C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors

Bioorganic & Medicinal Chemistry 12 (2004) 4313–4336

C_17,20-lyase inhibitors. Part 2: Design, synthesis and

structure–activity relationships of (2-naphthylmethyl)-

1H-imidazoles as novel C_17,20-lyase inhibitors^q

Nobuyuki Matsunaga,^a,*Tomohiro Kaku,^aAkio Ojida,^a,ꢀToshimasa Tanaka,^a

Takahito Hara,^bMasuo Yamaoka,^bMasami Kusaka^band Akihiro Tasaka^a

^aMedicinal Chemistry Research Laboratories, Pharmaceutical Research Division: Takeda Chemical Industries Ltd,

17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

^bPharmacology Research Laboratories I, Pharmaceutical Research Division: Takeda Chemical Industries Ltd, 17-85,

Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

Received 14 May 2004; revised 12 June 2004; accepted 12 June 2004

Available online 7 July 2004

Abstract—A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C_17;20-lyase

inhibitors. Several 6-methoxynaphthyl derivatives showed potent C_17;20-lyase inhibition, suppression of testosterone biosynthesis in

rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight

after consecutive administrations. The eﬀect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl

group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C_17;20-lyase over 11b-hydroxylase is also discussed, and

(S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone

biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the

treatment of androgen-dependent prostate cancer.

1. Introduction

combination strategy is termed combined androgen

blockade (CAB), although to date none of the androgen

antagonists achieve eﬀective therapeutic results due to

suboptimal pharmacokinetic properties or substantial

eﬃcacy-limiting adverse eﬀects. Furthermore, long term

treatment with androgen antagonists cause the selection

of androgen receptor mutations in prostate cancers, and

antagonists may become agonists.^4–7

Prostate cancer is now the second leading cause of

cancer death in men in the US. The prostate cancer in

about 80% of these patients grows androgen-depen-

dently and responds to ﬁrst-line endocrine therapy. At

present, the standard treatment includes orchidectomy

and its medical equivalent, the administration of gona-

dotropin-releasing hormone (GnRH) analogues, which

abolish the production of testosterone in the testes.

However, these treatments do not inhibit adrenal

androgen production and therefore are frequently

combined with an androgen receptor antagonist to

block the action of residual adrenal androgens.^2;3The

An alternative target would be C_17;20-lyase, one of the

key enzymes responsible for the biosynthesis of andro-

gens, that catalyzes the conversion of 17a-hydroxy-

pregnenolone and 17a-hydroxyprogesterone into the

weak androgens, dehydroepiandrosterone and andro-

stenedione, respectively, in testes and adrenal glands.

Since these weak androgens are subsequently converted

into more potent androgens, such as testosterone and

dihydrotestosterone in prostate cancer cells, the inhibi-

tion of C_17;20-lyase could prevent initial androgen

production and consequently prevent subsequent con-

version to more potent androgens. Therefore, the use of

C_17;20-lyase inhibitors may oﬀer a promising therapeutic

approach, either as a single agent or in combination

Keywords: C_17;20-lyase; 11b-Hydroxylase; Testosterone; Androgen.

^qSee Ref. 1.

* Corresponding author. Tel.: +81-6-63006909; fax: +81-6-63006306;

e-mail: matsunaga_nobuyuki@takeda.co.jp

ꢀ

Present address: Department of Chemistry and Biochemistry, Grad-

uate School of Engineering, Kyushu University, Fukuoka 812-8581,

Japan.

doi:10.1016/j.bmc.2004.06.016

4314

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

with castration, for the treatment of androgen-depen-

dent prostate cancer.^8;9Among C_17;20-lyase inhibitors,

ketoconazole has been used clinically in the treatment of

patients suﬀering from advanced prostate cancer.^10–12

However, ketoconazole has now been withdrawn

from clinical use because of signiﬁcant adverse eﬀects,

due to inhibition of other P450 enzymes at clinical

doses.¹³In recent years, C_17;20-lyase inhibitors have been

reported,^14–34and some of them have entered clinical

trials.

synthesis and SAR study of (2-naphthylmethyl)-1H-

imidazoles (3 and 4) as C_17;20-lyase inhibitors. Selected

compounds were also evaluated for suppression of

testosterone biosynthesis and reduction in the weight

of androgen-dependent organs in male rats. We also

discuss a possible binding mode for these inhibitors in

the human C_17;20-lyase model and the selectivity for

C_17;20-lyase over 11b-hydroxylase.

We started out the de novo design based on the sub-

strate mimic strategy, and we have previously reported

that 1-[(E)-3-(2-naphthyl)-2-propen-1-yl]-1H-imidazole

(1a) and 1-[(E)-3-(benzo[b]thiophen-2-yl)-2-propen-1-

yl]-1H-imidazole (1b) are potent C_17;20-lyase inhibitors

for rat and human enzymes, with suppression of tes-

tosterone biosynthesis in vivo in rats (Fig. 1).¹A number

of analogues were synthesized and evaluated, and con-

sequently 1c showed more potent in vivo eﬃcacy with

extended duration. In the course of our research, 1-(2-

naphthylmethyl)-1H-imidazole (2) was also found to be

a potent C_17;20-lyase inhibitor. The compound was

attractive because it has a simple structure that allows a

wide range of modiﬁcation. Therefore, we decided to

modify 2 as a new lead compound, to develop a novel

class of C_17;20-lyase inhibitors. We herein describe the

2. Molecular design

We ﬁrst performed the docking study on the homology

model of human C_17;20-lyase with a intrinsic ligand, 17a-

hydroxypregnenolone (Fig. 2). The docking mode sug-

gested that the 3b-hydroxy group of 17a-hydroxy-

pregnenolone (blue) should form a hydrogen-bond with

the OH of Thr101 in the enzyme. Next, we investigated

the docking mode of 2 (white) in the enzyme model, and

it was suggested that the 6-position on the naphthalene

ring of 2 may occupy the same regions of space as the

3b-hydroxy group of 17a-hydroxypregnenolone. We

thus proposed the incorporation of a hydrogen-bond

acceptor substituent at the 6-position on the naphtha-

lene ring, which could form a hydrogen-bond with

Thr101 of the enzyme. Furthermore, the model sug-

H

N

CH₃

F

N

S

CH₃

1c

1a

1b

R⁵

20

17

O

OH

R³

2

R²

imidazole

1

N

7

H

2

3

R¹

6

H

5

R⁴

HO

2

(2-Naphthylmethyl)-1H-imidazoles (3,4)

17α-Hydroxypregnenolone

3: 1-Imidazolyl

4: 4-Imidazolyl

Figure 1.

Figure 2. Proposed binding mode of 2 (white) and 17a-hydroxypregnenolone (blue) at the active site in a human C_17;20-lyase model. Selected active

site residues are labeled; orange, heme; magenta, polar residues; yellow, lipophilic residues.

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4315

gested that Ala367, Met369, Ile371, Pro372 and Phe484

in the enzyme might construct a small lipophilic pocket

near the heme, which prompted us to introduce a lipo-

philic group on the methylene bridge between the

naphthalene and the imidazole to interact with the

pocket.

benzylbromide in the presence of NaH to aﬀord the

benzyl ether 8e.

The sulﬁde, sulfoxide and sulfone derivatives were pre-

pared with naphthalene ring construction³⁵as shown in

Scheme 2. The acetal ester 9 was treated with LDA and

then reacted with 4-methylthiobenzaldehyde. The

intermediate was subjected to a ring closure reaction by

heating with polyphosphoric acid (PPA) at 120 ꢁC

aﬀording the naphthoate 10. Compound 10 was reduced

by LiAlH₄to give the alcohol 11a, and the sulﬁde was

oxidized with m-chloroperbenzoic acid (m-CPBA) to

yield the sulfoxide 11b. Compounds 11a and 11b were

mesylated and reacted with imidazole giving the

1-imidazolyl derivatives 12a and 12b, respectively. The

sulfone 12c was prepared by oxidation of the sulﬁde 12a

using ammonium heptamolybdate tetrahydrate and

hydrogen peroxide.

3. Chemistry

The synthesis of 1-imidazolyl compounds is shown in

Schemes 1–3. The alkoxy derivatives at the 6-position on

the naphthalene ring were synthesized as shown in

Scheme 1. 2-Bromonaphthalenes 5a–c were lithiated

with n-BuLi and treated with DMF to give the alde-

hydes 6a–c, which were reduced with NaBH₄to aﬀord

the alcohols 7a–c. The alcohols were converted to the

1-imidazolyl derivatives 8a–c in twosteps; chlorination

with SOCl₂or methanesulfonylation with MsCl in the

presence of triethylamine, followed by reaction with

imidazole. Demethylation of 8a was achieved with BBr₃

to yield the naphthol 8d, which was treated with

Compounds with an alkyl group (R²) on the methy-

lene bridge were synthesized as shown in Scheme 3.

The methyl naphthyl ketone 14a was readily

prepared from 5a via lithiation followed by addition of

1) SOCl₂or

MsCl, Et₃N

Br

CHO

NaBH₄

1) n-BuLi

2) DMF

OH

N

R¹

2)

imidazole

8a : R¹=MeO (83%)

8b : R¹=EtO (50%)

8c: R¹=i-PrO (58%)

8d : R¹=OH (93%)

5a : R¹=MeO

5b : R¹=EtO

5c: R¹=i-PrO

6a : R¹=MeO (97%)

6b : R¹=EtO (82%)

6c: R¹=i-PrO (65%)

7a : R¹=MeO (70%)

7b : R¹=EtO (79%)

7c: R¹=i-PrO (63%)

BBr₃

PhCH₂Br

NaH

8e: R¹=PhCH₂O (48%)

Scheme 1.

CHO

1)

MeS

1) MsCl, Et₃N

2) imidazole

CO₂Et

LiAlH ₄

97%

N

OH

O

R¹

CO₂Et

LDA

2) PPA

15%

MeS

12a: R¹=SMe (44%)

12b: R¹=SOMe (8% from 11a)

12c :R¹=SO₂Me (8%)

10

11a: R¹=SMe

11b: R¹=SOMe

9

(NH₄)₆Mo₇O₂₄4H₂O

H₂O₂, EtOH

mCPBA

73%

Scheme 2.

1) n-BuLi

5a

2) AcNMe(OMe)

R²

CDI, NaH

MeO

NaBH₄

N

O

OH

MeO

14a :R²=Me (68%)

14b:R²=i-Pr

15a :R²=Me (91%)

16a :R²=Me (60%)

16b:R²=i-Pr (52%)

15b:R²=i -Pr (70% from13)

i-PrCOCl

AlCl₃

MeO

13

Scheme 3.

4316

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

N-methoxy-N-methylacetamide. The isopropyl naphthyl

ketone 14b was obtained from the 2-methoxynaphtha-

lene 13 by a Friedel–Crafts acylation. Reduction of 14a

and14b with NaBH₄gave the alcohols 15a and 15b,

which were converted to the imidazolyl derivatives 16a

and 16b by treatment with carbonyldiimidazole (CDI) in

the presence of a catalytic amount of NaH.

the ketone 22 in two-steps. The addition of the appro-

priate aryl lithium reagents, or Grignard reagents, to 22

provided the tertiary alcohols 27a,d,i–k and removal of

the Tr group gave 28a,d,i–k (Method A). Compounds

28b,c,e–h were synthesized by the reverse two-step pro-

cedures. Namely, treatment of 22 with 90% HCO₂H

gave 29, which were reacted with the corresponding

Grignard reagent to yield 28b,c,e–h (Method B). Optical

resolution of the racemic compound 28d was accom-

plished by HPLC using Chiralpak^ꢂAD to give the

enantiomers (S)-28d and (R)-28d. Stereochemistry of

these enantiomers was determined by a single-crystal

X-ray analysis of (R)-28d (Fig. 3).

The 4-imidazolyl compounds were prepared as de-

scribed in Schemes 4–9. The synthesis of compound 21 is

shown in Scheme 4. Reaction of 5a with the aldehyde

17³⁶was carried out via lithiation to give the secondary

alcohol 18. Benzoylation of the hydroxy group aﬀorded

the ester 19, which was subjected to debenzoyloxygen-

ation with H₂/Pd–C to yield 20. The trityl (Tr) group in

20 was deprotected with 90% HCO₂H to furnish 21.

The compounds with an additional substituent on the

naphthalene ring were synthesized as described in

Scheme 7. Introduction of a formyl group at the 5-po-

sition of 5a was achieved by Vilsmeier reaction to aﬀord

the aldehyde 30. Reduction of the formyl group using

NaBH₄yielded the alcohol 31, and the hydroxyl group

was converted to the methyl group by methanesulfonyl-

ation, iodination and reduction to provide the 5-meth-

ylnaphthalene 32. Baeyer–Villiger reaction of 30 using

m-CPBA gave the formate 33, followed by hydrolysis

with LiOH and methylation of the resulting hydroxyl

group to yield the 5,6-dimethoxynaphthalene 34. The

naphthalenes 32 and 34 were lithiated and reacted with

the imidazolyl isopropyl ketone 35³⁷to give 36a and 36b,

respectively. The aldehyde 37 was subjected to naph-

thalene ring construction as described above, with some

modiﬁcation, to provide 38. The ester was reduced using

Compounds possessing an alkyl group (R²) on the

methylene bridge were synthesized as shown in Scheme

5. The alcohol 18 was oxidized with MnO₂to provide

the ketone 22. A Wittig reaction of 22 with methyltri-

phenylphosphonium bromide or isopropyltriphenyl-

phosphonium iodide gave the oleﬁns 23a and 23b, which

were detritylated to yield 24a and 24b. Catalytic

hydrogenation of these oleﬁns aﬀorded compounds 25a

and 25b.

Synthesis of the compounds with a hydroxyl group on

the methylene bridge, is shown in Scheme 6. The com-

pound 26 was prepared from 18 by detritylation with

90% HCO₂H. Compounds 28a,d,i–k were obtained from

OH

OCOPh

PhCOCl

H₂, Pd-C

N

1) n-BuLi

N

5a

Tr

2)

pyridine

quant.

N

Tr

MeO

DMF

82%

N

Tr

N

Tr

MeO

N

20

N

17

18

19

CHO

45%

90% HCO₂H

61%

N

H

MeO

21

Scheme 4.

R⁶

MePPh₃Br or

i-PrPPh₃I

O

N

MnO₂

N

90% HCO₂H

18

N

H

N

MeO

24a: R ⁶=CH₂(84%)

N

KOBu^t

MeO

CHCl₃

96%

MeO

Tr

23a: R⁶=CH₂(98%)

22

24b: R ⁶=C(CH₃)₂(99%)

23b: R ⁶=C(CH₃)₂(97%)

R²

H₂, Pd-C

N

H

MeO

25a: R²=Me(92%)

25b: R²=i-Pr(67%)

Scheme 5.

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4317

OH

Scheme 8. Allylation of 43 followed by a Claisen rear-

rangement at 190 ꢁC gave the 1-allyl-2-naphthol 44.

Ozonolysis of 44 followed by treatment with NaBH₄

aﬀorded the diol 45 and intramolecular dehydration

under acidic conditions provided 46. Lithiation of 46

and then addition to 35 furnished 47.

N

90% HCO₂H

71%

18

N

H

MeO

26

HO R²

Method A

R²Li or R²MgX

N

The 2,3-dihydronaphtho[2,3-b]furan derivative 56 was

synthesized as shown in Scheme 9. Bromination of

2,3-dihydro-1-benzofuran (48) followed by formylation

gave the aldehyde 50, which was converted to the

imidazolyl naphthyl ketone 55 by the similar method

described for 42. Since Katritzky’s imidazole introduc-

tion into 53 aﬀorded the alcohol 54, additional oxida-

tion with MnO₂was employed to obtain 55. A Grignard

reaction of 55 with i-PrMgCl provided 56.

N

Tr

MeO

22

( a, d, i-k)

27a: R²=Me (97%), 27d: R²=i-Pr (56%)

27i: R²=Ph (88%), 27j: R²=3-pyridyl (83%)

27k: R²=4-pyridyl (75%)

Method B

90% HCO₂H, 84%

90% HCO₂H

HO R²

O

R²MgX

( b, c, e-h)

N

H

MeO

N

H

MeO

4. Results and discussion

29

28a:R²=Me (Method A, 74%)

28b:R²=Et (Method B, 42%)

28c:R²=n-Pr (Method B, 20%)

4.1. Enzyme inhibitory activity (in vitro study)

2

28d:

R =i-Pr (Method A, 65%)

28e:R²=c-Pr (Method B, 32%)

28f :R²=i-Bu (Method B, 71%)

28g:R²=t-Bu (Method B, 35%)

28h:R²=c-pentyl (Method B, 10%)

28i :R²=Ph (Method A, 67%)

28j :R²=3-pyridyl (Method A, 78%)

28k:R²=4-pyridyl (Method A, 91%)

Test compounds were evaluated in vitro for the inhibi-

tion of rat and human C_17;20-lyase using the radiometric

assay described in our previous paper.¹The source of

the rat and human enzymes were testicular microsomes

and a recombinant enzyme,^1;41respectively.

The pharmacological activities of 1-imidazolyl and

4-imidazolyl series are shown in Tables 1 and 2,

respectively. In the 1-imidazolyl derivatives, small alk-

oxy substituents for R¹, such as in 8a and 8b, slightly

increased the inhibitory activity towards rat and human

enzymes compared to the unsubstituted compound 2

(Table 1). The isopropoxy compound 8c led to an in-

crease in the activity only against the rat enzyme. The

benzyloxy group, as in 8e, resulted in signiﬁcantly less

inhibition than the other alkoxy compounds. The

methylsulﬁde 12a showed potent activity, while the

methylsulfoxide and methylsulfone (12b and 12c) led to

a modest decrease in the inhibition. Alkyl groups for R²,

such as in 16a and 16b, resulted in the same level of

activity as for 8a.

