Benzo-fused lactams promote release of growth hormone

There are disclosed certain novel compounds identified as benzo-fused lactams which promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to increase the stature of those afflicted with a lack of a normal secretion of natural growth hormone. The compounds are prepared by substitution of an amino-lactam with a substituted amide function. Growth promoting compositions containing such bezno-fused lactams as the active ingredient thereof are also disclosed. ##STR1## where L is ##STR2##

BACKGROUND OF THE INVENTION 
Growth hormone, which is secreted from the pituitary, stimulates growth of 
all tissues of the body that are capable of growing. In addition, growth 
hormone is known to have the following basic effects on the metabolic 
process of the body: 
1. Increased rate of protein synthesis in all cells of the body; 
2. Decreased rate of carbohydrate utilization in cells of the body; 
3. Increased mobilization of free fatty acids and use of fatty acids for 
energy. 
A deficiency in growth hormone secretion can result in various medical 
disorders, such as dwarfism. 
Various ways are known to release growth hormone. For example, chemicals 
such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, 
vasopressin, and insulin induced hypoglycemia, as well as activities such 
as sleep and exercise, indirectly cause growth hormone to be released from 
the pituitary by acting in some fashion on the hypothalamus perhaps either 
to decrease somatostatin secretion or to increase the secretion of the 
known secretagogue growth hormone releasing factor (GRF) or an unknown 
endogenous growth hormone-releasing hormone or all of these. 
In cases where increased levels of growth hormone were desired, the problem 
was generally solved by providing exogenous growth hormone or by 
administering an agent which stimulated growth hormone production and/or 
release. In either case the peptidyl nature of the compound necessitated 
that it be administered by injection. Initially the source of growth 
hormone was the extraction of the pituitary glands of cadavers. This 
resulted in a very expensive product and carried with it the risk that a 
disease associated with the source of the pituitary gland could be 
transmitted to the recipient of the growth hormone. Recently, recombinant 
growth hormone has become available which, while no longer carrying any 
risk of disease transmission, is still a very expensive product which must 
be given by injection or by a nasal spray. 
Other compounds have been developed which stimulate the release of 
endogenous growth hormone such as analogous peptidyl compounds related to 
GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while 
considerably smaller than growth hormones are still susceptible to various 
proteases. As with most peptides, their potential for oral bioavailability 
is low. The instant compounds are non-peptidyl agents for promoting the 
release of growth hormone which may be administered parenterally, nasally 
or by the oral route. 
SUMMARY OF THE INVENTION 
The instant invention covers certain benzo-fused lactam compounds which 
have the ability to stimulate the release of natural or endogenous growth 
hormone. The compounds thus have the ability to be used to treat 
conditions which require the stimulation of growth hormone production or 
secretion such as in humans with a deficiency of natural growth hormone or 
in animals used for food production where the stimulation of growth 
hormone will result in a larger, more productive animal. Thus, it is an 
object of the instant invention to describe the benzo-fused lactam 
compounds. It is a further object of this invention to describe procedures 
of the preparation of such compounds. A still further object is to 
describe the use of such compounds to increase the secretion of growth 
hormone in humans and animals. A still further object of this invention is 
to describe compositions containing the benzo-fused lactam compounds for 
the use of treating humans and animals so as to increase the level of 
growth hormone secretions. Further objects will become apparent from a 
reading of the following description.

DESCRIPTION OF THE INVENTION 
The novel benzo-fused lactams of the instant invention are best described 
in the following structural formula I: 
##STR3## 
where L is 
##STR4## 
n is 0 or 1; p is 0 to 3; 
q is 0 to 4; 
w is 0 or 1; 
X is C.dbd.O, O, S(O).sub.m, 
##STR5## 
--CH.dbd.CH--; m is 0 to 2; 
R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are 
independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 
perfluoroalkyl, hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 
-C.sub.3 perfluoroalkyl, R.sup.7b O(CH.sub.2).sub.v --, R.sup.7b 
COO(CH.sub.2).sub.v --, R.sup.7b OCO(CH.sub.2).sub.v --, R.sup.4 R.sup.5 
N(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.4)(CH.sub.2).sub.v --, R.sup.4 
R.sup.5 NCO(CH.sub.2).sub.v --, phenyl or substituted phenyl where the 
substituents are from 1 to 3 or halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 
-C.sub.6 alkoxy, or hydroxy; R.sup.7a and R.sup.7b are independently 
hydrogen, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, 
substituted C.sub.1 -C.sub.6 alkyl, whee the substituents are phenyl or 
substituted phenyl; phenyl or substituted phenyl where the phenyl 
substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 
-C.sub.6 alkoxy, or hydroxy and v is 0 to 3; 
R.sup.3a and R.sup.3b are independently hydrogen or E-R.sup.9, with the 
proviso that either R.sup.3a or R.sup.3b must be other than hydrogen; 
E is --(CH.sub.2).sub.v --; 
--(CH.sub.2).sub.v N(R.sup.10)--, 
--(CH.sub.2).sub.v N(R.sup.10)CO(CH.sub.2).sub.y --, 
--(CH.sub.2).sub.v N(R.sup.10)COO(CH.sub.2).sub.y --, 
--(CH.sub.2).sub.v N(R.sup.10)CON(R.sup.11)(CH.sub.2).sub.y --, 
--(CH.sub.2).sub.v N(R.sup.10)CSN(R.sup.11)(CH.sub.2).sub.y --, 
--(CH.sub.2).sub.v OC(O)(CH.sub.2).sub.y --, or ----(CH.sub.2).sub.v 
OCON(R.sup.10)(CH.sub.2).sub.y --, 
and v and y are independently 0 to 3; 
R.sup.9 is: 
##STR6## 
where K is O, S, or NR.sup.13 and provided that when R.sup.9 is a 
tetrazole, E is other than --(CH.sub.2).sub.v, 
R.sup.4 and R.sup.5 are independently hydrogen, phenyl, substituted phenyl, 
C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, C.sub.3 
-C.sub.10 alkenyl, substituted C.sub.3 -C.sub.10 alkenyl, C.sub.3 
-C.sub.10 alkynyl, or substituted C.sub.3 -C.sub.10 alkynyl where the 
substituents on the phenyl, alkyl, alkenyl or alkynyl are from 1 to 5 of 
hydroxy, C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, fluoro, 
R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 
alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 
-C.sub.20 -alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, 
or --NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently 
hydrogen, C.sub.1 -C.sub.6 alkyl, phenyl, phenyl C.sub.1 -C.sub.6 alkyl, 
C.sub.1 -C.sub.5 -alkoxycarbonyl, or C.sub.1 -C.sub.5 -alkanoyl- C.sub.1 
-C.sub.6 alkyl; or R.sup.4 and R.sup.5 can be taken together to form 
--(CH.sub.2).sub.r B(CH.sub.2).sub.s -- where B is CHR.sup.1, O, 
S(O).sub.m or N-R.sup.10, r and s are independently 1 to 3 and R.sup.1 and 
R.sup.10 are as defined above; 
R.sup.12a and R.sup.12b are independently hydrogen, hydroxy, halogen, oxo, 
cyano, nitro, --S(O).sub.m R.sup.7a, C.sub.1 -C.sub.3 perfluoroalkyl, 
C.sub.1 -C.sub.3 perfluoroalkoxy, R.sup.4 R.sup.4 N(CH.sub.2).sub.v --, 
R.sup.7b CON(R.sup.4) (CH.sub.2).sub.v --, R.sup.4 R.sup.5 
NCO(CH.sub.2).sub.v --, C.sub.1 -C.sub.6 alkoxy, phenyl, substituted 
phenyl, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, 
where the substituents on the phenyl or alkyl are from 1 to 5 of hydroxy, 
C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, fluoro, R.sup.1, 
R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 
R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.6 
alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or 
--NR.sup.10 R.sup.11, where R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.7a, 
R.sup.7b, R.sup.10 and R.sup.11 are as defined above; 
R.sup.13 is hydrogen, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 
alkyl, where the substituents are from 1 to 3 of hydroxy, C.sub.1 -C.sub.6 
alkoxy, fluoro, R.sup.1, R.sup.2 independently disubstituted phenyl 
C.sub.1 -C.sub.3 alkoxy, R.sup.1, R.sup.2 independently disubstituted 
phenyl, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, 
carboxy, --NR.sup.10 R.sup.11, where R.sup.1, R.sup.2, R.sup.10 and 
R.sup.11 are as defined above, R.sup.1, R.sup.2 independently 
disubstituted phenyl or C.sub.1 -C.sub.5 alkanoyl-C.sub.1 -C.sub.6 alkyl; 
R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl or phenyl C.sub.1 
-C.sub.10 alkyl; 
A is 
##STR7## 
where x and y are independently 0-3; R.sup.8 and R.sup.8a are 
independently hydrogen, C.sub.1 -C.sub.10 alkyl, trifluoromethyl, phenyl, 
substituted C.sub.1 -C.sub.10 alkyl where the substituents are from 1 to 3 
of imidazolyl, indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 
-C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, R.sup.1, R.sup.2 
independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, 
R.sup.2 independently disbustituted phenyl, C.sub.1 -C.sub.5 -alkanoyloxy, 
C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, or --NR.sup.10 R.sup.11 
where R.sup.10 and R.sup.11 are as defined above; or R.sup.8 and R.sup.8a 
can be taken together to form --(CH.sub.2).sub.t -- where t is 2 to 6; and 
R.sup.8 and R.sup.8a can independently be joined to one or both of R.sup.4 
and R.sup.5 to form alkylene bridges between the terminal nitrogen and the 
alkyl portion of the A group wherein the bridge contains from 1 to 5 
carbon atoms; and pharmaceutically acceptable salts thereof. 
In the above structural formula and throughout the instant specification, 
the following terms have the indicated meanings: 
The alkyl groups specified above are intended to include those alkyl groups 
of the designated length in either a straight or branched configuration. 
Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, 
butyl, sec-butyl, tertiary butyl, phenyl, isopentyl, hexyl, isohexyl, and 
the like. 
The alkoxy groups specified above are intended to include those alkoxy 
groups of the designated length in either a straight or branched 
configuration. Exemplary of such alkoxy groups are methoxy, ethoxy, 
propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, 
isopentoxy, hexoxy, isohexoxy and the like. 
The term "halogen" is intended to include the halogen atom fluorine, 
chlorine, bromine and iodine. 
Certain of the above defined terms may occur more than once in the above 
formula and upon such occurrence each term shall be defined independently 
of the other. 
It is intended that the connecting group E can be bonded to any of the 
available carbon or heteroatoms of the heteroaromatic groups of R.sup.9, 
including both rings of the benzo-fused heterocyclic groups, when the 
bonding is represented by a serpentine line. 
In addition, it is well known to those skilled in the art that many of the 
foregoing heterocyclic groups can exist in more than one tautomeric form. 
It is intended that all such tautomers be included within the ambit of 
this invention. 
Preferred compounds of the instant invention are realized when in the above 
structural formula: 
n is 0 or 1; 
p is 0 to 3; 
q is 0 to 2; 
w is 0 or 1; 
X is 0, S(O).sub.m, 
##STR8## 
m is 0 to 2; R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b 
are independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 
-C.sub.3 perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v 
--, R.sup.7b COO(CH.sub.2).sub.v --, R.sup.7b OCO(CH.sub.2).sub.v --, 
phenyl or substituted phenyl where the substituents are from 1 to 3 of 
halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or hydroxy; 
R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.3 
perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 
alkyl, where the substituents are phenyl; phenyl and v is 0 to 2; 
R.sup.3a and R.sup.3b are as defined above; 
R.sup.4 and R.sup.5 are independently hydrogen, phenyl, substituted phenyl, 
C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 -C.sub.10 alkyl, where the 
substituents on the alkyl or phenyl are from 1 to 5 of hydroxy, C.sub.1 
-C.sub.6 alkoxy, C.sub.3 -C.sub.7 cycloalkyl, fluoro, R.sup.1, R.sup.2 
independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, R.sup.1, 
R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.20 
-alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or formyl; 
R.sup.4 and R.sup.5 can be taken together to form --(CH.sub.2).sub.r 
B(CH.sub.2).sub.s -- where B is CHR.sup.1, O, S(O).sub.m or N--R.sup.10 ; 
r and s are independently 1 to 3 and R.sup.1 and R.sup.10 are as defined 
above; 
R.sup.6 is hydrogen, C.sub.1 -C.sub.10 alkyl or phenyl C.sub.1 -C.sub.10 
alkyl; 
A is 
##STR9## 
where x and y are independently 0-2; R.sup.8 and R.sup.8a are 
independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 
-C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, 
indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, 
R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 
-alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy, formyl, 
--NR.sup.10 R.sup.11 where R.sup.10 and R.sup.11 are independently 
hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.1 -C.sub.5 alkanoyl-C.sub.1 
-C.sub.6 alkyl; or R.sup.8 and R.sup.8a can be taken together to form 
--(CH.sub.2).sub.t -- where t is 2 to 4; and R.sup.8 and R.sup.8a can 
independently be joined to one or both of R.sup.4 and R.sup.5 to form 
alkylene bridges between the terminal nitrogen and the alkyl portion of 
the A group wherein the bridge contains from 1 to 5 carbon atoms; 
and pharmaceutically acceptable salts thereof. 
Additional preferred compounds are realized in the above structural formula 
when: 
n is 0 or 1; 
p is 0 to 2; 
q is 0 to 2; 
w is 0 or 1; 
X is S(O).sub.m or --CH.dbd.CH--; 
m is 0 or 1; 
R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are 
independently hydrogen, halogen, C.sub.1-C.sub.7 alkyl, C.sub.1 -C.sub.3 
perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v --, 
R.sup.7b COO(CH.sub.2).sub.v --, R.sup.7b OCO(CH.sub.2).sub.v --, phenyl 
or substituted phenyl where the substituents are from 1 to 3 or halogen, 
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or hydroxy; 
R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.6 alkyl, 
substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl and 
v is 0 to 2; 
R.sup.3a and R.sup.3b are as defined above; 
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, 
substituted C.sub.1 -C.sub.10 alkyl, where the substituents on the alkyl 
are from 1 to 5 of hydroxy, C.sub.1 -C.sub.6 alkoxy, fluoro, R.sup.1, 
R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.20 
-alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl or carboxy; 
R.sup.6 is hydrogen or C.sub.1 -C.sub.10 alkyl; 
A is 
##STR10## 
where x and y are independently 0-2; R.sup.8 and R.sup.8a are 
independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 
-C.sub.10 alkyl where the substituents are from 1 to 3 or imidazolyl, 
indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1-C.sub.6 alkoxy, 
R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 
-alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; or R.sup.8 and 
R.sup.8a and R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- 
where t is 2; or R.sup.8 and R.sup.8a can independently be joined to one 
or both of R.sup.4 and R.sup.5 to form alkylene bridges between the 
terminal nitrogen and the alkyl portion of the A group wherein the bridge 
contains from 1 to 5 carbon atoms; and pharmaceutically acceptable salts 
thereof. 
Still further preferred compounds of the instant invention are realized in 
the above structural formula when; 
n is 0 or 1; 
p is 0 to 2; 
q is 1; 
w is 1; 
X is S(O).sub.m or --CH.dbd.CH--; 
m is 0 or 1; 
R.sup.1, R.sup.2, R.sup.1a, R.sup.2a, R.sup.1b, and R.sup.2b are 
independently hydrogen, halogen, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.3 
perfluoroalkyl, --S(O).sub.m R.sup.7a, R.sup.7b O(CH.sub.2).sub.v --, 
R.sup.7b COO(CH.sub.2).sub.v --, phenyl or substituted phenyl where the 
substituents are from 1 to 3 of halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 
-C.sub.6 alkoxy, or hydroxy; 
R.sup.7a and R.sup.7b are independently hydrogen, C.sub.1 -C.sub.6 alkyl, 
substituted C.sub.1 -C.sub.6 alkyl, where the substituents are phenyl, and 
v is 0 or 1; 
R.sup.3a and R.sup.3b are as defined above. 
R.sup.4 and R.sup.5 are independently hydrogen, C.sub.1 -C.sub.10 alkyl, 
substituted C.sub.1 -C.sub.10 alkyl, where the substituents on the alkyl 
are from 1 to 3 of hydroxy, C.sub.1 -C.sub.3 alkoxy, fluoro, R.sup.1, 
R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.20 alkanoyloxy, 
C.sub.1 -C.sub.5 alkoxycarbonyl or carboxy; 
R.sup.6 is hydrogen; 
A is 
##STR11## 
where x and y are independently 0-1; R.sup.8 and R.sup.8a are 
independently hydrogen, C.sub.1 -C.sub.10 alkyl, substituted C.sub.1 
-C.sub.10 alkyl where the substituents are from 1 to 3 of imidazolyl, 
indolyl, hydroxy, fluoro, S(O).sub.m R.sup.7a, C.sub.1 -C.sub.6 alkoxy, 
R.sup.1, R.sup.2 independently disubstituted phenyl, C.sub.1 -C.sub.5 
-alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy; or R.sup.8 and 
R.sup.8a can be taken together to form --(CH.sub.2).sub.t -- where t is 2; 
and R.sup.8 and R.sup.8a can independently be joined to one or both of 
R.sup.4 and R.sup.5 to form alkylene bridges between the terminal nitrogen 
and the alkyl portion of the A group wherein the bridge contains from 1 to 
5 carbon atoms; and pharmaceutically acceptable salts thereof. 
Representative preferred growth hormone releasing compounds of the present 
invention include the following: 
1. 3-[2(S),3-Dihydroxypropyl)amino-3-methyl-N-[2,3,4, 
5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1 
H-1-benzazepin-3(R)-yl]-butanamide 
2. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(1H-imidazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-but 
anamide 
3. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-([2,3,4,5-tetrahydro-2-oxo-1-[[ 
2'-(1H-imidazol-4-yl)(1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]- 
butanamide 
4. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(1H-1,2,3-triazol-4yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl] 
-butanamide 
5. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R) 
-yl]-butanamide 
6. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(1H-1,2,4-triazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl 
]-butanamide 
7. 
3-[2(S),3-Dihydroxypropyl)amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-(1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R) 
-yl]-butanamide 
8. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[(4,5-dihydro-2-oxazolyl)-amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepi 
n-3(R)-yl]-butanamide 
9. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-[(4,5-dihydro-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazep 
in-3(R)-yl]-butanamide 
10. 
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[ 
(1H-imidazol-4-yl)-acetamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benza 
zepin-3(R)-yl]-butanamide 
11. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-[[(1H-imidazol-4-yl)acetamido]methyl][1,1'-biphenyl]-4-yl]-methyl]-1H-1-b 
enzazepin-3(R)-yl]-butanamide 
12. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro-1H-imida 
zol-2-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butana 
mide 
13. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[4,5-dihydro-1H-imidazol-2-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benza 
zepin-3(R)-yl]-butanamide 
14. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-[(4,5-dihydro-1H-imidazoyl-2-yl)amino][1,1'-biphenyl]-4-yl]-methyl]-1H-1- 
benzazepin-3(R)-yl]-butanamide 
15. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(1H-imidazol-2-yl)ami 
no][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butanamide 
16. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[(1H-imidazol-2-yl)amino]-[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R) 
-yl]-butanamide 
17. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-[(1H-imidazol-2-yl 
amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
18. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(1H-tetrazol-5-yl)ami 
no][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
19. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[(1H-tetrazol-5-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)- 
yl]-butanamide 
20. 3-[2(S), 
3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(1H-t 
etrazol-5-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-bu 
tanamide 
21. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(4,5-dihydro-5-oxo-1H- 
1,2,4-triazol-1-yl)-[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-b 
utanamide 
22. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1- 
benzazepin-3(R)-yl]-butamide 
23. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2 
'-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)[1,1'-biphenyl]-4-yl]-methyl]-1H 
-1-benzazepin-3(R)-yl]-butanamide 
24. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(4,5-dihydro-3,5-dioxo 
-1,2,4-triazin-2(3H)-yl[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl 
]-butanamide 
25. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)[1,1'-bipenyl]-4-yl]methyl]-1 
H-1-benzazepin-3(R)-yl]-butanamide 
26 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[2' 
-[(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)[1,1'-biphenyl]-4-yl]methyl 
]-1H-1-benzazepin-3(R)-yl]-butanamide 
27. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-2-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
28. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-4-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
29. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,3-triazol-4-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl-propanamide 
30. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,4-triazol-3-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
31. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro-2-oxazol 
yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
32. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[(1H-imidazol-4-yl)ac 
etamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propan 
amide 
33. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(4,5-dihydro-3,5-dioxo 
-1,2,4-triazin-2-(3H)-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)- 
yl]-propanamide 
34. 
2-Amino-2-methyl-N-[2,3,4,5-tetahydro-2-oxo-1-[[2'-(4,5-dihydro-5-oxo-1H-1 
,2,4-triazol-1-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-pro 
panamide 
35. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(1H-imidazol-2-yl)ami 
no][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
36. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(1H-tetrazol-5-yl)ami 
no][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propanamide 
37. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro-1H-imida 
zol-2-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-propan 
amide 
38. 
3-Amino-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H- 
imidazol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanam 
ide 
39. 
3-Amino-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H- 
imidazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanam 
ide 
40. 
3-Amino-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H- 
1,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-bu 
tanamide 
41. 
3-Amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,4-tri 
azol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-outanamide 
42. 
