Orally active CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological activity of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives containing a tertiary amine moiety

DOI: 10.1248/cpb.52.577

Source and publish data:

Chemical and Pharmaceutical Bulletin p. 577 - 590 (2004)

Update date:2022-08-05

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Authors:

Seto, Masaki

Aramaki, Yoshio

Okawa, Tomohiro

Miyamoto, Naoki

Aikawa, Katsuji

Kanzaki, Naoyuki

Niwa, Shin-Ichi

Iizawa, Yuji

Baba, Masanori

Shiraishi, Mitsuru

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Article abstract of DOI:10.1248/cpb.52.577

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C_2-4 alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C_2-4 alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1- benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelopemediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC₅₀=2.7 nM) and inhibitory effect (IC₅₀=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.

Full text of DOI:10.1248/cpb.52.577

May 2004

Chem. Pharm. Bull. 52(5) 577—590 (2004)

577

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

Biological Activity of 1-Benzothiepine 1,1-Dioxide and 1-Benzazepine

Derivatives Containing a Tertiary Amine Moiety

Masaki S^ETO, ^,aYoshio A^RAMAKI,^aTomohiro O^KAWA,^aNaoki M^IYAMOTO,^aKatsuji A^IKAWA,^a

Naoyuki K^ANZAKI,^bShin-ichi N^IWA,^cYuji I^IZAWA,^dMasanori B^ABA,^eand Mitsuru S^HIRAISHI

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

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

& Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries Ltd.;

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

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

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

Received January 5, 2004; accepted February 24, 2004; published online February 25, 2004

The search for orally active CCR5 antagonists was performed by chemical modiﬁcation of the 1-benzo-

thiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of

methyl group with a 2-(C_2—4alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine

ring resulted in both enhanced activity and signiﬁcant improvement in the pharmacokinetic properties upon oral

administration in rats. Introduction of C_2—4alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on

the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-

benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found

to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-

mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activ-

ity (IC₅₀ꢀ2.7 nM) and inhibitory effect (IC₅₀ꢀ1.2 nM) on membrane fusion, together with good pharmacokinetic

properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biologi-

cal activity are described.

Key words CCR5 antagonist; HIV-1; 1-benzazepine; 1-benzothiepine 1,1-dioxide; 2-(alkoxy)ethoxy group

In 1996, it was found that the CC chemokine receptor 5 ring in the tertiary amine compound 2 (the chemical precur-

(CCR5) is a coreceptor for the entry of macrophage-tropic sor of 1) with the 1-benzothiepine 1,1-dioxide (3) or 1-ben-

(CCR5-using or R5) human immunodeﬁciency virus type 1 zoazepine (4) ring moieties enhanced the activity.¹⁸⁾We se-

(HIV-1) into host cells.^1—5)CCR5 is a member of the G-pro- lected the orally active 1-benzothiepine 1,1-dioxide (3) and

tein coupled seven-transmembrane domain receptors and its 1-benzazepine (4) compounds as new leads, and carried out

natural ligands [regulated on activation normal T-cell ex- their chemical modiﬁcation in order to enhance the activity

pressed and secreted (RANTES), macrophage inﬂammatory and to improve the pharmacokinetic proﬁles. In this paper,

protein (MIP)-1a and MIP-1b] are known to block R5 HIV-1 we describe the design, synthesis and structure–activity rela-

infection.⁶⁾It has been found that individuals with a 32-base- tionships (SAR) of the 1-benzothiepine 1,1-dioxide (5) and

pair deletion in the CCR5 coding region (CCR5D32) are 1-benzazepine (6) derivatives.

highly resistant to R5 HIV-1 infection, and interestingly,

these individuals don’t appear to have any signiﬁcant health Chemistry

problems.^7—9)

The syntheses of the target compounds (5, 6) are shown in

Recently, combination chemotherapy using HIV-1 protease Charts 1 and 2. Coupling reaction of the carboxylic acids 7

inhibitors and reverse transcriptase inhibitors, called highly with 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]ani-

active antiretroviral therapy (HAART), has achieved high line 8¹⁷⁾afforded the desired compounds (5, 6) (Chart 1,

level and long-term suppression of viral replication in HIV-1 Method A). An alternative synthetic method is outlined in

infected individuals.¹⁰⁾However, eradication of HIV-1 is im- Chart 2. The target compounds (5, 6) were prepared by the

possible even by HAART,¹¹⁾and there are several problems Suzuki coupling reaction of the anilide derivatives 9 with the

with HAART, such as the emergence of drug resistance, side- phenylboronic acids 10 (Chart 2, Method B).

effect proﬁles and difﬁcult dosing regimens.^12,13)Therefore,

The 1-benzothiepine-4-carboxylic acid key intermediates

the discovery of novel anti-HIV-1 agents with new mecha- 7a—e were synthesized according to Chart 3. Methoxycar-

nisms of action is still needed and CCR5 antagonists as HIV- bonylation of the ketone 11¹⁸⁾gave the b-keto ester, which

1 entry inhibitors are considered to be a new and attractive was then transformed by reduction and subsequent dehydra-

target.^14,15)

tion via methanesulfonylation to afford the 1-benzothiepine-

We previously discovered a small-molecule, nonpeptide 4-carboxylate 12. The 1-benzothiepine 1,1-dioxide 13a was

CCR5 antagonist 1 as an anti-HIV-1 agent for injection.^16,17)obtained by oxidation of 12 using 30% aqueous H₂O₂. The

Benzocycloheptene compound 1 exhibited highly potent carboxylic acids 7a—e were prepared by the Suzuki coupling

CCR5 antagonistic and anti-HIV activities but poor oral ab- reaction of the 7-bromide 13a followed by acid or alkaline

sorption because of its polar quaternary ammonium moiety. hydrolysis.

We then reported that replacement of the benzocycloheptene

The syntheses of the 1-benzazepines 13c—f are illustrated

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

578

Vol. 52, No. 5

Fig. 1. Compound 1 and Lead Compounds of Orally Active CCR5 Antagonists

Chart 1

Chart 2

Chart 3

Chart 4

in Charts 4 and 5. N-Alkylation of the N-Cbz protected 4- alternative method (Chart 5). The 1-benzazepine-5-one 19

aminobutyric acid 15, esteriﬁcation¹⁹⁾and subsequent re- was obtained by the one-pot alkylation of 18²⁰⁾with ethyl 4-

moval of the Cbz group afforded the tert-butyl 4-(alkyl- bromobutyrate and Dieckmann-type condensation, followed

amino)butyrates 16a, b. Reaction of the amines 16a, b with by removal of the tosyl group and decarboxylation reaction

5-bromo-2-ﬂuorobenzaldehyde gave the cyclization precur- using sulfuric acid and acetic acid.²¹⁾The 1-benzazepine-4-

sors 17a, b. The synthesis of 1-benzazepine derivatives carboxylate 20 was synthesized by a synthetic method simi-

13c, d was accomplished by the intramolecular Claisen– lar to that used for 1-benzothiepine-4-carboxylate 12 after N-

Schmidt type cyclization reaction of 17a, b using potassium Boc protection of 19. Removal of the N-Boc group of 20

tert-butoxide. The 1-benzazepines 13e, f were prepared by an gave the 1-unsubstituted 1-benzazepine 21. Reductive amina-

May 2004

579

tion of 21 with appropriate aldehydes afforded the 1-alkyl-1- gave the 1-benzazepine 24. The carboxylic acid 7p was pre-

benzazepines 13e, f.²²⁾

pared by acetylation of 24 and subsequent alkaline hydroly-

The key imtermediates 7f—o were prepared according to sis.

Chart 6. Suzuki coupling reaction of 21 and subsequent re-

The other key intermediates, the anilide derivatives 9a—e,

ductive amination of 22 with appropriate aldehydes gave were prepared according to Chart 8. Acid or alkaline hydrol-

14g—i, 14k—o.²²⁾The 1-phenyl-1-benzazepine 14j was syn- ysis of the compounds 13a—d, 13f provided the correspond-

thesized by phenylation of 22 using triphenylbismuth diac- ing carboxylic acids 25a—e. Conversion of the carboxylic

etate and copper(II) pivalate.²³⁾The ester 14f was obtained by acids 25a—e into the acid chlorides and subsequent conden-

the Suzuki coupling reaction of 13e. The 1-benzazepine-4- sation with the aniline 8 gave the key intermediates 9a—e.

carboxylic acids 7f—o were prepared by alkaline hydrolysis

of the esters 14f—o.

The requisite phenylboronic acids 10 utilized in the Suzuki

coupling reaction were available commercially or synthesized

The synthetic route to the 1-acetyl-1-benzazepine-4-car- according to Chart 9. The alkoxybromobenzenes 27a—f were

boxylic acid 7p is shown in Chart 7. Suzuki coupling reac- obtained by alkylation of the 4-bromophenol (26a) or 2-(4-

tion of 20 and subsequent deprotection of the N-Boc group bromophenoxy)ethanol (26b). Reaction of the Grignard

reagents, generated by reaction of magnesium metal and the

corresponding bromobenzenes 27b—f, or phenyllithium,

generated by halogen–metal exchange reaction of the bro-

mobenzene 27a, with trimethyl borate gave the 4-substituted

phenylboronic acids 10a—f.

The target compounds (5a—d, 6e, 6i, 6k—s) were pre-

pared by condensation of the acid chlorides, generated from

the carboxylic acids (7a—d, 7f—p), with the aniline 8 in the

presence of triethylamine (Et₃N) (Chart 1, Method A). The

compound 5e was synthesized by an activated-ester method

using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hy-

drochloride (EDC) and 1-hydroxybenzotriazole (HOBt)

(Chart 1, Method A). The other target compounds (5f—k,

6a—d, 6f—h, 6j) were prepared by the Suzuki coupling re-

Chart 5

Chart 6

Chart 7

Chart 8

580

Vol. 52, No. 5

action of the bromides 9a—e with the phenylboronic acids bulky morpholino-substituted compound 5e exhibited rela-

10 (Chart 2, Method B).

tively potent activity. Therefore, we examined the inhibitory

effect of compound 5g with the linear 2-(ethoxy)ethoxy

group, which represents a ring-opened morpholino group

Biological Results and Discussion

The compounds prepared were evaluated for their in- after replacing the nitrogen atom with oxygen atom. The 2-

hibitory effects on chemokine binding to CCR5-expressing (ethoxy)ethoxy-substituted compound 5g was as highly ac-

CHO cells. Binding reactions were performed in the pres- tive as compound 5d. Furthermore, we investigated the ef-

ence of [¹²⁵I]RANTES and various concentrations of the test fects of several alkoxyalkoxy groups in place of the 2-

compounds. The results are summarized in Tables 1 and 2 as (ethoxy)ethoxy group. Replacement of the 2-(ethoxy)ethoxy

IC₅₀values. The compounds with potent binding inhibitory group (5g) with the 2-(propoxy)ethoxy (5h) or 2-

activity were further evaluated for their inhibitory effects on (butoxy)ethoxy (5i) group retained activity, whereas substitu-

an HIV-1 envelope (Env)-mediated membrane fusion. The tion of the smaller 2-(methoxy)ethoxy (5f) or longer 2-

membrane fusion assay was carried out using R5 HIV-1 (JR- (pentyloxy)ethoxy (5j) group resulted in a relative decrease

FL strain) Env-expressing COS-7 cells and CCR5-expressing of activity. Replacement of the 2-(propoxy)ethoxy group (5h)

MOLT-4 cells. The results are summarized in Table 3 as IC₅₀with the 3-(ethoxy)propoxy group (5k) decreased the activity

values.

by about half. From these results, it was suggested that the

First, keeping the 1,1-dioxo-1-benzothiepine moiety in the length of alkoxyalkoxy group and position of the oxygen

lead compound 3, the effect of the substituent at the 4-posi- atom were important to exhibit potent activity. Secondly, we

tion on the 7-phenyl group was investigated (Table 1). As the examined the inhibitory effects of the potent compounds 5h,

size of the alkyl group was increased, the activity was found i in the binding assay on the HIV-1 Env-mediated membrane

to become more potent (5a, b). Thus, the propyl compound fusion. As shown in Table 3, their inhibitory effects were

5b had about 6 times greater activity than the methyl one 3. greatly weaker than their binding inhibitory activities

Replacement of the propyl group (5b) with the propoxy (IC₅₀ꢀ420, 410 nM, respectively).

group (5d) retained activity, but substitution with the bulkier

As described in our previous paper,¹⁸⁾change at the 5-po-

isopropyl group (5c) decreased the activity compared with sition (X) of the benzocycloheptene ring was considered to

5b. These results suggested that the linear alkyl or alkoxy inﬂuence the activity (Fig. 1). Therefore, we targeted another

group was necessary for potent activity. Interestingly, the lead compound, 1-benzazepine derivative 4, in order to en-

hance the activity. On the basis of the above-mentioned re-

sults in the 1-benzothiepine 1,1-dioxides, we mainly modi-

ﬁed the 1-substituent on the 1-benzazepine ring. The effect

of the 4-substituent on the 7-phenyl group was veriﬁed, keep-

ing the 1-methyl-1-benzazepine moiety (6a—c), and the 2-

(butoxy)ethoxy-substituted compound 6c was found to ex-

hibit the most potent activity, followed by the 1-benzothi-

epine derivative 5i. Replacement of the 1-methyl group of 6a

with the 1-ethyl group (6d) retained activity whereas the 1-

acetyl-1-benzazepine derivative 6e, which was considered as

an introduction of an oxygen atom at the 1-position of the

ethyl group of 6d, decreased the activity. The 1-ethyl-1-benz-

azepines with the 2-(propoxy)ethoxy (6f) and 2-(butoxy)-

Chart 9

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

Compd.

R²

IC₅₀^a)(nM)

mp (°C) Recrystln. solvent^b)

Method

Yield (%)

Formula

Anal.^c)

i-Pr

PrO

200

120

140

720

257—260

247—250

240—247

244—247

280—282

227—231

215—217

195—197

194—196

188—189

214—215

ET–E

C₃₂H₃₆N₂O₄S

C₃₃H₃₈N₂O₄S

C₃₃H₃₈N₂O₅S

C₃₄H₃₉N₃O₅S·1.5H₂O

C₃₃H₃₈N₂O₆S

C₃₄H₄₀N₂O₆S

C₃₅H₄₂N₂O₆S

C₃₆H₄₄N₂O₆S

C₃₇H₄₆N₂O₆S

C₃₅H₄₂N₂O₆S

CHN

Morpholino

MeO(CH₂)₂O

EtO(CH₂)₂O

PrO(CH₂)₂O

BuO(CH₂)₂O

PentylO(CH₂)₂O

EtO(CH₂)₃O

a) The concentration required to inhibit the binding of [¹²⁵I]RANTES to CCR5-expressing CHO cells by 50%. b) ETꢀethanol, Eꢀdiethyl ether. c) All compounds gave

satisfactory elemental analysis (ꢁ0.4%) for C, H and N.

May 2004

581

Table 2. Physical Properties and Inhibitory Effects of Compounds 6 on Chemokine Binding to CCR5-expressing CHO Cells

Compd.

