3-Aryl-1,2-diacetamidopropane derivatives as novel and potent NK-1 receptor antagonists

Article abstract of DOI:10.1021/jm950616c

Early structure-activity studies on racemic tryptophan ester and amide NK- 1 antagonists 5-7 led to the discovery that the potency of the series could be markedly increased by moving the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R stereoisomeric series (IC₅₀'s = 100 pM to >5 μM). Compounds in this series were shown to be competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32, blocked intrathecal NK-1 agonist-driven [Ac-[Arg⁶, Sar⁹, Met(O₂)¹¹]-substance P 6-11 (Ac-Sar⁹)] nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous administration. Further, upon oral administration in this model, (R)-32 was observed to be very potent (ID₅₀ = 91 ng/kg) and have a long duration of action (>8 h at 1 μg/kg). Compound (R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist with a long duration of action.

Full text of DOI:10.1021/jm950616c

736
J . Med. Chem. 1996, 39, 736-748
3-Ar yl-1,2-d ia ceta m id op r op a n e Der iva tives a s Novel a n d P oten t NK-1 Recep tor
An ta gon ists
Philip A. Hipskind,*,† J . J effry Howbert,†,‡ Robert F. Bruns,† Steven S. Y. Cho,† Thomas A. Crowell,†
Mark M. Foreman,† Donald R. Gehlert,† Smriti Iyengar,† Kirk W. J ohnson,† J oseph H. Krushinski,†
Dominic L. Li,† Karen L. Lobb,† Norman R. Mason,† Brian S. Muehl,† J ames A. Nixon,† Lee A. Phebus,†
Domenico Regoli,§ Rosa M. Simmons,† Penny G. Threlkeld,† Diane C. Waters,† and Bruce D. Gitter†
Central Nervous System Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center,
Indianapolis, Indiana 46285, and Department of Pharmacology, Medical School, University of Sherbrooke,
Sherbrooke Que., Canada J 1H5N4
Received August 18, 1995X
Early structure-activity studies on racemic tryptophan ester and amide NK-1 antagonists
5-7 led to the discovery that the potency of the series could be markedly increased by moving
the carbonyl function in these molecules to an off-chain position as in the 3-aryl-1,2-
diacetamidopropane 9. Further medicinal chemistry incorporating this change resulted in the
discovery of a novel series of highly potent aryl amino acid derived NK-1 antagonists of the R
stereoisomeric series (IC50’s ) 100 pM to >5 µM). Compounds in this series were shown to be
competitive antagonists using an in vitro NK-1 smooth muscle assay, and this data correlated
well with observed human NK-1 binding affinities. Two of these agents, (R)-25 and (R)-32,
blocked intrathecal NK-1 agonist-driven [Ac-[Arg6, Sar9, Met(O2)11]-substance P 6-11 (Ac-Sar9)]
nociceptive behavior in mice. Both compounds potently blocked the neurogenic dural
inflammation following trigeminal ganglion stimulation in the guinea pig after intravenous
administration. Further, upon oral administration in this model, (R)-32 was observed to be
very potent (ID50 ) 91 ng/kg) and have a long duration of action (>8 h at 1 µg/kg). Compound
(R)-32, designated LY303870, is currently under clinical development as an NK-1 antagonist
with a long duration of action.
In tr od u ction
The undecapeptide neurotransmitter substance P (SP)
is a member of the family of neuropeptides that includes
neurokinin A and neurokinin B.1 This family of pep-
tides exert their effects through three recognized
G-protein coupled receptor subtypes, NK-1, NK-2, and
NK-3, respectively.2 Besides potentially being a neu-
romediator of pain, SP, acting primarily at NK-1 recep-
tors, stimulates smooth muscle contraction, vasodila-
tion, plasma extravasation, and the release of inflam-
matory mediators.3 These latter actions, known col-
lectively as neurogenic inflammation, exacerbate the
transmission of nociception as well as local inflamma-
tion. It has been proposed that SP antagonists may
and 7 (0.15 µM), were uncovered.16 Analysis of the
therefore be useful for the treatment of various human
disease states including persistent pain,4 migraine,5 and
dihedral angle about the C-1 to heteroatom single bond
asthma.6 Numerous reports have appeared describing
of compounds 5-7 indicated the potential importance
the discovery of nonpeptide, small molecule antagonists
of the NK-1 receptor.7 Among those compounds dis-
closed to date (CP-96345 (1),8,9 RP-67580 (2),10 SR140333
(3),11 L-737,488 (4),12 and others13) there is a remarkable
level of structural variety. Further exemplifying this
diversity, we report our efforts toward the discovery of
a clinically useful SP antagonist.14
Following our own screening study based on the
hypothesized importance of the Phe7-Phe8 substructure
of SP for NK-1 receptor affinity and a subsequent
medicinal chemistry effort, R-N-acetylated tryptophan
amides and esters, such as 5 (4.9 µM),15 6 (0.75 µM),
of the ability of this bond to adopt an s-cis conformation
for highest potency. To test this possibility, compounds
8 and 9 were synthesized. Whereas compound 8 (4.7
µM) is rigidly held s-trans, compound 917 (0.068 µM)
should ostensibly have maximum flexibility to adopt an
s-cis conformation. Quite serendipitously, the dike-
topiperazine pseudodimer 1018 (0.028 µM) was isolated
in an attempted formation of 8. The most essential
elements of 10 were determined, by sequential sub-
structure deletion, to be embodied by 11 (0.030 µM).
Further medicinal chemistry combined the elements of
11 with those of 9 and led to discovery of the indolyl-
diacetamidopropane 12 as a potent inhibitor of [125I]SP
binding to the human NK-1 receptor (IC50 ) 1.14 ( 0.26
nM). Herein we describe our detailed studies centered
on 12 to further define this novel series of potent NK-1
antagonists.
* The author can be reached via Internet as hipskind philip a@
lilly.com.
† Lilly Research Laboratories.
‡ Current address: Darwin Molecular Corp., Bothell, WA 98021.
§ University of Sherbrooke.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
0022-2623/96/1839-0736$12.00/0 © 1996 American Chemical Society

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 737
Sch em e 1. General Method Aa
a
Reagents: (a) Ph3CCl, Et3N, CH2Cl2, room temperature; (b)
BH3‚DMS, THF, reflux; (c) 2-MeOC6H4CHO, toluene, -H2O; then
NaBH4, 1:1 THF/methanol, room temperature; (d) Ac2O, Et3N,
THF, room temperature; (e) HCO2H, CH2Cl2, 0 °C to room
temperature; (f) i-Pr2NEt, BrCOCH2Br, THF, 0 °C to room
temperature; (g) N-phenylpiperazine, K2CO3, CH2Cl2, room tem-
perature.
Ch em istr y
Initially, a structure-activity analysis based on ra-
cemic compounds was targeted. Replacements for the
2-(4-phenylpiperazinyl)acetamido and the 2-methoxy-
benzyl substituents of 12 were investigated using the
racemic synthetic strategy illustrated in Scheme 1
(method A). Tritylation of (RS)-tryptophan amide 13
proceeded under standard conditions.19 Next treatment
of a tetrahydrofuran solution of 14 at reflux with borane
dimethyl sulfide smoothly produced trityldiamine 15.
Without purification 15 was reductively alkylated with
an appropriate aryl aldehyde, and the resulting amine
was acylated with acetic anhydride to yield the crystal-
line tritylamine 16 in an 87% overall three-step yield.
Straightforward deprotection of the trityl group to give
aminoacetamide 17 was accomplished by treatment of
16 with formic acid in dichloromethane. The final
2-acetamido substituents were most conveniently ap-
pended using a two-step procedure: (1) acylation with
bromoacetyl bromide to give 18 followed by (2) alkyla-
tion with the appropriate amine using powdered, an-
hydrous potassium carbonate in dichloromethane. This
provided the racemic target structures exemplified in
Scheme 1 as 12. Compounds 9, 27, 30, 52, and 53 and
the compounds found in Tables 1 and 3 were prepared
using this general method A. Alternatively 2-acetamido
substituents, several N-benzyl replacements, and in-
dolyl methylene replacements for compound 12 were
investigated as outlined in Scheme 2. N-BOC-tryp-
tophan 19 (or other N-BOC-amino acid derivative as in
the case of the compounds found in Table 5) was coupled
with a variety of amines and then deprotected using
standard methodology to give 21. Borane dimethyl
sulfide reduction followed by selective primary amine
acylation with the acylimidazole of 2-(4-phenylpiper-
azinyl)acetic acid yielded 22. Finally 22 was acylated,
alkylated, or sulfonylated as necessary to produce the
target compounds. Compounds 5-8 and 10-12 and the
compounds found in Tables 2, 4, and 5 were made
employing this general method B. Synthesis of enan-
tiomerically pure materials from (R)-tryptophan has
been described elsewhere.20
Sch em e 2. General Method Ba
a
Reagents: (a) CDI, 2-MeO-benzylamine, dioxane, room tem-
perature; (b) aqueous TFA, anisole, 0 °C; (c) BH3‚DMS, THF,
reflux; (d) CDI, (4-phenylpiperazin-1-yl)CH2CO2H, NEt3, CH3CN,
room temperature; (e) Ac2O, i-Pr2NEt, THF, room temperature.
Resu lts a n d Discu ssion
Str u ctu r e-Affin ity Rela tion sh ip s. We first de-
cided to investigate the role of the phenylpiperazine
moiety in compound 12 (Table 1). Replacing the phenyl
group with methyl (e.g. 23) resulted in nearly a 5-fold
loss in activity. Inserting one methylene between the
nitrogen and phenyl groups of 12, as in 24, did not yield
a significant improvement. Interestingly, saturation of
the phenyl ring of 12 to the cyclohexyl analog 25
improved the potency 3-fold to 0.34 nM while increasing
the basicity and water solubility. Direct exchange of
the piperazine nitrogen attached to the phenyl ring of
12 for a carbon (26) resulted in a 4-fold loss in potency.
Although this loss in activity could have been due to a
conformational change in the side chain (ca. sp2 nitrogen
for sp3 carbon), preparation of ∆3-piperidine 27 (3.1 (
0.4 nM) showed that this was not the entire explanation.
The appendant phenyl group in 12, 26, and 27 would,
in each case, have distinct conformational biases (rela-

738 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Ta ble 1. In Vitro SAR: Variation of N2 Acetamide
Hipskind et al.
Ta ble 2. In Vitro SAR: Variation of N1 Acetamide
a
a
compd
X
R
IC50
compd
R
IC50
1
2
0.35 ( 0.01
30 ( 4.9
1.1 ( 0.3
5.3 ( 1.4
0.98 ( 0.1
0.34 ( 0.04
4.5 ( 1.5
33 ( 4
12
22
33
34
35
36
37
38
39
40
41
42
43
COCH3
H
CHO
COEt
COPh
COCH2COOCH3
COCH2COOH
COCH2N(CH3)2
COOEt
CONHCH3
SO2CH3
1.1 ( 0.3
51 ( 14
12
23
24
25
26
28
29
31
32
N
N
N
N
CH
CH
O
CH
CH
Ph
Me
CH2Ph
cyclohexyl
Ph
H
0.80 ( 0.3
0.81 ( 0.1
2.0 ( 0.6
1.28 ( 0.3
9.2 ( 1.2
1.54 ( 0.1
5.5 ( 2.8
3.0 ( 1.2
4.0 ( 0.4
85 ( 5.8
31 ( 14
27 ( 9
NMe2
1-piperidinyl
2.8 ( 1
0.23 ( 0.02
Et
a
Binding affinity for the NK-1 receptor in human IM-9 cells
CH2COOCH3
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration-response curves with each concentration
in triplicate. All values are the mean ( SEM, n ) 3-14
determinations.
a
Binding affinity for the NK-1 receptor in human IM-9 cells
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration response curves with each concentration
in triplicate. All values are the mean ( SEM, n ) 3 determina-
tions.
tive to the piperidine or piperazine ring) that would also
have an effect on binding potency.
Ta ble 3. In Vitro SAR: Variation of N1 Benzyl Substituent
a
compd
R
IC50
12
44
45
46
47
48
49
50
51
2-MeO
3-MeO
4-MeO
H
2-SMe
2-Cl
2-Me
2-CF3
2-NO2
1.1 ( 0.3
4.6 ( 0.06
2.5 ( 0.3
2.2 ( 0.4
7.2 ( 3
1.9 ( 0.4
3.2 ( 0.1
3.2 ( 0.9
3.0 ( 0.6
Simple substitution of piperidine (28) or morpholine
(29) for the entire 4-phenylpiperazine side chain present
in 12 produced compounds of substantially reduced
potency. Cleavage of two methylene units out of the
piperazine ring of 12, as in acyclic compound 30 (8.4 (
2.8 nM), yielded similar results. In contrast, reintro-
duction of a more basic, distal amine, as in the 4-(dim-
ethylamino)piperidine derivative 31 (2.8 nM), increased
the potency 12-fold with respect to the unsubstituted
piperidine analog 28. Further, reestablishing some
hydrophobic character to the diamine motif as in the
4-piperidinylpiperidine analog 32 resulted in the most
potent racemic compound in the series. Overall these
data established the importance of the distal, basic
nitrogen for activity (compound 28, 33 nM vs 31, 2.8
nM) while the exact nature of the groups attached to
this distal nitrogen (hydrophobicity) also played a key
role in obtaining compounds with subnanomolar activity
(23, 5.3 nM vs 25, 0.34 nM and 31, 2.8 nM vs 32, 0.23
nM).
The effect of varying the acetamide substituents at
the C-1 nitrogen while holding the 2-methoxybenzyl
group fixed was investigated (Table 2). All compounds
with amide or amide like character (33-41) were active
with IC50’s less than 10 nM. Changing the amide to a
sulfonamide resulted in a modest loss of activity (41,
4.0 nM vs 12, 1.1 nM). Removing the amide character
of the C-1 nitrogen (22, 42, and 43) had a substantially
deleterious effect on activity. A wide variety of size is
tolerated as demonstrated by the benzoyl (35, 2.0 nM)
a
Binding affinity for the NK-1 receptor in human IM-9 cells
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration-response curves with each concentration
in triplicate. All values are the mean ( SEM, n ) 3 determina-
tions.
and formyl (33, 0.8 nM) substituents. Also acidic and
basic groups could be installed on the acetamide sub-
stituent while maintaining reasonable activity (37, 38).
As expected, all compounds with an additional basic
group, such as 38, showed enhanced water solubility at
pH ) 7.
A limited survey of benzyl substituent variations was
also undertaken. In this study the core 3-(indol-3-yl)-
1,2-diacetamidopropane backbone of 12 was held con-
stant (Table 3). 2-Methoxy- and 2-chlorobenzyl groups
were modestly preferred over others examined. This
proved to be a general trend with other C-2 acetamido
substituents; additional 2-chlorobenzyl derivatives (52,
0.56 ( 0.1 nM and 53, 0.35 ( 0.07 nM) were prepared
and were found to be essentially equipotent to the
corresponding 2-methoxy derivatives (25 and 32).21
Further, the synthesis of several benzyl replacements
was undertaken (Table 4). A substantial loss of affinity

