HIV protease inhibitory bis-benzamide cyclic ureas: A quantitative structure-activity relationship analysis

Article abstract of DOI:10.1021/jm9602773

A series of N,N'-disubstituted cyclic urea 3-benzamides has been synthesized and evaluated for HIV protease inhibition and antiviral activity. Some of these benzamides have been shown to be potent inhibitors of HIV protease with K(i) < 0.050 nM and IC₉₀ < 20 nM for viral replication and, as such, may be useful in the treatment of AIDS. The synthesis and quantitative structure activity relationship for this benzamide series will be discussed.

Full text of DOI:10.1021/jm9602773

J . Med. Chem. 1996, 39, 4299-4312
4299
HIV P r otea se In h ibitor y Bis-ben za m id e Cyclic Ur ea s: A Qu a n tita tive
Str u ctu r e-Activity Rela tion sh ip An a lysis
Wendell W. Wilkerson,* Emeka Akamike, Walter W. Cheatham, Andrea Y. Hollis, R. Dale Collins,
Indawati DeLucca, Patrick Y. S. Lam, and Yu Ru
DuPont Merck Pharmaceutical Company, Chemical and Physical Sciences, E500/ 3203 Experimental Station,
P.O. Box 80500, Wilmington, Delaware 19880-0500
Received April 10, 1996X
A series of N,N′-disubstituted cyclic urea 3-benzamides has been synthesized and evaluated
for HIV protease inhibition and antiviral activity. Some of these benzamides have been shown
to be potent inhibitors of HIV protease with Ki < 0.050 nM and IC90 < 20 nM for viral replication
and, as such, may be useful in the treatment of AIDS. The synthesis and quantitative
structure-activity relationship for this benzamide series will be discussed.
In tr od u ction
The viral-encoded protease for human immunodefi-
ciency virus (HIV) is responsible for the processing of
viral polyprotein precursors to their mature polypep-
tides. Since correct processing of the viral polypeptides
is essential for the production of infectious virus, HIV
protease represents a potential target for therapeutic
agents which may prove beneficial in the treatment of
AIDS.1
We had previously determined (data not included)
that for the cyclic ureas,2-4 the best HIV protease
inhibitors (Figure 1) resulted when P2 and P2′ were
substituted benzyl (-CH2-Ph-X), where the regiochem-
istry of X showed that the 3-isomer produced a better
inhibitor than the 4-isomer that was far superior to the
2-isomer. We further determined that a hydrogen bond-
F igu r e 1. Lead progression to the carboxamides.
donating (HBD) X produced a more potent HIV protease
the antiviral activity of the benzamide series by apply-
ing classic quantitative structure-activity relationship
(QSAR) techniques.
inhibitor than the corresponding hydrogen bond accep-
tor (HBA). The importance of the HBD was demon-
strated early in the project as illustrated by the com-
parison between the highly potent secondary amide 6
(X ) CONHMe, Ki ) 0.066 nM) and the corresponding
amide 31 (X ) CON(Me)2, Ki ) 1.900 nM) (see Table
1). The implication was that a HBD was necessary but
not sufficient for potent Ki. Examination of other
physicochemical characteristics suggested that Ki is
related to the lipophilicity of the inhibitor (ClogP), the
electronic effect of the X-substituent (σ), and the hy-
drogen-bonding character [HB] of X. This relationship
can be expressed by eq 1:
Ch em istr y
Structures, methods of amide bond formation, and
corresponding physical data for the compounds in this
study are shown in Table 1. For this study, 2 was
synthesized from the corresponding nitrile using the
method described by Noller5 (see Scheme 1). Most of
the other compounds in this study were synthesized by
activating the carboxyl group of the cyclic ureas bis-
benzoic acid (1c, see Scheme 2) followed by reaction with
the appropriate amine (R-NH2).
-log(Ki) ) a(ClogP) + b(σX) + c[HB] + C (1)
Carboxyl-activating conditions involved reaction with
N,N′-dicyclohexylcarbodiimide (DCC) and N-hydroxy-
benzotriazole (HOBt) (DCC-HOBt method), reaction
with (benzotriazol-1-yloxy)tris(dimethylamino)phospho-
nium hexafluorophosphate (BOP, Castro’s reagent),6 or
oxalyl chloride. The ‘Acid Chloride Method’, when
conducted with oxalyl chloride under extremely anhy-
drous conditions, was able to effect some of the more
difficult acylations. These approaches are illustrated
in Scheme 3. Most of the syntheses, where R was
aromatic, were accomplished with difficulty as evi-
denced by extremely long reaction times and poor yields
(data not included). We believe that these results were
caused by the poor nucleophilicity of the amine (R-NH2).
By chromatographic methods (TLC and HPLC), we were
able to observe the rapid formation of HOBt active ester.
where X ) H, 3- and 4-alkyl, aryl, substituted aryl, CF3,
OR, OCF3, CN, NO2, F, Cl, Br, I, OH, CHO, COR′,
CO2Me, CO2H, CONH2, CONHR′, CH2OH, NH2, NHR′,
NHAc, SR, SOnR′, and B(OH)2.
One of the compounds discovered early in this work
was 2 (X ) CONH2). The benzamide 2 was found to
have excellent protease inhibitory activity (Ki ) 0.039
nM) but was determined to have poor antiviral activity
(IC90 ) 708.6 nM). This study was initiated in an
attempt to improve on both the protease inhibition and
* Address for correspondence: Dextron Corp., P.O. Box 713, Bear,
DE 19710-0713.
S0022-2623(96)00277-4 CCC: $12.00 © 1996 American Chemical Society

4300 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
Ta ble 1. Pharmacological, Structural, and Physical Chemical Data for Compounds 2-31
a
*Ki SD <(40%. **IC90 SD <(36%. BOP, (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DCC-HOBt,
N,N′-dicyclohexylcarbodiimide and N-hydroxybenzotriazole; acid chloride with oxalyl chloride; WSC, 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (water soluble carbodiimide); Weinreb, reaction of the amine with trimethylaluminum followed by reaction
b
with 1b. All compounds except 28 were analyzed for C, H, and N, and analytical results were within (0.4% of the theoretical values.
c The only disubstituted amide in the data set and was not used in any of the regression models.
Sch em e 1. Synthetic Approach to 2
column chromatography and fully characterize repre-
sentative samples of the HOBt ester and the mixed
HOBt ester-amide.
Carboxyl activation through the N-hydroxysuccini-
mide ester(s) has also been attempted to find the ester-
(s) even more resistant to amide formation. Amide bond
formation with poorly nucleophilic amines was ac-
complished in moderate to good yields by activation of
the amine using a modification of the method reported
by Basha et al.7 The ester 1b was reacted with excess
dimethylaluminum amide ((CH3)2AlNHR) prepared from
equal molar amounts of trimethylaluminum ((CH3)3Al)
and the amine (R-NH2) in dichloroethane and refluxing
until chromatographic methods indicated no 1b re-
mained. The method is illustrated in Scheme 4 and is
referred to as the Weinreb method. However, this
approach was unsuccessful in cases where the amine-
complex was insoluble in dichloroethane. Compound 12
However, acylation of the amine was extremely slow and
incomplete in some cases. We were able to isolate by

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4301
Sch em e 2. Synthetic Approach to the Ester 1b and the
Carboxylic Acid 1c
of gag p24 and recombinant HIV protease (PR) as
described by Erickson-Viitanen et al.9 Ki values were
measured with 62.5-250 pM HIV PR dimer and 1-10
nM inhibitor. Each compound was assayed at least
twice, and the mean values for the experimental com-
pounds are reported in Table 1. The standard deviation
(SD) for the assay has been found to be <(40%. The
Ki values for a series of reference compounds are also
included in Table 1.
HIV RNA Assa y.10 This assay determines cell-
associated viral RNA levels 3 days after infection of
susceptible T-cell lines grown in individual microtiter
wells. Viral RNA was quantified by a sandwich hybrid-
ization assay; the first step of which was performed
directly in crude infected cell lysates prepared in
quinaldinium isothiocyanate. Levels of cell-associated
viral RNA were shown to correlate with the yield of
infectious virus, and this correlation formed the basis
of the test. Antiviral potencies of a large series of
compounds tested in this RNA hybridization assay
correlated closely with potency values determined by a
sensitive but slower and more labor-intensive yield
reduction assay. Both laboratory strains and selected
clinical isolates of HIV can be detected in this RNA
hybridization assay. Results are reported as IC90 (the
concentration of antiviral compound required to inhibit
HIV RNA synthesis by 90%). Initial results are re-
ported in nanomolar (nM) for structure-activity rela-
tionship (SAR) studies (Table 1). The assay provides a
rapid, high-capacity assay for evaluating the potency
of anti-HIV compounds. The standard deviation (SD)
for the assay has been found to be <(37%. The data
obtained on reference compounds are listed in Table 1.
Cytotoxicity TC50. Compound cytotoxicity was des-
ignated as TC50 which is defined as the concentration
of compound that produced a 50% reduction in the
number of viable cells as determined by the metabolism
of a tetrazolium dye. None of the compounds in this
study had TC50 < 50 µg/mL. A correct interpretation
of the RNA assay requires that test molecules not be
cytotoxic at RNA assay dose levels.
Sch em e 3. Activated Carbonyl Approaches to the
Benzamides
Sta tistica l Meth od s a n d QSAR P a r a m eter s
Sch em e 4. Synthetic Approach to the Amides Using a
Modification of the Weinreb Procedure
Statistical analyses were conducted using J MP v3.0.2
by SAS Institute, Cary, NC. The statistical measures
used are as follows: n, number of samples in the
regression; r, correlation coefficient; s, root mean square
error of the regression; and F-ratio.
Computer-generated lipophilicity of the molecule
(ClogP) and bulk (CMR) were obtained using MedChem
Software v3.0, Pomona College, Claremont, CA. Many
of the parameters for the R-groups in Table 1 were not
available from literature sources, which required us to
derive other parameters that could be easily obtained
and used in our attempt to derive QSAR expressions
for protease inhibition (Ki) and viral replication (IC90).
The hydrogen-bonding property of the R-group was
indicated by hydrogen bond donor (HBD), (1, 1); hydro-
gen bond acceptor (HBA), (0, 1); and neither (0, 0). The
parameters for ionization potential (IP), energy of the
highest occupied orbital (ꢀHOMO), energy of the lowest
unoccupied orbital (ꢀLUMO), and molecular volume (MV)
were obtained using SYBYL v6.2 by Tripose Associates,
Inc., St. Louis, MO, on a Silicon Graphics workstation.
The molecules were minimized with Gasteiger Huckel
was synthesized by the mixed anhydride method utiliz-
ing ethyl chloroformate and 1c.
P h a r m a cology
The Ki values were determined with recombinant
single-chain dimeric HIV protease and a fluorescent
substrate (see Cheng et al.8). The use of single-chain
dimeric protease allows enzyme concentrations as low
as 0.0625 nM to be used. Reaction products were
separated by HPLC with a Pharmacia Mono Q anion-
exchange column, and the product was quantified by
fluorescence. The ability of test compounds to block
cleavage of the HIV-1 gag polyprotein was assessed with
[35S]methionine-labeled in vitro translation product
corresponding to gag p17 plus the first 78 amino acids

