Growth hormone secretagogues

Details Growth hormone secretagogues Growth hormone secretagogues

2001-04-17

2003-10-28

Chang, Ceila (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S016700, C514S018700, C514S019300, C514S222200, C514S231200, C514S249000, C514S255030, C514S315000, C514S396000, C514S397000, C530S331000, C546S207000, C546S208000, C546S209000, C546S212000, C548S300100, C548S311100, C548S314700, C548S315100, C548S315700

Reexamination Certificate

active

06639076

ABSTRACT:

Growth hormone is a secretory protein of the pituitary gland of animals having wide ranging developmental effects on the organism. Artificial manipulation of growth hormone levels has been demonstrated to have significant therapeutic utility. Human growth hormone supplementation has been shown to be an effective treatment for growth hormone deficiencies and their related disease states in humans. Apart from this application, studies have uncovered new and significant properties of growth hormone which lend further importance to the ability to control growth hormone levels. For example, recent clinical studies indicate that growth hormone supplementation may be useful in combating the maladies of aging in humans. Elevated growth hormone levels in animals have been shown to result in increased lean muscle mass. One application of this latter observation could result in higher production of leaner meat products or in the production of larger and/or stronger animals.
While growth hormone is naturally produced by the pituitary gland, the secretion of growth hormone into the bloodstream is controlled by a second protein, Growth Hormone Releasing Factor (GRF). This hormone is also commonly known in the art as somatocrinin, Growth Hormone Releasing Hormone (GHRH), and Growth Releasing Hormone (GRH).
There are two ways to approach the problem of increasing circulating levels of growth hormone: (1) increase the level of human growth hormone in the organism directly or (2) increase the organism's natural tendency to produce growth hormone. The latter strategy may be achieved via supplementation with GRF. GRF has been demonstrated to increase the circulatory levels of growth hormone in vivo. (Rivier, et al.,
Nature
(London), 300:276 (1982). The effect of GRF, including structural analogs thereof, on growth hormone production has been widely studied. A primary obstacle to the use of GRF as a direct supplement is its short lifespan in vivo. L. A. Frohman, et al.,
Journal of Clinical Investigation,
78:906 (1986). More potent and/or longer lasting GRF molecules are therefore desirable for the development of effective human therapeutic or animal husbandry agents.
The structure of GRF has been modified in numerous ways resulting in longer lasting and/or more potent GRF analogs. It has been demonstrated that the first 29 amino acids from the N-terminus are sufficient to retain full GRF activity. Speiss, et al.,
Biochemistry,
21:6037 (1982). One strategy has been the incorporation of novel D-amino acid residues in various regions of the GRF molecule. V. A. Lance, et al.,
Biochemical and Biophysical Research Communications,
119:265 (1984); D. H. Coy, et al.,
Peptides,
8(suppl. 1):49 (1986). Another strategy has modified the peptide backbone of GRF by the incorporation of peptide bond isosteres in the N-terminal region. D. Tourwe,
Janssen. Chim. Acta,
3:3 (1985); S. J. Hocart, et al.,
Journal of Medicinal Chemistry,
33:1954-58 (1990). A series of very active analogs of GHRH is described in European Patent Publication 511,003, published Oct. 28, 1992.
In addition to the actions of GHRH there are various ways 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 GHRH.
In cases where increased levels of growth hormone are desired, the problem has generally been solved by providing exogenous growth hormone or by administering GHRH, or a related peptidyl compounds which stimulates growth hormone production or release. In either instance the peptidyl nature of the compound has necessitated that it be administered by injection.