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 739
Ta ble 5. In Vitro SAR: Indole Replacements
Ta ble 4. In Vitro SAR: N1 Benzyl Replacements
compd
R
IC50 (nM)a
a
compd
R
IC50
12
46
54
55
56
57
58
2-MeO-benzyl
benzyl
Me
n-Bu
(cyclohexyl)-CH2
Ph
1.1 ( 0.3
2.2 ( 0.4
>5000
12
59
60
61
62
63
64
65
66
67
3-indolyl-CH2
Ph-CH2
1.1 ( 0.3
8.3 ( 3
1-naphthyl-CH2
2-naphthyl-CH2
3-benzo[b]thiophenyl-CH2
3-indolinyl-CH2
Ph
3,4-dichlorophenyl
H
i-Pr
2.73 ( 0.1
149 ( 17
21.9 ( 8.3
>5000
11
1.18 ( 0.36
27.4 ( 18
474 ( 122
338 ( 25
>5000
PhCH2CH2
126 ( 19
a
Binding affinity for the NK-1 receptor in human IM-9 cells
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration response curves with each concentration
in triplicate. All values are single determinations or the mean
(SEM, n ) 3 determinations.
>5000
a
Binding affinity for the NK-1 receptor in human IM-9 cells
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration-response curves with each concentration
in triplicate. All values are a single determination or the mean
( SEM, n ) 3 determinations.
was observed in all cases where the aryl ring was
deleted (compounds 54 and 55) or repositioned (com-
pounds 57 and 58). Only in the case of the cyclohexy-
lmethylene derivative, 56, was the activity maintained
within 1 order of magnitude of the parent 46.
Modifications to the 3-indolylmethylene were also
undertaken (Table 5). Of those examined, compounds
that held to the arylmethylene type substructure (59
to 62) maintained reasonable potency (IC50’s less than
12 nM). Those deviating from this general substructure
(64-67) were inactive. Even slight deviations, as that
found in the 3-indolinyl compound 63, resulted in a
marked decrease in potency. The data presented in
Tables 4 and 5 underscore the need for a distal display
of aryl-aryl functionality, separated by exactly five
atoms in the main chain of this series of compounds.
Next the enantiospecificity of the series was examined
(Table 6). Four pairs of isomers were synthesized, and
in each case the R isomer was clearly the most active
by 300-2800-fold. With the recent appearance of
similar, but optically antipodal NK-1 receptor antago-
nists derived from tryptophan,22 we were curious to see
how compounds such as (S)-4 would compare to (R)-12
using molecular modeling techniques.23 Both molecules
exhibited a clear preference for π-π-face stacking,24 but
when the appropriate aryl groups of the two molecules
were overlaid, the analysis was inconclusive for an
overlap of the corresponding distal basic nitrogen.
Further attempts to force an aryl-aryl-basic nitrogen
(or nitrogen lone pair) three point overlay inevitably
resulted in conformers of unreasonably high energy.
One explanation for this differential stereochemistry
could be that these two series are interacting at a
different site on the receptor surface or at sites that only
partially overlap.
F igu r e 1. Correlation of IM-9 cell binding data (pIC50) with
rabbit vena cava smooth muscle functional activity (pA2).
tide antagonists for NK-1 receptors has been previously
noted.25 Compounds in this study likewise exhibited
species differences (Table 7). In all cases tested, the
compounds had greater NK-1 receptor affinity in human
(IM-9 cells) and guinea pig brain membrane homoge-
nates when compared to rodent receptors (rat and
mouse brain membrane homogenates). Among those
compounds tested, 38 and 45 showed the largest dif-
ference.
F u n ction a l Activity a n d Sp ecificity. The ability
of the compounds to block NK-1 receptor mediated
contraction of the rabbit vena cava (RVC) tissue was
examined.26 The data obtained correlated well with the
observed binding to SP receptors expressed in IM-9 cells.
This is evidenced by a reasonable correlation (r2 ) 0.83)
of RVC responses (pA2) to IM-9 NK-1 affinities (IC50)
over an extensive list of antagonists from this series
(Figure 1). A more extensive functional activity and
specificity analysis of three enantiomerically pure com-
pounds was performed (Table 8). Inhibition of
SP-induced inositol phosphate accumulation in human
UC-11 MG astrocytoma cells was assayed as previously
described.27 Block of the SP induced interleukin-6
secretion from human U-373 MG astrocytoma cells was
measured also as previously described.28 Assay of NK-1
specificity (vs NK-2 and NK-3) in smooth muscle
systems was carried out using standard procedures.29
Sp ecies Differ en ces in Recep tor Bin d in g.
A
significant species difference in the affinity of nonpep-

740 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Ta ble 6. In Vitro SAR: Enantiospecificity
Hipskind et al.
a
IC50
compd
R
R′
(R)-isomer
(S)-isomer
12
25
32
52
4-phenylpiperazin-1-yl
2-MeO
2-MeO
2-MeO
2-Cl
0.85 ( 0.1
0.18 ( 0.04
0.15 ( 0.01
0.18 ( 0.03
358 ( 53
80.9 ( 5.9
420 ( 62
159 ( 9.9
4-cyclohexylpiperazin-1-yl
4-(piperidin-1-yl)piperidin-1-yl
4-(piperidin-1-yl)piperidin-1-yl
a
Binding affinity for the NK-1 receptor in human IM-9 cells using 125I-labeled Bolton-Hunter substance P as radioligand, given in nM
units; see ref 15. IC50 values were determined from 11-point concentration-response curves with each concentration in triplicate. All
values are the mean ( SEM, n ) 3 determinations.
Ta ble 7. Species Differences in Affinities: in Vitro NK-1
Binding Experiments
antagonist efficacy was assessed using a behavioral
response (biting and scratching) induced by an intrath-
IC50
ecal (it) injection of the selective NK-1 receptor agonist
Ac-[Arg6, Sar9, Met(O2)11]-SP 6-11 (Ac-Sar9).31 In this
model, (R)-25 and (R)-32 were found to enantiospecifi-
cally block the it NK-1 agonist induced nociceptive
behavioral response in the mouse with ED50’s of 0.31 (
0.22 nmol, it, and 0.21 ( 0.037 nmol, it, respectively.
Additionally, a less potent compound in mouse brain
binding assays, (R)-53 was found to be active but less
potent (ED50 ≈ 3 nmol, it). For comparison, RP67580
was also tested in this model and an ED50 of 0.92 ( 0.16
nmol, it, was observed. Intraperitoneal administration
of (R)-25 and (R)-32 also antagonized the effects of the
intrathecal injection of the NK-1 specific agonist (ED50’s
of ca. 8.40 ( 3.6 mg/kg, ip, and 1.73 ( 0.74 mg/kg, ip,
respectively). This suggests that compounds within this
series penetrate the blood-brain barrier and block
central NK-1 receptors following systemic administra-
tion.
human
(IM-9)a
guinea pig
rat
mouse
brainb
compd
brainb
brainb
1
2
0.35
30
0.85
0.98
0.18
3.1
0.15
1.54
2.5
0.40
32
0.26
0.88
ND
3.8
0.50
ND
ND
32
6.7
4.5
16
1.5
14
9.3
480
1100
24
8.7
2.5
NDc
1.3
ND
7.7
200
ND
(R)-12
24
(R)-25
27
(R)-32
38
45
a
Binding affinity for the NK-1 receptor in human IM-9 cells
using 125I-labeled Bolton-Hunter substance P as radioligand,
given in nM units; see ref 15. IC50 values were determined from
11-point concentration-response curves with each concentration
in triplicate. All values are the mean, n ) 1-3 determinations.
b
Binding affinity for the NK-1 receptor in guinea pig brain, rat
brain, or mouse brain homogenates using 125I-labeled Bolton-
Hunter substance P as radioligand, given in nM units; see ref 15.
IC50 values were determined from six-point concentration-
response curves with each concentration in triplicate. All values
are the mean, n ) 1-3 determinations. c ND ) not determined.
Compounds were also tested for their ability to block
the neurogenic dural inflammation and associated
plasma extravasation in the guinea pig induced by
direct ipsilateral electrical stimulation of the trigeminal
ganglion.32 Stimulation of this nerve bundle is pur-
ported to cause a release of inflammatory neuropeptides,
including SP, from the primary sensory terminals in the
dural tissue surrounding the brain.33 Therefore, in this
model of peripheral NK-1 activity, an NK-1 antagonist
should block the resulting inflammation and extrava-
sation. Experimentally, antagonism of plasma extrava-
sation was quantitated as the ratio of the leakage of a
plasma protein bound fluorescent dye (Evans blue) on
the stimulated versus unstimulated side of the dural
tissue. In this model (R)-25 and (R)-32 enantiospecifi-
cally blocked the neurogenic dural inflammation in-
duced by electrical stimulation. Both compounds were
extremely potent with ED50’s of 1.2 ng/kg, iv, and 15
ng/kg, iv, respectively. Their enantiomers, (S)-25 and
(S)-32, were much less active with ED50’s of >50 000
and 1300 ng/kg, respectively.34 The effects of (R)-32
were examined following oral administration and the
compound displayed an ED50 of 91 ng/kg. Duration of
action was estimated using various doses of (R)-32.
Compound (R)-32 had a long duration of action; at 1
µg/kg po (ca. ED100 at 35 min post oral administration)
full efficacy was observed for more than 8 h.
Ta ble 8. In Vitro Functional Activities in Cell Lines and
Monoreceptor Smooth Muscle Assays
Ki
pA2
PI
IL-6
NK-1
NK-2
NK-3
compd
turnovera
releaseb
(RVCc)
(RPAd)
(RPVe)
1
5.2
4.0
1.2
9.5
9.0
6.3
9.4
5.3
4.3
NAf
4.7
4.7
4.7
5.6
NA
NA
4.7
6.7
(R)-12
(S)-12
(R)-32
(S)-32
0.48
630
1.3
3500
5.5
5600
NA
a
Inhibition of substance P induced phosphotidyl inositol turn-
over in UC-11 MG astrocytoma cells, given in nM units; see ref
27. Values represent mean of two determinations. Inhibition of
b
substance P induced IL-6 secretion in U-373 MG astrocytoma cells,
given in nM units; see ref 28. Values represent mean of two
determinations. c Inhibition of substance P induced contraction of
d
rabbit vena cava (RVC) tissue; see ref 26. Inhibition of neurokinin
A induced contraction of rabbit pulmonary artery (RPA) tissue;
see ref 29. e Inhibition of neurokinin B induced contraction of rat
portal vein (RPV) tissue; see ref 29. f NA ) not active to 10-5 M.
In summary, all compounds tested were competitive
antagonists with high specificity for NK-1 (vs NK-2,
NK-3, and others30) systems.
In Vivo Activities. Compounds with high NK-1 recep-
tor binding affinity were evaluated further using in vivo
models of NK-1 activity. Central nervous system NK-1