4302 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
Ta ble 2. Substituent Constants21 Used in Deriving Regression Eq 2 for HIV Protease Inhibitors 2-15a
compd
R
π
MR
σI
σ*
F
R
L1
B1
B5
log(1/Ki)
2
3
4
5
6
7
8
9
H
NH2
OH
OCH3
CH3
CH2CH3
CH(CH3)2
CH2CH2CH3
CH2CH2CH2CH3
C(CH3)3
CH2-C3H5
CH2CF3
CH2CN
0.00
-1.23
-0.67
-0.02
0.56
1.02
1.53
1.55
2.13
0.10
0.54
0.28
0.79
0.56
1.03
1.50
1.50
1.96
1.96
1.82
0.97
1.01
2.54
2.30
2.30
0.00
0.12
0.29
0.49
0.62
1.37
1.77
0.00
-0.10
-0.19
-0.12
-0.13
-0.30
0.01
0.00
0.08
0.33
0.29
0.01
0.00
0.04
0.01
-0.01
-0.02
nd
0.15
0.17
0.12
0.21
0.40
0.00
-0.74
-0.70
-0.56
-0.18
-0.15
-0.19
-0.14
-0.15
-0.18
nd
-0.06
0.01
-0.13
0.23
-0.23
2.06
2.78
2.74
3.98
2.87
4.11
4.11
4.92
6.17
4.11
5.14
4.70
3.99
6.28
5.92
6.28
1.00
1.35
1.35
1.35
1.52
1.52
1.90
1.52
1.52
2.60
1.52
1.52
1.52
1.71
1.71
1.71
1.00
1.97
1.93
3.07
2.04
3.17
3.17
3.49
4.54
3.17
4.36
3.07
4.12
3.11
3.11
3.11
1.409
1.745
1.699
1.347
1.180
0.678
0.237
0.445
0.373
-0.380
0.130
0.678
1.201
0.367
0.27
-0.04
-0.01
0.01
-0.01
-0.04
-0.07
nd
0.16
nd
0.12
0.24
10
11
12
13
14
15
hypo- 1
hypo- 2
1.98
(1.39)
(1.80)
-0.57
1.96
0.46
0.50
0.92
1.25
0.60
Ph
4-Pyr
2-Pyr
0.40
a
Parentheses indicate not in the regressions, calculated from ClogP: π ) 0.644ClogP - 2.609; n ) 12, r2 ) 0.927, SE ) 0.332, F )
126.618.
Ta ble 3. Cross-Correlation Matrix for the Parameters in Eq 2
interest because of the possibility of influencing the
lipophilicity, size, and/or electronic effects by making
appropriate aromatic substitutions. Unfortunately, none
of the analogues (3-15) of 2 met our antiviral criteria
of an IC90 < 30.0 nM; only 6 (R ) CH3, IC90 ) 80.5 nM)
and 13 (R ) CH2CF3, IC90 ) 92.5 nM) came close.
variable
π
F
B1
π
1.000
-0.530
1.000
0.620
-0.300
1.000
F
B1
In an attempt to determine the optimal regiochem-
istry of the aromatic nitrogen in the pyridine moiety,
we synthesized the three isomeric pyridine derivatives
hypo-1 ) 16 (where R ) 4-Pyr), 17 (where R ) 3-Pyr),
and hypo-2 ) 18 (where R ) 2-Pyr). The isomeric
pyridine cyclic ureas had the same ClogP (6.70) and
CMR (21.64). However, as protease inhibitors, 18 (Ki
) 0.043 nM) was better than 17 (Ki ) 0.290 nM) which
was better than 16 (Ki ) 0.410 nM). These results were
very different from those predicted by eq 2. Unexpect-
edly, 18 had met our biological objectives. On the basis
of these teachings, we concluded that the presence and
regiochemistry of a potential hydrogen bond acceptor
(pyridyl nitrogen) contributed to overall protease inhibi-
tion which in turn influenced viral replication inhibition.
The best location for this HBA is ortho to the amide
nitrogen as represented by 18 (2-Pyr) (see Figure 2). It
is possible that the pyridyl nitrogen is acting as a base
to form a salt bridge, influence the ‘quality’ of hydrogen-
bonding properties of the amide proton, or influence the
pKa of the amide proton. Clearly the nitrogen is
important as demonstrated by the contrast in activity
charge, and the minimized structures were given MO-
PAC v5.011 charges (AM1, mmok, parasok, Mulliken
atomic charge population).12,13
Discu ssion
Because of the potent antiprotease activity of 2 (R )
H, Ki ) 0.039 nM), a small set of amides (2-15) was
synthesized and evaluated for antiprotease (Ki) and
antiviral (IC90) activity. For protease inhibitory activity
(log 1/Ki), the substituent constants (see Table 2) for
lipophilicity (π and π2), size, bulk, volume, or sterics
(MR, MR2, and STERIMOL parameters L1, B1, and B5),
and electronic effects (σI, σ*, Swain-Lupton’s F and R14)
were subjected to a stepwise ‘multiple linear regression’
(MLR) analysis. The result from this analysis was eq
2 which suggested that the π, F, and B1 for the R-group
log(1/Ki)2-15 ) -0.337((0.044)π +
0.591((0.382)F - 0.739((0.125)B1 +
2.210((0.192) (2)
n ) 13, r ) 0.983, s ) 0.134, F3,10 ) 87.945(0.0001)
of the phenylcarboxamide 15 (Ki ) 0.370 nM, IC90
)
483.0 nM) and the 2-pyridinyl derivative 18 (Ki ) 0.043
nM, IC90 ) 2.8 nM). Since the only difference among
the three isomers was the placement of the pyridinyl
nitrogen, it is possible that the nitrogen of the 2-pyridine
defined a new binding site with the enzyme as il-
lustrated in Figure 2b. This potential HBA resulted in
greater than predicted protease inhibition.
were important to activity. The cross-correlation matrix
for the parameters in eq 2 is shown in Table 3.
Equation 2 suggested that decreasing lipophilicity,
increasing the inductive effects, and keeping the B1 as
small as possible will result in increased activity.
Subsequent analyses showed that σI and σ* could
replace F without a loss in the significance of eq 2. Note
that Martin15 has reported that σ*, F, and R are related.
The lack of a quadratic term for π and/or MR in eq 2
further suggested that this data set did not contain
R-groups near the optima for these parameters.
Using these characteristics described by eq 2 as a
guide, we prepared a data set of hypothetical compounds
where the substituent parameters in Table 2 existed in
the literature.16-18 In this hypothetical data set were
the isomeric pyridines hypo-1 (where R ) 4-Pyr) and
hypo-2 (where 2-Pyr) with predicted Ki values of 0.122
and 0.097 nM, respectively. The pyridines were of
Having established that the 2-Pyr moiety produced
the best anti-HIV activity, we next investigated the
effect of substitutions on the 2-Pyr nucleus. A series of
2-picoline carboxamides (19, R ) 2-(3-Me-Pyr); 20, R )
2-(4-Me-Pyr); 21, R ) 2-(5-Me-Pyr); and 22, R ) 2-(6-
Me-Pyr)) was synthesized and evaluated. As can be
seen in the data in Table 1, moving the methyl group
from the 3-position to the 6-position resulted in im-
provements in Ki and IC90. All four isomers have the
same CMR, and only 19 has a different ClogP (6.08)
from the other picolines (ClogP ) 7.70). Pharmacologi-

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4303
2-(3,5-di-Cl-Pyr)) because of the electron-withdrawing
substituents. In terms of protease inhibition, 24 (Ki )
0.012 nM) < 26 (Ki ) 0.035 nM) , 25 (Ki ) 0.245 nM),
and similarly for viral replication, 24 (IC90 ) 14.7 nM)
< 26 (IC90 ) 28.2 nM) < 25 (IC90 ) 43.0 nM). The large
drop-off in Ki for 25 may be associated with the ‘steric
hindrance’ caused by the 3-Cl substituent. For this
small data set, we concluded that the introduction of
an electron-withdrawing group on the azine did not
enhance activity.
a
A comparison between 15 (R ) Ph, Ki ) 0.370 nM,
IC90 ) 483.0 nM), 29 (R ) Prz, Ki ) 0.034 nM, IC90
)
3.5 nM), 30 (R ) 2-Pym, Ki ) 0.152 nM, IC90 ) 220.3
nM), and 18 (R ) 2-Pyr, Ki ) 0.043 nM, IC90 ) 2.8 nM)
further demonstrated that the nitrogen in the R-group
was important for activity. The pharmacological dif-
ference between 29 and 30 was the first indication that
ClogP and CMR may not be the main contributors to
activity since both compounds had ClogP ) 5.36 and
CMR ) 21.21. These two diazines differed only in the
placement of the nitrogens in the aromatic nucleus
which may contribute to different degrees of binding to
the enzyme which resulted in different Kis. The Prz
derivative was a better protease inhibitor than the Pym
derivative, and 29 was a significantly better inhibitor
of replication than 30. These results were added
evidence that the placement of the nitrogen(s) in R was
important for both enzyme inhibition and viral replica-
tion inhibition.
QSAR for log(1/Ki). One of the major problems
encountered in this study was the lack of published
substituent constants for the R-groups which could be
used in a classical (traditional) QSAR. What was
needed was a set of parameters such as ClogP and CMR
that could be calculated (semiempirical) and used in a
multiple linear regression (MLR) analysis.21-23 By
using geometry-optimized structures, we were able to
generate a set of quantum mechanical constants for
ionization potential (IP), energy of the highest occupied
orbital (ꢀHOMO), energy of the lowest unoccupied orbital
(ꢀLUMO), dipole moment (DM), and molecular volume
(MV/100 and (MV/100)2), where ꢀHOMO ) -IP and ꢀLUMO
) electron affinity (EA). Because we believed that the
regiochemistry of the 2-Pyr nitrogen was important for
activity, an indicator variable (I) was added to regres-
sion models for all compounds containing a nitrogen
approximating that of the 2-Pyr nitrogen. These pa-
rameters along with the molecular parameters ClogP2,
ClogP, CMR2, and CMR were used in a stepwise MLR
to derive regression equations for Ki and IC90 for the
carboxamides 2-30. This analysis produced eq 3 (see
b
F igu r e 2. (a) Proposed interactions between 18 and HIV
protease active site and (b) proposed interaction between the
enzyme active site and (i) isomeric pyridine nitrogen and (ii)
3-substitution on the pyridine ring.
cally, 19 was determined to be different from the other
three isomers. (Note that from this series and other
carboxamides (not reported), the relationship between
isomerism and potency is as follows: 6-Me g 5-Me >
4-Me . 3-Me.) The results from the picoline series
suggested that a pocket existed (size and/or lipophilicity
limiting) as defined by the 5-position on the pyridine
ring (see Figure 2b). The less than anticipated activity
of 25 (R ) 3,5-di-Cl-Pyr) was further evidence for this
conclusion. The importance of this structural property
of the inhibitors was exemplified by the improvement
in protease inhibition by 21 (R ) 2-(5-Me-Pyr)) over 18
(R ) 2-Pyr).
Replacing the -CH3 of 20 with -CF3 of 28 resulted in
a loss of protease (Ki ) 0.027 vs 0.085 nM) and antiviral
(IC90 ) 7.70 vs 63.4 nM) potencies. The change resulted
in an increase in ClogP (18%), a smaller increase in
CMR (5%), and an upfield chemical shift of 0.51 ppm
for the amide proton. All individually or in combination
could be responsible for the reduction in potencies. The
replacement of -H on 30 (Ki ) 0.152 nM, IC90 ) 220.3
nM) with -CH3 produced 27 (Ki ) 0.085 nM, IC90 ) 124.4
nM), which was a better anti-HIV compound. Increas-
ing the size and lipophilicity of 18 with two methyl
groups to give 23 or by adding one methyl to 20 or 21
to give 23 did not significantly change Ki or IC90 values.
These results would suggest that for a given Ki, increas-
ing lipophilicity while decreasing or maintaining the size
of the R-group should improve translation (viral replica-
tion inhibition).
log(1/Ki)2-30 ) -1.273((0.512)IP +
0.076((0.021)ClogP2 - 0.866((0.270)ClogP -
1.006((0.330)MV/100 + 0.990((0.184)I +
20.770((5.267) (3)
ClogP0 ) 5.697, n ) 29, r ) 0.864, s ) 0.349,
F5,23 ) 13.495(0.0001)
Chart 1) which contained the parameters for lipophi-
licity (ClogP2 and ClogP), volume (MV/100), electronic
(IP), and the indicator variable (I). The cross-correlation
matrix for eq 3 is shown in Table 5. The comparison of
the predicted Ki values from eqs 3 and 2 was in good to
excellent agreement (n ) 13, r2 ) 0.797, s ) 0.278).
Compounds 19-23 are less electron deficient than 24
(R ) 2-(5-Cl-Pyr), 26 [R ) 2-(5-Br-Pyr)], and 25 (R )

