Novel (2E,4E,6Z)-7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta-2,4,6-trienoic acid retinoid X receptor modulators are active in models of type 2 diabetes

DOI: 10.1021/jm020340q

Source and publish data:

Journal of Medicinal Chemistry p. 2683 - 2696 (2003)

Update date:2022-08-04

Topics:

Authors:

Michellys

Ardecky Ardecky

Chen Chen

Crombie Crombie

Etgen Etgen

Faul Faul

Faulkner

Grese Grese

Heyman Heyman

Karanewsky

Klausing

Leibowitz

Liu Liu

Mais Mais

Mapes Mapes

Marschke

Reifel-Miller

Ogilvie Ogilvie

Rungta Rungta

Thompson

Tyhonas Tyhonas

Boehm Boehm

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Article abstract of DOI:10.1021/jm020340q

Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also produce dramatic increases in triglycerides and profound suppression

Full text of DOI:10.1021/jm020340q

J . Med. Chem. 2003, 46, 2683-2696

2683

Novel (2E,4E,6Z)-7-(2-Alk oxy-3,5-d ia lk ylben zen e)-3-m eth ylocta -2,4,6-tr ien oic Acid

Retin oid X Recep tor Mod u la tor s Ar e Active in Mod els of Typ e 2 Dia betes

P. Y. Michellys,*^,§R. J . Ardecky,^§J . H. Chen,^§D. L. Crombie,^∆,G. J . Etgen,³M. M. Faul,^‡A. L. Faulkner,^§,|

T. A. Grese,^†R. A. Heyman,^∞D. S. Karanewsky,^§,XK. Klausing,⁺M. D. Leibowitz,^∆S. Liu,^∆D. A. Mais,^#

C. M. Mapes,^§K. B. Marschke,^#A. Reifel-Miller,³K. M. Ogilvie,^∆,[D. Rungta,^#A. W. Thompson,^§,b

J . S. Tyhonas,^§and M. F. Boehm^§,

Department of Medicinal Chemistry, Ligand Pharmaceuticals, Incorporated, 10275 Science Center Drive,

San Diego, California 92121

Received August 6, 2002

Previous data have shown that RXR-selective agonists (e.g., 3 and 4) are insulin sensitizers in

rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Unfortunately, they also

produce dramatic increases in triglycerides and profound suppression of the thyroid hormone

axis. Here we describe the design and synthesis of new RXR modulators that retain the insulin-

sensitizing activity of RXR agonists but produce substantially reduced side effects. These

molecules bind selectively and with high affinity to RXR and, unlike RXR agonists, do not

activate RXR homodimers. To further evaluate the antidiabetic activity of these RXR

modulators, we have designed a concise and systematic structure-activity relationship around

the 2E,4E,6Z-7-aryl-3-methylocta-2,4,6-trienoic acid scaffold. Selected compounds have been

evaluated using insulin-resistant rodents (db/db mice) to characterize effects on glucose

homeostasis. Our studies demonstrate the effectiveness of RXR modulators in lowering plasma

glucose in the db/db mouse model.

Ch a r t 1

In tr od u ction

Retinoids are of considerable therapeutic interest as

evidenced by the many drugs from this class that are

currently marketed for diseases such as acne, psoriasis,

Kaposi’s sarcoma, cutaneous T-cell lymphoma (CTCL),

and various cutaneous disorders of keratinization.^1-4

The molecular targets of retinoids are two families of

homologous receptors: the retinoic acid receptors (RARs)

and the retinoid x receptors (RXRs). These receptors are

members of the intracellular nuclear receptor super-

family,⁵which function to regulate gene transcription.

Both RARs and RXRs are further divided into three

receptor subtypes, R, â, and γ, each encoded by a single

gene.⁶All-trans-retinoic acid (ATRA, 1) is the endog-

enous low-molecular weight ligand that modulates the

transcriptional activity of the RARs, whereas 9-cis-

* To whom correspondence should be addressed. E-mail:

pmichellys@ligand.com

retinoic acid (9-cis-RA, 2) is the endogenous ligand of

RXRs (Chart 1).^7,8

^§Department of Medicinal Chemistry, Ligand Pharmaceuticals, Inc.,

San Diego, CA.

^∆Department of Pharmacology, Ligand Pharmaceuticals, Inc., San

Diego, CA.

Recently, a new drug targeting RXRs has emerged.

Methyl-4-[(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-

naphthalenyl)ethenyl]-benzoate (LGD1069, 3) is an RXR

agonist,⁹which is administered for the treatment of

CTCL^10-12and is currently in clinical trials for non-

small cell lung cancer.¹³This compound is a member of

the series of RXR agonists, which include compounds

such as 4 (LG100268) and 5 (Chart 1).^14-16

Structural features of these molecules include a

p-benzoic acid linked to a 5,6,7,8-tetramethyl-5,5,8,8-

tetrahydronaphthyl moiety via a substituted methylene

bridge. Structure-activity relationship (SAR) studies

have revealed the critical importance of the 3 position

within such molecules. It has been found that any small

Current address: Conforma Therapeutics, San Diego, CA.

^|Current address: Procter and Gamble, Cincinnati, OH.

^∇Division of Endocrine Research, Lilly Research Laboratories,

Indianapolis, IN.

^‡Process Chemistry Research, Lilly Research Laboratories, India-

napolis, IN.

^†Discovery Chemistry Research, Lilly Research Laboratories, In-

dianapolis, IN.

Department of New Leads Discovery, Ligand Pharmaceuticals,

Inc., San Diego, CA.

^∞Current address: X-Ceptor Therapeutics, San Diego, CA.

⁺Department of Molecular and Cell Biology, Ligand Pharmaceuti-

cals Inc., San Diego, CA.

^[Current address: Pfizer Inc., San Diego, CA.

^XCurrent address, Genomics Institute of Norvartis Research Foun-

dation, San Diego, CA.

^bCurrent address: Roche Bioscience, Palo Alto, CA.

Published on Web 05/20/2003

2684 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

Ch a r t 2

Ch a r t 3

substitution in the 3 position (Chart 1) will increase

RXR selectivity by introducing conformational restric-

tions to the molecule. These results have been rational-

ized using molecular modeling.⁹Further exploration of

the SAR has led to the replacement of the exo olefin

present in 3 with a cyclopropyl (4) or an oxime (5).^15,16

These substitutions slightly change the torsional angle

of the two aromatic rings, which in turn leads to an

increase in their RXR potency and selectivity.

antagonists such as 7 and 8 (Chart 1) affect glucose

homeostasis in an animal model.^{26, 27}

Mod e of Action

Ch em istr y

RXRs function to regulate transcription either as

homodimers (RXR:RXR) or as heterodimers with other

nuclear receptors such as RARs, thyroid hormone recep-

tor (TR), vitamin D receptor (VDR), liver X receptor

(LXR), farnesoyl X receptor (FXR), peroxisome prolif-

erator-activated receptors (PPARs), and nerve growth

factor-induced receptor (NGFIB).^6,17It has been dem-

onstrated that for RXR:RAR, RXR:VDR, and RXR:TR

heterodimers, an RXR agonist will not activate the

heterodimer without the corresponding ligand for the

heterodimeric partner (nonpermissive heterodimers).

However, for other heterodimers such as RXR:PPARs,

RXR:LXR, RXR:FXR, and RXR:NGFIB, a ligand for

either or both of the heterodimer partners may serve

to activate the heterodimeric complex (permissive het-

erodimers). As a result, the presence of ligands for both

partners can lead to an additive or synergistic activation

of the heterodimer, or both.¹⁷

The new modulators we describe are based on the

(2E,4E,6Z)-7-(2-alkoxy-3,5-di-alkylbenzene)-3-methylocta-

2,4,6-trienoic acid scaffolds 11, 12, and 13 (Chart 2).

Previous SAR investigation of structurally similar

molecules led to the discovery of very potent trienoic

acids derivatives, 9 (ALRT1550) and 10 (Chart 3),

respectively (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-

methyl-octa-2,4,6-trienoic acid and (2E,4E,6Z)-7-(3,5-di-

tert-butylphenyl)-3-methyl-octa-2,4,6-trienoic acid.²⁸9 is

an RAR agonist, whereas 10 is a pan-agonist whose

activity is essentially identical to that of 9-cis-retinoic

acid. The receptor selectivity of these compounds is

undoubtedly determined by the configuration of the C-6

olefin bond precisely; the presence of the 6E olefin favors

RAR selectivity, whereas the presence of the 6Z olefin

induces RXR selectivity (pattern observed with all-trans-

retinoic acid 1 and 9-cis-retinoic acid 2).

Because of this unique capability to interact with a

variety of other nuclear receptors, RXRs are very

attractive targets for drug discovery.¹⁸We discuss the

advantages of a novel series of RXR ligands, which

exhibit heterodimer selectivity. Because these RXR

ligands activate specific heterodimers, we refer to the

compounds as selective RXR modulators. For the series

of compounds described herein, the focus will be on the

RXR:PPARγ heterodimer.

RXR:PPAR heterodimers play a major role in the

regulation of both glucose (RXR:PPARγ) and lipid

(RXR:PPARR) metabolism.^19-22Recent reports have

shown that synthetic RXR agonists (rexinoids) such as

3, 4, and 6 are insulin-sensitizing agents²³and are

capable of decreasing hyperglycemia and hyperinsuline-

mia.^17,24,25Unfortunately, RXR agonists also produce

various side effects including a dramatic increase of

triglycerides and a suppression of the thyroid hormone

axis.²⁴This undesirable side effect profile prevents their

use as chronic therapies for type 2 diabetic patients.

More recently, it was reported that RXR homodimer

As evidenced by their high potency and selectivity,

these molecules were very interesting as a starting point

for SAR studies. We have used these templates to design

and synthesize more selective RXR modulators than

those modulators previously described (Chart 2).

Conversion of the salicylic acids 14 and 15 into the

corresponding acetylphenols 16 and 17 using 3 equiv

of MeLi in THF at 0 °C was accomplished in good yield

(>75%).²⁹Treatment of 16 and 17 in refluxing toluene

with an excess (2.5 equiv) of ethyl(triphenylphosphora-

nilidene)acetate afforded the coumarins 18 and 19 in

good yield (>85%).³⁰This particular coumarin synthesis

is the most convenient and consistent route to these

structures that we have found so far.^31,32The sequence

is consistently effective independent of scale (milligrams

to multigrams). Reduction of 18 and 19 with LAH or

NaAlH₄in ether at 0 °C gives the corresponding

phenolic alcohols 20 and 21 in quantitative yield

without alteration of the established double bond.

Introduction of the alkoxy side chain is achieved by

selective alkylation of the phenol using Cs₂CO₃in DMF

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2685

Sch em e 1. Synthetic Scheme for the Synthesis of Compounds 11a -g and 12a -e^a

Reagents and conditions: (a) MeLi, THF, -78 °C to rt; (b) ethyl (triphenylphosphoranilidene)acetate, toluene, reflux; (c) NaAlH₄,

ether, 0 °C; (d) R₁-Br, Cs₂CO₃, DMF; (e) TPAP, NMO, CH₂Cl₂; (f) triethyl-3-methylphosphonocrotonate, n-BuLi, THF-DMPU, -78 °C

to rt; (g) 2 N aq LiOH, MeOH, THF reflux, then HCl and recrystallization from CH₃CN; (h) 1-bromo-2,2,2-trifluoroethane, Cs₂CO₃, DMF,

50 °C, sealed tube, 16 h.

at room temperature to afford 22a -g and 23a -e. These

conditions were effective except for the introduction of

the 2,2,2-trifluoroethoxy group. In this case, because of

the high volatility and reduced reactivity of the 2-bromo-

1,1,1-trifluoroethane, the reaction was conducted into

a sealed tube at 50 °C. Oxidation of the resultant allylic

alcohols 22a -g and 23a -e with a catalytic amount (5-

10%) of tetrapropylammonium perruthenate (TPAP)^33,34

and an excess of NMO (1.5 equiv) in methylene chloride

yields the corresponding unsaturated aldehydes 24a -g

and 25a -e in quantitative yield. The aldehydes 24a -g

and 25a -e are directly subjected to a Horner-Wad-

sworth-Emmons reaction with the anion of triethyl-3-

methylphosphonocrotonate (prepared by slow addition

of n-BuLi to a solution of triethyl phosphonocrotonate

in THF-DMPU at -78 °C)^28,30,35-37to afford in excellent

overall yield (>85%, two steps) the corresponding esters

26a -g and 27a -e. Hydrolysis of these esters with 2 N

aqueous LiOH in refluxing THF-MeOH (or, alterna-

tively, aqueous 5 N KOH in refluxing ethanol) affords

the crude corresponding trienoic acids 11a -g and 12a -

e. Recrystallization of these crude acids from acetonitrile

affords the desired pure (2E,4E,6Z)-trienoic acids 11a -g

and 12a -e in good yield and excellent isomeric purity

(>99%).

methylacetamide to the dianion of 29.³⁸The iodophenol

29 was obtained from the iodination of the inexpensive

2,4-di-tert-amylphenol 28 with a slight excess (1.1 equiv)

of N-iodosuccinimide and a catalytic amount (10%) of

TsOH in methylene chloride. Treatment of the 6-iodo-

2,4-di-tert-amylphenol 29 with 2.5 equiv of n-BuLi in

ether at -78 °C, followed by addition of an excess of

N,N-dimethylacetamide, affords the corresponding

acetylphenol 30, typically isolated in 30-40% yield.

Once compound 30 is obtained, its transformation into

series 13a -d was completed using the conditions de-

picted in Scheme 1. All yields are comparative, and we

once again obtain the final trienoic acids (13a -d ) as

single isomers by recrystallization from acetonitrile.

Resu lts

Biologica l Da ta . The binding of each compound to

RXRR and RARγ has been characterized using [H]-9-

cis-RA for RXR and ³[H]-ATRA for RAR (data shown

as K_i). The RXR homodimer transcriptional activation

profile of each compound was determined in CV-1 cells

(using an AOX response element as the reporter), with

the efficacy being measured relative to ATRA. The RXR

activation profiles of RXR:RAR and RXR:PPARγ het-

erodimers were also determined in CV-1 cells. 4 and

compounds with short alkoxy side chains (11a , 11b,

12a ) are full agonists of the RXR homodimer and both

RXR:RAR and RXR:PPARγ heterodimers. As the alkoxy

side chain is lengthened, both cotransfection activities

decrease (11g, 12c). However, when tested in combina-

Scheme 2 mirrors Scheme 1 in all respects except for

the method used for the synthesis of the acetylphenol

30. This alteration resulted from the lack of a com-

mercial source for 3,5-di-tert-amyl salicylic acid. The

acetyl moiety is introduced via addition of N,N-di-

2686 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

Sch em e 2. Synthetic Scheme for the Synthesis of Compounds 13a -d ^a

Reagents and conditions: (a) NIS, TsOH, CH₂Cl₂; (b) n-BuLi, Et₂O, -78 °C, then DMA; (c) ethyl(triphenylphosphoranilidene)acetate,

toluene, reflux; (d) NaAlH₄, ether, 0 °C; (e) R₁-X, Cs₂CO₃, DMF; (f) TPAP, NMO, CH₂Cl₂; (g) triethyl-3-methylphosphonocrotonate, nBuLi,

THF-DMPU, -78 °C to rt; (h) 2 N aq LiOH, MeOH, THF reflux, then HCl and recrystallization from CH₃CN.

Ta ble 1. In Vitro Profiling of Compounds 11a -g, 12a -e, and 13a -d ^a

RXRR

agonist

efficacy

RXRR

agonist

EC₅₀

RXRR

RXR:PPARγ

synergy

RXR:PPARγ

synergy

EC₅₀

RXR/RAR

synergy

(fold)

RXRR

antagonist antagonist

entries compounds

K_i

efficacy

IC₅₀

efficacy

RARγ K_i

18 ( 1

BRL49653 NB

70 ( 21

1 ( 1

11 ( 10

2 ( 1

7 ( 1

36 ( 15

18 ( 12

166 ( 57

38 ( 20

10000

1860

10000

4028

11a

11b

11c

11d

11e

11f

11g

12a

12b

12c

12d

12e

13a

13b

13c

13d

1 ( 2

83 ( 19

58 ( 18

43 ( 4

11 ( 1

3 ( 2

324 ( 55

146 ( 44

129 ( 9

91 ( 31

70 ( 23

62 (16

39 ( 17

180 ( 55

70 ( 19

60 ( 29

40 ( 3

80 ( 37

140 ( 46

129 ( 2

69 ( 16

58 ( 10

8 ( 5

2 ( 2

1 ( 0

2 ( 1

3 ( 2

3 ( 3

4 ( 5

1 (1

7 ( 8

1 ( 1

17 ( 23

65 ( 5

87 ( 2

85 ( 4

91 (4

5 ( 7

4 ( 3

4 ( 2

1 ( 1

6 ( 4

4 ( 3

10 ( 1

3 ( 1

4 ( 1

5 ( 4

2 ( 2

12 ( 9

7 ( 3

65 ( 12

11 ( 10 12 ( 6

61 ( 10

84 (10

93 ( 3

74 ( 1

15 ( 21

72 ( 2

90 ( 2

88 ( 1

8 ( 6

2 ( 2

3 ( 2

27 ( 14

14 ( 7

2 ( 1

29 ( 5

23 ( 6

4 ( 2

1 ( 0

9 ( 6

8 ( 4

3 ( 1

8 ( 4

2 ( 2

43 ( 12

154 ( 60

6 ( 1

10000

2503

10000

35 ( 15 506 ( 50

11 ( 5

2 ( 1

5 ( 2

17 ( 5

16 ( 10

13 ( 2

9 ( 4

11 ( 3

19 ( 5

K_i, EC₅₀, and IC₅₀are expressed in nM. RXR: RAR synergy is expressed as fold induction above an EC₃₀concentration of TTNPB.

