Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor α subtype-selective activators

J . Med. Chem. 2003, 46, 3581-3599

3581

Design , Syn th esis, a n d Eva lu a tion of Su bstitu ted P h en ylp r op a n oic Acid

Der iva tives a s Hu m a n P er oxisom e P r olifer a tor Activa ted Recep tor Activa tor s.

Discover y of P oten t a n d Hu m a n P er oxisom e P r olifer a tor Activa ted Recep tor r

Su btyp e-Selective Activa tor s

Masahiro Nomura, Takahiro Tanase, Tomohiro Ide, Masaki Tsunoda, Masahiro Suzuki, Hideharu Uchiki,

Koji Murakami, and Hiroyuki Miyachi*

Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1 Mitarai, Nogi-machi, Shimotsuga-gun,

Tochigi 329-0114, J apan

Received November 13, 2002

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-

selective human peroxisome proliferator activated receptor R (PPARR) activators. Structure-

activity relationship studies indicated that the nature and the stereochemistry of the substituent

at the R-position of the head part containing the carboxyl group, the distance between the

carboxyl group and the central benzene ring, the linking group between the central benzene

ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the

molecule all play key roles in determining the potency and selectivity of PPAR subtype

transactivation. This study has led to the identification of potent and human PPARR selective

optically active R-alkylphenylpropanoic acid derivatives, which will be useful not only as

pharmacological tools to investigate the physiology and pathophysiology of PPARR but also as

candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia,

obesity, and diabetes.

In tr od u ction

metabolic abnormalities are due to altered expression

levels of a range of metabolic enzymes.⁶These results

clearly indicate a pivotal role for PPARR in lipid

homeostasis in vivo.

Peroxisome proliferator activated receptors (PPARs)

are members of a huge nuclear hormone receptor

superfamily, a group of nuclear proteins that mediate

the specific effects of small lipophilic compounds, such

as steroids, retinoids, and fatty acids, on DNA tran-

scription. PPARs are heterogeneous, and three subtypes

have been isolated to date: PPARR [NR1C1], PPARδ

[NR1C2] (also known as PPARâ, NUCI, FAAR), and

PPARγ [NR1C3].¹Each PPAR subtype appears to be

differentially expressed in a tissue-specific manner and

to play a pivotal role in lipid and lipoprotein homeosta-

sis. Upon ligand binding, PPARs heterodimerize with

another nuclear receptor partner, retinoid X receptor

(RXR), and the heterodimers regulate gene expression

by binding to specific consensus DNA sequences, termed

PPRE (peroxisome proliferator responsive elements),²

which are located in the regulatory regions of target

genes.³

One of the subtypes, PPARR, which was originally

cloned as an orphan receptor from a mouse liver cDNA

library,⁴has since been cloned from many species,

including humans. PPARR is mostly expressed in organs

with a high rate of fatty acid catabolism, such as liver,

and regulates the expression of the genes encoding for

proteins involved in lipid and lipoprotein metabolism.¹

In mice lacking PPARR (PPARR-/-), inhibition of cellular

fatty acid flux caused massive hepatic and cardiac lipid

accumulation.⁵Detailed mRNA and protein expression

analysis of PPARR-/- mice has indicated that the

The antihyperlipidemic drugs of the fibrate class, such

as clofibrate, bezafibrate, and fenofibrate (Chart 1), are

widely used clinically as hypolipidemic drugs. These

drugs increase HDL cholesterol levels and lower LDL

and VLDL cholesterol levels.⁷Fibrates have a stronger

triglyceride-lowering effect than statins, which are

HMG-CoA reductase inhibitors. These beneficial phar-

macological effects of fibrates are thought to be medi-

ated in part by PPARR activation.⁸Although fibrates

are ligands of PPARs, their affinity is very weak (high

micromolar concentrations are needed to activate PPARR)

and the PPAR subtype-selectivity is poor. Consequently,

in humans, fibrates must be used at very high doses

(about 300-1200 mg/day) to achieve a sufficient lipid-

lowering effect. Therefore, the search for more potent

and selective activators of PPARR, especially human

PPARR, is important. Such activators should be superior

to both fibrates and statins for the treatment of altered

lipid homeostasis in the target organs, especially liver.

Here, we describe the design and synthesis of novel

phenylpropanoic acid derivatives as human PPARR

selective activators,⁹leading to the identification of some

human PPARR selective R-alkylphenylpropanoic acid

derivatives as candidate drugs for the treatment of

metabolic disorders such as hyperlipidemia, obesity, and

diabetes.

To develop structurally new human PPARR selective

activators, we selected KRP-297 (Chart 1) as a lead

compound.¹⁰Although KRP-297 belongs structurally to

* To whom correspondence should be addressed. Phone:

+81-0280-56-2201, extension 286. Fax: +81-0280-57-1293. E-mail:

hiroyuki.miyachi_mb2.kyorin-pharm.co.jp.

Published on Web 07/10/2003

3582 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Ch a r t 1. Chemical Structures of the PPAR Agonists

Nomura et al.

Sch em e 1. Synthetic Routes to the Phenylpropanoic Acids and Related Compounds^a

a

Reagents: (a) (EtO)₂POCH(Et)CO₂Et, NaH, THF; (b) (1) H₂, 10% Pd-C, EtOH, (2) amine, ClCO₂Et, TEA, CH₂Cl₂, (3) aqueous NaOH,

EtOH; (c) (1) (R)₂CdC(OTMS)OMe (R ) Me or Et), Mg(ClO₄)₂, CH₂Cl₂, (2) H₂, 10% Pd-C, EtOH; (d) (1) 4-(CF₃)PhCH₂NH₂, ClCO₂Et,

triethylamine, CH₂Cl₂, (2) same as in (b); (e) same as in (a2); (f) (1) same as in (b1), (2) NaNO₂, HBr, MeOH-acetone, (3) ethyl acrylate,

Cu₂O; (4) NaSR (R ) alkyl, phenyl, benzyl), EtOH, (5) same as in (b3).

Ch em istr y

Synthetic routes to the phenylpropanoic acids and

related compounds prepared in this study are outlined

in Schemes 1-9.

The R-monosubstituted phenylpropanoic acid deriva-

tives (8-20, 65-78) were prepared from 6 via four

F igu r e 1. Chemical structure of the lead compound KRP-

297 (MK-767).

steps. Compound 6, which was prepared from 5-formyl-

salicilic acid, was treated with Emmons reagents, fol-

lowed by hydrogenolysis, condensation with various

amine derivatives, and alkaline hydrolysis to afford the

desired product. The R,R-disubstituted phenylpropanoic

acid derivatives (23, 24) were prepared by the reaction

the glitazones (thiazolidine-2,4-dione class insulin sen-

sitizers), it binds directly to and activates both PPARγ

and PPARR isoforms with almost equal affinity.¹⁰This

is characteristic of classical glitazones, such as trogli-

tazone,¹¹pioglitazone,¹²and rosiglitazone,¹³which were

of 21 (which was prepared from 5-formyl-2-methoxy-

benzoic acid by benzyl esterification, reduction, and

reported to bind to and selectively activate the PPARγ

acylation) with silylketene acetal derivatives,¹⁵followed

isoform.¹⁴The reason KRP-297 exhibits coligand nature

by hydrogenation, condensation, and alkaline hydroly-

is unclear, but we anticipated that the replacement of

sis. Compound 25 was condensed with 4-(trifluorometh-

the thiazolidine-2,4-dione ring of KRP-297 with another

yl)benzylamine, followed by reduction. The Meerwein

acidic functionality, such as a carboxyl group, usually

used in fibrates, might favor PPARR selectivity and

that further chemical modification might improve the

potency and selectivity for the PPARR subtype.

Structurally, KRP-297can be regarded as having

three key regions: (A) the acidic head part, (B) the

linker part, and (C) the hydrophobic tail part (Figure

1). Therefore, chemical modification of each part of the

molecule was performed to understand the structure-

activity relationship in detail.

arylation¹⁶reaction provided the ethyl R-bromophenyl-

propanoate derivative, which was treated with alkyl-

or (aralkyl)mercaptan, followed by alkaline hydrolysis

to afford R-alkyl- (or aralkyl)thio-substituted derivatives

(27-29) (Scheme 1).

The CH₂CONH linker derivative (38) was synthesized

from 33. Oxidation of 33 with activated manganese

dioxide yielded the corresponding aldehyde (34), which

was treated with triethyl 2-phosphonobutyrate followed

by reduction to afford 36. This was converted into the

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3583

Sch em e 2. Synthetic Routes to the Phenylpropanoic Acids and Related Compounds^a

a

Reagents: (g) MnO_2,CH₂Cl₂; (h) (EtO)₂POCH(Et)CO₂Et, NaH, THF; (i) H₂, 10% Pd-C, EtOH; (j) (1) 4-(CF₃)PhCH₂CO₂H, EDCI‚HCl,

CH₂Cl₂, (2) aqueous NaOH, EtOH; (k) (1) 4-(CF₃)PhNCO, EtOH, (2) same as in (j2).

Sch em e 3. Synthetic Routes to the Phenylpropanoic Acids and the Related Compounds^a

a

Reagents: (l) (1) MeSCH(Cl)CO₂Et, TiCl₃, CH₂Cl_2,CCl₄, (2) aqueous NaOH, EtOH, (3) PhCH₂Br, K₂CO₃, DMF; (m) (EtO)₂POCH(Et)CO₂Et,

NaH, THF; (n) Zn, AcOH; (o) H₂, 10% Pd-C, EtOH, (p) (1) 4-(CF₃)PhNH₂, ClCO₂Et, triethylamine, CH₂Cl₂, (2) same as in (l2).

Sch em e 4. Synthetic Routes to the Phenylpropanoic Acids and Related Compounds^a

a

Reagents: (q) AcCl, AlCl₃, CH₂Cl₂; (r) (CO₂Et)₂CO, NaH; (s) 4-(CF₃)PhCH₂Br, NaH, THF; (t) AcOH, concentrated HCl; (u) H₂, 10%

Pd-C, EtOH.

Sch em e 5. Synthetic Routes to the Phenylpropanoic Acids and Related Compounds^a

a

Reagents: (v) 4-(CF₃)PhCH₂CH₂OH, P(Ph)₃, DEAD, THF; (w) (EtO)₂POCH(Et)CO₂Et, NaH, THF; (x) H₂, 10% Pd-C, EtOH; (y) aqueous

NaOH, EtOH.

desired compound (38) by a procedure similar to that

described for the synthesis of 8 (Scheme 2).

The NHCONH linker derivative (40) was also syn-

thesized from 36 by reaction with 4-(trifluoromethyl)-

phenyisocyanate and subsequent alkaline hydrolysis

(Scheme 2).

The CH₂CH₂CH₂linker derivative (52) was synthe-

sized from 44 via five steps. Friedel-Crafts acylation

of 44 followed by ethoxycarbonylation and benzylation

provided 48. Acid-catalyzed decarboxylation and dehy-

droxylation afforded the desired CH₂CH₂CH₂linker

derivative (52) (Scheme 4).

The phenolic hydroxyl group of isovaniline (49) was

alkylated, and the product was treated with triethyl

2-phosphonobutyrate followed by reduction and alkaline

hydrolysis to afford the CH₂CH₂O linker derivative (57)

(Scheme 5).

The CONHCH₂linker derivative (62) was also syn-

thesized from 44. Formylation of 44 followed by

hydroxylamine‚hydrochloride treatment and reduction

Friedel-Crafts reaction of 37 with ethyl 2-chloro-

methylthioacetate, followed by ester exchange, afforded

the benzyl ester (39), which was treated with triethyl

2-phosphonobutyrate. Desulfurization then provided 42,

which was reduced, hydrogenolyzed, and converted into

the desired NHCOCH₂linker derivative (46) by a

procedure similar to that described for the synthesis of

8 (Scheme 3).

3584 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

Sch em e 9. Asymmetric Synthetic Routes to (S)-10^a

Sch em e 6. Synthetic Routes to the Phenylpropanoic

Acids and Related Compounds^a

a

Reagents: (z) TiCl₄, MeOCHCl_2,CH₂Cl₂; (aa) NH₂OH‚HCl,

a

pyridine, EtOH; (bb) H₂, 10% Pd-C, EtOH; (cc) (1) 4-(CF₃)PhCO₂H,

ClCO₂Et, triethylamine, CH₂Cl₂, (2) aqueous NaOH, EtOH; (dd)

(1) 4-(CF₃)PhCH₂Br, K₂CO₃, DMF, (2) same as in (cc2).

Reagents: (gg) LiHMDS, benzyl 5-bromomethyl-2-methoxy-

benzoate, THF; (hh) H₂, 10% Pd-C, EtOH; (ii) 4-(CF₃)PhCH₂NH₂,

ClCO₂Et, TEA, CH₂Cl₂; (jj) LiOH‚H₂O, 30% H₂O₂.

Sch em e 7. Synthetic Routes to Optically Active

(-)-10 was deduced to be R and that of the antipodal

(+)-10 was deduced to be S.⁹

Phenylpropanoic Acids^a

Next, the asymmetric synthesis of R-monosubstituted

phenylpropanoic acid derivatives was exploited for the

large-scale preparation of the desired enantiomer to

provide a sufficient amount for investigation of the in

vivo activity (Scheme 9).²⁰Acylation of 4-(R)-benzylox-

azolidinone provided 79, which was treated with benzyl

5-bromomethyl-2-methoxybenzoate under Evans’s asym-

metric alkylation protocol,²¹followed by hydrogenolysis

to afford the key synthetic intermediate 81. This was

condensed with the appropriate benzylamine derivative,

followed by removal of the chiral auxiliary to afford the

desired (S)-configuration product (Scheme 9). By means

of this procedure, kilogram-scale preparation of the key

intermediate (81) was achieved with high enantiomeric

excess.

a

Reagents: (ee) (1) pivaloyl chloride, NEt₃, THF, (2) 4-(S)-

benzyloxazolidinone, t-BuOK, THF; (ff) LiOH, 30% H₂O₂, MeOH.

Sch em e 8. Synthetic Routes to (R)-10

Biology

The compounds prepared in this study were at first

evaluated for in vitro transactivation activity on human

PPARs transfected into Chinese hamster ovary (CHO)

K1 cells. The compounds that exhibited potent and/or

selective PPARR subtype transactivation activity were

then evaluated further, in vitro and in vivo. The in vitro

activity of the compounds showed some variation from

experiment to experiment. However, the order of efficacy

of the test compounds was reproducible.

afforded 58. This was converted into the desired com-

pound (62) by a procedure similar to that described for

the synthesis of 8 (Scheme 6). Furthermore, 58 was

alkylated and subjected to alkaline hydrolysis to afford

the CH₂NHCH₂linker derivative (64 ) (Scheme 6).

P la sm id s

cDNA encoding for the ligand-binding domain (LBD)

of human PPAR was cloned by reverse transcriptase

polymerase chain reaction (RT-PCR) using total RNA

from a human hepatoma cell line, HepG2. GAL4/human

PPARLBD receptor plasmid was prepared by inserting

the DNA fragment of human PPARLBD into the

pM vector containing the DNA-binding domain (DBD)

of a yeast transcriptional factor, GAL4. pFR-Luc, fire-

fly luciferase reporter plasmid, was purchased from

Stratagene (La J olla, CA). pRL-TK, renilla luciferase

internal standard plasmid, was obtained from Promega

(Madison, WI).

Each enantiomer of compound 10, one of the most

potent compounds, was obtained according to the pro-

cedure reported by Haigh et al.,¹⁷with slight modifica-

tions, i.e., by optical resolution of the corresponding

4-(S)-benzyloxazolidinoneimide derivative of 10, which

was prepared by the reaction of racemic 10 and 4-(S)-

benzyloxazolidinone via the mixed-anhydride method,

followed by alkaline removal of the chiral auxiliary

(Scheme 7).⁹The optical purity of the enantiomers was

estimated to be more than 95%.¹⁸The absolute config-

uration of the optically active 10 was determined by the

preparation of (R)-10, starting from the optically active

(R)-2-benzylbutanoic acid¹⁹(Scheme 8). The (R)-10

exhibited levo rotation, so the absolute configuration of

Tr a n sfection Assa y

CHO-K1 cells were seeded at 5 × 10⁴cells/well in

24-well plates and cultured in Ham’s F12 medium

containing 10% fetal calf serum for 24 h at 37 °C. Cells

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3585

Ta ble 1. Effect of the Acidic Part of the Present Series of

Compounds

were cotransfected for 2 h with 40 ng of GAL4/human

PPAR LBD, 400 ng of pFR-Luc, and 5 ng of pRL-TK

per well using lipofectamine (Gibco BRL, Grand Island,

NY). Transfected cells were treated with various con-

centrations of test compounds at 37 °C for 20 h. Cells

were washed with phosphate-buffered saline and dis-

solved in passive lysis buffer (Promega, Madison, WI).

