogue with a O-c-hex moiety, 9m,

showed poor C_maxlevels in spite of the moderate C log P level

(9m, C log P ) 1.95).

Second, as can be seen in Figure 3, we shifted our attention

to modiﬁcation of biphenyl series 10, in which substituents

were introduced at the R-position of the secondary amino

group, such as in compounds 5 and 6 (see Figure 1), to

improve ꢀ3-AR activity relative to 8b. From studies on the

ꢀ3-AR activity of the four optical isomers of 5¹²and {2-[4-

[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]pro-

pyl]phenoxy]}acetic acid (BRL-37344),²²the (R,R)-conﬁg-

uration was shown to be important for enhancing ꢀ3-AR

activity. As can be seen in Table 2, introduction of a methyl

group into the R-position of the phenethylamine moiety of

our nonsubstituted biphenyl series gave the (R)-methyl optical

isomer, which exhibited more potent ꢀ3-AR activity (10a,

EC₅₀) 0.18 nM) compared with the corresponding (S)

-methyl isomer (10b, EC₅₀) 6.0 nM). By analogy to previous

SAR studies, introducing at the R²position of the terminal

phenyl ring on the RHS with an O-iso-pr group maintained

ꢀ3-AR activity (10c, EC₅₀) 0.19 nM) and improved ꢀ3/ꢀ1

selectivity (10c, ꢀ3/ꢀ1 ) 195) relative to 10a. The nonsub-

stituted LHS phenyl ring derivatives with R²) H (10d), OMe

(10e), OEt (10f), O-i-pr (10g), O-i-butyl (10h), and O-c-hex

(10i) were next prepared and examined. Similar to the

previous SAR trends, the order of potency at the R²position

was OMe (10e) < H (10d), OEt (10f) < O-i-pr (10g) < O-i-

butyl (10h), O-c-hex (10i) and selectivity for ꢀ₁/ꢀ₃was H

(10d), OMe (10e) < OEt (10f) < O-i-pr (10g), O-c-hex (10i)

< O-i-butyl (10h). On the other hand, in the cassette dosing

assay, the order of their C_maxlevels was OMe (10e), OEt

(10f) > O-i-pr (10g) . O-i-butyl (10h), O-c-hex (10i). These

results also showed the same trends as previously demon-

strated. Furthermore, these compounds (10f, 10g, 10h, 10i)

were evaluated in the cassette dosing assay (iv) in dogs, and

their pharmacokinetic parameters are shown in Table 3. The

results indicated that introduction of more lipophilic substitu-

tion at the R²position increased total clearance (10f, OEt <

10g, O-i-pr , 10h, O-i-butyl < 10i, O-c-hex) and decreased

oral exposure (AUC) and bioavailability (10f, OEt > 10g,

O-i-pr . 10h, O-i-butyl, 10i, O-c-hex). Actually, both O-i-

pr analogue 10g and O-c-hex analogue 10i are predicted to

have good passive permeability as previously reported (based

on PAMPA data) and, in liver microsomes, 10g and 10i

showed good stability to dog and other species in terms of

in vitro clearance (see Table 4). These results suggested that

the high total clearance of the O-i-butyl (10h) and O-c-hex

(10i) analogues may be due to a conjugation metabolism and/

or elimination, hence these compounds showed poor C_max

levels and oral exposure. On the other hand, compound 10g

displayed an excellent balance of high ꢀ3-AR potency, high

selectivity, and good pharmacokinetic proﬁles.

Furthermore, replacement of the methyl group of 10g with a

dimethyl group (10j) resulted in a 10-fold decrease in ꢀ3-AR

activity. Compound 10k, having a hydroxy methyl group (R-

conﬁguration)²³exhibited signiﬁcantly decreased potency but

improved C_maxlevels in the cassette dosing assay relative to

10g. The Kissei group have studied a series of 4′-hydrox-

ynorepherine derivatives, such as compound 6 (see Figure 1).

In our study, compound 10l having a 4′-hydroxynorepherine

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4009

Table 2. Effect of Conversion of the Central Part of SGB Analogues

c

human ꢀ₃EC₅₀,

human ꢀ₁EC₅₀,

human ꢀ₂EC₅₀,

cassette (po)

compd R¹

8b 3-Cl CH H

X

A

B

R²

nM (IA^b)

ꢀ₁/ꢀ₃

nM

ꢀ₂/ꢀ₃

C_maxratio ^d

a

H

O-iso-Pr 1.1 ( 0.1 (0.98)

720 ( 106

654

>10000

>9090

1.0

10a 3-Cl CH H

10b 3-Cl CH H

10c 3-Cl CH H

Me (R)

Me (S)

Me (R)

Me₂

H

0.18 ( 0.02 (0.96)

6.0 ( 0.4 (0.98)

13 ( 2

12 ( 1

37 ( 2

22 ( 2

83

72

2

195

73

NT

>1000

NT

>10000

NT

>10000

NT

>1000

NT

>3300

NT

>10000

NT

>12300

>23200

NT

>2040

>10000

>15625

NT

0.80

NT

O-iso-Pr 0.19 ( 0.02 (0.96)

H

O-Me

O-Et

O-iso-Pr 0.091 ( 0.01 (1.01)

O-iso-Bu 0.041 ( 0.001 (0.97)

O-c-Hex 0.042 ( 0.006 (1.07)

O-iso-Pr 0.91 ( 0.09 (1.0)

10d

10e

10f

10g

10h

10i

10j

10k

10l

H

CH H

0.30( 0.02 (0.93)

0.79 ( 0.02 (0.90)

0.31 ( 0.07 (0.97)

105

200

945

3170

667

307

>135

3570

980

1607

2124

153

808

2930

348

2.82

2.83

0.63

0.01

0.00

0.43

1.37

0.04

0.42

0.13

0.16

2.3

62

86 ( 7

130 ( 17

28 ( 7

280 ( 38

>1000

500 ( 9.8

780 ( 26

690 ( 75

300 ( 17

75 ( 5

80 ( 10

190 ( 15

24 ( 4

CH₂OH(R) O-iso-Pr 7.4 ( 1 (0.98)

4-OH CH Me (S) H

O-iso-Pr 0.14 ( 0.01 (0.97)

O-iso-Pr 0.81 ( 0.04 (0.97)

O-n-Pr

iso-Bu

H

O-iso-Pr 0.099 ( 0.002 (1.0)

O-n-Pr 0.064 ( 0.002 (1.0)

O-c-Hex 0.069 ( 0.01 (1.06)

10m

10n

10o

10p

10q

10r

10s

H

CH Me (S) H

0.43 ( 0.07 (0.98)

0.14 ( 0.01 (0.98)

0.49 ( 0.005 (0.98)

N

H

Me (R)

0.58

0.29

NT

^aThe results are shown as the mean ( SE (n ) 3). ^bThe intrinsic activity (IA) was deﬁned as the ratio between the maximal effect of test compound and

the maximal effect produced by isoproterenol. ^cDose 0.1 or 0.2 mg/kg po (n ) 2-3). See References section for further details. ^dThe ratio was deﬁned

between the C_maxof test compounds and the C_maxof 8b. The ratio value of 8b was presented as 1.0. NT: not tested.

a,b

Table 3. Pharmacokinetic Proﬁles of Compounds 10f-i in Dogs

po, (n ) 2-3)

iv, (n ) 2-3)

compd

R

AUC_0-2h(ng·h/mL)

T_1/2ꢀ(hr)

V_dss(L/kg)

AUC_0-24h(ng·h/mL)

CL_tot(mL/min/kg)

F (%)^c

10f

10g

10h

10i

O-Et

350 ( 60

106

0.2 ( 0.2

0

9.9

15.5

17.7 ( 0.9

0.35

1.9

5.4

30.8 ( 3.4

1.13

477

260

44.5 ( 3.0

24.3

3.5

6.5

39.0 ( 2.4

68.9

73

41

0.4

0

O-iso-Pr

O-iso-Bu

O-c-Hex

^aCassette assay data. The results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. ^bDose 0.1 mg/kg. po and iv (n

) 2-3). ^cF ) bioavailability.

10o containing a O-n-pr and isobutyl group at the R²position,

respectively, showed good ꢀ3-AR activity, while their C_max

Table 4. In Vitro Metabolism in Liver Microsomes CL_int

(mL/min/kg)^a,b

compd

rat

dog

monkey

human

levels in the cassette dosing assay were decreased relative to

10m.

9l

10g

10i

<2.0

ND^c

NT

<2.0

ND^c

3.8

<1.0

NT

2.2

ND^c

NT

Pyridine derivatives with R²) H (10p), O-i-pr (10q), O-n-

pr (10r), and O-c-hex (10s) were next prepared. The O-n-pr

analogue (10r) provided the best in vitro proﬁle (ꢀ3-AR, EC₅₀

) 0.064 nM; ꢀ3/ꢀ1 ) 2930, ꢀ3/ꢀ2 > 15625), and the

nonsubstituted analogue 10p showed decreased potency relative

to the 3-chlorophenyl ring analogue 10a. The O-c-hex analogue

10s showed comparable high potency (EC₅₀) 0.069 nM) but

a lower selectivity for ꢀ3/ꢀ1 relative to 10r. In the cassette

dosing assay, the nonsubstituted analogue 10p exhibited a

signiﬁcantly higher C_maxlevel relative to 10b, and the O-n-pr

analogue 10r showed an acceptable C_maxlevel.

^aEach compound was incubated at 37 °C with live microsomes from

rats, dogs, monkeys and humans in the presence of the NADPH-generating

system. ^bThe results are presented as the average of two experiments. ^cND:

not determined (<0.1 mL/min/kg). NT: not tested.

unit with the (S,R)-conﬁguration in the LHS, was prepared and

characterized. Compound 10l showed greatly improved ꢀ3-AR

activity (ca. 8-fold) relative to the original compound 8b, while

the C_maxlevel showed a substantial loss, similar to the phenol

analogue 9c (see Table 1). On the basis of this result, we

examined the removal of the hydroxy group of 10l to improve

oral absorption. As expected, compound 10m showed improve-

ment at the C_maxlevel, however, the ꢀ3-AR activity of 10m

was decreased by ca. 6-fold relative to 10l. Analogues 10n and

Last, as can be seen in Table 5, we investigated modiﬁcation

of the two carbon linker between the secondary amine and the

biphenyl part. The Pﬁzer group have reported that replacement

of the two carbon linker with an ethoxy-based linker in their

4010 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

Table 5. Effect of Conversion of the Two Carbon Linker of SGB Analogues

a

b

c

d

compd

R¹

Cl

X

R²

human ꢀ₃EC₅₀, nM (IA^b)

human ꢀ₁EC₅₀, nM (IA^b)

ꢀ₁/ꢀ₃

cassette (po) C_maxRatio

8b

CH₂

O-iso-Pr

1.1 ( 0.1 (0.98)

720 ( 106

654

1.0

11a

11b

11c

11d

11e

11f

11g

11h

11i

Cl

H

Cl

CH₂O

(CH₂) ₂

CH₂NH

CH₂O

O-iso-Pr

O-n-Pr

O-iso-Bu

iso-Bu

O-c-Hex

O-iso-Pr

O-n-Pr

O-iso-Bu

O-c-Hex

O-n-Pr

0.50 ( 0.02 (0.96)

0.21 ( 0.03 (0.99)

0.32 ( 0.08 (0.98)

0.68 ( 0.07 (0.99)

0.27 ( 0.05 (1.0)

2.4 (0.95)

1.2 ( 0.05 (0.98)

0.55 ( 0.05 (0.99)

0.16 ( 0.03 (1.1)

0.7 (1.0)

84 ( 7

120 ( 13

110 ( 16

15 ( 0.6

52 ( 6

510

210 ( 35

400 ( 44

91 ( 6

180

168

571

340

22

193

212

175

727

570

126

52

NT

2.43

NT

1.12

NT

0.22

NT

11j

11k

O-n-Pr

iso-Bu

0.21 (0.97)

0.059 ( 0.006 (1.01)

11

12 ( 0.6

11l ^e

200

0.70

^aThe results are shown as the mean ( SE (n ) 3)or presented as the average of two experiments. ^bThe intrinsic activity (IA) was deﬁned as the ratio

between the maximal effect of test compound and the maximal effect produced by isoproterenol. ^cDose 0.1 mg/kg po (n ) 2-3). See References section

for further details. ^dThe ratio was deﬁned between the C_maxof test compounds and the C_maxof 8. The ratio value of 8b was presented as 1.0. NT: not tested.

e

series provided an increase in potency²⁴and discovered potent

and selective ꢀ3-AR agonists such as compound 4 (see Figure

1). This modiﬁcation was incorporated into the FGB series

compound 8b. The O-i-pr analogue 11a showed an improvement

in ꢀ3-AR activity, although ꢀ3/ꢀ1 selectivity was lower relative

to 8b. Furthermore, to improve the in vitro proﬁle of 11a, the

ethoxy-based linker derivatives of R²) O-n-pr (11b), O-i-u

(11c), isobutyl (11d), and O-c-hex (11e) were prepared. Interest-

ingly, the O-n-pr analogue 11b showed much more potent ꢀ3-

AR activity (EC₅₀) 0.21 nM) and better selectivity (ꢀ3/ꢀ1 )

571) compared with 11c, 11d, and 11e. These SAR results were

different from the previous SAR results for two carbon linker

derivatives, suggesting that the O-n-pr group (11b) had to the

most favorable lipophilicity for ꢀ3-AR binding afﬁnity. On the

other hand, analogues (11f-i) containing a LHS phenyl ring

showed a similar SAR trend to the previous two carbon linker

derivatives. Therefore, the O-c-hex analogue (11i) provided the

most potent ꢀ3-AR activity (EC₅₀) 0.16 nM). Next, we

investigated the effect of incorporation of oxygen into the two

carbon linker of pharmacokinetic properties. The O-n-pr ana-

logue (11b) displayed a signiﬁcant increase in C_maxlevel relative

to the lead compound 8b. Similar to this result, the isobutyl

analogue 11d showed an improved C_maxlevel compared with

the corresponding isobutyl analogue (8e in Table 1) having a

two carbon linker. However, the O-isobutyl analogue 11h

showed dramatically decreased C_maxlevels relative to the O-n-

pr analogue (11b). This trend in the PK property for R²

substituted analogues is similar to the two carbon linker

derivatives. We next investigated the replacement of the oxygen

atom in 11b with nitrogen and carbon atoms because the O-n-

pr analogue 11b exhibited better potency relative to 8b (5-fold),

good selectivity, and an excellent C_maxlevel. Analogue 11j,

having a three carbon linker, showed reduced potency (4.5-fold)

and ꢀ3/ꢀ1 selectivity (2.7-fold) relative to 11b. The ethylamine-

based linker derivative 11k maintained high potency for the

ꢀ3-AR relative to 11b but poor selectivity for ꢀ3/ꢀ1. On the

basis of these results, we attempted to utilize the effect of

incorporation of the oxygen in the two carbon linker with the

amino-pyridine analogue 9l. As expected, the amino-pyridine

analogue 11l displayed very high ꢀ3-AR potency (EC₅₀) 0.059

nM) and improved C_maxlevels (2-fold) relative to the original

compound 9l, although the ꢀ3/ꢀ1 selectivity was lower than

9l.