NB: No Binding; NA: Not Applicable.

tion with 100 nM BRL49653 (Rosiglitazone), the modu-

lators produce substantial activation of RXR:PPARγ

heterodimers. The same protocol was used to further

characterize the acids 11a -g, 12a -e, and 13a -d .

Results are summarized in Table 1.

11g, 12e, and 13d ), with the exception of the 2,2-

difluoroethoxy and 2,2,2-trifluoroethoxy side chain (11e,

12c, 12d , and 13c; Table 1, entries 7, 12, 13, and 17

respectively). These appear to be intermediate between

ethyl and propyl in activity as would be expected on the

basis of steric arguments. Fluorines are not only very

well tolerated but also allow a very smooth transition

from agonist to partial agonist to antagonist activity (see

Table 1, entries 5-7).

Cotransfection activities of selected RXR modulators

in RXR homodimer agonist mode (Figure 1), RXR

homodimer antagonist mode (Figure 2), and RXR:

PPARγ heterodimer synergy mode (Figure 3) are shown.

RXR agonists show a dramatic synergistic response

when tested in combination with BRL49653 (Table 1,

entries 1, 3, and 10). Evaluation of these compounds for

their RXR:PPARγ heterodimer activity showed the

expected activity for the RXR agonists 11a , 12a , and

All the compounds bind with high affinity to RXRR

(1 < K_i< 29 nM) independent of the size of the alkoxy

side chain. No high-affinity RARγ binding is observed;

only 11e, 12d , and 13b bind weakly to RARγ (1860,

4028, and 2503 nM respectively; entries 7, 13, and 16).

As expected, short alkoxy side chains (e.g., methoxy,

11a , 12a , and ethoxy, 11b) show excellent RXR homo-

dimer agonist activity (efficacy > 58% and EC₅₀< 19

nM; Table 1, entries 3, 4, and 10 respectively) except

compound 13a that has a partial agonist profile (see

Table 1, entry 15). When the alkoxy chain becomes

longer, RXR homodimer agonist activity slowly de-

creases and disappears entirely when R₁) C₃H₇(11f,

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2687

Ta ble 2. In Vivo Activity of Selected RXR Modulators^a,b,c

lean

db/db

drug-treated % normalization

compounds control^dcontrol^d

db/db^d

vs BRL46953

BRL 49653 205 ( 5 750 ( 15

412 ( 10

400 ( 5

502 ( 7

412 ( 10

409 ( 6

100

101

100

101

207 ( 5 740 ( 15

203 ( 5 750 ( 15

200 ( 5 748 ( 15

203 ( 5 749 ( 10

11g

12b

12c

Hypoglycemic activity of selected RXR modulators 11g,

12b, and 12c in the db/db mouse model after 7 days of dosing.

FA: compound used as the free acid; Na Salt: compound used

as the sodium salt. ^cBRL49653 used as reference compound for

efficacy (100%). In mg/dL.

F igu r e 1. RXRR cotransfection data (agonist mode) of com-

pounds 11a -g.

4-, and 3-fold induction respectively). However, as the

side chain is lengthened, the RXR:RAR synergy activity

progressively decreases and is absent (equal or less than

2-fold induction) for full RXR antagonists (Table 1,

entries 7, 8, 9, 12, 13, 14, 17, and 18). More interestingly,

it appears that the RXR:RAR synergy is not only related

to the length of the alkoxy side chain but can also be

modulated by using a combination of the side chain and

the aromatic ring substitutions. More precisely, when

bulkier aromatic substitution is used for a given alkoxy

side chain, a decrease of RXR:RAR synergy is observed.

As an example, when the ring substituents increase in

size (di-iso-propyl, di-tert-butyl, and di-tert-amyl, re-

spectively), synergy decreases from 3-fold to 2- and

1-fold (Table 1, entries 6, 12, and 17) for compounds 11d ,

12c, and 13c, respectively.

F igu r e 2. RXRR cotransfection data (antagonist mode) of

compounds 11a -g.

In Vivo Eva lu a tion . The ability of these compounds

to lower plasma glucose was evaluated in the db/db

mouse. These mice have a leptin receptor defect render-

ing them progressively obese, hyperglycemic, and hy-

pertriglyceridemic with age and are commonly used as

a model of type 2 diabetes. BRL49653 and 4 served as

positive controls for glucose-lowering efficacy in these

experiments, and the data were compared both to a

vehicle-treated group of db/db animals and to a group

of age-matched lean littermates. Each RXR modulator

was given orally as a single agent (as the Na salt to

enhance their solubility, except 12c) at 30 mg/kg/day.

4 (10 mg/kg/day) was used as the free acid. BRL49653

was used at 10 mg/kg/day. The data collected are shown

in Table 2.

F igu r e 3. RXRR:PPARγ cotransfection assay of compounds

11a -g in synergy mode with 100 nM of BRL 49653.

11b. However, measurement of RXR/PPARγ activity

proved to be more difficult for the RXR homodimer

modulators because they exhibit a concomitant decrease

in the RXR:PPARγ heterodimer activity when admin-

istered alone (data not shown). However, when the RXR

homodimer modulator and 100 nM BRL49653 were

used in combination, a much cleaner response and a

larger window of activity was observed. Responses

ranging from good to moderate are observed with the

modulators.

A similar activity profile was observed on the

RXR:RAR heterodimer. Synergy was observed when

RXR agonists were tested in combination with the

potent RAR agonist TTNPB. To assess the potential of

the described RXR modulators to synergize with RAR

agonists, we have developed an in vitro RXR:RAR

synergy assay using a combination of 3 nM TTNPB with

the test compounds. The RXR agonists and modulators

(4, 11a , 11b, 11c, 12a , and 13a ; Table 1, entries 1, 3, 4,

5, and 10) all show a synergistic response (7-, 10-, 5-,

After seven days of treatment, 4 shows very good

glucose-lowering activity and is as efficacious as BRL

49653 that typically gives 55% glucose reduction in our

hands. The compound 12b, which has some residual

RXR homodimer activity (Table 1, entry 11), shows the

same efficacy profile (i.e., same efficacy as BRL49653),

whereas 11g (LG101392), which has no RXR homodimer

activity, shows only a partial efficacy in lowering

glucose. However, 12c (LG101506), where the butoxy

side chain of 11g is replaced with a 2,2-difluoroethoxy,

shows a remarkable ability to lower glucose in these

animals at 30 mg/kg (single daily dose) as the free acid

(as good as BRL49653). These compounds achieve

maximal plasma concentration 1 h after an oral dose

(unpublished data). During our db/db mouse studies,

plasma drug concentrations were measured 1 h after

the final dose. Compound 12c produced a higher drug

concentration than 11g (3.50 ( 0.93 µg/mL vs 2.10 (

0.78 µg/mL). This increase in drug concentration is

2688 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Ta ble 3. Side Effect Profile of Selected RXR Modulators^a

Michellys et al.

compounds

control

BRL 49653

12b

12c

11g

triglycerides (mg/dL)

T4 (ng/mL)

72 ( 10

73 ( 4

78 ( 5

70 ( 3

152 ( 10

37 ( 2

92 ( 7

25 ( 4

75 ( 5

70 ( 5

63 ( 3

72 ( 5

Effects of triglycerides and T4 levels on selected RXR modulators (4, 11g, 12b, and 12c) in male Sprague-Dawley rats at 24 h.

Ta ble 4. RXR:LXR Activity of Selected RXR Modulators^a

maintaining comparable RXR binding.⁴¹However, these

compounds undesirably activate the RXR:RAR hetero-

dimer.^17,41-43The studies described in this communica-

tion were focused on identifying RXR ligands deprived

of RXR:RAR heterodimer activity or synergy.⁴⁴This was

realized by identifying a novel pharmacophore, namely

(2E,4E,6Z)-7-(2-alkoxy-3,5-di-alkylbenzene)-3-methylocta-

2,4,6-trienoic acid and by tuning the alkoxy side chain.

To facilitate this SAR exploration, a quick and efficient

synthetic strategy was developed. Through the course

of these SAR studies, we have found that the size of

the alkoxy side chain directly influences the biological

activity of the molecules. By varying the size of the

alkoxy side chain installed during the phenol protection

steps (20 and 21 to 22a -g and 23a -e, respectively, in

Scheme 1 and 32 to 33a -d in Scheme 2), we were able

to construct analogues that demonstrated the in vitro

profile of various RXR modulators (more precisely, RXR

agonists, partial agonists, and antagonists). As a gen-

eralized rule, we have found that as the chain size

increases, the agonist characteristic of the molecule

decreases. In other words, a short alkoxy chain leads

to an RXR agonist, whereas a long alkoxy chain will

produce an antagonist. This dramatic change in activity

is likely due to the alkoxy side chain, which may

interfere with the correct folding of helix 12. Similar

effects have been observed in other nuclear receptors

such as the ER, where antagonists block the folding of

helix 12 over the ligand-binding domain.⁴⁵In addition,

we have uncovered a delicate interplay between the

steric bulk of the other aryl substituents and the alkoxy

moiety, which allows for additional fine tuning of this

effect.

compounds

12b

12c

11g

RXR:LXR

activation

(fold)

6.30 ( 0.53 2.04 ( 0.31 1.20 ( 0.15 0.60 ( 0.12

RXR:LXR heterodimer cotransfection data. Data given in fold

elevation above DMSO background in CV-1 cells at 1 µM.

presumably a major factor responsible for the difference

in the ability of the compounds to lower plasma glucose.

Side effects (triglycerides and T4 levels) were evalu-

ated in the Sprague-Dawley rat, which is a more

sensitive model than the db/db mouse for triglycerides

and thyroid axis effects.³⁹Data for triglycerides and T4

were collected following administration of a single oral

dose (30 mg/kg) to na¨ıve animals. Triglycerides and T4

levels were measured at 2 and 24 h post dose, respec-

tively. Results collected at 24 h are shown in Table 3.

Again, 4 and 12b raise triglycerides substantially.

However, at the same dose, none of the RXR modulators

tested elevate triglycerides. In a separate series of

studies where Sprague-Dawley rats were dosed with

12c for seven days (1, 3, 10, or 30 mg/kg/day), triglyc-

erides were not evelevated at any time by any dose,

whereas in these same experiments, 4 consistently

produced elevated triglycerides at all times (data not

shown). T4 levels were measured in the animals treated

with a single oral dose of compound. Both 4 and 12b

cause a significant decrease in T4 levels (2.2-fold).

However, neither 11g nor 12c reduce T4 levels. It is

remarkable that 12c, which shows the same efficacy on

the glucose endpoint as either BRL49653 or 4, did not

raise triglycerides nor decrease T4 levels in Sprague-

Dawley rats, thus overcoming two of the physiological

side effects associated with RXR agonists.

Con clu sion

Activation of the RXR:LXR heterodimer has been

shown to produce elevations of triglycerides.⁴⁰As a

general trend, we found that RXR:LXR activation cor-

relates with RXR:RXR homodimer activation. Table 4

shows the cotransfection data of 4, 12b, 12c, and 11g

on the RXR:LXR heterodimer. Compound 4 strongly

activates RXR:LXR (6.30-fold), compound 12b moder-

ately activates RXR:LXR (2.04-fold), and 12c or 11g

does not activate the RXR:LXR heterodimer (1.20 and

0.60-fold respectively). However, whereas 4 dramatically

elevates triglycerides, none of the other three com-

pounds has any effect on triglycerides in Sprague-

Dawley rats, although 12b is a weak activator of the

RXR:LXR heterodimer. These results demonstrate that

in vitro activation of the RXR:LXR heterodimer does not

necessarily result in elevation of triglycerides in vivo.

In conclusion, we have described the synthesis and

biological evaluation of a novel series of RXR modulators

11, 12, and 13. These molecules possess the ability to

selectively bind to RXR over RAR and to activate the

RXR:PPARγ heterodimer in a selective manner. This

new series was produced using a simple and efficient

synthetic process that works well for either small- or

large-scale synthesis. Through our SAR efforts, we have

demonstrated the ability to smoothly transition between

RXR agonists and RXR antagonists in a stepwise and

predictable manner without altering the binding affinity

of these molecules for RXR. Furthermore, we have

demonstrated that the presence of fluorine in the alkoxy

side chain appears to have a major effect on the in vivo

efficacy of these compounds. This phenomenon may be

due to increased solubility, which in turn affects the

overall bioavailability of the fluorinated analogues.

During experiments conducted in vivo, we have dem-

onstrated that this series has the ability to lower glucose

in the db/db mouse model (oral administration at 30 mg/

kg/day). In a select subset of this series, this activity

rivals that of currently available TZDs (e.g., BRL49653).

One such compound, 12c, when tested as the free acid,

Discu ssion

Previously published results have demonstrated the

utility of similar molecules possessing a trienoic acid

moiety. These studies first indicated the ability of the

alkoxy side chain to modulate the RXR homodimer

cotransfection activity of such molecules while still

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2689

(NaAlH₄) portionwise. The reaction was stirred until comple-

tion (TLC) while slowly warming to room temperature. The

mixture was then cooled to 0 °C and quenched with 0.5 mL of

cold water, followed by addition of 1 mL of a 10% aqueous

NaOH solution and EtOAc. The precipitate was filtrated over

a Celite plug and washed with EtOAc. The organic layer was

dried (MgSO₄), concentrated, and purified by SiO₂chroma-

tography (eluant: 20% EtOAc/hexanes) to give 0.96 g (3.9

is as efficacious at 30 mg/kg/day as are 4 or BRL49653

(both dosed at 10 mg/kg/day). When tested in the

Sprague-Dawley rat, this series of RXR modulators

neither raises triglycerides, nor suppresses the thyroid

hormone axis, whereas agonists such as 4 produce both

undesirable side effects.

Moreover, these RXR modulators, including 12c, do

not show any significant RXR: RAR synergy activity

(<2-fold activation). In summary, 12c is a new RXR

modulator that exhibits promising activity in in vivo

models of type 2 diabetes.

mmol, yield: 91%) of 20 as a pale yellow oil. H NMR (CDCl₃,

500 MHz): δ 6.98 (d, J ) 2.0 Hz, 1H), 6.71 (d, J ) 2.0 Hz,

1H), 5.95 (td, J ) 7.0, 1.2 Hz, 1H), 5.43 (br s, H), 3.94 (d, J )

7.0 Hz, 2H), 3.14 (m, 1H), 2.91 (m, 1H), 2.07 (s, 3H), 1.80 (t, J

) 7.0 Hz, 1H), 1.26 (d, J ) 7.0 Hz, 6H), 1.22 (d, J ) 7.0 Hz,

6H).

Exp er im en ta l Section

(Z)-(3,5-Di-iso-p r op yl-2-b u t oxyp h en yl)b u t -2-en e-1-ol

(22g). To a mixture of 700 mg (2.82 mmol) of diol 20 and 620

mg (0.38 mL, 3.38 mmol) of 1-iodobutane in 20 mL of dry DMF

was added 2.76 g (8.46 mmol, 1.5 equiv) of Cs₂CO₃in one time.

The mixture was stirred overnight at room temperature, and

water (100 mL) was added. The solution was extracted three

times with EtOAc (15 mL), and the organic layers were washed

twice with water (10 mL) and brine (10 mL) and dried

(MgSO₄). After removal of the solvents, the crude oil was

purified over silica gel column chromatography (eluant: 20%

EtOAc/hexanes) to afford 0.77 g (2.54 mmol, yield: 90%) of

Gen er a l Exp er im en ta l Ch em ica l P r oced u r es. Proton

nuclear magnetic resonance (¹H NMR) spectra were recorded

on a Bru¨ker AC 400 or a Varian VXR 500 S spectrometer.

Melting points were taken on an Electrothermal IA9100

Digital apparatus and are uncorrected. Mass spectra were

taken on a Gilson 215 LC-MS apparatus. “Brine” refers to a

saturated aqueous solution of NaCl. Unless otherwise speci-

fied, solutions of common inorganic salts used in workups are

aqueous solutions. All moisture-sensitive reactions were car-

ried out using oven-dried or flame-dried round-bottomed flasks

and glassware under an atmosphere of dry nitrogen. All

reagents and solvents were used without further purification

unless otherwise noted. Most reactions were monitored by thin-

layer chromatography (TLC) using a Merck TLC glass plate

precoated with silica gel F254 (0.2 mm thick). Flash chroma-

tography was performed using Merck silica gel 60.

22g as a clear oil. H NMR (CDCl₃, 500 MHz): δ 7.01 (d, J )

2.1 Hz, 1H), 6.75 (d, J ) 2.1 Hz, 1H), 5.83 (td, J ) 7.9, 1.5 Hz,

1H), 3.08 (t, J ) 7.6 Hz, 2H), 3.67 (m, 2H), 3.30 (m, 1H), 2.85

(m, 1H), 2.62 (t, J ) 5.8 Hz, 1H), 2.11 (s, 3H), 1.71 (m, 2H),

1.42 (m, 2H), 1.23 (d, J ) 7.0 Hz, 12H), 0.96 (t, J ) 7.3 Hz,

3H).

