Diaminoindanes as microsomal triglyceride transfer protein inhibitors

Article abstract of DOI:10.1021/jm010294e

The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC₅₀ values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.

Full text of DOI:10.1021/jm010294e

J . Med. Chem. 2001, 44, 4677-4687
4677
Dia m in oin d a n es a s Micr osom a l Tr iglycer id e Tr a n sfer P r otein In h ibitor s
Gary M. Ksander,* Reynalda deJ esus, Andrew Yuan, Cynthia Fink, Michael Moskal, Eric Carlson,
Paivi Kukkola, Natalie Bilci, Eli Wallace, Alan Neubert, David Feldman, Therese Mogelesky, Kevin Poirier,
Michael J eune, Ronald Steele, J ong Wasvery, Zouhair Stephan, Edna Cahill, Randy Webb, Aida Navarrete,
Warren Lee, J oyce Gibson, Natalya Alexander, Haamid Sharif, and Ashok Hospattankar
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Reasearch, Summit, New J ersey 07901
Received J une 27, 2001
The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal
triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds,
8a R, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer
of triglycerides between synthetic acceptor and donor liposomes with IC50 values of 0.7 and 70
nM, respectively. In normolipidemic rats and dogs, oral administration of 8a R dose-dependently
reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8a R also
prevented the postprandial rise in plasma triglycerides following a bolus administration of a
fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver,
the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic
cholesterol and triglyceride contents were dose-dependently increased by 8a R. However, hepatic
lipid accumulation resulted in negligible change in total liver weight and was reversible after
withdrawal of the compound.
In tr od u ction
recombinant truncated apoB variants, apoB is secreted
only when MTP is coexpressed.4 Similar genetic and
cellular studies have indicated that MTP is integrally
involved in the lipidation and assembly of intestinal
chylomicrons and hepatic VLDL particles.5
Microsomal triglyceride transfer protein (MTP) is
involved in the assembly of triglyceride-rich chylomi-
crons in enterocytes and very low density lipoproteins
(VLDL) in hepatocytes. In the process of lipoprotein
assembly, MTP accelerates the transfer of neutral lipids
to apoB-containing lipoproteins.1 The production of apoB
is constitutive, but in the absence of triglycerides (TG),
the apoB is readily degraded within the endoplasmic
reticulum (ER) of enterocytes and hepatocytes. MTP
accelerates the transfer of triglycerides, cholesterol
esters, and phospholipids from the ER membranes of
hepatocytes and enterocytes to apoB-containing lipo-
proteins in the lumen of the rough ER. Therefore,
inhibition of the transfer of triglycerides and cholesterol
ester by MTP is expected to stimulate apoB degradation,
thus decreasing the intracellular pool of apoB available
for the assembly of chylomicron and VLDL particles. A
reduction in chylomicron particles should lead to de-
creased levels of postprandial plasma TG. Because
plasma VLDL is a precursor for LDL particle formation,
reduction in VLDL levels would lead to reduction in
levels of triglycerides and LDL cholesterol. Therefore,
an inhibitor of MTP and thus apoB secretion should
reduce both plasma TG and cholesterol levels.2
Elevated levels of plasma TG and cholesterol are
significant risk factors for myocardial infarction and the
progression of coronary artery lesions.6 There is a high
prevalence of combined hyperlipidemia (elevated plasma
cholesterol and triglycerides) among the hyperlipidemic
population. Because MTP inhibitors have the potential
to reduce both plasma cholesterol and TG, these agents
could provide the maximum benefit for subjects with
combined hyperlipidemia. In this paper we describe the
synthesis and biological activities of MTP inhibitors.
Ch em istr y
The preparation of diaminoindane derivatives is
outlined in Scheme 1. Substituted o-bromo or -hydroxy
benzoates were derivatized and coupled with aryl bo-
ronic acids under Suzuki coupling conditions to give the
biaryl derivatives 5 in good yields. Hydrolysis of the aryl
esters 5 to the carboxylic acid with 1 N NaOH followed
by treatment with oxalyl chloride afforded the biaryl
intermediates 7. The chiral diaminoindane carbamates
1R and 1S, outlined in Scheme 1, were prepared using
two routes from either R or S phenylalanine or via
resolution of racemic 5-bromo-2-aminoindane followed
by Buchwald amination. Synthetic details for the large-
scale resolution process have been published.7 The
racemic diaminoindane (1) was prepared from 2-NHAc
indane following a published procedure.8 Amide forma-
tion by coupling the monosubstituted diamines 1 and
acid chlorides 7 gave the biaryl-substituted diamino-
amides 8. Removal of the methyl carbamate with TMSI
produced the biaryl 2-aminoindanes 9. Reaction of 9
with the appropriate acylating agent gave the desired
The critical requirement of MTP for apoB secretion
has been demonstrated by the human disease abetali-
poproteinemia. In patients with this rare autosomal
recessive genetic disorder, it has been demonstrated
that mutations in the MTP gene are responsible for the
absence of apoB-containing lipoproteins (chylomicrons,
VLDL, IDL, and LDL) from the plasma.3 Moreover,
when nonhepatic, nonintestinal cells express certain
* Address correspondence to this author at the Novartis Pharma-
ceuticals Corp., 556 Morris Ave., Summit, NJ 07901-1398 [telephone
(908) 277-7529; fax (908) 277-2405; e-mail gary.ksander@pharma.
novartis.com].
10.1021/jm010294e CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/21/2001

4678 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Ksander et al.
Sch em e 1a
a
Reagents and conditions: (a) mesyl chloride, diisopropyl amine; (b) trifluoromethylbenzyne boronic acid, PdCl2 (dppf); (c) NaOH,
EtOH; (d) oxalyl chloride; (e) pyridine, methylene chloride; (f) TMSI; (g) R4X, base.
Sch em e 2
followed by sodium cyanide in dimethylformamide
(DMF) gave 2-cyanoindane, which was further reduced
to the corresponding amine. At this point it was
beneficial to prepare the methyl carbamate 23, which
met two objectives: a desired final substituent and a
protecting group for further elaboration. Nitration of 23
gave a good yield of the desired racemic nitro derivative
24. The regiochemistry in the nitration would be
expected to give substitution para to the alkyl fused five-
membered ring. Because of the symmetry of the mol-
ecule 23, both para positions are equivalent, therefore
producing the same racemic mixture. In the reaction
mixture ∼10% of the dinitration products were ob-
served, which were separated from the desired product
by flash chromatography. Hydrogenation of the nitro
intermediate gave the mono-protected diamine 25.
The two-carbon-extended analogue 34 was prepared
starting with 2-indanone. The two-carbon extension was
introduced by reacting 2-indanone with trimethylphos-
phonoacetate and sodium hydride (Scheme 4). Hydro-
genation of the double bond, amide formation from the
ester with ammonium hydroxide and ammonium hydro-
chloride, followed by lithium aluminum hydride reduc-
tion gave the desired amine 33. Following the same syn-
thetic sequence of nitration, reduction, and coupling as
described in Scheme 3 produced the desired target 34.
N-substituted 2-aminoindanes 10-15. The preparation
of the N-alkyl derivatives 16 and 17 was accomplished
by reductive amination of the free amines 9 with either
benzaldehyde or 2-pyridine carboxaldehyde.
The piperazinoindane 19 was prepared in low yield
by condensing N,N-bis(2-chloroethyl)carbamic acid meth-
yl ester under basic conditions with 9a (Scheme 2). The
low yield was probably due to consumption of the
alkylating agent under the reaction conditions.
The biaryl-substituted one-carbon-extended 2-indanes
26-29 were prepared by coupling the two intermediates
7 and 25 followed by deprotection and sulfonylation
(Scheme 3). Treatment of 2-indanol with mesyl chloride
The preparation of the seven-membered ring ana-
logues 37-9 is shown in Scheme 5. Condensation of
hydroxylamine hydrochloride with 5,6,8,9-tetrahydro-
7H-cycloheptabenen-7-one followed by reduction with

Diaminoindanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4679
Sch em e 3a
a
(a) Mesyl chloride, diisopropylethylamine; (b) NaCN, DMF; (c) lithium aluminum hydride; (d) methyl chloroformate; (e) HNO3/TFA;
(f) H2/Pd-C; (g) 7, pyridine; (h) TMSI; (i) R4-X.
Sch em e 4a
a
(a) Trimethylphosphonoacetate, NaH; (b) H2/Pd-C; (c) NH4OH,
NH4Cl; (d) lithium aluminum hydride; (e) sequence as described
in Scheme 3.
F igu r e 1. Random screening hit.
Sch em e 5a
Apolipoprotein B is synthesized and secreted by hu-
man hepatoma cells (Hep G2). The secreted apoB is
associated with lipids, and the rate of apoB secretion
from cells is dependent on the MTP-mediated lipidation
of apoB. The secondary screen (MTP-mediated transfer
activity) was designed to test the ability of compounds
to interfere with MTP-mediated transfer of triglycerides
from synthetic phospholipid donor vesicles to the syn-
thetic acceptor vesicles. The use of synthetic liposomes
in the MTP transfer assay creates a nonphysiological
condition that affects the assay sensitivity. Therefore,
the apoB secretion assay in Hep G2 cells provided data
under more physiological conditions. The structure-
activity relationship discussion will be based on the
cellular apoB secretion data.
a
(a) Hydroxylamine hydrochloride; (b) NaBH4; (c) sequence as
The simple amide, compound A (Figure 1), was iden-
tified in the high-throughput apoB secretion assay. The
described in Scheme 3.
general strategy was to keep either the acid or the
sodium borohydride gave the desired amine 36. Elabo-
amine constant and vary the other component. This ap-
ration of the monoamine 36 as described in Scheme 3
proach led to compounds B and C with improved in vitro
gave the desired seven-membered ring analogues
potency. Mixing and matching acids and amines led to
37-39.
the biarylindane structure D. An additional binding site,
needed for low nanomolar potency, was accessed by
substituting heteroatoms around the five-membered
In Vitr o Resu lts a n d Discu ssion
ring, which led to the diaminoindanes (Table 1).
