Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ETA antagonists

Article abstract of DOI:10.1021/jm010237l

The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ETA-selective antagonist.

Full text of DOI:10.1021/jm010237l

3978
J . Med. Chem. 2001, 44, 3978-3984
P yr r olid in e-3-ca r boxylic Acid s a s En d oth elin An ta gon ists. 5. High ly Selective,
P oten t, a n d Or a lly Active ETA An ta gon ists
Hwan-Soo J ae,* Martin Winn, Thomas W. von Geldern, Bryan K. Sorensen, William J . Chiou, Bach Nguyen,
Kennan C. Marsh, and Terry J . Opgenorth
Metabolic Diseases Research and Drug Analysis Department, Pharmaceutical Products Research Division,
Abbott Laboratories, Abbott Park, Illinois 60064-6098
Received May 30, 2001
The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic
acids as endothelin antagonists are described. The data shows an increase in selectivity when
the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced
with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides
a metabolically stable and orally bioavailable ETA-selective antagonist.
In tr od u ction
the C2- and C4-aromatic substituents. Metabolic studies
of 1 showed that the p-CH3O- group on the C2-anisyl
group is metabolized to p-OH- by demethylation. Others
have shown that a benzodioxole group can inhibit the
cytochrome P450 enzyme,9 though this effect seems to
be minor with 1.11 We found one solution to this first
problem through replacing the p-anisyl group with a 2,2-
dimethylpentyl, 2 (ABT-546), which gave us a highly
ETA-selective (>26,000-fold) antagonist.15a
Intrigued by these observations, we pursued ad-
ditional SAR studies focusing on modification on the
2-aryl group and replacing the benzodioxole group to
increase the selectivity and the binding affinity. This
paper provides the results, chemistry, and pharmacol-
ogy (Figure 1).
Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid
bicyclic peptides. ET-1 is one of the most powerful
pressor peptides isolated to date,1,2a,b a long-acting
constrictor of vascular smooth muscle, and a potent
mitogen.3
The production of ET-1 is enhanced by stimuli such
as hypoxia, shear stress, and various neurohumoral
factors, which induce the transcription of ET-1 RNA and
subsequent ET-1 synthesis. The biological effects of the
ETs are mediated by G-protein-linked receptors. Two
types of receptors, ETA and ETB, have been cloned and
are approximately 55% homologous in their amino acid
sequences.4 The ETA receptor has much greater affinity
for ET-1 and ET-2 than for ET-3, and it is abundantly
expressed in vascular smooth muscle cells, cardiomyo-
cytes, and fibroblasts. The ETB receptor has equal
affinity for ET-1 and ET-3. ETB is considered the
vasodilator receptor due to its mediation of nitric oxide
release.5 It now appears that ETB receptors are involved
in smooth muscle contraction in blood vessels such as
the rabbit saphenous vein6 and guinea pig bronchus.7
These diverse actions imply a role for endothelin in
various constrictive and/or proliferative disorders.
Our group has reported several families of selective
or balanced endothelin receptor antagonists,10,13,14,15
along with data to suggest that they may be of benefit
in diseases8 such as congestive heart failure,16 acute
myocardial infraction,17 pulmonary hypertension,18 re-
nal failure,19 asthma,20 and restenosis21 and as a
therapeutic agent for cancers.22 In particular we have
focused on the development of highly ETA-selective
agents. The conclusion of these studies on ETA-selectiv-
ity is reported herein.
Ch em istr y
The general procedures for preparation of most com-
pounds in this paper were described in previous
reports.10a,b The new compounds are synthesized ac-
cording to Schemes 1 and 2. The core pyrrolidines
employed in this study have been assembled (Scheme
1) by direct analogy to our earlier work. The â-ketoesters
3 were prepared by reacting an imidazolide of various
benzoic acids with ethyl malonate potassium salt fol-
lowed by decarboxylation (ca. 90% yield). The Michael
addition reaction between â-ketoester 3 and nitrosty-
rene 4 with potassium tert-butoxide catalyst provides a
mixture of diastereomeric nitroketones 5. These ni-
trostyrenes are derived from corresponding benzalde-
hydes11 by Henry reaction.
