Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors

Bioorganic & Medicinal Chemistry 9 (2001) 2727–2743

Synthesis and Biological Evaluations of Quinoline-based

HMG-CoA Reductase Inhibitors

Mikio Suzuki,^a,* Hiroshi Iwasaki,^bYoshihiro Fujikawa,^bMasaki Kitahara,^c

Mitsuaki Sakashita^band Ryozo Sakoda^a

^aCentral Research Laboratories, Nissan Chemical Industries, Ltd., 722-1 Tsuboi-cho, Funabashi, Chiba 274-8507, Japan

^bPharmaceuticals Division, Nissan Chemical Industries, Ltd., 7-1, Kanda Nishiki-cho 3-chome, Chiyoda-ku,

Tokyo 101-0054, Japan

^cBiological Research Laboratories, Nissan Chemical Industries, Ltd., 1470Shiraoka, Shiraoka-cho,

Minamisaitama-gun, Saitama 349-0294, Japan

Received 26 April 2001; accepted 10 June 2001

Abstract—Aseries of quinoline-based 3,5-dihydroxyheptenoic acid derivatives were synthesized from quinolinecarboxylic acid

esters by homologation, aldol condensation with ethyl acetoacetate dianion, and reduction of 3-hydroxyketone to evaluate their

ability to inhibit the enzyme HMG-CoAreductase in vitro. In agreement with previous literature, a strict structural requirement

exists on the external ring, and 4-ﬂuorophenyl is the most active in this system. For the central ring, substitution on positions 6, 7,

and 8 of the central quinoline nucleus moderately aﬀected the potency, whereas the alkyl side chain on the 2-position had a more

pronounced inﬂuence on activity. Among the derivatives, NK-104 (pitavastatin calcium), which has a cyclopropyl group as the

alkyl side chain, showed the greatest potency. We found that further modulation and improvement in potency at inhibiting HMG-

CoAreductase was obtained by having the optimal substituents ﬂanking the desmethylmevalonic acid portion, that is, 4-ﬂuor-

Introduction

cokinetic proﬁle.^3a,bAs a result of an early search, the

Merck group found biphenyl compound 1 as a potent

inhibitor, and proposed a structural motif allowing for

high aﬃnity against the target enzyme:⁴the desmethyl-

mevalonic acid portion, the pharmacophore that inter-

acts with the HMG binding domain of the target

enzyme, connected to a benzene ring (central ring) by a

linking element (a two-carbon spacer), ﬂanked on one

side by an aromatic ring (external ring) and on the other

side by an alkyl substituent (side chain).

3-Hydroxy-3-methylglutaryl-coenzyme A(HMG-CoA)

reductase is the major rate-limiting enzyme in choles-

terol biosynthesis. The inhibitors of this enzyme, termed

hypocholesterolemic agents, oﬀer an important remedy

for primary or secondary prevention of various kinds of

atherosclerotic diseases.¹Since the discovery of the

naturally occurring fungal metabolites compactin^2a,b

and lovastatin,^2c,dand the microbially transformed

pravastatin,^2ea HMG-CoAreductase inhibitor has

been the most attractive target for medicinal research-

ers. Because these lead compounds have the structurally

complicated hexahydronaphthalene ring system as a

lipophilic anchor, numerous attempts to ﬁnd a structu-

rally reﬁned artiﬁcial inhibitor with simple aromatic and

heteroaromatic motifs have been undertaken. These

eﬀorts have focused on an enhancement of the in vitro

and in vivo potency, and a reﬁnement of the pharma-

5

Afurther extensive optimization study by Kathawala

on the eﬀects of modulation of substituents R^a, R^b, and

R^cin an indole compound 2 (ﬁve- and six-member ring)

revealed that a 4-ﬂuorophenyl, and an isopropyl, group

are preferable substituents for the external ring and the

side chain, respectively (Fig. 1).

After this report, numerous monocyclic or polycyclic

ring systems have been used as the central ring to eval-

uate their potency. Roth et al.⁶carried out a systema-

tical leading QSAR study on a pyrrole compound 3 to

investigate the eﬀect of a monocyclic ﬁve-member

*Corresponding author. Fax: +81-47-465-9389; e-mail: suzukimi@

nissanchem.co.jp

PII: S0968-0896(01)00198-5

2728

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

heteroaromatic compound. Values of various steric

parameters for the structural requirements of the exter-

nal ring and the alkyl side chain R^awere also elucidated.

Regarding bicyclic ring systems, a limited examination

on a quinoline compound 4 (six- and six-member ring)

was reported by Sliskovic et al.⁷This study demon-

strated that an isopropyl group at position 2 of the

quinoline nucleus (i.e., R^a) is preferable to a methyl or a

dimethylamino, and the substituent R^bat position 6

does not aﬀect the inhibitory activity.

study this eﬀect, we prepared quinoline-based 3,5-dihy-

droxyheptenoic acid derivatives in which the des-

methylmevalonic acid portion was linked through a

trans-ethylene group to the 3-position of the quinoline.

We initially investigated more precisely the eﬀects of

modulation of substituents at other positions of the

central and external ring. Furthermore, comparatively

little eﬀort has been directed toward the modiﬁcation of

the alkyl side chain, despite the signiﬁcant eﬀect this

moiety has in vitro potency. Therefore, we also varied

the substituent at position 2 of the quinoline nucleus in

order to clarify these structural eﬀects in detail.

In this paper, we describe our eﬀorts toward optimiza-

tion of potency using a quinoline as the central ring. To

Chemistry

Synthesis of quinolinecarbaldehyde, 9

Preparation of the key intermediate, aldehyde

9

required for the elaboration of quinoline-based 3,5-

dihydroxyheptenoic acid derivatives, is shown in

Scheme 1. As for the derivative with an alkyl or an aryl

as the 2-position substituent R¹, ester 7 was prepared by

acid catalyzed Friedlander reaction of 2-aminobenzo-

phenone 5 with 3-ketoester 6. Such a bulky 3-ketoester

as methyl pivaloylacetate (i.e., R¹=tert-butyl) gave a

very low yield of the target ester using classical reaction

conditions, with H₂SO₄in acetic acid.⁸Our revised

reaction conditions, with methane sulfonic acid in

reﬂuxing benzene,⁹gave a more moderate yield. The

Dibal reduction and the PCC oxidation of the resulting

ester, 7, aﬀorded aldehyde 9. This aldehyde, with a

methoxy group on the 2-position (R¹=OMe, 9nn), was

prepared via ester 7nn following a slightly modiﬁed

Figure 1.

Scheme 1. Synthesis of 9. Reagents and conditions: (I) H₂SO₄, AcOH, reﬂux or methanesulfonic acid, benzene, reﬂux; (II): DIBAH, toluene,

ꢀ25 ^ꢁC; (III) PCC, AcONa, CH₂Cl₂, rt; (IV) piperidine, reﬂux; (V) POCl₃, reﬂux; (VI) 7nn Na, MeOH, rt; 7oo MeSNa aq, THF, MeOH, reﬂux;

(VII) 8nn: DIBAH, toluene, ꢀ40 ^ꢁC; 8oo DIBAH, toluene, ꢀ75 ^ꢁC; (VIII) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, ꢀ78 ^ꢁC; (IX) DIBAH, CH₂Cl₂, ꢀ78 ^ꢁC;

(X) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, ꢀ78 ^ꢁC; (XI) amine, toluene, 140 ^ꢁC in autoclave; (XII) ZnCl₂, toluene, reﬂux.

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2729

procedure of Tawada et al.¹⁰Condensation reaction of

2-aminobenzophenone 5 (R²=4-F, R³, R⁴and R⁵=H)

with diethyl malonate in the presence of piperidine

furnished 2-quinolone-3-carboxylate 10. Compound 10

was tranformed into chloroester 11 by chlorination with

phosphorus oxychloride. Subsequent reaction of 11 with

over 2.5 equivalent of sodium methoxide in methanol

resulted in conversion of the chlorine atom to a meth-

oxy group, with a concomitant ester exchange at the 3-

position to give ester 7nn (R¹=OMe, R⁰=Me). This

ester was converted to the corresponding aldehyde 9nn

(R¹=OMe) by the Dibal reduction and the following

DMSO oxidation of the resulting alcohol 8nn. Ester 7oo

(R¹=SMe, R⁰=Et) was obtained by the reaction of 11

with sodium methiolate applying the method of Natsu-

gari and his co-workers.¹¹It was transformed to alde-

hyde 9oo (R¹=SMe) in a manner analogous to that

employed in the synthesis of 9nn. The synthesis of alde-

hyde 9pp (R¹=NMe₂) was achieved by the method

described by Sliskovic et al.⁷Thus, the Dibal reduction

of 11 followed by DMSO oxidation of chloroalcohol 12

and nucleophilic substitution with dimethylamine of the

resulting chloroaldehyde 13 gave the aldehyde. Chloro-

aldehyde 13 was also transformed to aldehyde 9qq

(R¹=NMeEt) with N-ethyl-N-methylamine similarly to

9pp described above. The aldehyde with no substituent

on the 2-position (R¹=H, 9aa) was prepared by the ring

closure reaction of the 2-aminobenzophenone 5 (R²=4-

F, R³, R⁴and R⁵=H) with malonaldehyde bis(di-

methylacetal) in the presence of ZnCl₂, according to the

method described by Walser et al.¹²

aldehyde 9. This synthesis requires ﬁve steps to attach

the desmethylmevalonic acid portion to aldehyde 9.

Homologation of aldehydes 9a–t to the corresponding

propenals 14a–t was accomplished by the reaction of the

aldehydes with cis-2-ethoxyvinyllithium, which was

generated from the transmethalation of cis-1-ethoxy-2-

tri-n-butyl-stannyl-ethylene and hydrolysis of the

resulting intermediate adducts with p-toluenesulfonic

acid (Route A).^13a,bAlternatively, aldehydes 9aa–qq

were converted to propenals 14aa–qq by the Emmons–

Horner coupling reaction with diethyl cyanomethyl-

phosphonate, and the Dibal reduction of the resulting

a,b-unsaturated nitriles (Route B). An aldol condensa-

tion of 14 with ethyl acetoacetate dianion yielded race-

mic 5-hydroxy-3-ketoester 15. Partially stereoselective

reduction of 15a–t with NaBH₄in methanol at room

temperature

aﬀorded

3,5-dihydroxyesters

16a–t

(approximately syn/anti=7:3).¹⁴Highly stereoselective

chelation-controlled syn reduction¹⁵of 15aa–qq was

conducted with diethylmethoxyborane and sodium bor-

ohydride to give the corresponding 3,5-dihydroxyesters

16aa–qq (approximately syn/anti=>97:3).¹⁴

These 3,5-dihydroxyesters 16 were converted to the

corresponding sodium salts 17 for biological evaluations

by freeze-drying after saponiﬁcation with aqueous

NaOH.

Results and Discussion

Eﬀects of modiﬁcation of the substituents on the central

ring (R¹, R⁴and R⁵) and on the external ring (R²and

R³)

Synthesis of the quinoline-based 3,5-dihydroxyheptenoic

acid sodium salts, 17

Scheme 2 delineates the preparation of the quinoline-

based 3,5-dihydroxyheptenoic acid derivative of

At ﬁrst, the approximate eﬀects of modiﬁcation of the

substituents on the central and the external ring were

examined. Most of the known artiﬁcial inhibitors have

an isopropyl substituent as the alkyl side chain, R¹.

Since an isopropyl group on an aromatic ring is readily

metabolised by oxidation giving an aromatic carboxylic

acid,^16aꢀdwe tried to replace the isopropyl moiety with a

structurally similar, but more metabolically stable,

cyclopropyl group. The quinoline-based 3,5-dihydroxy-

heptenoic acid sodium salts 17a–t listed in Table 1 were

evaluated for their ability to inhibit sterol synthesis in a

cell-free system using a mixture of microsome fraction

and semipuriﬁed-cytosolic fraction isolated from rat

liver as the enzyme sources in vitro. All biological tests

were conducted under the same experimental conditions

with pravastatin as a reference for direct comparison.

The activities were determined by decreased incorpora-

tion of sodium [2-¹⁴C] acetate into non-saponiﬁable

lipids. The relative potencies were obtained by compar-

ison of IC₅₀values of compounds 17a–t with that of

pravastatin.

Summary of results obtained in each categories: (i)

Eﬀects of modiﬁcation of R¹(central ring); Replace-

ment of the isopropyl in 17b, 17m, and 17s with a

cyclopropyl group to provide 17c, 17p, and 17t, respec-

tively, resulted in retention or enhancement of activity.

In particular, with the external ring held constant as 4-

Scheme 2. Synthesis of 17. Reagents and conditions: (I) n-Bu₃Sn

CH¼CHOEt, n-Buli, THF, ꢀ78 ^ꢁC; (II): PTS, THF, H₂O, rt; (III):

(EtO)₂POCH₂CN, NaOHaq, (n-C₈H₁₇)₃MeNCl, toluene, rt; (IV)

DIBAH, toluene, ꢀ10 ^ꢁC; (V) CH₃COCH₂CO₂Et, NaH, n-Buli, THF,

ꢀ15 ^ꢁC; (VI) Method A: NaBH₄, EtOH, rt; Method B: Et₂BOMe,

NaBH₄, THF, MeOH, ꢀ78 ^ꢁC; (VII) (i) NaOHaq, EtOH, rt; (ii) freeze

dry.

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M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

ﬂuorophenyl, the cyclopropyl analogues displayed sev-

eral times more potency than the corresponding isopro-

pyl derivatives (17b vs 17c, 17s vs 17t), which were

comparable in potency to pravastatin. (ii) Eﬀects of

modiﬁcation of R²and R³(external ring); As shown in

the previous literature, holding the substituent R¹con-

stant as isopropyl, the strict structural requirement in

this moiety was found. Substitution on the external ring

(17d–l) was generally detrimental to potency, aside from

the known 4-ﬂuoro (17b), which was nearly equipotent

than the unsubstituted analogue (17a). Moreover,

movement of the ﬂuoro from the para (17b) to the ortho

position (17j), or addition of a methyl group in the meta

position (17d), diminished potency. (iii) Eﬀects of mod-

iﬁcation of R⁴and R⁵(central ring); The introduction of

chloro, methyl, and methoxy group to the 6-, 7-, and 8-

positions of the quinoline nucleus showed constant or

moderately increased potency (17a vs 17m and 17r; 17b

vs 17n, 17o, 17q, and 17s; 17c vs 17t).

Eﬀects of modiﬁcation of the substituent R¹on the

central ring

Using the optimal 4-ﬂuorophenyl as the external ring,

the structure–activity relationships of the 2-position

substituents were explored in detail. Quinoline-based

3,5-dihydroxyesters 17aa–qq (R²=4-F, R³, R⁴, R⁵=H)

were evaluated for their ability to inhibit HMG-CoA

reductase obtained from rat liver. IC₅₀measurements

showing the decreased rate of incorporation of [¹⁴C]

acetate into mevalonic acid demonstrated the inhibitory

activity of the compounds. The results of substitution

on position 2 are shown in Table 2.