4304 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
Ch a r t 1. Found vs Predicted Protease Inhibition Using
Eq 3
related to the ability of the compound to inhibit HIV
protease (Ki) and the volume (CMR) and lipophilicity
(ClogP) of the amide substituent (R). Increasing inhibi-
tor lipophilicity while decreasing molecular size im-
proved IC90. The SAR also showed that the amide
substituent should contain a hydrogen bond acceptor
whose position was best represented by the nitrogen in
2-pyridine. This represented one of the more important
findings from this study: the identification of an ad-
ditional binding site (hydrogen bond acceptor) as defined
by the location of the nitrogen in the 2-pyridyl series.
This inhibitor property was represented in the QSAR
equations by an indicator variable, I. The finding has
been extended to other heteroaromatic series with a
hydrogen bond acceptor ortho to the amide nitrogen.
The ability to develop a robust traditional QSAR for
protease inhibition was limited because of the lack of
available substituent constants for the R-group. Be-
cause of this limitation, the predictive value of the
QSAR was limited. Because of this limitation, we chose
to investigate the use of semiempirical constants to
develop the QSARs. Because the biological evaluation
of the compounds was faster than the synthesis of the
compounds, we were in need of structure-activity
information to facilitate our choices for synthetic targets.
The results from these studies have been instrumental
in our understandings of the enzyme-inhibitor interac-
tions and have been applied successfully to the discovery
of even more potent cyclic ureas. This study has also
been used to better understand the pharmacokinetics,
toxicity, and drug resistance profile of the anti-HIV
cyclic ureas and in the selection of other potential drug
development candidates.
In an attempt to develop a QSAR for viral replication
inhibition (IC90), we conducted a stepwise MLR on log-
(Ki), ClogP2, ClogP, CMR2, CMR, MV/100, (MV/100)2,
and the hydrogen-bonding property of the R-group
where hydrogen bond donor, to produce eq 4 (see Table
log(1/IC90)2-30 ) -0.863((0.135)log(Ki) +
.004((0.001)CMR2 - 1.062((0.337)HBD -
4.226((0.539) (4)
n ) 29, r ) 0.878, s ) 0.403, F3,25 ) 28.081(0.0001)
7 and Chart 2). Equation 4 suggests that larger less
hydrogen bond-donating protease inhibitors will produce
a better antiviral agent. However, the quadratic term
for CMR indicates that the relationship between mo-
lecular size and activity is not linear.
Exp er im en ta l Section
P r ed icta bility of Eqs 3 a n d 4. In an attempt to
determine the utility of eqs 3 and 4 as predictors of
protease inhibition and viral replication inhibition,
respectively, a series of heteroaromatic carboxamides
(test-1-test-8) was examined. Compounds test-1-
test-8 were synthesized contemporaneously with this
QSAR study.24 Using the parameters in Table 4 and eq
3 and the parameters in Table 6 and eq 4, we were able
to calculate and compare the Ki and IC90 values. Within
the error of the assay ((40%), we found the predicted
Ki values to be in good agreement with those observed.
All predicted IC90 values from eq 4 were in good
agreement with those found. In an attempt to extend
the utility of the QSAR, we also applied the predicted
Ki from eq 3 to eq 4 and found a good to excellent
agreement between the observed antiviral activity and
the predicted activity. These results buttressed our
confidence in eqs 3 and 4.
Melting points were determined with a Thomas-Hoover
melting point apparatus and are uncorrected. The NMR
spectra were recorded with a Varian-300S spectrometer, IR
spectra were recorded with a Perkin Elmer 1650 FTIR spec-
trophotometer, UV spectra were obtained with a Cary 2415
spectrophotometer, optical rotations (OR) were determined on
a Perkin-Elmer 241 polarimeter, and mass spectra (MS) were
obtained using the Hewlett Packard HP5988A GC-MS sys-
tem. Analytical HPLC determinations were obtained with a
system composed of two Varian 2510 pumps and a Varian 2550
variable wavelength detector using a 4.6 × 250 mm Zorbax
ODS column and CH3CN-water mobile phase. Thin layer
chromatography (TLC) was performed on silica gel plates.
Ch em ica l Syn th esis. Dimethyl (3aR,4â,8R,8aâ)-3,3′-[[Di-
hydro-2,2-dimethyl-6-oxo-4,8-bis(phenylmethyl)-4H-1,3-dioxolo-
[4,5-e][1,3]diazepine-5,7(6H,8H)-diyl]bis(methylene)]bis[ben-
zoate] (1b). A suspension of NaH (5.46 g, 136.4 mmol) in 250
mL of dry DMF was cooled in an ice bath and treated with
the cyclic urea 1a (10.00 g, 27.28 mmol). The mixture was
stirred in the ice bath for 30 min under dry nitrogen and
treated with methyl 3-(bromomethyl)benzoate (17.18 g, 75.02
mmol). The mixture was stirred at room temperature for 72
h and poured into a mixture of 500 g of cracked ice and
saturated NH4Cl. The mixture was stirred until the ice had
melted, and the resulting solid was collected by filtration,
washed with water, and dissolved in 200 mL of EtOAc. The
EtOAc solution was washed with water and brine, dried over
MgSO4, filtered, and concentrated in vacuo to a thick oil. The
crude product was purified by column chromatography over
silica gel using EtOAc-hexane (10:90). Appropriate fractions
were combined and concentrated. The desired product was
collected after recrystallization from hexanes in 66% (11.9 g)
yield: mp 101-102 °C; 1H NMR (DMSO-d6 TMS, 300 MHz) δ
1.33 (s, 6H, CH3CCH3), 2.70 (dd, 2H, Ar′CH), 2.84 (m, 2H,
Ar′CH), 3.35 (d, J ) 13.9 Hz, 2H, NCH), 3.81 (s, 6H, OCH3),
Con clu sion
A series of N,N′-disubstituted cyclic urea bis(3-ben-
zamides) was synthesized and evaluated for anti-HIV
activity. The objective was to find benzamides with HIV
protease activity with Ki < 0.050 nM that translated
into antiviral replication activity with IC90 < 20 nM.
The objective was met with the discovery of 18, 20-22,
24, and 29. These bis-carboxamide cyclic ureas are
more potent than the 'reference compounds’ DMP323,4
VX-478,25 ABT-538,26 Ro31-8959,27 and MK639 (L-735,-
524)28 (also see De Clercq29). A retrospective analysis
of the data showed that viral replication inhibition was

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4305
Ta ble 4. Found vs Predicted Ki Values for 2-30 Using Eq 3
Ki (nM)
compd
R
IP or -ꢀHOMO
MV
ClogP
CMR
I
found
pred (eq 3)
2
3
4
5
6
7
8
9
H
NH2
OH
OCH3
CH3
CH2CH3
CH(CH3)2
CH2CH2CH3
CH2CH2CH2CH3
C(CH3)3
CH2-C3H5
CH2CF3
9.416
9.303
9.318
9.314
9.391
9.379
9.373
9.376
9.378
9.360
9.379
9.469
9.498
9.110
9.520
9.394
9.233
9.105
9.183
9.057
9.106
9.059
9.332
9.448
9.443
9.375
9.526
9.468
9.390
494.20
532.05
521.74
544.04
527.90
560.40
610.05
593.80
660.70
625.00
592.30
575.70
557.70
623.60
616.30
616.70
616.30
648.10
649.10
648.40
648.70
681.30
639.60
663.30
650.50
640.10
662.40
608.10
607.50
3.850
2.990
3.050
4.630
4.262
5.320
5.938
6.378
7.436
6.736
6.208
6.838
2.999
7.840
6.700
6.700
6.700
6.078
7.698
7.698
7.698
8.696
8.487
8.294
8.787
6.357
9.098
5.359
5.359
17.035
17.770
17.341
18.269
17.962
18.890
19.818
19.818
20.745
20.745
20.470
18.983
18.918
22.057
21.635
21.635
21.635
22.563
22.563
22.563
22.563
23.490
22.618
23.601
23.189
22.140
22.656
21.213
21.213
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
0.060
0.018
0.020
0.080
0.060
0.210
0.580
0.280
0.424
2.600
0.710
0.210
0.063
0.370
0.410
0.290
0.010
0.260
0.030
0.010
0.020
0.020
0.010
0.240
0.040
0.120
0.090
0.020
0.150
0.028
0.024
0.021
0.098
0.072
0.207
0.652
0.421
1.278
0.744
0.425
0.315
0.079
0.187
0.986
0.687
0.043
0.072
0.047
0.032
0.037
0.029
0.031
0.089
0.040
0.126
0.047
0.083
0.065
10
11
12
13
14
15
16
17
18b
19
20
21
22
23
24
25
26
27
28
29
30
CH2CN
Ph
4-Pyr
3-Pyr
2-Pyr
2-(3-CH3-Pyr)
2-(4-CH3-Pyr)
2-(5-CH3-Pyr)
2-(6-CH3-Pyr)
2-(4,6-di-CH3-Pyr)
2-(5-Cl-Pyr)
2-(3,5-di-Cl-Pyr)
2-(5-Br-Pyr)
2-(4-CH3-Pym)
2-(5-CF3-Pyr)
2-Prz
2-Pym
Ta ble 5. Correlation Matrix for the Parameters in Eq 3
starting material remained. The mixture was made acidic
with citric acid, and the resulting gum was collected by
decanting the liquid phase. The gum was dissolved in 200 mL
of CH2Cl2, washed with water, dried over MgSO4, filtered, and
concentrated in vacuo to give the desired product 1c as a white
crystalline solid in 95% (12.1 g) yield: mp 218-220 °C dec;
1H NMR (300 MHz, CDCl3 TMS) δ 1.36 (s, 6H, CH3CCH3),
2.86 (dd, 2H, Ar′CH), 3.00 (d, 2H, Ar′CH), 3.21 (d, J ) 14.6
Hz, 2H, NCH), 3.82 (d, J ) 11.0 Hz, 2H, Ar′CCH), 3.95 (s, 2H,
OCH), 4.93 (d, J ) 14.6 Hz, 2H, NCH), 7.05-8.07 (m, 18H,
Ar); IR (KBr) 1694 (CdO), 1644 (CdO) cm-1; MS (NH3-DCI)
m/ e 635 (M + 1). Anal. Calcd for C38H38N2O7, MW 634.74:
C, 71.91; H, 6.03, 6.12; N, 4.41. Found: C, 71.69; H, 6.12; N,
4.44.
variable
IP
ClogP2
ClogP
MV/100
I
IP
1.000
-0.221
1.000
-0.229
0.988
1.000
-0.304
0.865
0.883
1.000
-0.321
0.564
0.550
0.667
1.000
ClogP2
ClogP
MV/100
I
4.00 (m, 4H, OCHCH), 4.54 (d, J ) 13.8 Hz, 2H, NCH), [6.86
(m, 4H), 7.21 (m, 6H), 7.51 (m, 4H), 7.84 (m, 4H), Ar]; IR (KBr)
1724 (CdO), 1634 (CdO) cm-1; MS (NH3-DCI) m/ e 680 (M +
NH4); [R]20 +113.88° (c ) 0.49, MeOH). Anal. Calcd for
D
C40H42N2O7, MW 662.78: C, 72.49; H, 6.40; N, 4.24. Found:
C, 72.42; H, 6.26; N, 4.19.
(3a r,4â,8r,8a â)-3,3′-[[Dih yd r o-2,2-d im et h yl-6-oxo-4,8-
b is(p h en ylm et h yl)-4H -1,3-d ioxolo[4,5-e][1,3]d ia zep in e-
5,7(6H,8H)-d iyl]bis(m eth ylen e)]bis[ben zon itr ile] (1h ). A
suspension of NaH (0.53 g, 22.2 mmol) in 30 mL of dry THF
was treated in small portions with 1a (3.7 g, 10.1 mmol). The
mixture was stirred at room temperature for 30 min and
treated with R-bromo-m-tolunitrile (4.3 g, 21.9 mmol). The
mixture was stirred at room temperature for 16 h under dry
nitrogen and inspected by MS that showed m/ e 482 (M + 1)
for monosubstituted cyclic urea and m/ e 597 (M + 1) for
disubstituted cyclic urea. An additional 1 equiv of NaH was
added, and the mixture was stirred for 30 min, treated with
an additional 1 equiv of R-bromo-m-tolunitrile, and refluxed
for 16 h. The mixture was cooled to room temperature and
poured onto 250 g of cracked ice. The mixture was stirred until
the ice had melted and extracted with 2 × 100 mL of EtOAc.
The EtOAc solution was washed with water and brine, dried
over MgSO4, filtered, and inspected by TLC (CHCl3-EtOAc,
3:2). The mixture contained two components (Rf ) 0.75 and
0.65), neither of which was the starting cyclic urea (Rf ) 0.55)
nor starting R-bromo-m-tolunitrile. The mixture was concen-
trated to a solid which was recrystallized from 50 mL of
2-propanol to give the desired product in 35% (2.10 g) yield:
(3a r,4â,8r,8a â)-3,3′-[[Dih yd r o-2,2-d im et h yl-6-oxo-4,8-
b is(p h en ylm et h yl)-4H -1,3-d ioxolo[4,5-e][1,3]d ia zep in e-
5,7(6H,8H)-d iyl]bis(m eth ylen e)]bis[ben zoic a cid ] (1c). A
suspension of 60% NaH in mineral oil (4.36 g, 109.12 mmol)
in 250 mL of dry DMF was treated with 1a (10.0 g, 27.28
mmol) and stirred at room temperature for 30 min, cooled in
an ice bath, treated with methyl 3-(bromomethyl)benzoate
(18.74 g, 81.84 mmol) in 20 mL of DMF, and stirred in the ice
bath for 1 h and at room temperature for 16 h. The mixture
was poured into 1 kg of ice containing 100 mL of saturated
NH4Cl and stirred until the ice had melted. The resulting
precipitate was collected by decanting the aqueous phase,
dissolved in 250 mL of CH2Cl2, washed with water and brine,
dried over MgSO4, filtered, and concentrated to a thick dark
oil. The crude product was column chromatographed on silica
gel (100 g/1 g crude product) using hexanes-EtOAc (4:1) as
mobile phase. Appropriate fractions were combined and
concentrated in vacuo to give the desired intermediate 1b as
a thin amber oil in 82% (14.77 g) yield: 1H NMR (300 MHz,
CDCl3 TMS) δ 1.36 (s, 6H, CH3CCH3), 2.9 (m, 4H, Ar′CH2),
3.15 (d, J ) 14.6 Hz, 2H, NCH), 3.77 (d, J ) 11.0 Hz, 2H,
Ar′CCH), 3.84 (s, 6H, OCH3), 3.91 (s, 2H, OCH), 4.95 (d, J )
14.6 Hz, 2H, NCH), [7.08 (d, 4H), 7.3 (m, 10H), 7.87 (s, 2H),
1
mp 155-156 °C; Rf 0.65 (CHCl3-EtOAc, 3:2); H NMR (300
7.92 (m, 2H), Ar]; IR (neat) 1724 (CdO), 1632 (CdO) cm-1
;
MHz, CDCl3 TMS) δ 1.44 (s, 6H, CH3), 2.75 and 3.0 (2m, 4,
PhCH2) 3.26 (d, J ) 14.6 Hz, 2H, NCH2), 3.77 (d, J ) 11.0 Hz,
2H, NCH), 3.96 (s, 2H, OCH), 4.73 (d, J ) 14.7 Hz, 2H, NCH2),
[6.97 (m, 4H), 7.26 (m, 6H), 7.4 (m, 6H), 7.54 (m, 2H), Ar]; IR
(Nujol) 2228 (CN), 1638 (CdO) cm-1; MS (NH3-DCI) m/ e 597
MS (NH3-DCI) m/ e 663 (M + 1) for C40H42N2O7 MW 662.30.
The ester 1b (12.23 g, 18.47 mmol) in 100 mL of dioxane
was treated with 1 N NaOH (40 mL) and stirred at room
temperature until TLC (CHCl3-EtOAc, 3:2) indicated that no