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 741
borane methyl sulfide complex. This solution was stirred
overnight in an 83 °C oil bath. After cooling to room temper-
ature, a 1:1 mixture of tetrahydrofuran:water (75 mL total)
was added to the solution. Sodium hydroxide (5 N, 230 mL)
was added to the mixture, and the reaction was heated to
reflux for about 30 min. After the biphasic mixture was cooled
to room temperature, the aqueous and organic layers were
separated and the organic layer was collected. The aqueous
layer was reextracted with tetrahydrofuran. The organic
layers were combined, and the solvents were removed by
evaporation. The resulting liquid was partitioned between
ethyl acetate and brine and was washed a second time with
brine. The solution was dried over sodium sulfate, and the
solvents were removed in vacuo to yield 48.68 g of the desired
intermediate 15. This material was used directly in the next
step without further purification. High-resolution mass spec-
tral analysis calculated for C30H30N3 432.2439, found 432.2420.
Step 3. (RS)-3-(1H-In d ol-3-yl)-1-[N-(2-m eth oxyben zyl)-
N-a cet yla m in o]-2-(N-(t r ip h en ylm et h yl)a m in o)p r op a n e
(16). To a solution of crude 15 (48.68 g, 0.109 mol) dissolved
in toluene (1.13 L) was added 2-methoxybenzaldehyde (23.12
g, 0.169 mol), the 2-methoxybenzaldehyde having been previ-
ously purified by base wash. The reaction mixture was stirred
overnight. The solvents were removed in vacuo. The recov-
ered solid was dissolved in 376 mL of a 1:1 tetrahydrofuran:
methanol mixture. To this solution was added sodium boro-
hydride (6.83 g, 0.180 mol). This mixture was stirred on ice
for about 4 h. The solvents were removed by evaporation. The
remaining liquid was partitioned between 1200 mL of ethyl
acetate and 1000 mL of a 1:1 brine/20 N sodium hydroxide
solution. This was extracted twice with 500 mL of ethyl
acetate each, and then the organic layer was dried over sodium
sulfate. The solvents were removed by evaporation, yielding
67.60 g (>99% yield) of the desired intermediate crude
material, (RS)-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-
2-(N-(triphenylmethyl)amino)propane, which was carried on
directly. To a stirring solution of this crude (0.109 mol) in
anhydrous tetrahydrofuran (325 mL) under a nitrogen atmo-
sphere at 0 °C was added triethylamine (17.8 mL, 0.129 mol)
and acetic anhydride (12.2 mL, 0.129 mol). After 4 h, the
mixture was concentrated on a rotary evaporator, redissolved
in methylene chloride and ethyl acetate, washed with water
(2×) and brine (2×), dried over anhydrous sodium sulfate,
filtered, and concentrated to a solid on a rotary evaporator.
The resulting solid was dissolved in chloroform and loaded onto
a silica gel 60 (230-400 mesh) column and eluted with a 1:1
mixture of ethyl acetate and hexanes. Fractions containing
desired material were concentrated in vacuo. Finally the
product was crystallized from an ethyl acetate/hexanes mix-
ture, yielding, over three crops, 56 g of 16 (87% two-step
yield): 1H NMR (300 MHz, CDCl3) 3:1 mixture of rotamers δ
1.92 (s, 3/4‚3H), 1.96 (s, 1/4‚1H), 2.30-2.48 (m, 1/4‚3H), 2.58-
2.78 (m, 3/4‚3H), 3.02-3.33 (m, 3H), 3.57 (s, 1/4‚3H), 3.69 (s,
3/4‚3H), 3.72 (dAB, J ) 17 Hz, 3/4‚3H), 4.03 (dAB, J ) 17 Hz,
3/4‚1H), 4.42 (dAB, J ) 16 Hz, 1/4‚1H), 4.66 (dAB, J ) 16 Hz,
1/4‚1H), 6.38 (d, J ) 7 Hz, 1H), 6.58-6.78 (m, 2H), 6.85-7.34
Con clu sion s
Our own early structure-activity studies on tryp-
tophan amide and ester NK-1 antagonists led to the
discovery that the carbonyl function in these molecules
could be moved to an off-chain position. This resulted
in highly potent tryptophan derived compounds of the
R stereoisomeric series. This series was found to have
higher affinity for human and guinea pig over rodent
NK-1 receptors, although compounds were found with
Ki’s < 10 nM in rodent binding assays. Compounds in
this series were shown to be competitive antagonists in
three different functional assays, and their potency in
a functional NK-1 assay correlated well with observed
receptor binding affinities for the NK-1 receptor. Two
of these agents were demonstrated to be antagonists
upon systemic administration in a central nervous
system in vivo NK-1 agonist-driven model. In a guinea
pig neurogenic dural inflammation model, a putative
model of endogenous release of substance P, both (R)-
25 and (R)-32 were highly active upon intravenous
administration, and further, upon oral administration,
(R)-32 was observed to be very potent and have a long
duration of action. Therefore compounds from this
series show potential to be therapeutically useful in
disease states where an excess of SP is implicated.
Exp er im en ta l Section
All chemical experiments were run under a positive pressure
of dry nitrogen or argon. All solvents and reagents were used
as obtained. Generally, materials were obtained as dry foams;
however, for crystalline materials, melting points were ob-
tained on a Hoover melting point apparatus and are uncor-
rected. Proton NMR were obtained at 300.15 MHz on a
General Electric QE300 spectrometer with tetramethylsilane
as an internal standard. High-resolution mass spectra were
recorded on a VG Analytical ZAB2-SE instrument. Elemental
analyses were carried out by the Physical Chemistry Depart-
ment of Lilly Research Laboratories and are within (0.4% of
theory unless otherwise noted. The following procedures serve
to exemplify the methods used to prepare the compounds in
the text above. Compounds not specifically detailed may be
prepared by analogy with these methods.
Meth od A. Step 1. (RS)-3-(1H-In d ol-3-yl)-2-(N-(tr ip h -
en ylm eth yl)a m in o)p r op a n a m id e (14). 13 (26.43 g, 0.130
mol) was suspended in 260 mL of methylene chloride, and this
mixture was flushed with nitrogen and then put under argon.
Trityl chloride (38.06 g, 0.136 mol) was dissolved in 75 mL of
methylene chloride. The trityl chloride solution was added
slowly to the tryptophan amide solution which sat in an ice
bath, the addition taking about 25 min. The reaction mixture
was allowed to stir overnight. The reaction mixture was
poured into a separation funnel and was washed with 250 mL
of water, followed by 250 mL of brine. As the organic layer
was filtering through sodium sulfate to dry, a solid precipi-
tated. The filtrate was collected and the solvent was evapo-
rated. Ethyl acetate was added to the pooled solid, and this
mixture was stirred and then refrigerated overnight. The next
day the resulting solid was washed several times with cold
ethyl acetate and then dried in vacuo: yield 49.76 g (86%);
3
1
(m, 15H), 7.43-7.58 (m, 6H), 8.12 (s, /4‚1H), 8.22 (s, /4‚1H).
Anal. (C40H39N3O2) C, H, N.
Step 4. (RS)-2-Am in o-3-(1H-in d ol-3-yl)-1-[N-(2-m eth -
oxyben zyl)-N-a cetyla m in o]p r op a n e (17). Formic acid (9.0
mL, 240 mmol) was added to a stirring solution of 16 (14.11
g, 23.8 mmol) in 240 mL of anhydrous methylene chloride
under a nitrogen atmosphere at 0 °C. After 4 h, the reaction
mixture was concentrated to an oil on a rotary evaporator and
redissolved in diethyl ether and 1.0 N hydrochloric acid. The
aqueous layer was washed twice with diethyl ether and
basified with sodium hydroxide to a pH greater than 12. The
product was extracted with methylene chloride (4×). The
organic extracts were combined, dried over anhydrous sodium
sulfate, filtered, and concentrated on a rotary evaporator to a
white foam (7.52 g) identified to be 17 (90% yield). No further
purification was necessary, and the material was used directly
in the next step; however an analytical sample (as the
dihydrochloride salt) was prepared by dissolving the crude
material in dichloromethane and adding an excess of gaseous,
anhydrous HCl. Data for this material is as follows: 1H (300
1
mp 209-210 °C; H NMR (300 MHz, CDCl3) δ 2.50 (dAB, J )
13.8, 7.2 Hz, 1H), 2.89 (d, J ) 6.6 Hz, 1H), 3.12 (dAB, J ) 13.8,
7.2 Hz, 1H), 3.49 (dd, J ) 7.2, 6.6 Hz, 1H), 5.45 (br s, 1H),
6.92 (d, J ) 1.8 Hz, 1H), 7.00 (t, J ) 7.2 Hz, 1H), 7.14 (m,
10H), 7.34 (m, 7H), 7.54 (d, J ) 7.2 Hz, 1H), 9.83 (br s, 1H).
Anal. (C30H27N3O) C, H, N.
Step 2. (RS)-1-Am in o-3-(1H-in d ol-3-yl)-2-(N-(tr ip h e-
n ylm eth yl)a m in o)p r op a n e (15). Under argon 14 (48.46 g,
0.108 mol) was suspended in 270 mL of tetrahydrofuran. This
mixture was heated to reflux. Borane methyl sulfide complex
(41.3 g, 0.543 mol) was slowly added to the reaction mixture.
All of the starting amide dissolved during the addition of the
3
MHz, DMSO-d6) 3:2 mixture of amide rotamers δ 1.94 (s, /5‚-

742 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Hipskind et al.
2
3H), 2.08 (s, /5‚3H), 2.88 (dd, 1H, J ) 14, 9 Hz), 2.96 (dd, 1H,
7.06 (d, J ) 3 Hz, 1H), 7.06-7.45 (m, 10H), 7.68 (d, J ) 8 Hz,
1H), 8.06 (br s, 1H). Anal. (C34H41N5O3) C, H, N.
J ) 14, 4 Hz), 3.42-3.49 (m, 3H), 3.49 (s, 3H), 3.69 (broad
doublet, 1H, J ) 5 Hz), 4.38 (d, 1H, J ) 17 Hz), 4.48, (d, 1H,
J ) 17 Hz), 6.76-6.80 (m, 2H), 6.94 (m, 2H), 7.05 (t, 1H, J )
7 Hz), 7.18 (m, 2H), 7.36 (d, 1H, J ) 8 Hz), 7.56 (d, 1H, J ) 8
Hz), 8.45 (br s, /5‚2H), 8.60 (br s, /5‚2H), 11.1 (broad singlet,
2H). Anal. (C21H27Cl2N3O2) H, N; C: calcd, 59.44; found,
59.86.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er id in -1-yl)a cetyl)a m i-
n o]p r op a n e (26): 1H NMR (300 MHz, CDCl3) δ 1.50-1.91 (m,
4H), 2.08 (s, 3H), 2.06-2.22 (m, 2H), 2.40 (m, 1H), 2.64 (br d,
J ) 11 Hz, 1H), 2.80 (br d, J ) 12 Hz, 1H), 2.86-2.98 (m, 3H),
3.04-3.18 (m, 2H), 3.73 (s, 3H), 4.01 (dd, J ) 10, 14 Hz, 1H),
4.46 (AB q, J ) 17 Hz, ∆ν ) 45 Hz, 2H), 4.54 (m, 1H), 6.76-
6.85 (m, 3H), 7.02-7.36 (m, 10H), 7.54 (d, J ) 8 Hz, 1H), 7.70
(d, J ) 8 Hz, 1H), 8.01 (br s, 1H). Anal. (C34H40N4O3) C, H,
N.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(4-p h en yl-∆3,4-p ip er id in -1-yl)a cety-
l)a m in o]p r op a n e (27): 1H NMR (300 MHz, CDCl3) δ 2.12 (s,
3H), 2.21-2.70 (m, 4H), 2.90-3.25 (m, 7H), 3.77 (s, 1H), 3.95
(dd, J ) 10, 14 Hz, 1H), 4.52 (AB q, J ) 17 Hz, ∆v ) 38 Hz,
2H), 4.61 (m, 1H), 5.95 (br s, 1H), 6.85 (m, 3H), 7.00-7.54 (m,
11H), 7.67 (d, J ) 8 Hz, 1H), 8.08 (br s, 1H). Anal.
(C34H38N4O3) C, H, N.
3
2
Step 5. (RS)-2-[(2-Br om oa cetyl)a m in o]-3-(1H-in d ol-3-
yl)-1-[N-(2-m eth oxyben zyl)-N-a cetyla m in o]p r op a n e (18).
To a stirring solution of 17 (7.51 g, 21.4 mmol) (free base form)
in anhydrous tetrahydrofuran (100 mL) under a nitrogen
atmosphere at 0 °C were added diisopropylethylamine (4.1 mL,
23.5 mmol) and bromoacetyl bromide (2.05 mL, 23.5 mmol).
After 2 h, ethyl acetate was added and the reaction mixture
washed with water twice, 1.0 N hydrochloric acid (2×),
saturated sodium bicarbonate solution (2×), and brine. The
organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated to a tan foam on a rotary evaporator.
In this manner 18 was obtained in quantitative yield. No
further purification was necessary: 1H NMR (300 MHz, CDCl3)
δ 2.15 (s, 3H), 2.81-2.96 (m, 2H), 3.15 (ABq, J ) 4.3 Hz, ∆ν )
14.6 Hz, 1H), 3.72 (s, 3H), 3.79 (s, 2H), 4.06-4.15 (m, 1H),
4.30 (m, 1H), 4.38 (ABq, J ) 16.7 Hz, ∆ν ) 49.0 Hz, 2H), 6.72-
6.81 (m, 3H), 7.01 (s, 1H), 7.13-7.30 (m, 3H), 7.35-7.41 (m,
2H), 7.71 (d, J ) 7.8 Hz, 1H), 8.04 (m, 1H). Anal. (C23H26N3O3-
Br) C, H, N.
Step 6. (RS)-2-[N-(2-(4-Cycloh exylp ip er a zin -1-yl)a cet-
yl)a m in o]-3-(1H -in d ol-3-yl)-1-[N-(2-m et h oxyb en zyl)-N-
a cetyla m in o]p r op a n e (25). 1-Cyclohexylpiperazine (3.65 g,
22.5 mmol) was added to a stirring solution of 18 (21.4 mmol)
and powdered potassium carbonate (3.56 g, 25.8 mmol) in
methylene chloride under a nitrogen atmosphere. The reaction
mixture was stirred overnight at room temperature. The salts
were filtered, and the solution was concentrated to a brown
foam on a rotary evaporator. The desired product was purified
on a Prep 500 column using a 10 L gradient starting with 100%
methylene chloride and ending with 5% methanol/94.5%
methylene chloride/0.5% ammonium hydroxide. Impure frac-
tions were combined and purified further by reverse phase
preparative high-performance liquid chromatography (methanol/
acetonitrile/water/ammonium acetate). After combining the
material from both chromatographic purifications, the title
compound 25 (10.4 g, 18.7 mmol) was isolated (87% yield): 1H
NMR (300 MHz, CDCl3) δ 1.05-1.34 (m, 6H), 1.55-1.95 (m,
4H), 2.09 (s, 3H), 2.20-2.60 (m, 9H), 2.90 (s, 2H), 2.85-3.16
(m, 3H), 3.77 (s, 3H), 4.02 (dd, J ) 11, 13 Hz, 1H), 4.47 (AB q,
J ) 16 Hz, ∆ν ) 44 Hz, 2H), 4.54 (m, 1H), 6.77-6.88 (m, 3H),
7.05-7.25 (m, 4H), 7.31-7.42 (m, 2H), 7.66 (d, J ) 7 Hz, 1H),
8.08 (br s, 1H). Anal. (C33H45N5O3) C, H, N.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cet yla m in o]-2-[N-(2-(p ip er id in -1-yl)a cet yl)a m in o]p r o-
1
p a n e (28): H NMR (300 MHz, CDCl3) δ 1.37-1.56 (m, 6H),
2.09 (s, 3H), 2.30 (br s, 4H), 2.80-3.19 (m, 5H), 3.75 (s, 3H),
3.95 (dd, J ) 11, 13 Hz, 1H), 4.46 (AB q, J ) 17 Hz, ∆ν ) 44
Hz, 2H), 4.53 (m, 1H), 6.75-6.88 (m, 3H), 7.04-7.24 (m, 5H),
7.34 (d, J ) 8 Hz, 1H), 7.68 (d, J ) 7 Hz, 1H), 8.04 (br s, 1H).
Anal. (C28H36N4O3) C, H, N.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(m or p h olin -4-yl)a cetyl)a m in o]p r o-
1
p a n e (29): H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 2.20-
2.29 (m, 2H), 2.31-2.41 (m, 2H), 2.85-2.97 (m, 3H), 3.01-
3.13 (m, 2H), 3.46-3.67 (m, 4H), 3.77 (s, 3H), 4.15 (dd, J )
10, 13 Hz, 1H), 4.47 (AB q, J ) 17 Hz, ∆ν ) 48 Hz, 2H), 4.52
(m, 1H), 6.77-6.89 (m, 3H), 7.02-7.28 (m, 4H), 7.36 (d, J ) 6
Hz, 1H), 7.46 (d, J ) 8 Hz, 1H), 7.68 (d, J ) 7 Hz, 1H), 8.02
(br s, 1H). Anal. (C27H34N4O4) C, H, N.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(N-(2-(p h en yla m in o)eth yl)a m in o)-
1
a cetyl)a m in o]p r op a n e (30): H NMR (300 MHz, CDCl3) δ
2.11 (s, 3H), 2.72-2.95 (m, 4H), 3.00-3.34 (m, 6H), 3.72 (s,
3H), 4.14 (dd, J ) 13 Hz, J ) 11 Hz, 1H), 4.40 (AB q, J ) 17
Hz, ∆ν ) 63 Hz, 2H), 4.42 (m, 1H), 4.78 (br s, 1H), 6.65-6.84
(m, 6H), 6.95 (d, J ) 3 Hz, 1H), 7.05-7.35 (m, 6H), 7.67 (d, J
) 8 Hz, 1H), 7.80-7.91 (m, 2H). Anal. (C31H37N5O3) C, H, N.
(RS)-2-[N-(2-(4-(Dim eth yla m in o)p ip er id in -1-yl)a cetyl)-
am in o]-3-(1H-in dol-3-yl)-1-[N-(2-m eth oxyben zyl)-N-acety-
la m in o]p r op a n e (31): 1H NMR (300 MHz, CDCl3) δ 1.26 (m,
1H), 1.48-1.76 (m, 3H), 1.90-2.11 (m, 3H), 2.09 (s, 3H), 2.25
(s, 6H), 2.51 (br d, J ) 13 Hz, 1H), 2.73 (br d, J ) 12 Hz, 1H),
2.85 (s, 2H), 2.85-3.23 (m, 3H), 3.75 (s, 3H), 3.94 (dd, J ) 10,
14 Hz, 1H), 4.47 (AB q, J ) 17 Hz, ∆ν ) 43 Hz, 2H), 4.51 (m,
1H), 6.77-6.88 (m, 3H), 7.01-7.28 (m, 4H), 7.35 (d, J ) 8 Hz,
1H), 7.41 (d, J ) 9 Hz, 1H), 7.66 (d, J ) 7 Hz, 1H), 8.09 (br s,
1H). Anal. (C30H41N5O3) C, H, N.
The following compounds were prepared from 18, by analogy
to 25 using the above method A, steps 1-6, and substituting
the appropriate amine for 1-cyclohexylpiperazine.
(RS)-2-(N-Acetyla m in o)-1-[N-a cetyl-N-(2-m eth oxyben -
zyl)a m in o]-3-(1H-in d ol-3-yl)p r op a n e (9): 1H NMR (300
MHz, CDCl3) δ 1.95 (s, 3H), 2.13 (s, 3H), 2.81 (dd, J ) 8, 16
Hz, 1H), 2.89 (dd, J ) 4, 14 Hz, 1H), 3.72 (s, 3H), 3.99 (t, J )
10 Hz, 1H), 4.35 (m, 1H), 4.37 (AB q, J ) 16 Hz, ∆ν ) 58 Hz,
2H), 7.65-7.82 (m, 4H), 6.99 (s, 1H), 7.01-7.22 (m, 3H), 7.37
(d, J ) 7 Hz, 1H), 7.66 (d, J ) 8 Hz, 1H), 9.19 (br s, 1H). Anal.
(C23H27N3O3) C, H, N.
(RS)-3-(1H-In dol-3-yl)-1-[N-(2-m eth oxyben zyl)-N-acetyl-
am in o]-2-[N-(2-(4-m eth ylpiper azin -1-yl)acetyl)am in o]pr o-
p a n e (23): 1H NMR (300 MHz, CDCl3) δ 2.10 (s, 3H), 2.26 (s,
3H), 2.33-2.40 (m, 8H), 2.86-3.14 (m, 5H), 3.75 (s, 3H), 4.01
(dd, J ) 10, 14 Hz, 1H), 4.54 (br s, 1H), 4.48 (AB q, J ) 17 Hz,
∆v ) 45 Hz, 2H), 6.82 (m, 2H), 7.04 (d, J ) 2 Hz, 1H), 7.08-
7.28 (m, 3H), 7.35 (d, J ) 8 Hz, 1H), 7.43 (d, J ) 9 Hz, 1H),
7.66 (d, J ) 8 Hz, 1H), 8.49 (br s, 1H); high-resolution mass
spec calcd for C28H37N5O3 492.2975, found 492.2977.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h o x y b e n zy l)-N -
a cet yla m in o]-2-[N-(2-(4-(p ip er id in -1-yl)p ip er id in -1-yl)-
1
a cetyl)a m in o]p r op a n e (32): H NMR (300 MHz, CDCl3) δ
1.30-1.72 (m, 6H), 1.90-2.20 (m, 6H), 2.10 (s, 3H), 2.33-2.60
(m, 6H), 2.68-3.20 (m, 6H), 3.76 (s, 3H), 3.99 (dd, J ) 11.4,
14.4 Hz, 1H), 4.48 (AB q, J ) 17 Hz, ∆ν ) 42 Hz, 2H), 4.55
(m, 1H), 6.78-6.89 (m, 3H), 7.04-7.25 (m, 4H), 7.35 (d, J )
7.8 Hz, 1H), 7.46 (d, J ) 8.5 Hz, 1H), 7.67 (d, J ) 7.9 Hz, 1H),
8.26 (br s, 1H). Anal. (C33H45N5O3) C, H, N.
The following compounds were prepared from 18, by analogy
to 25 using the above method A, steps 1-6, and substituting
the appropriate aldehyde for 2-methoxybenzaldehyde.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(3-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m i-
n o]p r op a n e (44): 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 3H),
2.15-2.63 (m, 4H), 2.72-3.27 (m, 8H), 3.75 (m, 1H), 3.78 (s,
3H), 4.04 (m, 1H), 4.51 (AB q, J ) 16 Hz, ∆ν ) 46 Hz, 2H),
4.56 (m, 1H), 6.60-6.70 (m, 2H), 6.72-6.94 (m, 5H), 7.04-
7.46 (m, 7H), 7.65 (d, J ) 8 Hz, 1H), 8.04 (br s, 1H). Anal.
(C33H39N5O3) C, H, N.
(RS)-2-[N-(2-(4-Ben zylp ip er a zin -1-yl)a cetyl)a m in o]-3-
(1H-in d ol-3-yl)-1-[N-(2-m eth oxyben zyl)-N-a cetyla m in o]-
p r op a n e (24): 1H NMR (300 MHz, CDCl3) δ 2.08 (s, 3H), 2.16-
2.62 m, 8H), 2.82-2.97 (m, 3H), 2.99-3.18 (m, 2H), 3.41-3.62
(m, 2H), 3.76 (s, 3H), 4.02 (dd, J ) 10, 13 Hz, 1H), 4.49 (AB q,
J ) 18 Hz, ∆ν ) 48 Hz, 2H), 4.53 (m, 1H), 6.76-6.88 (m, 3H),

