Orally active CCR5 antagonists as anti-HIV-1 agents 2: Synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety

DOI: 10.1248/cpb.52.818

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Chemical and Pharmaceutical Bulletin p. 818 - 829 (2004)

Update date:2022-08-05

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Authors:

Seto, Masaki

Aramaki, Yoshio

Imoto, Hiroshi

Aikawa, Katsuji

Oda, Tsuneo

Kanzaki, Naoyuki

Iizawa, Yuji

Baba, Masanori

Shiraishi, Mitsuru

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Article abstract of DOI:10.1248/cpb.52.818

In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previoiusly reported quaternary ammonium moiety. Among these compounds, the 2-(α-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC ₅₀=7.2 nM) and inhibitory effect (IC₅₀=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.

Full text of DOI:10.1248/cpb.52.818

818

Chem. Pharm. Bull. 52(7) 818—829 (2004)

Vol. 52, No. 7

Orally Active CCR5 Antagonists as Anti-HIV-1 Agents 2: Synthesis and

Biological Activities of Anilide Derivatives Containing a Pyridine N-Oxide

Moiety

Masaki S^ETO,*^,aYoshio A^RAMAKI,^aHiroshi I^MOTO,^aKatsuji A^IKAWA,^aTsuneo O^DA,^a

Naoyuki K^ANZAKI,^bYuji I^IZAWA,^cMasanori B^ABA,^dand Mitsuru S^HIRAISHI

^aMedicinal Chemistry Research Laboratries, Pharmaceutical Research Division, Takeda Chemical Industries Ltd.;

^bPharmaceutical Discovery Center, Pharmaceutical Research Division, Takeda Chemical Industries Ltd.; ^cPharmacology

Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries Ltd.; 2–17–85 Jusohonmachi,

Yodogawa-ku, Osaka 532–8686, Japan: and ^dDivision of Antiviral Chemotherapy, Center for Chronic Viral Diseases,

Faculty of Medicine, Kagoshima University; 8–35–1, Sakuragaoka, Kagoshima 890–8520, Japan.

Received February 25, 2004; accepted April 27, 2004; published online April 30, 2004

In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing

new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for

the previoiusly reported quaternary ammonium moiety. Among these compounds, the 2-(a-hydroxybenzyl)pyri-

dine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic proﬁle

in rats. Subsequent chemical modiﬁcation was performed and compound (S)-5f possessing the (S)-conﬁguration

hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-

methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in

the binding assay. In addition, introduction of a 3-triﬂuoromethyl group on the phenyl group of the anilide moi-

ety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular,

compound (S)-5s showed the most potent CCR5 antagonistic activity (IC₅₀ꢀ7.2 nM) and inhibitory effect

(IC₅₀ꢀ5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.

Key words CCR5 antagonist; HIV-1; 2-(a-hydroxybenzyl)pyridine N-oxide; (S)-conﬁguration; 1-benzazepine

Currently, human immunodeﬁciency virus type 1 (HIV-1) cause of its polar quaternary ammonium moiety. In order to

reverse transcriptase inhibitors and protease inhibitors are develop an orally active CCR5 antagonist, chemical modiﬁ-

used for the treatment of HIV-1 infection. Although combi- cation of the tertiary amine derivative was performed, which

nation chemotherapy, which uses these two types of anti- led to the discovery of the orally active 1-benzothiepine 1,1-

HIV-1 agents, has been successful for suppression of viral dioxide (3) and 1-benzazepine (4) derivatives.^12,13)In our pre-

load in HIV-1 infected individuals and reduction of vious paper, we described that incorporation of a 2-(butoxy)-

mortality,¹⁾it has been found that it can not achieve virus ethoxy group at the 4-position on the 7-phenyl group of the

eradication.²⁾Therefore, new anti-HIV-1 agents that target [6,7]fused nucleus resulted in both enhanced activity and im-

other events in the HIV-1 replication cycle are necessary and proved pharmacokinetic proﬁles, and introduction of an

recently, inhibition against HIV-1 cell entry or fusion, the isobutyl or 1-methylpyrazol-4-ylmethyl group as the 1-sub-

ﬁrst stage of the HIV-1 life cycle, is considered to be an at- stituent on the 1-benzazepine ring further increased the activ-

tractive target for viral coreceptor antagonists, gp120-medi- ity.¹³⁾We also searched for other polar substituents to replace

ated CD4 binding inhibitors and gp41-mediated HIV-1 fu- the quaternary ammonium moiety, and in our ﬁrst paper, we

sion inhibitors.³⁾Among these targets, the CC chemokine re- reported a phosphonium salt 2 as a lead compound of small-

ceptor 5 (CCR5), a coreceptor for macrophage-tropic (R5) molecule CCR5 antagonists.¹¹⁾We have now designed and

HIV-1 cell entry,^4—8)attracts many research groups to de- synthesized the anilide derivatives 5, containing phospho-

velop its antagonists.⁹⁾

nate, phosphine oxide or pyridine N-oxide moieties as new

The compound 1, which we ﬁrst reported as a small mole- polar substituents to replace the phosphonium salt and qua-

cule CCR5 antagonist, exhibited highly potent anti-HIV-1 ac- ternary ammonium salt moieties, and have examined their in-

tivity.^10,11)However, its oral absorption was very poor be- hibitory effects on chemokine binding (Fig. 1). In this paper,

Fig. 1

* To whom correspondence should be addressed. e-mail: Seto_Masaki@takeda.co.jp

July 2004

819

we describe the search for the new polar substituents, espe- quent catalytic hydrogenation of the resulting nitro com-

cially the 2-(a-hydroxybenzyl)pyridine N-oxides.

pounds 12a—d (Chart 3).

The optically active aniline derivatives (S)-8e and (R)-8e

were obtained by optical resolution of 8e utilizing a chiral

Chemistry

General synthetic methods to the target compounds are high-performance liquid chromatography (HPLC) (Chart 3).

outlined in Charts 6—8. The phosphonate 5a and phosphine The absolute conﬁguration was determined by X-ray crystal-

oxide 5b were prepared by condensation of the carboxylic lographic analysis (Fig. 2) of the m-bromobenzanilide (R)-

acid 19a with the aniline derivatives 8a, b (Chart 6). The tar- 13, which was prepared from the aniline (R)-8e (Chart 4).

get compounds 5c—s with the pyridine N-oxide moieties

The synthetic method for the anilines 8f—i, m is illus-

were synthesized by condensation of the carboxylic acids trated in Chart 5. Coupling reaction of the 4-ﬂuorobenzyl-

19a, b, 23 with aniline derivatives 8c—m, followed by m- cyanide with the 2-bromopyridines 14a—d and subsequent

chloroperbenzoic acid (mCPBA) oxidation (Charts 7, 8).

oxidative decyanation of the resulting 2-(a-cyanobenzyl)-

The aniline derivative 8a was prepared according to Chart pyridines 15a—d gave 2-(4-ﬂuorobenzoyl)pyridine deriva-

1. The nitro compound 7 with a cyclic phosphonate moiety tives 16a—d.¹⁶⁾The 2-benzoylpyridine 16e was synthesized

was synthesized by the reaction of 1,3-propanediol with the by coupling reaction of 2-lithiopyridine with the Weinreb

acid chloride, which was generated from the phosphonic acid amide 18, which was prepared from the benzoic acid 17. The

6. Catalytic hydrogenation of the nitro compound 7 gave the aniline derivatives 8f—i, m were prepared by reaction of the

key aniline 8a.

2-(4-ﬂuorobenzoyl)pyridines 16a—e with sodium azide and

The aniline derivatives 8b—d, containing a cyclic phos-

phine oxide or pyridyl moiety, were synthesized according to

Chart 2. Nitration of 9a—c¹⁴⁾gave the corresponding nitro

compounds 10a—c.¹⁵⁾The key anilines 8b—d¹⁵⁾were pre-

pared by catalytic hydrogenation of the nitro compounds

10a—c.

The 4-[hydroxyl(pyridin-2-yl)methyl]anilines 8e, 8j—l

were synthesized by coupling reaction of 2-lithiopyridine

with the corresponding benzaldehydes 11a—d and subse-

Chart 3

Chart 1

Fig. 2. Molecular Structure of (R)-13 as Determined by X-Ray Crystallo-

graphic Analysis

Chart 4

Chart 2

Chart 5

820

Vol. 52, No. 7

subsequent lithium aluminumhydride (LiAlH₄) reduction of acid 23. Coupling reaction of the carboxylic acid 23 with the

both the azide and carbonyl moieties. aniline derivatives 8e—m using 1-ethyl-3-(3-dimethylamino-

The target compounds 5a, b were prepared according to propyl)carbodiimide hydrochloride (EDC) and 1-hydroxy-

Chart 6. Coupling reaction of the 1-benzoxepine-4-car- benzotriazole (HOBt), followed by mCPBA oxidation gave

boxylic acid 19a¹¹⁾with the corresponding anilines 8a, b by the pyridine N-oxide derivatives 25a—i containing the N-tri-

the acid chloride method afforded the target phosphonate 5a ﬂuoroacetyl protected 1-benzazepine moiety. The target pyri-

and phospine oxide 5b.

dine N-oxide derivatives 5g—s were prepared by removal of

Synthesis of the target pyridine N-oxide compounds 5c—f the N-triﬂuoroacetyl group of 25a—i using sodium borohy-

containing the 1-benzoxepine or 1,1-dioxo-1-benzothiepine dride (NaBH₄)¹⁷⁾and subsequent reductive amination of the

ring moieties is illustrated in Chart 7. Conversion of the car- resulting 26a—i with the appropriate aldehydes.¹⁸⁾The opti-

boxylic acids 19a,¹¹⁾b¹³⁾into acid chlorides and subsequent cally active compounds (S)-5s and (R)-5s were obtained by

coupling with the aniline derivatives 8c—e gave the anilide optical resolution of racemate 5s utilizing chiral HPLC.

derivatives 20a—d containing the pyridine moieties. The tar-

get pyridine N-oxide derivatives 5c—f were prepared by Biological Results and Discussion

mCPBA oxidation of the pyridine derivatives 20a—d.

The compounds prepared were evaluated for their in-

The target 1-benzazepine derivatives 5g—s were prepared hibitory effects on chemokine binding to CCR5-expressing

according to Chart 8. Alkaline hydrolysis of the ester 21,¹³⁾CHO cells. Binding reactions were performed in the pres-

followed by triﬂuoroacetylation of the resulting carboxylic ence of [¹²⁵I]RANTES and various concentrations of the test

acid 22 gave 1-triﬂuoroacetyl-1-benzazepine-4-carboxylic compounds. The results are summarized in Tables 1 and 2 as

IC₅₀values. The compounds with potent binding inhibitory

activity were further evaluated for their inhibitory effects on

an HIV-1 envelope (Env)-mediated membrane fusion. The

membrane fusion assay was carried out using R5 HIV-1 (JR-

FL strain) Env-expressing COS-7 cells and CCR5-expressing

MOLT-4 cells. The results are summarized in Table 3 as IC₅₀

values.

First of all, the search for new polar substituents to replace

the quaternary ammonium moiety was performed while

keeping the 7-(4-methylphenyl)-1-benzoxepine moiety, which

contributed to the appearance of potent activity, as well as the

Chart 6

benzocycloheptane moiety of the quaternary ammonium de-

Chart 7

Chart 8

July 2004

821

Table 1. Physical Properties and Inhibitory Effects of Compounds 5 on Chemokine Binding to CCR5-Expressing CHO Cells

Compd.

Y¹

IC₅₀^a)(mM)

Yield (%)

mp (°C)

268—269

Recrystln solvent^c)

Formula

Anal.^d)

0.40

0.41

EA–ET

C₂₈H₂₈NO₅P

CHN

283—286

C₃₀H₃₂NO₃P

27%^b)

255—256 (dec.)

ET–C

C₂₉H₂₄N₂O₃·0.5H₂O

1.1

188—190

208—210

C₃₀H₂₆N₂O₃·0.3H₂O

C₃₀H₂₆N₂O₄·0.1H₂O

CHN

0.43

a) The concentration required to inhibit the binding of [¹²⁵I]RANTES to CCR5-expressing CHO cells by 50%. b) Percent inhibition at 10 mM. c) EAꢀethyl acetate,

ETꢀethanol, Cꢀchloroform. d) All compounds gave satisfactory elemental analysis (ꢁ0.4%) for C, H and N.

Table 2. Physical Properties and Inhibitory Effects of Compounds 5 on Chemokine Binding to CCR5-expressing CHO Cells

Compd.

R¹

R²

IC₅₀^a)(nM)

Yield (%)

mp (°C)

Recrystln solvent^b)

Formula

Anal.^c)

(S)-5f

(R)-5f

(S)-5g

(S)-5h

(S)-5i

SO₂

NPr

430

3600

125—128

104—107

87—89

amorphous

85—88

ET–EA

—

C₃₅H₃₆N₂O₇S·1.0H₂O

C₃₈H₄₃N₃O₅·0.5H₂O

C₃₉H₄₅N₃O₅·0.75H₂O

C₃₉H₄₃N₃O₅·1.0H₂O

CHN

N-i-Bu

EA–IPE

(S)-5j

(S)-5k

N-Bn

89—93

94—97

EA–IPE

C₄₂H₄₃N₃O₅·1.0H₂O

C₄₀H₄₃N₅O₅·0.75H₂O

CHN

(S)-5s

(R)-5s

N-i-Bu

3-Me

4-Me

5-Me

6-Me

130

210

180

7.2

—

amorphous

114—116

amorphous

105—107

amorphous

—

EA–IPE

—

EA–H

—

C₄₀H₄₇N₃O₅·1.25H₂O

C₄₀H₄₇N₃O₅·0.5H₂O

C₄₀H₄₇N₃O₅

C₄₀H₄₇N₃O₅·0.5H₂O

C₄₀H₄₇N₃O₆·0.25H₂O

C₃₉H₄₄ClN₃O₅·0.25H₂O

C₄₀H₄₄F₃N₃O₅·0.5H₂O

CHN

MeO

CF₃

—

a) The concentration required to inhibit the binding of [¹²⁵I]RANTES to CCR5-expressing CHO cells by 50%. b) ETꢀethanol, EAꢀethyl acetate, IPEꢀdiisopropyl ether,

H=hexane. c) All compounds gave satisfactory elemental analysis (ꢁ0.4%) for C, H and N.

rivatives. Based on our experience, we designed derivatives studies in SD (IGS) rats, it was found that the pyridine N-

with 6-membered phosphonate, phosphine oxide or pyridine oxide derivative 5e exhibited the best oral absorption among

N-oxide moieties as the polar substituents and examined their the compounds (5a, b, e) (details not shown). Thus, its C_max

inhibitory effects on chemokine binding (Table 1). The com- and AUC_{0—24 h}values were 0.09 mg/ml and 1.14 mg·h/ml

pounds with the polar phosphonate (5a) and phosphine oxide (10 mg/kg, p.o.), respectively. Therefore, we selected the 2-

(5b) moieties inhibited the binding with IC₅₀values of (a-hydroxybenzyl)pyridine N-oxide moiety as a new polar

0.40 mM and 0.41 mM, respectively. However, the biaryl type substituent to replace the quaternary ammonium moiety. For

pyridine N-oxide derivative 5c exhibited weak inhibitory ac- the previous tertiary amine derivatives, we described that

tivity. Insertion of the methylene group (5d) between the both replacement of the 1-benzoxepine ring with the 1,1-

pyridine and benzene moieties of 5c resulted in a moderate dioxo-1-benzothiepine or a 1-(bulky)alkyl-1-benzazepine ring

increase of activity. Interestingly, introduction of a hydroxy and substitution with the 2-(butoxy)ethoxy group at the 4-po-

group onto the methylene of 5d led to further enhancement sition on the phenyl group of the [6,7]fused nucleus, in-

of activity, and the compound 5e was as active as the phos- creased the activity. Therefore, we investigated the 1,1-dioxo-

phonate 5a and phosphine oxide 5b. It was considered that a 1-benzothiepine or 1-alkyl-1-benzazepine with the 4-[2-(bu-

further increase of polarity by introduction of a hydroxy toxy)ethoxy]phenyl group in place of the 1-benzoxepine with

group in the neighborhood of the pyridine N-oxide moiety the 4-methylphenyl group. The effect of the conﬁguration of

might contribute to improving the binding capability of the the hydroxy group was ﬁrst examined, keeping the 1,1-dioxo-

active site. From the results of preliminary pharmacokinetic 1-benzothiepine moiety. As shown in Table 2, compound (S)-

822

Vol. 52, No. 7

Table 3. Inhibitory Effects of Compounds 5 on HIV-1 Env-mediated

Membrane Fusion

5f possessing the (S)-conﬁguration hydroxy group was about

8 times more active than the (R)-isomer (R)-5f, which indi-

cated that not only the pyridine N-oxide moiety but also the

(S)-conﬁguration hydroxy group was necessary for inhibitory

activity. Although the optically active 1-benzothiepine 1,1-

dioxide (S)-5f was as active as the racemic 1-benzoxepine 5e,

the 1-propyl-1-benzazepine (S)-5g enhanced the activity

about 11 times.

