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. Growth promoting compositions containing such benzo-fused lactams as the active ingredient thereof are also disclosed.

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 
for 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: 
##STR1## 
where L is 
##STR2## 
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, 
##STR3## 
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, C.sub.1 -C.sub.3 perfluoroalkoxy, --S(O).sub.m 
R.sup.7a, cyano, nitro, 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.5b 
R.sup.12b N(CH.sub.2).sub.v --, R.sup.7b CON(R.sup.12b)(CH.sub.2).sub.v 
--, R.sup.5b R.sup.12b NCO(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; and v is 0 to 3; 
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 substitutents are phenyl or substituted phenyl; phenyl or 
substituted phenyl where the phenyl substitutents 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.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 
alkyl substituted with R.sup.9, phenyl substituted with R.sup.9 or phenoxy 
substituted with R.sup.9 ; 
R.sup.9 is 
##STR4## 
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.7b CO(CH.sub.2).sub.v --, R.sup.7b 
O(CH.sub.2).sub.v CO--, R.sup.5b R.sup.12b N(CH.sub.2).sub.v --, R.sup.5b 
R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCS(CH.sub.2).sub.v 
--, R.sup.5b R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, R.sup.5b 
R.sup.12a NN(R.sup.12b)CS(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCSN(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCOO(CH.sub.2).sub.v-- or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, 
where v is 0 to 3. 
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a, OR.sup.5a or 
COR.sup.5a. R.sup.12a and R.sup.12b, or R.sup.12b and R.sup.12c, or 
R.sup.12a and R.sup.12c, or R.sup.12b and R.sup.5b, or R.sup.12c and 
R.sup.5b, or R.sup.13 and R.sup.12a 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 NR.sup.10, m is 0, 1 or 2, r and s are independently 0 to 3 
and R.sup.1 and R.sup.10 are as defined. 
R.sup.13 is 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 hydroxy, 
--NR.sup.10 .sub.R.sup.11, carboxy, phenyl or substituted phenyl; phenyl 
or substituted phenyl where the substituents on the phenyl 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.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; 
R.sup.5, R.sup.5a and R.sup.5b 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 substitutents 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, R.sup.1, R.sup.2 
independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 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.1, R.sup.2, R.sup.10 and R.sup.11 are as 
defined above; 
R.sup.4 is R.sup.14 or C.sub.1 -C.sub.10 alkyl substituted with R.sup.14 ; 
R.sup.14 is 
##STR5## 
where K is O, S or NR.sup.16 : 
R.sup.15a and R.sup.15b 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.12a R.sup.12c N(CH.sub.2).sub.v 
--, R.sup.12a R.sup.12b NCO(CH.sub.2).sub.v --, C.sub.1 -C.sub.6 alkoxy, 
phenyl, substituted phenyl, C.sub.1 -C.sub.10 alkyl or substituted C.sub.1 
-C.sub.10 alkyl where the substitutents 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, R.sup.1, 
R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 
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.7a, R.sup.10, 
R.sup.11, R.sup.12a, R.sup.12b, R.sup.12c, m and v are as defined above; 
R.sup.16 is hydrogen, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 
-C.sub.6 alkyl where the substitutents are from 1 to 3 of hydroxy, C.sub.1 
-C.sub.6 alkoxy, fluoro, R.sup.1, R.sup.2 independently disubstituted 
phenyl, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 
-C.sub.3 alkoxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.5 
alkoxycarbonyl, carboxy, C.sub.1 -C.sub.5 alkanoyl-C.sub.1 -C.sub.6 alkyl 
or --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.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, phenyl or phenyl C.sub.1 
-C.sub.10 alkyl; 
A is 
##STR6## 
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 
substitutents 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, R.sup.1, 
R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 
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.1, R.sup.2, R.sup.7a, R.sup.10, 
R.sup.11 and m 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 R.sup.5 to form alkylene bridges 
between the terminal nitrogen and the alkyl portion of the A group wherein 
the bridge contains from one to five 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, pentyl, 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 is methoxy, ethoxy, 
propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, 
isopentoxy, hexoxy, isohexoxy and the like. 
The term "halogen" is intended to include the halogen atoms 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 bond to R.sup.14 can be to any of the available 
carbon or heteroatoms of the heteroaromatic group, including either ring 
of the benzo-fused heterocyclic groups, when the bonding is represented by 
a serpentine line. 
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; 
##STR7## 
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).sup.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 3; 
R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 
alkyl substituted with R.sup.9, phenyl substituted with R.sup.9 or phenoxy 
substituted with R.sup.9 ; 
R.sup.9 is 
##STR8## 
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.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
N(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b 
R.sup.12b NCS(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCSN(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCOO(CH.sub.2).sub.v -- or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, 
where v is 0 to 3. 