These nitroketones 5 are reductively cyclized over
Raney nickel to provide cyclic imines, which upon
further hydrogenation of the resulting cyclic iminium
TFA salts provide almost exclusively the cic,cis-isomers
of the pyrrolidines 6. These were epimerized with DBU
to afford the pure trans,trans-pyrrolidines 7 in ca. 80%
overall yield from 3 and 4. Alkylation of pyrrolidine 7
with N,N-dibutylbromoacetamide and subsequent hy-
drolysis of the ethyl ester furnished final compound 8
in good yield. Ethyl-3-fluoroacetophenone is not avail-
able, so it was synthesized12 from 3-fluoro-4-hydroxy-
acetophenone by treatment with trifluoromethanesulfon-
ic anhydride in TEA and CH2Cl2, and further reaction
Histor y of ETA-Selective An ta gon ists a t Abbott
Since the selection of 1 (Atrasentan)10a as a clinical
candidate, we have pursued greater selectivity for the
ETA receptor and increased metabolic stability in a
back-up compound. Our efforts focused in particular on
* Address correspondence to author at Abbott Laboratories, D4CB,
AP10/LL14, 100 Abbott Park Road, Abbott Park, IL 60064-6098.
E-mail: hwan-soo.jae@abbott.com. Fax: 847-938-1674.
10.1021/jm010237l CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/04/2001

Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3979
dine ester is converted in two steps to the corresponding
Boc acid; this hydrolysis step selects for the trans,trans
isomer. Formation of a chiral salt of racemic acid 7a
using R-(+)-R-methylbenzylamine produces product of
>99.5% ee after a single recrystallization as evaluated
by chiral HPLC. The resultant optically active acid is
reconverted to amino ester 7b under Fischer esterifi-
cation conditions. Optically pure antagonist 8a is pre-
pared by the steps already described in Scheme 1.
Str u ctu r e-Activity Rela tion sh ip s
The previous studies by our group have indicated that
the N-linked side chain amide carbonyl of 1 is important
to determine the receptor binding and selectivity. 2,6-
Dialkylphenylacetamides13 and diarylalkylacetamides14
exhibit high affinity and selectivity for ETB (IC50
)
1.1∼1.4 nM), while the corresponding dialkylacetamides
are ETA-selective.13,14 The N,S-dialkylsulfonamides re-
tain high affinity for ETA and simultaneously bind to
ETB receptors as well.10b However, our work also
indicated that the presence of both alkyl groups (e.g.,
n-dibutyl) are required to maintain high ETA selectivity,
thus only N,N-dibutylacetamide side chain compounds
will be discussed in this paper.
Our success replacing the C-2 aryl substituent with
an alkyl group led us to explore aryl groups with
increased hydrophobicity. When the p-anisyl substituent
of 1 was changed to tolyl 1a , a decrease of ETB affinity
was observed while retaining the ETA affinity (Table
1), resulting in an increase in selectivity. Furthermore,
as the p-alkyl group increased in size to p-ethylphenyl
1b and p-propylphenyl 1c, the ETA affinity was de-
creased slightly and ETA/ETB selectivity was less than
p-tolyl 1a . Placing a substituent adjacent to the methyl
group (1e-f) improved potency but decreased selectivity
for ETA.
F igu r e 1.
of palladium-catalyzed coupling of the triflate with
tetraethyltin in the presence of LiCl. This pyrrolidine
was assembled as described in Scheme 1 and subse-
quently hydrolyzed to get the final product 9.
The preparation of optically pure 8a as a single
enantiomer is accomplished by resolution of core pyr-
rolidine 7 (Scheme 2). In practice, the racemic pyrroli-
To avoid possible complications arising from cyto-
chrome P450 (3A4) inhibition, we studied a number of
compounds with benzodioxole replacements at C4.11
Sch em e 1a
a
(a) CDI, THF, K+O2CCH2CO2Et/MgCl2, on carboxylic acid; (b) NaH, (EtO)2CO, THF, on acetophenone; (c) CH3NO2, NH4OAc, HOAc,
heat; (d) cat. t-BuOK, THF, rt; (e) H2, Raney Ni, AcOH, THF, rt, then TFA, rt; (f) DBU, toluene, reflux; (g) BrCH2CO(n-Bu)2, i-Pr2NEt,
CH3CN, rt; (h) aq NaOH, EtOH.

3980 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Sch em e 2. Resolution of 8a
J ae et al.