HO

N

S

N

H

MeO

(S)-28d

CHIRALPAK ^RAD

28d

HO

N

R

N

H

(R)-28d

Scheme 6.

LiAlH₄to aﬀord the alcohol 39, which was oxidized

with MnO₂to yield the aldehyde 40. Then 40 was

treated with 1,4-dilithioimidazole, which was prepared

from 4-bromoimidazole and t-BuLi by Katritzky’s

procedure,³⁸to provide the imidazolyl naphthyl ketone

41. In this reaction, the product was not the corre-

sponding alcohol but the ketone as Katritzky obtained.

Grignard reaction of 41 with isopropylmagnesium

chloride furnished 42. Optical resolution of 42 was

accomplished by HPLC using Chiralpak^ꢂAD to give

(S)-42 and (R)-42, respectively, which were crystal-

lized as the fumarate salts. Stereochemistry of these

enantiomers was determined by a single-crystal X-ray

analysis of (S)-42 as the salt with ())-(4S)-5,5-dimethyl-

2-hydroxy-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide

[())-CPA]^39;40(Fig. 4).

Next, we investigated 4-imidazolyl compounds and

found that the orientation of the 4-imidazolyl group

corresponded with the potency of the corresponding 1-

imidazolyl compounds (comparison of 21 and 8a, 25a

and 16a, 25b and 16b). Alkyl substituents for R²had a

negligible eﬀect on the enzyme inhibition, as did 1-

imidazolyl compounds. The structure–activity relation-

ships regarding incorporation of a hydroxy group at R³

and an alkyl group at R²were interesting. The hydroxy

group at R³tended to lower the inhibitory activity, but

the activity depended on the size of R². The isopropyl

group was found to be optimum for R²in a rat enzyme

inhibition assay. Both smaller and larger alkyl groups

decreased the activity (comparison of 26 and 28a–h).

For the human enzyme, methyl to propyl R²groups

were appropriate size for the optimum enzyme inhi-

bition. An aromatic group for R², such as in 28i–k, led

to reduced activity. These results suggest a possible

The 1,2-dihydronaphtho[2,1-b]furan derivative 47 was

synthesized via the key intermediate 46 as shown in

4318

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

1) MsCl, Et₃N

2) NaI, DMSO

Br

NaBH₄

78%

POCl₃

MeO

3) NaBH₄

60%

MeO

DMF

26%

Me

32

CH₂OH

CHO

31

30

5a

Br

1) LiOH

mCPBA

78%

MeO

N

2) MeI, K₂CO₃

31%

OMe

OCHO

34

33

HO

1) n-BuLi

32, 34

H

N

2)

N

H

MeO

R⁴

N

36a: R⁴=Me (53%)

36b: R⁴=MeO (53%)

35

O

1)

O

LDA

CO₂Et

MeO

CHO

MnO₂

MeO

CO₂Et

MeO

CHO

LiAlH₄

81%

9

OH

2) H₂SO₄

45%

MeO

CH₂Cl₂

81%

39

38

40

37

O

4-bromoimidazole

HO

1) CHIRALPAK ^RAD

2) fumaric acid

MeO

i-PrMgCl

N

MeO

N

t-BuLi

N

S

N

H

N

H

MeO

N

H

THF

66%

34%

41

42

(S)-42 (fumarate)

HO

MeO

N

R

N

H

MeO

(R)-42 (fumarate)

Scheme 7.

1)

Br

NaH, 91%

Br

TsOH

1) O₃

Br

HO

toluene

34%

O

2) NaBH₄

24%

HO

2) 190˚C, quant

44

46

45

43

HO

1) n-BuLi

N

2)

35

N

H

O

48%

47

Scheme 8.

interaction with the enzyme and will be discussed in the

modeling section.

sion of testosterone biosynthesis. Test compounds were

orally administrated to male rats (n ¼ 5) at a dose of

25 mg/kg. After 2 and 5 h, the serum concentration of

testosterone was measured by a speciﬁc radioimmuno-

assay and expressed as the percentage of the control.

4.2. Suppression of testosterone biosynthesis in rats

(in vivo study)

The 1-imidazolyl compounds with a methoxy group at

R¹(8a, 16a and 16b), dramatically reduced the serum

testosterone concentration to 4–5% and 1% of the con-

Selected compounds with an IC₅₀of <50 nM towards

the rat enzyme were evaluated in vivo for the suppres-

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4319

1)

O

LDA

CO₂Et

Br

CHO

Br₂

1) n-BuLi

9

O

quant.

O

2) DMF

98%

O

2) PPA

26%

48

50

49

51

OH

4-bromoimidazole

t-BuLi

MnO₂

CHO

LiAlH₄

89%

N

OH

O

CH₂Cl₂

72%

O

N

H

52%

54

52

53

O

HO

i-PrMgCl

N

MnO₂

CH₂Cl₂

89%

O

N

H

O

N

H

THF

51%

56

55

Scheme 9.

were the key structural determinants for the in vivo ef-

fects with extended duration.

The 4-imidazolyl compounds 21, 25a and 25b showed

strong reduction in the serum testosterone level, as did

the corresponding 1-imidazolyl analogues (comparison

of 21 and 8a, 25a and 16a, 25b and 16b). It should be

noted that suppression of testosterone biosynthesis was

diminished by R³¼ OH (e.g. 28b and 28c), but incor-

poration of a hydroxy group and an isopropyl group at

R²and R³(compound 28d) resulted in preferable serum

testosterone reduction, to 4% and 13% of the control at

2 and 5 h after treatment, respectively.

Figure 3. Crystal structure of (R)-28d.

4.3. Eﬀects on the weight of prostate and seminal vesicles

in rats (in vivo study)

trol at 2 and 5 h after treatment, respectively. These

three compounds obviously had more potent in vivo

eﬀects than the lead compound 2. Ethoxy or isopropoxy

derivatives (8b and 8c) showed a potent reduction in the

serum testosterone concentration at 2 h after treatment,

while the duration of action was insuﬃcient at 5 h after

treatment. The methoxy and methylthio groups at R¹

Selected compounds were orally administrated to male

rats (n ¼ 5) at a dose of 50 mg/kg, twice a day, 9 times in

total. After the ﬁnal administration, the eﬀects of the

test compounds on the weight of androgen-dependent

organs, such as prostate and seminal vesicles, were

evaluated. These organ weights are shown as the % of the

control values, which were calculated by the equation;

Figure 4. Crystal structure of (S)-42 as the salt with ())-(4S)-5,5-dimethyl-2-hydroxy-4-phenyl-1,3,2-dioxaphosphorinane 2-oxide.

4320

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

Table 1. Pharmacological activities of 1-imidazolyl derivatives

R²

N

R¹

2, 8, 12, 16

Com-No.

R¹

R²

C_17;20-lyase inhibition IC₅₀(nM)

Human

T concn (in vivo)^a% of control

5 h

Rat

2 h

2

8a

H

53

27

43

27

13

5

55

1

MeO

EtO

H

8b

8c

H

26

24

23

46

8

15

31

Nt

1

i-PrO

PhCH₂O

MeS

H

8

8e

H

670

18

230

20

Nt

7

12a

12b

12c

16a

16b

H

MeSO

MeSO₂

MeO

H

270

230

22

240

200

21

Nt

4

Nt

1

H

Me

i-Pr

26

24

5

1

Nt: not tested.

^aTest compounds were administrated orally at a dose of 25 mg/kg to male rats (n ¼ 5). After 2 and 5 h, the serum testosterone (T) concentration was

measured by radioimmunoassay and shown as the % values of that of control.

Table 2. Pharmacological activities of 4-imidazolyl derivatives

R³R²

HO

N

H

N

H

N

H

MeO

(S)-28d

(R)-28d

Com-No.

R²

R³

C_17;20-lyase inhibition IC₅₀(nM)

T concn (in vivo)^a% of control

Rat

Human

2 h

5 h

21

H

13

28

18

23

30

63

35

27

36

32

35

41

83

42

110

270

54

28

54

1

3

6

25a

25b

26

Me

i-Pr

H

1

6

H

22

6

OH

170

130

41

Nt

17

18

4

Nt

62

28a

28b

28c

Me

Et

n-Pr

i-Pr

c-Pr

i-Bu

t-Bu

43

33

109

13

28d

28e

64

85

Nt

3

Nt

20

28f

28g

28h

28i

160

48

c-Pentyl

Ph

230

420

240

21

28j

3-Pyridyl

4-Pyridyl

(S)-i-Pr

(R)-i-Pr

28k

(S)-28d

(R)-28d

52

24

211

Nt: not tested.

^a25 mg/kg (po).

100 · (X ꢀ B)/(A ꢀ B), where A, B and X are the organ

weights for intact, castrated and treated groups,

respectively.

weight were almost comparable to those induced by

castration. Unfortunately 8a, 12a, 16a and 16b increased

the liver weight, while 28d did not have this adverse

eﬀect. The crucial element to remove the eﬀect on the

liver weight seems to be the hydroxyl group, which may

suitably adjust the molecular lipophilicity. In addition,

the 4-imidazolyl orientation is also an important be-

cause it allows the introduction of the hydroxyl group

Compounds 8a, 12a, 16a, 16b and 28d decreased the

weight of the prostate and seminal vesicles to 23–42%

and 6–48% of the controls, respectively (Table 3).

Especially, the eﬀects of 16b and 28d on seminal vesicle

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4321

Table 3. Eﬀects of C_17;20-lyase inhibitors on the weights of prostate

and seminal vesicles in male rats after nine times consecutive oral

administration (50 mg/kg/day, bid)

both an isopropyl group and a hydroxyl group produced

the optimum enzyme inhibition.

Com-no.

Tissue weight (% of control^a)

Prostate Seminal vesicles

4.5. Selectivity for C_17,20-lyase and steroid 11b-hydroxy-

lase

8a

12a

32

23

37

32

42

43

65

43

48

34

4

Compound (S)-28d was subjected to further evaluation

as a candidate. However, it was revealed that (S)-28d

showed relatively potent inhibitory activity for the rat

steroid 11b-hydroxylase, which is a P450 enzyme and

responsible for the production of corticosterone and

cortisol, with an IC₅₀value of 140 nM. Thus, more

selective inhibitors were required. As preliminary data,

insertion of a methyl group at the 5-position on the

naphthalene ring provided a more selective inhibitor

(Table 4, selectivity for rat C_17;20-lyase over rat 11b-

hydroxylase: 36a; 39 vs (S)-28d; 6.7), and the substituent

on the naphthalene ring was thus thought to be

important for a high selectivity. Derivatives modiﬁed at

the 5- or 7-position on the naphthalene ring, such as 36b,

42, 47 and 56, were designed and these compounds

showed equipotent C_17;20-lyase inhibition to (S)-28d and

changed the selectivity as predicted. A methoxy group at

the 5- or 7-position on the naphthalene increased the

selectivity, as did a 5-methyl group (selectivity: 36b; 30,

42; >100). The tricyclic inhibitor 56 was 17-fold more

selective, while 47 had poor selectivity. Compounds

36a,b and 42, which showed more than about 30-fold

selectivity, suppressed testosterone biosynthesis at a

dose of 50 mg/kg in rats, and the best results were

achieved in 42 (4% and 9% of the control at 2 and 5 h

after treatment, respectively). From the data for rat

C_17;20-lyase inhibition, the active enantiomer was iden-

tiﬁed to be the (S)-form as well as 28, and (S)-42 showed

the most potent activity (IC₅₀¼ 3.8 nM), with more than

260-fold selectivity for C_17;20-lyase over 11b-hydroxy-

lase. In addition, (S)-42 decreased the weight of prostate

and seminal vesicles without an increase in the liver

weight (Table 3). Biosynthesis of androgens in primates

is somewhat diﬀerent from that in rodents, so (S)-42 was

studied in male cynomolgus monkeys to determine the

eﬃcacy for testosterone suppression. When (S)-42 was

orally administrated at a dose of 1 mg/kg to monkeys,

the serum testosterone level was reduced to the castra-

tion level at 8 h after treatment.

16a

16b

28d

(S)-28d

(S)-42^b

6

)1

47

^aThe organ weights in castrated and intact groups were set to 0% and

100%, respectively. The % of control values ¼ 100 · (X ꢀ B)/(A ꢀ B),

where A, B and X are the organ weights in intact, castrated and

treatment groups, respectively.

^bFumarate.

into the methylene bridge. Compound 21, 25a and 25b

showed acute toxicity and therefore the examination

was not completed.

The enantiomers of 28d were examined to establish

which enantiomer was responsible for the pharmaceu-

tical activity. No deﬁnite diﬀerence of enzyme inhibition

was observed between the enantiomers (Table 2, IC₅₀s:

(S)-28d; rat 21 nM, human 28 nM, (R)-28d; rat 52 nM,

human 54 nM). However, the suppressive eﬀects on the

testosterone biosynthesis revealed that (S)-28 was more

active than (R)-28d (Table 2, testosterone concentration:

(S)-28d; 3% at 2 h, 20% at 5 h, (R)-28d; 24% at 2 h, 211%

at 5 h). The less active enantiomer (R)-28d led to an

increase in the serum testosterone concentration,

compared to the control, at 5 h after treatment. The

increase was probably due to cancellation of the nega-

tive feedback control, caused by transient suppression of

the testosterone levels, as previously reported.¹Com-

pound (S)-28d signiﬁcantly decreased the weight of

the prostate and seminal vesicles without an increase

in the liver weight after consecutive administrations

(Table 3).

4.4. Molecular modeling

A molecular modeling study of the human C_17;20-lyase

using a homology model helps us to understand the in

vitro structure–activity relationships (Fig. 5). According

to the docking mode, the methoxy oxygen of (S)-28d, as

expected, forms a hydrogen bond with the hydroxyl

group of Thr101 in the enzyme. The docking mode

suggests no interaction between the hydroxy group of

(S)-28d and the enzyme. Furthermore, the mode sug-

gests that the isopropyl group of (S)-28d ﬁts into the

lipophilic pocket, which is constructed by Ala367,

Met369, Ile371, Pro372 and Phe484 in the enzyme. As

mentioned in the enzyme inhibitory activity section, a

hydroxy group at the methylene bridge tends to lower

the inhibitory activity, while the activity was aﬀected by

the arrangement of the hydroxy group and the other

substituents. The ﬁt of the isopropyl group into the

pocket may account for the fact that incorporation of

5. Conclusions

We have synthesized 1- and 4-(2-naphthylmethyl)-1H-

imidazoles as C_17;20-lyase inhibitors. These compounds

were tested for enzyme inhibitory activities, suppressive

eﬀects on testosterone biosynthesis in rats, and reduc-

tion in the weight of prostate and seminal vesicles in

rats. Several 6-methoxynaphthyl compounds achieved

potent enzyme inhibition and strong suppression of

testosterone biosynthesis in rats, while most of these

compounds increased the liver weight after consecutive

administrations. The best results were achieved by the

incorporation of a hydroxy group and an isopropyl

group, as described for (S)-28d and (S)-42, which was

eﬀective in expressing pharmacological activities and

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N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

Figure 5. Proposed binding mode of (S)-28d at the active site in a human C_17;20-lyase model. Selected active site residues are labeled; orange, heme;

magenta, polar residues; yellow, lipophilic residues. White dotted line shows a hydrogen bond.

Table 4. Pharmacological activities of 4-imidazolyl derivatives

HO

R⁵

N

H

N

H

O

N

H

MeO

O

R⁴

36, 42

56

47

Com-No.

R⁴

R⁵

Enzyme inhibition; IC₅₀(nM)

Selectivity^b

T concn (in vivo, po)

% of control

C

_17;20-lyase

Human

11b-Hydroxylase

Rat

2 h

5 h

(S)-28d

36a

36b

H

Me

H

21

13

26

9.5

26

21

3.8

78

28

29

25

23

11

39

140

500

6.7

39

3

12

18

4

20 (25 mg/kg)

13 (50 mg/kg)

MeO

H

780

30

19 (50 mg/kg)

9 (50 mg/kg)

42

47

MeO

>1000

77

350

>100

3.0

17

See structure

Nt

56

(S)-42^a

(R)-42^a

>1000

>260

>13

Nt: not tested.

^aFumarate.

^bRat 11b-hydroxylase/rat C17,20-lyase.

removing the eﬀect of liver weight. Through the exam-

ination of selectivity for C_17;20-lyase over 11b-hydroxyl-

ase, (S)-42 was found to be a more than 260-fold

selective inhibitor. Finally, compound (S)-42 showed a

potent suppression of testosterone biosynthesis after a

single oral administration in monkeys. These data sug-

gest that (S)-42 may be a promising agent for the

treatment of androgen-dependent prostate cancer.

nance (¹H NMR) spectra were recorded on a Varian

Gemini-200 (200 MHz) spectrometer. Chemical shifts

are given in ppm with tetramethylsilane as the internal

standard, and coupling constants (J) are given in hertz

(Hz). The following abbreviations are used: s ¼ singlet,

d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,

br ¼ broad, br s ¼ broad singlet. Column chromatogra-

phy was carried out on Kieselgel 60 (230–400 mesh,

Merck).

6. Experimental

6.1. Chemistry

6.2. 2-Bromo-6-ethoxynaphthalene (5b)

To a suspension of NaH (60% oil dispersion, 2.10 g,

52.5 mmol) in DMF (50 mL) was added 6-bromo-2-

naphthol (11.2 g, 50.0 mmol) with ice-cooling, and the

stirring was continued at room temperature for 0.5 h.