After SAR examination and study in the cassette dosing assay,

we selected 9h, 9k, and 9l in Table 1, 10g, 10m, 10p and 10r

in Table 2 and 11b and 11l in Table 5 as potential candidates.

Table 6 shows the pharmacokinetic proﬁles in rats, dogs, and

monkeys for the selected compounds.²⁵The pyridine analogue

with an O-iso-pr moiety (9h) displayed good to moderate oral

bioavailability in all three species (rats, F ) 61.5%; dogs, F )

63.2%; monkeys, F ) 25.7%) and had a long plasma half-life

in dogs (t_1/2ꢀ) 9.9 h). On the other hand, the pyridine analogue

with a O-c-hex moiety (9k), which had higher ꢀ3-AR potency,

showed good oral bioavailability in dogs (F ) 60%) and rats

(F ) 82.5%). The amino-pyridine analogue with an isobutyl

moiety (9l) showed good to moderate oral bioavailability in dogs

and monkeys (dogs, F ) 27%; monkeys, F ) 48.6%) and had

a long plasma half-life in dogs (t_1/2ꢀ) 7.6 h). Next, both phenyl

analogues 10g and 10m, having a methyl group at the R-position

of the phenethylamine moiety, exhibited good oral bioavail-

ability in all three species (10g: F ) 69.7% in rats, F ) 79.6%

in dogs, F ) 52.8% in monkeys; 10m: F ) 100% in rats, F )

63.9% in dogs, F ) 88.2% in monkeys) and had a long plasma

half-life (10g: t_1/2ꢀ) 14.3 h in dogs; 10m: t_1/2ꢀ) 14.3 h in

dogs, t_1/2ꢀ) 29 h in monkeys). Pyridine analogue 10p exhibited

good to moderate oral bioavailability in rats and dogs (rats, F

) 25.2%; dogs, F ) 59.7%) and had a moderate plasma half-

life in dogs (t_1/2ꢀ) 6.4 h). A similar pyridine analogue with an

O-iso-pr moiety (10r) also showed good oral bioavailability in

dogs (F ) 55%) and monkeys (F ) 57%). Last, the ethoxy-

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4011

a

Table 6. Pharmacokinetic Proﬁles of Selected Members of the SGB Series

po (n ) 3)

AUC_0-24h(ng·h/mL)

iv (n ) 2-3)

b

compd

species

rat

dose (mg/kg)

C_max(ng/mL)

T_1/2ꢀ(hr)

CL_tot(mL/min/kg)

F (%)

9h

1.0

0.32

0.27

171.9 ( 5.7

27.0 ( 4.5

11.0 ( 1.0

548.2 ( 5.7

461.3 ( 85.7

77.5 ( 26.0

3.5 ( 1

9.9 ( 1

2.2

16.0 ( 0.6

6.4 ( 0.5

22.8

61.5

63.2

25.7

dog

monkey^c

9k

rat ^c

0.26

0.32

0.28

72.4 ( 12.7

11.4 ( 6.4

18.6 ( 2.5

245.1 ( 27.4

58.1 ( 10.3

153.3 ( 48.3

3.3

d

10.3

15.8

47.7 ( 3.3

3.4

82.5

60.0

10.7

dog

monkey^c

9l

rat

1.0

0.32

21.9 ( 0.5

49.1 ( 1.8

12.4 ( 6.2

208.0 ( 40.8

177.2 ( 70.1

90.8 ( 25.4

1.9 ( 0.7

7.6 ( 2

5.9

8.5 ( 0.3

7.9 ( 1

24.3

12.4

27.0

48.6

dog

monkey^c

10g

10m

rat^c

1.0

0.1

0.32

116.5 ( 5.9

8.5 ( 0.81

1640 ( 131

162.1 ( 21.3

1304.7 ( 345.4

d

7.2

7.83 ( 1.2

1.8 ( 0.3

69.7

79.6

52.8

dog

14.3 ( 2.9

d

monkey^c

128.3 ( 45.9

rat^c

0.34

0.1

0.32

125.1 ( 14.1

7.4 ( 0.1

178.2 ( 31.7

879.7 ( 41.9

134.3 ( 0.8

1803.1 ( 236.6

8.2

14.3 ( 0.6

29.0 ( 1.0

6.8

7.3 ( 0.6

2.5 ( 0.2

100

63.9

88.2

dog

monkey^c

10p

10r

rat

dog

1.0

0.1

22.0 ( 5.8

30.5 ( 5.5

102.9 ( 4.5

1.91

6.4 ( 0.3

34.3

4.4 ( 0.5

25.2

59.7

206.8 ( 72.3

dog

0.1

0.30

3.0 ( 0.5

8.2 ( 2.3

35.5 ( 5.4

65.2 ( 14.9

d

24.3 ( 2.1

47.0

54.9

57.2

monkey^c

11b

11l

dog^c

0.1

40.6 ( 1.8

11.6 ( 2.9

419.7 ( 14.5

38.2 ( 8.6

10.9

9.5

2.9

69.7

34.8

dog ^c

14.2

^aThe results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. ^bF ) bioavailability. ^cCassette assay data. ^dNot

calculated.

Table 7. Inhibitory Effect on Intraduodenal Administration of Selected Compounds and 62 (FK175)^f, 8d on Increase in IVP (Intravesical Pressure),

a

Induced by Carbachol in Anesthetized Dogs

in vitro

human ꢀ₃EC₅₀, nM (IA^b)

in vivo

ED₅₀(µg/kg)

compd

dog ꢀ₃EC₅₀, nM (IA^b)

30 ( 9.0 (0.91) ^c,d

EC₅₀(nM)

352 ( 16 ^c

dog serum protein binding

94% ^c

C log P^e

62

16 ( 2.0 (0.98)^c,d

270 ( 12

8d

2.0 ( 0.06 (0.97)

2.9 ( 0.4 (0.97)

25.9 ( 4.6

20 ( 4

86%

2.58

9h

9k

9l

1.5 ( 0.1 (0.97)

0.26 ( 0.02 (1.0)

0.066 ( 0.004 (0.97)

11 ( 0.8 (0.87)

1.3 ( 0.2 (0.94)

3.2 ( 0.4 (1.0)

28.4 ( 9.1

65.0 ( 32

16.1 ( 9.5

7.8 ( 0.8

4.0 ( 0.5

1.8 ( 1

77%

90%

80%

1.09

2.28

1.27

10g

10m

0.091 ( 0.01 (1.01)

0.81 ( 0.04 (0.97)

0.19 ( 0.04 (1.07)

3.7 ( 0.8 (0.89)

3.5 ( 1

20.0 ( 12

2.5 ( 0.3

9.5 ( 2

86%

2.89

10r

0.064 ( 0.002 (1.0)

0.51 ( 0.09 (1.03)

4.80 ( 2.5

0.28 ( 0.05

82%

1.62

^aThe results are shown as the mean ( SE (n ) 3) or presented as the average of two experiments. ^bThe intrinsic activity (IA) was deﬁned as the ratio

between the maximal effect of test compound and the maximal effect produced by isoproterenol. ^cData for the carboxylic acid form of 62. ^dResults are the

f

mean ( SE of ﬁve experiments. ^eBiobyte C log P ver 4.3.

based linker analogue 11b displayed good oral bioavailability

in dogs (F ) 70%) as well as a long plasma half-life (t_1/2ꢀ

10 h) and low clearance. Compound 11l had an improved PK

proﬁle in dogs (F ) 38%, t_1/2ꢀ) 9.5 h) relative to the

corresponding amino-pyridine analogue 9l.

Next, we examined the inhibitory effect of selected com-

pounds (9h,k,l, 10g,m,r) on carbachol-induced increase of

intravesical pressure (IVP) in anesthetized dogs as an OAB

model, and which has been previously described,²⁰in compari-

son with the effects of our previous clinical compound 62 and

FBG analogue 8d. Before conducting in vivo experiments, we

conﬁrmed the in vitro potency of these selected compounds for

not only human ꢀ3-AR activity but also dog ꢀ3-AR activity in

CHO cell lines, as shown in Table 7.²⁰In general, SBG

analogues have some species differences between human and

dog ꢀ3-AR activity, except for 10g, and the EC₅₀values for

dog ꢀ3-AR activity of all the selected compounds showed much

less potency relative to human ꢀ3-AR activity. Compounds 10g

and 10r, having a methyl group, showed more potent dog ꢀ₃-

AR activity relative to 8d. Compounds 9k, 9l, and 10m showed

the same potency level, and compound 9h showed less potent

dog ꢀ₃-AR activity relative to 8d. In the in vivo experiment,

)

4012 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

incorporation of the pyridine/amino pyridine moiety to the LHS

may result in the improved pharmacokinetic properties. Fur-

thermore, in a carbachol-induced IVP model in dogs, these

pyridine and amino-pyridine analogues 9h, 9k, 9l resulted in

improved in vivo EC₅₀values relative to FGB phenyl analogue

8d, probably due to both lower serum protein binding and

improvement of pharmacokinetic properties for the in vivo

efﬁcacy.

Next, we investigated the effect of substituents on the position

adjacent to the secondary amino group and discovered that

introduction of a methyl group (R-conﬁguration) into the

R-position of the phenethylamine moiety greatly enhanced

potency while keeping good oral availability. Amang these

analogues, compounds 10g and 10r provided an excellent

Figure 4. Time course of inhibitory effect of intraduodenal administra-

tion of 10g on increase in IVP (intravesical pressure) induced by

carbachol in anesthetized dogs. The results are presented as the average

of two or three experiments.

balance of high potency for human ꢀ3-AR (10g, EC₅₀

)

0.091nM; 10r, EC₅₀) 0.069nM), selectivity, and good oral

bioavailability (F > 50% in two or three species). Further, in

vivo, these two compounds resulted in 5-7-fold improved ED₅₀

values compared to FBG analogue 8d. In particular, compound

10r, having a combination of a methyl group at the R-position

and a pyridine ring in the LHS, resulted in a greater than 70-

fold increase in vivo EC₅₀value relative to the FBG analogue

8d.

Intraduodenally (i.d.) administered selected compounds inhibited

the IVP increase in a dose-dependent manner with the ED₅₀

and EC₅₀values listed in Table 7, respectively. Phenyl analogues

with a methyl group (10g) and (10m) possessed the same level

of lipophilicity (10g, 10m: C log P ) 2.89) and protein binding

(PB) in dog (10g, 10m: PB ) 86%) compared to 8d (8d: C log

P ) 2.58, PB ) 86%). Compound 10g resulted in a 7-8-fold

improvement in the in vivo EC₅₀values (10g: EC₅₀) 2.5 nM)

due to the improvement of the in vitro dog ꢀ3-AR potency

compared to 8d (EC₅₀) 20 nM). As shown in Figure 4,

intraduodenally administered 10g, which provided the best ED₅₀

of the selected compounds, inhibited the IVP increase in a dose-

dependent manner with a long duration of action. On the other

hand, compound 10m resulted in a 2-fold improvement in in

vivo EC₅₀value (10m: EC₅₀) 9.5 nM), in spite of the same

potency level for in vitro dog ꢀ3-AR activity, relative to 8d.

Similarly, the 3-pyridine and amino-pyridine analogues (9h, 9k,

9l), having comparable or less potency for in vitro dog ꢀ3-AR

activity, resulted in a 2.4-10-fold improvement in the in vivo

EC₅₀values compared to phenyl analogue 8d. Furthermore, the

3-pyridyl analogue 10r with a methyl group, which showed 2.6-

fold less potency for in vitro dog ꢀ3-AR activity compared to

the phenyl analogue with a methyl group 10g, was the most

potent of the selected compounds and showed more than 8 times

better in vivo activity (10r, EC₅₀) 0.28 nM) relative to 10g

(EC₅₀) 2.5 nM). These results suggested that the improvement

in the in vivo EC₅₀with pyridine or amino-pyridine ring

analogues relative to phenyl ring analogues (compare 9h, 9k,

9l vs 8d, and 10r vs 10g) may be due to not only lower protein

binding but also improvement in the pharmacokinetic properties

for the in vivo efﬁcacy. We will describe the correlation of in

vitro and in vivo activity for designing efﬁcacious compounds

in the near future.

Lastly, the replacement of the two carbon linker with an

ethoxy-based linker provided improved potency and PK proﬁles.

The O-n-pr analogue 11b exhibited good potency (EC₅₀) 0.21

nM) and an excellent PK proﬁle in dogs (F ) 70%, t_1/2ꢀ

)

10.9 h). This modiﬁcation was incorporated into amino-pyridine

analogue 9l. As a result, compound 11l maintained high potency

(EC₅₀) 0.059 nM) and an improved PK proﬁle in dogs (F )

38%, t_1/2ꢀ) 9.5 h).