3-Amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro 
-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-but 
anamide 
43. 
3-Amino-3-methyl-N-[7-fluoro-2,3,4-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-4- 
yl)acetamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-b 
utanamide 
44. 3-[2(S), 
3-Dihydroxypropyl]amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo-1-[[ 
2'-(1H-imidazol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]- 
butanamide 
45. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetrah 
ydro-2-oxo-1-[[2'-(1H-imidazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benza 
zepin-3(R)-yl]-butanamide 
46. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-ox 
o-1-[[2'-(1H-1,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepi 
n-3(R)-yl]-butanamide 
47. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2- 
oxo-1-[[2'-(1H-1,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaze 
pin-3(R)-yl]-butanamide 
48. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-trifluoromethyl-1,2,3,4,5-tetr 
ahydro-2-oxo-1-[[2'-(1H-1,2,4-triazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-1H- 
1-benzazepin-3(R)-yl]-butanamide 
49. 
3-[2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo 
-1-[[2'-[(4,5-dihydro-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-be 
nzazepin-3(R)-yl]-butanamide 
50. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[7-trifluoromethyl-1,2,3,4,5-te 
trahydro-2-oxo-1-[[2-[(4,5-dihydro-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]me 
thyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
51. 
3-[2(S),3-Dihydroxypropyl]amino-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetr 
ahydro-2-oxo-1-[[2'-[[(1H-imidazol-4-yl)acetamido]methyl][1,1'-biphenyl]-4- 
yl]methyl]-1H-1-benzazepin-3-(R)-yl]-butanamide 
52. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-ox 
o-1-[[2'-[(1H-imidazol-2-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaze 
pin-3(R)-yl]-butanamide 
53. 
3-[2(S),3-Dihydroxyproyl]amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-o 
xo-1-[[2'-(1H-tetrazol-5-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaze 
pin-3(R)-yl]-butanamide 
54. 
3-[2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-2-oxo 
-1-[[2'-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)[1,1'-biphenyl]-4-yl]methy 
l]-1H-1-benzazepin-3(R)-yl]-butanamide 
55. 3-[2(S), 
3-Dihydroxypropyl]amino-3-methyl-N-[7-trifluoromethyl-2,3,4,5-tetrahydro-2 
-oxo-1-[[2'-(4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl)[1,1'-biphenyl]-4-yl]m 
ethyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
56. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[7-methoxy-2,3,4,5-tetrahydro-2-o 
xo-1-[[2'-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)[1,1'-biphenyl]-4-y 
l]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
57. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-imidazol-2-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide 
58. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-imidazol-4-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide 
59. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-1,2,3-triazol-4-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide 
60. 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-[4,5-dihydro-2-oxazoly 
l)amino][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide 
61. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'- 
(1H-imidazol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]- 
butanamide 
62. 
3-Amino-3-methyl-N-2,3,4,5-tetrahydro-4-oxo-5-[[2'-[[(1H-imidazol-4-yl)ace 
tamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-buta 
namide 
63. 
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-[[ 
(1H-imidazol-4-yl)acetamido]methyl][[1,1'-biphenyl]-4-yl]methyl]-1,5-benzot 
hiazepin-3(S)-yl]-butanamide 
64. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'- 
(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S 
)-yl]-butanamide 
65. 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'- 
[(4,5-dihydro-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiaze 
pin-3(S)-yl]-butanamide 
66. 
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[7-fluoro-2,3,4,5-tetrahydro-4-oxo- 
5-[[2'-[[(1H-imidazol-4-yl)-acetamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1 
,5-benzothiazepin-3(S)-yl]-butanamide 
67. 3-[2(S), 
3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-[[(1H- 
imidazol-4-yl)acetamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiaze 
pin-3(S)-yl]-butanamide 
68. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-imidazol-2-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]propanamide 
69. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-imidazol-4-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-propanamide 
70. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1H-1,2,3-triazol-4-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-propanamide 
71. 
2Amino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-[[(1H-imidazol-4-yl)ace 
tamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-prop 
anamide 
72. 
2-Amino-2-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-[(4,5-dihydro-5-oxo-1H 
-1,2,4-triazol-1-yl)amino][1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3 
(S)-yl]-propanamide 
Representative examples of the nomenclature employed are given below: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(thizaol-2-yl)[1,1'-bip 
henyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
##STR12## 
N-[1-[[2'-[[(Thiazol-2-yl)aminocarbonyl]amono][1,1'-biphenyl]-4-yl]methyl] 
- 
7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-2-amino-2-methyl 
propanamide 
##STR13## 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[ 
(4,5-dihydro-2-thiazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin 
-3(R)-yl]-butanamide 
##STR14## 
3-[(2(S),3-Dihydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro 
3-[(2(S),3-Dihydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro 
[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]-butanamide 
##STR15## 
The compounds of the instant invention all have at least one asymmetric 
center as noted by the asterisk in the structural Formula I above. 
Additional asymmetric centers may be present on the molecule depending 
upon the nature of the various substituents on the molecule. Each such 
asymmetric center will produce two optical isomers and it is intended that 
all such optical isomers, as separated, pure or partially purified optical 
isomers or racemic mixtures thereof, be included within the ambit of the 
instant invention. In the case of the asymmetric center represented by the 
asterisk in Formula I, it has been found that the compound in which the 
3-amino substituent is above the plane of the structure, as seen in 
Formula Ia, is more active and thus more preferred over the compound in 
which the 3-amino substituent is below the plane of the structure. In the 
substituent (X).sub.n, when n=0, the asymmetric center is designated as 
the R-isomer. When n=1, this center will be designated according to the 
R/S rules as either R or S depending upon the value of X. 
##STR16## 
The instant compounds are generally isolated in the form of their 
pharmaceutically acceptable acid addition salts, such as the salts derived 
from using inorganic and organic acids. Examples of such acids are 
hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, 
trifluoroaetic, propionic, maleic, succinic, malonic and the like. In 
addition, certain compounds containing an acidic function such as a 
carboxy can be isolated in the form of their inorganic salt in which the 
counterion can be selected from sodium, potassium, lithium, calcium, 
magnesium and the like, as well as from organic bases. 
The compounds (I) of the present invention are prepared from aminolactum 
intermediates such as those of formula II. The preparation of these 
intermediates is described in the following reaction Schemes. 
##STR17## 
Benzo-fused lactams 3 wherein the lactam is a seven-membered ring are 
conveniently prepared from substituted tetralones 2 using known 
procedures. The substituted tetralones are, in some cases, commercially 
available or are prepared from a suitably substituted derivative of 
4-phenylbutyric acid 1. Cyclization of 1 can be achieved by a number of 
methods well known in the literature including treatment with 
polyphosphoric acid at elevated temperatures as shown in Scheme 1. 
##STR18## 
Conversion of substituted tetralones 2 to benzolactams 3 can be achieved by 
a number of methods familiar to those skilled in the art. A suitable 
method involves the use of hydrazoic acid (Schmidt reaction) to form the 
substituted benzolactam 3. 
Benzo-fused lactams wherein the lactam is an eight-membered ring (6) are 
prepared as described by D. E. Jones, et al, J. Chem. Soc. C, 2176-2181 
(1969) by an analogous series of transformations starting from a 
substituted derivative of 5-phenylpentanoic acid 4 as shown in Scheme 2. 
##STR19## 
As shown in Scheme 3, 3-aminobenzolactam analogs wherein the lactam is a 
six-membered ring (11) are prepared from a substituted derivative of 
2-nitrobenzyl chloride (or bromide) 7 by the method of A. L. David, et al, 
Arch. Biochem. Biophys, 102, 48-51 (1963) and reference cited therein. 
##STR20## 
Conversion of substituted benzo-fused lactams to the requisite 3-amino 
derivatives can be achieved by a number of methods familiar to those 
skilled in the art, including those described by Watthey, et al, J. Med. 
Chem., 28, 1511-1516 (1985) and reference cited therein. One common route 
proceeds via the intermediacy of a 3-halo (chloro. bromo or iodo) 
intermediate which is subsequently displaced by a nitrogen nucleophils, 
typically azide. A useful method of forming the 3-iodobenzolactam 
intermediate 12 involves treating the benzolactam with two equivalents 
each of iodotrimethylisilane and iodine at low temperature, as illustrated 
in Scheme 4 for the seven-membered ring analog 3. 
##STR21## 
Elaboration of the iodo-benzolactams to the desired aminolactam 
intermediates II is achieved by a two-step procedure illustrated in Scheme 
4. Typically, iodo-benzolactams 12 are treated with sodium azide in 
N,N-dimethylformamide at 50.degree.-100.degree. C. to give the 3-azido 
derivatives 13. Alternatively, tetramethylguanidinium azide in a solvent 
such as methylene chloride can be employed to achieve similar results. 
Hydrogenation with a metal catalyst, such as platinum on carbon, or 
alternatively, treatment with triphenylphosphine in wet toluene, results 
in formation of the amine derivative 14. Formation of the analogous 
derivatives of the eight-membered benzolactams is also achieved by the 
routes shown in Scheme 4. 
Chiral aminobenzolactams are obtained by resolution of the racemates by 
classical methods familiar to those skilled in the art. For example, 
resolution can be achieved by formation of diastereomeric salts of the 
racemic amines with optically active acids such as D- and L-tartaric acid. 
Determination of absolute stereochemistry can be achieved in a number of 
ways including X-ray analysis of a suitable crystalline derivative. 
A useful preparation of the chiral intermediate 19 is shown n Scheme 5. 
##STR22## 
Conversion of 1-tetralone to the seven-membered benzolactam 16 is achieved 
by Beckman rearrangement of the intermediate oxime 15. rearrangement of 
the intermediate oxime 15. gives the 3-iodo derivative 17 which is 
sequentially treated with ammonia and D-tartaric acid to give the 
diastereomeric D-tartrate salt 18 after recrystallization. Liberation of 
the free amine 19 is achieved by neutralization of the D-tartrate salt 
with potassium carbonate followed by extractive isolation. 
Intermediates of Formula II wherein X is a sulfur atom are prepared by 
methods described in the literature and known to those skilled in the art. 
As illustrated in Scheme 6, the seven-membered ring analog 27 is prepared 
from a protected derivative of cysteine 21 by the method of Slade, et al, 
J. Med. Chem., 28, 1517-1521 (1985) and references cited therein 
(CBz=benzyloxycarbonyl). 
##STR23## 
Sulfoxide and sulfone intermediates 28 and 29 are prepared by oxidation of 
24 with various oxidants such as sodium periodate or 
meta-chloro-perbenzoic acid. Eight-membered ring intermediates of Formula 
II wherein X is sulfur can be prepared by an analogous route starting from 
derivatives of homo-cysteine. 
Intermediates of Formula II wherein X is an oxygen atom are prepared by 
methods described in the literature and known to those skilled in the art. 
For example, the seven-membered ring analog 26 can be prepared from a 
substituted derivative of 3-(2-nitrophenoxy) propanoic acid 30 by the 
method of J. Ott, Arch. Pharm (Weinheim. Ger.), 323(9), 601-603 (1990). 
##STR24## 
Six-membered ring analogs wherein X is oxygen (33) may be prepared by 
reaction of a substituted derivative of 2-aminophenol 32 with chloroacetyl 
chloride by the method of Huang and Chen, Synthesis, 10, 851 (1984) and 
references cited therein. Subsequent incorporation of an amino group at 
the 3 position of either 31 or 33 is achieved by the methods described in 
Scheme 4. 
##STR25## 
Seven-membered ring analogs of Formula II wherein X is C=O can be prepared 
from derivatives of tryptophan as described in the Australian Journal of 
Chemistry, 33, 633-640 (1980). Seven-membered ring analogs of Formula II 
wherein X is CH=CH can be prepared from the aforementioned analogs wherein 
X is C=O. Treatment of 34 with chemical reducing agents such as sodium 
borohydride in a polar solvent such as methanol or ethanol results in 
reduction to give the secondary alcohol derivative 35 (X=CHOH). 
##STR26## 
Dehydraton of 35 can be achieved by several methods described in the 
literature and familiar to those skilled in the art. For examle, treatment 
of 35 in an inert solvent, such as benzene, with a strong acid such as 
p-toluenesulfonic acid, will result in dehydration to the unsatured analog 
36. 
##STR27## 
Intermediates of formula II can be further elaborated to new intermediates 
(formula III) which are substituted on the amino group (Scheme 9). 
Reductive alkylation of II with an aldehyde is carried out under 
conditions known in the art: for example, by catalytic hydrogenation with 
hydrogen in the presence of platinum, palladium or nickel catalysts or 
with chemical reducing agents such as sodium cyanoborohydride in an inert 
solvent such as methanol or ethanol. 
##STR28## 
Attachment of the amino acid sidechain to intermediates of formula III is 
accomplished by the route shown in Scheme 10. Coupling is conveniently 
carried out by the use of an appropriately protected amino acid 
derivative, such as that illustrated by formula IV, and a coupling reagent 
such as benzotriazol-1-yloxytris(dimethylamino)phosphonium 
hexafluorophosphate ("BOP") in an inert solvent such as methylene 
chloride. Separation of unwanted side products, and purification of 
intermediates is achieved by chromatography on silica gel, employing flash 
chromatography (W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923 
(1978) or by medium pressure liquid chromatography. 
##STR29## 
The protected amino acid derivatives IV are, in many cases, commercially 
available in t-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBz) forms. A 
useful method to prepare the preferred sidechain 41 is shown in Scheme 11. 
##STR30## 
Reaction of isobutylene with N-chlorosulfonylisocyanate 37 in diethyl ether 
gives the azetidinone derivative 38. Removal of the chlorosulfonyl group 
with aqueous sodium sulfite followed by reaction with 
di-t-butyl-dicarbonate gives the BOC-protected intermediate 40. Alkaline 
hydrolysis gives the protected amino acid derivative 41 in good overall 
yield. 
Intermediates of formula VII can be prepared as shown in Scheme 12 by 
treatment of the desired lactam intermediate V with an alkylating agent 
VI, wherein L is a good leaving group such as Cl, Br, I, O-methanesulfonyl 
or O-(p-toluenesulfonyl). Alkylation of intermediates of formula V is 
conveniently carried out in anhydrous dimethyl formamide (DMF) in the 
presence of bases such as sodium hydride or potassium t-butoxide for a 
period of 0.5 to 24 hours at temperaturs of 20.degree.-100.degree. C. 
Substituents on the alkylating agent VI may need to be protected during 
alkylation. A description of such protecting groups may be found in 
Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons, 
New York, 1981. 
##STR31## 
Alkylaying agents VI are in some cases commercially available or may be 
prepared by methods described in the literature and familiar to one 
skilled in the art. In general, compounds VIIa where R.sup.3a or R.sup.3b 
is R.sup.9 can be prepared from intermediates of formula VII wherein 
R.sup.3a or R.sup.3b is an appropriate functional group that can be 
elaborated into the desired heterocycle R.sup.9 by methods described in 
the literature and familiar to one skilled in the art. An alternative and 
preferred route is shown in Scheme 13 and involves reaction of 
intermediates of formula V with alkylating agents VIa, into which the 
heterocyclic moiety R.sup.9 has already been incorporated. 
##STR32## 
Compounds VIIa wherein R.sup.9 is a substituted 2-thiazolyl group may be 
prepared from nitrile intermediates 42 as indicated in Scheme 14. 
Formation of the thioamide intermediate 43 can be achieved through 
treatment of 42 with hydrogen sulfide in the presence of a base such as 
triethylamine, in a polar solvent such as pyridine. Reaction of 43 with 
bromo-ketal 44 in the presence of dilute aqueous acid will afford the 
thiazole product 45. 
##STR33## 
A convenient route to the useful thiazole intermediate 50 is shown in 
Scheme 15. Thioamide 46 is obtained from 2-bromobenzonitrile by treatment 
with hydrogen sulfide and trietylemine in pyridine. Conversion to the 
thiazole intermediate 47 is achieved by treatment of 46 with 
bromoacetaldehyde diethylacetal in the presence of aqueous hydrochloric 
acid at elevated temperature. Coupling of 47 with 
4-methylphenyltrimethylstannane 48 is conveniently carried out by 
treatment with a metal catalyst, such as 
bis(triphenylphosphine)palladium(II) chloride, in a polar solvent, such as 
dimethylformamide, at elevated temperature. Intermediate 49 is elaborated 
to the desired alkylating agent 50 by free readical bromination with 
N-bromo-succinimde and azobisisobutyronitrile (AIBN). Coupling of the 
alkylating agent 50 with compounds of formula V is carried out according 
to the conditions described in Scheme 13. 
##STR34## 
Scheme 16 describes a general route to 2-thienyl substituted compounds 54. 
Reduction of the nitro intermediate 51 is conveniently carried out by 
hydrogenation in the presence of a metal catalyst, such as palladium on 
carbon, in a polar solvent such as methanol or ethanol. It may be 
appreciated by one skilled in the art that the protecting group G in 51 
must therefore be compatible with the conditions employed for its 
reduction. Diazotization of 52 may be carried out by treatment with 
isomylnitrite; the intermediate diazonium species 53 can be converted in 
situ to the desired thiophene compound 54 by treatment with thiophene at 
elevated temperature. 
##STR35## 
A useful preparation of the thienyl intermediate 57 is presented in Scheme 
17. Thienylation of 2-bromoaniline is accomplished by formation of the 
diazonium salt, followed by treatment with thiophene. Coupling of 55 with 
4-methylphenyltrimethylstannane 48 and subsequent bromination to give the 
desired intermediate 57 is achieved by the conditions described previously 
in Scheme 15. Coupling of the alkylating agent 57 with compounds of 
formula V is carried out according to the conditions described in Scheme 
13. 
##STR36## 
Scheme 8 describes a general route to 3-substituted pyrazole compounds 60. 
Formylation of acetyl compound 58 can be carried out by treatment with 
ethyl formate and sodium in a polar solvent such as ethanol. The formyl 
derivative, 59, isolated as its sodium salt, can be converted directly to 
the pyrazole product 60 by treatment with hydrazine. 
##STR37## 
A convenient route to a preferred 3-substituted pyrazole intermediate 65 is 
shown in Scheme 19. Acetylbiphenyl 61, prepared from 2'-bromoacetophenone 
and 4-methylphenyl-trimethylstannane according to the conditions described 
in Scheme 15, is converted to the sodium salt of the formyl derivatives 62 
by treatment with sodium and ethyl formate. Reaction of 62 with hydrazine 
under basic conditions at elevated temperature affords the pyrazole 63 in 
moderate yield. Protection of the pyrazole ring as a tripheny methyl 
(trityl) derivative is achieved by treatment with triphenylmethylchloride 
in an inert solvent, such as methylene chloride, in the presence of a 
base, such as triethylamine. Bromination of 64 is accomplished with 
N-bromosuccinimide according to the procedure described in Scheme 15. 
Coupling of 65 with compounds of formula V is then carried out using the 
conditions described in Scheme 13. 
##STR38## 
4-Substituted-1,2,3-triazole derivatives can also be prepared by a 
convergent route involving initial assembly of the appropriate 
triazole-containing alkylating agent. A useful preparation of the 
intermediate 72 is described in Scheme 20. Formation of 
2'-nitro-4-methyl-1,1'-biphenyl 66 is carried out by coupling of the tin 
reagent 48 with 2-bromonitrobenzene under the conditions outlined in 
Scheme 15. Replacement of the 2'-nitro group with iodine is achieved by a 
three step sequence involving reduction to the amine compound 67 followed 
by diazotization and treatment with potassium iodide and iodine. Coupling 
of 68 with trimethylsilylacetylene is carried out with 
bis(triphenylphosphine)palladium(II) chloride, and cuprous iodide in 
triethylamine. Desilylation with aqueous sodium hydroxide gives 69 which 
is converted to the 1,2,3-triazole compound 70 by treatment with 
trimethylsilyl azide at elevated temperature. Tritylation and bromination 
by the methods described previously afford the alkylating reagent 72. 
Reaction of 72 with compounds of formula V is then carried out using the 
conditions described in Scheme 13. 
##STR39## 
Isomeric 3-substituted-1,2,4-triazole derivatives are prepared in a similar 
manner. As indicated in Scheme 21, formation of 
2'-cyano-4-methyl-1,1'-biphenyl 73 is carried out by coupling of the tin 
reagent 48 with 2-bromobenzonitrile using the conditions outlined in 
Scheme 15. Conversion to the thioamide 74 is performed at elevated 
temperature with hydrogen sulfide and triethylamine in pyridine under 
pressure. Treatment of 74 with methyl iodide gives the activated 
intermediate 75, which is elaborated to the 1,2,4-triazole compound 76 by 
treatment with formic hydrazide in dimethylformamide at elevated 
temperature. Protection as the trityl derivative 77 and conversion to the 
bromo compound 78 are carried out using the conditions described above. 
Reaction of 78 with compounds of formula V is then carried out using the 
conditions described in Scheme 13. 
##STR40## 
Scheme 22 describes a general route to 2-substituted imidazole compounds 
82. Methyl ester 79 can be reduced with a complex metal hydride reagent 
such as diisobutylaluminum hydride (DIBAL) to the aldehyde 80. An 
alternate four-step route would involve hydrolysis of ester 79 under basic 
conditions, followed by formation of a mixed anhydride using isobutyl 
chloroformate; reduction of the mixed anhydride with sodium borohydride 
and subsequent oxidation of the benzyl alcohol product with dimethyl 
sulfide and oxalyl chloride (Swern conditions). Elaboration of aldehyde 80 
to the desired imidazole compound 82 can be achieved by reaction with 
diketone 81 in the presence of an ammonium salt, such as ammonium acetate, 
in a polar solvent such as methanol or ethanol. 