By keeping the trifluoromethyl substituent (R) con-
stant on the distal biaryl ring and modifying R1-R4,
some general conclusions can be made concerning the
in vitro apoB secretion inhibitory activity of these
compounds (Table 1). Both R and S carbamates are
potent inhibitors of apoB secretion. However, the R
Presently there are no structural data available to
produce a molecular model for MTP. Therefore, we pro-
filed compounds by first using random screening for
inhibitors of apoB secretion5c,9 (primary screen) followed
by an assay that measured MTP-mediated transfer of
labeled triglycerides10 between synthetic vesicles (sec-
ondary screen).

4680 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Ksander et al.
Ta ble 1. In Vitro ApoB and MTP Inhibition of Substituted Diaminoindanes
apoB
IC50 (nM)
MTP
IC50 (nM)
compd
chirality
R
R1
R2
R3
R4
8a R
8a S
8bR
8bS
10bS
10bR
11a R
11a S
11b
8d R
8eR
8fR
12a S
12gS
12gR
8gS
8gR
13b
14b
15b
16b
17a R
17a S
10h
12h
11h
R
S
R
S
S
R
R
S
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
F
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
CF3
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
CO2Me
CO2Me
CO2Me
CO2Me
SO2Ph
SO2Ph
SO2CH3
SO2CH3
SO2CH3
CO2Me
0.7
6.4
1.9
5.2
1.3
42
8.8
1.8
60
2.2
1.8
7.5
0.9
1.0
2.6
2.5
1.1
120
270
120
340
1.7
30% at 100 nM
1.2
1.4
8.3
2.5
5.5
2.4
6.6
3.0
3.4
2
15
12
70
70
68
110
105
650
204
34
120
170
50
410
50
20
180
90
70
H
CH3
CH3
H
H
CF3
H
CH3
CH3
CH3
CH3
CH3
H
racemic
R
R
R
S
S
R
S
R
racemic
racemic
racemic
racemic
R
CO2Me
CO2Me
SO2-thienyl
SO2-thienyl
SO2-thienyl
CO2CH3
CO2CH3
COCH3
COPh
CON(CH3)2
CH2Ph
CH2-2-pyr
CH2-2-pyr
SO2Ph
SO2-thienyl
SO2CH3
SO2Ph
SO2Ph
SO2Ph
SO2CH3
SO2-thienyl
CO2Me
SO2Ph
SO2CH3
SO2Ph
80
H
H
H
>1000
80
4800
100
410
240
50
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
H
S
racemic
racemic
racemic
racemic
racemic
racemic
racemic
racemic
R
F
F
CH3
CN
Cl
Cl
Cl
Cl
Cl
170
93
10i
10j
10k
11k
12k
8lR
10m
11m
10n
120
100
100
120
120
110
70
racemic
racemic
racemic
Cl
H
710
enantiomer is 3-6-fold more active. In the sulfonamide
series the reverse appears to be the rule. The (S) methyl
and thienyl sulfonamides are ∼3-4-fold more potent
than the corresponding R enantiomer. A difference of
30-fold in potency of enantiomers was observed between
the phenyl sulfonamides 10b(S) and 10b(R). However,
the greatest difference in activity between enantiomers
was observed in the methylene 2-pyridyl compounds
17a (R) and 17a (S).
Ta ble 2. In Vitro ApoB and MTP Inhibition of Substituted
Piperazinoindanes
In general, compounds with a methyl group on the
proximal phenyl ring, R1 position, were more potent
than those with hydrogen in the R1 position. Methyl
substitution in the R3 position and in combination with
R1 methyl substitution resulted in compounds with
similar activities. Substitution on the 2-aminoindane,
R4, included carbamate, sulfonamide, amide, urea, and
alkylamine. The carbamates, phenyl, thienyl, methyl
sulfonamides, and methylene 2-pyridyl derivatives are
all potent inhibitors of apoB secretion. A significant
decrease in activity was observed with amides (13b and
14b), the urea 15b, and the benzylamine 16b. The
trifluoromethyl substituent (R) on the distal aromatic
biphenyl ring can be replaced by a fluoro, methyl, cyano,
or chloro substituent while maintaining or producing a
apoB
MTP
compd
R
R1
R2 R3 chirality IC50 (nM) IC50 (nM)
19a R CF3 CH3
19a S CF3 CH3
H
H
H
H
R
S
1.8
43
40
1000
slight 2-3-fold reduction of inhibitory activity. In the
absence of a para substituent (R ) H) a 10-fold reduc-
tion of apoB inhibitory activity was observed. It was
found that the 2-aminoindane nitrogen could be incor-
porated in a piperazine ring (Table 2) and maintain good
in vitro activity. The R-enantiomer was ∼20 times more
potent than the corresponding S-enantiomer. Although
only a limited number of racemic methylene- or ethyl-
ene-extended derivatives were prepared, good in vitro

Diaminoindanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4681
Ta ble 3. In Vitro ApoB and MTP Inhibition of Substituted
Aminoindanes
Ta ble 5. Time Course for Inhibition of Plasma Triglycerides
and Total Cholesterol in Normolipidemic Rats after Oral
Administration
TG % reductiona
2, 6, and 24 h
CH % reductiona
2, 6, and 24 h
compd
dose
post oral dosing
post oral dosing
8a R
8a R
8a R
8a S
8a S
8bR
50
10
5
50
5
81, 71, 63
84, 68, NS
78, 59, NS
78, 74, NS
85, 71, NS
69, 74, NS
NS, NS, NS
57, 30, NS
33, 33, NS
74, 68, NS
NS, NS, NS
88, 83, 76
83, 56, NS
74, 37, NS
77, 48, 46
79, 68, NS
91, 88, NS
86, 47, NS
80, 56, 44
70, NS, 29
58, NS, NS
49, NS, NS
NS, NS, NS
39, NS, NS
81, 53, NS
73, 44, 36
33, 52, 60
41, 58, 16
30, 47, NS
27, 43, NS
33, 45, NS
20, 39, NS
NS, NS, NS
21, NS, NS
12, 15, NS
27, 42, NS
NS, NS, NS
25, 50, 67
26, 39, NS
23, 34, NS
21, 34, 47
33, 46, NS
40, 57, 29
34, 35, NS
35, 50, 18
40, 29, 15
23, 20, NS
NS, NS, NS
NS, NS, NS
20, 20, NS
29, 41, 17
17, 21, 22
apoB
MTP
compd
X
R
R1 R2 R3
R4
IC50 (nM) IC50 (nM)
50
50
50
50
50
50
50
10
5
50
50
50
10
50
10
50
50
50
50
50
50
10bR
10bS
11a R
11a S
8d R
12a S
12a S
12a S
12gS
12gR
17a R
17a R
19a R
19a R
19a S
26a
28a
26a
29a
26g
26k
28k
34a
1
1
1
1
1
1
2
CF3 CH3
CF3 CH3
CF3 CH3
CF3 CH3
Cl CH3
Cl CH3
CF3 CH3
H
H
H
H
H
H
H
H
H
H
SO2CH3
CO2CH3
SO2-thienyl
6.5
4.1
1.9
2.2
8.7
16.0
10
150
24
14
CH3 CO2CH3
40
H
H
H
CO2CH3
SO2CH3
CO2CH3
100
500
70
Ta ble 4. In Vitro ApoB and MTP Inhibition of Substituted
Diaminocycloheptabenzenes
34a
37a
38a
37g
a
Values represent mean percent inhibition for drug-treated rats
versus a separate group of vehicle-treated animals. All values are
significant where p < 0.05 using an unpaired t test. N ) 6. NS,
no significant change.
apoB
MTP
compd
R
R1 R2 R3
R4
IC50 (nM) IC50 (nM)
37a
38a
39a
37g
38k
37k
CF3 CH3
CF3 CH3
CF3 CH3
CF3 CH3
Cl
Cl
H
H
H
H
H
H
H
H
H
CO2Me
SO2CH3
SO2-thienyl
1.6
2.3
1.6
2.4
5.0
2.0
20
80
140
20
90
80
at the 24 h time point. The presence of a methyl substit-
uent (R1) apparently increases the duration of action.
As mentioned earlier, the S-enantiomers in the sul-
fonamide series inhibited apoB secretion and MTP-
mediated transfer of triglycerides in vitro to a greater
extent as compared to their respective R-enantiomers.
The in vivo effects of the phenylsulfonamide enanti-
omers 10bS and 10bR correlate with their respective
in vitro activity. The phenylsulfonamide 10bS, although
weaker than the methyl carbamates 8a R and 8a S, did
reduce plasma TG and CH ,whereas the less in vitro
active 10bR enantiomer failed to reduce plasma lipids
even at a relatively high dose of 50 mg/kg. This trend
was also observed with the methyl sulfonamides 11a S
and 11a R and the thienyl sulfonamides 12gS and 12gR.
The most potent sulfonamide, equivalent to the car-
bamate 8a R, is 12a S. This inhibitor significantly re-
duced triglycerides and total cholesterol over the entire
24 h testing period.
CH3 CO2Me
H
H
CH3
CH3
SO2CH3
CO2CH3
activity was observed (Table 3). The in vitro potency of
the benzofused seven-membered ring compounds again
demonstrates the overall flexibility of the SAR in this
region of the molecule (Table 4).
In Vivo Resu lts a n d Discu ssion
In h ibition of P la sm a Tr iglycer id es a n d Tota l
Ch olester ol in Nor m olip id em ic Ra ts. Overnight-
fasted normolipidemic rats were administered a single
oral dose of inhibitor in a cornstarch vehicle (Table 5).
Blood samples were collected 2, 6, and 24 h postdosing
and assayed for triglycerides and total cholesterol. After
the 6 h time point the rats were given free access to
food. Therefore, the 2 and 6 h triglycerides and total
cholesterol blood levels are assumed to be a result of
MTP inhibition in the liver, whereas lipid reduction at
the 24 h time point results from MTP inhibition in both
gut and liver.