Ethyl iodide (8.19 g, 52.5 mmol) was added and the

Melting points were determined on a Yanaco MP-500V

micro melting point apparatus and are uncorrected.

Infrared (IR) spectra were taken on a Shimadzu FTIR-

8200PC spectrometer. Proton nuclear magnetic reso-

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4323

reaction was stirred at room temperature for an addi-

tional 16 h. The mixture was diluted with water and

Et₂O, and the organic layer was separated, dried over

Na₂SO₄and concentrated. The residue was suspended in

hexane and collected by ﬁltration to give 5b (10.9 g,

and the mixture was stirred at room temperature for 1 h

and concentrated. The residue was partitioned between

AcOEt and water, and the organic layer was separated,

dried over MgSO₄, and concentrated to give 7a (2.77 g,

70%) as colourless crystals. Mp 116–118 ꢁC (AcOEt–i-

Pr₂O). IR (KBr): 1633, 1608, 1487, 1269, 1030 cm^ꢀ1. ¹H

NMR (CDCl₃) d: 1.68 (1H, br), 3.93 (3H, s), 4.83 (2H, d,

J ¼ 5:2 Hz), 7.08–7.25 (3H, m), 7.46 (1H, d, J ¼ 8:8 Hz),

7.68–7.80 (3H, m). Anal. Calcd for C₁₂H₁₂O₂: C, 76.57;

H, 6.43. Found: C, 76.69; H, 6.23.

1

87%) as a colourless powder. H NMR (CDCl₃) d: 1.48

(3H, t, J ¼ 7:0 Hz), 4.13 (2H, q, J ¼ 7:0 Hz), 7.08 (1H,

d, J ¼ 2:6 Hz), 7.16 (1H, dd, J ¼ 9:0, 2.6 Hz), 7.48 (1H,

dd, J ¼ 8:8, 1.8 Hz), 7.58 (1H, d, J ¼ 9:0 Hz), 7.64 (1H,

d, J ¼ 8:8 Hz), 7.91 (1H, d, J ¼ 1:8 Hz).

6.3. 2-Bromo-6-isopropoxynaphthalene (5c)

6.8. (6-Ethoxy-2-naphthyl)methanol (7b)

Prepared from 6-bromo-2-naphthol and 2-iodopropane

by the procedure described for the synthesis of 5b in 85%

Yield 79%. ¹H NMR (CDCl₃) d: 1.48 (3H, t,

J ¼ 7:0 Hz), 4.16 (2H, q, J ¼ 4:8 Hz), 4.82 (2H, s), 7.13

(1H, s), 7.16 (1H, dd, J ¼ 8:4, 2.4 Hz), 7.45 (1H, dd,

J ¼ 8:4, 1.7 Hz), 7.73 (2H, d, J ¼ 8:4 Hz), 7.73 (1H, s).

yield. Mp 79 ꢁC. IR (KBr): 2980, 1590, 1391, 1211 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 1.40 (6H, d, J ¼ 6:0 Hz), 4.06–4.80

(1H, m), 7.06–7.20 (2H, m), 7.47 (1H, dd, J ¼ 8:8,

1.8 Hz), 7.57 (1H, d, J ¼ 8:8 Hz), 7.64 (1H, d,

J ¼ 8:8 Hz), 7.90 (1H, d, J ¼ 1:8 Hz). Anal. Calcd for

C₁₃H₁₃BrO: C, 58.89; H, 4.94. Found: C, 58.86; H, 4.98.

6.9. (6-Isopropoxy-2-naphthyl)methanol (7c)

Yield 63%. Mp 60–64 ꢁC. IR (KBr): 3252, 2971, 1605,

6.4. 6-Methoxy-2-naphthaldehyde (6a)

1481, 1271 cm^ꢀ^{1 1}H NMR (CDCl₃) d: 1.40 (6H, d,

.

J ¼ 6:0 Hz), 1.73 (1H, br s), 4.70 (1H, m), 4.81 (2H, s),

7.08–7.17 (2H, m), 7.44 (1H, dd, J ¼ 8:6, 1.6 Hz), 7.66–

7.77 (3H, m). Anal. Calcd for C₁₄H₁₆O₂: C, 77.75; H,

7.46. Found: C, 77.58; H, 7.43.

To a solution of 5a (42.27 g, 0.178 mol) in THF (600 mL)

was added n-BuLi (1.65 M solution in hexane; 125 mL,

0.199 mol) at )78 ꢁC, and the stirring was continued for

0.5 h. Then DMF (28 mL, 0.381 mol) was added and the

mixture was warmed up to room temperature, diluted

with aqueous NH₄Cl, and extracted with AcOEt. The

organic layer was dried over MgSO₄and concentrated

to give 6a as crystals (32.31 g, 97%). Mp 56–60 ꢁC

(hexane). IR (KBr): 2841, 1686, 1624, 1480, 1269, 1028,

6.10. 1-[(6-Methoxy-2-naphthyl)methyl]-1H-imidazole

(8a)

To a solution of 7a (3.76 g, 20.0 mmol) in CH₂Cl₂

(40 mL) was added SOCl₂(2.92 mL, 40.0 mmol) with

ice-cooling, and the mixture was stirred at 0 ꢁC for 1 h

and concentrated. The residue was partitioned between

AcOEt and saturated aqueous NaHCO₃, and the or-

ganic layer was separated, dried over MgSO₄and

concentrated to give 6-chloromethyl-2-methoxy-naph-

thalene. This compound was stirred at room tempera-

ture for 18 h with imidazole (6.81 g, 100 mmol) in DMF

(40 mL) and the mixture was poured into water and

extracted with AcOEt. The extract was dried over

MgSO₄and concentrated and the residue was chroma-

tographed on silica gel using CH₂Cl₂–MeOH (10:1) as

an eluent. The product was recrystallized from AcOEt

to give 8a (2.92 g, 61%) as colourless needles. Mp 129–

1

856 cm^ꢀ1. H NMR (CDCl₃) d: 3.96 (3H, s), 7.15–7.30

(2H, m), 7.75–7.97 (3H, m), 8.26 (1H, s), 10.10 (1H, s).

Anal. Calcd for C₁₂H₁₀O₂: C, 76.66; H, 5.47. Found: C,

76.64; H, 5.48.

6.5. 6-Ethoxy-2-naphthaldehyde (6b)

Yield 82%. ¹H NMR (CDCl₃) d: 1.51 (3H, t,

J ¼ 7:0 Hz), 4.19 (2H, q, J ¼ 7:0 Hz), 7.17 (1H, d,

J ¼ 2:4 Hz), 7.23 (1H, dd, J ¼ 8:8, 2.4 Hz), 7.79 (1H, d,

J ¼ 8:8 Hz), 7.89 (1H, d, J ¼ 8:8 Hz), 7.92 (1H, dd,

J ¼ 8:8, 1.6 Hz), 8.25 (1H, d, J ¼ 1:6 Hz), 10.08 (1H, s).

132 ꢁC. IR (KBr): 3092, 1609, 1507, 1227 cm^ꢀ1

.

¹H

6.6. 6-Isopropoxy-2-naphthaldehyde (6c)

NMR (CDCl₃) d: 3.92 (3H, s), 5.24 (2H, s), 6.94 (1H, s),

7.09–7.16 (2H, m), 7.19 (1H, d, J ¼ 2:6 Hz), 7.22 (1H,

dd, J ¼ 8:8, 1.8 Hz), 7.54 (1H, s), 7.60 (1H, s), 7.69 (1H,

d, J ¼ 8:8 Hz), 7.73 (1H, d, J ¼ 8:2 Hz). Anal. Calcd for

C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C,

75.42; H, 5.85; N, 11.68.

Yield 65%. Mp 50–51 ꢁC. IR (KBr): 2975, 1686, 1275,

1169 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 1.43 (6H, d,

J ¼ 6:0 Hz), 4.76 (1H, m), 7.14–7.25 (2H, m), 7.77 (1H,

d, J ¼ 8:6 Hz), 7.85–7.93 (2H, m), 8.24 (1H, s), 10.09

(1H, s). Anal. Calcd for C₁₄H₁₄O₂: C, 78.48; H, 6.59.

Found: C, 78.31; H, 6.68.

6.11. 1-[(6-Ethoxy-2-naphthyl)methyl]-1H-imidazole (8b)

6.7. (6-Methoxy-2-naphthyl)methanol (7a)

Prepared from 7b by the procedure described for the

synthesis of 8a in 50% yield. Mp 133.5 ꢁC. IR (KBr):

1

To a solution of 6a (3.90 g, 21.0 mmol) in MeOH (60 mL)

was added NaBH₄(0.50 g, 13.2 mmol) with ice-cooling,

2986, 1609, 1507, 1227 cm^ꢀ1. H NMR (CDCl₃) d: 1.48

(3H, t, J ¼ 7:0 Hz), 4.15 (2H, q, J ¼ 7:0 Hz), 5.24 (2H,

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N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

s), 6.94 (1H, s), 7.10–7.15 (3H, m), 7.22 (1H, dd, J ¼ 9:2,

2.6 Hz), 7.53 (1H, s), 7.60 (1H, s), 7.69 (1H, d,

J ¼ 9:2 Hz), 7.71 (1H, d, J ¼ 8:4 Hz). Anal. Calcd for

C₁₆H₁₆N₂O: C, 76.16; H, 6.39; N, 11.10. Found: C,

76.10; H, 6.57; N, 11.12.

mixture was stirred for 1 h. A solution of 4-methyl-

thiobenzaldehyde (16.43 g, 0.108 mol) in THF (30 mL)

was added, and the reaction was warmed up to room

temperature and then quenched with water. After the

separation of the layers, the aqueous phase was further

extracted with AcOEt, and the organic layers were

combined, dried over MgSO₄and concentrated. The

residue was chromatographed on silica gel using hex-

ane–AcOEt ¼ 2:1 as an eluent to give an oil. (21.2 g). A

mixture of the oil (9.11 g) and polyphosphoric acid

(27.3 g) in toluene (100 mL) was heated at 100 ꢁC for

0.5 h, poured into ice water and extracted with AcOEt.

The extract was dried over MgSO₄and concentrated

and the residue was chromatographed on silica gel using

hexane–AcOEt ¼ 8:1 as an eluent to give 10 (1.73 g,

15%) as colourless crystals. Mp 57 ꢁC. IR (KBr): 2990,

1705, 1267, 1227 cm^ꢀ1. ¹H NMR (CDCl₃) d: 1.44 (3H, t,

J ¼ 7:1 Hz), 2.60 (3H, s), 4.43 (2H, q, J ¼ 7:1 Hz), 7.41

(1H, dd, J ¼ 8:8, 1.8 Hz), 7.57 (1H, s), 7.75 (1H, d,

J ¼ 8:8 Hz), 7.83 (1H, d, J ¼ 8:8 Hz), 8.06 (1H, dd,

J ¼ 8:8, 1.8 Hz), 8.53 (1H, s). Anal. Calcd for

C₁₄H₁₄O₂S: C, 68.26; H, 5.73. Found: C, 68.27; H, 5.63.

6.12. 1-[(6-Isopropoxy-2-naphthyl)methyl]-1H-imidazole

(8c)

To a mixture of 7c (1.42 g, 6.57 mmol) and Et₃N (2.7 mL,

20.3 mmol) in THF (50 mL) was added methanesulfonyl

chloride (0.66 mL, 8.53 mmol) with ice-cooling. The

mixture was stirred at 0 ꢁC for 3 h and imidazole (0.75 g,

11.0 mmol) was added. The reaction was stirred at room

temperature for an additional 9 h and concentrated, and

the residue was partitioned between AcOEt and water.

The organic layer was separated, dried over MgSO₄and

concentrated. The residue was chromatographed on sil-

ica gel using AcOEt–MeOH ¼ 30:1 as an eluent. The

product was recrystallized from hexane–AcOEt to give

8c (1.01 g, 58%). Mp 96 ꢁC. IR (KBr): 2975, 1609, 1507,

1225 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 1.40 (6H, d,

J ¼ 6:2 Hz), 4.70 (1H, m), 5.23 (2H, s), 6.93 (1H, t,

J ¼ 1:3 Hz), 7.67–7.25 (4H, m), 7.50–7.73 (4H, m). Anal.

Calcd for C₁₇H₁₈N₂O: C, 76.66; H, 6.81; N, 10.52.

Found: C, 76.66; H, 6.56; N, 10.35.

6.16. [6-(Methylthio)-2-naphthyl]methanol (11a)

To a suspension of LiAlH₄(0.52 g, 13.8 mmol) in THF

(50 mL) was added 10 (1.56 g, 6.33 mmol) portionwise

with ice-cooling, and the stirring was continued for

0.5 h. After the reaction was quenched by the addition of

water, AcOEt and 1 N HCl were added. The organic

layer was separated, dried over MgSO₄and concen-

trated and the residue was recrystallized from hexane–

AcOEt to give 11a (1.27 g, 97%) as colourless crystals.

Mp 114 ꢁC (AcOEt–hexane). IR (KBr): 3175, 1593,

6.13. 6-(1H-Imidazol-1-ylmethyl)-2-naphthol (8d)

To a solution of boron tribromide (4.81 g, 19.2 mmol) in

CH₂Cl₂(10 mL) was added 8a (1.91 g, 8.0 mmol) with

ice-cooling. The mixture was stirred at room tempera-

ture for 4 h and poured onto ice. The aqueous phase was

separated, neutralized with NaHCO₃and extracted with

THF–AcOEt. The extract was dried over Na₂SO₄and

concentrated, and the residue was recrystallized from

THF to give 8d (1.67 g, 93%) as colourless prisms. Mp

1

1026, 872 cm^ꢀ1. H NMR (CDCl₃) d: 2.59 (3H, s), 4.84

(2H, d, J ¼ 5:6 Hz), 7.38 (1H, dd, J ¼ 8:6, 2.0 Hz), 7.47

(1H, dd, J ¼ 8:6, 1.6 Hz), 7.60 (1H, d, J ¼ 2:0 Hz), 7.69–

7.79 (3H, s). Anal. Calcd for C₁₂H₁₂OS: C, 70.55; H,

5.92. Found: C, 70.47; H, 5.97.

208.5 ꢁC. IR (KBr): 3112, 2548, 1508, 1451, 1306 cm^ꢀ1

.

¹H NMR (DMSO-d₆+D₂O) d: 5.29 (2H, s), 6.93 (1H, br

s), 7.10 (1H, dd, J ¼ 9:8, 2.2 Hz), 7.12 (1H, s), 7.24 (1H,

br s), 7.31 (1H, d, J ¼ 8:0 Hz), 7.67 (1H, d, J ¼ 8:0 Hz),

7.69 (1H, s), 7.74 (1H, d, J ¼ 9:8 Hz), 7.87 (1H, br s).

Anal. Calcd for C₁₄H₁₂N₂Oꢁ0.25H₂O: C, 73.50; H, 5.51;

N, 12.25. Found: C, 73.32; H, 5.34; N, 12.18.

6.17. [6-(Methylsulﬁnyl)-2-naphthyl]methanol (11b)

To a solution of 11a (401 mg, 1.96 mmol) in CH₂Cl₂

(30 mL) was added a solution of 3-chloroperoxybenzoic

acid (649 mg, 3.76 mmol) in CH₂Cl₂(10 mL) with ice-

cooling. The mixture was stirred for 2 h and then diluted

with saturated aqueous NaHCO₃. The separated or-

ganic layer was dried over MgSO₄and concentrated.

The product was suspended in AcOEt and collected by

ﬁltration to give 11b (317 mg, 73%) as colourless crys-

tals. Mp 217–221 ꢁC. IR (KBr): 3399, 1022, 901,

824 cm^ꢀ1. ¹H NMR (CDCl₃) d: 2.80 (3H, s), 4.91 (2H, d,

J ¼ 4:8 Hz), 7.54–7.64 (2H, m), 7.85–7.99 (3H, m), 8.17

(1H, s). Anal. Calcd for C₁₂H₁₂O₂Sꢁ0.1H₂O: C, 64.90; H,

5.54. Found: C, 64.73; H, 5.59.

6.14. 1-[(6-Benzyloxy-2-naphthyl)methyl]-1H-imidazole

(8e)

Prepared from 8d and benzyl bromide by a similar

procedure to that described for the synthesis of 5b in

48% yield. Mp 146 ꢁC. IR (KBr): 3106, 1607, 1508,

1

1223 cm^ꢀ1. H NMR (CDCl₃) d: 5.18 (2H, s), 5.24 (2H,

s), 6.94 (1H, s), 7.11 (1H, s), 7.20–7.28 (4H, m), 7.33–

7.60 (6H, m), 7.71 (2H, d, J ¼ 8:6 Hz). Anal. Calcd for

C₂₁H₁₈N₂O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.16;

H, 5.57; N, 9.07.

6.18. 1-{[6-(Methylthio)-2-naphthyl]methyl}-1H-imid-

azole (12a)

6.15. Ethyl 6-(methylthio)-2-naphthoate (10)

To a solution of LDA (0.6 mol/L in THF, 215 mL) was

added 9³⁵(20.0 g, 0.106 mol) dropwise at )78 ꢁC, and the

Prepared from 11a by the procedure described for the

synthesis of 8c in 44% yield. Mp 112 ꢁC (AcOEt–hex-

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4325

ane). IR (KBr): 3090, 1595, 1507, 1235, 1067 cm^ꢀ1. H

NMR (CDCl₃) d: 2.58 (3H, s), 5.25 (2H, s), 6.92–6.96

(1H, m), 7.12 (1H, s), 7.24 (1H, dd, J ¼ 8:6, 1.6 Hz), 7.39

(1H, dd, J ¼ 8:4, 2.0 Hz), 7.53 (1H, s), 7.54–7.62 (2H,

m), 7.64–7.76 (2H, m). Anal. Calcd for C₁₅H₁₄N₂S: C,

70.83; H, 5.55; N, 11.01. Found: C, 70.75; H, 5.47; N,

11.07.

