A potent, orally bioavailable benzazepinone growth hormone secretagogue

Article abstract of DOI:10.1021/jm970816j

The identification of L-739,9.43 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L- 692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the ne

Full text of DOI:10.1021/jm970816j

1716
J . Med. Chem. 1998, 41, 1716-1728
A P oten t, Or a lly Bioa va ila ble Ben za zep in on e Gr ow th Hor m on e Secr eta gogu e
Robert J . DeVita,*,† Richard Bochis,† Alison J . Frontier,† Andrew Kotliar,† Michael H. Fisher,†
William R. Schoen,†,‡ Matthew J . Wyvratt,† Kang Cheng,§ Wanda W.-S. Chan,§ Bridget Butler,§
Thomas M. J acks,§ Gerard J . Hickey,§ Klaus D. Schleim,§ Kwan Leung,| Zhesheng Chen,| S.-H. Lee Chiu,|
William P. Feeney, Paul K. Cunningham, and Roy G. Smith§
Departments of Medicinal Chemistry, Biochemistry & Physiology, Drug Metabolism, and Laboratory Animal Resources,
Merck Research Laboratories, P.O. Box 2000, Rahway, New J ersey 07065-0900
Received December 5, 1997
The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone
secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid
side chain and replacement of the acidic 2′-tetrazole with the neutral and potency enhancing
2′-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release
of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of
8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 ( 46 ng/mL. L-739,943 represents
a significant breakthrough in terms of both potency and oral bioavailability as compared to
the prototype benzolactam L-692,429.
In tr od u ction
Growth hormone (GH) release from the pituitary in
mammals was originally thought to be regulated by
growth hormone releasing hormone (GHRH) and soma-
tostatin, which are both secreted from the hypothala-
mus.1 Peptidomimetic growth hormone secretagogues2-4
have recently been identified as novel mediators of
growth hormone release in mammals by an alternate
mechanism.5,6 The breakthrough discovery of several
growth hormone releasing peptides (GHRP’s)7 led to a
search for nonpeptidyl, small molecule mimetics of the
extensively studied hexapeptide GHRP-6 (His-D-Trp-
Ala-Trp-D-Phe-Lys-NH2). The first nonpeptidyl GH
secretagogue,8,9 zwitterionic L-692,429 (1, Figure 1), was
shown to be well tolerated and effective in stimulating
GH release in humans after intravenous administra-
tion.10 The search for an orally active growth hormone
secretagogue led to the identification of MK-0677 (2)
from a new structural class.11 MK-0677 (2) has been
shown to be orally efficacious for the release of growth
hormone in humans12 and is being studied in the clinic
F igu r e 1.
for a variety of therapeutic uses.
which led to the identification of a potent and orally
bioavailable benzolactam growth hormone secretagogue,
L-739,943 (8b).
The prototype benzolactam secretagogue 1 has ex-
tremely low oral bioavaibility in rats and dogs. Since
the molecule is zwitterionic in nature, its poor oral
bioavailability was presumably attributed to poor oral
absorption. In earlier reports from this laboratory,13 we
have described several replacements of the acidic 2′-
tetrazole moiety of L-692,429. These neutral 2′-replace-
ments, most notably the 2′-carboxamide,14 gave orally
active secretagogues with potency equal to or greater
than L-692,429, but were not suitable for development
as oral drug candidates. We report herein the modifica-
tions and structure-activity relationships of L-692,429
Ch em istr y
Benzolactam growth hormone secretagogues were
prepared by an approach similar to that used for L-692,-
429 as shown in Scheme 1. The previously described
(R)-3-aminobenzolactam (3)9 was coupled with the ap-
propriately protected amino acid side chain (4a -d );
N-BOC- or N-CBZ-3,3-dimethyl-â-alanine and N-CBZ-
or N-BOC-2-methylalanine (R-aminoisobutyric acid,
AIB) using standard amide coupling procedures. Selec-
tive deprotonation of the benzolactam nitrogen of the
resulting amides 5a -d and alkylation with the 2′-
functionalized biphenyls 6a -d afforded the framework
of the benzolactam GHS structure. It was necessary
to keep the temperature below 5 °C for the alkylation
* To whom correspondence should be addressed.
† Department of Medicinal Chemistry.
‡ Current address: Bayer Corp. Pharmaceutical Div., Institute for
Chemistry, 400 Morgan Lane, West Haven, CT 06516-4175.
§ Department of Biochemistry & Physiology.
| Department of Drug Metabolism.
Department of Laboratory Animal Resources.
S0022-2623(97)00816-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/22/1998

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1717
Sch em e 1a
a
Reagents and conditions: (a) BOP or PyBOP, TEA, CH2Cl2, room temperature; (b) 60% NaH, DMF, 6, 0 °C or room temperature; (c)
for NO2, H2 (1 atm), Pd-C, MeOH; for (CH2)nNHBOC, TFA, anisole, CH2Cl2, then R1R2NCO, R1R2NCOCl or R3COCl, TEA, CH2Cl2; (d)
for PG ) BOC, TFA, anisole, CH2Cl2 or 9 N aqueous HCl; for PG ) CBZ, H2 (1 atom), Pd(OH)2 on C, MeOH; (e) RP MPLC on C8 MeOH/
0.1% aqueous TFA.
of the amides containing the AIB side chain since
hydantoin formation resulted as a major byproduct at
higher temperatures.
intermediate with NBS under radical conditions gave
the desired 4-bromomethyl-2′-nitrobiphenyl (6a ). The
2′-protected N-BOC amine was prepared in high yield
by cross-coupling 4-(tert-butyldiphenylsilyloxymethyl)-
phenylboronic acid (13), prepared in two steps from
4-bromobenzyl alcohol, with 2-N-BOC-aminomethyl-1-
bromobenzene (14). Removal of the silyl protecting
group and conversion to the O-methanesulfonate pro-
ceeded smoothly to afford the 4-methanesulfonyloxy-
methyl-2′-N-BOC-aminomethyl-1,1′-biphenyl (6b) in high
yield.
When the neutral 2′-urea was recognized as a potent
replacement of the 2′-tetrazole, two biphenyl electro-
philes containing that moiety were prepared to make
the synthetic sequence more convergent. The alcohol
of N-BOC intermediate 15 was acetylated with acetic
anhydride followed by deprotection of the amine with
TFA. Treatment with methyl isocyanate, basic cleavage
of the acetate, and conversion of the alcohol to the
O-methanesulfonate gave the 2′-functionalized biphenyl
6c. Preparation of the urea containing an ethylene
linkage to the 2′-position was completed in a similar
fashion. Cross-coupling of boronic acid 13 with 2-bro-
mophenylacetonitrile under anhydrous conditions17 pro-
vided the biphenylmethyl nitrile in 73% yield. Protect-
ing group manipulation followed by nitrile reduction
with tetra-n-butylammonium borohydride in refluxing
THF and acid hydrolysis gave 2′-(2-aminoethyl)-1,1′-
biphenyl-4-methanol. Selective formation of the urea
with methyl isocyanate and conversion of the alcohol
to the mesylate gave the eletrophilic biphenyl urea 6d .
A variety of functional groups were prepared by
derivatization of the 2′-position of these N-alkyl ben-
zolactam intermediates. 2′-Ureas were prepared by
revealing the latent amines by either nitro reduction
(for 7) or N-deprotection (for 8) followed by reaction with
the appropriate isocyanate or carbamoyl chloride. Simi-
larly, the aminomethyl intermediate gave the acetamide
derivative 9a (R3 ) acetyl) by reaction with acetyl
chloride and the 2′-amino methyl analogue 9b (R1 ) H)
by simple deprotection without nitrogen functionaliza-
tion. Two urea compounds were prepared by alkylation
of the amides 5a and 5d with the 2′-ureidobiphenyls
6c and 6d , respectively. Deprotection of the amino acid
side chain of the resulting intermediates by hydro-
genolysis with palladium hydroxide catalyst on carbon15
for the N-CBZ group or acid hydrolysis (TFA or 9 N
aqueous HCl) for the N-BOC group followed by reverse-
phase medium-pressure liquid chromatography on C-8
afforded the final secretagogue products 7, 8, 9, and 10
as amorphous solids.
Large-scale preparation of L-739,943 was achieved by
deprotection of the intermediate containing the 2′-urea
and N-CBZ group on the amino acid side chain by
hydrogenolysis followed by addition of 1 equiv of hy-
drochloric acid. The crude product was crystallized from
aqueous acetonitrile to afford the crystalline monohy-
drate HCl salt (mp 198-200 °C) which after dissolution
in water and lyophilization to remove trace amounts of
organic solvent provided material of high purity for
biological testing.
Resu lts a n d Discu ssion
The 1,1′-biphenyl-4-methyl alkylating agents 6a -d
were prepared by palladium catalyzed cross-coupling of
the appropriate 4-substituted aryl boronic acids with the
desired 2-substituted aryl halide16 (Scheme 2). Specif-
ically, 4-methylphenylboronic acid (11) was cross-
coupled with 2-nitrobromobenzene (12) to afford the
disubstituted biphenyl in good yield. Treatment of this
Str u ctu r e-Activity Rela tion sh ip s. The growth
hormone releasing activities of the GH secretagogues
discussed are shown in Table 1. The in vitro GH
releasing activities of the compounds prepared were
determined using rat primary pituitary cells as previ-
ously described.18 Potency is reported as an ED50,
defined as the dose at which a 50% maximal GH

1718 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
DeVita et al.
Sch em e 2a
a
Reagents and conditions: (a) cat. Pd(PPh3)4, toluene, 2-propanol, 5 N NaOH, reflux; (b) NBS, cat. AlBN, CCl4, reflux; (c) Bu4NF,
THF, room temperature; (d) CH3SO2Cl, TEA, CH2Cl2, 0 °C; (e) Ac2O, TEA, CH2Cl2; (f) TFA, anisole, CH2Cl2; (g) TEA, CH3NCO, CH2Cl2;
(h) LiOH, aqueous THF, room temperature; (i) TBDPSCl, imidazole, DMF, room temperature; (j) Bu4NBH4, THF, reflux; (k) 6 N HCl,
THF, reflux.
Ta ble 1. Growth Hormone Secretagogue Activity in Vitroa
pounds were assayed prior to the identification of the
GHS receptor. Several compounds of historical interest
have been included in the Table for completeness. The
parent tetrazole compound 1, L-692,429, has an in vitro
potency of 60 nM,9 while analogue 17, possessing the
shorter 2-methyl alanine side chain (AIB) is 2-fold more
potent at 30 nM.19 The 2′-carboxamide analogue 18, a
neutral tetrazole replacement, is of similar potency to
L-692,429 with an ED50 ) 80 nM.14
Our search for new 2′-pharmacophores led to other
neutral hydrogen bond donor or acceptor groups. A
compd
no.
R
n
formula analysis ED50 (nM)
benzylic amine acetamide 9a , a “reverse amide” ana-
logue of 18, is approximately 3-fold less potent with an
ED50 ) 200 nM while the benzylic amine analogue 9b,
with an ED50 > 1000 nM, demonstrates that a positively
charged amine at this position is detrimental to potency.
1
17
18
5-(1H)-tetrazolyl
5-(1H)-tetrazolyl
CONH2
1 C29H30N6O2 CHN
0 C28H28N6O2 CHN
1 C29H32N4O3 CHN
1 C31H36N4O3 CHN
1 C29H34N4O2 CHN
1 C30H35N5O3 CHN
1 C31H37N5O3 CHN
0 C30H35N5O3 CHN
60
30
80
9a CH2NHCOCH3
9b CH2NH2
200
>1000
50
7
NHCONHCH3
8a CH2NHCONHCH3
8b CH2NHCONHCH3
(L-739,943)
6
1
Another functional group with neutral hydrogen
bonding capability is the 2′-N-methylurea 7 which is
equipotent to L-692,429 (ED50 ) 50 nM). Homologation
at the 2′-position to the N-methyl benzylic urea 8a , led
to an 8-fold increase in GH releasing activity (ED50 ) 6
nM). Shortening of the amino acid side chain gave
analogue 8b (L-739,943) which has an ED50 ) 1 nM, a
60-fold increase in potency as compared to the prototype
benzolactam GH secretagogue, L-692,429 (1), and 10-
fold more potent than the peptidyl secretagogue GH-
RP-6 (ED50 ) 10 nM).9
8c CH2NHCONH2
8d CH2NHCONHCH2CH3
8e CH2NHCONHCH2CH2OH 0 C31H37N5O4 CHN
8f CH2NHCONHCH2CH2CH3 0 C32H39N5O3 CHN
8g CH2NHCONHCH(CH3)2
8h CH2NHCONH-cyclopropyl 0 C32H37N5O3 CHN
8i CH2NHCONHCH2Ph
8j CH2NHCON(CH3)2
0 C29H33N5O3 CHN
0 C31H37N5O3 CHN
21
6
2
144
270
45
390
60
0 C32H39N5O3 CHN
0 C36H39N5O3 CHN
0 C31H37N5O3 CHN
0 C31H37N5O3 CHN
10
CH2CH2NHCONHCH3
40
a
Rat pituitary cell assay.
response in vitro was achieved. Although a receptor
binding assay has been recently reported,6 these com-