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 743
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(4-m e t h o x y b e n zy l)-N -
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m i-
n o]p r op a n e (45): 1H NMR (300 MHz, DMSO-d6) 1:1 mixture
of amide rotamers δ 2.01 (s, 1/2‚3H), 2.05 (s, 1/2‚3H), 2.23-2.60
(m, 4H), 2.74-3.30 (m, 8H), 3.69 (m, 1H), 3.72 (s, 1/2‚3H), 3.74
(s, 1/2‚3H), 4.23 (AB q, J ) 16 Hz, ∆ν ) 42 Hz, 1/2‚2H), 4.52
1H), 7.63 (d, J ) 8 Hz, 1H), 8.19 (br s, 1H); high-resolution
mass spectral data, calcd for C32H42ClN5O2 564.3105, found
564.3135. Anal. (C32H42ClN5O2‚0.5H2O) C, H, N.
Meth od B. Step 1. 2-[(ter t-Bu toxyca r bon yl)a m in o]-
3-(1H-in d ol-3-yl)-N-(2-m eth oxyben zyl)p r op a n a m id e (20).
To a solution of 19 (46.4 g, 152.6 mmol) in 500 mL of dioxane
1
(m, 1H), 4.36 (AB q, J ) 14 Hz, ∆ν ) 164 Hz, /2‚2H), 6.70-
was added carbonyldiimidazole (25.4 g, 156 mmol) in
a
7.16 (m, 10H), 7.24 (m, 2H), 7.35 (m, 1H), 7.55 (m, 1/2‚1H +
portionwise manner. The resulting mixture was stirred for
about 2.5 h at room temperature and then stirred at 45 °C for
30 min. Next, 2-methoxybenzylamine (20.7 mL, 158.7 mmol)
was added to the reaction mixture which was stirred for 16 h
at room temperature. The dioxane was removed under
reduced pressure. The product was partitioned between ethyl
acetate and water and was washed successively with 1 N
hydrochloric acid, saturated sodium bicarbonate solution,
water, and brine, followed by drying over sodium sulfate and
removal of the solvent. Final crystallization from methanol
yielded 52.2 g of homogeneous product 20 as yellow crystals:
yield 80.8%; mp 157-160 °C; 1H NMR (300 MHz, CDCl3) δ
1.43 (s, 9H), 3.10 (m, 1H), 3.29 (m, 1H), 3.58 (3, 3H), 4.26 (m,
2H), 4.40 (m, 1H), 5.24 (m, 1H), 6.08 (m, 1H), 6.67-6.93 (m,
3H), 6.97-7.40 (m, 5H), 7.67 (d, J ) 8 Hz, 1H), 7.79 (br s,
1H). Anal. (C24H29N3O4) C, H, N.
Step 2. 2-Am in o-3-(1H-in d ol-3-yl)-N-(2-m eth oxyben -
zyl)p r op a n a m id e (21). To a mixture of 20 (25.1 g, 59.2
mmol) and anisole (12 mL, 110.4 mmol) at 0 °C was added
dropwise an aqueous solution of trifluoroacetic acid (118 mL,
1.53 moles) in 50 mL of water. This mixture was stirred for
1 h at 0 °C, followed by stirring for about 2.5 h at ambient
temperature. The volatile materials were removed under
reduced pressure. The product was partitioned between ethyl
acetate and saturated sodium bicarbonate solution and was
washed with water followed by brine and then dried over
sodium sulfate. The solvents were removed in vacuo. Recrys-
tallization from a 1:1 diethyl ether/cyclohexane solution yielded
18.0 g (94.2%) of 21 as an off-white powder: mp 104-108 °C;
1H NMR (300 MHz, CDCl3) δ 2.09 (m, 2H), 3.18 (AB q, J ) 16
Hz, ∆ν ) 120 Hz, 2H), 3.77 (s, 3H), 3.79 (m, 1H), 4.40 (m, 2H),
6.76-6.95 (m, 2H), 6.99 (s, 1H), 7.05 (t, J ) 8 Hz, 1H), 7.12-
7.31 (m, 3H), 7.34 (d, J ) 9 Hz, 1H), 7.54 (m, 1H), 7.63 (d, J
) 9 Hz, 1H), 8.07 (br s, 1H). Anal. (C19H21N3O2) C, H, N.
Step 3. 2-Am in o-3-(1H-in d ol-3-yl)-1-[N-(2-m eth oxyben -
zyl)a m in o]p r op a n e. To a refluxing solution of 21 (9.81 g,
30.3 mmol) in 100 mL of anhydrous tetrahydrofuran was
added dropwise a 10 M borane methyl sulfide complex (9.1
mL, 91.0 mmol). The resulting mixture was refluxed for about
2 h. The mixture was cooled to room temperature, and the
excess borane was quenched by the dropwise addition of 160
mL of methanol. The resulting mixture was refluxed for 15
min, and the methanol was removed under reduced pressure.
The residue was dissolved in a saturated methanol solution
of hydrochloride acid (250 mL) and the solution refluxed for
about 1 h. The methanol was removed in vacuo, and the
product was isolated by the addition of 5 N sodium hydroxide
followed by extraction with diethyl ether (2×). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Flash chromatography (silica gel, 10:
100:0.5 methanol/methylene chloride/ammonium hydroxide)
provided 7.1 g of a mixture of the intermediate 2-amino-3-(1H-
indol-3-yl)-1-[N-(2-methoxybenzyl)amino]propane (75%) and its
indoline derivative (25%) as an amber oil. This mixture was
used directly in the next step.
1
1H), 7.73 (m, /2‚1H), 10.84 (br s, 1H). Anal. (C33H39N5O3) C,
H, N.
(RS)-1-(N-Ben zyl-N-a cet yla m in o)-3-(1H -in d ol-3-yl)-2-
[N-(2-(4-ph en ylpiper azin -1-yl)acetyl)am in o]pr opan e (46):
1H NMR (300 MHz, DMSO-d6) 1:1 mixture of amide rotamers
δ 1.99 (s, 1/2‚3H), 2.07 (s, 1/2‚3H), 2.20-2.50 (m, 4H), 2.69-
1
2.95 (m, 4H), 2.95-3.12 (m, 4H), 3.12-3.52 (m, /2‚1H + 1H),
3.63 (m, 1/2‚1H), 4.40 (m, 1H), 4.51 (AB q, J ) 16 Hz, ∆ν )
1
1
140 Hz, /2‚2H), 4.54 (AB q, J ) 16 Hz, ∆ν ) 30 Hz, /2‚2H),
6.78 (t, J ) 8 Hz, 1H), 6.86-6.94 (m, 2H), 6.98 (m, 1H), 7.03-
7.15 (m, 4H), 7.15-7.38 (m, 6H), 7.50-7.60 (m, 1.5H), 7.74
1
(d, J ) 8 Hz, /2‚1H), 10.93 (br s, 1H). Anal. (C32H37N5O2) C,
H, N.
(RS)-3-(1H -In d ol-3-yl)-1-[N-(2-(m et h ylt h io)b en zyl)-N-
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m i-
n o]p r op a n e (47): mp 138 °C dec; 1H NMR (300 MHz, CDCl3)
δ 2.09 (s, 3H), 2.1-2.6 (m, 3H), 2.46 (s, 3H), 2.8-3.1 (m, 8H),
3.30 (m, 1H), 3.55 (m, 1H), 3.98 (m, 1H), 4.47 (AB q, J ) 12
Hz, ∆ν ) 52 Hz, 2H), 4.58 (m, 1H), 6.8-6.9 (m, 3H), 6.95 (d,
J ) 8 Hz, 2H), 7.0-7.4 (m, 9H), 7.66 (d, J ) 8 Hz, 1H), 8.08
(br s, 1H). Anal. (C33H39N5O2S) C, H, N.
(RS)-1-[N-(2-Ch lor oben zyl)-N-acetylam in o]-3-(1H-in dol-
3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r o-
p a n e (48): 1H NMR (300 MHz, DMSO-d6) 3:2 mixture of amide
rotamers δ 1.93 (s, 2/5‚3H), 2.09 (s, 3/5‚3H), 2.25-2.50 (m, 4H),
2.70-2.96 (m, 4H), 2.96-3.19 (m, 4H), 3.20-3.64 (m, 2H), 4.50
3
(m, 1H), 4.59 (AB q, J ) 16 Hz, ∆ν ) 70 Hz, /5‚2H), 4.64 (s,
2/5‚2H), 6.78 (t, J ) 7 Hz, 1H), 6.91 (d, J ) 8 Hz, 2H), 6.98 (t,
J ) 7 Hz, 1H), 7.02-7.10 (m, 2H), 7.12 (m, 1H), 7.16-7.37
2
(m, 5H), 7.44 (m, 1H), 7.50-7.62 (m, /5‚1H + 1H), 7.75 (d, J
3
) 8 Hz, /5‚1H), 10.83 (br s, 1H). Anal. (C32H36ClN5O2) C, H,
N.
(R S )-3-(1H -I n d o l-3-y l)-1-[N -(2-m e t h y lb e n z y l)-N -
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m i-
n o]p r op a n e (49): 1H NMR (300 MHz, CDCl3) δ 2.06 (s, 3H),
2.21 (s, 3H), 2.1-2.6 (m, 2H), 2.9-3.3 (m, 12H), 3.58 (m, 1H),
4.4-4.6 (m, 2H), 6.8-7.0 (m, 5H), 7.0-7.4 (m, 9H), 7.62 (d, J
) 7 Hz, 1H), 8.15 (br s, 1H). Anal. (C33H39N5O2) C, H, N.
(RS)-3-(1H-In d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)-
a cetyl)a m in o]-1-[N-(2-(tr iflu or om eth yl)ben zyl)-N-a cety-
1
la m in o]p r op a n e (50); H NMR (300 MHz, CDCl3) δ 2.03 (s,
3H), 2.15-2.80 (m, 5H), 2.80-3.73 (m, 8H), 3.88 (m, 1H), 4.47-
4.93 (m, 3H), 6.72-7.03 (m, 4H), 7.03-7.45 (m, 7H), 7.45-
7.76 (m, 4H), 8.22 (br s, 1H). Anal. (C33H36F3N5O2) C, H, N.
(RS)-3-(1H-In dol-3-yl)-1-[N-(2-n itr oben zyl)-N-acetylam i-
n o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r o-
p a n e (51): 1H NMR (300 MHz, CDCl3) δ 2.05 (s, 3H), 2.28 (m,
1H), 2.3-2.7 (m, 4H), 2.8-3.2 (m, 8H), 3.2-3.9 (m, 2H), 4.58
(m, 1H), 4.97 (m, 1H), 6.8-7.0 (m, 2H), 7.0-7.5 (m, 10H), 7.5-
7.7 (m, 2H), 8.12 (d, J ) 7 Hz, 1H), 8.15 (br s, 1H). Anal.
(C32H36N6O4) C, H, N.
The following compounds were prepared by analogy to 25
using the above method A, steps 1-6, and substituting
2-chlorobenzaldehyde for the 2-methoxybenzaldehyde.
(RS)-1-[N-(2-Ch lor oben zyl)-N-a cetyla m in o]-2-[N-(2-(4-
cycloh exylp ip er a zin -1-yl)a cetyl)a m in o]-3-(1H-in d ol-3-yl-
)p r op a n e (52): 1H NMR (300 MHz, CDCl3) δ 1.0-1.4 (m, 6H),
1.6 (m, 1H), 1.7-1.9 (m, 4H), 2.08 (s, 3H), 2.1-2.6 (m, 9H),
2.8-3.1 (m, 4H), 4.0 (m, 1H), 4.5-4.7 (m, 3H), 7.0-7.4 (m, 9H),
7.63 (d, J ) 6 Hz, 1H), 8.18 (br s, 1H). Anal. (C32H42ClN5O2)
C, H, N.
Step 4. 3-(1H-In dol-3-yl)-1-[N-(2-m eth oxyben zyl)am in o]-
2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r op a n e
(22). A mixture of 2-(4-phenylpiperazin-1-yl)acetic acid, so-
dium salt (1.64 g, 6.8 mmol), and triethylamine hydrobromide
(1.24 g, 6.8 mmol) in 35 mL of anhydrous dimethylformamide
was prepared and heated to 50 °C and held at that tempera-
ture for about 35 min. The mixture was allowed to cool to
room temperature. 1,1-Carbonyldiimidazole (1.05 g, 6.5 mmol)
and 10 mL of anhydrous dimethylformamide were added to
the mixture. The resulting mixture was stirred for about 3 h
at room temperature. Next, a solution of the above prepared
mixture of 2.17 g of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-meth-
oxybenzyl)amino]propane (75%) and its indoline derivative
(25%) (ca. 6.2 mmol) in 10 mL of anhydrous dimethylforma-
(R S )-1-[N -(2-C h lo r o b e n z y l)-3-(1H -i n d o l-3-y l)-N -
a cet yla m in o]-2-[N-(2-(4-(p ip er id in -1-yl)p ip er id in -1-yl)-
1
a cetyl)a m in o]p r op a n e (53): H NMR (300 MHz, CDCl3) δ
1.17-1.80 (m, 10H), 1.90-2.27 (m, 3H), 2.03 (s, 3H), 2.35-
2.59 (m, 5H), 2.67-3.23 (m, 6H), 3.97 (dd, J ) 10, 15 Hz, 1H),
4.53 (m, 1H), 4.58 (AB q, J ) 17 Hz, ∆ν ) 21 Hz, 21 Hz, 2H),
6.95-7.29 (m, 6H), 7.34 (d, J ) 8 Hz, 2H), 7.42 (d, J ) 9 Hz,