Our initial studies focused on replacing the benzo-
dioxole with simple carbocyclic analogues. An isosteric
5-indan substitution 2c which has no hydrogen-binding
capability, showed 10-fold less potency than benzodiox-
ole 1 but greater selectivity for ETA. Simple deletions
of each oxygen atom gave 5-substituted dihydrobenzo-
furan 2a and the 6-isomer 2b. Both are very potent ETA
receptor antagonists with IC50s of 0.36 and 1 nM,
respectively. Interestingly, the 6-substituted analogue
2b is 7-fold less selective than 5-isomer 2a . In contrast
to the saturated analogue, the unsaturated 5-benzo-
furan 2d has basically the same binding profile. The
benzodioxan 2e follows the same pattern, showing
increased affinity for both receptor subtypes.
Combinations of C-2 and C-4 substituents were
prepared in the hope of achieving simultaneous im-
provements in potency and selectivity. As a result, the
tolyl/dihydrobenzofuran combination 2f gave a highly
potent antagonist (ETA ) 0.78 nM) and improved
selectivity by nearly a factor of 3 (A/B ) 15 300)
Ta ble 1. SAR of Pyrrolidine-C-2 Aryl Modifications: Radioligand Binding
a
b
IC50 calculated using a mean of two measurements for 11 concentrations from 10-10 to 10-5 M unless otherwise noted. Standard
d
error of the mean. Expressed as IC50(ETA)/IC50(ETB).

Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3981
F igu r e 2.
compared to 2a . Adding a fluorine to 3-aryl of 2f
provides compound 8, a highly potent ET-A antagonist
(ETA ) 0.18 nM) which displays increased selectivity
over the ETB receptor (A/B ) 24 400). Our summary of
the functionality responsible for ETA versus ETB selec-
tivity is shown in Figure 2.
Ta ble 2. SAR of Non-Benzodioxole Analogues: Radioligand Binding
a
b
Binding to human endothelin receptors in CHO cells. Binding to MMQ cells, rETA(rat). c Expressed as pETB(porcine). n: Number
of determinations in parentheses. *The variation of IC50s from experiment to experiment is normally within 15%.

3982 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Ta ble 3. Pharmacokinetic Profiles of the Leading Compounds
J ae et al.
pharmacokinetic profiles (rats)a
log D (calc)
T1/2 iv (h)
T1/2 oral (h)
Cmax (µg/mL)
AUC (µg h/mL)
F (%)
1
2
8a
3.26
5.21
4.32
4.32
3.5 (( 1.93)b
1.6 (( 0.86)b
2.1 (( 1.03)b
4.7 (( 3.13)b
6.2 (( 3.62)b
2.5 (( 0.67)b
4.7 (( 2.10)b
5.8 (( 2.13)b
3.44 (( 1.77)b
1.69 ( 0.41c
1.84 ( 0.20c
0.93 ( 0.24c
7.36 (( 1.72)b
3.27 ( 0.45c
12.5 ( 2.2c
9.4 ( 1.3c
60.2 (( 14.0)b
47.7 ( 6.56c
71.7 ( 12.5c
65.6 ( 9.0c
8 (racemic)
a
T1/2 iv, half-life after intravenous dosing (5 mg/kg). T1/2 oral, Cmax, AUC, and F are half-life, maximum drug concentration, total drug
exposure (area under the curve), and oral bioavailability after oral dosing (10 mg/kg) in three rats. Standard deviation. c Standard error
b
of the mean.
pounds 1a -1d 15b and 2a -2e11 were reported. Unless otherwise
Com p ou n d Eva lu a tion s
specified, all solvents and reagents were obtained from com-
After synthesizing a series of very potent and highly
mercial suppliers and used without further purification. All
selective ETA antagonists with varying hydrophobicity
and hydrophilicity, a small set of compounds were
prepared in enantiomerically pure form to evaluate the
impact of this polarity swing on the pharmacokinetic
profiles of the compounds. These enantiomers were first
evaluated in our standard screening assay, which
employed a rodent ETA receptor derived from MMQ cells
(rETA) and ETB receptor (pETB) derived from porcine
cerebellar tissue. IC50 data are recorded by measuring
the displacement of [125I]ET-1 from ETA, or of [125I]ET-
3 from ETB, as well as in a second set of binding assays
employing human ETA and ETB receptors expressed in
CHO cells. Pharmacokinetic properties were examined
for the enantiomers of three leading ETA-selective
antagonists using a standard protocol which compares
the time course of plasma drug levels after dosing in
rats by intraveno injection and oral gavage (Table 3).
reactions were performed under nitrogen atmosphere unless
specifically noted. Flash column chromatography was done
using silica gel (230-400 mesh) from E. M. Science. H NMR
1
spectra were recorded at 300 MHz; all values are referenced
to tetramethylsilane as internal standard and are reported as
shift (multiplicity, coupling constants, proton count). Mass
spectral analysis is accomplished using fast atom bombard-
ment (FAB-MS) or direct chemical ionization (DCI-MS) tech-
niques. All elemental analyses are consistent with theoretical
values to within (0.4% unless indicated. Melting points were
measured on a Thomas-Hoover apparatus and are uncorrected.