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a, OR.sup.5a or 
COR.sup.5a. R.sup.12a and R.sup.12b, or R.sup.12b and R.sup.12c, or 
R.sup.12a and R.sup.12c, or R.sup.12b and R.sup.5b, or R.sup.12c and 
R.sup.5b, or R.sup.13 and R.sup.12a 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 NR.sup.10, m is 0, 1 or 2, r and s are independently 0 to 3 
and R.sup.1 and R.sup.10 are as defined. 
R.sup.13 is C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.1 -C.sub.6 alkyl, 
substituted C.sub.1 -C.sub.6 alkyl, where the substitutents are hydroxy, 
--NR.sup.10 R.sup.11, carboxy, phenyl or substituted phenyl; phenyl or 
substituted phenyl where the substituents on the phenyl 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.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, 
phenyl C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.5 alkanoyl-C.sub.1 
-C.sub.6 alkyl; 
R.sup.5, R.sup.5a and R.sup.5b are independently hydrogen, phenyl, 
substituted phenyl, C.sub.1 -C.sub.10 alkyl or substituted C.sub.1 
-C.sub.10 alkyl where the substitutents 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, R.sup.1, 
R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 
C.sub.1 -C.sub.20 alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or 
formyl where R.sup.1 and R.sup.2 are as defined above; 
R.sup.4 is R.sup.14 or C.sub.1 -C.sub.6 alkyl substituted with R.sup.14 ; 
R.sup.14 is as defined above; 
R.sup.15a and R.sup.15b are independently hydrogen, hydroxy, halogen, 
--S(O).sub.m R.sup.7a, C.sub.1 -C.sub.3 perfluoroalkyl, R.sup.12a 
R.sup.12c N(CH.sub.2).sub.v --, R.sup.12a R.sup.12b NCO(CH.sub.2).sub.v 
--, C.sub.1 -C.sub.6 alkoxy, phenyl, substituted phenyl, C.sub.1 -C.sub.10 
alkyl or substituted C.sub.1 -C.sub.10 alkyl where the substitutents on 
the phenyl or 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, R.sup.1, 
R.sup.2 independently disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 
C.sub.1 -C.sub.6 alkanoyloxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or 
formyl where R.sup.1, R.sup.2, R.sup.7a, R.sup.12a, R.sup.12b, R.sup.12c, 
m and v are as defined above; 
R.sup.16 is hydrogen, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 
-C.sub.6 alkyl where the substitutents are from 1 to 3 of hydroxy, C.sub.1 
-C.sub.6 alkoxy, fluoro, R.sup.1, R.sup.2 independently disubstituted 
phenyl, R.sup.1, R.sup.2 independently disubstituted phenyl C.sub.1 
-C.sub.3 alkoxy, C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or C.sub.1 
-C.sub.5 alkanoyl-C.sub.1 -C.sub.6 alkyl where R.sup.1 and R.sup.2 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 substitutents 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, R.sup.1, R.sup.2 independently 
disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 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.1, R.sup.2, R.sup.7a, R.sup.10, R.sup.11 
and m 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 4; and R.sup.8 and R.sup.8a 
can independently be joined to R.sup.5 to form alkylene bridges between 
the terminal nitrogen and the alkyl portion of the A group wherein the 
bridge contains from one to five 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 0to 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 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 or 
substituted C.sub.1 -C.sub.6 alkyl where the substitutents are phenyl and 
v is 0 to 2; 
R.sup.3a and R.sup.3b are independently hydrogen, R.sup.9, C.sub.1 -C.sub.6 
alkyl substituted with R.sup.9 or phenoxy substituted with R.sup.9 ; 
R.sup.9 is 
##STR10## 
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.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
N(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b 
R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CSN(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCOO(CH.sub.2).sub.v -- or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, 
where v is 0 to 2. 
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a or OR.sup.5a. 
R.sup.12a and R.sup.12b, or R.sup.12b and R.sup.12c, or R.sup.12a and 
R.sup.12c, or R.sup.12b and R.sup.5b, or R.sup.12c and R.sup.5b, or 
R.sup.13 and R.sup.12a 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 NR.sup.10, 
m is 0, 1 or 2, r and s are independently 0 to 2 and R.sup.1 and R.sup.10 
are as defined. 