##STR41## 
Intermediate 82 can be converted to a new intermediate 83 as indicated in 
Scheme 23 by alkylation with R.sup.13 -Cl in the presence of a base, such 
as sodium hydride, in a polar solvent, such as dimethyl formamide. 
##STR42## 
A convergent route to the useful intermediate 89 is outlined in Scheme 24. 
Metallation of 4-bromobenzyl t-butyldimethylsilylether 84 with 
t-butyllithium followed by treatment with zinc chloride gives the 
intermediate zinc compound 85 which is subsequently coupled with 86 
through the use of a transition metal catalyst, such as 
bis(triphenylphosphine)nickel(II) chloride. Elaboration of the biphenyl 
compound 87 to the alkylating agent 88 is accomplished by sequential 
removal of the silyl protecting group by treatment with 
tetra-n-butylammonium fluoride followed by reaction with methanesulfonic 
anhydride and triethylamine. Reaction of 88 with compounds of formula V to 
give 89 is carried out using the conditions described in Scheme 13. 
##STR43## 
A general route to 4-substituted imidazole derivatives 92 is depicted in 
Scheme 25. Acetyl compound 90 can be brominated through the use of bromine 
in acetic acid. Reaction of the bromide 91 with formamidine acetate in a 
polar solvent will give the imidazole product 92. 
##STR44## 
A useful route to the protected 4-substituted imidazole intermediate 96 is 
illustrated in Scheme 26. Coupling of 2'-bromoacetophenone and 
4-methylphenyltrimethylstannan according to the conditions described in 
Scheme 15 gives 2'-acetyl-4-methyl-1,1'-biphenyl 61 which is brominated 
with bromine in acetic acid to give the phenacyl derivative 93. Imidazole 
formation is achieved by reaction of 93 with formamidine acetate in a 
polar solvent at elevated temperature. Protection of 94 as the trityl 
derivative 95 and conversion to the bromo compound 96 are carried out 
using the conditions described above. Reaction of 96 with compounds of 
formula V is then carried out using the conditions described in Scheme 13. 
##STR45## 
Compounds of formula I wherein R.sup.9 is a substituted triazolinone, such 
as compound 99, can be prepared from intermediates described herein by 
methods described in the literature, such as those detailed by J. Lyga, et 
al. in Synth. Comm., 16, 163 (1986) and illustrated in Scheme 27. Amine 52 
can be transformed to the corresponding hydrazine derivative 97 by a 
two-step sequence involving formation of a diazonium salt, followed by 
reduction with tin(II) chloride. Treatment of 97 with an appropriately 
substituted pyruvic acid reagent 98 followed by reaction with 
diphenylphosphoryl acids will give the desired triazolinone 99. 
##STR46## 
Analogs wherein R.sup.9 is a substituted triazinone, such as compound 100, 
can be prepared from intermediates described herein by methods described 
in the literature, such as those detailed by M. Miller, et al, in J. Med. 
Chem., 24, 1337 (1981) and illustrated in Scheme 28. Diazonium salt 53, 
available from amine 52 by treatment with nitrous acid, can be converted 
into the desired compound 100 by a four-step sequence involving: 1) 
reaction with malonyldiurethane; 2) treatment with acetic acid and sodium 
acetate; 3) hydrolysis with aqueous hydrochloric acid, and 4) treatment 
with thioglycolic acid in xylene at elevated temperature. 
##STR47## 
Compounds of formula I wherein E is a carbamate or ester linkage can be 
prepared from acetophenone intermediates 58 as shown in Scheme 29. 
Reaction of 58 with a peroxy-carboxylic acid, such as m-chloroperbenzoic 
acid (Baeyer-Villager reaction), leads to formation of the corresponding 
ester 101 which can be hydrolyzed under basic conditions to give phenol 
102. 
##STR48## 
Illustrated in Scheme 30 are reactions of phenol 102 with suitable reagents 
to give carbamate compounds 103 and 104, and ester compounds 105. 
##STR49## 
Compounds of formula I wherein E is a urea or carbamate linkage can be 
prepared from nitro compounds 51 as shown in Scheme 31. Reduction of 51 is 
conveniently carried out by hydrogenation in the presence of a metal 
catalyst, such as palladium on carbon, in a polar solvent such as methanol 
or ethanol. It may be appreciated by one skilled in the art that the 
protecting group G in 51 must therefore be compatible with the conditions 
employed for its reduction, hence G is taken as t-butoxycarbonyl. Reaction 
of 52 with phosgene, or an equivalent reagent such as 
bis(trichloromethyl)carbonate (triphosgene), results in formation of 
isocyanate 106. 
##STR50## 
Scheme 32 illustrates the reactions of isocyanate 106 with appropriate 
reagents to form urea-linked compounds 107 and carbamate-linked compounds 
108. 
##STR51## 
Aniline derivative 52 may be further converted to a substituted amine 109 
by reductive amination with an aldehyde and a reducing agent such as 
sodium cyanoborohydride, as shown in Scheme 33. 
##STR52## 
Scheme 34 shows transformations of amine 109 with the appropriate reagents 
to form urea-linked compounds 110 and 111, carbamate-linked compounds 112 
and amide-linked analogs 113. 
##STR53## 
Compounds of formula I wherein E is --CH.sub.2 N(R.sup.10)-- can be 
prepared from the t-butyl ester intermediate 114 as described in Scheme 
35. Removal of the t-butyl ester through the use of trifluoroacetic acid 
will give the carboxylic acid 115. It may be appreciated by one skilled in 
the art that the protecting group G in 114 must therefore be compatible 
with the strongly acidic conditions employed for ester cleavage, hence G 
is taken as benzyloxycarbonyl. Conversion of the carboxylic acid to the 
benzylamine derivative 116 can be achieved by a five-step sequence 
consisting of: 1) formation of a mixed anhydride with isobutyl 
chloroformate; 2) reduction with sodium borohydride to the benzyl alcohol; 
3) formation of the mesylate with methanesulfonyl chloride; 4) formation 
of the azide by reaction with sodium azide, and finally, 5) reduction of 
the azide with tin(II) chloride. The benzylamine intermediate 116 can be 
further elaborated to 117 by the aforementioned reductive amination 
procedure. 
##STR54## 
Reactions of amine 117 with the appropriate reagents to form urea-linked 
compounds 118 and 119, carbamate linked compounds 120, and amide-linked 
structures 121 are illustrated in Scheme 36. 
##STR55## 
A useful preparatior of the protected benzylamine intermediate 125 is shown 
in Scheme 37. Metallation of 4-bromobenzyl t-butyldimethylsilylether 84 
with n-butyllithium followed by treatment with trimethyl borate gi es the 
aryl boronic acid 122. Reaction of 122 with 
2-bromo-N-(t-butoxycarbonyl)-benzylamine 123 in the presence of 
tetrakis(triphenyl-phosphine)palladium(0) and barium hydroxide in aqueous 
1,2-dimethoxyethane at elevated temperature gives the coupled product 124 
in good yield. Desilylation and conversion to the O-methanesulfonate 125 
is achieved using the conditions described in Scheme 24. Reaction of 125 
with compounds of formula V is carried out using the conditions described 
in Scheme 13. 
##STR56## 
Compounds of formula I wherein R.sup.3a or R.sup.3b is a 
(4,5-dihydro-2-oxazolyl)amino group are prepared from isocyanate 106 as 
demonstrated in Scheme 38. Reaction of 106 with ethanolamine in methylene 
chloride gives the hydroxyethyl urea 126 in high yield. Treatment of 126 
with methanesulfonyl chloride and triethylamine in methylene chloride in 
the presence of 4-dimethyl-aminopyridine leads to the 
(4,5-dihydro-2-oxazolyl)-amino product 127 in fair yield. 
##STR57## 
The six-membered ring analogs of 127 can also be prepared from isocyanate 
106 by the procedure of Y. Iwakura, et al, J. Org. Chem., 30, 3410 (1965). 
As shown in Scheme 39, reaction of isocyanate 106 with azetidine in 
methylene chloride will give the urea product 128. Rearrangement of 128 
through the use of picric acid in boiling toluene leads to the desired 
product 129. 
##STR58## 
Compounds of formula I wherein R.sup.3a or R.sup.3b is a 
(4,5-dihydro-2-imidazolyl)amino group can be prepared from amine 52 as 
demonstrated in Scheme 40. Formation of the isothiocyanate 130 by 
treatment with thiocarbonyldiimidazole, followed by reaction with 
ethylenediamine will give the intermediate aminoethyl urea 131. Thermal 
rearrangement of 131 in an inert solvent will give the desired 
(4,5-dihydro-2-imidazolyl)amino compound 132. 
##STR59## 
Conversion to the final products of formula I wherein R.sup.4 is hydrogen, 
is carried out by simultaneous or sequential removal of all protecting 
groups from intermediate VII as illustrated in Scheme 41. 
##STR60## 
Removal of benzyloxycarbonyl groups can be achieved by a number of methods 
known in the art; for example, catalytic hydrogenation with hydrogen in 
the presence of a platinum or palladium catalyst in a protic solvent such 
as methanol. In cases where catalytic hydrogenation is contraindicated by 
the presence of other potentially reactive functionality, removal of 
benzyloxycarbonyl groups can also be achieved by treatment with a solution 
of hydrogen bromide in acetic acid. Removal of t-butoxycarbonyl (BOC) 
protecting groups is carried out by treatment of a solution in a solvent 
such as methylene chloride or methanol, with a strong acid, such as 
hydrochloric acid or trifluoroacetic acid. Conditions required to remove 
other protecting groups which may be present can be found in Protective 
Groups in Organic Synthesis T. W. Greene, John Wiley & Sons, NY, 1981. 
Compounds of formula I wherein R.sup.4 and R.sup.5 are each hydrogen can be 
further elaborated by reductive alkylation with an aldehyde by the 
aforementioned procedures or by alkylations such as by reaction with 
various epoxides. The products, obtained as hydrochloride or 
trifluoroacetate salts, are conveniently purified by reverse phase high 
performance liquid chromatogrphy (HPLC) or by recrystallization. 
It is noted that the order of carrying out the foregoing reaction schemes 
is not significant and it is within the skill of one skilled in the art to 
vary the order of reactions to facilitate the reaction or to avoid 
unwanted reaction products. 
The growth hormone releasing compounds of Formula I are useful in vitro as 
unique tools for understanding how growth hormone secretion is regulated 
at the pituitary level. This includes use in the evaluation of many 
factors thought or known to influence growth hormone secretion such as 
age, sex, nutritional factors, glucose, amino acids, fatty acids, as well 
as fasting and non-fasting states. In addition, the compounds of this 
invention can be used in the evaluation of how other hormones modify 
growth hormone releasing activity. For example, it has already been 
established that somatostatin inhibits growth hormone release. Other 
hormones that are important and in need of study as to their effect on 
growth hormone release include the gonadal hormones, e.g., testosterone, 
estradiol, and progesterone; the adrenal hormones, e.g., cortisol and 
other corticoids, epinephrine and norepinephrine; the pancreatic and 
gastrointestinal hormones, e.g., insulin, glucagon, gastrin, secretin; the 
vasoactive intestinal peptides, e.g., bombesin; and the thyroid hormones, 
e.g., thyroxine and triidothyronine. The compounds of Formula I can also 
be employed to investigate the possible negative or positive feedback 
effects of some of the pituitary hormones, e.g., growth hormone and 
endorphin peptides in the pituitary to modify growth hormone release. Of 
particular scientific importance is the use of these compounds to 
elucidate the subcellular mechanisms mediating the release of growth 
hormone. 
The compounds of Formula I can be administered to animals, including man, 
to release growth hormone in vivo. For example, the compounds can be 
administered to commercially important animals such as swine, cattle, 
sheep and the like to accelerate and increase their rate and extent of 
growth, and to increase milk production in such animals. In addition, 
these compounds can be administered to humans in vivo as a diagnostic tool 
to directly determine whether the pituitary is capable of releasing growth 
hormone. For example, the compounds of Formula I can be administered in 
vivo to children. Serum samples taken before and after such administration 
can be assayed for growth hormone. Comparison of the amounts of growth 
hormone in each of these samples would be a means for directly determining 
the ability of the patient's pituitary to release growth hormone. 
Accordingly, the present invention includes within its scope pharmaceutical 
compositions comprising, as an active ingredient, at least one of the 
compounds of Formula I in association with a pharmaceutical carrier or 
diluent. Optionally, the active ingredient of the pharmaceutical 
compositions can comprise a growth promoting agent in addition to at least 
one of the compounds of Formula I or another composition which exhibits a 
different activity, e.g., an antibiotic or other pharmaceutically active 
material. 
Growth promoting agents include, but are not limited to, TRH, 
diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, 
compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and 
compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides 
disclosed in U.S. Pat. No. 4,411,890. 
A still further use of the disclosed novel benzo-fused lactam growth 
hormone secretagogues is in combination with other growth hormone 
secretagogues such as GHRP-6, GHRP-1 as described in U.S. Pat. Nos. 
4,411,890; and publications WO 89/07110 and WO 89/07111 and B-HT920 or 
growth hormone releasing factor and its analogs or growth hormone and its 
analogs or somatomedins including IGF-1 and IGF-2. 
A still further use of the instant novel benzo-fused lactam growth hormone 
secretagogues is in combination with a .sub.2 -adrenergic agonists in the 
treatment of obesity (see U.S. Pat. No. 5120713) or in combination with a 
parathyroid hormone in the treatment of osteoporosis (see WO 92/09304). 
As is well known to those skilled in the art, the known and potential uses 
of growth hormone are varied and multitudinous. Thus, the administration 
of the compounds of this invention for purposes of stimulating the release 
of endogenous growth hormone can have the same effects or uses as growth 
hormone itself. These varied uses of growth hormone may be summarized as 
follows: stimulating growth hormone release in elderly humans; Prevention 
of catabolic side effects of glucocorticoids, treatment of osteoporosis, 
stimulation of the immune system, treatment of retardation, acceleration 
of wound healing, accelerating bone fracture repair, treatment of growth 
retardation, treating renal failure or insufficiency resulting in growth 
retardation, treatment of physiological short stature, including growth 
hormone deficient children, treating short stature associated with chronic 
illness, treatment of obesity and growth retardation associated with 
obesity, treating growth retardation associated with Prader-Willi syndrome 
and Turner's syndrome; Accelerating the recovery and reducing 
hospitalization of burn patients; Treatment of intrauterine growth 
retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; 
Induction of pulsatile growth hormone release; Replacement of growth 
hormone in stressed patients; Treatment of osteochondrodysplasias, Noonans 
syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound 
healing, and psychosocial deprivation; treatment of pulmonary dysfunction 
and ventilator dependency; Attentuation of protein catabolic response 
after a major operation; reducing cachexia and protein loss due to chronic 
illness such as cancer or AIDS. Treatment of hyperinsulinemia including 
nesidioblastosis; Adjuvant treatment for ovulation induction; To stimulate 
thymic development and prevent the age-related decline of thymic function; 
Treatment of immunosuppressed patients; Improvement in muscle strength, 
mobility maintenance of skin thickness, metabolic homeostasis, renal 
hemeostasis in the frail elderly; Stimulation of osteoblasts, bone 
remodelling, and cartilage growth; Stimulation of the immune system in 
companion animals and treatment of disorders of aging in companion 
animals; Growth promotant in livestock; and stimulation of wool growth in 
sheep. 
The compounds of this invention can be administered by oral, parenteral 
(e.g., intramuscular, intraperitoneal, intravenous or subcutaneous 
injection, or implant), nasal, vaginal, rectal, sublingual, or topical 
routes of administration and can be formulated in dosage forms appropriate 
for each route of administration. 
Solid dosage forms for oral administration include capsules, tablets, 
pills, powders and granules. In such solid dosage forms, the active 
compound is admixed with at least one inert pharmaceutically acceptable 
carrier such as sucrose, lactose, or starch. Such dosage forms can also 
comprise, as is normal practice, additional substances other than inert 
diluents, e.g., lubricating agents such as magnesium stearate. In the case 
of capsules, tablets and pills, the dosage forms may also comprise 
buffering agents. Tablets and pills can additionally be prepared with 
enteric coatings. 
Liquid dosage forms for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups, the elixirs 
containing inert diluents commonly used in the art, such as water. Besides 
such inert diluents, compositions can also include adjuvants, such as 
wetting agents, emulsifying and suspending agents, and sweetening, 
flavoring, and perfuming agents. 
Preparations according to this invention for parenteral administration 
include sterile aqueous or non-aqueous solutions, suspensions, or 
emulsions. Examples of non-aqueous solvents or vehicles are propylene 
glycol, polyethylene glycol, vegetable oils, such as olive oil and corn 
oil, gelatin, and injectable organic esters such as ethyl oleate. Such 
dosage forms may also contain adjuvants such as preserving, wetting, 
emulsifying, and dispersing agents. They may be sterilized by, for 
example, filtration through a bacteria-retaining filter, by incorporating 
sterilizing agents into the compositions, by irradiating the compositions, 
or by heating the compositions. They can also be manufactured in the form 
of sterile solid compositions which can be dissolved in sterile water, or 
some other sterile injectable medium immediately before use. 
Compositions for rectal or vaginal administration are preferably 
suppositories which may contain, in addition to the active substance, 
excipients such as cocoa butter or a suppository wax. 
Compositions for nasal or sublingual administration are also prepared with 
standard excipients well known in the art. 
The dosage of active ingredient in the compositions of this invention may 
be varied; however, it is necessary that the amount of the active 
ingredient be such that a suitable dosage form is obtained. The selected 
dosage depends upon the desired therapeutic effect, on the route of 
administration, and on the duration of the treatment. Generally, dosage 
levels of between 0.0001 to 100 mg/kg. of body weight daily are 
administered to patients and animals, e.g., mammals, to obtain effective 
release of growth hormone. 
The following examples are provided for the purpose of further illustration 
only and are not intended to be limitations on the disclosed invention. 
EXAMPLE 1 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-2-yl)[(1,1 
'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
di(trifluoroacetate) 
Step A: 1-Tetralone oxime 
To 4.6 L of water at room temperature in a 4-neck 50 L flask sitting in a 
steam bath apparatus equipped with an overhead stirrer, a temperature 
probe and reflux condenser was added 3.72 Kg (27.36 mol) of sodium acetate 
with stirring, followed by 1.9 Kg of hydroxylamine hydrochloride (27.36 
mol). To this slurry at room temperature, 12 L of ethanol was added 
followed by 1.994 Kg (13.68 mol) of 1-tetralone. Additional ethanol (1.7 
L) was used to rinse off the funnel and added to the reaction mixture. The 
resulting light orange slurry was heated to 75.degree. C. over 40 minutes 
and maintained at 75.degree.-85.degree. C. for another 75 minutes. The 
reaction mixture was cooled with the aid of ice packed around the flask. 
When the internal temperature reached 32.degree. C., the reaction mixture 
was pumped over 15 minutes into 60 L of ice contained in a 200 L vessel. 
The reaction vessel was washed with an additional 2 L of water which was 
added to the 200 L vessel. When the ice melted, the mixture was filtered 
through a filter pad and the wet cake washed with 4 L of water. The wet 
cake was suction dried for 1 hour then transferred to two trays and dried 
under vacuum at 40.degree. C. for 2 days to give 2.094 Kg (13.01 mol, 95%) 
of product, .sup.1 H NMR (250 MHz, CDCl.sub.3): 1.90 (m, 2H), 2.80 (t, 6 
Hz, 2H), 2.88 (t, 6 Hz, 2H), 7.15-7.35 (m, 3H), 7.90 (d, 8 Hz, 1H), 8.9 
(br s, 1H). 
Step B: 2,3,4,5-Tetrahydro-1H-1-benzazepin-2-one 
To 10 L of methanesulfonic acid in a 22 L 3-neck flask equipped with an 
overhead stirrer, a temperature probe, nitrogen inlet and reflux condenser 
was added 2.6 Kg (18.61 mol) of phosphorus pentoxide. An additional 1.6 L 
of methansulfonic acid was used to wash all the phosphorus pentoxide into 
the vessel. The mixture was heated at 90.degree. C. for 2.5 hours then 
cooled to 50.degree. C. using an ice bath and treated with 2.00 Kg (12.41 
mol) of 1-tetralone oxime in several portions over 15 minutes. The mixture 
was heated at 63.degree. C. for 10 minutes then slowly heated to 
80.degree. C. and kept at 80.degree. C. for 3 hours. The reaction mixture 
was pumped into 70 L of ice then treated slowly with 11.25 L of 50% 
aqueous sodium hydroxide over 90 minutes at such a rate so as to maintain 
the temperature below 28.degree. C. The mixture was filtered and 4 L of 
the filtrate was used to rinse the vessel. The wet cake (pink) was washed 
with 8 L of water then suction dried for 45 minutes then transferred to 
two trays and dried under vacuum at 40.degree. C. for 2 days to give 1.9 
Kg (11.79 mol, 95%) of product, .sup.1 H NMR (250 MHz, CDCl.sub.3): 2.24 
(m, 2H), 2.38 (t, 6 Hz, 2H), 2.82 (t, 6 Hz, 2H), 7.03 (d, 8 Hz, 1H), 7.13 
(m, 1H), 7.24 (m, 2H), 8.63 (br s, 1H). 
