Growth-hormone secretagogues

Details Growth-hormone secretagogues Growth-hormone secretagogues

1999-12-22

2001-08-21

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06278000

ABSTRACT:

This invention relates to dipeptide compounds which are growth hormone secretagogues and are useful for the treatment and prevention of osteoporosis.
BACKGROUND OF THE INVENTION
Growth hormone (GH), which is secreted from the pituitary gland, 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 substantially 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.
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
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 an 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 (e.g., Jacob-Cruetzfeld disease). 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.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion include 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 (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
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. WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds are of the general structure shown below.
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure
where L is
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
SUMMARY OF THE INVENTION
This invention provides compounds of the formula:
the racemic-diastereomeric mixtures and optical isomers of said compounds and the pharmaceutically-acceptable salts and prodrugs thereof, wherein
e is 0 or 1;
n and w are each independently 0, 1 or 2, provided that w and n cannot both be 0 at the same time;
Y is oxygen or sulfur;
R
1
is hydrogen, —CN, —(CH
2
)
q
N(X
6
)C(O)X
6
, —(CH
2
)
q
N(X
6
)C(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)SO
2
(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)SO
2
X
6
, —(CH
2
)
q
N(X
6
)C(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
C(O)OX
6
, —(CH
2
)
q
C(O)O(CH
2
)
t
—A
1
, —(CH
2
)
q
OX
6
, —(CH
2
)
q
OC(O)X
6
, —(CH
2
)
q
OC(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
OC(O)N(X
6
)(CH
2
)
t
—A
1
, —(CH
2
)
q
OC(O)N(X
6
)(X
6
), —(CH
2
)
q
C(O)X
6
, —(CH
2
)
q
C(O)(CH
2
)
t
—A
1
, —(CH
2
)
q
N(X
6
)C(O)OX
6
, —(CH
2
)
q
N(X
6
)SO
2
N(X
6
)(X
6
), —(CH
2
)
q
S(O)
m
X
6
, —(CH
2
)
q
S(O)
m
(CH
2
)
t
—A
1
, —(C
1
-C
10
)alkyl, —(CH
2
)
t
—A
1
, —(CH
2
)
q
—(C
3
-C
7
)cycloalkyl, —(CH
2
)
q
—Y
1
—(C
1
-C
6
)alkyl, —(CH
2
)
q
—Y
1
—(CH
2
)
t
—A
1
or —(CH
2
)
q
—Y
1
—(CH
2
)
t
—(C
3
-C
7
)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R
1
are optionally substituted with (C
1
-C
4
)alkyl, hydroxyl, (C
1
-C
4
)alkoxy, carboxyl, —CONH
2
, —S(O)
m
(C
1
-C
6
)alkyl, —CO
2
(C
1
-C
4
)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro; Y
1
is O, S(O)
m
, —C(O)NX
6
—, —CH═CH—, —N(X
8
)C(O)—, —C(O)NX
6
—, —C(O)O—, —OC(O)N(X
8
)— or —OC(O)—;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH
2
)
q
group and (CH
2
)
t
group may each be optionally substituted with hydroxyl, (C
1
-C
4
)alkoxy, carboxyl, —CONH
2
, —S(O)
m
(C
1
-C
6
)alkyl, —CO
2
(C
1
-C
4
)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C
1
-C
4
)alkyl;
R
2
is hydrogen, (C
1
-C
8
)alkyl, —(C
0
-C
3
)alkyl-(C
3
-C
8
)cycloalkyl, —(C
1
-C
4
)alkyl-A
1
or A
1
; where the alkyl groups and the cycloalkyl groups in the definition of R
2
are optionally substituted with hydroxyl, —C(O)OX
6
, —C(O)N(X
6
)(X
6
), —N(X
6
)(X
6
), —S(O)
m
(C
1
-C
6
)alkyl, —C(O)A
1
, —C(O)(X
6
), CF
3
, CN or 1, 2 or 3 halogen;
R
3
is A
1
, (C
1
-C
10
)alkyl, —(C
1
-C
6
)alkyl—A
1
, —(C
1
-C
8
)alkyl-(C
3
-C
7
)cycloalkyl, —(C
1
-C
5
)alkyl-X
1
—(C
1
-C
5
)alkyl, —(C
1
-C
5
)alkyl-X
1
—(C
0
-C
5
)alkyl-A
1
or —(C
1
-C
5
)alkyl-X
1
—(C
1
-C
5
)alkyl-(C
3
-C
7
)cycloalkyl;
where the alkyl groups in the definition of R
3
are optionally substituted with —S(O)
m
(C
1
-C
6
)alkyl, —C(O)OX
3
, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX
3
; X
1
is O, S(O)
m
, —N(X
2
)C(O)—, —C(O)N(X
2
)—, —OC(O)—, —C(O)O—, —CX
2
═CX
2
—, —N(X
2
)C(O)O—, —OC(O)N(X
2
)— or —C═C—;
R
4
is hydrogen, (C
1
-C
6
)alkyl or (C
3
-C
7
)cycloalkyl, or R
4
is taken together with R
3
and the carbon atom to which they are attached and form (C
5
-C
7
)cycloalkyl, (C
5
-C
7
)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X
4
is hydrogen or (C
1
-C
6
)alkyl or X
4
is taken together with R
4
and the nitrogen atom to which X
4
is attached and the carbon atom to which R
4
is attached and form a five to seven membered ring;
R
6
is a

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