Secondly, we also examined the effects of the 1-substituent

on the 1-benzazepine ring (Table 2). Consequently, the 1-cy-

clopropylmethyl compound (S)-5i was found to be as active

as the propyl compound (S)-5g. Replacement of the propyl

group with the isobutyl ((S)-5h), benzyl ((S)-5j) or 1-

methylpyrazol-4-ylmethyl ((S)-5k) group led to slight in-

crease of activity. These results were generally similar to

those of the tertiary amine derivatives. Next, the inhibitory

effects of the compounds (S)-5h and (S)-5k on the HIV-1

Env-mediated membrane fusion were tested. As shown in

Table 3, the inhibitory effects in the fusion assay were signiﬁ-

cantly weaker than those in the binding assay.

In an attempt to alter the activity in the fusion assay, we

tried to sterically cover some parts of the 2-(a-hydroxyben-

zyl)pyridine N-oxide moiety. Namely, assuming that activity

might be related to protein binding in the fusion assay, we in-

vestigated introduction of substituents on the pyridine ring

and benzene ring of the anilide moiety. We selected the

isobutyl group as the 1-substituent on the 1-benzazepine ring

considering activity, ease of synthesis and molecular weight,

and the racemic compounds 5l—s were prepared and tested

(Table 2). Introduction of a methyl group at the 4-position on

the pyridine ring (5m) retained the activity in the binding

assay, whereas substitution of a methyl group at the 3-, 5- or

6-position (5l, n, o) decreased the activity. Introduction of a

methyl (5p), methoxy (5q) or chloro (5r) group at the 3-posi-

RANTES

IC₅₀^a)(nM)

Fusion

Compd.

R³

R¹

R²

IC₅₀^b)(nM)

—

i-Bu

—

1.4

4000

(S)-5h

(S)-5k

7100

(S)-5s

i-Bu

MeO

7.2

170

610

1500

2300

5.4

CF₃

a) The concentration required to inhibit the binding of [¹²⁵I]RANTES to CCR5-ex-

pressing CHO cells by 50%. b) The concentration required to inhibit the membrane

fusion between HIV-1 Env-expressing COS-7 cells and CCR5-expressing MOLT-4 cells

by 50%.

Table 4. Pharmacokinetic Parameters of Compound (S)-5s in Rats

p.o.

Dose (mg/kg)^a)

C_max(mg/ml)^b)

T_max(h)^c)

2.33

4.00

33.1

AUC_{0—24 h}(mg·h/ml)^d)

a) Compound (10 mg/kg) suspended in 0.5% methylcellulose was orally adminis-

tered to SD (IGS) rats (male, 8 weeks old, nꢀ3). b) Maximum plasma concentration

after 10 mg/kg oral dosing. c) Time to C_max

d) Area under the concentration time

curve for 0—24 h after 10 mg/kg oral dosing.

tion on the benzene ring, neighboring the hydroxy group, re- cated in Table 4. The C_maxand AUC_{0—24 h}values of com-

tained the activity. Compound 5s with a triﬂuoromethyl pound (S)-5s were 2.33 mg/ml and 33.1 mg·h/ml, respec-

group at the same position was as active as compound (S)- tively, and compound (S)-5s exhibited high plasma level in

5h. Optically active compound (S)-5s showed highly potent rats.

inhibitory activity (IC₅₀ꢀ7.2 nM), and was about 6 times

more active then the (R)-isomer. Additionally, the inhibitory Conclusion

effects of the compounds [5m, 5p—r, (S)-5s], with potent

In order to develop orally active CCR5 antagonists, a

binding inhibitory activity, on the HIV-1 Env-mediated mem- search for polar substituents, such as phosphonate, phosphine

brane fusion were examined (Table 3). Introduction of sub- oxide and pyridine N-oxide moieties, to replace the quater-

stituents onto the 2-(a-hydroxybenzyl)pyridine N-oxide moi- nary ammonium moiety of the anilide derivative 1 was per-

ety was generally effective in the fusion assay, when com- formed. Among the 1-benzoxepine and 1-benzothiepine 1,1-

pared with compound (S)-5h, which showed activity about dioxide derivatives containing the polar substituents, it was

270 times lower than that of the binding assay. The 4- found that the 2-(a-hydroxybenzyl)pyridine N-oxide showed

methylpyridine N-oxide 5m inhibited the membrane fusion CCR5 antagonistic activity and oral absorption in rats, and

with an IC₅₀value of 170 nM. Compound 5p, with 3-methyl that the compound possessing the (S)-conﬁguration hydroxy

group on the phenyl group, exhibited moderate activity. Sur- group was more active than the (R)-isomer. Further investiga-

prisingly, introduction of a 3-triﬂuoromethyl group on the tion of the 2-(a-hydroxybenzyl)pyridine N-oxide derivatives

phenyl group, led to a great enhancement of activity. Thus, containing the 1-benzazepine moiety led to discovering that

optically active compound (S)-5s strongly inhibited the mem- introduction of a triﬂuoromethyl group at the 3-position on

brane fusion with an IC₅₀value of 5.4 nM, and the effect was the phenyl group signiﬁcantly enhanced activity in the HIV-1

equivalent to that in the binding assay. Compound (S)-5s Env-mediated membrane fusion assay. In particular, the opti-

showed highly potent effects both in the binding and fusion cally active compound (S)-5s exhibited highly potent CCR5

assays, comparable to the quaternary ammonium compound antagonistic activity and inhibitory effect on the membrane

fusion, comparable to compound 1, together with good phar-

Finally, preliminary pharmacokinetic studies of compound macokinetic properties in rats. These results showed the pos-

(S)-5s were investigated. Compound (S)-5s was orally admin- sibility that the (S)-2-(a-hydroxybenzyl)pyridine N-oxide

istered at 10 mg/kg to SD (IGS) rats and the results are indi- moiety might replace the tertiary amine moiety as a polar

July 2004

823

2-(4-Aminobenzyl)pyridine (8d) This compound was prepared in 85%

yield from 10c by a method similar to that described for 8a, yellow oil. H-

substituent for orally active CCR5 antagonists.

NMR (CDCl₃) d: 3.41—3.75 (2H, m), 4.05 (2H, s), 6.50—6.69 (2H, m),

6.97—7.16 (4H, m), 7.51—7.60 (1H, m), 8.48—8.57 (1H, m).

Experimental

Melting points were determined on a Yanagimoto micro melting point ap-

paratus, and are uncorrected. Proton nuclear magnetic resonance (¹H-NMR)

spectra were recorded on a Varian Gemini-200 (200 MHz) spectrometer.

Chemical shifts are given in parts per million (ppm) with tetramethylsilane

as an internal standard, and coupling constants (J values) are given in Hertz

(Hz). Optical resolutions were recorded with a Jasco DIP-370 or P-1030 dig-

ital polarimeter. Elemental analyses were carried out by Takeda Analytical

Research Laboratories, Ltd., and results obtained were within ꢁ0.4% of the

theoretical values. Column chromatography was carried out on a silica gel

column (Kieselgel 60, 63—200 mesh, Merck). Yields were not optimized.

2-(4-Nitrobenzyl)-1,3,2-dioxaphosphorinane 2-oxide (7) To a mixture

of 6 (22.7 g, 105 mmol) and pyridine (17.8 ml, 220 mmol) in THF (500 ml)

was added oxalyl chloride (19.2 ml, 220 mmol) at ꢂ78 °C. The mixture was

stirred at ꢂ78 °C for 0.5 h and at room temperature for 1.5 h. The precipi-

tated solid was removed by ﬁltration, and the ﬁltrate was concentrated in

vacuo. To a solution of the residue in THF (500 ml) was added dropwise a

solution of 1,3-propanediol (8.00 g, 105 mmol) in acetonitrile (30 ml) at

ꢂ78 °C. Then pyridine (17.8 ml, 220 mmol) was added to the mixture at

ꢂ78 °C, and the mixture was stirred at room temperature for 15 h. The pre-

cipitate was ﬁltered off on a plug of MgSO₄, and the ﬁltrate was concen-

trated in vacuo. The residue was puriﬁed by column chromatography

(EtOAcÆEtOAc : MeOH : Et₃Nꢀ100 : 10 : 1) to give 7.00 g (26%) of 7 as

2-Methyl-4-nitrobenzaldehyde (11b) A mixture of 1,2-dimethyl-4-ni-

trobenzene (25.68 g, 170 mmol), N-bromosuccinimide (NBS) (31.8 g, 179

mmol) and 2,2ꢃ-azobis(isobutyronitrile) (AIBN) (cat. amount) in EtOAc

(400 ml) was reﬂuxed for 7.5 h. NBS (10.5 g, 59.0 mmol) and AIBN (cat.

amount) were added to the reaction mixture and the mixture was reﬂuxed for

20 h. The mixture was concentrated in vacuo and the residue was puriﬁed by

column chromatography (hexane : EtOAcꢀ20 : 1) to give a pale yellow oil.

A mixture of the oil and NaOAc (61.6 g, 751 mmol) in AcOH (200 ml) was

stirred at 120 °C for 7 h. The mixture was concentrated in vacuo. To the

residue was added aqueous NaHCO₃and the mixture was extracted with

EtOAc. The organic layer was washed with water and brine, dried over

MgSO₄, and concentrated in vacuo. The residue was puriﬁed by column

chromatography (hexane : EtOAcꢀ10 : 1) to give a pale yellow oil. To a so-

lution of the oil in MeOH (300 ml) was added NaOH (7.4 g, 185 mmol) at

room temperature, and the mixture was reﬂuxed for 2 h. The mixture was

concentrated in vacuo and the residue was neutralized using 1 N HCl. The

mixture was extracted with EtOAc. The organic layer was washed with water

and brine, dried over MgSO₄, and concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane : EtOAcꢀ2 : 1) to give yellow

crystals. A mixture of the crystals and activated MnO₂(8.90 g) in acetone

(100 ml) was stirred at room temperature for 20 h. MnO₂was removed by ﬁl-

tration, and the ﬁltrate was concentrated in vacuo. The residue was puriﬁed

by column chromatography (hexane : EtOAcꢀ20 : 1) to give 1.38 g (5%) of

11b as colorless crystals. Compound 11b was used in the next reaction with-

colorless crystals, mp 144—145 °C. H-NMR (CDCl₃) d: 1.85—1.97 (2H,

m), 3.36 (2H, d, Jꢀ22.0 Hz), 4.10—4.28 (2H, m), 4.46—4.62 (2H, m), 7.49

(2H, dd, Jꢀ9.0, 2.0 Hz), 8.20 (2H, d, Jꢀ8.0 Hz). Anal. Calcd for

C₁₀H₁₂NO₅P: C, 46.70; H, 4.70; N, 5.45. Found: C, 46.56; H, 4.75; N, 5.38.

4-[(2-Oxido-1,3,2-dioxaphosphorinan-2-yl)methyl]aniline (8a) A mix-

ture of 7 (7.00 g, 27.2 mmol) and 10% Pd–C (50% wet, 0.50 g) in EtOH

(100 ml) and EtOAc (50 ml) was stirred at room temperature for 19 h under a

hydrogen atmosphere. The catalyst was removed by ﬁltration and the ﬁltrate

was concentrated in vacuo. The residue was puriﬁed by recrystallization

from EtOAc–hexane to give 5.68 g (92%) of 8a as colorless crystals, mp

172—173 °C. ¹H-NMR (CDCl₃) d: 1.68—1.94 (2H, m), 3.16 (2H, d,

Jꢀ21.0 Hz), 3.66 (1H, br s), 3.99—4.16 (2H, m), 4.35—4.51 (2H, m), 6.65

(2H, dd, Jꢀ9.0, 1.0 Hz), 7.07 (1H, d, Jꢀ9.0, 3.0 Hz). Anal. Calcd for

C₁₀H₁₄NO₃P: C, 52.87; H, 6.21; N, 6.16. Found: C, 52.83; H, 6.26; N, 5.91.

1-(4-Nitrobenzyl)phosphorinane 1-Oxide (10a) To a mixture of nitric

acid (1.94 ml) and sulfuric acid (15 ml) was added 9a¹⁴⁾(5.39 g, 25.9 mmol)

under ice cooling. It was stirred at 50 °C for 2 d. The reaction mixture was

poured into ice. The mixture was neutralized using aqueous ammonia, and

the mixture was extracted with EtOAc. The organic layer was washed with

brine, dried over MgSO₄, and concentrated in vacuo. The residue was puri-

ﬁed by column chromatography (EtOAc : EtOHꢀ9 : 1Æ2 : 1) to give 2.47 g

out further puriﬁcation. H-NMR (CDCl₃) d: 2.80 (3H, s), 8.00 (1H, d, Jꢀ

8.0 Hz), 8.16—8.22 (2H, m), 10.40 (1H, s).

2-Methoxy-4-nitrobenzaldehyde (11c) This compounds was prepared

in 45% yield from 2-methoxy-4-nitrotoluene by a method similar to that de-

scribed for 11b; colorless crystals (EtOAc–hexane), mp 119—124 °C. H-

NMR (CDCl₃) d: 4.06 (3H, s), 7.86—7.91 (2H, m), 8.00 (1H, d, Jꢀ8.8 Hz),

10.53 (1H, s). Anal. Calcd. for C₈H₇NO₄: C, 53.04; H, 3.89; N, 7.73. Found:

C, 53.16; H, 3.81; N, 7.54.

2-Chloro-4-nitrobenzaldehyde (11d) To a suspension of NaBH₄(10.7

g, 283 mmol) in 1,2-dimethoxyethane (150 ml) was added 2-chloro-4-ni-

trobenzoyl chloride (25 g, 114 mmol) under ice cooling, and the mixture was

stirred at room temperature for 1 h. The mixture was concentrated in vacuo.

Water was added to the residue and the mixture was extracted with EtOAc.