4306 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
Ta ble 6. Found vs Predicted IC90 Using Eq 4, Predicted IC90 Using Eq 4, and Predicted Ki from Eq 3
IC90 (nM)
found IC90 (nM,
pred IC90 (eq 4)
compd
R
SD <(36%)
log Ki
ClogP CMR HBD HBA SD <(36% pred (eq 4) and pred Ki (eq 3)
2
3
4
5
6
7
8
9
H
NH2
OH
OCH3
CH3
CH2CH3
CH(CH3)2
CH2CH2CH3
CH2CH2CH2CH3
C(CH3)3
CH2-C3H5
CH2CF3
708.6
883.6
448.2
214.5
80.5
138.7
265.9
259.0
255.3
717.1
485.1
92.5
596.3
510.4
93.7
123.2
2.8
50.3
7.7
3.1
3.2
6.6
14.7
43.0
28.2
124.4
63.4
3.5
-1.409
-1.745
-1.699
-1.347
-1.180
-0.678
-0.237
-0.445
-0.373
0.380
-0.130
-0.678
-1.201
-0.367
-0.387
-0.538
-1.367
-0.585
-1.569
-1.959
-1.699
-1.796
-1.921
-0.611
-1.456
-0.939
-1.071
-1.745
-0.818
3.85
2.99
3.05
4.63
4.26
5.32
5.94
6.38
7.44
6.74
6.21
6.84
3.00
7.84
6.70
6.70
6.70
6.08
7.70
7.70
7.70
8.70
8.49
8.29
8.79
6.36
9.10
5.36
5.36
17.04
17.77
17.34
18.27
17.96
18.89
19.82
19.82
20.75
20.75
20.47
18.98
18.92
22.06
21.64
21.64
21.64
22.56
22.56
22.56
22.56
23.49
22.62
23.60
23.19
22.14
22.66
21.21
21.21
1
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
1
0
0
0
0
0
0
0
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
708.6
883.6
448.2
214.5
80.5
138.7
265.9
259.0
255.3
717.1
485.1
92.5
596.3
510.4
93.7
123.2
2.8
50.3
7.7
3.1
3.2
6.6
14.7
43.0
28.2
124.4
63.4
3.5
1065.1
442.1
548.6
72.8
111.1
227.2
404.8
268.0
226.5
1011.2
402.9
220.7
79.7
144.0
161.0
119.4
23.0
77.3
11.0
5.0
8.5
4.9
5.3
49.4
10.8
44.7
28.5
728.1
521.1
523.9
130.0
109.0
204.2
408.7
280.2
534.6
335.2
227.1
284.8
87.8
10
11
12
13
14
15
16
17a
18
19
20
21
22
23
24
25
26
27
28
29
30
CH2CN
Ph
4-Pyr
3-Pyr
64.1
312.3
228.9
21.1
23.4
16.3
11.7
13.3
7.5
10.9
18.8
11.0
44.2
15.6
43.1
34.9
2-Pyr
2-(3-Me-Pyr)
2-(4-Me-Pyr)
2-(5-Me-Pyr)
2-(6-Me-Pyr)
2-(4,6-di-Me-Pyr)
2-(5-Cl-Pyr)
2-(3,5-di-Cl-Pyr)
2-(5-Br-Pyr)
2-(4-Me-Pym)
2-(5-CF3-Pyr)
2-Prz
12.6
79.4
2-Pym
220.3
220.3
Ta ble 7. Cross-Correlation Matrix for the Parameter in Eq 4
acetonitrile (10 mL), treated with 1 N HCl (10 mL), and stirred
at 50 °C until no starting acetonide remained as evidenced by
TLC (CHCl3-MeOH, 9:1). The mixture was concentrated in
vacuo, and the residue was triturated with water at 70 °C and
placed in the cold for 3 h. The resulting white crystals were
collected by filtration, washed with cold water, and dried in
vacuo to give the desired product in 92% (0.305 g) yield: mp
variable
log Ki
CMR2
HBD
log Ki
CMR2
HBD
1.000
-0.047
1.000
-0.330
-0.584
1.000
1
143-145 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.75 (dd,
Ch a r t 2. Found vs Predicted Viral Replication
2H, Ar′CH), 3.03 (m, 4H, Ar′CH, NCH), 3.49 (s, 2H, OCH),
3.51 (d, J ) 11.9 Hz, 2H, OCCH), 4.65 (d, J ) 14.3 Hz, 2H,
NCH), 4.6 (br s, 2H, OH), [6.94 (d, 4H), 7.23 (m, 10H), 7.40
(dd, 2H), 7.7 (m, 2H, Ar)], 7.76 and 7.95 (2s, CONH2); IR (KBr)
3348 (OH), 1662 (CdO), 1616 (CdO) cm-1; UV-vis (c ) 0.016
mg/mL, MeOH) λmax 274 (1852), 222 (38 673) nm; MS (NH3-
Inhibition Using Eq 4
DCI) m/ e 610 (M + NH4); [R]20 +121.00° (c ) 0.100, MeOH).
D
Anal. Calcd for C35H36N4O5, MW 592.70: C, 70.93; H, 6.12;
N, 9.45. Found: C, 70.84; H, 5.91; N, 9.23.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[ben zoic a cid ] Dih yd r a zid e (3). A solu-
tion of 1b (0.500 g, 0.75 mmol) in 25 mL of MeOH was treated
with anhydrous hydrazine (0.5 mL, 15.3 mmol) and stirred at
room temperature for 16 h. The mixture was diluted to the
cloud point with water, allowed to stand for 2 h, and further
diluted to 250 mL with water. The resulting white crystals
were collected by filtration, washed with water, and dried in
vacuo to give the intermediate hydrazide-acetonide in 99%
(M + 1); [R]20 +124.56° (c ) 0.228, MeOH). Anal. Calcd for
1
D
(0.493 g) yield: mp 76-78 °C; H NMR (300 MHz, DMSO-d6
C
38H36N4O3‚H2O, MW 614.75: C, 74.24; H, 6.23; N, 9.11.
TMS) δ 1.33 (d, 6H, CH3CCH3), 2.74 (dd, 2H, Ar′CH), 2.85 (d,
2H, Ar′CH), 3.32 (d, 2H, NCH), 3.81 (s, 4H, NH2), 4.0 (m, 4H,
CHCHCHCH), 4.57 (d, 2H, NCH), [6.88 (m, 4H), 7.20 (m, 6H),
7.37 (m, 1H), 7.5 (m, 3H), 7.75 (m, 1H), 7.86 (m, 3H), Ar], 9.75
(s, 2H, NH); MS (NH3-DCI) m/e 663 (M + 1), 685 (M + NH4).
Found: C, 74.36; H, 6.47; N, 8.82.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[ben za m id e] (2). A solution of 1h (0.33 g,
0.56 mmol) in EtOH (10 mL) and KOH (0.325 g, 5.6 mmol)
was stirred at room temperature in a water bath for 30 min
and treated with 5 mL of 30% H2O2. The mixture was stirred
at room temperature for 24 h and inspected by TLC (CHCl3-
MeOH, 9:1) (Rf R-CN ) 0.85 and Rf R-CONH2 ) 0.33) and IR
A solution of the acetonide (0.450 g, 0.679 mmol) in 10 mL
of acetonitrile was treated with 10 mL of 1 N HCl and stirred
at room temperature until no acetonide was evidenced by TLC
(CHCl3-MeOH, 9:1). Fine white needles formed (HCl salt?).
The mixture was treated with 100 mL of 5% NaHCO3, stirred
for 1 h, and filtered to collect the white solid. The solid was
washed with water and dried in vacuo to give the desired
product in 92% (0.401 g) yield from the acetonide or 91% from
and found to contain no starting nitrile at 2228 cm-1
. The
mixture was concentrated in vacuo, and the residue was
triturated with 100 mL of 10% citric acid. The resulting white
solid was collected by filtration, washed with additional water,
and dried. The “benzamide-acetonide” was dissolved in
1
1b: mp 161-163 °C; H NMR (300 MHz, DMSO-d6 TMS) δ
2.72 (dd, 2H, Ar′CH), 2.97 (d, 2H, Ar′CH), 3.07 (d, J ) 13.9

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4307
Ta ble 8. Found vs Predicted Activity Using Eqs 3 and 4 for a Set of Compounds (test-1-test-8) Not Used To Generate the
Regression Equations
Hz, 2H, NCH), 3.49 (m, 4H, CHCHCHCH), 3.82 (s, 4H, NH2),
4.62 (d, 14.2H), 5.15 (s, 2H, OH), [6.92 (m, 4H), 7.23 (m, 6H),
7.44 (m, 4H), 7.6 (m, 1H), 7.8 (m, 3H), Ar], 7.24 (s, 2H, NH);
IR (KBr) 3440 (OH), 1724 (CdO), 1642 (CdO) cm-1; MS (ESI)
2.7 (m, 2H, Ar′CH), 2.96 (m, 4H, Ar′CH, NCH), 3.5 (m, 4H,
CHCHCHCH), 3.66 (s, 6H, OCH3), 4.64 (d, J ) 14.3 Hz, 2H,
NCH), 5.15 (br s, 2H, OH), [6.95 (d, 4H), 7.24 (m, 6H), 7.32 (d,
2H), 7.42 (dd, 2H), 7.61 (m, 4H), Ar], 11.74 (s, 2H, NH); IR
m/e 623 (M + 1); [R]20 +106.73° (c ) 0.208, MeOH). Anal.
(KBr) 3406 (OH), 3218 (NH), 1650 (CdO), 1628 (CdO) cm-1
;
D
Calcd for C35H38N6O5, MW 622.72: C, 67.51; H, 6.15; N, 13.50.
Found: C, 67.83; H, 6.31; N, 13.82.
UV-vis (c ) 0.017 mg/mL, MeOH) λmax 275 (2342) nm; MS
(NH3-DCI) m/ e 653 (M + 1); [R]20D +73.05° (c ) 0.204, MeOH).
Anal. Calcd for C37H40N4O7, MW 652.75: C, 68.08; H, 6.18;
N, 8.58. Found: C, 68.42; H, 6.17; N, 8.69.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-h yd r oxyben za m id e] (4). A solution of
1c (0.635 g, 1.000 mmol) in 20 mL of THF was treated with
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP, Castro’s reagent) (1.33 g, 3.0 mmol),
stirred for 15 min, and treated with hydroxylamine hydro-
chloride (0.5 g, 7.2 mmol) and triethylamine (0.25 g, 2.5 mmol).
The reaction mixture was stirred for 48 h and concentrated
in vacuo. The residue was partitioned between 100 mL of
water and 100 mL of EtOAc. The organic phase was washed
with 3 × 100 mL of 5% NaHCO3, water, and brine, dried over
MgSO4, filtered, concentrated to a foam (0.518 g, 78% yield),
and found to be homogenous by TLC (CHCl3-MeOH, 4:1): 1H
NMR (300 MHz, DMSO-d6 TMS) δ 1.27 (s, 6H, CH3CCH3),
2.7-2.9 (m, 4H, Ar′CH2), 3.22 (d, J ) 13.9 Hz, 2H, NCH), 4.0
(m, 4H, CHCHCHCH), 4.56 (d, J ) 13.9 Hz, 2H, NCH), 6.9-
7.7 (m, 18H, Ar), 9.04 (d, 4H, CONH), 11.24 (s, 2H, NOH); IR
(CH2Cl2 film) 3240 (OH and NH), 1636 (CdO) cm-1; MS (NH3-
DCI) m/e 665 (M + 1).
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-m eth ylben za m id e] (6). By substituting
methylamine hydrochloride in the procedure for 4, the desired
product was obtained in 99% (0.612 g) yield: mp 163-165 °C;
1H NMR (300 MHz, DMSO-d6 TMS) δ 2.75 (m, 8H, Ar′CH,
NCH3), 2.96 (m, 4H, Ar′CH, NCH), 3.49 (m, 4H, CHCHCHCH),
4.66 (d, J ) 14.0 Hz, 2H, NCH), 5.10 (br s, 2H, OH), [6.93 (d,
4H), 7.23 (m, 8H), 7.40 (dd, 2H), 7.7 (m, 4H), Ar], 8.41 (m, 2H,
NH); IR (KBr) 3352 (OH, NH), 1640 (CdO) cm-1; UV-vis (c
) 0.014 mg/mL, MeOH) λmax 275 (2017) nm; MS (NH3-DCI)
m/ e 621 (M + 1); [R]20 +105.19° (c ) 0.212, MeOH). Anal.
D
Calcd for C37H40N4O5, MW 620.76: C, 71.59; H, 6.50; N, 9.03;
Found: C, 71.27; H, 6.64; N, 8.81.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(1-m eth yleth yl)ben zam ide] (8). A mix-
ture of 1c (0.500 g, 0.787 mmol), HOBt (0.212 g, 1.57 mmol),
and isopropylamine (0.139 g, 2.36 mmol) in EtOAc (20 mL)
was stirred at room temperature and treated with DCC (0.357
g, 1.73 mmol). The mixture was purged with dry nitrogen,
capped, and stirred at room temperature for 48 h. The mixture
was treated with water (50 mL), stirred an additional 1 h, and
filtered to remove the DCU. The mixture was filtered, and
the organic layer was separated, washed with water, 5%
NaHCO3, water, and brine, dried over MgSO4, stored at -20
°C for 4 h, and filtered to remove additional DCU. The filtrate
was concentrated to a foam of constant weight (0.560 g): 1H
NMR (300 MHz, DMSO-d6 TMS) δ 1.12 (d, J ) 6.6 Hz, 6H,
CH3CCH3), 1.30 (s, 6H, CH3CCH3), 2.8 (m, 4H, Ar′CH2), 3.23
(d, J ) 14.3 Hz, 2H, NCH), 3.96 (d, J ) 13.2 Hz, 2H, Ar′CCH),
4.01 (s, 2H, OCH), 4.07 (m, 2H, CCHC), 4.61 (d, J ) 14.3 Hz,
2H, NCH), [6.92 (m, 4H), 7.22 (m, 6H), 7.39 (m, 4H), 7.74 (m,
4H), Ar], 8.21 (s, 2H, NH); MS (NH3-DCI) m/ e 734 (M + NH4)
for C44H52N4O5, MW 716.92.
The acetonide (0.450 g, 0.68 mmol) was dissolved in 10 mL
of MeOH and treated with 10 mL of 1 N HCl. The mixture
was stirred at room temperature until no acetonide remained
as evidenced by TLC (CHCl3-MeOH, 4:1). The organic solvent
was removed in vacuo, and the resulting solid was collected
by filtration and dried in vacuo to give the desired product in
95% (0.404 g) yield from the acetonide or 74% from 1c: mp
1
139-142 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.77 (dd,
2H, Ar′CH), 3.97 (m, 4H, Ar′CH, NCH), 3.49 (m, 4H, CHCH-
CHCH), 4.64 (d, J ) 14.3 Hz, 2H, Ar′CH), 5.13 (s, 2H, OH),
[6.9 (m, 4H), 7.24 (m, 8H), 7.40 (dd, 2H), 7.64 (m, 3H), 7.80
(m, 1H), Ar], 9.03 (s, 2H, CONH), 11.22 (s, 2H, NOH); IR (KBr)
3242 (broad), 1644 (CdO) cm-1; MS (NH3-DCI) m/e 625 (M +
1); [R]20 +109.13° (c ) 0.21, MeOH). Anal. Calcd for
D
C35H36N4O7‚0.5H2O, MW 633.71: C, 66.34; H, 5.89: N, 8.84.
Found: C, 66.60; H, 5.96; N, 8.90.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(m eth yloxy)ben za m id e] (5). By sub-
stituting methoxylamine hydrochloride in the procedure used
to synthesize 4, the desired product was obtained in 93% (0.606
The above intermediate acetonide was dissolved acetonitrile
(10 mL), treated with 1 N HCl (10 mL), stirred for 16 h, diluted
with 50 mL of water, and stirred for 1 h. The resulting white
solid was collected by filtration, washed with water, and dried
in vacuo to give the desired product in 77% (0.428 g) yield from
1
g) yield: mp 155° dec; H NMR (300 MHz, DMSO-d6 TMS) δ