Although our SGB compounds (9h, 9k, 9l, 10g, 10m, 10p,

10r, 11b, and 11l) were all of potential interest as possible drug

candidates, the pyridine and amino pyridine analogues 9h, 9l,

and 10r were of particular interest because of extremely

improved in vivo efﬁcacy compared to the FGB compound 8d

and 62, and phenyl analogue 10g was of particular interest

because of its high human ꢀ3-AR potency, selectivity, and

excellent PK proﬁles in three species. Therefore, these SGB

compounds may be attractive as new successful therapeutic

candidates for the treatment of OAB.²⁶

Experimental Section

Chemistry. General Methods. Reactions involving air- or

moisture-sensitive reagents were carried out under a nitrogen

atmosphere. If not speciﬁed, reactions were carried out at ambient

temperature. Silica gel (Kanto Chemical, 63-210 µm) was used

for chromatographic puriﬁcation unless otherwise indicated. An-

hydrous solvents were obtained from commercial sources. Proton

NMR spectra were recorded on a Brucker BIOSPIN AVANCE400

or DPX200. Values in ppm relative to tetramethylsilane are given.

The following abbreviations are used to describe peak patterns when

appropriate: br ) broad, s ) singlet, d ) doublet, t ) triplet, q )

quartet, m ) multiplet. High resolution mass spectra were recorded

with Micromass LCT. Chemical pPurity was given by HPLC

analysis with a Shiseido Capcell Pack C18 column (detection at

254 nm). Results of elemental analysis were recorded with Perkin-

Elmer 2400II, were within 0.4% of the theoretical values calculated

for C, H, and N unless otherwise noted.

4′-(2-{[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)-

3-isopropoxy-4-biphenylcarboxylic acid hydrochloride (9a). Com-

pound 9a was synthesized from 28 and 53b according to the

procedure D (71%). NMR (200 MHz, DMSO-d₆) δ: 1.29 (6H, t, J

) 6.0 Hz), 2.9-3.4 (6H, m), 4.84 (1H, m), 4.9-5.1 (1H, m), 6.30

(1H, m), 7.1-7.8 (11H, m). MS (ES) m/e: 454 (M + H). Anal.

(C₂₆H₂₈Cl₁N₁O₄·1.0HCl·0.5H₂O) C, H, N.

Conclusions

First, in this study, replacement of the 3-chlorophenyl moiety

in the LHS of FGB analogues with 3-pyridine afforded

compound (9k), having an O-c-hex group in the RHS, with not

only highly potency (EC₅₀) 0.26 nM) and selectivity but also

good oral bioavailability in both dogs (F ) 60%) and rats (F

) 82.5%), without loss of oral bioavailability, such as with 8c

and 8f (see Table 1). In addition, amino-pyridine analogues

resulted in increased potency relative to pyridine analogues, and

in particular, the isobutyl analogue 9l showed highly potent ꢀ3-

AR activity (EC₅₀) 0.066 nM) and displayed moderate to good

oral bioavailability in dogs (F ) 27%) and monkeys (F )

48.6%). It is interesting note that adjusting the lipophilicity by

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4013

4′-(2-{[(2R)-2-(3-Fluorophenyl)-2-hydroxyethyl]amino}ethyl)-

3-isopropoxy-1,1′-biphenyl-4-carboxylic acid hydrochloride (9b).

Compound 9b was synthesized from 29 and 53b according to the

procedure D (54%). NMR (200 MHz, DMSO-d₆) δ: 1.31 (6H, d,

J ) 6.0 Hz), 2.9-3.4 (6H, m), 4.81 (1H, m), 4.9-5.1 (1H, m),

6.22(1H, m), 7.1-7.8 (11H, m). MS (ES) m/e: 438 (M + H). Anal.

(C₂₆H₂₈F₁N₁O₄·1.0HCl·0.5H₂O) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-(3-hydroxyphenyl)ethyl]amino}ethyl)-

3-isopropoxy-4-biphenylcarboxylic acid hydrochloride (9c). Com-

pound 30 and 53b were reacted according to the typical Suzuki

coupling procedure (procedure D) to give methyl 4′-{2-[{(2R)-2-

[3-(benzyloxy)phenyl]-2-hydroxyethyl}(tert-butoxycarbonyl)ami-

no]ethyl}-3-isobutylbiphenyl-4-carboxylate (72%). MS (ES) m/e:

660 (M + Na).

(22.7%) of the title compound. NMR (200 MHz, DMSO-d₆) δ:

1.31 (6H, d, J ) 6.0 Hz), 2.95 (3H, s), 2.83-3.34 (6H, m),

4.76-4.88 (2H, m), 6.11 (1H, m), 6.92 (1H, d, J ) 6.0 Hz), 7.07

(1H, dd, J ) 1.7, 8.4 Hz), 7.25-7.39 (5H, m), 7.68-7.72 (3H, m),

8.81 (1H, br), 10.03 (1H, br). MS (ES) m/e: 527 (M-H). Anal.

(C₂₇H₃₂N₂O₇S₁·1.0HCl·2.0H₂O) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}ethyl)-3-isopro-

poxy-4-biphenylcarboxylic acid dihydrochloride (9h). Compound 9h

was synthesized from 17 and 53b according to the procedure D

(40%). NMR (200 MHz, DMSO-d₆) δ: 1.29 (6H, d, J ) 6.0 Hz),

2.9-3.4 (6H, m), 4.84 (1H, m), 4.9-5.1(1H, m), 7.2-7.5 (4H, m),

7.6-7.9 (4H, m), 8.2-8.5 (1H, m), 8.7-8.9 (2H, m), 9.0-9.4 (2H,

m). MS (ES) m/e: 421 (M

2.0HCl·0.2H₂O) C, H, N.

+ H). Anal. (C₂₅H₂₈N₂O₄·

The product was subjected to the hydrogenation procedure used

to supply compound 9g to give phenol product. 9c was synthesized

from the phenol product according to the hydrolysis, followed by

deprotection procedure used typical procedure D (48%). NMR (200

MHz, DMSO-d₆) δ: 1.26 (6H, d, J ) 5.9 Hz), 2.8-3.5 (6H, m),

4.76 (1H, m), 4.94(1H, m), 6.15 (1H, m), 6.6-7.8 (11H, m). MS

(ES) m/e: 436 (M + H). Anal. (C₂₆H₂₉N₁O₅·1.0HCl·1.8H₂O) C,

H, N.

4′-(2-{[(2R)-2-(3-Methansulfonylaminophenyl)-2-hydroxyethyl]-

amino}ethyl)-3-isopropoxy-4-biphenylcarboxylic acid dihydro-

chloride (9d). Methyl 4′-(2-{[(2R)-2-(3-aminophenyl)-2-hydroxy-

ethyl](tert-butoxycarbonyl)amino}ethyl)-3-isopropoxybiphenyl-4-

carboxylate and MsCl were reacted according to the procedure used

to supply intermediate 56, followed by hydrolysis and deprotection

procedure used typical procedure D to give 9d (55%). NMR (200

MHz, DMSO-d₆) δ: 1.25 (6H, d, J ) 5.9 Hz), 2.8-3.5 (6H, m),

4.89 (1H, m), 4.94 (1H, m), 6.15 (1H, m), 7.0-7.8 (11H, m). MS

(ES) m/e: 513 (M + H). Anal. (C₂₇H₃₂N₂O₆·1.0HCl·3.0H₂O) C,

H, N.

4′-(2-{[(2R)-2-(6-Amino-3-pyridinyl)-2-hydroxyethyl]amino}ethyl)-

3-isopropoxy-4-biphenylcarboxylic acid dihydrochloride (9i). Com-

pound 9i was synthesized from 43 and 53b according to the

procedure G (25%). HPLC purity: 98%. ¹H NMR (400 MHz,

DMSO-d₆) δ: 1.31 (6H, d, J ) 6.2 Hz), 3.02-3.26 (6H, m), 4.82

(1H, heptuplet, J ) 6,.2 Hz), 4.98 (1H, br), 6.44 (1H, br), 7.03

(1H, d, J ) 9.5 Hz), 7.27 (1H, dd, J ) 1.5, 8.1 Hz), 7.32 (1H, d,

J ) 1.5 Hz), 7.38 (2H, d, J ) 8.4 Hz), 7.70 (1H, d, J ) 8.1 Hz),

7.71 (2H, d, J ) 8.4 Hz), 7.93-7.96 (2H, m), 8.11 (2H, br), 9.07

(1H, br), 9.22 (1H, br), 12.5 (1H, br), 14.0 (1H, br). MS (ES) m/e:

434 (M - H). HRMS (M + H)⁺: found 436.2232; calcd for

C₂₅H₂₉N₃O₃436.2236.

4′-(2-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}ethyl)-3-isobutyl-

4-biphenylcarboxylic acid dihydrochloride (9j). Compound 9j was

synthesized from 17 and 53e according to the procedure D (37%).

NMR (200 MHz, DMSO-d₆) δ: 0.88 (6H, d, J ) 6.53 Hz),

1.73-1.97 (1H, m), 2.99-3.52 (6H, m), 5.24-5.38 (1H, m), 7.39

(2H, d, J ) 8.03 Hz), 7.49-7.62 (2H, m), 7.70 (2H, d, J ) 8.03

Hz), 7.87 (1H, d, J ) 8.53 Hz), 7.93-8.05 (1H, m), 8.50 (1H, d,

J ) 8.53 Hz), 8.79-8.96 (2H, m). MS (ES) m/e: 417 (M - H).

Anal. (C₂₆H₃₀N₂O₃·2.0HCl·0.5H₂O) C, H, N.

3-(Cyclohexyloxy)-4′-(2-{[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-

ethyl)-4-biphenylcarboxylic acid dihydrochloride (9k). Typical Pro-

cedure D. To a solution of 17 (1.3 g, 3.08 mol) in 1,2-

dimethoxyethane (20 mL) were added boronic acid 53f (0.95 g,

3.41 mol), Pd(PPh₃)₄(210 mg, 0.18 mmol), and aqueous solution

of Na₂CO₃(2 M, 3.4 mL), and the mixture was stirred at 70 °C for

5 h under nitrogen. The mixture was diluted with EtOAc and water.

The organic layer was separated, washed with brine, dried over

MgSO₄, and evaporated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (hexane/EtOAc

) 1/1-1/4) to give 1.12 g (63%) of methyl 4′-(2-{(tert-

butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}ethyl)-

3-(cyclohexyloxy)-4-biphenylcarboxylate as pale-yellow foam. ¹H

NMR (200 MHz, CDCl₃) δ: 1.17-1.98 (10H, m), 1.27 (9H, s),

2.65-2.81 (2H, m), 3.1-3.55 (4H, m), 3.79 (3H, s), 4.6-4.85 (2H,

m), 5.61-5.68 (1H, m), 7.22-7.72 (9H, m), 8.44-8.49 (2H, m).

MS (ESI): 575 (M + H).

To a solution of the product (750 mg, 1.3 mmol) in MeOH (7.5

mL) and THF (3.5 mL) was added 1 N aqueous NaOH (3.9 mL,

3.0 equiv), and the mixture was stirred at room temperature for

16 h. The solvent was removed by evaporation, and the aqueous

solution was neutralized with 1 N aqueous HCl and extracted with

EtOAc. The combined organic layers were washed with water and

brine, dried over MgSO₄, and evaporated under reduced pressure

to give a benzoic acid product. To a solution of the product in

EtOAc (7.0 mL) was added 4 N HCl in EtOAc (7 mL), and the

mixture was stirred at room temperature for 12 h. The resultant

solid was collected by ﬁltration and dried to give 574 mg (81%) of

the title compound. NMR (200 MHz, DMSO-d₆) δ: 1.0-2.0 (10H,

m), 2.9-3.4 (6H, m), 4.65 (1H, m), 5.02-5.31 (1H, m), 7.22-7.50

(4H, m), 8.4-8.6 (1H, m), 8.7-8.9 (2H, m). 9.0-9.4 (2H, m). MS

(ES) m/e: 461 (M - H). Anal. (C₂₈H₃₂N₂O₄·2.0HCl) C, H, N.

4′-(2-{[(2R)-2-(6-Amino-3-pyridinyl)-2-hydroxyethyl]amino}ethyl)-

3-isobutyl-4-biphenylcarboxylic acid dihydrochloride (9l). Typical

Procedure G. A mixture of bromide 43 (400 mg, 0.675 mol), boronic

acid 53e (191 mg, 0.81 mol), PdCl₂(dppf) ·CHCl₃(1:1, 82 mg, 0.10

4′-(2-{[(2R)-2-(3-Aminophenyl)-2-hydroxyethyl]amino}ethyl)-

3-isopropoxy-4-biphenylcarboxylic acid dihydrochloride (9e).

Compound 31 and 53b were reacted according to the typical Suzuki

coupling procedure (procedure D), followed by reduction procedure

used for 55 to give methyl 4′-(2-{[(2R)-2-(3-aminophenyl)-2-

hydroxyethyl](tert-but-

oxycarbonyl)amino}ethyl)-3-isopropoxybiphenyl-4-carboxylate (69%).

MS (ES) m/e: 549 (M + H).

Compound 9e was synthesized from the aniline product according

to the hydrolysis, followed by deprotection procedure used typical

procedure D (62%). NMR (200 MHz, DMSO-d₆) δ: 1.26 (6H, d,

J ) 5.9 Hz), 2.8-3.5 (6H, m), 4.82 (1H, m), 5.02 (1H, m), 6.15

(1H, m), 7.2-7.8 (11H, m). MS (ES) m/e: 435 (M + H). Anal.

(C₂₆H₃₀N₂O₄·2.0HCl·1.0H₂O) C, H, N.

4′-(2-{[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]amino}ethyl)-3-iso-

propoxy-4-biphenylcarboxylic acid dihydrochloride (9f). Compound

9f was synthesized from 32 according to the procedure described

for the conversion of 31 to 9e (42%). NMR (200 MHz, DMSO-d₆)

δ: 1.31 (6H, d, J ) 6.0 Hz), 3.0-3.3 (6H, m), 4.82 (1H, m), 5.02

(1H, m), 7.1-7.5 (8H, m), 7.6-7.9 (3H, m), 8.9 (1H, m), 9.2 (1H,

m). MS (ES) m/e: 435 (M + H). Anal. (C₂₆H₃₀N₂O₄· 2.0HCl ·

1.0H₂O) C, H, N.

