Naphtho-fused lactams promote release of growth hormone

Details Naphtho-fused lactams promote release of growth hormone Naphtho-fused lactams promote release of growth hormone

1998-09-24

2001-04-03

Kifle, Bruck (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S522000

Reexamination Certificate

active

06211174

ABSTRACT:

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 processes 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 GRF or a peptidal compound 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. 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. Non peptidal growth hormone secretagogues are disclosed in e.g., U.S. Pat. Nos. 5,206,235, 5,283,241, 5,284,841, 5,310,737, 5,317,017, 5,374,721, 5,430,144, 5,434,261, 5,438,136, 5,492,916, 5,494,919, 5,494,920, and 5,536,716. Other growth hormone secretagogues are disclosed e.g., in PCT Patent Publications WO 94/13696, WO 94/19367, WO 95/03289, WO 95/03290, WO 95/09633, WO 95/11029, WO 95/12598, WO 95/13069, WO 95/14666, WO 95/16675, WO 95/16692, WO 95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO 96/05195 and WO 96/22997. The instant compounds are low molecular weight peptide analogs for promoting the release of growth hormone which have good stability in a variety of physiological environments and which may be administered parenterally, nasally or by the oral route.
SUMMARY OF THE INVENTION
The instant invention is directed to certain naphtho-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 naphtho-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 naphtho-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 naphtho-fused lactams of the instant invention are described by structural Formula I:
wherein:
L is:
n is 0 or 1;
p is 0 to 3;
q is 0 to 4;
w is 0 or 1;
X is
m is 0 to 2;
R
1
, R
2
, R
1a
, R
2a
, R
1b
, R
2b
, R
1c
and R
2c
are independently selected from the group consisting of: hydrogen, halogen, C
1
-C
7
alkyl, C
1
-C
3
perfluoroalkyl, C
1
-C
3
perfluoroalkoxy, —S(O)
m
R
7a
, cyano, nitro, R
7b
O(CH
2
)
v
—, R
7b
COO(CH
2
)
v
—, R
7b
OCO(CH
2
)
v
, R
4
R
5
N(CH
2
)
v
—, R
7b
CON(R
4
)(CH
2
)
v
—, R
4
R
5
NCO(CH
2
)
v
—, phenyl, substituted phenyl where the substituents on phenyl are 1 to 3 of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy;
R
7a
and R
7b
are independently selected from the group consisting of: hydrogen, C
1
-C
3
perfluoroalkyl, C
1
-C
6
alkyl, C
1
-C
6
alkyl substituted with phenyl, phenyl and substituted phenyl where the substituents on phenyl are 1 to 3 of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy;
v is 0 to 3;
R
3a
, R
3b
and R
3c
are independently selected from the group consisting of: hydrogen, R
9
, C
1
-C
6
alkyl substituted with R
9
, phenyl substituted with R
9
, or phenoxy substituted with R
9
with the proviso that either R
3a
, R
3b
or R
3c
must be a substituent other than hydrogen;
R
9
is selected from the group consisting of: R
4b
R
12b
NCON(R
12a
)(CH
2
)
v
—, R
4b
R
12b
NCSN(R
12a
)(CH
2
)
v
—, R
4b
R
12c
NN(R
12b
)CSN(R
12a
)(CH
2
)
v
—, R
4b
R
12c
NN(R
12b
)CON(R
12a
)(CH
2
)
v
—, R
4b
R
12c
NN(R
12b
)COO(CH
2
)
v
—, R
4b
R
12b
NCOO(CH
2
)
v
— and R
13
OCON(R
12a
)(CH
2
)
v
—;
R
10
is selected from the group consisting of: hydrogen, C
1
-C
6
alkyl, phenyl C
1
-C
6
alyl and C
1
-C
5
alkanoyl-C
1
-C
6
alkyl; R
12a
, R
12b
and R
12c
are independently selected from the group consisting of: R
5a
, OR
5a
, and COR
5a
; or R
12a
and R
12b
, or R
12b
and R
12c
, or R
12a
and R
12c
, or R
12b
and R
4b
, or R
12c
and R
4b
, or R
13
and R
12a
can be taken together to form the group —CH
2
)
r
—B—(CH
2
)
s
—, where B is —CHR
1
—, —O—, —S(O)
m
— or —NR
10
—, m is 0, 1 or 2, and r and s are independently 0 to 3;
R
13
is selected from the group consisting of: C
1
-C
3
perfluoroalkyl; C
1
-C
6
alkyl; substituted C
1
-C
6
alkyl, where the substitutents on alkyl are hydroxy, NR
10
OR
11
, carboxy, or phenyl; phenyl; and substituted phenyl where the substituents on phenyl are 1 to 3 of halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or hydroxy;
R
4
, R
4b
, R
5
and R
5a
are independently selected from the group consisting of: hydrogen, phenyl, substituted phenyl, C
1
-C
10
alkyl, substituted C
1
-C
10
alkyl, C
3
-C
10
alkenyl, substituted C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, or substituted C
3
-C
10
alynyl where the substituents on the phenyl, alkyl, alkenyl or alkynyl are selected from:
1 to 5 of hydroxy, C
1
-C
6
alkoxy, C
3
-C
7
cycloalkyl, fluoro, phenyl disubstituted with R
1
and R
2
, C
1
-C
3
alkoxy-phenyl disubstituted with R
1
and R
2
, C
1
-C
20
-alkanoyloxy, C
1
-C
5
alkoxycarbonyl, carboxy, formyl and —NR
10
R
11
where R
10
and R
11
are independently hydrogen, C
1
-C
6
alkyl, phenyl, phenyl C
1
-C
6
alkyl, C
1
-C
5
-alkoxycarbonyl or C
1
-C
5
-alkanoyl-C
1
-C
6
alkyl;
or R
4
and R
5
can be taken together to form —CH
2
)
r
—B—(CH
2
)
s
— where B is CHR
1
, O, S(O)
m
or N—R
10
, r and s are independently 1 to 3;
R
6
is selected from the group consisting of: hydrogen, C
1
-C
10
alkyl, phenyl and phenyl C
1
-C
10
alkyl;
A is:
where x and y are independently 0-3;
R
8
and R
8a
are independently selected from the group consisting of: hydrogen, C
1
-C
10
alkyl, trifluoromethyl, phenyl, substituted C
1
-C
10
alkyl where the substituents on alkyl are selected from:
1 to 3 of imidazolyl, indolyl, hydroxy, fluoro, S(O)
m
R
7a
, C
1

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