Both carbamate enantiomers 8a R and 8a S reduce
plasma TG and total cholesterol (CH) in rats. Effective
reduction of plasma lipids (60-80%) was observed after
oral administration of 5 mg/kg at the 2 and 6 h time
points after dosing. The difference in efficacy between
these enantiomers was observed 24 h postdosing, when
the R-enantiomer at 50 mg/kg reduced TG and CH for
>24 h but the S-enantiomer was ineffective. The des-
methyl derivative 8bR reduced plasma TG and CH at
6 h after dosing; however, no reduction was observed
The methyl carbamate 8d R, where R1 is hydrogen
and R3 is methyl, did not reduce plasma TG or CH at
any time point. Interestingly, the corresponding methyl
carbamate 8gR, where R1 and R3 are methyl substitu-
ents, effectively reduced lipids for up to 6 h. Differences
in the metabolism of these two compounds could explain
these results.
The basic inhibitor N-methyl-2-pyridyl derivative,
17a R, reduced triglycerides and total cholesterol very
effectively over a 6 h period. Another basic inhibitor,
the pipirazine derivative 19a R, showed a slightly dif-
ferent profile from that of the previously mentioned
compounds. This compound appeared to lose efficacy
from 2 to 6 h after dosing at 50 mg/kg; however, activity

4682 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Ksander et al.
19a R, at 1 mg/kg p.o. completely blocked the prandial
increase in plasma TG induced by the administration
of 100 mL of cream. This effect persisted over 4 h
(Figure 3). This result is consistent with the hypothesis
that MTP inhibition in the gut decreases the synthesis
of gut-derived chylomicrons and thus atherogenic rem-
nant lipoproteins.
Hep a tic Lip id Accu m u la tion in Nor m olip id em ic
Ra ts. Because MTP inhibitors are known to suppress
apoB production and interfere with VLDL assembly in
liver without reducing hepatic triglyceride synthesis,
lipid accumulation in the liver is expected in animals
treated with MTP inhibitors. Accordingly, the effect of
8a R on hepatic triglyceride and cholesterol concentra-
tions was studied in normolipidemic rats.
In normolipidemic rats, hepatic lipid content was
dose-dependently increased by 8a R and was inversely
correlated with plasma lipid lowering (Table 7). In this
model, hepatic cholesterol and triglyceride content
started at about 0.1 and 0.4% of total liver weight,
respectively, in vehicle-treated rats. At an oral dose of
5 mg/kg/day with 8a R hepatic cholesterol and triglyc-
eride content never exceeded 0.3 and 1.8% of total liver
weight, respectively. Because lipids represent only a
minor fraction of total liver weight, it was not surprising
that these changes in hepatic lipid content had no
significant impact on total liver weight. The reversibility
of hepatic lipid accumulation was studied in the same
rat model. Both liver cholesterol and TG were increased
after 5 days of dosing of 8a R at 5 mg/kg (Table 8). Six
days after treatment withdrawal, hepatic lipid concen-
trations were fully returned too normal.
In summary, the series of substituted diaminoindanes
and the seven-membered ring homologues are novel
inhibitors of MTP that prevented the secretion of apoB-
containing lipoproteins from liver-derived Hep G2 cells.
The inhibitors 8aR and 19aR effectively reduced plasma
TG and CH levels in normolipidemic rats and dogs. In
addition, these compounds blocked the postprandial rise
in triglycerides after an oral fat load. Therefore, these
studies suggest that 8a R and 19a R reduce the forma-
tion of gut-derived chylomicrons and liver-derived VLDL/
LDL. Because MTP inhibitors have the potential to
reduce both plasma TG and CH, MTP inhibitors that
meet safety criteria could provide maximum benefit for
subjects with elevated lipids. Thus, MTP inhibitors
could provide an opportunity to treat combined hyper-
lipidemia and atherosclerosis.
F igu r e 2. Reduction of postprandial plasma TG by 8a R in
rats. Each point represents the mean ( SEM of baseline; n )
6 for each treatment group. Baseline TG values for rats were
46 ( 14 mg/dL.
was maintained over the next 6-24 h. After adminis-
tration of 10 mg/kg 19a R , there was no reduction of
plasma TG at 6 h. However, there was a modest but
significant reduction at 24 h. It should be noted again
that the rats were given free access to food after the
blood sample at 6 h. Therefore, the 24 h data point
reflects inhibition of MTP in both the gut and liver. The
vehicle control animals showed significant increased
levels of plasma TG due to a prandial response from
food intake. Blocking of the prandial rise in triglycerides
could explain the overall reduction of triglycerides noted
at the 24 h time point.
P ost p r a n d ia l E ffect s in Nor m olip id em ic R a t s.
Delayed clearance of postprandial lipemia has long been
proposed as a risk factor for atherosclerosis. Agents that
attenuate postprandial lipemia can act either by inhib-
iting the production of or accelerating the clearance of
intestinal triglyceride-rich particles. Inhibitors of MTP
are expected to interfere with the assembly of both gut-
derived (chylomicrons) and liver-derived (VLDL) par-
ticles. The effect of 8a R was tested on postprandial
lipemia after the consumption of a well-defined oral fat
load consisting of 320 mg of corn oil mixed with 430 mg
of sucrose in a total volume of 1 mL.
Male Sprague-Dawley rats were orally treated with
a single dose of 1 mg/kg of either 8a R or vehicle followed
immediately by an oral fat load. Blood samples were
collected at 0, 0.5, 1, 2, and 4 h, and plasma was assayed
for triglycerides. As shown in Figure 2, 8a R effectively
prevented the elevation of plasma TG after a bolus fat
load.
Exp er im en ta l Section
In h ibition of P la sm a Tr iglycer id es a n d Tota l
Ch olester ol in Nor m olip id em ic Dogs. The time
course for inhibition of plasma TG and CH in normo-
lipidemic dogs after daily oral administration for 4 days
is shown in Table 6. The MTP inhibitors were suspended
in cornstarch vehicle and administered by oral gavage.
Plasma samples were taken 24 h after dosing. Com-
pounds 8a R, 19a R, 17a R, and 12a S effectively reduced
plasma levels of triglycerides and total cholesterol after
daily oral doses of <10 mg/kg/day. Greater than 50%
reduction of lipids was observed with 8a R and 19a R at
2.5 mg/kg, and marginal activity was observed at a dose
of 1 mg/kg.
1H NMR spectra were recorded on VarianXL 400 MHz,
Varian 300 MHz, and/or Bruker AC 250 MHz spectometers
with trimethylsilane as internal standard. Optical rotations
were measured with a Perkin-Elmer model 241 polarimeter.
Melting points were taken on a Thomas-Hoover melting point
apparatus and are uncorrected. All reactions were carried out
under an atmosphere of nitrogen unless otherwise noted.
Chiral purity was determined using a Dynamax SD-200 HPLC
system.
[1,1′-Bip h en yl]-2-ca r boxylic Acid , 6-Meth yl-4′-(tr iflu o-
r om eth yl)-, Meth yl Ester (5a ). A mixture of methyl 2-bromo-
3-methylbenzoate (8.81 g, 38.5 mmol), 4-(trifluoromethyl)-
benzeneboronic acid (8.04 g, 42.3 mmol), PdCl2(dppf) (1.57 g,
1.92 mmol), K3PO4 (32.6 g, 153 mmol), and 150 mL of DME
was refluxed for 16 h under an atmosphere of nitrogen. The
reaction mixture was poured into water and extracted twice
P ostp r a n d ia l Effects in Nor m olip id em ic Dogs.
In male normolipidemic dogs both compounds, 8a R and

Diaminoindanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4683
Ta ble 6. Time Course for Inhibition of Plasma Total Cholesterol and Triglycerides in the Normolipidemic Dog after Daily Oral
Administration for 4 Days
plasma TGa (mg/dL)
plasma CHa (mg/dL)
dose
compd
(mg/kg/day)
day 0
day 2
day 3
day 4
day 0
day 2
day 3
day 4
8a R
5
2.5
1
10
5
2.5
1
10
5
48 ( 3
59 ( 9
46 ( 4
62 ( 8
37 ( 3
58 ( 9
38 ( 3
46 ( 9
36 ( 2
31 ( 2
22 ( 3*
32 ( 5*
42 ( 3
24 ( 6*
20 ( 2*
28 ( 5*
28 ( 4
26 ( 4*
38 ( 3
24 ( 2*
16 ( 3*
25 ( 4*
48 ( 6
18 ( 3*
17 ( 1*
20 ( 2*
26 ( 4
27 ( 4*
41 ( 2
24 ( 2*
12 ( 2* (-75%)
23 ( 5* (-61%)
45 ( 4
124 ( 9
113 ( 4
110 ( 6
143 ( 7
127 ( 9
109 ( 5
120 ( 8
125 ( 8
130 ( 8
120 ( 3
87 ( 11*
90 ( 10*
103 ( 9
79 ( 15*
79 ( 10*
67 ( 6
91 ( 16
69 ( 7*
110 ( 10*
81 ( 12*
68 ( 9*
76 ( 12*
101 ( 9
50 ( 12*
53 ( 8*
53 ( 5*
83 ( 14
54 ( 6*
99 ( 11*
72 ( 12*
54 ( 7* (-56%)
57 ( 8* (-50%)
89 ( 6* (-19%)
31 ( 10* (-78%)
38 ( 7* (-70%)
42 ( 4* (-61%)
73 ( 14* (-39%)
36 ( 4* (-71%)
94 ( 9* (-28%)
70 ( 14 (-42%)
19a R
17a R
19 ( 3* (-70%)
14 ( 2* (-61%)
25 ( 5* (-57%)
28 ( 4 (-27%)
23 ( 3* (-51%)
32 ( 2
12a S
5
20 ( 3* (-34%)
a
Lipid levels were measured 24 h postdosing. Values in parentheses represent mean percent inhibition for drug-treated dogs. n ) 6.
*, p < 0.05 (one-way ANOVA).