(Z)-2-(3,5-Di-iso-p r op yl-2-b u t oxyp h en yl)b u t -2-en -1-a l

(24g). To a mixture of 690 mg (2.27 mmol) of 22g and 400 mg

(3.41 mol, 1.5 equiv) of NMO in 20 mL of dry CH₂Cl₂was added

80 mg (0.23 mmol, 10%/substrate) of TPAP in one time. The

dark solution was stirred at room temperature until comple-

tion (TLC analysis) and then filtrated through a silica gel plug.

The plug was washed twice with CH₂Cl₂, and the solvents were

removed under reduced pressure to afford 0.62 g (2.04 mmol,

yield: 90%) of 24g as a colorless oil directly used in the next

Gen er a l P r oced u r e for th e Syn th esis of th e Sod iu m

Sa lt of th e Acid s 11, 12, a n d 13. The desired acid was

introduced into a round-bottomed flask and diluted in dry

dioxane (5 mL/mmol of acid). When the acid was completely

dissolved, an equimolar quantity of volumetric 1 N NaOH

aqueous solution was added via syringe. The cloudy solution

was stirred for 1 h at room temperature, and then deionized

water was added (15 mL/mmol of acid). The remaining milky

solution was stirred 30 min at room temperature and then

frozen. The frozen solution was then freeze-dried overnight

(or longer for large volumes). The sodium salt was usually

collected as a white, fluffy light solid directly used for formula-

tion.

2-Acetyl-3,5-d i-iso-p r op ylp h en ol (16). To 100.0 g (0.45

mol) of 14 in 500 mL of dry THF at -78 °C was added 965 mL

(1.35 mol, 3 equiv) of 1.4 M MeLi. The reaction was stirred

overnight while slowly warming to room temperature. EtOAc

(500 mL) was slowly added to the reaction mixture, which was

subsequently washed (500 mL of 1 N HCl, 500 mL of water,

and 500 mL of brine). After drying (MgSO₄) and concentration,

the residue was purified by SiO₂chromatography (eluant: 10%

EtOAc/hexanes) to afford 72.7 g (0.34 mol, yield: 75%) of 16

as a pale yellow oil that solidified upon standing (mp 36 °C).

¹H NMR (CDCl₃, 500 MHz): 12.56 (s, 1H), 7.40 (d, J ) 2.1

Hz, 1H), 7.30 (d, J ) 2.1 Hz, 1H), 3.29 (m, 1H), 2.93 (m, 1H),

1.26 (t, J ) 6.7 Hz, 6H), 1.24 (t, J ) 6.7 Hz, 6H).

4-Meth yl-6,8-d i-iso-p r op ylcou m a r in (18). To 100.0 g

(0.45 mol) of 16 suspended in 500 mL of toluene was added

316.0 g (0.91 mol, 2 equiv) of (carbethoxymethylene)tri-

phenylphosphorane. The mixture was heated to reflux and

allowed to stir overnight. The mixture was cooled, water was

added, and the organics were extracted with 500 mL of EtOAc.

The organic layer was washed (water and then brine), dried

(MgSO₄), concentrated, and purified by SiO₂chromatography

(eluant: 10% EtOAc/hexanes) to give 82.5 g (0.34 mol, yield:

76%) of 18 as a pale yellow oil that solidifies upon standing

(mp 54 °C). ¹H NMR (CDCl₃, 500 MHz): δ 7.33 (d, J ) 1.9 Hz,

1H), 7.26 (d, J ) 1.9 Hz, 1H), 6.28 (s, 1H), 3.63 (m, 1H), 2.98

(m, 1H), 2.45 (s, 3H), 1.30 (d, J ) 5.2 Hz, 6H), 1.29 (d, J ) 5.4

Hz, 6H).

step. H NMR (CDCl₃, 500 MHz): δ 9.44 (d, J ) 8.3 Hz, 1H),

7.11 (d, J ) 1.9 Hz, 1H), 6.80 (d, J ) 1.9 Hz, 1H), 6.12 (d, J )

8.0 Hz, 1H), 3.64 (t, J ) 7.5 Hz, 2H), 3.34 (m, 1H), 2.94 (m,

1H), 2.34 (s, 3H), 1.62 (m, 2H), 1.41 (m, 2H), 1.23 (d, J ) 7.2

Hz, 12H), 0.93 (t, J ) 7.8 Hz, 3H).

Eth yl (2E,4E,6Z)-7-(3,5-Di-iso-pr opyl-2-bu toxyben zen e)-

3-m eth ylocta -2,4,6-tr ien oa te (26g). To a mixture of 1.27 g

(4.79 mmol, 1.2 mL) of triethyl-3-methylphosphonocrotonate

diluted in a 15.0/1.5 mL mixture of THF/DMPU was added

dropwise 2.3 mL of nBuLi (2.5 M in hexane) at -78 °C. After

stirring for 30 min at this temperature, 580 mg (1.92 mmol)

of the aldehyde 24g diluted in 5 mL of dry THF was added

dropwise. The mixture was then allowed to warm up slowly

to room temperature and then quenched with water (50 mL)

and extracted twice with EtOAc (15 mL). The organic layer

was dried, and after filtration, the solvents were removed

under reduced pressure. The crude oil was purified over silica

gel column chromatography (eluant: 5% EtOAc/hexanes) to

afford 780 mg (1.89 mmol, yield: 98%) of 26g as an oil

(inseparable mixture of isomers). ¹H NMR (CDCl₃, 500 MHz):

δ, 7.02 (d, J ) 2.0 Hz, 1H), 6.75 (d, J ) 2.0 Hz, 1H), 6.58 (dd,

J ) 15.0, 11.1 Hz, 1H), 6.24 (d, J ) 15.0 Hz, 1H), 6.18 (d, J )

11.1 Hz, 1H), 5.72 (s, 1H), 4.14 (dd, J ) 14.4, 7.2 Hz, 2H),

3.64 (m, 2H), 3.32 (m, 1H), 2.83 (m, 1H), 2.21 (s, 3H), 2.14 (s,

3H), 1.61 (m, 2H), 1.41 (m, 2H), 1.29 (t, J ) 7.2 Hz, 3H), 1.26

(d, J ) 6.6 Hz, 6H), 1.24 (d, J ) 6.5 Hz, 6H), 0.91 (t, J ) 7.3

Hz, 3H). MS (EI, 70 eV) 413 m/e: 413 (MH⁺, 31), 367 (49), 285

(100), 205 (48).

(2E,4E,6Z)-7-(3,5-Di-iso-p r op yl-2-bu toxyben zen e)-3-m e-

th ylocta -2,4,6-tr ien oic Acid (11g). A mixture of 500 mg

(1.21 mmol) of 26g in 5 mL of THF, 5 mL of MeOH, and 2.5

mL of an aqueous 2 N LiOH solution was refluxed until

completion (TLC analysis). After cooling to room temperature,

the solvents were removed under reduced pressure, and 10

(Z)-3-(3,5-Di-iso-p r op yl-2-h yd r oxyp h en yl)bu t-2-en e-1-

ol (20). To 1.10 g (4.3 mmol) of 18 in 20 mL of Et₂O at 0 °C

was added 0.32 g (5.9 mmol) of sodium aluminum hydride

2690 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

mL of a 2 N aqueous HCl solution was added. The solution

was stirred at room temperature for 10 min and extracted

twice with EtOAc (5 mL), and the organic layers were dried

over MgSO₄. After filtration, the solvents were removed, and

the crude pasty oil was recrystallized from CH₃CN to afford

350 mg (0.91 mmol, yield: 75%) of pure 11g as a white crystal

(mp 130 and 139 °C) and a single stereoisomer. ¹H NMR

(CDCl₃, 500 MHz): δ, 7.06 (d, J ) 2.2 Hz, 1H), 6.72 (d, J )

2.2 Hz, 1H), 6.57 (dd, J ) 15.0, 11.0 Hz, 1H), 6.24 (d, J ) 15

Hz, 1H), 6.18 (d, J ) 11 Hz, 1H), 5.73 (s, 1H), 3.62 (m, 2H),

3.37 (m, 1H), 2.85 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.62 (m,

2H), 1.44 (m, 2H), 1.27 (d, J ) 6.6 Hz, 6H), 1.24 (d, J ) 6.5

Hz, 6H), 0.91 (t, J ) 6.3 Hz, 3H). Anal. (C₂₅H₃₆O₃‚(1/4)H₂O)

C, H. MS (EI, 70 eV) 385 m/e: 385 (MH⁺, 48), 285 (100), 243

(53), 205 (67). HRMS for C₂₅H₃₇O₃(MH⁺) calcd 385.2743; found

385.2763.

2-Acetyl-3,5-d i-ter t-bu tyl P h en ol (17). 2-Acetyl-3,5-di-

tert-butyl phenol 17 was synthesized according to the proce-

dure described for the synthesis of 16 by adding 965 mL (1.35

mol) of 1.4 M of MeLi to 110.0 g (0.44 mol) of 15 in 500 mL of

dry THF at -78 °C. After workup and chromatography (10%

EtOAc/hexanes), 83.0 g (0.33 mol, yield: 75%) of 17 was

isolated as a pale yellow oil that crystallized upon standing

(mp 45 °C, MeOH). ¹H NMR (CDCl₃, 500 MHz): δ 9.65 (s, 1H),

7.56 (m, 2H), 2.65 (s, 3H), 1.42 (s, 9H), 1.32 (s, 9H).

2,4-Di-ter t-a m yl-6-iod op h en ol (29). To a mixture of 14.1

g (60.0 mmol) of 28 and 1.14 g (6.0 mmol) of p-toluenesulfonic

acid in 100 mL of dry CH₂Cl₂was added portionwise 14.0 g

(66.0 mmol) of NIS at room temperature. After completion of

the reaction (TLC), 50 mL of a 10% aqueous solution Na₂S₂O₃

was added, and the mixture was stirred for 10 min at room

temperature. The organic layer was separated, and the aque-

ous layer was extracted twice with CH₂Cl₂. The organic layers

were collected and dried over MgSO₄. After removal of the

solvents under reduced pressure, the crude oil was purified

over silica gel chromatography (eluant: 5% EtOAc/hexanes)

to afford 18.0 g (50.0 mmol, yield: 83%) of 29 as a pale yellow

oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.42 (d, J ) 2.2 Hz, 1H),

7.13 (d, J ) 2.2 Hz, 1H), 5.30 (s, 1H), 1.83 (q, J ) 7.5 Hz, 2H),

1.58 (q, J ) 7.6 Hz, 2H), 1.34 (s, 6H), 1.23 (s, 6H), 0.67 (t, J )

7.4 Hz, 3H), 0.63 (t, J ) 7.5 Hz, 3H).

2-Acetyl-3,5-d i-ter t-a m yl P h en ol (30). To a mixture of

11.5 g (32.2 mmol) of 29 in 150 mL of dry ether was added 50

mL of n-BuLi (1.6 M in hexane) dropwise at -78 °C. A white

precipitate occured, and the mixture was slowly allowed to

warm up to room temperature. When the TLC showed no

traces of the starting material, the solution was cooled to

-78 °C, and 9.5 mL (8.9 g, 0.1 mol) of dry N,N-dimethylac-

etamide diluted in 50 mL of dry ether was added slowly. The

solution was warmed up to room temperature and carefully

quenched with cold water. The organic layer was separated,

and the aqueous layer was extracted twice with ethyl acetate.

The combined organic layers were washed with water and

brine, then dried over MgSO₄. After concentration under

reduced pressure, the remaining oil was purified over silica

gel column chromatography (eluant: 5% EtOAc/hexanes) to

yield 2.9 g (10.5 mmol, yield: 33%) of 30 as a pale yellow oil.

¹H NMR (CDCl₃, 400 MHz): δ 10.52 (s, 1H), 7.50 (d, J ) 2.4

Hz, 1H), 7.42 (d, J ) 2.4 Hz, 1H), 2.64 (s, 3H), 1.90 (q, J ) 7.6

Hz, 2H), 1.62 (q, J ) 7.4 Hz, 2H), 1.38 (s, 6H), 1.28 (s, 6H),

0.68 (t, J ) 7.4 Hz, 3H), 0.62 (t, J ) 7.6 Hz, 3H).

mmol) of 30 and 18.5 g (53.0 mmol) of (carbethoxymethylene)

triphenylphosphorane. After workup and SiO₂column chro-

matography (10% EtOAc/hexanes), 5.1 g (17.0 mmol, yield:

80%) of 31 was isolated as a pale brown solid. Pale brown

needles (mp 64 °C, hexanes). ¹H NMR (CDCl₃): δ 7.46 (d, J )

2.3 Hz, 1H), 7.37 (d, J ) 2.3 Hz, 1H), 6.27 (s, 1H), 2.45 (s,

3H), 2.00 (q, J ) 7.4 Hz, 2H), 1.67 (q, J ) 7.4 Hz, 2H), 1.46 (s,

6H), 1.32 (s, 6H), 0.69 (t, J ) 7.4 Hz, 3H), 0.62 (t, J ) 7.4 Hz,

3H).

(Z)-(3,5-Di-ter t-b u t yl-2-h yd r oxyp h en yl)b u t -2-en e-1-ol

(21). 21 was synthesized according to the procedure described

for the synthesis of 20 using 9.3 gm (34.2 mmol) of 19 in 120

mL of Et₂O and 34.2 mL (34.2 mmol) of 1.0 M lithium

aluminum hydride (LAH). After workup and SiO₂chromatog-

raphy (20% EtOAC/hexanes), 9.1 g (33.0 mmol, yield: 96%) of

21 was isolated as a white solid (mp 85 °C, hexanes). ¹H NMR

(CDCl₃, 400 MHz): δ 7.26 (d, J ) 2.0 Hz, 1H), 6.91 (d, J ) 2.0

Hz, 1H), 5.98 (dt, J ) 7.0, 2.0 Hz, 1H), 5.02 (s, 1H), 3.94 (m,

2H), 2.14 (d, J ) 1 Hz, 3H), 1.30 (s, 9H), 1.41 (s, 9H).

(Z)-3-(3,5-Di-ter t-a m yl-2-h yd r oxyp h en yl)bu t-2-en -1-ol

(32). 32 was synthesized from 1.00 g (3.3 mmol) of coumarin

31 in the presence of 0.23 g (4.3 mmol) of NaAlH₄according

to the procedure described for the synthesis of 20, and 0.90 g

(2.96 mmol, yield: 89%) of 32 was isolated as a pale yellow

oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.09 (d, J ) 2.0 Hz, 1H),

6.79 (d, J ) 2.5 Hz, 1H), 5.97 (td, J ) 7.0, 1.5 Hz, 1H), 5.38 (s,

1H), 3.91 (t, J ) 7.0 Hz, 2H), 2.07 (s, 3H), 1.57 (q, J ) 7.5 Hz,

2H), 1.36 (s, 6H), 1.25 (q, J ) 7.4 Hz, 2H), 1.24 (s, 6H), 0.66 (t,

J ) 8.0 Hz, 3H), 0.64 (t, J ) 7.5 Hz, 3H).

(Z)-3-(3,5-Di-iso-p r op yl-2-m eth oxyp h en yl)bu t-2-en e-1-

ol (22a ). 22a was synthesized from 400 mg (1.61 mmol) of 20

and 274 mg (1.93 mmol) of iodomethane in the presence of

786 mg (2.41 mmol) of Cs₂CO₃according to the procedure

described for the synthesis of 22g, and 393 mg (1.49 mmol,

yield: 93%) of 22a was isolated as a clear oil. ¹H NMR (CDCl₃,

500 MHz): δ 7.01 (d, J ) 2.3 Hz, 1H), 6.75 (d, J ) 2.3 Hz,

1H), 5.81 (t, J ) 7.9 Hz, 1H), 3.90 (t, J ) 5.8 Hz, 2H), 3.66 (s,

3H), 3.35 (m, 1H), 2.83 (m, 1H), 2.62 (t, J ) 5.8 Hz, 1H), 2.11

(s, 3H), 1.24 (d, J ) 6.8 Hz, 12H).

(Z)-3-(3,5-Di-iso-p r op yl-2-et h oxyp h en yl)b u t -2-en e-1-

ol (22b). 22b was synthesized from 300 mg (1.20 mmol) of 20

and 226 mg (1.45 mmol) of iodoethane in the presence of 590

mg (1.8 mmol) of Cs₂CO₃according to the procedure described

for the synthesis of 22g, and 320 mg (1.16 mmol, yield: 97%)

of 22b was isolated as a clear oil. ¹H NMR (CDCl₃, 500 MHz):

δ 7.00 (d, J ) 2.4 Hz, 1H), 6.74 (d, J ) 2.4 Hz, 1H), 5.82 (t, J

) 7.8 Hz, 1H), 3.92 (t, J ) 5.8 Hz, 2H), 3.76 (dd, J ) 14.6, 7.3

Hz, 2H), 3.31 (m, 1H), 2.81 (m, 1H), 2.61 (t, J ) 5.8 Hz, 1H),

2.11 (s, 3H), 1.34 (d, J ) 7.3 Hz, 3H), 1.22 (d, J ) 6.8 Hz,

12H).

(Z)-3-[3,5-Di-iso-p r op yl-2-(2-flu or oeth oxy)p h en yl]bu t-

2-en e-1-ol (22c). 22c was synthesized from 350 mg (1.40

mmol) of 20 and 196 mg (1.55 mmol) of 1-bromo-2-fluoroethane

in the presence of 684 mg (2.10 mmol) of Cs₂CO₃according to

the procedure described for the synthesis of 22g, and 379 mg

(1.3 mmol, yield: 92%) of 22c was isolated as an oil. H NMR

(CDCl₃, 400 MHz): δ 7.03 (d, J ) 2.0 Hz, 1H), 6.76 (d, J ) 2.0

Hz, 1H), 5.81 (dt, J ) 7.5, 1.0 Hz, 1H), 4.65 (dt, J ) 55.1, 4.0

Hz, 2H), 3.95 (m, 2H), 3.88 (d, J ) 7.5 Hz, 2H), 3.35 (m, 1H),

2.86 (m, 1H), 2.21 (br s, 1H), 2.11 (s, 3H), 1.24 (d, J ) 7.0 Hz,

12H).

