Compounds with growth hormone releasing properties

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

2000-07-19

2001-08-14

Oswecki, Jane C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S255020, C514S255040, C514S326000, C514S327000, C514S422000, C514S424000, C514S444000, C514S445000, C514S415000, C514S397000, C514S340000, C544S384000, C544S386000, C544S400000, C546S268400, C548S335100, C548S490000, C424S451000, C424S464000, C424S489000

Reexamination Certificate

active

06274584

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel compounds, pharmaceutical compositions containing them, a method of stimulating the release of growth hormone from the pituitary, a method for increasing the rate and extent of growth of animals to increase their milk and wool production, or for the treatment of ailments, and to use of the compounds for the preparation of medicaments.
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 mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acd 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-3,4dihydroxyphenylalanine (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 nonviable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason oral administration of them is not viable.
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 89107110, WO 8910171 1, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 95117422, WO 95/17423, WO 95114666, WO 96/15148 and WO 96/10040.
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.
SUMMARY OF INVENTION
Accordingly, the present invention relates to a compound of the general formula I
formula I
wherein
A is A
1
or A
2
;
G is G
1
or G
2
;
D is hydrogen, —O—(CH)
k
—R
5a
,
wherein R
5
, R
6
, R
7
, R
8
, and R
9
independently are hydrogen, halogen, aryl, C
1-6
alkyl or C
1-5
-alkoxy;
R
5a
is hydrogen, aryl optionally substituted with halogen or C
1-6
-alkyl, or C
1-6
-alkyl optionally substituted with halogen or C
1-6
-alkyl,
k is 0, 1, 2, or 3;
E is hydrogen, —O—(CH
2
)
l
—R
10a
,
wherein R
10
, R
11
, R
12
, R
13
and R
14
independently are hydrogen, halogen, aryl, C
1-6
-alkyl, C
1-6
-alkoxy, —CONR
15
R
16
, —(CH
2
)
v
—NR
15
SO
2
R
17
, —(CH
2
)
v
—NR
15
COR
16
, —(CH
2
)
v
—OR
17
, (CH
2
)
v
—OCOR
16
, —CH(R
15
)R
16
, —(CH
2
)
v
—NR
15
—CS—NR
16
R
18
, —(CH
2
)
v
—NR
15
—CO—NR
16
R
18
,
wherein
X
1
is —N(R
19
, —O— or —S—,
X
2
is —C(R
20
)═ or —N═,
X
3
is —C(R
21
)═ or —N═,
X
4
is —C(R
22
)═ or —N═;
R
2
and R
10
may be taken together to form —CH
2
— or —CH
2
—CH
2
—,
R
19
is hydrogen or C
1-6
-alkyl optionally substituted with aryl,
R
20
, R
21
and R
22
independently are hydrogen, —COOR
23
, —CONR
24
R
25
, —(CH
2
)
w
NR
24
R
25
, —(CH
2
)
w
OR
23
, —(CH
2
)
w
R
23
or halogen;
R
15
, R
16
, R
23
, R
24
and R
25
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen, —N(R
26
)R
27
, hydroxyl, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl, C
1-6
-alkyl-carbonyloxy or aryl,
or R
16
is
wherein
Q
1
is —CH< or —N<,
T
1
and J
1
are independently —CH
2
, —CO—, —O—, —S—, —NR
28
— or a valence bond,
where R
28
is hydrogen or linear or branched C
1-6
-alkyl;
t and u are independently 0, 1, 2, 3 or 4;
R
17
is C
1-6
alkyl or phenyl optionally substituted with hydroxyl or aryl;
R
18
is C
1-6
alkyl;
R
26
and R
27
are independently hydrogen or C
1-6
-alkyl;
v and w are independently 0, 1, 2 or 3;
R
10a
is hydrogen, aryl optionally substituted with halogen or C
