Method of treating cell proliferative disorders using growth hormone secretagogues

1 . A method of treating a subject having a cell proliferative disorder comprising administering to the subject an effective amount of a growth hormone secretagogue, 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 . thereby treating the subject.

2 . The method of claim 1 , wherein the growth hormone secretagogue is represented by the structural Formula II:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

3 . The method of claim 1 , wherein the growth hormone secretagogue is represented by the structural Formula III:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

4 . 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.

5 . The method of claim 4 , wherein the growth hormone secretagogue is represented by the structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

6 . 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.

7 . The method of claim 1 , wherein the cell proliferative disorder is cancer.

8 . The method of claim 7 , wherein the cancer is a solid-tumor cancer.

9 . The method of claim 8 , wherein the solid tumor cancer is selected from the group consisting of lung, colon and rectal cancer.

10 . The method of claim 7 , further comprising administering to the subject one or more additional anti-cancer agents.

11 . The method of claim 1 , wherein the growth hormone secretagogue is administered at an amount of between about 25 mg/day-150 mg/day.

12 . The method of claim 11 , wherein the growth hormone secretagogue is administered at an amount of between about 50 mg/day-100 mg/day.

13 . The method of claim 12 , wherein the growth hormone secretagogue is administered at an amount of about 50 mg/day.

14 . A method of treating a subject having a solid tumor cancer comprising administering to the subject an effective amount of the growth hormone secretagogue represented by structural Formula III:

thereby treating the subject.

15 . The method of claim 14 , wherein the cancer is lung, colon or rectal cancer.

16 . The method of claim 14 , further comprising administering to the subject one or more additional anti-cancer agents.

17 . The method of claim 14 , wherein the growth hormone secretagogue is administered at an amount of between about 25 mg/day-150 mg/day.

18 . The method of claim 17 , wherein the growth hormone secretagogue is administered at an amount of between about 50 mg/day-100 mg/day.

19 . The method of claim 18 , wherein the growth hormone secretagogue is administered at an amount of about 50 mg/day.

20 . A method of treating a subject having or at risk of developing lung, colon or rectal cancer comprising: administering to the subject an effective amount of the growth hormone secretagogue represented by structural Formula III:

thereby treating the subject.

21 . The method of claim 20 , further comprising administering to the subject one or more additional anti-cancer agents.

22 . The method of claim 20 , wherein the growth hormone secretagogue is administered at an amount of between about 25 mg/day-150 mg/day.

23 . The method of claim 22 , wherein the growth hormone secretagogue is administered at an amount of between about 50 mg/day-100 mg/day.

24 . The method of claim 23 , wherein the growth hormone secretagogue is administered at an amount of about 50 mg/day.

25 . A pharmaceutical composition comprising a growth hormone secretagogue, one or more additional anticancer agents and a pharmaceutically acceptable carrier, 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 .

26 . The pharmaceutical composition of claim 25 , wherein the growth hormone secretagogue is represented by the structural Formula II:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

27 . The pharmaceutical composition of claim 26 , wherein the growth hormone secretagogue is represented by the structural Formula III:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

28 . The pharmaceutical composition of claim 25 , 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;

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.

29 . The pharmaceutical composition of claim 28 , wherein the growth hormone secretagogue is represented by the structural Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

30 . The pharmaceutical composition of claim 25 , wherein the growth hormone secretagogue is selected from the group consisting of Formula VI,

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

31 . The pharmaceutical composition of claim 25 , further comprising one or more additional anti-cancer agents.

32 . The pharmaceutical composition of claim 31 , comprising between about 10 mg-150 mg of the growth hormone secretagogue.

33 . The pharmaceutical composition of claim 32 , comprising between about 25 mg-125 mg of the growth hormone secretagogue.

34 . The pharmaceutical composition of claim 33 , comprising between about 25 mg-100 mg of the growth hormone secretagogue.

35 . The pharmaceutical composition of claim 34 , comprising between about 10 mg-50 mg of the growth hormone secretagogue.

36 . The pharmaceutical composition of claim 25 , comprising about 50 mg to about 100 mg of the growth hormone secretagogue.

37 . A pharmaceutical composition for the treatment of a cell proliferative disorder comprising a growth hormone secretagogue represented by structural Formula III:

or a pharmaceutically acceptable salt, solvate or hydrate thereof, one or more cancer agents, and pharmaceutically acceptable carrier.

38 . The pharmaceutical composition of claim 37 , comprising between about 10 mg-150 mg of the growth hormone secretagogue.

39 . The pharmaceutical composition of claim 38 , comprising between about 25 mg-125 mg of the growth hormone secretagogue.

40 . The pharmaceutical composition of claim 39 , comprising between about 25 mg-100 mg of the growth hormone secretagogue.

41 . The pharmaceutical composition of claim 40 , comprising between about 25 mg-75 mg of the growth hormone secretagogue.

42 . The pharmaceutical composition of claim 37 , comprising about 50 mg- to about 100 mg of the growth hormone secretagogue.

43 . A kit for the treatment of a cell proliferative disorder comprising the pharmaceutical composition of claim 25 and instructions for use.

44 . The kit of claim 43 , for the treatment of a solid-tumor cancer.

45 . The kit of claim 44 , wherein the solid-tumor cancer is lung, colon, or rectal cancer.