R¹

R²

IC₅₀^a)(n^M)

mp (°C)

Recrystln. solvent^b)Method Yield (%)

Formula

Anal.^c)

130

200

5.6

3.5

3.6

Morpholino

PrO(CH₂)₂O

BuO(CH₂)₂O

Morpholino

PrO(CH₂)₂O

BuO(CH₂)₂O

209—211

136—138

107—110

193—194

141—145

106—108

102—106

118—121

74—75

EA–IPE

EA–H

EA–IPE

EA–H

—

C₃₅H₄₂N₄O₃

C₃₆H₄₅N₃O₄·0.25H₂O

C₃₇H₄₇N₃O₄·0.1H₂O

C₃₆H₄₄N₄O₃

CHN

C₃₆H₄₂N₄O₄

C₃₇H₄₇N₃O₄·0.25H₂O

C₃₈H₄₉N₃O₄·0.2H₂O

C₃₉H₅₁N₃O₄

i-Bu

i-Pentyl

C₄₀H₅₃N₃O₄

C₄₁H₅₅N₃O₄

C₄₀H₅₁N₃O₄

Amorphous

92—94

Amorphous

4.5

EA–H

—

C₄₁H₅₃N₃O₄·2HCl·1.5H₂O

BuO(CH₂)₂O

115—117

E–EA–H

C₄₃H₅₇N₃O₄

CHN

BuO(CH₂)₂O

5.6

5.3

Amorphous

127—131

—

EA–H

C₄₂H₄₉N₃O₄·0.25H₂O

C₄₃H₅₁N₃O₄·0.25H₂O

CHN

BuO(CH₂)₂O

Amorphous

—

C₄₀H₄₈N₄O₄S

CHN

BuO(CH₂)₂O

Amorphous

—

C₄₁H₅₁N₅O₄·0.5H₂O

CHN

BuO(CH₂)₂O

Amorphous

113—115

—

C₄₁H₅₁N₅O₄·0.25H₂O

C₄₁H₅₁N₅O₄

CHN

2.7

EA–H

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

Hꢀhexane, Eꢀdiethyl ether. c) All compounds gave satisfactory elemental analysis (ꢁ0.4%) for C, H and N.

Table 3. Inhibitory Effects of Compounds 4 and 5 on HIV-1 Env-Mediated

Membrane Fusion

ethoxy (6g) groups were more active than the corresponding

1-methyl-1-benzazepines 6b and 6c. These results suggested

that the 2-(butoxy)ethoxy group was optimal as the 4-sub-

stituent on the 7-phenyl group and that enlarging the size of

the 1-alkyl group led to enhancement of activity. Therefore,

we investigated the effects of various alkyl groups at the 1-

position on the 1-benzazepine ring, while retaining the 2-(bu-

toxy)ethoxy group (6h—m). Introduction of the propyl (6h)

or isobutyl (6i) group further increased the binding in-

hibitory activity. However, replacement with the bulkier

isopentyl group (6j) resulted in a relative reduction of activ-

ity. The cyclopropylmethyl compound 6k, which represents a

cyclized isobutyl group, retained the potent activity. Enlarg-

ing the ring size from cyclopropylmethyl group (6k) to cy-

clobutylmethyl (6l) or cyclohexylmethyl (6m) groups de-

creased the activity by about a third. In addition, we deter-

mined the effects of 1-phenyl and 1-(substituted)methyl

groups such as benzyl and 5-membered heteroarylmethyl

groups, considering the propyl, isobutyl and cyclopropyl-

methyl groups with appropriate bulkiness were most active

(6n—s). The phenyl (6n), benzyl (6o) and 1-methylpyrazol-

4-ylmethyl (6s) compounds were as highly active as the

isobutyl (6i) and cyclopropylmethyl (6k) compounds,

whereas the thiazol-2-ylmethyl (6p), 1-methylimidazol-2-yl-

RANTES

IC₅₀^a)(nM)

Fusion

Compd.

R²

IC₅₀^b)(nM)

—

SO₂

N–Et

N–Pr

N–i-Bu

—

1.4

5.6

3.5

3.6

4.5

5.6

5.3

1.4

420

410

1000

1.7

150

PrO(CH₂)₂O

BuO(CH₂)₂O

N–Ph

N–Bn

2.3

BuO(CH₂)₂O

2.7

1.2

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%.

methyl (6q) and 1-methylpyrazol-5-ylmethyl (6r) com- sites on CCR5 [for the tertiary amine moiety, the 1-sub-

pounds, the isomer of 6s, exhibited relatively weak activity. stituent and the 7-(4-substitutedphenyl) group on the 1-ben-

Among the 1-benzazepine derivatives 6, the propyl (6h), zazepine ring] and that the shape of molecules was essential

isobutyl (6i) and 1-methylpyrazol-4-ylmethyl (6s) com- for optimal CCR5 antagonistic activity.

pounds showed most potent CCR5 antagonistic activity, com-

We ﬁnally evaluated the inhibitory effects of the highly

parable to compound 1. From the results of the SAR study, it potent 1-benzazepines in the RANTES binding assay on the

was suggested that there might be 3 pockets in the binding HIV-1 Env-mediated membrane fusion (Table 3). The effects

582

Vol. 52, No. 5

Table 4. Pharmacokinetic Parameters of Compounds 5 and 6 in Rats

of the isobutyl (6i), benzyl (6o) and 1-methylpyrazol-4-yl-

methyl (6s) compounds in the fusion assay were similar to

those in the receptor binding assay. Additionally, the com-

pounds (6i, o, s) greatly increased the anti-HIV-1 potency as

compared with the ethyl (6g) and cyclopropylmethyl (6k)

compounds, which remarkably reduced activity. The propyl

(6h) and phenyl (6n) compounds showed moderate activity.

From these results, it was found that isobutyl or (hetero)aryl-

methyl groups with suitable bulkiness, such as benzyl or 1-

methylpyrazol-4-ylmtehyl, were necessary as the 1-sub-

stituent on the 1-benzazepine ring for highly potent in-

hibitory activity in the membrane fusion assay.

Oral administration^a)

Compd.

R²

C_max

T_max

AUC_{0—24 h}

(mg/ml)

(h)

(mg h/ml)

SO₂

N–Me

SO₂

N–Pr

N–i-Bu

PrO

0.16

0.11

0.17

1.02

0.26

4.48

13.6

11.8

1.15

0.08

0.59

3.3

4.0

5.3

1.7

5.3

4.0

10.7

5.3

1.55

1.56

2.23

13.0

2.55

64.1

213

5e^e)

Pharmacokinetic Studies

Morpholino

EtO(CH₂)₂O

PrO(CH₂)₂O

BuO(CH₂)₂O

Preliminary pharmacokinetic studies of typical com-

pounds with potent activity were investigated in rats. The

compounds were orally administered at 10 mg/kg to SD

(IGS) rats and the results are summarized in Table 4. The 1-

benzothiepine 1,1-dioxide 5d with a propoxy group showed

about 6 times higher plasma level than the methyl-substituted

compound 3, whereas plasma level of the ethyl compound 5a

was similar to that of 3. Reduction of the molecular

lipophilicity was considered to lead to the improvement in

the pharmacokinetic proﬁles. However, introduction of the

polar morpholino group (5e) resulted in only slight improve-

ment of pharmacokinetic proﬁles in comparison with com-

pound 3 owing to its probably low solubility. Surprisingly, re-

placing the rigid morpholino group with the ﬂexible 2-

(alkoxy)ethoxy group (5g—i) brought about remarkable im-

provement in the pharmacokinetic proﬁles together with in-

crease of activity. Especially, the 2-(propoxy)ethoxy (5h) and

2-(butoxy)ethoxy (5i) compounds had signiﬁcantly increased

oral plasma levels. Thus, the 2-(butoxy)ethoxy compound 5i

showed about 75-fold C_maxand 160-fold AUC values, when

compared with the methyl compound 3. Next, the 1-benz-

azepine derivatives with the 2-(butoxy)ethoxy group were ex-

amined. The 1-propyl-1-benzazepine 6h exhibited about 10

times higher plasma level after oral administration compared

with the lead compound 4. On the other hand, the plasma

level of the 1-isobutyl compound 6i was not very high, prob-

ably due to its high lipophilicity. The 1-methylpyrazol-4-yl-

244

17.2

1.03

8.35

a) Compounds (10 mg/kg) suspended in 0.5% methylcellulose were 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. e) 5e hydrochloride was used.

mediated membrane fusion assay. In particular, compound 6s

showed the most potent CCR5 antagonistic activity

(IC₅₀ꢀ2.7 n^M) and inhibitory effect (IC₅₀ꢀ1.2 n^M) on the

membrane fusion, together with good pharmacokinetic prop-

erties in rats.

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). Elemental analyses were carried out by Takeda Analytical Research

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

cal values. Column chromatography was carried out on a silica gel column

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

Methyl 7-Bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (12) To

a solution of 11¹⁸⁾(96.0 g, 373 mmol) in dimethyl carbonate (684 ml) was

added sodium methoxide (101 g, 1870 mmol) at room temperature, and the

methyl compound 6s had reduced lipophilicity and exhibited mixture was reﬂuxed for 5 h under a nitrogen atmosphere. The mixture was

acidiﬁed using 3 N HCl under ice cooling, and the mixture was extracted

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

and concentrated in vacuo to give 103 g (88%) of methyl 7-bromo-5-oxo-

a ca. 5-fold increase in both C_maxand AUC values when com-

pared with the lead compound 4.

2,3,4,5-tetrahydro-1-benzothiepine-4-carboxylate as a pale brown solid. To a

Conclusion

solution of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-4-car-

boxylate (71.2 g, 226 mmol) in tetrahydrofuran (THF) was added NaBH₄

(8.15 g, 215 mmol) at ꢂ40 °C. MeOH (100 ml) was added to the mixture at

ꢂ40 °C, and the mixture was stirred at ꢂ10—ꢂ20 °C for 1 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. To a solution of the residue and Et₃N (60.0 ml, 430 mmol) in

THF (500 ml) was added methanesulfonyl chloride (MsCl) (25.0 ml,

323 mmol) under ice cooling. The mixture was stirred under ice cooling for

0.5 h and at room temperature for 1 h. To the mixture was added 1,8-diazabi-

cyclo[5,4,0]undec-7-ene (DBU) (51.6 g, 339 mmol) at room temperature.

After being stirred at room temperature for 10 min, 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 (hexane : EtOAcꢀ4 : 1)

The search for orally active CCR5 antagonists was per-

formed by chemical modiﬁcation of the 1-benzothiepine 1,1-

dioxide 3 and 1-benzazepine 4 lead compounds containing a

tertiary amine moiety. Replacement of the methyl group with

a 2-(butoxy)- or 2-(propoxy)ethoxy group at the 4-position

on the 7-phenyl group of the 1-benzothiepine ring, not only

resulted in enhanced activity but also signiﬁcantly improved

the pharmacokinetic properties upon oral administration in

rats. Introduction of C_2—4alkyl, phenyl or (hetero)arylmethyl

groups as the 1-substituent on the 1-benzazepine ring to-

gether with the 2-(butoxy)ethoxy group led to further in-

crease in activity. Among the 1-benzazepine derivatives, the

isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s)

compounds exhibited highly potent inhibitory effects, equiv-

to give 37.2 g (55%) of 12 as pale yellow crystals, mp 94—95 °C. H-NMR

(CDCl₃) d 2.94—3.00 (2H, m), 3.15—3.21 (2H, m), 3.83 (3H, s), 7.28—

7.33 (2H, m), 7.51 (1H, d, Jꢀ1.2 Hz), 7.70 (1H, s). Anal. Calcd for

alent to the injectable CCR5 antagonist 1, in the HIV-1 Env- C₁₂H₁₁BrO₂S: C, 48.17; H, 3.71. Found: C, 48.37; H, 3.77.

May 2004

583

1.30 (6H, d, Jꢀ7.0 Hz), 2.92—3.05 (1H, m), 3.13—3.20 (2H, m), 3.63—

3.70 (2H, m), 7.36 (2H, d, Jꢀ8.5 Hz), 7.56 (2H, d, Jꢀ8.2 Hz), 7.69—7.78

(2H, m), 8.01 (1H, br s), 8.24 (1H, d, Jꢀ8.8 Hz). Anal. Calcd for

C₂₀H₂₀O₄S·0.2H₂O: C, 66.72; H, 5.71. Found: C, 66.63; H, 5.79.

7-(4-Propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic Acid

1,1-Dioxide (7d) Yield 90%, mp 270—273 °C. ¹H-NMR (DMSO-d₆) d

1.00 (3H, t, Jꢀ7.5 Hz), 1.65—1.86 (2H, m), 2.93—3.00 (2H, m), 3.71—

3.78 (2H, m), 4.00 (2H, t, Jꢀ6.6 Hz), 7.06 (2H, d, Jꢀ8.7 Hz), 7.78 (2H, d,

Jꢀ8.7 Hz), 7.83—7.93 (2H, m), 8.03—8.07 (2H, m). Anal. Calcd for

C₂₀H₂₀O₅S: C, 64.50; H, 5.41. Found: C, 64.34; H, 5.48.

Methyl 7-Bromo-2,3-dihydro-1-benzothiepine-4-carboxylate 1,1-Diox-

ide (13a) To a mixture of 12 (3.00 g, 10.0 mmol) and acetic acid (30 ml)

was added 30% aqueous H₂O₂(4.50 ml) at room temperature. After being

reﬂuxed for 1 h, the reaction mixture was poured into water. The precipitated

colorless crystals were collected by ﬁltration, washed with water and diiso-

propyl ether (i-Pr₂O) to give 3.06 g (90%) of 13a as colorless crystals, mp

162—164 °C. ¹H-NMR (CDCl₃) d 3.11 (2H, t, Jꢀ6.5 Hz), 3.62 (2H, t,

Jꢀ6.5 Hz), 3.87 (3H, s), 7.64—7.76 (3H, m), 8.03 (1H, d, Jꢀ8.4 Hz). Anal.

Calcd for C₁₂H₁₁BrO₄S: C, 43.52; H, 3.35. Found: C, 43.52; H, 3.18.

Methyl 7-(4-Ethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate

1,1-Dioxide (14a) A mixture of 13a (0.80 g, 2.42 mmol), 4-ethylphenyl-

boronic acid (0.40 g, 2.67 mmol) and K₂CO₃(0.67 g, 4.85 mmol) in toluene

(30 ml), EtOH (3.0 ml) and water (3.0 ml) was stirred at room temperature

under an argon atmosphere for 1 h. Tetrakis(triphenylphosphine)palladium

(Pd(PPh₃)₄) (0.14 g, 0.12 mmol) was added, and the mixture was reﬂuxed for

15 h under an argon atmosphere. The reaction 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) to give 732 mg (85%) of 14a as pale yellow crystals,

7-(4-Morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboylic

Acid 1,1-Dioxide (7e) To a solution of 14e (550 mg, 1.33 mmol) in EtOH

(15 ml) and THF (15 ml) was added 1 ^NNaOH (1.6 ml, 1.6 mmol) at room

temperature. After being stirred at room temperature for 18 h, 1 N HCl

(1.6 ml, 1.6 mmol) was added to the reaction mixture at room temperature.

The mixture was evaporated in vacuo. The precipitated crystals were col-

lected by ﬁltration, washed with 2-propanol and i-Pr₂O to give 269 mg

(51%) of 7e as pale yellow crystals. ¹H-NMR (DMSO-d₆) d 2.89—3.02

(2H, m), 3.15—3.26 (4H, m), 3.68—3.82 (6H, m), 7.06 (2H, d, Jꢀ9.0 Hz),

7.74 (2H, d, Jꢀ9.0 Hz), 7.83—7.91 (2H, m), 7.99—8.08 (2H, m). Anal.

Calcd for C₂₁H₂₁NO₅S: C, 61.75; H, 5.43; N, 3.43. Found: C, 61.60; H, 5.65;

N, 3.50.

tert-Butyl 4-(Ethylamino)butanoate (16a) To a solution of 15 (25.4 g,

107 mmol) and EtI (50.0 g, 321 mmol) in THF (350 ml) was added NaH

(60% dispersion in mineral oil, 12.8 g, 320 mmol) under ice cooling. The

mixture was stirred at 75 °C for 13 h under a nitrogen atmosphere. Water

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

EtOAc. The aqueous layer was acidiﬁed using 1 ^NHCl under ice cooling.