F igu r e 3. Reduction of postprandial TG in normolipidemic dogs. Dogs were dosed with 8a R and 19a R at 1 mg/kg. The fat
challenge (100 mL of cream) was administered 2 h after dosing. Each point represents the mean ( SEM of baseline, n ) 6 for
each treatment group.
Ta ble 7. Effect of 8a R on Lipid Accumulation in
Normolipidemic Rat Livers
for 5 h, cooled, and stirred overnight. The reaction mixture
was concentrated, diluted with water, and washed with ether.
The aqueous layer was acidified with 1 N HCl, extracted with
EtOAc, washed with brine, dried (MgSO4), filtered, and
concentrated to give 9.59 g of 6a as a white solid.
dose
cholesterola
triglyceridea
liver
(mg/kg)
(mg/g of liver)
(mg/g of liver)
wta (g)
vehicle
0.5
1
1.29 ( 0.04
1.40 ( 0.08
2.01 ( 0.13*
3.09 ( 0.28*
4.12 ( 0.24
4.61 ( 0.51
8.16 ( 0.81*
17.7 ( 1.25*
8.94 ( 0.27
9.13 ( 0.44
9.60 ( 0.28
9.79 ( 0.51
[1,1′-Bip h en yl]-2-ca r bon yl Ch lor id e, 6-Meth yl-4′-(tr i-
flu or om eth yl)- (7a ). To a 0 °C solution of 6a (9.59 g, 34.25
mmol) in 200 mL of CH2Cl2 was added oxalyl chloride (11.95
mL, 137 mmol) followed by 3 drops of DMF. The reaction
mixture was stirred at room temperature for 16 h and
concentrated to give 8.9 g of 7a as a yellow viscous oil.
Ca r ba m ic Acid , [(2R)-2,3-Dih yd r o-5-[[[6-m eth yl-4′-(tr i-
flu or om et h yl)[1,1′-b ip h en yl]-2-yl]ca r b on yl]a m in o]-1H -
in d en -2-yl]-, Meth yl Ester (8a R). To a 0 °C solution of 1R
(9.5 g, 46.12 mmol) in 200 mL of CH2Cl2 and pyridine (4.47
mL, 55.34 mmol) was added 0.63 M 7a (80.5 mL, 50.73 mmol
in CH2Cl2), and the reaction mixture was stirred for 15 min.
The organic layer was washed with 1 N HCl, NaHCO3, and
brine, dried (MgSO4), filtered, and concentrated. The residue
was triturated with 25 mL of warm EtOAc and 50 mL of
hexanes to give 12.8 g of 8a R as a white solid. The mother
liquor was chromatographed on silica gel eluting with EtOAc/
hexanes (1:1), which afforded another 6.93 g of 8a R (91%)
5
a
Data represent mean ( SEM (n ) 8 per group). *Statistically
different from vehicle by Student’s t test (p < 0.05)
Ta ble 8. Effect of Treatment Withdrawal of 8a R on the
Reversal of Hepatic Lipid Accumulation in Normolipidemic Rat
Livers
time of
cholesterola
triglyceridea
analysis
(mg/g of liver)
(mg/g of liver)
after treatment
vehicle
8a R
after washout
vehicle
8a R
1.33 ( 0.10
2. 81 ( 0.24
13.6 ( 1.78*
2.76 ( 0.15*
1.13 ( 0.08
1.12 ( 0.13
2.54 ( 0.26
2.38 ( 0.42
melting at 156-157 °C; [R] -12.85 (c 11.36 DMSO); 1H
D
a
Data represent mean ( SEM (n ) 8 per group). *Statistically
different from vehicle by Student’s t test (p < 0.05). Treatment
with 5 mg/kg and washout periods lasted 5 and 6 days, respec-
tively.
NMR (DMSO-d6) δ 10.03 (s, 1H), 7.74 (s, 1H), 7.72 (s, 1H),
7.48-7.38 (m, 5H), 7.27 (s, 1H), 7.12 (d, 1H, J ) 9.5 Hz), 7.03
(d, 1H, J ) 8 Hz), 4.19 (m, 1H), 3.52 (s, 3H), 3.33 (brs, 1H),
4.19 (q, 2H, J ) 7.1 Hz), 2.70 (m, 1H), 2.66 (m, 1H), 2.08 (s,
3H); chiral purity >99% (retention time ) 13.03 min using a
Daicel chirapak AD 0.46 cm × 25 cm eluting with 1:3 isopropyl
alcohol/hexanes). Anal. (C26H23F3N2O3) C, H, N.
with EtOAc. The organic layer was washed with sodium
bicarbonate and brine, dried (MgSO4), filtered, and concen-
trated. The residue was chromatographed on silica gel eluting
first with hexanes followed by EtOAc/hexanes (1:9) to give
10.75 g (95%) of 5a as an oil.
Prepared similarly was 8a S: [R]D +11.78 (c 10.466, DMSO);
chiral purity >99%. Anal. (C26H23F3N2O3) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxylic Acid , 6-Meth yl-4′-(tr iflu o-
r om eth yl)- (6a ). A mixture of ester 5a (10.75 g, 36.56 mmol)
in 250 mL of ethanol and 1 N NaOH (73.1 mmol) was refluxed
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2R)-2-Am in o-2,3-d i-
h ydr o-1H-in den -5-yl]-6-m eth yl-4′-(tr iflu or om eth yl)- (9aR).
A mixture of 8a R (1.53 g, 3.27 mmol), 75 mL of acetonitrile,

4684 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Ksander et al.
and trimethylsilyliodide (1.86 mL, 13 mmol) was stirred
overnight at room temperature. Methanol was added, and the
mixture was concentrated, cold 1 N NaOH added, and the
mixture was extracted with EtOAc. The organic layer was
washed with aqueous Na2S2O3 and brine, dried, filtered,
concentrated and recrystallized from ether to give 1.19 g (89%)
of 9a R as a white solid melting at 109-112 °C: 1H NMR
(CDCl3) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.4 (m, 5H), 7.05 (m, 2H),
6.86 (s, 1H), 6.74 (d, 1H), 3.81 (m, 1H), 3.09 (dd, 2H), 2.60
(dd, 2H), 2.18 (s, 3H), 1.6 (bs, 2H). Prepared similarly were
9bR, 9bS, 9gR, and 9gS.
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2R)-2,3-Dih yd r o-2-
[(p h en ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-4′-(tr i-
flu or om eth yl)- (10bR). To a 0 °C solution of 9bR (0.868 g,
2.19 mmol) in 20 mL of CH2Cl2 and diisopropylethylamine
(0.454 mL, 2.63 mmol) was added benzenesulfonyl chloride
(0.308 g, 2.41 mmol), and the mixture was stirred for 30 min.
An additional aliquot of diisopropylethylamine (0.045 mL) and
benzenesulfonyl chloride (0.031 mL) was added and the
reaction was stirred for 30 min. The organics were washed
with 1 N HCl, NaHCO3, and brine, dried, filtered, concen-
trated, chromatographed on silica gel eluting with EtOAc/
hexanes (1:1), and triturated with ether to give 765 mg (65%)
of 10bR as a white solid melting at 152-153 °C; [R]D +8.48 (c
10.79, CH3OH); 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 8.02 (d,
1H, J ) 7 Hz), 7.83 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.72 (s,
1H), 7.6-7.4 (m, 10H), 7.32 (s, 1H), 7.2 (d, 1H, J ) 9 Hz), 7.01
(d, 1H, J ) 8), 3.85 (m, 1H), 2.8 (m, 2H), 2.62 (m, 2H). Anal.
(C29H23F3N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[(m e t h ylsu lfon yl)a m in o]-1H -in d e n -5-yl]-4′-(t r iflu or o-
m eth yl)-11b: melting at 195-197 °C; 1H NMR (DMSO-d6) δ
10.25 (s, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.65-7.47 (m, 6H),
7.39 (s, 1H), 7.36 (d, 1H), 7.21 (d, 1H), 7.07 (d, 1H), 4.39 (m,
1H), 3.12 (m, 2H), 2.95 (s, 3H), 2.78 (m, 2H). Anal. (C24H21F3-
N2O3S) C, H, N.
Ca r ba m ic Acid , [(2R)-2,3-Dih yd r o-5-[[[4-m eth yl-4′-(tr i-
flu or om et h yl)[1,1′-b ip h en yl]-2-yl]ca r b on yl]a m in o]-1H -
in d en -2-yl]-, Meth yl Ester 8d R: 218-221 °C; [R]D -8.51 (c
9.088 DMSO); 1H NMR (CDCl3) δ 7.69-7.53 (m, 5H), 7.36 (m,
3H), 7.17 (s, 1H), 7.09 (d, 1H), 6.86 (d, 1H), 5.40 (br, 1H), 4.46
(m, 1H), 3.66 (s, 3H), 3.23 (d, 1H), 3.18 (d, 1H), 2.48 (s, 3H).
Anal. (C26H23F3N2O3) C, H, N.
Ca r b a m ic Acid , [(2R)-5-[[[4′,6-Bis(t r iflu or om et h yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-1H-in -
d en -2-yl]-, Meth yl Ester 8eR: melting at 203-205 °C; [R]D
1
-11.38 (c 9.74 in CH3OH); H NMR (CDCl3) δ 7.95 (d, 1H, J
) 7 Hz), 7.92 (d, 1H, J ) 7 Hz), 7.7-7.6 (m, 3H), 7.54 (s, 1H),
7.51 (s, 1H), 7.05 (d, 1H, J ) 8 Hz), 6.98 (s, 1H), 6.72 (m, 2H),
4.81 (m, 1H), 4.45 (m, 1H), 3.65 (s, 3H), 3.21 (d, 1H, J ) 6
Hz), 3.16 (d, 1H, J ) 6 Hz), 2.73 (d, 1H, J ) 4 Hz), 2.69 (d,
1H, J ) 4 Hz). Anal. (C26F6H20N2O3) C, H, N.