The potency was dramatically altered with the 2-posi-

tion substituent: (i) The 2-position unsubstituted deri-

vative 17aa (R¹=H) showed no detectable inhibition,

suggesting that a lipophilic interaction in this region is

essential in inhibiting the target enzyme. (ii) The inhibi-

tory potency increased with length of the 2-substituent

from methyl (17bb) through ethyl (17cc), with the

greatest eﬀect shown with isopropyl (17ee), which was

comparable to lovastatin in activity. However, increas-

ing the length of the substituent to three carbons, n-

propyl (17dd) resulted in loss of activity and showed a

length limitation of the 2-substituent. The analogues

with isobutyl (17gg) and sec-butyl (17hh) possessed

Table 1. Inhibition of hepatic cholesterol ‘de novo’ synthesis in

vitro^a,b(eﬀects of modiﬁcation of R¹, R², R³, R⁴, and R⁵)

Table 2. Inhibition of solubilized rat liver HMG-CoAreductase in

vitro^a,b(eﬀects of modiﬁcation of R¹)

No.

R¹

R²

R³

R⁴

R⁵

Relative

potency^c

17a

17b

17c

17d

17e

i-Pr

c-Pr

i-Pr

H

4-F

4-Cl

4-Me

4-CF₃

H

3-Me

H

5-Me

H

6-Cl

H

6-Cl

6-Me

7-Me

H

8-Cl

H

15

18

100

8

3

2

4

<1

11

3

No.

R¹

IC₅₀(nM)^c

17f

17g

17h

17i

17j

17k

17l

17m

17n

17o

17p

17q

17r

17s

17t

Pravastatin^d

17aa

17bb

17cc

17dd

17ee

17ﬀ

17gg

17hh^d

17ii

17jj

17kk

17ll

17mm

17nn

17oo

17pp

17qq

Lovastatin

H

Me

Et

n-Pr

i-Pr

n-Bu

>1000(5)

241(5)

44(5)

i-Pr 4-OMe

i-Pr

c-Pr

i-Pr

c-Pr

4-OPh

2-F

2-Cl

3-Me

H

4-F

H

4-F

H

4-F

76(5)

19(7)

618(5)

71(5)

74(5)

343(7)

4.1(7)

67(5)

377(5)

140(7)

124(7)

484(7)

184(7)

209(7)

12(5)

3

30

26

54

36

11

17

111

100

CH₂CHMe₂

CHMeEt

t-Bu

c-Pr

c-Hex

Ph

CF₃

OMe

SMe

6-OMe 7-OMe

H

^aCompounds were tested for their ability to inhibit hepatic cholesterol

bio-synthesis in vitro with semipuriﬁed-cytosolic fraction and micro-

some fraction from rat liver: a measure of the rate of decreased incor-

poration of [¹⁴C]acetate to non-saponiﬁable lipids.

NME₂

NMeEt

^aCompounds were assayed against HMG-CoAreductase with a par-

tially puriﬁed microsomal enzyme preparation from rat liver: a measure

of the direct conversion of [¹⁴C]HMG-CoAto [ ¹⁴C]-mavalonic acid.

^bCompounds tested had a diastereomeric purity of >97% ds of the syn

diastereomer as determined by HPLC and/or PNMR spectroscopy.

^cParameters were calculated using a logistic curve ﬁt of dose response

data with the indicated number (in parentheses) of dose points. The

response at each dose was the mean response of duplicate determina-

tions.

^bCompounds isolated as a 7:3 mixture of syn/anti diols as determined

by HPLC and/or PNMR spectroscopy.

^cPotencies were obtained by comparison of IC₅₀values of compounds

17a–t with that of the internal standard pravastatin. Parameters were

calculated using a logistic curve ﬁt of dose response data from three or

ﬁve dose points. The response at each dose was the mean response of

triplicate determinations.

^dPravastatin averaged IC₅₀=4.2 nM and was used in every run as an

internal standard. For estimation of relative inhibitory potencies, pra-

vastatin was assigned a value of 100.

^dCompound 17hh was prepared from dl-ethyl 2-methylbutyrylacetate.

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2731

potency similar to that of 17dd, but the n-butyl analo-

gue, 17ﬀ was practically inactive. (iii) The tert-butyl

derivative, 17ii showed a large decrease in activity when

compared with 17ee, taking into account the chain

length. Astructural limitation exists in not only the

chain length but also the bulkiness of the substituent R¹

(i.e., size and shape). Therefore, as Roth and his co-

workers noted,⁶other factors which may inﬂuence con-

formation of the 3,5-dihydroxyheptenoic acid portion

should be considered. (iv) As already described in the

previous test, approximately a 5-fold increase in

potency was realized when an isopropyl group in 17ee

was replaced by a more compact cyclopropyl moiety

(17jj). The IC₅₀value was as high as 4.1 nM, and turned

out to be the optimum potency in this investigation. (v)

The c-hexyl analogue, 17kk was a moderate inhibitor

considering its substituent volume. This showed nearly

1/3.5 times the potency of 17ee. However, aromatiza-

tion of the cyclohexane ring gave a phenyl derivative

17ll, with signiﬁcantly diminished activity. (vi) Chan-

ging the electronic property of the substituents R¹via

introduction of a triﬂuoromethyl group (17mm) failed

to improve the potency over the isopropyl derivative,

17ee. (vii) Replacement of the ethyl group in 17cc with

the methoxy and the methylthio gave 17nn and 17oo,

respectively. They displayed about one third and one

eleventh of the potency of 17cc, respectively. (viii) The

activity of the dimethylamino derivative 17pp was

reduced by a factor of about 10 relative to the isopropyl

derivative 17ee, as already reported in the quinoline

series by Sliskovic et al.⁷Replacement of the sec-butyl

group in 17hh with a N-ethyl-N-methylamino group to

provide 17qq also diminished activity. It is suggested

that not only a steric parameter but also an electric para-

meter would be involved. (ix) Interestingly, we found a

rank order of in vitro potency in the investigation on 3,5-

dihydroxyheptenoic acid derivatives with a six-member

quinoline as the central ring: cyclopropyl > isopropyl

> cyclohexyl > triﬂuoromethyl > methyl > tert-butyl,

which is quite diﬀerent from that of 3,5-dihy-

droxheptanoic acid derivatives with a ﬁve-member pyr-

role reported by Roth et al.,⁵namely, isopropyl >

triﬂuoromethyl > tert-butyl > cyclopropyl > methyl

> cyclohexyl. This may be due to the spatial relation-

ships between the desmethylmevalonic acid portion, the

external ring, and the alkyl side chain somewhat

exchanged by changing the central ring from a small

ring to a larger one. In addition, replacement of the

bridging group resulted in a substantial conformational

change in this moiety, namely, a single bond in Roth’s

study and a double bond in our series. Based on these

results, further precise QSAR analysis will be published

elsewhere.¹⁷

On the central ring, substitution at positions 6, 7, and 8

of the central quinoline nucleus moderately aﬀected the

potency, whereas the alkyl side chain on the 2-position

deﬁnitively inﬂuenced activity. We found that further

modulation and improvement in potency at inhibiting

HMG-CoAreductase was obtained with the optimal

substituents ﬂanking the desmethylmevalonic acid por-

tion, that is 4-ﬂuorophenyl and cyclopropyl, instead of

the usual isopropyl group.

NK-104 (pitavastatin calcium:¹⁸monocalcium bis [(3R,

5S, 6E)-7-(2-cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolyl)-

3,5-dihydroxy-6-heptenoate], the chiral calcium salt

form of 17jj, shows remarkably potent anti-lipidemic

activity,¹⁹and is now awaiting registration in Japan and

is under clinical development in America and European

countries. The lipophilic anchor moiety in each inhi-

bitor plays an important role, which aﬀects not only the

in vitro potency but also the pharmacokinetic proﬁle.

This drug has superior bio-availability and long-dura-

tion drug concentration in plasma, on the basis of

entero-hepatic circulation and metabolical resistance. It

has been speculated that these favorable metabolic and

pharmacokinetic characteristics of the drug support eﬃ-

cacy in clinical studies as a highly potent hypolipidemic

agent in humans (Fig. 2).²⁰

Figure 2. NK-104.

In the ﬁeld of medicinal chemistry, the rational

approach of analysing the three dimensional structure

of target proteins has become an important method for

the design and discovery of new targets. Recentry, X-

ray analysis of the co-crystallization of human HMG-

21

CoAreductase with the inhibitors was reported.

It

was demonstrated that the COOH-terminal residues of

HMGR are disordered, revealing a shallow hydro-

phobic groove that accommodates the hydrophobic

moieties of the inhibitors. The discovery of a further

optimized inhibitor would be possible in the future

using crystal structures and analysis of the target

enzyme–inhibitor complex.

Experimental

Syntheses

Conclusion

Aseries of quinoline-based 3,5-dihydroxyheptenoic acid

derivatives was synthesized to evaluate their ability to

inhibit the enzyme HMG-CoAreductase in vitro. First,

in agreement with the previous literature, a strict struc-

tural requirement exists on the external ring, and 4-

ﬂuorophenyl was found to be most active in this system.

General methods. Melting points were determined with a

Yanagimoto Micro Melting Point Apparatus; Yanaco

Model MP-500V, and are uncorrected. IR spectra were

recorded on a Horiba Fourier Transform Infrared

Spectrometer FT-210 and Spectradesk SD-20 with 3M

2732

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

IR Cards (Type 61-100-12) Microporous Polyethylene

Film. Electron-impact ionization (EI) mass spectra were

recorded on a JEOL JMS-D300 or a JEOL SX102A

spectrometer. Fast-atom bombardment (FAB) and

Field Disorption (FD) mass spectra were recorded on a

JEOL JMS-DX300 or a JOEL LX1000 spectrometer.

Matrix assisted laser disorption ionization (MALDI)

mass spectra were recorded on a Applied Biosystems

Vojager DE-Pro. FAB spectra were recorded in a gly-

cerol matrix. Time of ﬂight mass (TOFMS) spectra were

recorded with internal standard, PEG400. EI-High

resolution mass spectra (EI-HRMS) were recorded on a

JEOL SX102Aspectrometer. FBA-High resolution

mass spectra (FAB-HRMS) were recorded on a JEOL

(R¹=CHMeEt), and ethyl cyclohexanecarbonylacetate

(R¹=c-hexyl) were prepared by the reaction of dilithio

dianion of monoethyl malonate with isovaleryl chloride,

dl-2-methylbutyryl chloride, and cyclohexanecarbonyl

chloride, respectively.^23cTetrahydrofuran was freshly

distilled from sodium metal and benzophenone under

nitrogen. Methylene chloride was purchased anhydrous

and methanol-free from Kanto, and used as received.

Other reagents and solvents were reagent grade where

available and were used without further puriﬁcation

unless otherwise stated.

Friedlander synthesis of quinolinecarboxylate by Fehnel’s

procedure

1

LX1000 spectrometer. H and ¹³C NMR spectra were

measured at 300, 400, and 500 MHz using a JEOL

JNM-ECP 300 FT NMR SYSTEM, a Varian Unity

INOVA, and a JEOL JNM-ECP-500 FT NMR SYS-

TEM respectively. Chemical shifts are given in parts per

million downﬁeld from tetramethylsilane as the internal

standard, whereas coupling constants (J) are in hertz in

CDCl₃or DMSO-d₆. Two-dimensional DQF-COSY

and HMQC experiments were recorded in order to

assist with spectal assignment. HPLC analyses were

performed using a Shimadzu LC-10A, a SPD-10A UV

detector, a CTO-6AColumn Oven, and a C-R6A

Chromatopac.

Methyl 2-cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinecar-

boxylate, 7c (step I in Scheme 1). 3.39 g (15.8 mmol) of

2-amino-4⁰-ﬂuorobenzophenone, 2.91 g (20.5 mmol) of

methyl cyclopropanecarbonylacetate and 0.2 mL of

concentrated sulfuric acid were dissolved in 17 mL of

glacial acetic acid, and the mixture was heated at 100 ^ꢁC

for 10 h. The reaction mixture was then cooled and

poured slowly with stirring into an ice-cold solution of

45 mL of concentrated aqueous ammonia in 120 mL of

water. The resultant suspension was allowed to stand

overnight in a refrigerator. The crude product was col-

lected, washed with water, and recrystallized from a

small amount of ethanol to obtain 3.74 g (73.9%) of the

title compound as a white powder: mp 126.0–127 ^ꢁC;

All of the reactions at low temperature were carried out

in an atmosphere of inert gas. The usual work up refers

to washing of organic layers with brine, drying over

anhydrous magnesium or sodium sulfate, and evapor-

ating oﬀ the solvents under reduced pressure. Reaction

courses and product mixtures were routinely monitored

by thin-layer chromatography on silica gel precoated

Kieselgel 60F₂₅₄Merck plates, with detection under

254 nm UV lamp and/or by spraying with a diluted

potassium permanganate solution. Column chromato-

graphies were performed with Merck 60–200 mesh or

Daiso 63–210 mm silica gel.

1

MS [EI, M⁺] m/z 321; H MNR (300 MHz, CDCl₃) d

1.0 (m, 2H), 1.4 (m, 2H), 2.2 (m, 1H), 3.63 (s, 3H), 7.2–

7.5 (m, 6H), 7.7 (m, 1H), 8.0 (m, 1H) ppm.

The starting alkyl and aryl substituted esters, 7a–t were

prepared in a manner analogous to the method descri-

bed above by a classical-type acid catalyzed Friedlander

synthesis according to Fehnel.⁸

Friedlander synthesis of quinolinecarboxylate by the

revised procedure

Materials. Some of the substituted 2-aminobenzophe-

none 5 and 3-ketoester 6 are not commercially available,

and were prepared according to literature methods. The

substituted 2-aminobenzophenones with ﬂuoro, tri-

ﬂuoromethyl, methoxy, and benzyloxy substituents

were prepared through the inverse addition of a

Grignard reagent to a 3,1-benzoxazin-4-ones, which was

obtained by the reaction of anthranilic acid with acetic

anhydride,^22a,b2-amino-4⁰-ﬂuorobenzophenone was

also prepared from anthranilic acid, by protection of the

amino group with p-toluenesulfonyl, chlorination with

phosphorus pentachloride, and Friedel–Crafts reaction

with ﬂuorobenzene in the presence of AlCl₃.^22c,dMethyl

cyclopropanecarbonyl-acetate (R¹=cyclopropyl) was

prepared by acylation of Meldrum’s acid with cyclo-

propanecarbonyl chloride in the presence of pyridine,

followed by successive methanolysis.^23aEthyl cyclopro-

panecarbonylacetate, which was prepared from cyclo-

propyl methyl ketone by carbethoxylation with ethyl

carbonate in the presence of sodium hydride, was also

used as a starting material.^23bEthyl isovalerylacetate

(R¹=CH₂CHMe₂), dl-ethyl 2-methylbutyrylacetate

Ethyl

2-cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinecar-

boxylate, 7jj (step I in Scheme 1). 280.0 g (1.30 mol) of

2-amino-4⁰-ﬂuorobenzophenone and 213.3 g (1.37 mol)

of ethyl cyclopropanecarbonylacetate were suspended in

2.8 L of molecular sieve-dehydrated benzene. 125.0 g

(1.30 mol) of methanesulfonic acid was added with stir-

ring to the suspension. The mixture was reﬂuxed for

10 h for azeotropic dehydration with a Dean–Stark trap.

500 mL of water was added and the mixture cooled to

50 ^ꢁC. The resulting solution was neutralized with a

solution of 61.5 g of NaOH in 500 mL of water. After

separation, the organic layer was washed with water.