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

aqueous Na₂S₂O₃and brine, dried over MgSO₄, and concentrated in vacuo to

give 25.1 g (87%) of 4-{[(benzyloxy)carbonyl](ethyl)amino}butanoic acid

as a yellow oil. To a solution of 4-{[(benzyloxy)carbonyl](ethyl)amino}bu-

tanoic acid (8.24 g, 31.3 mmol) and di-tert-butyl dicarbonate (Boc₂O)

(14.3 ml, 62.2 mmol) in tert-BuOH (300 ml) was added 4-(N,N-dimethyl-

amino)pyridine (DMAP) (390 mg, 9.34 mmol) at room temperature. After

being stirred at room temperature for 4 h, the mixture was concentrated

in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtOAcꢀ4 : 1) to give 4.20 g (42%) of tert-butyl 4-{[(benzyloxy)-

carbonyl](ethyl)amino}butanoate as a pale yellow oil. A mixture of tert-

butyl 4-{[(benzyloxy)carbonyl](ethyl)amino}butanoate (3.38 g, 10.5 mmol),

conc. HCl (1 drop) and 10% Pd–C (50% wet, 0.34 g) in MeOH (35 ml) was

stirred at room temperature for 3 h under a hydrogen atmosphere. The cata-

lyst was removed by ﬁltration and the ﬁltrate was concentrated in vacuo to

give 2.30 g (quant.) of 16a as a pale yellow oil. ¹H-NMR (CDCl₃) d 1.12

(3H, t, Jꢀ7.2 Hz), 1.44 (9H, s), 1.78 (2H, quintet, Jꢀ7.2 Hz), 2.27 (2H, t,

Jꢀ7.2 Hz), 2.65 (2H, t, Jꢀ7.2 Hz), 2.67 (2H, q, Jꢀ7.2 Hz).

mp 173—176 °C. H-NMR (CDCl₃) d 1.29 (3H, t, Jꢀ7.5 Hz), 2.72 (2H, q,

Jꢀ7.5 Hz), 3.11—3.18 (2H, m), 3.62—3.68 (2H, m), 3.87 (3H, s), 7.33 (2H,

d, Jꢀ8.1 Hz), 7.54 (2H, d, Jꢀ8.1 Hz), 7.66—7.74 (2H, m), 7.92 (1H, br s),

8.21 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₂₀H₂₀O₄S: C, 67.39; H, 5.66.

Found: C, 67.36; H, 5.63.

The following compounds (14b—e) were prepared from 13a by a method

similar to that described for 14a.

Methyl 7-(4-Propylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylate

1,1-Dioxide (14b) Yield 62%, mp 155—156 °C. ¹H-NMR (CDCl₃) d 0.98

(3H, t, Jꢀ7.4 Hz), 1.63—1.77 (2H, m), 2.66 (2H, t, Jꢀ7.6 Hz), 3.11—3.18

(2H, m), 3.61—3.68 (2H, m), 3.87 (3H, s), 7.30 (2H, d, Jꢀ8.4 Hz), 7.54

(2H, d, Jꢀ8.4 Hz), 7.69—7.73 (2H, m), 7.92 (1H, br s), 8.22 (1H, d,

Jꢀ8.8 Hz). Anal. Calcd for C₂₁H₂₂O₄S: C, 68.08; H, 5.99. Found: C, 68.13;

H, 5.89.

Methyl 7-(4-Isopropylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxy-

late 1,1-Dioxide (14c) Yield 86%, mp 142—144 °C. H-NMR (CDCl₃) d

1.30 (6H, d, Jꢀ6.6 Hz), 2.90—3.06 (1H, m), 3.12—3.18 (2H, m), 3.62—

3.68 (2H, m), 3.87 (3H, s), 7.36 (2H, d, Jꢀ8.2 Hz), 7.55 (2H, d, Jꢀ8.2 Hz),

7.69—7.73 (2H, m), 7.92 (1H, br s), 8.22 (1H, d, Jꢀ8.8 Hz). Anal. Calcd for

C₂₁H₂₂O₄S: C, 68.08; H, 5.99. Found: C, 68.04; H, 6.15.

Methyl 7-(4-Propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxy-

late 1,1-Dioxide (14d) Yield 76%, mp 153—155 °C. H-NMR (CDCl₃) d

1.07 (3H, t, Jꢀ7.5 Hz), 1.76—1.93 (2H, m), 3.11—3.17 (2H, m), 3.61—

3.68 (2H, m), 3.87 (3H, s), 3.99 (2H, t, Jꢀ6.6 Hz), 7.01 (2H, d, Jꢀ9.0 Hz),

7.55 (2H, d, Jꢀ9.0 Hz), 7.66—7.70 (2H, m), 7.91 (1H, br s), 8.20 (1H, d,

Jꢀ8.4 Hz). Anal. Calcd for C₂₁H₂₂O₅S: C, 65.27; H, 5.74. Found: C, 65.35;

H, 5.63.

tert-Butyl 4-(Propylamino)butanoate (16b) This compound was pre-

pared in 34% yield from 15 by a method similar to that described for 16a.

¹H-NMR (CDCl₃) d 0.92 (3H, t, Jꢀ7.1 Hz), 1.45 (9H, s), 1.47—1.67 (4H,

m), 1.70—1.85 (2H, m), 2.25 (2H, q, Jꢀ7.9 Hz), 2.60 (2H, dt, Jꢀ11.6,

7.2 Hz), 3.21 (1H, m).

Methyl 7-(4-Morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-car-

boxylate 1,1-Dioxide (14e) Yield 71%, mp 215—217 °C. ¹H-NMR

(CDCl₃) d 3.10—3.17 (2H, m), 3.23—3.28 (4H, m), 3.61—3.67 (2H, m),

3.87 (3H, s), 3.84—3.95 (4H, m), 7.00 (2H, d, Jꢀ8.8 Hz), 7.56 (2H, d,

Jꢀ8.8 Hz), 7.66—7.74 (2H, m), 7.91 (1H, s), 8.18 (1H, d, Jꢀ8.8 Hz). Anal.

Calcd for C₂₂H₂₃NO₅S: C, 63.90; H, 5.61; N, 3.39. Found: C, 63.89; H, 5.74;

N, 3.51.

tert-Butyl 4-[(4-Bromo-2-formylphenyl)(ethyl)amino]butanoate (17a)

mixture of 16a (2.30 g, 10.5 mmol), 5-bromo-2-ﬂuorobenzaldehyde

(2.13 g, 10.5 mmol) and K₂CO₃(1.74 g, 12.6 mmol) in N,N-dimethylform-

amide (DMF) (20 ml) was stirred at 70—80 °C for 73 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 concentrated

in vacuo. The residue was puriﬁed by column chromatography

(hexane : EtOAcꢀ10 : 1) to give 1.46 g (38%) of 17a as a yellow oil. ¹H-

NMR (CDCl₃) d 1.05 (3H, t, Jꢀ7.1 Hz), 1.42 (9H, s), 1.77 (2H, quintet,

Jꢀ7.2 Hz), 2.21 (2H, t, Jꢀ7.1 Hz), 3.15 (2H, t, Jꢀ7.3 Hz), 3.18 (2H, q,

Jꢀ7.1 Hz), 7.07 (1H, d, Jꢀ8.8 Hz), 7.58 (1H, dd, Jꢀ8.8, 2.6 Hz), 7.91 (1H,

d, Jꢀ2.6 Hz), 10.25 (1H, s).

tert-Butyl 4-[(4-Bromo-2-formylphenyl)(propyl)amino]butanoate (17b)

This compound was prepared in 52% yield from 16b by a method similar to

that described for 17a. ¹H-NMR (CDCl₃) d 0.84 (3H, t, Jꢀ7.8 Hz), 1.45

(9H, s), 1.42—1.63 (2H, m), 1.81 (2H, quintet, Jꢀ7.4 Hz), 2.19 (2H, t,

Jꢀ7.5 Hz), 3.09 (2H, t, Jꢀ7.6 Hz), 3.17 (2H, t, Jꢀ7.5 Hz), 7.06 (1H, d,

Jꢀ8.8 Hz), 7.56 (1H, dd, Jꢀ8.7, 2.5 Hz), 7.90 (1H, d, Jꢀ2.6 Hz), 10.24 (1H,

s).

7-(4-Ethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic Acid 1,1-

Dioxide (7a) To

a solution of 14a (600 mg, 1.68 mmol) in 1,2-

dimethoxyethane (20 ml) was added 6 N HCl (10 ml) at room temperature,

and the mixture was reﬂuxed for 24 h. The mixture was extracted with

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

concentrated in vacuo. The precipitated crystals were collected by ﬁltration,

washed with hexane to give 501 mg (87%) of 7a as pale yellow crystals, mp

263—265 °C. ¹H-NMR (CDCl₃) d 1.29 (3H, t, Jꢀ7.6 Hz), 2.73 (2H, q,

Jꢀ7.6 Hz), 3.17 (2H, t, Jꢀ6.6 Hz), 3.67 (2H, t, Jꢀ6.6 Hz), 7.34 (2H, d,

Jꢀ8.4 Hz), 7.55 (2H, d, Jꢀ8.4 Hz), 7.70—7.78 (2H, m), 8.02 (1H, s), 8.24

(1H, d, Jꢀ8.8 Hz). Anal. Calcd for C₁₉H₁₈O₄S: C, 66.65; H, 5.30. Found: C,

66.47; H, 5.41.

The following compounds (7b—d) were prepared from the corresponding

esters (14b—d) by a method similar to that described for 7a.

7-(4-Propylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic

Acid

1,1-Dioxide (7b) Yield 90%. ¹H-NMR (DMSO-d₆)

0.92 (3H, t,

Jꢀ7.3 Hz), 1.58—1.69 (2H, m), 2.58—2.66 (2H, m), 2.93—3.01 (2H, m),

3.72—3.79 (2H, m), 7.34 (2H, d, Jꢀ8.2 Hz), 7.74 (2H, d, Jꢀ8.2 Hz), 7.88—

7.93 (2H, m), 8.06—8.09 (2H, m).

tert-Butyl 7-Bromo-1-ethyl-2,3-dihydro-1H-1-benzazepine-4-carboxy-

late (13c) A mixture of 17a (1.44 g, 3.89 mmol) and potassium tert-butox-

ide (480 mg, 4.28 mmol) in toluene (80 ml) and tert-BuOH (8.0 ml) was

stirred at 90 °C for 3 h. 1 ^NHCl (6.0 ml) was added to the reaction mixture

7-(4-Isopropylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxylic Acid

1,1-Dioxide (7c) Yield 96%, mp 281—282 °C (dec.). H-NMR (CDCl₃) d

584

Vol. 52, No. 5

under ice cooling and the mixture was extracted with EtOAc. The organic washed with water and brine, and dried over MgSO₄, and concentrated

layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. in vacuo. The residue was puriﬁed by column chromatography

The residue was puriﬁed by column chromatography (hexane : EtOAcꢀ (hexane : EtOAcꢀ4 : 1) to give 2.53 g (37%) of 20 as colorless crystals. H-

20 : 1) to give 964 mg (70%) of 13c as a yellow oil. ¹H-NMR (CDCl₃) d 1.26

(3H, t, Jꢀ7.1 Hz), 1.53 (9H, s), 2.76 (2H, td, Jꢀ4.9, 1.4 Hz), 3.19 (2H, t,

Jꢀ4.9 Hz), 3.34 (2H, q, Jꢀ7.1 Hz), 6.69 (1H, d, Jꢀ9.0 Hz), 7.23 (1H, dd,

Jꢀ9.0, 2.4 Hz), 7.40 (1H, d, Jꢀ2.4 Hz), 7.47 (1H, s).

NMR (CDCl₃) d 1.47 (9H, s), 2.89 (2H, t, Jꢀ4.8 Hz), 3.61 (2H, br s), 3.83

(3H, s), 7.27 (1H, br s), 7.39 (1H, dd, Jꢀ8.4, 1.8 Hz), 7.54—7.55 (2H, m).

Methyl 7-Bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (21)

To a solution of 20 (5.04 g, 13.2 mmol) in EtOAc (250 ml) was added 6 N

tert-Butyl 7-Bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carbox- HCl (80 ml) at room temperature. The mixture was stirred at 80 °C for 0.5 h.

ylate (13d) This compound was prepared in 60% yield from 17b by a To the reaction mixture was added 1 ^NNaOH (400 ml) and saturated aqueous

method similar to that described for 13c. H-NMR (CDCl₃) d 0.95 (3H, t, Na₂CO₃(300 ml). The mixture was extracted with EtOAc. The organic layer

Jꢀ7.5 Hz), 1.53 (9H, s), 1.68 (2H, sextet, Jꢀ7.6 Hz), 2.75 (2H, t, was washed with saturated aqueous NaHCO₃, water and brine, dried over

Jꢀ4.4 Hz), 3.18—3.26 (4H, m), 6.67 (1H, d, Jꢀ9.2 Hz), 7.22 (1H, dd, MgSO₄, and concentrated in vacuo to give 3.72 g (quant) of 21 as yellow

Jꢀ8.8, 2.6 Hz), 7.39 (1H, d, Jꢀ2.6 Hz), 7.46 (1H, s).

crystals. ¹H-NMR (CDCl₃) d 2.86 (2H, t, Jꢀ5.2 Hz), 3.36 (2H, t, Jꢀ5.2 Hz),

Methyl 5-Bromo-2-{[(4-methylphenyl)sulfonyl]amino}benzoate (18) 3.80 (3H, s), 4.57 (1H, br s), 6.49 (1H, d, Jꢀ8.4 Hz), 7.15 (1H, dd, Jꢀ8.4,

To a silution of methyl 5-bromo-2-aminobenzoate (28.2 g, 123 mmol) in

pyridine (70 ml) was added p-toluenesulfonyl chloride (35.1 g, 184 mmol) at

room temperature. After being stirred at 55 °C for 1 h, the mixture was con-

2.2 Hz), 7.38 (1H, d, Jꢀ2.2 Hz), 7.53 (1H, s).

Methyl 7-Bromo-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxy-

late (13e) To a solution of 21 (2.00 g, 7.09 mmol) and isobutyraldehyde

centrated in vacuo, poured into water, and extracted with EtOAc. The or- (3.22 ml, 35.4 mmol) in 1,2-dichloroethane (70 ml) was added triacetoxy-

ganic layer was washed with water, 1 ^NHCl, and brine, dried over MgSO₄,

borohydride (5.36 g, 24.8 mmol) under ice cooling. After being stirred at

room temperature for 12 h, 1 N NaOH was added to the reaction mixture, and

and concentrated in vacuo to give 41.5 g (88%) of 18 as colorless crystals,

mp 123—124 °C. H-NMR (CDCl₃) d 2.38 (3H, s), 3.89 (3H, s), 7.24 (2H, the mixture was extracted with EtOAc. The organic layer was washed with

d, Jꢀ8.6 Hz), 7.53 (1H, dd, Jꢀ9.2, 2.0 Hz), 7.61 (1H, d, Jꢀ9.2 Hz), 7.73

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

(2H, d, Jꢀ8.6 Hz), 8.03 (1H, d, Jꢀ2.0 Hz), 10.52 (1H, s). Anal. Calcd for was puriﬁed by column chromatography (hexane : EtOAcꢀ6 : 1) to give

C₁₅H₁₄BrNO₄S: C, 46.89; H, 3.67; N, 3.65. Found: C, 46.93; H, 3.53; N, 1.82 g (76%) of 13e as a yellow solid. ¹H-NMR (CDCl₃) d 0.92 (6H, d,

3.67.

7-Bromo-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one (19) To a solu-

Jꢀ6.6 Hz), 2.03 (1H, m), 2.77—2.82 (2H, m), 3.10 (2H, d, Jꢀ7.4 Hz),

3.21—3.26 (2H, m), 3.80 (3H, s), 6.71 (1H, d, Jꢀ8.8 Hz), 7.19—7.26 (1H,

m), 7.42 (1H, d, Jꢀ2.6 Hz), 7.58 (1H, s).

tion of 18 (38.1 g, 99.3 mmol) in DMF (100 ml) was added NaH (60% dis-

persion in mineral oil, 4.76 g, 119 mmol) and DMF (35 ml) under ice cool-

ing. The mixture was stirred at room temperature for 1 h under a nitrogen at-

mosphere. NaI (14.9 g, 99.3 mmol) and ethyl 4-bromobutyrate (21.3 g,

109 mmol) were added, and then the mixture was stirred at 80 °C for 14 h

under a nitrogen atmosphere. NaH (60% dispersion in mineral oil, 4.76 g,

119 mmol) and DMF (25 ml) were added to the mixture under ice cooling.