Luciferase activity was determined with a microplate

luminescence reader, LUCY2 (Anthos, Salzburg, Aus-

tria). The EC₅₀values of tested compounds were derived

from the curve fitting using the Prism program (Graph-

Pad Software, San Diego, CA).

transactivation

EC₅₀(µM)^a

compd

R

PPARR PPARγ PPARδ

4

8

9

CH₂TZD^b

(CH₂)₂CO₂H

1.0

1.3

0.8

ia^c

0.4

ia^c

2.5

ia^c

2.8

ia^c

2.8

ia^c

3.0

>137

ia^c

2.8

3.6

2.4

ia^c

3.0

ia^c

3.0

ia^c

>143

CH₂CH(Me)CO₂H^d

CH₂CH(Et)CO₂H^d

CH₂CH(n-Pr)CO₂H^d

CH₂CH(i-Pr)CO₂H^d

CH₂CH(n-Bu)CO₂H^d

CH₂CH(Ph)CO₂H^d

CH₂CH(OMe)CO₂H^d

CH₂CH(OEt)CO₂H^d

CH₂CH(OPh)CO₂H^d

CH₂C(Me)₂CO₂H

CH₂C(Et)₂CO₂H

CH₂CH(SEt)CO₂H^d

CH₂CH(SPh)CO₂H^d

CH₂CH(SCH₂Ph)CO₂H^d

CO₂H

0.24

0.040

0.36

0.29

1.0

10

11

12

13

14

15

16

17

23

24

27

28

29

30

31

32

An im a ls

ia^c

Male Sprague-Dawley rats were obtained from

Charles River J apan (Yokohama, J apan). All rats were

given a standard diet CE-2 (CLEA J apan, Tokyo, J apan)

and tap water ad libitum. (S)-10 or vehicle was sus-

pended in 0.5% (w/v) Arabic gum and administered

orally to 11-week-old SD rats once a day at 0.3, 3, or 30

mg/kg for 4 days. In the fructose diet study, all rats were

given an AIN-93 modified fructose diet (Oriental Yeast,

Tokyo, J apan) after having been deprived of food for 2

days, with tap water ad libitum. (S)-10 (10, 30 mg/kg),

bezafibrate (30 mg/kg), or vehicle was administered

orally to 11-week-old SD rats once a day for 4 days. At

the end of the treatment period, plasma samples were

obtained.

0.23

1.6

ia^c

2.9

2.8

1.6

ia^c

CH₂CO₂H

(CH₂)₃CO₂H

ia^c

2.2

>78

bezafibrate

a

Compounds were screened for agonist activity on PPAR-GAL4

chimeric receptors in transiently transfected CHO-K1 cells as

described. EC₅₀value is the molar concentration of the test

compound that causes 50% of the maximal reporter activity. n )

b

3. KRP-297. Data taken from ref 10. ^c“ia” means inactive at a

Deter m in a tion of Ser u m P a r a m eter s

d

concentration of 10 µM. Assayed as a racemate.

Plasma total cholesterol and free fatty acid levels were

determined by means of an enzymatic method using

Cholesterol E Test Wako and NEFA C Test Wako (Wako

Pure Chemical Industries, Osaka, J apan). Plasma tri-

glyceride levels were determined with a triglyceride

assay kit (Roche Diagnostics K. K., Tokyo, J apan).

Serum lipoproteins were separated to afford the HDL

fraction by using a precipitation reagent (Wako Pure

Chemical Industries). The supernatant was used for

cholesterol determination of HDL cholesterol. Total

cholesterol content of unfractionated whole serum and

that of the HDL fraction were determined by an

enzymatic method. VLDL and LDL cholesterol levels

were calculated as follows: total cholesterol level minus

HDL cholesterol level. Hepatic triglyceride content and

total cholesterol content were measured by an enzy-

matic procedure as described for plasma triglyceride and

cholesterol after extraction of total tissue lipid with

chloroform-methanol. Hepatic triglyceride content and

total cholesterol content were expressed as milligrams

of triglyceride or total cholesterol per gram of tissue wet

weight.

1).⁹The benzoic acid and phenylacetic acid derivatives

(30 and 31) were inactive at 10 µM, but the phenyl-

propanoic acid derivative (8) exhibited transactivation

activity, comparable to that of the lead compound (4).

Further elongation of the methylene chain to give

the phenylbutanoic acid derivative (32) decreased the

activity to some extent.

On the other hand, these surrogates (30-32) were

weak activators (32) or inactive (30, 31) at 10 µM on

PPARγ. These results support the prevailing hypothesis

that the thiazolidine-2,4-dione ring structure is a good

pharmacophore for potent and selective PPARγ trans-

activation activity.²³Furthermore, these surrogates (8,

30, 31, and 32) were also inactive at 10 µM on PPAR δ.

Considering that 8 possessed distinct (micromolar

order) PPARR transactivation activity and PPARR

subtype selectivity, we selected 8 as the next lead

compound and performed further chemical modification

focused on the R-position of the carboxyl group of 8. We

anticipated that the introduction of certain shapes of

substituents at the R-position of the carboxyl group of

8 would enhance the PPARR transactivation activity,

based on the results obtained from the X-ray crystal-

lographic analysis of the human PPARγ-rosiglitazone

complex.²⁴

Resu lts a n d Discu ssion

The transactivation activity of the present series of

compounds toward human PPARs is summarized in

Tables 1-3, together with the results for fibrates. The

fibrate class of antihyperlipidemic agents, such as beza-

fibrate and fenofibrate, exhibited weak and nonselective

PPARs activation, in accordance with reported data.²²

Str u ctu r e-Activity Rela tion sh ip : Effect of th e

Acid ic Hea d P a r t. For activity on the PPARR isoform,

the distance between the carboxyl group and the right

side benzene ring in the compound is important (Table

As also indicated in Table 1, introduction of appropri-

ate alkyl substituents at the R-position of the carboxyl

group of 8 strikingly affected PPARR transactivation

activity and subtype selectivity. Introduction of a methyl

group (9) increased the effect on PPARR transactivation

activity to some extent, but introduction of an ethyl

group (10) greatly enhanced the activity. Bulkier sub-

stituents generally decreased the activity. These data

3586 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

Ta ble 2. Effect of the Linker Part of the Present Series of

Compounds

group (18, 19) considerably decreased the activity. The

compounds with a secondary amide bond (-NHCO-)

(10, 46) or reversed secondary amide bond (-CONH-)

(38, 62) exhibited almost equipotent transactivation

activity, whereas other compounds with a three-atom

unit as a linking group showed moderate (51, 52, 57)

or weak activity (64). The tertiary amide derivative (20)

and urea-type derivative (40) did not show transacti-

vation activity at 10 µM. It is well recognized that the

three-dimensional distance and the alignment of the

acidic head part and the hydrophobic tail part of the

molecule are important for potent PPAR transactivation

activity.²⁶Therefore, we speculated that the two phar-

macophores of molecules with amide-type linkers (10,

46) and reversed amide-type linkers (38, 62) having a

three-atom unit are positioned favorably in the large

binding pocket of PPARR. In contrast, the two pharma-

cophores of molecules with other three-atom unit linkers

(51, 52, and 57) are not located at the proper position

in the binding pocket probably because of conforma-

tional flexibility of the linkers. Further, we thought that

the urea-type and the tertiary amide compounds (40,

20) did not form favorable conformations for potent

transactivation activity toward PPARR owing to the

introduction of the planar ureido bond or the existence

of cis/trans isomers (¹H NMR study indicated that 20

exists as a 2:1 mixture of regioisomers in CDCl₃). The

hydrogen-bonding interaction between the linker part

and the PPARR backbone might not be crucial because

all the secondary amide linker compounds exhibited

equipotent transactivation activity, although these com-

pounds have various kinds of amide bonds with respect

to position and alignment.

transactivation

EC₅₀(µM)^a

compd

A

PPARR

PPARγ

PPARδ

10

18

19

20

38

40

46

51

52

57

62

64

CH₂NHCO^c

NHCO^c

0.04

6.0

0.4

ia^b

3.6

ia^b

(CH₂)₂NHCO^c

CH₂N(CH₃)CO^c

CH₂CONH^c

NHCONH^c

0.74

ia^b

1.5

ia^b

0.13

ia^b

c

NHCOCH₂

0.02

0.32

0.86

0.68

0.04

4.9

ia^b

CH₂CH₂CO^c

7.4

ia^b

c

CH₂CH₂CH₂

ia^b

0.64

0.40

0.12

8.0

CH₂CH₂O^c

CONHCH₂

ia^b

c

>10

c

CH₂NHCH₂

ia^b

bezafibrate

>78

>137

>143

a

Compounds were screened for agonist activity on PPAR-GAL4

chimeric receptors in transiently transfected CHO-K1 cells as

described. EC₅₀value is the molar concentration of the test

compound that causes 50% of the maximal reporter activity. n )

b

3. “ia” means inactive at a concentration of 10 µM. ^cAssayed as

a racemate.

indicated that there are distinct structural requirements

for potent PPARR transactivation activity, and the ethyl

group is the most favorable.

On the other hand, as regards the PPARγ and PPARδ

isoforms, most of the compounds listed in Table 1 were

inactive at 10 µM. Thus, most of these R-alkyl-substi-

tuted derivatives have preferentiality on PPARR.

A similar tendency was seen in the case of R-alkoxy-

and R-alkylthio-substituted derivatives except for 16

and 27. Although some other structural types of R-ethoxy-

and R-ethylthio-substituted phenylpropanoic acid de-

rivatives were reported to exhibit potent PPAR trans-

activation activity,²⁵compounds bearing these substit-

uents in the present series exhibited weak transactivation

activity on all PPAR isoforms. Compounds 16 and 27

showed weak activity and poor subtype selectivity (pan-

agonistic activity), although the reason is not known.

Introduction of one more substituent at the R-position

of the R-monosubstituted phenylpropanoic acid deriva-

tives is unfavorable for PPARR activity; i.e., the R,R-

dimethyl- and the R,R-diethyl-substituted derivatives

(23, 24) exhibited decreased PPARR transactivation

activity compared to the corresponding R-monosubsti-

tuted compounds (9, 10).

Almost all the compounds listed in Table 1 showed

no significant PPARδ transactivation activity. These

results might indicate that the structural requirements

for transactivation of PPARδ are more restrictive,

though this isoform is ubiquitously expressed in many

organs and tissues²²(structural requirements for PPARδ

agonists will be discussed later).

Str u ctu r e-Activity Rela tion sh ip : Effect of th e

Lin ker P ar t. Interesting subtype-selective PPAR trans-

activation profiles were obtained by manipulation of the

linker part of 10 (Table 2). In the case of the PPARR

isoform, the length of the linking group is important for

potency. The transactivation activity of 10 (three-atom

unit, -C(H₂)-N(H)-C(O)-) was very potent, but short-

ening or lengthening (especially shortening) the linking

It has been determined on the basis of an X-ray

crystallographic study that potent PPARs agonists such

as rosiglitazone (PPARγ agonist; Chart 1) and AZ-242

(dual agonist of PPARγ and PPARR; Chart 1)²⁷take a

“U”-shaped conformation, wrapping around the helix 3

(H3) region of each PPAR with the central benzene ring

directly behind H3 and the acidic headgroup and

hydrophobic tail group wrapping around H3.²⁴There-

fore, we speculate that the potent PPARR activators in

the present series of compounds, such as 10 and 46,

might form “U”-shaped conformations, while the less

potent derivatives, such as 57 and 40, might not form

a proper “U”-shaped conformation probably because of

conformational flexibility or conformational restriction.

To investigate this point, computer-aided conforma-

tional analysis of representative compounds (10, 40, 46,

57) was performed using the Insight 2/Discover 3²⁸

system. The common part of the molecules, the 2-[4-

(methoxyphenyl)methyl]butyric acid moiety, was used

as an anchor. The anchor part of each molecule was

built using the crystal structure of GW 409544 bound

to the PPAR ligand binding domain homodimer (PDB

code 1k7l) as the reference structure. For the chiral

center of the R-position of the carboxyl group, the S-form

(the binding isomer) was used. The conformations of

each molecule were searched by a systematic rotation

of torsion angles. During the search, the structure of

the anchor moiety was fixed, while the conformation of

the rest of the molecule was calculated for each con-

former. The energies of conformations were minimized

with the cvff force field (conjugate gradient method and

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3587

because of the planar and transoid-preferential nature

of the ureido linkage. These data clearly support our

speculation.

In contrast to the activity toward PPARR, which

ranges over more than 2 orders of magnitude, none of

the compounds, except 10 and 51, exhibited significant

PPARγ transactivation activity at 10 µM. These results

might indicate that the chemical modification of the

linker part produced an unfavorable orientation of the

two pharmacophores for proper binding to the large

binding pocket of PPARγ.

F igu r e 2. Effect of the stereochemistry of the substituent

introduced at the R-position of the carboxylic acid group on

transactivation to PPARR.

As for PPARδ, the methylene linker compound (52)

and the ether linker compound (57), which showed

about 10-fold less potent PPARR transactivation activity

compared to 10, exhibited much more potent PPARδ

transactivation activity (about 5- to 9-fold more potent)

than 10. Improvement of PPARδ transactivation activity

rendered these compounds moderately potent dual

activators of PPARR and PPARδ. Recent X-ray crystal-

lographic studies of PPARδ and a naturally occurring

unsaturated fatty acid, eicosapentaenoic acid (EPA)

(Chart 1), which is a pan-agonist of PPARs, revealed

that EPA occupied the ligand binding pocket of PPARδ

in two distinct conformations (tail-up and tail-down

conformations).²⁹The numerous hydrophobic contacts

between the hydrophobic tail part of EPA and the

binding pocket of PPARδ are likely to be important for

potency. Therefore, we considered that the introduction

of flexible linkers, such as the methylene linker and the

ether linker, improved the conformational flexibility of

the hydrophobic tail part of 52 and 57, and as a result,

these compounds were stabilized through numerous

hydrophobic interactions with the PPARδ ligand binding

pocket.

0.01 kcal/mol energy convergence criterion). Figure 2

shows the rotated bonds and torsion angle values used

to generate conformers for each representative com-

pound, and the analytical results are summarized in

Figures 3 and 4. In the case of 10 and 46, which showed

potent PPARR transactivation activity, about 70 and

200 conformers, respectively, out of 845 conformers were

calculated to form “U”-shaped conformations having an

energy of no more than 0.3 kcal/mol above the minimum

energy structure (relative existence probability (RE)

versus the minimum energy structure was estimated

to be 65% and 61% for 10 and 46, respectively). In the

case of 57, only 10 conformers out of 10 985 conformers

was calculated to form “U”-shaped conformations, but

these conformers were energetically unfavorable, being

about 3.7 kcal/mol above the minimum energy structure

of 57 (RE was estimated to be only 0.2%). Moreover, the

ureido linker compound (40) was proved not to form “U”-

shaped conformations (RE was estimated to be 0%)

F igu r e 3. Chemical structures and torsion angle definitions of 10, 40, 46, and 57, together with values assigned in the systematic

search.

3588 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

F igu r e 4. Schematic presentation of a representative “U”-shaped conformation of 10 and 46 together with potential energy

results from the systematic search of the generated conformers: RE, relative existence probability versus minimum energy

conformer; ∆E, potential energy difference versus minimum energy conformer. Red circle indicates the area of the “U”-shaped

conformer.

Ta ble 3. Effect of the Substituents Introduced at the Left

Benzene Ring

An exceptionally interesting compound is 62, which

has the CONHCH₂group as a linker. Although almost

all amide-containing-linkers are unfavorable for PPARδ

activity, 62 exhibited potent PPARδ transactivation

activity compared to 10, with comparably potent PPARR

transactivation activity. Therefore, 62 is a dual activator

of PPARR and PPARδ, although the reason 62 showed

potency against PPARδ is not known.

transactivation

EC₅₀(µM)^a

compd

R²

PPARR

PPARγ

PPARδ

Although our primary goal in the present study was

to discover potent PPARR activators as candidate drugs

for the treatment of altered lipid and lipoprotein homeo-

stasis, 62 be of potential value as a dual activator of

PPARR and PPARδ, since a recent publication indicated

that PPARδ plays a key role in cholesterol metabolism

by contributing to reverse cholesterol transport.³⁰

Str u ctu r e-Activity Rela tion sh ip : Effect of th e

Su bstitu en t a t th e Hyd r op h obic Ta il P a r t. The

nonsubstituted compound (65) exhibited moderate

PPARR transactivation activity (Table 3). Introduction

of a small substituent such as a chlorine atom or

methoxyl group (66, 69-71) did not affect the activity,

but the introduction of a CF₃or an OCF₃group,

especially at the 4 position, greatly increased the

activity. The increase in activity might be explained by

the positive contribution of the steric effect and/or the

hydrophobic nature of the fluorine atoms of these groups

in binding to the hydrophobic ligand-binding pocket of

PPARR. In this case, the position of the substituent

introduced at the benzene ring is important because 67,

which has a CF₃group at the 3 position of the benzene

ring, did not show superior PPARR transactivation

65

66

67

10

68

69

70

71

72

73

74

7/5

76

77

78

H^c

2.3

3.0

1.8

0.040

0.043

9.4

10.0

ia^b

4-Cl^c

3-CF₃

4-CF₃

ia^b

c

0.4

3.6

0.90

ia^b

c

4-OCF₃

2-OCH₃

3-OCH₃

4-OCH₃

2-OPh^c

3-OPh^c

4-OPh^c

4-Ph^c

ia^b

c

3.1

nd^d

ia^b

1.2

6.60

ia^b

0.40

0.090

0.11

1.5

5.6

2.7

6.2

2.4

4.0

ia^b

5.4

3.0

>137

ia^b

3.0

ia^b

4-OCH₂Ph^c

ia^b

4-CH₂CH₂Ph^c

ia^b

4-OCH₂CH₂Ph^c

ia^b

bezafibrate

>78

>143

a

Compounds were screened for agonist activity on PPAR-GAL4

chimeric receptors in transiently transfected CHO-K1 cells as

described. EC₅₀value is the molar concentration of the test

compound that causes 50% of the maximal reporter activity. n )

b

3. “ia” means inactive at a concentration of 10 µM. ^cAssayed as

d

a racemate. nd means not determined.

activity compared with 65. On the other hand, some

compounds in which the benzene ring contains substit-

uents such as phenoxyl (74) and phenyl (75) also

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3589

exhibited potent PPARR transactivation activity. In this

case, the position of the introduced substituent is also

important, since the introduction of the phenoxyl group

at the 2 or 3 position of the benzene ring (72, 73)

decreased PPARR transactivation activity, especially in

the case of the 2-phenoxyl group. The distance between

the two phenyl groups is also important. Simple phen-

oxyl and phenyl groups are preferable, and benxyloxyl

(76), phenetyl (77), and phenetyloxyl (78) groups de-

creased the activity considerably.