4′-{2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-

phenyl}ethyl)amino]ethyl}-3-isopropoxy-4-biphenylcarboxylic acid

hydrochloride (9g). To a solution of 56 (200 mg, 0.31 mmol) and

benzoic acid 58 (120 mg, 0.39 mmol) in 1,2-dimethoxyethane (4

mL) were added Pd(PPh₃)₄(29 mg, 0.025 mmol) and aqueous

solution of Na₂CO₃(2M, 0.68 mL), and the mixture was stirred at

70 °C for 10 h under nitrogen. The mixture was poured into 1 N

aqueous HCl solution and EtOAc, added active carbon, and stirred

for 2 h. The mixture was ﬁltered and partitioned. The organic layer

was separated, washed with brine, dried over MgSO₄, and evapo-

rated. The residue was puriﬁed by column chromatography on silica

gel (hexane/EtOAc ) 2/3) to give a biphenyl product. A suspension

of the product in MeOH (6 mL) was hydrogenated over palladium

on carbon (10% w/w, 50% wet, 50 mg) under hydrogen atmosphere

for 40 min, and the catalyst was ﬁltered off. To the ﬁltrate was

added 4 N HCl in EtOAc (40 µL) and evaporated to give 62 mg

4014 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

mmol), dppf (56 mg, 0.10 mmol), DMF (8 mL), and 2 N sodium

carbonate solution (1.0 mL) was stirred at 80 °C for 3 h. After

cooling to room temperature, the mixture was quenched by the

addition of water and extracted with EtOAc. The combined extracts

were washed with water and brine, dried over MgSO₄, and

evaporated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (hexane/EtOAc ) 1/1) to

give 351 mg (74%) of methyl 4′-(2-{[(2R)-2-[6-(acetylamino)-3-

pyridinyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl](tert-

butoxycarbonyl)amino}ethyl)-3-isobutyl-4-biphenylcarboxylate. ¹H

NMR (400 MHz, DMSO-d₆) δ: -0.14 (3H, s), -0.01 (3H, s), 0.81

(9H, s), 0.87 (6H, d, J ) 6.6 Hz), 1.30 (9H, brs), 1.82(1H, m),

2.01 (s, 3H), 2.7-2.9 (4H, m), 3.2-3.4 (4H, m), 4.9-5.0 (1H, m),

7.1 -8.22 (10H, m), 10.5 (1H, s). MS (ES) m/e: 704 (M + H).

To a solution of the product (345 mg, 0.490 mmol) in EtOH

(3.45 mL) was added 1 N aqueous NaOH solution (4.9 mL, 4.90

mmol) and the mixture was stirred at 100 °C for 24 h. After cooling

to room temperature, the mixture was quenched by the addition of

1 N aqueous HCl solution (4.9 mL, 4.9 mmol) and the solvent was

removed by evaporation. To the residual brown solid were added

4 N HCl in dioxane (4 mL) and MeOH (1 mL) and the mixture

was stirred at room temperature for 6.5 h. The solvent was removed

by evaporation and the residual brown solid was chromatographed

on ODS column (eluent: water/methanol ) 100/0, 90/10, 80/20,

70/30, 60/40, 50/50, and 40/60). The fractions containing the target

compound were acidiﬁed by 1 N HCl (1 mL) and concentrated in

vacuo to give the title compound (103 mg, 42%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ: 0.88 (6H, d, J ) 6.6 Hz), 1.85

(1H, heptuplet, J ) 6.6 Hz), 2.91 (2H, d, J ) 6.6 Hz), 3.04-3.22

(6H, m), 4.98 (1H, d, J ) 7.3 Hz), 6.45 (1H, br), 7.03 (1H, d, J )

9.9 Hz), 7.38 (2H, d, J ) 8.1 Hz), 7.52 (1H, s), 7.58 (1H, dd, J )

1.8, 8.1 Hz), 7.70 (2H, d, J ) 8.1 Hz), 7.87 (1H, d, J ) 8.1 Hz),

7.93-7.98 (2H, m), 8.14 (2H, br), 9.07 (1H, br), 9.21 (1H, br),

12.8 (1H, br), 14.0 (1H, br). MS (ES) m/e: 432 (M - H). Anal.

(C₂₆H₃₁N₃O₃·2.0HCl·2.0H₂O) C, H, N.

4′-(2-{[(2R)-2-(6-Amino-3-pyridinyl)-2-hydroxyethyl]amino}ethyl)-

3-(cyclohexyloxy)-4-biphenylcarboxylic acid (9m). Compound 9m was

synthesized from 43 and 53f according to the procedure G. The

crude product 9m (187 mg, 0.393 mmol) was dissolved in 4 N

HCl in dioxane (3 mL) and the solution was stirred at room

temperature for 14 h. The solvent was concentrated in vacuo and

the residual solid was dissolved in water (5 mL) and treated with

activated carbon. The mixture was ﬁltered and the ﬁltrate was

adjusted to pH 7 by the addition of 1 N aqueous NaOH solution.

The precipitates were collected by ﬁltration, washed with water,

and dried under reduced pressure at 50 °C to give the title compound

(103 mg, 46%) as a off-white solid. ¹H NMR (400 MHz, DMSO-

d₆) δ: 1.28-1.61 (6H, m), 1.69-1.78 (2H, m), 1.82-1.91 (2H,

m), 2.72-2.98 (6H, m), 4.52-4.65 (2H, m), 5.82 (2H, brs), 6.41

(1H, d, J ) 8.1 Hz), 7.21-7.38 (5H, m), 7.61-7.66 (3H, m), 7.85

(1H, br). MS (ES) m/e: 474 (M - H). Anal. (C₂₈H₃₃N₃O₄·2.0H₂O)

C, H, N.

4′-((2R)-2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}propyl)-

3-isopropoxy-4-biphenylcarboxylic acid hydrochloride (10c). Com-

pound 10c was synthesized from 38 and 53b according to the

procedure D (71%). NMR (200 MHz, DMSO-d₆) δ: 1.14 (3H, d,

J ) 6.4 Hz), 1.30 (6H, d, J ) 5.8 Hz), 2.8-3.8 (5H, m), 4.6-4.9

(1H, m), 5.0-5.3 (1H, m), 6.2-6.4 (1H, m), 7.2-7.8 (11H, m),

8.82 (1H, br.s), 9.24 (1H, br.s). MS (ES) m/e: 468 (M + H). HRMS

(M + H)⁺: found 468.1949; calcd for C₂₇H₃₀Cl₁N₁O₄468.1942.

Anal. (C₂₇H₃₀Cl₁N₁O₄·1.0HCl·1.5H₂O) C, H, N.

4′-[(2R)-2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}propyl]biphenyl-

4-carboxylic acid hydrochloride (10d). Compound 10d was synthe-

sized from 39 and 53a according to the procedure D (67%). NMR

(400 MHz, DMSO-d₆) δ: 1.15 (3H, d, J ) 6.5 Hz), 2.6-2.8 (1H,

m), 3.0-3.3 (3H, m), 3.54 (1H, m), 5.00 (1H, m), 6.22 (1H, m),

7.32-7.46 (7H, m), 7.73 (2H, d, J ) 8.0 Hz), 7.80 (2H, d, J ) 8.0

Hz), 8.00-8.03 (2H, m), 8.77 (1H, br s), 9.02 (1H, br s), 12.9 (1H,

br s). MS (ES) m/e: 374 (M

(C₂₄H₂₅N₁O₃·1.0HCl·0.5H₂O) C, H, N.

-

H). Anal.

4′-((2R)-2-{[(2R)-2-Phenyl-2-hydroxyethyl]amino}propyl)-3-meth-

oxy-1,1′-biphenyl-4-carboxylic acid hydrochloride (10e). Compound

10e was synthesized from 39 and 53g according to the procedure

D (69%). NMR (200 MHz, DMSO-d₆) δ: 1.15 (3H, d, J ) 6.4

Hz), 2.8-3.8 (5H, m), 3.92 (3H, s), 5.0-5.2 (1H, m), 6.3-6.4 (1H,

m), 7.2-7.6 (9H, m), 7.7-7.9 (3H, m), 8.81 (1H, br.s), 9.31 (1H,

br.s). MS (ES) m/e: 406 (M + H). Anal. (C₂₅H₂₇N₁O₄·

1.0HCl·0.5H₂O) C, H, N.

3-Ethoxy-4′-[(2R)-2-{[(2R)-2-hydroxy-2-phenylethyl]amino}propyl]-

biphenyl-4-carboxylic acid hydrochloride (10f). Compound 10f was

synthesized from 39 and 53h according to the procedure D (75%).

NMR (200 MHz, DMSO-d₆) δ: 1.15 (3H, d, J ) 6.4 Hz), 1.36

(3H, t, J ) 7.0 Hz), 2.6-3.2 (5H, m), 4.21 (2H, q, J ) 7.0 Hz),

4.9-5.1 (1H, m), 6.23 (1H, m), 7.2-7.7 (11H, m). MS (ES) m/e:

418 (M - H). Anal. (C₂₆H₂₉N₁O₄·1.0HCl·0.8 H₂O) C, H, N.

4′-((2R)-2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}propyl)-3-isopro-

poxy-4-biphenylcarboxylic acid hydrochloride (10g). Compound 10g

was synthesized from 39 and 53b according to the procedure D

(59%). NMR (200 MHz, DMSO-d₆) δ: 1.12 (3H, d, J ) 6.4 Hz),

1.30 (6H, d, J ) 5.8 Hz), 2.8-3.8 (5H, m), 4.6-4.9 (1H, m),

5.0-5.3 (1H, m), 6.2-6.4 (1H, m), 7.2-7.8 (12H, m), 8.82 (1H,

br.s). MS (ES) m/e: 434 (M + H). Anal. (C₂₇H₃₁N₁O₄·1.0HCl) C,

H, N.

4′-((2R)-2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}propyl)-3-isobu-

toxy-4-biphenylcarboxylic acid hydrochloride (10h). Compound 10h

was synthesized from 39 and 53d according to the procedure D

(59%). NMR (200 MHz, DMSO-d₆) δ: 1.03 (6H, t, J ) 6.2 Hz),

1.16 (3H, d, J ) 6.4 Hz), 1.8-2.2 (1H, m), 2.6-3.2 (5H, m), 3.93

(2H, d, J ) 6.2 Hz), 4.9-5.1 (1H, m), 6.23 (1H, m), 7.2-7.7 (11H,

m). MS (ES) m/e: 448 (M

N₁O₄·1.0HCl·0.5H₂O) C, H, N.

+

H). Anal. (C₂₈H₃₃

4′-((2R)-2-{[(2R)-2-Phenyl-2-hydroxyethyl]amino}propyl)-3-cyclo-

hexyloxy-1,1′-biphenyl-4-carboxylic acid hydrochloride (10i). Com-

pound 10i was synthesized from 39 and 53f according to the

procedure D (55%). NMR (200 MHz, DMSO-d₆) δ: 1.14 (3H, d,

J ) 6.4 Hz), 1.2-2.0 (10H, m), 2.8-3.8 (5H, m), 4.65 (1H, m),

4.9-5.1 (1H, m), 6.23 (1H, m), 7.1-7.9 (12H, m). MS (ES) m/e:

474 (M + H). Anal. (C₃₀H₃₅N₁O₄·1.0HCl) C, H, N.

4′-[(2R)-2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}propyl]-

4-biphenylcarboxylic acid hydrochloride (10a). Compound 10a was

synthesized from 38 and 53a according to the procedure D (65%).

NMR (400 MHz, DMSO-d₆) δ: 0.88 (3H, d, J ) 6.5 Hz), 2.7-2.8

(1H, m), 3.1-3.4 (3H, m), 3.53 (1H, m), 5.05 (1H, m), 6.37 (1H,

m), 7.37-7.47 (6H, m), 7.73 (2H, d, J ) 8.3 Hz), 7.79-7.82 (2H,

m), 8.00-8.03 (2H, m), 8.81 (1H, br s), 9.18 (1H, br s), 12.9 (1H,

br s). MS (ES) m/e: 410 (M + H). Anal. (C₂₄H₂₄Cl₁N₁O₃·1.0HCl·

0.5H₂O) C, H, N.

4′-[(2S)-2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}propyl]-

4-biphenylcarboxylic acid hydrochloride (10b). Compound 10b was

prepared from (2R)-2-amino-3-phenyl-1-propanol according to the

same procedures described for the conversion of (2S)-2-amino-3-

phenyl-1-propanol 47 to 10a. NMR (400 MHz, DMSO-d₆) δ: 1.17

(3H, d, J ) 6.5 Hz), 2.7-2.8 (1H, m), 3.1-3.3 (2H, m), 3.27 (1H,

m), 3.50 (1H, m), 5.01 (1H, m), 6.36 (1H, m), 7.32-7.46 (6H, m),

7.72 (2H, d, J ) 8.3 Hz), 7.77-7.81 (2H, m), 8.00-8.03 (2H, m),

8.95 (1H, br s), 9.11 (1H, br s), 12.9 (1H, br s). MS (ES) m/e: 410

(M + H). Anal. (C₂₄H₂₄Cl₁N₁O₃·1.0HCl·0.5H₂O) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}-2-methylpropyl)-3-iso-

propoxy-4-biphenylcarboxylic acid hydrochloride (10j). Compound

10j was prepared from 61 according to the procedures described

for the conversion of 51 to 10g in 29% yield. NMR (200 MHz,

DMSO-d₆) δ: 1.31 (6H, d, J ) 6.0 Hz), 1.35 (6H, s), 2.8-3.5 (5H,

m), 4.82 (1H, m), 5.02 (1H, m), 6.17 (1H, m), 7.2-7.5 (9H, m),

7.6-7.9 (3H, m). MS (ES) m/e: 448 (M

(C₂₈H₃₃N₁O₄·1.0HCl·0.75H₂O) C, H, N.

+ H). Anal.