10 g of activated charcoal was added and ﬁltered on a

Celite bed. 3.2 L of the solvent was evaporated under

reduced pressure. The solution was diluted with 840 mL

of petroleum ether at 30–40 ^ꢁC, and stirred at 10 ^ꢁC for

1 h. The mixture was cooled to 0 ^ꢁC and a further

840 mL of petroleum ether was added and stirred for

2 h. The precipitated crystals were ﬁltered, washed with

420 mL of petroleum ether and dried at 40 ^ꢁC under

pressure to obtain 413.1 g (94.9%) of the title com-

pound as colorless prisms: mp 73.5–75.5 ^ꢁC; IR (ﬁlm)

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2733

1728, 1228 cm^ꢀ1; MS [EI, M⁺] m/z 335; HR-MS [EI,

M⁺] calcd for C₂₁H₁₈FNO₂m/z 335.1322, found

335.1340; ¹H MNR (400 MHz, CDCl₃) d1.02 (t, 3H,

J=7 Hz), 1.0–1.1 (m, 2H), 1.3–1.4 (m, 2H), 2.2–2.3 (m,

1H), 4.12 (q, 2H, J=7 Hz), 7.2 (m, 2H), 7.3–7.4 (m, 3H),

7.5 (m, 1H), 7.7 (m, 1H), 8.0 (m, 1H) ppm; ¹³C NMR

on silica gel eluting with CHCl₃to yield 1.69 g (56.5%)

of the title compound 9c as a white powder: mp 149–

150 ^ꢁC; IR (ﬁlm) 1696,1553, 1512, 1490, 1157, 768 cm^ꢀ1

;

MS [EI, M⁺] m/z 291; HR-MS [EI, M⁺] calcd for

1

C₁₉H₁₄FNO m/z 291.1059, found 291.1090; H MNR

(300 MHz, CDCl₃) d 1.1 (m, 2H), 1.4 (m, 2H), 3.2 (m,

1H), 7.2–7.5 (m, 6H), 7.7–7.8 (m, 1H), 8.0 (m, 1H),

10.06 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 193.6,

1

(100MHz, CDCl₃) d 168.6, 162.9 (d, J_C-F=248.0 Hz),

158.4, 148.0, 144.4, 131.8 (d, ⁴J_C-F=3.4 Hz), 131.4 (2C, d,

³J_C-F=8.0 Hz), 130.1, 129.2, 127.9, 126.1, 126.0, 125.0,

1

163.0 (d, J_C-F=249.8 Hz), 161.6, 152.8, 148.9, 131.9

2

3

4

115.4 (2C, d, J_C-F=21.8 Hz), 61.5, 15.5, 13.9,

10.5 ppm.

(2C, d, J_C-F=8.1 Hz), 131.8, 129.9 (d, J_C-F=4.0 Hz),

2

129.2, 126.5, 126.2, 126.1, 125.2, 115.8 (2C, d, J_C-

_F=21.9 Hz), 14.5, 11.3 (2C) ppm.

The starting alkyl and aryl substituted esters, 7bb–mm

were prepared in a manner analogous to the method

described above.

The alkyl and aryl substituted aldehydes, 9a–t and 9bb–

mm were prepared in a manner analogous to the

method described above.

2-Cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinemethanol, 8c

(step II in Scheme 1). 28.8 mL (28.8 mmol) of a 1.0 M

toluene solution of DIBAL-H was added to a solution

of methyl 2-cyclopropyl-4-(4-ﬂuorophenyl)-3-quinoline-

carboxylate, 7c (3.70 g, 11.5 mmol) in anhydrous toluene

(35 mL) at 0 ^ꢁC under an atmosphere of nitrogen. The

resulting solution was stirred for 2 h at 0 ^ꢁC before

quenching with a saturated aqueous ammonium chlo-

ride solution. The mixture was added to 50 mL of ethyl

ether and the organic layer was separated. Agelled

product was dissolved by the addition of an aqueous

sodium hydroxide solution and extracted with ethyl

ether. The organic layers were combined, dried over

magnesium sulfate and ﬁltered. The solvent was evapo-

rated to dryness to yield 3.23 g (95.7%) of the crude title

compound 8c as a white powder: mp 132–133 ^ꢁC; IR

The aldehyde with a methoxy group on the 2 position

(9nn) was synthesized through the reaction route

(IV!V!VI!VII!VIII in Scheme 1) in an analogous

manner to the preparation of some methoxyquinoline

derivatives reported by Tawada et al.⁹

Ethyl 4-(4-ﬂuorophenyl)-1,2-dihydro-2-oxo-3-quinoline-

carboxylate, 10 (step IV in Scheme 1). Amixture of

15.00 g (69.8 mmol) of 2-amino-4⁰-ﬂuorobenzophenone

5, 16.77 g (105 mmol) of diethyl malonate, and piper-

idine (2.99 g, 35.1 mmol) was heated at 170 ^ꢁC for 6

days. After cooling, the resulting mixture was recrys-

tallized from ethanol and dried under reduced pressure

at 40 ^ꢁC to aﬀord 13.12 g (60.4%) of 10 as a faintly yel-

1

low powder: H MNR (300 MHz, CDCl₃) d 1.02 (t, 3H,

J=7Hz), 4.12 (q, 2H, J=7 Hz), 7.10–7.60 (m, 8H), 12.80

(ﬁlm) 1605, 1513, 1494, 1224, 1159, 1065, 840, 764 cm^ꢀ1

;

MS [EI, M⁺] m/z 293; HRMS [EI, M⁺] calcd for

(bs, 1H) ppm. H NMR data of 10 were identical with

1

C₁₉H₁₆FNO m/z 293.1216, found 293.1262; H MNR

that of the literature data⁷prepared through an alter-

native method by the condensation reaction of 2-amino-

4⁰-ﬂuorobenzophenone 5 with ethyl malonyl chloride.

(300 MHz, CDCl₃) d 1.1 (m, 2H), 1.3–1.4 (m, 2H), 1.73

(m, 1H), 2.6 (m, 1H), 4.74 (s, 2H), 7.2–7.3 (m, 6H), 7.6

(m, 1H), 8.0 (m, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃)

d 162.6 (d, ¹J_C-F=247.5 Hz), 162.2, 147.3, 146.4, 132.4 (d,

Ethyl 2-chloro-4-(4-ﬂuorophenyl)-3-quinolinecarboxylate,

11 (Step V in Scheme 1). Amixture of 10 (23.95 g,

77 mmol) and phosphorus oxychloride (127.5 g,

83 mmol) was reﬂuxed for 2 h. After removal of the

excess POCl₃by distillation under reduced pressure, the

resulting mixture was extracted with 250 mL of ethyl

acetate, ﬁltered, washed with saturated aqueous

NaHCO₃solution and brine and dried over magnesium

sulfate. Removal of the solvent by evaporation to dry-

ness under reduced pressure aﬀorded 20.47 g (80.7%) of

the title compound 11 as a pale yellow powder: mp 104–

111 ^ꢁC; IR (ﬁlm) 1722, 1605, 1557, 1492, 1400, 1227,

1024, 768 cm^ꢀ1; MS [EI, M⁺] m/z 329; HRMS [EI, M⁺]

calcd for C₁₈H₁₃ClFNO₂m/z 329.0618, found 329.0612;

¹H MNR (300 MHz, CDCl₃) d1.09 (t, 1H, J=7 Hz),

4.17 (q, 2H, J=7 Hz), 7.2–7.3 (m, 2H), 7.3–7.4 (m, 2H),

7.5–7.6 (m, 2H), 7.8 (m, 1H), 8.1 (m, 1H) ppm; ¹³C NMR

3

⁴J_C-F=3.5 Hz), 131.3 (2C, d, J_C-F=8.1 Hz), 129.2 (2C),

128.9, 126.4, 126.1, 125.5, 115.5 (2C, d, ²J_C-F=21.9 Hz),

59.7, 14.5, 9.8 (2C) ppm.

The alkyl and aryl substituted alcohols, 8a–t and 8bb–

mm were prepared in a manner analogous to the

method described above.

2-Cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinecarboxalde-

hyde, 9c (step III in Scheme 1). 3.54 g (16.42 mmol) of

pyridinium chlorochromate and 0.42 g of anhydrous

sodium acetate (5.13 mmol) were suspended in 40 mL of

anhydrous dichloromethane. Asolution of 3.01 g

(10.26 mmol) of 2-cyclopropyl-4-(4-ﬂuorophenyl)-3-qui-

nolinemethanol, 8c in 10 mL of anhydrous dichloro-

methane was immediately added to this suspension at

room temperature. The mixture was stirred for 1 h.

Then, 100 mL of ethyl ether was added, and the mixture

was thoroughly mixed. The reaction mixture was ﬁl-

tered through a silica gel layer. The ﬁltrate was distilled

oﬀ under reduced pressure, and the residue was extrac-

ted with diisopropyl ether. The insoluble materials were

ﬁltered oﬀ, and the ﬁltrate was evaporated in vacuo to

give the crude product. This was ﬂash chromatographed

1

(75 MHz, CDCl₃) d 165.5, 163.1 (d, J_C-F=249.2 Hz),

147.9, 147.5, 145.8, 131.4, 131.2 (2C, d, J_C-

3

4

_F=8.7 Hz), 130.3 (d, J_C-F=3.5 Hz), 128.9, 127.8,

2

127.7, 126.4, 125.7, 115.6 (2C, d, J_C-F=21.9 Hz),

62.0, 13.7 ppm.

¹H NMR data of 11 were identical with that of the

literature data.⁷

2734

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

Methyl 4-(4-ﬂuorophenyl)-2-methoxy-3-quinolinecarbox-

ylate, 7nn (step VI in Scheme 1). 500 mg of sodium was

dissolved in anhydrous methanol (30 mL). To this solu-

tion was added 11 (3.00 g, 9.1 mmol) in anhydrous

methanol (100 mL) at room temperature. The resulting

solution was stirred for 1 day at room temperature.

After removal of the solvent by distillation under

reduced pressure, the residue was extracted with 100 mL

of ethyl acetate, washed with water and brine, dried

over magnesium sulfate, ﬁltered, and concentrated in

vacuo. This was ﬂash chromatographed on silica gel,

eluting with 20% ethyl acetate-hexanes, to yield 2.80 g

(98.9%) of the title compound 7nn as a pale yellow

powder: mp 105–109 ^ꢁC; IR (ﬁlm) 1734, 1599, 1500,

1445, 1386, 1232, 1091, 766 cm^ꢀ1; MS [EI, M⁺] m/z 311;

HR-MS [EI, M⁺] calcd for C₁₈H₁₄FNO₃m/z 311.0958,

3.65 g (95.5%) of the title compound 8nn as a pale yel-

low powder: mp 143–144 ^ꢁC; IR (ﬁlm) 1597, 1500, 1443,

1385, 1325, 1223, 1161, 1007, 844, 764 cm^ꢀ1; MS [EI,

M⁺] m/z 283; HRMS [EI, M⁺] calcd for C₁₇H₁₄FNO₂

m/z 283.1009, found 283.1023; ¹H MNR (300 MHz,

CDCl₃) d 2.56 (t, 1H, J=7 Hz), 4.19 (s, 3H), 4.52

(d, 2H, J=7 Hz), 7.2–7.3 (m, 6H), 7.6 (m, 1H), 7.9

(m, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 162.7

1

(d, J_C-F=247.5 Hz), 160.7, 148.0, 145.9, 131.6 (d,

3

⁴J_C-F=3.5 Hz), 131.4 (2C, d, J_C-F=8.1 Hz), 129.5,

2

127.3, 126.6, 125.1, 124.3, 122.1, 115.5 (2C, d, J_C-

_F=21.3 Hz), 58.6, 53.8 ppm.

4-(4-Fluorophenyl)-2-methylthio-3-quinolinemethanol, 8oo

(Step VII in Scheme 1). 34 mL (34 mmol) of a 1.0 M

toluene solution of DIBAL-H was added to a solution

of 7oo (3.38 g, 9.9 mmol) in anhydrous toluene (30 mL)

at ꢀ75 ^ꢁC under an atmosphere of nitrogen. The result-

ing solution was stirred for 5.5 h before quenching with

methanol (0.43 g). The mixture was warmed to room

temperature, and was added to 100 mL of 5% metha-

nol-chloroform. This was washed with 10% aqueous

sodium hydroxide solution and then brine, dried over

magnesium sulfate, ﬁltered, and evaporated to dryness

yielding 2.90 g (97.9%) of the title compound 8oo as a

faintly yellow powder: mp 143–144 ^ꢁC; IR (ﬁlm) 1597,

1

found 311.0995; H MNR (300 MHz, CDCl₃) d 3.63 (s,

3H), 4.14 (s, 3H), 7.2–7.3 (m, 6H), 7.6 (m, 1H), 7.9 (m,

1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 166.9, 162.9 (d,

¹J_C-F=248.1 Hz), 157.9, 147.6, 146.7, 131.2, 131.1 (2C,

d, ³J_C-F=8.7 Hz), 130.5, 127.6, 126.4 (d, ¹J_C-F=3.5 Hz),

2

124.7, 123.7, 118.9, 115.5 (2C, d, J_C-F=21.3 Hz), 54.0,

52.4 ppm.

Ethyl

4-(4-ﬂuorophenyl)-2-methylthio-3-quinolinecar-

boxylate, 7oo (step VI in Scheme 1). The methylthio

derivative was prepared from 11 in a manner analogous

to the preparation described by Natsugari et al.¹⁰56 mL

(120 mmol) of a 15% aqueous solution of methyl mer-

captan sodium salt was added to a solution of 11

(4.00 g, 12.1 mmol) in anhydrous tetrahydrofuran

(240 mL) and anhydrous methanol (80 mL) at room

temperature. The resulting solution was reﬂuxed for 6 h.

After removal of the solvent by distillation under

reduced pressure, the residue was extracted with 100 mL

of ethyl acetate, washed with water, dried over magne-

sium sulfate, ﬁltered, and concentrated in vacuo. The

resulting product was ﬂash chromatographed on silica

gel, eluting with CHCl₃, to yield 3.84 g (84.3%) of the

title compound 7oo as a pale yellow powder: mp 138–

140 ^ꢁC; IR (ﬁlm) 1716, 1604, 1571, 1550, 1513, 1491,

1393, 1236, 1161, 1122, 765 cm^ꢀ1; MS [EI, M⁺] m/z 341;

HRMS [EI, M⁺] calcd for C₁₉H₁₆FNO₂S m/z 341.0886,

1500, 1443, 1385, 1325, 1223, 1161, 1007, 844, 764 cm^ꢀ1

;

MS [EI, M⁺] m/z 283; HR-MS [EI, M⁺] calcd for

1

C₁₇H₁₄FNO₂m/z 283.1009, found 283.1023; H MNR

(300 MHz, CDCl₃) d 2.56 (t, 1H, J=7 Hz), 4.19 (s, 3H),

4.52 (d, 2H, J=7 Hz), 7.2–7.3 (m, 6H), 7.6 (m, 1H), 7.9

(m, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 162.7

1

(d, J_C-F=248.1 Hz), 159.6, 147.5, 146.1, 131.6 (d,

3

⁴J_C-F=3.5 Hz), 131.4 (2C, d, J_C-F=8.1 Hz), 129.6,

2

128.8, 128.1, 126.7, 125.6, 125.4, 115.5 (2C, d, J_C-

_F=21.9 Hz), 59,5, 13.1 ppm.