4-Meth yl-6,8-d i-ter t-bu tylcou m a r in (19). 4-Methyl-6,8-

di-tert-butylcoumarin 19 was synthesized according to the

procedure used for the synthesis of 15 by using 83.0 g (0.34

mol) of 17 and 232.9 g (0.67 mol) of (carbethoxymethylene)

triphenylphosphorane. After workup and SiO₂column chro-

matography (10% EtOAc/hexanes), 73.4 gm (0.27 mol, yield:

79%) of 19 was isolated as pale yellow needles (MeOH); mp

89 °C. ¹H NMR (CDCl₃, 500 MHz): δ 7.59 (d, J ) 2.0 Hz, 1H),

7.44 (d, J ) 2.0 Hz, 1H), 6.27 (s, 1H), 2.45 (s, 3H), 1.51 (s,

9H), 1.36 (s, 9H).

(Z)-3-[3,5-Di-iso-p r op yl-2-(2,2-d iflu or oeth oxy)p h en yl]-

bu t-2-en e-1-ol (22d ). 22d was synthesized from 330 mg (1.33

mmol) of 20 and 212 mg (1.46 mmol) of 1-bromo-2,2-fluoroet-

hane in the presence of 650 mg (1.99 mmol) of Cs₂CO₃

according to the procedure described for the synthesis of 22g,

and 386 mg (1.23 mmol, yield: 93%) of 22d was isolated as

an oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.04 (d, J ) 2.1 Hz, 1H),

6.76 (d, J ) 2.1 Hz, 1H), 5.96 (td, J ) 55.1, 4.0 Hz, 1H), 5.82

(td, J ) 7.3, 1.5 Hz, 1H), 4.05 (m, 2H), 3.94 (d, J ) 7.3 Hz,

2H), 3.36 (m, 1H), 2.96 (s, 1H), 2.81 (m, 1H), 2.11 (s, 3H), 1.24

(d, J ) 7.0 Hz, 6H), 1.23 (d, J ) 6.7 Hz, 6H).

4-Met h yl-6,8-d i-ter t-a m ylcou m a r in (31). 4-Methyl-6,8-

di-tert-amylcoumarin 31 was synthesized according to the

procedure described for the synthesis of 18 using 6.5 g (21.5

(Z)-3-(3,5-Di-iso-p r op yl-2-p r op oxyp h en yl)bu t-2-en e-1-

ol (22f). 22f was synthesized from 500 mg (2.01 mmol) of 20

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2691

and 272 mg (0.2 mL, 2.21 mmol) of 1-bromopropane in the

presence of 320 mg (3.02 mmol) of Cs₂CO₃according to the

procedure described for the synthesis of 22g, and 537 mg (1.84

(m, 2H), 4.00 (m, 1H), 3.96 (m, 1H), 2.13 (s, 3H), 1.42 (br s,

1H), 1.39 (s, 9H), 1.29 (s, 9H).

(Z)-(3,5-Di-ter t-a m yl-2-m et h oxyp h en yl)b u t -2-en e-1-ol

(33a ). 33a was synthesized from 0.66 g (2.17 mmol) of 32 and

0.35 g (0.15 mL, 2.38 mmol) of iodomethane in the presence

of 1.00 g (3.26 mmol, 1.5 eq.) of Cs₂CO₃according to the

procedure described for the synthesis of 22g, and 0.66 g (2.01

mmol, yield: 92%) of 22f was isolated as a clear oil. H NMR

(CDCl₃, 500 MHz): δ 7.00 (d, J ) 1.9 Hz, 1H), 6.74 (d, J ) 1.9

Hz, 1H), 5.81 (t, J ) 8.0 Hz, 1H), 3.80 (t, J ) 5.9 Hz, 2H), 3.63

(m, 2H), 3.34 (m, 1H), 2.82 (m, 1H), 2.59 (t, J ) 5.9 Hz, 1H),

2.11 (s, 3H), 1.83 (m, 2H), 1.23 (d, J ) 6.8 Hz, 12H), 1.00 (d,

J ) 7.8 Hz, 3H).

(Z)-3-(3,5-Di-ter t-bu tyl-2-m eth oxyp h en yl)bu t-2-en e-1-

ol (23a ). 23a was synthesized from 400 mg (1.45 mmol) of 21

and 0.11 mL (245 mg, 1.73 mmol) of iodomethane in the

presence of 1.7 g (5.19 mmol) of Cs₂CO₃according to the

procedure described for the synthesis of 22g, and 371 mg (1.28

mmol, yield: 88%) of 23a was isolated as an oil that solidifies

upon standing (mp 80 °C, hexanes). ¹H NMR (CDCl₃, 500

MHz): δ 7.29 (d, J ) 1.9 Hz, 1H), 6.95 (d, J ) 1.9 Hz, 1H),

5.83 (dt, J ) 7.0, 2.0 Hz, 1H), 3.85 (d, J ) 7.0 Hz, 2H), 3.62 (s,

3H), 2.08 (br s, 1H), 2.02 (s, 3H), 1.38 (s, 9H), 1.27 (s, 9H).

mmol, yield: 95%) of 33a was isolated as a clear oil. H NMR

(CDCl₃, 400 MHz): δ 7.01 (d, J ) 2.5 Hz, 1H), 6.84 (d, J ) 2.5

Hz, 1H), 5.83 (td, J ) 7.5, 1.0 Hz, 1H), 3.77 (t, J ) 7.9 Hz,

2H), 3.65 (s, 3H), 2.59 (t, J ) 6.4 Hz, 1H), 2.16 (s, 3H), 1.82

(m, 1H), 1.76 (m, 1H), 1.61 (m, 2H), 1.57 (s, 6H), 1.35 (s, 6H),

0.66 (t, J ) 8.0 Hz, 3H), 0.65 (t, J ) 7.0 Hz, 3H).

(Z)-(3,5-Di-t er t -a m yl-2-e t h oxyp h e n yl)b u t -2-e n e -1-ol

(33b). 33b was synthesized from 156 mg (0.51 mmol) of 32

and 88 mg (0.045 mL, 0.56 mmol) of iodoethane in the presence

of 250 mg (0.75 mmol, 1.5 eq.) of Cs₂CO₃according to the

procedure described for the synthesis of 22g, and 158 mg (0.47

mmol, yield: 93%) of 33b was isolated as a clear oil. H NMR

(CDCl₃, 400 MHz): δ 7.11 (d, J ) 2.0 Hz, 1H), 6.83 (d, J ) 2.0

Hz, 1H), 5.82 (td, J ) 7.5, 1.5 Hz, 1H), 3.95 (m, 1H), 3.89 (m,

2H), 3.65 (m, 1H), 2.76 (br t, J ) 6.1 Hz, 1H), 2.5 (s, 3H), 1.90

(m, 1H), 1.80 (m, 1H), 1.74 (m, 1H), 1.59 (m, 1H), 1.36 (s, 6H),

1.34 (t, J ) 7.0 Hz, 3H), 1.25 (s, 6H), 0.65 (t, J ) 7.5 Hz, 3H),

0.64 (t, J ) 7.6 Hz, 3H).

(Z)-3-(3,5-Di-ter t-bu tyl-2-eth oxyp h en yl)bu t-2-en e-1-ol

(23b). 23b was synthesized from 9.0 g (32.0 mmol) of 21 and

2.8 mL (35.2 mmol) of iodoethane in the presence of 14.6 g

(96.0 mmol) of cesium fluoride according to the procedure

described for the synthesis of 22g, and 9.2 g (30.5 mmol,

yield: 95%) of 23b was isolated as an oil that solidifies upon

standing (mp 75 °C, hexanes). H NMR (CDCl₃, 500 MHz): δ

(Z)-[3,5-Di-ter t-a m yl-2-(2,2-d iflu or oeth oxy)p h en yl]bu t-

2-en e-1-ol (33c). 33c was synthesized from 400 mg (1.31

mmol) of diol 32 and 209 mg (0.12 mL, 1.44 mmol) of 1-bromo-

2,2-difluoroethane in the presence of 640 mg (1.96 mmol, 1.5

equiv) of Cs₂CO₃according to the procedure described for the

synthesis of 22g, and 434 mg (1.18 mmol, yield: 90%) of 33c

was isolated as a clear oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.14

(d, J ) 2.4 Hz, 1H), 6.86 (d, J ) 2.4 Hz, 1H), 6.04 (tt, J )

55.4, 4.0 Hz, 1H), 5.81 (t, J ) 7.5 Hz, 1H), 3.90 (m, 2H), 3.85

(d, J ) 7.5 Hz, 2H), 2.14 (s, 3H), 1.82 (m, 1H), 1.75 (m, 2H),

1.65 (br m, 1H), 1.59 (q, J ) 7.3 Hz, 2H), 1.36 (s, 6H), 1.26 (s,

6H), 0.67 (t, J ) 7.3 Hz, 3H), 0.66 (t, J ) 7.3 Hz, 3H).

(Z)-(3,5-Di-ter t-a m yl-2-p r op oxyp h en yl)b u t -2-en e-1-ol

(33d ). 33d was synthesized from 350 mg (1.15 mmol) of 32

and 155 mg (0.11 mL, 1.26 mmol) of 1-bromopropane in the

presence of 562 mg (1.73 mmol, 1.5 equiv) of Cs₂CO₃according

to the procedure described for the synthesis of 22g, and 380

mg (1.10 mmol, yield: 96%) of 33d was isolated as a clear oil.

¹H NMR (CDCl₃, 400 MHz): δ 7.11 (d, J ) 2.4 Hz, 1H), 6.83

(d, J ) 2.4 Hz, 1H), 5.81 (t, J ) 7.6 Hz, 1H), 3.78 (d, J ) 7.6

Hz, 2H), 3.77 (m, 1H), 3.61 (m, 1H), 2.45 (br m, 1H), 2.15 (s,

3H), 1.82 (m, 1H), 1.78 (q, J ) 7.0 Hz, 2H), 1.72 (m, 1H), 1.58

(q, J ) 7.6 Hz, 2H), 1.36 (s, 6H), 1.25 (s, 6H), 0.98 (t, J ) 7.6

Hz, 3H), 0.66 (t, J ) 7.6 Hz, 3H), 0.65 (t, J ) 7.6 Hz, 3H).

(Z)-3-(3,5-Di-iso-p r op yl-2-m et h oxyp h en yl)b u t -2-en -1-

a l (24a ). 24a was synthesized from 200 mg (0.76 mmol) of 22a

in the presence of 25 mg (0.07 mmol) of TPAP and 133 mg

(1.14 mmol) of NMO according to the representative procedure

of the synthesis of 24g, and 186 mg (0.71 mmol, yield: 94%)

7.26 (d, J ) 2.0 Hz, 1H), 6.91 (d, J ) 2.0 Hz, 1H), 5.82 (dt, J

) 7.0, 2.0 Hz, 1H), 3.81 (m, 4H), 2.16 (d, J ) 2.0 Hz, 3H), 1.84

(br s, 1H), 1.41 (s, 9H), 1.36 (t, J ) 7.0 Hz, 3H), 1.30 (s, 9H).

MS (EI, 70 eV) 327 m/e: 327 (MH⁺, 5), 287 (100), 231 (70).

(Z)-3-[3,5-Di-ter t-bu tyl-2-(2,2-d iflu or oeth oxy)p h en yl]-

bu t-2-en e-1-ol (23c). 23c was synthesized from 2.0 g (7.23

mmol) of 21 and 1.26 g (8.68 mmol) of 1-bromo-2,2-difluoro-

ethane in the presence of 3.53 g (10.85 mmol) of Cs₂CO₃

according to the procedure described for the synthesis of 22g,

and 2.39 g (7.01 mmol, yield: 97%) of 23c was isolated as a

pasty oil. H NMR (CDCl₃, 500 MHz): δ 7.27 (d, J ) 2.5 Hz,

1H), 6.92 (d, J ) 2.5 Hz, 1H), 6.06 (td, J ) 55.4, 4.2 Hz, 1H),

5.79 (t, J ) 7.2 Hz, 1H), 3.95 (m, 2H), 3.90 (m, 2H), 2.14 (s,

3H), 1.68 (t, J ) 5.9 Hz, 1H), 1.39 (s, 9H), 1.29 (s, 9H).

(Z)-3-(3,5-Di-ter t-b u t yl-2-p r op oxyp h en yl)b u t -2-en e-1-

ol (23e). 23e was synthesized from 500 mg (1.81 mmol) of diol

21 and 245 mg (0.18 mL, 1.99 mmol) of 1-bromopropane in

the presence of 884 mg (2.72 mmol) of Cs₂CO₃according to

the procedure described for the synthesis of 22g, and 541 mg

(1.7 mmol, yield: 94%) of 23e was isolated as an oil. H NMR

(CDCl₃, 400 MHz): δ 7.22 (d, J ) 2.0 Hz, 1H), 6.96 (d, J ) 2.0

Hz, 1H), 5.80 (t, J ) 6.9, 2.0 Hz, 1H), 3.92 (m, 2H), 3.84 (m,

2H), 2.44 (br s, 1H), 2.18 (s, 3H), 1.79 (m, 2H), 1.39 (s, 9H),

1.24 (s, 9H), 0.99 (t, J ) 7.0 Hz, 3H).

(Z)-[(3,5-Di-iso-p r op yl-2-(2,2,2-tr iflu or oeth oxyp h en yl)]-

bu t-2-en e-1-ol (22e). To a mixture of 734 mg (2.96 mmol) of

20 and 1.45 g (0.82 mL, 8.88 mmol) of 2-bromo-1,1,1-trifluo-

roethane in 20 mL of dry DMF in a 30 mL pressure tube was

added 1.93 g (5.92 mmol, 1.5 equiv) of Cs₂CO₃in one time.

The mixture was stirred overnight at 50 °C, and water (50

mL) was added. The solution was extracted three times with

EtOAc (10 mL), and the organic layers were washed twice with

water (10 mL) and brine (10 mL) and dried (MgSO₄). After

removal of the solvents, the crude oil was purified over silica

gel column chromatography (eluant: 90/10 hexanes/EtOAc) to

afford 626 mg (1.90 mmol, yield: 64%) of 22e as a clear oil.

¹H NMR (CDCl₃, 500 MHz): δ 7.02 (d, J ) 1.9 Hz, 1H), 6.76

(d, J ) 1.9 Hz, 1H), 5.84 (t, J ) 7.9 Hz, 1H), 3.85 (d, J ) 7.9

Hz, 2H), 3.65 (m, 2H), 3.31 (m, 1H), 2.80 (m, 1H), 2.12 (s, 3H),

1.65 (br m, 1H), 1.23 (d, J ) 6.8 Hz, 12H).

of 24a was isolated as a clear oil. H NMR (CDCl₃, 500 MHz):

δ 9.44 (d, J ) 8.3 Hz, 1H), 7.11 (d, J ) 2.4 Hz, 1H), 6.80 (d, J

) 2.49 Hz, 1H), 6.17 (d, J ) 8.0 Hz, 1H), 3.62 (s, 3H), 3.36 (m,

1H), 2.83 (m, 1H), 2.34 (s, 3H), 1.23 (d, J ) 6.8 Hz, 12H).

(Z)-3-(3,5-Di-iso-p r op yl-2-et h oxyp h en yl)b u t -2-en -1-a l

(24b). 24b was synthesized from 220 mg (0.79 mmol) of 22b

in the presence of 28 mg (0.08 mmol) of TPAP and 139 mg

(1.19 mmol) of NMO according to the representative procedure

of the synthesis of 24g, and 199 mg (0.73 mmol, yield: 92%)

of 24b was isolated as a clear oil. ¹H NMR (CDCl₃, 500 MHz):

δ 9.44 (d, J ) 8.3 Hz, 1H), 7.11 (d, J ) 1.9 Hz, 1H), 6.81 (d, J

) 1.9 Hz, 1H), 6.11 (d, J ) 8.0 Hz, 1H), 3.71 (dd, J ) 13.7, 6.8

Hz, 2H), 3.36 (m, 1H), 2.86 (m, 1H), 2.34 (s, 3H), 1.29 (t, J )

6.8 Hz, 3H), 1.24 (d, J ) 7.1 Hz, 12H).

(Z)-3-[3,5-Di-iso-p r op yl-2-(2-flu or oeth oxy)p h en yl]bu t-

2-en -1-a l (24c). 24c was synthesized from 150 mg (0.60 mmol)

of 22c in the presence of 21 mg (0.06 mmol) of TPAP and 105

mg (0.90 mmol) of NMO according to the representative

procedure of the synthesis of 24g, and 163 mg (0.56 mmol,

yield: 93%) of 24c was isolated as a clear oil. ¹H NMR (CDCl₃,

(Z)-[3,5-Di-ter t-bu tyl-2-(2,2,2-tr iflu or oeth oxy)p h en yl]-

bu t-2-en e-1-ol (23d ). 23d was synthesized from 1.41 g (5.11

mmol) of diol 21 and 2.49 g (1.4 mL, 15.33 mmol) of 1-bromo-

2,2,2-trifluoroethane in the presence of 3.33 g (10.22 mmol) of

Cs₂CO₃according to the procedure described for the synthesis

of 22e, and 1.47 g (4.10 mmol, yield: 80%) of 23d was isolated

as an oil. H NMR (CDCl₃, 500 MHz): δ 7.29 (d, J ) 2.7 Hz,

1H), 6.93 (d, J ) 2.7 Hz, 1H), 5.80 (t, J ) 7.0 Hz, 1H), 4.09

2692 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

400 MHz): δ 9.46 (d, J ) 8.2 Hz, 1H), 7.14 (d, J ) 2.1 Hz,

1H), 6.82 (d, J ) 2.1 Hz, 1H), 6.13 (d, J ) 7.9 Hz, 1H), 4.62

(dt, J ) 55.1, 4.0 Hz, 2H), 3.97 (m, 1H), 3.94 (m, 1H), 3.39 (m,

1H), 2.92 (m, 1H), 2.34 (s, 3H), 1.24 (d, J ) 7.0 Hz, 12H).