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1719
dose (0.25 mg/kg) produces a similar GH response to
that obtained with L-739,943 at a dose of 0.5 mg/kg.11
The specificity of L-739,943 for the release of GH was
evaluated in comparison to cortisol, insulin-like growth
factor 1 (IGF-1), prolactin, luteinizing hormone, and
thryroxine release. At a dose of 1.0 mg/kg with GH
AUC(0-6 h) increased by 5.4-fold, cortisol AUC (0-6
h) was increased 2.5-fold while prolactin, lutenizing
hormone, and thyroxine were not significantly altered.
IGF-1 levels were increased by 32% at 6 h at this dose.
The increase in cortisol has been observed with other
nonpeptidyl8,11 and peptidyl GH secretagogues,20 and it
is still unclear whether this effect is related to its novel
mechanism of action or whether it is of any clinical
significance.
Comparison of plasma concentration after iv dosing
at 0.2 mg/kg and oral dosing at 2 mg/kg of body weight
determined the oral bioavailability and pharmacokinet-
ics of L-739,943 in beagle dogs. L-739,943 gave, after
an iv dose, an area under the curve (AUC) of 231 ( 61.4
ng h/mL, a clearance of 15.1 ( 4.0 mL/min/kg, and a
half-life of 2.4 ( 0.5 h. When dosed orally, Cmax was
145.1 ( 46.4 ng/mL and the AUC was 528.3 ( 16.5 ng
h/mL. The bioavailability in beagle dogs based on these
data was estimated to be 23.8 ( 5.7% (n ) 3, range
18.1-29.5%) assuming linear kinetics for the two dif-
ferent doses. L-739,943 is significantly more orally
bioavailable than the parent benzolactam compound
L-692,429 which was only 2% bioavailable in dogs.21
F igu r e 2. Geometric mean serum growth hormone levels ((
within dog SE) after single oral administration of L-739,943
in beagle dogs (n ) 8).
The structure-activity relationships of L-739,943
were explored by varying the N-alkyl groups of the 2′-
benzylic urea. The unsubstituted urea 8c was 21-fold
less potent (ED50 ) 21 nM) while substitution with an
ethyl group resulted in a 6-fold decrease in GH releasing
activity (8d , ED50 ) 6 nM). Addition of a 2-hydroxyl
group, to give the 2-hydroxyethyl urea 8e, restored
potency as was reported in the carboxamide series.14
This area of the pharmacophore (receptor) is sensitive
to large lipophilic groups as exemplified by the decrease
in GH releasing activity for n-propyl analogue 8f (ED50
) 144 nM) or 2-propyl analogue 8g (270 nM) with some
improvement observed for the slighly smaller cyclopro-
pyl analogue 8h (ED50 ) 45 nM). Similarly, the bulky
N-benzyl group was deleterious to GH releasing activity
(8i, ED50 ) 390 nM). In addition, the N,N-dimethylurea
8j (ED50 ) 60 nM) was 60-fold less active than the
monomethyl analogue 8b which is similar to the de-
crease observed for the carboxamide series previously
described.14
The homologous urea 10 (ED50 ) 40 nM), containing
an ethylene group between the 2′-position of the biphe-
nyl and the N-methyl urea, was 40-fold less potent than
8b, indicating the distance of the urea moiety from the
2′-position is important for interaction of this pharma-
cophore with the GHS receptor (cf. 8b , 10 ≈ 7).
In Vivo Effica cy a n d Or a l Bioa va ila bility of
L-739, 943 (8b) in Bea gle Dogs. The efficacy of
L-739,943 was evaluated orally in beagle dogs in a dose
range study with crossover design. Beagle dogs have
proven to be a good animal model of efficacy in humans
based on clinical studies with MK-0677. L-739,943 was
orally effective for the release of growth hormone at
doses as low as 0.5 mg/kg with a dose dependent
increase in GH levels observed for over 2 h postdosing
(Figure 2). Mean GH peak levels at 1.0 and 2.0 mg/kg
doses ranged from 8.3 to 74.6 and 35.7 to 188.4 ng/mL,
respectively. Likewise, the GH AUC (0-6 h) was 83.9
and 107.8 ng h/mL, respectively. The GH response was
biphasic in 14 of 24 dogs dosed with the first peak
occurring at 20 or 40 min and a second peak at 1.5 or 2
h postdosing. The mean serum GH AUC (0-6 h) levels
increased 3.5-, 5.4-, and 7.0-fold over control in a dose
dependent manner. These results compare favorably
with MK-0677, which though orally active at a lower
Con clu sion
We have reported the chemistry and biology of an
orally active benzolactam GH secretagogue L-739,943
(8b). The earlier benzolactam secretagogue L-692,429
was improved upon by key modifications of the amino
acid side chain and the 2′-tetrazole which removed its
zwitterionic nature. The critical positioning of the
methylurea moiety, a neutral tetrazole replacement,
from the 2′-biphenyl removed the ionic charge and
substantially increased potency. Similarly, potency was
also improved by use of the shortened amino acid side
chain which resulted in a decrease in basicity of this
amine (pKa changes from 9.2 to 7.5). The combination
of these changes resulted in a 60-fold increase in potency
in vitro compared to the parent compound L-692,429.
The zwitterionic L-692,429 has been converted to a near
neutral compound at physiological pH which improved
the oral absorption and bioavailability of L-739,943.
L-739,943 has an intrinsic in vitro potency of 1 nM
in the rat pituitary cell assay which is equipotent to MK-
0677 (2). Oral efficacy of compound 8b was demon-
strated in beagle dogs with a dose dependent GH release
observed at doses as low as 0.5 mg/kg and a maximum
serum GH level of 188 ng/mL at a dose of 2 mg/kg. Oral
bioavailability in beagle dogs was determined to be
23.8% with a Cmax of 145 ng/mL, a large AUC of 528 ng
h/mL after oral administration at 2 mg/kg. The GH
response in beagle dogs for L-739, 943 at oral doses from
0.5 to 2.0 mg/kg compare favorably to that of MK-0677
at similar doses even though the oral bioavailability of
L-739,943 is approximately 3-fold lower.

1720 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
DeVita et al.
4.53 (s, 2H), 7.2-7.7 (m, 7H), 7.85 (m, 1H). EI-MS: calculated
Exp er im en ta l Section
for C14H10BrN 272; found 272,274 (M+).
Ch em ist r y. Gen er a l Met h od s. 1H NMR spectra were
recorded on Varian XL series spectrometers at the indicated
field strengths. Low-resolution mass spectral analyses were
obtained with a LKB 9000 at an ionizing voltage of 70 eV.
Optical rotations were measured on a Perkin-Elmer model 241
polarimeter at ambient temperature. Reagents, solvents, and
drying agents were obtained from commercial sources and used
without further purification or drying unless stated otherwise.
GHRP-6 was obtained from BACHEM Bioscience, Inc., Phila-
delphia, PA, custom synthesis lot ZF892. Rat GRF was
obtained from Sigma Chemical Co., St. Louis, MO. Normal
phase column chromatography was carried out utilizing silica
gel 60 (E. Merck). Preparative reverse phase medium-pressure
liquid chromatography was carried out with Lobar LiChroprep
C-8 (E. Merck) prepacked columns. Elemental analyses were
performed by Robertson Microlit Laboratories, Inc., Madison,
NJ .
N-[1-[[(2′-Nitr o)[1,1′-bip h en yl]-4-yl]m eth yl]-2,3,4,5-tet-
r a h yd r o-2-oxo-1H -1-b en za zep in -3(R)-yl]-3-ter t-b u t oxy-
ca r bon yla m in o-3-m eth ylbu ta n a m id e. A solution of 1.28
g (3.4 mmol) of 3-tert-butoxycarbonylamino-3-methyl-N-[2,3,4,5-
tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]butanamide (5a ) in
6 mL of dry dimethylformamide was treated with 163 mg of
60% sodium hydride oil dispersion (4.07 mmol). The reaction
mixture was stirred at room temperature for 30 min. To the
solution was added 1.0 g (3.4 mmol) of solid 4-bromomethyl-
2′-nitro-1,1′-biphenyl (6a ). After stirring at room temperature
for 4 h, the reaction mixture was diluted with 200 mL of ethyl
acetate. The organic layer was washed with water (4 × 50
mL), dried over magnesium sulfate, filtered, and evaporated
under vacuum. The residue was purified by column chroma-
tography on silica gel, eluting with ethyl acetate/hexanes (1:
1) to give 1.81 g (90%) of the product as a white solid. 1H NMR
(400 MHz, CDCl3): δ 1.34 (s, 6H), 1.41 (s, 9H), 1.83 (m, 1H),
2.35-2.70 (m, 5H), 4.50 (m, 1H), 4.84 (d, 15 Hz, 1H), 5.23 (d,
15 Hz, 1H), 5.27 (s, 1H), 6.64 (d, 7 Hz, 1H), 7.1-7.6 (m, 11H),
7.80 (d, 8 Hz, 1H). FAB-MS: calculated for C33H38N4O6 586;
found 587 (M + H).
N-[1-[[2′-[(Meth ylam in ocar bon yl)am in o][1,1′-biph en yl]-
4-yl]m et h yl]-2,3,4,5-t et r a h yd r o-2-oxo-1H -1-b en za zep in -
3(R)-yl]-3-a m in o-3-m eth ylbu ta n a m id e, tr iflu or oa ceta te
(7). 3-ter t-Bu toxyca r bon yla m in o-3-m eth yl-N-[2,3,4,5-tet-
r ah ydr o-2-oxo-1H-1-ben zazepin -3(R)-yl]-bu tan am ide (5a).
A solution of 8.70 g (49.4 mmol) of 3(R)-amino-2,3,4,5-tetrahy-
dro-1H-1-benzazepin-2-one (3) in 100 mL of methylene chloride
was treated with 10.73 g (49.4 mmol) of 3-tert-butoxycarbo-
nylamino-3-methylbutanoic acid (4a ) and 13.8 mL of triethyl-
amine (10.0 g, 99 mmol, 2 equiv). The reaction flask was
immersed in an ambient temperature water bath. Benzotria-
zol-1-yloxytris(dimethylamino)phosphonium hexafluorophos-
phate (26 g, 59 mmol, 1.2 equiv) was added and the mixture
stirred at room temperature for 2 h. The reaction mixture was
added to 300 mL of ethyl acetate and washed three times with
5% aqueous citric acid, twice with saturated aqueous sodium
bicarbonate, and once with saturated aqueous sodium chloride.
The organic layer was removed, dried over magnesium sulfate,
and filtered and the filtrate concentrated under vacuum. The
residue was purified by preparative high-pressure liquid
chromatography on silica, eluting with ethyl acetate/hexane
(4:1), to afford 17.42 g (46.4 mmol, 94%) of product 5a as a
white solid. 1H NMR (200 MHz, CDCl3): δ 1.37 (s, 6H), 1.44
(s, 9H), 1.95 (m, 1H), 2.46 (d, 15 Hz, 1H), 2.59 (d, 15 Hz, 1H),
2.6-3.0, (m, 3H), 4.53 (m, 1H), 5.30 (br s, 1H), 6.72 (d, 7 Hz,
1H), 6.98 (d, 8 Hz, 1H), 7.1-7.3 (m, 3H), 7.82 (br s, 1H). FAB-
MS: calculated for C20H29N3O4 375; found 376 (M + H,70%).
4-Meth yl-2′-n itr o-1,1′-bip h en yl. A vigorously stirred mix-
ture of 4-tolylboronic acid (34 g, 0.25 mol) and 2-bromo-1-
nitrobenzene (34 g, 0.168 mol) in a mixture of 5 N sodium
hydroxide (170 mL), water (57 mL), 2-propanol (215 mL), and
benzene (1080 mL) under a nitrogen atmosphere was treated
with tetrakis(triphenylphosphine)palladium(0) (11.9 g). The
stirred bilayer reaction mixture was heated at reflux for 3 h.
The cooled reaction mixture was filtered through Celite and
the filter cake washed with fresh benzene. The organic layer
was separated and washed with water (3×), dried over
magnesium sulfate, and filtered. The filtrate was evaporated
under vacuum and the residue (46.1 g) purified by preparative
high-pressure liquid chromatography on silica gel, eluting with
hexane/ethyl acetate (20:1), gave 28.05 g of product 6a . EI-
MS: calculated for C13H11NO2 213; found 213 (M+). 1H NMR
(400 MHz, CDCl3): δ 2.38 (s, 3H), 7.20 (m, 4H), 7.43 (m, 2H),
7.59 (t, 1H), 7.8 (d, 1H).
N-[1-[[(2′-Am in o)[1,1′-b ip h en yl]-4-yl]m et h yl]-2,3,4,5-
tetr a h yd r o-2-oxo-1H-1-ben za zep in -3(R)-yl]-3-ter t-bu toxy-
ca r bon yla m in o-3-m eth ylbu ta n a m id e. A solution of 7.79
g (13.23 mmol) of the intermediate obtained above in 200 mL
of methanol containing 0.9 g of 5% palladium on carbon was
hydrogenated at 40 psi. When the uptake of hydrogen was
complete, the catalyst was removed by filtration through
Celite. The filtrate was concentrated under vacuum to yield
6.6 g (11.9 mmol, 90%) of product. FAB-MS: calculated for
C
33H4N4O4 556; found 557 (M + H). 1H NMR (400 MHz,
CDCl3): δ 1.32 (s, 6H), 1.39 (s, 9H), 1.87 (m, 1H), 2.51 (dd,
1H), 2.59 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.15 (d, 1H), 5.32
(br s, 1H), 6.71 (d, 1H), 6.81 (s, 1H), 7.21 (m, 10H).
N-[1-[[2′-[(Meth ylam in ocar bon yl)am in o][1,1′-biph en yl]-
4-yl]m et h yl]-2,3,4,5-t et r a h yd r o-2-oxo-1H -1-b en za zep in -
3(R)-yl]-3-ter t-b u t oxyca r b on yla m in o-3-m et h ylb u t a n a -
m id e. A solution of 88.4 mg (0.158 mmol) of the intermediate
obtained above in 4 mL of methylene chloride at room
temperature was treated with 0.5 mL of methyl isocyanate
(8.5 mmol). The reaction mixture was stirred at room tem-
perature for 18 h, when all starting material was consumed
as indicated by thin-layer chromatography. The reaction was
evaporated under vacuum and the residue passed over silica
gel. Elution with ethyl acetate/n-hexane (3:1) yielded 66 mg
(0.11 mmol, 68%) of product. 1H NMR (400 MHz, CDCl3): δ
1.21 (s, 3H), 1.23 (s, 3H), 1.39 (s, 9H), 1.89 (m, 1H), 2.49 (dd,
H), 2.60 (m, 2H), 2.69 (s, 3H), 4.50 (m, 1H), 4.95 (d, 1H), 5.06
(d, 1H), 5.26 (br s, 1H), 6.24 (br s, 1H), 6.70 (d, 1H), 7.22 (m,
11H), 7.71 (d, 1H).
N-[1-[[2′-[(Meth ylam in ocar bon yl)am in o][1,1′-biph en yl]-
4-yl]m et h yl]-2,3,4,5-t et r a h yd r o-2-oxo-1H -1-b en za zep in -
3(R)-yl]-3-a m in o-3-m eth ylbu ta n a m id e, tr iflu or oa ceta te
(7). A solution of 66 mg (0.11 mmol) of the intermediate
obtained above in 2 mL of methylene chloride was treated with
2 mL of trifluoroacetic acid. The reaction mixture was stirred
at room temperature for 1 h, when thin-layer chromatography
indicated that no starting material remained. The reaction
mixture was evaporated to dryness under vacuum, and the
residue was purified by medium-pressure liquid chromatog-
raphy on C8, eluting with methanol/0.1% aqueous trifluoro-
acetic acid (60:40). Fractions containing the product were
combined and evaporated under vacuum, and the residue was
lyophilized from water to give 26 mg (0.051 mmol, 46%) of the
title compound as a white solid. FAB-MS: calculated for
4-Br om om eth yl-2′-n itr o-1,1′-bip h en yl (6a ). A solution
of 4-methyl-2′-nitro-1,1′-biphenyl (6.0 g, 28.2 mmol), N-bro-
mosuccinimide (4.99 g, 28.2 mmol), and AIBN (653 mg) in 75
mL of carbon tetrachloride was heated at reflux until a
negative potassium iodide test was obtained (1.5 h). The
reaction mixture was cooled and filtered. The filtrate was
C
30H35N5O3 513; found 536 (M + Na). 1H NMR (400 MHz,
CD3OD): δ 1.34 (s, 3H), 1.37 (s, 3H), 2.13 (m, 1H), 2.39 (m,
1H), 2.54 (dd, 1H), 2.63 (s, 3H), 3.29 (dd, 1H), 4.95 (d, 1H),
5.11 (d, 1H), 7.22 (m, 10H), 7.60 (d, 1H).
1
evaporated under vacuum to yield 8.41 g of crude product. H
NMR revealed the product composition was approximately
75% monobromo and 10% dibromo, in addition to 15% of
unreacted starting material. The crude product was used
without further purification. 1H NMR (200 MHz, CDCl3): δ
2-Am in o-2-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[[(m e-
th yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Hy-