7.86 (1H, d, J ¼ 8:8 Hz), 8.01 (1H, dd, J ¼ 8:6, 1.8 Hz),

8.39 (1H, s). Anal. Calcd for C₁₃H₁₂O₂: C, 77.98; H,

6.04. Found: C, 77.97; H, 6.17.

1

6.22. 1-(6-Methoxy-2-naphthyl)ethanol (15a)

To a solution of 14a (5.71 g, 28.5 mmol) in THF–EtOH

(1:10, 44 mL) was added sodium borohydride (1.08 g,

28.5 mmol) with ice-cooling. The mixture was stirred at

room temperature for 3 h, diluted with water and ex-

tracted with several portions of AcOEt. The organic

layers were combined, dried over MgSO₄and concen-

trated and the residue was puriﬁed by column chroma-

tography on silica gel using hexane–AcOEt ¼ 5:1 to 1:1

as an eluent to give 15a (5.26 g, 91%) as colourless

crystals. Mp 114–115 ꢁC (AcOEt–hexane). IR (KBr):

3337, 1634, 1607, 1487, 1464, 1267, 1219, 1163, 1076,

1030, 893, 855, 816 cm^ꢀ1. ¹H NMR (CDCl₃) d: 1.57 (3H,

d, J ¼ 6:6 Hz), 1.90 (1H, br s), 3.92 (3H, s), 5.03 (1H, q,

J ¼ 6:6 Hz), 7.12–7.18 (2H, m), 7.47 (1H, dd, J ¼ 8:6,

1.8 Hz), 7.70–7.75 (3H, m). Anal. Calcd for C₁₃H₁₄O₂:

C, 77.20; H, 6.98. Found: C, 77.30; H, 7.12.

6.19. 1-{[6-(Methylsulﬁnyl)-2-naphthyl]methyl}-1H-imid-

azole (12b)

Prepared from 11b by the procedure described for the

synthesis of 8c in 8% yield. Mp 114–115 ꢁC. IR (KBr):

1

3102, 1505, 1069, 1038 cm^ꢀ1. H NMR (CDCl₃) d: 2.80

(3H, s), 5.33 (2H, s), 6.97 (1H, br s), 7.15 (1H, br s), 7.38

(1H, d, J ¼ 8:4 Hz), 7.52–7.70 (3H, m), 7.94 (2H, d,

J ¼ 8:8 Hz), 8.22 (1H, s). Anal. Calcd for C₁₅H₁₄N₂OS:

C, 66.64; H, 5.22; N, 10.36. Found: C, 66.42; H, 5.06; N,

10.27.

6.20. 1-{[6-(Methylsulfonyl)-2-naphthyl]methyl}-1H-

imidazole (12c)

To a solution of hexaammonium heptamolybdate tet-

rahydrate (136 mg, 0.11 mmol) in water (0.1 mL) was

added 30% H₂O₂(0.4 mL) with ice-cooling. This mixture

was stirred for 10 min and then added to a (0 ꢁC) solu-

tion of 12a (227 mg, 0.89 mmol) in EtOH (2 mL). The

stirring was continued at room temperature for 16 h,

and the mixture was diluted with AcOEt and THF.

After the catalyst was ﬁltered oﬀ, the ﬁltrate was washed

with water, dried over MgSO₄and concentrated. The

residue was chromatographed on silica gel using

AcOEt–MeOH ¼ 15:1 as an eluent, and the product was

suspended in diisopropylether and collected by ﬁltration

to give 12c (20 mg, 8%) as colourless crystals. Mp 139–

140 ꢁC. IR (KBr): 3000, 1304, 1142, 1125, 1074 cm^ꢀ1. ¹H

NMR (CDCl₃) d: 3.13 (3H, s), 5.35 (2H, s), 6.97 (1H, br

s), 7.16 (1H, br s), 7.42 (1H, dd, J ¼ 8:6, 2.0 Hz), 7.63

(2H, s), 7.88–7.04 (3H, m), 8.52 (1H, s). Anal. Calcd for

C₁₅H₁₄N₂O₂SÆ0.3H₂O: C, 61.75; H, 5.04; N, 9.60.

Found: C, 61.71; H, 5.21; N, 9.32.

6.23. 1-(6-Methoxy-2-naphthyl)-2-methylpropanol (15b)

To a mixture of 2-methoxynaphthalene (13, 10.0 g,

63.2 mmol) and AlCl₃(12.6 g, 94.8 mmol) in CH₂Cl₂

(150 mL) was added isobutyryl chloride (7.95 mL,

75.8 mmol) dropwise with ice-cooling. The reaction

mixture was stirred for 1 h, poured into ice water and

extracted with several portions of CH₂Cl₂. The organic

layers were combined, washed with saturated NaHCO₃,

dried over MgSO₄and concentrated give (6-methoxy-2-

naphthyl) isopropyl ketone (14b, 14.6 g) as a pale yellow

oil, which was used for the next step without further

puriﬁcation. To a solution of 14b in EtOH (100 mL) was

added sodium borohydride (2.42 g, 64.0 mmol) por-

tionwise with ice-cooling. The mixture was stirred

overnight at room temperature, diluted with water, and

extracted with several portions of AcOEt. The organic

layers were combined, dried over MgSO₄and concen-

trated and the residue was puriﬁed by column chroma-

tography on silica gel using hexane–AcOEt ¼ 6:1 as an

eluent to give 15b (10.2 g, 70%) as a colourless oil. IR

(KBr): 3334, 2955, 1607, 1485, 1466, 1265, 1233, 1175,

6.21. (6-Methoxy-2-naphthyl) methyl ketone (14a)

1032, 856 cm^ꢀ^{1 1}H NMR (CDCl₃) d: 0.81 (3H, d,

.

To a solution of 5a (10.0 g, 42.2 mmol) in THF (200 mL)

was added n-BuLi (1.6 M solution in hexane, 31.7 mL,

50.6 mmol) dropwise at )78 ꢁC, and the stirring was

continued for 30 min. A solution of N-methoxy-N-

methylacetamide (4.79 g, 46.4 mmol) in THF (30 mL)

was added dropwise, and the mixture was stirred at

)70 ꢁC for 1 h and then poured into 1N HCl (300 mL).

After the separation of the layers, the aqueous phase

was further extracted with AcOEt. The organic layers

were combined, dried over MgSO₄and concentrated

and the residue was recrystallized from cyclohexane to

give 14a (5.77 g, 68%) as colourless crystals. Mp 108–

109 ꢁC. IR (KBr): 1674, 1622, 1480, 1360, 1277, 1202,

J ¼ 6:6 Hz), 1.04 (3H, d, J ¼ 6:6 Hz), 1.94–2.14 (2H, m),

3.92 (3H, s), 4.48 (1H, d, J ¼ 7:0 Hz), 7.13–7.18 (2H, m),

7.42 (1H, dd, J ¼ 1:6, 8.4 Hz), 7.68–7.75 (3H, m).

6.24. 1-[1-(6-Methoxy-2-naphthyl)ethyl]-1H-imidazole

(16a)

A mixture of 15a (4.0 g, 19.8 mmol), carbonyldiimidaz-

ole (3.53 g, 21.8 mmol) and NaH (60% oil dispersion,

80 mg, 2.0 mmol) in THF (10 mL) was reﬂuxed for 3 h.

The reaction mixture was diluted with water and ex-

tracted with several portions of AcOEt. The organic

layers were combined, dried over MgSO₄and con-

centrated and the residue was puriﬁed by column

1

1022, 860, 822 cm^ꢀ1. H NMR (CDCl₃) d: 2.70 (3H, s),

3.95 (3H, s), 7.15–7.24 (2H, m), 7.77 (1H, d, J ¼ 8:8 Hz),

4326

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

chromatography on silica gel using CHCl₃–MeOH ¼

40:1 as an eluent to give 16a (2.99 g, 60%) as colourless

crystals. Mp 113–114 ꢁC (AcOEt–hexane). IR (KBr):

7.10–7.74 (25H, m), 7.91 (1H, s), 8.08 (1H, d,

J ¼ 1:6 Hz), 8.12 (1H, s). Anal. Calcd for

C₄₁H₃₂N₂O₃Æ0.2H₂O: C, 81.49; H, 5.40; N, 4.64. Found:

C, 81.50; H, 5.61; N, 4.64.

1609, 1507, 1487, 1265, 1221, 1032, 855, 820, 665 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 1.93 (3H, d, J ¼ 7:0 Hz), 3.91 (3H, s),

5.46 (1H, q, J ¼ 7:0 Hz), 6.94 (3H, s), 7.08–7.23 (4H, m),

7.52 (1H, s), 7.63 (1H, s), 7.68 (1H, d, J ¼ 4:0 Hz), 7.72

(1H, d, J ¼ 3:9 Hz). Anal. Calcd for C₁₆H₁₆N₂O: C, 76.16;

H, 6.39; N, 11.10. Found: C, 76.01; H, 6.28; N, 11.16.

6.28. 4-[(6-Methoxy-2-naphthyl)methyl]-1-trityl-1H-

imidazole (20)

A solution of 19 (15.0 g, 25.0 mmol) and 10% Pd–C

(1.50 g) in DMF (200 mL) was vigorously stirred under

H₂atmosphere at room temperature. The mixture was

stirred at room temperature for 12 h and the catalyst was

ﬁltered oﬀ. The ﬁltrate was concentrated and the residue

was chromatographed on silica gel using AcOEt as a

eluent. The eluate was washed with 1 M K₂CO₃, dried

over MgSO₄and concentrated to give 20 (9.79 g, 82%) as

pink crystals. Mp 144–145 ꢁC (THF–hexane). IR (KBr):

3058, 1605, 1491, 1443, 1262, 1229, 1175, 1032, 750,

702 cm^ꢀ1. ¹H NMR (CDCl₃) d: 3.89 (3H, s), 4.03 (2H, s),

6.57 (1H, d, J ¼ 1:4 Hz), 7.08–7.18 (8H, m), 7.25–7.40

(11H, m), 7.59–7.66 (3H, m). Anal. Calcd for

C₃₄H₂₈N₂O: C, 84.97; H, 5.87; N,5.83. Found: C, 84.73;

H, 5.86; N, 5.79.

6.25. 1-[1-(6-Methoxy-2-naphthyl)-2-methylpropyl]-1H-

imidazole (16b)

Prepared from 15b by the procedure described for the

synthesis of 16a in 52% yield. A pale yellow oil. IR

(KBr): 2963, 1634, 1607, 1507, 1485, 1269, 1223,

1030 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 0.91 (3H, d,

J ¼ 6:6 Hz), 0.96 (3H, d, J ¼ 6:6 Hz), 2.58–2.77 (1H, m),

3.91 (3H, s), 4.75 (1H, d, J ¼ 10:2 Hz), 7.05–7.19 (4H,

m), 7.37 (1H, dd, J ¼ 1:9, 8.5 Hz), 7.65–7.74 (4H, m).

Anal. Calcd for C₁₈H₂₀N₂O: C, 77.11; H, 7.19; N, 9.99.

Found: C, 77.01; H, 7.48; N, 10.20.

6.26. (6-Methoxy-2-naphthyl)-(1-trityl-1H-imidazol-4-

yl)methanol (18)

6.29. 4-[(6-Methoxy-2-naphthyl)methyl]-1H-imidazole

(21)

To a solution of 5a (15.6 g, 66.0 mmol) in THF (200 mL)

was added n-BuLi (1.6 M solution in hexane, 49.5 mL,

79.2 mmol) dropwise at )70 ꢁC, and the stirring was

continued for 30 min. A solution of 17³⁷(20.6 g,

60.0 mmol) in THF (300 mL) was added dropwise, and

the reaction mixture was stirred for 1.5 h at 0 ꢁC and

poured into 5% citric acid. After the separation of the

layers, the aqueous phase was further extracted with

AcOEt. The combined organic layers were washed with

brine, dried over MgSO₄, and concentrated and the

residue was puriﬁed by column chromatography on

silica gel using AcOEt as an eluent to give 18 (13.5 g,

45%) as colourless crystals. Mp 206–207 ꢁC (THF–hex-

ane). IR (KBr): 3166, 1603, 1478, 1451, 1260, 1171,

A mixture of 20 (6.02 g, 12.5 mmol) and 90% formic acid

(50 mL) was stirred at 50 ꢁC for 3 h and concentrated.

The residue was dissolved in AcOEt–THF (2:1) and

washed with saturated aqueous NaHCO₃. The organic

layer was extracted with 2 N HCl, and the aqueous

phase was made alkaline with aqueous NaHCO₃and

extracted with AcOEt–THF (2:1). The extract was dried

and concentrated, and the residue was recrystallized

from MeOH to give 21 as colourless crystals (1.81 g,

61%). Mp 199 ꢁC. IR (KBr): 2820, 2635, 1605, 1480,

1

1238 cm^ꢀ1. H NMR (CDCl₃+ DMSO-d₆) d: 3.90 (3H,

s), 4.05 (2H, s), 6.73 (1H, s), 7.10 (1H, d, J ¼ 9:6 Hz),

7.11 (1H, s), 7.35 (1H, d, J ¼ 7:8 Hz), 7.51 (1H, s), 7.60–

7.68 (3H, m). Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H,

5.92; N, 11.76. Found: C, 75.53; H, 5.93; N, 11.73.

1

1128, 754, 702 cm^ꢀ1. H NMR (CDCl₃) d: 3.90 (3H, s),

5.89 (1H, s), 6.60 (1H, d, J ¼ 1:4 Hz), 7.08–7.15 (8H, m),

7.26–7.34 (9H, m), 7.42–7.47 (2H, m), 7.63–7.69 (2H,

m), 7.78 (1H, s). Anal. Calcd for C₃₄H₂₈N₂O₂: C, 82.23;

H,5.68; N, 5.64. Found: C, 82.16; H,5.68; N, 5.55.

6.30. (6-Methoxy-2-naphthyl)-(1-trityl-1H-imidazol-4-

yl)ketone (22)

6.27. (6-Methoxy-2-naphthyl)-(1-trityl-1H-imidazol-4-

yl)methyl benzoate (19)

A mixture of 18 (6.00 g, 12.1 mmol) and MnO₂(24.8 g)

in CHCl₃(120 mL) was reﬂuxed for 6 h. The mixture

was ﬁltered through Celite, and the ﬁltrate was

concentrated. The residue was recrystallized from

Et₂O–hexane to give 22 (5.71 g, 96%) as colourless

crystals. Mp 202–203 ꢁC (AcOEt–hexane). IR (KBr):

1620, 1520, 1493, 1480, 1445, 1265, 1196, 1179, 909, 872,

To a solution of 18 (12.5 g, 25.2 mmol) in pyridine

(100 mL) was added benzoylchloride (3.5 mL,

30.2 mmol) dropwise with ice-cooling. The mixture was

stirred at room temperature for 3 h and concentrated.

Saturated aqueous NaHCO₃(150 mL) was added, and

the resulting mixture was stirred vigorously. The pre-

cipitate was ﬁltered, washed with water and Et₂O suc-

cessively, and dried to give 19 (15.3 g, quantitative yield)

as colourless crystals. Mp 192–194 ꢁC (THF–hexane).

IR (KBr): 1709, 1262, 1173, 1103, 1028, 860, 774,

704 cm^ꢀ1. ¹H NMR (CDCl₃) d: 3.89 (3H, s), 6.90 (1H, s),

1

747, 733, 702 cm^ꢀ1. H NMR (CDCl₃) d: 3.94 (3H, s),

7.15–7.23 (8H, m), 7.34–7.40 (9H, m), 7.58 (1H, d,

J ¼ 1:3 Hz), 7.77 (1H, d, J ¼ 1:3 Hz), 7.78 (1H, d,

J ¼ 8:6 Hz), 7.86 (1H, d, J ¼ 9:6 Hz), 8.26 (1H, dd,

J ¼ 8:6, 1.6 Hz), 8.95 (1H, s). Anal. Calcd for

C₃₄H₂₆N₂O₂: C,82.57; H, 5.30; N, 5.66. Found: C, 82.30;

H,5.40; N, 5.75.

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4327

6.31. 4-[1-(6-Methoxy-2-naphthyl)vinyl]-1-trityl-1H-

imidazole (23a)

6.88 (1H, s), 7.12–7.17 (2H, m), 7.53 (1H, dd, J ¼ 8:5,

1.7 Hz), 7.63 (1H, s), 7.71 (1H, s), 7.75 (1H, s), 7.83 (1H,

s). Anal. Calcd for C₁₆H₁₄N₂O: C, 76.78; H, 5.64; N,

11.19. Found: C, 76.57; H, 5.73; N, 11.26.

To a suspension of methyltriphenylphosphonium bro-

mide (7.22 g, 20.2 mmol) in THF (150 mL) was added t-

BuOK (2.49 g, 22.2 mmol) portionwise with ice-cooling.