4308 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
1
t
1c: mp 131-135 °C; H NMR (300 MHz, DMSO-d6 TMS) δ
NH); 1H NMR (300 MHz, CDCl3 TMS) δ 1.40 (s, 18H, Bu),
1.11 (2d, 12H, CH3CCH3), 2.77 (dd, 2H, Ar′CH), 2.96 (m, 4H,
Ar′CH, NCH), 3.44 (s, 2H, OCH), 3.51 (d, J ) 11.3 Hz, 2H,
OCCH), 4.70 (d, J ) 13.9 Hz, 2H, NCH), 5.14 (broad s, 2H,
OH), [6.98 (d, 4H), 7.24 (m, 8H), 7.40 (dd, 2H), 7.69 (s, 2H),
7.73 (d, 2H), Ar], 8.20 (d, J ) 7.7 Hz, 2H, NH); IR (KBr) 3346
(OH, NH), 1640 (CdO) cm-1; UV-vis (c ) 0.0290 mg/mL,
MeOH) λmax 267 (35 663), 218 (2264) nm; MS (NH3-DCI) m/ e
2.84 (m, 2H, Ar′CH), 3.05 (m, 4H, Ar′CH, NCH), 3.57 (d, J )
11.4 Hz, 2H, Ar′CCH), 3.64 (s, 2H, OCH), 3.75 (br s, 2, OH),
4.85 (d, J ) 13.6 Hz, 2H, NCH), 5.98 (s, 2H, NH), [7.21 (d,
4H), 7.3 (m, 10H), 7.43 (s, 2H), 7.54 (dd, 2H), Ar, Ar′]; IR (KBr)
3420 (OH, NH), 1646 (CdO) cm-1; UV-vis (c ) 0.019 mg/mL,
MeOH) no clearly defined λmax; MS (NH3-DCI) m/ e 703 (M +
1), 720 (M + NH4); [R]20 +73.33° (c ) 0.15, MeOH). Anal.
D
694 (M + NH4); [R]20 +90.23° (c ) 0.174, MeOH). Anal.
Calcd for C43H52N4O5, MW 704.92: C, 73.27; H, 7.44; N, 7.95.
Found: C, 72.88; H, 7.46; N, 7.90.
D
Calcd for C41H48N4O5‚2.5H2O, MW 721.90: C, 68.23; H, 7.40;
N, 7.76. Found: C, 68.35; H, 7.08; N, 7.63.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(cyclop r op ylm eth yl)ben za m id e] (12).
To a solution of 1c (0.54 g, 0.85 mmol) in dry THF (50 mL)
was added N-methylmorpholine (0.51 g, 5.0 mmol) and isobutyl
chloroformate (0.23 g, 1.68 mmol). The mixture was stirred
at room temperature for 1 h, cooled in an ice bath, and treated
with cyclopropylmethylamine hydrochloride (0.42 g, 3.9 mmol).
The reaction mixture was stirred at room temperature for 6
h, concentrated in vacuo, triturated with water, and extracted
with EtOAc. The EtOAc solution was dried over Na2SO4 and
concentrated to dryness. The crude product was column
chromatographed on silica gel using hexane-EtOAc (4:1).
Appropriate fractions were combined and concentrated to give
the intermediate as a foam: MS (NH3-DCI) m/e 758 (M +
NH4). The ‘amide-acetonide’ (0.17 g, 0.230 mmol) was dis-
solved in MeOH (20 mL), treated with pTsOH‚H2O (0.24 g,
0.94 mmol), stirred at room temperature for 4 h, and poured
into water (10 mL). The mixture was extracted with EtOAc,
and the EtOAc extract was washed with water, 5% NaHCO3,
water, and brine, dried over Na2SO4, filtered, and concentrated
to give the product as a white solid in 27% (0.160 g) yield: mp
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-eth ylben za m id e] (7). By substituting
ethylamine hydrochloride in the method for 8, the desired
product was obtained in 92% yield: mp 160-162 °C; 1H NMR
(300 MHz, DMSO-d6 TMS) δ 1.09 (t, 6H, CH3), 2.76 (m, 2H,
Ar′CH), 2.97 (m, 4H, Ar′CH, NCH), 3.26 (m, 4H, NCH2), 3.49
(m, 4H, CHCHCHCH), 4.69 (d, J ) 14.3 Hz, 2H, NCH), 6.9-
7.9 (m, 18H, Ar), 8.47 (m, 2H, NH); IR (KBr) 3348 (OH, NH),
1642 (CdO) cm-1; UV-vis (c ) 0.0180 mg/mL, MeOH) λmax
275 (1968) nm; MS (NH3-DCI) m/ e 649 (M + 1); [R]20
D
+100.47° (c ) 0.214, MeOH). Anal. Calcd for C39H44N4O5, MW
648.81: C, 72.20; H, 6.84; N, 8.64. Found: C, 72.33; H, 6.80;
N, 8.53.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-p r op ylben za m id e] (9). By substituting
propylamine hydrochloride in the method for 8, the desired
1
product was obtained in 90% yield: mp 166-168o; H NMR
(300 MHz, DMSO-d6 TMS) δ 0.85 (t, 6H, CH3), 1.48 (m, 4H,
CH2), 2.51 (m, 2H, Ar′CH), 2.96 (m, 4H, Ar′CH, NCH), 3.18
(m, 4H, NCH2), 3.47 (m, 4H, CHCHCHCH), 4.48 (d, J ) 14.3
Hz, 2H, NCH), 6.9-7.9 (m, 18H, Ar), 8.45 (m, 2H, NH); IR
(KBr) 3348 (OH, NH), 1640 (CdO) cm-1; UV-vis (c ) 0.0190
mg/mL, MeOH) λmax 275 (2230) nm; MS (NH3-DCI) m/ e 677
1
116-118 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 0.18 (m,
4H, CH2), 0.37 (m, 4H, CH2), 0.99 (m, 2H, CH), 2.78 (dd, 2H,
Ar′CH), 2.96 (d, J ) 14.3 Hz, 2H, NCH), 3.11 (dd, 2H, Ar′CH),
3.33 (d, 4H, NCH2), 3.5 (m, 4H, OCHCH), 4.66 (d, J ) 14.3
Hz, 2H, NCH), 5.13 (s, 2H, OH), [6.96 (d, 4H), 7.23 (m, 8H),
7.41 (dd, 2H), 7.69 (s, 2H), 7.73 (d, 2H), Ar], 8.82 (dd, 2H,
NH); MS (NH3-DCI) m/e calcd for C43H49N4O5 (M + 1)
701.368 959, found 701.370 296, 718 (M + NH4). Anal. Calcd
for C43H48N4O5, MW 700.89: C, 73.69; H, 6.90; N, 7.99.
Found: C, 73.32; H, 6.91; N, 8.02.
(M + 1); [R]20 +88.61° (c ) 0.202, MeOH). Anal. Calcd for
D
C41H48N4O5, MW 676.86: C, 72.76; H, 7.15; N, 8.28. Found:
C, 72.49; H, 7.16; N, 8.29.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-bu tylben za m id e] (10). By substituting
n-butylamine in the procedure used to synthesize 4, the desired
product was obtained in 98% yield from 1c: mp 132-134 °C;
1H NMR (300 MHz, DMSO-d6 TMS) δ 0.84 (t, 6H, CH3), 1.27
(m, 4H, CH2), 1.45 (m, 4H, CH2), 2.77 (dd, 2H, Ar′CH), 2.95
(m, 4H, Ar′CH, NCH), 3.21 (m, 4H, NCH2), 3.45 (s, 2H, OCH),
3.50 (d, J ) 11.1 Hz, 2H, Ar′CCH), 4.68 (d, J ) 13.9 Hz, 2H,
NCH), 5.12 (s, 2H, OH), [6.96 (d, 4H), 7.23 (m, 8H), 7.40 (dd,
2H), 7.68 (s, 2H), 7.70 (d, 2H), Ar], 8.40 (t, 2H, NH); IR (KBr)
3340 (OH, NH), 1640 (CdO) cm-1; MS (NH3-DCI) m/e 705 (M
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(2,2,2-tr iflu or oeth yl)ben za m id e] (13).
A mixture of 1c (0.635 g, 1.00 mmol), triethylamine (0.22 g,
2.2 mmol), and 2,2,2-trifluoroethylamine hydrochloride (0.30
g, 2.2 mmol) in 25 mL of DMF was stirred for 10 min and
treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (water soluble carbodiimide, WSC). The mix-
ture was stirred at room temperature for 16 h and diluted with
150 mL of water. The resulting gum was collected by decant-
ing the aqueous phase, dissolved in 100 mL of EtOAc, washed
+ 1); [R]20 +80.88° (c ) 0.0204, MeOH). Anal. Calcd for
D
C43H52N4O5, MW 704.92: C, 73.27; H, 7.45; N, 7.96. Found:
C, 73.20; H, 7.66; N, 8.11.
with water and brine, dried over MgSO4
, filtered, and concen-
trated in vacuo to give the crude bis-amide acetonide. The
crude acetonide was dissolved in 10 mL of CHCl3, treated with
40 mL of 1 N HCl/Et2O, and stirred at room temperature until
TLC (CHCl3-MeOH, 8:2) indicated no starting acetonide. The
mixture was concentrated in vacuo and purified by preparative
TLC on silica gel plates using CHCl3-MeOH (8:2) as mobile
phase. The desired product was isolated in 15% (0.114 g)
yield: mp 116-120 °C; Rf 0.66 (CHCl3-MeOH, 8:2); 1H NMR
(300 MHz, DMSO-d6 TMS) δ 2.74 (dd, 2H, Ar′CH), 2.98 (dd,
4H, Ar′CHCH), 3.51 (s, 2H, OCH), 3.55 (d, 2H, NCH), 4.09
(m, 4H, NCH2CF3), 4.63 (d, J ) 14.2 Hz, 2H, NCH), 5.20 (s,
2H, OH), [6.91 (m, 4H), 7.21 (m, 6H), 7.38 (m, 2H), 7.45 (dd,
2H), 7.72 (s, 2H), 7.78 (d, 2H), Ar], 9.10 (s, 2H, NH); 19F NMR
(282 MHz, DMSO-d6 TMS) δ -70.979; MS (NH3-DCI) m/ e 774
(M + NH4), 757 (M + 1). Anal. Calcd for C39H38F6N4O5, MW
756.75: C, 61.90; H, 5.06; N, 7.40. Found: C, 61.83; H, 5.11;
N, 7.44.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(1,1-d im eth yleth yl)ben za m id e] (11).
By substituting tert-butylamine in the procedure used to
synthesize 4, the desired product was obtained in 97% yield
from 1c: mp 131-133 °C; 1H NMR (300 MHz, DMSO-d6 TMS)
t
δ 1.32 (s, 9H, Bu), 2.79 (dd, 2H, Ar′CH), 2.95 (m, 4H, Ar′CH,
NCH), 3.41 (s, 2H, OCH), 3.50 (d, J ) 10.7 Hz, 2H, Ar′CCH),
4.73 (d, J ) 14.0 Hz, 2H, NCH), 5.13 (s, 2H, OH), [7.03 (d,
4H), 7.26 (m, 8H), 7.35 (dd, 2H), 7.61 (s, 2H), 7.68 (d, 2H),
Ar], 7.71 (s, 2H, NH); IR (KBr) 3384 (OH, NH), 1646 (CdO)
cm-1; MS (NH3-DCI) m/e 705 (M + 1); [R]20D +74.50° (c ) 0.20,
MeOH). Anal. Calcd for C43H52N4O5, MW 704.92: C, 73.27;
H, 7.44; N, 7.96, 7.84. Found: C, 73.23; H, 7.08; N, 7.84.
Alternatively, by substituting tert-butylamine in the modi-
fication of the Weinreb method, the desired product was
obtained in an overall yield of 86% (0.43 g) from 1b: mp 133
°C dec; 1H NMR (300 MHz, DMSO-d6 TMS) δ 1.32 (s, 18H,
tBu), 2.80 (dd, 2H, Ar′CH), 2.96 (m, 4H, Ar′CH, NCH), 3.40
(s, 2H, OCH), 3.50 (d, J ) 10.2 Hz, 2H, Ar′CCH), 4.68 (d, J )
14.3 Hz, 2H, NCH), 5.11 (s, 2H, OH), [7.03 (d, 4H), 7.26 (m,
8H), 7.38 (dd, 2H), 7.62 (s, 2H), 7.67 (d, 2H), Ar], 7.71 (s, 2H,
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(cya n om eth yl)ben za m id e] (14). A so-
lution of 1c (1.27 g, 2.0 mmol) in 50 mL of CH2Cl2 was treated
with oxalyl chloride (0.76 g, 3.0 mmol) and 1 drop of DMF.