Ca r b a m ic Acid , [(2R)-5-[[[4,4′-Bis(t r iflu or om et h yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-1H-in -
d en -2-yl]-, Meth yl Ester 8fR: melting at 199-200 °C; [R]D
-9.75 (c 5.49 in DMSO); 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.82
(d, 1H, J ) 8 Hz), 7.74 (s, 1H), 7.71 (s, 1H), 7.6 (m, 3H), 7.16
(s, 1H), 7.09 (d, 1H, J ) 8 Hz), 6.89 (s, 1H), 6.81 (d, 1H, J )
9 Hz), 4.80 (m, 1H), 4.48 (m, 1H), 3.23 (d, 1H, J ) 7 Hz), 3.19
(d, 1H, J ) 7 Hz), 2.77 (m, 1H), 2.71 (m, 1H). Anal.
(C26F6H20N2O3) C, H, N.
Ca r b a m ic Acid , [(2R)-5-[[[4,4′-Bis(t r iflu or om et h yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-1H-in -
d en -2-yl]-, Meth yl Ester 12a S: melting at 95-99 °C; [R]D
-4.82 (c 1.00, CH3OH); 1H NMR (DMSO-d6) δ 10.0 (s, 1H),
8.20 (d, 1H), 7.95 (d, 1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.62 (d,
1H), 7.5-7.35 (m, 5H), 7.20 (m, 2H), 7.09 (d, 1H), 6.98 (d, 1H),
3.95 (m, 1H), 2.90 (m, 2H), 2.65 (m, 2H), 2.09 (s, 3H); chiral
purity >98%. Anal. (C28F3H23N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2S)-2,3-Dih yd r o-2-
[(2-th ien ylsu lfon yl)a m in o]-1H-in d en -5-yl]-4,6-d im eth yl-
4′-(tr iflu or om eth yl)- 12gS: melting at 153-155 °C; [R]D
-2.53 (c 8.4, DMSO); 1H NMR (CDCl3) δ 7.70 (s, 1H), 7.67 (s,
1H), 7.63 (s, 1H), 7.62 (s, 1H), 7.44 (s, 1H), 7.41 (d, 1H), 7.24
(s, 1H), 7.12 (m, 1H), 7.00 (s, 1H), 6.96 (d, 1H), 6.75 (s, 1H),
6.67 (d, 1H), 4.97 (d, 1H), 4.18 (m, 1H), 3.1 (m, 2H), 2.68 (m,
2H), 2.40 (s, 3H), 2.15 (s, 3H); chiral purity >98%. Anal.
(C29H25F3N2O3S2).
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2R)-2,3-Dih yd r o-2-
[(2-th ien ylsu lfon yl)a m in o]-1H-in d en -5-yl]-4,6-d im eth yl-
4′-(tr iflu or om eth yl)- 12gR: melting at 161-162 °C; [R]D
+5.89 (c 1.21, CH3OH). Anal. (C29H25F3N2O3S2).
Prepared similiarly was 10bS melting at 152-153 °C: [R]D
-7.3 (c 10.15 CH3OH); Anal. (C29H23F3N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2R)-2,3-Dih yd r o-2-
[(2-p yr id in ylm eth yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-4′-
(tr iflu or om eth yl)- (17a R). A mixture of 9bR (2.46 g, 6.0
mmol) and 2-pyridinecarboxaldehyde (0.67 g, 6.3 mmol) in 60
mL of methanol was stirred for 5 h. The polymer-supported
borohydride resin (2.5 mmol/g, 2.6 g, 6.5 mmol) was added and
the mixture stirred overnight. The resin was removed by
filtration and the solution concentrated. The residue was
dissolved in 50 mL of ethyl acetate, and excess ether previously
saturated with HCl gas was added. The dihydrochloride salt
of 17a R crystallized (2.32 g, 67%) as a light yellow solid
1
melting at 281-283 °C: [R]D -23.2 (c 1.13 DMSO); H NMR
(DMSO-d6) δ 10.15 (s, 1H), 8.68 (d, 1H; J ) 4.9 Hz), 7.97 (t,
1H, J ) 6.2 Hz), 7.70 (m, 3H), 7.5 (m, 7H), 7.16 (d, 1H, J )
9.4 Hz), 7.10 (d, 1H, J ) 7.2 Hz), 4.4 (brs, 2H), 4.04 (m, 1H),
3.13 (m, 4H), 2.09 (s, 3H); chiral purity >99%. Anal. (C30
-
Cl2H28F3N3O) C, H, N. Prepared similarly was 17a S as the
non-HCl salt melting at 161-162 °C: [R]D +13.5 (c 0.915
DMSO). Anal. (C30H26F3N3O) C, H, N.
Prepared similarly as described above were the following:
Ca r ba m ic Acid , [(2S)-2,3-Dih yd r o-5-[[[4′-(tr iflu or o-
m eth yl)[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-1H-in d en -2-
yl]-, Meth yl Ester 8bS: melting at 172-174 °C; [R]D +5.506
(c 10.27 CH3OH); 1H NMR (DMSO-d6) δ 10.25 (s, 1H), 7.78 (s,
1H), 7.73 (s, 1H), 7.65-7.35 (m, 8H), 7.20 (d, 1H), 7.07 (d, 1H),
4.20 (m, 1H), 3.53 (s, 1H), 3.08 (d, 1H), 3.00 (d, 1H), 2.7 (m,
2H). Anal. (C25H21F3N2O3) C, H, N.
Ca r ba m ic Acid , [(2R)-2,3-Dih yd r o-5-[[[4′-(tr iflu or o-
m eth yl)[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-1H-in d en -2-
yl]-, Meth yl Ester 8bR: melting at 169-173 °C; [R]D -5.29
(c 8.88 CH3OH). Anal. (C25H21F3N2O3) C, H, N.
Ca r ba m ic Acid , [(2R)-5-[[[4,6-Dim eth yl-4′-(tr iflu or o-
m eth yl)[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-
1H-in d en -2-yl]-, Meth yl Ester 8gR: melting at 144-145 °C;
1
[R]D -12.82 (c 8.35, DMSO); H NMR (CDCl3) δ 7.71 (s, 1H),
7.66 (s, 1H), 7.45 (s, 2H), 7.42 (s, 1H), 7.24 (s, 1H), 7.05 (s,
1H), 7.02 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.69 (d, 1H), 4.81
(d, 1H), 4.47 (m, 1H), 3.65 (s, 3H), 3.21 (d, 1H), 3.15 (d, 1H),
2.73 (d, 1H), 2.67 (d, 1H), 2.42 (s, 3H), 2.13 (s, 3H). Anal.
(C27H25F3N2O3) C, H, N.
Ca r ba m ic Acid , [(2S)-5-[[[4,6-Dim eth yl-4′-(tr iflu or o-
m eth yl)[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-
1H-in d en -2-yl]-, Meth yl Ester 8gS: melting at 147-148 °C;
[R]D +10.20 (c 8.56, DMSO). Anal. (C27H25F3N2O3) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[2-(Acetyla m in o)-2,3-
d ih yd r o-1H-in d en -5-yl]-4′-(tr iflu or om eth yl)- 13b: melting
at 210-212 °C; 1H NMR (DMSO-d6) δ 10.2 (s, 1H), 8.10 (d,
1H), 7.77 (s, 1H), 7.74 (s, 1H), 7.50-7.65 (m, 6H), 7.42 (s, 1H),
7.22 (d, 1H), 7.10 (d, 1H), 4.40 (m, 1H), 3.09 (m, 2H), 3.04 (m,
2H), 1.77 (s, 3H).
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2S)-2,3-Dih yd r o-2-
[(m eth ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-4′-(tr i-
flu or om eth yl) 11a S: melting at 191-194 °C; [R]D +12.54 (c
1.052 CH2Cl2); 1H NMR (DMSO-d6) δ 10.05 (s, 1H), 7.77 (s,
1H), 7.73 (s, 1H), 7.5-7.3 (m, 6H), 7.29 (s, 1H), 7.11 (d, 1H),
7.02 (d, 1H), 4.05 (m, 1H), 3.10 (m, 2H), 2.96 (s, 3H), 2.75 (m,
2H), 2.08 (s, 3H); chiral purity >97%. Anal. (C25H23F3N2O3S)
C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[(2R)-2,3-Dih yd r o-2-
[(m eth ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-4′-(tr i-
flu or om eth yl) 11a R: melting at 95-100 °C; [R]D -10.94 (c
9.056 CH2Cl2). Anal. (C25H23F3N2O3S) C, H, N.
Ben za m id e, N-[2,3-Dih yd r o-5-[[[4′-(tr iflu or om eth yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-1H-in d en -2-yl]- 14b:

Diaminoindanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4685
melting at 253-255 °C; 1H NMR (DMSO-d6) δ 10.2 (s, 1H),
8.63 (d, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.75 (s,
1H), 7.65-7.40 (m, 10H), 7.22 (d, 1H), 7.10 (d, 1H), 4.69 (m,
1H), 3.18 (m, 2H), 2.90 (m, 2H); m/z 518.0 (M + NH4).
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[2-[[(Dim eth yla m i-
n o)ca r b on yl]a m in o]-2,3-d ih yd r o-1H -in d en -5-yl]-4′-(t r i-
flu or om eth yl)- 15b: melting at 231-233 °C; 1H NMR (DMSO-
d6) δ 10.20 (s, 1H), 7.76 (s 1H), 7.70 (s, 1H), 7.65-7.45 (m,
8H), 7.37 (s, 1H), 7.19 (d, 1H), 7.04 (d, 1H), 6.31 (d, 1H), 4.32
(m, 1H), 3.04 (d, 1H), 2.97 (d, 1H), 2.76 (s, 6h), 2.72 (m, 2H).
Anal. (C26H24F3N3O2) C, H, N.
3.23 (m, 2H), 2.73 (m, 2H), 2.40 (s, 3H), 2.12 (s, 3H). Anal.