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1721
d r och lor id e (8b, L-739,943). 2-Ben zyloxyca r bon yla m in o-
2-m eth yl-N-[2,3,4,5-tetr ah ydr o-2-oxo-1H-ben zazepin -3(R)-
yl]p r op a n a m id e (5b). Prepared from N-carbobenzyloxy-2-
methylalanine (4b) and 3(R)-amino-2,3,4,5-tetrahydro-1H-ben-
zazepin-2-one (3) substituting benzotriazol-1-yloxytripyrroli-
dinophosphonium hexafluorophosphate for benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate
according to the procedure described for 5a . 1H NMR (200
MHz, CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-
3.00 (m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-
7.40 (m, 10H), 8.65 (s, 1H). FAB-MS: calculated for C22H25N3O4
395; found 396 (M + H,100).
4-Br om oben zyl ter t-Bu tyld ip h en ylsilyl Eth er . To a
solution of 28.2 g (0.150 mol) of 4-bromobenzyl alcohol in 470
mL of dry dimethylformamide under nitrogen atmosphere was
added 31.4 mL (0.225 mol) of triethylamine. The reaction
mixture was cooled to 0 °C, and 43 mL (0.17 mol) of tert-
butylchlorodiphenylsilane was added dropwise by addition
funnel. The reaction mixture was stirred at ambient temper-
ature overnight and then poured into a separatory funnel
containing 1 L of diethyl ether and 500 mL of water. To this
mixture was added 125 mL of 2 N aqueous hydrochloric acid.
The layers were separated, and the aqueous layer was
extracted with diethyl ether (2 × 350 mL). The organic
extracts were combined, washed with water (2 × 250 mL), and
dried over magnesium sulfate. The solids were removed by
filtration, and the solvent was removed under vacuum to give
an oil which crystallized on standing. The flask containing
the crude product was placed in the freezer overnight and then
triturated with a minimal amount of methanol and filtered.
The solid was air-dried for several hours and then dried under
vaccuum overnight to afford 59.5 g (93%) of product as an off-
white solid (mp 44-47 °C). 1H NMR (200 MHz, CDCl3): δ
1.15 (s, 9H), 4.76 (s, 2H), 7.25 (d, 8 Hz, 2H), 7.45 (m, 8H), 7.75
(m, 4H). FAB-MS: calculated for C23H25BrOSi 424; found 425
(M+H, 7%).
4-(ter t-Bu tyldiph en ylsiloxym eth yl)ph en ylbor on ic Acid
(13). To a solution of 20 g (47 mmol) of 4-bromobenzyl tert-
butyldiphenyl silyl ether in 200 mL of dry tetrahydrofuran
under a nitrogen atmosphere at -78 °C was added dropwise
by syringe 19.74 mL (49.35 mmol) of a 2.5 M solution of
n-butyllithium in hexanes over 20 min. The resulting mixture
was stirred for 30 min, and then 11.6 mL (50.3 mmol) of
triisopropyl borate was added by syringe. The reaction
mixture was stirred at -78 °C for 30 min and then slowly
warmed to room temperature and stirred for an additional 2
h. The reaction mixture was then quenched by the addition
of 750 mL of water containing 100 mL of concentrated
hydrochloric acid and 500 mL of diethyl ether. The mixture
was strirred for 1 h, and then the organic layer was separated.
The aqueous layer was extracted with diethyl ether (2 × 400
mL). The combined ether extracts were washed with satu-
rated aqueous sodium chloride (4 × 100 mL), dried over
magnesium sulfate, and filtered. The solvent was removed
under vacuum to give an oil which was crystallized by
dissolving in hexanes and evaporation of the solvent under
vacuum to afford 15.6 g (85%) of a white solid (mp 171-174
°C). 1H NMR (200 MHz, CDCl3): δ 1.11 (s, 9H), 4.86 (s, 2H),
7.40 (m, 6H), 7.58 (d, 8 Hz, 2H), 7.70 (m, 4H), 8.22 (d, 8 Hz,
2H). FAB-MS: calculated for C23H27BrO3Si 390; found 372
(M - H2O).
N-(ter t-Bu toxyca r bon yl)-2-br om oben zyla m in e (14). To
a slurry of 8.88 g (39.9 mmol) of 2-bromobenzylamine hydro-
chloride in 100 mL of dry methylene chloride under a nitrogen
atmosphere was added by syringe 12.24 mL (87.80 mmol) of
triethylamine. The resulting solution was stirred at 0 °C for
5 min and then treated with 9.6 g (44 mmol) of di-tert-butyl
dicarbonate. The reaction was stirred at room temperature
for 2 h and then diluted with 350 mL of methylene chloride.
The solution was washed with water (2 × 150 mL), saturated
aqueous ammonium chloride (150 mL), saturated aqueous
sodium bicarbonate (4 × 150 mL), and saturated aqueous
sodium chloride (150 mL), dried over sodium sulfate, and
filtered. The solvent was removed under vacuum to give an
oil which was crystallized by dissolving in hot hexanes,
filtering and cooling the solution. The product was filtered
and dried under vacuum to afford 8.66 g (90%) of a white solid
(mp 51-53 °C). 1H NMR (200 MHz, CDCl3): δ 1.41 (s, 9H),
4.37 (d, 5 Hz, 2H), 5.00 (s, 1H), 7.10 (m, 1H), 7.25 (m, 1H),
7.35 (m, 1H), 7.40 (d, 6 Hz, 1H). FAB-MS: calculated for
C
12H16BrNO2 285; found 286 (M + H).
2′-[(ter t-Bu toxyca r bon yla m in o)m eth yl]-4-[(ter t-bu tyl-
d ip h en ylsiloxy)m eth yl]-1,1′-bip h en yl. To a solution of 3.2
g (8.2 mmol) of 4-(tert-butyldiphenylsilyoxymethyl)phenylboronic
acid in 64 mL of benzene was added 2.2 mL of water, 6.4 mL
of 5 N aqueous sodium hydroxide, and 8.3 mL of 2-propanol.
To this mixture was added 180 mg (0.16 mmol) of tetrakis-
(triphenylphosphine)palladium and 2.20 g (7.81 mmol) of
N-(tert-butoxycarbonyl)-2-bromobenzylamine. The resulting
mixture was heated under nitrogen at reflux for 2 h then cooled
to room temperature. The reaction mixture was diluted with
100 mL of water, transferred to a separatory funnel, and
extracted with ether (3 × 150 mL). The combined ether
extracts were washed with saturated aqueous sodium bicar-
bonate (100 mL) and saturated aqueous sodium chloride (100
mL), dried over magnesium sulfate, and filtered. The solvent
was removed under vacuum to give a crude product which was
purified by column chromatography on silica gel eluting with
hexanes/ethyl acetate (9:1) to afford 4.31 g (100%) of the
product as a clear oil. 1H NMR (200 MHz, CDCl3): δ 1.11 (s,
9H), 1.41 (s, 9H), 4.27 (d, 6 Hz, 2H), 4.45 (m, 1H), 4.81 (s, 2H),
7.20-7.49 (m, 14H), 8.72 (m, 4H). FAB-MS: calculated for
C
35H41NO3Si 551; found 552 (M + H).
2′-[(ter t-Bu toxyca r bon yla m in o)m eth yl]-1,1′-bip h en yl-
4-m eth a n ol. To a solution of 3.85 g (7.00 mmol) of 2′-[(tert-
butoxycarbonylamino)methyl]-4-[(tert-butyldiphenylsiloxy)-
methyl]-1,1′-biphenyl in 25 mL of dry tetrahydrofuran under
a nitrogen atmosphere was added by syringe 10.5 mL (0.530
mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride
in tetrahydrofuran. The reaction mixture was stirred for 2 h
and then diluted with 700 mL of diethyl ether. The mixture
was washed with water (3 × 150 mL), saturated aqueous
sodium bicarbonate (50 mL), and saturated aqueous sodium
chloride (50 mL), then dried over magnesium sulfate, and
filtered. The solvent was removed under vacuum to give an
oil which was purified by column chromatography on silica
gel eluting with hexanes/ethyl acetate (55:45) to afford 2.02 g
(92%) of the product as a white solid (mp 89-93 °C). 1H NMR
(200 MHz, CDCl3): δ 1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H),
4.70 (s, 2H), 7.18-7.45 (m, 8H). FAB-MS: calculated for
C19H23NO3 313; found 314 (M + H).
2′-[(ter t-Bu toxyca r bon yla m in o)m eth yl]-1,1′-bip h en yl-
4-m eth a n ol, Meth a n esu lfon a te Ester (6b). To a solution
of 53 mg (0.17 mmol) of 2′-[(tert-butoxycarbonylamino)methyl]-
1,1′-biphenyl-4-methanol in 1 mL of dry methylene chloride
under nitrogen at 0 °C was added by syringe 0.035 mL (0.25
mmol) of triethylamine followed by 0.016 mL (0.20 mmol) of
methanesulfonyl chloride. The reaction mixture was stirred
for 2 h at 0 °C, diluted with 75 mL of methylene chloride,
washed with water, saturated aqueous sodium bicarbonate,
and saturated aqueous sodium chloride, dried over sodium
sulfate, and filtered. The solvent was removed under vacuum
to give 61 mg (97%) of the product as a white solid which was
used in the next step without further purification. 1H NMR
(200 MHz, CDCl3): δ 1.38 (s, 9H), 2.95 (s, 3H), 4.20 (d, 5 Hz,
2H), 4.65 (s, 1H), 5.25 (s, 2H), 7.18-7.50 (m, 8H). FAB-MS:
calculated for C20H25NO5S 391; found 392 (M + H).
2-Ben zyloxyca r bon yla m in o-2-m eth yl-N-[2,3,4,5-tetr a -
h yd r o-2-oxo-1-[[2′-[(ter t-bu toxyca r bon yla m in o)m eth yl]-
[1,1′-bip h en yl]-4-yl]m eth yl]-1H-ben za zep in -3(R)-yl]-p r o-
p a n a m id e. To a solution of 819 mg (2.07 mmol) of 2-ben-
zyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-
benzazepin-3(R)-yl]propanamide (5b) in 7 mL of dry dimeth-
ylformamide under nitrogen at 0 °C was added 83 mg (2.1
mmol) of 60% sodium hydride/oil dispersion. After stirring for
15 min, a solution of 810 mg (2.1 mmol) of 2′-[(tert-butoxycar-
bonylamino)methyl]-1,1′-biphenyl-4-methanol, methanesulfonate
ester (6b) in 2 mL of dimethylformamide was added by