The organic layer was washed with 1 N HCl, 1 N NaOH, water and brine,

dried over MgSO₄, and concentrated in vacuo. A mixture of the residue

(17.0 g) and activated MnO₂(50.0 g) in acetone (200 ml) was stirred over

night at room temperature. MnO₂was removed by ﬁltration, and the ﬁltrate

was concentrated in vacuo. The residue was puriﬁed by column chromatog-

raphy (hexane : EtOAcꢀ9 : 1) to give 12.1 g (58%) of 11d as yellow crystals.

Compound 11d was used in the next reaction without further puriﬁcation.

¹H-NMR (200 MHz, CDCl₃) d: 8.11 (1H, d, Jꢀ9.2 Hz), 8.21—8.27 (1H, m),

8.36 (1H, d, Jꢀ2.2 Hz), 10.55 (1H, s).

(38%) of 10a as colorless crystals, mp 173—175 °C. H-NMR (CDCl₃) d:

1.46—2.18 (10H, m), 3.28 (2H, d, Jꢀ13.6 Hz), 7.48 (2H, dd, Jꢀ8.8,

2.2 Hz), 8.21 (2H, d, Jꢀ8.8 Hz). Anal. Calcd for C₁₂H₁₆NO₃P: C, 56.92; H,

6.37; N, 5.53. Found: C, 57.02; H, 6.42; N, 5.25.

(4-Nitrophenyl)(pyridin-2-yl)methanol (12a) To a solution of 2-bro-

mopyridine (9.09 g, 57.5 mmol) in Et₂O (200 ml) was added dropwise a so-

lution of n-BuLi in hexane (1.6 M, 39.6 ml, 63.3 mmol) at ꢂ78 °C. After

being stirred at ꢂ78 °C for 1 h under an argon atmosphere, a solution of 8a

(8.70 g, 57.5 mmol) in tetrahydrofuran (THF) (50 ml) was added to the reac-

tion mixture at ꢂ78 °C. The mixture was stirred at ꢂ78 °C for 3 h under an

argon atmosphere. Water was added to the reaction mixture and the mixture

was extracted with EtOAc. The organic layer was washed with brine, dried

over MgSO₄, and concentrated in vacuo. The residue was puriﬁed by column

chromatography (toluene : EtOAcꢀ10 : 1Æ4 : 1Æ2 : 1) and recrystallization

from diisopropyl ether (i-Pr₂O) to give 4.5 g (34%) of 9a as orange crystals,

4-[(1-Oxidophosphorinan-1-yl)methyl]aniline (8b) This compound

was prepared in 76% yield from 10a by a method similar to that described

for 8a, pale yellow crystals (EtOAc–hexane), mp 163—166 °C. ¹H-NMR

(CDCl₃) d: 1.27—2.16 (10H, m), 3.06 (2H, d, Jꢀ13.8 Hz), 3.53—3.80 (2H,

m), 6.65 (2H, d, Jꢀ8.3 Hz), 7.05 (2H, dd, Jꢀ8.3, 2.0 Hz). Anal. Calcd for

C₁₂H₁₈NOP: C, 64.56; H, 8.13; N, 6.27. Found: C, 64.19; H, 8.16; N, 6.15.

2-(4-Aminophenyl)pyridine (8c)¹⁵⁾This compound was prepared in

26% yield from 9b according to literature procedure, pale yellow crystals

(diethyl ether (Et₂O)), mp 75—76 °C. ¹H-NMR (CDCl₃) d: 3.63—4.02 (2H,

m), 6.73—6.83 (2H, m), 7.06—7.17 (1H, m), 7.58—7.74 (2H, m), 7.79—

7.89 (2H, m), 8.58—8.66 (1H, m). Anal. Calcd for C₁₁H₁₀N₂: C, 77.62; H,

5.92; N, 16.46. Found: C, 77.63; H, 5.90; N, 16.46.

mp 114—115 °C. H-NMR (CDCl₃) d: 5.44 (1H, br s), 5.86 (1H, s), 7.14—

7.29 (2H, m), 7.55—7.73 (3H, m), 8.20 (2H, d, Jꢀ8.8 Hz), 8.59 (1H, d,

Jꢀ5.0 Hz). Anal. Calcd for C₁₂H₁₀N₂O₃: C, 62.61; H, 4.38; N, 12.17. Found:

C, 62.61; H, 4.27; N, 12.16.

The following compounds (12b—d) were prepared from 11b—d by a

method similar to that described for 12a.

(2-Methyl-4-nitrophenyl)(pyridin-2-yl)methanol (12b) Yield 44%,

pale brown crystals (EtOAc–hexane), mp 119—121 °C (dec.). ¹H-NMR

(CDCl₃) d: 2.46 (3H, s), 5.22 (1H, s), 6.02 (1H, s), 7.00 (1H, d, Jꢀ7.8 Hz),

7.23—7.30 (1H, m), 7.48 (1H, d, Jꢀ8.8 Hz), 7.66 (1H, dt, Jꢀ1.8, 7.7 Hz),

8.00—8.05 (2H, m), 8.62 (1H, d, Jꢀ3.6 Hz). Anal. Calcd for C₁₃H₁₂N₂O₃: C,

63.93; H, 4.95; N, 11.47. Found: C, 64.12; H, 4.86; N, 11.34.

2-(4-Nitrobenzyl)pyridine (10c) To a mixture of nitric acid (2.1 ml)

and sulfuric acid (15 ml) was added 9c (4.5 ml, 28.0 mmol) under ice cool-

ing. The mixture was stirred at 50 °C for 5 min. The mixture was poured into

ice, and the mixture was basiﬁed using aqueous ammonia. The mixture was

extracted with Et₂O. The organic layer was washed with brine, dried over

MgSO₄, and concentrated in vacuo. The residue was puriﬁed by column

chromatography (hexane : EtOAcꢀ1 : 1) and recrystallization form

EtOAc–hexane to give 3.40 g (57%) of 10c as pale yellow crystals, mp 95—

96 °C. H-NMR (CDCl₃) d: 4.25 (2H, s), 7.11—7.23 (2H, m), 7.43 (2H, d,

Jꢀ8.8 Hz), 7.64 (1H, dt, Jꢀ7.6, 1.8 Hz), 8.16 (2H, d, Jꢀ8.8 Hz), 8.54—8.60

(1H, m). Anal. Calcd for C₁₂H₁₂N₂O₂: C, 67.28; H, 4.71; N, 13.08. Found: C,

67.33; H, 4.69; N, 13.34.

(2-Methoxy-4-nitrophenyl)(pyridin-2-yl)methanol (12c) Yield 55%,

824

Vol. 52, No. 7

pale yellow crystals (EtOAc–hexane), mp 126—129 °C (dec.). ¹H-NMR

(CDCl₃) d: 4.00 (3H, s), 5.40 (1H, d, Jꢀ4.2 Hz), 6.24 (1H, d, Jꢀ4.2 Hz),

7.19—7.31 (2H, m), 7.57 (1H, d, Jꢀ8.4 Hz), 7.64 (1H, dt, Jꢀ7.7, 1.8 Hz),

7.76 (1H, d, Jꢀ2.2 Hz), 7.84 (1H, dd, Jꢀ8.4, 1.8 Hz), 8.56 (1H, d,

Jꢀ5.2 Hz). Anal. Calcd for C₁₃H₁₂N₂O₄: C, 60.00; H, 4.65; N, 10.76. Found:

C, 60.09; H, 4.58; N, 10.60.

(2-Chloro-4-nitrophenyl)(pyridin-2-yl)methanol (12d) Yield 30%,

yellow crystals (EtOAc–hexane), mp 124—127 °C. ¹H-NMR (CDCl₃) d:

5.61 (1H, d, Jꢀ2.2 Hz), 6.32 (1H, d, Jꢀ2.2 Hz), 7.24—7.30 (2H, m), 7.63—

7.72 (2H, m), 8.10 (1H, dd, Jꢀ8.2, 2.6 Hz), 8.28 (1H, d, Jꢀ2.6 Hz), 8.58—

8.62 (1H, m). Anal. Calcd for C₁₂H₉ClN₂O₃: C, 54.46; H, 3.43; N, 10.58.

Found: C, 54.61; H, 3.38; N, 10.38.

reaction mixture was poured into water and the mixture was extracted with

EtOAc. The organic layer was washed with brine, dried over MgSO₄, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtOAcꢀ3 : 1) to give 5.14 g (77%) of 15a as a brown oil. ¹H-NMR

(CDCl₃) d: 2.27 (3H, s), 5.45 (1H, s), 7.00—7.10 (2H, m), 7.19—7.26 (1H,

m), 7.32—7.39 (2H, m), 7.48—7.57 (1H, m), 8.51—8.54 (1H, m).

The following compounds (15b—d) were prepared from 14b—d by a

method similar to that described for 15a.

(4-Fluorophenyl)(4-methylpyridin-2-yl)acetonitrile (15b) Yield 46%,

brown oil. H-NMR (CDCl₃) d: 2.36 (3H, s), 5.26 (1H, s), 7.02—7.11 (3H,

m), 7.21 (1H, s), 7.39—7.46 (2H, m), 8.44 (1H, d, Jꢀ5.0 Hz).

(4-Fluorophenyl)(5-methylpyridin-2-yl)acetonitrile (15c) Yield 69%,

yellow oil. ¹H-NMR (CDCl₃) d: 2.34 (3H, s), 5.26 (1H, s), 7.02—7.10 (2H,

m), 7.28 (1H, d, Jꢀ8.0 Hz), 7.37—7.44 (2H, m), 7.52 (1H, dd, Jꢀ8.0,

2.0 Hz), 8.42 (1H, d, Jꢀ2.2 Hz).

(4-Fluorophenyl)(6-methylpyridin-2-yl)acetonitrile (15d) Yield 83%,

yellow oil. ¹H-NMR (CDCl₃) d: 2.56 (3H, s), 5.26 (1H, s), 7.02—7.18 (4H,

m), 7.39—7.46 (2H, m), 7.59 (1H, t, Jꢀ7.7 Hz).

2-(4-Fluorobenzoyl)-3-methylpyridine (16a) A solution of 15a (5.14

g, 22.7 mmol) and K₂CO₃(2.90 g, 21.0 mmol) in dimethylsulfoxide (DMSO)

(250 ml) and water (50 ml) was stirred at room temperature for 6 d under an

oxygen atmosphere. The reaction mixture was poured into water and the

mixture was extracted with EtOAc. The organic layer was washed with

brine, dried over MgSO₄, and concentrated in vacuo. The residue was puri-

ﬁed by column chromatography (hexane : EtOAcꢀ4 : 1) to give 5.17 g

(quant.) of 16a as an orange oil. ¹H-NMR (200 MHz, CDCl₃) d: 7.10—7.20

(2H, m), 7.35 (1H, dd, Jꢀ7.6, 4.8 Hz), 7.68 (1H, d, Jꢀ7.6 Hz), 7.89—7.96

(2H, m), 8.33 (1H, d, Jꢀ4.4 Hz).

The following compounds (8e, j, k) were prepared from 12a—c by a

method similar to that described for 8a.

(4-Aminophenyl)(pyridin-2-yl)methanol (8e) Yield 95%, pale yellow

crystals (EtOAc–hexane), mp 139—140 °C. H-NMR (CDCl₃) d: 3.65 (2H,

br s), 5.14 (1H, br s), 5.65 (1H, s), 6.65 (2H, d, Jꢀ8.8 Hz), 7.10—7.22 (4H,

m), 7.61 (1H, dt, Jꢀ1.8, 7.6 Hz), 8.55 (1H, d, Jꢀ4.8 Hz). Anal. Calcd for

C₁₂H₁₂N₂O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.76; H, 6.01; N, 13.82.

(4-Amino-2-methylphenyl)(pyridin-2-yl)methanol (8j) Yield 58%,

colorless crystals, mp 102—104 °C. ¹H-NMR (CDCl₃) d: 2.24 (3H, s), 3.60

(2H, br), 5.00 (1H, d, Jꢀ3.2 Hz), 5.86 (1H, d, Jꢀ3.2 Hz), 6.45—6.50 (2H,

m), 6.95 (1H, d, Jꢀ8.0 Hz), 7.05 (1H, d, Jꢀ7.8 Hz), 7.15—7.22 (1H, m),

7.60 (1H, dt, Jꢀ7.7, 1.4 Hz), 8.57 (1H, d, Jꢀ5.2 Hz). Anal. Calcd for

C₁₃H₁₄N₂O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.68; H, 6.23; N, 13.00.

(4-Amino-2-methoxyphenyl)(pyridin-2-yl)methanol (8k) Yield 95%,

colorless crystals (EtOAc–hexane), mp 123—125 °C (dec.). ¹H-NMR (CDCl₃

)

d: 3.67 (2H, br), 3.80 (3H, s), 5.00 (1H, br), 6.08 (1H, s), 6.21—6.27 (2H,

m), 6.98 (1H, d, Jꢀ8.8 Hz), 7.12—7.26 (2H, m), 7.60 (1H, dt, Jꢀ7.7,

1.8 Hz), 8.54 (1H, d, Jꢀ4.4 Hz). Anal. Calcd for C₁₃H₁₄N₂O₂·0.1H₂O: C,

67.28; H, 6.17; N, 12.07. Found: C, 67.36; H, 6.26; N, 11.79.

The following compounds (16b—d) were prepared from 15b—d by a

method similar to that described for 16a.

2-(4-Fluorobenzoyl)-4-methylpyridine (16b) Yield 55%, brown crys-

tals (EtOAc–hexane), mp 98—100 °C. ¹H-NMR (CDCl₃) d: 2.48 (3H, s),

7.11—7.20 (2H, m), 7.30—7.33 (1H, m), 7.88 (1H, s), 8.12—8.19 (2H, m),

8.57 (1H, d, Jꢀ5.0 Hz). Anal. Calcd for C₁₃H₁₀FNO: C, 72.55; H, 4.68; N,

6.51. Found: C, 72.61; H, 4.63; N, 6.48.

(4-Amino-2-chlorophenyl)(pyridin-2-yl)methanol (8l) To a solution

of 12d (1.00 g, 4.05 mmol) in THF (15 ml), EtOH (15 ml) and water (15 ml)

was added Na₂S₂O₄(3.30 g, 19.0 mmol) at room temperature, and the mix-

ture was stirred at room temperature for 0.5 h. The reaction mixture was

concentrated in vacuo and the mixture was extracted with EtOAc. The or-

ganic layer was washed with water and brine, dried over MgSO₄, and con-

centrated in vacuo to give 0.21 g (24%) of 8l as colorless crystals, mp 142—

2-(4-Fluorobenzoyl)-5-methylpyridine (16c) Yield 57%, colorless

crystals (EtOAc–hexane), mp 127—128 °C. H-NMR (CDCl₃) d: 2.46 (3H,

s), 7.11—7.22 (2H, m), 7.68—7.74 (1H, m), 7.99 (1H, d, Jꢀ8.0 Hz), 8.12—

8.19 (2H, m), 8.54—8.55 (1H, m). Anal. Calcd for C₁₃H₁₀FNO: C, 72.55; H,

4.68; N, 6.51. Found: C, 72.68; H, 4.64; N, 6.59.

