Compounds with growth hormone releasing properties

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

1999-11-19

2002-02-26

Higel, Floyd D. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S326000, C514S616000, C514S666000, C546S209000, C548S131000, C564S153000, C564S155000, C564S345000, C564S502000

Reexamination Certificate

active

06350767

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 mobilization 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 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 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711, WO 93/04081, WO 95/17422, WO 95/17423 and WO 95/14666.
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 with growth hormone releasing properties which have improved properties relative to known peptides of this type.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a compound of general formula I
Wherein
n is 0 or 1;
m is 1 or 2;
p is 0, 1 or 2;
A is
wherein R
1
is hydrogen or C
1-6
-alkyl,
W is ═0 or ═S;
B is
wherein R
2
is hydrogen or C
1-6
-alkyl,
W′ is ═0 or ═S;
D is
wherein R
3
, R
4
, R
5
, R
6
, R
7
and R
8
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen, amino, hydroxy or aryl;
R
5
and R
6
, R
6
and R
7
, R
5
and R
8
or R
7
and R
8
optionally forming —(CH
2
)
i
—U—(CH
2
)
j
—, wherein i and j independently are 1 or 2, and
U is —O—, —S—or a valence bond;
M is —O—, —S—, —CH═CH—,
optionally substituted with halogen, amino, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy;
o, r and t are independently 0, 1, 2, 3 or 4;
q and s are independently 0 or 1;
and r+s+t is 1, 2, 3 or 4;
E is hydrogen,
wherein L is hydrogen, —OR
9
, —CONR
9
R
10
, C
1-6
-alkyl obtionally substituted with hydroxy or C
1-6
-alkoxy,
or L is
wherein R
9
and R
10
are independently hydrogen, C
1-6
-alkyl or together form —(CH
2
)
k
—U′—(CH
2
)
l
—,
wherein k and l independently are 1, 2 or 3, and k+l is 3, 4, 5 or 6,
U′ is —O—, —S— or a valence bond;
X is —N(R
11
)—, —O— or —S—,
V is —C(R
12
)═ or —N═,
Y is —C(R
13
)═ or —N═,
Z is —C(R
14
)═ or —N═,
R
12
, R
13
and R
14
independently are hydrogen, —COOR
15
, —CONR
16
R
17
, —(CH
2
)
v
NR
16
R
17
, —(CH
2
)
u
OR
15
, halogen, hydroxy, branched or linear C
1-6
-alkyl, phenyl, oxazol-5-yl, 5-methyl-[1,2,4]oxadiazol-3-yl, R
11
, R
15
, R
16
and R
17
independently are hydrogen or branched or linear C
1-6
-alkyl obtionally substituted with aryl, and u and v are independently 0 or 1, 2, 3, 4, 5 or 6;
K is hydrogen or
wherein R
18
, R
19
, R
20
and R
21
are independently hydrogen, C
1-6
-alkyl optionally substituted with halogen, amino, C
1-6
-alkylamino, hydroxy or aryl; R
18
and R
19
, R
18
and R
21
, R
19
and R
20
or R
20
and R
21
optionally forming —(CH
2
)
k′
—Z—(CH
2
)
l′
— where k′ and l′ independently are 1, 2 or 3, and k′+l′ are 3, 4, 5 or 6;
Z is —O—, —S—or avalence bond;
b is 0 or 1;
a and d are independently 0, 1, 2, 3 or 4;
and a+b is 1 to 4;
Q is >CR
22
— or >N—,
wherein R
22
is hydrogen or C
1-6
-alkyl,
F is
wherein R
23
is hydrogen or C
1-6
-alkyl,
W″ is ═O or ═S;
G is hydrogen,
optionally substituted with halogen, amino, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy;
J is
optionally substituted with halogen, amino, hydroxy, C
1-6
-alkyl or C
1-6
-alkoxy;
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.
Regarding the above compounds of the general formula I preferred substituents are mentioned in the dependent claims. Furthermore, especially preferred substituents are those mentioned below.
Preferred groups of A are
wherein R
1
and W are as defined above.
Preferred groups of R
1
is C
1-6
-alkyl, and more preferred C
1-3
-alkyl such as methyl, ethyl, cyclopropyl and isopropyl.
Preferably m is 1 and/or p is 1.
Preferred groups of B are
wherein R
2
and W
1
are as defined above.
Preferably R
2
is C
1-6
-alkyl, and more preferred C
1-3
-alkyl such as methyl, ethyl, cyclopropyl and isopropyl.
Preferably D is
wherein R
5
, R
6
, R
7
, R
8
, M, s, t, q and o are as defined above. Preferably R
5
and R
6
, R
6
and R
7
, R
5
and R
8
or R
7
and R
8
are optionally forming —(CH
2
)
i
—U—(CH
2
)
j
—, wherein U, i and j are as defined above.
Preferably U is a valence bond.
Preferably M is —O—,—CH═CH— or
Preferably o, r and t are independently 0, 1, 2 or 3.
Specifically preferred D is 4-piperidinyl, 3-piperidinyl, 3-aminomethylphenyl, 3-amino-3-methyl-butenyl or 4-amino-4-methyl-pentenyl.
Preferably K is hydrogen.
Preferably F is
wherein R
23
is as defined above.
Preferably G is
The meanings of the above preferred substituents should in no way be construed as limiting the invention to such substituents Representative compounds of the present invention include the following:
3-Aminomethyl-N-((1R, 2E, 4S)-4-carbamoyl-5-(2-naphthyl)-1-(2-naphthyl)methylpent-2-enyl)benzamide:
Piperidine-4-carboxylic acid ((1R, 2E, 4S)-4-carbamoyl-5-(2-naphthyl)-1-(2-naphthyl)methylpent-2-enyl) amide:
N-((1R)-1-((1R)-1-((1S)-5-Amino-1-(dimethylcarbamoyl)pentylcarbamoyl)-2-phenylethoxy)methyl-2-(2-naphthyl)ethyl)-3-aminomethylbenzamide:
N-((1R, 4S)-4-(((1S)-5-Amino-1-(dimethylcarbamoyl)pentyl)carbamoyl)-1-((2-naphthyl)methyl)-2-oxo-5-phenylpentyl)-3-aminomethylbenzamide:
N-((1R, 2R, 4S)-4-(((1S)-5-Amino-1-(dimethylcarbamoyl)pentyl)carbamoyl)-2-hydroxy-1-((2-naphthyl)methyl)-5-phenylpentyl)-3-aminomethylbenzamide:
Piperidine-3-carboxylic acid ((1R, 2R, 4S)-4-(((1S)-5-amino-1-(dimethylcarbamoyl)pentyl)carbamoyl)-2-hydroxy-1-(2-naphthyl)methyl)-5-phenylpentyl)amide:
5-((1R)-1-(N-Methyl-N-((2R)-3-(2-naphthyl)-2-(piperidine-4-carbonylamino)propionyl)amino)-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethylester:
5-((1R)-1-(N-((2R)-2-(3-Aminomethylbenzoylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-2-(2-naphthyl)ethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethylester:
5-((1R)-1-(N-(2R)-2-(3-Aminomethylbenzoylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-2-phenylethyl)-[1,3,4]oxadiazole-2-carboxylic acid amide:
It is believed that compounds of formula

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