R.sup.13 is C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, 
where the substitutents are phenyl or substituted phenyl; phenyl or 
substituted phenyl where the substituents on the phenyl 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.10 and R.sup.11 are independently hydrogen, C.sub.1 -C.sub.6 alkyl, 
phenyl C.sub.1 -C.sub.6 alkyl, or C.sub.1 -C.sub.5 alkanoyl-C.sub.1 
-C.sub.6 alkyl; 
R.sup.5, R.sup.5a and R.sup.5b are independently hydrogen, C.sub.1 
-C.sub.10 alkyl or substituted C.sub.1 -C.sub.10 alkyl where the 
substitutents 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 where R.sup.1 and 
R.sup.2 are as defined above; 
R.sup.4 is R.sup.14 or C.sub.1 -C.sub.3 alkyl substituted with R.sup.14 ; 
R.sup.14 is as defined above; 
R.sup.15a and R.sup.15b are independently hydrogen, hydroxy, halogen, 
--S(O).sub.m R.sup.7a, R.sup.12a R.sup.12c N(CH.sub.2).sub.v --, R.sup.12a 
R.sup.12b NCO(CH.sub.2).sub.v --, C.sub.1 -C.sub.6 alkoxy, phenyl, 
substituted phenyl, C.sub.1 -C.sub.10 alkyl or substituted C.sub.1 
-C.sub.10 alkyl where the substitutents on the phenyl or alkyl are from 1 
to 5 of hydroxy, C.sub.1 -C.sub.6 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 or formyl where R.sup.1, R.sup.2, R.sup.7a, 
R.sup.12a, R.sup.12b, R.sup.12c, m and v are as defined above; 
R.sup.16 is hydrogen, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 
-C.sub.6 alkyl where the substitutents are from 1 to 3 of hydroxy, C.sub.1 
-C.sub.6 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, 
C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or C.sub.1 -C.sub.5 
alkanoyl-C.sub.1 -C.sub.6 alkyl where R.sup.1 and R.sup.2 are as defined 
above; 
R.sup.6 is hydrogen or C.sub.1 -C.sub.10 alkyl; 
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 substitutents 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, R.sup.1, R.sup.2 independently 
disubstituted phenyl C.sub.1 -C.sub.3 alkoxy, 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.1, R.sup.2, R.sup.7a, R.sup.10, R.sup.11 
and m 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; and R.sup.8 and R.sup.8a can 
independently be joined to R.sup.5 to form alkylene bridges between the 
terminal nitrogen and the alkyl portion of the A group wherein the bridge 
contains from one to five 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 0or 1; 
p is 0 to 2; 
q is 1; 
w is 1; 
X is S(O).sub.m or --CH.dbd.CH--; 
m is 0to 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 or 
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 independently hydrogen, R.sup.9 or C.sub.1 
-C.sub.6 alkyl substituted with R.sup.9 ; 
R.sup.9 is 
##STR12## 
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.7b CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
N(CH.sub.2).sub.v --, R.sup.5b R.sup.12b NCO(CH.sub.2).sub.v --, R.sup.5b 
R.sup.12c NN(R.sup.12b)CO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCON(R.sup.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CON(CH.sub.12a)(CH.sub.2).sub.v --, R.sup.5b R.sup.12c 
NN(R.sup.12b)COO(CH.sub.2).sub.v --, R.sup.5b R.sup.12b 
NCOO(CH.sub.2).sub.v --, or R.sup.13 OCON(R.sup.12a)(CH.sub.2).sub.v --, 
where v is 0 to 2. 
R.sup.12a, R.sup.12b and R.sup.12c are independently R.sup.5a. R.sup.12a 
and R.sup.12b, or R.sup.12b and R.sup.12c, or R.sup.12a and R.sup.12c, or 
R.sup.12b and R.sup.5b, or R.sup.12c and R.sup.5b, or R.sup.13 and 
R.sup.12a 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 NR.sup.10, 
m is 0, 1 or 2, r and s are independently 0 to 2 and R.sup.1 and R.sup.10 
are as defined. 
R.sup.13 is C.sub.1 -C.sub.6 alkyl, substituted C.sub.1 -C.sub.6 alkyl, 
where the substitutents are phenyl or substituted phenyl; phenyl or 
substituted phenyl where the substituents on the phenyl 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.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; 
R.sup.5, R.sup.5a and R.sup.5b are independently hydrogen, C.sub.1 
-C.sub.10 alkyl or substituted C.sub.1 -C.sub.10 alkyl where the 
substitutents 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 where R.sup.1 and 
R.sup.2 are as defined above; 
R.sup.15a and R.sup.15b are independently hydrogen, hydroxy, halogen, 
--S(O).sub.m R.sup.7a, R.sup.12a R.sup.12c N(CH.sub.2).sub.v --, R.sup.12a 
R.sup.12b NCO(CH.sub.2).sub.v --, C.sub.1 -C.sub.6 alkoxy, phenyl, 
substituted phenyl, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 -C.sub.6 
alkyl where the substitutents on the phenyl or alkyl are from 1 to 5 of 
hydroxy, 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 or formyl where R.sup.1, R.sup.2, R.sup.7a, 
R.sup.12a, R.sup.12b, R.sup.12c, m and v are as defined; 
R.sup.16 is hydrogen, C.sub.1 -C.sub.6 alkyl or substituted C.sub.1 
-C.sub.6 alkyl where the substitutents are from 1 to 3 of hydroxy, C.sub.1 
-C.sub.6 alkoxy, R.sup.1, R.sup.2 independently disubstituted phenyl, 
C.sub.1 -C.sub.5 alkoxycarbonyl, carboxy or C.sub.1 -C.sub.5 
alkanoyl-C.sub.1 -C.sub.6 alkyl where R.sup.1 and R.sup.2 are as defined; 
R.sup.6 is hydrogen; 
A is 
##STR13## 
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 substitutents 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.5 alkanoyloxy, C.sub.1 
-C.sub.5 alkoxycarbonyl or carboxy, where R.sup.1, R.sup.2, R.sup.7a, and 
m are as defined; 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 R.sup.5 to form alkylene bridges between the 
terminal nitrogen and the alkyl portion of the A group wherein the bridge 
contains from one to five carbon atoms; 
and pharmaceutically acceptable salts thereof. 