The stirring was continued for 10 min, and 22 (5.0 g,

10.1 mmol) was added portionwise. The reaction mix-

ture was stirred at room temperature for 1 h. Then

6.34. 4-[1-(6-Methoxy-2-naphthyl)-2,2-dimethylvinyl]-

1H-imidazole (24b)

methyltriphenylphosphonium

bromide

(3.61 g,

Prepared from 23b by the procedure described for

the synthesis of 21 in 99% yield. A pale yellow amor-

phous powder. IR (KBr): 2908, 1632, 1603, 1499, 1481,

10.1 mmol), t-BuOK (1.25 g, 11.1 mmol) and THF

(50 mL) were added and the mixture was stirred at room

temperature for an additional 1 h. After removal of the

solvent, the residue was diluted with water and extracted

with several portions of AcOEt. The combined organic

layers were washed with brine and dried over MgSO₄.

The solvent was concentrated to ca. 50 mL, and then the

precipitate was collected by ﬁltration to give 23a (3.45 g,

70%) as colourless crystals. The ﬁltrate was concentrated

and the residue was puriﬁed by column chromatography

on silica gel using hexane–AcOEt ¼ 1:1 as an eluent to

give additional 23a (1.38 g, 28%) as colourless crystals.

Mp 212–213 ꢁC (AcOEt–hexane). IR (KBr): 1632, 1601,

1489, 1445, 1391, 1262, 1229, 1196, 1182, 1128, 1117,

1034, 907, 855, 747, 733, 702 cm^ꢀ1. ¹H NMR (CDCl₃) d:

3.90 (3H, s), 5.32 (1H, d, J ¼ 1:6 Hz), 5.99 (1H, d,

J ¼ 1:6 Hz), 6.70 (1H, d, J ¼ 1:4 Hz), 7.09–7.21 (8H, m),

7.27–7.35 (9H, m), 7.45–7.52 (2H, m), 7.58–7.65 (2H,

m), 7.75 (1H, d, J ¼ 1:2 Hz). Anal. Calcd for

C₃₅H₂₈N₂O: C, 85.34; H, 5.73; N, 5.69. Found: C, 85.29;

H, 5.67; N, 5.76.

1264, 1225, 1177, 1032, 851 cm^ꢀ^{1 1}H NMR (CDCl₃)

.

d: 1.77 (3H, s), 2.06 (3H, s), 3.90 (3H, s), 6.89 (1H, s),

7.10–7.20 (2H, m), 7.35 (1H, m), 7.51 (1H, s), 7.63–7.69

(3H, m).

6.35. 4-[1-(6-Methoxy-2-naphthyl)ethyl]-1H-imidazole

(25a)

A mixture of 24a (1.20 g, 4.8 mmol) and 10% Pd–C

(0.12 g) in DMF (15 mL) was vigorously stirred at

room temperature for 12 h under a H₂atmosphere. The

catalyst was ﬁltered oﬀ and the ﬁltrate was concen-

trated. The residue was chromatographed on silica gel

using CHCl₃–MeOH ¼ 10:1 as an eluent. The product

was recrystallized from THF–hexane to give 25a

(1.11 g, 92%) as colourless needles. Mp 193–194 ꢁC. IR

(KBr): 3056, 2907, 1603, 1264, 1225, 1117, 1032,

1

851 cm^ꢀ1. H NMR (CDCl₃+CD₃OD) d: 1.67 (3H, d,

J ¼ 7:2 Hz), 3.91 (3H, s), 4.09 (1H, s), 4.22 (1H, q,

J ¼ 7:2 Hz), 6.75 (1H, s), 7.09–7.15 (2H, m), 7.32 (1H,

dd, J ¼ 8:4, 1.9 Hz), 7.51 (1H, d, J ¼ 1:2 Hz), 7.59 (1H,

s), 7.65–7.70 (2H, m). Anal. Calcd for C₁₆H₁₆N₂O: C,

76.16; H, 6.39; N, 11.10. Found: C, 76.03; H, 6.07; N,

11.05.

6.32. 4-[1-(6-Methoxy-2-naphthyl)-2,2-dimethylvinyl]-1-

trityl-1H-imidazole (23b)

To a suspension of isopropyltriphenylphosphonium

iodide (13.1 g, 30.3 mmol) in THF (100 mL) was added

t-BuOK (3.40 g, 30.3 mmol) portionwise with ice-cool-

ing. The stirring was continued for 10 min, and 22

(10.0 g, 20.2 mmol) was added. The reaction mixture was

stirred for 2 h at room temperature, diluted with water

and extracted with several portions of AcOEt. The or-

ganic layers were combined, dried over MgSO₄and

concentrated, and the residue was puriﬁed by column

chromatography on silica gel using hexane–AcOEt ¼ 2:1

to 1:1 as an eluent to give 23b (10.2 g, 97%) as a pale

yellow powder. IR (KBr): 1603, 1493, 1483, 1445, 1264,

6.36. 4-[1-(6-Methoxy-2-naphthyl)-2-methylpropyl]-1H-

imidazole (25b)

Prepared from 24b by the procedure described for the

synthesis of 25a in 67% yield. Colourless crystals. Mp

153–154 ꢁC (AcOEt). IR (KBr): 2953, 1605, 1483, 1464,

1264, 1227, 1034, 856, 839, 818 cm^ꢀ1. ¹H NMR (CDCl₃)

d: 0.83 (3H, d, J ¼ 6:6 Hz), 1.00 (3H, d, J ¼ 6:6 Hz),

2.40–2.58 (1H, m), 3.68 (1H, d, J ¼ 9:6 Hz), 3.89 (3H, s),

5.64 (1H, br s), 6.90 (1H, s), 7.08–7.13 (2H, m), 7.40

(1H, dd, J ¼ 8:4, 1.6 Hz), 7.47 (1H, s), 7.63–7.67 (3H,

m). Anal. Calcd for C₁₈H₂₀N₂O: C, 77.11; H, 7.19; N,

9.99. Found: C, 76.92; H, 6.99; N, 10.01.

1

1177, 1159, 1136, 1034, 851, 747, 700 cm^ꢀ1. H NMR

(CDCl₃) d: 1.76 (3H, s), 2.08 (3H, s), 3.89 (3H, s), 6.50

(1H, d, J ¼ 1:4 Hz), 7.08–7.19 (9H, m), 7.23–7.31 (10H,

m), 7.42 (1H, d, J ¼ 1:6 Hz), 7.56 (1H, d, J ¼ 1:2 Hz),

7.62 (1H, d, J ¼ 2:8 Hz), 7.66 (1H, d, J ¼ 4:2 Hz).

6.37. (1H-Imidazol-4-yl)-(6-methoxy-2-naphthyl)metha-

nol (26)

6.33. 4-[1-(6-Methoxy-2-naphthyl)vinyl]-1H-imidazole

(24a)

A solution of 18 (424 mg, 0.85 mmol) in 90% HCO₂H

(3 mL) was stirred for 45 min at 50 ꢁC. The mixture

was diluted with 1 N HCl and the precipitate was ﬁltered

oﬀ. The aqueous ﬁltrate was washed with Et₂O,

neutralized with K₂CO₃and extracted with several

portions of CHCl₃–MeOH (10:1). The combined

Prepared from 23a by the procedure described for the

synthesis of 21 in 84% yield. Colourless crystals. Mp

198–200 ꢁC (THF–hexane). IR (KBr): 2625, 1603, 1466,

1260, 1217, 1026, 891, 839, 814 cm^ꢀ1. ¹H NMR (CDCl₃)

d: 3.94 (3H, s), 4.31 (1H, br s), 5.33 (1H, s), 5.73 (1H, s),

4328

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

organic layers were concentrated and the residue was

puriﬁed by column chromatography on silica gel using

CHCl₃–MeOH ¼ 5:1 as an eluent to give 26 (153 mg,

71%) as colourless crystals. Mp 162.5–163.5 ꢁC

(THF–hexane). IR (KBr): 3106, 2998, 1611, 1264, 1198,

AcOEt. The organic layers were combined, dried over

MgSO₄and concentrated and the residue was puriﬁed

by column chromatography on silica gel using AcOEt–

hexane ¼ 3:1 to 1:1 as an eluent to give 27i (1.04 g, 88%)

as colourless crystals. Mp 120–121 ꢁC (AcOEt). IR

(KBr): 3167, 1742, 1609, 1485, 1447, 1265, 1165, 1132,

1161, 1032, 847 cm^ꢀ^{1 1}H NMR (CDCl₃+CD₃OD) d:

.

1

1.94 (1H, s), 3.92 (3H, s), 5.94 (1H, s), 6.69 (1H, s),

7.11–7.17 (2H, m), 7.48 (1H, dd, J ¼ 8:5, 1.7 Hz), 7.56

(1H, d, J ¼ 1:0 Hz), 7.70 (1H, s), 7.75 (1H, d,

J ¼ 1:8 Hz), 7.84 (1H, s). Anal. Calcd for C₁₅H₁₄N₂O₂:

C, 70.85; H, 5.55; N, 11.02. Found: C, 70.77; H, 5.49; N,

10.76.

1030, 889, 849, 756, 700 cm^ꢀ1. H NMR (DMSO-d₆) d:

3.85 (3H, s), 6.49 (1H, s), 6.83 (1H, d, J ¼ 1:4 Hz), 7.11–

7.15 (7H, m), 7.25 (1H, d, J ¼ 1:4 Hz), 7.37–7.43 (13H,

m), 7.67–7.74 (3H, m), 8.44–8.47 (2H, m). Anal. Calcd

for C₄₀H₃₂N₂O₂Æ0.4H₂O: C, 82.85; H, 5.70; N, 4.83.

Found: C, 82.82; H, 5.74; N, 4.67.

6.38. Introduction of alkyl or aryl group into 22. 1-(6-

Methoxy-2-naphthyl)-1-(1-trityl-1H-imidazol-4-yl)etha-

nol (27a)

6.41. (6-Methoxy-2-naphthyl)-3-pyridyl-(1-trityl-1H-imid-

azol-4-yl)methanol (27j)

Prepared from 22 and 3-bromopyridine by a similar

procedure to that described for the synthesis of 27i in

83% yield. Colourless crystals. Mp 170 ꢁC decomp

(AcOEt–hexane). IR (KBr): 3216, 1609, 1485, 1443,

To a solution of 22 (2.50 g, 5.1 mmol) in THF (20 mL)

was added methylmagnesium bromide (3.0 M solution

in Et₂O, 3.4 mL, 10.1 mmol) dropwise with ice-cooling.

The mixture was stirred for 20 min, diluted with satu-

rated NH₄Cl and extracted with several portions of

AcOEt. The organic layers were combined, dried over

MgSO₄and concentrated to give 27a (2.51 g, 97%) as

colourless crystals. Mp 169–170 ꢁC (AcOEt–hexane). IR

(KBr): 3150, 1605, 1493, 1445, 1264, 1177, 1165, 909,

1385, 1269, 1171, 1067, 1028, 878, 849, 748, 702 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 3.90 (3H, s), 6.40 (1H, d,

J ¼ 1:4 Hz), 7.09–7.23 (9H, m), 7.27–7.41 (10H, m), 7.50

(1H, d, J ¼ 1:6 Hz), 7.57–7.65 (3H, m), 7.70–7.76 (1H,

m), 8.47 (1H, dd, J ¼ 4:8, 1.6 Hz), 8.54 (1H, d,

J ¼ 2:2 Hz). Anal. Calcd for C₃₉H₃₁N₃O₂Æ0.3H₂O: C,

80.89; H, 5.50; N, 7.26. Found: C, 80.82; H, 5.50; N,

7.04.

1

747, 733, 702 cm^ꢀ1. H NMR (CDCl₃) d: 1.85 (3H, s),

3.62 (1H, br s), 3.90 (3H, s), 6.77 (1H, d, J ¼ 1:4 Hz),

7.09 (1H, s), 7.13–7.21 (7H, m), 7.30–7.36 (9H, m), 7.41

(1H, d, J ¼ 1:4 Hz), 7.45 (1H, dd, J ¼ 8:7, 1.8 Hz), 7.62–

7.69 (2H, m), 7.80 (1H, d, J ¼ 1:6 Hz). Anal. Calcd for

C₃₅H₃₀N₂O₂: C, 82.33; H, 5.92; N, 5.49. Found: C,

82.18; H, 5.89; N, 5.39.

6.42. (6-Methoxy-2-naphthyl)-4-pyridyl-(1-trityl-1H-imid-

azol-4-yl)methanol (27k)

Prepared from 22 and 4-bromopyridine by a similar

procedure to that described for the synthesis of 27i in

75% yield. Colourless crystals. IR (KBr): 1605, 1483,

1447, 1265, 1223, 1169, 1130, 1063, 1036, 762, 748,

6.39. 1-(6-Methoxy-2-naphthyl)-2-methyl-1-(1-trityl-1H-

imidazol-4-yl)propan-1-ol (27d)

1

702 cm^ꢀ1. H NMR (DMSO-d₆) d: 3.85 (3H, s), 6.49

Prepared from 22 and isopropylmagnesium bromide

(2.0 M solution in THF) by a similar procedure to that

described for the synthesis of 27a in 56% yield. Mp

186–187 ꢁC (ether). IR (KBr): 1605, 1483, 1445, 1264,

(1H, s), 6.83 (1H, d, J ¼ 1:4 Hz), 7.11–7.15 (7H, m), 7.25

(1H, d, J ¼ 1:4 Hz), 7.37–7.43 (13H, m), 7.67–7.74 (3H,

m), 8.44–8.47 (2H, m). Anal. Calcd for C₃₉H₃₁N₃O₂: C,

81.65; H, 5.45; N, 7.32. Found: C, 81.55; H, 5.35; N,

7.28.

1

1223, 1167, 909, 747, 733, 702 cm^ꢀ1. H NMR (CDCl₃)

d: 0.74 (3H, d, J ¼ 6:8 Hz), 0.94 (3H, d, J ¼ 6:6 Hz),

1.90 (1H, br s), 2.46–2.59 (1H, m), 3.91 (3H, s), 6.80

(1H, d, J ¼ 1:4 Hz), 7.09–7.17 (8H, m), 7.29–7.37 (10H,

m), 7.53 (1H, dd, J ¼ 8:7, 1.7 Hz), 7.62–7.71 (2H, m),

7.93 (1H, d, J ¼ 1:2 Hz). Anal. Calcd for C₃₇H₃₄N₂O₂:

C, 82.50; H, 6.36; N, 5.20. Found: C, 82.29; H, 6.34; N,

5.22.

6.43. Deprotection of the trityl group

Compounds 28a,i,j,k and 29 were prepared from

27a,i,j,k and 22, respectively, by the procedure described

for the synthesis of 26.

6.40. (6-Methoxy-2-naphthyl)(phenyl)(1-trityl-1H-imid-

azol-4-yl)methanol (27i)

6.44. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-

ethanol (28a)

To a solution of bromobenzene (0.85 mL, 8.1 mmol) in

Et₂O (20 mL) was added n-BuLi (1.6 M solution in

hexane, 5.1 mL, 8.1 mmol) dropwise at )78 ꢁC. The

stirring was continued for 20 min and a solution of 22

(1.0 g, 2.0 mmol) in THF (10 mL) was added dropwise.

The mixture was stirred at )78 ꢁC for 30 min, quenched

with water and extracted with several portions of

Yield 74%. Colourless crystals. Mp 159–160 ꢁC

(THF–hexane). IR (KBr): 3200, 1609, 1485, 1453,

1264, 1173, 1115, 1034, 905, 893, 847, 802 cm^ꢀ^{1 1}H

.

NMR (CDCl₃+CD₃OD) d: 1.94 (3H, s), 3.92

(3H, s), 6.88 (1H, s), 7.11–7.16 (2H, m), 7.46 (1H, dd,

J ¼ 8:5, 1.9 Hz), 7.53 (1H, d, J ¼ 1:0 Hz), 7.67 (1H,

d, J ¼ 3:4 Hz), 7.72 (1H, d, J ¼ 5:2 Hz), 7.82 (1H,

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4329

d, J ¼ 1:2 Hz). Anal. Calcd for C₁₆H₁₆N₂O₂: C,

71.62; H, 6.01; N, 10.44. Found: C, 71.44; H, 5.79; N,

10.39.

tion in THF, 8.9 mL, 17.9 mmol) dropwise at )10 ꢁC.

The mixture was stirred for 30 min, diluted with satu-

rated NH₄Cl and extracted with several portions of

AcOEt. The organic layers were combined, dried over

MgSO₄and concentrated and the residue was puriﬁed

by column chromatography on silica gel using CHCl₃–

MeOH ¼ 20:1 to 10:1 as an eluent. The product was

recrystallized from AcOEt to give 28d (1.14 g, 65%) as

colourless crystals. Mp 171–172 ꢁC. IR (KBr): 3140,

6.45. 1H-Imidazol-4-yl-(6-methoxy-2-naphthyl)(phenyl)

methanol (28i)

Yield 67%. Colourless crystals. Mp 180 ꢁC decomp

(AcOEt). IR (KBr): 3362, 2838, 1607, 1389, 1264,

1

2984, 2957, 1464, 1222, 1028, 856, 806, 652 cm^ꢀ1. H

1221, 1167, 1034, 862, 756 cm^ꢀ1

.

¹H NMR (CDCl₃+

NMR (CDCl₃+CD₃OD) d: 0.81 (3H, d, J ¼ 6:8 Hz),

1.00 (3H, d, J ¼ 6:8 Hz), 2.64–2.78 (1H, m), 3.91 (3H, s),

7.00 (1H, d, J ¼ 1:0 Hz), 7.09–7.15 (2H, m), 7.51–7.56

(2H, m), 7.65–7.75 (2H, m), 7.91 (1H, d, J ¼ 1:4 Hz).

Anal. Calcd for C₁₈H₂₀N₂O₂: C,72.95; H, 6.80; N, 9.45.