As regards PPARγ and PPARδ transactivation activ-

ity, all compounds except 10 and 68 are weak activators.

Compound 68, which exhibited potent PPARR trans-

activation activity comparable to that of 10, exhibited

very weak PPARγ transactivation activity but signifi-

cant PPARδ transactivation activity. Therefore, 10

exhibited a much higher R/δ selectivity ratio compared

to that of 68, while the R/γ selectivity ratio is reversed

between the two compounds. It is of interest to note that

the subtype-selectivity ratio can be dramatically changed

by a small manipulation of the substituents at the

peripheral benzene ring. These results might indicate

that the shape and environment of the hydrophobic

cavity hosting the 4-substituted benzene ring differ

somewhat among the three PPAR isoforms.

F igu r e 5. Schematic presentation of a representative “U”-

shaped conformation of 40 and 57 together with potential

energy results from the systematic search of the generated

conformers: RE, relative existence probability versus mini-

mum energy conformer; ∆E, potential energy difference versus

minimum energy conformer. Red circle indicates the area of

the “U”-shaped conformer.

Str u ctu r e-Activity Rela tion sh ip : Effect of th e

Ster eoch em istr y of th e r-P osition of th e Ca r boxyl

Gr ou p . The compounds that have substituents at the

R-position of the carboxyl group discussed above were

assayed as racemates. It has already been reported that

the in vitro and in vivo pharmacological properties of

other structural series of R-alkoxyphenylpropanoic acid

derivatives differ between the enantiomers.³¹Therefore,

we decided to investigate the enantio-dependent trans-

activation activity of a representative compound, opti-

cally active 10, on PPARR isoform. Compound 10 has

an asymmetric center at the R-position of the carboxylic

acid functionality, and it is important to determine

which enantiomer is the true eutomer.⁹

Optically active 10 ((+)-10 and (-)-10) was obtained

by optical resolution (Scheme 7), and the absolute

configuration was determined by the preparation of the

(R)-form of 10 starting from optically active (R)-2-

benzylbutanoic acid (Scheme 8).⁹

As can be seen from Figure 5, a clear enantio

dependence of the transactivation activity toward the

PPARR isoform was found. (S)-10 exhibited much more

potent transactivation activity, while the antipodal (R)-

10 exhibited less potency. Therefore, we concluded that

the activity was found to reside almost exclusively in

the (S)-enantiomer.

In the case of rosiglitazone, a potent and selective

PPARγ agonist used for the treatment of non-insulin-

dependent diabetes mellitus (type 2 diabetes), enantio

dependency was also noted and (S)-rosiglitazone exhib-

ited much more potent binding to PPARγ than (R)-

rosiglitazone.³²However, the enantio dependency of (S)-

rosiglitazone decreased time-dependently probably

because of rapid racemization at the C-5 position of the

thiazolidine-2,4-dione ring at physiological pH.³³There-

fore, rosiglitazone is optically labile and was launched

as a racemate. However, unlike rosiglitazone, (S)-10 is

expected to be a potent and optically stable agent for

the treatment of metabolic disorders.

F igu r e 6. Summary of the SAR of the present series of

compounds.

The X-ray crystallographic analysis of the ligand

binding domain in the complex with the dual PPARR

and PPARγ agonist AZ 242 (an R-ethoxyphenylpro-

panoic acid derivative) indicated that the side chain

ethoxyl group of AZ 242 is positioned in a hydrophobic

region of the PPARR ligand binding pocket, surrounded

by the side chains of the amino acids Phe273, Cys276,

Ile354, and Met355.²⁷Because the three-dimensional

structure of the acidic head part of (S)-10 appears to be

quite similar to that of AZ 242, we speculated that the

side chain ethyl group of (S)-10 interacts hydrophobi-

cally with the same region of the PPARR ligand-binding

pocket. In contrast to AZ 242 (having an ethoxyl group

(three-atom unit) as a substituent at the R-position of

the carboxylic acid), the two-carbon ethyl group was the

most potent R-substituent in the present series of

compounds. This difference in length may indicate that

the ethyl group of (S)-10 is located deeper in the

hydrophobic pocket formed by the side chains of Phe273,

Cys276, Ile354, and Met355.

Figure 6 summarizes the structure-activity relation-

ships of the present series of compounds.

Sp ecies-Dep en d en t P P ARr Tr a n sa ctiva tion by

th e P r esen t Ser ies of Com p ou n d s. Some peroxisome

proliferators show species-dependent transactivation

characteristics for PPARR.³⁴The classical PPARR ago-

nist WY-14643 is more effective on rodent PPARR than

on human PPARR. Moreover, GW-9578, a recently

disclosed ureidothioisobutyric acid derivative with po-

tent PPARR activity, also transactivates rodent PPARR

3590 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

Ta ble 4. Species Differences in the Transactivation of PPARR

Isoform

Ta ble 5. Influence of (S)-10 on Serum Lipid Parameters in

Rats

transactivation

% reduction after 5 days of oral dosing^a

total LDL, VLDL

FFA cholesterol cholesterol

EC₅₀(µM)^a

compd

(S)-10

fenofibrate

human

dog

rat

treatment

TG

0.06

41

0.16

50

5.2

49

0.3 mg/kg

3 mg/kg

30 mg/kg

bezafibrate, 30 mg/kg

15

25

56

41

12

28

69

46

22

29

35

27

29

58

60

22

a

Compounds were screened for agonist activity on PPAR-GAL4

chimeric receptors in transiently transfected CHO-K1 cells as

described. EC₅₀value is the molar concentration of the test

compound that causes 50% of the maximal reporter activity.

n ) 3.

a

Data represent the mean of the percent reduction. N ) 5 or 6.

Normal SD rats were treated as descried in the text. Blood samples

from animals in the fed state were analyzed for triglycerides

(TG), free fatty acids (FFA), total cholesterol, and LDL, VLDL

cholesterol.

preferentially over human PPARR.³⁵5,8,11,14-Eicosa-

tetraynoic acid (ETYA) showed the reverse preference;

i.e., it is 10-fold more effective on human PPARR than

rodent PPARR. On the other hand, clofibric acid and

fenofibric acid, which are active metabolites of the

fibrate class antihyperlipidemic agents clofibrate and

fenofibrate, respectively, did not show clear species

differences. Therefore, three types of PPARR activators

have been identified to date, i.e., rodent-selective, human-

selective, and non-species-selective PPARR activators.

For clinical application, the human PPARR selective

nature would be preferred, so we evaluated the species-

selective PPARR transactivation profile of (S)-10.

As can be seen from Table 4, (S)-10 activated human,

dog, and rat PPARR with EC₅₀values of 0.06, 0.16, and

5.2 µM, respectively. Thus, to our surprise, (S)-10

showed species preference for humans and the trans-

activation activity of (S)-10 for PPARR was approxi-

mately 100-fold and 30-fold less potent in rats than in

humans and dogs, respectively.

The (S)-10 was thus proved to be a highly potent,

subtype-selective, and species-selective PPARR activa-

tor. It exhibited potent activity on human PPARR, with

a higher species selectivity over rats than ETYA.

Although the reason (S)-10 exhibits human selectivity

is not yet known, we speculate that the species-depend-

ent differences in activation by (S)-10 may be related

to different affinities of (S)-10 for the three different

PPARR receptors. To understand the situation at the

molecular level, mutational studies using chimeric

PPARR are in progress.

investigated whether activation of PPARR by (S)-10

might be a possible option to treat obesity-related

steatosis and associated complications. As can be seen

from Table 6, oral dosing of (S)-10 (30 mg/kg) for 5 days

to fructose-fed fatty-liver rats effectively lowered the

hepatic levels of both triglyceride (by 80%) and total

cholesterol (by 50%). The effect was much more potent

than that of a representative fibrate, bezafibrate (30 mg/

kg).

In summary, we have developed the potent human

PPARR selective activator (S)-10, which possesses much

more potent PPARR transactivation activity with higher

selectivity for PPARR over other PPAR isoforms com-

pared to those of classical fibrates. Further in vivo

pharmacological evaluation of (S)-10 and related com-

pounds is underway.

Exp er im en ta l Section

Gen er a l. Melting points were determined on a Yanagimoto

1

micromelting point apparatus and are uncorrected. H NMR

spectra were measured in CDCl₃or DMSO-d₆with TMS and

the solvent peak as internal standards, on a J EOL J MN-A400

spectrometer. Mass spectra (MS) were obtained on a J EOL

J MS-HX110 spectrometer. Column chromatography was car-

ried out on Merck silica gel 60. Analytical thin-layer chroma-

tography (TLC) was performed on Merck precoated silica gel

60F₂₅₄plates, and the compounds were visualized by UV

illumination (254 nm) or by heating after spraying with

phosphomolybdic acid in ethanol. Elemental analysis was

performed in the microanalytical laboratory of Kyorin Phar-

maceutical Co., Ltd.

In Vivo P h a r m a cology. To determine the ability of

(S)-10 to impact lipid/cholesterol homeostasis, normal

rats were used to investigate the effects of (S)-10 on the

serum levels of triglyceride, free fatty acid, total cho-

lesterol, and the sum of LDL and VLDL cholesterol.

When administered orally to normal rats (N ) 5) once

a day for 5 days, (S)-10 (0.3, 3, and 30 mg/kg) lowered

the serum levels of triglyceride (-1%, 26%, and 33%),

free fatty acid (11%, 27%, and 72%), total cholesterol

(19%, 26%, and 32%), and the sum of LDL and VLDL

cholesterol (46%, 56%, and 58%) in a dose-dependent

fashion (Table 5). Upon withdrawal of (S)-10, the serum

levels of all parameters recovered to the pretreat-

ment levels (data not shown). The finding that (S)-10

effectively lowered both triglyceride and total cholesterol

indicates that (S)-10 might have therapeutic advantages

over statins in the treatment of hyperlipidemia and

atherosclerosis, since currently marketed statins do not

effectively lower serum triglyceride.

Ch em ica ls. Syntheses and physicochemical properties of

30-32 were described previously.⁹

Eth yl (3-Ben zyloxyca r bon yl-4-m eth oxyp h en yl)-2-eth -

yla cr yla te (7). Sodium hydride (214 mg, 5.35 mmol; 60% oil

dispersion) was suspended in 10 mL of dehydrated tetra-

hydrofuran under argon and cooled with ice. Triethyl 2-phos-

phonobutyrate (1.34 g, 5.31 mmol) dissolved in 20 mL of

dehydrated tetrahydrofuran was added dropwise. When the

addition was completed, the mixture was stirred for 1 h, and

then benzyl 5-formyl-2-methoxybenzoate (1.44 g, 5.33 mmol)

dissolved in 25 mL of dehydrated tetrahydrofuran was added

dropwise. When the addition was completed, the mixture was

stirred for a further 4.5 h at room temperature and then

poured into ice/water. The whole was extracted with ethyl

acetate, and the organic phase was washed with water and

brine, dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by silica gel column chromatography

(eluant, n-hexane/ethyl acetate ) 5:1 v/v) to afford 1.45 g (74%)

of the title compound as a yellow oil.

This product (4.00 g, 10.9 mmol) was dissolved in 200 mL

of ethanol, 10% palladium on carbon (1.10 g) was added, and

hydrogenation was carried out for 3 h at an initial pressure of

353 kPa. After completion of the reaction, the catalyst was

removed by filtration and the filtrate was concentrated to

Since PPARR is highly expressed in the liver¹and is

a potent activator of hepatic fatty acid oxidation, we

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3591

Ta ble 6. Influence of(S)-10 on Serum Total Cholesterol and Triglyceride Levels in Rats^a

a

Data represent the mean ( SE. N ) 5. Fructose diet fed SD rats were treated as described in the text. Heparic triglycerides and total

cholesterol accumulation were measured in rats given the fructose diet with or without the indicated treatment.

afford 3.0 g (98%) of ethyl 3-(3-carboxy-4-methoxyphenyl)-2-

ethylpropionate as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ

0.93 (3H, t, J ) 7.3 Hz), 1.18 (3H, t, J ) 7.3 Hz), 1.52-1.59

(1H, m), 1.59-1.70 (1H, m), 2.55-2.61 (1H, m), 2.76 (1H, dd,

J ) 14.2, 6.4 Hz), 2.92 (1H, dd, J ) 14.2, 6.4 Hz), 4.03-4.12

(2H, m), 4.06 (3H, s), 6.97 (1H, d, J ) 8.8 Hz), 7.38 (1H, dd, J

) 8.8, 2.4 Hz), 8.00 (1H, d, J ) 2.4 Hz); low-resolution MS

(EI⁺) m/e 280 (M⁺).

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (8). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 140-142 °C; ¹H NMR (400 MHz, CDCl₃)

δ 2.68 (2H, t, J ) 7.8 Hz), 2.96 (2H, t, J ) 7.8 Hz), 3.93 (3H,

s), 4.74 (2H, d, J ) 5.9 Hz), 6.92 (1H, d, J ) 8.8 Hz), 7.33 (1H,

dd, J ) 8.3, 2.4 Hz), 7.47 (2H, d, J ) 7.8 Hz), 7.59 (2H, d, J )

7.8 Hz), 8.09 (1H, d, J ) 2.4 Hz), 8.33 (1H, t, J ) 5.9 Hz);

low-resolution MS (EI⁺) m/e 381 (M⁺). Anal. (C₁₉H₁₈F₃NO₄) C,

H, N.

Ethyl 3-(3-carboxy-4-methoxyphenyl)-2-ethylpropionate (5.00

g, 17.8 mmol) was dissolved in 80 mL of dehydrated dichlo-

romethane, and the solution was cooled to -10 to -15 °C.

Triethylamine (6.21 mL, 44.5 mmol) was added under stirring,

followed by the addition of ethyl chlorocarbonate (1.86 mL,

19.5 mmol) dissolved in 10 mL of dehydrated dichloromethane.

The mixture was stirred for 10 min at -10 °C, and then

4-(trifluoromethyl)benzylamine (2.51 mL, 17.8 mmol) dissolved

in 10 mL of dehydrated dichloromethane was added dropwise.

Stirring was continued for 30 min at -10 °C and then for 7 h

at room temperature, and finally, the mixture was left to stand

overnight. It was washed with aqueous citric acid, aqueous

sodium hydrogen carbonate and brine and then dried over

anhydrous sodium sulfate and concentrated. The residue was

recrystallized from a mixed solvent of n-hexane and ethyl

acetate to afford 7.20 g (93%) of ethyl 2-ethyl-3-[4-methoxy-

3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamoyl]phenyl]-

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m oyl]p h en yl]-2-m eth ylp r op a n oic Acid (9). This

compound was prepared using the same procedures as de-

1

scribed for the preparation of 10: mp 155-156 °C; H NMR

(400 MHz, CDCl₃) δ 1.18 (3H, d, J ) 6.9 Hz), 2.67-2.83 (2H,

m), 3.05 (1H, dd, J ) 6.4, 13.2 Hz), 3.93 (3H, s), 4.73 (2H, d,

J ) 5.9 Hz), 6.92 (1H, d, J ) 8.3 Hz), 7.30 (1H, dd, J ) 2.4,

8.3 Hz), 7.47 (2H, d, J ) 8.3 Hz), 7.59 (2H, d, J ) 8.3 Hz),

8.08 (1H, d, J ) 2.4 Hz), 8.32 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/e 395 (M⁺). Anal. (C₂₀H₂₀F₃NO₄) C, H, N.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]car bam oyl]ph en yl]-2-n -pr opylpr opan oic Acid (11). This

compound was prepared using the same procedures as de-

1

scribed for the preparation of 10: mp 147 °C; H NMR (400

MHz, CDCl₃) δ 1.28-1.53 (3H, m), 1.60-1.69 (1H, m), 2.66-

2.73 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.4 Hz), 2.95 (1H, dd, J

) 13.7, 8.3 Hz), 3.92 (3H, s), 4.73 (2H, d, J ) 5.9 Hz), 6.90

(1H, d, J ) 8.8 Hz), 7.29 (1H, dd, J ) 8.3, 2.4 Hz), 7.47 (2H,

d, J ) 7.8 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.08 (1H, d, J ) 2.4

Hz), 8.32 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 423

(M⁺). Anal. (C₂₂H₂₄F₃NO₄) C, H, N.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m oyl]p h en yl]-2-isop r op ylp r op a n oic Acid (12).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 174-175 °C; ¹H NMR

(400 MHz, CDCl₃) δ 1.02 (3H, d, J ) 6.4 Hz), 1.05 (3H, d, J )

6.9 Hz), 1.92-2.01 (1H, m), 2.51 (1H, q, J ) 7.3 Hz), 2.86 (2H,

d, J ) 7.3 Hz), 3.91 (3H, s), 4.72 (2H, d, J ) 5.9 Hz), 6.88 (1H,

d, J ) 8.3 Hz), 7.29 (1H, dd, J ) 8.3, 2.4 Hz), 7.46 (2H, d, J )

8.3 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.07 (1H, d, J ) 2.4 Hz),

8.31 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 423 (M⁺).