Abbr evia tion s: DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene;
EtOAc, ethyl acetate; TFA, trifluoroacetic acid.
E t h yl 3-(3-F lu or o-4-m et h ylp h en yl)-3-oxo-p r op ion a t e
(3a ). A solution: Ethyl malonate potassium salt (3.27 g, 0.0219
mol) and MgCl2 (1.57 g, 0.0165 mol) was mixed in 32 mL of
THF stirred and heated at 65 °C for 4 h. B solution: To the
solution of 3-fluoro-4-methylbenzoic acid (2.5 g, 0.0165 mol)
in 18 mL of THF was added 1,1′-carbonyldiimidazole (3.15 g,
0.0194 mol) in portion and heated for 30 min. The B solution
added to A. The mixture was stirred overnight at room
temperature to allow a white solid to suspend. The flask was
cooled in an ice bath, and a dilute HCl solution (5 mL of
concentrated HCl and 10 mL of H2O) was added. EtOAc was
added to extract the product, and the organic layer was washed
with H2O and brine and dried over Na2SO4. Yield: 3.45 g
(95%). This crude product was used for the next step without
further purification.
Eth yl 2-(3-F lu or o-4-m eth ylben zoyl)-4-n itr o-3-(2,3-d i-
h yd r oben zofu r a n -5-yl)bu tyr a te (5a ). To a stirred solution
of the nitrostyrene (2.94 g, 0.0154 mol) in 26 mL of THF were
added the ketoester (3.45 g, 0.0154 mol) of 3a and 30 mg of
potassium tert-butoxide. The resulting mixture was warmed
to dissolve the nitro compound, and stirring was continued for
3.5 h at room temperature. To the mixture were added 5 drops
of concentrated HCl, water, and EtOAc to extract the product.
The organic layer was washed with water and brine and dried
over Na2SO4. This crude product (7.2 g) was used for next step
without further purification.
Eth yl tr a n s,tr a n s-2-(3-F lu or o-4-m eth ylp h en yl)-4-(2,3-
d ih yd r oben zofu r a n -5-yl)p yr r olid in e-3-ca r boxyla te (7).
The product of 5a (7.0 g, 16.87 mmol) in EtOAc (35 mL)
solution was added to a 250 mL pressure bottle containing
RaNi (16 g) which was washed with THF (4×) and with EtOAc
(3×), and the mixture was shaken on a Parr hydrogenator for
4 h at room temperature under 60 psi of H2. Then 2.6 mL of
TFA was added, and the mixture was shaken for 24 h under
H2. The mixture was filtered, and most of the solvent was
evaporated. Saturated NaHCO3 solution was added and
extracted with EtOAc (200 × 2), and the organic layers were
combined, washed with H2O and brine, and dried over Na2-
SO4 to give mostly cis,cis-isomer. This crude cis,cis-isomer (6.0
g, 16.26 mmol) was dissolved in toluene (50 mL), and 5.25 g
of DBU was added. The mixture was refluxed for 12 h for
epimerization. Solvent was evaporated and purified by silica
column chromatography to elute with hexane and EtOAc (3:
2) to give 4.2 g of trans,trans-isomer.
Resu lts a n d Discu ssion
Structure-activity studies reveal that the compound
8a is very potent and highly selective for ETA vs ETB
receptors, with a half-life of ∼5 h, AUC of 12.5 µg h/mL,
and oral bioavailability of >70% in rats. We note that
the half-life of the compound 8a is similar to that of 1.
This suggests that the o-demethylation is not a rate-
limiting metabolic event. However, replacement of the
4-OCH3 group with 4-OH is well tolerated and has a
little less binding affinity than 1. Our clinical studies
of 1 (Atrasentan) indicate a long half-life (28-32 h) in
humans, suggesting that these second-generation agents
should also have desirable profiles.
Con clu sion s
We have developed highly selective and very potent
ETA receptor antagonists to meet our back-up goal,
based on the pyrrolidine-3-carboxylic acid template.