4-(4-Fluorophenyl)-2-methoxy-3-quinolinecarboxaldehyde,

9nn (step VIII in Scheme 1). Dimethyl sulfoxide (2.65 g,

33.9 mmol) was added to a solution of oxalyl chloride

(2.19 g, 17.3 mmol) in anhydrous dichloromethane

(30 mL), at ꢀ78 ^ꢁC under an atmosphere of nitrogen.

After complete addition the resulting solution was stir-

red for 20 min at ꢀ78 ^ꢁC and then a solution of 8nn

(3.61 g, 12.8 mmol) in dichloromethane (40 mL) was

added dropwise. This was stirred for a further 2 h at

ꢀ70 ^ꢁC and then quenched by the addition of triethyla-

mine (6.67 g, 65.9 mmol) and saturated aqueous ammo-

nium chloride solution (15 mL). The organic layer was

separated and washed with brine, dried over magnesium

sulfate, ﬁltered, and concentrated in vacuo. This was

ﬂash chromatographed on silica gel, eluting with 10%

ethyl acetate-hexanes, to yield 2.44 g (67.8%) of the title

compound as a pale yellow powder: mp 160–161 ^ꢁC; IR

(ﬁlm) 1694, 1579, 1517, 1498, 1382, 1224, 760 cm^ꢀ1; MS

[EI, M⁺] m/z 281; HR-MS [EI, M⁺] calcd for

1

found 341.0833; H MNR (300 MHz, CDCl₃) d 1.03 (t,

3H, J=7 Hz), 4.11 (q, 2H, J=7 Hz), 7.2–7.5 (m, 6H),

7.7 (m, 1H), 8.0 (m, 1H) ppm; ¹³C NMR (75 MHz,

1

CDCl₃) d 166.9, 162.9 (d, J_C-F=248.1 Hz), 156.2,

148.1, 144.8, 131.4 (d, J_C-F=3.5 Hz), 131.2 (2C, d,

4

³J_C-F=8.7 Hz), 130.6, 130.5, 128.3, 126.4, 125.9,

2

124.4, 115.4 (2C, d, J_C-F=21.3 Hz), 61.6, 13.7,

13.5 ppm.

4-(4-Fluorophenyl)-2-methoxy-3-quinolinemethanol, 8nn

(step VII in Scheme 1). To a solution of 7nn (4.20 g,

13.5 mmol) in anhydrous toluene (30 mL) at ꢀ40 ^ꢁC

under an atmosphere of nitrogen was added 31 mL

(31 mmol) of a 1.0 M toluene solution of DIBAL-H.

The resulting solution was stirred for 2.5 h before

quenching with methanol (0.14 g). The mixture was

warmed to room temperature, and was added to 50 mL

of toluene, washed with 10% of aqueous sodium

hydroxide solution then brine, dried over magnesium

sulfate, ﬁltered, and evaporated to dryness yielding

1

C₁₇H₁₂FNO₂m/z 281.0852, found 281.0833; H MNR

(300 MHz, CDCl₃) d 4.21 (s, 3H), 7.2–7.4 (m, 6H), 7.7

(m, 1H), 7.9 (m, 1H), 10.17 (s, 1H) ppm; ¹³C NMR

1

(75 MHz, CDCl₃) d 190.3, 162.9 (d, J_C-F=248.6 Hz),

160.2, 154.0, 148.1, 132.2, 131.3 (2C, d, J_C-F=8.1 Hz),

3

130.3 (d, ⁴J_C-F=3.5 Hz), 127.5 (2C), 124.9, 124.7, 118.2,

2

115.6 (2C, d, J_C-F=21.9 Hz), 54.0 ppm.

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2735

4-(4-Fluorophenyl)-2-methylthio-3-quinolinecarboxalde-

hyde, 9oo (step VIII in Scheme 1). Dimethyl sulfoxide

(2.25 g, 28.8 mmol) was added to a solution of oxalyl

chloride (1.83 g, 14.4 mmol) in anhydrous dichloro-

methane (30 mL), at ꢀ78 ^ꢁC under an atmosphere of

nitrogen. After complete addition the resulting solution

was stirred for 15 min at ꢀ78 ^ꢁC and then a solution of

8oo (2.15 g, 71.9 mmol) in dichloromethane (40 mL) was

added dropwise. This was stirred for a further 5 h at

ꢀ70 ^ꢁC and then quenched by the addition of triethyla-

mine (5.53 g, 54.6 mmol) and saturated aqueous ammo-

nium chloride solution (15 mL). The organic layer was

separated and washed with brine, dried over magnesium

sulfate, ﬁltered, and concentrated in vacuo. This was

ﬂash chromatographed on silica gel, eluting with 5%

methanol–CHCl₃, to yield 1.64 g (76.8%) of the title

compound as a pale yellow powder: mp 136–140 ^ꢁC; IR

(ﬁlm) 1686, 1607, 1539, 1512, 1227, 1054, 764 cm^ꢀ1; MS

[EI, M⁺] m/z 297; HRMS [EI, M⁺] calcd for

was stirred for 15 min at ꢀ78 ^ꢁC and then a solution of

12 (5.30 g, 18.4 mmol) in dichloromethane (50 mL) was

added dropwise. This was stirred for a further 4 h at

ꢀ78 ^ꢁC and then quenched by the addition of triethyla-

mine (9.59 g, 94.8 mmol) and saturated aqueous ammo-

nium chloride solution (15 mL). The organic layer was

separated and the organic layer was dried, ﬁltered, con-

centrated in vacuo, and washed with hexanes to yield a

pale yellow powder. This was ﬂash chromatographed on

silica gel, eluting with 50% ethyl acetate–hexanes, to

yield 4.82 g (91.8%) of the title compound 13 as a

faintly yellow powder: mp 166–167 ^ꢁC; IR (ﬁlm) 1698,

1544, 1515, 1491, 1382, 1224, 1044, 851, 765 cm^ꢀ1; MS

[EI, M⁺] m/z 285; HR-MS [EI, M⁺] calcd for

1

C₁₆H₉ClFNO m/z 285.0357, found 285.0304; H MNR

(300 MHz, CDCl₃) d 7.1–7.4 (m, 6H), 7.6 (m, 1H), 7.7–

7.8 (m, 1H), 9.84 (s, 1H) ppm; ¹³C NMR (75 MHz,

1

CDCl₃) d 189.8, 163.1 (d, J_C-F=249.2 Hz), 153.5,

148.7, 148.4, 133.0, 131.3 (2C, d, J_C-F=8.1 Hz), 129.3

3

1

4

C₁₇H₁₂FNOS m/z 297.0623, found 297.0598; H MNR

(300 MHz, CDCl₃) d 2.70 (s, 3H), 7.2–7.5 (m, 6H), 7.8

(d, J_C-F=4.0 Hz), 128.9, 128.0, 127.4, 126.7, 125.1,

2

115.8 (2C, d, J_C-F=21.9 Hz) ppm.

(m, 1H), 8.0 (m, 1H), 9.95 (s, 1H) ppm; ¹³C NMR

1

(75 MHz, CDCl₃) d 191.4, 163.1 (d, J_C-F=249.8 Hz),

159.8, 154.4, 148.9, 132.7, 131.9 (2C, d, J_C-F=8.7 Hz),

¹H NMR data of 13 were identical with that of the

literature data.⁷

3

129.3 (d, ²J_C-F=4.0 Hz), 128.5, 127.0, 126.0 (2C), 124.3,

2

115.8 (2C, d, J_C-F=21.9 Hz), 13.8 ppm.

2-(Dimethylamino)-4-(4-ﬂuorophenyl)-3-quinolinecarbox-

aldehyde, 9pp (R¹=NMe₂, step XI in Scheme 1). A

solution of 13 (2.50 g, 8.76 mmol) and dimethylamine

(17 g) in toluene (50 mL) was heated in an autoclave at

130–140 ^ꢁC for 5.5 h. It was then cooled and con-

centrated in vacuo. The residue was extracted with

CHCl₃, washed with saturated aqueous sodium hydro-

gen carbonate and brine, and dried over magnesium

sulfate. The solvent was evaporated and the residue was

ﬂash chromatographed on silica gel, eluting with CHCl₃

to yield 2.18 g (84.6%) of the title compound as a yellow

powder: mp 125–128 ^ꢁC; IR (ﬁlm) 1684, 1605, 1547,

1513, 1389, 1226, 760 cm^ꢀ1; MS [EI, M⁺] m/z 294;

HRMS [EI, M⁺] calcd for C₁₈H₁₅FN₂O m/z 294.1168,

The aldehyde with a dimethylamino group on the 2

position was prepared from 11 according to the method

described by Sliskovic et al.⁷

2-Chloro-4-(4-ﬂuorophenyl)-3-quinolinemethanol, 12 (step

IX in Scheme 1). 70 mL (70 mmol) of a 1.0 M toluene

solution of DIBAL-H was added to a solution of 11

(10.00 g, 30.3 mmol) in anhydrous dichloromethane

(130 mL) at ꢀ78 ^ꢁC under an atmosphere of nitrogen.

The resulting solution was stirred for 5 h before

quenching with saturated aqueous sodium sulfate

(26 mL). The mixture was warmed to room tempera-

ture, and the resulting precipitate was ﬁltered oﬀ. The

cake was washed with dichloromethane, and the wash-

ings were combined with the ﬁltrate and evaporated to

dryness yielding 8.30 g (95.3%) of the title compound 12

as a pale yellow powder: mp 154–159 ^ꢁC; IR (ﬁlm) 1605,

1

found 294.1163; H MNR (300 MHz, CDCl₃) d 3.13 (s,

6H), 7.2–7.4 (m, 6H), 7.6–7.7 (m, 1H), 7.8 (m, 1H), 9.84

(s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 190.6, 163.0

(d, J_C-F=248.6 Hz), 157.1, 155.4, 149.2, 132.3, 132.0

1

3

4

(2C, d, J_C-F=8.7 Hz), 130.7 (d, J_C-F=3.5 Hz), 127.1,

2

1558, 1513, 1492, 1394, 1228, 1159, 1047, 842, 765 cm^ꢀ1

;

127.0, 123.0 (2C), 118.3, 115.5 (2C, d, J_C-F=21.9 Hz),

41.9 ppm.

MS [EI, M⁺] m/z 287; HR-MS [EI, M⁺] calcd for

C₁₆H₁₁ClFNO m/z 287.0513, found 287.0517; ¹H MNR

(300 MHz, CDCl₃) d 2.35 (bs, 1H), 4.66 (s, 2H), 7.2–7.5

(m, 6H), 7.7–7.8 (m, 1H), 8.0–8.1 (m, 1H) ppm; ¹³C

¹H NMR data of 9pp were identical with that of the

literature data.⁷

1

NMR (75 MHz, CDCl₃) d 162.9 (d, J_C-F=249.2 Hz),

151.5, 150.3, 147.0, 131.3 (2C, d, J_C-F=8.1 Hz), 131.1

3

The aldehyde with a N-ethyl-N-methylamino group on

the 2 position was prepared from 13 analogously to

compound 9pp.

4

(d, J_C-F=3.5 Hz), 130.6, 129.4, 128.6, 127.3, 127.0,

2

126.8, 115.7 (2C, d, J_C-F=21.9 Hz), 60.3 ppm.

¹H NMR data of 12 were identical with that of the

4-(4-Fluorophenyl)-N-ethyl-N-methylamino-3-quinoline-

carboxaldehyde, 9qq (R¹=NMeEt, step XI in Scheme

1). The N-methyl-N-ethylamino derivative was pre-

pared analogously to the dimethyl derivative. Asolu-

tion of 13 (2.20 g, 7.71 mmol) and N-ethylmethylamine

(10.0 g, 169 mmol) in toluene (40 mL) was heated in an

autoclave at 140 ^ꢁC for 6 h. It was then cooled and con-

centrated in vacuo. The residue was extracted with

CHCl₃, washed with saturated aqueous sodium hydrogen

literature data.⁷

2-Chloro-4-(4-ﬂuorophenyl)-3-quinolinecarboxaldehyde,

1

1 3 (R=Cl, step X in Scheme 1). Dimethyl sulfoxide

(3.81 g, 48.8 mmol) was added to a solution of oxalyl

chloride (3.15 g, 24.8 mmol) in anhydrous dichloro-

methane (50 mL), at ꢀ78 ^ꢁC under an atmosphere of

nitrogen. After complete addition the resulting solution

2736

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

carbonate and brine, and dried over magnesium sulfate.

The solvent was evaporated and the residue was ﬂash

chromatographed on silica gel, eluting with 10% ethyl

acetate-hexanes, to yield 2.11 g (88.9%) of the title

compound as an orange powder: mp 77–79 ^ꢁC; IR (ﬁlm)

1684, 1605, 1545, 1513, 1397, 1228, 760 cm^ꢀ1; MS [EI,

M⁺] m/z 308; HR-MS [EI, M⁺] calcd for C₁₉H₁₇FN₂O

m/z 308.1325, found 308.1250; ¹H MNR (300 MHz,

CDCl₃) d 1.30 (t, 3H, J=7 Hz), 3.03 (s, 3H), 3.62 (q, 2H,

J=7 Hz), 7.1–7.4 (m, 6H), 7.6 (m, 1H), 7.7–7.8 (m, 1H),

9.84 (s, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 190.7,

over magnesium sulfate, and ﬁltered. The solvent was

distilled oﬀ under reduced pressure, and the residue was

extracted with acetonitrile. The solution was washed

with n-hexane repeatedly to remove the stannyl ingre-

dient. The solvent was evaporated in vacuo to yield the

title compound as a colorless oil. This material was

submitted to the next step without puriﬁcation.

The other aldehydes, 9a–t were analogously converted

to the corresponding adducts, and the intermediate was

submitted to the next step without puriﬁcation.

1

162.9 (d, J_C-F=248.6Hz), 157.0, 154.6, 149.1, 132.0,

3

4

131.9 (2C, d, J_C-F=8.1 Hz), 130.8 (d, J_C-F=3.5 Hz),

2

(E)-3-[2-Cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinyl]-2-

propenal, 14c (route A: step II in Scheme 2). The

ethoxypropenylquinoline was dissolved in 20 mL of tet-

rahydrofuran, and 5 mL of water and 100 mg of p-

toluenesulfonic acid were added. The mixture was stir-

red for 24 h at room temperature. The reaction solution

was extracted with diethyl ether a few times. The

extracts were washed with brine and dried over magne-

sium sulfate, and evaporated in vacuo. The residue was

chromatographed over silica, eluting with 2.5% metha-

nol-chloroform, to yield 1.06 g (67.1%) of the title

compound as a white powder: mp 136–142 ^ꢁC; IR (ﬁlm)

1685, 1605, 1554, 1513, 1489, 1225, 1159, 1122,

765 cm^ꢀ1; MS [EI, M⁺] m/z 317; HR-MS [EI, M⁺]

calcd for C₂₁H₁₆FNO m/z 317.1216, found 317.1245; ¹H

MNR (300 MHz, CDCl₃) d 1.1 (m, 2H), 1.4 (m, 2H), 2.4

(m, 1H), 6.45 (dd, 1H, J=8 and 16 Hz), 7.2–7.4 (m, 6H),

7.56 (d, 1H, J=16 Hz), 8.0 (m, 1H), 9.51 (d, 1H,

J=8Hz) ppm; ¹³C NMR (75 MHz, CDCl₃) d 193.4, 162.7

127.1 (2C), 123.0, 118.7, 115.4 (2C, d, J_C-F=21.9Hz),

48.1, 38.8, 12.5 ppm.