Anal. (C₂₂H₂₄F₃NO₄) C, H, N.

2-n -Bu t yl-3-[4-m e t h oxy-3-[N -[[4-(t r iflu or om e t h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (13).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 150 °C; ¹H NMR (400

MHz, CDCl₃) δ 1.25-1.39 (4H, m), 1.47-1.56 (1H, m), 1.61-

1.72 (1H, m), 2.64-2.71 (1H, m), 2.78 (1H, dd, J ) 13.7, 6.4

Hz), 2.95 (1H, dd, J ) 13.7, 8.3 Hz), 3.92 (3H, s), 4.73 (2H, d,

J ) 5.9 Hz), 6.90 (1H, d, J ) 8.3 Hz), 7.29 (1H, dd, J ) 8.3,

2.5 Hz), 7.47 (2H, d, J ) 8.3 Hz), 7.59 (2H, d, J ) 8.3 Hz),

1

propionate as colorless crystals: mp 77.5-79.5 °C; H NMR

(400 MHz, CDCl₃) δ 0.91 (3H, t, J ) 7.3 Hz), 1.18 (3H, t, J )

7.3 Hz), 1.51-1.69 (2H, m), 2.54-2.61 (1H, m), 2.75 (1H, dd,

J ) 13.7, 6.8 Hz), 2.92 (1H, dd, J ) 13.7, 8.8 Hz), 3.92 (3H, s),

4.04-4.12 (2H, m), 4.73 (2H, d, J ) 5.9 Hz), 6.89 (1H, d, J )

8.8 Hz), 7.25-7.28 (1H, m), 7.47 (2H, d, J ) 7.8 Hz), 7.59 (2H,

d, J ) 8.3 Hz), 8.06 (1H, d, J ) 2.4 Hz), 8.30 (1H, t, J ) 5.4

Hz); low-resolution MS (EI+) m/z 437 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[N-[[4-(tr iflu or om eth yl)ph en yl]-

m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (10). Ethyl

2-ethyl-3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]-

carbamoyl]phenyl]propionate (1.26 g, 2.88 mmol), 15 mL of

ethanol, and 15 mL of 1 M aqueous solution of sodium

hydroxide were stirred for 4 h at 50 °C, and then the reaction

mixture was concentrated under reduced pressure. The residue

was dissolved in water and acidified with diluted HCl. The

precipitate formed was collected by filtration, dried, and

recrystallized from ethyl acetate to afford 1.26 g (95%) of the

title compound as colorless prisms: mp 144.5-146.5 °C; ¹H

NMR (400 MHz, CDCl₃) δ 0.96 (3H, t, J ) 7.3 Hz), 1.53-1.72

(2H, m), 2.59-2.66 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.8 Hz),

2.96 (1H, dd, J ) 13.7, 8.3 Hz), 3.92 (3H, s), 4.73 (2H, d, J )

5.9 Hz), 6.90 (1H, d, J ) 8.3 Hz), 7.29 (1H, dd, J ) 8.3, 2.4

Hz), 7.47 (2H, d, J ) 8.3 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.08

(1H, d, J ) 2.4 Hz), 8.32 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/e 409 (M⁺). Anal. (C₂₁H₂₂F₃NO₄) C, H, N.

3592 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

8.07 (1H, d, J ) 2.5 Hz), 8.32 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/e 437 (M⁺). Anal. (C₂₃H₂₆F₃NO₄) C, H, N.

preparation of 10: foam; low-resolution MS (EI⁺) m/e 423 (M⁺).

Anal. (C₂₂H₂₄F₃NO₄) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-(ben zyl)ca r ba m oyl]p h en yl]-

p r op a n oic Acid (65). This compound was prepared using the

same procedures as described for the preparation of 10: mp

116-117 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.96 (3H, t, J ) 7.3

Hz), 1.55-1.70 (2H, m), 2.59-2.67 (1H, m), 2.77 (1H, dd, J )

13.7, 6.8 Hz), 2.96 (1H, dd, J ) 13.7, 6.8 Hz), 3.88 (3H, s),

4.69 (2H, d, J ) 5.4 Hz), 6.88 (1H, d, J ) 8.8 Hz), 7.27-7.29

(2H, m), 7.32-7.37 (4H, m), 8.09 (1H, d, J ) 2.4 Hz), 8.23 (1H,

br); low-resolution MS (EI⁺) m/e 341 (M⁺). Anal. (C₂₀H₂₃NO₄‚

¹/₂H₂O) C, H, N.

2-E t h yl-3-[4-m et h oxy-3-[N-[(4-ch lor op h en yl)m et h yl]-

ca r ba m oyl]p h en yl]p r op a n oic Acid (66). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 138-140 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.56-1.69 (2H, m), 2.61-2.64 (1H,

m), 2.77 (1H, dd, J ) 13.7, 8.3 Hz), 2.95 (1H, dd, J ) 13.7, 8.3

Hz), 3.90 (3H, s), 4.63 (2H, d, J ) 5.9 Hz), 7.27-7.32 (5H, m),

8.06 (1H, d, J ) 2.4 Hz), 8.23 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/e 375 (M⁺). Anal. (C₂₀H₂₂ClNO₄) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[[3-(tr iflu or om eth yl)ph en yl]-

m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (67). This com-

pound was prepared using the same procedures as described

for the preparation of 10: mp 144-146 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.96 (3H, t, J ) 7.6 Hz), 1.55-1.721 (2H, m), 2.62-

2.67 (1H, m), 2.78 (1H, dd, J ) 13.7, 6.3 Hz), 2.96 (1H, dd, J

) 13.7, 7.8 Hz), 3.92 (3H, s), 4.73 (2H, d, J ) 5.9 Hz), 6.90

(1H, d, J ) 8.8 Hz), 7.29 (1H, m), 7.46 (1H, t, J ) 7.8 Hz),

7.55 (2H, t, J ) 7.8 Hz), 7.61 (1H, s), 8.07 (1H, d, J ) 2.4 Hz),

8.28 (1H, br); low-resolution MS (EI⁺) m/e 409 (M⁺). Anal.

(C₂₁H₂₂F₃NO₄‚¹/₃H₂O) C, H, N.

2-E t h yl-3-[4-m e t h oxy-3-[N -[[4-(t r iflu or om e t h oxy)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (68).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 135-137 °C; ¹H NMR

(400 MHz, CDCl₃) δ 0.95 (3H, t, J ) 7.3 Hz), 1.55-1.70 (2H,

m), 2.59-2.66 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.3 Hz), 2.96

(1H, dd, J ) 13.8, 7.8 Hz), 3.91 (3H, s), 4.67 (2H, d, J ) 5.9

Hz), 6.89 (1H, d, J ) 8.3 Hz), 7.18 (1H, d, J ) 8.3 Hz), 7.27-

7.30 (1H, m), 7.38 (2H, d, J ) 8.8 Hz), 8.08 (1H, d, J ) 2.4

Hz), 8.27 (1H, t, J ) 5.4 Hz); low-resolution MS (EI⁺) m/e 425

(M⁺). Anal. (C₂₁H₂₂F₃NO₅) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[(2-m eth oxyp h en yl)m eth yl]-

ca r ba m oyl]p h en yl]p r op a n oic Acid (69). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 120-121 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.94 (3H, t, J ) 7.3 Hz), 1.56-1.67 (2H, m), 2.60-2.63 (1H,

m), 2.75 (1H, dd, J ) 14.2, 6.8 Hz), 2.94 (1H, dd, J ) 13.7, 8.3

Hz), 3.90 (6H, s), 4.66 (2H, d, J ) 5.9 Hz), 6.85-6.94 (3H, m),

7.22-7.28 (2H, m), 7.34 (1H, dd, J ) 7.3, 1.5 Hz), 8.06 (1H, d,

J ) 2.4 Hz), 8.42 (1H, br); low-resolution MS (EI⁺) m/e 371

(M⁺). Anal. (C₂₁H₂₅NO₅‚¹/₁₀H₂O) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[(3-m eth oxyp h en yl)m eth yl]-

ca r ba m oyl]p h en yl]p r op a n oic Acid (70). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 103-105 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.57-1.69 (2H, m), 2.62-2.67 (1H,

m), 2.77 (1H, dd, J ) 13.7, 6.8 Hz), 2.96 (1H, dd, J ) 13.7, 7.8

Hz), 3.80 (3H, s), 3.89 (3H, s), 4.66 (2H, d, J ) 5.4 Hz), 6.81

(1H, dd, J ) 8.3, 2.4 Hz), 6.90 (2H, d, J ) 3.9 Hz), 6.94 (1H,

d, J ) 7.3 Hz), 7.24-7.28 (2H, m), 8.08 (1H, d, J ) 2.4 Hz),

8.21 (1H, br); low-resolution MS (EI⁺) m/e 371 (M⁺). Anal.

(C₂₁H₂₅NO₅‚¹/₂H₂O) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[(4-m eth oxyp h en yl)m eth yl]-

ca r ba m oyl]p h en yl]p r op a n oic Acid (71). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 143-144 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.55-1.70 (2H, m), 2.61-2.67 (1H,

m), 2.77 (1H, dd, J ) 14.2, 6.8 Hz), 2.96 (1H, dd, J ) 13.7, 8.3

Hz), 3.80 (3H, s), 3.87 (3H, s), 4.60 (2H, d, J ) 5.4 Hz), 6.86-

6.90 (3H, m), 7.25-7.30 (3H, m), 8.08 (1H, d, J ) 2.4 Hz), 8.15

(1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 371 (M⁺). Anal.

(C₂₁H₂₅NO₅‚¹/₃H₂O) C, H, N.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m oyl]p h en yl]-2-p h en ylp r op a n oic Acid (14). This

compound was prepared using the same procedures as de-

1

scribed for the preparation of 10: mp 159-161 °C; H NMR

(400 MHz, CDCl₃) δ 3.01 (1H, dd, J ) 13.7, 6.8 Hz), 3.39 (1H,

dd, J ) 13.7, 8.8 Hz), 3.87-3.90 (1H, m), 3.88 (3H, s), 4.71

(2H, d, J ) 5.9 Hz), 6.81 (1H, d, J ) 8.3 Hz), 7.16 (1H, dd, J

) 8.3, 2.5 Hz), 7.23-7.32 (5H, m), 7.45 (2H, d, J ) 7.8 Hz),

7.58 (2H, d, J ) 7.8 Hz), 8.09 (1H, d, J ) 2.5 Hz), 8.29 (1H, t,

J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 457 (M⁺). Anal.

(C₂₅H₂₂F₃NO₄) C, H, N.

2-Me t h oxy-3-[4-m e t h oxy-3-[N -[[4-(t r iflu or om e t h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (15).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 161-163 °C; ¹H NMR

(400 MHz, DMSO-d₆) δ 2.84 (1H, dd, J ) 14.2, 7.8 Hz), 2.95

(1H, dd, J ) 14.2, 4.9 Hz), 3.23 (3H, s), 3.89 (3H, s), 3.88-

3.92 (1H, m), 4.57 (2H, d, J ) 6.4 Hz), 7.07 (1H, d, J ) 8.3

Hz), 7.33 (1H, dd, J ) 8.3, 2.4 Hz), 7.54 (2H, d, J ) 8.3 Hz),

7.61 (1H, d, J ) 2.4 Hz), 7.70 (2H, d, J ) 7.8 Hz), 8.81 (1H, t,

J ) 6.4 Hz), 12.74 (1H, br); low-resolution MS (EI⁺) m/e 411

(M⁺). Anal. (C₂₀H₂₀F₃NO₅) C, H, N.

2-E t h oxy-3-[4-m e t h oxy-3-[N -[[4-(t r iflu or om e t h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (16).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 146-148 °C; ¹H NMR

(400 MHz, DMSO-d₆) δ 1.04 (3H, t, J ) 6.8 Hz), 2.82 (1H, dd,

J ) 14.2, 7.8 Hz), 2.93 (1H, dd, J ) 14.2, 4.9 Hz), 3.26-3.33

(1H, s), 3.52 (1H, dq, J ) 9.3, 6.8 Hz), 3.88 (3H, s), 3.96 (1H,

dd, J ) 7.8, 4.9 Hz), 4.57 (2H, d, J ) 5.9 Hz), 7.07 (1H, d, J )

8.8 Hz), 7.34 (1H, dd, J ) 8.8, 2.4 Hz), 7.54 (2H, d, J ) 7.8

Hz), 7.63 (1H, d, J ) 2.4 Hz), 7.70 (2H, d, J ) 8.3 Hz), 8.81

(1H, t, J ) 5.9 Hz), 12.67 (1H, br); low-resolution MS (EI⁺)

m/e 425 (M⁺). Anal. (C₂₁H₂₂F₃NO₅) C, H, N.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]car bam oyl]ph en yl]-2-ph en oxypr opan oic Acid (17). This

compound was prepared using the same procedures as de-

1

scribed for the preparation of 10: mp 142-143 °C; H NMR

(400 MHz, DMSO-d₆) δ 3.12 (1H, dd, J ) 14.2, 7.8 Hz), 3.18

(1H, dd, J ) 14.2, 4.9 Hz), 3.88 (3H, s), 4.57 (2H, d, J ) 6.4

Hz), 4.89 (1H, dd, J ) 5.8, 4.9 Hz), 6.83 (2H, d, J ) 8.8 Hz),

6.92 (1H, t, J ) 7.3 Hz), 7.09 (1H, d, J ) 8.3 Hz), 7.24 (1H, dd,

J ) 8.8, 7.3 Hz), 7.44 (1H, dd, J ) 8.8, 2.4 Hz), 7.54 (2H, d, J

) 8.3 Hz), 7.69 (2H, d, J ) 8.3 Hz), 7.72 (1H, d, J ) 2.4 Hz),

8.81 (1H, t, J ) 6.4 Hz), 13.12 (1H, br); low-resolution MS

(FAB⁺) m/e 474 (M + H)⁺. Anal. (C₂₅H₂₂F₃NO₅) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[4-(tr iflu or om eth yl)p h en yl]-

ca r ba m oyl]p h en yl]p r op a n oic Acid (18). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 141-142 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.97 (3H, t, J ) 7.3 Hz), 1.56-1.72 (2H, m), 2.60-2.67 (1H,

m), 2.80 (1H, dd, J ) 14.2, 8.3 Hz), 2.98 (1H, dd, J ) 14.2, 8.3

Hz), 4.05 (3H, s), 6.96 (1H, d, J ) 8.3 Hz), 7.34 (1H, dd, J )

8.3, 2.4 Hz), 7.61 (2H, d, J ) 8.3 Hz), 7.79 (2H, d, J ) 8.8 Hz),

8.10 (1H, d, J ) 2.0 Hz), 10.0 (1H, s); low-resolution MS (EI⁺)

m/e 395(M⁺). Anal. (C₂₀H₂₀F₃NO₄) C, H, N.

2-E t h yl-3-[4-m e t h oxy-3-[N -[2-[4-(t r iflu or om e t h yl)-

ph en yl]eth yl]car bam oyl]ph en yl]pr opan oic Acid (19). This

compound was prepared using the same procedures as de-

1

scribed for the preparation of 10: mp 146-147 °C; H NMR

(400 MHz, CDCl₃) δ 0.95 (3H, t, J ) 7.8 Hz), 1.54-1.70 (2H,

m), 2.58-2.65 (1H, m), 2.76 (1H, dd, J ) 13.7, 8.3 Hz), 2.94

(1H, dd, J ) 13.7, 8.3 Hz), 2.99 (2H, t, J ) 6.8 Hz), 3.72 (3H,

s), 3.73 (2H, m), 6.83 (1H, d, J ) 8.3 Hz), 7.24 (1H, d, J ) 2.4

Hz), 7.37 (2H, d, J ) 7.8 Hz), 7.58 (2H, d, J ) 7.8 Hz), 7.89

(1H, t, J ) 4.9 Hz), 8.04 (1H, d, J ) 2.4 Hz); low-resolution

MS (EI⁺) m/e 423 (M⁺). Anal. (C₂₂H₂₄F₃NO₄) C, H, N.