(Z)-3-[3,5-Di-iso-p r op yl-2-(2,2-d iflu or oeth oxy)p h en yl]-

bu t-2-en -1-a l (24d ). 24d was synthesized from 250 mg (0.80

mmol) of 22d in the presence of 28 mg (0.08 mmol) of TPAP

and 140 mg (1.20 mmol) of NMO according to the representa-

tive procedure of the synthesis of 24g, and 223 mg (0.72 mmol,

yield: 90%) of 24d was isolated as a clear oil. ¹H NMR (CDCl₃,

400 MHz): δ 9.43 (d, J ) 8.0 Hz, 1H), 7.14 (d, J ) 2.0 Hz,

1H), 6.83 (d, J ) 2.0 Hz, 1H), 6.15 (dd, J ) 8.0, 1.0 Hz, 1H),

5.96 (tt, J ) 55.0, 4.0 Hz, 1H), 3.88 (td, J ) 13.5, 4.0 Hz, 2H),

3.32 (m, 1H), 2.88 (m, 1H), 2.34 (d, J ) 1.0 Hz, 3H), 1.24 (d, J

) 7.0 Hz, 6H), 1.23 (d, J ) 7.0 Hz, 6H).

(Z)-3-[3,5-Di-iso-pr opyl-2-(2,2,2-tr iflu or oeth oxy)ph en yl]-

bu t-2-en -1-a l (24e). 24e was synthesized from 600 mg (2.42

mmol) of 22e in the presence of 84 mg (0.24 mmol) of TPAP

and 424 mg (3.64 mmol) of NMO according to the representa-

tive procedure of the synthesis of 24g, and 698 mg (2.12 mmol,

yield: 88%) of 24e was isolated as a clear oil. ¹H NMR (CDCl₃,

400 MHz): δ 9.46 (d, J ) 8.2 Hz, 1H), 7.15 (d, J ) 2.1 Hz,

1H), 6.84 (d, J ) 2.1 Hz, 1H), 6.18 (dd, J ) 8.2, 1.5 Hz, 1H),

4.03 (dd, J ) 16.4, 8.2 Hz, 2H), 3.33 (m, 1H), 2.82 (m, 1H),

2.34 (d, J ) 1.5 Hz, 3H), 1.24 (d, J ) 7.0 Hz, 12H).

6.17 (d, J ) 8.2 Hz, 1H), 4.10 (m, 1H), 4.02 (m, 1H), 2.36 (s,

3H), 1.41 (s, 9H), 1.30 (s, 9H).

(Z)-3-(3,5-Di-ter t-b u t yl-2-p r op oxyp h en yl)b u t -2-en -1-

a l (25e). 25e was synthesized from 250 mg (0.78 mmol) of 23e

in the presence of 28 mg (0.08 mmol) of TPAP and 137 mg

(1.17 mmol) of NMO according to the representative procedure

of the synthesis of 24g, and 234 mg (0.74 mmol, yield: 95%)

of 25e was isolated as a clear pasty oil. H NMR (CDCl₃, 400

MHz): δ 9.43 (d, J ) 8.5 Hz, 1H), 7.38 (d, J ) 2.0 Hz, 1H),

6.92 (d, J ) 2.0 Hz, 1 H), 6.07 (d, J ) 8.5 Hz, 1H), 3.89 (m,

1H), 3.81 (m, 1H), 2.34 (s, 3H), 1.72 (m, 2H), 1.40 (s, 9H), 1.27

(s, 9H), 0.98 (t, J ) 6.5 Hz, 3H).

(Z)-(3,5-Di-ter t-a m yl-2-m et h oxyp h en yl)b u t -2-en -1-a l

(34a ). 34a was synthesized from 493 mg (1.55 mmol) of 33a

in the presence of 273 mg (2.33 mmol) of NMO and 55.0 mg

(0.16 mmol) of TPAP according to the procedure described for

the synthesis of 24g, and 480 mg (1.52 mmol, yield: 98%) of

34a was isolated as an oil directly used in the next step. H

NMR (CDCl₃, 400 MHz): δ 9.45 (d, J ) 8.5 Hz, 1H), 7.21 (d,

J ) 2.5 Hz, 1H), 6.89 (d, J ) 2.5 Hz, 1H), 6.12 (d, J ) 8.5 Hz,

1H), 3.61 (s, 3H), 2.35 (s, 3H), 1.90 (m, 2H), 1.59 (m, 2H), 1.36

(s, 6H), 1.26 (s, 6H), 0.67 (t, J ) 7.5 Hz, 3H), 0.65 (t, J ) 7.5

Hz, 3H).

(Z)-(3,5-Di-ter t-am yl-2-eth oxyph en yl)bu t-2-en -1-al (34b).

34b was synthesized from 140 mg (0.42 mmol) of 33b in the

presence of 74 mg (0.63 mmol) of NMO and 15 mg (0.04 mmol)

of TPAP according to the procedure described for the synthesis

of 24g, and 136 mg (0.41 mmol, yield: 98%) of 34b was isolated

(Z)-3-(3,5-Di-iso-p r op yl-2-p r op oxyp h en yl)b u t -2-en -1-

a l (24f). 24f was synthesized from 500 mg (1.72 mmol) of 22f

in the presence of 59 mg (0.17 mmol) of TPAP and 302 mg

(2.58 mmol) of NMO according to the representative procedure

of the synthesis of 24g, and 466 mg (1.61 mmol, yield: 94%)

as an oil directly used in the next step. H NMR (CDCl₃, 400

MHz): δ 9.44 (d, J ) 8.2 Hz, 1H), 7.21 (d, J ) 2.4 Hz, 1H),

6.89 (d, J ) 2.4 Hz, 1H), 6.08 (dd, J ) 8.2, 1.2 Hz, 1H), 3.82

(m, 1H), 3.65 (m, 1H), 2.35 (s, 3H), 1.80 (m, 2H), 1.59 (m, 2H),

1.35 (s, 6H), 1.29 (t, J ) 7.0 Hz, 3H), 1.26 (s, 6H), 0.66 (t, J )

7.5 Hz, 3H), 0.65 (t, J ) 7.0 Hz, 3H).

(Z)-[3,5-Di-ter t-a m yl-2-(2,2-d iflu or oeth oxy)p h en yl]bu t-

2-en -1-a l (34c). 34c was synthesized from 400 mg (1.09 mmol)

of 33c in the presence of 191 mg (1.63 mmol) of NMO and 35

mg (0.10 mmol) of TPAP according to the procedure described

for the synthesis of 24g, and 363 mg (0.99 mmol, yield: 91%)

of 34c was isolated as an oil directly used in the next step. ¹H

NMR (CDCl₃, 400 MHz): δ 9.45 (d, J ) 8.1 Hz, 1H), 7.24 (d,

J ) 2.4 Hz, 1H), 6.89 (d, J ) 2.4 Hz, 1H), 6.05 (dd, J ) 8.0,

1.1 Hz, 1H), 5.94 (tt, J ) 55.0, 4.0 Hz, 1H), 3.65 (m, 2H), 2.38

(s, 3H), 1.90 (m, 2H), 1.71 (m, 2H), 1.34 (s, 6H), 1.24 (s, 6H),

0.67 (t, J ) 7.4 Hz, 3H), 0.66 (t, J ) 7.5 Hz, 3H).

of 24f was isolated as a clear oil. H NMR (CDCl₃, 500 MHz):

δ 9.44 (d, J ) 8.3 Hz, 1H), 7.11 (d, J ) 1.9 Hz, 1H), 6.80 (d, J

) 1.9 Hz, 1H), 6.10 (d, J ) 8.0 Hz, 1H), 3.61 (t, J ) 6.3 Hz,

2H), 3.37 (m, 1H), 2.82 (m, 1H), 2.33 (s, 3H), 1.63 (m, 2H),

1.24 (t, J ) 7.3 Hz, 6H), 1.23 (d, J ) 7.3 Hz, 6H), 0.97 (t, J )

7.3 Hz, 3H).

(Z)-3-(3,5-Di-ter t-b u t yl-2-m et h oxyp h en yl)b u t -2-en -1-

a l (25a ). 25a was synthesized from 210 mg (0.72 mmol) of 23a

in the presence of 25 mg (0.07 mmol) of TPAP and 127 mg

(1.08 mmol) of NMO according to the representative procedure

of the synthesis of 24g, and 180 mg (0.62 mmol, yield: 86%)

of 25a was isolated a pasty oil directly used in the next step.

¹H NMR (CDCl₃, 500 MHz): δ 9.48 (d, J ) 8.3 Hz, 1H), 7.39

(d, J ) 1.9 Hz, 1H), 6.95 (d, J ) 1.9 Hz, 1 H), 6.09 (d, J ) 8.4

Hz, 1H), 3.66 (s, 3H), 2.33 (s, 3H), 1.40 (s, 9H), 1.34 (s, 9H).

(Z)-3-(3,5-Di-ter t-b u t yl-2-et h oxyp h en yl)b u t -2-en -1-a l

(25b). 25b was synthesized from 10.3 g (33.90 mmol) of 23b

in the presence of 600 mg (1.69 mmol) of TPAP and 5.95 g

(50.82 mmol) of NMO according to the representative proce-

dure of the synthesis of 24g, and 8.49 g (28.11 mmol, yield:

83%) of 25b was isolated as a pasty solid directly used in the

(Z)-(3,5-Di-ter t-a m yl-2-p r op oxyp h en yl)b u t -2-en -1-a l

(34d ). 34d was synthesized from 200 mg (0.58 mmol) of 33d

in the presence of 101 mg (0.87 mmol) of NMO and 21 mg (0.06

mmol) of TPAP according to the procedure described for the

synthesis of 24g, and 186 mg (0.53 mmol, yield: 93%) of 34d

was isolated as an oil directly used in the next step. H NMR

next step. H NMR (CDCl₃, 500 MHz): δ 9.47 (d, J ) 8.5 Hz,

(CDCl₃, 400 MHz): δ 9.44 (d, J ) 8.2 Hz, 1H), 7.22 (d, J ) 2.4

Hz, 1H), 6.88 (d, J ) 2.4 Hz, 1H), 6.08 (dd, J ) 8.2, 1.2 Hz,

1H), 3.67 (m, 1H), 3.60 (m, 1H), 2.39 (s, 3H), 1.91 (m, 2H),

1.70 (m, 2H), 1.59 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H), 0.96 (t, J

) 7.6 Hz, 3H), 0.67 (t, J ) 7.4 Hz, 3H), 0.66 (t, J ) 7.5 Hz,

3H).

1H), 7.37 (d, J ) 2.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1 H), 6.10

(d, J ) 8.5 Hz, 1H), 3.87 (t, J ) 6.3 Hz, 1H), 3.73 (t, J ) 6.3

Hz, 1H), 2.36 (s, 3H), 1.41 (s, 9H), 1.31(t, J ) 6.3 Hz, 3H),

1.30 (s, 9H).

(Z)-3-[3,5-Di-ter t-bu tyl-2-(2,2-d iflu or oeth oxy)p h en yl]-

bu t-2-en -1-a l (25c). 25c was synthesized from 2.20 g (6.46

mmol) of 23c in the presence of 227 mg (0.65 mmol) of TPAP

and 1.13 g (9.69 mmol) of NMO according to the representative

procedure of the synthesis of 24g, and 2.08 g (6.14 mmol,

yield: 95%) of 25c was isolated as a pasty solid directly used

E t h yl (2E,4E,6Z)-7-(3,5-Di-iso-p r op yl-2-m et h oxyb en -

zen e)-3-m eth ylocta -2,4,6-tr ien oa te (26a ). 26a was synthe-

sized from 150 mg (0.58 mmol) of 24a in the presence of 0.36

mL (380 mg, 1.44 mmol) of triethyl-3-methylphosphonocroto-

nate and 0.7 mL of n-BuLi (2.5 M in hexane) according to the

procedure described for the synthesis of 26g, and 208 mg (0.56

mmol, yield: 97%) of 26a was isolated as a clear pale yellow

in the next step. H NMR (CDCl₃, 400 MHz): δ 9.47 (d, J )

8.1 Hz, 1H), 7.39 (d, J ) 2.4 Hz, 1H), 6.98 (d, J ) 2.4 Hz, 1 H),

6.15 (d, J ) 8.0 Hz, 1H), 5.87 (td, J ) 55.0, 4.0 Hz, 1H), 4.05

(m, 1H), 3.91 (m, 1H), 2.36 (s, 3H), 1.41 (s, 9H), 1.30 (s, 9H).

(Z)-3-[3,5-Di-ter t-bu tyl-2-(2,2,2-tr iflu or oeth oxy)p h en yl]-

bu t-2-en -1-a l (25d ). 25d was synthesized from 1.4 g (3.9

mmol) of 23d in the presence of 137 mg (0.39 mmol) of TPAP

and 685 mg (5.85 mmol) of NMO according to the representa-

tive procedure of the synthesis of 24g, and 1.31 g (3.67 mmol,

yield: 94%) of 25d was isolated as a pasty solid directly used

oil (mixture of isomers). H NMR (CDCl₃, 500 MHz): δ, 7.02

(d, J ) 2.4 Hz, 1H), 6.75 (d, J ) 2.4 Hz, 1H), 6.57 (dd, J )

15.0, 11.0 Hz, 1H), 6.23 (d, J ) 11.0 Hz, 1H), 6.20 (d, J ) 15.0

Hz, 1H), 5.82 (s, 1H), 4.14 (dd, J ) 14.6, 7.3 Hz, 2H), 3.59 (s,

3H), 3.34 (m, 1H), 2.93 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.29

(t, J ) 7.2 Hz, 3H), 1.26 (d, J ) 6.3 Hz, 6H), 1.24 (d, J ) 6.5

Hz, 6H).

Eth yl (2E,4E,6Z)-7-(3,5-Di-iso-pr opyl-2-eth oxyben zen e)-

3-m eth ylocta -2,4,6-tr ien oa te (26b). 26b was synthesized

from 200 mg (0.73 mmol) of 24b in the presence of 0.45 mL

in the next step. H NMR (CDCl₃, 500 MHz): δ 9.50 (d, J )

8.2 Hz, 1H), 7.40 (d, J ) 2.7 Hz, 1H), 6.98 (d, J ) 2.7 Hz, 1 H),

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2693

(481 mg, 1.82 mmol) of triethyl-3-methylphosphonocrotonate

and 0.9 mL of n-BuLi (2.5 M in hexane) according to the

procedure described for the synthesis of 26g, and 267 mg (0.69

mmol, yield: 95%) of 26b was isolated as a clear pale yellow

1H), 6.24 (d, J ) 15.1 Hz, 1H), 6.23 (d, J ) 11.0 Hz, 1H), 5.78

(s, 1H), 4.18 (dd, J ) 15.0,7.2 Hz, 2H), 3.61 (s, 3H), 2.23 (s,

3H), 2.16 (s, 3H), 1.41 (s, 9H), 1.28 (s, 9H), 1.15 (t, J ) 7.2 Hz,

3H).

oil (mixture of isomers). H NMR (CDCl₃, 500 MHz): δ, 7.03

Eth yl (2E,4E,6Z)-7-(3,5-Di-ter t-bu tyl-2-eth oxyben zen e)-

3-m eth ylocta -2,4,6-tr ien oa te (27b). 27b was synthesized

from 8.49 g (28.11 mmol) of 25b according to the procedure

described for the synthesis of 26g, and 10.5 g (24.5 mmol,

yield: 87%) of 27b (mixture of isomers) was isolated as a

colorless oil. ¹H NMR (CDCl₃, 500 MHz): δ 7.29 (d, J ) 2.0

Hz, 1H), 6.92 (d, J ) 2.0 Hz, 1H), 6.68 (dd, J ) 15.2, 11.0 Hz,

1H), 6.26 (d, J ) 15.2 Hz, 1H), 6.23 (d, J ) 11.0 Hz, 1H), 5.76

(s, 1H), 4.15 (m, 2H), 3.87 (t, J ) 6.3 Hz, 1H), 3.69 (t, J ) 6.3

Hz, 1H), 2.21 (s, 3H), 2.15 (s, 3H), 1.41 (s, 9H), 1.31 (s, 9H),

1.25 (m, 6H).

(d, J ) 2.4 Hz, 1H), 6.75 (d, J ) 2.4 Hz, 1H), 6.59 (dd, J )

15.0, 11.2 Hz, 1H), 6.22 (d, J ) 15.0 Hz, 1H), 6.20 (d, J ) 11.2

Hz, 1H), 5.74 (s, 1H), 4.15 (dd, J ) 14.2, 7.1 Hz, 2H), 3.67 (m,

2H), 3.37 (m, 1H), 2.82 (m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.26

(t, J ) 7.1 Hz, 3H), 1.23 (d, J ) 6.6 Hz, 12H).