4′-((2S)-3-Hydroxy-2-{[(2R)-2-hydroxy-2-phenylethyl]amino}propyl)-

3-isopropoxy-4-biphenylcarboxylic acid hydrochloride (10k). Com-

pound 10k was synthesized from 41 and 53b according to the

procedure D (66%). NMR (200 MHz, DMSO-d₆) δ: 1.31(6H, d, J

) 6 Hz), 2.8-3.5 (7H, m), 4.82 (1H, m), 5.00 (1H, m), 5.41 (1H,

m), 6.23 (1H, m), 7.2-7.8 (12H, M). MS (ES) m/e: 450 (M + H).

Anal. (C₂₇H₃₁N₁O₅·1.0HCl·1.3H₂O) C, H, N.

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4015

4′-(2-{[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-

amino}ethyl)-3-isopropoxy-4-biphenylcarboxylic acid hydrochlo-

ride (10l). Compound 10l was synthesized from 46 and 53b

according to the procedure D (51%). NMR (200 MHz, DMSO-d₆)

δ: 0.98 (3H,d, J ) 6.6 Hz), 1.31 (6H, d, J ) 6.0 Hz), 2.8-3.5

(5H, m), 4.79 (1H, q, J ) 6.0 Hz), 5.0-5.2 (1H, m), 6.0 (1H, m),

6.7-7.9 (11H, m). MS (ES) m/e: 450 (M + H). HRMS (M + H)⁺

found 450.2290; calcd for C₂₇H₃₁N₁O₅450.2280. Anal. (C₂₇H₃₁N₁O₅·

2.0HCl·0.9H₂O) C, H, N.

the title compound. NMR (200 MHz, DMSO-d₆) δ: 1.70 (3H, d, J

) 6 Hz) 3.30-3.90 (6H, m), 5.10-5.20 (1H, m), 7.40-7.70 (7H,

m), 7.80-7.90 (1H, m), 8.25 (1H, d, J ) 8 Hz), 8.70-8.85 (2H,

m). MS (ES) m/e: 377 (M

2.0HCl·1.2H₂O) C, H, N.

+ H). Anal. (C₂₃H₂₄N₂O₃·

4′-((2R)-2-{[(2R)-2-Hydroxy-2-(3-pyridyl)ethyl]amino}propyl)-3-iso-

propyloxy-1,1′-biphenyl-4-carboxylic acid dihydrochloride (10q). Com-

pound 10q was synthesized from 40 and 53b according to the

procedure F (61%). NMR (200 MHz, DMSO-d₆) δ: 1.19 (3H, d, J

) 6.4 Hz), 1.31 (6H, d, J ) 6.0 Hz), 2.8-3.8 (5H, m), 4.6-4.9

(1H, m), 5.1-5.3 (1H, m), 7.2-7.5 (4H, m), 7.6-8.0 (4H, m), 8.37

(1H, d, J ) 8.2 Hz), 8.80 (1H, d, J ) 4.6 Hz), 8.88 (1H, s), 9.02

(1H, br, s), 9.35 (1H, br, s). MS (ES) m/e: 435 (M + H). Anal.

(C₂₆H₃₀N₂O₄·2.0HCl·1.25H₂O) C, H, N.

4′-((2R)-2-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}propyl)-3-

propoxy-4-biphenylcarboxylic acid hydrochloride (10r). Compound

10r was synthesized from 40 and 53c according to the procedure

F (39%). NMR (200 MHz, DMSO-d₆) δ: 1.07 (3H, t, J ) 7.4 Hz),

1.13 (3H, d, J ) 6.8 Hz), 1.5-1.9 (2H, m), 2.7-3.4 (5H, m), 4.04

(2H, q, J ) 7.4 Hz), 5.1-5.3 (1H, m), 6.32 (1H, m), 7.2-7.9 (8H,

m), 8.25 (1H, d, J ) 8 Hz), 8.7-8.9 (2H, m), 8.94 (1H, m), 9.20

(1H, m). MS (ES) m/e: 435 (M + H). Anal. (C₂₆H₃₀N₂O₄·

2.0HCl·0.25H₂O) C, H, N.

3-(Cyclohexyloxy)-4′-((2R)-2-{[(2R)-2-hydroxy-2-(3-pyridinyl)eth-

yl]amino}propyl)-4-biphenylcarboxylic acid dihydrochloride (10s).

Compound 10s was synthesized from 40 and 53f according to the

procedure F (61%). HPLC purity: 97%. NMR (200 MHz, DMSO-

d₆) δ: 1.15 (3H, d, J ) 6.4 Hz), 1.2-2.0 (10H, m), 2.7-3.8 (5H,

m), 4.65 (1H, m), 5.31 (1H, m), 7.2-7.5 (5H, m), 7.6-7.8 (2H,

m), 7.9-8.0 (1H, m), 8.45 (1H, m), 8.82 (1H, d, J ) 2.6 Hz), 8.90

(1H, s), 8.94 (1H, m), 9.07 (1H, br, s), 9.43 (1H, br, s). MS (ES)

m/e: 475 (M + H). HRMS (M + H)⁺: found 475.2592; calcd for

C₂₉H₃₄N₂O₄475.2597.

4′-(2-{[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino}ethyl)-3-

isopropoxy-4-biphenylcarboxylic acid hydrochloride (10m). Com-

pound 10m was synthesized from 18 and 53b according to the

procedure D (59%). NMR (200 MHz, DMSO-d₆) δ: 0.97 (3H, d,

J ) 6.6 Hz), 1.32 (6H, d, J ) 6.0 Hz), 3.0-3.6 (5H, m), 4.82 (1H,

m), 5.21 (1H, m), 6.15 (1H, m), 7.1-7.5 (9H, m), 7.7-7.9 (3H,

m). MS (ES) m/e: 434 (M

1.0HCl·0.5H₂O) C, H, N.

+ H). Anal. (C₂₇H₃₁N₁O₄·

4′-(2-{[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino}ethyl)-3-

propoxy-4-biphenylcarboxylic acid hydrochloride (10n). Compound

10n was synthesized from 18 and 53c according to the procedure

D (59%). NMR (200 MHz, DMSO-d₆) δ: 0.8-1.1 (6H, m), 1.6-1.9

(2H, m), 3.0-3.7 (5H, m), 4.11 (2H, q, J ) 6.8 Hz), 5.24 (1H, m),

6.16 (1H, m), 7.1-7.8 (12H, m). MS (ES) m/e: 434 (M + H). Anal.

(C₂₇H₃₁N₁O₄·1.0HCl) C, H, N.

4′-(2-{[(1S,2R)-2-Hydroxy-1-methyl-2-phenylethyl]amino}ethyl)-3-

isobutyl-4-biphenylcarboxylic acid hydrochloride (10o). Compound

10o was synthesized from 18 and 53e according to the procedure

D (15%). NMR (200 MHz, DMSO-d₆) δ: 0.88 (6H, d, J ) 6.5

Hz), 0.96 (3H, d, J ) 6.5 Hz), 1.79-1.92 (1H, m), 2.92 (2H, d, J

) 7.0 Hz), 3.02-3.10 (2H, m), 3.33-3.52 (3H, m), 5.15 (1H, br

s), 6.12 (1H, br s), 7.26-7.61 (9H, m), 7.71 (2H, d, J ) 8.0 Hz),

7.87 (1H, d, J ) 8.0 Hz). MS (ES) m/e: 432 (M + H). Anal.

(C₂₈H₃₃N₁O₃·1.0HCl·0.25H₂O) C, H, N.

4′-((2R)-2-{[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]amino}propyl)-1,1′-

biphenyl-4-carboxylic acid dihydrochloride (10p). Typical procedure

F. To a solution of 40 (287 mg, 0.55 mol) in 1,2-dimethoxyethane

(4 mL) were added boronic acid 53a (110 mg, 0.61 mol), Pd(PPh₃)₄

(64 mg, 0.055 mmol), and aqueous solution of Na₂CO₃(2 M, 0.58

mL), and the mixture was stirred at 70 °C for 2 h under nitrogen.

The mixture was diluted with EtOAc and water. The organic layer

was separated, washed with brine, dried over MgSO₄, and evapo-

rated under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (hexane/EtOAc ) 3/1-2/1) to give

250 mg (85.7%) of methyl 4′-((2R)-2-{(tert-butoxycarbonyl)[(2R)-

2-(6-chloro-3-pyridinyl)-2-hydroxyethyl]amino}propyl)-1,1′-biphe-

nyl-4-carboxylate. MS(ESI): 524 (M + H).

To a solution of the product (250 mg, 0.476 mmol) in MeOH

(2.5 mL) was added 1 N aqueous NaOH (1.0 mL), and the mixture

was stirred at room temperature for 2 h. The solvent was removed

by evaporation, and the aqueous solution was neutralized with 1 N

aqueous HCl and extracted with EtOAc. The combined organic

layers were washed with water and brine, dried over MgSO₄, and

evaporated under reduced pressure. The residue was puriﬁed by

column chromatography on silica gel (hexane/EtOAc ) 1/1) to give

150 mg (61.6%) of 4′-((2R)-2-{(tert-butoxycarbonyl)[(2R)-2-(6-

chloro-3-pyridinyl)-2-hydroxyethyl]amino}propyl)-1,1′-biphenyl-4-

carboxylic acid. MS(ESI): 511 (M + H).

The above product (150 mg, 0.29 mmol), ammonium formate

(73 mg, 1.16 mmol) and palladium on carbon powder (10% w/w,

50% wet, 30 mg) in methanol (7.5 mL) and water (1.5 mL) was

reﬂuxed for 30 min, and the catalyst was ﬁltered off. To the ﬁltrate

was added water and extracted with ethyl acetate. The organic layer

was washed with brine, dried over magnesium sulfate, and

evaporated under reduced pressure to give 140 mg (90%) of 4′-

((2R)-2-{(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-

pyridinyl)ethyl]amino}propyl)-1,1′-biphenyl-4-carboxylic acid as a

colorless form. MS(ESI): 477 (M + H).

4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethoxy)-3-

isopropoxy-4-biphenylcarboxylic acid hydrochloride (11a). Compound

11a was synthesized from 24 and 53b according to the procedure

E (28%). NMR (200 MHz, DMSO-d₆) δ: 1.31 (6H, d, J ) 6.0

Hz), 3.1-3.3 (2H, m), 3.4-3.5 (2H, m), 4.3-4.4 (2H, m), 4.8-4.9

(1H, m), 4.9-5.0 (1H, m), 6.3(1H, br), 7.1 (2H, d, J ) 8.8 Hz),

7.2-7.5 (6H, m), 7.67-7.74 (3H, m). MS (ES) m/e: 468 (M -

H). Anal. (C₂₆H₂₈Cl₁N₁O₅·1.0HCl·0.25H₂O) C, H, N.

4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethoxy)-3-

propoxy-4-biphenylcarboxylic acid hydrochloride (11b). Compound

11b was synthesized from 24 and 53c according to the procedure

E (28%). NMR (200 MHz, DMSO-d₆) δ: 1.02 (3H, t, J ) 7.3 Hz),

1.67-1.85 (2H, m), 3.1-3.2 (2H, m), 3.4-3.5 (2H, m), 4.1 (2H,

t, J ) 6.3 Hz), 4.3-4.4 (2H, m), 5.0-5.1 (1H,m), 6.3 (1H, br), 7.1

(2H, d, J ) 8.7 Hz), 7.2-7.3 (2H, m), 7.35-7.48 (4H, m), 7.7-7.8

(3H, m). MS (ES) m/e: 468 (M - H). Anal. (C₂₆H₂₈Cl₁-

N₁O₅·1.0HCl) C, H, N.

4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethoxy)-3-

isobutoxy-4-biphenylcarboxylic acid hydrochloride (11c). Compound

11c was synthesized from 24 and 53d according to the procedure

E (57%). NMR (200 MHz, DMSO-d₆) δ: 1.02 (6H, d, J ) 6.6

Hz), 2.0-2.1 (1H, m), 3.0-3.2 (2H, m), 3.4-3.5 (2H, m), 3.92

(2H, d, J ) 6.4 Hz), 4.38 (2H, t, J ) 4.8 Hz), 4.9-5.0 (1H, m),

6.2 (1H, br), 7.1 (2H, d, J ) 8.8 Hz), 7.2-7.5 (6H, m), 7.7-7.8

(3H, m). MS (ES) m/e: 482 (M - H). Anal. (C₂₇H₃₀Cl₁N₁O₅·

1.0HCl) C, H, N.

4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethoxy)-3-

isobutyl-4-biphenylcarboxylic acid hydrochloride (11d). Compound

11d was synthesized from 24 and 53e according to the procedure

E (11%). NMR (200 MHz, DMSO-d₆) δ: 0.88 (6H, d, J ) 6.6

Hz), 1.8-1.9 (1H, m), 2.9 (2H, d, J ) 6.9 Hz), 3.0-3.2 (2H, m),

3.4-3.5 (2H, m), 4.3-4.4 (2H, m), 5.0-5.1 (1H, m), 6.35 (1H,

br), 7.1 (2H, d, J ) 8.7 Hz), 7.3-7.6 (6H, m), 7.71 (2H, d, J ) 8.7

Hz), 7.85 (1H, d, J ) 8.1 Hz). MS (ES) m/e: 466 (M - H). HRMS

(M + H)⁺: found 468.1942; calcd for C₂₇H₃₀Cl₁N₁O₄468.1928.

Anal. calcd for C₂₇H₃₀Cl₁N₁O₄·1.0HCl: C, 64.29; H, 6.19; N, 2.78;

found: C, 64.91; H, 6.28; N, 2.82.

To a solution of the above product (140 mg, 0.26 mmol) in 1,4-

dioxane (2 mL) was added 4 N HCl in 1,4-dioxane (2 mL), and

the mixture was stirred at room temperature for 3 h. The resultant

solid was collected by ﬁltration and dried to give 100 mg (86%) of

4016 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

4′-(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethoxy)-3-

(cyclohexyloxy)-4-biphenylcarboxylic acid hydrochloride (11e). Com-

pound 11e was synthesized from 24 and 53f according to the

procedure E (49%). NMR (200 MHz, DMSO-d₆) δ: 1.3-1.9 (10H,

m), 3.1-3.2 (2H, m), 3.4-3.5 (2H, m), 4.3-4.4 (2H, m), 4.6 (1H,

m), 5.0-5.1 (1H,m), 6.3 (1H, br), 7.1(2H, d, J ) 8.7 Hz), 7.2-7.5

(6H, m), 7.69-7.74(3H, m). MS (ES) m/e: 508 (M-H). Anal.