2-E t h yl-3-[4-m e t h oxy-3-[N -m e t h yl-N -[[4-(t r iflu or o-

m eth yl)ph en yl]m eth yl]car bam oyl]ph en yl]pr opan oic Acid

(20). This compound (2:1 mixture of the geometric isomers)

was prepared using the same procedures as described for the

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3593

2-Eth yl-3-[4-m eth oxy-3-[N-[[2-(p h en oxy)p h en yl]m eth -

yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (72). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 146-147 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.95 (3H, t, J ) 7.3 Hz), 1.51-1.71 (2H, m), 2.57-2.64 (1H,

m), 2.75 (1H, dd, J ) 13.7, 6.8 Hz), 2.93 (1H, dd, J ) 13.7, 8.3

Hz), 3.72 (3H, s), 4.70 (2H, d, J ) 6.4 Hz), 6.82 (1H, d, J ) 8.8

Hz), 6.88 (1H, dd, J ) 8.3, 1.0 Hz), 6.97-7.00 (2H, m), 7.07-

7.12 (2H, m), 7.22 (2H, dt, J ) 8.3, 2.0 Hz), 7.29-7.34 (2H,

m), 7.50 (2H, dd, J ) 7.8, 2.0 Hz), 8.06 (1H, d, J ) 2.5 Hz),

8.47 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 433 (M⁺).

Anal. (C₂₆H₂₇NO₅) C, H, N.

s), 4.16 (2H, t, J ) 7.3 Hz), 4.59 (2H, d, J ) 5.4 Hz), 6.85-

6.89 (3H, m), 7.21-7.34 (8H, m), 8.07 (1H, d, J ) 2.4 Hz), 8.15

(1H, t, J ) 5.4 Hz); low-resolution MS (EI⁺) m/e 461 (M⁺). Anal.

(C₂₈H₃₁NO₅) C, H, N.

Ben zyl 5-Acet oxym et h yl-2-m et h oxyb en zoa t e (21).

5-Formyl-2-methoxybenzoic acid (1.76 g, 9.77 mmol), benzyl

bromide (1.26 mL, 10.3 mmol), potassium hydrogen carbonate

(2.94 g, 29.3 mmol), and 40 mL of N,N-dimethylformamide

were mixed and stirred for 4 h at room temperature. Then

the insolubles were removed by filteration. Ethyl acetate was

added to the filtrate. It was washed with water and brine and

then dried over anhydrous sodium sulfate and concentrated

to afford benzyl 5-formyl-2-methoxybenzoate: mp 58.5-59.5

°C; low-resolution MS (EI⁺) m/e 270 (M⁺). This product (1.10

g, 4.07 mmol) and 30 mL of methanol were mixed and stirred

under ice-cooling, and then sodium borohydride (155 mg, 4.10

mmol) was added potionwise. After being stirred for 2 h, the

mixture was poured into ice-water and acidified with 1 M

HCl. The whole was extracted with ethyl acetate. The extract

was washed with water and brine and then dried over

anhydrous sodium sulfate and concentrated to afford 1.11 g

(99%) of benzyl 5-hydroxymethyl-2-methoxybenzoate. This

compound and 100 mL of methylene chloride were mixed,

followed by the addition of pyridine (660 µL, 8.16 mmol), acetic

anhydride (460 µL, 4.88 mmol), and N,N-(dimethylamino)-

pyridine (25 mg, 0.205 mmol) under stirring and ice-cooling.

The mixture was stirred overnight. The mixture was washed

with 1 M HCl, aqueous solution of sodium hydrogen carbonate,

and brine, dried over anhydrous sodium sulfate, and concen-

trated to afford 1.27 g (99%) of the title compound as a colorless

oil: ¹H NMR (400 MHz, CDCl₃) δ 2.08 (3H, s), 3.91 (3H, s),

5.03 (2H, s), 5.35 (2H, s), 6.97 (1H, d, J ) 8.3 Hz), 7.31-7.50

(6H, m), 7.83 (1H, d, J ) 2.4 Hz); low-resolution MS (EI⁺) m/e

314 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[N-[[3-(p h en oxy)p h en yl]m eth -

yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (73). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 91-92 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.95 (3H, t, J ) 7.3 Hz), 1.52-1.72 (2H, m), 2.58-2.65 (1H,

m), 2.77 (1H, dd, J ) 13.7, 6.8 Hz), 2.95 (1H, dd, J ) 13.7, 8.3

Hz), 3.87 (3H, s), 4.66 (2H, d, J ) 5.9 Hz), 6.88 (1H, d, J ) 8.8

Hz), 6.89-6.91 (1H, m), 6.99-7.02 (3H, m), 7.08-7.12 (2H,

m), 7.26-7.35 (4H, m), 8.06 (1H, d, J ) 2.4 Hz), 8.23 (1H, t, J

) 5.9 Hz); low-resolution MS (EI⁺) m/e 433 (M⁺). Anal. (C₂₆H₂₇

NO₅) C, H, N.

-

2-Eth yl-3-[4-m eth oxy-3-[N-[[4-(p h en oxy)p h en yl]m eth -

yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (74). This compound

was prepared using the same procedures as described for the

preparation of 10: mp 127-128 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.55-1.71 (2H, m), 2.60-2.67 (1H,

m), 2.78 (1H, dd, J ) 13.7, 6.4 Hz), 2.96 (1H, dd, J ) 13.7, 7.8

Hz), 3.90 (3H, s), 4.65 (2H, d, J ) 5.4 Hz), 6.88 (1H, d, J ) 8.3

Hz), 6.96-7.01 (4H, m), 7.08-7.11 (1H, m), 7.26-7.29 (1H,

m), 7.31-7.35 (4H, m), 8.08 (1H, d, J ) 2.5 Hz), 8.22 (1H, t, J

) 5.4 Hz); low-resolution MS (EI⁺) m/e 433 (M⁺). Anal. (C₂₆H₂₇

NO₅) C, H, N.

-

2-Eth yl-3-[4-m eth oxy-3-[N-[[4-(bip h en ylyl)]m eth yl]ca r -

ba m oyl]p h en yl]p r op a n oic Acid (75). This compound was

prepared using the same procedures as described for the

preparation of 10: mp 159-160 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.53-1.73 (2H, m), 2.60-2.68 (1H,

m), 2.78 (1H, dd, J ) 13.7, 6.9 Hz), 2.97 (1H, dd, J ) 13.7, 7.8

Hz), 3.90 (3H, s), 4.72 (2H, d, J ) 5.9 Hz), 6.89 (1H, d, J ) 8.8

Hz), 7.28 (1H, dd, J ) 8.3, 2.4 Hz), 7.32-7.36 (4H, m), 7.41-

7.45 (4H, m), 7.56-7.59 (4H, m), 8.11 (1H, d, J ) 2.4 Hz), 8.28

(1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 417 (M⁺). Anal.

(C₂₆H₂₇NO₄) C, H, N.

Meth yl 3-(3-Ben zyloxyca r bon yl-4-m eth oxyp h en yl)-2,2-

d im eth ylp r op a n oa te. To a solution of 21 (630 mg, 2.00

mmol), methyl trimethylsilyldimethylketeneacetal (730 mg,

4.02 mmol), and 25 mL of methylene chloride was added

magnesium perchlorate (45.0 mg, 0.202 mmol) under argon,

and the mixture was stirred for 6 h at room temperature. The

mixture was washed with water and brine, dried over anhy-

drous sodium sulfate, and concentrated. The residue was

purified by silica gel column chromatography (eluant, n-

hexane/ethyl acetate ) 8:1 v/v) to afford 131 mg (18%) of the

title compound as colorless crystals: ¹H NMR (400 MHz,

CDCl₃) δ 1.16 (6H, s), 2.79 (2H, s), 3.56 (3H, s), 3.88 (3H, s),

5.33 (2H, s), 6.88 (1H, d, J ) 8.8 Hz), 7.20 (1H, dd, J ) 8.3,

2.4 Hz), 7.30-7.47 (5H, m), 7.56 (1H, d, J ) 2.4 Hz);

low-resolution MS (EI⁺) m/e 356 (M⁺).

Meth yl 3-(3-Ca r boxy-4-m eth oxyp h en yl)-2,2-d im eth yl-

p r op a n oa te (22). To a solution of methyl 3-(3-benzyloxycar-

bonyl-4-methoxyphenyl)-2,2-dimethylpropionate (310 mg, 0.870

mmol) in 7 mL of a mixed solvent of ethanol and tetrahydro-

furan at a ratio of 1:1 was added 10% palladium on carbon

(20 mg), and hydrogenation was carried out for 5 h. After

completion of the reaction, the catalyst was removed by

filtration and the filtrate was concentrated to afford 290 mg

(90%) of the title compound as a colorless oily product: ¹H

NMR (400 MHz, CDCl₃) δ 1.18 (6H, s), 2.85 (2H, s), 3.68 (3H,

s), 4.06 (3H, s), 6.96 (1H, d, J ) 8.3 Hz), 7.31 (1H, dd, J ) 8.3,

2.0 Hz), 7.94 (1H, d, J ) 2.0 Hz), 10.46-11.00 (1H, br s); low-

resolution MS (EI⁺) m/e 266 (M⁺).

Meth yl 3-[4-Meth oxy-3-[N-[[4-(tr iflu or om eth yl)-ph en yl]-

m eth yl]ca r ba m oyl]p h en yl]-2,2-d im eth ylp r op a n oa te. By

use of 22 (204 mg, 0.766 mmol), triethylamine (135 µL, 0.969

mmol), ethyl chlorocarbonate (82.0 µL, 0.843 mmol), 4-(tri-

fluoromethyl)benzylamine (120 µL, 0.842 mmol), and 8 mL of

dehydrated dichloromethane, 309 mg (95%) of the title com-

pound was afforded as a colorless oil: ¹H NMR (400 MHz,

CDCl₃) δ 1.18 (6H, s), 2.85 (2H, s), 3.69 (3H, s), 3.92 (3H, s),

4.73 (2H, d, J ) 5.9 Hz), 6.89 (1H, d, J ) 8.3 Hz), 7.20 (1H,

dd, J ) 8.3, 2.4 Hz), 7.47 (2H, d, J ) 7.8 Hz), 7.59 (2H, d, J )

7.8 Hz), 7.99 (1H, d, J ) 2.4 Hz), 8.29 (1H, brs); low-resolution

MS (EI⁺) m/e 266(M⁺).

2-E t h yl-3-[4-m e t h oxy-3-[N -[[4-(b e n zyloxy)p h e n yl]-

m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (76). This com-

pound was prepared using the same procedures as described

for the preparation of 10: mp 127-128 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.96 (3H, t, J ) 7.3 Hz), 1.55-1.72 (2H, m), 2.59-

2.67 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.9 Hz), 2.96 (1H, dd, J

) 13.7, 8.3 Hz), 3.87 (3H, s), 4.60 (2H, d, J ) 5.4 Hz), 5.06

(2H, s), 6.87 (1H, d, J ) 8.3 Hz), 6.95 (2H, d, J ) 8.3 Hz),

7.24-7.44 (8H, m), 8.08 (1H, d, J ) 2.4 Hz), 8.16 (1H, t, J )

5.4 Hz); low-resolution MS (EI⁺) m/e 447 (M⁺). Anal. (C₂₇H₂₉

-

NO₅) C, H, N.

2-Eth yl-3-[4-m eth oxy-3-[N-[[4-[2-(p h en yl)eth yl]p h en yl]-

m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (77). This com-

pound was prepared using the same procedures as described

for the preparation of 10: mp 129-130 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.96 (3H, t, J ) 7.3 Hz), 1.53-1.73 (2H, m), 2.59-

2.66 (1H, m), 2.78 (1H, dd, J ) 13.7, 6.8 Hz), 2.91 (4H, s), 2.96

(1H, dd, J ) 13.7, 8.3 Hz), 3.88 (3H, s), 4.65 (2H, d, J ) 5.9

Hz), 6.88 (1H, d, J ) 8.8 Hz), 7.15-7.21 (5H, m), 7.26-7.30

(5H, m), 8.09 (1H, d, J ) 2.4 Hz), 8.21 (1H, t, J ) 5.9 Hz);

low-resolution MS (EI⁺) m/e 445 (M⁺). Anal. (C₂₈H₃₁F₃NO₄) C,

H, N.

2-E t h y l-3-[4-m e t h o x y -3-[N -[[4-[2-(p h e n y l)e t h o x y ]-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid (78).

This compound was prepared using the same procedures as

described for the preparation of 10: mp 117-118 °C; ¹H NMR

(400 MHz, CDCl₃) δ 0.95 (3H, t, J ) 7.3 Hz), 1.52-1.72 (2H,

m), 2.58-2.66 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.8 Hz), 2.95

(1H, dd, J ) 13.7, 8.3 Hz), 3.09 (2H, t, J ) 7.3 Hz), 3.86 (3H,

3594 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m oyl]p h en yl]-2,2-d im eth ylp r op a n oic Acid (23).

By use of methyl 3-[4-methoxy-3-[N-[[4-(trifluoromethyl)phenyl]-

methyl]carbamoyl]phenyl]-2,2-dimethylpropionate (300 mg,

0.708 mmol), 5 mL of ethanol, and 2 mL of 10% aqueous

solution of sodium hydroxide, 206 mg (90%) of the title com-

pound was afforded as colorless crystals: mp 151.0-152.0 °C;

¹H NMR (400 MHz, DMSO-d₆) δ 1.06 (6H, s), 2.96 (2H, s), 3.88

(3H, s), 4.56 (2H, d, J ) 6.4 Hz), 7.06 (1H, d, J ) 8.8 Hz), 7.25

(1H, dd, J ) 8.8, 2.4 Hz), 7.51-7.58 (2H, m), 7.70 (1H, d, J )

7.8 Hz), 8.80 (1H, t, J ) 5.9 Hz), 12.24 (1H, s); low-resolution

MS (EI⁺) m/e 409 (M⁺). Anal. (C₂₁H₂₂F₃NO₄) C, H, N.

7.46 (2H, d, J ) 7.8 Hz), 7.59 (3H, m), 8.43 (1H, br s); low-

resolution MS (EI⁺) m/e 324 (M⁺).

2-E t h ylt h io-3-[4-m et h oxy-3-[N-[[4-(t r iflu or om et h yl)-

p h en yl]m et h yl]ca r b a m yl]p h en yl]p r op a n oic Acid (27).

This compound was prepared from ethyl 2-ethylthio-3-[4-

methoxy-3-[N-[[4-(trifluoromethyl)phenyl]methyl]carbamyl]-

phenyl]propanoate, using the same procedures as described

for the preparation of 10: mp 155-157 °C; ¹H NMR (400 MHz,

CDCl₃) δ 1.25 (3H, t, J ) 7.3 Hz), 2.69 (2H, q, J ) 7.3 Hz),

2.99 (1H, dd, J ) 14.2, 6.3 Hz), 3.20 (1H, dd, J ) 14.2, 9.3

Hz), 3.56 (1H, dd, J ) 9.3, 6.3 Hz), 3.93 (3H, s), 4.73 (2H, d, J

) 5.9 Hz), 6.92 (1H, d, J ) 8.3 Hz), 7.35 (1H, dd, J ) 8.3, 2.4

Hz), 7.46 (2H, d, J ) 7.8 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.12

(1H, d, J ) 2.4 Hz), 8.32 (1H, br s); low-resolution MS (CI⁺)

m/e 442 (M + H)⁺. Anal. (C₂₁H₂₂F₃NO₄S) C, H, N.

3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)p h en yl]m et h -

yl]ca r ba m yl]p h en yl]-2-p h en ylth iop r op a n oic Acid (28).

This compound was prepared using the same procedures as

described for the preparation of 27: mp 130-132 °C; ¹H NMR

(400 MHz, CDCl₃) δ 3.07 (1H, dd, J ) 14.2, 6.3 Hz), 3.18 (1H,

dd, J ) 14.2, 9.3 Hz), 3.89-3.93 (4H, m), 4.71 (2H, d, J ) 5.9

Hz), 6.91 (1H, d, J ) 8.3 Hz), 7.27-7.34 (4H, m), 7.44-7.46

(4H, m), 7.58 (2H, d, J ) 7.8 Hz), 8.10 (1H, d, J ) 2.4 Hz),

8.32 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e 489 (M⁺).

Anal. (C₂₅H₂₂F₃NO₄S) C, H, N.

2-Ben zylth io-3-[4-m eth oxy-3-[N-[[4-(tr iflu or om eth yl)-

p h en yl]m et h yl]ca r b a m yl]p h en yl]p r op a n oic Acid (29).

This compound was prepared using the same procedures as

described for the preparation of 27: foam; ¹H NMR (400 MHz,

CDCl₃) δ 2.90 (1H, dd, J ) 14.2, 6.8 Hz), 3.16 (1H, dd, J )

14.2, 8.8 Hz), 3.44 (1H, dd, J ) 8.8, 6.8 Hz), 3.82 (1H, d, J )

13.2 Hz), 3.86 (1H, d, J ) 13.2 Hz), 3.91 (3H, s), 4.72 (2H, d,

J ) 5.9 Hz), 6.87 (1H, d, J ) 8.8 Hz), 7.20-7.28 (6H, m), 7.46

(2H, d, J ) 7.8 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.03 (1H, d, J )

2.4 Hz), 8.31 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/e

503 (M⁺). Anal. (C₂₆H₂₄F₃NO₄S) C, H, N.