The 2 position unsubstituted derivative, 9aa was pre-

pared from 2-amino-4⁰-ﬂuorobenzophenone and

1,1,3,3-tetramethoxypropane in a manner analogous to

the preparation described by Walser et al.¹²

4-(4-Fluorophenyl)-3-quinolinecarboxaldehyde, 9aa (R¹=H,

step XII in Scheme 1). Amixture of 2.50 g (11.6 mmol)

of 2-amino-4⁰-ﬂuorobenzophenone, 2.86 g (17.4 mmol)

of 1,1,3,3-tetramethoxypropane, 1.58 g (11.6 mmol) of

zinc chloride and 50 mL of toluene was heated to reﬂux

for 2 h. After the solvent was removed by evaporation,

the residue was extracted with 100 mL of CHCl₃. The

solution was washed with water and brine, dried over

magnesium sulfate, and evaporated. The resulting

brown oil was chromatographed with silica gel using

50% (v/v) of ethyl acetate in n-hexane. Washing of the

eluent with n-hexane yielded 1.01 g (34.7%) of the title

compound as a pale yellow powder: mp 122–128 ^ꢁC; IR

(ﬁlm) 1694, 1607, 1575, 1513, 1498, 1228, 765 cm^ꢀ1; MS

[EI, M⁺] m/z 251; HR-MS [EI, M⁺] calcd for C₁₆H₁₀FNO

m/z 251.0746, found 251.0822; ¹H MNR (300MHz,

CDCl₃) d 7.3–7.4 (m, 4H), 7.5–7.7 (m, 2H), 7.8–7.9 (m,

1H), 8.2 (m, 1H), 9.43 (s, 1H), 9.97 (s, 1H) ppm; ¹³C NMR

1

(d, J_C-F=248.6 Hz), 159.4, 150.0, 147.6, 146.4, 135.6,

4

3

131.9 (d, J_C-F=4.0Hz), 131.5 (2C, d, J_C-F=8.1 Hz),

130.2, 129.0, 126.4, 126.3, 126.1, 125.6, 115.9 (2C, d,

²J_C-F=21.3 Hz), 16.5, 10.6 (2C) ppm.

The other aldehydes, 9a–t were converted to the corre-

sponding propenals 14a–t in a manner analogously.

1

(75 MHz, CDCl₃) d 191.2, 163.3 (d, J_C-F=250.4 Hz),

152.1, 150.1, 148.2, 132.2 (2C, d, J_C-F=8.1 Hz), 132.5,

The propenals 14aa–qq were synthesized via a Emmons–

Horner coupling of aldehydes 9aa–qq with diethyl (cya-

nomethyl)phosphonate, and a DIBAL-H reduction of

the corresponding adducts.

3

130.1, 128.4 (d, ⁴J_C-F=3.5 Hz), 127.8, 127.1, 126.6, 125.5,

2

115.9 (2C, d, J_C-F=21.9 Hz) sppm.

The propenals, 14a–t were synthesized via a carbonyl

homologation with cis-2-ethoxyvinyllithium according

to Wollenberg et al.¹³

(E)-3-[2-Cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinyl]-2-

propenenitrile (route B: step III in Scheme 2). A20%

aqueous sodium hydroxide solution (25 g) was added

dropwise under vigorous stirring at room temperature

to a solution of aldehyde 9jj (11.0 g, 37.9 mmol), diethyl

(cyanomethyl)phosphonate (8.1 g, 45.5 mmol), and

trioctylmethylammonium chloride (306.5 mg, 0.8 mmol)

in anhydrous toluene (88 mL). The mixture was stirred

for 2 h at room temperature, and 50 mL of water was

added. The organic layer was separated, and then 25 mL

of brine was added. The mixture was neutralized with

1 N hydrochloric acid, washed with water then brine,

dried over sodium sulfate, ﬁltered, and concentrated in

reduced pressure. The resulting solution was heated at

100 ^ꢁC, and 75 g of n-hexane was added. After cooling,

the precipitate was collected, washed with n-hexane, and

dried in high vacuum to yield 10.1 g (85.1%) of the title

compound as a white crystal: mp 145–146 ^ꢁC; IR (ﬁlm)

1605, 1558, 1513, 1489, 1224, 1159, 766 cm^ꢀ1; MS [EI,

2-Cyclopropyl-3-(3-ethoxy-1-hydroxy-2-propenyl)-4-(4-

ﬂuorophenyl) quinoline (route A: step I in Scheme 2).

6.28 g (17.43 mmol) of cis-1-ethoxy-2-(tri-n-butyl-

stannyl)ethylene was dissolved in anhydrous tetra-

hydrofuran (10 mL), and the solution was cooled to

ꢀ78 ^ꢁC under an atmosphere of nitrogen. To this solu-

tion, 10.25 mL of 15 wt% n-butyllithium in n-hexane

solution was added dropwise. The mixture was stirred

for 1 h. Then, a solution of aldehyde 9c (1.45 g,

4.98 mmol) in 10 mL of anhydrous tetrahydrofuran was

added dropwise. The reaction mixture was stirred for

2 h at ꢀ78 ^ꢁC. Then, 2 mL of saturated aqueous ammo-

nium chloride solution was added to quench the reac-

tion. Diethyl ether was added to the mixture, and the

organic layer was separated, washed with brine, dried

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2737

M⁺] m/z 314; HR-MS [EI, M⁺] calcd for C₂₁H₁₅FN₂

m/z 314.1219, found 314.1252; ¹H MNR (300 MHz,

CDCl₃) d 1.1 (m, 2H), 1.4 (m, 2H), 2.3 (m, 1H), 5.58 (d,

1H, J=17 Hz), 7.2–7.4 (m, 6H), 7.52 (d, 1H, J=17 Hz),

7.6–7.7 (m, 1H), 8.0 (m, 1H) ppm; ¹³C NMR

mixture was recrystallized from 80 mL of cyclohexane

and 40 mL of n-hexane, washed with n-hexane, and

dried at 60 ^ꢁC in high vacuum to yield 4.66 g (83.5%) of

15jj as a faintly yellow powder: mp 90–93 ^ꢁC; IR (ﬁlm)

1740, 1713, 1604, 1513, 1489, 1222, 1158, 1026, 835,

765 cm^ꢀ1; MS [EI, M⁺] m/z 447; HR-MS [EI, M⁺]

calcd for C₂₇H₂₆FNO₄m/z 447.1846, found 447.1870;

¹H MNR (300 MHz, CDCl₃) d 1.0 (m, 2H), 1.29 (t, 3H,

J=7 Hz), 1.3 (m, 2H), 2.4 (m, 1H), 2.54 (d, 2H,

J=5 Hz), 2.7 (m, 1H), 3.43 (s, 2H), 4.21 (q, 2H,

J=7 Hz), 4.6 (m, 1H), 5.58 (dd, 1H, J=6 and 16 Hz),

6.67 (d, 1H, J=16 Hz), 7.2–7.3 (m, 6H), 7.6 (m, 1H), 8.0

(m, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 202.5, 166.7,

1

(75 MHz, CDCl₃) d 162.8 (d, J_C-F=249.2 Hz), 159.1,

147.9, 147.6, 146.3, 131.6 (d, J_C-F=4.0 Hz), 131.4

4

3

(2C, d, J_C-F=8.1 Hz), 130.3, 129.0, 126.4, 126.2, 125.8,

2

125.6, 117.4, 116.1 (2C, d, J_C-F=21.4 Hz), 104.0, 16.5,

10.4 (2C) ppm.

The other aldehydes, 9aa–qq were analogously con-

verted to the corresponding adduct, and the inter-

mediate was submitted to the next step without

puriﬁcation.

1

162.2 (d, J_C-F=246.9 Hz), 160.6, 146.8, 144.3, 138.0,

4

3

133.4 (d, J_C-F=3.5 Hz), 131.9 (2C, d, J_C-F=8.2 Hz),

131.8, 129.0, 128.9, 128.8, 126.4, 126.0, 125.4, 115.3 (2C,

d, ²J_C-F=21.3 Hz), 68.2, 61.6, 49.8, 49.0, 15.9, 14.1, 10.2

(2C) ppm.

(E)-3-[2-Cyclopropyl-4-(4-ﬂuorophenyl)-3-quinolinyl]-2-

propenal, 14jj (route B: step IV in Scheme 2). 37.6 mL

(37.6 mmol) of a 1 M solution of diisobutylaluminum

hydride in toluene at ꢀ10 ^ꢁC was added dropwise under

an atmosphere of nitrogen to a solution of the nitrile

(9.9 g, 31.6 mmol) in anhydrous toluene (100 mL). The

mixture was stirred for 1 h at ꢀ15 ^ꢁC, and was then

quenched with ethanol. 8.5 mL of 1 N hydrochloric acid

was then added to this solution, and the resulting sus-

pension was ﬁltered over Celite. The cake was washed

repeatedly with ethyl acetate, and the washings were

combined with the ﬁltrate. The solution was washed

with 1 N hydrochloric acid then brine. 60 mL of water

was added to the organic layer and this was neutralized

with saturated aqueous sodium hydrogen carbonate

solution, washed with water then brine, dried over

sodium sulfate, and ﬁltered. 80 mL of cyclohexane was

added and the solution was then concentrated under

reduced pressure until the total weight became 30 g. The

resulting solution was heated at 60 ^ꢁC, 40 mL of n-hex-

ane was added, and the solution was cooled to 0 ^ꢁC. The

precipitate was collected, washed with n-hexane, and

dried in high vacuum at 60 ^ꢁC for 1.5 h to yield 8.66 g

(86.5%) of the title compound as a white crystal: The

spectra of 14jj were identical with those of 14c from

route A.

All other propenals, 14a–t and 14aa–qq, were analo-

gously converted to the corresponding 5-hydroxy-3-keto

esters 15a–t and 15aa–qq.

Ethyl (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-ﬂuorophe-

nyl)-3-quinolinyl]-hept-6-enoate (step VI in Scheme 2)

Method A: partially stereoselective reduction. 1.04 g

(2.33 mmol) of compound 15c was dissolved in 10 mL of

anhydrous ethanol in an atmosphere of nitrogen, and

was cooled at 0 ^ꢁC. 94 mg (2.49 mmol) of sodium boro-

hydride was added to the solution, and stirred for 1 h.

To quench the reaction, 1 mL of a 10% hydrochloric

acid was then added to the mixture. This was extracted

with diethyl ether three times, and the organic layer

separated. The organic layer was washed with brine,

dried over magnesium sulfate, ﬁltered, and evaporated

to dryness in vacuo. The residue was chromatographed

over silica, eluting with 5% methanol–chloroform to

yield 429 mg (41.1%) of 16c as a white powder: mp 103–

104 ^ꢁC; MS [EI, M⁺] m/z 449; ¹H MNR (400 MHz,

CDCl₃) d 1.0 (m, 2H), 1.29 (t, 3H, J=7 Hz), 1.3–1.6 (m,

2H), 2.3–2.4 (m, 1H), 2.42 (s, 2H), 3.2 (m, 1H), 3.7 (m,

1H), 4.1 (m, 1H), 4.19 (q, 2H, J=7 Hz), 4.4 (m, 1H),

5.58 (dd, 1H, J=6, 16 Hz), 6.64 (d, 1H, J=16 Hz), 7.2–

7.4 (m, 6H), 7.6 (m, 1H), 7.9–8.0 (m, 1H) ppm. The syn/

anti ratio of the sample was determined by HPLC

(68.2:31.8; Nucleosil 50-5, 4.6ꢂ250 mm, 10% iso-

propanol and n-hexane, 1.0 mL/min, 35 ^ꢁC, 254 nm;

retention time: erythro 10.3 min, threo 9.2 min) and by

¹H NMR (68:32; 500 MHz by comparing the relative

intensities of the methylene proton signal on the 3 posi-

tion in the desmethylmavalonic acid chain; chemical

shift: erythro 4.15 ppm, threo 4.05 ppm). All other 5-

hydroxy-3-keto esters 15a–t were analogously converted

to the corresponding 3,5-dihydroxyesters 16a–t.

Ethyl (E)-7-[2-cyclopropyl-4-(4-ﬂuorophenyl)-3-quinoli-

nyl]-5-hydroxy-3-oxo-6-heptenoate, 15jj (step

V

in

Scheme 2). Asolution of ethyl acetoacetate (3.26 g,

25.0 mmol) in anhydrous tetrahydrofuran (10 mL) at

ꢀ40 ^ꢁC was added dropwise during oversp=0.25>min

under an atmosphere of nitrogen to a suspension of

sodium hydride (661 mg, 27.6 mmol, 60%) in anhydrous

tetrahydrofuran (30 mL). The solution was stirred for

30 min at ꢀ30 ^ꢁC. Asolution of n-butyllithium in hex-

ane (15.7 mL of a 1.6 M solution, 25.0 mmol) was added

over 5 min. The reaction mixture was stirred for 30 min

at ꢀ20 ^ꢁC. Asolution of 4.0 g (12.5 mmol) of propenal

14jj in dry tetrahydrofuran (10 mL) was added dropwise

at ꢀ15 ^ꢁC over 6 min to this solution. The reaction

mixture was stirred for 3 h at ꢀ10 ^ꢁC. To quench the

reaction, 15 mL of acetic acid in tetrahydrofuran

(15 mL) was slowly added. 30 mL of water and 40 mL of

ethyl acetate were added to this solution, separated,

washed with brine, dried over sodium sulfate, ﬁltered,

and concentrated under reduced pressure. The resulting

Method B: stereoselective reduction. Asolution of

diethylmethoxyborane in tetrahydrofuran (10.7 mL of a

1 M solution, 10.7 mmol) was added dropwise under an

atmosphere of nitrogen at room temperature to a solu-

tion of 5-hydroxy-3-keto ester 15jj (3.09 g, 8.9 mmol) in

anhydrous tetrahydrofuran (56 mL) and anhydrous

methanol (6.7 g). After stirring for 1 h at ꢀ75 ^ꢁC,

2738

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

sodium borohydride (404 mg, 10.7 mmol) was added

over 1 min. The solution was stirred for 3 h at ꢀ75 ^ꢁC,

and was quenched with 2.14 g of acetic acid in 2 mL of

tetrahydrofuran at ꢀ75 ^ꢁC. The resulting mixture was

added to 70 mL of ethyl acetate and 60 mL of water,

separated, washed with brine and saturated aqueous

sodium hydrogencarbonate solution, dried over sodium

sulfate, ﬁltered, and concentrated in vacuo. The residue

was taken up several times in 50 mL of methanol and

this solvent was evaporated in vacuo at 60 ^ꢁC to com-

plete the conversion of the unpolar boron ester of the

diol to free diol. The residue was recrystallized from

methylenechloride and n-hexane twice to yield 2.34 g

(58.5%) of 16jj as a white powder: mp 102–105 ^ꢁC; IR

(ﬁlm) 1717, 1604, 1564, 1513, 1489, 1411, 1221, 1158,

835, 764 cm^ꢀ1; MS [EI, M⁺] m/z 449; HR-MS [EI, M⁺]

calcd for C₂₇H₂₈FNO₄m/z 449.2003, found 449.2021;

¹H MNR (300 MHz, CDCl₃) d 1.0 (m, 2H), 1.29 (t, 3H,

J=7 Hz), 1.3–1.6 (m, 2H), 2.3–2.4 (m, 1H), 2.43 (s, 2H),

3.2 (m, 1H), 3.6 (m, 1H), 4.1–4.2 (m, 1H), 4.19 (q, 2H,

J=7 Hz), 4.4 (m, 1H), 5.58 (dd, 1H, J=6, 16 Hz), 6.64

(d, 1H, J=16 Hz), 7.2–7.3 (m, 6H), 7.6 (m, 1H), 7.9–8.0

(m, 1H) ppm; ¹³C NMR (75 MHz, CDCl₃) d 172.5,

1

162.2 (d, J_C-F=246.9 Hz), 160.8, 146.8, 144.2, 139.8,

4

3

133.5 (d, J_C-F=3.5 Hz), 132.0 (d, J_C-F=7.5 Hz), 131.8

3

(d, J_C-F=8.1 Hz), 129.4, 128.9, 128.7, 126.1, 126.0,

2

125.7, 125.4, 115.3 (2C, d, J_C-F=21.3 Hz), 68.0, 60.9,

42.4, 41.5, 15.9, 14.2, 10.3, 10.2 (2C) ppm; The syn/anti

Table 3. Characterization of the target compounds 17a–t

No.