146 °C (dec.). H-NMR (CDCl₃) d: 3.71 (2H, br), 5.32 (1H, d, Jꢀ4.2 Hz),

6.15 (1H, d, Jꢀ4.2 Hz), 6.53 (1H, dd, Jꢀ8.4, 2.4 Hz), 6.70 (1H, d, Jꢀ2.4

Hz), 7.08 (1H, d, Jꢀ8.4 Hz), 7.17—7.23 (2H, m), 7.62 (1H, dt, Jꢀ1.8,

7.7 Hz), 8.56 (1H, d, Jꢀ4.4 Hz). Anal. Calcd for C₁₂H₁₁ClN₂O: C, 61.41; H,

4.72; N, 11.94. Found: C, 61.11; H, 4.82; N, 11.61.

2-(4-Fluorobenzoyl)-6-methylpyridine (16d) Yield 96%, pale yellow

crystals (EtOAc–hexane), mp 53—54 °C. ¹H-NMR (CDCl₃) d: 2.64 (3H, s),

7.09—7.21 (2H, m), 7.33—7.37 (1H, m), 7.73—7.85 (2H, m), 8.15—8.25

(2H, m). Anal. Calcd for C₁₃H₁₀FNO: C, 72.55; H, 4.68; N, 6.51. Found: C,

72.52; H, 4.74; N, 6.39.

(S)-(4-Aminophenyl)(pyridin-2-yl)methanol ((S)-8e) and (R)-(4-

Aminophenyl)(pyridin-2-yl)methanol ((R)-8e) The racemate 8e was re-

solved with HPLC to afford optically pure (S)-8e and (R)-8e [column, CHI-

4-Fluoro-N-methoxy-N-methyl-2-(triﬂuoromethyl)benzamide (18) To

a solution of 17 (6.70 g, 32.2 mmol) of THF (50 ml) was added SOCl₂

(3.40 ml, 46.6 mmol) and DMF (cat. amount) under ice cooling. After being

stirred at room temperature for 1 h, the mixture was concentrated in vacuo.

A solution of the residue in CHCl₂(30 ml) was added dropwise to a solution

of N,O-dimethylhydroxylamine hydrochloride (3.80 g, 39.0 mmol) and tri-

ethylamine (Et₃N) (6.7 ml, 48.1 mmol) in CHCl₂(50 ml) under ice cooling.

The reaction mixture was stirred at room temperature for 24 h. Water was

added to the reaction mixture and the mixture was extracted with EtOAc.

The organic layer was washed with water and brine, dried over MgSO₄, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtAOcꢀ2 : 1) to give 9.7 g (quant) of 18 as a colorless oil. ¹H-

NMR (CDCl₃) d: 3.36 (3H, s), 3.42 (3H, s), 7.26—7.47 (3H, m).

RAL CEL OD (50 mmꢄ500 mm); column temperature, 25 °C; mobile phase

hexane : EtOHꢀ80 : 20; ﬂow rate 60 ml/min; UV detection, 254 nm; amount

injected, 260 mg]. Compound (S)-8e: pale yellow crystals (EtOAc–hexane),

mp 149—150 °C. [a]_Dꢀꢅ43.4° (cꢀ1.00, MeOH). Anal. Calcd for

C₁₂H₁₂N₂O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.77; H, 6.02; N, 13.97.

Compound (R)-8e: pale yellow crystals (EtOAc–hexane), mp 149—150 °C.

[a]_Dꢀꢂ43.6° (cꢀ1.00, MeOH). Anal. Calcd for C₁₂H₁₂N₂O: C, 71.98; H,

6.04; N, 13.99. Found: C, 71.80; H, 6.04; N, 13.96. ¹H-NMR data of the chi-

ral compounds were identical with those of 8e.

(R)-3-Bromo-N-{4-[hydroxy(pyridin-2-yl)methyl]phenyl}benzamide

((R)-13) To a solution of (R)-8e (0.50 g, 2.50 mmol) and Et₃N (1.1 ml,

7.90 mmol) in THF (10 ml) was added 3-bromobenzoyl chloride (0.54 g,

2.46 mmol) under ice cooling. After being stirred at room temperature for

20 h, water was added to the mixture, and the mixture was extracted with

EtOAc. The organic layer was washed with brine, dried over MgSO₄, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtOAcꢀ1 : 1Æ2 : 1) to and recrystallization from EtOAc–i-Pr₂O to

give 349.9 mg (37%) of (R)-13 as pale yellow crystals, mp 153—154 °C.

[a]_Dꢀꢅ5.87° (cꢀ0.296, EtOH). ¹H-NMR (CDCl₃) d: 5.34 (1H, d,

Jꢀ4.2 Hz), 5.75 (1H, d, Jꢀ4.2 Hz), 7.09—7.25 (2H, m), 7.32—7.43 (3H,

m), 7.54—7.81 (6H, m), 7.96—8.02 (1H, m), 8.56—8.61 (1H, m). Anal.

Calcd for C₁₉H₁₅BrN₂O₂: C, 59.55; H, 3.95; N, 7.31. Found: C, 59.49; H,

4.09; N, 7.21.

2-[4-Fluoro-2-(triﬂuoromethyl)benzoyl]pyridine (16e) To a solution

of 2-bromopyridine (4.10 g, 25.9 mmol) in Et₂O (50 ml) was added dropwise

a solution of n-BuLi in hexane (1.6 M, 19.4 ml, 31.0 mmol) at ꢂ78 °C. The

reaction mixture was stirred at ꢂ78 °C under an argon atmosphere for 1 h. A

solution of 18 (5.00 g, 19.9 mmol) in Et₂O (50 ml) was added dropwise to

the reaction mixture at ꢂ78 °C. After being stirred at room temperature for

1.5 h, water was added to the reaction mixture, and the mixture was neutral-

ized using 1 N HCl under ice cooling. The mixture was extracted with

EtOAc. The organic layer was washed with brine, dried over MgSO₄, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtOAcꢀ1 : 1) and recrystallization from hexane to give 3.40 g

(63%) of 16e as brown crystals, mp 85—86 °C. H-NMR (CDCl₃) d: 7.33

(4-Fluorophenyl)(3-methylpyridin-2-yl)acetonitrile (15a) To a mix-

ture of 4-ﬂuorobenzylcyanide (3.97 g, 29.2 mmol), 11a (5.0 g, 29.1 mmol)

and sodium p-toluenesulﬁnate (10.48 g, 58.8 mmol) in THF (125 ml) was

added NaH (60% dispersion in mineral oil, 2.35 g, 58.8 mmol) under ice

cooling. The mixture was reﬂuxed for 3.5 h under an argon atmosphere. The

(1H, td, Jꢀ8.2, 2.2 Hz), 7.45—7.54 (3H, m), 7.93 (1H, td, Jꢀ8.0, 1.8 Hz),

8.23 (1H, dd, Jꢀ8.0, 1.0 Hz), 8.65 (1H, d, Jꢀ4.0 Hz). Anal. Calcd for

C₁₃H₇F₄NO: C, 58.00; H, 2.62; N, 5.20. Found: C, 58.02; H, 2.87; N, 5.03.

(4-Aminophenyl)(3-methylpyridin-2-yl)methanol (8f) A solution of

July 2004

825

16a (4.00 g, 18.6 mmol) and sodium azide (6.70 g, 103 mmol) in DMSO (80

ml) was stirred at 90 °C for 21 h. Water was added to the reaction mixture

and the mixture was extracted with Et₂O. The organic layer was washed with

brine, dried over MgSO₄, and concentrated in vacuo. A solution of the

residue (3.90 g) in THF (40 ml) was added dropwise to a suspension of

LiAlH₄(1.24 g, 32.7 mmol) in THF (40 ml) under ice cooling. The reaction

mixture was stirred at room temperature for 3 h. To the reaction mixture was

added dropwise successively water (1.24 ml), 15% aqueous NaOH (1.24 ml),

and water (3.72 ml) under ice cooling. After being stirred at room tempera-

ture for 16 h, MgSO₄was added to the mixture and the solid was removed by

ﬁltration. The ﬁltrate was concentrated in vacuo and the residue was puriﬁed

by recrystallization from EtOAc to give 2.60 g (65%) of 8f as pale yellow

crystals, mp 153—154 °C. ¹H-NMR (CDCl₃) d: 2.07 (3H, s), 3.56—3.66

(2H, m), 5.64 (1H, d, Jꢀ6.2 Hz), 5.93 (1H, d, Jꢀ6.2 Hz), 6.60 (2H, d,

Jꢀ8.4 Hz), 7.01 (2H, d, Jꢀ8.4 Hz), 7.17 (1H, dd, Jꢀ7.8, 4.8 Hz), 7.41—

7.45 (1H, m), 8.45—8.47 (1H, m). Anal. Calcd for C₁₃H₁₄N₂O: C, 72.87; H,

6.59; N, 13.07. Found: C, 72.77; H, 6.81; N, 12.93.

Jꢀ8.4 Hz), 7.19—7.29 (5H, m), 7.44—7.48 (3H, m), 7.53 (1H, d, Jꢀ2.6

Hz), 7.59 (2H, d, Jꢀ8.4 Hz), 8.09 (1H, br s). Anal. Calcd for C₃₀H₃₂NO₃P:

C, 74.21; H, 6.64; N, 2.88. Found: C, 73.96; H, 6.53; N, 3.11.

The following compounds (20a—c) were prepared from 19a and the cor-

responding anilines 8c—e by a method similar to that described for 5b.

7-(4-Methylphenyl)-N-[4-(pyridin-2-yl)phenyl]-2,3-dihydro-1-benzox-

epine-4-carboxamide (20a) Yield 76%, pale yellow crystals (EtOAc–

THF), mp 228—229 °C. ¹H-NMR (CDCl₃) d: 2.39 (3H, s), 3.09 (2H, t,

Jꢀ4.4 Hz), 4.36 (2H, t, Jꢀ4.4 Hz), 7.06 (1H, d, Jꢀ8,2 Hz), 7.16—7.32 (4H,

m), 7.42—7.56 (4H, m), 7.68—7.82 (5H, m), 8.02 (2H, dd, Jꢀ8.8, 2.0 Hz),

8.65—8.73 (1H, dt, Jꢀ4.8, 1.4 Hz). Anal. Calcd for C₂₉H₂₄N₂O₂: C, 80.53;

H, 5.59; N, 6.48. Found: C, 80.46; H, 5.62; N, 6.46.

7-(4-Methylphenyl)-N-{4-[(pyridin-2-yl)methyl]phenyl}-2,3-dihydro-1-

benzoxepine-4-carboxamide (20b) Yield 47%, colorless crystals

(EtOAc), mp 189—190 °C. H-NMR (CDCl₃) d: 2.39 (3H, s), 3.06 (2H, t,

Jꢀ4.6 Hz), 4.14 (2H, s), 4.35 (2H, t, Jꢀ4.6 Hz), 7.03—7.16 (3H, m), 7.18—

7.31 (5H, m), 7.40—7.64 (8H, m), 8.52—8.58 (1H, m). Anal. Calcd for

C₃₀H₂₆N₂O₂: C, 80.69; H, 5.87; N, 6.27. Found. C, 80.63; H, 5.80; N, 6.37.

N-{4-[Hydroxy(pyridin-2-yl)methyl]phenyl}-7-(4-Methylphenyl)-2,3-

dihydro-1-benzoxepine-4-carboxamide (20c) Yield 47%, pale yellow

The following compounds (8g—i, m) were prepared from 16b—e by a

method similar to that described for 8f.

(4-Aminophenyl)(4-methylpyridin-2-yl)methanol (8g) Yield quant.,

pale yellow crystals (EtOAc), mp 156—158 °C. H-NMR (CDCl₃) d: 2.28

crystals (EtOH–EtOAc), mp 215—217 °C. H-NMR (CDCl₃) d: 2.39 (3H,

(3H, s), 3.65 (2H, br), 5.18 (1H, br), 5.60 (1H, s), 6.65 (2H, d, Jꢀ8.4 Hz),

6.93 (1H, s), 6.99 (1H, d, Jꢀ5.0 Hz), 7.14 (2H, d, Jꢀ8.4 Hz), 8.40 (1H, d,

Jꢀ5.0 Hz). Anal. Calcd for C₁₃H₁₄N₂O·0.1H₂O: C, 72.26; H, 6.62; N, 12.97.

Found: C, 72.34; H, 6.62; N, 12.69.

s), 3.06 (2H, t, Jꢀ4.4 Hz), 4.34 (2H, t, Jꢀ4.4 Hz), 5.26—5.38 (1H, m),

5.70—5.78 (1H, m), 7.03—7.27 (6H, m), 7.33—7.79 (10H, m), 8.57 (1H, d,

Jꢀ4.8 Hz). Anal. Calcd for C₃₀H₂₆N₂O₃·0.2H₂O: Calcd. C, 77.30; H, 5.71;

N, 6.01. Found. C, 77.21; H, 5.75; N, 5.86.

(4-Aminophenyl)(5-methylpyridin-2-yl)methanol (8h) Yield 70%,

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(pyridin-2-yl)-

methyl]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Dioxide

((S)-20d) To a solution of 19b (0.30 g, 0.70 mmol) in THF (10 ml) was

added SOCl₂(0.10 ml, 1.37 mmol) and DMF (cat. amount) at room tempera-

ture. After being stirred at room temperature for 1 h, the mixture was con-

centrated in vacuo. A solution of the residue in THF (20 ml) was added to a

solution of (S)-8e (0.15 g, 0.75 mmol) and Et₃N (0.58 ml, 4.2 mmol) in THF

(5.0 ml) under ice cooling. After being stirred at room temperature for 40 h,

water was added to the mixture, and the mixture was extracted with EtOAc.

The organic layer was washed with water and brine, dried over MgSO₄, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(EtOAc) and recrystallization from EtOAc–i-Pr₂O to give 273 mg (64%) of

(S)-20d as colorless crystals, mp 173—174 °C. [a]_Dꢀꢂ3.26° (cꢀ0.302,

pale yellow crystals (EtOAc), mp 114—115 °C. H-NMR (CDCl₃) d: 2.32

(3H, s), 3.53—3.72 (2H, m), 5.09 (1H, d, Jꢀ4.0 Hz), 5.62 (1H, d, Jꢀ4.0

Hz), 6.64 (2H, d, Jꢀ8.4 Hz), 7.02 (1H, d, Jꢀ8.0 Hz), 7.12 (2H, d, Jꢀ8.4

Hz), 7.42 (1H, dd, Jꢀ8.0, 2.2 Hz), 8.37 (1H, d, Jꢀ2.2 Hz). Anal. Calcd for

C₁₃H₁₄N₂O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.68; H, 6.88; N, 12.81.

(4-Aminophenyl)(6-methylpyridin-2-yl)methanol (8i) Yield 72%,

pale yellow crystals (EtOAc), mp 165—166 °C. H-NMR (CDCl₃) d: 2.58

(3H, s), 3.51—3.73 (2H, m), 5.55—5.61 (2H, m), 6.65 (2H, d, Jꢀ8.4 Hz),

6.88 (1H, d, Jꢀ7.8 Hz), 7.03 (1H, d, Jꢀ7.6 Hz), 7.13 (2H, d, Jꢀ8.4 Hz),

7.49 (1H, dd, Jꢀ7.8, 7.6 Hz). Anal. Calcd for C₁₃H₁₄N₂O: C, 72.87; H, 6.59;

N, 13.07. Found: C, 72.64; H, 6.68; N, 12.87.