(C₂₉H₃₂Cl₁N₁O₅·1.0HCl) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethoxy)-3-isopropoxy-

4-biphenylcarboxylic acid hydrochloride (11f). Compound 11f was

synthesized from 25 and 53b according to the procedure E (29%).

NMR (200 MHz, DMSO-d₆) δ: 1.31 (6H, d, J ) 6.0 Hz), 3.0-3.3

(2H, m), 3.45 (2H,d, J ) 4.7 Hz), 4.38 (2H, t, J ) 4.8 Hz), 4.8-4.9

(1H, m), 4.9-5.0 (1H, m), 6.2 (1H, br), 7.1 (2H, d, J ) 8.8 Hz),

7.2-7.4 (7H, m), 7.67-7.74 (3H, m). MS (ES) m/e: 434 (M -

H). Anal. (C₂₆H₂₉N₁O₅·1.0HCl) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethoxy)-3-propoxy-4-

biphenylcarboxylic acid hydrochloride (11g). Compound 11g was

synthesized from 25 and 53c according to the procedure E (33%).

NMR (200 MHz, DMSO-d₆) δ: 1.02 (3H, t, J ) 7.3 Hz), 1.7-1.8

(2H, m), 3.1-3.2 (2H, m), 3.4-3.5 (2H, m), 4.1 (2H, t, J ) 6.3

Hz), 4.3-4.4 (2H, m), 4.9-5.0 (1H,m), 6.2 (1H, br), 7.1 (2H, d, J

) 8.8 Hz), 7.2-7.4 (7H, m), 7.7-7.8 (3H, m). MS (ES) m/e: 434

(M - H). Anal. (C₂₆H₂₉N₁O₅·1.0HCl) C, H, N.

4′-(2-{[(2R)-2-Hydroxy-2-phenylethyl]amino}ethoxy)-3-isobutyl-4-

biphenylcarboxylic acid hydrochloride (11h). Compound 11h was

synthesized from 25 and 53e according to the procedure E (14%).

NMR (200 MHz, DMSO-d₆) δ: 0.88 (6H, d, J ) 6.6 Hz), 1.8-1.9

(1H, m), 2.89 (2H, d, J ) 6.9 Hz), 3.04-3.25 (2H, m), 3.45 (2H,

m), 4.3-4.4 (2H, m), 4.9-5.0 (1H, m), 6.2 (1H, br), 7.1(2H, d, J

) 8.8 Hz), 7.3-7.6 (7H, m), 7.71 (2H, d, J ) 8.7 Hz), 7.85 (1H,

d, J ) 8.1 Hz). MS (ES) m/e: 432 (M - H). Anal. (C₂₇H₃₁N₁O₅·

1.0HCl) C, H, N.

4′-[(2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}ethyl)amino]-

3-propoxy-4-biphenylcarboxylic acid dihydrochloride (11k). Com-

pound 11k was synthesized from 26 and 53c according to the

procedure E (20%). NMR (200 MHz, DMSO-d₆) δ: 1.02 (3H, d, J

) 7.3 Hz), 1.67-1.85 (2H, m), 3.0-3.3 (4H, m), 3.4-3.5 (2H,

m), 4.09 (2H, t, J ) 6.3 Hz), 4.95-5.05 (1H, m), 6.77 (2H, d, J )

8.6 Hz), 7.25 (1H, d, J ) 7.7 Hz), 7.29 (1H, s), 7.3-7.7 (7H, m),

8.9 (1H, br), 9.2 (1H, br). MS (ES) m/e: 503 (M - H). Anal.

(C₂₆H₂₉Cl₁N₂O₄·2.0HCl·1.0H₂O) C, H, N.

4′-(2-{[(2R)-2-(6-Amino-3-pyridinyl)-2-hydroxyethyl]amino}ethoxy)-

3-isobutyl-4-biphenylcarboxylic acid trihydrochloride (11l). Com-

pound 11l was synthesized from 44 and 53e according to the

procedure G. The ﬁnal product was recrystallized from ethanol-water

to give 11l as colorless solid (28%). NMR (400 MHz, DMSO-d₆)

δ: 0.88 (6H, d, J ) 6.6 Hz), 1.85 (1H, heptuplet, J ) 6.6 Hz), 2.91

(2H, d, J ) 7.0 Hz), 3.15-3.43 (4H, m), 4.39 (2H, d, J ) 5.5 Hz),

5.02 (1H, d, J ) 8.4 Hz), 6.47 (1H, brs), 7.05 (1H, d, J ) 9.5 Hz),

7.11 (2H, d, J ) 8.8 Hz), 7.49 (1H, d, J ) 1.8 Hz), 7.55 (1H, dd,

J ) 1.8, 8.1 Hz), 7.70 (2H, d, J ) 8.8 Hz), 7.85 (1H, d, J ) 8.1

Hz), 7.93-7.97 (2H, m), 8.20 (2H, brs), 9.27 (1H, br), 9.40 (1H,

br), 12.8 (1H, br), 14.2 (1H, br). MS (ES) m/e: 444 (M - H). Anal.

(C₂₆H₃₁N₃O₄·3.0HCl) C, H, N.

tert-Butyl [2-(4-bromophenyl)ethyl][(2R)-2-hydroxy-2-(3-

pyridinyl)ethyl]carbamate (17). Typical procedure A. To a

mixture of 4-bromophenylacetic acid 15 (26.7 g, 124 mmol), (1R)-

2-amino-1-(3-pyridinyl)ethanol dihydrochloride 12 (25 g, 118

mmol), and 1-hydroxybenzotriazole (16.8 g, 124 mmol) in N,N-

DMF (125 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcar-

bodiimide hydrochloride (23.8 g, 124 mmol) and Et₃N (34.6 mL,

249 mmol) under ice-bath, and the mixture was stirred at room

temperature for 16 h. The mixture was poured into water under

ice-bath below 10 °C, and the pH value was kept ca. 10 by using

24% aqueous NaOH solution. The mixture was stirred at room

temperature for 4 h, and the resultant solid was collected by

ﬁltration, washed with water, and dried to give 35.7 g (90%) of

2-(4-bromophenyl)-N-[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]aceta-

mide as a white crystal.¹H NMR (200 MHz, DMSO-d₆) δ:

2.49-2.51 (1H, m), 3.25-3.38 (2H, m), 3.33 (2H, s), 4.61-4.70

(1H, m), 4.79-4.87 (1H, m), 5.64 (1H, d, J ) 4.5 Hz), 7.14 (2H,

d, J ) 8.3 Hz), 7.28-7.35 (1H, m), 7.45 (2H, d, J ) 8.3 Hz),

7.65-7.69 (1H, m), 8.15 (1H, m), 8.44-8.49 (2H, m). MS (ES)

m/e: 358, 359 (M + Na)

To a THF (326 mL) solution of the product (32.6 g, 97.2 mmol),

2M-boran-dimethylsulﬁde complex in THF (146 mL) was added

at room temperature, and the mixture was reﬂuxed for 1.5 h. To

the mixture, 6 N HCl (195 mL) was added dropwise below 10 °C,

and the mixture was stirred at room temperature for 15 h. To the

reaction mixture, 3 N aqueous NaOH solution (350 mL) below 10

°C was added, and a solution of di-tert-butyl dicarbonate (23.3g,

107 mmol) in THF (70 mL) was added portionally at room

temperature. The pH value was kept between 7 and 8 by using 1

N aqueous NaOH solution. The mixture was stirred at room

temperature for 2 h. The mixture was partitioned between EtOAc

and water. The organic layer was separated, washed with brine,

dried over MgSO₄, and evaporated under reduced pressure. The

residue was puriﬁed by column chromatography on silica gel

(CHCl₃/MeOH ) 200/1-30/1) to give 32.9 g (80%) of the title

compound. ¹H NMR (200 MHz, CDCl₃) δ: 1.43 (9H, s), 2.70 (2H,

br), 3.15-3.50 (4H, m), 4.93-4.97 (1H, m), 6.95-7.01 (2H, m),

7.28-7.43 (3H, m), 7.72-7.80 (1H, m), 8.51 (1H, dd, J ) 1.6, 4.8

Hz), 8.57 (1H, d, J ) 2.2 Hz). MS (ES) m/e: 421 (M + H).

4-(2-{[(1S,2R)-2-Hydroxy-2-phenyl-1-methylethyl]-tert-butyloxycar-

bonyl-amino}ethyl)phenylbromide (18). Compound 18 was synthe-

sized from 13 and 15 according to the procedure A (91%). NMR

(200 MHz, CDCl₃) δ: 1.25 (3H, d, J ) 7.0 Hz), 1.47 (9H, s),

3.4-3.5 (2H, m), 3.8-4.0 (2H, m), 4.2-4.3 (1H, m), 6.7 (2H, d,

J ) 8.7 Hz), 7.2-7.4 (6H, m), 7.5-7.6 (2H, m). MS (ES) m/e:

434 (M + H).

3-(Cyclohexyloxy)-4′-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}-

ethoxy)-4-biphenylcarboxylic acid hydrochloride (11i). Typical

procedure E. To a solution of 25 (350 mg, 0.724 mmol) in toluene

(6.0 mL) and EtOH (1.5 mL) was added boric acid 53f (222 mg,

0.80 mmol), PdCl₂(dppf)·CHCl₃(1:1, 59 mg, 0.072 mmol), dppf

(20 mg, 0.036 mmol), and aqueous solution of sodium carbonate

(2M, 0.8 mL), and the mixture was stirred at 75 °C for 4 h under

nitrogen. The mixture was partitioned between with ethyl acetate

and water. The organic layer was separated, washed with brine,

dried over magnesium sulfate, and evaporated under reduced

pressure. The residue was puriﬁed by column chromatography on

silica gel (hexane/ethyl acetate ) 3/1) to give biphenyl product

(285 mg, 0.483 mmol). To a solution of the product in methanol

(5.0 mL) was added 1 N aqueous NaOH solution (1.5 mL), and

the mixture was stirred at 40 °C for 3 h. The solvent was removed

by evaporation, and the aqueous solution was acidiﬁed with 1 N

aqueous HCl solution and extracted with ethyl acetate. The

combined organic layers were washed with water and brine, dried

over magnesium sulfate, and evaporated under reduced pressure

to give a benzoic acid product. To a solution of the product in

ethyl acetate (2.0 mL) was added 4 N HCl in ethyl acetate (2.0

mL), and the mixture was stirred at room temperature for 12 h.

The resultant solid was collected by ﬁltration and dried to give

210 mg (56%) of the title compound. NMR (200 MHz, DMSO-d₆)

δ: 1.3-1.9 (10H, m), 3.0-3.3 (2H, m), 3.4 (2H, br), 4.4 (2H, t, J

) 5.0 Hz), 4.6-4.7 (2H, m), 4.9-5.0 (2H, m), 6.2 (1H, m), 7.1

(2H, d, J ) 8.8 Hz), 7.2-7.4 (7H, m), 7.67-7.73 (3H, m), 9.0

(2H, br). MS (ES) m/e: 474 (M - H). Anal. (C₂₉H₃₃N₁O₅·1.0HCl)

C, H, N.

4′-(3-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}propyl)-3-

propoxy-4-biphenylcarboxylic acid hydrochloride (11j). Compound

11j was synthesized from 19 and 53c according to the procedure

D (24%). NMR (200 MHz, DMSO-d₆) δ: 1.02 (3H, t, J ) 7.3 Hz),

1.7-1.8 (2H, m), 1.9-2.1(2H, m) 2.7 (2H, t, J ) 7.3 Hz), 2.9-3.2

(4H, m), 4.1 (2H, t, J ) 6.3 Hz), 4.9-5.0 (1H, m), 6.3 (1H, br),

7.2-7.5 (8H, m), 7.67-7.73 (3H, m), 8.9(2H, br). MS (ES) m/e:

466 (M - H). Anal. (C₂₇H₃₀Cl₁N₁O₄·1.0HCl) C, H, N.

tert-Butyl [3-(4-bromophenyl)propyl][(2R)-2-(3-chlorophenyl)-2-hy-

droxyethyl]carbamate (19). Compound 19 was synthesized from 14

1

and 16 according to the procedure A (50%). H NMR (200 MHz,

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4017

CDCl₃) δ: 1.46 (9H, s), 1.7-1.9 (2H, m), 2.51 (2H, t, J ) 7.4 Hz),

3.1-3.5 (4H, m), 4.88-4.95 (1H, m), 7.0-7.4 (8H, m). MS (ES)

m/e: 490, 492 (M + Na).

N aq NaOH. The mixture was stirred at room temperature for 1 h.