Eth yl 3-(4-Meth oxy-3-n itr op h en yl)-2-eth ylp r op en oa te

(35). Sodium hydride (795 mg, 19.9 mmol) was suspended in

120 mL of dehydrated tetrahydrofuran under argon and cooled

with ice. Triethyl 2-phosphonobutyrate (5.00 g, 19.8 mmol)

dissolved in 30 mL of dehydrated tetrahydrofuran was added

dropwise. When the addition was completed, the mixture was

stirred for 1 h. Then 4-methoxy-3-nitrobenzaldehyde (3.26 g,

18.0 mmol) dissolved in 50 mL of dehydrated tetrahydrofuran

was added dropwise. The mixture was stirred for 1 h at 0 °C

and then for 3 h at room temperature. The reaction mixture

was concentrated and mixed with ice-water. The whole was

extracted with ethyl acetate, washed with water and brine,

dried over anhydrous sodium sulfate, and concentrated. The

residue was purified by silica gel column chromatography

(eluant, n-hexane/ethyl acetate ) 8:1 and then 2:1 v/v) to afford

4.69 g (93%) of the title compound as colorless crystals (6:1

mixture of the geometric isomers): low- resolution MS (EI⁺)

m/e 279 (M⁺).

2,2-Diet h yl-3-[4-Met h oxy-3-[N-[[4-(t r iflu or om et h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a on ic Acid (24).

This compound was prepared using the same procedures as

described for the preparation of 23: mp 156-157 °C; ¹H NMR

(400 MHz, DMSO-d₆) δ 0.82 (6H, t, J ) 7.3 Hz), 1.32-1.53

(4H, m), 2.75 (2H, s), 3.88 (3H, s), 4.56 (2H, d, J ) 5.9 Hz),

7.06 (1H, d, J ) 8.3 Hz), 7.22 (1H, dd, J ) 8.3, 2.4 Hz), 7.52-

7.56 (3H, m), 7.70 (2H, d, J ) 8.3 Hz), 8.80 (1H, t, J ) 5.9

Hz), 12.28 (1H, br); low-resolution MS (EI⁺) m/e 437 (M⁺).

Anal. (C₂₃H₂₆F₃NO₄) C, H, N.

2-Me t h oxy-5-n it r o-N -[[4-(t r iflu or om e t h yl)p h e n yl]-

m eth yl]ben za m id e (26). This compound was prepared from

25, using the same procedures as described for the preparation

of 7: ¹H NMR (400 MHz, CDCl₃) δ 4.09 (3H, s), 4.75 (2H, d, J

) 5.9 Hz), 7.11 (1H, d, J ) 8.8 Hz), 7.47 (2H, d, J ) 7.8 Hz),

7.61 (2H, d, J ) 7.8 Hz), 8.05 (1H, br s), 8.36 (1H, dd, J ) 8.8,

3.0 Hz), 9.12 (1H, t, J ) 3.0 Hz); low-resolution MS (EI⁺) m/e

354 (M⁺).

5-Am in o-2-m et h oxy-N-[[4-(t r iflu or om et h yl)p h en yl]-

m eth yl]ben za m id e. This compound was prepared from 2-

m et h oxy-5-n it r o-N-[[4-(t r iflu or om et h yl)ph en yl]m et h yl]-

benzamide, using the same procedures as described for the

preparation of 36: ¹H NMR (400 MHz, CDCl₃) δ 3.87 (3H, s),

4.72 (2H, d, J ) 5.9 Hz), 6.80 (1H, dd, J ) 8.8, 3.0 Hz), 6.83

(1H, d, J ) 8.8 Hz), 7.47 (2H, d, J ) 7.8 Hz), 7.59 (3H, m),

8.43 (1H, br s); low-resolution MS (EI⁺) m/e 324 (M⁺).

Eth yl 2-Br om o-3-[4-m eth oxy-3-[N-[[4-(tr iflu or om eth -

yl)p h en yl]m eth yl]ca r ba m oyl]p r op a n oa te. To a solution of

5-amino-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-

benzamide (7.00 g, 21.6 mmol), 85 mL of acetone, and 34 mL

of methanol was added 17.5 mL of 47% hydrobromic acid,

sodium nitrite (1.65 g, 23.9 mmol), and 6.2 mL of water with

ice-cooling. The mixture was stirred for 10 min. To the solution

was added ethyl acrylate (13.4 mL, 128 mmol) and CuO (416

mg, 2.91 mmol) at room temperature. After being stirred for

30 min, the mixture was poured into a saturated sodium

hydrogen carbonate solution and extracted with ethyl acetate.

The mixture was washed with brine, dried over anhydrous

magnesium sulfate, and concentrated. The residue was re-

crystallized to afford 683 mg (71%) of the title compound as

colorless crystals: ¹H NMR (400 MHz, CDCl₃) δ 1.21-1.26 (6H,

m), 2.61-2.67 (2H, m), 2.96 (1H, dd, J ) 14.2, 6.8 Hz), 3.18

(1H, dd, J ) 14.2, 9.3 Hz), 3.53 (1H, dd, J ) 9.3, 6.8 Hz), 3.93

(3H, s), 4.10-4.19 (2H, m), 4.73 (2H, d, J ) 5.9 Hz), 6.91 (1H,

d, J ) 8.3 Hz), 7.32 (1H, dd, J ) 8.3, 2.4 Hz), 7.47 (2H, d, J )

7.8 Hz), 7.59 (2H, d, J ) 7.8 Hz), 8.11 (1H, d, J ) 2.4 Hz),

8.30 (1H, br s); low-resolution MS (EI⁺) m/e 469 (M⁺).

Eth yl 3-(3-Am in o-4-m eth oxyph en yl)-2-eth ylpr opan oate

(36). Compound 35 (4.68 g, 16.8 mmol) was dissolved in a

mixed solvent of 150 mL of tetrahydrofuran and ethanol (1:1

v/v), 10% palladium on carbon (1.50 g) was added, and

hydrogenation was carried out at an initial pressure of 294.3

kPa. After completion of the reaction, the catalyst was removed

by filtration and the filtrate was concentrated to afford 3.96 g

(94%) of the title compound as a colorless oil: ¹H NMR (400

MHz, CDCl₃) δ 0.90 (3H, t, J ) 7.3 Hz), 1.19 (3H, t, J ) 7.3

Hz), 1.48-1.67 (2H, m), 2.47-2.55 (1H, m), 2.59 (1H, dd, J )

13.2, 6.8 Hz), 2.81 (1H, dd, J ) 13.7, 7.8 Hz), 3.72 (2H, br),

3.82 (3H, s), 4.04-4.12 (2H, m), 6.51 (1H, dd, J ) 7.8, 2.9 Hz),

6.53 (1H, d, J ) 2.0 Hz), 6.68 (1H, d, J ) 7.8 Hz); low-resolution

MS (EI⁺) m/e 251 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[2-[4-(tr iflu or om eth yl)p h en yl]-

a cetyla m in o]p h en yl]p r op a n oic Acid (38). 4-(Trifluoro-

methyl)phenylacetic acid (188 mg, 0.893 mmol) and com-

pound 36 (224 mg, 0.891 mmol) were dissolved in 10 mL of

dichloromethane. 1-[3-(Dimethylaminopropyl)]-3-ethylcarbo-

diimide hydrochloride (171 mg, 0.892 mmol) was added, and

E t h yl

2-E t h ylt h io-3-[4-m et h oxy-3-[N-[[4-(t r iflu or o-

m eth yl)p h en yl]m eth yl]ca r ba m yl]p h en yl]p r op a n oa te. To

a solution of ethyl 2-bromo-3-[4-methoxy-3-[N-[[4-(trifluoro-

methyl)phenyl]methyl]carbamyl]propanoate (1.00 g, 2.05 mmol)

and 56 mL of ethanol was added sodium thioethoxide (268 mg,

2.55 mmol), and the mixture was refluxed for 1.5 h. The

mixture was concentrated, and water was added. The whole

was extracted with ethyl acetate. The extract was washed with

brine, dried over anhydrous magnesium sulfate, and concen-

trated. The residue was purified by silica gel column chroma-

tography (eluant, n-hexane/ethyl acetate ) 2:1 v/v) to afford

3.40 g (43%) of the title compound as colorless crystals: ¹H

NMR (400 MHz, CDCl₃) δ 3.87 (3H, s), 4.72 (2H, d, J ) 5.9

Hz), 6.80 (1H, dd, J ) 8.8, 3.0 Hz), 6.83 (1H, d, J ) 8.8 Hz),

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3595

the mixture stood overnight at room temperature. The mixture

was washed with diluted HCl, saturated NaHCO₃solution,

water, and brine, dried over anhydrous sodium sulfate, and

concentrated to afford ethyl 2-ethyl-3-[4-methoxy-3-[2-[4-(tri-

fluoromethyl)phenyl]acetylamino]phenyl]propanoate as a brown

oil: ¹H NMR (400 MHz, CDCl₃) δ 0.88 (3H, t, J ) 7.3 Hz),

1.17 (3H, t, J ) 6.8 Hz), 1.46-1.67 (2H, m), 2.50-2.57 (1H,

m), 2.66 (1H, dd, J ) 13.7, 6.8 Hz), 2.86 (1H, dd, J ) 13.7, 8.3

Hz), 3.75 (3H, s), 3.79 (2H, s), 4.02-4.13 (2H, m), 6.71 (1H, d,

J ) 8.3 Hz), 6.81 (1H, dd, J ) 8.3, 2.0 Hz), 7.48 (2H, d, J )

8.3 Hz), 7.65 (2H, d, J ) 8.3 Hz), 7.74 (1H, br), 8.19 (1H, d, J

) 2.0 Hz); low-resolution MS (EI⁺) m/e 437 (M⁺).

This compound was hydrolyzed using the same procedures

as described for the preparation of 10 to afford the title

compound as a foam: ¹H NMR (400 MHz, CDCl₃) δ 0.93 (3H,

t, J ) 7.3 Hz), 1.50-1.69 (2H, m), 2.55-2.62 (1H, m), 2.69 (1H,

dd, J ) 13.7, 6.8 Hz), 2.89 (1H, dd, J ) 13.7, 8.3 Hz), 3.74

(3H, s), 3.79 (2H, s), 6.92 (1H, d, J ) 8.3 Hz), 6.84 (1H, dd, J

) 8.3, 2.0 Hz), 7.47 (2H, d, J ) 7.8 Hz), 7.64 (2H, d, J ) 7.8

Hz), 7.74 (1H, br), 8.21 (1H, d, J ) 2.0 Hz); low-resolution MS

(EI⁺) m/e 409 (M⁺). Anal. (C₂₁H₂₂F₃NO₄) C, H, N.

same procedures as described for the preparation of 35: low-

resolution MS (EI⁺) m/e 428 (M⁺).

Ben zyl 2-[5-[1-(2-Eth oxyca r bon yl)bu ten yl]-2-m eth oxy-

p h en yl]a ceta te (42). To a mixture of 41 (2.14 g, 4.99 mmol)

and 100 mL of acetic acid was added zinc powder (13.0 g, 199

mmol) at room temperature. The mixture was stirred for 6 h

at room temperature. The insolubles were removed by filtra-

tion, and the filtrate was concentrated. The residue was

redissolved in 50 mL of ethyl acetate, washed with water and

brine, dried over anhydrous sodium sulfate, and concentrated

to afford 1.86 g (97%) of the title compound (mixture of the

geometric isomers) as a yellow oil: low-resolution MS (EI⁺)

m/e 382 (M⁺).

Eth yl 2-Eth yl-3-[4-m eth oxy-3-[[N-[4-(tr iflu or om eth yl)-

p h en yl]ca r ba m oyl]m eth yl]p h en yl]p r op a n oa te. This com-

pound was prepared from 42 by hydrogenolysis and amidation

with 4-(trifluoromethyl)aniline using the same procedures as

described for the preparation of 10: ¹H NMR (400 MHz,

CDCl₃) δ 0.92 (3H, t, J ) 7.3 Hz), 1.15 (3H, t, J ) 7.3 Hz),

1.50-1.72 (2H, m), 2.50-2.58 (1H, m), 2.72 (1H, dd, J ) 13.7,

6.3 Hz), 2.86 (1H, dd, J ) 13.7, 8.8 Hz), 3.69 (2H, s), 3.93 (3H,

s), 3.99-4.11 (2H, m), 6.87 (1H, d, J ) 9.3 Hz), 7.08-7.12 (1H,

m), 7.52 (2H, d, J ) 8.8 Hz), 7.56 (2H, d, J ) 8.8 Hz), 7.89

(1H, s); low-resolution MS (EI⁺) m/e 437 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[[N-[4-(tr iflu or om eth yl)ph en yl]-

ca r b a m oyl]m et h yl]p h en yl]p r op a n oic Acid (46). This

compound was prepared from ethyl 2-ethyl-3-[4-methoxy-3-

[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]-

propanoate, using the same procedures as described for the

preparation of 10: mp 136-137 °C; ¹H NMR (400 MHz, CDCl₃)

δ 0.96 (3H, t, J ) 7.3 Hz), 1.54-1.73 (2H, m), 2.55-2.62 (1H,

m), 2.74 (1H, dd, J ) 14.2, 5.9 Hz), 2.88 (1H, dd, J ) 14.2, 5.9

Hz), 3.68 (3H, s), 3.91 (3H, s), 6.87 (1H, d, J ) 9.3 Hz), 7.11-

7.14 (2H, m), 7.51 (2H, d, J ) 8.8 Hz), 7.54 (2H, d, J ) 8.8

Hz), 7.90 (1H, s); low-resolution MS (EI⁺) m/z 409 (M⁺). Anal.

(C₂₁H₂₂F₃NO₄) C, H, N.

Eth yl 2-Eth yl-3-(4-m eth oxyp h en yl)a cr yla te. This com-

pound (mixture of the geometrical isomers) was prepared from

4-methoxybenzaldehyde, using the same procedures as de-

scribed for the preparation of 36: low-resolution MS (EI⁺) m/e

234 (M⁺).

E t h yl 2-E t h yl-3-(4-m et h oxyp h en yl)p r op a n oa t e (44).

This compound was prepared from ethyl 2-ethyl-3-(4-methoxy-

phenyl)acrylate, using the same procedures as described for

the preparation of 36: ¹H NMR (400 MHz, CDCl₃) δ 0.91 (3H,

t, J ) 7.3 Hz), 1.17 (3H, t, J ) 7.3 Hz), 1.49-1.69 (2H, m),

2.49-2.56 (1H, m), 2.69 (1H, dd, J ) 13.7, 6.8 Hz), 2.86 (1H,

dd, J ) 13.7, 8.3 Hz), 3.78 (3H, s), 4.07 (1H, dq, J ) 7.8, 2.0

Hz), 6.81 (2H, d, J ) 8.8 Hz), 7.08 (2H, d, J ) 8.3 Hz); low-

resolution MS (EI⁺) m/e 236 (M⁺).

Eth yl 3-(3-Acetyl-4-m eth oxyph en yl)-2-eth ylpr opan oate

(45). To a suspension of anhydrous AlCl₃and 30 mL of

dichloromethane was added acetyl chloride (1.00 mL, 14.1

mmol) under ice-cooling. The mixture was stirred for 30 min

at ambient temperature. A mixture of 44 (2.10 g, 8.89 mmol)

and 10 mL of dichloromethane was added. The mixture was

stirred for 1 h at 0 °C and then for overnight at room

temperature. The mixture was poured into ice-water and

extracted with dichloromethane. The extract was washed with

water and brine, dried over anhydrous sodium sulfate, and

concentrated. The residue was purified by silica gel column

chromatography (eluant, n-hexane/ethyl acetate ) 6:1 v/v) to

afford 1.21 g (49%) of the title compound as a yellow oil: ¹H

NMR (400 MHz, CDCl₃) δ 0.91 (3H, t, J ) 7.3 Hz), 1.18 (3H,

t, J ) 7.3 Hz), 1.49-1.70 (2H, m), 2.51-2.58 (1H, m), 2.60 (3H,

s), 2.71 (1H, dd, J ) 13.7, 6.3 Hz), 2.88 (1H, dd, J ) 13.7, 8.8

Hz), 3.89 (3H, s), 4.02-4.13 (2H, m), 6.87 (1H, d, J ) 8.3 Hz),

7.26 (1H, dd, J ) 8.3, 2.4 Hz), 7.54 (1H, d, J ) 2.4 Hz); low-

resolution MS (EI⁺) m/e 278 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[2-[4-(tr iflu or om eth yl)p h en yl]-

u r eid o]p h en yl]p r op a n oic Acid (40). This compound was

prepared from 36, using the same procedures as described for

1

the preparation of 38: mp 205-206 °C; H NMR (400 MHz,

DMSO-d₆) δ 0.87 (3H, t, J ) 7.3 Hz), 1.46-1.55 (2H, m), 2.37-

2.44 (1H, m), 2.60 (1H, dd, J ) 13.2, 6.8 Hz), 2.75 (1H, dd, J

) 13.2, 8.3, Hz), 3.85 (3H, s), 6.78 (1H, dd, J ) 8.3, 2.0 Hz),

6.92 (1H, d, J ) 8.3 Hz), 7.63 (2H, d, J ) 9.3 Hz), 7.66 (2H, d,

J ) 9.3 Hz), 8.01 (1H, d, J ) 2.0 Hz), 8.29 (1H, s), 9.70 (1H,

s), 12.07 (1H, br); low-resolution MS (EI⁺) m/e 410 (M⁺). Anal.

(C₂₀H₂₁F₃N₂O₄) C, H, N.