Representative preferred growth hormone releasing compounds of the present 
invention include the following: 
1. 
N-[1-[[2'-[(Methoxycarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tet 
rahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]amino-3-methyl 
butanamide; 
2. 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]-methyl]-2,3,4, 
5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]amino-3-m 
ethylbutanamide; 
3. 
N-[1-[[2'-[(Morpholinocarbonyl)amino][1,1'-biphenyl]-4-yl]-methyl]-2,3,4,5 
-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]amino-3-me 
thylbutanamide; 
4. 
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-[(furan-2-yl)methyl] 
amino-3-methylbutanamide; 
5. 
N-[1-[[2'-[(Methylaminocarbonyl)oxy][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-t 
etrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]amino-3-meth 
ylbutanamide; 
6. 
N-[1-[[2'-[(Methoxycarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-7-fluoro-2, 
3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]amino 
-3-methylbutanamide; 
7. 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-7-fluor 
o-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]a 
mino-3-methylbutanamide; 
8. 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-7-trifl 
uoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl 
)methyl]amino-3-methylbutanamide; 
9. 
N-[1-[[2'-[(Morpholinocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-7-triflu 
oromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl) 
methyl]amino-3-methylbutanamide; 
10. 
N-[1-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[( 
furan-2-yl)methyl]amino-3-methylbutanamide; 
11. 
N-[1-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-y 
l)methyl]amino-3-methylbutanamide; 
12. 
N-[1-[[2'-[(Methylaminocarbonyl)oxy][1,1'-biphenyl]-4-yl]methyl]-7-fluoro- 
2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(furan-2-yl)methyl]ami 
no-3-methylbutanamide; 
13. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]-methyl]-2-oxo-1H-benzaz 
epin-3(R)-yl]butanamide; 
14. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-fluoro-2-oxo-1 
H-benzazepin-3(R)-yl]butanamide; 
15. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methoxy-2-oxo- 
1H-benzazepin-3(R)-yl]butanamide; 
16. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methylthio-2-o 
xo-1H-benzazepin-3(R)-yl]butanamide; 
17. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-trifluoromethy 
l-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
18. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H-benzazepin-3(R) 
-yl]butanamide; 
19. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-fluoro-2-oxo-1H-benzaz 
epin-3(R)-yl]butanamide; 
20. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methoxy-2-oxo-1H-benza 
zepin-3(R)-yl]butanamide; 
21. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methylthio-2-oxo-1H-be 
nzazepin-3(R)-yl]butanamide; 
22. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-trifluoromethyl-2-oxo- 
1H-benzazepin-3(R)-yl]butanamide; 
23. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H-benzazep 
in-3(R)-yl]butanamide; 
24. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-fluoro-2-oxo-1H 
-benzazepin-3(R)-yl]butanamide; 
25. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methoxy-2-oxo-1 
H-benzazepin-3(R)-yl]butanamide; 
26. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methylthio-2-ox 
o-1H-benzazepin-3(R)-yl]butanamide; 
27. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-trifluoromethyl 
-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
28. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H 
-benzazepin-3(R)-yl]butanamide; 
29. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-fluoro 
-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
30. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methox 
y-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
31. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-methyl 
thio-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
32. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-7-triflu 
oromethyl-2-oxo-1H-benzazepin-3(R)-yl]butanamide; 
33. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(1 
H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butana 
mide; 
34. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-6-fluoro-2-oxo- 
1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)- 
yl]butanamide; 
35. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-7-fluoro-2-oxo- 
1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)- 
yl]butanamide; 
36. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-7-trifluorometh 
yl-2-oxo-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzaze 
pin-3(R)-yl]butanamide; 
37. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-7-methylthio-2- 
oxo-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3 
(R)-yl]butanamide; 
38. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-7-methoxy-2-oxo 
-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R) 
-yl]butanamide; 
39. 
4'-[[3(R)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-2,3,4,5 
-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-carboxamide 
; 
40. 
4'-[[3(R)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-7-fluor 
o-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-ca 
rboxamide; 
41. 
4'-[[3(R)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-7-trifl 
uoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2 
-carboxamide; 
42. 
4'-[[3(R)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-7-methy 
lthio-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]- 
2-carboxamide; 
43. 
4'-[[3(R)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-7-metho 
xy-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-c 
arboxamide; 
44. 
N-Ethyl-4'-[[3(R)-[[3-[(furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-car 
boxamide; 
45. 