744 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Hipskind et al.
mide was added to the activated acylimidazole mixture
prepared above. The resulting mixture was stirred for about
16 h at room temperature. The dimethylformamide was
removed under reduced pressure. The products were parti-
tioned between ethyl acetate and water, then washed with
brine, and dried over sodium sulfate. The solvents were
removed in vacuo. This process yielded 3.2 g of a mixture of
the title compound 22 and its indoline derivative as a yellow
oil. These two compounds were separated using high-
performance liquid chromatography using a reverse phase
column followed by a silica gel column to give the title product
22, (266 mg, ca. 5.2% overall two-step yield) as a yellow foam:
1H NMR (300 MHz, CDCl3) δ 2.30-2.43 (m, 2H), 2.43-2.54
(m, 2H), 2.70-3.10 (m, 11H), 3.82 (s, 3H), 3.84 (m, 2H), 4.44
(m, 1H), 6.74-6.94 (m, 6H), 7.04 (m, 1H), 7.07-7.36 (m, 7H),
7.64 (d, J ) 8 Hz, 1H), 8.09 (br s, 1H). Anal. (C31H37N5O2) C,
H, N.
7.45 (d, J ) 10 Hz, 1H), 7.68 (d, J ) 9 Hz, 1H), 8.12 (s, 1H).
Anal. (C35H41N5O5) C, H, N.
3-(1H-In d ol-3-yl)-1-[N-((m eth yla m in o)ca r bon yl)-N-(2-
m eth oxyben zyl)a m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)-
a cetyl)a m in o]p r op a n e (40): 1H NMR (300 MHz, DMSO-d6)
δ 2.32-2.46 (m, 4H), 2.55 (d, J ) 5 Hz, 3H), 2.78-2.90 (m,
4H), 2.96-3.10 (m, 4H), 3.18 (dd, J ) 5, 14 Hz, 1H), 3.44 (dd,
J ) 8, 13 Hz, 1H), 3.70 (s, 3H), 4.30 (m, 1H), 4.37 (AB q, J )
18 Hz, ∆ν ) 42 Hz, 2H), 6.32 (br d, J ) 5 Hz, 1H), 6.77 (t, J
) 7 Hz, 1H), 6.82-7.00 (m, 6H), 7.05 (t, J ) 8 Hz, 1H), 7.11
(d, J ) 3 Hz, 1H), 7.16-7.25 (m, 3H), 7.32 (d, J ) 9 Hz, 1H),
7.53 (d, J ) 8 Hz, 1H), 7.61 (d, J ) 9 Hz, 1H), 10.82 (br s, 1H).
Anal. (C33H40N6O3) C, H, N.
3-(1H -In d ol-3-yl)-1-[N-(2-m et h oxyb en zyl)-N-(m et h yl-
su lfon yl)a m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)-
a m in o]p r op a n e (41): 1H NMR (300 MHz, DMSO-d6) δ 2.28-
2.46 (m, 4H), 2.83 (d, J ) 7 Hz, 4H), 2.90 (s, 3H), 2.98-3.04
(m, 4H), 3.26-3.34 (m, 2H), 3.67 (s, 3H), 4.30 (m, 1H), 4.36
(d, J ) 5 Hz, 2H), 6.77 (t, J ) 8 Hz, 1H), 6.84-6.92 (m, 3H),
6.92-7.00 (m, 2H), 7.03-7.09 (m, 2H), 7.18-7.30 (m, 4H), 7.33
(d, J ) 8 Hz, 1H), 7.46 (d, J ) 8 Hz, 1H), 7.54 (d, J ) 9 Hz,
1H), 10.82 (br s, 1H). Anal. (C32H39N5O4S) C, H, N.
The following compounds were prepared from 19 using the
above method B, steps 1, 2, 4, and 5a (skipping step 3), and
substituting the appropriate amine for 2-methoxybenzylamine.
(RS)-2-(N-Acetyla m in o)-3-(1H-in d ol-3-yl)-N-ben zylp r o-
p a n a m id e (5): 1H NMR (300 MHz, DMSO) δ 1.79 (s, 3H), 2.92
(ddAB, J ) 8, 15 Hz, 1H), 3.12 (ddAB, J ) 6, 15 Hz, 1H), 4.25
(d, J ) 6 Hz, 2H), 4.56 (m, 1H), 6.97 (t, J ) 7 Hz, 1H), 7.06 (t,
J ) 7 Hz, 1H), 7.08-7.29 (m, 6H), 7.33 (d, J ) 8 Hz, 1H), 7.61
(d, J ) 8 Hz, 1H), 8.08 (d, J ) 8 Hz, 1H), 8.47 (t, J ) 6 Hz,
1H), 10.80 (br s, 1H). Anal. (C20H21N3O2) C, H, N.
The above intermediate 22 was used in the following steps
5a-d.
Step 5a . 1-[N-(Eth oxyca r bon yl)-N-(2-m eth oxyben zyl)-
a m in o]-3-(1H -in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-
yl)a cetyl)a m in o]p r op a n e (39). Ethyl chloroformate (89 µL,
0.93 mmol) was added slowly to a 0 °C solution of 3-(1H-indol-
3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-(4-phenylpiperazin-
1-yl)acetyl)amino]propane (22) (0.43 g, 0.85 mmol) and trieth-
ylamine (130 µL, 0.93 mmol) in anhydrous tetrahydrofuran
(5 mL). The resulting mixture was stirred for 16 h at room
temperature. The tetrahydrofuran was removed under re-
duced pressure. The residue was partitioned between ethyl
acetate and 0.2 N NaOH, washed with water and brine
successively, and then dried over sodium sulfate. Flash
chromatography (silica gel, methanol:methylene chloride, 2.5:
97.5) provided chromatographically homogeneous product 39
as a white foam: yield 390 mg (79%); 1H NMR (300 MHz,
DMSO-d6) δ 1.05 (t, J ) 8 Hz, 3H), 2.37 (br s, 4H0, 2.83 (br s,
4H), 3.03 (br s, 4H), 3.22-3.48 (m, 2H), 3.66 (s, 3H), 3.87-
4.03 (m, 2H), 4.26-4.55 (m, 3H), 6.77 (t, J ) 7 Hz, 1H), 6.80-
7.00 (m, 6H), 7.05 (t, J ) 8 Hz, 1H), 7.11 (br s, 1H), 7.20 (t, J
) 9 Hz, 3 H), 7.32 (d, J ) 10 Hz, 1H), 7.52 (br d, J ) 6 Hz,
2H). Anal. (C34H41N5O4) C, H, N.
(RS)-2-(N-Acetyla m in o)-3-(1H-in d ol-3-yl)-N-ben zyl-N-
m eth ylp r op a n a m id e (6): 1H NMR (300 MHz, DMSO-d6) 2:1
1
2
mixture of amide rotamers δ 1.75 (s, /3‚3H), 1.83 (s, /3‚3H),
2.70 (s, 1/3‚3H), 2.72 (s, 2/3‚3H), 2.92 (m, 1H), 3.23 (m, 1H), 4.40
2
(AB q, J ) 15 Hz, ∆ν ) 55 Hz, /3‚2H), 4.50 (AB q, J ) 18 Hz,
∆ν ) 45 Hz, 1/3‚2H), 4.95 (m, 1/3‚1H), 5.14 (m, 2/3‚1H), 6.80-
7.40 (m, 8H), 7.60 (d, J ) 8 Hz, 1H), 8.41 (d, J ) 7 Hz, 2/3‚1H),
8.46 (d, J ) 7 Hz, 1/3‚1H), 10.8 (s, 1/3‚1H), 10.9 (s, 2/3‚1H). Anal.
(C21H23N3O2) C, H, N.
The following compounds were prepared from 22, by analogy
to 39 using the above method B, step 5a, and substituting with
the appropriate acylating (or sulfonylating) agent.
(RS)-Ben zyl 2-(N-a cet yla m in o)-3-(1H -in d ol-3-yl)p r o-
p a n oa te (7): 1H NMR (300 MHz, DMSO-d6) δ 1.65 (s, 3H),
3.18 (m, 2H), 4.55 (m, 1H), 5.06 (AB q, J ) 12 Hz, ∆ν ) 18
Hz, 2H), 6.94-7.44 (m, 8H), 7.5 (d, J ) 8 Hz, 1H), 8.35 (d, J
) 9 Hz, 1H), 10.8 (s, 1H). Anal. (C20H20N2O3) C, H, N.
(RS)-N-(2-Ch lor ob en zyl)-3-(1H -in d ol-3-yl)-2-[N-(2-(4-
p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r op a n a m id e (11):
1H NMR (300 MHz, CDCl3) δ 2.45 (m, 4H), 2.91 (m, 4H), 2.97
(d, J ) 9 Hz, 2H), 3.21 (ddAB, J ) 8, 14 Hz, 1H), 3.34 (ddAB, J
) 7, 14 Hz, 1H), 4.44 (d, J ) 7 Hz, 2H), 4.82 (q, J ) 8 Hz, 1H),
6.37 (t, J ) 6 Hz, 1H), 6.81-6.94 (m, 4H), 7.08-7.38 (m, 9H),
7.68 (m, 2H), 7.99 (br s, 1H). Anal. (C30H32N5O2Cl) C, H, N.
The following compounds were prepared from 19, by analogy
to 12 using the above method B, steps 1-4 and 5a, and
substituting the appropriate amine for 2-methoxybenzylamine.
(RS)-1-(N-Acet yl-N-m et h yla m in o)-3-(1H-in d ol-3-yl)-2-
[N-(2-(4-ph en ylpiper azin -1-yl)acetyl)am in o]pr opan e (54):
mp 128-129 °C; 1H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H),
2.38-2.78 (m, 3H), 2.8-3.3 (m, 11H), 3.42 (m, 1H), 3.67 (m,
1H), 3.95 (m, 1H), 4.58 (m, 1H), 6.8-7.0 (m, 3H), 7.1-7.4 (m,
7H), 7.68 (d, J ) 7 Hz, 1H), 8.21 (br s, 1H). Anal. (C26H33N5O2)
C, H, N.
(RS)-1-(N-Acetyl-N-bu tyla m in o)-3-(1H-in d ol-3-yl)-2-[N-
(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r op a n e (55):
1H NMR (300 MHz, CDCl3) δ 0.88 (t, J ) 6 Hz, 3H), 1.1-1.40
(m, 2H), 1.4-1.6 (m, 2H), 2.08 (s, 3H), 2.2-2.4 (m, 4H), 2.8-
3.1 (m, 8H), 3.1-3.4 (m, 3H), 3.9 (m, 1H), 4.5 (br s, 1H), 6.8-
7.0 (m, 3H), 7.0-7.5 (m, 7H), 7.68 (d, J ) 6 Hz, 1H), 8.31 (br
s, 1H). Anal. (C29H39N5O2) C, H, N.
(RS)-1-[N-a cet yl-N-(cycloh exylm et h yl)a m in o]-3-(1H -
in dol-3-yl)-2-[N-(2-(4-ph en ylpiper azin -1-yl)acetyl)am in o]-
p r op a n e (56): 1H NMR (300 MHz, CDCl3) δ 0.65-1.02 (m,
2H), 1.02-1.36 (m, 3H), 1.36-1.87 (m, 9H), 2.07 (s, 3H), 2.15-
3.70 (m, 12H), 3.95 (m, 1H), 4.57 (m, 1H), 6.70-7.03 (m, 4H),
(RS)-1-[N-Acetyl-N-(2-m eth oxyben zyl)a m in o]-3-(1H-in -
d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m in o]-
1
p r op a n e (12): H NMR (300 MHz, DMSO-d6) 3:2 mixture of
amide rotamers δ 1.97 (s, 1.8H), 2.07 (s, 1.2H), 2.26-2.50 (m,
4H), 2.70-2.96 (m, 4H), 2.96-3.16 (m, 4H), 3.16-3.65 (m, 2H),
2
3
3.72 (s, /5‚3H), 3.74 (s, /5‚3H), 4.40 (m, 1H), 4.42 (AB q, J )
18 Hz, ∆ν ) 30 Hz, 3/5‚2H), 4.46 (AB q, J ) 16 Hz, ∆ν ) 62
2
Hz, /5‚2H), 6.70-7.03 (m, 7H), 7.03-7.13 (m, 2H), 7.13-7.29
3
(m, 3H), 7.34 (d, J ) 8 Hz, 1H), 7.49-7.62 (m, /5H‚1H), 7.72
(d, J ) 6 Hz, 2/5H), 10.93 (br s, 1H). Anal. (C33H39N5O3) C, H,
N.
3-(1H -In d ol-3-yl)-1-[N-(2-m et h oxyb en zyl)-N-p r op ion -
yla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m in o]-
p r op a n e (34): 1H NMR (300 MHz, CDCl3) δ 1.12 (t, J ) 9
Hz, 3H), 2.38 (q, J ) 9 Hz, 2H), 2.33-2.60 (m, 4H), 2.83-3.13
(m, 8H), 3.22 (br d, J ) 15 Hz, 1H), 3.80 (s, 3H), 4.03 (br t, J
) 13 Hz, 1H), 4.55 (AB q, J ) 20 Hz, ∆ν ) 40 Hz, 2H), 4.60
(m, 1H), 6.83-6.97 (m, 6H), 7.10-7.57 (m, 8H), 7.68 (d, J ) 8
Hz, 1H), 8.24 (br s, 1H). Anal. (C34H41N5O3) C, H, N.
1-[N-Ben zoyl-N-(2-m eth oxyben zyl)a m in o]-3-(1H-in d ol-
3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)a m in o]p r o-
1
p a n e (35): H NMR (300 MHz, CDCl3) δ 2.28-2.57 (m, 4H),
2.77-3.17 (m, 9H), 3.65 (s, 3H), 4.22 (t, J ) 13 Hz, 1H), 4.60
(AB q, J ) 15 Hz, ∆ν ) 30 Hz, 2H), 4.82 (m, 1H), 6.70-6.92
(m, 5H), 7.02-7.55 (m, 14H), 7.68 (d, J ) 7 Hz, 1H), 8.22 (br
s, 1H). Anal. (C38H41N5O3) C, H, N.
1-[N -(Ca r b om e t h oxya ce t yl)-N -(2-m e t h oxyb e n zyl)-
a m in o]-3-(1H -in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-
yl)a cetyl)a m in o]p r op a n e (36): 1H NMR (300 MHz, CDCl3)
δ 2.37-2.47 (m, 2H), 2.50-2.60 (m, 2H), 2.82-3.18 (m, 9H),
3.57 (s, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.02 (dd, J ) 10, 14 Hz,
1H), 4.47 (AB q, J ) 20 Hz, ∆ν ) 40 Hz, 2H), 4.60 (m, 1H),
6.77-6.92 (m, 6H), 7.03-7.30 (m, 6H), 7.37 (d, J ) 7 Hz, 1H),

