Compounds with growth hormone releasing properties

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

2000-03-23

2003-04-29

Seaman, D. Margaret (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S566000, C548S567000, C548S568000

Reexamination Certificate

active

06555570

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 cyclase activating peptide), muscarinic receptor agonists and a synthethic 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 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 9517422, WO 9517423 and WO 9514666.
The composition of growth hormone releasing compounds is important for their growth hormone releasing potency as well as their bioavailability. It is therefore the object of the present invention to provide compounds of peptide mimetic nature with growth hormone releasing properties which have improved properties relative to known compounds of this type.
SUMMARY OF THE INVENTION
In accordance with the present invention there is provided 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 growth hormone release.
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 hydrogen, —O—(CH
2
)
k
—R
27
,
J is hydrogen, —O—(CH
2
)
l
—R
32
,
 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;
k and l are independently 0, 1 or 2;
D is
 wherein
R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are independently hydrogen or C
1-6
-alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
n, m and q are independently 0, 1, 2, or 3;
p is 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;
with the proviso that at least one of R
3
, R
4
, R
5
and R
6
is different from hydrogen,
when E is
—CONR
12
R
13
, —(CH
2
)
v
—NR
12
SO
2
R
14
, —(CH
2
)
v
—NR
12
COR
13
, —(CH
2
)
v
—OR
13a
, —CH
2
)
v
—OCOR
13
, —CH(R
12
)R
13
, —(CH
2
)
v
—NR
12
—CS—NR
13
R
14
, —(CH
2
)
v
—NR
12
—CO—NR
13
R
14
,
 wherein
X is —N(R
15
)—, —O— or —S—,
V is —C(R
16
)=or —N=,
Y is —C(R
17
)=or —N=,
Z is —C(R
18
)=or —N=,
R
15
is hydrogen or C
1-6
-alkyl optionally substituted with aryl, R
16
, R
17
and R
18
independently are hydrogen, —COOR
19
, —CONR
20
R
21
, —(CH
2
)
w
NR
20
R
21
, —CH
2
)
w
OR
19
, —(CH
2
)
w
R
19
or halogen;
R
12
, R
13
, R
19
, R
20
, and R
21
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen, —CONR
22
R
23
, —N(R
22
)R
23
, —CF
3
, hydroxyl, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl, C
1-6
-alkylcarbonyloxy or aryl,
or R
13
is
 wherein
Q is —CH<or —N<,
K and L are independently —CH
2
—, —CO—, —O—, —S—, —NR
26
— or a valence bond, where R
26
is hydrogen or C
1-6
-alkyl;
t and u are independently 0, 1, 2, 3 or 4;
R
13a
is C
1-6
alkyl substituted with aryl;
R
14
is C
1-6
alkyl;
R
22
and R
23
are independently hydrogen or C
1-6
-alkyl;
v and w are independently 0, 1, 2 or 3;
D is
R
7
—NH—(CR
8
R
9
)
p
—(CH
2
)
m
—M—(CHR
10
)
o
—(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
optionally forming —(CH
2
)
i
—U—(CH
2
)
j
—, wherein i and j are independtly are 1 or 2 and U is —O—, —S—or a valence bond;
n and m are independently 0, 1, 2, or 3;
o and p 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,
when E is
—CONR
12
R
13
, —(CH
2
)
v
—NR
12
SO
2
R
14
, —(CH
2
)
v
—NR
12
COR
13
, —(CH
2
)
v
—OR
13a
, —CH
2
)
v
—OCOR
13
, —CH(R
12
)R
13
, —(CH
2
)
v
—NR
12
—CS—NR
13
R
14
or —(CH
2
)
v
—NR
12
—CO—NR
13
R
14
,
 wherein
R
12
and R
13
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen, —CONR
22
R
23
, —N(R
22
)R
23
, —CF
3
, hydroxyl, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl, C
1-6
-alkylcarbonyloxy or aryl;
or R
13
is
 wherein
Q is—CH< or —N<,
K and L are independently —CH
2
—, —CO—, —O—, —S—, —NR
26
— or a valence bond, where R
26
is hydrogen or C
1-6
alkyl;
t and u are independently 0, 1, 2, 3 or 4;
R
13a
is C
1-6
alkyl substituted with aryl;
R
14
is C
1-6
alkyl;
R
22
and R
23
are independently hydrogen or C
1-6
alkyl;
v and w are independently 0, 1, 2 or 3;
or a pharmaceutically acceptable salt thereof, and the compounds of formula I comprise any optical isomers thereof, in the form of separated, pure or partially purified optical isomers or racemic mixtures thereof.
In the compound of the above formula I D is preferably 3-(1-aminoethyl)phenyl, 4-amino-4-ethylhex-1-enyl, (1E)-2-(azetidin-3-yl)ethenyl, piperidin-4-ylidenyl, 2-methylpiperidin-4-yl, 2-methylpiperidin-3-yl, 2-methylpiperidin-5-yl, (1,2,3,4-tetrahydroisoquinolin-1-yl)methyl, 4-aminocyclohexyl, 2-piperidylmethoxymethyl, 4-piperidyloxymethyl, 2-(2-amino-2-methylpropyl)cyclopropyl, (((2R)-pyrrolidin-2-yl)methoxy)methyl, (1E)-4-amino-1-benzyl-4-methylpent-1-enyl, (1E)-4-amino-4-methylpent-1-enyl, (2-amino-2-methylpropoxy)methyl, (2S)—(2-pyrrolidinyl)methoxymethyl, (2R)-(2-pyrrolidinyl)methoxymethyl, (1E)-4-amino-2,4-dimethylpent-1-enyl, (1E)-4-methyl-4-(methylamino)pent-1-enyl, (1Z)-4-amino-4-methylpent-1-enyl, (1E)-4-((2R)-2-hydroxypropylamino)-4-methylpent-1-enyl, (2-aminobutoxy)methyl, 3-(1-aminoethyl)phenyl, 3-aminomethylphenyl, 3-(1-amino-1-methylethyl)phenyl, 2-(1-amino cyclopropyl)ethenyl, 3-(1-aminocyclobutyl)-1-propenyl, 3-(1-aminocyclopropyl)-1-propenyl or 2-(1-aminocyclobutyl)ethenyl.
In the compound of the above formula I E is preferably methylcarbamoyl, ethylcarbamoyl, N,N-dimethylcarbamoyl, 2-methoxyethylcarbamoyl, (2S)-2-hydroxypropylcarbamoyl, (2R)-2-hydroxypropylcarbamoyl, (cyclopropylmethyl)carbamoyl

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