The mixture was partitioned between ethyl acetate and water. The

organic layer was separated, washed brine, dried over magnesium

sulfate, and evaporated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (Hex/EtOAc )

5/1) to give 1.5 g (44%) of the title compound. ¹H NMR (200 MHz,

CDCl₃) δ: 1.44 (9H, s), 2.69 (2H, m), 3.15-3.45 (4H, m), 4.47

(1H, br), 4.82-4.92 (1H, m), 6.95-7.04 (2H, m), 7.31-7.39 (6H,

m). MS (ES) m/e: 478 and 480 (M + Na).

tert-Butyl [2-(4-bromophenyl)ethyl][(2R)-2-(3-ﬂuorophenyl)-2-hy-

droxyethyl]carbamate (29). Compound 29 was synthesized from 27

and (2R)-2-(3-ﬂuorophenyl)oxirane according to the procedure B

(42%). ¹H NMR (200 MHz, CDCl₃) δ: 1.44 (9H, s), 2.69 (2H, m),

3.15-3.42 (4H, m), 4.35 (1H, br), 4.82-4.91 (1H, m), 6.95-7.04

(2H, m), 7.18-7.52 (6H, m). MS (ES) m/e: 460 and 462 (M +

Na).

tert-Butyl {(2R)-2-[3-(benzyloxy)phenyl]-2-hydroxyethyl}[2-(4-bro-

mophenyl)ethyl]carbamate (30). Compound 30 was synthesized from

27 and (2R)-2-[3-(benzyloxy)phenyl]oxirane according to the

procedure B (39%). MS (ES) m/e: 548 and 550 (M + Na).

tert-Butyl [2-(4-bromophenyl)ethyl][(2R)-2-hydroxy-2-(3-nitrophe-

nyl)ethyl]carbamate (31). Compound 31 was synthesized from 27

and (2R)-2-(3-nitrophenyl)oxirane according to the procedure B

(40%). ¹H NMR (200 MHz, CDCl₃) δ: 1.44 (9H, s), 2.69 (2H, m),

3.15-3.45 (4H, m), 4.47 (1H, br), 4.82-4.92 (1H, m), 6.95-7.04

(2H, m), 7.4-8.1 (6H, m). MS (ES) m/e: 487 and 489 (M + Na).

tert-Butyl [2-(4-bromophenyl)ethyl][(2R)-2-hydroxy-2-(4-nitrophe-

nyl)ethyl]carbamate (32). Compound 32 was synthesized from 27

and (2R)-2-(4-nitrophenyl)oxirane according to the procedure B

(33%). ¹H NMR (200 MHz, CDCl₃) δ: 1.44 (9H, s), 2.69 (2H, m),

3.14-3.40 (4H, m), 4.75 (1H, br), 4.97-5.0 (1H, m), 6.97-7.02

(2H, m), 7.40 (2H, d, J ) 8.3 Hz), 7.52 (2H, d, J ) 8.3 Hz),

8.19-8.22 (2H, m). MS (ES) m/e: 487 and 489 (M + Na).

[(1R)-2-(4-Iodophenyl)-1-methylethyl]amine (36). To a solution of

51 (10 g, 28 mmol) in 1,4-dioxane (100 mL) was added aqueous

1 N NaOH solution (56 mL) dropwise. The mixture was stirred at

50 °C for 1 h. The solvent was removed under reduced pressure.

The residue was extracted with CHCl₃-MeOH (5:1). The organic

layer was dried over MgSO₄and evaporated under reduced pressure

to give 7.33 g (quant) of the title compound. MS (ES) m/e: 262

(M + H).

[2-(4-Iodophenoxy)ethyl]amine hydrochloride (22). To a solution

of 4-iodophenol (13.5 g, 61.4 mmol) and tert-butyl (2-hydroxy-

ethyl)carbamate (12.9 g, 80 mmol) in THF (110 mL) were added

PPh₃(20.9 g, 80 mmol) and 40% diethyl 1,2-diazenedicarboxylate

in toluene solution (36.2 mL, 92 mmol) at 4 °C, and the mixture

was stirred at room temperature for 16 h under nitrogen. The

mixture was evaporated under reduced pressure. The residue was

puriﬁed by column chromatography on silica gel (hexane/ethyl

acetate ) 3/1) to give phenylether product (19.3 g, 53.1 mmol).

To a solution of the product in EtOAc (100 mL) was added 4 N

HCl in EtOAc (100 mL), and the mixture was stirred at room

temperature for 2.5 h. The resultant solid was collected by ﬁltration

and dried to give 15.5 g (84%) of the title compound. NMR (200

MHz, DMSO-d₆) δ: 3.2 (2H, t, J ) 5.0 Hz), 4.1(2H, t, J ) 5.0

Hz), 6.8-6.9 (2H, m), 7.6-7.7 (2H, m), 8.2 (2H, br). MS (ES)

m/e: 264 (M + H).

2-Amino-N-(4-iodophenyl)acetamide hydrochloride (23). To a

mixture of 4-iodoaniline (10 g, 45.6 mmol), [(tert-butoxycarbony-

l)amino]acetic acid (8.8 g, 50.2 mmol) and hydroxbenzotriazole

(6.8 g, 50.2 mmol) in N,N-DMF (80 mL) was added 1-(3-

dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.63 g,

50.2 mmol), and the mixture was stirred at room temperature for

16 h. The mixture was partitioned between ethyl acetate and water.

The organic layer was separated, washed by 1 N HCl solution

followed by saturated sodium bicarbonate solution, dried over

magnesium sulfate, and evaporated under reduced pressure to give

an amide product (15.6 g, 41.7 mmol). To a solution of the product

in 1,4-dioxane (80 mL) was added 4 N HCl in 1,4-dioxane (80

mL), and the mixture was stirred at room temperature for 16 h.

The resultant solid was collected by ﬁltration. The solid was

triturated with EtOAc:n-Hex solution (1:1, 90 mL) to give 11.6 g

(90%) of the title compound. NMR (200 MHz, DMSO-d₆) δ: 3.8

(2H, d, J ) 5.3 Hz), 7.4-7.5 (2H, m), 7.7-7.8 (2H, m), 8.2 (2H,

br). MS (ES) m/e: 299 (M + Na).

tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-iodophe-

noxy)ethyl]carbamate (24). Compound 24 was synthesized from 20

1

and 22 according to the procedure A (60%). H NMR (200 MHz,

CDCl₃) δ: 1.48 (9H, s), 3.5-3.6 (4H, m), 3.9-4.0 (2H, m), 4.9-5.0

(1H, m), 6.6-6.7 (2H, m), 7.26 (3H, br), 7.4 (1H,s), 7.5-7.6

(2H,m). MS (ES) m/e: 540 (M + Na).

tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][2-(4-iodophen-

oxy)ethyl]carbamate (25). Compound 25 was synthesized from

21 and 22 according to the procedure A (99%). ¹H NMR (200 MHz,

CDCl₃) δ: 1.48 (9H, s), 3.5-3.6 (4H, m), 3.9-4.0 (2H, m), 4.9-5.0

(1H, m), 6.6-6.7 (2H, m), 7.3-7.6 (7H, m). MS (ES) m/e: 506

(M + Na).

tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]{2-[(4-iodophe-

nyl)amino]ethyl} carbamate (26). Compound 26 was synthesized

from 20 and 23 according to the procedure A (55%). ¹H NMR

(200 MHz, CDCl₃) δ: 1.49 (9H, s), 3.1-3.5 (6H, m), 4.9-5.0 (1H,

m), 6.3-6.4 (2H, m) 7.2-7.45 (6H, m). MS (ES) m/e: 539 (M +

Na).

tert-Butyl [2-(4-bromophenyl)ethyl][(2R)-2-(4-chlorophenyl)-2-hy-

droxyethyl]carbamate (28). Typical procedure B. Under nitrogen

at room temperature, to a mixture of [2-(4-bromophenyl)ethyl]amine

27 (2.0 g, 10mmol) in DMSO (16 mL) was added bis(trimethyl-

silyl)urea (1.5 g, 7.3 mmol), and the mixture was stirred at 65 °C

for 1 h. To the mixture was added (2R)-2-(4-chlorophenyl)oxirane

(1.4 g, 9.1 mmol), and the mixture was stirred at 65 °C for 18 h.

The resulting mixture was cooled to room temperature, and 1 N

aqueous HCl (20 mL) was added. After being stirred for 20 min,

the mixture was neutralized with saturated aqueous NaHCO₃(20

mL), and the aqueous mixture was extracted with EtOAc. The

organic layer was washed successively with water and brine, dried

over anhydrous MgSO₄, and evaporated under reduced pressure.

To a solution of the product in THF (30 mL) and water (20 mL)

was added di-tert-butyl dicarbonate (1.5 g, 6.9 mmol) at room

temperature. The pH value was kept between 7 and 8 by using 1

(2S)-2-Amino-3-(4-iodophenyl)-1-propanol (37). To a suspension

of NaBH₄(9.75 g, 258 mmol) in THF (300 mL) was added (2S)-

2-amino-3-(4-iodophenyl)propanoic acid 52 (30 g, 103 mmol) under

ice-bath, followed by conc H₂SO₄(7.2 mL, 129 mmol) in ether

(10 mL) dropwise, and the mixture was stirred at room temperature

for 24 h. To the mixture, MeOH (10 mL) was added carefully below

10 °C, followed by addition of 5 N aqueous NaOH solution (300

mL), and the solvent was removed by evaporation. The mixture

was reﬂuxed for 3 h. After cooling to room temperature, to the

mixture was added CHCl₃and water. The resulting mixture was

extracted with CHCl₃(× 3), and the combined organic layers were

dried over MgSO₄and evaporated under reduced pressure to give

1

22.3g (78.1%) of the title compound as a white solid. H NMR

(400 MHz, DMSO-d₆) δ: 1.35 (2H, br), 2.33-2.38 (1H, m),

2.61-2.67 (1H, m), 2.77-2.83 (1H, m), 3.13-3.27 (2H, m), 4.57

(1H, br s), 4.7-4.8 (2H, m), 5.31 (1H, br s), 7.02 (2H, d, J ) 8.0

Hz), 7.61 (2H, d, J ) 8 Hz). MS (ES) m/e: 278 (M + H).

tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][(1R)-2-(4-io-

dophenyl)-1-methylethyl]carbamate (38). Typical procedure C. The

mixture of 36 (7.74 g, 29.6 mmol) and (2R)-2-(3-chlorophenyl)ox-

irane 33 (4.12 g, 26.7 mmol) in EtOH (150 mL) was reﬂuxed for

30 h. After cooling to room temperature, the mixture was evaporated

under reduced pressure. The residue was puriﬁed by column

chromatography on silica gel (CHCl₃/MeOH ) 20/1) to give 6.67 g

(54%) of (1R)-1-(3-chlorophenyl)-2-{[(1R)-2-(4-iodophenyl)-1-

methylethyl]amino}ethanol. MS (ES) m/e: 416 (M + H). To a

solution of the product in THF (66 mL) and water (66 mL) was

added di-tert-butyl dicarbonate (3.84 g, 17.6 mmol) at room

temperature. The pH value was kept between 8 and 8.5 by using 1

N aqueous NaOH solution. The mixture was stirred at room

4018 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13

Imanishi et al.

temperature for 2 h. The mixture was partitioned between ethyl

acetate and water. The organic layer was separated, washed brine,

dried over magnesium sulfate, and evaporated under reduced

m), 4.9-5.1 (1H, m), 6.62 (2H, d, J ) 8.0 Hz), 7.52 (2H, d, J )

8.4 Hz), 7.66-7.81 (1H, m), 8.1-8.2 (2H, m). MS (ES) m/e: 654

(M-H).

1

pressure to give 8.32 g (quant) of title compound. H NMR (200

4-(2-{[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-tert-

butyloxycarbonyl-amino}ethyl)phenylbromide (46). To a solution of

(aS,bR)-4-hydroxynorephedrine 45 (500 mg, 3.65 mmol) and

4-bromophenylethylbromide (500 mg, 1.89 moml) in DMF (5 mL)

was added diisopropylethylamine (0.5 mL), and the mixture was

stirred for 6 h at 80 °C. The mixture was partitioned between EtOAc

and water. The organic layer was washed with brine, dried over

MgSO₄, and concentrated in vacuo. The residual oil was diluted in

THF (10 mL). To the solution was added di-tert-butyl dicarbonate

(1g, 4.58 mmol) at room temperature, and the mixture was stirred

at the same temperature for 12 h. The resulting mixture was

evaporated under pressure, and the residue was puriﬁed by column

chromatography on silica gel to give 520 mg (31.6%) of the title

compound. MS (ES) m/e: 550 (M + H).

MHz, CDCl₃) δ: 1.24 (3H, d, J ) 7 Hz), 1.36 (9H, s), 2.59 (2H,

m), 3.07-3.14 (1H, m), 3.51 (1H, br s), 4.10-4.17 (1H, m),

4.73-4.78 (2H, m), 5.43 (1H, br s), 6.8 (2H, d, J ) 8 Hz), 7.27

(3H, m), 7.40 (1H, br s), 7.60 (2H, d, J ) 8 Hz). MS (ES) m/e:

537 (M + Na).

tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][(1R)-2-(4-iodophenyl)-1-

methylethyl]carbamate (39). Compound 39 was prepared following

the procedure C using (2R)-2-phenyloxirane 34 instead of 33 in

30% yield. ¹H NMR (200 MHz, CDCl₃) δ: 1.07 (3H, d, J ) 7

Hz), 1.42 (9H, s), 2.6-2.7 (2H, m), 3.0-3.2 (1H, m), 3.52 (1H, br

s), 4.1-4.2 (1H, m), 4.7-4.8 (2H, m), 5.31 (1H, br s), 6.82-6.86

(2H, m), 6.93 (2H, d, J ) 8 Hz), 7.32-7.39 (3H, m), 7.60 (2H, d,

J ) 8 Hz). MS (ES) m/e: 482 (M + H).

N-[(1S)-1-benzyl-2-hydroxyethyl]-2,2,2-triﬂuoroacetamide (48). To

a solution of (2S)-2-amino-3-phenyl-1-propanol 47 (100 g, 661

mmol) in MeOH (500 mL) was added CF₃CO₂Et (94.4 mL, 794

mmol) dropwise. The mixture was stirred at room temperature for

2.5 h and evaporated under reduced pressure to give 166 g (quant)

of the title compound as a white solid. ¹H NMR (200 MHz, CDCl₃)

δ: 2.95 (1H, d, J ) 7.3 Hz), 3.62-3.79 (2H, m), 4.16-4.31 (1H,

m), 6.65 (1H, br), 4.89 (1H, m), 7.20-7.38 (5H, m). MS (ES) m/e:

270 (M + Na).