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 745
7.03-7.23 (m, 4H), 7.31-7.44 (m, 2H), 7.69 (d, J ) 10 Hz, 1H),
8.16 (br s, 1H). Anal. (C32H43N5O2) C, H, N.
(RS)-2-(3,4-Dich lor op h en yl)-1-[N-(2-m et h oxyb en zyl)-
N-a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)-
a m in o]eth a n e (65): 1H NMR (300 MHz, CDCl3) δ 2.19 (s, 3H),
2.63-2.83 (m, 2H), 2.93-3.20 (m, 4H), 3.20-3.50 (m, 3H),
3.50-3.70 (m, 2H), 3.85 (s, 3H), 4.23 (m, 1H), 4.30-4.60 (m,
2H), 5.00 (m, 1H), 6.85-7.06 (m, 5H), 7.13 (m, 1H), 7.20-7.45
(m, 6H), 8.41 (br s, 1H). Anal. (C30H34Cl2N4O3) C, H, N.
(RS)-1-[N-(2-Meth oxyben zyl)-N-a cetyla m in o]-2-[N-(2-
(4-ph en ylpiper azin -1-yl)acetyl)am in o]eth an e (66): 1H NMR
(300 MHz, CDCl3) δ 2.11 (s, 3H), 2.63-2.78 (m, 4H), 3.03 (s,
2H), 3.18-3.32 (m, 4H), 3.39-3.48 (m, 2H), 3.50-3.59 (m, 2H),
3.84 (s, 3H), 4.52 (s, 2H), 6.83-6.98 (m, 4H), 7.04 (br d, J ) 8
Hz, 1H), 7.22-7.38 (m, 4H), 7.61 (br s, 1H). Anal. (C24H32N4O3)
C, H, N.
(RS)-1-[N-(2-Meth oxyben zyl)-N-a cetyla m in o]-3-m eth -
yl-2-[N -(2-(4-p h e n ylp ip e r a zin -1-yl)a c e t yl)a m in o]b u -
ta n e (67): 1H NMR (300 MHz, CDCl3) δ 0.91 (d, J ) 7 Hz,
6H), 1.80 (m, 1H), 2.08 (s, 3H), 2.70 (t, J ) 6 Hz, 4H), 2.87 (br
d, J ) 11 Hz, 1H), 3.07 (d, J ) 3 Hz, 2H), 3.20-3.38 (m, 4H),
3.85 (s, 3H), 4.04-4.18 (m, 2H), 4.55 (AB q, J ) 17 Hz, ∆ν )
39 Hz, 2H), 6.84-7.00 (m, 4H), 7.07 (d, J ) 8 Hz, 1H), 7.24-
7.39 (m, 5H). Anal. (C27H38N4O3) C, H, N.
(RS)-1-(N-Acet yl-N-p h en yla m in o)-3-(1H-in d ol-3-yl)-2-
[N-(2-(4-ph en ylpiper azin -1-yl)acetyl)am in o]pr opan e (57):
mp 183-184 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.71 (s, 3H),
2.23-2.43 (m, 4H), 2.71-2.94 (m, 4H), 2.94-3.10 (m, 4H), 3.61
(m, 1H), 4.03 (m, 1H), 4.24 (m, 1H), 6.77 (t, J ) 8 Hz, 1H),
6.92-6.99 (m, 3H), 6.99-7.12 (m, 2H), 7.21 (t, J ) 8 Hz, 2H),
7.24-7.35 (m, 3H), 7.4 (m, 1H), 7.40-7.54 (m, 4H), 10.92 (br
s, 1H). Anal. (C31H35N5O2) C, H, N.
(RS)-1-(N-Acetyl-N-p h en eth yla m in o)-3-(1H-in d ol-3-yl)-
2-[N-(2-(4-ph en ylpip er a zin -1-yl)a cetyl)a m in o)a m in o]p r o-
p a n e (58): 1H NMR (300 MHz, DMSO-d6) 3:2 mixture of amide
rotamers δ 1.69 (s, 3/5‚3H), 2.00 (s, 2/5‚3H), 2.50-2.60 (m, 5H),
2.70-3.05 (m, 5H), 3.05-3.19 (m, 4H), 3.19-3.36 (m, 2H),
3.36-3.64 (m, 2H), 4.32 (m, 1H), 6.76 (t, J ) 8 Hz, 1H), 6.90
(d, J ) 8 Hz, 2H), 6.95-7.39 (m, 11H), 7.56 (m, 1H), 7.76 (m,
2/5‚1H), 7.92 (m, 3/5‚1H), 10.81 (br s, 2/5‚1H), 10.85 (br s, 3/5‚-
1H). Anal. (C33H39N5O2) C, H, N.
The following compounds were prepared from the appropri-
ate amino acid starting material, by analogy to 12 using the
above method B, steps 1-4 and 5a.
(RS)-1-[N-(2-Meth oxyben zyl)-N-a cetyla m in o]-3-p h en -
yl-2-[N -(2-(4-p h e n ylp ip e r a zin -1yl)a ce t yl)a m in o]p r o-
p a n e (59): 1H NMR (300 MHz, DMSO-d6) 3:2 mixture of amide
rotamers δ 1.93 (s, 3/5‚3H), 2.09 (s, 2/5‚3H), 2.23-2.46 (m, 4H),
2.60-2.90 (m, 4H), 3.00-3.20 (m, 2H), 3.30-3.53 (m, 4H), 3.75
(s, 3H), 4.20-4.60 (m, 3H), 6.70-7.04 (m, 7H), 7.04-7.30 (m,
7H), 7.57 (d, J ) 9 Hz, 3/5‚1H), 7.71 (d, J ) 9 Hz, 2/5‚1H). Anal.
(C31H38N4O3) C, H, N.
Step 5b. 1-[N-((Dim eth yla m in o)a cetyl)-N-(2-m eth oxy-
ben zyl)a m in o]-3-(1H-in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er -
azin -1-yl)acetyl)am in o]pr opan e (38). 1-(3-(Dimethylamino)-
propyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol)
was added to a mixture of a secondary amine 22 (350 mg, 0.68
mmol), N,N-dimethylglycine (70 mg, 0.68 mmol), and 1-hy-
droxybenzotriazole hydrate (92 mg, 0.68 mmol) in anhydrous
tetrahydrofuran (25 mL). The resulting mixture was stirred
at room temperature for 16 h. The tetrahydrofuran was
removed under reduced pressure. The residue was dissolved
in ethyl acetate, washed successively with saturated sodium
bicarbonate solution, water, and brine, and dried over sodium
sulfate. Flash chromatography (silica gel, methanol:methylene
chloride:ammonium hydroxide, 4:96:0.5) provided homoge-
(RS)-1-[N-(2-Meth oxyben zyl)-N-acetylam in o]-3-(1-n aph -
th yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m in o]p r o-
1
p a n e (60): H NMR (300 MHz, CDCl3) δ 2.13 (s, 3H), 2.38-
2.70 (m, 4H), 2.82-3.07 (m, 4H), 3.07-3.30 (m, 4H), 3.56 (dd,
J ) 7, 14 Hz, 1H), 3.66 (s, 3H), 4.14 (m, 1H), 4.34 (AB q, J )
16 Hz, ∆ν ) 58 Hz, 2H), 4.47 (m, 1H), 6.52-6.67 (m, 2H), 6.73
(d, J ) 8 Hz, 1H), 6.77-7.00 (m, 3H), 7.09-7.20 (m, 1H), 7.20-
7.40 (m, 4H), 7.43-7.70 (m, 3H), 7.73 (d, J ) 8 Hz, 1H), 7.86
(d, J ) 8 Hz, 1H), 8.34 (d, J ) 8 Hz, 1H). Anal. (C35H40N4O3)
C, H, N.
1
neous product 38 as a yellow foam: yield 300 mg (74%); H
NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 2.32-2.50 (m, 4H),
2.87-3.05 (m, 8H), 3.20 (s, 2H), 3.33 (dd, J ) 6, 9 Hz, 1H),
3.78 (s, 3H), 3.85 (m, 1H), 4.58 (m, 1H), 4.65 (AB q, J ) 18
Hz, ∆ν ) 42 Hz, 2H), 6.81-6.93 (m, 6H), 7.10-7.40 (m, 8H),
7.65 (d, J ) 11 Hz, 1H), 8.17 (br s, 1H). Anal. (C35H44N6O3)
C, H, N.
(RS)-1-[N-(2-Meth oxyben zyl)-N-acetylam in o]-3-(2-n aph -
th yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m in o]p r o-
1
p a n e (61): H NMR (300 MHz, CDCl3) δ 2.12 (s, 3H), 2.26-
2.50 (m, 4H), 2.59-3.30 (m, 9H), 3.78 (s, 3H), 3.98 (m, 1H),
4.51 (AB q, J ) 17 Hz, ∆ν ) 30 Hz, 2H), 4.53 (m, 1H), 6.55-
7.03 (m, 6H), 7.05-7.39 (m, 5H), 7.39-7.53 (m, 2H), 7.60 (m,
1H), 7.71-7.85 (m, 3H). Anal. (C35H40N4O3) C, H, N.
(RS)-3-(Ben zo[b]th iop h en yl)-1-[N-(2-m eth oxyben zyl)-
N-a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)-
Step 5c. 1-[N-Eth yl-N-(2-m eth oxyben zyl)am in o]-3-(1H-
in dol-3-yl)-2-[N-(2-(4-ph en ylpiper azin -1-yl)acetyl)am in o]-
p r op a n e (42). 3-(1H-Indol-3-yl)-1-[N-(2-methoxybenzyl)-
amino]-2-[N-(2-(4-phenylpiperazin-1-yl)acetyl)amino]pro-
pane (22) (0.41 g, 0.80 mmol), ethyl iodide (120 µL, 1.5 mmol),
and potassium carbonate (120 mg, 0.80 mmol) in anhydrous
N,N-dimethylformamide (5 mL) were heated to 50 °C for 4 h
and then stirred at room temperature for 16 h. The N,N-
dimethylformamide was removed under reduced pressure. The
residue was dissolved in ethyl acetate, washed with water and
brine successively, and then dried over sodium sulfate. Radial
thin-layer chromatography (silica gel, methanol:methylene
chloride:ammonia atmosphere, 1:99) provided homogeneous
product 43 as a yellow foam: yield 360 mg (83%); 1H NMR
(300 MHz, CDCl3) δ 1.04 (t, J ) 8 Hz, 3H), 2.32-2.43 (m, 2H),
2.43-2.66 (m, 6H), 2.83-2.91 (m, 4H), 2.94 (d, J ) 5 Hz, 2H),
3.08 (t, J ) 6 Hz, 2H), 3.65 (AB q, J ) 14 Hz, ∆ν ) 22 Hz,
2H), 3.77 (s, 3H), 4.41 (q, J ) 6 Hz, 1H), 6.78-6.96 (m, 6H),
7.06-7.29 (m, 6H), 7.33 (d, J ) 8 Hz, 1H), 7.40 (d, J ) 7 Hz,
1H), 7.64 (d, J ) 8 Hz, 1H), 7.99 (br s, 1H). Anal. (C33H41N5O2)
C, H, N.
1
a m in o]p r op a n e (62): H NMR (300 MHz, CDCl3) δ 2.15 (s,
3H), 2.44-2.60 (m, 4H), 2.89-3.26 (m, 9H), 3.73 (s, 3H), 4.07
(dd, J ) 10.4, 13.9 Hz, 1H), 4.43 (AB q, J ) 16.5 Hz, ∆ν )
45.4 Hz, 2H), 4.50 (m, 1H), 6.74-6.92 (m, 6H), 7.15 (s, 1H),
7.18-7.30 (m, 3H), 7.39 (m, 2 H), 7.57 (d, J ) 8.1 Hz, 1H),
7.87 (d, J ) 7.4 Hz, 1H), 7.98 (d, J ) 7.6 Hz, 1H). Anal.
(C33H38N4O3S) C, H, N.
(R S )-3-(1H -In d olin -3-yl)-1-[N -(2-m e t h oxyb e n zyl)-N -
a cetyla m in o]-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m i-
n o]p r op a n e (63). The titled compound was obtained starting
from 3-(1H-indolin-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-
(2-(4-phenylpiperazin-1-yl)acetyl)amino]propane (obtained in
method B, step 3 and proceeding as in method B, step 5a):
mp 102-105 °C; 1H NMR (300 MHz, CDCl3) 1:1 mixture of
diastereomers δ 1.57-2.08 (m, 2H), 2.15 (s, 1/2‚3H), 2.17 (s,
1/2‚3H), 2.75-3.60 (m, 13H), 3.65-4.00 (m, 2H), 3.82 (s, 1/2‚-
3H), 3.85 (s, 1/2‚3H), 4.18-4.48 (m, 2H), 4.58 (s, 2H), 6.70-
7.40 (m, 13H), 7.67 (m, 1H); high-resolution mass spectral data
calcd for C33H41N5O3 556.3287, found 556.3280.
(RS)-1-[N-(2-Meth oxyben zyl)-N-a cetyla m in o]-2-p h en -
yl-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)a m in o]eth a n e
(64): 1H NMR (300 MHz, CDCl3) δ 2.14 (s, 3H), 2.60-2.80 (m,
4H), 3.00-3.20 (m, 2H), 3.20-3.43 (m, 5H), 3.82 (s, 3H), 4.30
(m, 1H), 4.40-4.63 (m, 2H), 5.18 (m, 1H), 6.80-7.06 (m, 6H),
7.03-7.40 (m, 8H), 8.24 (br s, 1H). Anal. (C30H36N4O2) C, H,
N.
The following compounds were prepared from 22, by analogy
to 42 using the above method B, steps 1-4 and 5c, and
substituting with the appropriate alkylating agent.
(RS)-1-[N-(Car boxyacetyl)-N-(2-m eth oxyben zyl)am in o]-
3-(1H-in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cetyl)-
a m in o]p r op a n e (37): 1H NMR (300 MHz, CDCl3) δ 2.68-
2.90 (m, 4H), 2.90-3.37 (m, 9H), 3.57 (br s, 2H), 3.78 (s, 3H),
3.93 (t, J ) 12 Hz, 1H), 4.53 (AB q, J ) 17 Hz, ∆ν ) 47 Hz,
2H), 4.70 (m, 1H), 6.77-6.97 (m, 6H), 7.07-7.33 (m, 7H), 7.37
(d, J ) 8 Hz, 1H), 7.63 (d, J ) 8 Hz, 1H), 7.85 (br s, 1H), 8.33
(br s, 1H). High-resolution mass spectral data calcd for