(C26H25ClN2O3) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
dr o-2-[(ph en ylsu lfon yl)am in o]-1H-in den -5-yl]-6-m eth oxy-
1
10m : melting at 148-150 °C; H NMR (CDCl) δ 7.91 (s, 1H),
7.86 (s, 1H), 7.65-7.30 (m, 9H), 7.07 (m, 2H), 6.96 (d, 2H),
6.75 (s, 1H), 6.65 (d, 1H), 4.67 (d, 1H), 4.12 (m, 1H), 3.75 (s,
3H), 3.05 (m, 2H), 2.65 (m, 2H). Anal. (C29H25ClN2O4S) C, H,
N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
dr o-2-[(m eth ylsu lfon yl)am in o]-1H-in den -5-yl]-6-m eth oxy-
1
11m : melting at 99-102 °C; H NMR (DMSO-d6) δ 10.01 (s,
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
1H), 7.5-7.0 (m, 11H), 4.08 (m, 1H), 3.70 (s, 3H), 3.15 (d, 1H),
3.08 (d, 1H), 2.94 (s, 3H), 2.77 (m, 2H). Anal. (C24H23ClN2O4S)
C, H, N.
[(p h e n ylm e t h yl)a m in o]-1H -in d e n -5-yl]-4′-(t r iflu or o-
m eth yl)- 16b: melting at 179-183 °C; 1H NMR (DMSO-d6) δ
10.2 (s, 1H), 7.78 (s, 1H), 7.74 (s, 1H), 7.67-7.50 (m, 7H), 7.40-
7.18 (m, 6H), 7.05 (d, 1H), 3.74 (s, 2H), 3.49 (m, 1H), 3.01 (m,
1H), 2.66 (m, 2H). Anal. (C30H25F3N2O) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[(p h en ylsu lfon yl)a m in o]-1H-in d en -5-yl]- 10n : melting at
100-103 °C; 1H NMR (DMSO-d6) δ 10.10 (s, 1H), 8.03 (d, 1H),
7.85 (s, 1H), 7.82 (s, 1H), 7.7-7.25 (m, 13H), 7.17 (d, 1H), 6.98
(d, 1H), 3.87 (m, 1H), 2.75 (m, 2H), 2.62 (m, 2H). Anal.
(C28H24N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[(p h en ylsu lfon yl)a m in o]-1H-in d en -5-yl]-4′-flu or o-6-m eth -
1
yl- 10h : melting at 192-195 °C; H NMR (CDCl3) δ 7.92 (s,
1H), 7.90 (s, 1H), 7.7-7.5 (m, 3H), 7.4-6.6 (m, 11H), 4.69 (d,
1H), 4.12 (m, 1H), 3.05 (m, 2H), 2.70 (m, 2H), 2.12 (s, 3H).
Anal. (C29H25FN2O3S) C, H, N.
1-P ip er a zin eca r boxylic Acid , 4-[(2R)-2,3-Dih yd r o-5-
[[[6-m et h yl-4′-(t r iflu or om et h yl)[1,1′-b ip h en yl]-2-yl]ca r -
bon yl]a m in o]-1H-in d en -2-yl]-, Meth yl Ester (19a R). To a
solution of 18 (0.339, 1.705 mmol) in 3 mL of diisopropylethyl-
amine was added 9a (0.70 g, 1.705 mmol). The mixture was
heated to reflux for 3 h, cooled, and concentrated, and the
residue was taken up in aqueous NaHCO3 and EtOAc. The
organic layer was dried, filtered, concentrated, and chromato-
graphed on silica gel eluting with EtOAc to give 130 mg (14%)
of 19a R as a solid melting at 177-178 °C: [R]D -2.9 (c 10.26,
DMSO); 1H NMR (CDCl3) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.60 (m,
1H), 7.4 (m, 4H), 7.03 (m, 2H), 6.91 (s, 1H), 6.72 (d, 1H), 3.70
(s, 3H), 3.54 (m, 4H), 3.19 (m, 1H), 3.0 (m, 2H), 2.71 (m, 2H),
2.52 (m, 2H); chiral purity >99%. Anal. (C30H30F3N3O3) C, H,
N. Prepared similarly was 19a S: melting at 94-97 °C; [R]D
+3.5 (c 5.00, DMSO); chiral purity >99%. Anal. (C30H30F3N3O3)
C, H, N.
1H-In d en -2-ol, 2,3-Dih yd r o-, Meth a n esu lfon a te (20). To
a 0 °C solution of 2-indanol (20 g, 149 mmol) in 300 mL of
CH2Cl2 and diisopropylethylamine (28.6 mL, 164 mmol) was
added methylsulfonyl chloride (11.5 mL, 149 mmol) and
(dimethylamino)pyridine (1.82 g, 14.9 mmol). The mixture was
stirred for 30 min without cooling. An additional 0.2 equiv of
diisopropylamine and methylsulfonyl chloride was added and
the mixture stirred for 16 h. The organic layer was washed
with 1 N HCl, NaHCO3, and brine, dried, filtered, concen-
trated, and recrystallized from ethanol to give 28.4 g (90%) of
20 as a solid.
1H-In d en e-2-ca r bon itr ile, 2,3-Dih yd r o- (21). A mixture
of 20 (10 g, 47.17 mmol) and sodium cyanide (3.10 g, 63.7
mmol) in 100 mL of DMF was heated to 90 °C for 3 h. The
mixture was poured into ice water and extracted with ether.
The ether layer was washed with brine and aqueous lithium
chloride, dried, filtered, concentrated, and chromatographed
on silica gel eluting with EtOAc/hexanes (1:4) to give 3.3 g
(49%) of 21 as a yellow oil.
1H-In d en e-2-m eth a n a m in e, 2,3-Dih yd r o- (22). To a 0 °C
solution of 21 (3.5 g, 24.47 mmol) in 100 mL of ether was added
lithium alluminum hydride (0.929 g, 24.27 mmol). The mixture
was stirred for 3 h, and 1.8 mL of water, 0.93 mL of 15%
NaOH, another 4.5 mL of water, and 100 mL of EtOAc were
added. To this mixture was added MgSO4, and the solids were
removed by filtration. The filtrate was concentrated to give
2.65 g (93%) of 22. This material was used as is in the next
step.
[1,1′-Bip h en yl]-2-ca r b oxa m id e, N-[2,3-Dih yd r o-2-[(2-
th ien ylsu lfon yl)a m in o]-1H-in d en -5-yl]-4′-flu or o-6-m eth -
1
yl- 12h : melting at 114-115 °C; H NMR (DMSO-d6) δ 9.95
(s, 1H), 8.20 (d, 1H), 7.95 (d, 1H), 7.61 (d, 1H), 7.4-7.1 (m,
7H), 6.98 (d, 1H), 3.93 (m, 1H), 2.9 (m, 2H), 2.55 (m, 2H), 2.18
(s, 3H). Anal. (C27H23FN2O3S2) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[(m eth ylsu lfon yl)am in o]-1H-in den -5-yl]-4′-flu or o-6-m eth yl-
1
11h : melting at 208-210 °C; H NMR (DMSO-d6) δ 9.95 (s,
1H), 7.45-7.1 (m, 10H), 7.02 (d, 1H), 4.06 (m, 1H), 3.12 (d,
1H), 3.08 (d, 1H), 2.94 (s, 3H), 2.75 (m, 2H), 2.10 (s, 3H). Anal.
(C24H23FN2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[(ph en ylsu lfon yl)am in o]-1H-in den -5-yl]-4′,6-dim eth yl- 10i:
1
melting at 104-107 °C; H NMR (CDCl) δ 7.90 (s, 1H), 7.88
(s, 1H), 7.76 (d, 1H), 7.65-7.50 (m, 3H), 7.4-7.2 (m, 6H), 7.07
(s, 1H), 6.93 (d, 1H), 6.86 (s, 1H), 6.52 (d, 1H), 4.68 (d, 1H),
4.11 (m, 1H), 3.05 (m, 2H), 2.64 (m, 2H), 2.41 (s, 3H), 2.16 (s,
3H). Anal. (C30H28N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Cya n o-N-[2,3-d ih y-
d r o-2-[(p h en ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-
1
10j: melting at 133-136 °C; H NMR (DMSO-d6) δ 10.1 (s,
1H), 8.0 (m, 2H), 7.90-7.77 (m, 4H), 7.70-7.55 (m, 4H), 7.46-
7.0 (m, 6H), 3.86 (m, 1H), 2.82 (m, 2H), 2.60 (m, 2H), 2.50 (s,
3H); m/z 508.6 (M + 1).
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
d r o-2-[(p h en ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-
1
10k : melting at 224-226 °C; H NMR (CDCl3) δ 7.91 (s, 1H),
7.89 (s, 1H), 7.65-7.5 (m, 4H), 7.4 (m, 4H), 7.25 (s, 1H), 7.23
(s, 1H), 7.12 (s, 1H), 6.98 (d, 1H), 6.87 (s, 1H), 6.70 (d, 1H),
4.68 (d, 1H), 4.10 (m, 1H), 3.0 (m, 2H), 2.68 (m, 2H), 2.14 (s,
3H). Anal. (C29H25ClN2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
d r o-2-[(m eth ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth yl-
11k : melting at 160-163 °C; 1H NMR (CDCl3) δ 7.64 (m, 2H),
7.45-7.0 (m, 7H), 6.86 (s, 1H), 6.75 (d, 1H), 4.48 (d, 1H), 4.35
(m, 1H), 3.30 (d, 1H), 3.23 (d, 1H), 3.01 (s, 3H), 2.86 (m, 2H),
2.12 (s, 3H). Anal. (C24H23ClN2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
d r o-2-[(2-th ien ylsu lfon yl)a m in o]-1H-in d en -5-yl]-6-m eth -
1
yl- 12k : melting at 217-219 °C; H NMR (CDCl3) δ 7.64 (m,
2H), 7.45-7.10 (m, 9H), 7.03 (d, 1H), 6.86 (s, 1H), 6.70 (d, 1H),
4.76 (d, 1H), 4.21 (m, 1H), 3.10 (m, 2H), 2.7 (m, 2H), 2.18 (s,
3H). Anal. (C27H23ClN2O3S2) C, H, N.
