Method of stimulating the motility of the gastrointestinal system using growth hormone secretagogues
The present invention relates to a method of stimulating the motility of the gastrointestinal system in a subject in need thereof, wherein the subject suffers from maladies (i.e., disorders or diseases) of the gastrointestinal system. The method comprises administering to a subject in need thereof a therapeutically effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof. The growth hormone secretagogue can be co-administered with a laxative, a H 2 receptor antagonist, a serotonin 5-HT 4 agonist, an antacid, an opioid antagonist, a proton pump inhibitor, a motilin receptor agonist, dopamine antagonist, a cholinergic agonist, a cholinesterase inhibitor, somatostatin, octreotide, or any combination thereof.
1 . A method of treating opioid induced constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.
2 . The method of claim 1 , wherein the growth hormone secretagogue is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O+(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
3 . The method of claim 2 , wherein the growth hormone secretagogue is represented by the structural Formula II:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
4 . The method of claim 2 , wherein the growth hormone secretagogue is represented by the structural Formula III:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
5 . The method of claim 1 , wherein the growth hormone secretagogue is represented by the structural Formula IV:
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) l —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
6 . The method of claim 5 , wherein the growth hormone secretagogue is represented by the structural Formula V:
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
7 . The method of claim 1 , wherein the growth hormone secretagogue is selected from the group consisting of Formula VI,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
8 . The method of claim 1 , wherein the subject is a human.
9 . The method of claim 1 , wherein the growth hormone secretagogue is orally administered.
10 . The method of claim 1 , wherein the subject is using opioids for post-surgical pain management.
11 . The method of claim 1 , wherein the subject is using opioids for chronic pain management.
12 . The method of claim 1 , wherein the opioid is selected from the group consisting of: percocet; morphine; vicoden; methadone; oxycodone; and fentanyl.
13 . The method of claim 1 , wherein the method further comprises administering a therapeutically effective amount of a laxative, peripherally acting opioid antagonist, or any combination thereof.
14 . A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O—(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 —R 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
15 . The method of claim 14 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
16 . The method of claim 14 , wherein the growth hormone secretagogue compound is represented by the structural Formula III
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
17 . A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) l —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
18 . The method of claim 17 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
19 . The method of claim 17 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
20 . A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
21 . The method of any one of claims 14 , 17 and 20 , wherein the subject is a human.
22 . The method of any one of claims 14 , 17 and 20 , wherein the growth hormone secretagogue is orally administered.
23 . A method of treating diabetes related gastroparesis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —(CH 2 ) k —R 8 ,
J is —(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
24 . The method of claim 23 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
25 . The method of claim 23 , wherein the growth hormone secretagogue compound is represented by the structural Formula III
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
26 . A method of treating diabetes related gastroparesis in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogue compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) 1 —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
27 . The method of claim 26 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
28 . The method of claim 26 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
29 . A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
30 . The method of any one of claims 23 , 26 and 29 , wherein the subject is a human.
31 . The method of any one of claims 23 , 26 and 29 , wherein the growth hormone secretagogue is orally administered.
32 . The method of any one of claims 23 , 26 and 29 , wherein the method further comprises administering a therapeutically effective amount of a dopamine antagonist.
33 . A method of treating gastroesophageal reflux disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O—(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
34 . The method of claim 33 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
35 . The method of claim 33 , wherein the growth hormone secretagogue compound is represented by the structural Formula III,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
36 . A method of treating gastroesophageal reflux disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) l —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
37 . The method of claim 36 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
38 . The method of claim 36 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
39 . A method of stimulating the motility of the gastrointestinal system in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
40 . The method of any one of claims 33 , 36 and 39 , wherein the subject is a human.
41 . The method of any one of claims 33 , 36 and 39 , wherein the growth hormone secretagogue is orally administered.
42 . The method of any one of claims 33 , 36 and 39 , wherein the gastroesophageal reflux disease is nocturnal gastroesophageal reflux disease.
43 . The method of any one of claims 33 , 36 and 39 , wherein the method further comprises administering to said subject a therapeutically effective amount of a H 2 receptor antagonist; an antacid; a proton pump inhibitor; or any combination thereof.
44 . The method of treating irritable bowel syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O—(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
45 . The method of claim 44 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
46 . The method of claim 44 , wherein the growth hormone secretagogue compound is represented by the structural Formula III
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
47 . A method of treating irritable bowel syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV:
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) n —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
48 . The method of claim 47 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
49 . The method of claim 47 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
50 . A method of treating irritable bowel syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
51 . The method of any one of claims 44 , 47 and 50 , wherein the subject is a human.
52 . The method of any one of claims 44 , 47 and 50 , wherein the growth hormone secretagogue is orally administered.
53 . The method of any one of claims 44 , 47 and 50 , wherein the irritable bowel syndrome is constipation-predominant irritable bowel syndrome.