1722 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
DeVita et al.
cannula. The flask which originally contained the methane-
sulfonate ester was rinsed with 1 mL of dimethylformamide
which was added to the reaction mixture. After 15 min of
stirring at 0 °C, the reaction mixture was diluted with 400
mL of ethyl acetate and 50% saturated ammonium chloride.
The mixture was transferred to a separatory funnel, and the
aqueous layer was separated. The organic layer was washed
with 100 mL of saturated aqueous sodium bicarbonate and
saturated aqueous sodium chloride. The organic layer was
dried over magnesium sulfate and filtered and the solvent
removed under vacuum. The residue was purified by flash
chromatography on silica gel eluting with ethyl acetate/hexane
(55:45) to afford 1.2 g (84%) of a white foam. 1H NMR (200
MHz, CDCl3): δ 1.38 (s, 9H), 1.48 (s, 3H), 1.52 (s, 3H), 1.78 (s,
1H), 2.35-2.70 (m, 3H), 4.18 (d, 6 Hz, 2H), 4.38-4.62 (m, 2H),
4.82 (d, 16 Hz, 1H), 5.05 (s, 2H), 5.25 (d, 16 Hz, 1H), 5.32 (s,
1H), 7.08 (d, 6 Hz, 1H), 7.12-7.43 (m, 18H). FAB-MS:
calculated for C41H46N4O6 690; found 691(M + H).
2-Ben zyloxycar bon ylam in o-2-m eth yl-N-[2,3,4,5-tetr ah y-
dr o-2-oxo-1-[[2′-(am in om eth yl)[1,1′-biph en yl]-4-yl]m eth yl]-
1H-ben za zep in -3(R)-yl]p r op a n a m id e, Hyd r och lor id e. To
a solution of 9.83 g (0.55 mmol) of 2-benzyloxycarbonylamino-
2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2′-[(tert-butoxycarbo-
nylamino)methyl][1,1′-biphenyl]-4-yl]methyl]-1H-benzazepin-
3(R)-yl]propanamide in 170 mL of methanol was added 120
mL of 9 N aqueous hydrochloric acid. Periodically, 10 mL
portions of methanol were added to the reaction mixture to
dissolve precipitates which form during the reaction (50 mL
total). The reaction mixture was stirred overnight at room
temperature, and then the solvent was removed under vacuum.
The resulting oil was dissolved in methanol, and the solvent
was removed under vacuum to afford 8.57 g (96%) of the title
compound as an off-white foam. 1H NMR (200 MHz, CD3-
OD): δ 1.40 (s, 6H), 1.90 (m, 1H), 2.20-2.65 (m, 3H), 4.02 (s,
2H), 4.32 (m, 1H), 4.96 (d, 16 Hz, 1H), 5.00 (s, 2H), 5.25 (d, 16
Hz, 1H), 7.08-7.65 (m, 17H). FAB-MS: calculated for
C36H38N4O4 590; found 591 (M + H, 100%).
2-Ben zyloxycar bon ylam in o-2-m eth yl-N-[2,3,4,5-tetr ah y-
d r o-1-[[2′-[[[(m eth yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-
bip h en yl]-4-yl]m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r o-
p a n a m id e. To a solution of 8.57 g (13.7 mmol) of 2-ben-
zyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-
[[2′-(aminomethyl)[1,1′-biphenyl]-4-yl]methyl]-1H-benzazepin-
3(R)-yl]propanamide hydrochloride in 75 mL of dry methylene
chloride under nitrogen was added 2.28 mL (16.4 mmol) of
triethylamine followed by 0.89 mL (15 mmol) of methyl
isocyanate. After 45 min of stirring at room temperature, the
solvent was removed under vacuum. The resulting material
was dissolved in methylene chloride and purified by flash
column chromatography on silica gel eluting with ethyl
acetate/methanol (96:4) to afford 7.73 g (87%) of product as a
white foam. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H), 1.82
(m, 1H), 2.15-2.60 (m, 3H), 2.63 (s, 3H), 4.13 (s, 2H), 4.36 (m,
1H), 4.86 (d, 15 Hz, 1H), 4.85 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.08-
7.43 (m, 17H). FAB-MS: calculated for C38H41N5O5 647; found
648(M + H, 80%).
2-Am in o-2-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[[(m e-
th yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Hy-
d r och lor id e (8b, L-739,943). To a solution of 5.00 g (7.72
mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tet-
rahydro-1-[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-bi-
phenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propana-
mide in 100 mL of dry methanol was added 0.50 g (0.1 equiv
by weight) of palladium hydroxide. The mixture was stirred
under a hydrogen atmosphere for 2 h. The mixture was
filtered through Celite. The filter pad was washed with 50
mL of methanol. The filtrate was combined, and the solvent
was removed under vacuum. The resulting oil was dissolved
in 50 mL of methanol and treated with 17 mL (8.5 mmol) of a
0.5 N aqueous hydrochloric acid solution. The solvent was
removed under vacuum to give a solid which was crystallized
by refluxing in 480 mL of acetonitrile/ethanol (7:1). The
mixture was cooled to room temperature with gentle stirring.
After 3 h the solids were filtered and washed with 80 mL of
ice cold acetonitrile/ethanol (7:1) and then air-dried for 3 h.
The resulting solid (containing trace amounts of acetonitrile;
mp 198-200°) was dissolved in 40 mL of water, filtered, and
lyophilized overnight to afford 3.78 g (89%) of the title
compound as a white solid.
1.55 (s, 3H), 1.64 (s, 3H), 2.28 (m, 2H), 2.62 (m, 2H), 2.67 (s,
3H), 4.16 (dd; 16, 14 Hz; 2H), 4.39 (dd; 12, 8 Hz; 1H), 5.00 (d,
15 Hz, 1H), 5.22 (d, 15 Hz, 1H), 7.14 (d, 7 Hz, 1H), 7.20-7.41
(m, 11H). FAB-MS: calculated for C30H35N5O3 513; found 514
(M + H, 100%). [R]D ) +121° (c ) 1, methanol).
1H NMR (400 MHz, CD3OD): δ
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[((2-h y-
dr oxyeth yl)am in o)car bon yl]am in o]m eth yl][1,1′-biph en yl]-
4-y l]m e t h y l]-2-o x o -1H -b e n za ze p in -3(R )-y l]p r o p a n a -
m id e, tr iflu or oa ceta te (8e). 2-Ben zyloxyca r bon yla m in o-
2-m e t h y l-N -[2,3,4,5-t e t r a h y d r o -2-o x o -1-[[2′-(a m in o -
m eth yl)[1,1′-bip h en yl]-4-yl]m eth yl]-1H-ben za zep in -3(R)-
yl]p r op a n a m id e, Tr iflu or oa ceta te. To a solution of 380 mg
(0.55 mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-
tetrahydro-2-oxo-1-[[2′-[(tert-butoxycarbonylamino)methyl][1,1′-
biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide in
2 mL of dry methylene chloride was added 5 drops of anisole
followed by 2 mL of trifluoroacetic acid. The reaction mixture
was stirred for 1.5 h at room temperature at which time the
solvent was removed under vacuum. The resulting oil was
dissolved in 5 mL of carbon tetrachloride, and the solvent was
removed under vacuum. The process was repeated with 5 mL
of chloroform followed by 5 mL of methylene chloride to give
427 mg (>100%) of the product containing minor amount of
anisole as an off-white foam which was used without further
purification. 1H NMR (200 MHz, CDCl3): δ 1.45 (s, 6H), 1.90
(m, 1H), 2.25-2.65 (m, 3H), 4.12 (s, 2H), 4.38 (m, 1H), 4.85
(d, 16 Hz, 1H), 4.96 (s, 2H), 5.05 (d, 16 Hz, 1H), 5.55 (s, 1H),
6.91 (m, 1H), 7.05-7.60 (m, 19H). FAB-MS: calculated for
C
36H38N4O4 590; found 591 (M + H, 100%).
2-Ben zyloxycar bon ylam in o-2-m eth yl-N-[2,3,4,5-tetr ah y-
d r o-1-[[2′-[[[((2-h yd r oxyet h yl)a m in o)ca r b on yl]a m in o]-
m eth yl][1,1′-biph en yl]-4-yl]m eth yl]-2-oxo-1H-ben zazepin -
3(R)-yl]p r op a n a m id e. To a solution of 160 mg (0.23 mmol)
of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-
2-oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-4-yl]methyl]-1H-ben-
zazepin-3(R)-yl]propanamide trifluoroacetate in 1 mL of dry
methylene chloride under nitrogen atmosphere was added
0.063 mL (0.45 mmol) of triethylamine followed by 0.039 mL
(0.25 mmol) of 2-isocyanatoethyl methacrylate. The reaction
mixture was stirred at room temperature for 30 min, and then
the solvent was removed under vacuum.
The residue was dissolved in 2 mL of tetrahydrofuran/water
(3:1), and to the resulting solution was added 42 mg (1.0 mmol)
of lithium hydroxide monohydrate. After 3 h of stirring at
room temperature, the reaction mixture was diluted with 100
mL of ethyl acetate and washed with 50 mL of brine. The
organic layer was dried over magnesium sulfate and filtered
and the solvent removed under vacuum to afford 149 mg (97%)
of the product as a white foam. 1H NMR (200 MHz, CDCl3):
δ 1.48 (m, 9H), 1.82 (m, 1H), 2.10-2.70 (m, 3H), 3.05 (m, 2H),
3.15 (t, 4 Hz, 2H), 2.55 (t, 4 Hz, 2H), 4.20 (s, 2H), 4.45 (m,
1H), 4.68 (s, 1H), 5.03 (s, 2H), 5.38 (s, 1H), 7.05-7.43 (m, 19H).
FAB-MS: calculated for C39H43N5O6 677; found 678 (M + H,
60%).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[((2-h y-
d r oxyeth yl)a m in o)-ca r bon yl]a m in o]m eth yl][1,1′-bip h e-
n yl]-4-yl]m et h yl]-2-oxo-1H -b en za zep in -3(R)-yl]p r op a n -
a m id e, Tr iflu or oa ceta te (8e). To a solution of 149 mg (0.22
mmol) of 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tet-
rahydro-1-[[2′-[[[((2-hydroxyethyl)amino)carbonyl]amino]methyl]-
[1,1′-biphenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]pro-
panamide in 3 mL of dry methanol was added 30 mg (0.2 equiv
by weight) of palladium hydroxide. The mixture was stirred
under a hydrogen atmosphere for 2 h. The mixture was
filtered through Celite. To the filtrate was added 3 drops of
trifluoroacetic acid, and the solvent was removed under
vacuum to give a solid which was purified by reverse phase
medium-pressure liquid chromatography on C8, eluting with