The mixture was stirred at 80 °C for 15 h under a nitrogen atmosphere. The

reaction mixture was concentrated in vacuo, and the residue was diluted

with EtOAc. The mixture was washed successively with water and brine,

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

column chromatography (hexane : EtOAcꢀ9 : 1→4 : 1) to give 25.1 g of

white crystals. A mixture of the crystals (25.1 g), conc. H₂SO₄(90 ml) and

acetic acid (150 ml) was stirred at 90 °C for 2.5 h. The reaction mixture was

poured into ice. The mixture was neutralized using 12 ^NNaOH under ice

cooling. 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 : EtOAcꢀ3 : 1) to give 5.01 g (21%) of 19 as yellow crystals. ¹H-

NMR (CDCl₃) d 2.18 (2H, quintet, Jꢀ7.1 Hz), 2.82 (2H, t, Jꢀ7.2 Hz), 3.25

Methyl 7-Bromo-1-(3-methylbutyl)-2,3-dihydro-1H-1-benzazepine-4-

carboxylate (13f) This compound was prepared in 87% yield from 21 by a

method similar to that described for 13e. H-NMR (CDCl₃) d 0.95 (6H, d,

Jꢀ6.2 Hz), 1.48—1.62 (3H, m), 2.79 (2H, t, Jꢀ4.4 Hz), 3.21 (2H, t,

Jꢀ4.4 Hz), 3.24—3.33 (2H, m), 3.80 (3H, s), 6.68 (1H, d, Jꢀ8.8 Hz),

7.20—7.26 (1H, m), 7.41 (1H, d, Jꢀ2.2 Hz), 7.56 (1H, s).

The following compounds (14f, 22) were prepared from the correspond-

ing bromides (13e, 21) by a method similar to that described for 14a.

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

benzazepine-4-carboxylate (14f) Yield 62%. ¹H-NMR (CDCl₃) d 0.93

(3H, t, Jꢀ7.2 Hz), 0.95 (6H, d, Jꢀ6.6 Hz), 1.37—1.67 (4H, m), 1.99—2.16

(1H, m), 2.82 (2H, t, Jꢀ4.8 Hz), 3.17 (2H, d, Jꢀ7.4 Hz), 3.30 (2H, t,

Jꢀ4.8 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.77—3.83 (5H, m), 4.13—4.18 (2H,

m), 6.89 (1H, d, Jꢀ8.4 Hz), 6.97 (2H, d, Jꢀ8.8 Hz), 7.36—7.52 (4H, m),

7.77 (1H, s).

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

4-carboxylate (22) Yield 56%. ¹H-NMR (CDCl₃)

Jꢀ7.3 Hz), 1.29—1.48 (2H, m), 1.51—1.69 (2H, m), 2.88 (2H, t,

Jꢀ4.6 Hz), 3.37—3.44 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.78—3.83 (2H,

d 0.93 (3H, t,

(2H, t, Jꢀ6.6 Hz), 4.65 (1H, br s), 6.65 (1H, d, Jꢀ8.6 Hz), 7.20 (1H, dd, m), 4.16 (2H, t, Jꢀ5.0 Hz), 4.5—4.64 (1H, m), 6.67 (1H, d, Jꢀ8.2 Hz), 6.97

Jꢀ8.6, 2.2 Hz), 7.82 (1H, d, Jꢀ2.2 Hz).

(2H, d, Jꢀ8.8 Hz), 7.33 (1H, dd, Jꢀ8.2, 2.2 Hz), 7.43—7.48 (3H, m), 7.71

(1H, s).

The following compounds (14g—i, 14k—o) were prepared from 22 by a

method similar to that described for 13e.

Methyl 7-Bromo-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-1-benz-

azepine-4-carboxylate (20) To a solution of 19 (4.31 g, 18.0 mmol) and

Boc₂O (13.8 g, 63.2 mmol) in THF (36 ml) was added DMAP (2.19 g,

17.9 mmol) at room temperature. The mixture was reﬂuxed for 1.5 h. Water

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-cyclopropylmethyl-2,3-dihy-

was added to the reaction mixture, and the mixture was extracted with dro-1H-1-benzazepine-4-carboxylate (14g) Yield quant. ¹H-NMR

EtOAc. The organic layer was washed with water and brine, dried over (CDCl₃) d 0.24—0.32 (2H, m), 0.58—0.67 (2H, m), 0.93 (3H, t, Jꢀ7.3 Hz),

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

chromatography (hexane : EtOAcꢀ9 : 1) to give a yellow oil. To a solution of Jꢀ4.4 Hz), 3.23 (2H, d, Jꢀ6.6 Hz), 3.39 (2H, t, Jꢀ4.7 Hz), 3.55 (2H, t,

the oil in dimethyl carbonate (100 ml) was added sodium methoxide (4.86 g, Jꢀ6.6 Hz), 3.73—3.83 (5H, m), 4.11—4.18 (2H, m), 6.92—7.01 (3H, m),

90.0 mmol) at room temperature, and the mixture was reﬂuxed for 2.5 h. The 7.38—7.53 (4H, m), 7.77 (1H, s).

1.08—1.15 (1H, m), 1.34—1.49 (2H, m), 1.55—1.68 (2H, m), 2.86 (2H, t,

reaction mixture was poured into ice water. To the mixture was added 1 M

citric acid (100 ml) 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

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-cyclobutylmethyl-2,3-dihy-

dro-1H-1-benzazepine-4-carboxylate (14h) Yield quant. ¹H-NMR

(CDCl₃) d 0.93 (3H, t, Jꢀ7.3 Hz), 1.34—1.45 (2H, m), 1.54—2.13 (8H, m),

2.70—2.81 (3H, m), 3.26 (2H, t, Jꢀ4.8 Hz), 3.38 (2H, d, Jꢀ7.4 Hz), 3.55

(hexane : EtOAcꢀ9 : 1→4 : 1) to give 3.89 g of b-keto ester as a pale yellow (2H, t, Jꢀ6.6 Hz), 3.78—3.83 (5H, m), 4.16 (2H, t, Jꢀ4.9 Hz), 6.87 (1H, d,

amorphous. To a mixture of b-keto ester (3.89 g) and NaBH₄(0.38 g,

10 mmol) in THF (100 ml) was added MeOH (10 ml) at ꢂ40 °C. The mix-

ture was stirred at ꢂ15 °C for 1 h. To the reaction mixture was added 1 M cit-

ric acid (20 ml) and water at ꢂ40 °C, and the mixture was extracted with

EtOAc. The organic layer was washed with water and brine, dried over Jꢀ6.6 Hz), 3.29 (2H, t, Jꢀ4.8 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.78—3.82 (5H,

MgSO₄, and concentrated in vacuo. To a solution of the residue and Et₃N m), 4.15 (2H, t, Jꢀ4.9 Hz), 6.87 (H, d, Jꢀ8.8 Hz), 6.97 (2H, d, Jꢀ8.8 Hz),

Jꢀ8.8 Hz), 6.97 (2H, d, Jꢀ8.8 Hz), 7.37—7.51 (4H, m), 7.75 (1H, s).

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-cyclohexylmethyl-2,3-dihy-

dro-1H-1-benzazepine-4-carboxylate (14i) Yield quant. ¹H-NMR

(CDCl₃) d 0.89—1.81 (18H, m), 2.81 (2H, t, Jꢀ4.2 Hz), 3.19 (2H, d,

(4.1 ml, 29.4 mmol) in THF (750 ml) was added MsCl (1.15 ml, 14.9 mmol)

under ice cooling. After being stirred at room temperature for 14 h, DBU

(7.30 ml, 48.9 mmol) was added to the reaction mixture at room temperature.

The mixture was reﬂuxed for 10 min. Water was added to the reaction mix-

7.36—7.51 (4H, m), 7.76 (1H, s).

Methyl 1-Benzyl-7-{4-[2-(butoxy)ethoxy]phenyl}-2,3-dihydro-1H-1-

benzazepine-4-carboxylate (14k) Yield quant. H-NMR (CDCl₃) d 0.93

(3H, t, Jꢀ7.3 Hz), 1.30—1.48 (2H, m), 1.54—1.68 (2H, m), 2.77 (2H, t,

ture, and the mixture was extracted with EtOAc. The organic layer was Jꢀ4.7 Hz), 3.31 (2H, t, Jꢀ4.7 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.78—3.82 (5H,

May 2004

585

m), 4.15 (2H, t, Jꢀ4.8 Hz), 4.59 (2H, s), 6.86 (1H, d, Jꢀ8.8 Hz), 6.97 (2H,

d, Jꢀ8.8 Hz), 7.26—7.68 (7H, m), 7.82—7.91 (3H, m).

Jꢀ5.0 Hz), 6.88 (1H, d, Jꢀ8.0 Hz), 6.98 (2H, d, Jꢀ8.8 Hz), 7.39—7.51 (4H,

m), 7.85 (1H, s). Anal. Calcd for C₂₈H₃₅NO₄: C, 74.80; H, 7.85; N, 3.12.

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(thiazol-2-yl)methyl]-2,3- Found: C, 74.51; H, 7.92; N, 2.98.

dihydro-1H-1-benzazepine-4-carboxylate (14l) Yield 88%. ¹H-NMR

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

(CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.34—1.45 (2H, m), 1.57—1.70 (2H, m), 1-benzazepine-4-carboxylic Acid (7i) Yield 89%, mp 124—125 °C. ¹H-

2.87 (2H, t, Jꢀ4.4 Hz), 3.42 (2H, t, Jꢀ4.4 Hz), 3.55 (2H, t, Jꢀ6.6 Hz),

3.78—3.82 (5H, m), 4.16 (2H, t, Jꢀ5.6 Hz), 4.86 (2H, s), 6.95—7.00 (3H, Jꢀ6.6 Hz), 3.32 (2H, t-like), 3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, d, Jꢀ5.0 Hz),

m), 7.30 (1H, d, Jꢀ3.2 Hz), 7.40 (1H, dd, Jꢀ8.4, 2.2 Hz), 7.46 (2H, d, 4.16 (2H, t, Jꢀ5.0 Hz), 6.89 (1H, d, Jꢀ8.8 Hz), 6.98 (2H, d, Jꢀ8.8 Hz),

NMR (CDCl₃) d 0.90—1.85 (18H, m), 2.83 (3H, t-like), 3.22 (2H, d,

Jꢀ8.6 Hz), 7.56 (1H, d, Jꢀ2.6 Hz), 7.78—7.81 (2H, m).

7.39—7.53 (4H, m), 7.88 (1H, s). Anal. Calcd for C₃₀H₃₉NO₄: C, 75.44; H,

8.23; N, 2.93. Found: C, 75.46; H, 8.23; N, 2.96.

Methyl

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-imidazol-2-

yl)methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (14m) Yield

59%. ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.38—1.45 (2H, m),

1.54—1.65 (2H, m), 2.41 (2H, t, Jꢀ4.7 Hz), 3.30 (2H, t, Jꢀ4.7 Hz), 3.51

(3H, s), 3.56 (2H, t, Jꢀ6.2 Hz), 3.79—3.83 (5H, m), 4.17 (2H, t, Jꢀ4.4 Hz),

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

azepine-4-carboxylic Acid (7j) Yield 75%, mp 129—131 °C. ¹H-NMR

(CDCl₃) d 0.94 (3H, t, Jꢀ7.2 Hz), 1.34—1.49 (2H, m), 1.55—1.69 (2H, m),

2.86 (2H, t, Jꢀ4.4 Hz), 3.56 (2H, t, Jꢀ6.6 Hz), 3.79—3.84 (4H, m), 4.17

4.61 (2H, s), 6.88 (1H, d, Jꢀ1.0 Hz), 6.97—7.06 (4H, m), 7.44—7.50 (3H, (2H, t, Jꢀ4.8 Hz), 6.90—7.04 (5H, m), 7.17 (1H, d, Jꢀ8.6 Hz), 7.23—7.31

m), 7.56 (1H, d, Jꢀ2.2 Hz), 7.77 (1H, s).

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-5-yl)

methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (14n) Yield 67%.

¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.4 Hz), 1.34—1.45 (2H, m), 1.55—

1.70 (2H, m), 2.58 (2H, t, Jꢀ4.8 Hz), 3.27 (2H, t, Jꢀ4.8 Hz), 3.56 (2H, t,

(2H, m), 7.40 (1H, dd, Jꢀ8.6, 2.0 Hz), 7.50 (2H, d, Jꢀ7.2 Hz), 7.64 (1H, d,

Jꢀ2.0 Hz), 7.90 (1H, s). Anal. Calcd for C₂₉H₃₁NO₄: C, 76.12; H, 6.83; N,

3.06. Found: C, 76.18; H, 6.85; N, 3.21.

1-Benzyl-7-{4-[2-(butoxy)ethoxy]phenyl}-2,3-dihydro-1H-1-benz-

azepine-4-carboxylic Acid (7k) Yield 89%, mp 133—138 °C. ¹H-NMR

Jꢀ7.0 Hz), 3.79—3.83 (8H, m), 4.17 (2H, t, Jꢀ4.4 Hz), 4.52 (2H, s), 6.22 (CDCl₃) d 0.93 (3H, t, Jꢀ7.4 Hz), 1.34—1.45 (2H, m), 1.54—1.65 (2H, m),

(1H, d, Jꢀ1.8 Hz), 6.92 (1H, d, Jꢀ8.8 Hz), 6.99 (2H, d, Jꢀ8.8 Hz), 7.40— 2.80 (2H, br), 3.34 (2H, br), 3.56 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, t, Jꢀ5.0 Hz),

7.50 (4H, m), 7.57 (1H, d, Jꢀ2.2 Hz), 7.79 (1H, s).

4.16 (2H, t, Jꢀ5.0 Hz), 4.61 (2H, s), 6.88 (1H, d, Jꢀ8.8 Hz), 6.98 (2H, d,

Jꢀ8.8 Hz), 7.26—7.49 (8H, m), 7.57 (1H, d, Jꢀ2.2 Hz), 7.94 (1H, s). Anal.

Calcd for C₃₀H₃₃NO₄: C, 76.41; H, 7.05; N, 2.97. Found: C, 76.06; H, 7.15;

Methyl 7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-4-yl)-

methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (14o) Yield 63%.

¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.4 Hz), 1.34—1.45 (2H, m), 1.50— N, 2.68.

1.70 (2H, m), 2.76 (2H, t, Jꢀ5.0 Hz), 3.27 (2H, t, Jꢀ5.0 Hz), 3.56 (2H, t,

Jꢀ7.0 Hz), 3.78—3.83 (5H, m), 3.89 (3H, s), 4.16 (2H, t, Jꢀ5.2 Hz), 4.42

(2H, s), 6.92—7.00 (3H, d), 7.29 (1H, s), 7.40 (1H, dd, Jꢀ8.4, 2.0 Hz),

7.45—7.49 (3H, m), 7.54 (1H, d, Jꢀ2.0 Hz), 7.78 (1H, s).

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(thiazol-2-yl)methyl]-2,3-dihydro-

1H-1-benzazepine-4-carboxylic Acid (7l) Yield 78%, mp 105—107 °C.

¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.6 Hz), 1.34—1.45 (2H, m), 1.54—

1.65 (2H, m), 2.89 (2H, br), 3.45 (2H, br), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H,

t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 4.88 (2H, s), 6.96—7.01 (3H, m), 7.31

(1H, d, Jꢀ3.3 Hz), 7.46—7.49 (3H, m), 7.57 (1H, d, Jꢀ2.6 Hz), 7.80 (1H, d,

Jꢀ3.3 Hz), 7.91(1H, s). Anal. Calcd for C₂₇H₃₀N₂O₄S: C, 67.76; H, 6.32; N,

5.85. Found: C, 67.76; H, 6.39; N, 5.70.

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

benzazepine-4-carboxylate (14j) To

solution of 22 (500 mg,

1.26 mmol), copper(II) pivalate (70 mg, 0.26 mmol) in CH₂Cl₂was added

triphenylbismuth diacetate (780 mg, 1.40 mmol) at room temperature. After

being stirred at room temperature over night, the reaction mixture was

poured into 3 N HCl. The mixture was neutralized using 1 N NaOH, and ex-

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-imidazol-2-yl)-

methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic Acid (7m) Yield

tracted with EtOAc. The organic layer was washed with water and brine, 80%. ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.4 Hz), 1.30—1.50 (2H, m),

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

1.54—1.70 (2H, m), 2.47 (2H, br), 3.32 (2H, br), 3.54—3.59 (5H, m), 3.80

column chromatography (hexane : EtOAc) to give 0.42 g (71%) of 14j as yel- (2H, t, Jꢀ4.9 Hz), 4.16 (2H, t, Jꢀ4.9 Hz), 4.68 (2H, s), 6.88 (1H, s), 6.98

low crystals, mp 80—82 °C. ¹H-NMR (CDCl₃) d 0.94 (3H, t, Jꢀ7.1 Hz),

1.31—1.49 (2H, m), 1.56—1.69 (2H, m), 2.85 (2H, t, Jꢀ4.4 Hz), 3.56 (2H,

t, Jꢀ6.6 Hz), 3.79—3.84 (7H, m), 4.17 (2H, t, Jꢀ4.9 Hz), 6.87—7.02 (5H,

(2H, d, Jꢀ8.4 Hz), 7.03—7.07 (2H, m), 7.45—7.49 (3H, m), 7.57 (1H, d,

Jꢀ2.2 Hz), 7.85 (1H, s).

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-5-yl)-

m), 7.16—7.30 (3H, m), 7.40 (1H, dd, Jꢀ8.8, 2.2 Hz), 7.51 (2H, d, methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic Acid (7n) Yield

Jꢀ8.4 Hz), 7.64 (1H, d, Jꢀ2.2 Hz), 7.80 (1H, s). Anal. Calcd for 77%, mp 145—148 °C. H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.0 Hz), 1.34—

C₃₀H₃₃NO₄: C, 76.41; H, 7.05; N, 2.97. Found: C, 76.30; H, 7.17; N, 2.90.

7-{4-[2-(Butoxy)etoxy]phenyl}-1-isobutyl-2,3-dihydro-1H-1-benz-

azepine-4-carboxylic Acid (7f) To a solution of 14f (750 mg, 1.66 mmol)

in THF (15 ml) and MeOH (15 ml) was added 1 N NaOH (7.5 ml, 7.5 mmol)

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

reaction mixture was acidiﬁed using 1 N HCl under ice cooling. The mixture

1.45 (2H, m), 1.55—1.65 (2H, m), 2.62 (2H, br s), 3.30 (2H, br s), 3.56 (2H,

t, Jꢀ7.0 Hz), 3.79—3.84 (5H, m), 4.17 (2H, t, Jꢀ5.0 Hz), 4.54 (2H, s), 6.22

(1H, d, Jꢀ1.8 Hz), 6.93 (1H, d, Jꢀ8.8 Hz), 6.99 (2H, d, Jꢀ8.8 Hz), 7.43—

7.50 (4H, m), 7.58 (1H, d, Jꢀ2.2 Hz), 7.89 (1H, s). Anal. Calcd for

C₂₈H₃₃N₃O₄: C, 70.71; H, 6.99; N, 8.84. Found: C, 70.48; H, 6.90; N, 8.80.

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-4-yl)-

was extracted with EtOAc. The organic layer was washed with brine, dried methyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic Acid (7o) Yield

over MgSO₄, and concentrated in vacuo. The precipitated crystals were col-

69%, mp 131—133 °C. H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.4 Hz), 1.34—

1.49 (2H, m), 1.55—1.65 (2H, m), 2.79 (2H, t, Jꢀ4.2 Hz), 3.30 (2H, t,

Jꢀ4.2 Hz), 3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ4.8 Hz), 3.90 (3H, s),

lected by ﬁltration, washed with hexane : EtOAc (6 : 1) to give 610 mg (84%)

of 7f as yellow crystals. H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.0 Hz), 0.96

(6H, d, Jꢀ6.6 Hz), 1.34—1.47 (2H, m), 1.54—1.66 (2H, m), 1.96—2.18 4.16 (2H, t, Jꢀ5.2 Hz), 4.44 (2H, s), 6.94—7.01 (3H, m), 7.30 (1H, s),

(1H, m), 2.79—2.85 (2H, m), 3.19 (2H, d, Jꢀ6.8 Hz), 3.30—3.35 (2H, m),

3.56 (2H, t, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ4.8 Hz), 4.16 (2H, t, Jꢀ4.8 Hz), 6.90

(1H, d, Jꢀ8.8 Hz), 6.98 (2H, d, Jꢀ8.8 Hz), 7.38—7.53 (4H, m), 7.89 (1H,

s).

The following compounds (7g—o) were prepared from the corresponding

esters (14g—o) by a method similar to that described for 7f.

7.40—7.50 (4H, m), 7.56 (1H, d, Jꢀ2.0 Hz), 7.90 (1H, s). Anal. Calcd for

C₂₈H₃₃N₃O₄: C, 70.71; H, 6.99; N, 8.84. Found: C, 70.52; H, 6.90; N, 8.70.

Methyl 1-(tert-Butoxycarbonyl)-7-(4-morpholinophenyl)-2,3-dihydro-

1H-1-benzazepine-4-carboxylate (23) This compound was prepared in

82% yield from 20 by a method similar to that described for 14a, mp 183—

185 °C. ¹H-NMR (CDCl₃) d 1.49 (9H, s), 2.90 (2H, t, Jꢀ5.0 Hz), 3.19—

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-cyclopropylmethyl-2,3-dihydro-1H- 3.24 (4H, m), 3.69 (2H, t, Jꢀ5.0 Hz), 3.83 (3H, s), 3.87—3.91 (4H, m), 6.98

1-benzazepine-4-carboxylic Acid (7g) Yield 96%, mp 152—155 °C. H- (2H, d, Jꢀ9.0 Hz), 7.48 (2H, m), 7.52 (2H, d, Jꢀ9.0 Hz), 7.58 (1H, s), 7.73

NMR (CDCl₃) d 0.25—0.33 (2H, m), 0.59—0.68 (2H, m), 0.93 (3H, t, (1H, s). Anal. Calcd for C₂₇H₃₂N₂O₅: C, 69.81; H, 6.94; N, 6.03. Found: C,

Jꢀ7.3 Hz), 1.05—1.20 (1H, m), 1.30—1.49 (2H, m), 1.55—1.69 (2H, m), 69.57; H, 6.76; N, 5.76.

2.87 (2H, t, Jꢀ4.6 Hz), 3.25 (2H, d, Jꢀ6.4 Hz), 3.42 (2H, t, Jꢀ4.6 Hz), 3.56

Methyl 7-(4-Morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-car-

(2H, t, Jꢀ6.6 Hz), 3.81 (2H, t, Jꢀ5.0 Hz), 4.16 (2H, t, Jꢀ5.0 Hz), 6.93— boxylate (24) This compound was prepared in 93% yield from 23 by a

7.00 (3H, m), 7.40—7.54 (4H, m), 7.89 (1H, s). Anal. Calcd for C₂₇H₃₃NO₄: method similar to that described for 21, mp 175—182 °C. ¹H-NMR (CDCl₃)

C, 74.45; H, 7.64; N, 3.22. Found: C, 74.27; H, 7.45; N, 3.21.

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

d 2.89 (2H, t, Jꢀ4.5 Hz), 3.17—3.22 (4H, m), 3.41 (2H, t, Jꢀ4.5 Hz), 3.81

(3H, s), 3.87—3.91 (4H, m), 6.67 (1H, d, Jꢀ8.3 Hz), 6.97 (2H, d,

benzazepine-4-carboxylic Acid (7h) Yield 87%, mp 110—112 °C. ¹H- Jꢀ8.8 Hz), 7.33 (1H, dd, Jꢀ8.3, 2.0 Hz), 7.45—7.50 (3H, m), 7.73 (1H, s).

NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.3 Hz), 1.30—2.00 (8H, m), 2.00—2.15 Anal. Calcd for C₂₂H₂₄N₂O₃·0.2H₂O: C, 71.80; H, 6.68; N, 7.61. Found: C,

(2H, m), 2.71—2.80 (3H, m), 3.29 (2H, t, Jꢀ4.8 Hz), 3.39 (2H, d, 71.51; H, 6.72; N, 7.47.

Jꢀ7.0 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.80 (2H, d, Jꢀ5.0 Hz), 4.16 (2H, t,

Methyl 1-Acetyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzaze-

586

Vol. 52, No. 5

pine-4-carboxylate (14p) To a solution of 24 (369 mg, 1.01 mmol) and

pyridine (0.106 ml, 1.31 mmol) in THF (10 ml) was added acetyl chloride

(0.086 ml, 1.2 mmol) under ice cooling. After being stirred at room tempera-

ture for 0.5 h, EtOAc was added to the reaction mixture and the mixture was

washed with water. The organic layer was dried over MgSO₄and concen-

trated in vacuo to give 400 mg (97%) of 14p as a pale yellow amorphous.

¹H-NMR (CDCl₃) d 2.05 (3H, s), 2.74—3.19 (3H, m), 3.24 (4H, t,

Jꢀ4.8 Hz), 3.83 (3H, s), 3.90 (4H, t, Jꢀ4.8 Hz), 4.73—4.85 (1H, m), 7.01

(2H, d, Jꢀ8.8 Hz), 7.23 (1H, d, Jꢀ8.2 Hz), 7.54 (2H, d, Jꢀ8.8 Hz), 7.51—

7.56 (1H, m), 7.67 (1H, d, Jꢀ1.8 Hz), 7.74 (1H, s).

1-Acetyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-

carboxylic Acid (7p) This compound was prepared in 98% yield from

14p by a method similar to that described for 7f. ¹H-NMR (DMSO-d₆) d

1.95 (3H, s), 2.75 (3H, m), 3.17 (4H, t, Jꢀ4.8 Hz), 3.76 (4H, t, Jꢀ4.8 Hz),

4.54 (1H, m), 7.03 (2H, d, Jꢀ8.8 Hz), 7.46 (1H, d, Jꢀ8.2 Hz), 7.63—7.72

(4H, m), 7.88 (1H, s).

(9b) Yield 75%, mp 62—64 °C. H-NMR (CDCl₃) d 1.63—1.79 (4H, m),

2.21 (3H, s), 2.57—2.72 (1H, m), 2.94 (2H, t, Jꢀ4.2 Hz), 3.03 (3H, s),

3.27—3.44 (4H, m), 3.57 (2H, s), 4.00—4.07 (2H, m), 6.70 (1H, d,

Jꢀ8.8 Hz), 7.20 (1H, s), 7.26—7.30 (2H, m), 7.30 (1H, dd, Jꢀ8.6, 2.4 Hz),

7.42 (1H, d, Jꢀ2.4 Hz), 7.50—7.55 (3H, m). Anal. Calcd. for

C₂₅H₃₀BrN₃O₂·0.25H₂O: C, 61.41; H, 6.29; N, 8.59. Found: C, 61.45; H,

6.25; N, 8.32.

7-Bromo-1-ethyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)-

amino]methyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide

(9c) Yield 70%, mp 135—137 °C. ¹H-NMR (CDCl₃) d 1.28 (3H, t,

Jꢀ7.0 Hz), 1.63—1.76 (4H, m), 2.20 (3H, s), 2.56—2.72 (1H, m), 2.89 (2H,

t, Jꢀ4.4 Hz), 3.24—3.43 (6H, m), 3.56 (2H, s), 4.01—4.07 (2H, m), 6.72

(1H, d, Jꢀ8.8 Hz), 7.18 (1H, s), 7.24 (1H, dd, Jꢀ8.8, 2.6 Hz), 7.29 (2H, d,

Jꢀ8.8 Hz), 7.39 (1H, d, Jꢀ2.6 Hz), 7.53 (2H, d, Jꢀ8.8 Hz), 7.55 (1H, s).

Anal. Calcd for C₂₆H₃₂BrN₃O₂: C, 62.65; H, 6.47; N, 8.43. Found: C, 62.44;

H, 6.57; N, 8.22.

7-Bromo-2,3-dihydro-1-benzothiepine-4-carboxylic Aicd 1,1-Dioxide

(25a) This compound was prepared in 95% yield from 13a by a method

similar to that described for 7a, mp 290—300 °C. ¹H-NMR (DMSO-d₆) d

2.91—2.97 (2H, m), 3.73—3.80 (2H, m), 7.73 (1H, s), 7.84 (1H, dd, Jꢀ8.4,

2.0 Hz), 7.94 (1H, d, Jꢀ8.4 Hz), 8.08 (1H, d, Jꢀ2.0 Hz). Anal. Calcd for

C₁₁H₉BrO₄S: C, 41.66; H, 2.86. Found: C, 41.82; H, 3.02.

7-Bromo-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

phenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide

(9d)

Yield 80%, mp 134—136 °C. H-NMR (CDCl₃) d 0.97 (3H, t, Jꢀ7.5 Hz),

1.60—1.80 (6H, m), 2.21 (3H, s), 2.57—2.70 (1H, m), 2.89 (2H, t,

Jꢀ4.6 Hz), 3.22—3.30 (4H, m), 3.37 (2H, td, Jꢀ11.1, 2.8 Hz), 3.57 (2H, s),

4.01—4.07 (2H, m), 6.71 (1H, d, Jꢀ9.0 Hz), 7.19 (1H, s), 7.24 (1H, dd,

Jꢀ9.0, 2.6 Hz), 7.30 (2H, d, Jꢀ8.4 Hz), 7.41 (1H, d, Jꢀ2.6 Hz), 7.50 (1H,

s), 7.52 (2H, d, Jꢀ8.4 Hz). Anal. Calcd for C₂₇H₃₄BrN₃O₂: C, 63.28; H,

6.69; N, 8.20. Found: C, 63.19; H, 6.54; N, 8.05.

7-Bromo-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic Acid

(25d) To a solution of 13d (8.05 g, 22.0 mmol) in EtOAc (80 ml) was

added 4 N HCl in EtOAc (80 ml, 320 mmol) at room temperature. After

being stirred at room temperature for 12.5 h, the mixture was adjusted to

pHꢀ3 with saturated aqueous NaHCO₃. The mixture was extracted with

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

MgSO₄, and concentrated in vacuo. The precipitated yellow crystals were

collected by ﬁltration to give 0.98 g (14%) of 25d as yellow crystals, mp

7-Bromo-1-(3-methylbutyl)-N-(4-{[methyl(tetrahydro-2H-pyran-4-

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

(9e) Yield 54%. H-NMR (CDCl₃) d 0.96 (6H, d, Jꢀ6.2 Hz), 1.54—1.86

(7H, m), 2.21 (3H, s), 2.55—2.76 (1H, m), 2.84—2.97 (2H, m), 3.20—3.42

(6H, m) 3.57 (2H, s), 3.98—4.11 (2H, m), 6.70 (1H, d, Jꢀ8.8 Hz), 7.19—

7.23 (2H, m), 7.30 (2H, d, Jꢀ8.4 Hz), 7.39 (1H, d, Jꢀ2.2 Hz), 7.54 (2H, d,

Jꢀ8.4 Hz), 7.64 (1H, s).

172—173 °C. H-NMR (CDCl₃) d 0.95 (3H, t, Jꢀ7.3 Hz), 1.70 (2H, sextet,

Jꢀ7.3 Hz), 2.81 (2H, t, Jꢀ4.6 Hz), 3.22—3.29 (4H, m), 6.70 (1H, d,

Jꢀ8.8 Hz), 7.25 (1H, dd, Jꢀ8.8, 2.3 Hz), 7.43 (1H, d, Jꢀ2.3 Hz), 7.69 (1H,

s). Anal. Calcd for C₁₄H₁₆BrNO₂: C, 54.21; H, 5.20; N, 4.52. Found: C,

54.17; H, 5.05; N, 4.42.