Step C: 3-Iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 
A suspension of 1.8 Kg (11.17 mol) of 
2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in a mixture of 22.33 L of 
methylene chloride and 11.78 L (55.83 mol) of hexamethyldisilazane was 
heated at reflux for 10 minutes then cooled to 30.degree. C. and treated 
with 8.503 Kg (33.5 mol) of iodine in one portion. The mixture was heated 
at reflux for 2.5 hours then cooled to room temperature. Aqueous sodium 
sulfite containing 4.926 Kg of sodium sulfite in 44 L of water was cooled 
to 0.degree. C. and into it was poured the reaction mixture in several 
portions with vigorous stirring while maintaining the temperature below 
10.degree. C. The reaction vessel was rinsed with 22.33 L of methylene 
chloride and the washing transferred to the quenching mixture. The 
quenching mixture was stirred vigorously and the layers allowed to 
separate. The aqueous layer was removed and reextracted with 22.33 L of 
methylene chloride. The combined organic layers were washed with 11 L of 
water and concentrated under vacuum to a final volume of /5 L. The residue 
was treated with 55 L of toluene and concentrated under vacuum to a final 
volume of 10 L. The resulting slurry was removed by filtration and the 
filter cake washed with an additional 5 L of toluene and dried under 
vacuum at ambient temperature for 24 hours to give 1.842 Kg (6.42 mol. 
57%) of product. .sup.1 H NMR (200 MHz, CDCl.sub.3): 2.6-2.8 (m,3H), 2.93 
m, 1H), 4.64 (t, 8 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.10-7.35 (m, 3H), 7.55 
(br s, 1H). 
Step D: 3(R)-Amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, D-tartaric 
acid salt 
3-Iodo-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (1.79 Kg, 6.24 mol) was 
slurried in 6.2 L of methanol and the slurry charged into an autoclave. 
Condensed ammonia (1.55 L) was added and the autoclave closed, with 
stirring, and heated to 100.degree. C. over 1 hour. Heating at 100.degree. 
C. was continued for 2 hours then the autoclave was allowed to cool to 
room temperature over 1 hour, during which time the internal pressure was 
150-155 psi. The reaction mixture was transferred to a polyethylene jug 
and the autoclave rinsed with 2.times.8 L of methanol. The washings were 
concentrated under vacuum at 30.degree. C. then combined with the reaction 
mixture and concentrated to near dryness under vacuum at 30.degree. C. The 
resulting residue was dissolved in 4 L of ethyl acetate then concentrated 
to dryness under vacuum at 30.degree. C. 
Sodium chloride (712 g) was dissolved in 2 L of water and 1.0 Kg of sodium 
carbonate was dissolved in 6 L of water. Two liters of the sodium 
carbonate solution was added to the concentrated residue and the resulting 
slurry transferred to an extraction flask. Another 2 L portion of the 
sodium carbonate solution was added to the residue flask and the solution 
transferred to the extraction flask. The remaining sodium carbonate 
solution was used in the same way. The sodium chloride solution was added 
to the sodium carbonate/aminolactam emulsion and the resulting mixture 
stirred for 10 minutes then extracted with four 6 L portions of methylene 
chloride. The combined methylene chloride layers were concentrated to 
dryness; the residue was treated with 2 L of 200 proof ethanol and the 
resulting slurry concentrated to dryness under vacuum to give 1.171 Kg of 
crude product. 
The crude product was slurried in 8 L of ethanol and treated with 900 g of 
D-tartaric acid in one portion. Water (7 L) was added and the mixture 
heated to 77.degree. C., then additional ethanol (45 L) was added and 
heating continued. The solution was cooled to 43.degree. C. and treated 
with the seed slurry. (The seed slury was prepared by the route described 
above starting with 10.50 g of crude product and 9.1 g of D-tartaric 
acid.) The solution was aged at room temperature for 48 hours. The slurry 
formed was removed by filtration and the wet cake washed with 1.8 L of 
ethanol. The resulting filter cake was suction dried with nitrogen 
bleeding for 20 hours then transferred into a drying tray and dried under 
vacuum for 24 hours to give 354 g (1.085 mol, 17.4%) of the product. 
.sup.1 H NMR (250 MHz, CDCl.sub.3); 2.13 (m, 1H), 2.51 (m, 2H), 2.73 (m, 
2H), 3.68 (t, 6 Hz, 1H), 3.98 (s, 2H), 7.05 (d, 8 Hz, 1H), 7.16 (t, 8 Hz), 
1H), 7.30 (m, 2H), 7.6 (br s, 5H), 10.26 (br s, 1H). 
Step E: 3(R)-Amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one 
A Solution of 229.23 g (0.700 mol) of 
3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, D-tartrate in 4.1 L 
of water was treated with 194 g (1.40 mol) of potassium carbonate. 
Subsequent portions of 100 g and 135 g of potassium carbonate were added 
until the pH was 10.5. The mixture was extracted with four 4 L portions of 
methylene chloride which were then combined and dried over magnesium 
sulfate. The aqueous layer was treated with 1.4 Kg of sodium chloride and 
reextracted with four 4 L portions of methylene chloride which were then 
combined and dried over magnesium sulfate. The two 16 L batches of 
extracts were combined, filtered and concentrated to dryness under vacuum 
to give 115.5 g of product which contained 1.6% of an impurity identified 
as 7-iodo-3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one. 
A solution of 107.02 g (0.607 mol) of the intermediate obtained above in 
1.712 L of ethanol was hydrogenated at room temperature and 40 psi over 
4.00 g of 10% palladium on carbon for 4 hours. The catalyst was removed by 
filtration through solkaflok and the filtrate concentrated to dryness 
under vacuum to give 101.08 g (0.574 mol, 94.4%) of product. 
Step F: 4,4-Dimethylazetidin-2-one 
A 3-neck 3 L round bottom flask equipped with a magnetic stirrer, 
thermometer, cold finger condenser and nitrogen bubbler was charged with 1 
L of ether. The flask was cooled to -65.degree. C. and into it was 
condensed 500-600 mL of isobutylene. The cold finger condenser was 
replaced with a dropping funnel and 200 mL (325 g, 2.30 mol) of 
chlorosulfonyl isocyanate was added dropwise over 1.5 hours. The mixture 
was maintained at -65.degree. C. for 1.5 hours then the dry ice/acteone 
cooling bath replaced with methanol/ice and the internal temperature 
slowly increased to -5.degree. C. at which time the reaction initiated and 
the internal temperature rose to 15.degree. C. with evolution of gas. The 
internal temperature remained at 15.degree. C. for several minutes then 
dropped back down to -5.degree. C. and the mixture stirred at -5.degree. 
C. for 1 hour. The methanol/ice bath was removed and the reaction mixture 
warmed to room temperature and stirred overnight. 
The reaction mixture was transferred to a 3-neck 12 L round bottom flask 
fitted with a mechanical stirrer and diluted with 2 L of ether. The well 
stirred reaction mixture was treated with 2 L of saturated aqueous sodium 
sulfite. After 1 hour, an additional 1 L of saturated aqueous sodium 
sulfite was added followed by sufficient sodium bicarbonate to adjust the 
pH to approximately 7. The mixture was stirred another 30 minutes then the 
layers allowed to separate. The ether layer was removed and the aqueous 
layer reextracted with 2.times.1 L of ether. The combined ether extracts 
were washed once with 500 mL of saturated aqueous sodium bicarbonate and 
once with 500 mL of saturated aqueous sodium chloride. The ether layer was 
removed, dried over magnesium sulfate, filtered and concentrated under 
vacuum to give 33 g of a pale yellow oil. The aqueous layer was made basic 
by the addition of solid sodium bicarbonate and extracted with 3.times.1 L 
of ether. The combined ether extracts were washed and dried as described 
above, then combined with the original 33 g of pale yellow oil and 
concentrated under vacuum to give 67.7 g of product. Further extraction of 
the aqueous layer with 4.times.1 L of methylene chloride and washing and 
drying as before gave an additional 74.1 g of product. Still further 
extraction of the aqueous layer with 4.times.1 L of methylene chloride 
gave an additional 21.9 g of product. The combined product (163.7 g, 1.65 
mol, 72%) was used in Step G without purification. .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 1.45 (s, 6H), 2.75 (d, 3 Hz, 2H), 5.9 (br s, 1H). 
Step G: N-(t-Butoxycarbonyl)-4,4-dimethylazetidin-2-one 
A 5 L, 3-neck round bottom flask equipped with a magnetic stirrer, 
thermometer, nitrogen bubbler and addition funnel was charged with 88.2 g 
(0.89 mol) of 4,4-dimethylazetidin-2-one (Step F), 800 mL of methylene 
chloride, 150 mL of triethylamine (1.08 mol) and 10.9 g (0.089 mol) of 
4-dimethylaminopyridine. To the stirred solution at room temperature was 
added dropwise over 15 minutes a solution of 235 g (1.077 mol) of 
di-t-butyl-dicarbonate in 300 mL of methylene chloride. The reaction 
mixture was stirred at room temperature overnight then diluted with 1 L of 
methylene chloride and washed with 500 mL of saturated aqueous ammonium 
chloride, 500 mL of water, and 500 mL of saturated aqueous sodium 
chloride. The organic layer was separated, dried over magnesium sulfate, 
filtered and concentrated under vacuum to afford 180.3 g of crude product 
as an organic solid. The material was used directly in Step H without 
purification. .sup.1 H NMR 200 MHz, CDCl.sub.3): 1.50 (s, 9H), 1.54 (s, 
6H), 2.77 (s, 2H). Step H: 3-t-Butoxycarbonylamino-3-methylbutanoic acid 
A 3 L, 3-neck round bottom flask equipped with a magnetic stirrer, 
thermometer, nitrogen bubbler and addition funnel was charged with 180.3 g 
(0.89 mol) of N-(t-butoxycarbonyl)-4,4-dimethylazetidin-2-one dissolved in 
1 L of tetrahydrofuran. The solution was cooled to 0.degree.-5.degree. C. 
and treated dropwise with 890 mL of 1.0M aqueous lithium hydroxide over 30 
minutes. The reaction mixture was stirred at 0.degree.-5.degree. C. for 2 
hours then diluted with 1 L of ether and 1 L of water. The layers were 
allowed to separate and the aqueous layer reextracted with an additional 1 
L of ether. The aqueous layer was acidified by the addition of 1 L of 
saturated aqueous sodium bisulfate, then extracted with 1.times.1 L and 
2.times.500 mL of ether. The combined organic layer and ether extracts 
were washed with 500 mL of saturated aqueous sodium chloride, dried over 
magnesium sulfate and concentrated under vacuum to 173 g of a yellow oil 
that solidified upon standing. The material was slurried with warm hexane 
then filtered and dried under high vacuum to afford 168.5 g (0.775 mol, 
87%) of product as a white solid. .sup.1 H NMR (200 MHz, CDCl.sub.3): 1.39 
(s, 6H), 1.44 (s, 9H), 2.72 (s, 2H). FAP-MS calculated for C.sub.10 
H.sub.19 NO.sub.4 217; found 218 (M+H, 54%). 
Step I: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3(R)-yl]-butanamide 
A solution of 8.70 g (49.4 mmol) of 
3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Step E) in 100 mL of 
methylene chloride was treated with 10.73 g (49.4 mmol) of 
3-t-butoxycarbonylamino-3-methylbutanoic acid (Step H) and 13.8 mL of 
triethylamine (10.0 g, 99 mmol, 2 eq.). The reaction flask was immersed in 
an ambient temperature water bath then 26 g of 
benzotriazol-1-yloxytris(dimethylamino) phosphonium hexafluorophosphate 
(59 mmol, 1.2 eq) was added all at once and the mixtrue stirred at room 
temperature for 2 hours. 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, 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 the product as a white solid. .sup.1 H NMR (200 MHz, CDCl.sub.3): 
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 C.sub.20 H.sub.29 N.sub.3 O.sub.4 375; found 376 (M+H, 
70%). 
Step J: 4-(t-Butyldimethylsiloxymethyl)bromobenzene 
A solution of 26.28 g (0.141 mol) of 4-bromobenzyl alcohol and 19.1 g (0.28 
mol) of imidazole in 100 mL of methylene chloride was treated dropwise 
with a solution of 21.18 g (0.14 mol) of t-butyldimethylsilyl chloride in 
50 mL of methylene chloride. The reaction mixture was stirred at room 
temperature for 30 minutes then transferred to a separatory funnel and 
washed with water, 1N hydrochloric acid, saturated aqueous sodium 
bicarbonate and saturated aqueous sodium chloride. The organic layer was 
removed, dried over magnesium sulfate, filtered and solvents removed under 
vacuum giving 41 g of the product as a colorless, viscous oil. .sup.1 H 
NMR (200 MHz, CDCl.sub.3): 0.09 (s, 6H), 0.93 (s, 9H), 4.67 (s, 2H), 7.18 
(d, 8 Hz, 2H), 7.43 (d, 8 Hz, 2H). 
Step K: 1-(4-Toluenesulfonyl)-2-(2-bromophenyl) imidazole 
A solution of 2.50 g (11.6 mmol ) of 2-(2-bromophenyl)imidazole in 10 mL of 
methylene chloride was treated with 1.9 mL of triethylamine (13.8 mmol), 
2.64 g (13.8 mmol) of p-toluenesulfonyl chloride and 100 mg of 
4-dimethylaminopyridine. The reaction mixture was stirred at room 
temperature for 15 minutes then transferred to a separatory funnel and 
washed with water, 5% aqueous citric acid, saturated aqueous sodium 
bicarbonate and saturated aqueous sodium chloride. The organic layer was 
removed, dried over magnesium sulfate, filtered and solvents removed under 
vacuum. The crude product was chromatographed on silica, eluting with 
hexane/ethyl acetate (1:1), to give 4.16 g (11.0 mmol 95%) of the product 
which was recrystallized from hexane. FAB-MS: calculated for C.sub.16 
H.sub.13 BrN.sub.2 O.sub.2 S 376,378; found 377,379 (M+H, 50%). .sup.1 H 
NMR (200 MHz, CDCl.sub.3): 2.32 (s, 3H), 7.09 (d, 2 Hz, 1H), 7.12 (d, 8 
Hz, 2H), 7.28 (m, 5H), 7.46 (m, 1H), 7.57 (d, 2 Hz, 1H). 
Step L: 
1-(4-Toluenesulfonyl)-2-[4'-(t-butyldimethylsiloxymethyl)-1,1'-biphen-2-yl 
]imidazole 
A solution of 1.50 g (5.0 mmol) of 4-(t-butyl-dimethylsiloxymethyl) 
bromobenzene in 10 mL of dry tetrahydrofuran under a nitrogen atmosphere 
was cooled to -15.degree. C. and treated with 5.88 mL of 1.7M (10.0 mmol) 
t-butyllithium in hexane slowly over several minutes. The mixture was 
stirred at -15.degree. C. for one hour over which time it slowly turned 
green. A solution of anhydrous zinc chloride in ether (5.0 mL of 1.7M 
solution; 5.0 mmol; pre-treated with 0.5 mL of 1.7M t-butyllithium to 
remove traces of water) was added and the reaction mixture warmed to room 
temperature. In a separate flask, 1.68 g (5.0 mmol) of 
1-(4-toluenesulfonyl)-2-(2-bromophenyl)imidazole and 98 mg (0.15 mmol) of 
bis(triphenylphosphine)nickel(II) chloride were dissolved in 10 mL of dry 
tetrahydrofuran and the solution cooled to 0.degree. C. and treated with 
0.10 mL of 3M methylmagnesium bromide in ether. This solution was then 
added by cannula to the original solution containing the zinc reagent and 
the resulting mixture stirred at room temperature for three hours. The 
reaction was treated with 10 mL of dilute aqueous acetic acid, then 
extracted several times with ethyl acetate. The combined extracts were 
dried over magnesium sulfate, filtered and solvents removed under vacuum 
to give 3.5 g of a brown oil which was chromatographed on silica, eluting 
wth hexane/ethyl acetate (1:1) giving 1.15 g (2.22 mmol, 44%) of the 
product. FAB-MS: calculated for C.sub.29 H.sub.34 N.sub.2 O.sub.3 Ssi 518; 
found 519 (M+H, 23%). .sup.1 H NMR (200 MHz, CDCl.sub.3): 0.09 (s, 6H), 
0.94 (s, 9H), 2.37 (s, 3H), 4.70 (s, 2H), 6.94 (d, 8 Hz, 2H), 6.98 (d, 2 
Hz, 1H), 7.13 (m, 5H), 7.30 (m, 3H), 7.4-7.6 (m, 3H). 
Step M: 
1-(4-Toluenesulfonyl)-2-[4'-(hydroxymethyl)-1,1'-biphen-2-yllimidazole 
A solution of 313 mg (0.60 mmol) of the intermediate obtained in Step L in 
2 mL of dry tetrahydrofuran at 0.degree. under a nitrogen atmosphere was 
treated with 190 mg (0.60 mmol) of tetrabutylammonium fluoride trihydrate 
and the mixture stirred at 0.degree. C. for 90 minutes. Saturated aqueous 
sodium bicarbonate (2 mL) was added and the mixture extracted several 
times with methylene chloride. The combined extracts were dried over 
magnesium sulfate, filtered and solvents removed under vacuum giving 220 
mg of residue. Chromatography on silica, eluting with hexane/ethyl acetate 
(1:1), gave 96 mg (0.24 mmol, 40%) of the product as a colorless oil. 
.sup.1 H NMR (200 MHz, CDCl.sub.3): 2.36 (s, 3H), 4.57 (s, 2H), 6.95 (m, 
3H), 7.12 (m, 5H), 7.29 (m, 3H), 7.40 (m, 2H), 7.51 (m, 1H). 
Step N: 
1-(4-Toluenesulfonyl)-2-[4'-(methyanesulfonyl-oxymethyl)-1,1'-biphen-2-yl] 
imidazole 
A solution of 45 mg (0.11 mmol) of the intermediate obtained in Step M in 2 
mL of methylene chloride at room temperature under a nitrogen atmosphere 
was treated with 0.03 mL of triethylamine (0.22 mmol) followed by 19 mg 
(0.11 mmol) of methanesulfonic anhydride. The mixture was stirred at room 
temperature for 2.5 hours. The reaction mixture was washed with water and 
saturated aqueous sodium chloride, then dried over magnesium sulfate, 
filtered and solvents removed under vacuum giving 49 mg of crude product 
which was used in the next step without purification. 
Step O: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[1-(4- 
toluenesulfonyl) 
imidazol-2-yl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butana 
mide 
A solution of 37 mg (0.10 mmol) of 
3-t-butoxy-carbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzaze 
pin-3(R)-yl]-butanamide in 1 mL of dry dimethylformamide at room 
temperature under a nitrogen atmosphere was treated with 5 mg of 60% 
sodium hydride oil dispersion (3 mg NaH, 0.13 mmol) and the resulting 
yellow solution stirred at room temperature for 20 minutes. A solution of 
49 mg (0.10 mmol) of the intermediate obtained in Step N in 1 mL of dry 
dimethylformamide was added and the reaction mixture stirred at room 
temperature for two hours. To the reaction mixture was added ethyl acetate 
and water; the organic layer was removed, washed with water, dried over 
magnesium sulfate, filtered and solvents removed under vacuum. The crude 
product was purified by chromatography on silica, eluting with 
hexane/ethyl acetate (1:1), to give 28 mg (37%) of the product. FAB-MS: 
calculated for C.sub.43 H.sub.47 N.sub.5 O.sub.6 S 761; found 768(M+Li, 
22%), .sup.1 H NMR (200 MHz, CDCl.sub.3); 1.33 (s, 6H), 1.39 (s, 9H), 1.79 
(m, 1H), 2.30-2.65 (m, 5H), 4.46 (m, 1H), 4.67 (d, 15 Hz, 1H), 5.24 (d, 15 
Hz, 1H), 5.33 (s, 1H), 6.67 (d, 7 Hz, 1H), 6.88 (d, 8 Hz, 2H), 6.90-7.55 
(m, 16H). 
Step F: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1[[(2'-(1H-imidazol-2-yl)[1,1 
'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
di(trifluoroacetate) 
A solution of 28 mg (0.037 mmol) of the intermediate obtained in Step O in 
1 mL of methylene chloride was treated with 10 mg (0.073 mmol) of 
1-hydroxybenzotriazole hydrate. The reaction mixture was stirred for 4 
hours at room temperature then evaporated to dryness under vacuum. The 
residue was redissolved in 1 mL of methanol and treated with 0.5 mL of 
concentrated hydrochloric acid. The mixture was stirred at room 
temperature for 14 hours then evaporated to dryness under vacuum. The 
residue was initially purified by reverse phase high pressure liquid 
chromatography on C18, eluting with methanol/0.1% aqueous trifluoroacetic 
acid (linear gradient: 40% methanol increased to 70% methanol over 10 
minutes). Final purification by reverse phase high pressure liquid 
chromatography on C18, eluting with methanol/0.1% aqueous trifluoroacetic 
acid (isocratic 50:50) gave 15 mg of the title compound as a colorless 
glass, FAB-MS: calculated for C.sub.31 H.sub.33 N.sub.5 O.sub.2 507: found 
508 (M+H, 80%). .sup.1 H NMR (200 MHz, CD.sub.3 OD): 1.31 (s, 3H), 1.35 
(s, 3H), 2.08 (m, 1H), 2.2-2.6 (m, 5H), 4.36 (dd; 8.11 Hz; 1H), 4.80 (d, 
15 Hz, 1H), 5.36 (d, 15 Hz, 1H), 7.04 (d, 8 Hz, 2H), 7.21 (m, 4H), 7.35 
(m, 2H), 7.45 (d, 2 Hz, 1H), 7.5-7.8 (m, 5H). 
