Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-06
2001-10-16
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S199000, C546S201000, C546S202000, C546S205000, C546S209000, C546S218000, C546S187000, C546S189000, C546S195000, C546S196000, C546S197000, C546S198000, C546S200000, C546S207000, C546S208000, C546S210000, C546S212000, C546S214000, C548S127000, C548S128000, C548S205000, C548S214000, C548S253000, C548S306100, C548S467000, C548S468000, C514S211070, C514S247000, C514S315000, C514S316000, C514S317000, C514S318000, C514S320000, C514S321000, C514S322000, C514S323000, C514S324000, C514S326000, C514S330000, C540S
Reexamination Certificate
active
06303620
ABSTRACT:
FIELD OF INVENTION
The present invention relates to novel compounds, in particular 4,4-disubstituted and 3,3-disubstituted piperidine 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 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 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, WO 9514666, WO9419367, WO9534311, WO9602530, WO9615148, WO9613265, WO9622997, WO9635713, WO9638471, WO9632943, WO9700894, WO9706803, WO9709060, WO9707117, WO9711697, WO9722620, WO9723508, WO9724369, and WO9734604.
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.
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, in a broad aspect the present invention relates to a compound of formula I
wherein
R
1
is hydrogen, or C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently of each other 0, 1, 2 or 3;
b and c are independently of each other 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5,
D is
R
2
—NH—(CR
3
R
4
)
e
—(CH
2
)
f
—M—(CHR
5
)
g
—(CH
2
)
h
—
wherein R
2
, R
3
, R
4
and R
5
are independently hydrogen or C
1-6
alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl; or
R
2
and R
3
or R
2
and R
4
or R
3
and R
4
may optionally form —(CH
2
)
i
—U—(CH
2
)
j
—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is a valence bond, —CR
6
═CR
7
—, arylene, hetarylene, —O— or —S—;
R
6
and R
7
are independently hydrogen, or C
1-6
alkyl optionally substituted with one or more aryl or hetaryl;
wherein R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
independently of each other are hydrogen, halogen, aryl, hetaryl, C
1-6
-alkyl or C
1-6
-alkoxy; k and l are independently 0, 1 or 2;
E is —CONR
18
R
19
, —COOR
19
, —(CH
2
)
m
—NR
18
SO
2
R
20
, —(CH
2
)
m
—NR
18
COR
20
, —(CH
2
)
m
—OR
19
, —(CH
2
)
m
—OCOR
20
, —CH(R
18
)R
19
, —(CH
2
)
m
—NR
18
—CS—NR
19
R
21
or —(CH
2
)
m
—NR
18
—CO—NR
19
R
21
; or
E is —CONR
22
NR
23
R
24
, wherein R
22
is hydrogen, C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl, or aryl or hetaryl optionally substituted with one or more C
1-6
-alkyl; R
23
is C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl, or C
1-7
-acyl; and R
24
is hydrogen, C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl; or aryl or hetaryl optionally substituted with one or more C
1-6
-alkyl; or
R
22
and R
23
together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C
1-6
-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or
R
22
and R
24
together with the nitrogen atoms to which they are attached may form a heterocyclic system optionally substituted with one or more C
1-6
-alkyl, halogen, amino, hydroxyl, aryl or hetaryl; or
R
23
and R
24
together with the nitrogen atom to which they are attached may form a heterocyclic system optionally substituted with one or more C
1-6
-alkyl, halogen, amino, hydroxyl, aryl or hetaryl;
wherein m is 0, 1, 2 or 3,
R
18
, R
19
and R
20
independently are hydrogen or C
1-6
-alkyl optionally substituted with halogen, —N(R
25
)R
26
, wherein R
25
and R
26
are independently hydrogen or C
1-6
alkyl; hydroxyl, C
1-6
-alkoxy, C
1-6
-alkoxycarbonyl, C
1-6
-alkylcarbonyloxy or aryl;
wherein
Q is —CH< or —N<,
K and L are independently —CH
2
—, —CO—, —O—, —S—, —NR
27
— or a valence bond,
where R
27
is hydrogen or C
1-6
alkyl;
n and o are independently 0, 1, 2, 3 or 4;
R
20
is C
1-6
alkyl, aryl or hetaryl;
or a pharmaceutically acceptable salt thereof;
with the proviso that if M is a valence bond then E is —CONR
22
NR
23
R
24
.
In a more narrow aspect the present invention relates to a compound of formula I
wherein
R
1
is hydrogen, or C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl;
a and d are independently of each other 0, 1, 2 or 3;
b and c are independently of each other 0, 1, 2, 3, 4 or 5, provided that b+c is 3, 4 or 5,
D is
R
2
—NH—(CR
3
R
4
)
e
—(CH
2
)
f
—M—(CHR
5
)
g
—(CH
2
)
h
—
wherein R
2
, R
3
, R
4
and R
5
are independently hydrogen or C
1-6
alkyl optionally substituted with one or more halogen, amino, hydroxyl, aryl or hetaryl; or
R
2
and R
3
or R
2
and R
4
or R
3
and R
4
may optionally form —(CH
2
)
i
—U—(CH
2
)
j
—, wherein i and j are independently 1 or 2 and U is —O—, —S— or a valence bond;
h and f are independently 0, 1, 2, or 3;
g and e are independently 0 or 1;
M is —CR
6
═CR
7
—, arylene, hetarylene, —O— or —S—;
R
6
and R
7
are independently hydrogen, or C
1-6
-alkyl optionally substituted with one or more aryl or hetaryl;
G is —O—(CH
2
)
k
—R
8
,
wherein R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
and R
17
independently of each other are hydrogen, halogen, aryl, hetaryl, C
1-6
alkyl or C
1-6
-alkoxy;
k and l are independently 0, 1 or 2;
E is —CO
Ankersen Michael
Hansen Thomas Kruse
Covington Raymond
Novo Nordisk A S
Rotman Alan L.
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