1-Bromo-4-[2-(methoxy)ethoxy]benzene (27a) To a mixture of 26a

(15.0 g, 86.7 mmol), NaI (13.0 g, 86.7 mmol) and K₂CO₃(14.4 g,

104.2 mmol) in DMF (200 ml) was added 2-chloroethyl methyl ether

(9.00 ml, 98.5 mmol) at room temperature. The mixture was stirred at 80 °C

for 3 d. Water was added to the reaction mixture and the mixture was ex-

tracted with diethyl ether (Et₂O). The organic layer was washed with water

and brine, dried over MgSO₄, and concentrated in vacuo to give 17.7 g

(87%) of 27a as an orange oil. ¹H-NMR (CDCl₃) d 3.45 (3H, s), 3.72—3.77

(2H, m), 4.06—4.11 (2H, m), 6.81 (2H, d, Jꢀ8.9 Hz), 7.37 (2H, d,

Jꢀ8.9 Hz).

The following compounds (25b—c) were prepared form the correspond-

ing esters (13b¹⁸⁾—c) by a method similar to that described for 25d.

7-Bromo-1-methyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic Acid

(25b) Yield quant. H-NMR (CDCl₃) d 2.85 (2H, t, Jꢀ4.8 Hz), 3.03 (3H,

s), 3.25 (2H, t, Jꢀ4.9 Hz), 6.67 (1H, d, Jꢀ9.2 Hz), 7.29 (1H, dd, Jꢀ8.8,

2.2 Hz), 7.44 (1H, d, Jꢀ2.6 Hz), 7.67 (1H, s).

7-Bromo-1-ethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic

Acid

(25c) Yield 94%, mp 198—201 °C. ¹H-NMR (DMSO-d₆) d 1.19 (3H, t,

Jꢀ6.9 Hz), 2.69 (2H, t, Jꢀ4.4 Hz), 3.17 (2H, t, Jꢀ4.8 Hz), 3.34 (2H, q,

Jꢀ6.9 Hz), 6.81 (1H, d, Jꢀ9.0 Hz), 7.28 (1H, dd, Jꢀ9.0, 2.4 Hz), 7.49 (1H,

s), 7.50 (1H, d, Jꢀ1.4 Hz). Anal. Calcd for C₁₃H₁₄BrNO₂: C, 52.72; H, 4.76;

N, 4.73. Found: C, 52.32; H, 4.72; N, 4.54.

The following compounds (27b—d, 27f) were prepared from 26a by a

method similar to that described for 27a.

1-Bromo-4-[2-(ethoxy)ethoxy]benzene (27b) Yield 76%. ¹H-NMR

(CDCl₃) d 1.24 (3H, t, Jꢀ7.0 Hz), 3.66 (2H, q, Jꢀ7.0 Hz), 3.78 (2H, t,

Jꢀ4.8 Hz), 4.09 (2H, t, Jꢀ4.8 Hz), 6.77—6.84 (2H, m), 7.33—7.39 (2H,

m).

7-Bromo-1-(3-methylbutyl)-2,3-dihydro-1H-1-benzazepine-4-car-

boxylic Acid (25e) This compound was prepared in 91% yield from 13f

by a method similar to that described for 14f. ¹H-NMR (CDCl₃) d 0.96 (6H,

d, Jꢀ6.2 Hz), 1.52—1.71 (3H, m), 2.78—2.84 (2H, m), 3.21—3.26 (2H, m),

3.32 (2H, m), 6.69 (1H, d, Jꢀ8.8 Hz), 7.22—7.29 (1H, m), 7.43 (1H, d,

Jꢀ2.2 Hz), 7.68 (1H, s).

1-Bromo-4-[2-(propoxy)ethoxy]benzene (27c) Yield 78%. ¹H-NMR

(CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.55—1.71 (2H, m), 3.48 (2H, t,

Jꢀ6.8 Hz), 3.74—3.79 (2H, m), 4.05—4.10 (2H, m), 6.77—6.83 (2H, m),

7.33—7.38 (2H, m).

1-Bromo-4-[2-(butoxy)ethoxy]benzene (27d) Yield 64%. ¹H-NMR

(CDCl₃) d 0.92 (3H, t, Jꢀ7.4 Hz), 1.27—1.65 (4H, m), 3.53 (2H, t,

Jꢀ6.6 Hz), 3.74—3.79 (2H, m), 4.05—4.11 (2H, m), 6.81 (2H, d,

Jꢀ9.0 Hz), 7.36 (2H, d, Jꢀ9.0 Hz).

7-Bromo-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

phenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Dioxide (9a)

To a solution of 25a (4.47 g, 14.1 mmol) in THF (90 ml) was added SOCl₂

(1.03 ml, 14.1 mmol) and DMF (1.0 ml) at room temperature. The mixture

was stirred at room temperature for 2 h. The mixture was added dropwise to

a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)-aminomethyl]aniline (8)

(3.41 g, 15.5 mmol) and Et₃N (7.90 ml, 56.7 mmol) in THF (30 ml) at room

temperature. After being stirred at room temperature for 2 h, the mixture was

concentrated in vacuo. To the residue was added water and precipitated col-

orless crystals were collected by ﬁltration. The crystals were washed with

water, EtOH, 2-propanol and i-Pr₂O to give 4.94 g (67%) of 9a as colorless

crystals, mp 232—235 °C. ¹H-NMR (CDCl₃) d 1.54—1.83 (4H, m), 2.21

(3H, s), 2.54—2.73 (1H, m), 3.11—3.18 (2H, m), 3.30—3.44 (2H, m), 3.58

(2H, s), 3.66—3.73 (2H, m), 3.99—4.10 (2H, m), 7.19 (1H, s), 7.33 (2H, d,

Jꢀ8.3 Hz), 7.53 (2H, d, Jꢀ8.3 Hz), 7.62—7.71 (2H, m), 7.88 (1H, br s),

8.04 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₂₄H₂₇BrN₂O₄S: C, 55.49; H, 5.24;

N, 5.39. Found: C, 55.56; H, 4.98; N, 5.22.

1-Bromo-4-[3-(ethoxy)propoxy]benzene (27f) Yield 43%. ¹H-NMR

(CDCl₃) d 1.20 (3H, t, Jꢀ7.0 Hz), 1.98—2.08 (2H, m), 3.49 (2H, q,

Jꢀ7.0 Hz), 3.58 (2H, d, Jꢀ6.0 Hz), 4.03 (2H, d, Jꢀ6.4 Hz), 6.79 (2H, d,

Jꢀ9.0 Hz), 7.36 (2H, d, Jꢀ9.0 Hz).

1-Bromo-4-[2-(pentyloxy)ethoxy]benzene (27e) To a solution of 26b

(19.5 g, 89.8 mmol) in DMF (166 ml) was added sodium hydride (65% in

mineral oil, 5.30 g, 143 mmol) under ice cooling. After being stirred at room

temperature for 1.5 h, 1-iodopentane (17.7 ml, 135 mmol) was added to the

reaction mixture at room temperature. The mixture was stirred at room tem-

perature for 2 h, poured into water and 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 : EtOAcꢀ

10 : 1) gave 12.0 g (57%) of 27e as a colorless oil. ¹H-NMR (CDCl₃) d 0.90

(3H, t, Jꢀ6.6 Hz), 1.25—1.37 (4H, m), 1.57—1.68 (2H, m), 3.52 (2H, t,

Jꢀ6.6 Hz), 3.74—3.79 (2H, m), 4.05—4.11 (2H, m), 6.78—6.83 (2H, m),

7.33—7.39 (2H, m).

The following compounds (9b—e) were prepared from the corresponding

carboxylic acids (25b—e) by a method similar to that described for 9a.

7-Bromo-1-methyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)-

amino]methyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide

{4-[2-(Methoxy)ethoxy]phenyl}boronic Acid (10a) To a solution of

27a (17.0 g, 73.6 mmol) in THF (50 ml) and Et₂O (150 ml) was added drop-

May 2004

587

Dioxide (5c) ¹H-NMR (CDCl₃) d 1.30 (6H, d, Jꢀ7.0 Hz), 1.52—1.83 (4H,

m), 2.21 (3H, s), 2.55—2.77 (1H, m), 2.90—3.04 (1H, m), 3.17 (2H, t,

Jꢀ6.6 Hz), 3.37 (2H, dt, Jꢀ2.8, 11.0 Hz), 3.58 (2H, s), 3.70—3.76 (2H, m),

3.98—4.09 (2H, m), 7.31—7.38 (5H, m), 7.52—7.58 (4H, m), 7.66—7.73

(2H, m), 7.98 (1H, br s), 8.21 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for

C₃₃H₃₈N₂O₄S: C, 70.94; H, 6.86; N, 5.01. Found: C, 70.89; H, 6.61; N, 7.75.

N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-7-(4-

propoxyphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Dioxide

(5d) To a suspension of 7d (170 mg, 0.456 mmol) in THF (5.0 ml) was

added SOCl₂(0.070 ml, 0.96 mmol) and DMF (cat. amount) at room temper-

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

centrated in vacuo. A solution of the residue in THF (10 ml) was added

dropwise to a solution of 8 (111 mg, 0.50 mmol) and Et₃N (0.18 ml,

1.29 mmol) in THF (2.0 ml) at room temperature. The reaction mixture was

stirred at room temperature for 21 h under a nitrogen atmosphere. Water was

added to the reaction mixture at room temperature, and the mixture was ex-

tracted 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 : EtOHꢀ3 : 1) and recrystallization from

EtOH gave 148 mg (56%) of 5d as pale yellow crystals. ¹H-NMR (CDCl₃) d

1.06 (3H, t, Jꢀ7.4 Hz), 1.57—1.90 (6H, m), 2.21 (3H, s), 2.54—2.75 (1H,

m), 3.13—3.20 (2H, m), 3.31—3.44 (2H, m), 3.58 (2H, s), 3.69—3.76 (2H,

m), 3.98 (2H, t, Jꢀ6.6 Hz), 3.99—4.11 (2H, m), 7.01 (2H, d, Jꢀ8.8 Hz),

7.31—7.35 (3H, m), 7.52—7.56 (4H, m), 7.62 (1H, d, Jꢀ1.8 Hz), 7.67 (1H,

dd, Jꢀ8.0, 1.8 Hz), 7.92 (1H, br s), 8.19 (1H, d, Jꢀ8.0 Hz). Anal. Calcd for

C₃₃H₃₈N₂O₅S: C, 68.96; H, 6.66; N, 4.87. Found: C, 68.72; H, 6.70; N, 4.88.

The following compounds (6e, 6i, 6k, 6m—s) were prepared from the

corresponding carboxylic acids (7f—g, 7i—o, 7p) by a method similar to

that described for 5d.

1-Acetyl-7-(4-morpholinophenyl)-N-(4-{[methyl(tetrahydro-2H-

pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (6e) ¹H-NMR (CDCl₃) d 1.65—1.87 (4H, m), 2.09 (3H, s), 2.23

(3H, s), 2.61—2.78 (1H, m), 2.81—3.05 (3H, m), 3.24 (4H, t, Jꢀ4.7 Hz),

3.37 (2H, td, Jꢀ11.4, 2.7 Hz), 3.60 (2H, s), 3.90 (4H, t, Jꢀ4.8 Hz), 4.02—

4.07 (2H, m), 4.75—4.91 (1H, m), 7.01 (2H, d, Jꢀ8.8 Hz), 7.23—7.27 (1H,

m), 7.34 (2H, d, Jꢀ8.4 Hz), 7.52—7.69 (8H, m). Anal. Calcd for

C₃₆H₄₂N₄O₄: C, 72.70; H, 7.12; N, 9.42. Found: C, 72.79; H, 7.07; N, 9.38.

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

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

carboxamide (6i) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 0.97 (6H,

d, Jꢀ6.6 Hz), 1.33—1.46 (2H, m), 1.54—1.77 (6H, m), 1.95—2.16 (1H, m),

2.20 (3H, s), 2.64 (1H, m), 2.88—2.95 (2H, m), 3.18 (2H, d, Jꢀ7.4 Hz),

3.30—3.43 (4H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.56 (2H, s), 3.77—3.83 (2H,

m), 3.98—4.07 (2H, m), 4.12—4.18 (2H, m), 6.91 (1H, d, Jꢀ8.8 Hz), 6.99

(2H, d, Jꢀ8.4 Hz), 7.29 (2H, d, Jꢀ8.4 Hz), 7.36—7.58 (8H, m). Anal. Calcd

for C₄₀H₅₃N₃O₄: C, 75.08; H, 8.35; N, 6.57. Found: C, 74.99; H, 8.16; N,

6.69.

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

(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-

benzazepine-4-carboxamide (6k) ¹H-NMR (CDCl₃) d 0.26—0.33 (2H,

m), 0.60—0.69 (2H, m), 0.93 (3H, t, Jꢀ7.4 Hz), 1.05—1.18 (1H, m), 1.22—

2.05 (8H, m), 2.21 (3H, s), 2.59—2.67 (1H, m), 2.95 (2H, t-like), 3.25 (2H,

d, Jꢀ6.2 Hz), 3.32—3.58 (8H, m), 3.80 (2H, t, Jꢀ5.0 Hz), 3.93—4.18 (4H,

m), 6.95—7.00 (3H, m), 7.29 (2H, d, Jꢀ8.8 Hz), 7.41—7.58 (8H, m). Anal.

Calcd for C₄₀H₅₁N₃O₄: C, 75.32; H, 8.06; N, 6.59. Found: C, 75.21; H, 8.12;

N, 6.49.

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

(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-

benzazepine-4-carboxamide (6m) ¹H-NMR (CDCl₃) d 0.93 (3H, t,

Jꢀ7.3 Hz), 0.93—1.84 (19H, m) 2.21 (3H, s), 2.58—2.66 (1H, m), 2.91

(2H, t-like), 3.22 (2H, d, Jꢀ6.6 Hz), 3.30—3.46 (4H, m), 3.50—3.58 (4H,

m), 3.80 (2H, t, Jꢀ4.9 Hz), 4.01—4.06 (2H, m), 4.16 (2H, t, Jꢀ4.9 Hz),

6.91 (1H, d, Jꢀ8.8 Hz), 6.98 (2H, d, Jꢀ8.8 Hz), 7.30 (2H, d, Jꢀ8.4 Hz),

7.37—7.56 (8H, m). Anal. Calcd for C₄₃H₅₇N₃O₄: C, 75.96; H, 8.45; N,

6.18. Found: C, 75.93; H, 8.58; N, 6.21.

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-

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

carboxamide (6n) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.3 Hz), 1.27—

1.49 (2H, m), 1.55—1.74 (6H, m), 2.19 (3H, s), 2.58—2.66 (1H, m), 2.93

(2H, t, Jꢀ4.8 Hz), 3.36 (2H, dt, Jꢀ3.2, 10.8 Hz), 3.52—3.59 (4H, m), 3.81

(2H, t, Jꢀ5.0 Hz), 3.89 (2H, t, Jꢀ4.8 Hz), 4.00—4.06 (2H, m), 4.17 (2H, t,

Jꢀ5.0 Hz), 6.88—7.02 (5H, m), 7.21—7.30 (4H, m), 7.41 (1H, dd, Jꢀ8.6,

2.2 Hz), 7.48—7.53 (7H, m), 7.64 (1H, d, Jꢀ2.2 Hz). Anal. Calcd for

C₄₂H₄₉N₃O₄·0.25H₂O: C, 75.93; H, 7.51; N, 6.32. Found: C, 75.80; H, 7.40;

wise a solution of n-BuLi in hexane (1.6 M, 50.0 ml, 80.0 mmol) at ꢂ78 °C.

After being stirred at ꢂ78 °C for 1 h, a solution of trimethyl borate (24.8 ml,

221 mmol) in THF (25 ml) at ꢂ78 °C. The mixture was stirred at room tem-

perature for 2 h. To the reaction mixture was added 10% aqueous H₂SO₄

(50 ml) and the mixture was stirred for 30 min. 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 chromatog-

raphy (hexane : EtOAcꢀ1 : 1) gave 7.17 g (50%) of 10a as a colorless solid.