1-6
-alkyl, or C
1-6
-alkyl optionally substituted with halogen or C
1-6
-alkyl,
l is 0, 1, 2, or 3;
A
1
is
or R
33
—NH—(CR
34
R
35
)
p
.(CH
2
)
m
—M—(CHR
36
)
o
—(CH
2
)
n
—
wherein R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
35
and R
36
are independently hydrogen or C
1-6
-alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
R
33
and R
34
, R
33
and R
35
, or R
34
and R
35
may optionally form —(CH
2
)
i
—Z—(CH
2
)
i
, wherein i and j independently are 1 or 2 and Z is —O—, —S— or a valence bond;
n, m and q are independently 0, 1, 2, or 3;
o and p are independently 0 or 1;
M is —CR
37
═CR
38
—, —O—, —S—, or a valence bond;
R
37
and R
38
are independently hydrogen, or C
1-6
-alkyl optionally substituted with aryl;
A
2
is
or R
33
—NH—(CR
34
R
35
)
p
.(CH
2
)
m
—M—(CHR
36
)
o
—(CH
2
)
n
—
wherein R
29
, R
30
, R
31
, R
32
, R
33
, R
34
, R
35
and R
36
are independently hydrogen or C
1-6
-alkyl optionally substituted with halogen, amino, hydroxyl or aryl;
R
33
and R
34
, R
33
and R
35
or R
34
and R
35
may optionally form —(CH
2
)
i
—Z—(CH
2
)
j
—, wherein i and j independently are 1 or 2 and Z is —O—, —S— or a valence bond;
n, m and q are independently 0, 1, 2, or 3;
o and p are independently 0 or 1;
M is —CR
37
═CR
38
, —O—, or —S—;
R
37
and R
38
are independently hydrogen, or C
1-6
-alkyl optionally substituted with aryl;
G
1
is hydrogen, halogen, aryl, C
1-6
-alkyl, C
1-6
-alkoxy, —CONR
39
R
40
, —(CH
2
)
e
—NR
39
SO
2
R
41
, —(CH
2
)
e
—NR
39
COR
40
, —(CH
2
)
e
—OR
41
, —(CH
2
)
e
—OCOR
40
, —CH(R
39
)R
40
, —CON
39
—NR
40
R
42
, —(CH
2
)
e
—NR
39
—CS—NR
40
R
42
, —(CH
2
)
e
NR
39
—CO—NR
40
R
42
,
wherein
X
5
is —N(R
43
)—, —O— or —S—,
X
6
is —C(R
44
)═ or —N═,
X
7
is —C(R
45
)═ or —N═,
X
8
is —C(R
46
)═ or —N═,
R
43
is hydrogen or C
1-6
-alkyl optionally substituted with aryl,
R
44
, R
45
and R
46
independently are hydrogen, —COOR
47
, —CONR
48
R
49
, —(CH
2
)
f
NR
48
R
49
, —(CH
2
)
f
OR
47
, —(CH
2
)
f
R
47
or halogen;
R
39
,R
40
, R
47
, R
48
and R
49
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen,
—N(R
50
)R
51
, hydroxyl, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl,
C
1-6
-alkylcarbonyloxy or aryl,
or R
40
is
wherein
Q
2
is —CH< or —N<,
J
2
and T
2
are independently —CH
2
—, —CO—, —O—, —S—, —NR
52
— or a valence bond,
where R
52
is hydrogen or C
1-6
-alkyl;
x and y are independently 0, 1, 2, 3 or 4;
R
41
is C
1-6
alkyl substituted with aryl;
R
42
is C
1-6
alkyl;
R
50
and R
51
are independently hydrogen or C
1-6
-alkyl;
e and f are independently 0, 1, 2 or 3;
G
2
is hydrogen or C
1-6
-alkyl;
R
1
is hydrogen or C
1-6
-alkyl;
R
2
is hydrogen, —C(═O)—R
54
or C
1-6
-alkyl;
R
1
and R
2
may be taken together to form a bridge of type
wherein R
55
and R
56
independently of each other are hydrogen, C
1-6
-alkyl, optionally substituted with hydroxyl, C
1-6
-alkoxyl or aryl;
R
55
and R
56
may be taken together to form ═O or ═S;
c and d are independently 0, 1, or 2;
c+d is 0, 1, or 2;
R
54
is hydrogen or C
1-6
-alkyl,
R
3
and R
4
are hydrogen, C
1-6
-alkyl, optionally substituted with hydroxyl, C
1-6
-alkoxyl, halogen, or aryl;
R
3
and R
4
may be taken together to form ═S, ═O;
L
1
is CR
57
or N;
L
2
is CR
58
or N;
R
57
and R
58
independently are hydrogen, C
1-6
-alkyl, optionally substituted with hydroxyl, halogen,

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