R¹

R²

R³

R⁴

R⁵

Mp (^ꢁC)^a

IR n C¼O (cm^{ꢀ1 b}

)

MALDI-TOFMS (m/z) [MꢀNa+2H]⁺

Without I.S.

With I.S.^c

Calculated for

Measured for

406.2076

17a

17b

17c

17d

17e

17f

17g

17h

17i

i-Pr

c-Pr

i-Pr

c-Pr

i-Pr

c-Pr

H

4-F

H

196–197

207–209

197–199

195–200

193–202

187–200

200–212

178–193

180–189

193–201

203–209

192–197

195–198

193–198

183–187

204–210

204–208

170–175

239–245

234–238

1569

1570

1569

1570

1572

1570

1589

1570

1566

1565

1570

1564

1572

1571

406

424

422

438

440

420

474

436

498

424

474

434

440

458

492

438

420

484

482

C₂₅H₂₈NO₄

406.2013

C₂₅H₂₇NO₄F

424.1919

C₂₅H₂₅NO₄F

422.1762

C₂₆H₂₉NO₄F

438.2075

C₂₅H₂₇NO₄Cl

440.1623

C₂₆H₃₀NO₄

420.2169

C₂₆H₂₇NO₄F₃

474.1887

C₂₆H₃₀NO₅

436.2119

C₃₁H₃₂NO₅

498.2275

C₂₅H₂₇NO₄F

424.1919

C₂₅H₂₆NO₄Cl₂

474.1233

C₂₇H₃₂NO₄

434.2326

C₂₅H₂₇NO₄Cl

440.1623

C₂₅H₂₆NO₄FCl

458.1529

C₂₅H₂₅NO₄FCl₂

492.1139

C₂₅H₂₅NO₄Cl

438.1467

C₂₆H₂₉NO₄F

438.2075

424.1929

422.1852

438.2055

440.1659

420.2215

474.1982

436.2195

498.2338

424.1935

474.1283

434.2390

440.1699

458.1522

492.1232

438.1517

438.2166

420.2194

484.2133

482.2014

4-F

H

4-F

3-Me

H

4-Cl

4-Me

4-CF3

4-OMe

4-OPh

2-F

H

17j

H

17k

17l

2-Cl

3-Me

H

6-Cl

H

5-Me

H

17m

17n

17o

17p

17q

17r

17s

17t

6-Cl

6-Me

7-Me

6-OMe

H

4-F

H

4-F

H

8-Cl

H

4-F

H

C₂₆H₃₀NO₄

420.2169

C₂₇H₃₁NO₆F

484.2130

C₂₇H₂₉NO₆F

482.1973

4-F

H

7-OMe

4-F

H

^aAll compounds melted with decomposition.

^bFilm (3M IR Cards).

^cInternal standard: PEG400.

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2739

ratio of the sample was determined by HPLC (98.2:1.8,

1

444.1587, found 444.1554; ¹H MNR (300 MHz, DMSO-

d₆) d 1.0–1.5 (m, 6H), 1.7–2.1 (m, 2H), 2.5 (m, 1H), 3.5

(m, 1H), 4.1 (m, 1H), 5.61 (dd, 1H, J=6, 16 Hz), 6.49

(d, 1H, J=16 Hz), 7.2–7.4 (m, 6H), 7.6 (m, 1H), 7.86 (d,

1H, J=9 Hz) ppm; ¹³C NMR (75 MHz, DMSO-d₆) d

vide supra) and by H NMR (98 : 2, vide supra).

All other 5-hydroxy-3-keto esters 15aa–qq were analo-

gously converted to the corresponding 3,5-dihydroxy-

esters 16aa–qq.

1

176.4, 161.6 (d, J_C-F=244.6 Hz), 160.6, 145.9, 143.6,

142.4, 133.1 (d, ⁴J_C-F=2.9 Hz), 132.1 (d, ³J_C-F=8.1 Hz),

3

Sodium (E)-3,5-dihydroxy-7-[2-cyclopropyl-4-(4-ﬂuoro-

phenyl)-3-quinolinyl]-hept-6-enoate (step VII in Scheme 2).

0.5 N aqueous sodium hydroxide solution (0.96 mL,

0.48 mmol) was added dropwise to a solution of com-

pound 16jj (0.22 g, 0.49 mmol) in ethanol (10 mL). This

was stirred for 1 h at room temperature. The mixture

was concentrated under reduced pressure, 5 mL of dis-

tilled water was added, washed with diethyl ether, and

the layers were separated. The aqueous layer was ﬁl-

tered, and was freeze-dried to obtain 200 mg (92.0%) of

17jj as a hygroscopic white powder: mp 97–125 ^ꢁC; IR

(ﬁlm) 1602, 1569, 1513, 1489, 1411, 1221, 1158, 1065,

835, 761 cm^ꢀ1; MS [FAB, (M+H)⁺] m/z 444; FAB-

HR-MS [(M+H)⁺] calcd for C₂₅H₂₄FNNaO₄m/z

131.8 (d, J_C-F=8.1 Hz), 129.7, 128.8, 128.4, 125.7,

2

125.6 (2C), 122.9, 115.2 (2C, d, J_C-F=21.3 Hz), 68.8,

65.7, 44.8, 43.5, 15.3, 10.7 (2C) ppm.

All other 3,5-dihydroxyesters 16 were converted to the

corresponding sodium salts 17. The spectra data of 17a–t

and 17aa–qq were shown in Tables 3–6.

Biological evaluations

Inhibition of hepatic cholesterol ‘de novo’ synthesis in vitro.

Compounds 17a–17t were evaluated for their ability to

inhibit hepatic cholesterol ‘De Novo’ synthesis in vitro.

Enzyme solution was prepared from liver of male Wistar

Table 4. Characterization of the target compounds 17aa–qq

No.

R¹

MP (^ꢁC)^a

IR n C¼O (cm^{ꢀ1 b}

)

MS (FAB) (m/z)

FAB-HR-MS

Calculated for

Measured

404.1459

17aa

17bb

17cc

17dd

17ee

17ﬀ

H

Me

139–147

124–130

134–137

139–142

121–138

120–131

91–126

1570

1569

1570

1571

1568

1570

404

[M+H]⁺

418

C₂₂H₂₀FNNaO₄

404.1274

C₂₃H₂₂FNNaO₄

418.1430

C₂₄H₂₄FNNaO₄

432.1587

C₂₅H₂₆FNNaO₄

446.1744

C₂₅H₂₆FNNaO₄

446.1743

C₂₆H₂₈FNNaO₄

460.1900

C₂₆H₂₈FNNaO₄

460.1900

C₂₆H₂₈FNNaO₄

460.1900

C₂₆H₂₈FNNaO4

460.1900

C₂₅H₂₄FNNaO₄

444.1587

C₂₈H₃₀FNNaO₄

486.2056

C₂₈H₂₄FNNaO₄

480.1588

C₂₃H₁₉F₄NnaO₄

472.1147

C₂₃H₂₂FNNaO₅

434.1380

C₂₃H₂₂FNNaO₄S

450.1152

C₂₄H₂₅FN₂NaO₄

447.1696

418.1303

432.1559

446.1805

446.1780

460.1891

460.2015

460.2062

460.1970

444.1554

486.2169

480.1541

472.1194

434.1305

450.1177

447.1620

461.1797

[M+H]⁺

432

Et

[M+H]⁺

446

n-Pr

[M+H]⁺

446

i-Pr

[M+H]⁺

460

n-Bu

[M+H]⁺

460

17gg

17hh

17ii

CH₂CHMe₂

CHMeEt

t-Bu

[M+H]⁺

460

88–124

[M+H]⁺

460

101–132

97–125

[M+H]⁺

444

17jj

c-Pr

[M+H]⁺

486

17kk

17ll

c-Hex

Ph

104–144

112–147

104–116

106–128

116–138

110–133

87–119

[M+H]⁺

480

[M+H]⁺

472

17mm

17nn

17oo

17pp

17qq

CF₃

[M+H]⁺

434

OMe

SMe

[M+H]⁺

450

[M+H]⁺

447

NMe₂

NMeEt

[M+H]⁺

461

C₂₅H₂₇FN₂NaO₄

461.1853

[M+H]⁺

^aAll compounds melted with decomposition.

^bFilm (3M IR Cards).

2740

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

Table 5. ¹H and ¹³C NMR spectra of 17a–t

No.

17a

17b

17c

17d

17e

17f

17g

17h

17i

¹H NMR (d; ppm)

300 MHz in DMSO-d₆

¹³C NMR (d; ppm)^a

75 MHz in DMSO-d₆

C-1

R¹/R²-R⁵

0.8–1.3 (m, 2H), 1.32 (d, 6H, J=7 Hz), 1.7–2.0 (m,

2H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.39 (dd, 1H, J=6,

16 Hz), 6.47 (d, 1H, J=16 Hz), 7.2–7.5 (m, 7H),

7.6 (m, 1H), 7.98 (d, 1H, J=8 Hz)

176.1

43.5

65.6

44.9

68.6

i-Pr: 22.0 (2C), 32.2

0.9–1.3 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.6–2.0 (m,

2H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.39 (dd, 1H, J=6,

16 Hz), 6.47 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H),

7.7 (m, 1H), 7.99 (d, 1H, J=8 Hz)

176.5

176.4

176.3

176.4

176.2

176.0

176.4

43.4

43.5

43.3

43.4

43.7

65.7

64.4

65.7

66.0

65.7

65.9

64.4

44.8

44.7

44.9

44.5

44.9

44.7

44.9

68.6

68.8

68.6

68.7

68.8

68.7

67.2

i-Pr: 22.0 (2C), 32.3

0.9–1.4 (m, 6H), 1.7–2.1 (m, 2H), 2.5 (m, 1H), 3.5 (m,

1H), 4.1 (m, 1H), 5.60 (dd, 1H, J=6, 16 Hz), 6.48

(d, 1H, J=16 Hz), 7.2–7.4 (m, 6H), 7.6 (m, 1H), 7.87

(d, 1H, J=9 Hz)

c-Pr: 10.7 (2C), 15.3

0.9–1.3 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.7–2.1 (m,

2H), 2.28 (s, 3H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.42

(dd, 1H, J=6 and 16 Hz), 6.46 (d, 1H, J=16 Hz),

7.0–7.5 (m, 5H), 7.7 (m, 1H), 7.98 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.3

Me: 14.2

0.9–1.3 (m, 2H), 1.29 (d, 6H, J=7 Hz), 1.7–2.1 (m,

2H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.40 (dd, 1H, J=6,

16 Hz), 6.48 (d, 1H, J=16 Hz), 7.2–7.6 (m, 6H),

7.7 (m, 1H), 7.99 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.3

0.8–1.3 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.7–2.0 (m,

2H), 2.41 (s, 3H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.40

(dd, 1H, J=6, 16 Hz), 6.46 (d, 1H, J=16 Hz),

7.0–7.4 (m, 6H), 7.7 (m, 1H), 7.97 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.2

Me: 20.9

0.7–1.3 (m, 2H), 1.33 (d, 6H, J=7 Hz), 1.6–2.0 (m,

2H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.2–5.4 (m, 1H),

6.50 (d, 1H, J=16 Hz), 7.2–7.9 (m, 7H), 8.01 (d, 1H,

J=8 Hz)

i-Pr: 21.9 (2C), 32.3

0.9–1.3 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.7–2.0 (m,

2H), 3.4–3.6 (m, 2H), 3.85 (s, 3H), 4.1 (m, 1H), 5.40

(dd, 1H, J=6, 16 Hz), 6.46 (d, 1H, J=16 Hz),

7.0–7.5 (m, 6H), 7.7 (m, 1H), 7.96 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.2

OMe: 55.1

1.0–1.4 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.7–2.1 (m,

2H), 3.4–3.6 (m, 2H), 3.85 (s, 3H), 4.1 (m, 1H), 5.41

(dd, 1H, J=6, 16 Hz), 6.51 (d, 1H, J=16 Hz),

7.1–7.5 (m, 11H), 7.7 (m, 1H), 7.98 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.3

i-Pr: 21.9 (2C), 32.4

i-Pr: 21.8 (2C), 32.4

17j

0.8–1.3 (m, 2H), 1.33 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H),

3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.42 (dd, 1H, J=6, 16 Hz),

6.55 (d, 1H, J=16 Hz), 7.2–7.6 (m, 6H), 7.7 (m, 1H), 8.01

(d, 1H, J=8 Hz)

17k

17l

0.8–1.3 (m, 2H), 1.32 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H),

3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.4–5.5 (m, 1H), 6.52 (d, 1H,

J=16 Hz), 7.0–7.7 (m, 6H), 8.04 (d, 1H, J=8 Hz)

176.3

176.4

43.5

43.4

65.5

65.6

44.9

45.1

68.3

68.6

0.8–1.3 (m, 2H), 1.32 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H), 2.32

(s, 6H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.44 (dd, 1H, J=6,

16 Hz), 6.26 (d, 1H, J=16 Hz), 6.8–7.4 (m, 5H), 7.6 (m, 1H),

7.96 (d, 1H, J=8 Hz)

i-Pr: 22.0 (2C), 32.2

Me: 20.9 (2C)

17m

17n

0.8–1.3 (m, 2H), 1.32 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H), 2.32

(s, 6H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.41 (dd, 1H, J=6,

16 Hz), 6.48 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m, 1H),

8.01 (d, 1H, J=8 Hz)

176.4

176.0

43.4

65.5

65.7

44.8

68.4

68.5

i-Pr: 21.9 (2C), 32.3

0.9–1.3 (m, 2H), 1.31 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H),

3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.41 (dd, 1H, J=6, 16 Hz),

6.46 (d, 1H, J=16 Hz), 7.2–7.4 (m, 5H), 7.7 (m, 1H), 8.02 (d,

1H, J=8 Hz)

i-Pr: 21.9 (2C), 32.3

(continued on next page)

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2741

Table 5 (continued)

No.