[4-Amino-2-(triﬂuoromethyl)phenyl](pyridin-2-yl)methanol (8m)

Yield 86%, colorless crystals (EtOAc–hexane), mp 163—164 °C. H-NMR

EtOH). H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.30—1.46 (2H, m),

(CDCl₃) d: 3.84 (2H, br), 5.57 (1H, d, Jꢀ4.0 Hz), 6.05 (1H, d, Jꢀ4.0 Hz),

6.74 (1H, dd, Jꢀ8.4, 2.6 Hz), 6.94 (1H, d, Jꢀ2.4 Hz), 7.01—7.10 (2H, m),

7.18—7.24 (1H, m), 7.61 (1H, td, Jꢀ7.6, 1.8 Hz), 7.58 (1H, d, Jꢀ5.2 Hz).

Anal. Calcd for C₁₃H₁₁F₃N₂O: C, 58.21; H, 4.13; N, 10.44. Found: C, 58.17;

H, 4.12; N, 10.33.

1.52—1.66 (2H, m), 3.11—3.18 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.68—

3.75 (2H, m), 3.79—3.84 (2H, m), 4.16—4.20 (2H, m), 5.32 (1H, d, Jꢀ4.4

Hz), 5.75 (1H, d, Jꢀ4.4 Hz), 7.04 (2H, d, Jꢀ8.8 Hz), 7.12—7.28 (2H, m),

7.34 (1H, s), 7.39 (2H, d, Jꢀ8.6 Hz), 7.52—7.69 (7H, m), 7.96 (1H, s), 8.19

(1H, d, Jꢀ8.4 Hz), 8.56—8.59 (1H, m). Anal. Calcd for C₃₅H₃₆N₂O₆S: C,

68.61; H, 5.92; N, 4.57. Found: C, 68.60; H, 5.98; N, 4.53.

7-(4-Methylphenyl)-N-{4-[(2-oxido-1,3,2-dioxaphosphorinan-2-yl)-

methyl]phenyl}-2,3-dihydro-1-benzoxepine-4-carboxamide (5a) To

(R)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(pyridin-2-yl)-

methyl]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Dioxide

((R)-20d) This compound was prepared in 85% yield from 19b and (R)-8e

by a method similar to that describe for (S)-20d, colorless crystals (EtOAc),

mp 171—173 °C. [a]_Dꢀꢅ5.30° (cꢀ0.313, EtOH). ¹H-NMR (CDCl₃) d:

0.93 (3H, t, Jꢀ7.1 Hz), 1.30—1.46 (2H, m), 1.52—1.72 (2H, m), 3.11—

3.17 (2H, m), 3.56 (2H, t, Jꢀ6.8 Hz), 3.68—3.75 (2H, m), 3.79—3.84 (2H,

m), 4.16—4.20 (2H, m), 5.34 (1H, br s), 5.75 (1H, br s), 7.03 (2H, d,

Jꢀ8.8 Hz), 7.12—7.28 (2H, m), 7.33 (1H, s), 7.38 (2H, d, Jꢀ8.4 Hz),

7.52—7.69 (7H, m), 8.02 (1H, s), 8.18 (1H, d, Jꢀ8.2 Hz), 8.56—8.58 (1H,

m). Anal. Calcd for C₃₅H₃₆N₂O₆S·0.25H₂O: C, 68.11; H, 5.96; N, 4.54.

Found. C, 68.09; H, 5.84; N, 4.50.

solution of 19a¹¹⁾(0.15 g, 0.54 mmol) in CH₂Cl₂(7.0 ml) was added oxalyl

chloride (0.14 ml, 1.60 mmol) and DMF (cat. amount) under ice cooling.

After being stirred at room temperature for 3 h, the mixture was concen-

trated in vacuo. A solution of the residue in THF (10 ml) was added drop-

wise a solution of 8a (0.13 g, 0.57 mmol) and Et₃N (0.23 ml, 1.65 mmol) in

THF (10 ml) under ice cooling. The mixture was stirred at room temperature

for 14 h. The mixture was concentrated in vacuo, and water was added to the

residue. The mixture was extracted with EtOAc. The organic layer was

washed with water and brine, dried over MgSO₄, and concentrated in vacuo.

The residue was puriﬁed by recrystallization from EtOAc to give 0.227 g

(87%) of 5a as colorless crystals. ¹H-NMR (CDCl₃) d: 1.64—1.97 (2H, m),

2.40 (2H, s), 3.09 (2H, t, Jꢀ4.5 Hz), 3.24 (2H, d, Jꢀ21.6 Hz), 4.00—4.20

(2H, m), 4.32—4.52 (4H, m), 7.06 (1H, d, Jꢀ8.4 Hz), 7.20—7.33 (4H, m),

7.44—7.60 (6H, m), 7.81 (1H, br s). Anal. Calcd for C₁₃H₁₁F₃N₂O: C, 58.21;

H, 4.13; N, 10.44. Found: C, 58.17; H, 4.12; N, 10.33.

7-(4-Methylphenyl)-N-[4-(1-oxidopyridin-2-yl)phenyl]-2,3-dihydro-1-

benzoxepine-4-carboxamide (5c) To a solution of 20a (0.40 g, 0.92

mmol) in CH₂Cl₂(10 ml) was added mCPBA (70%, 0.25 g, 1.10 mmol)

under ice cooling. After being stirred at room temperature for 70 h, aqueous

Na₂S₂O₃was added to the mixture, and the mixture was extracted with

CH₂Cl₂. The organic layer was washed with aqueous NaHCO₃and brine,

dried over MgSO₄, and concentrated in vacuo. The residue was purifed by

column chromatography (EtOAc : EtOHꢀ1 : 1) and recrystallization from

7-(4-Methylphenyl)-N-{4-[(1-oxidophosphorinan-1-yl)methyl]phenyl}-

2,3-dihydro-1-benzoxepine-4-carboxamide (5b) To a solution of 19a

(0.25 g, 0.89 mmol) in THF (10 ml) was added oxalyl chloride (0.12 ml, 1.38

mmol) and DMF (cat. amount) at room temperature. After being stirred at

room temperature for 1 h, the mixture was concentrated in vacuo. A solution

of the residue in THF (15 ml) was added to a solution of 8b (0.22 g,

0.98 mmol) and Et₃N (0.25 ml, 1.79 mmol) in THF (5.0 ml) under ice cool-

ing. After being stirred at room temperature for 4 h, water was added to the

mixture, and the mixture was extracted with EtOAc. The organic layer was

washed with water and brine, dried over MgSO₄, and concentrated in vacuo.

The residue was puriﬁed by recrystallization from EtOH to give 253 mg

CHCl₃–EtOH to give 59.5 mg (14%) of 5c as colorless crystals. H-NMR

(CDCl₃) d: 2.40 (3H, s), 3.06 (2H, t, Jꢀ4.4 Hz), 4.36 (2H, t, Jꢀ4.4 Hz),

7.00—7.14 (2H, m), 7.16—7.30 (4H, m), 7.38—7.51 (5H, m), 7.67 (2H, d,

Jꢀ8.6 Hz), 7.78 (2H, d, Jꢀ8.8 Hz), 8.19 (1H, d, Jꢀ7.0 Hz), 8.38—8.48 (1H,

m). Anal. Calcd for C₂₉H₂₄N₂O₃·0.5H₂O: C, 76.13; H, 5.51; N, 6.12. Found:

C, 75.82; H, 5.27; N, 6.18.

The following compounds (5d—f) were prepared from 20b—d by a

method similar to that described for 5c.

7-(4-Methylphenyl)-N-{4-[(1-oxidopyridin-2-yl)methyl]phenyl}-2,3-di-

(59%) of 5b as colorless crystals. H-NMR (CDCl₃) d: 1.32—2.09 (10H,

m), 2.39 (3H, s), 3.04—3.18 (4H, m), 4.36 (2H, t, Jꢀ4.6 Hz), 7.06 (1H, d,

826

Vol. 52, No. 7

hydro-1-benzoxepine-4-carboxamide (5d) ¹H-NMR (CDCl₃) d: 2.39

(3H, s), 3.09 (2H, t, Jꢀ4.6 Hz), 4.24 (2H, s), 4.36 (2H, t, Jꢀ4.6 Hz), 6.90—

7.01 (1H, m), 7.06 (1H, d, Jꢀ8.4 Hz), 7.11—7.16 (2H, m), 7.22—7.29 (5H,

m), 7.43—7.51 (4H, m), 7.54—7.76 (3H, m), 8.24—8.31 (1H, m). Anal.

Calcd for C₃₀H₂₆N₂O₃·0.3H₂O: C, 77.00; H, 5.73; N, 5.99. Found: C, 76.98;

H, 5.59; N, 6.10.

N-{4-[Hydroxy(1-oxidopyridin-2-yl)methyl]phenyl}-7-(4-methylphenyl)-

2,3-dihydro-1-benzoxepine-4-carboxamide (5e) ¹H-NMR (CDCl₃) d:

2.40 (3H, s), 3.09 (2H, t, Jꢀ4.4 Hz), 4.37 (2H, t, Jꢀ4.5 Hz), 6.07 (1H, d, Jꢀ

4.5 Hz), 6.41 (1H, d, Jꢀ4.6 Hz), 6.93—6.98 (1H, m), 7.06 (1H, d, Jꢀ8.4

Hz), 7.20—7.31 (5H, m), 7.41—7.55 (6H, m), 7.65 (2H, d, Jꢀ8.8 Hz), 7.73

(1H, br s), 8.24—8.28 (1H, m). Anal. Calcd for C₃₀H₂₆N₂O₄·0.1H₂O: C,

75.01; H, 5.50; N, 5.83. Found. C, 74.96; H, 5.36; N, 5.73.

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Diox-

ide ((S)-5f) [a]_Dꢀꢂ21.6° (cꢀ0.326, EtOH). ¹H-NMR (CDCl₃) d: 0.93

(3H, t, Jꢀ7.3 Hz), 1.30—1.46 (2H, m), 1.54—1.68 (2H, m), 3.14—3.20

(2H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.68—3.75 (2H, m), 3.79—3.84 (2H, m),

4.16—4.21 (2H, m), 6.07 (1H, d, Jꢀ4.6 Hz), 6.38 (1H, d, Jꢀ4.6 Hz), 6.94—

7.01 (1H, m), 7.04 (2H, d, Jꢀ9.2 Hz), 7.24—7.28 (1H, m), 7.37 (1H, s),

7.44—7.56 (5H, m), 7.62—7.69 (4H, m), 8.06 (1H, s), 8.18 (1H, d,

Jꢀ8.0 Hz), 8.24—8.28 (1H, m). Anal. Calcd for C₃₅H₃₆N₂O₇S·1.0H₂O: C,

65.00; H, 5.92; N, 4.33. Found: C, 65.02; H, 5.90; N, 4.16.

(cꢀ0.315, EtOH). H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.4 Hz), 1.32—1.48

(2H, m), 1.51—1.66 (2H, m), 2.86—3.27 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz),

3.82 (2H, t, Jꢀ4.9 Hz), 4.18 (2H, t, Jꢀ4.9 Hz), 4.74—4.89 (1H, m), 5.34

(1H, d, Jꢀ3.0 Hz), 5.75 (1H, d, Jꢀ3.0 Hz), 7.03 (2H, d, Jꢀ8.8 Hz), 7.13—

7.27 (3H, m), 7.30—7.42 (4H, m), 7.51—7.69 (7H, m), 8.5—8.62 (1H, m).

Anal. Calcd for C₃₇H₃₆F₃N₃O₅·0.25H₂O: C, 66.91; H, 5.54; N, 6.33. Found:

C, 66.93; H, 5.60; N, 6.32.

The following compounds (24b—i) were prepared from 23 and the corre-

sponding anilins 8f—m by a method similar to that described for 24a.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-[4-[hydroxy(3-methylpyridin-2-yl)-

methyl]phenyl]-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24b) Yield 45%, colorless amorphous. ¹H-NMR (CDCl₃) d:

0.93 (3H, t, Jꢀ7.4 Hz), 1.30—1.48 (2H, m), 1.51—1.68 (2H, m), 2.09 (3H,

s), 2.87—3.34 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.9 Hz), 4.18

(2H, t, Jꢀ4.9 Hz), 4.75—4.88 (1H, m), 5.73 (1H, d, Jꢀ5.9 Hz), 6.06 (1H, d,

Jꢀ5.9 Hz), 7.02 (2H, d, Jꢀ8.8 Hz), 7.17—7.35 (5H, m), 7.42—7.43 (1H,

m), 7.47—7.54 (6H, m), 7.62—7.66 (1H, m), 8.45—8.50 (1H, m). Anal.

Calcd for C₃₈H₃₈F₃N₃O₅·0.25H₂O: C, 67.29; H, 5.72; N, 6.20. Found: C,

67.13; H, 5.56; N, 6.05.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(4-methylpyridin-2-yl)-

methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24c) Yield 95%, colorless crystals (Et₂O–hexane), mp 101—

105 °C. H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 1.30—1.49 (2H, m),

(R)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Diox-

ide ((R)-5f) [a]_Dꢀꢅ22.8° (cꢀ0.318, EtOH). ¹H-NMR (CDCl₃) d: 0.93

(3H, t, Jꢀ7.1 Hz), 1.30—1.46 (2H, m), 1.54—1.68 (2H, m), 3.14—3.20

(2H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.68—3.75 (2H, m), 3.79—3.84 (2H, m),

4.16—4.21 (2H, m), 6.06 (1H, s), 6.94—7.01 (1H, m), 7.04 (2H, d,

Jꢀ8.8 Hz), 7.24—7.28 (1H, m), 7.37 (1H, s), 7.44—7.56 (5H, m), 7.62—

7.69 (4H, m), 8.13 (1H, s), 8.18 (1H, d, Jꢀ8.0 Hz), 8.24—8.28 (1H, m).

Anal. Calcd for C₃₅H₃₆N₂O₇S·1.0H₂O: C, 65.00; H, 5.92; N, 4.33. Found: C,

65.06; H, 5.81; N, 4.28.

7-{4-[2-(Butoxy)ethoxy]phenyl}-2,3-dihydro-1H-1-benzazepine-4-car-

boxylic Acid (22) To a solution of 21¹³⁾(500 mg, 1.26 mmol) in THF (5

ml) and MeOH (5 ml) was added 1 ^NNaOH (2.50 ml, 2.50 mmol) at room

temperature. After being stirred at room temperature for 20 h, the mixture

was concentrated in vacuo. 1 ^NHCl (2.5 ml) was added to the mixture and

the mixture was extracted with EtOAc. The organic layer was washed with

water and brine, dried over MgSO₄, and concentrated in vacuo to give

405 mg (84%) of 22 as yellow crystals, mp 205—207 °C. ¹H-NMR (CDCl₃)

d: 0.93 (3H, t, Jꢀ7.3 Hz), 1.29—1.49 (2H, m), 1.55—1.68 (2H, m), 2.86—

2.95 (2H, m), 3.41—3.45 (2H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t,

Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.68 (1H, d, Jꢀ8.6 Hz), 6.98 (2H, d,

Jꢀ8.8 Hz), 7.34 (1H, dd, Jꢀ8.6, 2.0 Hz), 7.43—7.48 (3H, m), 7.85 (1H, s).

Anal. Calcd for C₂₃H₂₇NO₄: C, 72.42; H, 7.13; N, 3.67. Found: C, 72.32; H,

7.01; N, 3.84.

