Compounds with growth hormone releasing properties

Details Compounds with growth hormone releasing properties Compounds with growth hormone releasing properties

1999-11-02

2003-05-20

Low, Christopher S. F. (Department: 1653)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C562S445000, C562S553000

Reexamination Certificate

active

06566337

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone which stimulates growth of all tissues capable of growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilisation and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyctase activating peptide), muscarinic receptor agonists and a synthetic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason parenteral administration is preferred.
The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 8302272, WO 8907110, WO 8901711, WO 8910933, WO 8809780, WO 9118016, WO 9201711, WO 9304081, WO 9413696, WO 9517423, WO 9514666, WO 9615148, WO 9622997, WO 9635713, WO 9700894, WO 9722620, WO 9723508, WO 9740023, and WO 9810653.
The composition of growth hormone releasing compounds is important for their growth hormone releasing potency as well as their bioavailability. It is therefore an object of the present invention to provide novel compounds with growth hormone releasing properties. Moreover, it is an object to provide novel growth hormone releasing compounds (growth hormone secretagogues) which are specific and/or selective and have no or substantially no side-effects, such as e.g. release of LH, FSH, TSH, ACTH, vasopressin, oxytocin, cortisol and/or prolactin. It is also an object to provide compounds which have good oral bioavailability. A further object of the present invention is to provide compounds with a relatively short plasma elimination half-life. A still further object of the present invention is to provide compounds which have a good oral biovailability together with a relatively short plasma elimination half-life.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided novel compounds which act directly on the pituitary cells under normal experimental conditions in vitro to release growth hormone therefrom.
These growth hormone releasing compounds can be utilized in vitro as unique research tools for understanding, inter alia, how growth hormone secretion is regulated at the pituitary level.
Moreover, the growth hormone releasing compounds of the present invention can also be administered in vivo to increase endogenous growth hormone release.
DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to a compound of the general formula I
wherein
R
1
and R
2
are independently hydrogen or
C
1-6
-alkyl optionally substituted with aryl;
a and b are independently 1 or 2;
G is
J is
wherein R
27
, R
28
, R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
35
and R
36
independently are hydrogen, halogen, aryl, C
1-6
-alkyl or C
1-6
-alkoxy;
D is
R
7
—NH—(CR
8
R
9
)
p
—(CH
2
)
m
—M—(CHR
10
)
q
—(CH
2
)
n
—
wherein R
7
, R
8
, R
9
and R
10
are independently hydrogen or C
1-6
alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
R
7
and R
8
or R
7
and R
9
or R
8
and R
9
may optionally form —(CH
2
)
i
—U—(CH
2
)
j
—, wherein i and j are independently are 1 or 2 and U is —O—, —S— or a valence bond;
m and n are independently 0, 1, 2, or 3;
p and q are independently 0 or 1;
M is —CR
11
═CR
11a
—, arylene, —O—, or —S—;
R
11
and R
11a
are independently hydrogen, or C
1-6
-alkyl optionally substituted with aryl;
E is
—CONR
12
R
13
,
wherein
R
12
is C
1-6
-alkyl;
R
13
is hetaryl or C
1-6
-alkyl substituted with hetaryl;
or a pharmaceutically acceptable salt thereof.
Moreover, the compounds of formula I may comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof. Whenever one or more chiral carbon atoms are present such chiral center or centers may be in the R- and/or S-configuration, or a mixture of R and S.
Furthermore, the compounds of formula I may have one or more carbon-carbon double bonds with the possibility of geometric isomeri, and it is intended that possible stereoisomers (E or Z isomers) are included in the scope of the invention, unless a special geometric isomer is specified.
In one embodiment of the compound of formula I R
1
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl.
In a further embodiment of the compound of formula I R
2
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl.
In a still further embodiment of the compound of formula I a is 1.
In a further embodiment of the compound of formula I b is 1.
In a still further embodiment of the compound of formula I G is
wherein R
27
, R
28
, R
29
, R
30
and R
31
independently are hydrogen, halogen, aryl, C
1-6
-alkyl or C
1-6
-alkoxy. In one embodiment R
27
is hydrogen. In a second embodiment R
28
is hydrogen. In a third embodiment R
29
is hydrogen. In a further embodiment R
30
is hydrogen. In a still further embodiment R
31
is hydrogen. In the compound of the above formula I G is preferably phenyl or naphthyl, in particular 2-naphthyl.
In a further embodiment of the compound of formula I J is
wherein R
32
, R
33
, R
34
, R
35
and R
36
independently are hydrogen, halogen, aryl, C
1-6
alkyl or C
1-6
-alkoxy. In one embodiment R
32
is hydrogen. In a second embodiment R
33
is hydrogen. In a third embodiment R
34
is hydrogen. In a further embodiment R
35
is hydrogen. In a still further embodiment R
36
is hydrogen. In the compound of the above formula I J is preferably naphthyl, thienyl or phenyl, in particular phenyl.
In a still further embodiment of the compound of formula I D is
R
7
—NH—(CR
8
R
9
)
p
—(CH
2
)
m
—M—(CHR
10
)
q
—(CH
2
)
n
—
wherein R
7
, R
8
, R
9
and R
10
are independently hydrogen or C
1-6
alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
m and n are independently 0, 1, 2, or 3;
p and q are independently 0 or 1;
M is —CR
11
═CR
11a
—, aryl, —O—, or —S—;
R
11
and R
11a
are independently hydrogen, or C
1-6
-alkyl optionally substituted with aryl. In one embodiment R
7
is hydrogen. In a second embodiment R
7
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl. In a third embodiment R
8
is hydrogen. In a further embodiment R
8
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl. In a still further embodiment R
9
is hydrogen. In a further embodiment R
9
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl. In a still further embodiment R
10
is hydrogen. In a further embodiment R
10
is C
1-6
-alkyl, such as C
1-4
-alkyl, in particular methyl. In a further embodiment n is 0. In a still further embodiment q is 0. In a further embodiment m is 1. In a still further embodiment p is 1. In a further embodiment M is —CR
11
═CR
11a
—. In a still

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