N-Ethyl-4'-[[3(R)-[[3-[(furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-7-fluoro-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphen 
yl]-2-carboxamide; 
46. 
N-Ethyl-4'-[[3(R)-[[3-[(furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-7-trifluoromethyl-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1, 
1'-biphenyl]-2-carboxamide; 
47. 
N-Ethyl-4'-[[3(R)-[[3-[(furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-7-methylthio-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-bi 
phenyl]-2-carboxamide; 
48. 
N-Ethyl-4'-[[3(R)-[[3-[(furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-7-methoxy-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphe 
nyl]-2-carboxamide; 
49. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-hy 
droxymethyl[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butanamide; 
50. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-(1 
H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]but 
anamide; 
51. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[8-fluoro-2,3,4,5-tetrahydro-4-oxo- 
5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3( 
S)-yl]butanamide; 
52. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[8-trifluoromethyl-2,3,4,5-tetrahyd 
ro-4-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothi 
azepin-3(S)-yl]butanamide; 
53. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[8-methylthio-2,3,4,5-tetrahydro-4- 
oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepi 
n-3(S)-yl]butanamide; 
54. 
4'-[[3(S)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino]-2,3,4,5 
-tetrahydro-4-oxo-1,5-benzothiazepin-5(2H)-yl]methyl][1,1'-biphenyl]-2-carb 
oxamide; 
55. 
N-Ethyl-4'-[[3(S)-[[3-[(Furan-2-yl)methyl]amino-3-methyl-1-oxobutyl]amino] 
-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-5(2H)-yl]methyl][1,1'-biphenyl 
]-2-carboxamide; 
56. 
N-[5-[[2'-[(Methoxycarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tet 
rahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(furan-2-yl)methyl]amino-3-met 
hylbutanamide; 
57. 
N-[5-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5 
-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(furan-2-yl)methyl]amino-3 
-methylbutanamide; 
58. 
N-[5-[[2'-[(Morpholinocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5- 
tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(furan-2-yl)methyl]amino-3- 
methylbutanamide; 
59. 
N-[5-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(furan-2-yl)meth 
yl]amino-3-methylbutanamide; 
60. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1,5-benzot 
hiazepin-3(S)-yl]butanamide; 
61. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-fluoro-4-oxo-1 
,5-benzothiazepin-3(S)-yl]butanamide; 
62. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methoxy-4-oxo- 
1,5-benzothiazepin-3(S)-yl]butanamide; 
63. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methylthio-4-o 
xo-1,5-benzothiazepin-3(S)-yl]butanamide; 
64. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(meth 
ylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-trifluoromethy 
l-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
65. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]4-oxo-1,5-benzothiazepin- 
3(S)-yl]butanamide; 
66. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-fluoro-4-oxo-1,5-benzo 
thiazepin-3(S)-yl]butanamide; 
67. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methoxy-4-oxo-1,5-benz 
othiazepin-3(S)-yl]butanamide; 
68. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methylthio-4-oxo-1,5-b 
enzothiazepin-3(S)-yl]butanamide; 
69. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[(amino 
carbonyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-trifluoromethyl-4-oxo- 
1,5-benzothiazepin-3(S)-yl]butanamide; 
70. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1,5-benzoth 
iazepin-3(S)-yl]butanamide; 
71. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-fluoro-4-oxo-1, 
5-benzothiazepin-3(S)-yl]butanamide; 
72. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methoxy-4-oxo-1 
,5-benzothiazepin-3(S)-yl]butanamide; 
73. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methylthio-4-ox 
o-1,5-benzothiazepin-3(S)-yl]butanamide; 
74. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(ethy 
lamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-trifluoromethyl 
-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
75. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1, 
5-benzothiazepin-3(S)-yl]butanamide; 
76. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-fluoro 
-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
77. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methox 
y-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
78. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-methyl 
thio-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
79. 
3-[(Furan-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[[(hyd 
roxyethyl)amino]carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-8-triflu 
oromethyl-4-oxo-1,5-benzothiazepin-3(S)-yl]butanamide; 
80. 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5 
-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(oxazol-5-yl)methyl]amino-3-m 
ethylbutanamide; 
81. 
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-[(oxazol-5-yl)methyl 
]amino-3-methylbutanamide; 
82. 
3-[(Oxazol-5-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(met 
hylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H-benzaz 
epin-3(R)-yl]butanamide; 
83. 
3-[(Oxazol-5-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-( 
1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]butan 
amide; 
84. 
N-Ethyl-4'-[[3(R)-[[3-[(oxazol-5-yl)methyl]amino-3-methyl-1-oxobutyl]amino 
]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-ca 
rboxamide; 
85. 
3-[(Oxazol-5-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[2'-( 
1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-yl]bu 
tanamide; 
86. 
N-Ethyl-4'-[[3(S)-[[3-[(oxazol-5-yl)methyl]amino-3-methyl-1-oxobutyl]amino 
]-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-5(2H)-yl]methyl][1,1'-bipheny 
l]-2-carboxamide; 
87. 