1.58—1.69 (2H, m), 2.30 (3H, s), 2.93—3.15 (3H, m), 3.56 (2H, t,

Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ5.0 Hz), 4.18 (2H, t, Jꢀ5.0 Hz), 4.79—4.90 (1H,

m), 5.39 (1H, br), 5.69 (1H, s), 6.93 (1H, s), 7.00—7.04 (3H, m), 7.31—

7.65 (11H, m), 8.41 (1H, d, Jꢀ5.2 Hz). Anal. Calcd for C₃₈H₃₈F₃N₃O₅: C,

67.74; H, 5.69; N, 6.24. Found: C, 67.47; H, 5.81; N, 6.42.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(5-methylpyridin-2-yl)-

methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24d) Yield 75%, pale yellow crystals (EtOAc–hexane), mp

110—113 °C. ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3 Hz), 1.28—1.48 (2H,

m), 1.53—1.68 (2H, m), 2.33 (3H, s), 2.85—3.31 (3H, m), 3.56 (2H, t,

Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.8 Hz), 4.18 (2H, t, Jꢀ4.8 Hz), 4.74—4.89 (1H,

m), 5.31 (1H, d, Jꢀ4.2 Hz), 5.71 (1H, d, Jꢀ4.2 Hz), 7.01—7.05 (3H, m),

7.31—7.57 (11H, m), 7.62—7.67 (1H, m), 8.36—8.42 (1H, m). Anal. Calcd

for C₃₈H₃₈F₃N₃O₅: C, 67.74; H, 5.69; N, 6.24. Found: C, 67.43; H, 5.76; N,

6.01.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(6-methylpyridin-2-yl)-

methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24e) Yield 54%, colorless amorphous. ¹H-NMR (CDCl₃) d:

0.93 (3H, t, Jꢀ7.1 Hz), 1.29—1.48 (2H, m), 1.52—1.70 (2H, m), 2.60 (3H,

s), 2.88—3.26 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.9 Hz), 4.18

(2H, t, Jꢀ4.9 Hz), 4.74—4.89 (1H, m), 5.64—5.76 (2H, m), 6.89 (1H, d,

Jꢀ7.6 Hz), 7.00—7.07 (3H, m), 7.30—7.65 (12H, m). Anal. Calcd for

C₃₈H₃₈F₃N₃O₅·0.25H₂O: C, 67.29; H, 5.72; N, 6.20. Found: C, 67.25; H,

5.58; N, 6.35.

7-[4-(2-Butoxyethoxy)phenyl]-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxylic Acid (23) To a solution of 22 (12.5 g, 32.7 mmol)

and Et₃N (18.4 ml, 13.2 mmol) in THF (150 ml) was added triﬂuoroacetic

anhydride (18.4 ml, 13.0 mmol) under ice cooling. After being stirred at

room temperature for 1 h, aqueous NaHCO₃was added to the reaction mix-

ture, and the mixture was stirred over night at room temperature. The mix-

ture was neutralized using 1 N HCl under ice cooling, and extracted with

EtOAc. The organic layer was washed with brine, dried over MgSO₄, and

concentrated in vacuo to give 11.19 g (72%) of 23 as colorless crystals, mp

134—135 °C. ¹H-NMR (CDCl₃) d: 0.94 (3H, t, Jꢀ7.3 Hz), 1.31—1.49 (2H,

m), 1.56—1.69 (2H, m), 2.79—3.28 (3H, m), 3.57 (2H, t, Jꢀ6.6 Hz), 3.83

(2H, t, Jꢀ4.7 Hz), 4.19 (2H, t, Jꢀ4.7 Hz), 4.72—4.89 (1H, m), 7.03 (2H, d,

Jꢀ8.8 Hz), 7.33 (1H, d, Jꢀ8.4 Hz), 7.52—7.60 (3H, m), 7.69 (1H, d, Jꢀ1.8

Hz), 7.87 (1H, s). Anal. Calcd for C₂₅H₂₆F₃NO₅: C, 62.89; H, 5.49; N, 2.93.

Found: C, 62.74; H, 5.51; N, 2.68.

(S)-7-[4-(2-Butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)-

methyl]phenyl]-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24a) To a solution of 23 (3.36 g, 7.04 mmol) and HOBt (2.47 g,

18.3 mmol) in DMF (60 ml) was added EDC (3.43 g, 17.9 mmol) at room

temperature. After being stirred at room temperature for 1.5 h, a solution of

(S)-8e (1.83 g, 9.74 mmol) and Et₃N (1.96 ml, 14.1 mmol) in DMF (10 ml)

was added to the reaction mixture at room temperature. After being stirred at

room temperature for 19 h, water was added to the reaction mixture, and the

mixture was extracted with EtOAc. The organic layer was washed with water

and brine, dried over MgSO₄, and concentrated in vacuo. The residue was

puriﬁed by column chromatography (hexane : EtOAcꢀ2 : 1Æ1 : 1) to give

3.59 g (71%) of 24a as pale yellow crystals, mp 100—102 °C. [a]_Dꢀꢂ2.48°

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(pyridin-2-yl)methyl]-

3-methylphenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24f) Yield 72%, colorless crystals (EtOAc–hexane), mp 122—

125 °C. H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.30—1.68 (4H, m),

2.33 (3H, s), 2.91—3.19 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t,

Jꢀ4.9 Hz), 4.17 (2H, t, Jꢀ4.9 Hz), 4.80—4.84 (1H, m), 5.19 (1H, s), 5.93

(1H, s), 6.99—7.04 (3H, m), 7.19—7.41 (6H, m), 7.50—7.66 (6H, m), 8.58

(1H, d, Jꢀ5.2 Hz). Anal. Calcd for C₃₈H₃₈F₃N₃O₅: C, 67.74; H, 5.69; N,

6.24. Found: C, 67.47; H, 5.65; N, 6.22.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(pyridin-2-yl)methyl]-

3-methoxyphenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-

carboxamide (24g) Yield 78%, colorless crystals (EtOAc–hexane), mp

123—125 °C. ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 1.26—1.65 (4H,

m), 2.90—3.25 (3H, m), 3.56 (2H, t, Jꢀ6.8 Hz), 3.82 (2H, t, Jꢀ4.9 Hz),

3.91 (3H, s), 4.18 (2H, t, Jꢀ4.9 Hz), 4.80—4.90 (1H, m), 5.23 (1H, d, Jꢀ

5.0 Hz), 6.18 (1H, d, Jꢀ5.0 Hz), 6.84—6.88 (1H, m), 7.03 (2H, d, Jꢀ8.4

Hz), 7.19—7.65 (11H, m), 8.55 (1H, d, Jꢀ4.8 Hz). Anal. Calcd for

C₃₈H₃₈F₃N₃O₆: C, 66.17; H, 5.55; N, 6.09. Found: C, 65.99; H, 5.69; N,

5.74.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{3-chloro-4-[hydroxy(pyridin-2-yl)-

methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (24h) Yield 31%, yellow amorphous. ¹H-NMR (CDCl₃) d: 0.93

(3H, t, Jꢀ7.1 Hz), 1.29—1.49 (2H, m), 1.54—1.72 (2H, m), 2.90—3.19

(3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ4.8 Hz), 4.17 (2H, t, Jꢀ4.8

Hz), 4.80—4.86 (1H, m), 5.51 (1H, s), 6.23 (1H, s), 7.01 (2H, d, Jꢀ8.8 Hz),

7.19—7.68 (11H, m), 7.78—7.82 (2H, m), 8.56 (1H, d, Jꢀ4.4 Hz).

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(pyridin-2-yl)methyl]-

July 2004

827

3-(triﬂuoromethyl)phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (24i) Yield 40%, colorless amorphous. ¹H-NMR

(CDCl₃) d: 0.93 (3H, t, Jꢀ7.4 Hz), 1.30—1.50 (2H, m), 1.55—1.70 (2H,

m), 2.90—3.30 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.8 Hz),

4.17 (2H, t, Jꢀ4.8 Hz), 4.75—4.90 (1H, m), 5.75 (1H, br), 6.14 (1H, s),

7.00—7.04 (3H, m), 7.21—7.80 (11H, m), 7.94 (1H, d, Jꢀ5.0 Hz), 8.60

(1H, d, Jꢀ3.6 Hz). Anal. Calcd for C₃₈H₃₅F₆N₃O₅: C, 62.72; H, 4.85; N,

5.77. Found: C, 62.44; H, 4.87; N, 5.85.

(2H, t, Jꢀ4.7 Hz), 4.78—4.90 (1H, m), 6.33 (1H, s), 6.65—6.75 (1H, m),

6.90—7.05 (4H, m), 7.20—7.36 (2H, m), 7.46—7.69 (9H, m), 8.22—8.26

(1H, m). Anal. Calcd for C₃₈H₃₈F₃N₃O₇·0.5H₂O: C, 63.86; H, 5.50; N, 5.88.

Found: C, 64.07; H, 5.36; N, 5.79.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{3-chloro-4-[hydroxy(1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25h) Yield 63%, pale red oil. ¹H-NMR (CDCl₃)

d: 0.93 (3H, t, Jꢀ7.2 Hz), 1.26—1.48 (2H, m), 1.54—1.68 (2H, m), 2.92—

3.22 (3H, m), 3.55 (2H, t, Jꢀ6.7 Hz), 3.81 (2H, t, Jꢀ4.7 Hz), 4.17 (2H, t,

Jꢀ4.7 Hz), 4.78—4.88 (1H, m), 6.38 (1H, s), 6.60 (1H, s), 6.89—7.02 (3H,

m), 7.23—7.34 (2H, m), 7.46—7.56 (6H, m), 7.63—7.71 (2H, m), 7.87 (1H,

d, Jꢀ6.2 Hz), 8.21—8.35 (2H, m).

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]-3-(triﬂuoromethyl)phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-

1-benzazepine-4-carboxamide (25i) Yield 78%, colorless amorphous.

¹H-NMR (CDCl₃) d: 0.94 (3H, t, Jꢀ7.0 Hz), 1.30—1.65 (4H, m), 2.80—

3.35 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.8 Hz), 4.18 (2H, t,

Jꢀ5.6 Hz), 4.80—4.95 (1H, m), 6.48—6.64 (2H, m), 6.71 (1H, d, Jꢀ3.0

Hz), 7.03 (2H, d, Jꢀ8.8 Hz), 7.22—7.37 (3H, m), 7.49—7.67 (5H, m), 7.79

(1H, s), 7.90—8.05 (3H, m), 8.29—8.32 (1H, m). Anal. Calcd. for

C₃₈H₃₅F₆N₃O₆·0.5H₂O: C, 60.63; H, 4.82; N, 5.58. Found: C, 60.61; H,

4.69; N, 5.52.

The following compounds (25a—i) were prepared from 24a—i by a

method similar to that described for 5c.

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-benzazepine-4-

carboxamide (25a) Yield 76%, colorless crystals (EtOH–i-Pr₂O), mp

107—110 °C. [a]_Dꢀꢂ24.0° (cꢀ0.295, EtOH). ¹H-NMR (CDCl₃) d: 0.93

(3H, t, Jꢀ7.2 Hz), 1.29—1.48 (2H, m), 1.51—1.67 (2H, m), 2.86—3.34

(3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.9 Hz), 4.18 (2H, t, Jꢀ4.9

Hz), 4.76—4.91 (1H, m), 6.07 (1H, d, Jꢀ3.8 Hz), 6.41 (1H, d, Jꢀ3.8 Hz),

6.91—7.05 (3H, m), 7.20—7.38 (4H, m), 7.45—7.67 (9H, m), 8.24—8.28

(1H, m). Anal. Calcd for C₃₇H₃₆F₃N₃O₆·0.5H₂O: C, 64.90; H, 5.45; N, 6.14.

Found: C, 64.97; H, 5.37; N, 6.10.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(3-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25b) Yield 71%, pale yellow crystals (EtOAc–

i-Pr₂O), mp 109—112 °C. ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz),

1.29—1.48 (2H, m), 1.55—1.68 (2H, m), 2.46 (3H, s), 2.88—3.30 (3H, m),

3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ4.9 Hz), 4.18 (2H, t, Jꢀ4.9 Hz),

4.72—4.88 (1H, m), 6.03 (1H, d, Jꢀ10.2 Hz), 7.02 (2H, d, Jꢀ8.8 Hz),

7.15—7.64 (13H, m), 7.90—8.02 (1H, m), 8.08—8.11 (1H, m). Anal. Calcd

for C₃₈H₃₈F₃N₃O₆·1.0H₂O: C, 64.49; H, 5.70; N, 5.94. Found: C, 64.75; H,

5.42; N, 5.75.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(4-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25c) Yield 52%, colorless crystals (EtOAc), mp

121—123 °C. ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3 Hz), 1.26—1.45 (2H,

m), 1.55—1.65 (2H, m), 2.29 (3H, s), 2.94—3.17 (3H, m), 3.56 (2H, t,

Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ5.0 Hz), 4.18 (2H, t, Jꢀ5.0 Hz), 4.78—4.88 (1H,

m), 6.00—6.03 (1H, m), 6.70—6.75 (2H, m), 7.00—7.06 (3H, m), 7.33 (1H,

d, Jꢀ8.4 Hz), 7.45—7.22 (9H, m), 8.13 (1H, d, Jꢀ6.2 Hz). Anal. Calcd for

C₃₈H₃₈F₃N₃O₆·0.25H₂O: C, 65.74; H, 5.59; N, 6.05. Found: C, 65.72; H,

5.64; N, 5.93.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(5-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25d) Yield 79%, colorless crystals (EtOAc–i-

Pr₂O), mp 201—204 °C. ¹H-NMR (CDCl₃) d: 0.94 (3H, t, Jꢀ7.2 Hz),

1.30—1.49 (2H, m), 1.54—1.70 (2H, m), 2.32 (3H, s), 2.89—3.35 (3H, m),

3.56 (2H, t, Jꢀ6.6 Hz), 3.82 (2H, t, Jꢀ4.9 Hz), 4.18 (2H, t, Jꢀ4.9 Hz),

4.78—4.97 (1H, m), 6.03 (1H, d, Jꢀ4.2 Hz), 6.52 (1H, d, Jꢀ4.2 Hz), 6.81

(1H, d, Jꢀ8.2 Hz), 7.01—7.10 (3H, m), 7.26—7.36 (1H, m), 7.44—7.66

(10H, m), 8.11 (1H, s). Anal. Calcd for C₃₈H₃₈F₃N₃O₆: C, 66.17; H, 5.55; N,

6.09. Found: C, 66.11; H, 5.40; N, 6.21.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(6-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25e) Yield 75%, colorless crystals (EtOAc–i-

Pr₂O), mp 170—173 °C. ¹H-NMR (CDCl₃) d: 0.94 (3H, t, Jꢀ7.2 Hz),

1.29—1.48 (2H, m), 1.54—1.68 (2H, m), 2.57 (3H, s), 2.93—3.27 (3H, m),

3.56 (2H, t, Jꢀ6.8 Hz), 3.82 (2H, t, Jꢀ4.9 Hz), 4.18 (2H, t, Jꢀ4.9 Hz),

4.76—4.91 (1H, m), 6.06 (1H, d, Jꢀ4.6 Hz), 6.68 (1H, d, Jꢀ4.6 Hz), 6.78—

6.84 (1H, m), 7.03 (2H, d, Jꢀ8.8 Hz), 7.13—7.36 (3H, m), 7.46—7.66

(10H, m). Anal. Calcd for C₃₈H₃₈F₃N₃O₆: C, 66.17; H, 5.55; N, 6.09. Found:

C, 65.97; H, 5.48; N, 6.10.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]-3-methylphenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25f) Yield 84%, colorless crystals (EtOAc), mp

142—144 °C. ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.4 Hz), 1.31—1.65 (4H,

m), 2.23 (3H, s), 2.95—3.25 (3H, m), 3.56 (2H, t, Jꢀ6.8 Hz), 3.82 (2H, t,

Jꢀ5.0 Hz), 4.18 (2H, t, Jꢀ5.0 Hz), 4.79—4.93 (1H, m), 6.28 (2H, s), 6.74

(1H, dd, Jꢀ7.7, 2.5 Hz), 7.03 (2H, d, Jꢀ8.6 Hz), 7.18—7.66 (11H, m), 8.31

(1H, dd, Jꢀ6.6, 1.0 Hz). Anal. Calcd. for C₃₈H₃₈F₃N₃O₆·0.5H₂O: C, 65.32;

H, 5.63; N, 6.01. Found: C, 65.56; H, 5.37; N, 5.98.