Ca r ba m ic Acid , [(2,3-Dih yd r o-1H-in d en -2-yl)m eth yl],
Meth yl Ester (23). To a 0 °C solution of 22 (2.2 g, 14.9 mmol)
and diisopropylethylamine (3.31 mL, 17.9 mmol) in 50 mL of
CH2Cl2 was added methyl chloroformate. The mixture was
stirred for 1 h, and the organics were washed with 1 N HCl,
NaHCO3, and brine, dried, filtered, concentrated, and chro-
matographed on silica gel eluting with EtOAc/hexanes (1:4)
to give 2.18 g (71%) of 23.
Ca r ba m ic Acid , [(2R)-5-[[(4′-Ch lor o-4,6-d im eth yl[1,1′-
bip h en yl]-2-yl)ca r bon yl]a m in o]-2,3-d ih yd r o-1H-in d en -2-
yl]-, Meth yl Ester 8lR: melting at 140-141 °C; [ø]D -10.06
1
(c 9.21 DMSO); H NMR (CDCl3) δ 7.48 (s, 1H), 7.43 (s, 1H),
7.40 (s, 1H), 7.3-7.2 (m, 3H), 7.26 (s, 1H), 7.05 (d, 1H), 6.83
(s, 1H), 6.72 (d, 1H), 4.87 (br, 1H), 4.48 (m, 1H), 3.66 (s, 3H),

4686 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Ksander et al.
Ca r ba m ic Acid , [(2,3-Dih yd r o-5-n itr o-1H-in d en -2-yl)-
m eth yl]-, Meth yl Ester (24). To a 0 °C solution of 23 (2.18
g, 10.6 mmol) in 13.2 mL of trifluoroacetic acid was added
fuming nitric acid (2.71 mL, 66.5 mmol). The mixture was
stirred for 3 h, and CH2Cl2 and ice water were added. The
organic layer was washed with water, NaHCO3, and brine,
dried, filtered, concentrated, and chromatographed on silica
gel eluting with EtOAc/hexanes (1:3) to give 2.6 g (98%) of 24.
Ca r ba m ic Acid , [(5-Am in o-2,3-d ih yd r o-1H-in d en -2-yl)-
m eth yl]-, Meth yl Ester (25). A mixture of 24 (2.6 g, 10.4
mmol) and 0.3 g of 10% palladium on carbon in 50 mL of
EtOAc at room temperature was hydrogenated at 50 psi of 16
h. The mixture was filtered and concentrated to give 2.05 g
(82%) of 25.
Ca r ba m ic Acid , [[2,3-Dih yd r o-5-[[[6-m eth yl-4′-(tr iflu o-
r om eth yl)[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-1H-in d en -
2-yl]m eth yl]-, Meth yl Ester (26a ). To a 0 °C solution of 25
(183 mg, 0.832 mmol) in 10 mL of CH2Cl2 was added pyridine
(0.081 mL, 0.998 mmol) followed by 7a (1.93 mL, 0.998 mmol,
0.516 M in CH2Cl2). The mixture was stirred for 30 min,
washed with 1 N HCl, NaHCO3, and brine, dried, filtered,
concentrated, and chromatographed on silica gel eluting with
EtOAc/hexanes (2:3) to give 360 mg (90%) of 26a as a foam.
Crystallization from EtOAc/hexanes/Et2O gave a sample melt-
ing at 137-139 °C: 1H NMR (CDCl3) δ 7.70 (s, 1H), 7.67 (s,
1H), 7.57 (m, 1H), 7.5-7.3 (m, 4H), 7.1-6.9 (m, 3H), 6.72 (d,
1H), 4.87 (bs, 1H), 3.64 (s, 3H), 3.20 (m, 2H), 2.9 (m, 2H), 2.7-
2.5 (m, 3H), 2.15 (s, 3H). Anal. (C27H25F3N2O3) C, H, N.
Prepared similarly as previously described are the following:
fate, filtered, concentrated under reduced pressure, and puri-
fied by silica gel chromatography eluting first with hexanes
followed with CH2Cl2 to give 5.8 g (76%) of 30 as a yellow oil.
1H-In d en e-2-a cetic Acid , 2,3-Dih yd r o-, Meth yl Ester
(31). A solution of 30 (5.5 g, 29.2 mmol) in 100 mL of EtOAc
was degassed, and 10% palladium on carbon (1.5 g) was added.
The mixture was shaken under 50 psi of H2 gas for 1 h. The
mixture was filtered and concentrated under reduced pressure
to give 5.6 g (100%) of 31 a white solid.
1H-In d en e-2-a ceta m id e, 2,3-Dih yd r o- (32). A mixture of
31 (2.85 g, 15 mmol), concentrated ammonium hydroxide (60
mL), and ammonium chloride (2.4 g, 45 mmol) was stirred in
a pressure bottle at 100 °C for 16 h. The mixture was cooled
to room temperature and then placed in an ice bath. The solid
was collected, washed with water, and dried under reduced
pressure to give 1.85 g (71%) of 32.
1H-In d en e-2-eth a n a m in e, 2,3-Dih yd r o- (33). To a room
temperature solution of 32 (3.5 g, 20 mmol) in 200 mL of THF
was added in portions lithium aluminum hydride (1.14 g, 30
mmol). The mixture was stirred for 30 min, refluxed for 4 h,
and stirred at room temperature overnight. The reaction was
quenched with the sequential addition of water (4.2 mL), 15%
NaOH (4.2 mL), and water (12.6 mL), diluted with EtOAc,
dried with magnesium sulfate, filtered, and concentrated
under reduced pressure to give 3.6 g of 33 as a brown oil. The
crude material was used as is and purified as the methyl
carbamate.
Prepared similarly as previously described was ca r ba m ic
a cid , [2-[2,3-d ih yd r o-5-[[[6-m eth yl-4′-(tr iflu or om eth yl),
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-1H-in d en -2-yl]eth -
yl], m eth yl ester (34a ): melting at 162-165 °C; 1H NMR
(CDCl3) δ 7.81 (d, 1H), 7.7-7.4 (m, 6H), 7.09 (s, 1H), 7.04 (d,
1H), 6.86 (s, 1H), 6.79 (d, 1H), 4.65 (br, 1H), 3.66 (s, 3H), 3.24
(m, 2H), 3.00 (dd, 2H), 2.50 (m, 3H), 1.68 (t, 2H), 1.57 (s, 3H).
Anal. (C28H27F3N2O3) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e,
N-[2,3-Dih yd r o-2-
[[(m eth ylsu lfon yl)a m in o]m eth yl]-1H-in d en -5-yl]-6-m eth -
yl-4′-(tr iflu or om eth yl)- 28a : melting at 178-180 °C; 1H
NMR (CDCl3) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.63 (m, 1H), 7.5-
7.4 (m, 4H), 7.03 (m, 2H), 6.80 (s, 1H), 6.72 (d, 1H), 4.22 (t,
1H), 3.16 (t, 2H), 3.02 (m, 2H), 2.96 (s, 3H), 2.63 (m, 3H), 2.18
(s, 3H). Anal. (C26H25F3N2O3S) C, H, N.
Hyd r oxyla m in e, N-(6,7,8,9-Tetr a h yd r o-5H-ben zo[a ]cy-
cloh ep ten -7-yl)- (35). To 5,6,8,9-tetrahydro-7H-cyclohepta-
benzen-7-one (3.33 g, 20.7 mmol) and hydroxylamine hydro-
chloride (2.17 g, 31.2 mmol) in 40 mL of water was slowly
added a solution of sodium carbonate (1.65 g, 15.59 mmol) in
20 mL of water. The mixture was stirred overnight. The solid
was filtered off, washed with water, and dried at 50 °C under
reduced pressure to give 2.04 g (56%) of 35 as a white solid.
5H-Ben zo[a ]cycloh ep ten -7-a m in e, 6,7,8,9-Tetr a h yd r o-
(36). To a suspension of NaBH4 (1.72 g, 45.5 mmol) in 40 mL
of DMF cooled in an ice bath was added TiCl4 (4.11 g, 21.7
mmol). To this mixture was added 35 (1.9 g, 10.8 mmol) in 40
mL of DMF dropwise. The mixture was stirred overnight,
poured into ice water (150 mL), made basic with 28% ammonia
(20 mL), and extracted with ethyl acetate. The organic extracts
were dried over magnesium sulfate, filtered, and concentrated
under reduced pressure to give 1.8 g of 36 as an oil. The crude
material was used as is and purified as the methyl carbamate.
Prepared similarly as previously described are the following:
Ca r ba m ic Acid , [6,7,8,9-Tetr a h yd r o-2-[[[6-m eth yl-4′-
(t r iflu or om et h yl)[1,1′-b ip h en yl]-2-yl]ca r b on yl]a m in o]-
5H-ben zo[a ]cycloh ep ten -7-yl]-, Meth yl Ester (37a ): melt-
[1,1′-Bip h en yl]-2-ca r boxa m id e, N-[2,3-Dih yd r o-2-[[(2-
th ien ylsu lfon yl)a m in o]m eth yl]-1H-in d en -5-yl]-6-m eth yl-
4′-(tr iflu or om eth yl)- 29a : melting at 107-108 °C; H NMR
(CDCl3) δ 7.75 (s, 1H), 7.70 (s, 1H), 7.65-7.57 (m, 3H), 7.5-
7.4 (m, 4H), 7.09 (t, 1H), 7.0 (m, 2H), 6.81 (s, 1H), 6.70 (d,
1H), 4.53 (t, 1H), 3.08 (t, 2H), 2.97 (m, 2H), 2.6 (m, 3H), 2.16
(s, 3H). Anal. (C29H25F3N2O3S2) C, H, N.
1
Car bam ic Acid, [[5-[[[4,6-Dim eth yl-4′-(tr iflu or om eth yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-2,3-d ih yd r o-1H-in -
d en -2-yl]m eth yl]-, Meth yl Ester 26g: melting at 108-110
1
°C; H NMR (CDCl3) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.47 (s, 2H),
7.43 (s, 1H), 7.25 (s, 1H), 7.01 (d, 1H), 6.97 (s, 1H), 6.78 (s,
1H), 6.71 (d, 1H), 4.75 (br, 1H), 3.70 (s, 3H), 3.24 (t, 2H), 3.01
(d, 1H), 2.96 (d, 1H), 2.7-2.5 (m, 3H), 2.41 (s, 3H). Anal.