746 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Hipskind et al.
C34H39N5O5 598.3029, found 598.3046. Anal. (C34H39N5O5‚CH3-
COOH) C, H, N.
butyl acetate intermediate as a foam (1.29 g, 2.68 mmol). This
ester was treated with 70% aqueous trifluoroacetic acid (5 mL)
containing anisole (0.5 mL) for 18 h at room temperature. The
reaction mixture was evaporated. Acetonitrile was added and
evaporated twice. The residue was partitioned with ether and
a dilute aqueous sodium hydroxide solution. The basic aque-
ous extract was extracted with ether, acidified with 1 N
hydrochloric acid, and extracted three times with ethyl acetate.
The combined ethyl acetate extract was dried over sodium
sulfate, filtered, and evaporated to give an intermediate acetic
acid (1.0 g, 2.35 mmol) as a foam. This intermediate (0.40 g,
0.94 mmol) was treated in acetone (11 mL) with triethylamine
(RS)-1-[N-(Ca r bom eth oxym eth yl)-N-(2-m eth oxyben z-
yl)a m in o]-3-(1H-in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-
yl)a cetyl)a m in o]p r op a n e (43): 1H NMR (300 MHz, CDCl3)
δ 2.37-2.47 (m, 2H), 2.50-2.58 (m, 2H), 2.78-2.98 (m, 6H),
3.00 (s, 2H), 3.12 (t, J ) 6 Hz, 2H), 3.37 (AB q, J ) 18 Hz, ∆ν
) 26 Hz, 2H), 3.65 (s, 3H), 3.77 (s, 3H), 3.83 (s, 2H), 4.45 (m,
1H), 6.80-6.92 (m, 5H), 7.00 (s, 1H), 7.10-7.40 (m, 8H), 7.70
(d, J ) 9 Hz, 1H), 8.08 (s, 1H). Anal. (C34H41N5O4) C, H, N.
Step 5d . 1-[N-F or m yl-N-(2-m eth oxyben zyl)a m in o]-3-
(1H -in d ol-3-yl)-2-[N-(2-(4-p h en ylp ip er a zin -1-yl)a cet yl)-
a m in o]p r op a n e (33). Acetic anhydride (240 mL, 2.5 mmol)
and formic acid (98%, 120 µL, 3.1 mmol) were heated at 50 °C
for 2 h. This solution was cooled to room temperature, and
anhydrous tetrahydrofuran (5 mL) was added. A solution of
secondary amine 22 (500 mg, 0.98 mmol) and triethylamine
(1.5 mL, 10.7 mmol) in anhydrous tetrahydrofuran (5 mL) was
added to the acetic anhydride/formic acid solution. The
resulting solution was stirred for 1 h at room temperature.
The reaction mixture was diluted with ice/water and extracted
with ethyl acetate. The extract was washed with water and
brine and dried over sodium sulfate. Liquid chromatography
(silica gel, methanol:methylene chloride, 5:95) provided ho-
mogeneous product 33 as a white foam: yield 440 mg (84%);
1H NMR (300 MHz, CDCl3) δ 2.33-2.47 (m, 2H), 2.50-2.65
(m, 2H), 2.87-3.10 (m, 9H), 3.75 (s, 3H), 3.77 (m, 1H), 4.40
(AB q, J ) 15 Hz, ∆ν ) 35 Hz, 2H), 4.65 (m, 1H), 6.75-6.95
(m, 6H), 7.03-7.42 (m, 8H), 7.67 (d, J ) 9 Hz, 1H), 8.20 (br s,
1H), 8.33 (s, 1H). Anal. (C32H37N5O3) C, H, N.
(0.13 mL, 0.94 mmol) at ice bath temperature under nitrogen
1
with stirring for
/ h. Ethyl chloroformate (0.10 mL, 1.03
6
mmol) was added, and the reaction mixture was stirred at ice
5
bath temperature for /6 h. (RS)-N-(2-Chlorobenzyl)tryptopha-
namide35 (0.34 g, 1.03 mmol) was added, and the reaction was
stirred at room temperature for 16 h and then heated briefly
to reflux and evaporated. The residue was dissolved in ethyl
acetate and washed successively with dilute aqueous hydro-
chloric acid, water, dilute aqueous sodium hydroxide solution,
water, and a saturated aqueous sodium chloride solution. This
ethyl acetate extract was dried over sodium acetate, filtered,
and evaporated to give, after silica gel chromatography, 0.459
g of 10 (57% overall three step yield): 1H NMR (300 MHz,
CDCl3) δ 2.62 (AB q, J ) 18 Hz, ∆ν ) 275 Hz, 2H), 3.10-3.66
(m, 3H), 3.94 (AB q, J ) 16 Hz, ∆ν ) 60 Hz, 2H), 4.12 (AB q,
J ) 15 Hz, ∆ν ) 336 Hz, 2H), 4.25 (m, 1H), 4.40 (m, 3H), 4.83
(m, 1H), 6.65 (m, 1H), 6.70 (d, J ) 8 Hz, 1H), 6.76 (d, J ) 10
Hz, 1H), 6.91 (d, J ) 3 Hz, 1H), 7.02 (m, 2H), 7.05-7.48 (m,
12H), 7.59 (d, J ) 9 Hz, 1H), 7.68 (d, J ) 6 Hz, 1H), 7.99 (br
s, 1H), 8.03 (br s, 1H). Anal. (C40H36N6O4Cl2‚1.4H2O) C, H,
N.
The following compounds were also prepared from 19 using
the following procedures:
(RS)-N-(2-Ch lor oben zyl)-2,5-dioxo-3-(in dol-3-ylm eth yl)-
p ip er a zin e (8). Triethylamine (2.78 mL, 20 mmol) was added
to a slurry of 19 (6.08 g, 20 mmol) in acetone (40 mL) under
nitrogen at ice bath temperature, and the reaction was stirred
Biologica l Meth od s. Su bsta n ce P In d u ced Con tr a c-
tion of Ra bbit Ven a Ca va Tissu e. Procedures used were
essentially as was reported by Regoli et al. with the following
modifications.36 Compounds were evaluated using loops of
rabbit vena cava and performing noncumulative dose-
response curves with antagonists and substance P. The pA2
values were estimated on the basis of nonlinear curve fitting.
Tr igem in a l Electr ica l Stim u la tion In d u ced Neu r o-
gen ic Du r a l Extr a va sa tion . Male guinea pigs from Charles
River Laboratories (225-325 g) were anesthetized with sodium
pentobarbital (45 mg/kg). Two pairs of bilateral holes were
drilled through the skull, and stainless steel stimulating
electrodes, insulated except at the tip, were implanted. The
femoral vein was exposed, and a dose of the test compound
was injected intravenously (1 mL/kg). Approximately 7 min
later, a 50 mg/kg dose of Evans Blue, a fluorescent dye, was
also injected intravenously. Exactly 10 min after injection of
the test compound, the left trigeminal ganglion was stimulated
for 3 min at a current intensity of 1.0 mA (5 Hz, 4 ms duration).
Fifteen minutes following the stimulation, the animals were
euthanized by exsanguination. The dural membranes were
removed from both hemispheres and mounted on microscope
slides. A Zeiss fluorescence microscope equipped with a
grating monochromator and a spectrophotometer was used to
quantify the amount of Evans Blue dye in each sample. An
excitation wavelength of approximately 535 nm was utilized,
and the emission intensity at 600 nm was determined. The
ratio of the amount of extravasation in the dura from the
stimulated side compared to the unstimulated (control) side
dura was calculated. A dose-response curve was generated
3
for /4 h. Ethyl chloroformate (2.02 mL, 21.2 mmol) was added,
and the reaction mixture was stirred for 1 h at ice bath
temperature. Ethyl N-(2-chlorobenzyl)glycinate (4.83 g, 21.2
mmol) was added, the reaction mixture was stirred at room
temperature for 18 h, and the reaction mixture was evapo-
rated. The residue dissolved in ethyl acetate was washed
successively with dilute hydrochloric acid, water, dilute sodium
hydroxide solution, water, and saturated aqueous sodium
chloride. The ethyl acetate extract was dried over sodium
sulfate, filtered, and evaporated to yield, after crystallization,
an intermediate amide (4.52 g, 9.17 mmol). This amide (4.52
g, 9.17 mmol) was treated with 70% aqueous trifluoroacetic
acid (30 mL) containing anisole (3 mL) for 18 h at ambient
temperature. The reaction mixture was evaporated, and the
residue was dissolved in ether and washed with a sodium
hydroxide solution (100 mL, 1 N), water, and saturated
aqueous sodium chloride. This ethereal solution was dried
over sodium sulfate, filtered, and evaporated to give an oil
which could be crystallized slowly from ether containing a
small amount of ethyl acetate to give 2.31 g of 8 (31%
overall): 1H NMR (300 MHz, CDCl3) δ 3.32 (AB q, J ) 18 Hz,
∆ν ) 141 Hz, 2H), 3.38 (d, J ) 6 Hz, 2H), 4.39 (m, 1H), 4.53
(AB q, J ) 15 Hz, ∆ν ) 149 Hz, 2H), 6.45 (br s, 1H), 7.02 (m,
1H), 7.03 (s, 1H), 7.12-7.24 (m, 4H), 7.25 (d, J ) 6 Hz, 1H),
7.39 (d, J ) 6 Hz, 1H), 7.65 (d, J ) 9 Hz, 1H), 8.29 (br s, 1H).
Anal. (C20H18N3O2Cl) C, H, N.
(RS)-N-(2-Ch lor oben zyl)-3-(1H-in d ol-3-yl)-2-[N-(2-(N4-
(2-ch lor oben zyl)-3,6-dioxo-2-(in dol-3-ylm eth yl)piper azin -
1-yl)a cetyl)a m in o]p r op a n a m id e (10). Under nitrogen at
ice bath temperature, a solution of lithium diisopropylamide
(2.86 mmol) was added dropwise to a solution of 8 (0.99 g, 2.7
mmol) and tert-butyl bromoacetate (0.40 mL, 2.72 mmol) in
tetrahydrofuran (18 mL). The reaction mixture was permitted
to warm to room temperature and stirred for 18 h. The
reaction mixture was evaporated, and the residue was dis-
solved in ether and washed succesively with water, dilute
aqueous hydrochloric acid, water, dilute aqueous sodium
hydroxide solution, water, and a saturated aqueous sodium
chloride solution. The resulting ethereal solution was dried
over sodium sulfate, filtered, and evaporated to give a tert-
and the dose that inhibited the extravasation by 50% (ID50
)
was approximated. For oral studies, test compounds were
administrated by gavage (2 mL/kg) to conscious fasted animals
approximately 45 min prior to injection of the anesthetic. To
determine the duration of action, the time between oral dosing
and injection of anesthetic was lengthened.
In tr a th eca l NK-1 Agon ist In d u ced Nocicep tive Be-
h a vior . Conscious male mice from Charles River Laboratories
(20-25 g) were coinjected intrathecally (it, into the spinal cord)
between the L5/L6 intravertebral space according to previously
published procedures with the test compound and Ac-[Sar9-
Met(O2)11]SP 6-11, [Ac-(Sar9)] (0.5 pmol) in a volume of 5 µL
using a 30 gauge needle connected to a 50-µL Hamilton