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4309
desired product was obtained in 23% (0.348 g) yield from 1c:
The mixture was stirred for 30 min and treated with ami-
noacetonitrile hydrochloride (0.556 g, 6.0 mmol). The mixture
was stirred for an additional 10 min and treated with diiso-
propylethylamine (1.56 g, 12.0 mmol). The mixture was
stirred at room temperature for 16 h and concentrated in
vacuo. The residue was diluted with 100 mL of water,
triturated, and filtered to collect the tan solid. The solid was
washed with water, dried, and chromatographed on silica gel
using EtOAc-CHCl3 (3:2) as mobile phase. Appropriate
fractions were combined and concentrated to an off-white solid
of constant weight (0.780 g): 1H NMR (300 MHz, DMSO-d6
TMS) δ 1.34 (s, 6H, CH3CCH3), 2.70 (dd, 2H, Ar′CH), 2.83 (m,
2H, Ar′CH), 3.31 (d, J ) 14.0 Hz, 2H, NCH), 4.0 (m, 4H,
CHCHCHCH), 4.31 (d, J ) 5.5 Hz, 4H, CH2CN), 4.52 (d, J )
14.0 Hz, 2H, NCH), 6.8-7.8 (m, 18H, Ar), 9.22 (t, 2H, NH).
The above acetonide was dissolved in 10 mL of acetonitrile,
treated with 10 mL of 1 N HCl, and stirred at room temper-
ature for 4 h. The mixture was diluted with 100 mL of
water and triturated. The resulting solid was collected by
filtration, washed with additional water, and dried in vacuo
to give the desired product in 41% (0.544 g) yield from 1c: mp
1
mp 153-154 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.76
(dd, 2H, Ar′CH), 2.98 (d, J ) 12.8 Hz, 2H, Ar′CH), 3.06 (d, J
) 14.0 Hz, 2H, NCHAr′), 3.51 (s, 2H, OCH), 3.56 (d, J ) 11.0
Hz, 2H, NCHC), 4.71 (d, J ) 14.0 Hz, 2H, NCHAr′), 5.17 (s,
2H, OH), [6.97 (m, 4H), 7.22 (m, 6H), 7.42 (d, 2H), 7.52 (dd,
2H), 7.85 (m, 2H), 7.88 (d, 2H), Ar, Ar′′], [7.77 (d, 4H), 8.47 (d,
4H), 4-Pyr], 10.59 (s, 2H, NH); IR (KBr) 3414 (broad OH), 1686
(CdO) cm-1; MS (NH3-DCI) m/ e 728 (M - H2O); [R]20D 75.00°
(c ) 0.300, MeOH). Anal. Calcd for C45H42N6O5, MW 746.87:
C, 72.37; H, 5.67; N, 11.25. Found: C, 72.33; H, 5.67; N, 11.19.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-3-p yr id in ylben za m id e] (17). By sub-
stituting 3-aminopyridine in the Weinreb method for 15, the
desired product was obtained in 50% (0.585 g) yield from the
acid: mp 163-165 °C dec;
1H NMR (300 MHz, DMSO-d6 TMS)
δ 2.78 (dd, 2H, Ar′CH), 2.99 (d, J ) 12.8 Hz, 2H, Ar′CH), 3.05
(d, J ) 13.9 Hz, 2H, NCH), 3.45-3.65 (m, 4H, OCHCH), 4.72
(d, J ) 13.9 Hz, 2H, NCH), 5.18 (s, 2H, OH), [6.97 (d, 4H),
7.23 (m, 6H), 7.40 (m, 4H), 7.52 (dd, 2H), 7.81 (s, 2H), 7.90 (d,
2H), 8.18 (d, 2H), 8.31 (s, 2H), 8.91 (s, 2H), Ar], 10.47 (s, 2H,
1
141-143 °C dec; H NMR (300 MHz, DMSO-d6 TMS) δ 2.72
NH); IR (KBr) 3320 (OH), 1654 (CdO) cm-1
; MS (NH3-DCI)
(dd, 2H, Ar′CH), 2.96 (m, 2H, Ar′CH), 3.04 (d, J ) 14.0 Hz,
2H, NCH), 3.53 (m, 4H, CHCHCHCH), 4.61 (d, J ) 13.9 Hz,
2H, NCH), 5.16 (s, 2H, OH), [6.89 (d, 4H), 7.21 (m, 6H), 7.39
(d, 2H), 7.46 (dd, 2H), 7.72 (m, 4H), Ar], 9.21 (t, 2H, NH); IR
(KBr) 3388 (OH, NH), 1654 (CdO) cm-1; MS (NH3-DCI) m/e
m/ e 747 (M + 1); [R]20 +80.70° (c ) 0.228, MeOH). Anal.
D
Calcd for C45H42N6O5, MW 746.87: C, 72.37; H, 5.68; N, 11.25.
Found: C, 72.56; H, 5.28; N, 11.16.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-2-p yr id in ylben za m id e] Dih yd r och lo-
r id e (18a ). A solution of 1c (2.0 g, 3.15 mmol) in 75 mL of
EtOAc, HOBt (0.98 g, 7.24 mmol), and DCC (1.49 g, 7.24 mmol)
was stirred for 30 min, treated with 2-aminopyridine (1.48 g,
15.75 mmol), and stirred for 24 h. TLC (hexanes-EtOAc, 3:7)
showed a mixture of bis-OBt ester {1H NMR (300 MHz, CDCl3
TMS) δ 1.43 (s, 6H, CH3CCH3), 2.90 (m, 2H, Ar′CH), 3.05 (m,
2H, Ar′CH), 3.38 (d, J ) 14.6 Hz, 2H, NCH), 3.86 (d, J ) 10.2
Hz, 2H, Ar′CCH), 4.06 (s, 2H, OCH), 4.88 (d, J ) 14.6 Hz, 2H,
NCH), [7.0 (m, 4H), 7.26 (m, 8H), 7.4-7.65 (m, 8H), 8.06 (m,
4H), 8.16 (d, 2H), Ar]; MS (NH3-DCI) m/ e 869 (M + 1), 886
(M + NH4) for C50H44N8O7, MW 868.96}, OBt ester/2-aminopy-
ridine benzamide {1H NMR (300 MHz, CDCl3 TMS) δ 1.41 (s,
6H, CH3CCH3), 2.85-3.1 (m, 4H, Ar′CH2), 3.25-3.43 (m, 2H,
NCH), 3.84 (m, 2H, Ar′CCH), 4.03 (m, 2H, OCH), 4.85 (m, 2H,
NCH), [6.9 (d, 1H), 7.03 (d, 4H), 7.26 (m, 7H), 7.35-7.6 (m,
5H), 7.62 (s, 2H), 7.79 (m, 1H), 8.03-8.2 (m, 6H), Ar], 8.52 (s,
1H, NH); MS (NH3-DCI) m/ e 828(M + 1) for C49H45N7O6, MW
827.95}, and the desired bis-2-aminopyridine benzamide ac-
etonide. The mixture was filtered to remove the DCU, the
filtrate was treated with triethylamine (1 g), and stirring was
continued until all of the bis-OBt ester and the OBt ester/2-
aminopyridine benzamide had been converted to the desired
bis-benzamide (1-4 days) as indicated by TLC (hexanes-
EtOAc, 3:7). The mixture was diluted with 100 mL of water,
and the organic phase was washed with water, 5% NaHCO3,
water, and brine, dried over MgSO4, filtered, and concentrated
in vacuo to an impure solid. The crude product was column
chromatographed on silica gel (100 g/1 g crude material) using
CHCl3-EtOAc (7:3) as mobile phase. Appropriate fractions
were collected, combined, and concentrated to give the desired
intermediate as a white foam in 88% (2.17 g) yield: 1H NMR
(300 MHz, DMSO-d6 TMS) δ 1.30 (s, 6H, CH3CCH3), 2.74 (dd,
2H, Ar′CH), 2.86 (m, 2H, Ar′CH), 3.32 (d, J ) 14.0 Hz, 2H,
NCH), 4.03 (d, J ) 11.0 Hz, 2H, Ar′CCH), 4.06 (s, 2H, OCH),
4.60 (d, J ) 14.0 Hz, 2H, NCH), [6.91 (m, 4H), 7.19 (m, 8H),
7.48 (m, 4H), 8.83 (m, 2H), 7.92 (m, 2H), 7.95 (s, 2H), 8.17 (d,
2H), 8.40 (d, 2H), Ar], 10.79 (s, 2H, NH); IR (Nujol) 3246 (NH),
671 (M + 1); [R]20 +98.72° (c ) 0.16, MeOH). Anal. Calcd
D
for C39H38N6O5‚1.5H2O, MW 697.80: C, 67.13; H, 5.92; N,
12.04. Found: C, 67.23; H, 5.59; N, 12.16.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[p h en ylben za m id e] (15). The compound
was synthesized using a modification of the Weinreb method.7
A solution of aniline (0.93 g, 9.98 mmol) in dichloroethane (5
mL) was treated with 2 M trimethylaluminum (TMA) (5.0 mL,
10 mmol), stirred at room temperature for 10 min, and added
to a solution of 1b (0.500 g, 0.754 mmol) in dichloroethane (15
mL). The mixture was refluxed under dry nitrogen for 25 h
and inspected by TLC (CHCl3-EtOAc, 3:2) which showed no
1b. Mass spectral analysis showed m/ e 802 (M + NH4). The
mixture was diluted with 100 mL of CH2Cl2 and 50 mL of
water, stirred for 1 h, and filtered through a bed of Celite. The
filtrate was washed with water (50 mL), 5% NaHCO3 (2 × 25
mL), water, and brine, dried over MgSO4, filtered, and
concentrated to a brown solid (0.300 g) whose mass spec.
showed 745 (M + 1) and NMR (DMSO-d6 TMS) showed no
acetonide group. (Note: Most preps do not show the loss of
the acetonide protecting group.) The crude product was
triturated with 25 mL of 1 N HCl for 1 h, collected by filtration,
washed with water, dried in vacuo, and recrystallized from
warm acetonitrile to give the desired product in 43% (0.2401
1
g) yield as fine slightly yellow crystals: mp 156-159 °C; H
NMR (300 MHz, DMSO-d6 TMS) δ 2.79 (dd, 2H, Ar′CH), 3.00
(m, 4H, Ar′CH, NCH), 3.51 (s, 2H, OCH), 3.56 (d, J ) 12.4
Hz, 2H, Ar′CCH), 4.73 (d, J ) 14.3 Hz, 2H, NCH), 5.17 (s, 2H,
OH), [6.98 (d, 4H), 7.09 (dd, 2H), 7.2-7.45 (m, 12H), 7.50 (dd,
2H), 7.77 (m, 6H), 7.87 (d, 2H), Ar], 10.25 (s, 2H, NH); MS
(NH3-DCI) m/ e 762 (M + NH4).
Alternatively, by substituting aniline in the method for 8,
the desired amide was obtained in 94% (0.550 g) yield as a
pure amorphous white solid. A small amount was recrystal-
lized from warm acetonitrile to give white opaque plates: mp
1
157-160 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.79 (dd,
2H, Ar′CH), 3.01 (m, 4H, Ar′CH, NCH), 3.5 (m, 4H, OCHCH),
4.73 (d, J ) 13.9 Hz, 2H, NCH), 5.17 (s, 2H, OH), [6.98 (d,
4H), 7.09 (dd, 2H), 7.15-7.40 (m, 12H), 7.50 (dd, 2H), 7.8 (m,
6H), 7.87 (d, 2H), Ar], 10.25 (s, 2H, NH); IR (KBr) 3420 (OH,
NH), 1660 (CdO), 1600 (CdO) cm-1; MS (NH3-DCI) m/ e 762
(M + NH4); [R]20D +85.83° (c ) 0.12, MeOH). Anal. Calcd for
C47H44N4O5‚0.5H2O, MW 753.90: C, 74.88; H, 6.02; N, 7.43.
Found: C, 75.24; H, 5.91; N, 7.41.
1680 (CdO), 1631 (CdO) cm-1
1) for C48H46N6O5, MW 786.35.
; MS (NH3-DCI) m/ e 787 (M +
The acetonide (1.93 g, 2.45 mmol) in 20 mL of CH3CN was
treated with 10 mL of 1 N HCl and stirred at room temper-
ature until no starting material remained as demonstrated by
TLC (CHCl3-MeOH, 9:1). The mixture was concentrated in
vacuo at 60 °C to give a white solid which was triturated with
10 mL of water and placed in the cold for 16 h. The resulting
crystals were collected by filtration, washed with a small
amount of cold water, and air-dried to give the desired product
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-4-p yr id in ylben za m id e] (16). By sub-
stituting 4-aminopyridine in the Weinreb method for 15, the

