Method of reducing C-reactive protein using growth hormone secretagogues

1 . A method of reducing C-reactive protein in a subject in need thereof comprising administering a therapeutically effective amount of at least one growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.

2 . The method of claim 1 , wherein the subject is at risk of having a vascular event.

3 . The method of claim 1 , wherein the subject has already had a vascular event.

4 . The method of claim 2 or claim 3 , wherein the vascular event is a cardiovascular event.

5 . The method of claim 4 , wherein the cardiovascular event is a myocardial infarction.

6 . The method of claim 2 or claim 3 , wherein the vascular event is a cerebrovascular event.

7 . The method of claim 6 , wherein the cerebrovascular event is a stroke.

8 . The method of claim 2 or claim 3 , wherein the vascular event is a peripheral vascular event.

9 . The method of claim 8 , wherein the peripheral vascular event is intermittent claudication.

10 . The method of claim 1 , 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 1 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 .

11 . The method of claim 10 , wherein the growth hormone secretaogue is represented by Formula II:

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

12 . The method of claim 10 , wherein the growth hormone secretagogue is represented by Formula III:

or a pharmaceutically acceptable salt thereof.

13 . The method of claim 1 , wherein the growth hormone secretagogue is represented by 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 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 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.

14 . The method of claim 13 , wherein the growth hormone secretagogue is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

15 . The method of claim 13 , wherein the growth hormone secretagogue is represented by Formula VI:

a pharmaceutically acceptable salt, solvate or hydrate thereof.

16 . The method of claim 1 , wherein the growth hormone secretagogue is administered orally.

17 . The method of claim 1 , wherein the subject is a human.

18 . The method of claim 1 , further comprising administering a therapeutically effective amount of a second growth hormone secretagogue, a HMG CoA reductase inhibitor, an ACAT inhibitor, a CETP inhibitor, an anti-inflammatory agent, an ACE inhibitor, a Beta blocker, a cholesterol absorption inhibitor, a nicotonic acid, a fibric acid derivative, bile acid sequestering agent or a combination thereof.

19 . The method of claim 18 , wherein the growth hormone secretagogue activates the GHS-R1a receptor and the second growth hormone secretagogue activates the GHRH receptor.

20 . The method of claim 19 , further comprising administering a therapeutically effective amount of a HMG CoA reductase inhibitor.

21 . The method of claim 20 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or a combination thereof.

22 . The method of claim 18 , wherein the ACAT inhibitor is selected from the group consisting of: avasimibe, FCE 27677, RP 73163 or a combination thereof.

23 . The method of claim 18 , wherein the CETP inhibitor is selected from the group consisting of: JTT-705, torcetrapib or a combination thereof.

24 . The method of claim 18 , wherein the anti-inflammatory agent is selected from the group consisting of: salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen sulindac, etodolac,tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, piroxicam, celecoxib, rofecoxib or a combination thereof.

25 . The method of claim 18 , wherein the ACE inhibitor is selected from the group consisting of: captopril, benazepril, enalapril, fosinopril, lisinopril, quinapril, ramipril, imidapril, perindopril erbumine, trandolapril or a combination thereof.

26 . The method of claim 18 , wherein the Beta blocker is selected from the group consisting of: sotalol, timolol, esmolol, careolol, carvedilol, nadolol, propanolol, betaxolol, penbutolol, metoprolol, acebutolol, atenolol, labetolol, pindolol or bisoprolol or a combination thereof.

27 . The method of claim 18 , wherein the cholesterol absorption inhibitor is selected from the group consisting of: ezetimibe, tiqueside, pamaqueside or a combination thereof.

28 . The method of claim 18 , wherein the nicotonic acid is selected from the group consisting of: niacin, niceritrol or a combination thereof.

29 . The method of claim 18 , wherein the fibric acid derivative is selected from the group consisting of: clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate or a combination thereof.

30 . The method of claim 18 , wherein the bile acid sequestering agent is selected from the group consisting of: cholestyramine, colestipol or a combination thereof.

31 . A method of reducing C-reactive protein in a subject in need thereof suffering from an inflammatory disease or disorder comprising administering a therapeutically effective amount of at least one growth hormone secretagogue compound or a pharmaceutically acceptable salt, hydrate or solvate thereof.