Found: C, 72.77; H, 6.79; N, 9.31. Compounds 28b,c

and 28e–h were prepared from 29 using the corre-

sponding Grignard reagent by a similar procedure to

that described for the synthesis of 28d.

CD₃OD) d: 3.91 (3H, s), 6.41 (1H, s), 7.08–7.13 (2H,

m), 7.25–7.39 (5H, m), 7.44 (1H, dd, J ¼ 8:7,

1.7 Hz), 7.59 (1H, d, J ¼ 1:2 Hz), 7.63–7.64 (2H, m), 7.68

(1H, d, J ¼ 2:6 Hz). Anal. Calcd for C₂₁H₁₈N₂O₂: C,

76.34; H, 5.49; N, 8.48. Found: C, 76.21; H, 5.30; N, 8.40.

6.46. (1H-Imidazol-4-yl)-(6-methoxy-2-naphthyl)-3-pyr-

idylmethanol (28j)

Yield 78%. Colourless crystals. Mp180 ꢁC decomp

(THF). IR (KBr): 3058, 2840, 1422, 1265, 1167, 1152,

1034, 891, 851, 806 cm^ꢀ1. ¹H NMR (CDCl₃+CD₃OD) d:

3.92 (3H, s), 6.44 (1H, s), 7.12–7.16 (2H, m), 7.25–7.29

(1H, m), 7.43 (1H, dd, J ¼ 8:5, 1.7 Hz), 7.64–7.71 (4H,

m), 7.80 (1H, dd, J ¼ 8:0. 1.6 Hz), 8.44 (1H, dd, J ¼ 3:4.

1.2 Hz), 8.54 (1H, d, J ¼ 2:4 Hz). Anal. Calcd for

C₂₀H₁₇N₃O₂: C, 72.49; H, 5.17; N, 12.68. Found: C,

72.34; H, 5.04; N, 12.44.

6.50. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphthyl)pro-

pan-1-ol (28b)

Yield 42%. Colourless crystals. Mp 168–169 ꢁC (THF–

AcOEt). IR (KBr): 3160, 2971, 1607, 1483, 1265, 1223,

.

1169, 1032, 853 cm^ꢀ^{1 1}H NMR (CDCl₃+CD₃OD) d:

0.87 (3H, t, J ¼ 7:3 Hz), 2.19–2.41 (2H, m), 3.92 (3H, s),

6.91 (1H, d, J ¼ 1:2 Hz), 7.11–7.16 (2H, m), 7.42 (1H,

dd, J ¼ 8:8, 1.2 Hz), 7.54 (1H, d, J ¼ 1:2 Hz), 7.66–7.75

(2H, m), 7.86 (1H, d, J ¼ 1:4 Hz). Anal. Calcd for

C₁₇H₁₈N₂O₂: C, 72.32; H, 6.43; N, 9.92. Found: C,

72.18; H, 6.24; N, 9.82.

6.47. (1H-Imidazol-4-yl)-(6-methoxy-2-naphthyl)-4-pyr-

idylmethanol (28k)

Yield 91%. Colourless crystals. Mp 153–155 ꢁC (AcOEt–

hexane). IR (KBr): 3067, 2840, 1601, 1414, 1265, 1167,

6.51. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-

butan-1-ol (28c)

1

893, 866, 853 cm^ꢀ1. H NMR (CDCl₃+CD₃OD) d: 3.92

(3H, s), 6.50 (1H, d, J ¼ 1:4 Hz), 7.10–7.16 (2H, m), 7.39–

7.44 (3H, m), 7.64–7.72 (4H, m), 8.67 (2H, dd, J ¼ 4:6,

1.6 Hz). Anal. Calcd for C₂₀H₁₇N₃O₂Æ0.3H₂O: C, 71.33;

H, 5.27; N, 12.48. Found: C, 71.31; H, 5.35; N, 12.17.

Yield 20%. Colourless crystals. Mp 164–165 ꢁC

(AcOEt). IR (KBr): 2955, 1605, 1505, 1483, 1265, 1221,

1

1167, 1032, 850 cm^ꢀ1. H NMR (CDCl₃) d: 0.89 (3H, t,

J ¼ 7:3 Hz), 1.10–1.30 (1H, m), 1.37–1.55 (1H, m), 2.20–

2.30 (2H, m), 3.91 (3H, s), 6.90 (1H, s), 7.10–7.15 (2H,

m), 7.45 (1H, dd, J ¼ 8:6, 1.8 Hz), 7.50 (1H, s), 7.65–

7.73 (2H, m), 7.91 (1H, s). Anal. Calcd for

C₁₈H₂₀N₂O₂Æ0.1AcOEt: C, 72.42; H, 6.87; N, 9.18.

Found: C, 72.45; H, 6.78; N, 9.02.

6.48. (1H-Imidazol-4-yl)-(6-methoxy-2-naphthyl)ketone

(29)

Prepared from 22 by the procedure described for

the synthesis of 26 in 84% yield. Colourless crystals.

Mp 200 ꢁC decomp (CHCl₃–MeOH–AcOEt). IR

(KBr): 3146, 2649, 2579, 1636, 1624, 1481, 1346, 1264,

1169, 860 cm^ꢀ1. ¹H NMR (CDCl₃+CD₃OD) d: 3.97 (3H,

s), 7.21–7.26 (2H, m), 7.78 (1H, s), 7.82–7.91 (3H, m),

7.99 (1H, dd, J ¼ 8:5, 1.7 Hz), 8.49 (1H, s). Anal. Calcd

for C₁₅H₁₂N₂O₂Æ0.2H₂O: C, 70.41; H, 4.88; N, 10.95.

Found: C, 70.32; H, 4.62; N, 10.69.

6.52. Cyclopropyl-(1H-imidazol-4-yl)-(6-methoxy-2-

naphthyl)methanol fumarate (28e)

Yield 32%. Isolated as the fumarate salt. Colourless

crystals. Mp 167–168 ꢁC (MeOH). IR (KBr): 3117,

1

1609, 1265, 1227, 1179, 1163, 1063, 851 cm^ꢀ1. H NMR

(DMSO-d₆) d: 0.32–0.62 (4H, m), 1.62–1.76 (1H, m),

2.49–2.52 (1H, m), 3.86 (3H, s), 6.61 (2H, s), 7.04 (1H, d,

J ¼ 1:2 Hz), 7.12 (1H, dd, J ¼ 8:8, 2.4 Hz), 7.25 (1H, d,

J ¼ 2:4 Hz), 7.52 (1H, dd, J ¼ 8:7, 1.7 Hz), 7.65–7.79

(3H, m), 7.89 (1H, s). Anal. Calcd for C₁₈H₁₈-

N₂O₂ÆC₄H₄O₄: C, 64.38; H, 5.40; N, 6.83. Found: C,

64.39; H, 5.33; N, 6.86.

6.49. Introduction of alkyl group into 29. 1-(1H-Imidazol-

4-yl)-1-(6-methoxy-2-naphthyl)-2-methylpropan-1-ol (28d)

To a solution of 29 (1.50 g, 6.0 mmol) in THF (30 mL)

was added isopropylmagnesium bromide (2.0 M solu-

4330

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

6.53. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-3-

methylbutan-1-ol (28f)

6.59. X-ray structure of (R)-28d

An analytical sample of (R)-28d for X-ray analysis was

obtained by recrystallization from AcOEt. The X-ray

measurement was preformed on a Rigaku AFC5R dif-

fractometer with Cu-Ka radiation. Crystal data for (R)-

28d: C₁₈H₂₀N₂O₂, M ¼ 296:4, monoclinic, space group

Yield 71%. Colourless crystals. Mp 172–174 ꢁC (AcOEt-

i-Pr₂O). IR (KBr): 2953, 1607, 1505, 1483, 1466, 1389,

1

1265, 1219, 1169, 1032, 853 cm^ꢀ1. H NMR (CDCl₃) d:

0.72 (3H, d, J ¼ 6:8 Hz), 0.94 (3H, d, J ¼ 6:8 Hz),

1.63–1.82 (1H, m), 2.20 (2H, d, J ¼ 5:8 Hz), 3.90 (3H,

s), 6.82 (1H, s), 7.10–7.14 (2H, m), 7.38 (1H, s), 7.42

(1H, dd, J ¼ 8:4, 1.8 Hz), 7.63–7.72 (2H, m), 7.93

(1H, d, J ¼ 1:4 Hz). Anal. Calcd for C₁₉H₂₂N₂O₂:

C, 73.52; H, 7.14; N, 9.03. Found: C, 73.34; H, 7.35; N,

8.83.

ꢀ

P2₁

(#4), a ¼ 6:601(2) A, b ¼ 7:323(3) A, c ¼

3

ꢀ

16:053(2) A, b ¼95.07(2)ꢁ, V ¼ 773:0(4) A , D_calc

¼

1:273 gcm^ꢀ3, Z ¼ 2; Final R-values were R1 ¼ 0:032 for

2056 reﬂections with Fo > 4r (Fo), wR2 ¼ 0:093 for all

the 2297 reﬂections. The absolute conﬁguration was

supported by the Flack parameter⁴²of 0.04(28). Further

details of the X-ray structure data are available on

request from the Cambridge Crystallographic Data

Centre (deposition number CCDC 230602).

6.54. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-

2,2-dimethylpropan-1-ol fumarate (28g)

Yield 35%. Isolated as the fumarate salt. Pale yellow

crystals. Mp 168–170 ꢁC (EtOH). IR (KBr): 3416,

3152, 2976, 1535, 1391, 1271, 1215, 1167, 899,

6.60. 6-Bromo-2-methoxy-1-naphthaldehyde (30)

Phosphorous oxychloride (32.83 g, 0.214 mol) was

added to DMF (50 mL) with ice-cooling and the mixture

was stirred at room temperature for 0.5 h. Then 5a

(21.10 g, 89 mmol) was added, and the reaction mixture

was stirred at 100 ꢁC for 7 h, cooled to room tempera-

ture, and poured into ice water. The precipitate was

ﬁltered, washed with water and EtOH and recrystallized

from diisopropylether to give 30 (6.20 g, 26%) as col-

ourless crystals. Mp 107 ꢁC. IR (KBr): 1665, 1501, 1269,

851 cm^ꢀ^{1 1}H NMR (CD₃OD) d: 1.06 (9H, s), 3.89

.

(3H, s), 6.71 (2H, s), 7.62 (1H, dd, J ¼ 8:8, 2.0 Hz),

7.69–7.70 (2H, m), 7.80 (1H, d, J ¼ 1:2 Hz), 7.93 (1H,

s), 8.50 (1H, s). Anal. Calcd for C₁₉H₂₂N₂O₂ÆC₄H₄O₄: C,

64.78; H, 6.14; N, 6.57. Found: C, 64.65; H, 6.07; N,

6.50.

6.55. Cyclopentyl-(1H-imidazol-4-yl)-(6-methoxy-2-

naphthyl)methanol (28h)

1

1154 cm^ꢀ1. H NMR (CDCl₃) d: 4.06 (3H, s), 7.33 (1H,

d, J ¼ 9:2 Hz), 7.66 (1H, dd, J ¼ 2:2, 9.2 Hz), 7.93 (1H,

d, J ¼ 2:2 Hz), 7.96 (1H, d, J ¼ 9:2 Hz), 9.18 (1H, d,

J ¼ 9:2 Hz). Anal. Calcd for C₁₂H₉BrO₂: C, 54.37; H,

3.42. Found: C, 54.22; H, 3.38.

Yield 10%. Colourless crystals. Mp 177–178 ꢁC

(AcOEt). IR (KBr): 2959, 1607, 1483, 1265, 1221,

1

1169, 1032, 851 cm^ꢀ1. H NMR (CDCl₃) d: 1.72–1.34

(8H, m), 2.92–3.06 (1H, m), 3.90 (3H, s), 7.02 (1H, s),

7.09–7.14 (2H, m), 7.51–7.56 (2H, m), 7.63–7.74 (2H,

m), 7.97 (1H, s). Anal. Calcd for C₂₀H₂₂N₂O₂Æ0.1H₂O:

C, 74.09; H, 6.90; N, 8.64. Found: C, 73.97; H, 6.76; N,

8.66.

6.61. (6-Bromo-2-methoxy-1-naphthyl)methanol (31)

To a solution of 30 (4.07 g, 15.4 mmol) in MeOH

(50 mL) was added NaBH₄(1.30 g, 34.4 mmol) with ice-

cooling. The mixture was stirred at room temperature

for 0.5 h and concentrated. The residue was partitioned

between AcOEt and water and the organic layer was

separated, dried over MgSO₄and concentrated to give

31 as colourless crystals (3.20 g, 78%). Mp 117 ꢁC

6.56. Optical resolution of 28d

Separation of 28d into its enantiomers was carried out

by HPLC using Chiralpak^ꢂAD (20 mm id ·250 mm)

with detection at 254 nm. Elution with a mixture of n-

hexane–EtOH (70:30) at a ﬂow rate of 8 mL/min at

30 ꢁC gave (S)-28d and (R)-28d, respectively.

(hexane). IR (KBr): 3330, 1589, 1503, 1267, 1250 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 3.98 (3H, s), 5.14 (2H, s), 7.30 (1H,

d, J ¼ 9:2 Hz), 7.57 (1H, dd, J ¼ 2:2, 9.2 Hz), 7.74 (1H,

d, J ¼ 9:2 Hz), 7.95 (1H, d, J ¼ 2:2 Hz), 7.99 (1H, d,

J ¼ 9:2 Hz). Anal. Calcd for C₁₂H₁₁BrO₂: C, 53.96; H,

4.15. Found: C, 54.26; H, 4.05.

6.57. ())-(S)-1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naph-

thyl)-2-methylpropan-1-ol [(S)-28d]

Retention time ¼ 9.26 min (Chiralpak^ꢂAD (4.6 mm id

23

6.62. 6-Bromo-2-methoxy-1-methyl naphthalene (32)

·250 mm), detection at 254 nm, elution with n-hexane–

EtOH (80:20), ﬂow rate of 0.8 mL/min). ½aꢂ )48.4 (c

D

To a mixture of 31 (2.05 g, 7.67 mmol) and Et₃N

(3.2 mL, 23.0 mmol) in THF (20 mL) was added meth-

anesulfonyl chloride (0.9 mL, 11.6 mmol) with ice-cool-

ing. The mixture was stirred at room temperature for 1 h

and concentrated. The residue was partitioned between

AcOEt and water and the separated organic layer was

dried over Na₂SO₄and concentrated. The residue was

dissolved in DMSO (20 mL) and the solution was stirred

0.5, MeOH). Mp 179–181 ꢁC (AcOEt).

6.58. (+)-(R)-1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naph-

thyl)-2-methylpropan-1-ol [(R)-28d]

Retention time ¼ 24.84 min (the same conditions for the

23

analysis of (S)-28d). ½aꢂ +46.7 (c 0.5, MeOH).

D

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4331

at room temperature for 1 h with NaI (1.49, 9.90 mmol).

Then NaBH₄(1.09 g, 28.8 mmol) was added and the

mixture was stirred at room temperature for an addi-

tional 1 h, poured into water and extracted with AcOEt.

The extract was washed with water, dried over Na₂SO₄

and concentrated. The residue was chromatographed on

silica gel using hexane as an eluent to give 32 (1.16 g,

60%) as colourless crystals. Mp 71–72 ꢁC. IR (KBr):

diluted with aqueous NH₄Cl and extracted with AcOEt.

The extract was dried over MgSO₄and concentrated

and the residue was chromatographed on silica gel using

CH₂Cl₂–MeOH ¼ 15:1 as an eluent to give 36a (0.18 g,

53%) as colourless crystals. Mp 156–160 ꢁC. IR (KBr):

1

2967, 1267, 1254, 1105, 816 cm^ꢀ1. H NMR (CDCl₃) d:

0.81 (3H, d, J ¼ 6:8 Hz), 1.01 (3H, d, J ¼ 6:8 Hz), 2.52

(3H, s), 2.60–2.80 (1H, m), 3.92 (3H, s), 6.98 (1H, d,

J ¼ 1:0 Hz), 7.24 (1H, d, J ¼ 9:2 Hz), 7.48 (1H, d,

J ¼ 1:0 Hz), 7.59 (1H, dd, J ¼ 2:0, 9.0 Hz), 7.69 (1H, d,

J ¼ 9:2 Hz), 7.87 (1H, d, J ¼ 9:0 Hz), 7.97 (1H, d,

J ¼ 2:0 Hz). Anal. Calcd for C₁₉H₂₂N₂O₂: C, 73.52; H,

7.14; N, 9.03. Found: C, 73.46; H, 7.26; N, 8.94.

1588, 1499, 1264, 1250, 1103, 883 cm^ꢀ1

.