N-[5-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5 
-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(oxazol-5-yl)methyl]amino- 
3-methylbutanamide; 
88. 
N-[5-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(oxazol-5-yl)met 
hyl]amino-3-methylbutanamide; 
89. 
3-[(Oxazol-5-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[(met 
hylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1,5-benzo 
thiazepin-3(S)-yl]butanamide; 
90. 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5 
-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[((benzofuran-2-yl)methyl]amin 
o-3-methylbutanamide; 
91. 
N-[1-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]4-yl]methyl 
]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(benzofuran-2-yl)met 
hyl]amino-3-methylbutanamide; 
92. 
3-[(Benzofuran-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[ 
(methylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-2-oxo-1H-be 
nzazepin-3(R)-yl]butanamide; 
93. 
3-[(Benzofuran-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[ 
2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-1-benzazepin-3(R)-yl]b 
utanamide; 
94. 
N-Ethyl-4'-[[3(R)-[[3-[(benzofuran-2-yl)methyl]amino-3-methyl-1-oxobutyl]a 
mino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]- 
2-carboxamide; 
95. 
3-[(Benzofuran-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-4-oxo-5-[[ 
2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3(S)-y 
l]butanamide; 
96. 
N-Ethyl-4'-[[3(S)-[[3-[(benzofuran-2-yl)methyl]amino-3-methyl-1-oxobutyl]a 
mino-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-5(2H)-yl]methyl][1,1'-biph 
enyl]-2-carboxamide; 
97. 
N-[5-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5 
-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(benzofuran-2-yl)methyl]am 
ino-3-methylbutanamide; 
98. 
N-[5-[[2'-[[(2-Hydroxyethylamino)carbonyl]amino][1,1'-biphenyl]-4-yl]methy 
l]-2,3,4,5-tetrahydro-4-oxo-1,5-benzothiazepin-3(S)-yl]-3-[(benzofuran-2-yl 
)methyl]amino-3-methylbutanamide; and 
99. 
3-[(Benzofuran-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[[[ 
(methylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1,5-b 
enzothiazepin-3(S)-yl]butanamide. 
Representative examples of the nomenclature employed are given below: 
N-[1-[[2'-[(Methylaminocarbonyl)amino][1,1'-biphenyl]-4-yl]methyl]-2,3,4,5- 
tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-[(imidazol-2-yl)methyl]amino-3- 
methylbutanamide 
##STR14## 
N-Ethyl-4'-[[3(R)-[[2-[(furan-2-yl)methyl]amino-2-methyl-1-oxopropyl]amino] 
-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-1-yl]methyl][1,1'-biphenyl]-2-car 
boxamide 
##STR15## 
3-[(Oxazol-5-yl)methyl]amino-3-methyl-N-[7-methyl-2,3,4,5-tetrahydro-4-oxo 
- 
5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,5-benzothiazepin-3( 
S)-yl]butanamide 
##STR16## 
3-[(Benzofuran-2-yl)methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-5-[[2'-[2-[ 
[4-morpholinocarbonyl]amino]ethyl][1,1'-biphenyl]-4-yl]methyl]-4-oxo-1,5-be 
nzothiazepin-3(S)-yl]butanamide 
##STR17## 
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. 
##STR18## 
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, 
trifluoroacetic, propionic, maleic, succinic, malonic and the like. In 
addition, certain compounds containing an acidic function such as a 
tetrazole or 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 derived from intermediates 
such as those of formula II. The preparation of compounds of formula II 
wherein R.sup.3a or R.sup.3b is tetrazole or R.sup.7b OCO(CH.sub.2).sub.v 
-- has been previously described by Fisher, et al, U.S. Pat. No. 5,206,235 
and references cited therein. The preparation of other compounds of 
formula II is described in the following reaction schemes. 
##STR19## 
Compounds of formula II are prepared by alkylation of intermediates of 
formula III as shown in Scheme 1. The preparation of compounds of formula 
III has also been previously described by Fisher, et al, U.S. Pat. No. 
5,206,235 and references cited therein. Alkylation of intermediates of 
formula III 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 temperatures of 
20.degree.-100.degree. C., with an alkylating agent IV, wherein Y is a 
good leaving group such as Cl, Br, I, O-methanesulfonyl or 
O-(p-toluenesulfonyl). Substituents on the alkylating agent IV 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. 
##STR20## 
Alkylating agents IV are in some cases commercially available or may be 
prepared by methods described in the literature and familiar to one 
skilled in the art. Intermediates of formula II where R.sup.3a or R.sup.3b 
is a carbamate, semicarbazide or urea derivative, wherein this 
functionality is attached to the phenyl ring by a nitrogen atom are 
prepared from intermediate 1, obtained by alkylation with a derivative of 
formula IV wherein R.sup.3a or R.sup.3b is a nitro group as shown in 
Scheme 2. 