EXAMPLE 2 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(2-thienyl) 
[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoracetate 
Step A: 4-Methylphenyltrimethylstannane 
41.4 L of 1.0M p-tolylmagnesium bromide in diethyl ether (41.4 mol) was 
added dropwise, maintaining the temperature below -5.degree. C., over 4 
hours to a solution of 546 g (2.79 mol) of trimethyltin chloride in 
tetrahydrofuran (4 L) under nitrogen at -10.degree. C. The suspension was 
allowed to warm slowly to room temperature over 12 h then saturated 
ammonium chloride solution (1 L) was added followed by sufficient water 
(approximately 1 L) to dissolve the precipitate. The solution was 
extracted with ether-hexane (1:1) (1.times.4 L, 3.times.2 L). The combined 
organic phases were washed with brine, dried over magnesium sulfate and 
the solvents removed under vacuum. Purification by flash chromatography on 
silica gel, eluting with hexane/ethyl acetate (95:5), gave a pale yellow 
oil containing white crystals of 4,4'-dimethylbiphenyl which were removed 
by filtration to leave 711.3 g (100%) of product. .sup.1 H NMR (300 MHz, 
CDCl.sub.3): 0.30 (s 9H), 2.34 (s, 3H), 7.19 (d, 7.7 Hz, 2H), 7.40 (d, 7.7 
Hz, 2H). 
Step B: 1-Bromo-2-(2-thienyl)benzene 
A solution of 8.8 mL of isoamylnitrite (65.5 mmol) in 85 mL of thiophene 
under a nitrogen atmosphere was heated to 50.degree. C. and treated 
dropwise with a solution of 7.5 g of 2-bromoaniline (43.5 mmol) dissolved 
in 20 mL of thiophene. After addition was complete, the temperature was 
raised to 90.degree. C. After 90 minutes, no starting aniline was observed 
by thin layer chromatography (hexane/ether;100:5). The reaction mixture 
volume was reduced by atmospheric distillation. The residue was dissolved 
in ether and the organic layer was washed twice with water, dried over 
magnesium sulfate and evaporated under vacuum. The residue was dissolved 
in n-hexane/ether (100:5) and passed over silica gel, eluting with 
n-hexane/ether (100:5) to give 3.5 g (14.6 mmol, 34%) of the product, 
.sup.1 H NMR (200 MHz, CDCl.sub.3): 7.11 (m, 1H), 7.16 (dd, 1H), 7.27 (m, 
2H), 7.37 (dd, 1H), 7.42 (dd, 1H), 7.66 (dd, 1H). 
Step C: 4-Methyl-2'-(2-thienyl)-1,1'-biphenyl 
A vigorously stirred solution of 3.4 g (14 mmol) of 
1-bromo-2-(2-thienyl)benzene and 3.77 g (15 mmol) of 
4-methylphenyltrimethylstannane in 50 mL of dimethylformamide under a 
nitrogen atmosphere was treated with 427 mg of bis(triphenylphosphine) 
palladium(II) chloride and the resulting mixture heated at 100.degree. C. 
for 4.5 hours. The reaction mixture was cooled, poured into 250 mL of 
water and the resultant mixture extracted with ethyl ether. The combined 
extracts were washed with water (4.times.), dried over magnesium sulfate 
and evaporated under vacuum. The residue was dissolved in hexane/ether 
(100:5) and chromatographed on silica gel, eluting with hexane/ether 
(100:5) to give 2.25 g of he product. .sup.1 H NMR (200 MHz, CDCl.sub.3): 
2.33 (s, 3H), 6.48 (dd, 1H), 6.83 (dd, 1H), 7.08 (m, 4H), 7.16 (dd, 1H), 
7.35 (m, 3H), 7.46 (dd, 1H). 
Step D: 4-Bromomethyl-2'-(2-thienyl)-1,1'-biphenyl 
A solution of 123 mg (0.492 mmol) of 4-methyl-2'-(2-thienyl)-1,1'-biphenyl, 
18.5 mg of AIBN and 110 mg (0.62 mmol) of N-bromosuccinimide in 50 mL of 
carbon tetrachloride was heated at reflux until a negative starch iodide 
reaction was obtained (2 hr). The reaction mixture was evaporated under 
vacuum and the residue triturated with hexane. The hexane washes were 
filtered and the filtrate evaporated under vacuum to give 158 mg of 
product. .sup.1 H NMR (300 MHz, CDCl.sub.3): 4.48 (s, 2H), 6.68 (dd, 1H), 
6.88 (dd, 1H), 7.11 (m, 5H), 7.36 (m, 3H), 7.50 (dd, 1H). 
Step E: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(2-thi 
enyl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
A solution of 174 mg (0.465 mmol) of 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2oxo-1H-1-benzazepi 
n-3(R)-yl]-butanamide (Example 1, Step I) in 3.0 mL of dry 
dimethylformamide was treated with 22.2 mg of 60% sodium hydride oil 
dispersion (13.3 mg NaH, 0.558 mmol, 1.2 eq). The reaction mixture was 
stirred at room temperature for 30 minutes. To the solution was added 153 
mg (0.465 mmol) of a solution of 
4-bromomethyl-2'-(2-thienyl)-1,1'-biphenyl dissolved in 3 mL of dry 
dimethylformamide. After stirring at room temperature for 3 hours, the 
reaction mixture was diluted with ethyl acetate. The organic layer was 
washed with water (4.times.), dried over magnesium sulfate, filtered and 
evaporated under vacuum. The residue was purified by chromatography on 
silica gel, eluting with hexane/ethyl acetate (1:1) to give 160 mg of the 
product. 
Step F: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(2-thienyl)[1,1'-biphe 
nyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate 
A solution of 154 mg (0.247 mmol) of the intermediate obtained in Step E 
dissolved in 12.3 mL of methanol was treated with an equivalent volume of 
9N aqueous hydrochloric acid. After stirring at room temperature for 16 
hours, all volatiles were removed under vacuum and the residue purified by 
medium pressure liquid chromatography on C8, eluting with methanol/0.1% 
aqueous trifluoroacetic acid (75:25). The fractions containing the product 
were combined and solvents removed under vacuum. The residue was 
lyophilized from water to give 36 mg (0.056 mmol, 23%) of the title 
compound as a white solid. FAB-MS: calculated for C.sub.31 H.sub.32 
N.sub.4 O.sub.2 S 524; found 524 (M.sup.+). .sup.1 H NMR (300 MHz, 
CD.sub.3 OD): 1.39 (s, 3H), 1.42 (s, 3H), 2.13 (m, 1H), 3.35 (m, 1H), 2.55 
(m, 4H), 4.41 (dd, 1H), 4.85 (d, 1H), 5.39 (d, 1H), 6.61 (dd, 1H), 6.81 
(d, 1H), 7.35 (dd, 2H), 7.19 (m, 2H), 7.55 (m, 8H), 7.54 (dd, 1H). 
EXAMPLE 3 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(thiazol-2-yl)[1,1'-bip 
henyl]-4-yl]methyl]-1H-1-benzazepin-3-(R)-yl]-butanamide, trifluoroacetate 
Step A: 2-Bromo-(thiobenzamide) 
Gaseous hydrogen sulfide was bubbled into a stirred solution of 1.82 g 
(10.0 mmol) of 2-bromobenzonitrile, 13 mL of triethylamine and 10 mL of 
pyridine. After 4 hours, the reaction mixture was poured into 200 mL of 
ice-water mixture. The resultant oil slowly crystallized. The precipitate 
was removed by filtration, washed with water (3.times.) and dissolved in 
methylene chloride. The organic layer was separated, dried over magnesium 
sulfate and filtered. The filtrate was evaporated under vacuum to give 
1.46 g (6.76 mmol, 68%) of the product. .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 7.24 (m, 4H), 7.52 (dt, 1H), 8.59 (dd, 1H). 
Step E: 1-Bromo-2-(thiazol-2-yl) enzene 
A solution of 2.16 g (10.0 mmol) of the intermediate obtained in Step A 
dissolved in 8 mL of 95% ethanol was treated with 2.0 g (10.0 mmol) of 
bromoacetaldehyde diethyl acetal. The mixture was then treated with 
concentrated hydrochloric acid. After heating at reflux for 3 hours, the 
reaction mixture was cooled, diluted with 100 mL of water and the pH was 
adjusted to 10 with aqueous 5N sodium hydroxide. The reaction mixture was 
extracted with ether. The combined extracts were washed with water, dried 
over magnesium sulfate, filtered and evaporated under vacuum. The residue 
was purified by chromography over silica gel, eluting with hexane/ether 
(100:5), to give 1.61 g (6.70 mmol), 67%) of the product. .sup.1 H NMR 
(200 MHz, CDCl.sub.3): 7.32 (dt, 1H), 7.46 (dt, 1H), 7.55 (d, 1H), 7.73 
(dd, 1H), 7.99 (d, 1H), 8.02 (dd, 1H). 
Step C: 4-Methyl-2'-(thiazol-2-yl)-1,1'-biphenyl 
A solution of 1.18 g (4.92 mmol) of 1-bromo-2-(thiazol-2-yl)benzene and 
1.67 g (6.55 mmol) of 4-metylphenyltrimethylstannane in 20 mL of 
dimethylformamide was treated with 621 mg of 
bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was 
heated at 150.degree. C. for 6 hours, cooled and poured into 300 mL of 
water. The resultant mixture was extracted with ether (3.times.100 mL). 
The combined ether extracts were washed with water (4.times.), dried over 
magnesium sulfate and evaporated under vacuum. The residue was purified by 
chromatography on silica gel, eluting with hexane/ether (100:10) to give 
381 mg of the product. EI-MS: calculated for C.sub.16 H.sub.13 NS 251; 
found 250. .sup.1 H NMR (200 MHz, CDCl.sub.3): 2.36 (s, 3H), 7.14 (s, 4H), 
7.24 (d, 1H), 7.40 (m, 1H), 7.42 (m, 2H), 7.73 (d, 1H), 8.20 (dt, 1H). 
Step D: 4-Bromomethyl-2'-(thiazol-2-yl)-1,1'-biphenyl 
Prepared from 4-methyl-2'-(thiazol-2-yl)-1,1'-biphenyl by the procedure 
described in Example 2, Step D. 
Step E: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(thiaz 
ol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
Prepared from 
3-t-butoxycarbonylamino-3-methyl-N-[2,2,4,5-tetrahydro-2-oxo-1H-1-benzaepi 
n-3(R)-yl]-butanamide (Example 1, Step I) and 
4-bromomethyl-2'-(thiazol-2-yl)-1,1'-biphenyl by the procedure described 
in Example 2, Step E. 
Step F: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(thiazol-2-yl)[1,1'-bi 
phenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, trifluoroacetate 
Prepared from the intermediate obtained in Step E by the procedure 
described in Example 2. Step F FAB-MS: calculated for C.sub.31 H.sub.32 
N.sub.4 O.sub.2 S 524; found 525 (M+1), .sup.1 H NMR (400 MHz, CD.sub.3 
OD); 1.34 (s, 3H), 1.38 (s, 3H), 2.11 (m, 1H), 2.32 (m, 1H), 2.52 (dd, 
2H), 2.57 (m, 2H), 4.39 (dd, 1H), 4.87 (d, 1H), 5.38 (d, 1H), 7.08 (d, 
2H), 7.20 (d, 2H), 7.27 (m, 2H), 7.36 (m, 4H), 7.47 (m, 1H), 7.52 (m, 1H), 
7.70 (d, 1H), 7.80 (dd, 1H). 
EXAMPLE 4 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-pyrazol-3-yl) 
[1,1'-biphenyl]-4yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
Step A: 4-Methyl-2'-acetyl-1,1'-biphenyl 
A vigorously stirred solution of 13.25 g (66 mmol) of 2-bromoacetophenone 
and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of 
dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 
mmol) of bis(triphenylphosphine) palladium(II) chloride and the resulting 
mixture heated at 150.degree. C. for 6 hours. The reaction mixture was 
cooled, poured into water (1000 mL) and the resultant suspension extracted 
with ethyl ether. The combined extracts were washed with water (4.times.), 
dried over magnesium sulfate and evaporated under vacuum. The residue was 
purified by preparative high pressure liquid chromatography on silica gel, 
eluting with hexane/ethyl acetate (10:1), to give 9.8 g (47 mmol, 71%) of 
the product as an oil. EI-MS: calculated for C.sub.15 H.sub.14 O 210: 
found 210 (M+). .sup.1 H NMR (200 MHz, CDCl.sub.3): 1.98 (s, 3H), 2.37 (s, 
3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H). 
Step B: 4-Methyl-2'-[3-hydroxypropenoyl]-1,1'-biphenyl, sodium salt 
A rapidly stirred suspension of 133 mg (5.78 mmol) of finely cut sodium 
pieces in 25 mL of ether was treated, dropwise, with a solution of 1.05 g 
(5.0 mmol) of 4-methyl-2'-acetyl-1,1'-biphenyl dissolved in 1.5 mL of 
ethyl formate. After the addition of approximately 25% of the solution, a 
vigorous reaction occurred. The rate of addition was adjusted so as to 
moderate the reaction. After the addition was complete, the reaction 
mixture was stirred for an additional hour. The reaction mixture was 
filtered and the cake was washed with ether (4.times.) to yield 1.34 g of 
crude product which was used in the next step without purification. 
Step C: 4-Methyl-2'-[1H-pyrazol-3-yl]-1,1'-biphenyl 
A solution of 600 mg (2.3 mmol) of the crude intermediate obtained in Step 
B, dissolved in 7 mL of ethanol and 3 mL of water, was treated with 1 mL 
of an aqueous solution of 243 mg (2.3 mmol) of sodium carbonate. The 
reaction mixture was treated with 315 mg (4.6 mmol) of hydrazine 
hydrochloride, then heated at reflux for 30 minutes. The reaction mixture 
was partially concentrated under vacuum and then diluted with 70 mL of 
water. The resultant mixture was extracted several times with ether. The 
combined extracts were washed with water, dried over magnesium sulfate, 
filtered and evaporated under vacuum. The residue was purified by 
chromatography over silica gel, eluting with hexane/ethyl acetate (2:1), 
to yield 458 mg (1.96 mmol, 85%) of the product. FAB-MS: calculated for 
C.sub.16 H.sub.14 N.sub.2 234; found 233 (M-1). .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 2.40 (s, 3H), 6.16 (d, 1H), 7.28 (m, 8H), 7.64 (dd, 1H). 
Step D: 4-Methyl-2'-[(2-triphenylmethyl)pyrazol-3-yl]-1,1'-biphenyl and 
4-methyl-2'-[(1-triphenylmethyl)pyrazol-3-yl]-1,1'-biphenyl 
A solution of 1.01 g (4.32 mmol) of the intermediate obtained in Step C in 
6.8 mL of dry dimethylformamide was treated with 184 mg of 60% sodium 
hydride oil dispersion (110 mg NaH, 4.5 mmol, 1.07 eq). After stirring at 
room temperature for 30 minutes, the reaction mixture was treated with 
1.29 g (4.62 mmol) of triphenylmethyl chloride. After stirring at room 
temperature for 2 hours, the reaction mixture was poured into 100 mL of 
water and the resultant suspension extracted several times with ether. The 
combined extracts were washed with water (4.times.), dried over magnesium 
sulfate, filtered and evaporated under vacuum. The residue was purified by 
preparative thin layer chromatography with multiple elutions of 
hexane/ethyl acetate (5:1) to yield 40 mg of a faster minor isomer 
4-methyl-2'-[(2-triphenylmethyl)pyrazol-3-yl)-1,1'-biphenyl (200 MHz, 
CDCl.sub.3); 2.34 (s, 3H), 6.38 (d, 1H), 7.20 (m, 23H), 7.50 (dd, 1H); as 
well as 310 mg of a slower major component, 
4-methyl-2'-[(1-triphenylmethyl)pyrazol-3-yl]-1,1-biphenyl, (200 MHz, 
CDCl.sub.3): 2.38 (s, 3H), 5.68 (d, 1H), 7.20 (m, 23H), 7.68 (dd, 1H). 
Step E: 4-Bromomethyl-2'-[(1-triphenylmethyl)pyrazol-3-yl]-1,1'-biphenyl 
Prepared from 4-methyl-2'-[(1-triphenylmethyl)pyrazol-3-yl]-1,1'-biphenyl 
by the procedure described in Example 2, Step D. .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 4.40 (s, 2H), 5.70 (d, 1H), 7.20 (m, 23H), 7.62 (dd, 1H). 
Step F: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[(2'-triph 
enylmethyl)pyrazol-3-yl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaepin-3(R)-yl 
]-butanamide 
Prepared from 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3-(R)-yl]-butanamide (Example 1, Step I) and 
4-bromomethyl-2'-[(1-triphenylmethyl)pyrazol-3-yl]-1,1'-biphenyl by the 
procedure described in Example 2, Step E. 
Step G: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2-(1H-pyrazol-3-yl)[1,1'- 
biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
The title compound was prepared from the intermediate obtained in Step F by 
the procedure described in Example 2, Step F. FAB-MS: calculated for 
C.sub.31 H.sub.33 N.sub.5 O.sub.2 507; found 508 (M+1). .sup.1 H NMR (400 
MHz, CD.sub.3 OD), 1.35 (s, 3H), 1.38 (s, 3H), 2.10 (m, 1H), 2.30 (m, 1H), 
4.38 (dd, 1H), 4.82 (d, 1H), 5.32 (d, 1H), 5.55 (br s, 1H), 7.06 (d, 1H), 
7.15 (d, 1H), 7.24 (m, 1H), 7.38 (m, 10H), 7.68 (dd, 1H). 
EXAMPLE 5 
3-Amino-3-Methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-4-yl)[1,1' 
-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
di(trifluoroacetate) 
Step A: 4-Methyl-2'-bromoacetyl-1,1'-biphenyl 
A solution of 2.06 g (9.79 mmol) of 4'-methyl-2-acetyl-1,1'-biphenyl 
(Example 4, Step A) in 10 mL of glacial acetic acid was treated dropwise 
with a solution of bromine (1.722 g, 1.07 mmol) dissolved in 3.0 mL of 
glacial acetic acid. After initiating the reaction with the first few 
drops of the bromine/acetic acid reagent by heating the reaction mixture 
at 30.degree.C., the remainder of the bromine solution was added dropwise 
at 25.degree.-30.degree. C. The reaction mixture was stirred at room 
temperature until the consumption of bromine was complete (approximately 2 
hrs). The reaction mixture was diluted with 150 mL of hexane then washed 
with water (3.times.50 mL). The organic layer was removed, dried over 
magnesium sulfate, filtered and evaporated under vacuum to give 2.92 g of 
an oil that was used in the next step without purification. .sup.1 H NMR 
(crude product) (200 MHz, CDCl.sub.3): 2.38 (s, 3H), 3.66 (s, 2H), 7.21 
(s, 4H), 7.3-7.6 (m, 4H). 
Step B: 4-Methyl-2'-(1H-imidazol-4-yl)-1,1'-biphenyl 
A vigorously stirred solution of 1.0 g (3.5 mmol) of 
4-methyl-2'-bromoacetyl-1,1'-biphenyl and 1.86 g of formamidine acetate in 
10 mL of formamide was heated at 150.degree. C. for 6 hours. The reaction 
mixture was cooled, poured into 100 mL of water and the resultant mixture 
extracted several times with ether. The combined extracts were washed with 
water (3.times.), dried over magnesium sulfate, filtered and evaporated 
under vacuum. The residue was purified by chromatography over silica gel, 
eluting with hexane/ethyl acetate (1:1) to yield 200 mg (0.86 mmol, 24%) 
of the product. FAB-MS (Li spike): calculated for C.sub.16 H.sub.14 
N.sub.2 234; found 241 (M+Li). .sup.1 H NMR (200 MHz, CDCl.sub.3); 2.34 
(s, 3H), 6.61 (s, 1H), 7.10 (m, 4H), 7.30 (m, 3H), 7.48 (s, 1H), 7.68 (dd, 
1H). 
Step C: 4-Methyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl 
A solution of 474 mg (2.03 mmol) of the intermediate obtained in Step B in 
2 mL of dry dimethylformamide was treated with 25 mg of 60% sodium hydride 
oil dispersion (15 mg NaH, 0.63 mmol). After stirring at room temperature 
for 30 minutes, the reaction mixture was treated with 160 mg (0.575 mmol) 
of triphenylmethyl chloride. After stirring at room temperature for 2 
hours, the reaction mixture was poured into 100 mL of water and the 
resultant suspension extracted several times with ether. The combined 
extracts were washed with water (4.times.), dried over magnesium sulfate, 
filtered and evaporated under vacuum. The residue was purified by 
preparative thin layer chromatography with multiple elutions of 
hexane/ethyl acetate (2:1) to yield 110 mg (0.23 mmol, 11%) of the 
product. FAB-MS (Li spike): calculated for C.sub.35 H.sub.28 N.sub.2 476; 
found 483 (M+Li). .sup.1 H NMR (200 MHz, CDCl.sub.3); 2.32 (s, 3H), 5.85 
(d, 1H), 7.02 (m, 10H), 7.73 (m, 15H). 