Other compounds have been developed which stimulate the release of endogenous growth hormone, such as analogous peptidyl compounds related to GHRH. These peptides, while considerably smaller than growth hormones are still susceptible to metabolic instability.
Administration of the hexapeptide growth hormone releasing peptide-6 (GHRP-6) results in the secretion of growth hormone in many species, including humans. This peptide is one of a series of synthetic peptides, the structures of which were based on the pentapeptide Met-enkephalin. It has been shown that GHRP binds specifically to the pituitary, although the binding does not involve the opioid, GHRH, or the somatostatin receptors.
In recent years significant efforts have been taken to develop nonpeptidyl analogs of this series of compounds. Such compounds, termed growth hormone secretagogues, should be orally bioavailable, induce the production or release of growth hormone, and act in concert, or synergistically with GHRH.
Representative growth hormone secretagogues are disclosed in U.S. Pat. Nos. 3,239,345; 4,036,979; 4,411,890; 5,206,235; 5,248,841; 5,310,737; 5,310,017; European Patent Publication 144,230; European Patent Publication 513,974; Patent Cooperation Treaty Patent Publication WO 94/07486; Patent Cooperation Treaty Patent Publication WO 94/08583; Patent Cooperation Treaty Patent Publication WO 94/13696; U.S. Ser. No. 08/704,494, filed Aug. 20, 1996, U.S. Ser. No. 08/700,206, filed Aug. 20, 1996, and
Science,
260:1640-1643 (1993).
U.S. Pat. No. 5,206,235, issued Apr. 27, 1993, describes a series of benzolactam compounds typified by the following structure.
These compounds have demonstrated clinical activity in humans in raising the growth hormone secretory levels. B. J. Gertz,
Journal of Clinical Endocrinology and Metabolism,
77:1393-1397 (1993).
Another group of growth hormone secretagogues is described in Patent Cooperation Treaty Patent Publication WO 94/13696, published Jun. 23, 1994. These compounds are typified by the following two structures.
The present invention provides a series of compounds that have activity as growth hormone secretagogues. These compounds are non-peptidyl in nature and are, therefore, more metabolically stable than growth hormone, growth hormone releasing hormone, or analogs of either of these proteins. The compounds employed in the present invention are preferred for human pharmaceutical uses as well as veterinary uses, particularly in cattle, swine, sheep, poultry and fish.
The present invention relates to compounds of formula I
wherein:
A is C
1
-C
6
alkyl, aryl, C
1
-C
6
alkylaryl, C
1
-C
6
alkyl(O)C
1
-C
6
alkylaryl, C
1
-C
6
alkyl(S)C
1
-C
6
alkylaryl, indolyl, indolinyl, thienyl, (C
1
-C
6
alkyl)thienyl, benzothienyl, benzofuranyl, naphthanyl, cyclohexyl, (C
1
-C
6
alkyl)indolyl, (C
1
-C
6
alkyl)benzothienyl, (C
1
-C
6
alkyl)naphthanyl, (C
1
-C
6
alkyl)benzofuranyl, and (C
1
-C
6
alkyl)cyclohexyl;
B is NH
2
, NHR
1
, C
1
-C
6
alkylNH
2
, C
1
-C
6
alkylNHR
1
, C
1
-C
6
alkylarylNH
2
, C
1
-C
6
alkylarylNHR
1
, C
1
-C
6
alkylcyclohexylNH
2
, C
1
-C
6
alkylcyclohexylNHR
1
, R
1
-piperidin-3-yl(C
1
-C
6
alkyl), R
1
-piperidin-2-yl(C
1
-C
6
alkyl), R
1
-piperidin-4-yl(C
1
-C
6
alkyl), R
1
-quinolin-2-yl(C
1
-C
6
alkyl), R
1
-(2,4-dihydroquinolin-2-yl(C
1
-C
6
alkyl), R
1
-isoquinolin-2-yl(C
1
-C
6
alkyl), and R
1
-(2,4-dihydroisoquinolin-2-yl(C
1
-C
6
alkyl);
R
1
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkyl(OH), or C
1
-C
6
alkylidenyl(OH)R
2
;
R
2
is C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
alkyl(O)C
1
-C
6
alkyl, C(O)O-C
1
-C
6
alkyl, aryl, or C
1
-C
6
alkylaryl;
X is C
1
-C
6
alkylidenyl, O, S, NH, or N(C
1
-C
6
alkyl);
V is selected from the group consisting of
 and
W is S, O, NH, or CH
2
;
Y is N or CH;
Z is N or CH;
Y′ is N or CH;
Z′ is N or CH;
R
4
and R
5
are independently hydrogen, C
1
-C
6
alkyl, aryl, C
1
-C
6
alkylaryl, C(O)O(C
1
-C
6
alkyl), C(O)N(C
1
-C
6
alkyl)
2
, or C
1
-C
6
alkylCOR
7
;
R
7
is hydrogen, C
1
-C
6
alkyl, pyrrolidinyl, piperidinyl, homoproline, or proline;
D is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkyl(O)(CO)C
1
-C
6
alkyl, C
1
-C
6
alkyl(O)(C

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