Ben zyl 2-Meth ylth io-2-(5-for m yl-2-m eth oxyp h en yl)-

a ceta te (39). To a solution of 4-methoxybenzaldehyde (7.46

g, 57.3 mmol) and 250 mL of dichloromethane was added

dropwise anhydrous tin chloride (6.49 mL, 57.3 mmol) in 100

mL of dichloromethane under argon atmosphere. When the

addition was completed, the mixture was stirred for 15 min

at room temperature. A mixture of ethyl 2-chloro-2-methyl-

thioacetate (9.24 g, 54. 8 mmol) and 50 mL of 1:1 v/v mixture

of dichloromethane and carbon tetrachloride was added to the

mixture and refluxed for 24 h. The mixture was poured into

ice-water, and the whole was extracted with dichloromethane.

The extract was washed with saturated NaHCO₃solution and

brine, dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by silica gel column chromatography

(eluant, n-hexane/ethyl acetate ) 5:1 v/v) to afford 7.59 g (52%)

of ethyl 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetate as

a yellowish oil: low-resolution MS (EI⁺) m/e 268 (M⁺). A

mixture of this product (4.80 g, 17.9 mmol), 30 mL of ethanol,

and 20 mL of 10% sodium hydroxide was stirred for 3 h at

room temperature. The mixture was poured into ice-water,

acidified with concentrated HCl, and extracted with ethyl

acetate. The extract was washed with water and then dried

over anhydrous sodium sulfate and concentrated to afford 4.00

g of crude 2-methylthio-2-(5-formyl-2-methoxyphenyl)acetic

acid as a yellow crystal. A mixture of this product (4.00 g, 16.4

mmol), anhydrous potassium carbonate (3.71 g, 26.8 mmol),

benzyl bromide (3.06 g, 17.9 mmol), and 50 mL of N,N-

dimethyformamide was stirred for 5 h at room temperature.

The mixture was poured into ice-water and extracted with

ether. The extract was washed with water and brine, dried

over anhydrous sodium sulfate, and concentrated. The residue

was purified by silica gel column chromatography (eluant,

n-hexane/ethyl acetate ) 6:1 v/v) to afford 4.50 g (76%) of the

title compound as a pale-brown oil: ¹H NMR (400 MHz, CDCl₃)

δ 2.15 (3H, s), 3.82 (3H, s), 4.92 (1H, s), 5.20 (2H, s), 6.98 (1H,

d, J ) 8.8 Hz), 7.26-7.36 (5H, m), 7.85 (1H, dd, J ) 8.8, 2.0

Hz), 8.06 (1H, d, J ) 2.0 Hz), 9.88 (1H, s); low-resolution MS

(EI⁺) m/e 330 (M⁺).

Eth yl 3-[3-(2-Eth oxycar bon ylacetyl)-4-m eth oxyph en yl]-

2-eth ylp r op a n oa te (47). Sodium hydride (1.27 g, 52.9 mmol;

60% oil dispersion) was suspended in 20 mL of anhydrous

ether at 0 °C. Then diethyl carbonate (2.25 g, 19.0 mmol) was

added and the mixture was stirred for 30 min at room

Ben zyl 2-Meth ylth io-2-[5-[1-(2-eth oxyca r bon yl)bu ten -

yl]-2-m eth oxyp h en yl]a ceta te (41). This compound (mixture

of the geometric isomers) was prepared from 39, using the

3596 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

temperature. A mixture of 45 (3.53 g, 12.7 mmol), 10 mL of

anhydrous ether, and 0.24 mL of anhydrous ethanol was added

dropwise for 20 min and refluxed for 6 h. After cooling to room

temperature, the mixture was poured into a mixed solvent of

45 mL of 2 M HCl and 80 mL of ethyl acetate. The organic

layer was separated, and the aqueous layer was extracted with

ethyl acetate. The extract was mixed and washed with water

and brine, dried over anhydrous sodium sulfate, and concen-

trated. The residue was purified by silica gel column chroma-

tography (eluant, n-hexane/ethyl acetate ) 9:1 v/v) to afford

2.59 g (58%) of the title compound (mixture of the geometrical

isomer) as a yellow oil: low-resolution MS (EI⁺) m/e 350 (M⁺).

of diethyl azodicarboxylate (3.80 mL, 8.38 mmol) under ice-

cooling and an argon atmosphere. The mixture was stirred for

1 h under ice-cooling and stood overnight at room temperature.

The mixture was evaporated off, and the residue was purified

by silica gel column chromatography (eluant, n-hexane/ethyl

acetate ) 6:1 v/v) to afford 1.96 g (72%) of the title compound

as a colorless crystals: ¹H NMR (400 MHz, CDCl₃) δ 3.23 (2H,

t, J ) 6.8 Hz), 3.95 (3H, s), 4.30 (2H, t, J ) 6.8 Hz), 6.99 (1H,

d, J ) 8.3 Hz), 7.39 (1H, d, J ) 2.0 Hz), 7.43 (2H, d, J ) 7.8

Hz), 7.47 (1H, dd, J ) 8.3, 2.0 Hz), 7.58 (2H, d, J ) 8.3 Hz),

9.83 (1H, s); low-resolution MS (EI⁺) m/e 324 (M⁺).

Eth yl 2-Eth yl-3-[4-m eth oxy-3-[2-[4-(tr iflu or om eth yl)-

p h en yl]eth oxy]p h en yl]a cr yla te (53). This compound (mix-

ture of the geometrical isomer) was prepared from 50, using

the same procedures as described for the preparation of 35:

low-resolution MS (EI⁺) m/e 422 (M⁺).

Eth yl 2-Eth yl-3-[4-m eth oxy-3-[2-[4-(tr iflu or om eth yl)-

p h en yl]eth oxy]p h en yl]p r op a n oa te (54). This compound

was prepared from 53, using the same procedures as described

for the preparation of 36: ¹H NMR (400 MHz, CDCl₃) δ 0.90

(3H, t, J ) 7.3 Hz), 1.14 (3H, t, J ) 7.3 Hz), 1.48-1.68 (2H,

m), 2.45-2.55 (1H, m), 2.65 (1H, dd, J ) 13.7, 6.8 Hz), 2.84

(1H, dd, J ) 13.7, 8.8 Hz), 3.19 (2H, t, J ) 6.8 Hz), 3.82 (3H,

s), 3.99-4.11 (2H, m), 4.20 (2H, t, J ) 6.8 Hz), 6.67 (1H, d, J

) 2.0 Hz), 6.72 (1H, dd, J ) 8.3, 2.0 Hz), 6.78 (1H, d, J ) 7.8

Hz), 7.43 (2H, d, J ) 8.3 Hz), 7.57 (2H, d, J ) 8.3 Hz); low-

resolution MS (EI⁺) m/e 424 (M⁺).

2-Eth yl-3-[4-m eth oxy-3-[2-[4-(tr iflu or om eth yl)p h en yl]-

eth oxy]p h en yl]p r op a n oic Acid (57). This compound was

prepared from 54, using the same procedures as described for

the preparation of 10: mp 64-66 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.93 (3H, t, J ) 7.3 Hz), 1.51-1.68 (2H, m), 2.51-

2.58 (1H, m), 2.66 (1H, dd, J ) 13.7, 6.8 Hz), 2.87 (1H, dd, J

) 13.7, 7.8 Hz), 3.18 (2H, t, J ) 7.3 Hz), 3.82 (3H, s), 4.20

(2H, t, J ) 7.3 Hz), 6.68 (1H, d, J ) 2.0 Hz), 6.73 (1H, dd, J )

7.8, 2.0 Hz), 6.79 (1H, d, J ) 8.3 Hz), 7.41 (2H, d, J ) 8.3 Hz),

7.56 (2H, d, J ) 8.3 Hz); low-resolution MS (EI⁺) m/z 396 (M⁺).

Anal. (C₂₁H₂₃F₃O₄) C, H.

Eth yl 2-Eth yl-3-(3-for m yl-4-m eth oxyph en yl)pr opan oate

(55). To a solution of 44 (10.0 g, 42.3 mmol) and 500 mL of

anhydrous dichloromethane was added titanium tetrachloride

(35.0 mL, 318 mmol), followed by dichloromethyl methyl ether

(13.4 mL, 148 mmol) at -20 °C, under an argon atmosphere.

The mixture was stirred for 6 h at -20 °C. The mixture was

poured into a dilute HCl solution and separated from the

dichloromethane layer. The organic layer was washed with

water and brine, dried over anhydrous sodium sulfate, and

concentrated. The residue was purified by silica gel column

chromatography (eluant, n-hexane/ethyl acetate ) 4:1 v/v) to

afford 10.9 g (97%) of the title compound as a pale-brown oil:

¹H NMR (400 MHz, CDCl₃) δ 0.92 (3H, t, J ) 7.3 Hz), 1.17

(3H, t, J ) 7.3 Hz), 1.49-1.71 (2H, m), 2.51-2.55 (1H, m),

2.73 (1H, dd, J ) 13.7, 6.3 Hz), 2.89 (1H, dd, J ) 13.7, 8.8

Hz), 3.91 (3H, s), 4.03-4.11 (2H, m), 6.90 (1H, d, J ) 8.3 Hz),

7.36 (1H, dd, J ) 8.3, 2.4 Hz), 7.63 (1H, d, J ) 2.4 Hz), 10.44

(1H, s); low-resolution MS (EI⁺) m/e 264 (M⁺).

Eth yl 2-Eth yl-3-[3-(h yd r oxyim in o)-4-m eth oxyp h en yl]-

p r op a n oa te (56). A mixture of 55 (1.06 g, 4.01 mmol),

hydroxylamine hydrochloride (293 mg, 4.22 mmol), 1 mL of

pyridine, and 20 mL of ethanol was refluxed for 6 h. After

cooling to room temperature, the mixture was concentrated

and redissolved in ethyl acetate, washed with 1 M HCl,

saturated sodium hydrogen carbonate, and brine, dried over

anhydrous sodium sulfate, and concentrated. The residue was

purified by silica gel column chromatography (eluant, n-

hexane/ethyl acetate ) 6:1 v/v) to afford 1.00 g (89%) of the

title compound as a pale-yellow oil: ¹H NMR (400 MHz, CDCl₃)

δ 0.91 (3H, t, J ) 7.3 Hz), 1.17 (3H, t, J ) 7.3 Hz), 1.51-1.68

(2H, m), 2.51-2.58 (1H, m), 2.69 (1H, dd, J ) 13.7, 6.8 Hz),

2.87 (1H, dd, J ) 13.7, 8.3 Hz), 3.83 (3H, s), 4.04-4.11 (2H,

m), 6.81 (1H, d, J ) 8.3 Hz), 7.15 (1H, dd, J ) 8.3, 2.4 Hz),

7.51 (1H, s), 8.46 (1H, s); low-resolution MS (EI⁺) m/e 279 (M⁺).

E t h yl

3-[3-[2-E t h oxyca r b on yla cet yl-3-[4-(t r iflu or o-

m eth yl)p h en yl]p r oion yl]-4-m eth oxyp h en yl]-2-eth ylp r o-

p a n oa te (48). To a solution of 47 (2.59 g, 7.39 mmol) and 30

mL of anhydrous tetrahydrofuran was added sodium hydride

(296 mg, 7.40 mmol; 60% oil dispersion) portionwise under ice

cooling and an argon atmosphere. The mixture was stirred for

20 min under ice-cooling and then for 30 min at room

temperature. A mixture of 4-(trifluoromethyl)benzyl bromide

(1.77 g, 7.40 mmol) and 10 mL of anhydrous tetrahydrofuran

was added dropwise, and the whole was refluxed for 6 h. After

the mixture was cooled to room temperature, 15 mL of 1 M

HCl and 100 mL of ice-water were added, and the whole was

extracted with ethyl acetate. The extract was washed with

water and brine, dried over anhydrous sodium sulfate, and

concentrated. The residue was purified by silica gel column

chromatography (eluant, n-hexane/ethyl acetate ) 8:1 v/v) to

afford 3.70 g (98%) of the title compound as a yellow oil: ¹H

NMR (400 MHz, DMSO-d₆) δ 0.84 (3H, t, J ) 7.3 Hz), 0.98-

1.08 (6H, m), 1.45-1.55 (2H, m), 2.68-2.77 (2H, m), 3.15 (1H,

dd, J ) 14.2, 7.3 Hz), 3.25 (1H, dd, J ) 14.2, 6.8 Hz), 3.79

(3H, s), 3.91-4.16 (2H, m), 4.68 (1H, dt, J ) 7.8, 2.4 Hz), 7.07

(1H, d, J ) 8.3 Hz), 7.34-7.38 (2H, m), 7.42 (2H, d, J ) 7.3

Hz), 7.61 (2H, d, J ) 8.3 Hz); low-resolution MS (EI⁺) m/e 508

(M⁺).

2-Eth yl-3-[3-[3-[4-(tr iflu or om eth yl)p h en yl]p r oion yl]-4-

m eth oxyp h en yl]p r op a n oic a cid (51). A mixture of 50 (2.62

g, 5.15 mmol), 10 mL of glacial acetic acid, and 5 mL of

concentrated HCl was refluxed for 5 h. After cooling to room

temperature, the mixture was poured into ice-water and

extracted with ethyl acetate. The extract was washed with

water and brine, dried over anhydrous sodium sulfate, and

concentrated. The residue was purified by silica gel column

chromatography (eluant, n-hexane/ethyl acetate/acetic acid )

400:100:1.5 v/v/v) to afford 1.47 g (70%) of the title compound

as a pale-yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 0.95 (3H, t,

J ) 7.3 Hz), 1.54-1.69 (2H, m), 2.54-2.61 (1H, m), 2.73 (1H,

dd, J ) 13.7, 6.8 Hz), 2.92 (1H, dd, J ) 13.7, 7.8 Hz), 3.06

(2H, t, J ) 7.3 Hz), 3.31 (2H, t, J ) 7.3 Hz), 3.85 (3H, s), 6.87

(1H, d, J ) 8.8 Hz), 7.28 (1H, dd, J ) 8.3, 2.4 Hz), 7.34 (2H,

d, J ) 7.8 Hz), 7.52-7.54 (2H, m); low-resolution MS (EI⁺)

m/z 408 (M⁺). Anal. (C₂₂H₂₃F₃O₄) C, H.

2-E t h yl-3-[3-[3-[4-(t r iflu or om et h yl)p h en yl]p r op yl]-4-

m et h oxyp h en yl]p r op a n oic Acid (52). 51 (224 mg, 0.548

mmol), 30 mL of ethanol, and 250 mg of palladium on carbon

was mixed, and hydrogenation was carried out at an initial

hydrogen pressure of 392 kPa at room temperature for 7 h.

The catalyst was removed by filtration, and the filtrate was

evaporated off. The residue was purified by silica gel column

chromatography (eluant, n-hexane/ethyl acetate/acetic acid )

200:100:2 v/v/v) to afford 185 mg (86%) of the title compound

as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 0.94 (3H, t, J )

7.3 Hz), 1.52-1.67 (2H, m), 1.52-1.67 (2H, m), 1.87-1.94 (2H,

m), 2.53-2.71 (6H, m), 2.88 (1H, dd, J ) 13.7, 7.8 Hz), 3.78

(3H, s), 6.74 (1H, d, J ) 8.3 Hz), 6.92 (1H, d, J ) 2.4 Hz), 6.98

(1H, dd, J ) 8.3, 2.4 Hz), 7.29 (2H, d, J ) 8.3 Hz), 7.52 (2H,

d, J ) 8.3 Hz); low-resolution MS (EI⁺) m/z 394 (M⁺). Anal.

(C₂₂H₂₅F₃O₃) C, H.

4-Met h oxy-3-[2-[4-(t r iflu or om et h yl)p h en yl]et h oxy]-

ben za ld eh yd e (50). To a solution of 2-[4-(trifluoromethyl)-

phenyl]ethanol (1.59 g, 8.36 mmol), isovaniline (1.28 g, 8.41

mmol), triphenylphosphin (2.20 g, 8.39 mmol), and 50 mL of

anhydrous tetrahydrofuran was added a 40% toluene solution

Eth yl 3-[3-(Am in om eth yl)-4-m eth oxyp h en yl]-2-eth yl-

p r op a n oa te Hyd r och lor id e (58). This compound was pre-

Substituted Phenylpropanoic Acid Derivatives

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17 3597

pared from 56, using the same procedures as described for the

preparation of 36: ¹H NMR (400 MHz, DMSO-d₆) δ 0.85 (3H,

t, J ) 7.3 Hz), 1.12 (3H, t, J ) 7.3 Hz), 1.47-1.54 (2H, m),

2.50-2.57 (1H, m), 2.64 (1H, dd, J ) 13.7, 6.3 Hz), 2.78 (1H,

dd, J ) 13.7, 8.3 Hz), 3.80 (3H, s), 3.91 (2H, s), 3.97-4.09 (2H,

m), 6.97 (1H, d, J ) 8.8 Hz), 7.17 (1H, d, J ) 8.3 Hz), 7.21

(1H, s), 8.22 (2H, br s); low-resolution MS (EI⁺) m/e 265 (M⁺).

m), 2.70 (1H, dd, J ) 13.2, 9.8 Hz), 2.78 (1H, dd, J ) 13.7, 6.4

Hz), 3.00 (1H, dd, J ) 13.7, 8.3 Hz), 3.29 (1H, dd, J ) 13.2,

2.9 Hz), 3.92 (3H, s), 3.98-4.07 (3H, m), 4.61-4.67 (1H, m),

4.71 (2H, d, J ) 5.9 Hz), 6.91 (1H, d, J ) 8.8 Hz), 7.20-7.38

(6H, m), 7.44 (2H, d, J ) 8.3 Hz), 7.57 (2H, d, J ) 8.3 Hz),

8.00 (1H, d, J ) 2.4 Hz), 8.24 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/z 568 (M⁺).