Eth yl (2E,4E,6Z)-7-[3,5-Di-iso-pr opyl-2-(2-flu or oeth oxy)-

ben zen e]-3-m eth ylocta -2,4,6-tr ien oa te (26c). 26c was syn-

thesized from 150 mg (0.51 mmol) of 24c in the presence of

0.32 mL (339 mg, 1.28 mmol) of triethyl-3-methylphosphono-

crotonate and 0.6 mL of n-BuLi (2.5 M in hexane) according

to the procedure described for the synthesis of 26g, and 189

mg (0.47 mmol, yield: 92%) of 26c was isolated as a clear pale

yellow oil (mixture of isomers). ¹H NMR (CDCl₃, 400 MHz):

δ, 7.05 (d, J ) 2.5 Hz, 1H), 6.77 (d, J ) 2.5 Hz, 1H), 6.56 (dd,

J ) 15.5, 11.0 Hz, 1H), 6.24 (d, J ) 9.5 Hz, 1H), 6.22 (d, J )

15.5 Hz, 1H), 5.75 (s, 1H), 4.60 (dt, J ) 55.1, 4.0 Hz, 2H), 4.15

(dd, J ) 14.0, 7.0 Hz, 2H), 3.96 (br m, 2H), 3.39 (m, 1H), 2.81

(m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.27 (t, J ) 7.0 Hz, 3H),

1.24 (d, J ) 7.1 Hz, 6H), 1.22 (d, J ) 7.1 Hz, 6H).

E t h yl (2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-(2,2-d iflu or o-

eth oxy)ben zen e]-3-m eth ylocta -2,4,6-tr ien oa te (26d ). 26d

was synthesized from 200 mg (0.73 mmol) of 24d in the

presence of 0.45 mL (481 mg, 1.82 mmol) of triethyl-3-

methylphosphonocrotonate and 0.9 mL of n-BuLi (2.5 M in

hexane) according to the procedure described for the synthesis

of 26g, and 276 mg (0.66 mmol, yield: 90%) of 26d was isolated

as a clear pale yellow oil (mixture of isomers). ¹H NMR (CDCl₃,

400 MHz): δ, 7.06 (d, J ) 2.0 Hz, 1H), 6.78 (d, J ) 2.0 Hz,

1H), 6.51 (dd, J ) 15.5, 11.0 Hz, 1H), 6.27 (d, J ) 11.0 Hz,

1H), 6.24 (d, J ) 15.5 Hz, 1H), 5.94 (td, J ) 55.0, 4.0 Hz, 1H),

5.76 (s, 1H), 4.18 (dd, J ) 14.2, 7.1 Hz, 2H), 3.92 (br m, 2H),

3.36 (m, 1H), 2.83 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.29 (t, J

) 7.0 Hz, 3H), 1.23 (d, J ) 7.6 Hz, 6H), 1.21 (d, J ) 7.6 Hz,

6H).

Eth yl (2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-(2,2,2-tr iflu or -

eth oxy)ben zen e)]-3-m eth ylocta -2,4,6-tr ien oa te (26e). 26e

was synthesized from 650 mg (1.98 mmol) of 24e in the

presence of 1.22 mL (1.31 g, 4.94 mmol) of triethyl-3-meth-

ylphosphonocrotonate and 2.4 mL of n-BuLi (2.5 M in hexane)

according to the procedure described for the synthesis of 26g,

and 781 mg (1.78 mmol, yield: 90%) of 26e was isolated as a

clear pale yellow oil (mixture of isomers). ¹H NMR (CDCl₃,

500 MHz): δ, 7.07 (d, J ) 2.1 Hz, 1H), 6.78 (d, J ) 2.1 Hz,

1H), 6.48 (dd, J ) 15.2, 11.0 Hz, 1H), 6.28 (d, J ) 11.0 Hz,

1H), 6.26 (d, J ) 15.4 Hz, 1H), 5.76 (s, 1H), 4.16 (dd, J ) 14.5,

7.2 Hz, 2H), 4.02 (br m, 2H), 3.37 (m, 1H), 2.83 (m, 1H), 2.19

(s, 3H), 2.13 (s, 3H), 1.27 (t, J ) 7.3 Hz, 3H), 1.24 (d, J ) 7.3

Hz, 6H), 1.23 (d, J ) 7.4 Hz, 6H).

E t h yl (2E,4E,6Z)-7-[3,5-Di-ter t-b u t yl-2-(2,2-d iflu or o-

eth oxy)ben zen e]-3-m eth ylocta -2,4,6-tr ien oa te (27c). 27c

was synthesized from 2.00 g (5.91 mmol) of 25c according to

the procedure described for the synthesis of 26g, and 2.46 g

(5.49 mmol, yield: 93%) of 27c (mixture of isomers) was

isolated as a colorless oil. H NMR (CDCl₃, 400 MHz): δ 7.32

(d, J ) 2.4 Hz, 1H), 6.96 (d, J ) 2.4 Hz, 1H), 6.54 (dd, J )

15.2, 10.9 Hz, 1H), 6.28 (d, J ) 15.0 Hz, 1H), 6.24 (d, J ) 11.0

Hz, 1H), 5.96 (tt, J ) 55.2, 4.1 Hz, 1H), 5.63 (s, 1H), 4.17 (dd,

J ) 14.2, 7.1 Hz, 2H), 4.04 (m, 1H), 3.86 (m, 1H), 2.22 (s, 3H),

2.14 (s, 3H), 1.42 (s, 9H), 1.31 (s, 9H), 1.28 (t, J ) 7.0 Hz, 3H).

Eth yl (2E,4E,6Z)-7-[3,5-Di-ter t-bu tyl-2-(2,2,2-tr iflu or o-

eth oxy)ben zen e]-3-m eth ylocta -2,4,6-tr ien oa te (27d ). 27d

was synthesized from 1.25 g (3.51 mmol) of 25d according to

the procedure described for the synthesis of 26g, and 1.52 g

(3.26 mmol, yield: 93%) of 27d (mixture of isomers) was

isolated as a colorless oil. H NMR (CDCl₃, 500 MHz): δ 7.32

(d, J ) 2.4 Hz, 1H), 6.94 (d, J ) 2.4 Hz, 1H), 6.55 (dd, J )

15.5, 10.9 Hz, 1H), 6.29 (d, J ) 10.9 Hz, 1H), 6.26 (d, J ) 15.7

Hz, 1H), 5.77 (s, 1H), 4.21 (m, 1H), 4.15 (dd, J ) 14.3, 7.1 Hz,

2H), 4.02 (m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.42 (s, 9H), 1.30

(s, 9H), 1.27 (t, J ) 7.3 Hz, 3H).

Eth yl (2E,4E,6Z)-7-(3,5-Di-ter t-bu tyl-2-pr opoxyben zen e)-

3-m eth ylocta -2,4,6-tr ien oa te (27e). 27e was synthesized

from 120 mg (0.38 mmol) of 25e according to the procedure

described for the synthesis of 26g, and 149 mg (0.35 mmol,

yield: 92%) of 27e (mixture of isomers) was isolated as a

colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.26 (d, J ) 2.0

Hz, 1H), 6.93 (d, J ) 2.0 Hz, 1H), 6.60 (dd, J ) 15.0, 11.0 Hz,

1H), 6.21 (d, J ) 15.0 Hz, 1H), 6.19 (d, J ) 11.0 Hz, 1H), 5.72

(s, 1H), 4.16 (dd, J ) 14.9, 7.1 Hz, 2H), 3.78 (m, 1H), 3.61 (m,

1H), 2.21 (s, 3H), 2.17 (s, 3H), 1.68 (m, 2H), 1.40 (s, 9H), 1.14

(s, 9H), 1.12 (t, J ) 7.1 Hz, 3H).

E t h yl (2E,4E,6Z)-7-[3,5-Di-ter t-a m yl-2-m et h oxy)b en -

zen e]-3-m eth ylocta -2,4,6-tr ien oa te (35a ). 35a was synthe-

sized from 412 mg (1.30 mmol) of 34a according to the

procedure described for the synthesis of 26g, and 480 mg (1.12

mmol, yield: 87%) of 35a (mixture of isomers) was isolated as

a colorless oil. H NMR (CDCl₃, 400 MHz): δ 7.13 (d, J ) 2.5

E t h yl (2E,4E,6Z)-7-(3,5-Di-iso-p r op yl-2-p r op oxyb en -

zen e)-3-m eth ylocta -2,4,6-tr ien oa te (26f). 26f was synthe-

sized from 400 mg (1.38 mmol) of 24f in the presence of 0.86

mL (916 mg, 3.46 mmol) of triethyl-3-methylphosphonocroto-

nate and 1.7 mL of n-BuLi (2.5 M in hexane) according to the

procedure described for the synthesis of 26g, and 506 mg (1.26

mmol, yield: 92%) of 26f was isolated as a clear pale yellow

Hz, 1H), 6.85 (d, J ) 2.5 Hz, 1H), 6.57 (dd, J ) 15.0, 11.0 Hz,

1H), 6.24 (d, J ) 11.0 Hz, 1H), 6.21 (d, J ) 15.0 Hz, 1H), 5.74

(s, 1H), 4.15 (dd, J ) 14.6, 7.3 Hz, 2H), 3.58 (s, 3H), 2.21 (s,

3H), 2.12 (s, 3H), 1.92 (m, 2H), 1.58 (m, 2H), 1.37 (s, 6H), 1.27

(t, J ) 7.3 Hz, 3H), 1.26 (s, 6H), 0.67 (t, J ) 7.5 Hz, 3H), 0.66

(t, J ) 7.5 Hz, 3H).

oil (mixture of isomers). H NMR (CDCl₃, 500 MHz): δ, 7.02

Eth yl (2E,4E,6Z)-7-[3,5-Di-ter t-am yl-2-eth oxy)ben zen e]-

3-m eth ylocta -2,4,6-tr ien oa te (35b). 35b was synthesized

from 125 mg (0.38 mmol) of 34b according to the procedure

described for the synthesis of 26g, and 186 mg (0.42 mmol,

yield: 90%) of 35b (mixture of isomers) was isolated as a

colorless oil. ¹H NMR (CDCl₃): δ 7.13 (d, J ) 2.4 Hz, 1H), 6.83

(d, J ) 2.4 Hz, 1H), 6.60 (dd, J ) 15.2, 10.9 Hz, 1H), 6.22 (d,

J ) 15.3 Hz, 1H), 6.20 (d, J ) 11.0 Hz, 1H), 5.73 (s, 1H), 4.15

(dd, J ) 14.0, 7.0 Hz, 2H), 3.81 (m, 1H), 3.62 (m, 1H), 2.20 (s,

3H), 2.13 (s, 3H), 1.80 (m, 2H), 1.59 (q, J ) 7.4 Hz, 2H), 1.36

(s, 6H), 1.28 (t, J ) 7.4 Hz, 3H), 1.25 (s, 6H), 0.66 (t, J ) 7.4

Hz, 3H), 0.64 (t, J ) 7.4 Hz, 3H).

(d, J ) 2.4 Hz, 1H), 6.74 (d, J ) 2.4 Hz, 1H), 6.58 (dd, J )

15.6, 11.1 Hz, 1H), 6.20 (d, J ) 15.6 Hz, 1H), 6.20 (d, J ) 11.1

Hz, 1H), 5.73 (s, 1H), 4.13 (dd, J ) 14.2, 7.1 Hz, 2H), 3.60 (m,

2H), 3.35 (m, 1H), 2.81 (m, 1H), 2.20 (s, 3H), 2.13 (s, 3H), 1.27

(t, J ) 7.3 Hz, 3H), 1.23 (d, J ) 6.8 Hz, 12H), 0.96 (t, J ) 7.3

Hz, 3H).

Eth yl (2E,4E,6Z)-7-(3,5-Di-ter t-bu tyl-2-m eth oxyben zen e)-

3-m eth ylocta -2,4,6-tr ien oa te (27a ). 27a was synthesized

from 180 mg (0.55 mmol) of 25a according to the procedure

described for the synthesis of 26g, and 207 mg (0.52 mmol,

yield: 94%) of 27a (mixture of isomers) was isolated as a

colorless oil. ¹H NMR (CDCl₃, 500 MHz): δ 7.28 (d, J ) 1.9

Hz, 1H), 6.96 (d, J ) 1.9 Hz, 1H), 6.61 (dd, J ) 15.1, 11.0 Hz,

E t h yl (2E,4E,6Z)-7-[3,5-Di-ter t-a m yl-2-(2,2-d iflu or o-

eth oxy)ben zen e]-3-m eth ylocta -2,4,6-tr ien oa te (35c). 35c

2694 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

was synthesized from 150 mg (0.41 mmol) of 34c according to

the procedure described for the synthesis of 26g, and 179 mg

(0.38 mmol, yield: 92%) of 35c (mixture of isomers) was

70.39; found, 69.98; H: calcd, 7.70; found, 7.33. MS (EI, 70

eV) 393 m/e: 393 (MH⁺, 1), 374 (100), 356 (45), 293 (60), 275

(75). HRMS for C₂₃H₃₁F₂O₃(MH⁺): calcd, 393.2241; found,

393.2191.

isolated as a colorless oil. H NMR (CDCl₃, 400 MHz): δ 7.17

(d, J ) 2.4 Hz, 1H), 6.87 (d, J ) 2.4 Hz, 1H), 6.61 (dd, J )

15.4, 10.9 Hz, 1H), 6.26 (d, J ) 15.4 Hz, 1H), 6.24 (d, J ) 10.9

Hz, 1H), 5.94 (td, J ) 55.4, 4.5 Hz, 1H), 5.75 (s, 1H), 4.18 (dd,

J ) 14.4, 7.3 Hz, 2H), 4.05 (m, 1H), 3.89 (m, 1H), 2.20 (s, 3H),

2.12 (s, 3H), 1.79 (q, J ) 7.6 Hz, 2H), 1.59 (q, J ) 7.5 Hz, 2H),

1.37 (s, 6H), 1.26 (t, J ) 7.3 Hz, 3H), 1.25 (s, 6H), 0.67 (t, J )

7.4 Hz, 3H), 0.65 (t, J ) 7.4 Hz, 3H).

Eth yl (2E,4E,6Z)-7-[3,5-Di-ter t-am yl-2-pr opoxy)ben zen e]-

3-m eth ylocta -2,4,6-tr ien oa te (35d ). 35d was synthesized

from 150 mg (0.43 mmol) of 34d according to the procedure

described for the synthesis of 26g, and 180 mg (0.39 mmol,

yield: 91%) of 35d (mixture of isomers) was isolated as a

colorless oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.13 (d, J ) 2.4

Hz, 1H), 6.84 (d, J ) 2.4 Hz, 1H), 6.60 (dd, J ) 15.2, 10.9 Hz,

1H), 6.22 (d, J ) 15.2 Hz, 1H), 6.19 (d, J ) 10.9 Hz, 1H), 5.74

(s, 1H), 4.15 (dd, J ) 14.3, 7.3 Hz, 2H), 3.72 (m, 1H), 3.59 (m,

1H), 2.24 (s, 3H), 2.13 (s, 3H), 1.81 (m, 2H), 1.70 (m, 2H), 1.60

(q, J ) 7.4 Hz, 2H), 1.37 (s, 6H), 1.26 (s, 6H), 0.95 (t, J ) 7.6

Hz, 3H), 0.67 (t, J ) 7.6 Hz, 3H), 0.66 (t, J ) 7.4 Hz, 3H).

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-m et h oxyb en zen e]-3-

m eth ylocta -2,4,6-tr ien oic Acid (11a ). Saponification of 200

mg (0.54 mmol) of 26a according to the procedure described

for the synthesis of 11g affords 111 mg (0.32 mmol, yield: 60%)

of 11a as a white solid (mp 177 and 193 °C, CH₃CN). ¹H NMR

(CDCl₃, 500 MHz): δ 7.05 (d, J ) 2.0 Hz, 1H), 6.76 (d, J ) 2.0

Hz, 1H), 6.60 (dd, J ) 15.5, 11.0 Hz, 1H), 6.26 (dd, J ) 11.0,

1.5 Hz, 1H), 6.24 (d, J ) 15.5 Hz, 1H), 5.76 (s, 1H), 3.59 (s,

3H), 3.35 (m, 1H), 2.81 (m, 1H), 2.22 (d, J ) 1.5 Hz, 3H), 2.14

(s, 3H), 1.25 (d, J ) 7.0 Hz, 6H), 1.23 (d, J ) 7.1 Hz, 6H).

Anal. (C₂₂H₃₀O₃) C, H: calcd, 8.83; found, 8.34. MS (EI, 70 eV)

343 m/e: 343 (MH⁺, 20), 301 (33), 283 (40), 243 (100). HRMS

for C₂₂H₃₁O₃(MH⁺): calcd, 343.2273; found, 343.2191.