(2S)-3-Phenyl-2-[(triﬂuoroacetyl)amino]propyl methanesulfonate

(49). To a solution of 48 (160 g, 647 mmol) in THF (1.6 L) was

added Et₃N (117 mL, 841 mmol) under ice-bath, followed by MsCl

(55.1 mL, 712 mmol), and the mixture was stirred at room

temperature for 2 h. The mixture was poured into water (8.0 L)

and stirred for 0.5 h. The resultant solid was collected by ﬁltration,

washed with water, and dried to give 203 g (96%) of the title

compound. NMR (200 MHz, DMSO-d₆) δ: 2.65-3.04 (2H, m),

3.20 (3H, s), 4.14-4.44 (3H, m), 7.10-7.40 (5H, m), 9.51 (1H,

br, d, J ) 8 Hz). MS (ES) m/e: 348 (M + Na).

tert-Butyl [(2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl][(1R)-2-(4-

iodophenyl)-1-methylethyl]carbamate (40). Compound 40 was pre-

pared following the procedure C using 2-chloro-5-[(2R)-2-

1

oxiranyl]pyridine 35 instead of 33 in 35% yield. H NMR (400

MHz, CDCl₃) δ: 1.17 (3H, d, J ) 6.5 Hz), 1.36 (9H, s), 2.51-2.65

(2H, m), 3.0-3.1 (2H, m), 3.5-3.6 (1H, m), 4.1-4.2 (1H, m),

4.7-4.8 (1H, m), 5.49 (1H, br), 6.82-6.85 (2H, m), 6.34 (2H, d,

J ) 8.2 Hz), 7.58-7.62 (2H, m), 7.74-7.77 (1H, m), 8.36 (1H, d,

J ) 1.7 Hz). MS (ES) m/e: 517 (M + H).

tert-Butyl[(1S)-2-hydroxy-1-(4-iodobenzyl)ethyl][(2R)-2-hydroxy-2-

phenylethyl] carbamate (41). A solution of 37 (5 g, 18.0 mmol) and

(2R)-2-phenyloxirane 34 (2 g, 16.6 mmol) in ethanol (50 mL) was

reﬂuxed for 18 h. The mixture was evaporated under reduced

pressure. The residual oil was diluted in THF (50 mL). To the

solution was added di-tert-butyl dicarbonate (5 g, 22.9 mmol) at

room temperature, and the mixture was stirred at the same

temperature for 12 h. The resulting mixture was evaporated under

pressure, and the residue was puriﬁed by column chromatography

on silica gel (hexane/EtOAc ) 2/1)to give 5.5 g (45%) of title

compound. MS (ES) m/e: 498 (M + H).

2,2,2-Triﬂuoro-N-[(1R)-1-methyl-2-phenylethyl]acetamide (50). To

a solution of 49 (90 g, 277 mmol) in DME (1.8 L) and AcOH

(31.7 mL) was added NaI (166 g, 1.11 mol) by portions, followed

by Zn powder (145 g, 2.21 mol), and the mixture was reﬂuxed for

1.5 h. After cooling to room temperature, the mixture was quenched

by the addition of water (90 mL) and stirred for 0.5 h. The insoluble

materials was removed by ﬁltration and washed with EtOH. The

ﬁltrate was evaporated under reduced pressure. The residue was

partitioned between EtOAc (700 mL) and 1 N aqueous HCl solution

(900 mL). The organic layer was separated, washed with 5%

aqueous NaHSO₃solution, saturated aqueous NaHCO₃solution,

and brine, dried over MgSO₄, and evaporated under reduced

pressure to give 58.4 g (91%) of the title compound. ¹H NMR (200

MHz, CDCl₃) δ: 1.21 (3H, d, J ) 7.0 Hz), 2.80 (1H, dd, J ) 14.0

and 7.0 Hz), 4.29 (1H, m), 6.12 (1H, br s), 7.14-7.37 (5H, m).

tert-Butyl

[(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-{[tert-

butyl(dimethyl)silyl]oxy}ethyl][2-(4-bromophenyl)ethyl]carbamate (43).

To a mixture of 42 (3.50 g, 7.53 mmol), 27 (3.01 g, 15.1 mmol),

and DMSO (1.75 mL) was added diisopropylethylamine (1.31 mL,

7.53 mmol), and the mixture was stirred at 80 °C for 24 h. After

cooling to room temperature, the mixture was diluted with ethyl

acetate (35 mL) and water (35 mL) and the organic layer was

separated. The organic layer was washed with water (35 mL × 2)

and brine (35 mL), and dried over magnesium sulfate. Filtration

followed by evaporation gave a yellow paste (5.36 g), which was

chromatographed on silica gel (eluent: Hex/EtOAc ) 2/8-0/10)

to give 3.33 g (90%) of N-{5-[(1R)-2-{[2-(4-bromophenyl)ethy-

l]amino}-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]-2-

pyridinyl}acetamide as a colorless paste. ¹H NMR (200 MHz,

CDCl₃) δ: -0.17 (3H, s), -0.01 (3H, s), 0.81 (9H, s), 2.20 (s,

3H), 2.7-2.9 (6H, m), 4.76-4.82 (1H, m), 7.06 (2H, d, J ) 8.3

Hz), 7.40 (2H, d, J ) 8.3 Hz), 7.64 (1H, dd, J ) 2.2, 8.3 Hz),

8.1-8.2 (2H, m). MS (ES) m/e: 492, 494 (M + H).

MS (ES) m/e: 254 (M + Na). [R]²⁰+42.30° (c ) 1.00, CHCl₃).

D

2,2,2-Triﬂuoro-N-[(1R)-2-(4-iodophenyl)-1-methylethyl]aceta-

mide (51). To a mixture of 50 (3.76 g, 16.2 mmol) in H₂O (6.5

mL), AcOH (32.0 mL) and conc H₂SO₄was added I₂(1.65 g, 6.5

mol), followed by HIO₄·2H₂O (740 mg, 3.25 mol), and the mixture

was stirred at 70-80 °C for 5 h. After cooling to room temperature,

to the mixture was added water and extracted with EtOAc-Hex

(1:1, × 3). The combined extracts were washed with water, aqueous

Na₂SO₃solution, and brine, dried over MgSO₄, and evaporated

under reduced pressure to give crude product. The solid was

recrystallized from i-Pr₂O to give the title compound (2.16 g, 37%)

as a white solid. ¹H NMR (200 MHz, CDCl₃) δ: 1.21 (3H, d, J )

7 Hz), 2.74 (1H, dd, J ) 14 and 7 Hz), 2.85 (1H, dd, J ) 14 and

6 Hz), 4.26 (1H, m), 6.04 (1H, br s), 6.92 (2H, d, J ) 8 Hz), 7.65

(2H, d, J ) 8 Hz). MS (ES) m/e: 380 (M + Na).

To a solution of the product (3.32 g, 6.74 mmol) in THF (33

mL) was added Boc₂O (1.7 mL, 7.41 mmol), and the solution was

stirred at room temperature for 16 h. The solvent was removed by

evaporation, and the residue was chromatographed on silica gel

(Hex/EtOAc ) 2/1) to give 3.30 g (83%) of the title compound as

1

a white solid (foam). H NMR (200 MHz, CDCl₃) δ: <232 (3H,

s), -0.01 (3H, s), 0.86 (9H, s), 1.42 (9H, brs), 2.23 (s, 3H), 2.6-3.5

(6H, m), 4.8-5.1 (1H, m), 6.95-7.05 (1H, m), 7.38 (2H, d, J )

8.0 Hz), 7.67-7.80 (1H, m), 8.1-8.2 (2H, m). MS (ES) m/e: 614

and 616 (M + Na).

tert-Butyl

[(2R)-2-[6-(acetylamino)-3-pyridinyl]-2-{[tert-

butyl(dimethyl)silyl]oxy}ethyl] [2-(4-iodophenoxy)ethyl]carbamate (44).

Compound 44 was prepared from 42 and 22 according to the

procedures described for the conversion of 42 to 43 in 69% yield.

¹H NMR (200 MHz, CDCl₃) δ: -0.10 (3H, s), 0.05 (3H, s), 0.88

(9H, s), 1.45 (9H, s), 2.23 (s, 3H), 3.2-3.7 (4H, m), 3.9-4.0 (2H,

Benzyl [(2R)-2-{4-(benzyloxy)-3-nitro-phenyl}-2-hydroxyethyl][2-

(4-bromophenyl)ethyl]carbamate (55). Compound 55 was prepared

following the similar procedure B using oxirane 54 and Cbz-Cl

instead of (2R)-2-(4-chlorophenyl)oxirane and Boc₂O in 38% yield.

¹H NMR (200 MHz, CDCl₃) δ: 2.71 (2H, m), 3.18-3.42 (4H, m),

Biphenyl Benzoic Acid DeriVatiVes. Part II

Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 4019

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bioavailable ꢀ₃-adrenergic receptor agonists. Curr. Med. Chem. 2006,

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characterization of ꢀ-adrenoceptor agonists and antagonists. Curr. Top.

Med. Chem. 2007, 7, 207–216.

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3.95 (1H, br), 4.89 (1H, m), 5.11 (2H, s), 5.22 (2H, s), 6.9-7.1

(4H, m), 7.3-7.5 (12H, m), 7.83 (1H, m). MS (ES) m/e: 627 (M

+ Na).

Benzyl [(2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenyl}-2-

hydroxyethyl][2-(4-bromophenyl)ethyl]carbamate (56). To a solution

of 55 (7.5 g, 12.4 mmol) in a mixed solution of EtOH (150 mL)

and water (50 mL) were added iron powder (2.08 g, 37.2 mmol)

and NH₄Cl (331 mg, 6.19 mmol). The solution was reﬂuxed for

1.5 h. After cooling to room temperature, the precipitate was ﬁltered

through a pad of celite. After concentrated under reduced pressure,

the residue was partitioned between EtOAc and water. The organic

layer was separated, washed with water and brine, dried over

MgSO₄, and evaporated under reduced pressure to give aniline

product (6.88 g, 96.5%). To a solution of the product (6.87 g, 11.9

mmol) in pyridine (70 mL) was added MsCl (1.58 g, 13.7 mmol)

under ice-bath, and the mixture was stirred at room temperature

for 4.5 h. The mixture was partitioned between EtOAc and 1 N

aqueous HCl. The organic layer was separated, washed with water

and brine, dried over MgSO₄, and evaporated under reduced

pressure. The residue was puriﬁed by column chromatography on

silica gel (hexane/EtOAc ) 3/1-1/1) to give 4.18 g (53.6%) of

1

the title compound. H NMR (200 MHz, DMSO-d₆) δ: 2.70 (2H,

m), 2.86 (3H, s), 3.2-3.4 (4H, m), 4.6-4.7 (1H, m), 4.89 (1H,

m), 5.01 (2H, s), 5.15 (2H, s), 5.47 (1H, m), 7.01-7.15 (4H, m),

7.3-7.6 (13H, m), 8.95 (1H, s). MS (ES) m/e: 651, 653 (M + H).

3-Isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ben-

zoic acid (58). To a solution of methyl-4-bromo-3-methylbenzoate

57 (1.5 g, 5.79 mmol) in dioxane (30 mL) was added bis(pinaco-

late)diboron (1.47 g, 5.79 mmol), PdCl₂(dppf)·CHCl₃(473 mg, 0.58

mmol), and KOAc (2.27 g, 23.1 mmol), and the mixture was stirred

at 90 °C for 8 h under nitrogen. The mixture was diluted with

EtOAc and water. The organic layer was separated, washed with

brine, dried over MgSO₄, and evaporated to give 1.37 g (77%) of

the title compound, which was used in next step without further

1

puriﬁcation. H NMR (200 MHz, CDCl₃) δ: 1.26 (6H, d, J ) 6.8

Hz), 1.30 (s, 12H), 4.56-4.07 (1H, m), 7.25-7.29 (2H, m), 7.56

(1H, d, J ) 7.7 Hz).

N-(1,1-dimethyl-2-phenylethyl)-2,2,2-triﬂuoroacetamide (60). To an

ice-cooled solution of 59 (13.9 g) in THF (56 mL) were added

Et₃N (17 mL) and triﬂuoroacetic anhydride (14.5 mL). The mixture

was stirred at the same temperature for 6 h and partitioned between

ethyl acetate and saturated sodium bicarbonate solution. The organic

layer was separated, washed with brine, dried over magnesium

sulfate, and ﬁltered to give 19.8 g (86%) of the title compound.

NMR (200 MHz, DMSO-d₆) δ: 1.42 (6H, s), 3.05 (2H, s), 5.85

(1H, br s), 7.00-7.42 (5H, m). MS (ES) m/e: 268 (M + Na).

2,2,2-Triﬂuoro-N-[2-(4-iodophenyl)-1,1-dimethylethyl]acetamide (61).

Compound 61 was prepared from 60 according to the procedures

(10) Washburn, N. W.; Sher, M. P.; Poss, M. K.; Girotra, N. R.; McCann,

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1

described for the conversion of 50 to 51 in 55% yield. H NMR

(200 MHz, CDCl₃) δ: 1.40 (6H, s), 3.02 (2H, s), 5.79 (1H, br s),

6.86 (2H, d, J ) 8 Hz), 7.63 (2H, d, J ) 8 Hz). MS (ES) m/e: 394

(M + Na).

(12) Harada, H.; Hirokawa, Y.; Suzuki, K.; Hiyama, Y.; Oue, M.;

Kawashima, H.; Kato, H.; Yoshida, N.; Furutani, Y.; Shiro Kato, S.

Discovery of a Novel and Potent Human and Rat ꢀ₃-Adrenergic

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B. W.; Milliken, T.; Faison, W.; Brown, K.; Adkison, K. K.; Lee, F.

Synthesis and evaluation of potent and selective ꢀ₃adrenergic receptor

Acknowledgment. We express our thanks to Dr. David

Barrett for his critical reading for manuscript.

Supporting Information Available: Biological materials and

methods and combustion analysis data. This material is available

free of charge via the Internet at http://pubs.acs.org.

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penetration.

(20) See Supporting Information.

(21) (a) A dosing solution containing 9b, 9c, and 8b was prepared in

PEG400 and the dose of each compound was 0.1 mg/kg. After

administration of the dosing solution to dogs, the blood was collected

and centrifuged to separate plasma. The plasma samples were analyzed

by LC/MS/MS for determination of plasma concentrations of 9b, 9c,

JM8000345

Article Doi

Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human β3 adrenergic receptor agonists with good oral bioavailability. Part II

DOI: 10.1021/jm8000345

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