Placement of a p-tolyl group at the 2-position and a
5-substituted dihydrobenzofuran at the 4-position of the
pyrrolidine was required for this high level of selectivity
for ETA. Introducing a fluorine at 3-aryl further in-
creases the binding affinity and improves the bioavail-
ablity. In addition, these analogues no longer contain a
benzodioxole moiety, eliminating any potential for in-
hibition cytochrome P450-enzymes (CYP 3A4). This type
of metabolism may lead to nonlinear pharmacokinetics.
The optimized analogue, A-306552 (8a ), is a promising
compound to meet our back-up goal as a ETA-selective
antagonist.
Exp er im en ta l Section
Gen er a l. Compounds were prepared in a previous fashion
tr a n s,tr a n s-2-(3-F lu or o-4-m et h ylp h en yl)-4-(2,3-d ih y-
d r ob en zofu r a n -5-yl)-1-(N,N-d ib u t yla m in oca r b on ylm e-
analogous to substituting the appropriate aldehyde.11 Com-

Pyrrolidine-3-carboxylic Acids as Endothelin Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3983
th yl)-p yr r olid in e-3-ca r boxylic Acid (8). This final com-
pound was prepared by hydrolysis of the product from a
reaction of 7 and N,N-di-n-butyl bromoacetamide with diiso-
propylethylamine in CH3CN:10a white solid; 1H NMR (300
MHz, CD3OD) δ 0.82 (t, J ) 7.5 Hz, 3H), 0.88 (t, J ) 7.5 Hz,
3H), 1.09 (sextet, J ) 7.5 Hz, 2H), 1.20-1.35 (m, 3H), 1.37-
1.52 (m, 3H), 2.25 (s, 3H), 2.86-2.96 (m, 2H), 3.03-3.12 (m,
2H), 3.20 (t, J ) 9 Hz, 3H), 3.32-3.50 (m, 4H), 3.62 (sextet, J
) 4.5 Hz, 1H), 3.83 (d, J ) 9 Hz, 1H), 4.53 (t, J ) 9 Hz, 2H),
6.67 (d, J ) 7.5 Hz, 1H), 7.08-7.15 (m, 3H), 7.21 (t, J ) 7.5
Hz, 1H), 7.30 (s, 1H); MS (ESI) m/e 511 (M + H)+. Anal.
(C30H39N2FO4‚0.25H2O) C, H, N.
Resolu tion of Ra cem ic Com p ou n d 7a . To the racemic
compound (3.69 g, 10 mmol), dissolved in 25 mL of dichloro-
methane and cooled in an ice bath, was added di-tertert-butyl
dicarbonate (2.40 g, 11 mmol). After being stirred for 2 h at
room temperature, the solution was concentrated in vacuo; the
residue was dissolved in ethanol (20 mL) and treated with a
solution of 400 mg of NaOH in 5 mL of water. The solution
was stirred for 2 h at room temperature, concentrated, and
redissolved in 40 mL of water. The resultant mixture was
extracted with 25 mL of diethyl ether; the ether layer was
extracted with 10 mL of water. The combined aqueous phases
were acidified with acetic acid; the mixture was stirred until
a solid formed. The solid was filtered, washed with water, and
dried in vacuo. The product was recrystallized from 1:1 ether-
hexane to get 3.97 g (90% yield). The crude acid (1.76 g, 3.99
mmol) was dissolved in 60 mL of dry ether and treated with
484 mg (3.99 mmol) of (R)-(+)-R-methylbenzylamine. The
solution was kept in a freezer overnight. A white crystal was
collected and washed with ether to give 1.55 g (69%), mp 163-
165 °C. Mother liquid was left at room temperature to give
more crystal (590 mg, 26%), mp 125-126 °C. The first crop
was recrystallized from EtOAc. After one recrystallization,
chiral HPLC analysis, using a Regis Whelk-O column, indi-
cated >98.0% ee. All mother liquids were combined, and the
amine was washed out, treated with 0.5 equiv of (R)-(+)-R-
methylbenzylamine, crystallized from EtOAc (89% ee), and
recrystallized from CH3CN (99% ee).