¹H-NMR (DMSO-d₆) d 3.47 (3H, s), 3.79 (2H, t, Jꢀ4.7 Hz), 4.19 (2H, t,

Jꢀ4.7 Hz), 7.00 (2H, d, Jꢀ8.7 Hz), 7.76 (2H, d, Jꢀ8.7 Hz).

{4-[2-(Ethoxy)ethoxy]phenyl}boronic Acid (10b) This compound was

prepared in 27% yield from 27b by a method similar to that described for

10a. ¹H-NMR (DMSO-d₆) d 1.13 (3H, t, Jꢀ7.0 Hz), 3.50 (2H, q, Jꢀ7.0 Hz),

3.66—3.71 (2H, m), 4.06—4.11 (2H, m), 6.89 (2H, d, Jꢀ8.4 Hz), 7.14 (2H,

d, Jꢀ8.4 Hz).

{4-[2-(Propoxy)ethoxy]phenyl}boronic Acid (10c) To a mixture of Mg

(2.17 g, 89.3 mmol) and THF (43 ml) was added 1,2-dibromoethane (cat.

amount) at room temperature. Then a solution of 27c (22.0 g, 86.2 mmol) in

THF (176 ml) was added dropwise to the mixture under reﬂux. The mixture

was reﬂuxed for 15 min. The mixture was cooled to ꢂ78 °C and a solution

of trimethyl borate (13.2 g, 118 mmol) in THF (13 ml) at ꢂ78 °C. The mix-

ture was stirred at room temperature for 6 h and 5% aqueous H₂SO₄(5.0 ml)

was added to the mixture. The mixture was stirred at room temperature for

15 min and the mixture was extracted with EtOAc. The organic layer was

washed with brine, dried over MgSO₄, and concentrated in vacuo to give

8.6 g (45%) of 10c as a colorless solid. H-NMR (DMSO-d₆) d 0.87 (3H, t,

Jꢀ7.4 Hz), 1.44—1.62 (2H, m), 3.41 (2H, t, Jꢀ6.6 Hz), 3.67—3.72 (2H,

m), 4.07—4.12 (2H, m), 6.89 (2H, d, Jꢀ8.8 Hz), 7.73 (2H, d, Jꢀ8.8 Hz).

The following compounds (10d—f) were prepared from the correspond-

ing bromides (27d—f) by a method similar to that described for 10c.

{4-[2-(Butoxy)ethoxy]phenyl}boronic Acid (10d) Yield 64%. ¹H-

NMR (CDCl₃) d 0.94 (3H, t, Jꢀ7.2 Hz), 1.29—1.47 (2H, m), 1.53—1.66

(2H, m), 3.56 (2H, t, Jꢀ6.6 Hz), 3.83 (2H, t, Jꢀ4.9 Hz), 4.21 (2H, t,

Jꢀ4.9 Hz), 7.03 (2H, d, Jꢀ8.8 Hz), 8.15 (1H, d, Jꢀ8.8 Hz).

{4-[2-(Pentyloxy)ethoxy]phenyl}boronic Acid (10e) Yield 54%. ¹H-

NMR (DMSO-d₆) d 0.86 (3H, t, Jꢀ6.6 Hz), 1.22—1.59 (6H, m), 3.44 (2H,

t, Jꢀ6.6 Hz), 3.66—3.71 (2H, m), 4.05—4.13 (2H, m), 6.88 (2H, d,

Jꢀ8.6 Hz), 7.72 (2H, d, Jꢀ8.6 Hz).

{4-[3-(Ethoxy)propoxy]phenyl}boronic Acid (10f) Yield 65%. ¹H-

NMR (DMSO-d₆) d 1.11 (3H, t, Jꢀ7.0 Hz), 1.89—1.98 (2H, m), 3.42 (2H,

q, Jꢀ7.0 Hz), 3.50 (2H, t, Jꢀ6.2 Hz), 4.02 (2H, t, Jꢀ6.2 Hz), 6.84—6.93

(2H, m), 7.69—7.81 (2H, m).

7-(4-Ethylphenyl)-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]-

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

(5a) To a solution of 7a (180 mg, 0.53 mmol) in THF (10 ml) was added

oxalyl chloride (0.090 ml, 1.03 mmol) and DMF (cat. amount) at room tem-

perature. 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

dropwise to a solution of 8 (128 mg, 0.58 mmol) and Et₃N (0.15 ml,

1.08 mmol) in THF (5.0 ml) under ice cooling. The reaction mixture was

stirred at room temperature for 64 h under a nitrogen atmosphere. Water was

added to the reaction mixture at room temperature and the mixture was ex-

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

dried over MgSO₄, and concentrated in vacuo to give crystals. Recrystalliza-

tion from EtOH gave 174 mg (60%) of 5a as pale yellow crystals. H-NMR

(CDCl₃) d 1.29 (3H, t, Jꢀ6.7 Hz), 1.56—1.83 (4H, m), 2.21 (3H, s), 2.54—

2.71 (1H, m), 2.72 (2H, q, Jꢀ6.7 Hz), 3.17 (2H, t, Jꢀ6.7 Hz), 3.31—3.44

(2H, m), 3.58 (2H, s), 3.70—3.76 (2H, m), 3.98—4.11 (2H, m), 7.31—7.35

(5H, m), 7.54 (2H, d, Jꢀ8.0 Hz), 7.55 (2H, d, Jꢀ8.4 Hz), 7.66 (1H, s), 7.71

(1H, dd, Jꢀ8.4, 1.8 Hz), 7.92 (1H, br s), 8.21 (1H, d, Jꢀ8.4 Hz). Anal. Calcd

for C₃₂H₃₆N₂O₄S: C, 70.56; H, 6.66; N, 5.14. Found: C, 70.30; H, 6.73; N,

5.29.

The following compounds (5b—c) were prepared from the corresponding

carboxylic acids (7b—c) by a method similar to that described for 5a.

N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-7-(4-

propylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1-Dioxide

(5b) ¹H-NMR (CDCl₃) d 0.98 (3H, t, Jꢀ7.3 Hz), 1.56—1.83 (6H, m), 2.21

(3H, s), 2.52—2.74 (3H, m), 3.18 (2H, t, Jꢀ6.6 Hz), 3.31—3.44 (2H, m),

3.58 (2H, s), 3.70—3.76 (2H, m), 3.97—4.10 (2H, m), 7.28—7.35 (5H, m),

7.52 (2H, d, Jꢀ8.4 Hz), 7.55 (2H, d, Jꢀ8.4 Hz), 7.66—7.73 (2H, m), 7.94

(1H, br s), 8.21 (1H, d, Jꢀ8.0 Hz). Anal. Calcd for C₃₃H₃₈N₂O₄S: 70.94; H,

6.86; N, 5.01. Found: C, 70.99; H, 6.51; N, 5.05.

7-(4-Isopropylphenyl)-N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)-

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

588

Vol. 52, No. 5

N, 6.30.

7.38 (3H, m), 7.49—7.60 (4H, m), 7.62—7.71 (2H, m), 7.89—7.95 (1H, m),

1-Benzyl-7-{4-[2-(butoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro- 8.19 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₃₄H₃₉N₃O₅S·1.5H₂O: C, 64.95; H,

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

6.73; N, 6.68. Found: C, 64.74; H, 6.57; N, 6.43. The hydrochloride salts

carboxamide (6o) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.1 Hz), 1.30— were prepared by mixing 5e with an excess of conc. HCl in EtOH and

1.75 (8H, m), 2.21 (3H, s), 2.55—2.70 (1H, m), 2.85 (2H, t-like), 3.31— MeOH, followed by evaporation of the solvent and crystallization. ¹H-NMR

3.38 (4H, m), 3.52—3.58 (4H, m), 3.80 (2H, t, Jꢀ4.9 Hz), 4.01—4.05 (2H, (DMSO-d₆) d 1.65—2.18 (4H, m), 2.60 (3H, s), 3.01—3.12 (2H, m), 3.16—

m), 4.16 (2H, t, Jꢀ4.9 Hz), 4.61 (2H, s), 6.90 (1H, d, Jꢀ8.4 Hz), 6.98 (2H,

3.51 (7H, m), 3.62—3.87 (6H, m), 3.93—4.07 (2H, m), 4.10—4.22 (1H, m),

d, Jꢀ8.8 Hz), 7.26—7.56 (15H, m). Anal. Calcd for C₄₃H₅₁N₃O₄·0.25H₂O: 4.39—4.51 (1H, m), 7.08 (2H, d, Jꢀ8.8 Hz), 7.53—7.58 (3H, m), 7.72 (2H,

C, 76.13; H, 7.65; N, 6.19. Found: C, 76.19; H, 7.55; N, 6.19.

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

d, Jꢀ8.8 Hz), 7.80—7.92 (3H, m), 8.02—8.10 (2H, m), 10.42 (1H, br s).

7-{4-[2-(Methoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-

{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro- pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1-benzothiepine-4-car-

1H-1-benzazepine-4-carboxamide (6p) ¹H-NMR (CDCl₃) d 0.93 (3H, t, boxamide 1,1-Dioxide (5f) A mixture of 9a (300 mg, 0.578 mmol), 10a

Jꢀ7.3 Hz), 1.33—1.45 (2H, m), 1.58—1.80 (6H, m), 2.21 (3H, s), 2.51— (124 mg, 0.633 mmol) and K₂CO₃(160 mg, 1.16 mmol) in toluene (10 ml),

2.73 (1H, m), 2.88—2.99 (2H, m), 3.30—3.57 (8H, m), 3.80 (2H, t, EtOH (1.0 ml) and water (1.0 ml) was stirred at room temperature for 1 h

Jꢀ4.8 Hz), 3.96—4.10 (2H, m), 4.16 (2H, t, Jꢀ4.8 Hz), 4.88 (2H, s), 6.96— under an argon atmosphere. Pd(PP₃)₄(44.0 mg, 0.038 mmol) was added, and

7.03 (3H, m), 7.26—7.60 (11H, m), 7.80 (1H, d, Jꢀ3.2 Hz). Anal. Calcd for the mixture was reﬂuxed for 6 h under an argon atmosphere. The reaction

C₄₀H₄₈N₄O₄S: C, 70.56; H, 7.11; N, 8.23. Found: C, 70.38; H, 7.12; N, 8.18.

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

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-imidazol-2-yl)- brine, dried over MgSO₄, and concentrated in vacuo. The residue was puri-

methyl]-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}- ﬁed by recrystallization from EtOH to give 246 mg (72%) of 5f as colorless

phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (6q) ¹H-NMR crystals. H-NMR (CDCl₃) d 1.64—1.84 (4H, m), 2.21 (3H, s), 2.55—2.74

(CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.30—1.45 (2H, m), 1.55—1.80 (6H, m), (1H, m), 3.13—3.19 (2H, m), 3.32—3.44 (2H, m), 3.47 (3H, s), 3.58 (2H,

2.20 (3H, s), 2.43—2.70 (3H, m), 3.30—3.45 (4H, m), 3.52—3.59 (7H, m), s), 3.69—3.81 (4H, m), 3.99—4.09 (2H, m), 4.16—4.21 (2H, m), 7.04 (2H,

3.81 (2H, t, Jꢀ5.0 Hz), 3.97—4.08 (2H, m), 4.17 (2H, t, Jꢀ5.0 Hz), 4.62

d, Jꢀ8.8 Hz), 7.30—7.35 (3H, m), 7.52—7.56 (4H, m), 7.62—7.69 (2H, m),

(2H, s), 6.90 (1H, d, Jꢀ1.2 Hz), 6.97—7.01 (3H, m), 7.07 (1H, d, 7.92 (1H, s), 8.19 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₃₃H₃₈N₂O₆S: C,

Jꢀ8.0 Hz), 7.27—7.32 (2H, m), 7.46—7.57 (8H, m). Anal. Calcd for 67.10; H, 6.48; N, 4.74. Found: C, 66.85; H, 6.40; N, 4.62.

C₄₁H₅₁N₅O₄·0.5H₂O: C, 71.69; H, 7.63; N, 10.30. Found: C, 71.80; H, 7.75;

N, 10.38.

The following compounds (5g—k, 6a—d, 6f—h, 6j) were prepared form

the corresponding bromides (9a—e) by a method similar to that described

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-[(1-methyl-1H-pyrazol-5-yl)- for 5f.

methyl]-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

7-{4-[2-(Ethoxy)ethoxy]phenyl}-N-(4-{[methyl(tetrahydro-2H-pyran-

phenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (6r) ¹H-NMR 4-yl)amino]methyl}phenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide

(CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.34—1.45 (2H, m), 1.50—1.80 (6H, m), 1,1-Dioxide (5g) ¹H-NMR (CDCl₃) d 1.26 (3H, t, Jꢀ7.0 Hz), 1.60—1.81

2.21 (3H, s), 2.40—2.70 (3H, m), 3.30—3.45 (4H, m), 3.55 (2H, t, (4H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13—3.21 (2H, m), 3.31—3.44 (2H,

Jꢀ6.6 Hz), 3.57 (2H, s), 3.79—3.84 (5H, m), 3.97—4.09 (2H, m), 4.17 (2H, m), 3.57 (2H, s), 3.63 (2H, q, Jꢀ7.0 Hz), 3.67—3.75 (2H, m), 3.83 (2H, t,

t, Jꢀ5.0 Hz), 4.55 (2H, s), 6.25 (1H, d, Jꢀ1.8 Hz), 6.95 (1H, d, Jꢀ8.4 Hz),

6.99 (2H, d, Jꢀ8.8 Hz), 7.30 (2H, d, Jꢀ8.4 Hz), 7.42—7.57 (9H, m). Anal.

Jꢀ5.0 Hz), 3.98—4.09 (2H, m), 4.19 (2H, t, Jꢀ5.0 Hz), 7.24 (2H, d,

Jꢀ8.8 Hz), 7.30 (1H, s), 7.35 (1H, s), 7.51—7.69 (6H, m), 7.81 (1H, s), 8.19

Calcd for C₄₁H₅₁N₅O₄·0.25H₂O: C, 72.17; H, 7.61; N, 10.26. Found: C, (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₃₄H₄₀N₂O₆S: C, 67.53; H, 6.67; N, 4.63.

72.02; H, 7.46; N, 10.03.

Found: C, 67.55; H, 6.58; N, 4.71.

7-[4-[2-(Butoxy)ethoxy]phenyl]-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-

N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-7-{4-

N-[4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-di- [2-(propoxy)ethoxy]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxamide

hydro-1H-1-benzazepine-4-carboxamide (6s) ¹H-NMR (CDCl₃) d 0.93 1,1-Dioxide (5h) ¹H-NMR (CDCl₃) d 0.95 (3H, t, Jꢀ7.2 Hz), 1.60—1.80

(3H, t, Jꢀ7.2 Hz), 1.34—1.45 (2H, m), 1.50—1.80 (6H, m), 2.21 (3H, s), (6H, m), 2.21 (3H, s), 2.65 (1H, m), 3.13—3.20 (2H, m), 3.31—3.44 (2H,

2.51—2.72 (3H, m), 2.79—2.88 (2H, m), 3.28—3.45 (4H, m), 3.55 (2H, t, m), 3.52 (2H, t, Jꢀ6.8 Hz), 3.57 (2H, s), 3.68—3.75 (2H, m), 3.82 (2H, t,

Jꢀ6.4 Hz), 3.57 (2H, s), 3.80 (2H, d, Jꢀ4.9 Hz), 3.90 (3H, s), 3.97—4.09 Jꢀ4.8 Hz), 4.10—4.20 (2H, m), 4.19 (2H, t, Jꢀ4.8 Hz), 7.04 (2H, d,

(2H, m), 4.16 (2H, t, Jꢀ4.9 Hz), 4.44 (2H, s), 6.96—7.01 (3H, m), 7.26— Jꢀ8.8 Hz), 7.30—7.35 (3H, m), 7.51—7.68 (6H, m), 7.83 (1H, s), 8.19 (1H,

7.39 (3H, m), 7.45—7.55 (9H, m). Anal. Calcd for C₄₁H₅₁N₅O₄: C, 72.64; H, d, Jꢀ8.0 Hz). Anal. Calcd for C₃₅H₄₂N₂O₆S: C, 67.94; H, 6.84; N, 4.53.