Step D: 4-Bromomethyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl 
Prepared from 4-methyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl 
by the procedure described in Example 2, Step D. .sup.1 D NMR (200 MHz, 
CDCl.sub.3): 4.2 (s, 2H), 5.92 (d, 1H), 6.92 (m, 6H), 7.25 (m, 18H), 8.01 
(d, 1H). 
Step E: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[1-(tr 
iphenylmethyl) 
imidazol-4-yl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butana 
mide 
Prepared from 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3(R)-yl]-butanamide (Example 1, Step I) and 
4-bromomethyl-2'-[1-(triphenylmethyl)imidazol-4-yl]-1,1'-biphenyl by the 
procedure described in Example 2, Step E. 
Step F: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-imidazol-4-yl)[1,1 
'-biphenyl]-4yl]methyl]-1H-1-benzazepin-3(R)-yl]-butamide, 
di(trifluoroacetate) 
The title compound was prepared from the intermediate obtained in Step E by 
the procedure described in Example 2, Step F. FAB-MS (Li spike); 
calculated for C.sub.31 H.sub.33 N.sub.5 O.sub.2 507; found 514 (M+Li). 
.sup.1 H NMR (400 MHz, CD.sub.3 OD): 1.34 (s, 3H), 1.38 (s, 3H), 2.10 (m, 
1H), 3.32 (m, 1H), 2.52 (dd, 2H), 2.57 (m, 2H), 4.38 (dd, 1H), 4.84 (d, 
1H), 5.33 (d, 1H), 6.91 (br, s, 1H), 7.11 (d, 2H), 7.21 (d, 4H), 7.39 (m, 
3H), 7.51 (m, 3H), 8.86 (brs, 1H). 
EXAMPLE 6 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,3-triazol-4-yl) 
[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
Step A: 4-Methyl-2'-nitro-1,1'-biphenyl 
A vigorously stirred mixture of 4-tolylboronic acid (34 g, 0.25 mol) and 
2-bromo-1-nitrobenzene (34 g, 0.168 mol) in a mixture of 5N sodium 
hydroxide (170 mL), water (57 mL), isopropanol (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 hours. 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.times.), 
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), to give 28.05 g of the product. EI-MS: calculated for 
C.sub.13 H.sub.11 NO.sub.2 213; found 213 (M+). .sup.1 H NMR (400 MHz, 
CDCl.sub.3); 2.38 (s, 3H), 7.20 (m, 4H), 7.43 (m, 2H), 7.59 (t, 1H), 7.8 
(d, 1H). 
Step B: 4-Methyl-2'-amino-1,1'-biphenyl 
A solution of 15 g (70 mmol) of 4-methyl-2'-nitro-1,1'-biphenyl in 160 mL 
of methanol containing 900 mg of 5% palladium on carbon was hydrogenated 
for 1.5 hours at 40 psi. The reaction mixture was filtered through Celite 
and the filtrate evaporated under vacuum to yield 11.94 g (65.2 mmol, 93%) 
of the product. FAB-MS: calculated for C.sub.13 H.sub.13 N 183; found 184 
(M+1). 
Step C: 4-Methyl-2'-iodo-1,1'-biphenyl 
A suspension of 10.0 g (54.6 mmol) of 4-methyl-2'-amino-1,1'-biphenyl in 
135 mL of water containing 15 mL of concentrated hydrochloric acid was 
cooled at -5.degree. C. and treated dropwise with a solution of 3.94 g 
(57.1 mmol) of sodium nitrite in 9.24 mL of water while maintaining the 
temperature below 0.degree. C. After the addition was complete, the 
reaction mixture was stirred an additional 10 minutes. The reaction 
mixture was slowly poured into a vigorously stirred solution of 29.6 g 
(178 mmol) of potassium iodide and 643 mg (2.5 mmol) of iodine dissolved 
in 80 mL of water. When the addition was complete, the reaction mixture 
was slowly warmed to 35.degree. C. and stirred for an additional 25 
minutes. The reaction mixture was cooled, and extracted with ethyl ether. 
The combined extracts were washed with aqueous 10% sodium thiosulfate 
(3.times.). aqueous saturated sodium bicarbonate (1.times.), and water 
(1.times.). The extracts were dried over magnesium sulfate, filtered and 
evaporated under vacuum to yield 14 g of crude product. The product was 
purified by chromatography over silica gel, eluting with hexanes to yield 
9.34 g (31.8 mmol, 58%) of the product. FAB-MS: calculated for C.sub.13 
H.sub.11 I 294; found 295 (M+1). .sup.1 H NMR (200 MHz, CDCl.sub.3): 2.42 
(s, 3H): 7.14 (dt, 1H), 7.32 (m, 5H), 7.95 (dd, 1H). 
Step D: 4-Methyl-2'-trimethylsilyethynyl-1,1'-biphenyl 
A suspension of 5.2 g (17.7 mmol) of 4-methyl-2'-iodo-1,1'-biphenyl, 77 mL 
of triethylamine, 3.1 mL (22 mmol) of trimethylsilyl acetylene containing 
234 mg of cuprous iodide was treated with 470 mg of 
bis(triphenylphosphine) palladium (II) chloride. After stirring at room 
temperature for 16 hours, the reaction mixture was evaporated under 
vacuum. The residue was triturated with ether and filtered. The cake was 
washed with ether (2.times.). The combined etheral solutions were 
evaporated under vacuum to yield 5.23 g of crude product. FAB-MS: 
calculated for C.sub.18 H.sub.20 Si 264; found 264. .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 0.14 (s, 9H), 2.40 (s, 3H), 7.24 (m, 3H), 7.39 (m, 2H), 58 
(m, 3H). 
Step E: 4-Methyl-2'-ethynyl-1,1'-biphenyl 
A solution of 5.23 g (19.8 mmol) of 
4-methyl-2'-trimethylsilylethynyl-1,1'-biphenyl in 60 mL of methanol was 
treated with 6 mL of 1.25N aqueous sodium hydroxide. The reaction mixture 
was stirred at room temperature for 30 minutes and evaporated under 
vacuum. The residue was extracted with ether. The combined ether extracts 
were washed with water, dried over magnesium sulfate and evaporated under 
vacuum. The residue was purified by chromatography over silica gel, 
eluting will hexane, to yield 2.52 g (13.1 mmol, 66%) of the product. 
FAB-MS: calculated from C.sub.15 H.sub.12 192; found 191 (M-1). .sup.1 H 
NMR (200 MHz, CDCl.sub.3): 2.40 (s, 3H), 5.26 (s, 1H), 7.3 (m, 8H). 
Step F: 4-Methyl-2'-(1H-1,2,3-triazol-4-yl)-1,1'-biphenyl 
A solution of 2.52 g (13.1 mmol) of 4-methyl-2'-ethynyl-1,1'-biphenyl in 18 
mL of trimethylsilyl azide under a nitrogen atmosphere was heated at 
120.degree. C. for 72 hours. The volume was reduced by distillation at 
atmosphere pressure. The residue was dissolved in methylene chloride. The 
organic layer was washed with water (3.times.) dried over magnesium 
sulfate, filtered and evaporated under vacuum to yield 3.1 g of crude 
product which was purified over silica gel, eluting with hexane/ethyl 
acetate (3:1) to yield 1.35 g (5.77 mmol, 44%) of the product. FAB-MS: 
calculated for C.sub.15 H.sub.13 N.sub.3 235; found 237. .sup.1 H NMR (400 
MHz, CDCl.sub.3): 2.38 (s, 3H), 7.0 (s, 1H), 7.20 (dd, 4H), 7.40 (m, 3H), 
7.80 (dd, 1H). 
Step G. 4-Methyl-2'-(1-triphenylmethyl-1,2,3-triazol-4yl)-1,1'-biphenyl and 
4-methyl-2'-(3-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl 
Prepared from 4-methyl-2'-(1H-1,2,3-triazol-4-yl)-1,1'-biphenyl by the 
procedure described in Example 4, Step D: the faster moving, less polar 
iosmer: .sup.1 H NMR (200 MHz, CDCl.sub.3): 2.35 (s, 3H), 6.95 (s, 1H), 
7.70 (m, 9H), 7.37 (m, 9H), 7.74 (dt, 1H). 
The more polar, slower moving isomer: .sup.1 H NMR (200 MHz, CDCl.sub.3): 
2.30 (s, 3H), 6.43 (s, 1H), 7.0 (m, 9H), 7.32 (m, 9H), 8.15 (dd, 1H). 
Step H: 
4-bromomethyl-2'-(1-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl and 
4-bromomethyl-2'-(2-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl 
Prepared from 
4-methyl-2'-(1-triphenylmethyl)-1,2,3-triazol-4-yl)-1,1'-biphenyl and 
4-methyl-2'-(2-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl by the 
procedure described in Example 2, Step D. 
Step I: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(N-tri 
phenylmethyl-1,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepi 
n-3(R)-yl]-butanamide 
Prepared from 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3(R)-yl]-butanamide (Example 1, Step I) and 
4-bromomethyl-2'-(1-triphenylmethyl-1,2,3-triazol-4-y)-1,1'-biphenyl and 
4-bromomethyl-2'-(2-triphenylmethyl-1,2,3-triazol-4-yl)-1,1'-biphenyl by 
the procedure described in Example 2, Step E. 
Step J: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,3-triazol-4-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)--yl]-butanamide, 
trifluoroacetate 
The title compounds was prepared from the intermediate obtained in Step I 
by the procedure described in Example 2, Step F. FAB-MS: calculated for 
C.sub.30 H.sub.32 N.sub.6 O.sub.2 508; found 509 (M+H). .sup.1 H NMR (400 
MHz, CD.sub.3 OD): 1.38 (s, 3H), 1.44 (s, 3H), 2.18 (m, 1H), 2.38 (m, 1H), 
2.59 (dd, 2H), 2.63 (m, 2H), 4.44 (dd, 1H), 4.92 (d, 1H), 5.39 (d, 1H), 
6.82 (s, 1H), 7.20 (dd, 4H), 7.30 (m, 1H), 7.4 (m, 4H), 7.5 (m, 2H), 7.79 
(m, 1H). 
EXAMPLE 7 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-( 
1H-1,2,4-triazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl] 
-butanamide, trifluoroacetate 
Step A: 4-Methyl-2'-cyano-1,1'-biphenyl 
A solution of 2.0 g (11 mmol) of 2-bromobenzonitrile, 2.93 g (11.5 mmol) of 
4-methylphenyltrimethylstannane and 0.39 g (0.55 mmol) of 
bis-triphenylphosphine palladium (II) chloride in 50 mL of dry 
dimethylformamide under nitrogen was heated at 100.degree. C. for 5.5 
hours. The reaction was cooled to room temperature. The reaction was 
poured into 150 mL of water and extracted with ether (3.times.150 mL). The 
combined ether extracts were washed with water (4.times.100 mL) and brine 
(100 mL), dried over magnesium sulfate, filtered and the solvents removed 
under vacuum. Purification by flash chromatography on silica gel, eluting 
with hexane/ether (85:15), afforded 1.69 g (80%) of the product 
contaminated with approximately 10% of 2-methylbenzonitrile. .sup.1 H NMR 
(200 MHz, CDCl.sub.3): 2.40 (s, 3H), 7.27 (d, 7 Hz, 2H), 7.30-7.65 (m, 
5H), 7.72 (d, 6 Hz, 1H). FAB-MS: calculated for C.sub.14 H.sub.11 N 193; 
found 193 (M+, 100%). 
Step B: 4-Methyl-2'-thiocarboxamido-1,1'-biphenyl 
A cooled, stainless steel vessel was charged with 2.5 g (13 mmol) of 
4-methyl-2'-cyano-1,1'-biphenyl, 25 mL of pyrridine, 25 mL of 
triethylamine and 9.6 g of hydrogen sulfide then was sealed and heated in 
a rocking autoclave for 12 hours at 90.degree. C. The reaction vessel was 
cooled, vented and the contents poured into water. The mixture was 
extracted several times with ether. The combined extracts were washed with 
water (5.times.), dried over magnesium sulfate, filtered and evaporated 
under vacuum. The residue was purified by chromatography over silica gel, 
eluting with hexane/ethyl acetate (3:1) to yield 1.88 g (8.28 mmol, 64%) 
of the product. .sup.1 H NMR (200 MHz, CDCl.sub.3): 2.4 (s, 3H), 6.48 (br 
s, 2H), 7.3 (m, 7H), 7.9 (dd, 1H). 
Step C: 4-Methyl-2'-isothiocarboximino-1,1'-biphenyl, methiodide 
A solution of 200 mg (0.88 mmol) of 
4-methyl-2'-thiocarboxamido-1,1'-biphenyl in 8 mL of ethyl ether was 
treated with 0.40 mL (6.4 mmol) of iodomethane. After stirring at room 
temperature for 24 hours, the reaction mixture was filtered. The 
precipitate was washed wth ether (3.times.) and dried under vacuum to 
yield 270 mg (0.73 mmol, 83%) of the product. .sup.1 H NMR (200 MHz, 
CDCl.sub.3), 2.42 (s, 3H), 2.9 (s, 3H), 7.27 (s, 4H), 7.5 (m, 2H), 7.65 
(t, 2H). 
Step D: 4-Methyl-2'-(1H-1,2,4-triazol-3-yl)-1,1'-biphenyl 
A stirred solution of 250 mg (0.68 mmol) of the intermediate obtained in 
Step C dissolved 2.5 mL of dry dimethylforamide under a nitrogen 
atmosphere was treated with 81 mg (1.4 mmol) of formic hydrazide. The 
reaction was stirred at room temperature for 16 hours, then heated at 
90.degree. C. for 4 hours. The cooled reaction mixture was poured into 
water and extracted wth ether. The combind extracts were washed with water 
(4.times.), dried over magnesium sulfate, filtered and evaporated under 
vacuum to yield 85 mg (0.36 mmol, 53%) of crude product. .sup.1 H NMR (200 
MHz, CDCl.sub.3): 2.40 (s, 3H), 7.15 (d, 2H), 7.21 (d, 2H), 7.34 (m, 1H), 
7.44 (m, 2H), 8.05 (s, 1H), 8.15 (dd, 1H). 
Step E: 4-Methyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl 
Prepared from 4-methyl-2'-(1,2,4-triazol-3-yl)-1,1'-biphenyl by the 
procedure described in Example 4, Step D. 
Step F: 
4-Bromomethyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl 
Prepared from 
4-methyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl by the 
procedure described in Example 2, Step D. 
Step G: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1-tri 
phenylmethyl-1, 
2,4-triazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-but 
anamide 
Prepared from 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3(R)-yl]-butanamide (Examle 1, Step I) and 
4-bromomethyl-2'-(1-triphenylmethyl-1,2,4-triazol-3-yl)-1,1'-biphenyl by 
the procedure described in Example 2, Step E. 
Step H: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1H-1,2,4-triazol-3-yl 
)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
trifluoroacetate 
The title compound was prepared from the intermediate obtained in Step G by 
the procedure described in Example 2, Step F. FAB-MS: calculated for 
C.sub.30 H.sub.32 N.sub.6 O.sub.2 508: found 509 (M+H). .sup.1 H NMR (400 
MHz, CD.sub.3 OD): 1.34 (s, 3H) 1.39 (s, 3H), 2.1 (m, 1H), 2.3 (m, 1H), 
2.52 (dd, 2H), 2.54 (m, 2H), 4.38 (dd, 1H), 4.86 (d, 1H), 5.24 (d, 1H), 
7.1 (dd, 4H), 7.22 (m, 2H), 7.32 (m, 2H), 7.48 (m, 2H), 7.59 (m, 2H), 8.20 
(s, 1H). 
EXAMPLE 8 
N-[1-[[2'-[[(Thiazol-2-yl)aminocarbonyl]amino][1,1'-biphenyl]-4-yl]methyl]- 
2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-amino-3-methylbutanamid 
e, trifluoroacetate 
Step A: 4-Bromomethyl-2'-nitro-1,1'-biphenyl 
Prepared from 4-methyl-2'-nitro-1,1'-biphenyl by the procedure described in 
Example 2. Step D. BI-MS: calculated for C.sub.14 H.sub.10 BrN 272,274; 
found 272, 274 (M+). .sup.1 H NMR (200 MHz, CDCl.sub.3): 4.53 (s, 2H), 
7.2-7.7 (m, 7H), 7.85 (m, 1H). 
Step B: 
N-[1-[[(2'-Nitro)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H- 
1-benzazepin-3(R)-yl ]-3-t-butoxycarbonylamino-3-methylbutanamide 
Prepared from 4-bromomethyl-2'-nitro-1,1'-biphenyl and 3-t-butoxyca, 
bonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-b 
utanamide (Example 1, Step I) by the procedure described in Example 2, Step 
E. FAB-MS: calculated for C.sub.33 H.sub.38 N.sub.4 O.sub.6 586; found 587 
(M+H). .sup.1 H NMR (400 MHz, CDCl.sub.3): 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). 
Step C: 
N-[1-[[2'-Amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1 
-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide 
A solution of 7.79 g (13.23 mmol) of the intermediate obtained in Step B 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 
concentrate under vacuum to yield 6.6 g (11.9 mmol, 90%) of product. 
FAB-MS: calculated for C.sub.33 H.sub.40 N.sub.4 O.sub.4 556; found 557 
(M+H). .sup.1 H NMR (400 MHz, CDCl.sub.3): 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). 
Step D: 
N-[1-[[(2'-Isocyanato)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-ox 
o-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide 
A solution of 2.0 g (3.6 mmol) of the intermediate obtained in Step C and 
2.0 mL of triethylamine (14 mmol) in 40 mL of methylene chloride under a 
nitrogen atmosphere was cooled to -10.degree. C. and treated with 2.12 g 
(7.15 mmol) of triphosgene in one portion. An exotherm ocurred. The 
reaction was stirred at room temperature for 1.5 hours when no starting 
amine was detected by thin layer chromatography on silica, eluting with 
hexane/ethyl acetate (1:1). The reaction mixture was diluted with 40 mL of 
hexane and filtered. The filtrate was passed over 150 g of silica gel and 
eluted with hexane/ethyl acetate (1:1) to give 1.65 g (2.84 mmol, 79%) of 
the product. .sup.1 H NMR (400 MHz, CDCl.sub.3): 1.34 (s, 6H), 1.39 (s, 
9H), 1.84 (m, 1H), 2.40 (m, 1H), 2.49 (dd, 1H), 2.52 (m, 1H), 4.51 (m, 
1H), 4.88 (d, 1H), 5.25 (d, 1H), 5.34 (br s, 1H), 6.71 (d, 1H), 7.20 (m, 
12H). 
Step E: 
N-[1-[[2'-[[(Thiazol-2-yl)aminocarbonyl]amino][1,1'-biphenyl]-4-yl]methyl] 
-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-amino-3-methylbutanami 
de, trifluoroacetate 
A solution of 116 mg (0.20 mmol) of the intermediate obtained in Step D in 
1 mL of methylene chloride under a nitrogen atmosphere was treated with 
2-aminothiazole (40 mg, 0.363 mmol). The reaction mixture was stirred at 
room temperature for 2 hours, when thin layer chromatography (hexane/ethyl 
acetate; 1:1) showed no starting isocyanate. The reaction mixture was 
treated with trifluoroacetic acid (0.5 mL). After 1 hr, the reaction 
mixture was evaporated under vacuum. The residue was purified by reverse 
phase medium pressure liquid chromatography on C8, eluting with 
methanol/0.1% aqueous trifluoroacetic acid (55:45). Fractions containing 
the product were combined, solvents removed under vacuum and the residue 
lyophilized from water to give 110 mg of impure product. The impure 
material was further chromatographed on silica gel, eluting with methylene 
chloride/methanol/concentrated ammonium hydroxide (9:1:0.1) to give 30 mg 
of product which was lyophilized from water to give 25 mg (0.036 mmol, 
18%) of the title compound as a white solid. FAB-MS: calculated for 
C.sub.32 H.sub.34 N.sub.6 O.sub.3 S 582: found 605 (M+Na). .sup.1 H NMR 
(400 MHz, CD.sub.3 OD): 1.22 (s, 3H), 1.26 (s, 3H), 2.12 (m, 1H), 2.36 (m, 
1H), 2.40 (dd, 2H), 2.60 (m, 2H), 4.40 (dd, 1H), 5.06 (d, 1H), 5.20 (d, 
1H), 6.98 (d, 1H), 7.28 (m, 13H), 7.88 (d, 1H). 
EXAMPLE 9 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro-2-oxoazol 
yl)amino][1,1'-biphenyl]-4-yl]-methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
Step A: 
N-[1-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-buboxycarbonylamin 
o-3-methylbutanamide 
Prepared from N-[1-[[(2'-isocyanato) 
[1,1'-biphenyl]-4-yl]methyl]2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)- 
yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 8, Step D) and 
ethanolamine by the procedure described in Example 6, Step A. FAB-MS: 
calculated for C.sub.36 H.sub.45 N.sub.5 O.sub.6 643; found 666 (M+Na). 