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxamide (26a)

To a solution of 25a (180 mg, 0.27 mmol) in EtOH (30 ml) was added

NaBH₄(10 mg, 0.26 mmol) at room temperature, and it was stirred at room

temperature for 2 h. NaBH₄(10 mg, 0.26 mmol) was added to the reaction

mixture and the mixture was stirred at room temperature for 2 h. Water was

added to the reaction mixture, and the mixture was extracted with EtOAc.

The organic layer was washed with brine, dried over MgSO₄, and concen-

trated in vacuo. The residue was puriﬁed by column chromatography

(EtOAc : EtOHꢀ2 : 1) to give 141.4 mg (90%) of 26a as yellow amorphous.

[a]_Dꢀꢂ22.0° (cꢀ0.300, EtOH). H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3

Hz), 1.28—1.48 (2H, m), 1.51—1.68 (2H, m), 2.89—3.01 (2H, m), 3.41—

3.51 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t,

Jꢀ5.0 Hz), 6.07 (1H, br s), 6.31—6.45 (1H, m), 6.71 (1H, d, Jꢀ8.0 Hz),

6.92—6.99 (3H, m), 7.20—7.36 (5H, m), 7.39—7.52 (4H, m), 7.62—7.66

(3H, m), 8.24—8.28 (1H, m). Anal. Calcd for C₃₅H₃₇N₃O₅·1.5H₂O: C,

69.27; H, 6.65; N, 6.93. Found: C, 69.05; H, 6.31; N, 6.67.

The following compounds (26b—i) were prepared from 25b—i by a

method similar to that described for 26a.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(3-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam-

ide (26b) Yield 56%, yellow crystals (EtOAc–i-Pr₂O), mp 101—104 °C.

¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.28—1.47 (2H, m), 1.52—

1.89 (2H, m), 2.46 (3H, s), 2.90—2.97 (2H, m), 3.39—3.49 (2H, m), 3.55

(2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.9 Hz), 4.15 (2H, t, Jꢀ4.9 Hz), 4.52—

4.64 (1H, m), 6.03 (1H, d, Jꢀ11.2 Hz), 6.69 (1H, d, Jꢀ8.4 Hz), 6.97 (2H, d,

Jꢀ8.8 Hz), 7.15—7.58 (12H, m), 8.00 (1H, d, Jꢀ11.2 Hz), 8.08—8.11 (1H,

m). Anal. Calcd for C₃₆H₃₉N₃O₅·1.0H₂O: C, 70.68; H, 6.76; N, 6.87. Found:

C, 70.72; H, 6.43; N, 6.86.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(4-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam-

ide (26c) Yield quant., yellow crystals (EtOAc), mp 198—201 °C (dec.).

¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.34—1.45 (2H, m), 1.57—

1.65 (2H, m), 2.28 (3H, s), 2.97 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t,

Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.9 Hz), 4.16 (2H, t, Jꢀ4.9 Hz), 4.61 (1H, br),

6.03—6.04 (1H, m), 6.69—6.73 (3H, m), 6.95—7.17 (3H, m), 7.26—7.34

(2H, m), 7.43—7.48 (5H, m), 7.63—7.67 (3H, m), 8.14 (1H, d, Jꢀ6.6 Hz).

Anal. Calcd for C₃₆H₃₉N₃O₅·0.25H₂O: C, 72.28; H, 6.66; N, 7.02. Found: C,

71.99; H, 6.57; N, 6.91.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(5-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam-

ide (26d) Yield 94%, yellow crystals (EtOAc–i-Pr₂O), mp 119—121 °C.

¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3 Hz), 1.29—1.46 (2H, m), 1.53—

1.70 (2H, m), 2.30 (3H, s), 2.90—3.01 (2H, m), 3.21—3.50 (2H, m), 3.55

(2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.9 Hz), 4.15 (2H, t, Jꢀ4.9 Hz), 4.56—

4.65 (1H, m), 6.03 (1H, br s), 6.45—6.54 (1H, m), 6.70 (1H, d, Jꢀ8.0 Hz),

6.79 (1H, d, Jꢀ8.0 Hz), 6.97 (2H, d, Jꢀ8.8 Hz), 6.99—7.07 (1H, m), 7.29—

7.33 (2H, m), 7.41—7.47 (5H, m), 7.64 (2H, d, Jꢀ8.4 Hz), 7.74 (1H, s),

8.10 (1H, s). Anal. Calcd for C₃₆H₃₉N₃O₅·0.5H₂O: C, 71.74; H, 6.69; N,

6.97. Found: C, 71.76; H, 6.98; N, 6.91.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]-3-methoxyphenyl}-1-triﬂuoroacetyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (25g) Yield 79%, colorless amorphous. ¹H-NMR

(CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 1.26—1.49 (2H, m), 1.57—1.69 (2H,

m), 2.90—3.30 (3H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.74—3.84 (5H, m), 4.18

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(6-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam-

828

Vol. 52, No. 7

ide (26e) Yield 94%, yellow crystals (EtOAc–i-Pr₂O), mp 175—177 °C.

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-1-cyclopropylmethyl-N-{4-[hy-

¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.28—1.44 (2H, m), 1.48— droxy(1-oxidopyridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-ben-

1.68 (2H, m), 2.56 (3H, s), 2.92—3.01 (2H, m), 3.41—3.49 (2H, m), 3.55 zazepine-4-carboxamide ((S)-5i) [a]_Dꢀꢂ25.2° (cꢀ0.303, EtOH). ¹H-

(2H, t, Jꢀ6.8 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 4.46— NMR (CDCl₃) d: 0.24—0.35 (2H, m), 0.60—0.70 (2H, m), 0.93 (3H, t,

4.72 (1H, m), 6.06 (1H, s), 6.70 (1H, d, Jꢀ8.4 Hz), 6.78—6.84 (1H, m),

Jꢀ7.1 Hz), 1.02—1.22 (1H, m), 1.30—1.46 (2H, m), 1.53—1.66 (2H, m),

6.97 (2H, d, Jꢀ8.8 Hz), 7.11—7.18 (1H, m), 7.20—7.34 (3H, m), 7.43— 2.91—3.02 (2H, m), 3.26 (2H, d, Jꢀ6.2 Hz), 3.43—3.50 (2H, m), 3.55 (2H,

7.47 (5H, m), 7.61—7.65 (3H, m). Anal. Cacld for C₃₆H₃₉N₃O₅·1.0H₂O: C,

t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.04—6.09

70.68; H, 6.76; N, 6.87. Found. C, 70.53; H, 6.15; N, 6.93.

(1H, m), 6.36—6.46 (1H, m), 6.91—7.00 (4H, m), 7.24—7.28 (2H, m),

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)- 7.39—7.52 (7H, m), 7.63—7.67 (3H, m), 8.25—8.29 (1H, m). Anal. Calcd

methyl]-3-methylphenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxamide for C₃₉H₄₃N₃O₅·1.0H₂O: C, 71.87; H, 6.96; N, 6.45. Found: C, 72.10; H,

(26f) Yield 97%, yellow crystals (EtOAc), mp 179—182 °C (dec.). ¹H-

NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3 Hz), 1.22—1.64 (4H, m), 2.21 (3H, s),

2.96 (2H, t, Jꢀ4.4 Hz), 3.46 (2H, t, Jꢀ4.4 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80

(2H, t, Jꢀ4.9 Hz), 4.15 (2H, t, Jꢀ4.9 Hz), 4.63 (1H, br), 6.27 (2H, s),

6.93; N, 6.50.

(S)-1-Benzyl-7-{4-[2-(butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxi-

dopyridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carbox-

amide ((S)-5j) [a]_Dꢀꢂ23.5° (cꢀ0.314, EtOH). ¹H-NMR (CDCl₃) d: 0.93

6.68—6.76 (2H, m), 6.97 (2H, d, Jꢀ8.8 Hz), 7.16—7.33 (3H, m), 7.43— (3H, t, Jꢀ7.1 Hz), 1.28—1.48 (2H, m), 1.51—1.67 (2H, m), 2.81—2.89

7.47 (4H, m), 7.56—7.60 (2H, m), 7.70 (1H, s), 8.30 (1H, dd, Jꢀ1.0, (2H, m), 3.32—3.42 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.9

5.8 Hz). Anal. Calcd for C₃₆H₃₉N₃O₅·0.5H₂O: C, 71.74; H, 6.69; N, 6.97. Hz), 4.16 (2H, t, Jꢀ4.9 Hz), 4.62 (2H, s), 6.07 (1H, d, Jꢀ4.3 Hz), 6.41 (1H,

Found: C, 71.75; H, 6.65; N, 6.81.

d, Jꢀ4.9 Hz), 6.88—7.06 (4H, m), 7.24—7.67 (17H, m), 8.25—8.28 (1H,

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)- m). Anal. Calcd for C₄₂H₄₃N₃O₅·1.0H₂O: C, 73.34; H, 6.59; N, 6.11. Found:

methyl]-3-methoxyphenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam- C, 73.70; H, 6.66; N, 5.99.

ide (26g) Yield quant., yellow crystals (EtOAc), mp 116—118 °C. ¹H-

NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.26—1.57 (4H, m), 2.96 (2H, t-

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]phenyl}-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-2,3-dihydro-

like), 3.48 (2H, t-like), 3.55 (2H, t, Jꢀ6.6 Hz), 3.73—3.90 (5H, m), 4.16 1H-1-benzazepine-4-carboxamide ((S)-5k) [a]_Dꢀꢂ24.7° (cꢀ0.317,

(2H, t, Jꢀ5.0 Hz), 4.61 (1H, br), 6.33 (1H, d, Jꢀ4.8 Hz), 6.67—6.73 (2H, EtOH). H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.32—1.46 (2H, m),

m), 6.87—7.00 (4H, m), 7.21—7.48 (7H, m), 7.63—7.75 (3H, m), 8.22— 1.51—1.68 (2H, m), 2.80—2.89 (2H, m), 3.29—3.39 (2H, m), 3.55 (2H, t,

8.26 (1H, m). Anal. Calcd for C₃₆H₃₉N₃O₆·0.75H₂O: C, 69.38; H, 6.55; N, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ5.0 Hz), 3.90 (3H, s), 4.16 (2H, t, Jꢀ5.0 Hz),

6.74. Found: C, 69.55; H, 6.66; N, 6.38.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{3-chloro-4-[hydroxy(1-oxidopy- (4H, m), 7.24—7.28 (2H, m), 7.32 (1H, s), 7.38—7.63 (8H, m), 7.62—7.67

ridin-2-yl)methyl]phenyl}-2,3-dihydro-1H-1-benzazepine-4-carboxam- (3H, m), 8.24—8.28 (1H, m). Anal. Calcd for C₄₀H₄₃N₅O₅·0.75H₂O: C,

4.44 (2H, s), 6.07 (1H, d, Jꢀ4.4 Hz), 6.43 (1H, d, Jꢀ4.4 Hz), 6.91—7.00

ide (26h) Yield quant., yellow amorphous. ¹H-NMR (CDCl₃) d: 0.93 (3H, 69.90; H, 6.53; N, 10.19. Found: C, 69.98; H, 6.77; N, 9.90.

t, Jꢀ7.3 Hz), 1.29—1.48 (2H, m), 1.54—1.72 (2H, m), 2.92 (2H, br), 3.43

(2H, br), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.8 Hz), 4.12 (2H, t,

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(3-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

Jꢀ4.8 Hz), 4.60 (1H, br), 6.39 (1H, s), 6.69 (1H, d, Jꢀ8.4 Hz), 6.85—6.98 carboxamide (5l) ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.3 Hz), 0.97 (6H,

(3H, m), 7.23—7.55 (9H, m), 7.60—8.00 (3H, m), 8.26 (1H, br).

d, Jꢀ6.6 Hz), 1.30—1.48 (2H, m), 1.50—1.70 (2H, m), 1.96—2.17 (1H, m),

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)- 2.46 (3H, s), 2.84—2.95 (2H, m), 3.18 (2H, d, Jꢀ7.4 Hz), 3.29—3.40 (2H,

methyl]-3-(triﬂuoromethyl)phenyl}-2,3-dihydro-1H-1-benzazepine-4-

carboxamide (26i) Yield 94%, yellow crystals (EtOAc–i-Pr₂O). H-NMR

m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz),

6.03 (1H, d, Jꢀ10.8 Hz), 6.91 (1H, d, Jꢀ8.8 Hz), 6.98 (2H, d, Jꢀ9.2 Hz),

(200 MHz, CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 1.33—1.45 (2H, m), 1.54— 7.15—7.24 (2H, m), 7.38—7.58 (10H, m), 8.01 (1H, d, Jꢀ10.8 Hz), 8.08—

1.64 (2H, m), 2.97 (2H, t, Jꢀ4.8 Hz), 3.48 (2H, t, Jꢀ4.8 Hz), 3.55 (2H, t,

Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.8 Hz), 4.15 (2H, t, Jꢀ4.8 Hz), 6.47 (1H, s),

6.61 (1H, dd, Jꢀ7.8, 2.2 Hz), 6.71 (1H, d, Jꢀ8.4 Hz), 6.97 (2H, d, Jꢀ8.8

8.11 (1H, m). Anal. Calcd for C₄₀H₄₇N₃O₅·1.25H₂O: C, 71.46; H, 7.42; N,

6.25. Found: C, 71.50; H, 7.32; N, 6.00.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(4-methyl-1-oxidopy-

Hz), 7.18—7.37 (4H, m), 7.43—7.47 (4H, m), 7.85—7.91 (3H, m), 8.03 ridin-2-yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

(1H, s), 8.28—8.32 (1H, m). Anal. Calcd for C₃₆H₃₆F₃N₃O₅·1.0H₂O: C,

64.95; H, 5.75; N, 6.31. Found: C, 65.14; H, 5.84; N, 6.10.

carboxamide (5m) ¹H-NMR (CDCl₃) d: 0.85—0.99 (9H, m), 1.22—1.45

(2H, m), 1.54—1.65 (2H, m), 2.08 (1H, br), 2.28 (3H, s), 2.93 (2H, t-like),

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2- 3.19 (2H, d, Jꢀ7.4 Hz), 3.37 (2H, t-like), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H,

yl)methyl]phenyl}-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxam-

ide ((S)-5g) To a solution of 26a (120 mg, 0.207 mmol) and propionalde-

hyde (0.15 ml, 2.08 mmol) in 1,2-dichloroethane (10 ml) was added

NaBH(OAc)₃(0.13 g, 0.613 mmol) at room temperature. After being stirred

at room temperature for 20 h, water was added to the reaction mixture, and

t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.05 (1H, s), 6.65 (1H, br), 6.72—6.73

(1H, m), 6.90—7.06 (5H, m), 7.38—7.68 (10H, m), 8.16 (1H, d, Jꢀ6.6 Hz).