758; N, 10.33. Found: C, 72.34; H, 7.59; N, 10.34.

Found: C, 67.87; H, 6.98; N, 4.45.

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

(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-

7-{4-[2-(Butoxy)ethoxy]phenyl}-N-(4-{[Methyl(tetrahydro-2H-pyran-

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

benzazepine-4-carboxamide Dihydrochloride (6l) The free amine was 1,1-Dioxide (5i) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.33—1.55

prepared from 7h by a method similar to that described for 5d. To a solution

of the free amine in EtOAc and EtOH was added 6 N HCl and the mixture

was concentrated in vacuo. To the residue was added Et₂O and the pale

yellow amorphous solid was collected by ﬁltration to give 6l. ¹H-NMR

(2H, m), 1.57—1.77 (6H, m), 2.21 (3H, s), 2.65 (1H, m), 3.16 (2H, t,

Jꢀ6.4 Hz), 3.31—3.44 (2H, m), 3.52—3.59 (2H, m), 3.57 (2H, s), 3.67—

3.74 (2H, m), 3.79—3.84 (2H, m), 3.98—4.08 (2H, m), 4.18 (2H, t,

Jꢀ4.8 Hz), 7.03 (2H, d, Jꢀ8.8 Hz), 7.30—7.35 (3H, m), 7.50—7.66 (6H,

(DMSO-d₆) d 0.89 (3H, t, Jꢀ7.1 Hz), 1.24—1.58 (4H, m), 1.73—2.15 (1H, m), 7.88 (1H, s), 8.18 (1H, d, Jꢀ8.0 Hz). Anal. Calcd for C₃₆H₄₄N₂O₆S: C,

m), 2.57 (2H, d, Jꢀ4.8 Hz), 2.60—2.85 (3H, m), 3.20—3.49 (10H, m), 68.33; H, 7.01; N, 4.43. Found: C, 68.33; H, 6.85; N, 4.39.

3.96—4.13 (5H, m), 4.38—4.44 (1H, m), 6.97—7.02 (3H, m), 7.40—7.63

N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-7-{4-

(7H, m), 7.80 (2H, d, Jꢀ8.8 Hz), 10.02 (1H, s), 10.41 (1H, s). Anal. Calcd [2-(pentyloxy)ethoxy]phenyl}-2,3-dihydro-1-benzothiepine-4-carboxam-

for C₄₁H₅₃N₃O₄·2HCl·1.5H₂O: C, 65.50; H, 7.78; N, 5.59. Found: C, 65.51; ide 1,1-Dioxide (5j) ¹H-NMR (CDCl₃) d 0.90 (3H, t, Jꢀ6.6 Hz), 1.38—

H, 7.77; N, 5.24.

1.40 (4H, m), 1.56—1.77 (6H, m), 2.20 (3H, s), 2.64 (1H, m), 3.10—3.19

N-(4-{[Methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-7-(4- (2H, m), 3.30—3.44 (2H, m), 3.55 (2H, t, Jꢀ6.6 Hz), 3.56 (2H, s), 3.65—

morpholinophenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide 1,1- 3.73 (2H, m), 3.79—3.85 (2H, m), 3.98—4.10 (2H, m), 4.15—4.21 (2H, m),

Dioxide (5e) A mixture of 7e (177 mg, 0.44 mmol) and HOBt (90 mg,

0.67 mmol) in DMF (5.0 ml) was added EDC (127 mg, 0.66 mmol) at room

temperature. After being stirred for 1 h at room temperature, a solution of 8

(107 mg, 0.49 mmol) and Et₃N (0.12 ml, 0.86 mmol) in DMF (5.0 ml) and

7.00—7.06 (2H, m), 7.29—7.34 (2H, m), 7.47—7.66 (7H, m), 7.95 (1H, s),

8.17 (1H, d, Jꢀ8.4 Hz). Anal. Calcd for C₃₇H₄₆N₂O₆S: C, 68.70; H, 7.17; N,

4.33. Found: C, 68.64; H, 7.03; N, 4.31.

7-{4-[3-(Ethoxy)propoxy]phenyl}-N-(4-{[Methyl(tetrahydro-2H-

DMAP (cat. amount) was added to the reaction mixture at room tempera- pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1-benzothiepine-4-car-

ture. The mixture was stirred at room temperature for 64 h. The mixture was

boxamide 1,1-Dioxide (5k) ¹H-NMR (CDCl₃) d 1.21 (3H, t, Jꢀ7.0 Hz),

evaporated in vacuo, and water was added to the residue. The mixture was 1.69—1.77 (4H, m), 2.05—2.13 (2H, m), 2.21 (3H, s), 2.65 (1H, m), 3.16

extracted with CH₂Cl₂. The organic layer was washed with brine, dried over (2H, t, Jꢀ6.6 Hz), 3.31—3.44 (2H, m), 3.51 (2H, q, Jꢀ7.0 Hz), 3.57 (2H, s),

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

3.62 (2H, t, Jꢀ6.2 Hz), 3.67—3.75 (2H, m), 3.98—4.16 (4H, m), 7.01 (2H,

chromatography (EtOAc : EtOHꢀ1 : 1) gave 31.6 mg (12%) of 5e as pale d, Jꢀ8.8 Hz), 7.29—7.35 (3H, m), 7.50—7.67 (6H, m), 7.86 (1H, s), 8.18

yellow crystals. ¹H-NMR (CDCl₃) d 1.38—1.84 (4H, m), 2.23 (3H, s), (1H, d, Jꢀ8.0 Hz). Anal. Calcd for C₃₅H₄₂N₂O₆S: C, 67.94; H, 6.84; N, 4.53.

2.58—2.80 (1H, m), 3.10—3.45 (8H, m), 3.61 (2H, s), 3.67—3.78 (2H, m), Found: C, 67.67; H, 6.77; N, 4.54.

3.83—3.94 (4H, m), 3.99—4.09 (2H, m), 7.00 (2H, d, Jꢀ8.8 Hz), 7.19—

1-Methyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

May 2004

589

Receptor Binding Assays CHO-K1 and CCR5-expressing CHO cells¹⁶⁾

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 p^M[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^ꢃcells, 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 3 : 1 : 5 and co-transfected into COS-7 cells using Lipofectamine 2000

(Invitrogen). After 2 d incubation, transfected COS-7 cells and MOLT-

4/CCR5/Luc^ꢃcells were seeded in a 96-well plate at 10⁴cells each per well,

and various concentrations of the test compounds were added to the wells.

The cell suspension was incubated at 37 °C. The mixture of D-MEM and

RPMI 1640 medium supplemented with 10% FBS, 100 U/ml penicillin, and

100 mg/ml streptomycin was used as medium for membrane fusion. After an

overnight incubation, Luc-Screen (Tropix) was added to each well, and the

mixtures were incubated at room temperature for 10 min. The luciferase ac-

tivity was measured with a luminometer (Wallac 1420 ARVOsx).

phenyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (6a) ¹H-NMR (CDCl₃) d 1.64—1.77 (4H, m), 2.21 (3H, s),

2.57—2.75 (1H, m), 2.96 (2H, t, Jꢀ5.2 Hz), 3.09 (3H, s), 3.20 (2H, t,

Jꢀ4.8 Hz), 3.18—3.22 (2H, m), 3.33—3.43 (4H, m), 3.58 (2H, s), 3.89 (4H,

t, Jꢀ4.8 Hz), 4.01—4.06 (2H, m), 6.88 (1H, d, Jꢀ8.4 Hz), 6.97 (2H, d,

Jꢀ8.8 Hz), 7.30 (2H, d, Jꢀ8.8 Hz), 7.41—7.56 (8H, m). Anal. Calcd for

C₃₅H₄₂N₄O₃: C, 74.18; H, 7.47; N, 9.89. Found: C, 73.92; H, 7.36; N, 9.95.

1-Methyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

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

4-carboxamide (6b) ¹H-NMR (CDCl₃) d 0.94 (3H, t, Jꢀ7.3 Hz), 1.65

(2H, sextet, Jꢀ7.2 Hz), 1.69—1.76 (4H, m), 2.21 (3H, s), 2.57—2.72 (1H,

m), 2.96 (2H, t, Jꢀ4.4 Hz), 3.09 (3H, s), 3.32—3.43 (4H, m), 3.51 (2H, t,

Jꢀ6.8 Hz), 3.56 (2H, s), 3.81 (2H, t, Jꢀ5.0 Hz), 4.01—4.06 (2H, m), 4.16

(2H, t, Jꢀ5.0 Hz), 6.88 (1H, d, Jꢀ8.4 Hz), 6.98 (2H, d, Jꢀ8.8 Hz), 7.30 (2H,

d, Jꢀ8.6 Hz), 7.40—7.56 (8H, m). Anal. Calcd for C₃₆H₄₅N₃O₄·0.25H₂O: C,

73.50; H, 7.80; N, 7.14. Found: C, 73.12; H, 7.67; N, 7.08.

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

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

carboxamide (6c) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.2 Hz), 1.39 (2H,

sextet, Jꢀ7.3 Hz), 1.55—1.79 (6H, m), 2.21 (3H, s), 2.57—2.75 (1H, m),

2.96 (2H, t, Jꢀ4.4 Hz), 3.09 (3H, s), 3.31—3.38 (2H, m), 3.37 (2H, td,

Jꢀ11.6, 2.7 Hz), 3.55 (2H, t, Jꢀ6.6 Hz), 3.57 (2H, s), 3.81 (2H, t,

Jꢀ5.0 Hz), 4.00—4.08 (2H, m), 4.16 (2H, t, Jꢀ5.0 Hz), 6.88 (1H, d,

Jꢀ8.6 Hz), 6.96—7.01 (2H, m), 7.30 (2H, d, Jꢀ8.4 Hz), 7.40—7.56 (4H,

m), 7.48 (2H, d, Jꢀ9.0 Hz), 7.54 (2H, d, Jꢀ8.6 Hz). Anal. Calcd for

C₃₇H₄₇N₃O₄·0.1H₂O: C, 74.12; H, 7.93; N, 7.01. Found: C, 73.90; H, 7.82;

N, 7.12.

1-Ethyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

phenyl)-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (6d) ¹H-NMR (CDCl₃) d 1.32 (3H, t, Jꢀ7.1 Hz), 1.65—1.77

(4H, m), 2.21 (3H, s), 2.57—2.72 (1H, m), 2.92 (2H, t, Jꢀ4.2 Hz), 3.20 (4H,

t, Jꢀ4.9 Hz), 3.31—3.38 (4H, m), 3.44 (2H, q, Jꢀ6.9 Hz), 3.57 (2H, s), 3.89

(4H, t, Jꢀ4.8 Hz), 4.01—4.07 (2H, m), 6.92 (1H, d, Jꢀ8.6 Hz), 6.97 (2H, d,

Jꢀ8.8 Hz), 7.30 (2H, d, Jꢀ8.4 Hz), 7.40—7.56 (8H, m). Anal. Calcd for

C₃₆H₄₄N₄O₃: C, 74.45; H, 7.64; N, 9.65. Found: C, 74.34; H, 7.54; N, 9.61.

1-Ethyl-N-(4-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}-

phenyl)-7-{4-[2-(propoxy)ethoxy]phenyl}-2,3-dihydro-1H-1-ben-

zazepine-4-carboxamide (6f) ¹H-NMR (CDCl₃) d 0.94 (3H, t, Jꢀ7.5 Hz),

1.32 (3H, t, Jꢀ6.9 Hz), 1.65 (2H, sextet, Jꢀ7.1 Hz), 1.70—1.76 (4H, m),

2.21 (3H, s), 2.56—2.69 (1H, m), 2.92 (2H, t, Jꢀ4.0 Hz), 3.31—3.46 (6H,

m), 3.51 (2H, t, Jꢀ6.8 Hz), 3.56 (2H, s), 3.81 (2H, t, Jꢀ4.9 Hz), 4.01—4.06

(2H, m), 4.16 (2H, t, Jꢀ5.0 Hz), 6.92 (1H, d, Jꢀ8.4 Hz), 6.98 (2H, d,

Jꢀ8.8 Hz), 7.30 (2H, d, Jꢀ8.8 Hz), 7.40 (1H, s), 7.47 (2H, d, Jꢀ8.8 Hz),

7.54 (2H, d, Jꢀ8.8 Hz), 7.40—7.56 (3H, m). Anal. Calcd for

C₃₇H₄₇N₃O₄·0.25H₂O: C, 73.78; H, 7.95; N, 6.98. Found: C, 73.52; H, 7.76;

N, 6.95.

7-{4-[2-(Butoxy)ethoxy]phenyl}-1-ethyl-N-(4-{[methyl(tetrahydro-2H-

pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-benzazepine-4-car-

boxamide (6g) ¹H-NMR (CDCl₃) d 0.93 (3H, t, Jꢀ7.1 Hz), 1.32 (3H, t,

Jꢀ7.0 Hz), 1.39 (2H, sextet, Jꢀ7.4 Hz), 1.54—1.76 (6H, m), 2.21 (3H, s),

2.54—2.72 (1H, m), 2.92 (2H, t, Jꢀ4.6 Hz), 3.31—3.50 (6H, m), 3.55 (2H,

t, Jꢀ6.6 Hz), 3.57 (2H, s), 3.81 (2H, t, Jꢀ4.9 Hz), 4.01—4.07 (2H, m), 4.16

(2H, t, Jꢀ5.0 Hz), 6.92 (1H, d, Jꢀ8.6 Hz), 6.98 (2H, d, Jꢀ8.8 Hz), 7.30 (2H,

d, Jꢀ8.4 Hz), 7.40 (1H, s), 7.44—7.56 (3H, m), 7.47 (2H, d, Jꢀ9.0 Hz),

7.54 (2H, d, Jꢀ8.4 Hz). Anal. Calcd for C₃₈H₄₉N₃O₄·0.2H₂O: C, 74.16; H,

8.09; N, 6.83. Found: C, 73.92; H, 8.19; N, 6.59.

Preliminary pharmacokinetic Analysis Compounds (10 mg/kg) sus-

pended in 0.5% methylcellulose were orally administered to SD (IGS) rats

(male, 8 weeks old). Blood samples were collected at different time points

(pre, 15, 30 min, 1, 2, 4, 8, 24 h) from the tail vein. Acetonitrile (200 ml) was

added to each plasma sample (100 ml), and the precipitated plasma proteins

were removed by centrifugation. The compound concentrations in the super-

natant were measured by HPLC (column; Inertsil ODS-3, 4.6ꢄ150 mm,

5 mm particle size, GL Science: mobile phase; acetonitrile–0.01 mol/l am-

monium acetate or acetonitrile–0.01 mol/l phosphate buffer (pH 7) at a ﬂow

rate of 1.0 ml/min at 40 °C: UV detection; 280 or 285 nm).

Acknowledgment We thank Mr. Kenichi Kuroshima for the CCR5

binding assay; Mr. Katsunori Takashima, Dr. Hiroshi Miyake, and Ms.

Shikiko Shiki for the membrane fusion assay.

References

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t, Jꢀ7.3 Hz), 1.39 (2H, sextet, Jꢀ7.2 Hz), 1.54—1.80 (8H, m), 2.20 (3H, s),

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(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-2,3-dihydro-1H-1-

benzazepine-4-carboxamide (6j) ¹H-NMR (CDCl₃)

d 0.93 (3H, t,

Jꢀ7.4 Hz), 0.99 (3H, t, Jꢀ6.2 Hz), 1.30—1.46 (2H, m), 1.49—1.81 (9H,

m), 2.21 (3H, s), 2.52—2.71 (1H, m), 2.86—2.98 (2H, m), 3.27—3.46 (6H,

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DOI: 10.1248/cpb.52.577

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Article abstract of DOI:10.1248/cpb.52.577

Full text of DOI:10.1248/cpb.52.577

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