¹H NMR (d; ppm) 300 MHz in DMSO-d₆

¹³C NMR (d; ppm)^a75 MHz in DMSO-d₆

C-1

R¹/R²-R⁵

17o

17p

17q

0.9–1.3 (m, 2H), 1.34 (d, 6H, J=7 Hz), 1.7–2.1 (m, 2H),

3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.45 (dd, 1H, J=6, 16 Hz),

6.47 (d, 1H, J=16 Hz), 7.1–7.4 (m, 5H), 8.00 (s, 1H)

176.3

43.4

65.6

44.7

68.4

i-Pr: 21.9 (2C), 32.7

c-Pr: 11.0 (2C), 15.4

0.9–1.4 (m, 6H), 1.7–2.0 (m, 2H), 2.5–2.6 (m, 1H), 3.5–3.6

(m, 1H), 4.1 (m, 1H), 5.5–5.7 (m, 1H), 6.50 (d, 1H, J=16 Hz),

7.1–7.7 (m, 7H), 7.88 (d, 1H, J=8 Hz)

176.5

175.8

43.6

43.4

65.5

65.7

44.8

44.9

68.6

68.7

0.9–1.4 (m, 6H), 1.30 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H), 2.34

(s, 3H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.36 (dd, 1H, J=6,

16 Hz), 6.44 (d, 1H, J=16 Hz), 7.0–7.5 (m, 6H), 7.88 (d, 1H,

J=8 Hz)

i-Pr: 22.0 (2C), 32.1

Me: 21.3

17r

17s

0.9–1.4 (m, 2H), 1.30 (d, 6H, J=7 Hz), 1.7–2.1 (m, 2H), 2.48

(s, 3H), 3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.36 (dd, 1H, J=6,

16 Hz), 6.46 (d, 1H, J=16 Hz), 7.1–7.5 (m, 7H), 7.78 (s, 1H)

175.3

176.1

43.2

43.5

65.3

65.8

44.7

44.8

68.6

68.8

i-Pr: 22.1 (2C), 32.2

Me: 21.1

0.9–1.4 (m, 2H), 1.27 (d, 6H, J=7 Hz), 1.7–2.0 (m, 2H), 2.48

(s, 3H), 3.4–3.6 (m, 2H), 3.58 (s, 3H), 3.92 (s, 3H), 4.1 (m,

1H), 5.29 (dd, 1H, J=6, 16 Hz), 6.39 (d, 1H, J=16 Hz),

7.1–7.4 (m, 6H)

i-Pr: 22.2 (2C), 31.9

OMe: 55.2, 55.7

17t

0.9–1.3 (m, 6H), 1.7–2.0 (m, 2H), 2.4–2.5 (m, 1H), 3.4–3.6

(m, 1H), 3.58 (s, 3H), 3.91 (s, 3H), 4.1 (m, 1H), 5.5–5.6 (m,

1H), 6.42 (d, 1H, J=16 Hz), 7.1–7.4 (m, 6H)

176.4

43.6

65.8

44.7

69.0

c-Pr: 10.2 (2C), 15.1

OMe: 55.1, 55.6

^aOnly characteristic signals are shown, because of the complexity caused by contamination of the anti-isomer.

Table 6. ¹H and ¹³C NMR spectra of 17aa–qq

No.

¹H NMR (d; ppm)

300 MHz in DMSO-d₆

¹³C NMR (d; ppm)

75 MHz in DMSO-d₆

17aa

1.4–1.7 (m, 2H), 1.8–2.2 (m, 2H), 3.8 (m, 1H), 4.2 (m, 1H),

6.33 (d, 1H, J=16 Hz), 6.54 (dd, 1H, J=6, 16 Hz), 7.3–7.6

(m, 6H), 7.7 (m, 1H), 8.06 (d, 1H, J=8 Hz), 9.24 (s, 1H)

176.5, 161.9 (d, ¹J_C-F=245.2 Hz), 148.7, 146.5, 142.5,

137.9, 131.9 (2C, d, ³J_C-F=8.1 Hz), 131.6 (d, ⁴J_C-F=2.9

Hz), 129.2, 128.8, 127.6, 127.1, 126.8, 125.8, 122.9,

2

115.7 (2C, d, J_C-F=21.9 Hz), 69.0, 66.0, 44.8, 43.7

17bb

17cc

17dd

17ee

17ﬀ

1.0–1.1 (m, 1H), 1.3–1.4 (m, 1H), 1.7–1.9 (m, 1H), 1.9–2.1 (m,

1H), 2.70 (s, 3H), 3.5 (m, 1H), 4.1 (m, 1H), 5.48 (dd, 1H, J=6,

16 Hz), 6.38 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m,

1H), 7.96 (d, 1H, J=8 Hz)

176.4, 161.6 (d, ¹J_C-F=244.6 Hz),157.4, 145.8, 143.8,

142.1, 133.0 (d, ⁴J_C-F=3.5 Hz), 132.2 (d, ³J_C-F=8.1 Hz),

131.8 (d, ³J_C-F=8.1 Hz), 129.7, 128.7, 128.3, 126.1,

126.0, 125.7, 123.2, 115.3 (2C, d, ²J_C-F=19.6 Hz), 68.8,

65.6, 44.8, 43.5, 24.9

0.9–1.4 (m, 2H), 1.32 (t, 3H, J=7 Hz), 1.7–2.1 (m, 2H), 3.01 (q,

2H, J=7 Hz), 3.5 (m, 1H), 4.1 (m, 1H), 5.42 (dd, 1H, J=6,

16 Hz), 6.43 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m, 1H),

7.99 (d, 1H, J=8 Hz)

176.4, 161.6 (d, ¹J_C-F=244.1 Hz), 161.6, 145.9, 144.1,

142.3, 133.2 (d, ⁴J_C-F=3.5 Hz), 132.2 (d, ³J_C-F=7.5 Hz),

132.0 (d, ³J_C-F=8.1 Hz), 129.6, 128.7, 128.6, 126.0 (2C),

2

125.7, 122.7, 115.2 (d, ²J_C-F=21.3 Hz), 115.1 (d, J_C-F=21.3 Hz),

68.7, 65.7, 44.8, 43.4, 29.6, 12.7

0.9–1.4 (m, 2H), 1.00 (t, 3H, J=7 Hz), 1.7–2.1 (m, 2H), 1.8 (m,

2H), 2.97 (t, 2H, J=8 Hz), 3.5 (m, 1H), 4.1 (m, 1H), 5.41 (dd,

1H, J=6, 16 Hz), 6.43 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H),

7.7 (m, 1H), 7.98 (d, 1H, J=8 Hz)

161.6 (d, ¹J_C-F=244.6 Hz),160.6, 145.9, 144.1, 142.2,

3

133.2 (d, ⁴J_C-F=2.9 Hz), 132.2 (d, J_C-F=8.1 Hz), 132.0

(d, ³J_C-F=8.7 Hz), 129.7, 128.7, 128.6, 126.0 (2C), 125.7,

122.8, 115.2 (d, ²J_C-F=21.9 Hz), 115.1 (d, ²J_C-F=21.9 Hz),

68.7, 65.6, 44.9, 43.4, 38.4, 21.5, 14.1

0.9–1.4 (m, 2H), 1.32 (d, 6H, J=7 Hz), 1.7–2.1 (m, 2H),

3.4–3.6 (m, 2H), 4.1 (m, 1H), 5.40 (dd, 1H, J=6, 16 Hz), 6.48

(d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m, 1H), 7.99 (d, 1H,

J=8 Hz)

176.4, 165.0, 161.5 (d, ¹J_C-F=244.0 Hz), 146.0, 144.3, 142.3,

3

133.4 (d, ⁴J_C-F=2.9 Hz), 132.2 (d, J_C-F=8.1 Hz), 132.0

(d, ³J_C-F=7.5 Hz), 129.5, 128.7, 128.6, 126.0 (2C), 125.7,

122.6, 115.0 (2C, d, ²J_C-F=21.3 Hz), 68.6, 65.7, 44.8, 43.4,

32.3, 22.0 (2C)

0.9–1.5 (m, 2H), 0.95 (t, 3H, J=7 Hz), 1.4 (m, 2H), 1.7–2.1 (m,

2H), 1.8 (m, 2H), 2.99 (t, 2H, J=8 Hz), 3.5 (m, 1H), 4.1 (m,

1H), 5.42 (dd, 1H, J=6, 16 Hz), 6.43 (d, 1H, J=16 Hz),

7.2–7.5 (m, 6H), 7.7 (m, 1H), 7.98 (d, 1H, J=8 Hz)

176.5, 161.6 (d, ¹J_C-F=244.0 Hz), 160.8, 145.9, 144.1,

142.2, 133.2 (d, ⁴J_C-F=3.5 Hz),132.2 (d, ³J_C-F=8.1 Hz),

132.0 (d, ³J_C-F=8.1 Hz),129.7, 128.7, 128.6, 126.0 (2C),

2

125.7, 122.7, 115.2 (d, ²J_C-F=21.3 Hz), 115.1 (d, J_C-F=21.3 Hz),

68.7, 65.7, 44.9, 43.4, 36.1, 30.4, 22.2, 13.9

(continued on next page)

2742

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

Table 6 (continued)

No.

¹H NMR (d; ppm)

300 MHz in DMSO-d₆

¹³C NMR (d; ppm)

75 MHz in DMSO-d₆

17gg

17hh

17ii

0.9–1.5 (m, 2H), 0.96 (d, 6H, J=7 Hz), 1.7–2.1 (m, 2H), 2.3 (m,

1H), 2.89 (d, 2H, J=7 Hz), 3.5 (m, 1H), 4.1 (m, 1H), 5.39 (dd,

1H, J=6, 16 Hz), 6.42 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H),

7.7 (m, 1H), 7.99 (d, 1H, J=8 Hz)

176.4, 161.5 (d, ¹J_C-F=244.0 Hz), 160.1, 145.8, 144.1,

142.3, 133.3 (d, ⁴J_C-F=2.9 Hz), 132.2 (d, ³J_C-F=8.1 Hz),

132.0 (d, ³J_C-F=8.7 Hz), 130.1, 128.7, 128.6, 126.0,

125.9, 125.7, 122.9, 115.2 (2C, d, ²J_C-F=24.2 Hz), 68.6,

65.6, 45.0, 43.4, 27.6, 22.6 (2C)

0.85 (t, 3H, J=7 Hz), 0.9–1.4 (m, 2H), 1.28 (d, 3H, J=6 Hz),

1.5–2.1 (m, 4H), 3.4 (m, 1H), 4.1 (m, 1H), 5.38 (dd, 1H, J=6,

16 Hz), 6.46 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m,

1H), 7.98 (d, 1H, J=8 Hz)

176.5, 164.5, 161.5 (d, ¹J_C-F=244.0 Hz), 146.1, 144.3,

142.3, 133.4 (d, ⁴J_C-F=3.5 Hz), 132.2 (d, ³J_C-F=7.5 Hz),

132.0 (d, ³J_C-F=9.2 Hz), 130.1, 128.7, 128.6, 125.9,

125.8, 125.7, 122.8, 115.1 (2C, d, ²J_C-F=21.3 Hz), 68.6,

65.7, 44.8, 43.4, 29.0, 19.9, 12.1

0.8–0.9 (m, 1H), 1.50 (s, 9H), 1.2–1.3 (m, 1H), 1.7–2.1 (m,

2H), 3.5 (m, 1H), 4.1 (m, 1H), 5.23 (dd, 1H, J=5, 16 Hz),

6.67 (d, 1H, J=16 Hz), 7.2–7.3 (m, 5H), 7.4–7.5 (m, 1H), 7.7

(m, 1H), 7.97 (d, 1H, J=8 Hz)

176.4, 165.6, 161.4 (d, ¹J_C-F=244.0 Hz), 146.1, 144.7,

141.2, 134.1 (d, ⁴J_C-F=3.5 Hz), 132.2 (d, ³J_C-F=8.7 Hz),

132.0 (d, ³J_C-F=8.1 Hz), 130.6, 129.1, 128.7, 126.2,

125.9, 125.6, 125.0, 115.0 (2C, d, ²J_C-F=20.8 Hz), 68.5,

66.0, 44.5, 43.3, 30.1 (3C)

17jj

1.0–1.5 (m, 6H), 1.7–2.1 (m, 2H), 2.5 (m, 1H), 3.5 (m, 1H),

4.1 (m, 1H), 5.61 (dd, 1H, J=6, 16 Hz), 6.49 (d, 1H,

J=16 Hz), 7.2–7.4 (m, 6H), 7.6 (m, 1H), 7.86 (d, 1H,

J=9 Hz)

176.4, 161.6 (d, ¹J_C-F=244.6 Hz), 160.6, 145.9, 143.6, 142.4,

3

133.1 (d, ⁴J_C-F=2.9 Hz), 132.1 (d, J_C-F=8.1 Hz), 131.8 (d,

³J_C-F=8.1 Hz), 129.7, 128.8, 128.4, 125.7, 125.6 (2C), 122.9,

2

115.2 (2C, d, J_C-F=21.3 Hz), 68.8, 65.7, 44.8, 43.5, 15.3,

10.7 (2C)

17kk

17ll

0.9–2.1 (m, 14H), 3.2 (m, 1H), 3.5 (m, 1H), 4.1 (m, 1H),

5.41 (dd, 1H, J=6, 16 Hz), 6.44 (d, 1H, J=16 Hz),

7.2–7.5 (m, 6H), 7.7 (m, 1H), 7.97 (d, 1H, J=8 Hz)

176.4, 164.3, 161.5 (d, ¹J_C-F=244.0 Hz), 146.0, 144.3, 142.2,

3

133.4 (d, ⁴J_C-F=2.9 Hz), 132.2 (d, J_C-F=8.7 Hz), 132.0 (d,

³J_C-F=8.1 Hz), 129.5, 128.7, 128.6, 125.9, 125.8, 125.7, 122.6,

2

115.1 (2C, d, J_C-F=21.9 Hz), 68.6, 65.7, 45.0, 43.4, 42.5, 31.9

(2C), 26.1 (2C), 25.8

0.7–0.9 (m, 1H), 1.1–1.3 (m, 1H), 1.6–2.0 (m, 2H), 3.5 (m,

1H), 3.9 (m, 1H), 5.19 (dd, 1H, J=6, 16 Hz), 6.24 (d,

1H, J=16 Hz), 7.3–7.8 (m, 12H), 8.06 (d, 1H, J=8 Hz)

176.4, 161.7 (d, ¹J_C-F=244.6 Hz), 158.5, 145.9, 145.1, 142.3,

140.9, 133.0 (d, ⁴J_C-F=2.9 Hz), 132.1 (d, ³J_C-F=7.5 Hz), 131.9

(d, ³J_C-F=8.1 Hz), 129.8 (2C), 129.3, 129.1, 128.5, 128.0, 127.8

2

(2C), 126.9, 126.4, 125.8, 123.4, 115.5 (d, J_C-F=20.8 Hz),

115.4 (d, ²J_C-F=21.3 Hz), 68.7, 65.5, 44.6, 43.4

17mm

17nn

17oo

17pp

17qq

0.9–1.0 (m, 1H), 1.2–1.4 (m, 1H), 1.7–2.1 (m, 2H), 3.5 (m,

1H), 4.1 (m, 1H), 5.50 (dd, 1H, J=6, 16 Hz), 6.51 (d,

1H, J=16 Hz), 7.3–7.5 (m, 5H), 7.7 (m, 1H), 7.9 (m, 1H),

8.21 (d, 1H, J=8 Hz)