(C28H27F3N2O3) C, H, N.
Ca r ba m ic Acid , [[5-[[(4′-Ch lor o-6-m eth yl[1,1′-bip h en -
yl]-2-yl)ca r b on yl]a m in o]-2,3-d ih yd r o-1H -in d e n -2-yl]-
m eth yl]-, Meth yl Ester 26k : melting at 133-135 °C; 1H
NMR (CDCl3) δ 7.65 (m, 1H), 7.48-7.35 (m, 4H), 7.36 (m, 2H),
7.11 (s, 1H), 7.03 (d, 1H), 6.86 (s, 1H), 6.74 (d, 1H), 4.79 (br,
1H), 3.67 (s, 3H), 3.23 (t, 2H), 2.97 (m, 2H), 2.61 (m, 3H), 2.16
(s, 3H). Anal. (C26H25ClN2O3) C, H, N.
1
ing at 190-193 °C; H NMR (CDCl3) δ 7.73 (s, 1H), 7.71 (s,
1H), 7.63 (m, 1H), 7.47-7.37 (m, 4H), 6.96 (d, 1H), 6.86 (d,
1H), 6.79 (s, 1H), 6.76 (s, 1H), 4.62 (br, 1H), 3.76 (m, 1H), 3.66
(s, 3H), 2.67 (m, 4H), 2.17 (s, 3H), 2.11 (m, 2H), 1.23 (m, 2H).
Anal. (C28H27F3N2O3) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-N-[2,3-d ih y-
d r o-2-[[(m eth ylsu lfon yl)a m in o]m eth yl]-1H-in d en -5-yl]-6-
1
m eth yl- 28k : melting at 65-66 °C; H NMR (CDCl3) δ 7.62
(m, 1H), 7.4-7.2 (m, 4H), 7.27 (m, 2H), 7.25 (s, 1H), 7.05 (d,
1H), 6.86 (s, 1H), 6.74 (d, 1H), 4.30 (br, 1H), 3.17 (t, 2H), 3.05
[1,1′-Bip h en yl]-2-ca r boxa m id e, 6-Meth yl-N-[6,7,8,9-tet-
r a h yd r o-7-[(m et h ylsu lfon yl)a m in o]-5H -b en zo[a ]cyclo-
h ep ten -2-yl]-4′-(tr iflu or om eth yl)- 38a : melting at 131-134
°C; 1H NMR (CDCl3) δ 7.75 (s, 1H), 7.72 (s, 1H), 7.64 (m, 1H),
7.5-7.4 (m, 4H), 6.97 (d, 1H), 6.86 (d, 1H), 6.81 (s, 2H), 4.19
(d, 1H), 3.62 (m, 1H), 2.98 (s, 3H), 2.68 (m, 4H), 2.18 (m, 2H),
2.15 (s, 3H), 1.41 (m, 2H). Anal. (C27H27F3N2O3S) C, H, N.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 6-Meth yl-N-[6,7,8,9-tet-
r a h yd r o-7-[(2-th ien ylsu lfon yl)a m in o]-5H-ben zo[a ]cyclo-
h ep ten -2-yl]-4′-(tr iflu or om eth yl)- 39a : melting at 209-212
°C; 1H NMR (CDCl3) δ 7.72 (s, 1H), 7.69 (s, 1H), 7.63 (m, 3H),
7.43 (m, 4H), 7.10 (m, 1H), 6.93 (d, 1H), 6.82 (d, 1H), 6.78 (s,
(m, 2H), 2.95 (s, 3H), 2.65 (m, 3H), 2.16 (s, 3H). Anal. (C25H25
ClN2O3S) C, H, N.
-
Acetic Acid , (1,3-Dih yd r o-2H-in d en -2-ylid en e)-, Meth yl
Ester (30). To an ice bath cooled suspension of sodium hydride
(4.74 g, 118 mmol) in 100 mL of THF was added trimeth-
ylphosphonoacetate (21.6 g, 118 mmol). The mixture was
stirred at room temperature for 30 min and cooled with an
ice bath, and 2-indanone (6.5 g, 49.4 mmol) in 100 mL of THF
was added dropwise. The mixture was stirred overnight,
poured into saturated sodium chloride, and extracted with
EtOAc. The organic extracts were dried over magnesium sul-

Diaminoindanes
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4687
258, 999-1001. (b) Rader, D. J .; Brewer, H. B. Abetalipopro-
teinemia: New insights into lipoprotein assembly and vitamin
E metabolism from a rare genetic disease. J AMA-J . Am. Med.
Assoc. 1993, 270, 865-869. (c) Shoulders, C. C.; Brett, D. J .;
Bayliss, J . D.; Narcisi, T.; J aruz, A.; Grantham, T. T., et al.
Abetalipoproteinemia is caused by defects of the gene encoding
the 97 kDa subunit of a microsomal triglyceride transfer protein.
Hum. Mol. Genet. 1993, 2, 2109-2116.
2H), 4.53 (d, 1H), 3.54 (m, 1H), 2.7-2.5 (m, 4H), 2.16 (s, 3H),
2.0 (m, 2H), 1.45 (m, 2H). Anal. (C30H27F3N2O3S2) C, H, N.
Ca r ba m ic Acid , [2-[[[4,6-Dim eth yl-4′-(tr iflu or om eth yl)-
[1,1′-bip h en yl]-2-yl]ca r bon yl]a m in o]-6,7,8,9-tetr a h yd r o-
5H-ben zo[a ]cycloh ep ten -7-yl]-, Meth yl Ester 37g: melting
1
at 158-161 °C; H NMR (CDCl3) δ 7.71 (s, 1H), 7.69 (s, 1H),
7.45 (s, 2H), 7.43 (s, 1H), 7.24 (s, 1H), 6.95 (d, 1H), 6.84 (d,
1H), 6.73 (s, 1H), 6.72 (s, 1H), 4.6 (br, 1H), 3.7 (m, 1H), 3.66
(s, 3H), 2.70-2.62 (m, 4H), 2.42 (s, 3H), 2.13 (s, 3H), 2.10 (m,
2H), 1.24 (m, 2H). Anal. (C29H29F3N2O3) C, H, N.
(4) (a) Leiper, J . M.; Bayliss, J . D.; Pease, R. J .; Brett, D. J .; Scott,
J .; Shoulders, C. C. Microsomal triglyceride transfer protein, the
abetalipoproteinemia gene product, mediates the secretion of
apolipoprotein B containing lipoproteins from heterologous cells.
J . Biol. Chem. 1994, 269, 21951-21954. (b) Gordon, D. A.; J amil,
H.; Sharp, D.; Mullaney, D.; Yao, Z.; Gregg, R. E.; Wetterau, J .
R. Secretion of apoB containing lipoproteins from HeLA cells
dependent on expression of the microsomal triglyceride transfer
protein and is regulated by lipid availability. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 7628-7632.
[1,1′-Bip h en yl]-2-ca r boxa m id e, 4′-Ch lor o-6-m eth yl-N-
[6,7,8,9-tetr a h yd r o-7-[(m eth ylsu lfon yl)a m in o]-5H-ben zo-
[a ]cycloh ep ten -2-yl]- 38k : melting at 138-141 °C; 1H NMR
(CDCl3) δ 7.65 (d, 1H), 7.45-7.38 (m, 4H), 7.27 (m, 2H), 6.98
(d, 1H), 6.9-6.8 (m, 3H), 4.21 (d, 1H), 3.62 (m, 1H), 3.00 (s,
3H), 2.68 (m, 4H), 2.21 (m, 2H), 2.16 (s, 3H), 1.21 (m, 2H).
Anal. (C26H27ClN2O3S) C, H, N.
Ca r ba m ic Acid , [2-[[(4′-Ch lor o-6-m eth yl[1,1′-bip h en yl]-
2-yl)ca r bon yl]a m in o]-6,7,8,9-tetr a h yd r o-5H-ben zo[a ]cy-
cloh ep ten -7-yl]-, Meth yl Ester 37k : melting at 184-187 °C;
1H NMR (CDCl3) δ 7.65 (d, 1H), 7.45-7.35 (m, 4H), 7.28 (m,
2H), 6.97 (d, 1H), 6.9-6.8 (m, 3H), 4.62 (m, 1H), 3.80 (m, 1H),
3.66 (s, 3H), 2.69 (m, 4H), 2.16 (s, 3H), 2.13 (m, 2H), 1.3 (m,
2H). Anal. (C27H27ClN2O3) C, H, N.
(5) (a) Lin, M. C.; Arbeeny, C.; Bergquist, K.; Kienzle, B.; Gordon,
D. A.; Wetterau, J . R. Cloning and regulation of hamster
microsomal triglyceride transfer protein. The regulation is
independent from that of other hepatic and intestinal proteins
which participates in the transport of fatty acids and triglycer-
ides. J . Biol. Chem. 1994, 269, 29138-29145. (b) Patel, S. B.;
Grundy, S. M. Heterologous expression of apolipoprotein
B
carboxy terminal truncates: a model for the study of lipoprotein
biogenesis. J . Lipid Res. 1995, 36, 2090-2103. (c) Hahn, S. E.;
Goldberg, D. M. Factors affecting the regulation of apoB secre-
tion by liver cells. J . Clin. Lab. Anal. 1995, 9, 431-449. (d)
Lamberg, A.; J auhiainen, M.; Metso, J .; Ehnholm, C.; Shoulders,
C.; Scott, J .; Pihlajaniemi, T.; Kivirikko, K. I. The role of protein
disulfide isomerase in the microsomal triacylglycerol transfer
protein does not reside in its isomerase activity. Biochem. J .
1996, 315, 533-536.
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(8) For the preparation of racemic 1 see patent WO 0005201.
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