Diacetamidopropane NK-1 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 747
nists Derived from L-Tryptophan. J . Med. Chem. 1995, 38, 934-
941. Merchant, K. J .; Lewis, R. T.; MacLeod, A. M. Synthesis
Of Homochiral Ketones Derived From L-Tryptophan: Potent
Substance P Receptor Antagonists. Tetrahedron Lett. 1994, 35,
4205-4208.
microsyringe. Animals were lightly restrained to maintain the
position of the needle. Puncture of the dura was indicated by
the flick of the tail, which was evident throughout the infusion
of the agonist. Only animals that showed this response were
included in the study. The number of caudally directed
scratching and biting events induced by Ac-Sar9 was scored
for 5 min after the injections. A dose-response curve was
generated, and the dose that blocked the selective NK-1
agonist induced scratching and biting events by 50% (ID50) was
approximated. Alternatively the test compound was admin-
istered intraperitoneally 15 min prior to agonist challenge.
(13) Mills, S. G.; Wu, M. T.; MacCoss, M.; Budhu, R.; Dorn, C. P.,
J r., Cascieri, M. A.; Sadowski, S.; Strader, C. D.; Greenlee, W.
J . 1,4-Diacylpiperazine-2-(S)-[(N-Aminoalkyl)Carboxamides] As
Novel, Potent Substance P Receptor Antagonists. Bioorg. Med.
Chem. Lett. 1993, 3, 2707-2712. Achard, D.; Truchon, A.;
Peyronel, J .-F.; Perhydrothio-Pyranopyrroles Derivatives:
A
Novel Series Of Potent And Selective Nonpeptide NK1 Antago-
nists. Bioorg. Med. Chem. Lett. 1994, 4, 669-672. Fujii, T.;
Murai, M.; Morimoto, H.; Maeda, Y.; Yamaoka, M.; Hagiwara,
D.; Miyake, H.; Ikari, N.; Matsuo, M. Pharmacological Profile
Of A High Affinity Dipeptide NK1 Receptor Antagonist, FK888.
Br. J . Pharmacol. 1992, 107, 785-789.
Refer en ces
(1) (a) von Euler, U. S.; Gaddum, J . H. An Unidentified Depressor
Substance In Certain Tissue Extracts. J . Physiol. 1931, 72, 74-
87. (b) Chang, M. M.; Leeman, S. E. Isolation Of A Sialogogic
Peptide From Bovine Hypothalamic Tissue And Its Character-
ization As Substance P. J . Biol. Chem. 1970, 245, 4784-4790.
(c) Chang, M. M.; Leeman, S. E.; Nial, H. D. Amino Acid
Sequence Of Substance P. Nature, New Biol. 1971, 232, 86-87.
(d) Pernow, B. Substance P. Pharmacol. Rev. 1983, 35, 85-141.
(e) Maggio, J . E. Tachykinins. Annu. Rev. Neurosci. 1988, 11,
13-28.
(2) (a) Henry, J . L. Discussion of nomenclature for tachykinin
receptors. In Substance P and Neurokinins; Henry, J . L.,
Couture, R., Cuello, A. C., Pelletier, G., Quirion, R., Regoli, D.,
Eds.; Springer-Verlag: New York, 1987; pp 17-18. (b) Regoli,
D.; Drapeau, G.; Dion, S.; D’Orleans-J uste, P. Receptors for
Substance P and Related Neurokinins. Pharmacology 1989, 378,
1-15. (c) Guard, S.; Watson, S. P. Techykinin Receptor Sub-
types: Classification And Membrane Signalling Mechanisms.
Neurochem. Int. 1991, 18, 149-165.
(3) For review of general neurokinin pharmacology and physiology,
see: (a) Maggi, C. A.; Patacchini, R.; Rovero, P.; Giachetti, A.
Tachykinin Receptors And Tachykinin Receptors Antagonists.
J . Auton. Pharmacol. 1993, 13, 23-93. (b) Otsuka, M.; Yoshioka,
K. Neurotransmitter Functions Of Mammalian Tachykinins.
Physiol. Rev. 1993, 73, 229-308.
(4) (a) Levine, J . D.; Fields, H. L.; Basbaum, A. I. Peptides and the
Primary Afferent Nociceptor J . Neurosci. 1993, 13, 2273-2286.
(b) Otsuka, M.; Yanagisawa, M. Pain and Neurotransmitters.
Cell Mol. Neurobiol. 1990, 10, 293-302. (c) Lotz, M.; Carson,
D. A.; Vaughan, J . H.; Substance P Activation of Rheumatoid
Synoviocytes: Neural Pathway in Pathogenesis of Arthritis.
Science 1987, 235, 893-895. (d) Marabini, S.; Matucci-Cerinic,
M.; Geppetti, P.; Del Bianco, E.; Marchesoni, A.; Tosi, S.;
Cagnoni, M.; Partsch, G. Substance P And Somatostain Levels
In Rheumatoid Arthritis, Osteoarthritis And Psoriatic Arthritis
Synovial Fluid. Ann. N.Y. Acad. Sci. 1991, 632, 435-436.
(5) Moskowitz, M. A. Neurogenic Versus Vascular Mechanisms Of
Sumatriptan And Ergot Alkaloids In Migraine. Trends Phar-
macol. Sci. 1992, 13, 307-311.
(6) (a) Bertrand, C.; Geppetti, P.; Baker, J .; Yamawaki, I.; Nadel,
J . A. Role Of Neurogenic Inflammation In Antigen-Induced
Vascular Extravasation In Guinea Pig Trachea. J . Immunol.
1993, 150, 1479-1485. (b) Frossard, N.; Advenier, C. Tachyki-
nin Receptors And The Airways. Life Sci. 1991, 19541-19543.
(7) Lowe, J . A.; McLean, S. Tachykinin Antagonists Curr. Pharm.
Des. 1995, 1, 269-278.
(8) Snider, R. M.; Constantine, J . W.; Lowe, J . A., III; Longo, K. P.;
Lebel, W. S.; Woody, H. A.; Drozda, S. E.; Desai, M. C.; Vinick,
F. J .; Spencer, R. W.; Hess, H. J . A Potent Nonpeptide Antago-
nist Of The Substance P (NK1) Receptor. Science 1991, 251,
435-437.
(9) Mclean, S.; Ganong, A.; Seymour, P. A.; Snider, R. M.; Desai,
M. C.; Rosen, T.; Bryce, D. K.; Longo, K. P.; Reynolds, L. S.;
Robinson, G.; Schmidt, A. W.; Siok, C.; Heym, J . Pharmacology
Of CP-99,994, A Nonpeptide Antagonist Of The Tachykinin
Neurokinin-1 Receptor J . Pharmacol. Exp. Ther. 1993, 267, 472-
479.
(10) Garret, C.; Carruette, A.; Fardin, V.; Moussaoui, S.; Peyronel,
J . F.; Blanchard, J . C.; Laduron, P. M. Pharmacological Proper-
ties Of A Potent And Selective Nonpeptide Substance P Antago-
nist. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 10208-10211.
(11) Emonds-Alt, X.; Doutremepuich, J .-D.; Heaulme, M.; Neliat, G.;
Santucci, V.; Steinberg, R.; Vilain, P.; Bichon, D.; Ducoux, J .-
P.; Proietto, V.; Van Broeck, D.; Soubrie, P.; Le Fur, G.; Breliere,
J .-C. In Vitro And In Vivo Biological Activities Of SR140333, A
Novel Potent Non-Peptide, Tachykinin NK1 Recepotr Antagonist.
Eur. J . Pharmacol. 1993, 250, 403-413.
(14) This series was recently disclosed as part of a larger group of
compounds. See: Cho, S. S.; Crowell, T. A.; Gitter, B. D.;
Hipskind, P. A.; Howbert, J . J .; Krushinski, J . H.; Lobb, K. L.;
Muehl, B. S.; Nixon, J . A. Int. Pat. Appl. WO 95/14017, May 26,
1995, Eli Lilly & Co.
(15) NK-1 receptor binding affinities (IC50’s) for all compounds were
determined in
[
125I]Bolton-Hunter SP binding experiments
using the human IM-9 cell line which expresses NK-1 receptors
or in guinea pig brain, rat brain or mouse brain membrane
preparations. See: (a) Gitter, B. D.; Bruns, R. F.; Howbert, J .
J .; Waters, D. C.; Threlkeld, P. G.; Cox, L. M.; Nixon, J . A.; Lobb,
K. L.; Mason, N. R.; Stengel, P. W., Cockerham, S. L.; Silbaugh,
S.; Gehlert, D. R.; Schober, D. A.; Phebus, L. A.; Iyengar, S.;
Calligaro, D. O.; Regoli, D.; Hipskind, P. A. Pharmacological
Characterization Of LY303870: A Novel, Potent And Selective
Nonpeptide Substance P (NK-1) Receptor Antagonist. J . Phar-
macol. Exp. Ther. 1995, 275, 737-744. (b) Payan, D. G.;
Brewster, D. R.; Goetzl, E. J . Stereospecific Receptors for
Substance
P on Cultured Human IM-9 Lymphoblasts. J .
Immunol. 1984, 133, 3260-3265. These data are presented
throughout the text and in Tables 1-7. Values are the mean of
three separate determinations unless otherwise stated.
(16) Recently detailed accounts of tryptophan ester and amide SAR’s
have appeared. See: (a) MacLeod, A. M.; Merchant, K. J .;
Cascieri, M. A.; Sadowski, S.; Ber, E.; Swain, C. J .; Baker, R.
N-Acyl-L-Tryptophan Benzyl Esters: Potent Substance P Recep-
tor Antagonists. J . Med. Chem. 1993, 36, 2044-2045. (b)
MacLeod, A. M.; Merchant, K. J .; Brookfield, F.; Kelleher, F.;
Stevenson, G.; Owens, A. P.; Swain, C. J .; Cascieri, M. A.;
Sadowski, S.; Ber, E.; Strader, C. D.; MacIntyre, D. E.; Metzger,
J . M.; Ball, R. G.; Baker, R. Identification of L-Tryptophan
Derivatives with Potent and Selective Antagonist Activity at the
NK-1 Receptor. J . Med. Chem. 1994, 37, 1269-1274. (c) Lewis,
R. T.; MacLeod, A. M.; Merchant, K. J .; Kelleher, F.; Sanderson,
I.; Herbert, R. H.; Cascieri, M. A.; Sadowski, S.; Ball, R. G.;
Hoogsteen, K. Tryptophan-Derived NK-1 Antagonists: Confor-
mationally Constrained Heterocyclic Bioisosteres of the Ester
Linkage. J . Med. Chem. 1995, 38, 923-933.
(17) It is noteworthy to consider the importance of compound 9. In
retrospect, it would seem to be the key differentiating element
between the series which is the subject of this paper and the
recently disclosed Merck tryptophan based NK-1 antagonists.
See ref 16.
(18) Compound 10 was independently synthesized via the route
which is found in the Experimental Section.
(19) Protection of 13 as either the tert-butyl or benzyl carbamate led
to difficulties in the next step.
(20) Hipskind, P. A.; Howbert, J . J .; Lobb, K. L.; Cho, S. Y.; Hansen,
G. J .; Cronin, J . S.; Murray, A. R.; Ginah, F. O.; Fort, S. L.; Copp,
J . A Practical and Enantiospecific Synthesis Of LY303870 a
novel NK-1 Antagonist. J . Org. Chem. 1995, 60, 7033-7036.
(21) This trend has also been observed in the quinuclidine (see: Lowe,
J . A.; Drozda, S. E.; Snider, R. M.; Longo, K. P.; Zorn, S. H.;
Morrone, J .; J ackson, E. R.; McLean, S.; Bryce, D. K.; Bordner,
J .; Nagahisa, A.; Kanai, Y.; Suga, O.; Tsuchiya, M. The Discovery
of (2S,3S)-cis-2-(Diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-
1-azabicyclo[2.2.2]-octan-3-amine as a Novel, Nonpeptide Sub-
stance P Antagonist J . Med. Chem. 1992, 35, 2591-2600) and
triarylperhydroisoindole (Tabart, M. unpublished results) NK-1
antagonist SAR’s.
(22) See ref 16.
(23) Conformational analysis was performed first by random confor-
mational generation and then energy minimization using MAC-
ROMODEL version 4.5 and the MM2 force field. Superimpo-
sitions were performed using both the rigid and flexible
superimposition routines in the same MACROMODEL package.
(24) For discussions regarding this type of π/π-interaction, see: (a)
Hunter, C. A.; Sanders, J . K. M. The Nature of π-π Interactions.
J . Am. Chem. Soc. 1990, 112, 5525-5534. (b) J orgensen, W.
L.; Severance, D. L. Aromatic-Aromatic Interactions: Free
Energy Profiles for the Benzene Dimer in Water, Chloroform
(12) MacLeod, A. M.; Cascieri, M. A.; Merchant, K. J .; Sadowski, S.;
Hardwicke, S.; Lewis, R. T.; MacIntyre, D. E.; Metzger, J . M.;
Fong, T. M.; Shepheard, S.; Tattersall, F. D.; Hargreaves, R.;
Baker, R.; Synthesis and Biological Evaluation of NK-1 Antago-

748 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Hipskind et al.
and Liquid Benzene. J . Am. Chem. Soc. 1990, 112, 4768-4774.
(c) Trost, B. M.; O’Krongly, D.; Belletire, J . L. A Model for
Asymmetric Induction in the Diels-Alder Reaction. J . Am.
Chem. Soc. 1980, 102, 7595-7596.
(31) Hylden, J . L. K.; Wilcox, G. L. Intrathecal Substance-P Elicits
A Caudally Directed Biting and Scratching Behavior in Mice.
Brain Res. 1981, 217, 212-215. Takahashi, K.; Sakurada, T.;
Behavioral Characterization of Substance P Induced Nociceptive
Response in Mice. Neuropharmacology 1987, 26, 1289-1293.
Regoli, D.; Drapeau, J . New Selective Agonists for Neurokinin
Receptors: Pharmacological Tools for Receptor Characterization.
Trends Pharm. Sci. 1988, 9, 290-295.
(32) Markowitz, S.; Saito, K.; Moskowitz, M. A. Neurogenically
Mediated Leakage of Plasma Protein Occurs from Blood Vessels
in Dura Mater but not Brain J . Neurosci. 1987, 7, 4129-4136.
(33) Buzzi, M. G.; Moskowitz, M. A. The Anti-migraine Drug,
Sumatriptan (GR43175), Selectively Blocks Neurogenic Plasma
Extravasation from Blood Vessels in Dura Mater Br. J . Phar-
macol. 1990, 99, 202-206.
(34) For reference, an ED50 of 19 ng/kg, iv, was obtained in our labs
for sumatriptan, an unrelated 5-HT agonist known to be active
in this model. See: (a) Buzzi, M. G.; Moskowitz, M. A. The
Trigemino-Vascular System and Migraine Pathol. Biol. 1992,
40, 313-317. (b) Buzzi, M. G.; Moskowitz, M. A. Evidence for
5-HT1B/1D Receptors Mediating the Antimigraine Effect of
Sumatriptan and Dihydroergotamine Cephalalgia 1991, 10,
165-168.
(35) This compound was obtained from its tert-butyl carbamate by
treatment with 70% aqueous trifluoroacetic acid containing
anisole by analogy with compound 21 using the above method
B, steps 1 and 2.
(25) Gitter, B. D.; Waters, D. C.; Bruns, R. F.; Mason, N. R.; Nixon,
J . A.; Howbert, J . J . Species Differences in Affinities of Non-
peptide Antagonists for Substance P Receptors Eur. J . Phar-
macol. 1991, 187, 237-238.
(26) Nantel, F.; Rouissi, N.; Rhaleb, N.; J ukic, D.; Regoli, D.
Pharmacological Evaluation of the Angiotensin, Kinin and
Neurokinin Receptors on the Rabbit Vena Cava J . Cardiovasc.
Pharmacol. 1991, 18, 398-405.
(27) J ohnson, C. L.; J ohnson, C. G.; Characterization Of Receptors
For Substance P In Human Astrocytoma Cells: Radioligand
Binding And Inositol Phosphate Formation. J . Neurochem.
1992, 58, 471-477.
(28) Gitter, B. D.; Regoli, D.; Howbert, J . J .; Glasebrook, A. L.;
Waters, D. C. Interleukin-6 Secretion From Human Astrocytoma
Cells Induced By Substance P. J . Neuroimmunol. 1994, 51, 101-
108.
(29) Rouissi, N.; Gitter, B. D.; Waters, D. C.; Howbert, J . J .; Nixon,
J . A.; Regoli, D. Selectivity And Specificity Of New, Non-Peptide,
Quinuclidine Antagonists Of Substance P. Biochem. Biophys.
Res. Commun. 1991, 176, 894-901. Gaudreau, P.; Barabe, J .;
St. Pierre, S.; Regoli, D. Pharmacological Studies of Kinins in
Venous Smooth Muscles. Can. J . Physiol. Pharmacol. 1981, 59,
371-379.
(30) Sixty-five different in vitro assays, including T-, L-, and N-type
calcium channel assays, were performed with (R)-32. In no case
were any observed affinities greater than 1 µM. See ref 15a for
a listing of the assays and results.
(36) See ref 26.
J M950616C