2.92 (m, 2H), 3.08 (m, 2H), 3.20 (t, J ) 9 Hz, 2H), 3.32-3.49
(m, 5H), 3.60 (m, 1H), 3.83 (d, J ) 9 Hz, 1H), 4.53 (t, J ) 9
Hz, 2H), 6.67 (d, J ) 9 Hz, 1H), 7.13 (m, 3H), 7.25 (t, J ) 7.5
Hz, 1H), 7.32 (s, 1H). MS (ESI) m/z 525 (M + H)+. Anal.
(C31H41N2FO4) C, H, N.
tr a n s,tr a n s-2-(3-Flu or o-4-eth ylp h en yl)-4-(1,4-bezod iox-
an -6-yl)-1-(N,N-dibu tylam in ocar bon ylm eth yl)-pyr r olidin e-
3-ca r boxylic a cid (9a ): white solid; 1H NMR (300 MHz,
CD3OD) δ 0.82 (t, J ) 7.5 Hz, 3H), 0.88 (t, J ) 7.5 Hz, 3H),
1.07 (sextet, J ) 7.5 Hz, 2H), 1.20 (t, J ) 7.5 Hz, 3H), 1.28 (m,
3H), 1.45 (m, 3H), 2.65 (q, J ) 7.5 Hz, 2H), 2.83 (d, J ) 12 Hz,
1H), 2.92 (dd, J ) 9 Hz, 9 Hz, 1H), 3.06 (m, 3H), 3.34 (m, 1H),
3.49 (m, 4H), 3.77 (d, J ) 9 Hz, 1H), 4.22 (s, 4H), 6.77 (d, J )
7.5 Hz, 1H), 6.85 (dd, J ) 7.5 Hz, 2 Hz, 1H), 6.96 (d, J ) 2 Hz,
1H), 7.11 (m, 2H), 7.34 (t, J ) 7.5 Hz, 1H). MS (ESI) m/z 541
(M + H)+. Anal. (C31H41N2FO5) C, H, N.
tr a n s,tr a n s-2-(4-Meth ylp h en yl)-4-(2,3-d ih yd r oben zofu -
r a n -5-yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr r oli-
d in e-3-ca r boxylic Acid (2f): white solid; 1H NMR (300 MHz,
CDCl3) δ 0.83 (t, J ) 9 Hz, 3H), 0.95 (t, J ) 9 Hz, 3H), 1.14
(m, 2H), 1.32 (m, 4H), 1.53 (m, 2H), 2.37 (s, 3H), 2.98 (m, 2H),
3.22 (m, 2H), 3.38 (m, 2H), 3.59 (m, 1H), 3.70-4.30 (m, 4H),
4.56 (t, J ) 12 Hz, 2H), 5.45 (m, 1H), 6.72 (d, J ) 8 Hz, 2H),
7.22 (m, 3H), 7.60 (m, 3H); MS (DCI/NH3) m/z 493 (M + H)+.
Anal. (C30H40N2O4‚1.25TFA) C, H, N.
tr a n s,tr a n s-2-(4-Eth ylp h en yl)-4-(2,3-d ih yd r oben zofu -
r a n -5-yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr r oli-
d in e-3-ca r boxylic a cid (2g): white solid; 1H NMR (300 MHz,
CDCl3) δ 7.40 (m, 3H), 7.22 (d, J ) 8 Hz, 2H), 7.13 (dd, J ) 8
and 3 Hz, 1H), 6.72 (d, J ) 9 Hz, 1H), 5.28 (d, J ) 12 Hz, 1H),
4.55 (t, J ) 9 Hz, 2H), 4.15 (d, J ) 18 Hz, 1H), 4.03 (m, 2H),
3.75 (m, 2H), 3.40 (m, 2H), 3.20 (t, J ) 9 Hz, 2H), 3.15 (m,
1H), 3.10-2.90 (m, 2H), 2.63 (q, J ) 9 Hz, 2H), 1.47 (m, 2H),
1.31 (m, 4H), 1.12 (t, J ) 8 Hz, 3H), 1.10 (m, 2H), 0.92 (t, J )
9 Hz, 3H), 0.80 (t, J ) 9 Hz, 3H); MS (DCI/NH3) m/z 507 (M
+ H)+. Anal. (C31H42N2O4‚1TFA) C, H, N.