32 . The method of claim 31 , wherein the inflammatory disease or disorder is selected from the group consisting of: inflammatory conditions of a joint; rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; Sjorgren's syndrome; lung diseases; ARDS; acute pancreatitis; ALS; Alzheimer's disease; cachexia; anorexia; asthma; atherosclerosis; chronic fatigue syndrome; diabetes; insulin diabetes; glomerulonephritis; graft versus host rejection; hemohorragic shock; hyperalgesia; inflammatory bowel disease; multiple sclerosis; myopathies; muscle protein metabolism; osteoporosis; Parkinson's disease; pain; pre-term labor; psoriasis; septic shock; cardiac, allograft; vasculopathy; side effects from radiation therapy; temporal mandibular joint disease; tumor metastasis; or an inflammatory condition resulting from strain, sprain, cartilage damage, trauma such as burn, orthopedic surgery, infection or other disease processes.

33 . The method of claim 31 , 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 1 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 secretaogue is represented by Formula II:

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

35 . The method of claim 33 , wherein the growth hormone secretagogue is represented by Formula III:

or a pharmacuetically acceptable salt thereof.

36 . The method of claim 31 , wherein the growth hormone secretagogue is represented by 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 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 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 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 is represented by Formula V:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

38 . The method of claim 36 , wherein the growth hormone secretagogue is represented by Formula VI:

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

39 . The method of claim 31 , wherein the growth hormone secretagogue is administered orally.

40 . The method of claim 31 , wherein the subject is a human.

41 . The method of claim 31 , further comprising administering a therapeutically effective amount of a second growth hormone secretagogue, a HMG CoA reductase inhibitor, an ACAT inhibitor, a CETP inhibitor, an anti-inflammatory agent, an ACE inhibitor, a Beta blocker, a cholesterol absorption inhibitor, a nicotonic acid, a fibric acid derivative, bile acid sequestering agent or a combination thereof.

42 . The method of claim 41 , wherein the growth hormone secretagogue activates the GHS-R1a receptor and the second growth hormone secretagogue activates the GHRH receptor.

43 . The method of claim 42 , further comprising administering a therapeutically effective amount of a HMG CoA reductase inhibitor.

44 . The method of claim 43 , wherein the HMG CoA reductase inhibitor is selected from the group consisting of: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or a combination thereof.

45 . The method of claim 41 , wherein the ACAT inhibitor is selected from the group consisting of: avasimibe, FCE 27677, RP 73163 or a combination thereof.

46 . The method of claim 41 , wherein the CETP inhibitor is selected from the group consisting of: JTT-705, torcetrapib or a combination thereof.

47 . The method of claim 41 , wherein the anti-inflammatory agent is selected from the group consisting of: salicylic acid, aspirin, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen sulindac, etodolac, tolmetin, ketorolac, diclofenac, ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, indomethacin, piroxicam, celecoxib, rofecoxib or a combination thereof.

48 . The method of claim 41 , wherein the ACE inhibitor is selected from the group consisting of: captopril, benazepril, enalapril, fosinopril, lisinopril, quinapril, ramipril, imidapril, perindopril erbumine, trandolapril or a combination thereof.

49 . The method of claim 41 , wherein the Beta blocker is selected from the group consisting of: sotalol, timolol, esmolol, careolol, carvedilol, nadolol, propanolol, betaxolol, penbutolol, metoprolol, acebutolol, atenolol, labetolol, pindolol or bisoprolol or a combination thereof.

50 . The method of claim 41 , wherein the cholesterol absorption inhibitor is selected from the group consisting of: ezetimibe, tiqueside, pamaqueside or a combination thereof.

51 . The method of claim 41 , wherein the nicotonic acid is selected from the group consisting of: niacin, niceritrol or a combination thereof.

52 . The method of claim 41 , wherein the fibric acid derivative is selected from the group consisting of: clofibrate, gemfibrozil, fenofibrate, ciprofibrate, bezafibrate or a combination thereof.

53 . The method of claim 41 , wherein the bile acid sequestering agent is selected from the group consisting of: cholestyramine, colestipol or a combination thereof.