4310 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Wilkerson et al.
in 77% (1.415 g) yield (68% yield from 1c): mp 158-161 °C;
1H NMR (300 MHz, DMSO-d6 TMS) δ 2.77 (dd, 2H, Ar′CH),
2.99 (d, J ) 12.4 Hz, 2H, Ar′CH), 3.07 (d, J ) 14.3 Hz, 2H,
NCH), 3.55 (s, 2H, OCH), 3.60 (d, J ) 11.7 Hz, 2H, Ar′CCH),
4.68 (d, J ) 14.3 Hz, 2H, NCH), [6.95 (d, 2H), 7.22 (m, 6H),
7.4 (m, 4H), 7.52 (dd, 2H), 7.92 (s, 2H), 8.04 (d, 2H), 8.16 (m,
4H), 8.45 (d, 2H), Ar], 11.59 (s, 2H, NH); IR (Nujol) 3334 (OH),
1676 (CdO), 1640 (CdO) cm-1; MS (NH3-DCI) m/ e 747 (M +
(c ) 0.082, MeOH). Anal. Calcd for C47H46N6O5‚0.5H2O, MW
783.93: C, 72.01; H, 6.04; N, 10.72. Found: C, 71.84; H, 6.08;
N, 10.47.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(6-m eth yl-2-pyr idin yl)ben zam ide] (22).
By substituting 2-amino-6-picoline in the Weinreb method for
15, the desired product was obtained in 17% (0.219 g) yield:
1); [R]20 +57.14° (c ) 0.098, DMSO). Anal. Calcd for
1
mp 135-136 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.47
D
C45H42N6O5‚2HCl, MW 819.80: C, 65.93; H, 5.41; N, 10.25.
Found: C, 65.72; H, 5.64; N, 10.10.
(s, 6H, ArCH3), 2.76 (dd, 2H, Ar′CH), 3.0 (m, 4H, Ar′CHC-
NCH), 3.55 (m, 4H, Ar′CCHCHO), 4.6 (br s, 2H, OH), 4.68 (d,
J ) 14.3 Hz, 2H, NCH), [6.95 (d, 4H), 7.08 (d, 2H), 7.2 (m,
6H), 7.40 (d, 2H), 7.46 (dd, 2H), 7.79 (dd, 2H), 7.89 (s, 2H), 8.0
(m, 4H), Ar], 10.80 (s, 2H, NH); IR (Nujol) 3385 (OH), ∼1660
(CdO) cm-1; UV-vis (c ) 0.0200 mg/mL, MeOH) λmax 285
(29 408), 251 (19 412), 216 (45 178) nm; MS (NH3-DCI) m/ e
775 (M + 1), 388 (M + 2H)2+; [R]20D +81.69° (c ) 0.142, MeOH).
Anal. Calcd for C47H46N6O5‚H2O, MW 792.94: C, 71.19; H,
6.10; N, 10.60. Found: C, 71.02; H, 6.04; N, 10.39.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-2-p yr id in ylben za m id e] (18b). A solu-
tion of 18a (0.240 g, 0.030 mmol) in 10 mL of acetonitrile was
treated with 10 mL of 1 N HCl and stirred at room temper-
ature until no starting material remained (2.5 h) as evidenced
by TLC (CHCl3-MeOH, 9:1). The mixture was made alkaline
with 5% NaHCO3 and stirred at room temperature for an
additional 3 h. The resulting white solid was collected by
filtration, washed with water, and air dried to give the desired
product in 91% (0.2046 g) yield: 1H NMR (300 MHz, DMSO-
d6 TMS) δ 2.78 (dd, 2H, Ar′CH), 3.0 (m, 4H, Ar′CHCNCH),
3.5 (m, 4H, OCHCH), 4.64 (d, J ) 13.9 Hz, 2H, NCH), 5.16 (s,
2H, OH), [6.95 (d, 4H), 7.2 (m, 8H), 7.37 (d, 2H), 7.44 (dd, 2H),
7.85 (m, 4H), 7.95 (d, 2H), 8.18 (d, 2H), 8.40 (d, 2H), Ar], 10.77
(s, 2H, NH); IR (Nujol) 3397 (OH), 1678 (CdO), 1635 (CdO)
cm-1; UV-vis (c ) 0.0149 mg/mL, MeOH) λmax 281 (29 686),
246 (25 352), 214 (57 591) nm; MS (NH3-DCI) m/ e 747 (M +
1). Anal. Calcd for C45H42N6O5, MW 746.78: C, 72.37; H, 5.67;
N, 11.25. Found: C, 71.98; H, 5.98; N, 11.06.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m e t h y le n e )]b is [N -(4,6-d im e t h y l-2-p y r id in y l)b e n z-
a m id e] (23). By substituting 2-amino-4,6-dimethylpyridine
in the DCC-HOBt method for 8, the desired product was
obtained in 66% yield from 1c: mp 166-170 °C; 1H NMR
(300 MHz, DMSO-d6 TMS) δ 2.40 (s, 6H, ArCH3), 2.51 (s,
6H, ArCH3), 2.78 (dd, 2H, Ar′CH), 3.00 (d, J ) 13.2 Hz, 2H,
Ar′CH), 3.07 (d, J ) 14.3 Hz, 2H, NCH), 3.6 (m, 4H, OCHCH),
4.67 (d, J ) 14.3 Hz, 2H, NCH), [6.94 (d, 4H), 7.10 (s, 2H),
7.2 (m, 6H), 7.42 (d, 2H), 7.51 (dd, 2H), 7.92 (s, 2H), 7.96 (s,
2H), 8.05 (d, 2H), Ar], 11.27 (s, 2H, NH); IR (KBr) 3418 (OH,
1680 (CdO), 1644(CdO) cm-1; MS (NH3-DCI) m/ e 803 (M +
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(3-m eth yl-2-pyr idin yl)ben zam ide] (19).
By substituting 2-amino-3-picoline in the Weinreb method
described for 15, the desired product was obtained in 24%
1); [R]20 +74.66° (c ) 0.446, MeOH). Anal. Calcd for
D
C49H50N6O5‚3.5H2O, MW 866.00: C, 67.95; H, 6.64; N, 9.71.
Found: C, 67.72; H, 6.26; N, 9.66.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(5-ch lor o-2-pyr idin yl)ben zam ide] (24).
By substituting 2-amino-5-chloropyridine in the Weinreb
method for 15, the desired product was isolated in 85% (1.042
g) yield: mp 261-264 °C; 1H NMR (300 MHz, DMSO-d6 TMS)
δ 2.77 (dd, 2H, Ar′CH), 2.98 (d, J ) 12.4 Hz, 2H, Ar′CH), 3.04
(d, J ) 14.28 Hz, 2H, NCH), 3.52 (2d, 4H, OCHCH), 4.68 (d,
J ) 14.28 Hz, 2H, NCH), 5.15 (s, 2H, OH), [6.95 (d, 4H), 7.22
(m, 6H), 7.39 (d, 2H), 7.47 (dd, 2H), 7.87 (s, 2H), 7.95 (d, 4H),
8.223 (d, 2H), 8.44 (d, 2H), Ar], 10.99 (s, 2H, NH); IR (KBr)
3420 (OH, NH), 1680 (CdO) cm-1; MS (NH3-DCI) m/ e 832 (M
1
(0.296 g) yield: mp 142-143 °C; H NMR (300 MHz, DMSO-
d6 TMS) δ 2.13 (s, 6H, ArCH3), 2.81 (dd, 2H, Ar′CH), 3.0 (m,
4H, Ar′CH, NCH), 3.5 (m, 6H, Ar′CCHCH(OH)), 4.68 (d, J )
14.3 Hz, 2H, NCH), [6.95 (d, 4H), 7.22 (m, 8H), 7.35 (m, 2H),
7.48 (dd, 2H), 7.72 (d, 2H), 7.86 (s, 2H), 7.92 (d, 2H), 8.31 (d,
2H), Ar], 10.56 (s, 2H, NH); IR (Nujol) 3420 (OH), 1674 (CdO),
1630 (CdO) cm-1; MS (NH3-DCI) m/ e 775 (M + 1), 388 (M +
2H)2+; [R]20 +86.49° (c ) 0.074, MeOH). Anal. Calcd for
D
C47H46N6O5‚H2O, MW 792.94, 774.93: C, 71.19; H, 6.10; N,
10.60. Found: C, 71.27; H, 6.05; N, 10.49.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(4-m eth yl-2-pyr idin yl)ben zam ide] (20).
By substituting 2-amino-4-picoline in the Weinreb method for
15, the desired product was obtained in 18% (0.221 g) yield:
+ NH4); [R]20 +59.13° (c ) 0.504, DMSO). Anal. Calcd for
D
C45H40N6O5Cl2‚0.5H2O: C, 65.53; H, 5.01; N, 10.19. Found:
C, 65.34; H, 4.82; N, 10.00.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m e t h y le n e )]b is [N -(3,5-d ic h lo r o -2-p y r id in y l)b e n z -
a m id e] (25). By substituting 2-amino-3,5-dichloropyridine in
the Weinreb method for 15, the desired product was isolated
in 66% yield from 1b: mp 238-241 °C dec; 1H NMR (300 MHz,
DMSO-d6 TMS) δ 2.79 (dd, 2H, Ar′CH), 3.01 (m, 4H, Ar′CH-
CNCH), 3.53 (m, 4H, OCHCH), 4.65 (d, J ) 13.92 Hz, 2H,
NCH), 5.16 (s, 2H, OH), [6.94 (d, 4H), 7.21 (m, 6H), 7.39 (d,
2H), 7.49 (dd, 2H), 7.83 (s, 2H), 7.89 (d, 2H), 8.34 (d, 2H), 8.54
(d, 2H), Ar], 10.83 (s, 2H, NH); IR (KBr) 3420 (OH, NH), 1680
(CdO), 1644 (CdO) cm-1; MS (NH3-DCI) m/ e 885 (M + 1),
1
mp 139-140 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.37
(s, 6H, ArCH3), 2.79 (m, 2H, Ar′CH), 3.0 (m, 4H, Ar′CHCNCH),
3.5 (m, 4H, Ar′CCHCHO), 4.68 (d, J ) 14.3 Hz, 2H, NCH),
[6.97 (m, 4H), 7.05 (d, 2H), 7.23 (m, 6H), 7.39 (d, 2H), 7.47
(dd, 2H), 7.88 (s, 2H), 7.96 (d, 2H), 8.00 (s, 2H), 8.25 (d, 2H),
Ar], 10.85 (s, 2H, NH); IR (Nujol) 3385 (OH), 1678 (CdO), 1650
(CdO) cm-1; UV-vis (c ) 0.0190 mg/mL, MeOH) λmax 280
(28 631), 256 (24 226), 216 (50 778) nm; MS (NH3-DCI) m/ e
775 (M + 1), 388 (M + 2H)2+; [R]20D +80.00° (c ) 0.080, MeOH).
Anal. Calcd for C47H46N6O5‚1.5H2O, MW 791.94: C, 70.39; H,
6.16; N, 10.48. Found: C, 70.56; H, 6.08; N, 10.36.
902 (M + NH4); [R]20 +53.87° (c ) 0.698, DMSO). Anal.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(5-m eth yl-2-pyr idin yl)ben zam ide] (21).
By substituting 2-amino-5-picoline in the Weinreb method for
15, the desired product was obtained in 13% (0.157 g) yield:
D
Calcd for C45H38N6O5Cl4, MW 884.65: C, 61.10; H, 4.33; N,
9.50; Cl, 16.03. Found: C, 61.41; H, 4.35; N, 9.31; Cl, 16.04.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m e t h yle n e )]b is[N -(5-b r om o-2-p yr id in yl)b e n za m id e ]
Mon oh yd r a te (26). By substituting 2-amino-5-bromopyri-
dine in the modified Weinreb method for 15, the desired
product was obtained in 30% (0.406 g) yield: mp 162-164 °C;
1H NMR (300 MHz, DMSO-d6 TMS) δ 2.77 (dd, 2H, Ar′CH),
3.00 (m, 4H, Ar′CH, NCH), 3.5 (m, 4H, OCHCH), 4.68 (d, J )
13.9 Hz, 2H, NCH), [6.95 (d, 4H), 7.2 (m, 6H), 7.38 (d, 2H),
7.47 (dd, 2H), 7.87 (s, 2H), 7.93 (m, 2H), 8.19 (d, 2H), 8.51 (m,
2H), Ar], 10.98 (s, 2H, NH); IR (KBr) 3422 (OH, NH), 1688
1
mp 132-133 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.28
(s, 6H, ArCH3), 2.78 (dd, 2H, Ar′CH), 3.0 (m, 4H, Ar′CHC-
NCH), 3.45 (2, OH), 3.5 (m, 4H, Ar′CCHCHO), 4.68 (d, J )
14.3 Hz, 2H, NCH), [6.96 (d, 4H), 7.22 (m, 6H), 7.37 (d, 2H),
7.46 (dd, 2H), 7.68 (m, 2H), 7.87 (s, 2H), 7.95 (d, 2H), 8.08 (d,
2H), 8.22 (s, 2H), Ar], 10.72 (s, 2H, NH); IR (Nujol) 3392 (OH),
1676 (CdO), 1646 (CdO) cm-1; UV-vis (c ) 0.0170 mg/mL,
MeOH) λmax 287 (28 399), 258 (24 980), 215 (50 962) nm; MS
(NH3-DCI) m/ e 775 (M + 1), 388 (M + 2H)2+; [R]20 +82.93°
D