176.4, 161.9 (d, ¹J_C-F=244.6 Hz), 148.3, 144.8, 144.4, 144.1,

132.2 (2C, d, J_C-F=9.8 Hz), 132.0 (d, J_C-F=3.5 Hz), 130.5,

129.7, 129.4, 128.2 (2C), 126.1, 121.9 (q, J_C-F=276.9 Hz),

119.4, 115.4 (2C, d, ²J_C-F=21.4 Hz), 68.3, 65.7, 44.7, 43.4

3

4

1.1–1.2 (m, 1H), 1.3–1.6 (m, 1H), 1.8–2.1 (m, 2H), 3.6 (m,

1H), 4.08 (s, 3H), 4.1 (m, 1H), 6.08 (dd, 1H, J=6,

16 Hz), 6.30 (d, 1H, J=16 Hz), 7.18 (d, 1H, J=7 Hz), 7.2–7.5

(m, 5H), 7.81 (d, 1H, J=8 Hz)

176.6, 161.8 (d, ¹J_C-F=244.6 Hz), 159.6, 146.4, 144.1, 141.5,

3

132.7 (d, ⁴J_C-F=3.5 Hz), 132.0 (d, J_C-F=8.1 Hz), 131.6 (d,

³J_C-F=7.5 Hz), 129.2, 126.7, 125.9, 124.9, 124.4, 120.4, 120.0,

2

115.6 (2C, d, J_C-F=21.3 Hz), 69.3, 65.8, 53.5, 44.9, 43.6

1.0–1.1 (m, 1H), 1.3–1.4 (m, 1H), 1.7–2.1 (m, 2H), 2.63 (s,

3H),3.6 (m, 1H), 4.1 (m, 1H), 5.62 (dd, 1H, J=6,

16 Hz), 6.29 (d, 1H, J=16 Hz), 7.2–7.5 (m, 6H), 7.7 (m,

1H), 7.93 (d, 1H, J=8 Hz)

176.5, 161.7 (d, ¹J_C-F=244.6 Hz), 159.2, 146.0, 143.5, 143.2,

3

132.5 (d, ⁴J_C-F=3.5 Hz), 132.1 (d, J_C-F=8.1 Hz), 131.9 (d,

³J_C-F=8.1 Hz), 129.2, 128.8, 127.6, 126.0, 125.5, 125.1, 120.6,

2

115.3 (2C, d, J_C-F=21.3 Hz), 68.5, 65.7, 44.8, 43.4, 13.2

1.0–1.1 (m, 1H), 1.3–1.4 (m, 1H), 1.7–2.1 (m, 2H), 2.96

(s, 6H), 3.5–3.6 (m, 1H), 4.1 (m, 1H), 5.58 (dd, 1H, J=6,

16 Hz), 6.28 (d, 1H, J=16 Hz), 7.06 (d, 1H, J=8 Hz), 7.1–7.4

(m, 5H), 7.5 (m, 1H), 7.72 (d, 1H, J=8 Hz)

176.5, 161.5 (d, ¹J_C-F=244.0 Hz), 159.7, 145.7, 145.1, 139.2,

3

133.4 (d, ⁴J_C-F=3.5 Hz), 132.0 (d, J_C-F=8.1 Hz), 131.5 (d,

³J_C-F=8.1 Hz), 128.8, 126.8, 125.7, 124.3, 123.5, 123.4, 122.3,

2

115.3 (2C, d, J_C-F=20.2 Hz), 69.1, 65.8, 44.8, 43.5, 41.8 (2C)

1.0–1.1 (m, 1H), 1.15 (t, 3H, J=7 Hz), 1.3–1.4 (m, 1H),

1.7–2.1 (m, 2H), 2.94 (s, 3H), 3.3 (m, 2H), 3.5 (m, 1H), 4.1

(m, 1H), 5.49 (dd, 1H, J=6, 16 Hz), 6.28 (d, 1H,

J=16 Hz), 7.06 (d, 1H, J=9 Hz), 7.1–7.4 (m, 5H), 7.5 (m,

1H), 7.72 (d, 1H, J=8 Hz)

176.4, 161.5 (d, ¹J_C-F=244.0 Hz), 159.5, 145.6, 145.1, 139.3,

3

133.6 (d, ⁴J_C-F=3.5 Hz), 132.0 (d, J_C-F=7.5 Hz), 131.5 (d,

³J_C-F=8.1 Hz), 128.7, 126.8, 125.7, 124.3, 123.4 (2C), 122.8,

2

115.2 (2C, d, J_C-F=20.8 Hz), 69.1, 65.8, 47.7, 44.8, 43.5,

38.1, 12.5

rat billialy cannulated and discharged bile for over 24 h.

Liver was cut at mid-dark, then the microsomal and

supernatant fractions which could be precipitated with

40–80% saturated ammonium sulfate (sup fraction),

were prepared from liver homogenate according to the

modiﬁed method of Knauss et al.²⁴For the cholesterol

biosynthesis assay, microsome (1.0 mg protein) and sup

fractions (1.0 mg protein) were incubated for 2 h at

37 ^ꢁC in 200 mL of a reaction mixture containing ATP;

1 mM, glutathione; 6 mM, glucose-1-phosphate; 10 mM,

and; 0.25 mM, NADP; 0.25 mM, CoA; 0.04 mM and

0.2 mM sodium [2-¹⁴C] acetate (56 mCi/mmol, 0.2 mCi)

with 4 mL of test compound solution dissolved in water

or dimethyl sulfoxide. To stop the reaction and saponify

the product, 1 mL of 15% EtOH–KOH was added to

the mixture and heated at 75 ^ꢁC for 1 h. Lipids that were

unable to be saponiﬁed were extracted with petroleum

ether and incorporated [¹⁴C] radioactivity was counted.

Inhibitory activity of compounds was followed with

IC₅₀to show the rate of decreased incorporation of

[¹⁴C] acetate into lipids that cannot be saponiﬁed. Rela-

tive potencies were obtained by comparison of IC₅₀values

M. Suzuki et al. / Bioorg. Med. Chem. 9 (2001) 2727–2743

2743

of compounds 17a–17t with that of the internal standard

pravastatin. Pravastatin averaged IC₅₀=4.2 nM and was

assigned a value of 100.²⁵

Ferguson, E.; Krause, B. R.; Newton, R. S.; Sekerke, C.;

Shaw, M. K. J. Med. Chem. 1991, 34, 367.

8. Fehnel, E. A. J. Org. Chem. 1966, 31, 2899.

9. Suzuki, M.; Tanikawa, K.; Sakoda, R. Heterocycles 1999,

50, 479.

Inhibition of solubilized rat liver HMG-CoA reductase in

vitro. The inhibitory activity of compounds 17aa–17qq

on rat liver HMG-CoAreductase was estimated with

soluble-enzyme preparations obtained from the micro-

somal fraction.²⁶The test was performed according to

the method described by Heller.^27a,bHMG-CoAreduc-

tase was isolated from rat liver and incubated with

[¹⁴C]-HMG-CoAand test compounds for 15 min at

37 ^ꢁC. The reaction was terminated by addition of HCl,

and [¹⁴C]-mevalonic acid was separated from the intact

substrate by column ﬁltration. Areference compound,

lovastatin, was tested concurrently at ﬁve concentra-

tions to ensure the validity of the results obtained.

10. Tawada, H.; Natsugari, H.; Ishikawa, E.; Sugiyama, Y.;

Ikeda, H.; Meguro, K. Chem. Pharm. Bull. 1995, 43, 616.

11. Natsugari, H.; Ikeda, H.; Ishimaru, T.; Doi, T. JP Patent

7010844, 1995.

12. Walser, A.; Flynn, T.; Fryer, R. I. J. Heterocycl. Chem.

1975, 12, 737.

13. (a) Leusink, A. J.; Budding, H. A.; Marsman, J. W. J.

Organomet. Chem. 1967, 9, 285. (b) Wollenberg, R. H.; Albi-

zati, K. F.; Peries, R. J. Amer. Chem. Soc. 1977, 99, 7365.

14. The syn/anti ratio of 20 was determined by ¹H NMR

spectroscopy or normal phase HPLC. See the experimental

sections.

15. Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.;

Shapiro, M. J. Tetrahedron Lett. 1987, 28, 155.

16. (a) Ishida, T.; Matsumoto, T. Xenobiotica 1992, 22, 1291

Matsumoto, T., Ishida, T.. (b) Terao, H.; Takeda, Y.; Asa-

kawa, Y. Chem. Pharm. Bull. 1992, 40, 1721. (c) Matsumoto,

T.; Ishida, T.; Takeda, Y.; Soh, K.; Kubo, I.; Sakamoto, M.

Chem. Pharm. Bull. 1995, 43, 216. (d) Riley, P.; Hanzlik, R. P.

Xenobiotica 1994, 24, 1.

17. (a) Mutsukado, M.; Suzuki, M. Abstracts of Papers,

XVIth International Symposium on Medicinal Chemistry,

Bologna, Italy, Sept 18–22, 2000. (b) Mutsukado, M.; Suzuki,

M. Abstracts of Papers, 28th Symposium on Structure–Activ-

ity Relationships, Kyoto, Japan, Oct 26–27, 2000; The Phar-

maceutical Society of Japan: Tokyo, Japan.

Acknowledgements

The authors would like to thank Dr. Wei in Panlabs for

HMG-CoAreductase assays. We wish to acknowledge

valuable discussions with Mr. Motoo Mutsukado, Mr.

Hitoshi Nakabeppu, and Mr. Hiroyuki Narushima. We

also acknowledge Ms. Hisae Miyamoto for chemical

assignments. We are grateful to Dr. Keizo Tanikawa

and Dr. Yoshio Ohara for their continued support and

encouragement of our research.

18. Proposed INN.

19. (a) Kajinami, K.; Koizumi, J.; Ueda, K.; Miyamoto, S.;

Takegoshi, T.; Mabuchi, H. Amer. J. of Cardiol. 2000, 85, 178.

(b) Yamada, N.; Saito, Y.; Akanuma, Y. Abstracts of Papers,

12th Intrenational Symposium on Atherosclerosis, Stockholm,

Sweden, June 25–29, 2000; MoP62:W6. (c) Mabuchi, H.

Abstracts of Papers, 12th Intrenational Symposium on Ather-

osclerosis, Stockholm, Sweden, June 25–29, 2000; MoP81:W6.

(d) Teramoto, T.; Saito, Y.; Nakaya, N. Abstracts of Papers,

12th Intrenational Symposium on Atherosclerosis, Stockholm,

Sweden, June 25–29, 2000; MoP82:W6. (e) Saito, Y.; Goto,

Y. Abstracts of Papers, 12th Intrenational Symposium on

Atherosclerosis, Stockholm, Sweden, June 25–29, 2000;

TuT1:W16.

20. Fujino, H.; Kojima, J.; Yamada, Y.; Kanda, H.; Kimata,

H. Xenobio. Metabol. and Dispos. 1999, 14, 79.

21. (a) Istvan, E. S.; Palnitkar, M.; Buchanan, S. K.; Dei-

senhofer, J. EMBO J. 2000, 19, 819. (b) Istvan, E. S.; Dei-

senhofer, J. Science 2001, 292, 1160.

22. (a) Lothrop, W. C.; Goodwin, P. A. J. Amer. Chem. Soc.

1943, 65, 363. (b) Mulholland, T. P. C.; Ward, G. J. Chem.

Soc 1954, 4676. (c) Scheifele, H. J., Jr.; DeTar, D. F. Org.

Synth. 1952, 32, 8. (d) Scheifele, H. J., Jr.; DeTar, D. F. Org.

Synth. 1963, IV, 34.

23. (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem.

1978, 43, 2087. (b) Soloway, S. B.; LaForge, F. B. J. Amer.

Chem. Soc. 1947, 69, 2677. (c) Wierenga, W.; Skulnick, H. I. J.

Org. Chem. 1979, 44, 310.

References and Notes

1. (a) Meta-analysis: Byington, R. P.; Jukema, J. W.; Salonen,

J. T.; Pitt, B.; Bruschke, A. V.; Hoen, H.; Furberg, C. D.;

Mancini, G. B. Circulation 1995, 92, 2419. (b) WOS: Shep-

herd, J.; Cobbe, S. M.; Ford, I.; Isles, C. G.; Lorimer, A. R.;

MacFarlane, P. W.; McKillop, J. H.; Packard, C. J. N. Engl.

J. Med. 1995, 333, 1301. (c) CARE: Sacks, F. M.; Pfeﬀer,

M. A.; Moye, L. A.; Rouleau, J. L.; Rutherford, J. D.; Cole,

J. G.; Brown, L.; Warnica, J. W.; Arnold, J. M.; Wun, C. C.;

Davis, B. R.; Braunwald, E. N. Engl. J. Med. 1996, 335, 1001.

2. (a) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29,

1346. (b) Brown, A. G.; Smale, T. C.; King, T. J.; Hasenkamp,

R.; Thompson, R. H. J. Chem. Soc. Perkin Trans 1 1976, 1165.

(c) Endo, A. J. Antibiot. 1979, 32, 852. (d) Alberts, A. W.;

Chen, J.; Kuron, G.; Hunt, V.; Huﬀ, J.; Hoﬀman, C.;

Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.; Patchett, A.;

Monaghan, R.; Currie, S.; Stapley, E.; Albers-Schonberg, G.;

Hensens, O.; Hirshﬁeld, J.; Hoogsteen, K.; Liesch, J.;

Springer, J. Proc. Natl. Acad. Sci. U.S.A. 1980, 77, 3957. (e)

Tsujita, Y.; Kuroda, M.; Shimada, Y.; Tanzawa, K.; Arai, M.;

Kaneko, I.; Tanaka, M.; Masuda, H.; Tarumi, C.; Watanabe,

Y. Biochim. Biophys. Acta 1986, 877, 50.

3. (a) Lee, T.-J. Trends Pharm. Sci. 1987, 8, 443. (b) Jahng, Y.

Drugs of the Future 1995, 20, 387 and references therein.

4. Stokker, G. E.; Alberts, A. W.; Anderson, P. S.; Cragoe,

E. J., Jr.; Deana, A. A.; Gilﬁllan, J. L.; Hirshﬁeld, J.; Holtz,

W. J.; Hoﬀman, W. F.; Huﬀ, J. W.; Lee, T. J.; Novello, F. C.;

Prugh, J. D.; Rooney, C. S.; Smith, R. L.; Willard, A. K. J.

Med. Chem. 1986, 29, 170.

5. (a) Kathawala, F. G. Med. Res. Rev. 1991, 11, 121. (b)

Kathawala, F. G. WO Patent 8402131, 1984.

6. Roth, B. D.; Ortwine, D. F.; Hoeﬂe, M. L.; Stratton, C. D.;

Sliskovic, D. R.; Wilson, M. W.; Newton, R. S. J. Med. Chem.

1990, 33, 21.

24. Knauss, H.; Porter, J. W.; Wasson, G. J. Biol. Chem.

1959, 234, 2835.

25. Cohen, L. H.; van Vliet, A.; Roodenburg, L.; Jansen,

L. M. C.; Griﬃoen, M. Biochem. Pharmacol. 1993, 45, 2203.

26. The biological evaluations were conducted by MDS

Pharma Services (formerly MDS Panlabs), PO Box 26-127,

158 Li-The Road, Peitou, Taipei, Taiwan, ROC.

27. (a) Kubo, M.; Strott, C. A. Endocrinology 1987, 120, 214.

(b) Heller, R. A.; Gould, R. G. Biochem. Biophys. Res. Comm.

1973, 50, 859.

7. Sliskovic, D. R.; Picard, J. A.; Roark, W. H.; Roth, B. D.;

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