54 . The method of any one of claims 44 , 47 and 50 , wherein the irritable bowel syndrome is alternating constipation/diarrhea irritable bowel syndrome.
55 . The method of any one of claims 44 , 47 and 50 , wherein the method further comprises administering to said subject a therapeutically effective amount of a H 2 receptor antagonist; a serotonin 5-HT 4 agonist; a laxative; or any combination thereof.
56 . A method of treating constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O—(CH 2 ) l —R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
57 . The method of claim 56 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
58 . The method of claim 56 , wherein the growth hormone secretagogue compound is represented by the structural Formula III
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
59 . A method of treating constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) l —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
60 . The method of claim 59 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
61 . The method of claim 59 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
62 . A method of treating constipation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
63 . The method of any one of claims 56 , 59 and 62 , wherein the subject is a human.
64 . The method of any one of claims 56 , 59 and 62 , wherein the growth hormone secretagogue is orally administered.
65 . The method of any one of claims 56 , 59 and 62 , wherein the method further comprises administering to said subject a therapeutically effective amount of a laxative.
66 . A method of treating post-operative ileus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural 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 0, 1, 2 or 3;
b and c are independently 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 can 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;
G is —O—(CH 2 ) k —R 8 ,
J is —O—(CH 2 ) l R 13 ,
wherein:
R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 independently 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 can 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 can 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 can 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 21 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;
or R 19 is
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 .
67 . The method of claim 66 , wherein the growth hormone secretagogue compound is represented by the structural Formula II
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
68 . The method of claim 66 , wherein the growth hormone secretagogue compound is represented by the structural Formula III
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
69 . A method of treating post-operative ileus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a growth hormone secretagogues compound, wherein the growth hormone secretagogue compound is represented by the structural Formula IV
wherein
R 1 is hydrogen or C 1-6 -alkyl;
R 2 is hydrogen or C 1-6 -alkyl;
L is
wherein
R 4 is hydrogen or C 1-6 alkyl;
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein:
o is 0, 1 or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl or hetaryl;
Or L is
wherein
p is 0 or 1;
q, s, t, u are independently 0, 1, 2, 3, or 4;
r is 0 or 1;
the sum q+r+s+t+u is 0, 1, 2, 3, or 4;
R 9 , R 10 , R 11 , and R 12 are independently hydrogen or C 1-6 alkyl;
Q is >N—R 13 or
wherein
o is 0, 1, or 2;
T is —N(R 15 )(R 16 ) or hydroxyl;
R 13 , R 15 , and R 16 are independently from each other hydrogen or C 1-6 alkyl;
R 14 is hydrogen, aryl, or hetaryl;
G is —O—(CH 2 )—R 17 ,
wherein:
R 17 , R 18 , R 19 , R 20 and R 21 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
K is 0, 1 or 2;
J is —O—(CH 2 ) l —R 22 ,
wherein:
R 22 , R 23 , R 24 , R 25 and R 26 independently are hydrogen, halogen, aryl, hetaryl, C 1-6 -alkyl or C 1-6 -alkoxy;
l is 0, 1 or 2;
a is 0, 1, or 2;
b is 0, 1, or 2;
c is 0, 1, or 2;
d is 0 or 1;
e is 0, 1, 2, or 3;
f is 0 or 1;
R 5 is hydrogen or C 1-6 -alkyl optionally substituted with one or more hydroxyl, aryl or hetaryl;
R 6 and R 7 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 8 is hydrogen or C 1-6 -alkyl, optionally substituted with one or more halogen, amino, hydroxyl, aryl, or hetaryl;
R 6 and R 7 or R 6 and R 8 or R 7 and R 8 can optionally form —(CH 2 ) i —U—(CH 2 ) j —, wherein i and j independently are 1, 2 or 3 and U is —O—, —S—, or a valence bond;
M is arylene, hetarylene, —O—, —S— or —CR 27 ═CR 28 —;
R 27 and R 28 are independently hydrogen or C 1-6 -alkyl, optionally substituted with one or more aryl or hetaryl;
or a pharmaceutically acceptable salt thereof.
70 . The method of claim 69 , wherein the growth hormone secretagogue compound is represented by the structural Formula V
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
71 . The method of claim 69 , wherein the growth hormone secretagogue compound is represented by the structural Formula VI
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
72 . A method of treating post-operative ileus in a subject in need thereof comprising administering to said subject a therapeutically effective amount of growth hormone secretagogue compound, wherein the growth hormone secretagogue is selected from the group consisting of Formula VII,
or a pharmaceutically acceptable salt, solvate or hydrate thereof.
73 . The method of any one of claims 66 , 69 and 72 , wherein the subject is a human.
74 . The method of any one of claims 66 , 69 and 72 , wherein the growth hormone secretagogue is orally administered.
75 . The method of any one of claims 66 , 69 and 72 , wherein the method further comprises administering to said subject a therapeutically effective amount of a dopamine antagonist.