HIV Protease Inhibitory Bis-benzamide Ureas
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4311
(CdO), 1642 (CdO) cm-1; MS (NH3-DCI) m/ e 922 (M + NH4);
[R]20D +51.30° (c ) 0.31, DMSO). Anal. Calcd for C45H40N6O5-
Br2‚H2O, MW 922.68: C, 58.58; H, 4.59; N, 9.11; Br, 17.32.
Found: C, 58.51; H, 4.22; N, 8.99; Br, 17.43.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N,N′-d im eth ylben za m id e] (31). By sub-
stituting dimethylamine in the BOP method, the desired
product was obtained in 94% yield as a glass: 1H NMR (300
MHz, DMSO-d6 TMS) δ 2.69 (m, 2H, Ar′CH), 2.9-3.03 (m, 4H,
Ar′CH, NCH), 3.38 (s, 12H, N(CH3)2), 3.47 (m, 4H, CHCH-
CHCH), 4.56 (d, J ) 14.0 Hz, 2H, NCH), 5.16 (s, 2H, OH),
6.8-7.7 (m, 18H, Ar); MS (NH3-DCI) m/e 649 (M + 1). Anal.
Calcd for C39H44N4O5, MW 648.81: C, 72.20; H, 6.84; N, 8.64.
Found: C, 71.89; H, 7.02; N, 8.57.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m e t h y le n e )]b is [N -(4-m e t h y l-2-p y r im id in y l)b e n za -
m id e] Sesqu ih yd r a te (27). By substituting 2-amino-4-
methylpyrimidine in the modified Weinreb method for 15, the
desired product was obtained in 24% (0.245 g) yield: mp 154-
159 °C; 1H NMR (300 MHz, DMSO-d6 TMS) δ 2.47 (s, 6H,
CH3), 2.79 (dd, 2H, Ar′CH), 3.0 (m, 4H, Ar′CH, NCH), 3.35 (s,
HOD), 3.5 (m, 4H, OCHCH), 4.68 (d, J ) 13.9 Hz, 2H, NCH),
5.17 (s, 2H, OH), [6.95 (m, 4H), 7.12 (d, 2H), 7.25 (m, 6H),
7.35 (d, 2H), 7.46 (dd, 2H), 7.83 (s, 2H), 7.88 (d, 2H), 8.55 (d,
2H), Ar], 10.90 (s, 2H, NH); IR (KBr) 3420(OH and NH), 1694
(CdO), 1640 (CdO) cm-1; MS (NH3-DCI) m/ e 777 (M + 1);
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-(4-m eth yl-2-oxazolyl)ben zam ide] (Test-
1). By substituting 2-amino-4-methyloxazole in the DCC-
HOBt method, the desired product was obtained in 8% yield:
mp 155-157 °C dec; 1H NMR (300 MHz, DMSO-d6 TMS) δ
2.08 (s, 6H, CH3), 2.76 (dd, 2H, Ar′CH), 3.0 (m, 4H, Ar′CH,
NCH), 3.53 (m, 4H, OCHCH), 4.65 (d, J ) 13.9 Hz, 2H, NCH),
5.16 (s, 2H, OH), 6.9-7.95 (m, 20H, Ar), 11.44 (s, 2H, NH); IR
(KBr) 3420 (OH, NH), 1694 (CdO), 1602 (CdO) cm-1; UV-
vis (c ) 0.0160 mg/mL, MeOH) λmax 267 (19 862), 218 (41 187)
nm; MS (NH3-DCI) m/ e 755 (M + 1); [R]20D +78.75° (c ) 0.08,
MeOH). Anal. Calcd for C43H42N6O7 0.5H2O, MW 763.82: C,
67.61; H, 5.67; N, 11.00. Found: C, 67.30; H, 5.60; N, 10.76.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-[5-(tr iflu or om eth yl)-1,3,4-th ia d ia zol-
2-yl]ben za m id e] (Test-2). By substituting 2-amino-5-(tri-
fluoromethyl)-1,3,4-thiadiazole in the DCC-HOBt method, the
desired product was obtained in 91% yield: mp 196 °C dec;
1H NMR (300 MHz, DMSO-d6 TMS) δ 2.79 (m, 2H, Ar′CH),
3.04 (m, 2H, Ar′CH), 3.36 (d, J ) 14.3 Hz, 2H, NCH), 3.45-
3.75 (m, 4H, CHCHCHCH), 4.62 (d, J ) 14.3 Hz, 2H, NCH),
5.23 (s, 2H, OH), 6.9-8.3 (m, 18H, Ar), 8.05 (s, 2H, NH); 19F
NMR (282 MHz, DMSO-d6 TMS) δ -58.739; IR (Nujol) 3464
(OH, NH), 1648 (CdO) cm-1; MS (NH3-DCI) m/e 897 (M + 1).
Anal. Calcd for C41H34F6N8O5S2, MW 896.89: C, 54.91; H,
3.82; N, 12.49. Found: C, 54.86; H, 4.01; N, 12.38.
[R]20 +68.22° (c
) 0.26, MeOH). Anal. Calcd for
D
C45H44N8O5‚1.5H2O, MW 803.89: C, 67.24; H, 5.89; N, 13.94.
Found: C, 67.05; H, 5.58; N, 13.72.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-[5-(tr iflu or om eth yl)-2-p yr id in yl]ben -
za m id e] (28). By substituting 2-amino-5-(trifluoromethyl)-
pyridine in the acid chloride method for 14, the desired product
was obtained in 22% overall yield: mp 251-252 °C; 1H NMR
(300 MHz, DMSO-d6 TMS) δ 2.75 (dd, 2H, Ar′CH), 2.98 (m,
2H, Ar′CH), 3.05 (d, J ) 14.3 Hz, 2H, NCH), 3.56 (m, 4H,
CHCHCHCH), 4.68 (d, J ) 14.3 Hz, 2H, NCH), 5.15 (s, 2H,
OH), [6.95 (d, 4H), 7.21 (m, 6H), 7.40 (d, 2H), 7.48 (dd, 2H),
7.88 (s, 2H), 7.96 (d, 2H), 8.23 (m, 2H), 8.39 (d, 2H), 8.78 (s,
2H), Ar], 11.27 (s, 2H, NH); UV-vis (c ) 0.0190 mg/mL,
MeOH) λmax 282 (36 476), 254 (32 387) nm; MS (NH3-DCI) m/ e
+
calcd for C47H41F6N6O5 883.306 949, found 883.305 332.
(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-2-p yr a zin ylben za m id e] (29). By sub-
stituting 2-aminopyrazine in the Weinreb method for 15, the
desired product was obtained in 58% (0.659 g) yield from 1b:
1
mp 146-148 °C; H NMR (300 MHz, DMSO-d6 TMS) δ 2.77
(dd, 2H, Ar′CH), 2.99 (d, J ) 13.18 Hz, 2H, Ar′CH), 3.07 (d, J
) 14.28 Hz, 2H, NCH), 3.55 (m, 4H, OCHCH), 4.69 (d, J )
14.28 Hz, 2H, NCH), 5.17 (s, 2H, OH), [6.95 (d, 4H), 7.22 (m,
6H), 7.42 (d, 2H), 7.50 (dd, 2H), 7.90 (s, 2H), 7.98 (d, 2H), 8.42
(d, 2H), 8.48 (d, 2H), 9.41 (s, 2H), Ar], 11.13 (s, 2H, NH); IR
(KBr) 4312 (OH), 1686 (CdO), 1642 (CdO) cm-1; UV-vis (c )
0.0210 mg/mL, MeOH) λmax 298 (20 076), 284 (25 140), 245
(25 140), 217 (42 898) nm; MS (NH3-DCI) m/ e 749 (M + 1),
375 (M + 2)2+; [R]20D +78.57° (c ) 0.084, MeOH). Anal. Calcd
for C43H40N8O5, MW 748.84: C, 68.97; H, 5.38; N, 14.96.
Found: C, 68.70; H, 5.38; N, 14.72.
Ack n ow led gm en t. The authors would like to thank
Ronald Klabe and J ames Meek for providing the pro-
tease inhibition Ki values and Lee Bacheler and Beverly
Cordova for providing the viral replication inhibition
IC90 values.
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(4r,5r,6â,7â)-3,3′-[[Tetr a h yd r o-5,6-d ih yd r oxy-2-oxo-4,7-
b is(p h e n ylm e t h yl)-1H -1,3-d ia ze p in e -1,3(2H )-d iyl]b is-
(m eth ylen e)]bis[N-2-p yr im id in ylben za m id e] (30). Alter -
n a te Meth od . By substituting 2-aminopyrimidine in the
Weinreb method for 15, the desired product was obtained in
81% yield from 1b: mp 149-151 °C; 1H NMR (300 MHz,
DMSO-d6 TMS) δ 2.80 (dd, 2H, Ar′CH), 2.99 (m, 4H, Ar′CH-
CNCH), 3.52 (m, 4H, OCHCH), 4.69 (d, J ) 13.92 Hz, 2H,
NCH), 5.17 (s, 2H, OH), [6.95 (d, 4H), 7.23 (m, 8H), 7.37 (d,
2H), 7.47 (dd, 2H), 7.83 (s, 2H), 7.94 (d, 2H), 8.73 (d, 4H), Ar],
11.01 (s, 2H, NH); IR (KBr) 3410 (OH, NH), 1694 (CdO), 1638
(CdO) cm-1; MS (NH3-DCI) m/ e 749 (M + 1), 375 (M + 2)2+
;
[R]20D +80.75° (c ) 0.40, MeOH). Anal. Calcd for C43H40N8O5,
MW 748.85: C, 68.97; H, 5.38; N, 14.96. Found: C, 68.98; H,
5.53; N, 14.75.
Alternatively, by substituting 2-aminopyrimidine in the
method for 8, the desired product was obtained in 7% (0.055
1
g) yield: mp 147 °C dec; H NMR (300 MHz, CDCl3 TMS) δ
2.93 (m, 2H), 3.17 (m, 2H, Ar′CH2), 3.31 (d, J ) 14.5 Hz, 2H,
NCH), 3.68 (d, J ) 10.3 Hz, 2H, Ar′CCH), 3.94 (s, 2H, OCH),
4.76 (d, J ) 14.5 Hz, 2H, NCH), 6.95-8.2 (m, 26H, Ar, NH);
IR (Nujol) 3410 (OH), 1798 (CdO), 1640 (CdO) cm-1; MS (NH3-
DCI) m/ e 749 (M + 1). Anal. Calcd for C43H40N8O5, MW
748.85: C, 68.97; H, 5.38; N, 14.96. Found: C, 69.01; H, 5.43;
N, 14.88.

4312 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
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J M9602773