.sup.1 H NMR (400 MHz, CDCl.sub.3): 1.29 (s, 3H), 1.31 (s, 3H), 1.38 (s, 
9H), 1.90 (m, 1H), 2.5 (dd, 2H), 2.58 (m, 2H), 2.7 (m, 1H), 3.21 (t, 2H), 
3.54 (m, 2H), 4.49 (m, 1H), 4.88 (d, 1H), 5.10 (d, 1H), 6.81 (d. 1H), 7.21 
(m, 11H), 7.74 (d, 1H). 
Step B: 
3-t-Butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5- 
dihydro-2-oxazolyl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)- 
yl]-butanamide 
A solution containing 500 mg (0.78 mmol) of the intermediate obtained in 
Step A, 0.125 mL of triethylamine and 50 mg (0.41 mmol) of 
4-dimethylaminopyridine dissolved in 8 mL of methylene chloride under a 
nitrogen atmosphere was cooled to 0.degree. C. and treated dropwise with 
0.070 mL of methanesulfonyl chloride. The reaction mixture was stirred at 
ambient temperature for 1 hour when an additional 0.50 mL of 
methanesulfonyl chloride was added. After stirring at room temperature for 
an additional hour, the reaction mixture was diluted to 100 mL with 
methylene chloride. The organic layer was washed with water, dried over 
magnesium sulfate, filtered and evaporated under vacuum. The residue was 
purified by chromatography over silica gel, eluting with methylene 
chloride/2-propanol (100:5) to yield 190 mg of product. FAB-MS: calculated 
for C.sub.36 H.sub.43 N.sub.5 O.sub.5 625; found 626 (M+H), .sup.1 H NMR 
(400 MHz, CDCl.sub.3): 1.33 (s, 3H), 1.34 (s, 3H), 1.39 (s, 9H), 1.87 (m, 
1H), 2.48 (dd, 2H), 2.69 (m, 2H), 3.62 (m, 2H), 4.15 (dt, 2H), 4.51 (m, 
1H), 4.90 (d, 1H), 5.20 (d, 1H), 6.69 (d, 1H), 7.20 (m, 12H). 
Step C: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(4,5-dihydro-2-oxazol 
yl)amino][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
The title compound was prepared from the intermediate obtained in Step B by 
the procedure described in Example 2, Step F. FAB-MS: calculated for 
C.sub.31 H.sub.35 N.sub.5 O.sub.3 525: found 527. .sup.1 H NMR (400 MHz, 
CD.sub.3 OD): 1.34 (s, 3H), 1.39 (s, 3H), 1.23 (m, 1H), 2.34 (m, 1H), 2.56 
(dd, 2H), 2.64 (m, 2H), 4.39 (dd, 1H), 4.48 (d, 1H), 5.44 (d, 1H), 7.35 
(m, 12H). 
EXAMPLE 10 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-( 
1H-imidazol-2-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-di(trifl 
uoroacetate) 
Step A: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-buta 
namide, trifluoroacetate 
To a solution of 150 mg (0.040 mmol) of 
3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazep 
in-3(R)-yl]-butanamide (Example 1, Step I) in 2 mL of methylene chloride at 
0.degree. C. was added 2 mL of trifluoroacetic acid and the mixture 
stirred at room temperature for 1 hour. All volatiles were removed under 
vacuum to give 130 mg (0.33 mmol, 84%) of the product. .sup.1 H NMR (200 
MHz, CD.sub.3 OD): 1.33 (s, 3H), 1.37 (s, 3H), 2.12 (m, 1H), 2.3-2.6 (m, 
3H), 2.6-3.0 (m, 2H), 4.37 (dd; 8, 12Hz; 1H), 7.02 (d, 8 Hz, 1H), 7.1-7.3 
(m, 3H). FAB-MS: calculated for C.sub.15 H.sub.21 N.sub.3 O.sub.2 275; 
found 276 (M+H, 100%). 
Step B: 
3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-be 
nzazepin-3 (R)-yl]-butanamide, trifluoroacetate 
To a solution of 1.0 g (2.57 mmol) of 
3-amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-buta 
namide, trifluoroacetate in 25 mL of dry methanol was added 3.0 g of dry 3A 
powdered molecular sieves followed by a solution of 2.5 g (17 mmol) of 
(R)-2-benzyloxypropanal (prepared from ethyl-D-lactate according to the 
procedure of Hanessian and Kloss, Tetrahedron Lett. 1985, 26, 1261-1264) 
in 5 mL of dry methanol. The pH of the mixture was carefully adjusted to 6 
by the addition of trifluoroacetic acid. The reaction was stirred for 2 
hours at room temperature at which time 15.4 mL (15.4 mmol) of a 1.0 M 
solution of sodium cyanoborohydride in tetrahydrofuran was added by 
syringe. The reaction was stirred for 72 hours then filtered through a pad 
of Celite. To the filtrate was added 5 mL of trifluoroacetic acid 
(CAUTION! evolution of hydrogen cyanide) and the resulting mixture was 
stirred for three hours. The solvent was removed under vacuum to afford a 
clear oil which was purified by reverse phase medium pressure liquid 
chromatography on C-8, eluting with methanol/0.1% aqueous trifluoroacetic 
acid (60:40), to afford 1.27 g (2.36 mmol, 92%) of the product as a white 
solid. .sup.1 H NMR (200 MHz, CD.sub.3 OD): 1.31 (d, 6 Hz, 3H), 1.40 (s, 
3H), 1.43 (s, 3H), 2.17 (m, 1H), 2.30 (m, 1H), 2.6-3.1 (m, 5H), 3.22 (dd; 
3, 12 Hz; 1H), 3.86 (m, 1H), 4.48 (dd; 7, 12 Hz; 1H), 4.50 (d, 12 Hz, 1H), 
4.70 (d, 12 Hz, 1H), 7.11 (d, 8 Hz, 1H), 7.15-7.45 (m, 8H). FAB-MS: 
calculated for C.sub.25 H.sub.33 N.sub.3 O.sub.3 423; found 424 (M+H, 
100%). 
Step C: 
3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetranydro-2-oxo-1-[[2'- 
[1-(4-toluenesulfonyl)imidazol-2-yl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benza 
zepin-3(R)-yl]-butanamide 
Prepared from 
3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-be 
nzazepin-3(R)-yl]-butanamide trifluoroacetate and 
1-(4-toluenesulfonyl)-2-[4'-(methanesulfonyloxymethyl)-1,1'-biphen-2-yl]im 
idazole (Example 1, Step N) by the procedure described in Example 1, Step 
O. The crude product thus obtained was used directly in the next step 
without purification. 
Step D: 
3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(1H-imidazol-2-yl) 
[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
di(trifluoroacetate) 
A solution of 50 mg (0.06 mmol) of the crude intermediate obtained in Step 
C in 0.5 mL of methylene chloride was treated with 25 mg of 
1-hydroxybenzotriazole hydrate. The mixture was stirred at room 
temperature for one hour then all volatiles removed under vacuum and the 
residue purified by reverse phase medium pressure liquid chromatography on 
C8, eluting with methanol/0.1% aqueous trifluoroacetic acid (60:40) to 
give 17 mg (0.02 mmol, 33%) of the product as a colorless glass. FAB-MS: 
calculated for C.sub.41 H.sub.45 N.sub.5 O.sub.3 655; found 656 (M+H, 
93%). .sup.1 H NMR (200 MHz, CD.sub.3 OD); 1.26 (d, 6 Hz, 3 H), 1.36 (br 
s, 6H), 2.11 (m, 1H), 2.25-2.70 (m 5H), 2.5 (m, 1H), 3.19 (m, 1H), 3.83 
(m, 1H), 4.44 (m, 2H), 4.67 (d, 12Hz, 1H), 5.31 (d, 15 Hz, 1H), 7.04 (d, 8 
Hz, 2 H), 7.1-7.8 (m, 17H). 
Step E: 
3-[(2(R)-Hydroxypropyl)amino]-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
(1H-imidazol-2-yl) 
[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
di(trifluoroacetate) 
A solution of 51 mg (0.058 mmol) of the intermediate obtained in Step D in 
2 mL of methanol was treated with two drops of trifluoroacetic acid and 
the resulting mixture was hydrogenated at ambient temperature and 40 psi 
overt 50 mg of 20% palladium on carbon for 24 hours. The reaction mixture 
was filtered through Celite and the filtrate exaporated to dryness under 
vacuum. The residue was purified by reverse phase medium pressure liquid 
chromatography on C8, eluting with methanol/0.1% aqueous trifluoroacetic 
acid (50:50) to give 15 mg (0.019 mmol, 33%) of the title compound as a 
colorless glass. FAB-MS: calculated for C.sub.34 H.sub.39 N.sub.5 O.sub.3 
565; found 566 (M+H, 26%). .sup.1 H NMR (200 MHz, CD.sub.3 OD): 1.20 (d, 7 
Hz, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 2.12 (m, 1H), 2.2-2.6 (m, 5H), 2.80 
(dd; 12,14 Hz; 1H), 3.10 (dd; 2.12 Hz; 1H), 3.93 (m, 1H), 4.36 (dd: 8, 12 
Hz; 1H), 5.35 (d, 15 Hz, 1H), 7.08 (d, 8 Hz, 2H), 7.26 (m, 4H), 7.37 (m, 
2H), 7.44-7.90 (m, 6H). 
EXAMPLE 11 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[(1H-imidazol-4-yl)ace 
tamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanam 
ide, di(trifluoroacetate) 
Step A: 2,2-Dimethylbutanedioic acid, 4-methyl ester 2,2-Dimethylsuccinic 
acid (20 g, 137 mmol) dissolved in 200 mL of absolute methanol at 
0.degree. 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 stir for 16 hours. 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.times.) and the aqueous 
layer removed and cooled in an ice bath. The mixture was acidified to pH 2 
by slow addition of 6N HCl then extracted with ether (8.times.). The 
combined extracts were washed with brine, dried over magnesium sulfate, 
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 the product 
as a viscous oil that slowly solidified upon standing. .sup.1 H NMR (200 
MHz, CDCl.sub.3): 1.29 (s, 6H), 2.60 (s, 2H), 3.65 (s, 3H). 
Step B: 3-Benzyloxycarbonylamino-3-methylbutanoic acid, methyl ester 
To 14.7 g (91.8 mmol) of 2,2-dimethylbutanedioic acid-4-methyl ester in 150 
mL of benzene was added 13 mL of triethylamine (9.4 g, 93 mmol) followed 
by 21.8 mL of diphenylphosphoryl azide (27.8 g, 101 mmol). The mixture was 
heated under nitrogen at reflux for 45 minutes, then 19 mL (19.9 g, 184 
mmol) of benzyl alcohol was added and refluxing continued for 16 hours. 
The mixtue was cooled, filtered and the filtrate concentrated to a minimum 
volume under vacuum. The residue was redissolved in 250 mL of ethyl 
acetate, washed with water, saturated aqueous sodium bicarbonate 
(2.times.) and brine. The organic layer was removed, dried over magnesium 
sulfate, filtered and the filtrate concentrated to a minimum volume under 
vacuum. The crude product was purified by medium pressure liquid 
chromatography on silica, eluting with hexane/ethyl acetate (4:1), to 
afford 18.27 g (68.9 mmol, 75%) of the product. .sup.1 H NMR (200 MHz, 
CDCl.sub.3): 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). 
Step C: 3-Benzyloxycarbonylamino-3-methylbutanoic acid 
A solution of 18.27 g (68.9 mmol) of 
3-benzyloxycarbonylamino-3-methylbutanoic acid methyl ester in 20 mL of 
methanol at room temperature was treated dropwise with 51 mL of 2N NaOH 
(102 mmol). The mixture was stirred at room temperature for 16 hours then 
transferred to a separatory funnel and washed with hexane (3.times.). The 
aqueous layer was removed, cooled to 0.degree. C. and slowly acidified to 
pH 2 (paper) by dropwise addition of 6N HCl. This mixture was extracted 
with ether (6.times.); combined extracts were washed with 1N HCl and 
brine, then dried over magnesium sulfate, filtered and solvent removed 
under vacuum to afford 17.26 g (68.7 mmol, 99%) of the product. .sup.1 H 
NMR (200 MHz, CDCl.sub.3): 1.42 (s, 6H), 2.77 (s, 2H), 5.06 (s, 2H), 5.2 
(br s, 1H), 7.3 (s, 5H). 
Step D: 
3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzaze 
pin-3(R)-yl]-butanamide 
Prepared from 3-benzyloxycarbonylamino-3-methylbutanoic acid and 
3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step E) by 
the procedure described in Example 1, Step I. FAB-MS: calculated for 
C.sub.23 H.sub.27 N.sub.3 O.sub.4 409; found 410 (M+H, 100%). .sup.1 H NMR 
(200 MHz, CDCl.sub.3): 1.38 (s, 3H), 1.39 (s, 3H), 1.82 (m, 1H), 2.52 s, 
2H), 2.5-3.0 (m, 3H), 4.51 (m, 1H), 5.07 (br s, 2H), 5.57 (br s, 1H), 6.68 
(d, 7 Hz, 1H), 6.97 (d, 8 Hz, 1H), 7.1-7.4 (m, 8H), 7.61 (br s, 1H). 
Step E: 4-(t-Butyldimethylsiloxymethyl)phenylboronic acid 
To a solution of 1.8 g (5.97 mmol) of 4-bromobenzyl-t-butyldimethyl silyl 
ether (prepared according to the procedure of Nassal, Liebigs Ann. Chem. 
1983, 1510-1523) in 9 mL of dry tetrahydrofuran under a nitrogen 
atmosphere at -78.degree. C. was added dropwise by syringe 4.1 mL (6.57 
mmol) of a 1.6M solution of n-butyl lithium in hexanes over twenty 
minutes. The resulting mixture was stirred for twenty minutes, then 2.03 
mL (17.9 mmol) of trimethyl borate was added by syringe. The reaction 
mixture was stirred at -78.degree. C. for thirty minutes then slowly 
warmed to room temperature and stirred for an additional three hours. The 
reaction mixture was then re-cooled to 0.degree. C. and quenched by the 
addition of 40 mL of saturated aqueous ammonium chloride. Precipitated 
solids were dissolved by addition of a minimal amount of water and the 
mixture stirred for 25 minutes. The solution was transferred to a 
separatory funnel and extracted with ether (3.times.75 mL). The combined 
ether extracts were washed with saturated aqueous sodium chloride, 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 (55:45) to afford 1.0 g 
(63%) of the product as a white solid. .sup.1 H NMR (200 MHz, CDCl.sub.3): 
0.10 (s, 6H), 0.91 (s, 9H), 1.50 (s, 2H), 4.80 (s, 2H), 7.43 (d, 8 Hz, 
2H), 8.18 (d, 8 Hz, 2H). 
Step F: N-(t-Butoxycarbonyl)-2-bromobenzylamine 
To a slurry of 1.0 g (4.5 mmol) of 2-bromobenzylamine hydrochloride in 10 
mL of dry methylene chloride under a nitrogen atmosphere was added by 
syringe 1.4 mL (9.9 mmol) of triethylamine. To the resulting solution 
after five minutes was added 1.08 g (4.94 mmol) of di-t-butyldicarbonate. 
The reaction was stirred at room temperatue for one hour then diluted with 
200 mL of ethyl acetate. The solution was 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 an oil which was purified by 
column chromatography on silica gel eluting with hexanes/ethyl acetate 
(9:1), to afford 1.29 g (100%) of the product as a white solid. FAB-MS: 
calculated for C.sub.12 H.sub.16 BrNO.sub.2 285; found 286 (M+1). .sup.1 H 
NMR (200 MHz, CDCl.sub.3): 1.41 (s, 5H), 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). 
Step G: 
2'-[(t-Butoxycarbonylamino)methyl]-4-[(t-butyldimethylsiloxy)methyl]-1,1'- 
biphenyl 
To a solution of 1.0 g (3.8 mmol) of 
4-(t-butyldimethaylsilyoxymethyl)phenylboronic acid (Step E) in 24 mL of 
1,2-dimethyoxyethane was added 4 mL of water,m 1.02 g (5.37 mmol) of 
barium hydroxide hexahydrate, 1.02 g (3.58 mmol) of 
N-(t-butoxycarbonyl)-2-bromobenzylamine (Step F) and 206 mg (0.18 mmol) of 
tetrakis(triphenylphosphine) palladium. The resulting mixture was heated 
under nitrogen at 80.degree. C. for 2.5 hours then cooled to room 
temperature. The reaction mixture was diluted with 40 mL of saturated 
aqueous ammonium chloride. The solution was transferred to a separatory 
funnel and extracted with ether (3.times.75 mL). The combined ether 
extracts were washed with saturated aqueous sodium bicarbonate and 
saturated aqueous sodium chloride, dried over magnesium sulfate and then 
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 (85:15) to afford 1.15 g (75%) of the product as a 
clear oil. FAB-MS: calculated for C.sub.25 H.sub.37 NO.sub.3 Si 427; found 
314. .sup.1 H NMR (200 MHz, CDCl.sub.3): 0.10 (s, 6H), 0.92 (s, 9H), 1.40 
(s, 9H), 4.27 (d, 5 Hz, 2H), 4.60 (s, 1H), 4.78 (s, 2H), 7.18-7.45 (m, 
8H). 
Step H: 2'-[(t-Butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol 
To a solution of 150 mg (0.35 mmol) of 
2'-[(t-butoxycarbonylamino)methyl]-4-[(t-butyldimethylsiloxy)-methyl]-1,1' 
-biphenyl (Step G) in 2 mL of dry tetrahydrofuran under a nitrogen 
atmosphere was added by syringe 0.52 mL (0.53 mmol) of 1.0M solution of 
tetra-n-butylammonium fluoride in tetrahydrofuran. The reaction mixture 
was stirred for one hour then diluted with 100 mL of ethyl acetate. The 
mixture was washed with water (3.times.20 mL), then saturated aqueous 
sodium chloride, 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 101 mg (93%) of the product as a white solid. FAB-MS: calculated 
for C.sub.19 H.sub.23 NO.sub.3 313; found 314 (M+H). .sup.1 H NMR (200 
MHz, CDCl.sub.3): 1.40 (s, 9H), 2.50 (s, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 
7.18-7.45 (s, 8H). 
Step I: 2'-[(t-Butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol, 
methanesulfonate ester 
To solution of 53 mg (0.17 mmol) of 
2'-[(t-butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol (Step H) in 1 
mL of dry methylene chloride under nitrogen atmosphere at 0.degree. C. was 
added by syringe 0.035 mL (0.25 mmol) of triethylamine followed by 0.016 
mL of (0.20 mmol) methanesulfonyl chloride. The reaction mixture was 
stirred for 2 hours at 0.degree. C. then diluted with 75 mL 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 (96%) of the product as 
a white solid which was used in the next step without further 
purification. FAB-MS: calculated for C.sub.20 H.sub.25 NO.sub.5 S 391; 
found 392 (M+H). .sup.1 H NMR (200 MHz, CDCl.sub.3): 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). 
Step J: 
3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[(t-b 
utoxycarbonylamino)methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R) 
-yl]-butanamide 
To a solution of 60 mg (0.15 mmol) of 
3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzaze 
pin-3(R)-yl]butanamide (Step D) in 0.5 mL of dry dimethylformamide under 
nitrogen was added 6.4 mg (0.16 mmol) of 60% sodium hydride/oil 
dispersion. After stirring for 15 minutes, a solution of 60 mg (0.15 mmol) 
of 2'-[(t-butoxycarbonylamino)methyl]-1,1'-biphenyl-4-methanol, 
methanesulfonate ester (Step I) in 0.5 mL of dimethylformamide was aded by 
cannula. The flask which originally contained the methanesulfonate ester 
was rinsed with 0.5 mL of dimethylformamide which was added to the 
reaction mixture. After stirring at room temperature for two hours, the 
reaction mixture was diluted with 75 mL of ethyl acetate, washed with 20 
mL of water and 20 mL of saturated aqueous sodium chloride. The organic 
layer was dried over magnesium sulfate, filtered and the solvent removed 
under vacuum. The residue was purified by flash chromatography on silica 
gel eluting with ethyl acetate/hexane (60:40) to afford 89 mg (96%) of the 
product as a white foam. FAB-MS: calculated for C.sub.42 H.sub.48 N.sub.4 
O.sub.6 704; found 705 (M+H). .sup.1 H NMR (200 MHz, CDCl.sub.3); 1.31 (s, 
3H), 1.32 (s, 3H), 1.37 (s, 9H), 1.76 (s, 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). 
Step K: 
3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(amin 
omethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, 
trifluoroacetate 
To a solution of 89 mg (0.13 mmol) of the intermediate obtained in Step J 
in 2 mL of dry methylene chloride was added 2 drops of anisole followed by 
2 mL of trifluoroacetic acid. The mixture was stirred for two hours at 
room temperature then the solvent was removed under vacuum. The residue 
was dissolved in 5 mL of carbon tetrachloride and the solvent was removed 
under vacuum. This was repeated twice, then the residue was dissolved in 
methylene chloride and the solvent removed under vacuum to give 100 mg 
(&gt;100%) of the product as a white foam (containing a minor amount of 
anisole). The resulting crude product was used without further 
purification but could be purified by reverse phase medium pressure liquid 
chromatography on C8 eluting with methanol/0.1% aqueous trifluoroacetic 
acid (65:35). FAB-MS: calculated for C.sub.37 H.sub.40 N.sub.4 O.sub.4 
604; found 605 (M+H, 80%). .sup.1 H NMR (200 MHz, CD.sub.3 OD: 1.40 (s, 
6H), 2.04 (m, 1H), 2.31 (m, 2H), 2.55 (d, 12Hz, 1H), 2.62 (m, 2H), 4.08 
(s, 2H), 4.42 (dd; 8, 12Hz; 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). 