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1723
methanol/0.1% aqueous trifluoroacetic acid (60:40) to afford
87 mg (60%) of the title compound as a white solid. 1H NMR
(200 MHz, CD3OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.28 (m, 2H),
2.60 (m, 2H), 3.19 (t, 6 Hz, 2H), 3.53 (t, 6 Hz, 2H), 4.15 (s,
2H), 4.39 (dd, 12, 8 Hz; 1H), 4.99 (d, 15 Hz, 1H), 5.20 (d, 15
Hz, 1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for
described for 8e. 1H NMR (200 MHz, CD3OD): δ 0.86 (t, 7.5
Hz, 3H), 1.39 (s, 6H), 1.42 (m, 2H), 1.82 (m, 1H), 2.19-2.55
(m, 3H), 3.01 (t, 7 Hz, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d,
15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m,
17H), 7.63 (d, 8 Hz, 1H). FAB-MS: calculated for C40H45N5O5
675; found 676 (M + H, 85).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(1-p r o-
p yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8f). The title compound was prepared from
2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-
[[2′-[[[(1-propylamino)carbonyl]amino]methyl][1,1′-biphenyl]-
4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propanamide accord-
ing to the procedure described for 8e. 1H NMR (200 MHz,
CD3OD): δ 0.87 (t, 7 Hz, 3H), 1.44 (dd; 16, 8 Hz; 2H), 1.53 (s,
3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 3.08 (t, 7 Hz,
2H), 4.14 (s, 2H), 4.37 (dd; 12, 9 Hz; 1H), 4.97 (d, 15 Hz, 1H),
5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 12H). FAB-MS: calculated
for C32H39N5O3 541; found 542 (M + H, 100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h ydr o-1-[[2′-[[[[(1-m e-
th yleth yl)am in o]car bon yl]-am in o]m eth yl][1,1′-biph en yl]-
4-y l]m e t h y l]-2-o x o -1H -b e n za ze p in -3(R )-y l]p r o p a n a -
m ide, Tr iflu or oacetate (8 g). 2-Ben zyloxycar bon ylam in o-
2-m e t h y l -N -[2 ,3 ,4 ,5 -t e t r a h y d r o -1-[[2′-[[[[(1 -m e t h -
yleth yl)a m in o]ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-
yl]m eth yl]-2-oxo-1H-ben zazepin -3(R)-yl]pr opan am ide. The
title compound was prepared from 2-benzyloxycarbonylamino-
2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2′-(aminomethyl)[1,1′-
biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, tri-
fluoroacetate and isopropyl isocyanate according to the
procedure described for 8e. 1H NMR (200 MHz, CD3OD): δ
1.06 (d, 6.5 Hz, 6H), 1.39 (s, 6H), 1.82 (m, 1H), 2.19-2.58 (m,
3H), 3.74 (m, 1H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz,
1H), 5.01 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-
MS: calculated for C40H45N5O5 675; found 676 (M + H, 80).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h ydr o-1-[[2′-[[[[(1-m e-
th yleth yl)a m in o]ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-
yl]m et h yl]-2-oxo-1H -b en za zep in -3(R)-yl]p r op a n a m id e,
Tr iflu or oa ceta te (8g). The title compound was prepared
from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahy-
dro-1-[[2′-[[[[(1-methylethyl)amino]carbonyl]amino]methyl][1,1′-
biphenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propana-
mide according to the procedure described for 8e. 1H NMR
(200 MHz, CD3OD): δ 1.06 (d, 6.5 Hz, 6H), 1.53 (s, 3H), 1.62
(s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 3.74 (m, 1H), 4.14 (s, 2H),
4.37 (dd; 12, 8 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz,
1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for C32H39N5O3
541; found 542 (M + H, 100).
C
31H37N5O4 543; found 544 (M + H, 80).
2-Am in o-2-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[(a m i-
n oca r bon yl)a m in o]m eth yl][1,1′-bip h en yl]-4-yl]m eth yl]-
2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr iflu or oa c-
etate (8c). 2-Ben zyloxycar bon ylam in o-2-m eth yl-N-[2,3,4,5-
tetr a h yd r o-1-[[2′-[[(a m in oca r bon yl)a m in o]m eth yl][1,1′-
b ip h e n yl]-4-yl]m e t h yl]-2-oxo-1H -b e n za ze p in -3(R )-yl]-
p r op a n a m id e. The title compound was prepared from 2-ben-
zyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-
[[2′-(aminomethyl)[1,1′-biphenyl]-4-yl]methyl]-1H-benzazepin-
3(R)-yl]propanamide, trifluoroacetate and trimethylsilyl iso-
cyanate according to the procedure described for 8e. 1H NMR
(200 MHz, CD3OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60
(m, 3H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00
(s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.43 (m, 17H). FAB-MS:
calculated for C37H39N5O5 633; found 644 (M + H, 100).
2-Am in o-2-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[(a m i-
n oca r bon yl)a m in o]m eth yl][1,1′-bip h en yl]-4-yl]m eth yl]-
2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr iflu or oa c-
et a t e (8c). The title compound was prepared from 2-ben-
zyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-[[2′-
[[(aminocarbonyl)amino]methyl][1,1′-biphenyl]-4-yl]methyl]-2-
oxo-1H-benzazepin-3(R)-yl]propanamide according to the pro-
cedure described for 8e. 1H NMR (200 MHz, CD3OD): δ 1.53
(s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 4.13 (s, 2H),
4.37 (dd, 12, 8 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz,
1H), 7.10-7.41 (m, 12H). FAB-MS: calculated for C29H33N5O3
499; found 500 (M + H, 100).
2-Am in o-2-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[[(et h -
yla m in o)ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8d ). 2-Ben zyloxyca r bon yla m in o-2-m eth -
y l-N -[2,3,4,5-t e t r a h y d r o -1-[[2′-[[[(e t h y la m i n o )c a r -
bon yl]a m in o]m eth yl]-[1,1′-bip h en yl]-4-yl]m eth yl]-2-oxo-
1H-ben za zep in -3(R)-yl]p r op a n a m id e. The title compound
was prepared from 2-benzyloxycarbonylamino-2-methyl-N-
[2,3,4,5-tetrahydro-2-oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-
4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroac-
etate and ethyl isocyanate according to the procedure described
for 8e. 1H NMR (200 MHz, CD3OD): δ 1.03 (t, 7 Hz, 3H), 1.39
(s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 3H), 3.07 (q, 2H), 4.12 (s,
2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15
Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated for
C
39H43N5O5 661; found 662 (M + H, 100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(cyclo-
p r op yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-
yl]m et h yl]-2-oxo-1H -b en za zep in -3(R)-yl]p r op a n a m id e,
Tr iflu or oa cet a t e (8h ). 2-Ben zyloxyca r b on yla m in o-2-
m eth yl-N-[2,3,4,5-tetr ah ydr o-1-[[2′-[[[(cyclopr opylam in o)-
ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]m et h yl]-2-
oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e. Prepared from
2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-
oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-4-yl]methyl]-1H-benza-
zepin-3(R)-yl]propanamide, hydrochloride and cyclopropyl iso-
cyanate (prepared in situ from cyclopropylamine and carbonyl-
1,1′-diimidazole according to the procedure described in for 8e.
1H NMR (200 MHz, CD3OD): δ 0.39 (m, 2H), 0.61 (m, 2H),
1.38 (s, 6H), 1.82 (m, 1H), 2.18-2.58 (m, 4H), 4.18 (s, 2H), 4.32
(m, 1H), 4.86 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.21 (d, 15 Hz, 1H),
7.10 (m, 1H), 7.14-7.40 (m, 16H). FAB-MS: calculated for
C40H43N5O5 673; found 674 (M + H, 70).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(cyclo-
p r op yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-
yl]m et h yl]-2-oxo-1H -b en za zep in -3(R )-yl]p r op a n a m id e,
Tr iflu or oa ceta te (8h ). The title compound was prepared
from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahy-
dro-1-[[2′-[[[(cyclopropylamino)carbonyl]amino]methyl][1,1′-bi-
phenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propana-
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(1-eth -
yla m in o)ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8d ). The title compound was prepared from
2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-
[[2′-[[[(1-ethylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-
yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propanamide accord-
ing to the procedure described for 8e. 1H NMR (200 MHz,
CD3OD): δ 1.05 (t, 7 Hz, 3H), 1.53 (s, 3H), 1.62 (s, 3H), 2.25
(m, 2H), 2.58 (m, 2H), 3.09 (q, 2H), 4.14 (s, 2H), 4.37 (dd, 11,
8 Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10-7.41
(m, 12H). FAB-MS: calculated for C31H37N5O3 527; found 528
(M + H, 100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(1-p r o-
p yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8f). 2-Ben zyloxyca r bon yla m in o-2-m eth yl-
N -[2,3,4,5-t e t r a h y d r o -1-[[2′-[[[(1-p r o p y la m in o )c a r -
bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]m eth yl]-2-oxo-
1H-ben za zep in -3(R)-yl]P r op a n a m id e. The title compound
was prepared from 2-benzyloxycarbonylamino-2-methyl-N-
[2,3,4,5-tetrahydro-2-oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-
4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroac-
etate and 1-propyl isocyanate according to the procedure