Anal. Calcd for C₄₀H₄₇N₃O₅·0.5H₂O: C, 72.92; H, 7.34; N, 6.38. Found: C,

72.81; H, 7.43; N, 6.38.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(5-methyl-1-oxidopy-

the mixture was extracted with EtOAc. The organic layer was washed with ridin-2-yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

brine, dried over MgSO₄, and concentrated in vacuo. The residue was puri- carboxamide (5n) ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 0.98 (6H,

ﬁed by column chromatography (EtOAc : EtOHꢀ2 : 1) to give 105 mg (82%)

of (S)-5g as yellow crystals. [a]_Dꢀꢂ26.5° (cꢀ0.303, EtOH). ¹H-NMR

d, Jꢀ6.6 Hz), 1.30—1.46 (2H, m), 1.52—1.68 (2H, m), 1.98—2.16 (1H, m),

2.31 (3H, s), 2.89—2.97 (2H, m), 3.19 (2H, d, Jꢀ7.0 Hz), 3.31—3.42 (2H,

(CDCl₃) d: 0.93 (3H, t, Jꢀ7.1 Hz), 1.00 (3H, t, Jꢀ7.0 Hz), 1.29—1.48 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz),

m), 1.53—1.82 (4H, m), 2.86—2.96 (2H, m), 3.25—3.40 (4H, m), 3.55 (2H, 6.03 (1H, s), 6.79 (1H, d, Jꢀ8.0 Hz), 6.90—7.08 (4H, m), 7.38—7.52 (7H,

t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.06 (1H, br s),

m), 7.64 (2H, d, Jꢀ8.4 Hz), 7.65 (1H, s), 8.11 (1H, s). Anal. Calcd for

6.35—6.45 (1H, m), 6.88—7.00 (4H, m), 7.23—7.28 (2H, m), 7.38—7.51 C₄₀H₄₇N₃O₅· 0.5H₂O: C, 71.94; H, 7.40; N, 6.29. Found: C, 71.90; H, 7.53;

(7H, m), 7.62—7.67 (3H, m), 8.24—8.28 (1H, m). Anal. Calcd for N, 6.13.

C₃₈H₄₃N₃O₅·0.5H₂O: C, 72.36; H, 7.03; N, 6.66. Found. C, 72.07; H, 7.01;

N, 6.51.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(6-methyl-1-oxidopy-

ridin-2-yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

The following compounds ((S)-5h—k, 5l—s) were prepared from 26a—i carboxamide (5o) ¹H-NMR (CDCl₃) d: 0.93 (3H, t, Jꢀ7.2 Hz), 0.98 (6H,

and corresponding aldehydes by a method similar to that described for (S)-

5g.

d, Jꢀ6.6 Hz), 1.30—1.46 (2H, m), 1.50—1.71 (2H, m), 1.98—2.16 (1H, m),

2.57 (3H, s), 2.88—2.97 (2H, m), 3.19 (2H, d, Jꢀ6.6 Hz), 3.33—3.43 (2H,

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2- m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz),

yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carbox- 6.07 (1H, s), 6.77—6.84 (1H, m), 6.91—7.00 (3H, m), 7.15 (1H, t, Jꢀ7.7

amide ((S)-5h) [a]_Dꢀꢂ22.2° (cꢀ0.319, EtOH). ¹H-NMR (CDCl₃) d: Hz), 7.37—7.51 (8H, m), 7.63—7.70 (3H, m). Anal. Calcd for C₄₀H₄₇N₃O₅:

0.93 (3H, t, Jꢀ7.4 Hz), 0.98 (6H, d, Jꢀ6.6 Hz), 1.27—1.47 (2H, m), 1.53— C, 73.93; H, 7.29; N, 6.47. Found: C, 73.83; H, 7.21; N, 6.45.

1.68 (2H, m), 1.98—2.18 (1H, m), 2.89—2.98 (2H, m), 3.19 (2H, d,

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)-

methyl]-3-methylphenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

Jꢀ7.4 Hz), 3.32—3.42 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t,

Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.07 (1H, d, Jꢀ4.1 Hz), 6.42 (1H, d, carboxamide (5p) ¹H-NMR (CDCl₃) d: 0.85—0.99 (9H, m), 1.26—1.68

Jꢀ4.1 Hz), 6.90—7.00 (4H, m), 7.23—7.28 (2H, m), 7.38—7.52 (7H, m), (4H, m), 2.04—2.14 (1H, m), 2.21 (3H, s), 2.93 (2H, t-like), 3.19 (2H, d,

7.63—7.68 (3H, m), 8.24—8.28 (1H, m). Anal. Calcd for C₃₉H₄₅N₃O₅·

0.75H₂O: C, 72.14; H, 7.22; N, 6.47. Found: C, 72.22; H, 7.29; N, 6.57.

Jꢀ7.0 Hz), 3.36 (2H, t-like), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz),

4.15 (2H, t, Jꢀ5.0 Hz), 6.27 (2H, br), 6.73 (1H, dd, Jꢀ7.8, 2.4 Hz), 6.90—

July 2004

829

6.99 (3H, m), 7.16—7.30 (2H, m), 7.37—7.60 (7H, m), 7.72 (1H, s), 8.30 3 : 1 : 5 and co-transfected into COS-7 cells using Lipofectamine 2000 (Invit-

(1H, d, Jꢀ4.8 Hz). Anal. Calcd for C₄₀H₄₇N₃O₅·0.5H₂O: C, 72.92; H, 7.34; rogen). After 2 d incubation, transfected COS-7 cells and MOLT-

N, 6.38. Found C, 72.74; H, 7.47; N, 6.18.

4/CCR5/Luc^ꢅcells were seeded in a 96-well plate at 10⁴cells each per well,

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)- and various concentrations of the test compounds were added to the wells.

methyl]-3-methoxyphenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4- The cell suspension was incubated at 37 °C. The mixture of D-MEM and

carboxamide (5q) ¹H-NMR (CDCl₃) d: 0.90—1.00 (9H, m), 1.26—1.65 RPMI 1640 medium supplemented with 10% FBS, 100 U/ml penicillin, and

(4H, m), 2.00—2.15 (1H, m), 2.93 (2H, t-like), 3.20 (2H, d, Jꢀ7.2 Hz), 3.38

100 mg/ml streptomycin was used as medium for membrane fusion. After an

(2H, t-like), 3.55 (2H, t, Jꢀ6.5 Hz), 3.74—3.83 (5H, m), 4.16 (2H, t, overnight incubation, Luc-Screen (Tropix) was added to each well, and the

Jꢀ4.8 Hz), 6.33 (1H, d, Jꢀ4.8 Hz), 6.69 (1H, d, Jꢀ4.8 Hz), 6.88—7.00 (5H, mixtures were incubated at room temperature for 10 min. The luciferase ac-

m), 7.21—7.26 (1H, m), 7.40—7.52 (6H, m), 7.63—7.68 (2H, m), 7.77 (1H, tivity was measured with a luminometer (Wallac 1420 ARVOsx).

s), 8.22—8.24 (1H, m). Anal. Calcd for C₄₀H₄₇N₃O₆·0.25H₂O: C, 71.67; H,

Preliminary Pharmacokinetic Analysis Compound (S)-5s (10 mg/kg)

7.14; N, 6.27. Found: C, 71.51; H, 7.24; N, 6.17.

suspended in 0.5% methylcellulose was orally administered to SD (IGS) rats

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{3-chloro-4-[hydroxy(1-oxidopy- (male, 8 weeks old). Blood samples were collected at different time points

ridin-2-yl)methyl]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-

(pre, 15, 30 min, 1, 2, 4, 8, 24 h) from the tail vein. Acetonitrile (250 ml) was

carboxamide (5r) ¹H-NMR (CDCl₃) d: 0.85—0.99 (9H, m), 1.22—1.68 added to each plasma sample (100 ml), and the precipitated plasma proteins

(4H, m), 2.00—2.11 (1H, m), 2.92 (2H, t, Jꢀ4.6 Hz), 3.19 (2H, d, Jꢀ7.6 were removed by centrifugation. The compound concentrations in the super-

Hz), 3.37 (2H, t, Jꢀ4.6 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ4.9 Hz),

4.16 (2H, t, Jꢀ4.9 Hz), 6.39 (1H, d, Jꢀ3.7 Hz), 6.68 (1H, d, Jꢀ3.7 Hz),

natant were measured by HPLC (column, Inertsil ODS-3, 4.6ꢄ150 mm,

5 mm particle size, GL Science; column temperature, 35 °C; mobile phase,

6.82—7.00 (4H, m), 7.20—7.30 (1H, m), 7.38—7.51 (6H, m), 7.72 (1H, s), acetonitrile–0.01 mol/l ammonium acetate; ﬂow rate, 1.0 ml/min; UV detec-

7.78 (1H, d, Jꢀ8.8 Hz), 7.94 (1H, d, Jꢀ2.2 Hz), 8.26—8.30 (1H, m). Anal.

Calcd. for C₃₉H₄₄ClN₃O₅·0.25H₂O: C, 69.42; H, 6.65; N, 6.23. Found: C,

69.45; H, 6.52; N, 6.23.

tion, 280 nm).

Acknowledgments We thank Mr. Kenichi Kuroshima for the CCR5

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)- binding assay; Mr. Katsunori Takashima, Dr. Hiroshi Miyake, and Ms.

methyl]-3-(triﬂuoromethyl)phenyl}-1-isobutyl-2,3-dihydro-1H-1-ben-

Shikiko Shiki for the membrane fusion assay; Mr. Koichi Iwanaga for opti-

zazepine-4-carboxamide (5s) ¹H-NMR (CDCl₃) d: 0.90—1.00 (9H, m), cal resolution by HPLC; Mr. Akira Fujishima and Ms. Keiko Higashikawa

1.26—1.70 (4H, m), 2.00—2.20 (1H, m), 2.90—3.00 (2H, m), 3.21 (1H, d, for X-ray crystallographic analysis; Mr. Atsutoshi Furuta for pharmacoki-

Jꢀ7.4 Hz), 3.35—3.45 (2H, m), 3.56 (2H, t, Jꢀ7.0 Hz), 3.81 (2H, t, Jꢀ5.2

Hz), 4.16 (2H, t, Jꢀ5.2 Hz), 6.45—6.49 (1H, m), 6.57—6.63 (1H, m), 6.71

netic analysis.

(1H, d, Jꢀ2.6 Hz), 6.92—7.01 (3H, m), 7.17—7.53 (7H, m), 7.77 (1H, s), Reference

1) Carpenter C. C., Fischl M. A., Hammer S. M., Hirsch M. S., Jacobsen

7.93 (2H, s), 8.04 (1H, s), 8.31 (1H, d, Jꢀ5.8 Hz). Anal. Calcd for

C₄₀H₄₄F₃N₃O₅·0.5H₂O: C, 67.40; H, 6.36; N, 5.89. Found: C, 67.58; H,

6.28; N, 5.85.

D. M., Katzenstein D. A., Montaner J. S., Richman D. D., Saag M. S.,

Schooley R. T., Thompson M. A., Vella S., Yeni P. G., Volberding P.

A., J. Am. Med. Assoc., 280, 78—86 (1998).

(S)-7-{4-[2-(Butoxy)ethoxy]phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-

yl)methyl]-3-(triﬂuoromethyl)phenyl}-1-isobutyl-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide ((S)-5s) and (R)-7-{4-[2-(Butoxy)ethoxy]-

phenyl}-N-{4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(triﬂuoromethyl)-

phenyl}-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide ((R)-

5s) The racemate 5s was resolved with HPLC to afford optically pure (S)-

5s and (R)-5s [column, CHIRAL PAK AD (50 mmꢄ500 mm), column tem-

perature, 25 °C; mobile phase, hexane : EtOHꢀ50 : 50; ﬂow rate 70 ml/min;

UV detection, 254 nm, amount injected 210 mg]. Compound (S)-5s:

[a]_Dꢀꢅ13.7° (cꢀ0.30, EtOH). Anal. Calcd for C₄₀H₄₄F₃N₃O₅·0.5H₂O: C,

67.40; H, 6.36; N, 5.90. Found: C, 67.31; H, 6.26; N, 5.96. Compound (R)-

5s; [a]_Dꢀꢂ13.8° (cꢀ0.26, EtOH). Anal. Calcd for C₄₀H₄₄F₃N₃O₅·0.5H₂O:

C, 67.40; H, 6.36; N, 5.90. Found: C, 67.01; H, 6.30; N, 5.87. ¹H-NMR data

of the chiral compounds were identical with those of 5s.

X-Ray Crystallographic Analysis Colorless platelet crystals of (R)-13

were obtained from methanol solution. A diffractometer, Rigaku AFC5R,

was used with graphite monochromated Cu-Ka radiation to obtain the fol-

lowing crystal data: aꢀ19.293(2), bꢀ20.023(2), cꢀ8.419(3) Å, Vꢀ3252(1)

Å³, orthorhombic, P2₁2₁2₁, Zꢀ8. Of the 5612 collected reﬂections, 2987

were unique (Rintꢀ0.053). Final R-values were R1ꢀ0.051 and wR2(F²; all

data)ꢀ0.140. The absolute conﬁguation was determinated using the Flack

parameter¹⁹⁾of ꢂ0.06(4). Further details of the X-ray structure data are

available on request from the Cambridge Crystallographic Data Centre (de-

position number CCDC 230601).

2) Finzi D., Blankson J., Siliciano J. D., Margolick J. B., Chadwick K.,

Pierson T., Smith K., Lisziewicz J., Lori F., Flexner C., Quinn T. C.,

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ciano R. F., Nat. Med., 5, 512—517 (1999).

3) Blair W. S., Lin P. F., Meanwell N. A., Wallace O. B., Drug Discov.

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Marzio P., Marmon S., Sutton R. E., Hill C. M., Davis C. B., Peiper S.

C., Schall T. J., Littman D. R., Landau N. R., Nature (London), 381,

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6) Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E.,

Murphy P. M., Berger E. A., Science, 272, 1955—1958 (1996).

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droski J., Cell, 85, 1135—1148 (1996).

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(1996).

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Receptor Binding Assays CHO-K1 and CCR5-expressing CHO cells¹⁰⁾

were incubated with various concentrations of test compound in the binding

buffer (Ham’s F-12 medium containing 20 mM HEPES and 0.5% bovine

serum albumin, pH 7.2) containing 200 pM [¹²⁵I]RANTES. Binding reac-

tions were performed at room temperature for 40 min. The binding reaction

was terminated by washing out the free ligand with cold phosphate-buffered

saline, and the cell-associated radioactivity was counted using a TopCount

scintillation counter (Packard).

HIV-1 Envelope-Mediated Membrane Fusion Assay COS-7 cells

were maintained in Dulbecco’s modiﬁed Eagle medium (D-MEM) supple-

mented with 10% FBS, 100 U/ml penicillin, and 100 mg/ml streptomycin.

MOLT-4/CCR5/Luc^ꢅcells, a lymphoblastoid cell line that expresses human

CCR5 and that has an integrated copy of the HIV-1 long terminal repeat-dri-

ven luciferase reporter gene, were maintained in RPMI 1640 medium sup-

plemented with 10% FBS, 100 U/ml penicillin, 100 mg/ml streptomycin, and

500 mg/ml geneticin. Tat, rev, and envelope cDNA were ampliﬁed from total

RNA of R5 HIV-1 (JR-FL)-infected cells and cloned into an expression vec-

tor for mammalian cells. Those expression vectors were mixed at a ratio of

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Chem. Pharm. Bull., 52, 254—258 (2004).

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52, 577—590 (2004).

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