Step L: 1-(2-Trimethylsilylethoxy)methyl-1H-imidazole-4-acetic acid, ethyl 
ester; and 3-(2-trimethylsilylethoxy)methyl-1H-imidazole-4-acetic acid, 
ethyl ester 
To a solution of 383 gm (2.48 mmol) of 1H-imidazole-4-acetic acid ethyl 
ester (prepared according to the procedure of Bashkin et al; J. Org. 
Chem., 1990, 55, 5125-5132.) in 5 mL of dry tetrahydrofuran under a 
nitrogen atmosphere was added 109 mg (2.73 mmol) of 60% sodium hydride/oil 
dispersion. The resulting mixture was stirred for 30 minutes at which time 
was added dropwise by syringe 0.53 mL (3.0 mmol) of 
2-trimethylsilylethoxymethyl chloride. The reaction mixture was stirred 
for 4 hours at room temperature then diluted with 150 mL of ethyl acetate. 
The solution was washed with saturated aqueous sodium bicarbonate, dried 
over magnesium sulfate, filtered and the solvent removed under vacuum. The 
resulting material was purified by column chromatography on silica gel, 
eluting with chloroform/10% concentrated ammonium hydroxide in methanol 
(96:4), to afford 342 mg (48%) of the products in a 1.5:1 ratio of N-1:N-3 
imidazole regioisomers as a colorless oil. FAB-MS: calculated for C.sub.13 
H.sub.24 N.sub.2 O.sub.3 Si 284; found 285 (M+H, 100%). .sup.1 H NMR (200 
MHz, CDCl.sub.3): 0.00 (s, 18H), 0.90 (m, 4H), 1.25 (t, 7 Hz, 6H), 3.45 
(m, 4H), 3.65 (s, 2H), 3.70 (s, 2H), 4.15 (m, 4H), 5.20 (s, 2H), 5.35 (s, 
2H), 7.00 (s, 1H), 7.02 (s, 1H), 7.65 (s, 1H), 7.97 (s, 1H). 
Step M: 1-(2-Trimethylsilyethoxy)methyl-1H-imidazole-4-acetic acid, lithium 
salt, and 3-(2-trimethylsilylethoxy)methyl-1 H-imidazole-4-acetic acid, 
lithium salt 
To a solution of 312 mg (1.10 mmol) of the mixture of intermediates 
obtained in Step L in 2 mL of tetrahydrofuran/water (3:1) was added 48 mg 
(1.2 mmol) of lithium hydroxide monohydrate. The mixture was stirred for 
30 minutes at room temperature and then the solvent was removed under 
vacuum. Excess water was removed by azeotroping with benzene (3.times.5 
mL) and the resulting solid was dried under vacuum overnight to afford 288 
mg (100%) of the products as a white solid. FAB-MS (Li spike): calculated 
for C.sub.11 H.sub.19 LiN.sub.2 O.sub.3 Si 262; found 269 (M+Li, 100%). 
.sup.1 H NMR (200 MHz, D.sub.2 O): -0.1 (s, 18H), 0.85 (t, 8 Hz, 4H), 3.37 
(s, 2H), 3.52 (s, 2H), 3.55 (m, 4H), 4.15 (m, 4H), 5.28 (s, 2H), 5.30 (s, 
2H), 6.80 (s, 1H), 7.00 (s, 1H), 7.67 (s, 1H), 7.70 (s, 1H). 
Step N: 
3-Benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[[[1 
-(2-trimethylsilylethoxy)methyl]imidazol-4-yl]acetamido]-methyl][1,1'-biphe 
nyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide, and 
3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[[[3 
-(2-trimethylsilylethoxy)methyl]imidazol-4-yl]acetamido]methyl]-[1,1'-biphe 
nyl]-4-yl]-methyl]1H-1-benzazepin-3(R)-yl]-butanamide 
To a slurry of 25 mg (0.09 mmol) of the mixture of intermediates obtained 
in Step M in 1.0 mL of dry methylene chloride under nitrogen at room 
temperature was added 0.013 mL (0.17 mmol) of triethylamine followed by 44 
mg (0.10 mmol) of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium 
hexafluorophosphate. In a separate flask was placed 45 mg (0.063 mmol) of 
3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(amin 
omethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butanamide, 
trifluoroacetate (Step K) in 1.0 mL of dry methylene chloride under 
nitrogen. To this mixture was added to 0.013 mL (0.17 mmol) triethylamine. 
After 15 minutes, the amine free base mixture was added by cannula to the 
carboxylic acid lithium salt mixture. The flask which originally contained 
the amine salt was rinsed with 1.0 mL of methylene chloride and the 
resulting solution was added to the reaction mixture. The reaction mixture 
was stirred at room temperature for three hours. The reaction was diluted 
with 75 mL of ethyl acetate, and washed consecutively with 15 mL of water, 
15 mL of saturated aqueous sodium bicarbonate and 15 mL of saturated 
aqueous sodium chloride. The organic layer was dried over sodium sulfate, 
filtered and the solvent removed under vacuum. The residue was purified by 
flash colum chromatography on silica gel eluting with chloroform/10% 
concentrated ammonium hydroxide in methanol (95:5) to afford 46 mg (87%) 
of the products as a white foam in a 1.5:1 ratio of N-1:N-3 imidazole 
ragioisomers. FAB-MS: calculated for C.sub.48 H.sub.58 N.sub.6 O.sub.6 Si 
842; found 843 (M+H, 40%). .sup.1 H NMR (200 MHz, CD.sub.3 OD): -0.07 (s, 
9H), -0.06 (s, 9H), 0.85 (m, 4H), 1.32 (s, 12H), 1.92 (m, 2H), 2.25 (m, 
2H), 2.42-2.68 (m, 8H), 3.40 (s, 2H), 3.48 (m, 4H), 3.58 (s, 2H), 4.20 (s, 
4H), 4.35 (dd, 6.12 Hz, 2H), 4.92 (dd, 2.14 Hz, 2H), 4.96 (d, 12 Hz, 2H), 
5.05 (d, 12 Hz, 2H), 5.25 (dd; 2, 14 Hz; 2H), 5.29 (s, 2H), 5.32 (s, 2H), 
6.83 (s, 1H), 7.05 (s, H), 7.10-7.40 (m, 34H), 7.69 (d, 1 Hz, 1H), 7.71 
(d, 1Hz, 1H). 
Step O: 
3-Amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[(1H-imidazol-4-yl)ac 
etamido]methyl]-[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butan 
amide, di(trifluoracetate) 
A solution of 46 mg (0.055 mmol) of a mixture of the intermediates obtained 
in Step N in 2 mL of methanol was hydrogenated at room tmeperature and one 
atmosphere over 5 mg of palladium hydroxide catalyst for 2 hours. The 
mixture was filtered through Celite and the solvent removed under vacuum 
to give 40 mg of a white solid. 
The solid thus obtained was dissolved in 1 mL of ethanol and treated with 2 
mL of 5N aqueous hydrochloric acid. The mixture was heated at 80.degree. 
C. for one hour. The solvent was removed under vacuum and the resulting 
material was purified by reverse phase medium pressure liquid 
chromatography on C8 eluting with methanol/0.1% aqueous trifluoroacetic 
acid (55:45) to afford 24 mg (55%) of the title compound as a white solid. 
FAB-MS: calculated for C.sub.34 H.sub.38 N.sub.6 O.sub.3 578; found 579 
(M+H, 100%). .sup.1 H NMR (200 MHz, CD.sub.3 OD): 1.42 (s, 3H), 1.47 (s, 
3H), 2.0-2.4 (m, 2H), 2.47 (d, 14 Hz, 1H), 2.50-2.70 (m, 3H), 3.65 (s, 
2H), 4.25 (s, 2H), 4.40 (dd; 8, 12 Hz; 1H), 4.98 (d, 14 Hz, 1H), 5.22 (d, 
14 Hz, 1H), 7.10-7.45 (m, 12H), 8.78 (d, 1 Hz, 1H). 
EXAMPLE 12 
3-[2(S), 
3-Dihydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[(1H, 
imidazol-4-yl)acetamido]-methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazep 
in-3-(R)-yl]-butanamide, di(trifluoroacetate) 
A solution of 513 mg (0.609 mmol) of a mixture of the intermediates 
obtained in Example 11, Step N in 15 mL of methanol was hydrogenated at 
room temperature and one atmosphere over 52 mg of palladium hydroxide for 
two hours. The mixture was filtered through Celite and the filtrate 
evaporated to dryness under vacuum to give a white solid. 
To a solution of the solid in 5 mL of dry methanol was added a solution of 
427 mg (3.28 mmol) of D-glyceraldehyde acetonide (used crude as prepared 
according to the procedure of Hertal, L. W.; Grossman, C. S.; Kroin, J. S. 
Syn. Comm. 1991, 21, 151-154.) in 5 mL of dry methanol. The pH of the 
mixture was carefully adjusted to 6.5 with glacial acetic acid 
(approximately 1 drop). To this mixture was added 2.5 g of dry powdered 4A 
molecular sieves. The resulting mixture was stirred for four hours at 
which time 3.0 mL (3.0 mmol) of a 1.0M solution of sodium cyanoborohydride 
in tetrahydrofuran was added by syringe. The reaction was stirred for 20 
hours, then filtered through a pad of Celite and the solvent removed under 
vacuum. 
The residue was dissolved in 5 mL of ethanol and 5 mL of 5N aqueous 
hydrochloric acid was carefully added dropwise. The resulting mixture was 
heated for 5 hours at 80.degree. C. The solvent was removed under vacuum 
and the residue dissolved in 5 mL of methanol and treated with 3 mL of 
trifluoroacetic acid. The solvent was removed under vacuum and the 
resulting crude product purified by reverse phase sodium pressure liquid 
chromatography on C8, eluting with methanol/0.1% aqueous trifluoroacetic 
acid (50:50), to afford 293 mg (55%) of the title compound as a white 
solid. FAB-MS: calculated for C.sub.37 H.sub.44 N.sub.6 O.sub.5 652; found 
653 (M+H, 40%). .sup.1 H NMR (200 MHz, CD.sub.3 OD): 1.35 (s, 3H), 1.37 
(s, 3H), 2.0-2.4 (m, 2H), 2.50-2.72 (m, 4H), 2.94 (dd; 9, 12 Hz; 1H), 3.16 
(dd; 3, 12 Hz; 1H), 3.52 (m, 2H), 3.66 (s, 2H), 3.80 (m, 1H), 4.28 (s, 
2H), 4.38 (dd; 8, 12 Hz; 1H), 5.03 (d, 15 Hz, 1H), 5.13 (d, 15 Hz, 1H), 
7.10-7.40 (m, 12H), 8.77 (d, 1.5 Hz, 1H). 
EXAMPLE 13 
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-[[( 
1H-imidazol-4-yl)acetamido]-methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaz 
epin-3-(R)-yl]-butanamide, di(trifluoroacetate) 
Step A: 
3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-be 
nzazepin-3(R)-yl]-butanamide 
To a solution of 2.03 g (3.788 mmol) of 
3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-be 
nzazepin-3(R)-yl]-butanamide trifluoroacetate (Example 10, Step B) in 40 mL 
of methylene chloride was added 40 mL of water. The mixture was stirred 
vigorously while sufficient solid potassium carbonate was added to adjust 
the pH of the aqueous layer to 10-11. Stirring was discontinued and the 
layers allowed to separate. The organic layer was removed and the aqueous 
layer extracted twice more with methylene chloride. The combined extracts 
were dried over potassium carbonate, filtered and solvents removed under 
vacuum to afford 1.53 g (3.62 mmol, 95%) of the product as a white solid. 
.sup.1 H NMR (400 MHz, DMSO-d.sub.6): 1.04 (s, 3H), 1.06 (s, 3H), 1.14 (d, 
7 Hz, 3H), 1.90 (m, 1H), 2.21 (m,3H), 2.60 (m,4H), 3.59 (m,1H), 4.23 
(m,1H), 4.45 (d,10 Hz,1H),4.53 (d,10 Hz,1H),6.99 (d,8 Hz,1H), 7.12 (t,8 
Hz,1H), 7.20-7.35 (m,7H), 8.72 (d,8 Hz,1H), 9.79 (s,1H). 
Step B: 3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2, 
3,4,5-tetrahydro-2-oxo-1-[[2'-[(t-butoxycarbonylamino)methyl][1,1'-bipheny 
l]-4-yl]-methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
To a solution of 514 mg (1.22 mmol) of 
3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-be 
nzazepin-3(R)-yl]-butanamide in 5 mL of dry dimethylformamide under 
nitrogen was added 53 mg (1.34 mmol) of 60% sodium hydride/oil dispersion. 
After stirring for 15 minutes, a solution of 499 mg (1.28 mmol) of 
2'-[(t-Butoxycarbonylamino)methyl]-1,1-biphenyl-4-methanol, 
methanesulfonate ester (Example 11, Step I) in 2 mL of dry 
dimethylformamide was added by cannula. The flask which originally 
contained the mesylate was rinsed with 1 mL of dimethylformamide which was 
added to the reaction mixture. After stirring at room temperature for 2 
hours, the reaction mixture was diluted with 200 mL of ethyl acetate, 
washed with water (2.times.40 mL) and 40 mL of saturated aqueous sodium 
chloride. The organic layer was removed, dried over sodium sulfate, 
filtered and the solvent removed under vacuum. The residue was purified by 
flash chromatography on silica gel eluting with chloroform/10% 
concentrated ammonium hydroxide in methanol (94:6) to afford 872 mg (100%) 
of the product as a white foam. FAB-MS: calculated for C.sub.44 H.sub.54 
N.sub.4 O.sub.5 718; found 719 (M+H,40%). .sup.1 H NMR (200 MHz, CD.sub.3 
OD): 1.11 (s,3H), 1.12 (s,3H), 1.18 (d,6 Hz,3H), 1.39 (s,9H), 1.80-2.05 
(m,1H), 2.15-2.38 (m,3H), 2.45-2.70 (m,4H), 3.70 (m,1H), 4.05 (s,2H), 4.42 
(dd;5.11 Hz,1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 
1H), 4.47 (d,11 Hz, 1H, 4.60 (d,11 Hz, 1H), 4.93 (d,15 Hz, 1H), 7.05-7.40 
(m,17H). 
Step C: 3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2, 
3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)-[1,1'-biphenyl]-4-yl]methyl]-1 
H-1-benzazepin-3(R)-yl]-butanamide, dihydrochloride 
To a solution of 872 mg (1.21 mmol) of the intermediate obtained in Step B 
in 5 mL of dry methylene chloride was added 0.198 mL (1.81 mmol) of 
anisole followed by 5 mL of trifluoroacetic acid. The mixture was stirred 
for two hours at room temperature then all volatiles were removed under 
vacuum. The residue was dissolved in 5 mL of carbon tetrachloride and the 
solvent was removed under vacuum. This was repeated twice, then the 
residue was dissolved in methylene chloride and the solvent removed under 
vacuum. The residue was dissolved in a minimal amount of methanol and 
treated with 20 mL of 6N aqueous hydrochloric acid. The solvent was 
removed under vacuum. This was repeated twice more, then the resulting 
solid was dried under vacuum overnight at room temperature to afford 822 
mg (98%) of the product as an off-white solid. FAB-MS: calculated for 
C.sub.39 H.sub.46 N.sub.4 O.sub.3 618; found 619 (M+H,100%), .sup.1 H NMR 
(200 MHz, CD.sub.3 OD): 1.20 (d,6 Hz,3H), 1.35 (s,6H), 2.05-2.25 (m,1H), 
2.25-2.48 (m,1H), 2.55-2.75 (m,4H), 2.92 (dd;2.13 Hz;1H), 3.19 (dd;2.13 
Hz;1H), 3.84 (m,1H), 3.98 (s,2H), 4.45 (m,2H), 4.62 (d,11 Hz,1H), 5.03 
(d,15 Hz,1H), 5.19 (d,15 Hz,1H), 7.10-7.55 (m,17H). 
Step D: 3-[2(R)-Benzyloxypropyl]amino-3-methyl-N-[2, 
3,4,5-tetrahydro-2-oxo-1[[2'-[[[[1-(2-trimethylsilylethoxy)methyl]imidazol 
-4-yl]acetamido]methyl][1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl 
]-butanamide, and 
3-[2(R)-benzyloxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'- 
[[[[3-(2-trimethylsilylethoxy)methyl]imidazol-4-yl]acetamido]-methyl][1,1'- 
biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]-butanamide 
To a slurry of 227 mg (0.094 mmol) of the intermediates obtained in Example 
11 (Step N) in 7.0 mL of dry methylene chloride under nitrogen at room 
temperature was added 0.16 mL (1.15 mmol) of triethylamine followed by 409 
mg (0.925 mmol) of benzotriazol-1-yloxy-tris(dimehtylamino)phosphonium 
hexafluorophosphate. In a separate flask was placed 400 mg (0.578 mmol) of 
the intermediate obtained in Example 13 (Step C) in 2.0 mL of dry 
methylene chloride under nitrogen. To this mixture was added 0.161 mL 
(1.15 mmol) of triethylamine. After 15 minutes the amine free base mixture 
was added dropwise by pipette to the carboxylic acid lithium salt mixture. 
The flask which originally contained the amine salt was rinsed with 1.0 mL 
of methylene chloride and the resulting solution was added to the reaction 
mixture. The reaction mixture was stirred at room temperature for 1.5 
hours. The reaction was diluted with 200 mL of ethyl acetate, washed with 
50 mL of water, saturated aqueous sodium bicarbonate (2.times.50 mL) and 
50 mL saturated aqueous sodium chloride. The organic layer was removed, 
dried over sodium sulfate, filtered and the solvent removed under vacuum. 
The residue was purified by flash column chromatography on silica gel, 
eluting with chloroform/10% concentrated ammonium hydroxide in methanol 
(93:7), to afford 492 mg (99%) of the products as a white solid as a 
mixture of N-1:N-3 regioisomers in the ratio of 1.5:1. FAB-MS: calculated 
for C.sub.50 H.sub.64 N.sub.6 O.sub.5 Si 856; found 857 (M+H,100). .sup.1 
H NMR (200 MHz, CD.sub.3 OD): -0.074 (s,9H), -0.067 (s,9H), 0.81 (q,4H), 
1.10 (s,6H), 1.12 (s,6H), 1.18 (d,6 Hz,6H), 1.92 (m,2H), 2.15-2.35 (m,6H), 
2.42-2.68 (m,8H), 3.40 (s,2H), 3.45 (m,4H), 3.56 (s,2H), 4.20 (s,4H), 4.42 
(dd;6.10 Hz;2H), 4.48 (d,12 Hz,2H), 4.59 (d,12 Hz,2H), 4.92 (dd;2.16 
Hz;2H), 5.22 (dd;2.16 Hz;2 H), 5.27 (s,2H), 5.32 (s,2H), 6.83 (s,1H), 7.05 
(s,1H), 7.09-7.40 (m,34H), 7.69 (d,1 Hz,1H), 7.71 (d,1 Hz,1H). 
Step E: 
3-[2(R)-Hydroxypropyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxy-1-[[2'-[[ 
(1H-imidazol-4-yl)acetamido]methyl][1,1'-biphenyl]-45-yl]-methyl]-1H-1-benz 
azepin-3(R)-yl]-butanamide, di(trifluoroacetate) 
To a solution of 490 mg (0.572 mmol) of a mixture of the intermediates 
obtained in Step D in 5 mL of ethanol was added 5 mL of 5N aqueous 
hydrochloric acid. The resulting mixture was heated at 80.degree. C. for 3 
hours. The solvent was removed under vacuum and the resulting material 
dried overnight under vacuum to afford 500 mg of an off-white solid. 
A portion of the solid (429 mg) was dissolved in 15 mL of methanol and 
hydrogenated at ambient temperature and 50 psi over 80 mg of 50% palladium 
on carbon for 16 hours. The mixture was filtered through Celite and the 
solvent was removed under vacuum. The residue was purified by reverse 
phase medium pressure liquid chromatography on C8, eluting with 
methanol/0.1% aqueous trifluoroacetic acid (50:50), to afford 221 mg (50%) 
of the title compound as a white solid. FAB-MS: calculated for C.sub.37 
H.sub.44 N.sub.6 O.sub.4 636; found 637 (M+H,60%). .sup.1 H NMR (200 MHz, 
CD.sub.3 OD): 1.18 (d,5 Hz,3H), 1.35 (s,3H), 1.37 (s,3H), 2.03-2.22 
(m,1H), 2.25-2.42 (m,1H), 2.50-2.70 (m,4H), 2.78 (dd;10,12 Hz,1H), 3.06 
(dd;3.12 Hz;1H), 3.65 (s,2H), 3.90 (m,1H), 4.27 (s,2H), 4.38 (dd;7.11 
Hz;1H), 5.03 (d,14 Hz;1H), 5.14 (d,14 Hz,1H), 7.10-7.40 (m,12H), 8.78 (d,1 
Hz,1H).