1724 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
DeVita et al.
mide according to the procedure described for 8e. 1H NMR
(200 MHz, CD3OD): δ 0.39 (m, 2H), 0.62 (m, 2H), 1.53 (s, 3H),
1.62 (s, 3H), 2.10-2.45 (m, 3H), 2.58 (m, 2H), 4.19 (s, 2H), 4.37
(m, 1H), 4.98 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.08-7.40
(m, 12H). FAB-MS: calculated for C32H37N5O3 539; found 540
(M + H, 80).
The mixture was concentrated under vacuum to 50 mL and
slowly treated with 200 mL of saturated aqueous sodium
bicarbonate. The mixture was washed with hexane (3×) and
the aqueous layer removed and cooled in an ice bath. The
mixture was acidified to pH 2 by slow addition of 6 N HCl
and then extracted with ether (8×). The combined extracts
were washed with brine, dried over magnesium sulfate, and
filtered and solvents removed under vacuum. The residue was
dried at room temperature under vacuum to afford 14.7 g (91.8
mmol, 67%) of a viscous oil that slowly solidified upon
standing. 1H NMR analysis indicates the product is a mixture
of the desired compound and 15% of the isomeric 2,2-dimeth-
ylbutanedioic acid, 1-methyl ester. NMR (200 MHz, CDCl3)
of desired compound: δ 1.29 (s, 6H), 2.60 (s, 2H), 3.66 (s, 3H).
NMR (200 MHz, CDCl3) isomer: d 1.28 (s, 6H), 2.63 (s, 2H),
3.68 (s, 3H).
3-[Ben zyloxyca r bon yla m in o]-3-m eth ylbu ta n oic Acid ,
Meth yl Ester . To 14.7 g (91.8 mmol) of 2,2-dimethylbutane-
dioic acid 4-methyl ester, containing 15% of the isomeric
1-methyl ester compound, in 150 mL of benzene was added
13 mL of triethylamine (9.4 g, 93 mmol, 1.01 equiv) followed
by 21.8 mL of diphenylphosphoryl azide (27.8 g, 101 mmol,
1.1 equiv). The mixture was heated under nitrogen at reflux
for 45 min then 19 mL (19.9 g, 184 mmol, 2 equiv) of benzyl
alcohol was added and refluxing continued for 16 h.
The mixture was cooled and filtered and the filtrate
concentrated to a minimum volume under vacuum. The
residue was redissolved in 250 mL of ethyl acetate and washed
with water, saturated aqueous sodium bicarbonate (2×), and
brine. The organic layer was removed, dried over magnesium
sulfate, and filtered and the filtrate concentrated to a mini-
mum volume under vacuum. The crude product was purified
by medium-pressure liquid chromatography on silica, eluting
with hexane/ethyl acetate (4:1), to afford 18.3 g (68.9 mmol,
75%) of the product as a pale yellow liquid in addition to a
small amount of pure 3-[benzyloxycarbonylamino]-2,2-di-
methylpropanoic acid, methyl ester. 1H NMR (200 MHz,
CDCl3) of major product: δ 1.40 (s, 6H), 2.69 (s, 2H), 3.63 (s,
3H), 5.05 (s, 2H), 5.22 (br s, 1H), 7.32 (s, 5H). 1H NMR (200
MHz, CDCl3) of 3-[benzyloxycarbonylamino]-2,2-dimethylpro-
panoic acid, methyl ester (200 MHz, CDCl3): δ 1.19 (s, 6H),
3.30 (d, 7 Hz, 2H; resonance collapses to singlet in CD3OD),
3.67 (s, 3H), 5.09 (s, 2H), 5.22 (br s; 1H; resonance absent in
CD3OD), 7.3 (br s, 5H).
3-Ben zyloxycar bon ylam in o-3-m eth ylbu tan oic Acid (5c).
A solution of 18.3 g (68.9 mmol) of methyl 3-benzyloxycarbo-
nylamino-3-methylbutanoate in 20 mL of methanol at room
temperature was treated dropwise with 51 mL of 2 N NaOH
(102 mmol, 1.5 equiv). The mixture was stirred at room
temperature for 16 h, transferred to a separatory funnel, and
washed with hexane (3×). The aqueous layer was removed,
cooled to 0 °C, and slowly acidified to pH 2 (paper) by dropwise
addition of 6 N HCl. This mixture was extracted with ether
(6×); combined extracts were washed with 1 N HCl and brine,
then over magnesium sulfate, and filtered, and solvent was
removed under vacuum to afford 17.3 g (68.7 mmol, 99%) of
the product. 1H NMR (200 MHz, CDCl3): δ 1.42 (s, 6H), 2.77
(s, 2H), 5.06 (s, 2H), 5.2 (br s, 1H), 7.3 (s, 5H).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(N,N-
d im eth yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-
4-y l]m e t h y l]-2-o x o -1H -b e n za ze p in -3(R )-y l]p r o p a n a -
m id e, Tr iflu or oa ceta te (8i). 2-Ben zyloxyca r bon yla m in o-
2 -m e t h y l -N -[2 ,3 ,4 ,5 -t e t r a h y d r o -1 -[[2 ′-[[[(N ,N -d i -
m eth yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-
yl]m et h yl]-2-oxo-1H -b en za zep in -3(R)-yl]p r op a n a m id e.
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-
tetrahydro-2-oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-4-yl]me-
thyl]-1H-benzazepin-3(R)-yl]propanamide, hydrochloride and
dimethylcarbamyl chloride according to the procedure de-
scribed for 8b. 1H NMR (200 MHz, CD3OD): δ 1.39 (s, 6H),
1.82 (m, 1H), 2.18-2.58 (m, 3H), 2.81 (s, 6H), 4.20 (d, 5 Hz,
2H), 4.32 (m, 1H), 4.86 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.31 (d, 15
Hz, 1H), 6.40 (t, 5 Hz, 1H), 7.06-7.40 (m, 17H). FAB-MS:
calculated for C39H43N5O5 661; found 662 (M + H, 80).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(N,N-
d im eth yla m in o)ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-
4-y l]m e t h y l]-2-o x o -1H -b e n za ze p in -3(R )-y l]p r o p a n a -
m id e, Tr iflu or oa ceta te (8i). The title compound was pre-
pared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-
tetrahydro-1-[[2′-[[[(N,N-dimethylamino)carbonyl]amino]methyl]-
[1,1′-biphenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]pro-
panamide according to the procedure described for 8e. 1H
NMR (200 MHz, CD3OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25
(m, 2H), 2.58 (m, 2H), 2.83 (s, 6H), 4.22 (s, 2H), 4.38 (dd; 11,
9 Hz; 1H), 4.98 (d, 15 Hz, 1H), 5.20 (d, 15 Hz, 1H), 7.10 (m,
1H), 7.17-7.37 (m, 11H). FAB-MS: calculated for C31H37N5O3
527; found 528 (M + H, 100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(ben -
zyla m in o)ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8j). 2-Ben zyloxyca r bon yla m in o-2-m eth yl-
N -[2 ,3 ,4 ,5 -t e t r a h y d r o -1 -[[2′-[[[(b e n z y l a m i n o )c a r -
bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]m eth yl]-2-oxo-
1H-ben za zep in -3(R)-yl]p r op a n a m id e. The title compound
was prepared from 2-benzyloxycarbonylamino-2-methyl-N-
[2,3,4,5-tetrahydro-2-oxo-1-[[2′-(aminomethyl)[1,1′-biphenyl]-
4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroac-
etate and benzyl isocyanate according to the procedure for 8e.
FAB-MS: calculated for C44H45N5O5 723; found 724 (M + H,
100). 1H NMR (200 MHz, CD3OD): δ 1.38 (s, 6H), 1.82 (m,
1H), 2.15-2.55 (m, 3H), 4.14 (s, 2H), 4.24 (s, 2H), 4.32 (m, 1H),
4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-
7.42 (m, 22H).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(ben -
zyla m in o)ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (8j). The title compound was prepared from
2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-
[[2′-[[[(benzylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-
yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]propanamide accord-
ing to the procedure for 8e. FAB-MS: calculated for C36H39N5O3
589; found 590 (M + H, 80). 1H NMR (200 MHz, CD3OD): δ
1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.58 (m, 2H), 4.17 (s,
2H), 4.26 (s, 2H), 4.37 (dd, 11, 8 Hz; 1H), 4.96 (d, 15 Hz, 1H),
5.20 (d, 15 Hz, 1H), 7.10-7.41 (m, 17H).
3-Am in o-3-m et h yl-N-[2,3,4,5-t et r a h yd r o-1-[[2′-[[[(m e-
th yla m in o)-ca r bon yl]a m in o]m eth yl][1,1′-bip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]bu ta n a m id e, Tr i-
flu or oa cet a t e (8a ). 2,2-Dim et h ylb u t a n ed ioic Acid , 4-
Meth yl Ester . 2,2-Dimethylsuccinic acid (20 g, 140 mmol)
dissolved in 200 mL of absolute methanol at 0° was treated
dropwise with 2 mL of concentrated sulfuric acid. After the
addition was complete, the mixture was allowed to warm to
room temperature and stirred for 16 h.
3-Ben zyloxycar bon ylam in o-3-m eth yl-N-[2,3,4,5-tetr ah y-
d r o-2-oxo-1H-ben za zep in -3(R)-yl]bu ta n a m id e (4c). Pre-
pared from 3-benzyloxycarbonylamino-3-methylbutanoic acid
(4c) and 3(R)-amino-2,3,4,5-tetrahydro-1H-benzazepin-2-one
(3) substituting benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate for benzotriazol-1-yloxytris(dimethylami-
no)phosphonium hexafluorophosphate according to the proce-
dure described for 5a . 1H NMR (200 MHz, CDCl3): δ 1.37 (s,
6H), 1.82 (m, 1H), 2.45-2.75 (m, 4H), 2.86 (m, 1H), 4.49 (m,
1H), 5.05 (dd; 10, 6 Hz; 2H), 5.55 (s, 1H), 6.73 (s, 1H), 6.96 (d,
4 Hz, 1H), 7.10-7.40 (m, 8H), 8.68 (s, 1H). FAB-MS: calcu-
lated for C23H27N3O4 409; found 410 (M + H, 100).
2′-[(ter t-Bu toxyca r bon yla m in o)m eth yl]-1,1′-bip h en yl-
4-m eth a n ol, Aceta te Ester . To solution of 500 mg (1.60
mmol) of 2′-[(tert-butoxycarbonylamino)methyl]-1,1′-biphenyl-
4-methanol in 1 mL of dry methylene chloride under a nitrogen