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-eth oxyben zen e]-3-m e-

th ylocta -2,4,6-tr ien oic Acid (11b). Saponification of 235 mg

(0.61 mmol) of 26b according to the procedure described for

the synthesis of 11g affords 137 mg (0.38 mmol, yield: 63%)

of 11b as a white solid (mp 156 °C, CH₃CN). ¹H NMR (CDCl₃,

500 MHz): δ 7.04 (d, J ) 2.0 Hz, 1H), 6.75 (d, J ) 2.0 Hz,

1H,), 6.63 (dd, J ) 15.5, 11.0 Hz, 1H), 6.26 (d, J ) 15.5 Hz,

1H), 6.23 (d, J ) 11.0 Hz, 1H), 5.77 (s, 1H), 3.36 (m, 2H), 3.28

(m, 1H), 2.85 (m, 1H), 2.27 (s, 3H), 2.15 (s, 3H), 1.28 (t, J )

7.0 Hz, 3H), 1.25 (d, J ) 6.5 Hz, 6H), 1.23 (d, J ) 7.0 Hz, 6H).

Anal. (C₂₃H₃₂O₃‚(1/4)H₂O) C, H. MS (EI, 70 eV) 357 m/e: 357

(MH⁺, 18), 297 (38), 257 (100), 205 (55). HRMS for C₂₃H₃₃O₃

(MH⁺): calcd, 357.2430; found, 357.2408.

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-(2,2,2-t r iflu or oet h -

oxy)ben zen e]-3-m eth ylocta -2,4,6-tr ien oic Acid (11e). Sa-

ponification of 700 mg (1.59 mmol) of 26e according to the

procedure described for the synthesis of 11g affords 426 mg

(1.04 mmol, yield: 65%) of 11e as a white solid (mp 148 °C,

CH₃CN). H NMR (CDCl₃, 500 MHz): δ 7.07 (d, J ) 2.1 Hz,

1H), 6.77 (d, J ) 2.0 Hz, 1H), 6.55 (dd, J ) 15.3, 11.0 Hz, 1H),

6.30 (d, J ) 10.3 Hz, 1H), 6.28 (d, J ) 15.3 Hz, 1H), 5.78 (s,

1H), 3.99 (m, 2H), 3.35 (m, 1H), 2.87 (m, 1H), 2.21 (s, 3H),

2.14 (s, 3H), 1.25 (d, J ) 6.1 Hz, 6H), 1.23 (d, J ) 6.9 Hz, 6H).

Anal. (C₂₃H₂₉F₃O₃) C, H. MS (EI, 70 eV) 411 m/z: 411 (MH⁺,

40), 393 (62), 311 (100). HRMS for C₂₃H₃₀F₃O₃(MH⁺): calcd,

411.2147; found, 411.2160.

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-p r op oxyb en zen e]-3-

m eth ylocta -2,4,6-tr ien oic Acid (11f). Saponification of 455

mg (1.14 mmol) of 26f according to the procedure described

for the synthesis of 11g affords 262 mg (0.71 mmol, yield: 62%)

of 11f as a white solid (mp 144 °C, CH₃CN). H NMR (CDCl₃,

500 MHz): δ 7.04 (d, J ) 2.0 Hz, 1H), 6.75 (d, J ) 2.0 Hz,

1H,), 6.63 (dd, J ) 15.0, 11.0 Hz, 1H), 6.25 (d, J ) 15.0 Hz,

1H), 6.23 (d, J ) 11.0 Hz, 1H), 5.76 (s, 1H), 3.60 (m, 2H), 3.38

(m, 1H), 2.82 (m, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 1.64 (m, 2H),

1.24 (d, J ) 6.5 Hz, 6H), 1.23 (d, J ) 6.5 Hz, 6H), 0.97 (t, J )

8.0 Hz, 3H). Anal. (C₂₄H₃₄O₃‚(1/4)H₂O) H; C: calcd, 77.80;

found, 76.94. MS (EI, 70 eV) 371 m/e: 371 (MH⁺, 50), 311 (50),

271 (95), 229 (100), 205 (72). HRMS for C₂₄H₃₅O₃(MH⁺): calcd,

371.2455; found, 371.2486.

(2E,4E,6Z)-7-(3,5-Di-ter t-b u t yl-2-m et h oxyb en zen e)-3-

m eth ylocta -2,4,6-tr ien oic Acid (12a ). Saponification of 193

mg (0.48 mmol) 27a according to the procedure described for

the synthesis of 11g affords 113 mg (0.31 mmol, yield: 63%)

of 12a as a white solid (mp 147 and 206 °C, CH₃CN): ¹H NMR

(CDCl₃, 500 MHz) δ 7.29 (d, J ) 2.2 Hz, 1H), 6.95 (d, J ) 2.0

Hz, 1H), 6.67 (dd, J ) 15.0, 11.0 Hz, 1H), 6.26 (d, J ) 15.0

Hz, 1H), 6.23 (d, J ) 11.0 Hz, 1H), 5.79 (s, 1H), 3.62 (s, 3H),

2.30 (s, 3H), 2.16 (s, 3H), 1.42 (s, 9H), 1.29 (s, 9H). Anal.

(C₂₄H₃₄O₃) C; H: calcd, 9.25; found, 9.36. MS (EI, 70 eV) 393

m/e: 393 (MH⁺, 12), 315 (74), 297 (85), 275 (78), 241 (100), 233

(83). HRMS for C₂₄H₃₅O₃(MH⁺): calcd, 395.2006; found,

393.2061.

(2E ,4E ,6Z)-7-(3,5-Di-t er t -b u t yl-2-e t h oxyb e n ze n e )-3-

m eth ylocta -2,4,6-tr ien oic Acid (12b). Saponification of 2.0

g (4.85 mmol) of 27b according to the procedure described for

the synthesis of 11g affords 949 mg (2.47 mmol, yield: 51%)

of 12b as a white solid (mp 165 and 194 °C, CH₃CN). ¹H NMR

(CDCl₃, 500 MHz): δ 7.29 (d, J ) 2.0 Hz, 1H), 6.92 (d, J ) 2.0

Hz, 1H), 6.68 (dd, J ) 15.1, 11.0 Hz, 1H), 6.26 (d, J ) 15.1

Hz, 1H), 6.23 (dd, J ) 11.0, 1.3 Hz, 1H), 5.77 (s, 1H), 3.87 (t,

J ) 6.3 Hz, 1H), 3.69 (t, J ) 6.3 Hz, 1H), 2.24 (s, 3H), 2.16 (d,

J ) 1.3 Hz, 3H), 1.42 (s, 9H), 1.31 (s, 9H), 1.28 (t, J ) 6.3 Hz,

3H). Anal. (C₂₅H₃₆O₃) H; C: calcd, 78.08; found, 77.36. MS (EI,

70 eV) 385 m/e: 385 (MH⁺, 11), 273 (99), 255 (100), 233 (93).

HRMS for C₂₅H₃₇O₃(MH⁺): calcd, 385.2763; found, 385.2753.

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-(2-flu or oeth oxy)ben -

zen e]-3-m eth ylocta -2,4,6-tr ien oic Acid (11c). Saponifica-

tion of 150 mg (0.37 mmol) of 26c according to the procedure

described for the synthesis of 11g affords 84 mg (0.22 mmol,

yield: 60%) of 11c as a white solid (mp 162 °C, CH₃CN). H

NMR (CDCl₃, 400 MHz): δ 7.06 (d, J ) 2.0 Hz, 1H), 6.76 (d,

J ) 2.0 Hz, 1H,), 6.60 (dd, J ) 15.5, 11.0 Hz, 1H), 6.28 (d, J

) 11.0 Hz, 1H), 6.27 (d, J ) 15.5 Hz, 1H), 5.77 (s, 1H), 4.58

(dt, J ) 55.1, 4.0 Hz, 2H), 3.91 (m, 2H), 3.40 (m, 1H), 2.85 (m,

1H), 2.22 (s, 3H), 2.15 (s, 3H), 1.24 (d, J ) 6.2 Hz, 6H), 1.22

(d, J ) 6.3 Hz, 6H). Anal. (C₂₃H₃₁FO₃) C, H: calcd, 8.34; found,

8.45. MS (EI, 70 eV) 357 m/e: 357 (MH⁺, 1), 339 (30), 297 (40),

257 (100), 205 (55). HRMS for C₂₃H₃₂FO₃(MH⁺): calcd,

375.2335; found, 375.2316.

(2E,4E,6Z)-7-(3,5-Di-ter t-b u t yl-2-(2,2-d iflu or oet h oxy)-

ben zen e)-3-m eth ylocta -2,4,6-tr ien oic Acid (12c). Saponi-

fication of 2.40 g (5.34 mmol) of 27c according to the procedure

described for the synthesis of 11g affords 1.37 g (3.26 mmol,

yield: 61%) of 12c as a white solid (mp 165 and 178 °C, CH₃-

CN). H NMR (CDCl₃, 400 MHz): δ 7.31 (d, J ) 2.4 Hz, 1H),

6.95 (d, J ) 2.4 Hz, 1H), 6.59 (dd, J ) 15.3, 11.0 Hz, 1H), 6.29

(d, J ) 11.0 Hz, 1H), 6.28 (d, J ) 15.3 Hz, 1H), 5.96 (dt, J )

55.3 Hz, 4.3 Hz, 1H), 5.78 (s, 1H), 3.95 (m, 2H), 2.22 (s, 3H),

2.15 (s, 3H), 1.41 (s, 9H), 1.30 (s, 9H). Anal. (C₂₅H₃₄F₂O₃‚(1/

4)H₂O) C, H. MS (EI, 70 eV) 421 m/z: 421 (MH⁺, 17), 365 (80),

347 (100), 291 (86). HRMS for C₂₅H₃₅F₂O₃(MH⁺): calcd,

421.2554; found, 421.2696.

(2E,4E,6Z)-7-[3,5-Di-ter t-bu tyl-2-(2,2,2-tr iflu or oeyth oxy)-

ben zen e]-3-m eth ylocta -2,4,6-tr ien oic Acid (12d ). Saponi-

fication of 1.4 g (3.00 mmol) of 27d according to the procedure

described for the synthesis of 11g affords 674 mg (1.65 mmol,

(2E,4E,6Z)-7-[3,5-Di-iso-p r op yl-2-(2,2-d iflu or oeth oxy)-

ben zen e]-3-m eth ylocta -2,4,6-tr ien oic Acid (11d ). Saponi-

fication of 250 mg (0.59 mmol) of 26d according to the

procedure described for the synthesis of 11g affords 150 mg

(0.38 mmol, yield: 65%) of 11d as a white solid (mp 141 °C,

CH₃CN). H NMR (CDCl₃, 400 MHz): δ 7.06 (d, J ) 2.0 Hz,

1H), 6.78 (d, J ) 2.0 Hz, 1H), 6.56 (dd, J ) 15.0, 11.0 Hz, 1H),

6.29 (d, J ) 11.0 Hz, 1H), 6.27 (d, J ) 15.0 Hz, 1H), 5.94 (tt,

J ) 55.5, 4.0 Hz, 1H), 5.78 (s, 1H), 3.86 (m, 2H), 3.33 (m, 1H),

2.87 (m, 1H), 2.14 (s, 3H), 2.13 (s, 3H), 1.24 (d, J ) 6.3 Hz,

6H), 1.22 (d, J ) 6.3 Hz, 6H). Anal. (C₂₃H₃₀F₂O₃) C: calcd,

New RXR Modulators for Type 2 Diabetes

J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13 2695

yield: 55%) of 12d as a white solid (mp 178 °C, CH₃CN). H

NMR (CDCl₃, 500 MHz): δ 7.33 (d, J ) 2.4 Hz, 1H), 6.94 (d,

J ) 2.4 Hz, 1H), 6.60 (dd, J ) 15.6, 10.7 Hz, 1H), 6.29 (d, J )

10.7 Hz, 1H), 6.27 (d, J ) 15.6 Hz, 1H), 5.78 (s, 1H), 4.11 (m,

1H), 4.02 (m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.42 (s, 9H), 1.30

(s, 9H). Anal. (C₂₅H₃₃F₃O₃) C; H: calcd, 7.59; found, 7.87. MS

(EI, 70 eV) 439 m/e: 411 (MH⁺, 61), 383 (99), 365 (100) 309

(51). HRMS for C₂₅H₃₄F₃O₃(MH⁺): calcd, 439.2460; found,

439.2417.

(2E,4E,6Z)-7-(3,5-Di-ter t-b u t yl-2-p r op oxyb en zen e)-3-

m eth ylocta -2,4,6-tr ien oic Acid (12e). Saponification of 120

mg (0.28 mmol) of 27e according to the procedure described

for the synthesis of 11g affords 69 mg (0.17 mmol, yield: 62%)

of 12e as a white solid (mp 155 °C, CH₃CN). ¹H NMR (CDCl₃,

400 MHz): δ 7.30 (d, J ) 2.0 Hz, 1H), 6.92 (d, J ) 2.0 Hz,

1H), 6.67 (dd, J ) 15.0, 11.1 Hz, 1H), 6.26 (d, J ) 15.0 Hz,

1H), 6.23 (d, J ) 11.1 Hz, 1H), 5.75 (s, 1H), 3.89 (m, 1H), 3.69

(m, 1H), 2.27(s, 3H), 2.18 (s, 3H), 1.68 (m, 2H), 1.42 (s, 9H),

1.29 (s, 9H), 0.97 (t, J ) 6.3 Hz, 3H). Anal. (C₂₆H₃₈O₃) C; H:

calcd, 9.61; found: 9.48. MS (EI, 70 eV) 399 m/z: 399 (MH⁺,

20), 343 (43), 287 (100), 269 (91), 233 (82). HRMS for C₂₆H₃₉O₃

(MH⁺): calcd, 399.2989; found, 399.3052.

(2E,4E,6Z)-7-(3,5-Di-ter t-a m yl-2-m eth oxyp h en yl)-3-m e-

th ylocta -2,4,6-tr ien oic Acid (13a ). Saponification of 400 mg

(0.28 mmol) of 35a according to the procedure described for

the synthesis of 11g affords 240 mg (0.18 mmol, yield: 65%)

of 13a as a white solid (mp 140 °C, CH₃CN): ¹H NMR (CDCl₃,

400 MHz) δ 7.14 (d, J ) 3.0 Hz, 1H), 6.85 (d, J ) 3.0 Hz, 1H),

6.62 (dd, J ) 15.5, 11.5 Hz, 1H), 6.26 (d, J ) 15.5 Hz, 1H),

6.23 (d, J ) 11.5 Hz, 1H), 5.76 (s, 1H), 3.58 (s, 3H), 2.23 (s,

3H), 2.13 (s, 3H), 1.90 (m, 2H), 1.59 (q, J ) 7.5 Hz, 2H), 1.37

(s, 6H), 1.27 (s, 6H), 0.67 (t, J ) 7.5 Hz, 3H), 0.66 (t, J ) 7.5

Hz, 3H). Anal. (C₂₆H₃₈O₃); C: calcd, 78.35, found, 77.79; H:

calcd, 9.01; found, 9.68. MS (EI, 70 eV) 399 m/z: 399 (MH⁺,

14), 329 (92), 311 (80), 261 (95), 241 (100). HRMS for C₂₆H₃₉O₃

(MH⁺): calcd, 399.2317; found, 399.2399.

0.66 (s, 6H). Anal. (C₂₈H₄₂O₃) C; H: calcd, 9.92; found, 10.15.

MS (EI, 70 eV) 427 m/e: 427 (MH⁺, 22), 357 (38), 287 (100),

269 (92), 261 (89). HRMS for C₂₈H₄₃O₃(MH⁺): calcd, 427.2628;

found, 427.2661.

Biology.

Cotr a n sfection Assa y. All cotransfections were carried out

in 96-well plates in an automated workstation with CV-1 cells

as previously described.

Bin d in g Stu d ies. Receptor binding assays for RARs and

RXRs were performed in a similar manner as described in

Boehm et al.⁹We used [³H]-9-cis-RA as the radioligand for

RXRs, and [³H]-ATRA (purchased from NEN-DuPont) for the

RARs. K_ivalues for the analogues were determined by ap-

plication of the Cheng-Prussof equation.

d b/d b Mou se Stu d ies. db/db mice were obtained from

J ackson Laboratories (Bar Harbor, ME) at 5 weeks of age.

Animals were housed in groups of 6 on a 12L:12D light cycle

(lights on at 0600 h) with food (Purina 5008) and tap water

continuously available. Blood samples were obtained via the

tail vein 3 h after dosing on the indicated day. For chronic

treatment, mice were gavaged with vehicle and the compound

of interest. At the end of the experiments, the animals were

weighed and anesthetized. Blood was collected by cardiac

puncture prior to euthanization with CO₂. Plasma was used

within 1 week for analysis of glucose and triglycerides.

Sp r a gu e-Da w ley Ra t Stu d ies. Seven-week-old male

Sprague-Dawley rats (∼200 g body weight) were purchased

from Harlan Sprague-Dawley (Indianapolis, IN). The animals

had free access to Purina 5008 diet (Ralston Purina Co., St.

Louis, MO) and tap water, with a 12-h dark, 12-h light cycle

(lights on from 06:00 to 18:00). Animals were acclimated in

our facility for 5 to 6 days before treatment and were dosed

via oral gavage with 1 mL of vehicle each day for 3 days prior

to the experiment to acclimate them to the dosing procedure.

The vehicle consists of 0.085% povidone (ISP Technologies Inc.,

New Milford, CT), 1.5% lactose (Quest International, New

York, NY), 0.026% Tween-80 (Sigma, St. Louis, MO), and 0.2%

v/v antifoam (Dow Corning, Midland, MI). For experiments,

the animals were dosed by oral gavage either with the vehicle

alone or with a suspension of compounds in the vehicle. Blood

was collected from the tail vein of conscious animals, and

plasma was prepared and kept frozen at -20 °C until

analyzed.