¹H NMR

(CDCl₃) d: 2.52 (3H, s), 3.94 (3H, s), 7.25 (1H, d,

J ¼ 9:0 Hz), 7.52 (1H, dd, J ¼ 1:8, 9.0 Hz), 7.61 (1H, d,

J ¼ 9:0 Hz), 7.81 (1H, d, J ¼ 9:0 Hz), 7.92 (1H, d,

J ¼ 1:8 Hz). Anal. Calcd for C₁₂H₁₁BrO: C, 57.39; H,

4.42. Found: C, 57.67; H, 4.38.

6.66. 1-(5,6-Dimethoxy-2-naphthyl)-1-(1H-imidazol-4-

yl)-2-methylpropan-1-ol (36b)

6.63. 6-Bromo-2-methoxy-1-naphthyl formate (33)

To a solution of 30 (1.15 g, 4.3 mmol) in CH₂Cl₂

(100 mL) was added 3-chloroperoxybenzoic acid (1.70 g,

9.9 mmol) with ice-cooling, and the stirring was con-

tinued for 2 h. The mixture was diluted with aqueous

NaHCO₃, and the layers were separated. The organic

layer was washed with brine, dried over MgSO₄and

concentrated and the residue was washed with AcOEt to

give 33 (0.96 g, 78%) as colourless crystals. Mp 149 ꢁC

(hexane). IR (KBr): 1728, 1591, 1499, 1281, 1177, 1140,

Prepared from 34 and 35 by a similar procedure to that

described for the synthesis of 36a in 53% yield. Mp 103–

108 ꢁC. IR (KBr): 2969, 1360, 1270, 1100, 1061,

733 cm^ꢀ1. ¹H NMR (CDCl₃) d: 0.80 (3H, d, J ¼ 6:8 Hz),

1.00 (3H, d, J ¼ 6:8 Hz), 2.60–2.80 (1H, m), 3.96 (3H, s),

6.97 (1H, d, J ¼ 1:1 Hz), 7.24 (1H, d, J ¼ 8:8 Hz), 7.46

(1H, d, J ¼ 1:1 Hz), 7.56 (1H, dd, J ¼ 1:8, 8.8 Hz), 7.98

(1H, d, J ¼ 1:8 Hz), 8.02 (1H, d, J ¼ 8:8 Hz). Anal.

Calcd for C₁₉H₂₂N₂O₃Æ0.1H₂O: C, 69.53; H, 6.82; N,

8.54. Found: C, 69.34; H, 6.84; N, 8.63.

1

1084 cm^ꢀ1. H NMR (CDCl₃) d: 3.96 (3H, s), 7.36 (1H,

d, J ¼ 9:0 Hz), 7.56 (1H, dd, J ¼ 1:8, 8.8 Hz), 7.68 (1H,

d, J ¼ 9:0 Hz), 7.72 (1H, d, J ¼ 8:8 Hz), 7.97 (1H, d,

J ¼ 1:8 Hz), 8.42 (1H, s). Anal. Calcd for C₁₂H₉BrO₃: C,

51.27; H, 3.23. Found: C, 50.97; H, 3.30.

6.67. Ethyl 6,7-dimethoxy-2-naphthoate (38)

To a solution of LDA (0.57 M in THF, 70 mL) was

added 9 (5.71 g, 30 mmol) dropwise at )78 ꢁC and the

stirring was continued for 1 h. A solution of 3,4-di-

methoxybenzaldehyde (37, 4.98 g, 30 mmol) in THF

(10 mL) was added, and the mixture was allowed to

warm to room temperature, quenched with water, ex-

tracted with AcOEt. The extract was dried over MgSO₄

and concentrated and the residue was dissolved in EtOH

(30 mL). This solution was added to reﬂuxing 20%

H₂SO₄(300 mL), and the reﬂux was continued for an

additional 2 h. The reaction mixture was cooled to room

temperature and extracted with several portions of

AcOEt. The organic layers were combined, dried over

MgSO₄and concentrated and the residue was chroma-

tographed on silica gel using hexane–AcOEt (4:1) as an

eluent. The product was recrystallized from hexane–

AcOEt to give 38 (3.53 g 45%) as colourless crystals. Mp

6.64. 6-Bromo-1,2-dimethoxynaphthalene (34)

A mixture of 33 (757 mg, 2.69 mmol), LiOHÆH₂O

(176 mg, 4.19 mmol), ethanol (8 mL) and water (4 mL)

was stirred at 60 ꢁC for 2 h. After removal of the solvent,

the residue was dissolved in DMF (10 mL) and K₂CO₃

(483 mg, 3.49 mmol) and MeI (0.5 mL, 8.03 mmol) were

added. The mixture was stirred at room temperature for

6 h, diluted with water and extracted with AcOEt. The

extract was washed with water, dried over MgSO₄and

concentrated and the residue was chromatographed on

silica gel using hexane–AcOEt ¼ 20:1 as an eluent to give

34 (223 mg, 31%) as colourless needles. Mp 57 ꢁC. IR

1

(KBr): 1588, 1354, 1273, 1069 cm^ꢀ1. H NMR (CDCl₃)

d: 3.98 (3H, s), 3.99 (3H, s), 7.29 (1H, d, J ¼ 8:8 Hz),

7.49 (1H, d, J ¼ 8:8 Hz), 7.51 (1H, dd, J ¼ 1:8, 8.8 Hz),

7.92 (1H, d, J ¼ 1:8 Hz), 7.99 (1H, d, J ¼ 8:8 Hz). Anal.

Calcd for C₁₂H₁₁BrO₂: C, 53.96; H, 4.15. Found: C,

53.79; H, 4.13.

109 ꢁC. IR (KBr): 2978, 1713, 1489, 1238 cm^ꢀ1

.

¹H

NMR (CDCl₃) d: 1.44 (3H, t, J ¼ 7:2 Hz), 4.01 (3H, s),

4.02 (3H, s), 4.42 (2H, q, J ¼ 7:2 Hz), 7.14 (1H, s), 7.21

(1H, s), 7.70 (1H, d, J ¼ 8:5 Hz), 7.94 (1H, dd, J ¼ 8:5,

1.8 Hz), 8.45 (1H, m). Anal. Calcd for C₁₅H₁₆O₄: C,

69.22; H, 6.20. Found: C, 69.31; H, 6.33.

6.65. 1-(1H-Imidazol-4-yl)-1-(6-methoxy-5-methyl-2-

naphthyl)-2-methylpropan-1-ol (36a)

6.68. (6,7-Dimethoxy-2-naphthyl)methanol (39)

To a solution of 32 (0.95 g, 3.8 mmol) in THF (15 mL)

was added n-BuLi (1.6 M in hexane, 3.0 mL, 4.8 mmol)

at )78 ꢁC, and the stirring was continued for 1 h. A

solution of 35³⁷(0.16 g, 1.1 mmol) in THF (10 mL) was

added and the mixture was stirred at )78 ꢁC for 1 h,

To a suspension of LiAlH₄(2.77 g, 73.0 mmol) in THF

(200 mL) was added 38 (14.30 g, 54.9 mmol) portionwise

with ice-cooling. The mixture was stirred for 0.5 h,

and the reaction was quenched by the addition of

4332

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

water. Then AcOEt and 1 N HCl were added, and the

layers were separated. The organic layer was washed

with brine, dried over MgSO₄and concentrated. The

residue was recrystallized from hexane–AcOEt to

give 39 (9.73 g, 81%) as colourless crystals. Mp 111–

112 ꢁC (i-Pr₂O–AcOEt). IR (KBr): 3299, 1514, 1497,

1262, 1161, 856 cm^ꢀ1. ¹H NMR (CDCl₃) d: 3.99 (3H, s),

4.00 (3H, s), 4.80 (2H, s), 7.10 (1H, s), 7.11 (1H, s), 7.33

(1H, dd, J ¼ 8:4, 1.8 Hz), 7.60–7.72 (2H, m). Anal.

Calcd for C₁₃H₁₄O₃: C, 71.54; H, 6.47. Found: C, 71.57;

H, 6.42.

66%) as colourless crystals. Mp 162–163 ꢁC (AcOEt–

hexane). IR (KBr): 3322, 2965, 1510, 1254, 1163,

731 cm^ꢀ1. ¹H NMR (CDCl₃) d: 0.81 (3H, d, J ¼ 6:6 Hz),

1.00 (3H, d, J ¼ 6:6 Hz), 2.60–2.78 (1H, m), 3.96 (3H, s),

3.97 (3H, s), 6.98 (1H, d, J ¼ 1:0 Hz), 7.07 (1H, s), 7.11

(1H, s), 7.41–7.49 (2H, m), 7.61 (1H, d, J ¼ 8:4 Hz), 7.89

(1H, d, J ¼ 1:4 Hz). Anal. Calcd for C₁₉H₂₂N₂O₃: C,

69.92; H, 6.79; N, 8.58. Found: C, 69.83; H, 6.76; N,

8.42.

6.72. Optical resolution of 42

6.69. 6,7-Dimethoxy-2-naphthaldehyde (40)

Separation of 42 into its enantiomers was carried out by

HPLC using Chiralpak^ꢂAD (50 mm id · 500 mm) with

detection at 254 nm. Elution with a mixture of n-hex-

ane–EtOH (85:15) at a ﬂow rate of 60 mL/min at 40 ꢁC

gave (S)-42 and (R)-42, respectively.

A mixture of 39 (9.26 g, 42.5 mmol) and MnO₂(9.37 g)

in CH₂Cl₂(100 mL) was stirred at room temperature for

48 h. The mixture was ﬁltered through Celite, and the

ﬁltrate was concentrated to give 40 as colourless crystals

(7.40 g, 81%). Mp 95–97 ꢁC (AcOEt–hexane–i-Pr₂). IR

1

(KBr): 1688, 1487, 1211, 1157 cm^ꢀ1. H NMR (CDCl₃)

6.73. ())-(S)-1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-

imidazol-4-yl)-2-methylpropan-1-ol [(S)-42]

d: 4.04 (6H, s), 7.17 (1H, s), 7.26 (1H, s), 7.76 (1H, d,

J ¼ 8:4 Hz), 7.83 (1H, dd, J ¼ 8:4, 1.6 Hz), 8.19 (1H,

m). Anal. Calcd for C₁₃H₁₂O₃: C, 72.21; H, 5.59. Found:

C, 72.20; H, 5.72.

An amorphous solid. Retention time ¼ 14.9 min

(Chiralpak^ꢂAD (4.6 mm id · 250 mm), detection at

254 nm, elution with n-hexane–EtOH (85:15), ﬂow rate

of 1.0 mL/min).

6.70. (6,7-Dimethoxy-2-naphthyl)(1H-imidazol-4-yl)-

methanone (41)

6.74. (+)-(R)- 1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-

imidazol-4-yl)-2-methylpropan-1-ol [(R)-42]

To a solution of 4-bromoimidazole (2.01 g, 13.7 mmol)

in THF (35 mL) was added t-BuLi (1.7 M in pentane,

22.0 mL, 37.4 mmol) at )78 ꢁC. The mixture was allowed

to warm to 0 ꢁC and stirred for 1.5 h. Then the mixture

was cooled to )78 ꢁC, and a solution of 40 (3.84 g,

17.8 mmol) in THF (20 mL) was added dropwise. The

mixture was warmed to room temperature, stirred for an

additional 16 h, quenched with aqueous NH₄Cl, and

extracted with AcOEt. The extract was dried over

MgSO₄and concentrated, and the residue was chro-

matographed on silica gel using CH₂Cl₂–MeOH

(20:1) as an eluent to give 41 (1.31 g, 34%) as colourless

crystals. Mp 232 ꢁC. IR (KBr): 3088, 1636, 1508, 1489,

1260, 1159, 883 cm^ꢀ1. ¹H NMR (CDCl₃) d: 3.93 (3H, s),

3.94 (3H, s), 7.39 (1H, s), 7.53 (1H, s), 7.80–8.03 (5H,

m), 8.72 (1H, br s). Anal. Calcd for C₁₆H₁₄N₂O₃: C,

68.07; H, 5.00; N, 9.92. Found: C, 67.96; H, 4.74; N,

9.88.

An amorphous solid. Retention time ¼ 29.3 min (the

same conditions for the analysis of (S)-42).

6.75. (S)-42 Fumarate

To a solution of (S)-42 (8.5 mmol) in methanol (10 mL)

was added fumaric acid (8.6 mmol). The mixture was

concentrated to ca half its volume, and then diluted with

AcOEt (10 mL). The crystals that separated out of the

solution were collected by ﬁltration to give (S)-42

fumarate (69%). Mp 116–120 ꢁC. ½a²⁰ꢂ )35.3 (c 1.01,

MeOH). Anal. Calcd for C₁₉H₂₂N₂O₃Æ^DC₄H₄O₄Æ0.5H₂O:

C, 61.19; H, 6.03; N, 6.20. Found: C, 61.01; H, 5.99; N,

6.19.

Similarly, (R)-42 fumarate was obtained.

6.76. X-ray structure of (S)-42

6.71. 1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-imidazol-4-

yl)-2-methylpropan-1-ol (42)

To a solution of 41 (0.80 g, 2.9 mmol) in THF (20 mL)

was added isopropylmagnesium chloride (2.0 M in THF,

6 mL, 12.0 mmol) dropwise at )30 ꢁC. The mixture was

warmed up to room temperature, diluted with saturated

aqueous NH₄Cl, and made alkaline with 1 N NaOH.

The layers were separated, and the aqueous layer was

further extracted with AcOEt. The organic layers were

combined, dried over MgSO₄and concentrated and the

residue was chromatographed on silica gel using

CH₂Cl₂–MeOH (20:1) as an eluent to give 42 (0.61 g,

An analytical sample of (S)-42 as the salt with ())-(4S)-

5,5-dimethyl-2-hydroxy-4-phenyl-1,3,2-dioxaphosphor-

inane 2-oxide for X-ray analysis was obtained by

recrystallization from MeOH. The X-ray measurement

was preformed on a Rigaku AFC5R diﬀractometer with

Cu-Ka radiation. Crystal data for this salt:

[C₁₉H₂₃N₂O₃]^þ[C₁₁H₁₄O₄P]^ꢀÆ2CH₃OH,

M ¼ 632:7,

ꢀ

monoclinic, space group C2 (#5), a ¼ 36:232(3) A,

ꢀ

b ¼ 6:604(2) A, c ¼ 15:732(2) A, b ¼ 114:619(9)ꢁ, V ¼

3422:3(9) A , D_calc¼ 1:228 gcm^ꢀ3, Z ¼ 4; Final R-values

3

ꢀ

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4333

were R1 ¼ 0:043 for 4216 reﬂections with Fo>4r (Fo),

6.79. 7-Bromo-1,2-dihydronaphtho[2,1-b]furan (46)

wR2 ¼ 0:116 for all the 5888 reﬂections. The absolute

conﬁguration was determined by the Flack parameter⁴²

of 0.00(3). Further details of the X-ray structure data

are available on request from the Cambridge Crystal-

lographic Data Centre (deposition number CCDC

231387).

A mixture of 45 (30.2 g, 113 mmol), p-toluenesulfonic

acid (0.49 g, 2.57 mmol) and toluene (500 mL) was ref-

luxed for 2 h. After removal of the solvent, the residue

was partitioned between AcOEt and water. The organic

layer was separated, washed with saturated aqueous

NaHCO₃, dried over Na₂SO₄and concentrated, and the

residue was chromatographed on silica gel using hex-

ane–CH₂Cl₂¼ 2:1 as an eluent to give 46 (8.12 g, 34%) as

colourless crystals. Mp 64 ꢁC. IR (KBr): 2922, 1510,

6.77. 1-Allyl-6-bromo-2-naphthol (44)

1

1348, 1244, 970, 878 cm^ꢀ1. H NMR (CDCl₃) d: 3.45

To a solution of NaH (60% oil dispersion, 4.97 g,

124 mmol) in DMF (150 mL) was added 43 (20.09 g,

90.1 mmol) with ice-cooling, and the stirring was con-

tinued at room temperature for 0.5 h. Then 3-bromo-1-

propene (12.0 mL, 138.7 mmol) was added, and the

reaction mixture was stirred at room temperature for

16 h and then poured into water and Et₂O. The organic

layer was separated, dried over MgSO₄and concen-

trated and the residue was washed with n-hexane to give

2-(allyloxy)-6-bromonaphthalene (21.67 g, 91%) as col-

ourless crystals. Mp 65 ꢁC (hexane). IR (KBr): 2901,

(2H, t, J ¼ 9:0 Hz), 4.75 (2H, t, J ¼ 9:0 Hz), 7.11 (1H, d,

J ¼ 8:8 Hz), 7.43 (1H, d, J ¼ 8:8 Hz), 7.47–7.60 (2H, m),

7.93 (1H, d, J ¼ 1:9 Hz). Anal. Calcd for C₁₂H₉BrO: C,

57.86; H, 3.64. Found: C, 57.92; H, 3.37.

6.80. 1-(1,2-Dihydronaphtho[2,1-b]furan-7-yl)-1-(1H-imid-

azol-4-yl)-2-methylpropan-1-ol (47)

Prepared from 46 and 35 by a similar procedure to that

described for the synthesis of 36a in 48% yield. Mp 177–

178 ꢁC (AcOEt). IR (KBr): 3125, 2967, 1470, 1244, 970,

1

1591, 1499, 1458, 1262, 1022 cm^ꢀ1. H NMR (CDCl₃):

4.60–4.70 (2H, m), 5.26–5.54 (2H, m), 6.00–6.23 (1H,

m), 7.10 (1H, d, J ¼ 2:6 Hz), 7.19 (1H, dd, J ¼ 2:6,

8.9 Hz), 7.49 (1H, dd, J ¼ 1:8, 8.9 Hz), 7.59 (1H, d,

J ¼ 8:9 Hz), 7.65 (1H, d, J ¼ 8:9 Hz), 7.92 (1H, d,

J ¼ 1:8 Hz). Anal. Calcd for C₁₃H₁₁BrO: C, 59.34; H,

4.21. Found: C, 59.41; H, 3.98.

909, 731 cm^ꢀ1

.

¹H NMR (CDCl₃) d: 0.81 (3H, d,

J ¼ 6:6 Hz), 1.00 (3H, d, J ¼ 6:6 Hz), 2.61–2.78 (1H, m),

3.45 (2H, t, J ¼ 9:0 Hz), 4.74 (2H, t, J ¼ 9:0 Hz), 6.98

(1H, t, J ¼ 0:8 Hz), 7.08 (1H, t, J ¼ 8:8 Hz), 7.46–7.78

(4H, m), 7.99 (1H, d, J ¼ 1:6 Hz). Anal. Calcd for

C₁₉H₂₀N₂O₂Æ0.2H₂O: C, 73.15; H, 6.59; N, 8.98. Found:

C, 73.26; H, 6.46; N, 8.78.