tr a n s,tr a n s-2-(4-E t h ylp h en yl)-4-(1,4-b en zod ioxa n -6-
yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr r olid in e-3-
ca r boxylic a cid (2h ): white solid; 1H NMR (300 MHz,
CD3OD) δ 0.95 (t, J ) 7 Hz, 3H), 1.03 (t, J ) 7 Hz, 3H), 1.18
(q, J ) 7 Hz, 2H), 1.37 (t, J ) 7 Hz, 3H), 1.42 (m, 3H), 1.58
(m, 3H), 2.78 (q, J ) 7 Hz, 2H), 3.18 (m, 4H), 3.30 (t, J ) 8
Hz, 1H), 3.56 (m, 3H), 3.70 (d, J ) 10 Hz, 1H), 3.73 (m, 1H),
4.08 (d, J ) 8 Hz, 1H), 4.38 (s, 4H), 6.93 (d, J ) 7 Hz, 1H),
7.03 (dd, J ) 1.5 and 7 Hz, 1H), 7.13 (d, J ) 1.5 Hz, 1H), 7.37
(d, J ) 8 Hz, 2H), 7.50 (d, J ) 8 Hz, 2H); MS (APCI) at m/z
523 (M + H)+. Anal. (C31H42N2O5‚1.1HOAc) C, H, N.
tr a n s,tr a n s-2-(3,4-Dim eth oxyph en yl)-4-(1,3-ben zodioxol-
5-yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr r olid in e-
3-ca r boxylic a cid (1e): white solid; 1H NMR (CDCl3, 300
MHz) δ 0.80 (t, J ) 7 Hz, 3H), 0.88 (t, J ) 7 Hz, 3H), 1.05 (q,
J ) 7 Hz, 2H), 1.26 (m, 4H), 1.44 (q, J ) 7 Hz, 2H), 2.83 (d, J
) 13.5 Hz, 1H), 2.98 (m, 3H), 3.12(t, J ) 9 Hz, 1H), 3.25 (m,
1H), 3.45 (m, 3H), 3.62 (m, 1H), 3.82 (s, 3H), 3.86 (s, 4H), 5.94
(s, 2H), 6.73 (d, J ) 7.5 Hz, 1H), 6.80 (d, J ) 7.5 Hz, 1H), 6.92
(m, 3H), 7.06 (s, 1H); MS (DCI/NH3) (M + H)+ at m/z 541. Anal.
(C30H40N2O7‚0.5H2O) C, H, N.
Refer en ces
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tr a n s,tr a n s-2-(3-F lu or o-4-m eth oxyp h en yl)-4-(1,3-ben -
zod ioxol-5-yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr -
r olid in e-3-ca r boxylic a cid (1f): white solid; 1H NMR (CDCl3,
300 MHz) δ 0.82 (t, J ) 7 Hz, 3H), 0.88 (t, J ) 7 Hz, 3H), 1.10
(q, J ) 7 Hz, 2H), 1.25 (m, 3H), 1.43 (m, 3H), 2.82 (d, J ) 13.5
Hz, 1H), 2.93 (dd, J ) 7.5 Hz, 1H), 3.06 (m, 3H), 3.28 (m, 1H),
3.40 (d, J ) 13.5 Hz, 1H), 3.94 (m, 2H), 3.61 (m, 1H), 3.82 (d,
J ) 7.5 Hz, 1H), 3.88 (s, 3H), 5.93 (s, 2H), 6.72 (d, J ) 8 Hz,
1H), 6.88 (m, 2H), 7.00 (s, 1H), 7.12 (m, 2H); MS (DCI/NH3)
(M + H)+ at m/z 529. Anal. (C29H37N2FO6) C, H, N.
tr a n s,tr a n s-2-(3,4-Diflu or op h en yl)-4-(1,3-ben zod ioxol-
5-yl)-1-(N,N-d ibu tyla m in oca r bon ylm eth yl)-p yr r olid in e-
3-ca r boxylic a cid (1g): white solid; 1H NMR (CDCl3, 300
MHz) δ 0.82 (t, J ) 7 Hz, 3H), 0.90 (t, J ) 7 Hz, 3H), 1.15 (q,
J ) 7 Hz, 2H), (m, 3H), 1.44 (m, 3H), 2.90 (m, 2H), 3.03-3.18
(m, 4H), 3.42 (m, 3H), 3.63 (m, 1H), 4.96 (d, J ) 9 Hz, 1H),
5.93(s, 2H), 6.75 (d, J ) 7.5 Hz, 1H), 6.87 (d, J ) 7.5 Hz, 1H),
6.98 (s, 1H), 7.12 (m, 2H), 7.26 (m, 1H); MS (APCI) (M + H)+
at m/z 517. Anal. (C28H34N2F2O5) C, H, N.
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