(2E,4E,6Z)-7-(3,5-Di-ter t-a m yl-2-eth oxyben zen e)-3-m e-

th ylocta -2,4,6-tr ien oic Acid (13b). Saponification of 150 mg

(0.34 mmol) of 35b according to the procedure described for

the synthesis of 11g affords 84 mg (0.20 mmol, yield: 60%) of

13b as a white solid (mp 138 °C, CH₃CN). ¹H NMR (CDCl₃,

400 MHz): δ 7.13 (d, J ) 2.1 Hz, 1H), 6.83 (d, J ) 2.1 Hz,

1H), 6.65 (dd, J ) 15.3, 11.1 Hz, 1H), 6.24 (d, J ) 15.3 Hz,

1H), 6.21 (d, J ) 11.1 Hz, 1H), 5.75 (s, 1H), 3.82 (m, 1H), 3.64

(m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.81 (m, 2H), 1.58 (q, J )

7.4 Hz, 2H), 1.37 (s, 6H), 1.26 (t, J ) 7.3 Hz, 3H), 1.25 (s, 6H),

0.66 (t, J ) 7.3 Hz, 3H), 0.65 (t, J ) 7.4 Hz, 3H). Anal.

(C₂₇H₄₀O₃) C; H: calcd, 9.77; found, 9.92. MS (EI, 70 eV) 413

m/e: 413 (MH⁺, 100), 343 (23), 305 (30), 273 (39). HRMS for

Su p p or tin g In for m a tion Ava ila ble: HPLC trace of

compounds 11a -g, 12a -e, and 13a -d . This material is

available free of charge via the internet at http://pubs.acs.org.

Refer en ces

₂₇H₄₁O₃(MH⁺): calcd, 413.3056; found, 413.3090.

(1) Orfanos, C. E.; Ehlert, R.; Gollnick, H. The Retinoids. A Review

of Their Clinical Pharmacology and Therapeutic Use. [Review]

Drugs 1987, 34, 459-503.

(2) Peck, G. L.; DiGiovanna, J . J .; Synthetic Retinoids in Dermatol-

ogy. In The Retinoids: Biology, Chemistry, and Medicine, 2nd

ed.; Raven Press: New York, 1994; pp 631-658.

(3) Orfanos, C. E.; Zoubouli, C. C.; Almond-Roesler, B.; Geilen, C.

C. Current Use and Future Potential Role of Retinoids in

Dermatology. [Review] J . Clin. Oncol. 1997, 53, 358-388.

(4) Boehm, M. F.; Heyman, R. A.; Patel, S.; Stein, R. B.; Nagpal, S.

Retinoids: Biological Function and Use in the Treatment of

Dermatological Diseases. Expert Opin. Invest. Drugs 1995, 4,

593-612.

(5) Rosen, J .; Day, A.; J ones, T. K.; Turner J ones, T.; Nadzan, A.

M.; Stein, R. B. Intracellular Receptors and Signal Transducers

and Activators of Transcription Superfamilies: Novel Targets

for Small-Molecule Drug Discovery. J . Med. Chem. 1995, 38,

4855-4874.

(2E,4E,6Z)-7-[3,5-Di-ter t-a m yl-2-(2,2-d iflu or oet h oxy)-

ben zen e]-3-m eth ylocta -2,4,6-tr ien oic Acid (13c). Saponi-

fication of 163 mg (0.34 mmol) of 35c according to the

procedure described for the synthesis of 11g affords 95 mg

(0.21 mmol, yield: 62%) of 13c as a white solid (mp 140 °C,

CH₃CN). H NMR (CDCl₃, 400 MHz): δ 7.31 (d, J ) 2.4 Hz,

1H), 6.95 (d, J ) 2.4 Hz, 1H), 6.59 (dd, J ) 15.3, 11.0 Hz, 1H),

6.29 (d, J ) 11.0 Hz, 1H), 6.28 (d, J ) 15.3 Hz, 1H), 5.96 (dt,

J ) 55.3, 4.3 Hz, 1H), 5.78 (s, 1H), 3.95 (m, 2H), 2.22 (s, 3H),

2.15 (s, 3H), 1.82 (m, 2H), 1.59 (q, J ) 7.4 Hz, 2H), 1.33 (s,

6H), 1.25 (s, 6H), 0.67 (t, J ) 7.3 Hz, 3H), 0.65 (t, J ) 7.4 Hz,

3H). Anal. (C₂₇H₃₈F₂O₃) C; H: calcd, 8.54; found, 8.69. MS (EI,

70 eV) 449 m/e: 449 (MH⁺, 20), 379 (90), 361 (100), 291 (78).

HRMS for C₂₇H₃₉F₂O₃(MH⁺): calcd, 449.2680; found, 449.2867.

(6) Mangelsdorf, D. J .; Unesono, K.; Evans, R. M.; The Retinoid

Receptor. In The Retinoids: Biology, Chemistry, and Medicine,

2nd ed.; Raven Press: New York, 1994; pp 319-349.

(7) Heyman, R. A.; Mangelsdorf, D. J .; Dyck, J . A.; Stein, R. B.;

Eichele, G.; Evans, R. M.; Thaller, C. 9-Cis Retinoic Acid Is a

High Affinity Ligand for the Retinoid Receptor. Cell 1992, 68,

397-406.

(8) Levin, A. A.; Sturzenbecker, L. J .; Kazmer, S.; Bosakowski, T.;

Huselton, C.; Allenby, G.; Speck, J .; Kratzeisen, C.; Rosenberg,

M.; Lovey, A.; Grippo, J . F. 9-Cis Retinoic Acid Stereoisomer

Binds and Activates the Nuclear Receptor RXRR. Nature 1992,

355, 359-361.

(2E,4E,6Z)-7-(3,5-Di-ter t-a m yl-2-p r op oxyb en zen e)-3-

m eth ylocta -2,4,6-tr ien oic Acid (13d ). Saponification of 165

mg (0.36 mmol) of 35d according to the procedure described

for the synthesis of 11g affords 99 mg (0.23 mmol, yield: 64%)

of 13d as a white solid (mp 151 °C, CH₃CN). ¹H NMR (400

MHz, CDCl₃): δ 7.13 (d, J ) 2.4 Hz, 1H), 6.83 (d, J ) 2.4 Hz,

1H), 6.63 (dd, J ) 15.2, 11.0 Hz, 1H), 6.23 (d, J ) 15.2 Hz,

1H), 6.20 (d, J ) 11.0 Hz, 1H), 5.75 (s, 1H), 3.69 (m, 1H), 3.58

(m, 1H), 2.21 (s, 3H), 2.14 (s, 3H), 1.81 (m, 2H), 1.67 (m, 2H),

1.59 (m, 2H), 1.36 (s, 6H), 1.25 (s, 6H), 0.94(t, J ) 7.0 Hz, 3H),

2696 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 13

Michellys et al.

(9) Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D.

E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A.

Synthesis and Structure-Activity Relationships of Novel Ret-

inoid X Receptor-Selective Retinoids. J . Med. Chem. 1994, 37,

2930-2941.

(28) Zhang, L.; Nazdan, A. M.; Heyman, R. A.; Love, D. L.; Mais, D.

E.; Croston, G. E.; Lamph, W. W.; Boehm, M. F. Discovery of

Novel Retinoic Acid Receptor Agonists Having Potent Antipro-

liferative Activity in Cervical Cells. J . Med. Chem. 1996, 39,

2659-2663.

(29) J orgenson, M.; Preparation of Ketones from the Reaction of

Organolithium Reagents with Carboxylic Acids. Org. React. 1970

18, 1-97.

(30) Hamann, L. G.; An Efficient Stereospecific Synthesis of the

Dimer-Selective Retinoid X Receptor Modulator (2E,4E,6Z)-7-

[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-(n-propoxy)naphthalen-

3-yl]-3-methylocta-2,4,6-trienoic Acid. J . Org. Chem. 2000, 65,

3233-3235.

(31) Nishinaga, A.; Iwasaki, H.; Shimizu, T.; Toyoda, Y.; Matsuura,

T. Oxygenation of tert-Butylphenols with an Unsaturated Side

Chain. J . Org. Chem. 1986, 51, 2257-2266.

(32) Kallianos, A. G.; Warfield, A. H.; Melvyn, I. S. 3,5-Disubstituted-

2-hydroxy Acetophenones. U.S. Patent 3,787,501, 1974.

(33) Wada, A.; Nomoto, Y.; Tano, K.; Yamashita, E.; Ito, M. Synthesis

of 9Z-9-Substituted Retinoic Acids by Palladium Catalyzed

Coupling Reaction of a Vinyl Triflate with Alkenyl Stannanes.

Chem. Pharm. Bull. 2000, 49, 1391-1394.

(34) Pazos, Y.; De Lera, A. Stereoselective Synthesis of 9-cis-Retinoic

Acid by Suzuki Reaction. Tetrahedron. Lett. 1999, 40, 8287-

8290.

(35) Wada, A.; Hiraishi, S.; Ito, M. Stereoselective Synthesis of 7E,9E-

and 7E,9E-â-Ionyldeneacetaldehydes by Use of Tricarbonyl Iron

Complex. Chem. Pharm. Bull. 1994, 42, 757-760.

(36) J ansen, F. J . H. M.; Lugtenburg, J . Synthesis and Characteriza-

tion of all-E-(4,4′-13C2)-Astaxanthin. Strategies for Labelling the

C15-End Groups of Carotenoids. Eur. J . Org. Chem. 2000, 5,

829-836.

(37) Dominguez, B.; Pazos, Y.; De Lera, A. R. Stereocontrolled

Synthesis of 6-s-cis- and 6-s-trans-Locked 9Z-Retinoids by Hy-

droxyl-Accelerated Stille Coupling of (Z)-tri-n-Butylstannylbut-

2-en-1-ol and Bicyclic Dienyl Triflates. J . Org. Chem. 2000, 65,

5917-5925.

(38) For a review of dianion chemistry, see: Thompson, C. M. Dianion

Chemistry in Organic Synthesis; CRC Press: Boca Raton, FL,

1994.

(39) Liu, S.; Ogilvie, K. M.; Klausing, K.; Lawson, M. A.; J olley, D.;

Danmei, L.; Bilakovics, J .; Pascual, B.; Hein, N.; Urcan, M.;

Leibowitz, M. D. Mechanism of Selective Retinoid X Receptor

Agonist-Induced Hypothyroidism in the Rat. Endocrinology, in

press.

(40) Schultz, Tu, H., J r.; Luk, A.; Repa, J . J .; Medina, J . C.; Li, L.;

Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J .;

Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis.

Genes Dev. 2000, 14 , 2831-2838.

(41) Cannan Koch, S. S.; Dardashti, L. J .; Hebert, J . J .; White, S.

K.; Croston, G. E.; Flatten, K. S.; Heyman, R. A.; Nazdan, A. M.

Identification of the First Retinoic X Receptor Homodimer

Antagonist. J . Med. Chem. 1996, 39, 3229-3234.

(42) Lala, D. S.; Mukherjee, R.; Schulman, I. G.; Cannan Koch, S.

S.; Dardashti, L. J .; Nazdan, A. M.; Croston, G. E.; Evans, R.

M.; Heyman, R. A. Activation of Specific Heterodimers by an

Antagonist of RXR Homodimers. Nature 1996, 383, 450-453.

(43) This unusual effect is know as the phantom ligand effect. See:

Schulman, I. G.; Chuan, L.; Scwabe, J . W. R.; Evans, R. M. The

Phantom Ligand Effect: Allosteric Control of Transcription by

the Retinoid X Receptor. Genes & Dev. 1997, 11, 299-308.

(44) Standeven, A. M.; Thacher, S. M.; Yuan, Y.-D.; Escobar, M.;

Vuligonda, V.; Beard, R. L.; Chadraratna, A. S. Retinoid X

Receptor Agonist Elevation of Serum Triglycerides in Rats by

Potentiation of Retinoic Acid Receptor Agonist Induction or by

Action as Single Agents. Biochem. Pharmacol. 2001, 62, 1501-

1509.

(10) Sola, X. C.; Kupper, T. A New Rexinoid for Cutaneous T-Cell

Lymphoma. Arch. Dermatol. 2001, 137, 649-652.

(11) Duvic, M.; Hymes, K.; Heald, P.; Breneman, D.; Martin, A. G.;

Mykowski, P.; Crowley, C.; Yocum, R. C. Bexarotene Is Effective

and Safe for Treatment of Refractory Advanced-Stage Cutaneous

T-cells Lymphoma: Multinational Phase II-III Trial Results.

J . Clin. Oncol. 2001, 19, 2456-2471.

(12) Wong, S.-F. Oral Bexarotene in the Treatment of Cutaneous

T-cell Lymphoma. Ann. Pharmacother. 2001, 35, 1056-1065.

(13) Khuri, F. R.; Rigas, J . R.; Figlin, R. A.; Gralla, R. J .; Shin, D.

M.; Munden, R.; Fox, N.; Huyghe, M. R.; Kean, Y.; Reich, S. D.;

Hong, W. K. Multi-Institutional Phase I/II Trial of Oral

Bexarotene in Combination with Cisplatin and Vinorelbine in

Previously Untreated Patients with Advanced Nonsmall-Cell

Lung Cancer. J . Clin. Oncol. 2001, 19, 2626-2637.

(14) Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, R.; Berger, E.;

Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J . A.; Heyman,

R. A.; Nazdan A. M. Design and Synthesis of Potent Retinoid X

Receptor Selective Ligands That Induce Apoptosis in Leukemia

Cells. J . Med. Chem. 1995, 38, 3146-3155.

(15) Canan Koch, S. S.; Dardashti, L. J .; Cesario, R. M.; Croston, G.

E.; Boehm, M. F.; Heyman R. A.; Nazdan A. M. Synthesis of

Retinoid X Receptor-Specific Ligands That Are Potent Inducers

of Adipogenesis in 3T3-L1 Cells. J . Med. Chem. 1999, 42, 742-

750.

(16) Faul, M. M.; Ratz, A. M.; Sullivan, K. A.; Trankle, W. G.;

Winneroski, L. L. Synthesis of Novel Retinoid X Receptor-

Selective Retinoids. J . Org. Chem. 2001, 66, 5772-5782.

(17) Schulman, I. G.; Crombie, D.; Bissonnette, R. P.; Cesario, R.;

Roegner, K.; Shao, G.; Heyman, R. A. RXR-Specific Agonists and

Modulators: A New Retinoid Pharmacology. In Handbook of

Experimental Pharmacology; Springer-Verlag: Berlin, 1999; Vol.

139, pp 215-235 and references therein.

(18) Nagpal, S.; Chandraratna, R. A. S. Recent Development in

Receptor-Selective Retinoids. Curr. Pharm. Des. 2000, 6, 919-

931 and references therein.

(19) Willson, T. M.; Brown, P. J .; Sternbach, D. D.; Henke, B. R. The

PPARs: From Orphan Receptors to Drug Discovery. J . Med.

Chem. 2000, 44, 527-550 and references therein.

(20) Lehnard, J . M. PPARγ/RXR as a Molecular Target for Metabolic

Diseases. Recept. Channels 2001, 7, 249-258.

(21) J ones, A. B. Peroxisome Proliferator-Activated Receptor (PPAR)

Modulators: Diabetes and Beyond. Med. Res. Rev. 2001, 21,

540-552.

(22) Isserman, I.; Green, S. Activation of a Member of the Steroid

Hormone Receptor Superfamily by Peroxisome Proliferators.

Nature 1990, 347, 645-650.

(23) Stumvoll, M.; Haring, H. Insulin Resistance and Insulin Sen-

sitizers. Horm. Res. 2001, 55 (Suppl. 2), 3-13.

(24) Mukherkjee, R.; Davies, P. J . A.; Crombie, D. L.; Bischoff, E.

D.; Cesario, R. M.; J ow, L.; Hamann, L. G.; Boehm, M. F.;

Mondon, C. E.; Nazdan, A. M.; Paterniti, J . R.; Heyman, R. A.

Sensitization of Obese Mice to Insulin by Retinoid X Receptor

Agonists. Nature 1997, 386, 407-410.

(25) Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. S. Enantio-

selective Syntheses of Potent Retinoid X Receptor Ligands:

Differential Biological Activities of Individual Antipodes. J . Med.

Chem. 2001, 44, 2298-2303.

(26) Cesario, R. M.; Klausing, K.; Razzaghi, H.; Crombie, D. L.;

Rungta, D.; Heyman, R. A.; Lala, D. The Retinoid LG100754 Is

a Novel RXR/PPARγ Agonist and Decreases Glucose Levels In

Vivo. Mol. Endocrinol. 2001, 15, 1360-1369.

(27) Yamauchi, T.; Waki, H.; Kamon, J .; Murakami, K.; Motojima,

K.; Komeda, K.; Miki, H.; Kubota, N.; Terauchi, Y.; Tsuchida,

A.; Tsuboyama-Kasaoda, N.; Yamauchi, N.; Ide, T.; Hori, W.;

Kato, S.; Fukayama, M.; Akanuma, Y.; Ezaki, O.; Itai, A.; Nagai,

R.; Kimura, S.; Tobe, K.; Kagechika, H.; Shudo, K.; Kadowaki,

T. Inhibition of RXR and PPARγ Ameliorates Diet-Induced

Obesity and Type 2 Diabetes. J . Clin. Invest. 2001, 108, 1001-

1013.

(45) Weatherman, R. V.; Fletterick, R. J .; Scanlan, T. S. Nuclear-

Receptor Ligands and Ligand-Binding Domains. Annu. Rev.

Biochem. 1999, 68, 559-581.

J M020340Q

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