This compound (19.95 g, 76 mmol) was heated at 190 ꢁC

for 3 h and cooled to room temperature to give 44

(19.78 g, quantitative yield) as colourless crystals. Mp

86–87 ꢁC. IR (KBr): 3314, 1590, 1497, 1346, 1204,

6.81. 2,3-Dihydro-1-benzofuran-5-carbaldehyde (50)

1

878 cm^ꢀ1. H NMR (CDCl₃) d: 3.79 (2H, dt, J ¼ 5:4;

To a solution of 49⁴⁵(38.86 g, 195 mmol) in THF

(300 mL) was added n-BuLi (1.6M in hexane, 160 mL,

256 mmol) at )78 ꢁC, and the stirring was continued for

0.5 h. Then DMF (40 mL) was added, and the mixture

was allowed to warm to room temperature. The reac-

tion was quenched by the addition of water, and the

mixture was extracted with AcOEt. The extract was

washed with water and brine, dried over MgSO₄and

concentrated to give 50 as an oil (28.47 g, 98%). ¹H

NMR (CDCl₃) d: 3.27 (2H, t, J ¼ 8:8 Hz), 4.69 (2H, t,

J ¼ 8:8 Hz), 6.87 (1H, d, J ¼ 8:4 Hz), 7.62–7.71 (1H, m),

7.74 (1H, d, J ¼ 1:2 Hz), 9.83 (1H, s).

1.6 Hz), 4.95–5.16 (3H, m), 5.92–6.16 (1H, m), 7.10 (1H,

d, J ¼ 9:1 Hz), 7.52 (1H, dd, J ¼ 8:8; 2.2 Hz), 7.57 (1H,

d, J ¼ 9:1 Hz), 7.76 (1H, d, J ¼ 8:8 Hz), 7.92 (1H, d,

J ¼ 2:2 Hz). Anal. Calcd for C₁₃H₁₁BrO: C, 59.34; H,

4.21. Found: C, 59.63; H, 4.19.

6.78. 6-Bromo-1-(2-hydroxyethyl)-2-naphthol (45)

Ozone gas was introduced into a cooled ()78 ꢁC) solu-

tion of 44 (3.29 g, 12.5 mmol) in MeOH (80 mL) and the

reaction mixture was stirred at )78 ꢁC for 4 h. Then

NaBH₄(1.00 g, 26.4 mmol) was added, and the whole

mixture was allowed to warm to room temperature,

concentrated and then partitioned between AcOEt and

water. The organic layer was separated, dried over

MgSO₄and concentrated and the residue was chroma-

tographed on silica gel using hexane–AcOEt ¼ 3:1 as an

eluent. The product was recrystallized from hexane–

AcOEt to give 45 (0.81 g, 24%) as colourless crystals.

Mp 144 ꢁC. IR (KBr): 3196, 1519, 1501, 1348, 1038,

812 cm^ꢀ1. ¹H NMR (CDCl₃) d: 2.32 (1H, br s), 3.30 (2H,

t, J ¼ 5:4 Hz), 4.09 (2H, t, J ¼ 5:4 Hz), 7.20 (1H, d,

J ¼ 8:8 Hz), 7.51 (1H, dd, J ¼ 2:2, 9.2 Hz), 7.58 (1H, d,

J ¼ 8:8 Hz), 7.70 (1H, d, J ¼ 9:2 Hz), 7.78 (1H, br s),

7.93 (1H, d, J ¼ 2:2 Hz). Anal. Calcd for C₁₂H₁₁BrO₂:

C, 53.96; H, 4.15. Found: C, 53.79; H, 4.40.

6.82. Ethyl 2,3-dihydronaphtho[2,3-b]furan-6-carboxylate

(51)

To a solution of LDA (0.70 M in THF, 310 mL) was

added a solution of 9 (30.50 g, 162 mmol) in THF

(50 mL) dropwise at )78 ꢁC, and the stirring was con-

tinued for 1 h. A solution of 50 (25.85 g, 174.5 mmol) in

THF (50 mL) was added, and the mixture was allowed

to warm to room temperature and diluted with water.

The layers were separated, and the aqueous layer was

further extracted with AcOEt. The combined organic

layers were dried over MgSO₄and concentrated, and the

residue was heated at 100 ꢁC with polyphosphoric acid

(141 g) in toluene (500 mL) for 0.5 h. The mixture was

4334

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

poured onto crushed ice and extracted with AcOEt. The

extract was washed with aqueous NaHCO₃, dried over

MgSO₄and concentrated and the residue was chroma-

tographed on silica gel using CH₂Cl₂–hexane (1:1) as an

eluent to give 51(10.15 g, 26%) as colourless crystals. Mp

115 ꢁC (AcOEt–hexane). IR (KBr): 2982, 1703, 1466,

6.87. 1-(2,3-Dihydronaphtho[2,3-b]furan-6-yl)-1-(1H-

imidazol-4-yl)-2-methylpropan-1-ol (56)

Prepared from 55 by the procedure described for the

synthesis of 42 in 51% yield. Mp 186 ꢁC (AcOEt). IR

(KBr): 2973, 1460, 1219, 990, 853 cm^ꢀ^{1 1}H NMR

.

1

1285, 1204, 1096, 868 cm^ꢀ1. H NMR (CDCl₃) d: 1.43

(CDCl₃) d: 0.80 (3H, d, J ¼ 6:7 Hz), 0.99 (3H, d,

J ¼ 6:7 Hz), 2.56–2.77 (1H, m), 3.34 (2H, t, J ¼ 8:1 Hz),

4.62 (2H, t, J ¼ 8:1 Hz), 6.98 (1H, s), 7.04 (1H, s), 7.44

(1H, d, J ¼ 8:8 Hz), 7.50 (1H, s), 7.55–7.66 (2H, m), 7.85

(1H, s). Anal. Calcd for C₁₉H₂₀N₂O₂Æ0.1H₂O: C, 73.57;

H, 6.56; N, 9.03. Found: C, 73.28; H, 6.77; N, 8.83.

(3H, t, J ¼ 7:2 Hz), 3.38 (2H, dt, J ¼ 1:0, 8.5 Hz), 4.42

(2H, q, J ¼ 7:2 Hz), 4.68 (2H, t, J ¼ 8:5 Hz), 7.11 (1H,

s), 7.68 (1H, d, J ¼ 9:2 Hz), 7.72 (1H, s), 7.96 (1H, dd,

J ¼ 1:4, 9.2 Hz), 8.46 (1H, m). Anal. Calcd for

C₁₅H₁₄O₃: C, 74.36; H, 5.82. Found: C, 74.39; H, 5.54.

6.83. 2,3-Dihydronaphtho[2,3-b]furan-6-ylmethanol (52)

6.88. Molecular modeling

Prepared from 51 by the procedure described for the

synthesis of 39 in 89% yield. Mp 177 ꢁC. IR (KBr): 3322,

The amino acid sequence of C_17;20-lyase was aligned to

those of six P450s (CYP2C5, P450cam, P450BM-3,

P450terp, P450eryF and P450nor), which had been

aligned based on their three-dimensional structures.

2901, 1478, 1240, 1034, 988, 866 cm^ꢀ1

.

¹H NMR

(CDCl₃) d: 3.35 (2H, dt, J ¼ 1:4, 8.3 Hz), 4.63 (2H, t,

J ¼ 8:3 Hz), 4.75 (2H, s), 7.07 (1H, s), 7.37 (1H, dd,

J ¼ 1:6, 8.6 Hz), 7.57–7.70 (3H, m). Anal. Calcd

for C₁₃H₁₂O₂: C, 77.98; H, 6.04. Found: C, 77.99; H,

6.14.

According to the alignment, a homology model of C_17;20

-

lyase was constructed based on the crystal structure of

CYP2C5⁴³and P450BM-3.⁴⁴The modeling procedure

was performed using the Homology module of the In-

sight II program (ver. 2000, Molecular Simulation Inc.

San Diego, CA, USA). After connecting the imidazole

nitrogen to the heme iron, a docking mode of (S)-28d

was explored by systematic analysis around the rotat-

able bonds in the inhibitor. During that procedure en-

ergy values were estimated based on the Discover CVFF

force ﬁeld (ver. 98.0, Molecular Simulation Inc. San

Diego, CA, USA). A hydrogen bond between the

inhibitor and the enzyme was then displayed when fol-

lowing two criteria were satisﬁed. The distance between

the proton on the donor atom and the heavy atom

acceptor must be less than a speciﬁed distance, and the

heavy atom donor, the proton and the heavy atom

acceptor must be a minimum angle of 120ꢁ and linear.

6.84. 2,3-Dihydronaphtho[2,3-b]furan-6-carbaldehyde

(53)

Prepared from 52 by the procedure described for the

synthesis of 40 in 72% yield. Mp 158 ꢁC (AcOEt). IR

(KBr): 1698, 1464, 1175, 988, 868 cm^ꢀ^{1 1}H NMR

.

(CDCl₃) d: 3.41 (2H, t, J ¼ 8:7 Hz), 4.71 (2H, t,

J ¼ 8:7 Hz), 7.14 (1H, s), 7.60–7.90 (3H, m), 8.20 (1H,

s), 10.07 (1H, s). Anal. Calcd for C₁₃H₁₀O₂: C, 78.77; H,

5.09. Found: C, 78.47; H, 5.09.

6.85. 2,3-Dihydronaphtho[2,3-b]furan-6-yl(1H-imidazol-

4-yl)methanol (54)

6.89. Assay of inhibitory activity on rat C_17,20-lyase

Prepared from 53 by the procedure described for the

synthesis of 41 in 52% yield. Mp 220 ꢁC (decomp). IR

1

(KBr): 3069, 1460, 1229, 1028, 886, 839 cm^ꢀ1. H NMR

Inhibitory activity against rat C_17;20-lyase was deter-

mined by the method described previously.¹Testes ex-

cised from 13-week old, male SD rats were homogenized

and testicular microsomes were prepared by a series of

centrifugations. The reaction mixture contains 75 mM

phosphate buﬀer (pH 7.4), 7 lg of the microsome pro-

tein, 10 nM [1,2-³H]-17a-hydroxyprogesterone (NEN),

5 mM NADPH (Oriental Yeast) and test compounds in

a total volume of 20 lL. The test compounds were

serially diluted with dimethylformamide, and then 5-

fold diluted with distilled water. Test compound solu-

tion, 5 lL, was added to the reaction mixture. The

reaction was terminated by addition of 40 lL of ethyl

acetate after 15 min incubation at 37 ꢁC, then vortexed

for 30 s and brieﬂy centrifuged. The organic phase,

30 lL, was applied to silica gel thin layer chromatogra-

phy plates (Whatman, LHPK). The substrate and the

products (androstenedione and testosterone) were sep-

arated in the toluene–acetone (7:2) solvent system.

Detection of the spots and measurement of the radio-

activity as PSL were performed with a BAS2000 Bio-

(DMSO-d₆) d: 3.33 (2H, t, J ¼ 8:2 Hz), 4.59 (2H, t,

J ¼ 8:2 Hz), 5.79 (1H, s), 6.79 (1H, s), 7.07 (1H, s), 7.40

(1H, d, J ¼ 8:8 Hz), 7.57 (1H, s), 7.65 (1H, d,

J ¼ 8:8 Hz), 7.70 (1H, s), 7.76 (1H, s). Anal. Calcd for

C₁₆H₁₂N₂O₂Æ0.25AcOEt: C, 71.32; H, 4.93; N, 9.78.

Found: C, 71.17; H, 5.24; N, 10.17.

6.86. 2,3-Dihydronaphtho[2,3-b]furan-6-yl(1H-imidazol-

4-yl)methanone (55)

Prepared from 54 by the procedure described for the

synthesis of 40 in 89% yield. Mp 219–222 ꢁC. IR (KBr):

2892, 1632, 1458, 1171, 1148, 880 cm^ꢀ1

.

¹H NMR

(DMSO-d₆) d: 3.85 (2H, t, J ¼ 8:1 Hz), 4.67 (2H, t,

J ¼ 8:1 Hz), 7.21 (1H, s), 7.80 (1H, d, J ¼ 8:7 Hz), 7.91

(1H, s), 7.94 (2H, s), 8.00 (1H, d, J ¼ 8:7 Hz), 8.71

(1H, s). Anal. Calcd for C₁₆H₁₂N₂O₂Æ0.2H₂O: C,

71.74; H, 4.67; N, 10.46. Found: C, 71.89; H, 4.54; N,

10.45.

N. Matsunaga et al. / Bioorg. Med. Chem. 12 (2004) 4313–4336

4335

image analyzer (FUJIX). The concentration of the test

compounds necessary to reduce the concentration of the

products by 50% (The concentration in the control

group in which no test compound is added is set to

100%.) was calculated.

The serum testosterone concentration was measured by

a radioimmunoassay kit (CIS Diagnostics). Five hours

after the ﬁnal administration, the rats were sacriﬁced by

exsanguination under ether anesthesia. Dorsal and

ventral prostates, seminal vesicles and liver were excised

and weighed. The suppressive eﬀects of test compounds

on the prostate and seminal vesicle weight were ex-

pressed as the relative potency to castration. The eﬀect

on the liver weight was expressed as the percent values

of those of intact rats.

6.90. Assay of inhibitory activity on human C_17,20-lyase

Human C_17;20-lyase was expressed in E. Coli with N-

terminal sequence modiﬁcation (MALLLAVF) as de-

scribed previously.⁴¹The vector pCWori^þwas obtained

as a generous gift from Dr. F. W. Dahlquist (University

of Oregon). The membrane fraction prepared from E.

Coli expressing human C_17;20-lyase was used for the

following assay.

6.93. Assay of inhibitory activity on rat steroid 11b-

hydroxylase

Adrenals excised from SD rats were homogenized, and

mitochondria fraction were prepared by a series of

centrifugation. Rat 11-hydroxylase activity was mea-

sured according to the method described for side-chain

cleavage activity by Uzgiris⁴⁶with some modiﬁcations.

The reaction mixture contains 200 mM mannitol,

4.5 mM HEPES, 2.3 mM potassium phosphate (pH 7.4),

0.1 mM EDTAÆ2K, 0.03% BSA (crystallized, Miles),

4.5 mM NADPH (Oriental Yeast), 11 mM calcium

The reaction mixture contains 75 mM phosphate

buﬀer (pH 7.4), 1 mM magnesium chloride, 0.5 pmol of

recombinant C_17;20-lyase, 0.5 pmol of recombinant

cytochrome b5 (Pan Vera), 20.8 ng of recombinant

NADPH-cytochrome P450 reductase (Pan Vera), 10 nM

[1,2-³H]-17a-hydroxypregnenolone (Amersham), 5 mM

NADPH (Oriental Yeast), and test compounds in a

total volume of 20 lL. The reaction was terminated by

addition of 40 lL of ethyl acetate after 15 min incuba-

tion at 37 ꢁC, then vortexed for 30 s and brieﬂy centri-

fuged. The organic phase, 30 lL, was applied to silica gel

thin layer chromatography plates (Whatman, LHPK).

The substrate and the product (DHEA) were separated

in the cyclohexane–ethyl acetate (3:2) solvent system.

The following procedures were the same as the assay of

rat enzyme inhibitory activity described above, and IC₅₀

value was determined.

chloride, 4 lg of mitochondria protein, 10 nM [1,2-³H]-

~

(11-deoxycortisol,

hydroxy-11-deoxycorticosterone

NEN, dissolved in 0.02% Tween-80) and test com-

pounds in a total volume of 150 lL. The test compounds

were serially diluted with dimethylformamide and 1.5 lL

of them was directly added to the reaction mixture. The

reaction was terminated by addition of 400 lL of ethyl

acetate and 100 lL of distilled water after 30 min incu-

bation at 37 ꢁC, then vortexed for 30 s and brieﬂy cen-

trifuged. The organic phase, 300 lL, were transferred to

new tubes, and evaporated to the dryness with nitrogen

gas. The steroids were dissolved with 30 lL of ethyl

acetate. The whole volume was applied to silica gel thin

layer chromatography plates (Whatman, LHPK). The

substrate and the products (11-deoxycortisol and corti-

sol) were separated in the toluene–acetone (7:2) solvent

system.

6.91. Assay of suppressive eﬀects on testosterone biosyn-

thesis in rats

Test compounds were suspended in 0.5% methylcellu-

lose and orally administered to 9 or 10-week old, male

SD (Sprague–Dawley) rats at a dose of 25 mg/kg. The

rats in the control group received 0.5% methylcellulose.

Blood samples were obtained 2 and 5 h after the

administration. The serum testosterone concentrations

were determined by a speciﬁc radioimmunoassay kit

(Dia Sorin srl, Italy). The percentage of the testosterone

concentration of the group of rats, which received test

compounds to that of the control group was calculated

(T/C, %), and regarded as the inhibitory activity.

Acknowledgements

We thank Drs. A. Miyake and T. Naka for helpful

discussions throughout this work, Ms. M. Adachi for

the salt of (S)-42 with ())-CPA, and Mr. A. Fujishima

and Ms. K. Higashikawa for single-crystal X-ray anal-

ysis.

6.92. Eﬀects on weight of prostate, seminal vesicles and

liver in rat

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Article Doi

C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors

DOI: 10.1016/j.bmc.2004.06.016

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Full text of DOI:10.1016/j.bmc.2004.06.016

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