3-[3-[4-(Tr iflu or om eth yl)ben zoylam in om eth yl]-4-m eth -

oxyp h en yl]-2-eth ylp r op a n oic Acid (62). This compound

was prepared from 58, using the same procedures as described

for the preparation of 10: mp 132-133 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.95 (3H, t, J ) 7.3 Hz), 1.54-1.70 (2H, m), 2.51-

2.59 (1H, m), 2.71 (1H, dd, J ) 13.7, 6.3 Hz), 2.88 (1H, dd, J

) 13.7, 8.3 Hz), 3.85 (3H, s), 4.58 (2H, d, J ) 5.9 Hz), 6.78-

6.82 (2H, m), 7.10 (1H, dd, J ) 8.3, 2.4 Hz), 7.16 (2H, d, J )

2.4 Hz), 7.56 (2H, d, J ) 8.3 Hz), 7.85 (2H, d, J ) 8.3 Hz);

low-resolution MS (EI⁺) m/z 409 (M⁺). Anal. (C₂₁H₂₂F₃NO₄) C,

H, N.

E t h yl 2-E t h yl-3-[3-[4-(t r iflu or om et h yl)b en zyla m in o-

m et h yl]-4-m et h oxyp h en yl]p r op a n oa t e. To a solution of

58 (203 mg, 0.673 mmol) and 4 mL of N,N-dimethyformamide

was added potassium carbonate (232 mg, 1.68 mmol) and

4-(trifluoromethyl)benzyl bromide (169 mg, 0.707 mmol). The

mixture was stirred for 3 h at room temperature and then for

4 h at 60 °C. After cooling to room temperature, the mixture

was poured into ice-water and the whole was extracted with

ether. The organic layer was washed with water and brine,

dried over anhydrous sodium sulfate, and concentrated. The

residue was purified by silica gel column chromatography

(eluant, n-hexane/ethyl acetate ) 2:1 v/v) to afford 92.3 mg

(32%) of the title compound as a colorless oil: ¹H NMR (400

MHz, CDCl₃) δ 0.91 (3H, t, J ) 7.3 Hz), 1.17 (3H, t, J ) 7.3

Hz), 1.50-1.70 (2H, m), 2.50-2.57 (1H, m), 2.68 (1H, dd, J )

13.7, 6.8 Hz), 2.87 (1H, dd, J ) 13.1, 8.3 Hz), 3.76 (2H, s),

3.80 (3H, s), 3.81 (2H, s), 4.01-4.13 (2H, m), 6.77 (1H, d, J )

8.3 Hz), 7.01-7.05 (2H, m), 7.47 (2H, d, J ) 7.8 Hz), 7.58 (2H,

d, J ) 8.3 Hz); low-resolution MS (EI⁺) m/e 424 (M⁺).

(+)-2-E t h yl-3-[4-m et h oxy-3-[N-[[4-(t r iflu or om et h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid ((+)-

10). 59 (90.9 g, 0.160 mol) was dissolved in 802 mL of a mixed

solvent of tetrahydrofuran and water (4:1 v/v) under an argon

atmosphere with ice-cooling. To this solution was added 30%

aqueous hydrogen peroxide (63.7 mL, 0.630 mol). Then lithium

hydroxide monohydrate (10.7 g, 0.256 mol) dissolved in 267

mL of water was added, and the mixture was stirred further

for 1 h under ice-cooling. Sodium hydrogen sulfite (64%, 102

g, 0.627 mol) dissolved in 401 mL of water was added dropwise.

The reaction mixture was concentrated, poured into ice-water,

acidified with 5% HCl, and then extracted with methylene

chloride. The extract was washed with brine, dried over

anhydrous magnesium sulfate, and concentrated. The residue

was dissolved in ethyl acetate and n-hexane and allowed to

stand. The precipitated crystals were collected by filtration and

dried. A second crop of crystals was obtained from the filtrate.

The first and second crops were combined, washed with a

mixed solvent of n-hexane and ethyl acetate (4:1 v/v), and dried

to afford 52.4 g (80%) of the title compound as a colorless

crystalline powder: mp 128-130 °C; ¹H NMR (400 MHz,

CDCl₃) δ 0.95 (3H, dd, J ) 7.3, 7.3 Hz), 1.54-1.70 (2H, m),

2.58-2.65 (1H, m), 2.77 (1H, dd, J ) 13.7, 6.3 Hz), 2.96 (1H,

dd, J ) 13.7, 8.3 Hz), 3.92 (3H, s), 4.38 (1H, br s), 4.72 (2H, d,

J ) 5.9 Hz), 6.90 (1H, d, J ) 8.3 Hz), 7.29 (1H, dd, J ) 8.3,

2.4 Hz), 7.46 (2H, d, J ) 7.8 Hz), 7.58 (2H, d, J ) 7.8 Hz),

8.07 (1H, d, J ) 2.4 Hz), 8.34 (1H, t, J ) 5.9 Hz); low-resolution

MS (EI⁺) m/z 409 (M⁺); [R]_D+24° (c 0.8, MeOH). Anal.

(C₂₁H₂₂F₃NO₄) C, H, N.

(-)-2-E t h yl-3-[4-m et h oxy-3-[N-[[4-(t r iflu or om et h yl)-

p h en yl]m eth yl]ca r ba m oyl]p h en yl]p r op a n oic Acid ((-)-

10). This compound was prepared from racemic 10, using the

same procedures as described for the preparation of (+)-10:

mp 128-130 °C; ¹H NMR (400 MHz, CDCl₃) δ 0.95 (3H, dd, J

) 7.3, 7.3 Hz), 1.54-1.70 (2H, m), 2.58-2.65 (1H, m), 2.77 (1H,

dd, J ) 13.7, 6.3 Hz), 2.96 (1H, dd, J ) 13.7, 8.3 Hz), 3.92

(3H, s), 4.38 (1H, br s), 4.72 (2H, d, J ) 5.9 Hz), 6.90 (1H, d,

J ) 8.3 Hz), 7.29 (1H, dd, J ) 8.3, 2.4 Hz), 7.46 (2H, d, J )

7.8 Hz), 7.58 (2H, d, J ) 7.8 Hz), 8.07 (1H, d, J ) 2.4 Hz),

8.34 (1H, t, J ) 5.9 Hz); low-resolution MS (EI⁺) m/z 409 (M⁺);

[R]_D-24° (c 0.8, MeOH). Anal. (C₂₁H₂₂F₃NO₄) C, H, N.

2-Eth yl-3-[3-[4-(tr iflu or om eth yl)ben zyla m in om eth yl]-

4-m eth oxyp h en yl]p r op a n oic Acid (64). This compound,

obtained as an oil, was prepared from ethyl 2-ethyl-3-[3-[4-

(trifluoromethyl)benzylaminomethyl]-4-methoxyphenyl]pro-

panoate, using the same procedures as described for the

preparation of 10: ¹H NMR (400 MHz, CDCl₃) δ 0.99 (3H, t,

J ) 7.3 Hz), 1.54-1.61 (1H, m), 1.71-1.78 (1H, m), 2.52-2.57

(1H, m), 2.71-2.83 (2H, m), 3.72 (3H, s), 3.88-3.98 (4H, m),

6.67 (1H, d, J ) 8.8 Hz), 7.10 (1H, dd, J ) 8.8, 2.0 Hz), 7.30

(1H, d, J ) 2.0 Hz), 7.63 (2H, d, J ) 8.3 Hz), 7.71 (2H, d, J )

8.3 Hz); low-resolution MS (EI⁺) m/z 394 (M⁺). Anal. (C₂₁H₂₄F₃-

NO₃HCl) C, H, N.

(R)-3-(1-Bu tyr yl)-4-ben zyloxa zolid in -2-on e (79). Potas-

sium tert-butoxide (6.18 g, 55.1 mmol) and 100 mL of dehy-

drated tetrahydrofuran were mixed under an argon atmo-

sphere, and (R)-4-benzyloxazolidin-2-one (8.86 g, 50.0 mmol)

dissolved in 100 mL of dehydrated tetrahydrofuran was added

dropwise under stirring and cooling with ice. The mixture was

stirred for 30 min under cooling with ice, and then n-butyryl

chloride (5.20 mL, 50.1 mmol) dissolved in 40 mL of dehy-

drated tetrahydrofuran was added dropwise. After completion

of the addition, the mixture was stirred for 1 h and a saturated

aqueous solution of ammonium chloride was added. The whole

was extracted with ethyl acetate. The organic solution was

washed with water, saturated sodium hydrogen carbonate, and

brine, dried over anhydrous sodium sulfate, and concentrated.

The residue was purified by silica gel chromatography (eluant,

n-hexane/ethyl acetate ) 5:1 v/v) to afford 9.63 g (78%) of the

title compound as a pale-yellow oil: ¹H NMR (400 MHz, CDCl₃)

δ 1.01 (3H, t, J ) 7.3 Hz), 1.73 (2H, m), 2.77 (1H, dd, J )

13.9, 9.8 Hz), 2.84-3.00 (2H, m), 3.30 (1H, dd, J ) 13.2, 3.4

Hz), 4.15-4.22 (2H, m), 4.68 (1H, m), 7.20-7.36 (2H, m); low-

resolution MS (EI⁺) m/z 247 (M⁺).

[3(2S),4S]-3-[2-E t h yl-3-[4-m et h oxy-3-[N-[[4-(t r iflu or o-

m et h yl)p h en yl]m et h yl]ca r b a m oyl]p h en yl]p r op ion yl]-

4-ben zyloxa zolid in -2-on e (59). Racemic 10 (26.8 g, 65.6

mmol) and 34 mL of dehydrated tetrahydrofuran were mixed

under an argon atmosphere, and triethylamine (9.14 mL, 65.8

mmol) and pivaloyl chloride (8.07 mL, 65.6 mmol) were added

dropwise with ice-cooling. The mixture was stirred for 1.5 h

at room temperature to afford the mixed acid anhydride

derivative. In another vessel, potassium tert-butoxide (8.83 g,

78.7 mmol) and 88 mL of dehydrated tetrahydrofuran were

mixed under an argon atmosphere and (S)-4-benzyloxazolidin-

2-one (13.9 g, 78.7 mmol) dissolved in 70 mL of dehydrated

tetrahydrofuran was added dropwise. The mixture was stirred

for 45 min. Then, the suspension of the mixed acid anhydride

derivative described above was added dropwise. The reaction

mixture was concentrated, poured into water, and extracted

with ethyl acetate. The extract was washed with 5% HCl,

saturated sodium hydrogen carbonate, and brine and then

dried over anhydrous magnesium sulfate and concentrated.

The residue was purified by silica gel column chromatography

(eluant, n-hexane/ethyl acetate ) 3:2 v/v and then methylene

chloride/methanol ) 15:1 v/v) and recrystallized from diiso-

propyl ether and ether to afford 5.62 g (15%) of the title

compound as colorless crystals: ¹H NMR (400 MHz, CDCl₃) δ

0.98 (3H, t, J ) 7.3 Hz), 1.56-1.67 (1H, m), 1.78-1.87 (1H,

[3(2S),4R]-3-[2-Eth yl-3-[4-m eth oxy-3-(ben zyloxyca r bo-

n yl)p h en yl]p r op ion yl]-4-ben zyloxa zolid in -2-on e (80). (R)-

3-(1-Butyryl)-4-benzyloxazolidin-2-one (3.37 g, 13.6 mmol) and

70 mL of dehydrated tetrahydrofuran were mixed under an

argon atmosphere and cooled to -78 °C. Under stirring, a 1

3598 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 17

Nomura et al.

(9) (a) Nomura, M.; Takahashi, Y.; Tanase, T.; Miyachi, H.; Ide, T.;

Tsunoda, M.; Murakami, K. Substituted Phenylpropanoic Acid

Derivatives. PCT Int. Appl. WO 00/75103, 2000. (b) Miyachi, H.;

Nomura, M.; Tanase, T.; Takahashi, Y.; Ide, T.; Tsunoda, M.;

Murakami, K.; Awano, K. Design, Synthesis and Evaluation of

Substituted Phenylpropanoic Acid Derivatives as Peroxisome

Proliferator-Activated Receptor (PPAR) Activators: Novel Hu-

man PPARalpha-selective Activators. Bioorg. Med. Chem. Lett.

2002, 12, 77-80. (c) Miyachi, H.; Nomura, M.; Tanase, T.;

Suzuki, M.; Murakami, K.; Awano, K. Enantio-dependent Bind-

ing and Transactivation of Optically Active Phenylpropanoic

Acid Derivatives at Human Peroxisome Proliferator-Activated

Receptor Alpha. Bioorg. Med. Chem. Lett. 2002, 12, 333-335.

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PPAR-alpha Activation on Abnormal Lipid Metabolism in

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thiazolidine-2,4-diones as Structurally New Antihyperglycemic

Agents. Bioorg. Med. Chem. Lett. 1998, 8, 533-538.

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M solution of sodium bis(trimethylsilyl)amide in tetrahydro-

furan (15.0 mL, 15.0 mmol) was added dropwise. After

completion of the addition, the mixture was stirred for 1 h at

-78 °C and then a solution of benzyl 5-bromomethyl-2-

methoxybenzoate (5.04 g, 15.0 mmol) in tetrahydrofuran (20

mL) was added dropwise. After completion of the addition, the

mixture was further stirred for 6 h at -78 °C. A saturated

aqueous solution of ammonium chloride was added to the

reaction mixture, and the whole was extracted with ethyl

acetate. The extract was washed with water and brine, dried

over anhydrous sodium sulfate, and concentrated. The residue

was purified by silica gel chromatography (eluant, n-hexane/

ethyl acetate ) 4:1 v/v) to afford 4.38 g (64%) of the desired

compound as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 0.98

(3H, t, J ) 7.3 Hz), 1.51-1.63 (1H, m), 1.71-1.82 (1H, m),

2.43 (1H, dd, J ) 13.2, 9.8 Hz), 2.75 (1H, dd, J ) 13.7, 6.3

Hz), 2.99-3.08 (2H, m), 3.86 (3H, s), 4.03-4.15 (3H, m), 4.64

(1H, m), 5.27 (1H, d, J ) 12.2 Hz), 5.31 (1H, d, J ) 12.7 Hz),

6.91 (1H, d, J ) 8.8 Hz), 7.03 (2H, dd, J ) 7.8, 2.0 Hz), 7.20-

7.42 (9H, m), 7.72 (1H, d, J ) 2.0 Hz); low-resolution MS (EI⁺)

m/z 501 (M⁺).

[5(2S,4R)]-2-Meth oxy-5-[[2-(2-oxo-4-ben zyloxa zolid in -

3-yl)ca r bon yl]p en tyl]ben zoic Acid (81). [3(2S),4R]-3-[2-

Ethyl-3-[4-methoxy-3-(benzyloxycarbonyl)phenyl]propionyl]-4-

benzyloxazolidin-2-one (4.38 g, 8.73 mmol), 400 mg of 10%

palladium on carbon, and 100 mL of ethyl acetate were mixed,

and catalytic hydrogenation was carried out at an initial

hydrogen pressure of 294 kPa. After completion of the reaction,

the catalyst was removed by filtration and the filtrate was

washed with ethyl acetate. The reaction mixture and the

washings were combined and concentrated to afford 3.45 g

(96%) of the title compound as a colorless oil: ¹H NMR (400

MHz, CDCl₃) δ 0.93 (3H, t, J ) 7.3 Hz), 1.49-1.59 (1H, m),

1.78 (1H, m), 2.58 (1H, dd, J ) 13.2, 9.8 Hz), 2.78 (1H, dd, J

) 13.7, 6.8 Hz), 3.09 (1H, dd, J ) 13.7, 7.3 Hz), 3.15 (1H, dd,

J ) 13.2, 3.4 Hz), 3.99-4.05 (1H, m), 4.05 (3H, m), 4.10-4.19

(2H, m), 4.68 (1H, m), 7.00 (1H, d, J ) 8.3 Hz), 7.09 (2H, dd,

J ) 7.8, 2.0 Hz), 7.23-7.31 (9H, m), 7.55 (1H, dd, J ) 8.8, 2.4

Hz), 8.06 (1H, d, J ) 2.4 Hz), 10.70 (1H, br s); low-resolution

MS (EI⁺) m/z 411 (M⁺).

(15) Grieco, P. A.; Handy, S. T. Magnesium Trifluoromethanesulfona-

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Benzylic Acetates. Magnesium Triflimide as a Substitute for

Magnesium Perchorate. Tetrahedron Lett. 1997, 38, 2645-2648.

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(R)-(+)- and (S)-(-)-Enantiomers of 2-Oxy-3-arylpropanoic Acids.

Tetrahedron: Asymmetry 1999, 10, 1335-1351.

Ack n ow led gm en t. The authors thank H. Saitoh

and H. Furuta of Kyorin Pharmaceutical Co., Ltd., for

their analytical work.

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J M0205144

Article Doi

Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor α subtype-selective activators

DOI: 10.1021/jm0205144

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Article abstract of DOI:10.1021/jm0205144

Full text of DOI:10.1021/jm0205144

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