##STR21## 
A useful method of synthesizing a preferred alkylating agent 5 is shown in 
reaction Scheme 3. 
##STR22## 
Reaction of 4-tolylboronic acid 2 with 2-bromonitrobenzene 3 in the 
presence of a transition metal catalyst such as 
(tetrakis)triphenylphosphine palladium (0) in a mixed solvent system 
containing aqueous sodium hydroxide, water, 2-propanol and benzene at 
elevated temperatures for several hours gives the coupled product 4 in 
good overall yield. Chromatographic purification and separation of 
unwanted by-products is conveniently performed on silica, eluting with 
common organic solvents such as hexane, ethyl acetate and methylene 
chloride. Conversion of 4 to the bromide derivative 5 is accomplished by 
treatment with N-bromosuccinimide in refluxing carbon tetrachloride in the 
presence of a radical initiator such as benzoyl peroxide or 
2,2'-azobisisobutyronitrile (AIBN). 
As shown in Scheme 4, reduction of the nitro group of 1 is achieved by 
hydrogenation in the presence of a metal catalyst, such as palladium on 
carbon, in a protic solvent such as methanol or ethanol. It may be 
appreciated by one skilled in the art that for certain compounds where 
catalytic hydrogenation is incompatible with existing functionality, 
alternative methods of reduction are indicated, such as chemical reduction 
with stannous chloride under acidic conditions. It should also be noted 
that the protecting group G in intermediate 1 must be compatible with the 
experimental conditions anticipated for reduction. For example, 
intermediate 1 wherein G is t-butoxycarbonyl (BOC) is stable to the 
conditions of catalytic reduction employed in the conversion to 6. 
Intermediate 6 may also be further elaborated to a new intermediate 7 by 
reductive alkylation 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. 
##STR23## 
Elaboration of 7 to carbamate compound 8 is achieved by reaction with the 
appropriate chloroformate reagent in pyridine or in methylene chloride 
with triethylamine as shown in Scheme 5. 
##STR24## 
Transformation of amine intermediate 7 to urea derivatives is accomplished 
in several ways. Terminally disubstituted compounds 10 can be obtained 
directly by reaction of 7 with a disubstituted carbamoyl chloride 9 in an 
inert solvent such as methylene chloride in the presence of triethylamine 
or 4-dimethylaminopyridine. In addition, mono-substituted compound 12 
wherein either R.sup.5b or R.sup.12b is hydrogen is obtained from 7 by 
reaction with an isocyanate 11 as shown in Scheme 6. Terminally 
unsubstituted urea 12, wherein R.sup.12b is hydrogen, is also prepared 
from amine 7 by reaction with trimethylsilyl isocyanate (11; R.sup.12b is 
(CH.sub.3).sub.3 Si). 
##STR25## 
Alternatively, amine 6 is converted to an isocyanate 13 by treatment with 
phosgene or an equivalent reagent such as bis(trichloromethyl)carbonate 
(triphosgene) as indicated in Scheme 7. Subsequent reaction of 13 with 
primary or secondary amines in an inert solvent such as methylene chloride 
gives the corresponding urea derivative 10 in good yield. Isocyanate 13 is 
also converted to substituted semicarbazides 14 or hydroxy- or alkoxyureas 
15 by reaction with substituted hydrazines or hydroxy- or alkoxylamines, 
respectively. 
##STR26## 
Intermediates of formula II where R.sup.3a or R.sup.3b is a carbazate or 
carbamate derivative where attachment to the phenyl ring is through the 
oxygen atom of the carbazate or carbamate linkage are prepared from 
acetophenone intermediate 16 as indicated in Scheme 8. 
##STR27## 
Oxidative rearrangement of 16 through the use of a peroxy-carboxylic acid 
(Baeyer-Villager reaction) such as m-chloroperbenzoic acid gives the ester 
17 which is hydrolyzed in the presence of a strong base such as sodium or 
lithium hydroxide to give phenol 18. Reaction of 18 with an isocyanate 
leads directly to carbamate 19. Additionally, treatment of 18 with 
N,N'-carbonyldiimidazole in dimethylformamide can form an activated 
intermediate which will react with substituted hydrazine reagents to give 
a carbazate product 20. 
Intermediates of formula II wherein R.sup.3a or R.sup.3b is R.sup.5b 
R.sup.12b NCON(R.sup.12a)CH.sub.2 --, R.sup.5b R.sup.12b 
NCSN(R.sup.12a)CH.sub.2 --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CSN(R.sup.12a)CH.sub.2 --, R.sup.5b R.sup.12c 
NN(R.sup.12b)CON(R.sup.12a)CH.sub.2 -- or R.sup.13 OCON(R.sup.12a)CH.sub.2 
-- can be prepared from the t-butyl ester intermediate 21 as described in 
Scheme 9. Removal of the t-butyl ester through the use of trifluoroacetic 
acid will give the carboxylic acid 22. It may be appreciated by one 
skilled in the art that the protecting group G in 21 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 23 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 
23 can be further elaborated to 24 by the aforementioned reductive 
amination procedure. 