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1725
atmosphere at room temperature was added by syringe 0.267
mL (1.91 mmol) of triethylamine followed by 0.165 mL (1.76
mmol) of acetic anhydride. The reaction mixture was stirred
for 1 h, diluted with 150 mL of ethyl acetate, washed with
saturated aqueous ammonium chloride, saturated aqueous
sodium bicarbonate, and saturated aqueous sodium chloride,
dried over magnesium sulfate, and filtered. The solvent was
removed under vacuum to give 583 mg (>100%, containing a
minor amount of ethyl acetate) of the product as a white solid
which was used in the next step without further purification.
1H NMR (200 MHz, CDCl3): δ 1.39 (s, 9H), 2.10 (s, 3H), 4.22
(d, 6 Hz, 2H), 4.65 (s, 1H), 5.12 (s, 2H), 7.18-7.48 (m, 8H).
FAB-MS: calculated for C21H25NO4 355; found 356 (M + H).
2′-Am in om eth yl-1,1′-bip h en yl-4-m eth a n ol, Aceta te Es-
ter , Tr iflu or oa ceta te. Prepared from 2′-[(tert-butoxycarbo-
nylamino)methyl]-1,1′-biphenyl-4-methanol, acetate ester ac-
cording to the procedure described for 8e. 1H NMR (200 MHz,
CDCl3): δ 2.03 (s, 3H), 3.98 (s, 2H), 5.07 (s, 2H), 7.18-7.48
(m, 8H), 7.75 (s, 3H). FAB-MS: calculated for C16H17NO2 255;
found 256 (M + H, 80).
3-Am in o-3-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[[[(m eth -
yl-a m in o)ca r b on yl]a m in o]m et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]bu ta n a m id e, Tr i-
flu or oa ceta te (8a ). The title compound was prepared from
3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-1-
[[2′-[[[(methylamino)carbonyl]amino]methyl][1,1′-biphenyl]-4-
yl]methyl]-2-oxo-1H-benzazepin-3(R)-yl]butanamide according
to the procedure described for 8e. 1H NMR (200 MHz, CD3-
OD): δ 1.32 (s, 3H), 1.35 (s, 3H), 2.0-2.35 (m, 2H), 2.40-2.62
(m, 4H), 2.65 (s, 3H), 4.14 (dd; 17, 15 Hz; 2H), 4.40 (dd; 12, 8
Hz; 1H), 4.97 (d, 15 Hz, 1H), 5.21 (d, 15 Hz, 1H), 7.10-7.41
(m, 12H). FAB-MS: calculated for C31H37N5O3 527; found 528
(M + H, 100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[2-[[m e-
t h yla m in oca r b on yl]a m in o]et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (10). 2-ter t-Bu toxyca r bon yla m in o-2-m eth -
yl-N-[2,3,4,5-t et r a h yd r o-2-oxo-1H -b en za zep in -3(R)-yl]-
p r op a n a m id e (5d ). Prepared from N-tert-butoxycarbonyl-
2-methylalanine (4d ) and 3(R)-amino-2,3,4,5-tetrahydro-1H-
1-benzazepin-2-one (3) substituting benzotriazol-1-yloxytripyr-
rolidinophosphonium hexafluorophosphate for benzotriazol-1-
yloxytris(dimethylamino)phosphonium hexafluorophosphate
according to the procedure for 5a . 1H NMR (200 MHz,
CDCl3): δ 1.47 (s, 3H), 1.52 (s, 3H), 1.82 (m, 1H), 2.50-3.00
(m, 3H), 4.45 (m, 1H), 5.05 (s, 2H), 5.37 (s, 1H), 6.80-7.40 (m,
10H), 8.65 (s, 1H). FAB-MS: calculated for C22H25N3O4 395;
found 396 (M + H, 100).
2′-[[(Meth yla m in o)ca r bon yl]a m in o]m eth yl-1,1′-bip h e-
n yl-4-m eth a n ol, Aceta te Ester . Prepared from 2′-amino-
methyl-1,1′-biphenyl-4-methanol, acetate ester, trifluoroac-
etate according to the procedure described for 8e. 1H NMR
(200 MHz, CDCl3): δ 2.10 (s, 3H), 2.65 (d, 4.8 Hz, 3H), 4.27
(d, 4.8 Hz, 2H), 4.52 (m, 1H), 5.12 (s, 2H), 7.18-7.48 (m, 8H).
FAB-MS: calculated for C18H20N2O3 312; found 313 (M + H,
100).
2′-(Cya n om eth yl)-1,1′-bip h en yl-4-m eth a n ol, ter t-Bu tyl-
d ip h en ylsilyl Eth er . To a solution of 1.50 g (3.84 mmol) of
4-(tert-butyldiphenylsilyoxymethyl)phenylboronic acid in 8 mL
of dry dimethylformamide was added 220 mg (0.19 mmol) of
tetrakis(triphenylphosphine) palladium, 1.2 g (5.8 mmol) of
tripotassium phosphate and 0.791 g (4.03 mmol) of 2-bro-
mophenylacetonitrile. The resulting mixture was heated
under nitrogen at 100 °C for 3 h and then cooled to room
temperature. The reaction mixture was diluted with 100 mL
of saturated aqueous ammonium chloride, transferred to a
separatory funnel, and extracted with ether (3 × 150 mL). The
combined ether extracts were washed with saturated aqueous
sodium bicarbonate (100 mL) and saturated aqueous sodium
chloride (100 mL), dried over magnesium sulfate, and filtered.
The solvent was removed under vacuum to give a crude
product which was purified by flash column chromatography
on silica gel eluting with hexanes/ethyl acetate (9:1) to afford
1.3 g (73%) of the product as a clear oil. 1H NMR (200 MHz,
CDCl3): δ 1.10 (s, 9H), 3.82 (s, 2H), 4.82 (s, 2H), 7.18-7.47
(m, 11H), 7.50-7.62 (m, 3H), 7.73 (m, 4H). FAB-MS: calcu-
lated for C31H31NOSi 461; found 462 (M + H, 20).
2′-[[(Meth yla m in o)ca r bon yl]a m in o]m eth yl-1,1′-bip h e-
n yl-4-m eth a n ol. To a solution of 498 mg (1.60 mmol) of 2′-
[[(methylamino)carbonyl]amino]methyl-1,1′-biphenyl-4-metha-
nol, acetate ester in 10 mL of THF/water (3:1) was added 335
mg (7.98 mmol) of lithium hydroxide monohydrate. After 16
h of stirring at room temperature, the reaction mixture was
diluted with 150 mL of ethyl acetate and washed with brine
(3 × 50 mL). The organic layer was dried over magnesium
sulfate and filtered and the solvent removed under vacuum
to afford 411 mg (95%) of the product as a white solid. 1H
NMR (200 MHz, CD3OD): δ 2.64 (s, 3H), 4.20 (s, 2H), 4.62 (s,
2H), 7.12-7.45 (m, 8H). FAB-MS: calculated for C16H18N2O2
270; found 271 (M + H, 100).
2′-[[(Meth yla m in o)ca r bon yl]a m in o]m eth yl-1,1′-bip h e-
n yl-4-m eth a n ol, Meth a n esu lfon a te Ester (6c). To solution
of 100 mg (0.17 mmol) of 2′-[[(methylamino)carbonyl]amino]-
methyl-1,1′-biphenyl-4-methanol (step H) in 5 mL of dry
methylene chloride and 1 mL dry dimethylformamide under
a nitrogen atmosphere at 0 °C was added by syringe 0.077
mL (0.56 mmol) of triethylamine followed by 0.034 mL (0.44
mmol) of methanesulfonyl chloride. The reaction mixture was
stirred for 30 min at 0 °C, diluted with 75 mL of methylene
chloride, washed with water, saturated aqueous sodium
bicarbonate, and saturated aqueous sodium chloride, dried
over sodium sulfate, and filtered. The solvent was removed
under vacuum to give 128 mg (100%) of the product as a white
solid which was used in the next step without further purifica-
tion. 1H NMR (200 MHz, CDCl3): δ 2.66 (d, 4 Hz, 3H), 2.97
(s, 3H), 4.26 (d, 5 Hz, 2H), 4.42 (m, 1H), 5.26 (s, 2H), 7.18-
7.48 (m, 8H). FAB-MS: calculated for C17H20N2O4S 348; found
349 (M + H, 100).
3-Ben zyloxycar bon ylam in o-3-m eth yl-N-[2,3,4,5-tetr ah y-
d r o-1-[[2′-[[[(m eth yl-a m in o)ca r bon yl]a m in o]m eth yl][1,1′-
bip h en yl]-4-yl]m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]bu -
t a n a m id e. Prepared from 3-benzyloxycarbonylamino-3-
methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]-
butanamide (5c) and 2′-[[(methylamino)carbonyl]amino]-
methyl-1,1′-biphenyl-4-methanol, methanesulfonate ester (6c)
according to the procedure described for 8b. 1H NMR (200
MHz, CDCl3): δ 1.33 (s, 6H), 1.78 (m, 1H), 2.37-2.63 (m, 3H),
2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.72 (t, 6
Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15 Hz, 1H),
5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m,
1H). FAB-MS: calculated for C39H43N5O5 661; found 662 (M
+ H, 40).
2′-(Cya n om eth yl)-1,1′-bip h en yl-4-m eth a n ol. Prepared
from 2′-(cyanomethyl)-1,1′-biphenyl-4-methanol, tert-butyl-
diphenylsilyl ether according to the procedure described for
6b. 1H NMR (200 MHz, CDCl3): δ 1.93 (s, 1H), 3.60 (s, 2H),
4.73 (d, 4 Hz, 2H), 7.27 (m, 3H), 7.33-7.63 (m, 5H). FAB-
MS: calculated for C15H13NO 223; found 222 (M - H), 205 (M
- H2O, 100).
2′-(Cya n om et h yl)-1,1′-b ip h en yl-4-m et h a n ol, ter t-b u -
tyld im eth ylsilyl Eth er . To a solution of 145 mg (0.65 mmol)
of 2′-(cyanomethyl)-1,1′-biphenyl-4-methanol in 2 mL of dry
dimethylformamide under a nitrogen atmosphere was added
66 mg (0.97 mmol) of imidazole. The reaction mixture was
cooled to 0 °C, and 117 mg (0.78 mmol) of tert-butyldimeth-
ylsilyl chloride was added. The resulting solution was stirrred
at 0 °C for 15 min and then at room temperature for 16 h.
The reaction mixture was poured into 100 mL of water and
extracted with ether (3 × 35 mL). The combined ether extracts
were washed with water (25 mL), saturated aqueous sodium
bicarbonate (25 mL), and brine (25 mL). The organic layer
was dried over magnesium sulfate and filtered and the solvent
removed under vacuum to give 222 mg (100%) of an oil which
used without further purification. 1H NMR (200 MHz,
CDCl3): δ 0.94 (s, 9H), 3.60 (s, 2H), 4.77 (s, 2H), 7.24 (m, 3H),
7.40 (m, 4H), 7.52 (m, 1H). FAB-MS: calculated for C21H27
-
NOSi 337; found 336 (M - H, 10), 206 (100).

1726 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
DeVita et al.
2′-(2-Am in oeth yl)-1,1′-bip h en yl-4-m eth a n ol. To a solu-
tion of 219 mg (0.65 mmol) of 2′-(2-cyanomethyl)-1,1′-biphenyl-
4-methanol, tert-butyldimethylsilyl ether in 6 mL of dry
methylene chloride under a nitrogen atmosphere was added
501 mg (1.95 mmol) of tetra-n-butylammonium borohydride.
The reaction mixture was heated at reflux for 9 h and cooled
to room temperature and the solvent removed under vacuum
to give an oil which was dissolved in 2 mL of tetrahydrofuran
and treated with 2 mL of 10% aqueous hydrochloric acid. The
resulting solution was heated at reflux for 1 h, cooled in an
ice bath, and treated with 5 N aqueous sodium hydroxide until
pH ) 12. The mixture was extracted with ethyl acetate (3 ×
35 mL). The organic extracts were washed with water (25
mL), saturated aqueous sodium bicarbonate (25 mL), and brine
(25 mL). The organic layer was dried over sodium sulfate and
filtered and the solvent removed under vacuum to give an oil
which was purified by flash column chromatography on silica
gel, eluting with chloroform/10% ammonium hydroxide (33%)
in methanol (9:1) to afford 129 mg (87%) of the product as an
off-white solid. 1H NMR (200 MHz, CD3OD): δ 2.63 (m, 2H),
2.75 (m, 2H), 4.63 (s, 2H), 7.10-7.32 (m, 6H), 7.39 (d, 8 Hz,
2H). FAB-MS: calculated for C15H17NO 227; found 242 (M +
2Li, 100).
2′-[2-[Meth ylam in ocar bon yl]am in o]eth yl-1,1′-biph en yl-
4-m eth a n ol. Prepared from 2′-(2-aminoethyl)-1,1′-biphenyl-
4-methanol according to the procedure described for 6c. 1H
NMR (200 MHz, CDCl3): δ 2.56 (d, 5 Hz, 3H), 2.70 (t, 8 Hz,
2H), 2.89 (t, 5 Hz, 1H), 3.10 (m, 2H), 4.37 (m, 1H), 4.52 (t, 6
Hz, 1H), 4.67 (d, 5 Hz, 2H), 7.12-7.30 (m, 6H), 7.35 (d, 8 Hz,
1H). FAB-MS: calculated for C17H20N2O2 284; found 285 (M
+ H, 100).
2′-[2-[Meth ylam in ocar bon yl]am in o]eth yl-1,1′-biph en yl-
4-m eth a n ol, Meth a n esu lfon a te Ester (6d ). Prepared from
2′-[2-[methylaminocarbonyl]amino]ethyl-1,1′-biphenyl-4-metha-
nol and methanesulfonyl chloride according to the procedure
described for 6c and used in the next step without purification.
2-ter t-Bu t oxyca r b on yla m in o-2-m et h yl-N-[2,3,4,5-t et -
r a h yd r o-1-[[2′-[2-[[m eth yla m in oca r bon yl]a m in o]eth yl]-
[1,1′-b ip h en yl]-4-yl]m et h yl]-2-oxo-1H -b en za zep in -3(R)-
yl]pr opan am ide. Prepared from 2-tert-butoxycarbonylamino-
2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-
yl]propanamide (5d ) and 2′-[2-[methylaminocarbonyl]amino]-
ethyl-1,1′-biphenyl-4-methanol, methanesulfonate ester (6d )
according to the procedure described in for 8b. 1H NMR (200
MHz, CDCl3): δ 1.39 (s, 12H), 1.41 (s, 3H), 1.85 (m, 1H), 2.40-
2.80 (m, 8H), 3.13 (m, 2H), 4.25 (m, 2H), 4.47 (m, 1H), 4.94 (d,
16 Hz, 1H), 4.96 (s, 1H), 5.11 (d, 16 Hz, 1H), 7.08-7.20 (m,
12H). FAB-MS: calculated for C36H45N5O5 627; found 628 (M
+ H, 20), 528 (100).
2-Am in o-2-m eth yl-N-[2,3,4,5-tetr a h yd r o-1-[[2′-[2-[[m e-
t h yla m in oca r b on yl]a m in o]et h yl][1,1′-b ip h en yl]-4-yl]-
m eth yl]-2-oxo-1H-ben za zep in -3(R)-yl]p r op a n a m id e, Tr i-
flu or oa ceta te (10). The title compound was prepared from
2-tert-butoxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-1-
[[2′-[2-[[methylaminocarbonyl]amino]ethyl][1,1′-biphenyl]-4-yl]-
methyl]-2-oxo-1H-benzazepin-3(R)-yl]propanamide according
to the procedure described for 8b. 1H NMR (200 MHz, CD3-
OD): δ 1.53 (s, 3H), 1.62 (s, 3H), 2.25 (m, 2H), 2.59 (m, 5H),
2.67 (t, 7 Hz, 2H), 4.37 (dd; 12, 9 Hz; 1H), 4.96 (d, 15 Hz,1H),
5.21 (d, 15 Hz, 1H), 7.08-7.38 (m, 12H). FAB-MS: calculated
for C31H37N5O3 527; found 528 (M + H, 100).
3-Am in o-3-m et h yl-N-[2,3,4,5-t et r a h yd r o-2-oxo-1-[[2′-
a m in om eth yl-[1,1′-bip h en yl]-4yl]m eth yl]-1H-ben za zepin -
3(R)-yl]bu ta n a m id e, Ditr iflu or oa ceta te (9b). 3-(Ben zyl-
oxycar bon yl)am in o-3-m eth yl-N-[2,3,4,5-tetr ah ydr o-2-oxo-
1-[[2′-[(t er t -b u t o x y c a r b o n y la m i n o )m e t h y l][1,1′-b i -
p h e n yl]-4yl]m e t h yl]-1H -b e n za ze p in -3(R )-yl]b u t a n a -
m id e. The title compound was prepared from 3-(benzyloxy-
carbonyl)amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-
benzazepin-3(R)-yl]butanamide (5c) and 2′-[(tert-butoxycar-
bonylamino)methyl]-1,1-biphenyl-4-methanol methanesulfonate
ester (6b) according to the procedure for 8b. 1H NMR (200
MHz, CDCl3): δ 1.31 (s, 3H), 1.32 (s, 3H), 1.37 (s, 9H), 1.76
(m, 1H), 2.30-2.62 (m, 5H), 4.15 (d, 5 Hz, 2H), 4.40-4.60 (m,
2H), 4.85 (d, 14 Hz, 1H), 4.95 (d, 10 Hz, 1H), 5.04 (d, 10 Hz,
1H), 5.18 (d, 14 Hz, 1H), 5.65 (s, 1H), 6.70 (d, 6 Hz, 1H), 7.10-
7.42 (m, 17H). FAB-MS: calculated for C42H48N4O6 704; found
705 (M + 1, 40).
3-(Ben zyloxyca r b on yl)a m in o-3-m et h yl-N-[2,3,4,5-t et -
r a h yd r o-2-oxo-1-[[2′-a m in om et h yl-[1,1′-b ip h en yl]-4yl]-
m eth yl]-1H-ben za zep in -3(R)-yl]bu ta n a m id e, Tr iflu or o-
a ceta te. The title compound was prepared from 3-(benzyloxy-
carbonyl)amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2′-
[(tert-butoxycarbonylamino)methyl][1,1′-biphenyl]-4-yl]methyl]-
1H-benzazepin-3(R)-yl]butanamide according to the procedure
for 8e. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 2.04 (m,
1H), 2.31 (m, 2H), 2.55 (d, 12 Hz, 1H), 2.62 (m, 2H), 4.08 (s,
2H), 4.42 (dd; 12, 8 Hz; 1H), 5.01 (d, 12 Hz, 1H), 5.07 (d, 14
Hz, 1H), 5.10 (d, 12 Hz, 1H), 5.15 (d, 14 Hz, 1H), 7.20-7.60
(m, 17H). FAB-MS: calculated for C37H40N4O4 604; found 605
(M + 1, 80).
3-Am in o-3-m et h yl-N-[2,3,4,5-t et r a h yd r o-2-oxo-1-[[2′-
a m in om eth yl-[1,1′-bip h en yl]-4yl]m eth yl]-1H-ben za zep in -
3(R)-yl]bu ta n a m id e, Ditr iflu or oa ceta te. The title com-
pound was prepared from 3-(benzyloxycarbonyl)amino-3-
methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2′-aminomethyl[1,1′-
biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]butanamide
1
trifluoroacetate according to the procedure for 8e H NMR (200
MHz, CD3OD): 1.34 (s, 3H), 1.37 (s, 3H), 2.0-2.70 (m, 6H),
4.02 (s, 2H), 4.40 (dd; 13, 7 Hz; 1H), 4.93 (d; 14 Hz; 1H), 5.22
(d; 14 Hz; 1H), 7.1-7.55 (m, 12H). FAB-MS: calculated for
C
29H34N4O2 470; found 471 (M + H, 90).
3-Am in o-3-m et h yl-N-[2,3,4,5-t et r a h yd r o-2-oxo-1-[[2′-
[a ceta m id om eth yl][1,1′-bip h en yl]-4yl]m eth yl]-1H-ben za -
zep in -3(R)-yl]bu ta n a m id e, Tr iflu or oa ceta te (9a ). 3-(Ben -
zyloxyca r bon yl)a m in o-3-m eth yl-N-[2,3,4,5-tetr a h yd r o-2-
oxo-1-[[2′-a cet a m id om et h yl[1,1′-b ip h en yl]-4yl]m et h yl]-
1H-ben za zep in -3(R)-yl]bu ta n a m id e. To a solution of 24 mg
(0.038 mmol) of 3-(benzyloxycarbonyl)amino-3-methyl-N-
[2,3,4,5-tetrahydro-2-oxo-1-[[2′-aminomethyl[1,1′-biphenyl]-4-
yl]methyl]-1H-benzazepin-3(R)-yl]butanamide, trifluoroacetate
dissolved in 1 mL of dry methylene chloride was added by
syringe 0.011 mL (0.076 mmol) of triethylamine followed by
0.005 mL (0.076 mmol) of acetyl chloride. The resulting
mixture was stirred overnight. The reaction mixture was
diluted with 75 mL of ethyl acetate, washed with water,
saturated sodium bicarbonate, and then brine, dried over
magnesium sulfate, and filtered. The solvent was removed
under vacuum to give an oil which was purified by by flash
column chromatography on silica gel eluting with ethyl
acetate/methanol (96:4) to afford 17 mg (71%) of the title
compound as a white solid. 1H NMR (200 MHz, CDCl3): 1.37
(s, 3H), 1.39 (s, 3H), 1.78 (m, 1H), 1.90 (s, 3H), 2.35-2.62 (m,
5H), 4.31 (d, 5 Hz, 2H), 4.50 (m, 1H), 4.90 (d, 14 Hz, 1H), 4.98
(d, 12 Hz, 1H), 5.05 (d, 12 Hz, 1H), 5.17 (d, 14 Hz, 1H), 5.62
(m, 2H), 6.68 (d, 7 Hz, 1H), 7.10-7.70 (m, 17H). FAB-MS:
calculated for C39H42N4O5 646; found 647 (M + 1, 60).
3-Am in o-3-m et h yl-N-[2,3,4,5-t et r a h yd r o-2-oxo-1-[[2′-
[a ceta m id om eth yl][1,1′-bip h en yl]-4yl]m eth yl]-1H-ben za -
zep in -3(R)-yl]bu ta n a m id e, Tr iflu or oa ceta te (9a ). To the
title compound was prepared from 3-(benzyloxycarbonyl)-
amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2′-[acetami-
domethyl[1,1′-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]-
butanamide according to the procedure for 8e 1H NMR (200
MHz, CD3OD): 1.31 (s, 3H), 1.34 (s, 3H), 1.88 (s, 3H), 2.0-
2.68 (m, 6H), 4.20 (s, 2H), 4.40 (dd; 11, 8 Hz; 1H), 4.97 (d, 14
Hz, 1H), 5.24 (d, 14 Hz, 1H), 7.1-7.40 (m, 12H). FAB-MS:
calculated for C31H36N4O3 512; found 513 (M + H, 100).
Ra t P itu ita r y Cell Assa y. Cell Cu ltu r e. Wistar male
rats (150-200 g) were obtained from Charles River Labora-
tories (Wilmington, MA). Rats were maintained at a constant
temperature (25 °C) on a 14-h light, 10-h dark cycle. Rat chow
and water were available ad libitum. Animals were sacrificed
by decapitation and anterior lobes of the pituitary quickly
removed. Rat pituitary cells were isolated from pituitaries by
enzymatic digestion with 0.2% collagenase and 0.2% hyalu-
ronidase in Hank’s Balanced Salt Solution as described previ-
ously.22 For culture, cells were suspended in culture medium