##STR28## 
Reactions of amine 24 with the appropriate reagents to form urea-linked 
compounds 25 and 26 and carbamate-linked compound 27 are illustrated in 
Scheme 10. Terminally unsubstituted urea 25, wherein R.sup.12b is 
hydrogen, is also prepared from amine 24 by reaction with trimethylsilyl 
isocyanate (11; R.sup.12b is (CH.sub.3).sub.3 Si). 
##STR29## 
As shown in Scheme 11, hydrazide compound 27 can be prepared from 
intermediate 24 by a two-step procedure consisting of activation of the 
amine via treatment with N,N'-carbonyldiimidazole followed by treatment 
with the appropriately substituted hydrazine derivative R.sup.5b R.sup.12c 
NN(R.sup.12b)H. 
##STR30## 
A useful preparation of the protected benzylamine intermediate 32 is shown 
in Scheme 12. Metallation of 4-bromobenzyl t-butyldiphenylsilylether 28 
with n-butyllithium followed by treatment with triisopropyl borate gives 
the aryl boronic acid 29. Reaction of 29 with 
2-bromo-N-(t-butoxycarbonyl)benzylamine 30 in the presence of 
tetrakis(triphenylphosphine)palladium(0) and sodium hydroxide in a mixed 
solvent system at elevated temperature gives the coupled product 31 in 
good yield. Desilylation and conversion to the O-methanesulfonate 32 is 
achieved by treatment with tetrabutylammonium fluoride followed by 
methanesulfonyl chloride. Reaction of 32 with compounds of formula III is 
carried out using the conditions described in Scheme 1. 
##STR31## 
Conversion to intermediates of formula II is carried out by simultaneous or 
sequential removal of all protecting groups from intermediate V as 
illustrated in Scheme 13. 
##STR32## 
Removal of benzyloxycarbonyl (CBz) 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 
and Sons, New York. 1981. 
As shown in Scheme 14, intermediates of formula II are elaborated to 
compounds of formula I by reductive alkylation with an aldehyde by the 
aforementioned procedures. The products, obtained as hydrochloride or 
trifluoroacetate salts, are conveniently purified by reverse phase high 
performance liquid chromatography (HPLC) or by recrystallization. 
##STR33## 
Compounds of formula I wherein R.sup.4 is taken as C.sub.1 -C.sub.10 alkyl 
substituted with R.sup.14 are prepared from intermediate II by the 
aforementioned reductive amination procedure using an aldehyde 
appropriately substituted with the heterocycle, R.sup.14. For example, as 
shown in Scheme 15, compounds of formula I wherein R.sup.4 is --CH.sub.2 
R.sup.14 are conveniently prepared using the aldehyde, R.sup.14 --CHO (33) 
and the reducing agent, sodium cyanoborohydride. 
##STR34## 
A route to the sub-class of compounds of formula I that can be described by 
formula VII is shown in Scheme 16. 
##STR35## 
Thus, intermediates of formula VI are reacted with R.sup.14 --NH.sub.2 neat 
or in a polar solvent such as dimethylsulfoxide at temperatures of 
50.degree. C. to 200.degree. C., to give compounds of formula VII. 
Intermediates of formula VI may themselves be prepared by the 
transformations described by Fisher, et al, U.S. Pat. No. 5,206,235 and 
references cited therein. 
It should be appreciated by one skilled in the art that the order of the 
alkylation step (Scheme 1) and the reductive alkylation step (Scheme 14) 
may be reversed to facilitate the reaction or to avoid unwanted reaction 
products. Thus, as demonstrated in Scheme 16, intermediate III is 
deprotected using the aforementioned conditions, and the resulting amine 
intermediate VIII is reacted with the appropriate aldehyde under the 
reductive alkylation conditions described previously. The new intermediate 
thus obtained (IX), may then be treated with alkylating agent IV following 
the procedures described in Scheme 1 to give, after removal of any 
protecting groups, compounds of formula I. 
##STR36## 
It is again 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 triiodothyronine. 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, on 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 s 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 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 or GHRP-2 as described in U.S. Pat. No. 4,411,890; 
and publications WO 89/07110 and WO 89/07111 and B-HT 920 or in 
combination with growth hormone releasing factor and its analogs or growth 
hormone and its analogs. A still further use of the disclosed novel 
benzo-fused lactam growth hormone secretagogues is in combination with 
.alpha..sub.2 adrenergic agonists or .beta..sub.3 adrenergic agonists in 
the treatment of obesity or in combination with parathyroid hormone or 
bisphosphonates, such as MK-217 (alendronate), in the treatment of 
osteoporosis. A still further use of the disclosed novel benzo-fused 
lactam growth hormone secretagogues is in combination with IGF-1 to 
reverse the catabolic effects of nitrogen wasting as described by Kupfer, 
et al, J. Clin. Invest., 91, 391 (1993). 
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; attenuation 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.