Benzazepinone Growth Hormone Secretagogue
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1727
and adjusted to a final concentration of 1.5 × 105 cells/mL;
1.0 mL of this suspension was placed in each well of a 24-well
tray (Costar; Cambridge, MA). Cells were maintained in a
humidified 5% CO2-95% air atmosphere at 37 °C for 3-4 days.
The culture medium consisted of Dulbecco’s Modified Eagle’s
Medium containing 0.37% NaHCO3, 10% horse serum, 2.5%
fetal bovine serum, 1% nonessential amino acids, 1% glutamine,
1% nystatin, and 0.1% gentamycin.
Exp er im en ts for GH Relea se. On the day of an experi-
ment, cells were washed twice 90 min prior to and once more
immediately before the start of the experiment with the above
culture medium containing 25 mM HEPES, pH 7.4. Stock
solutions of 2 mg/mL of the test agents were prepared in
dimethyl sulfoxide, and serial dilutions in the culture medium
were made from the stock solutions. The final concentration
of DMSO in the assay medium was 1%. GH release was
initiated by adding 1 mL of fresh medium containing test
agents to each well in quadruplicate. Incubation was carried
out at 37 °C for 15 min. After incubation, medium was
removed and centrifuged at 2000g for 15 min to remove any
cellular material. The supernatant fluid was removed and
assayed for GH content.
Ra d ioim m u n oa ssa ys. Rat GH in culture medium was
measured by a double antibody RIA procedure using materials
obtained from Dr. A. F. Parlow (Harbor-UCLA Medical Center,
Torrance, CA) and expressed in terms of the standard rat GH
RP-2.
Da ta An a lyses. ED50 values for test compounds were
computed by fitting a four-parameter logistic function to the
dose-response curve.23 Least squares estimates of the four-
parameter logistic function coefficients and their variances
were derived using the iterative algorithm described by Bates
and Watts.24
the residue was reconstituted in 100 µL of acetonitrile/water
(90:10) and an aliquot of 1-20 µL was analyzed by LC/MS/
MS.
The HPLC system consisted of two Shimadzu LC-600
pumps. an SCL-6B controller, and an SIL-6B autoinjector.
Chromatography was carried out at on a Spheresorb C8 (5 µm,
4.6 × 50 mm) column using isocratic mobile phase consisting
of either (A) 47% acetonitrile/23% methanol/10% 5 mM am-
monium acetate/0.1% formic acid or (B) 90% acetonitrile/30%
5 mM ammonium acetate/0.1% formic acid. The flow rate was
1.0 mL/min.
LC/MS/MS assays were performed on a SCIEX API II
tandem mass spectrometer using the heated nebulizer inter-
face. Mass spectra and production spectra were obtained using
an ionspray interface and positive ion detection was used with
argon as the collision gas. The column effluent was split
(splitter ratio 1:25) such that 4% entered the ion spray
interface.
Areas under the plasma concentration versus time curve
(AUC) were determined by the UNICUE program with linear
trapezoidal interpolation in the ascending slope and logarith-
mic trapezoidal interpolation in the descending slope.25 The
concentration of L-739,943 at to after intravenous dosing was
estimated by the Levenberg/Marquardt nonlinear optimization
algorithm using the RSTRIP Program (MicroMath Scientific
Software). The portion of the AUC from the last measurable
plasma concentration to infinity was estimated by Ct/λ where
Ct represents the last measurable plasma concentration and
λ is the terminal rate constant determined from the plasma
concentration versus time curve by the linear regression of the
elimination phase of the semilogarithmic plot. The portion of
the AUMC from the last measurable plasma concentration to
infinity was estimated by tCt/λ + Ct/λ2. The volume of
distribution at steady state (Vdss), elimination half-life (t1/2),
plasma clearance (Clp), and oral bioavailability (F) were
calculated by the following equations:
In Vivo Effica cy in Bea gle Dogs. Formulations of the
hydrochloride salt of L-739,943 were prepared at 0.10, 0.20,
and 0.40 mg/mL in distilled water. All formulations were
calcultaed as base compound and were administered at 5 mL/
kg of body weight resulting in dosages of 0 (placebo), 0.50, 1.0,
and 2.0 mg/kg of L-739,943.
2
Vdss ) dose × AUMC(0-∞)/AUC(0-∞)
Eight beagle dogs, four male and four female, 3 years of age
and 10-16 kg in weight were used. The four dosages were
allocated to the eight dogs in a crossover design. There was a
7 day interval between each treatment in each dog. Dogs were
fasted for 15 h prior to and during treatment. Treatments
were administered via stomach tube in a volume of water equal
to 5 mL/kg of body weight. Dogs were bled from the jugular
vein at -0.33, 0 (before dosing), 0.33, 0.66, 1.0, 1.5, 2.0, 3.0,
4.0, and 6 h after dosing. From the blood collected at each
sampling, the sera were separated and asayed for GH and
other hormones by RIA.
t1/2 ) 0.693/λ
Clp ) dose/AUC(0-∞)
F (%) ) AUC(po) × dose(iv)/AUC(iv) × dose(po)
The dose was converted to mg of free base/kg in the
calculation of Clp and Vdss. Concentrations lower than the
limit of quantification were treated as zero for the purpose of
calculation of means.
Bioa va ila bility in Bea gle Dogs. In a two period crossover
study, beagle dogs (11.5-16.5 kg body weight) were dosed
orally by gavage with L-739,943 (HCl or TFA salt) at 1.6 mg/
kg or intravenously at 0.16 mg/kg by bolus injection into the
cephalic vein by an indwelling catheter (22 gauge) at 0.16 mg/
kg (all doses calculated as base compound). There was a 7
day interval between each treatment in each dog. Dogs were
bled from the jugular vein into a heparin containing Vacu-
tainer tube at 2.5 min (iv only), 5, 15, and 30 min., and at 1,
2, 4, 6,8, 24, 48, and 72 h after dosing. From the blood collected
at each sampling, plasma was obtained by centrifugation at
2000g for 10 min and stored at -20 °C until analyzed by LC/
MS/MS versus an internal standard.
Concentrations of L-739,943 in plasma were determined
using LC/MS/MS assay following solid-phase extraction (SPE)
on a BondElut Certify cartridge (Varian). An aliquot of plasma
was mixed with 20 ng of an internal standard and acidified
with an equal volume of 1% phosphoric acid. The resulting
mixture was applied to the SPE cartridge which had been
preconditioned with 2.5 mL of methanol followed by 2 mL of
water and 2 mL of 0.1 M phosphate buffer, pH 2.5. After
washing with 2 mL of water, the cartridge was eluted with
methanol containing 5% ammonium hydroxide. The methanol
extract was dried under nitrogen at room temperature and
Ack n ow led gm en t. We would like to thank Dr.
Lawrence Colwell and Ms. Amy Bernick for providing
mass spectrometry services; Mr. Glen Reynolds and Mr.
J oe Leone for preparation of several synthetic interme-
diates; and Dr. Mark Goulet, Dr. Tom Walsh, and Mr.
David Krupa for assistance with the manuscript.
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