Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors

1. A method for increasing or decreasing growth hormone levels in a mammal or for increasing or decreasing food intake of a mammal comprising:

administering to a mammal in need of treatment at least one compound according to formula (I):

wherein:

R1 and R2 are independently of one another a hydrogen atom or are selected from the group of radicals consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, alkylsulfonyl, arylsulfonyl, and arylalkylsulfonyl;

wherein said radicals at R1 or R2 are optionally substituted in an alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl group by up to 3 substituents independently selected from the group consisting of halogen, —F, —Cl, —Br, —I, —N 3 , —CN, —NR7R8, —OH, —NO 2 , alkyl, aryl, arylalkyl, —O-alkyl, —O-aryl, and —O-arylalkyl;

R3 is selected from the group of radicals consisting of alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -alkyl-O-aryl, -alkyl-O-arylalkyl, -alkyl-O-heteroaryl, -alkyl-O-heteroarylalkyl, -alkyl-O-heterocyclyl, alkyl-O-heterocyclylalkyl, -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, -alkyl-CO-heterocyclylalkyl, -alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl, -alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl, -alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO—NH 2 , -alkyl-CO—OH, -alkyl-NH 2 , -alkyl-NH—C(NH)—NH 2 , alkyl-S-alkyl, and alkyl-S—H;

wherein said radicals are optionally substituted in the aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and/or heterocyclylalkyl group by up to 3 substituents independently selected from the group consisting of halogen, —F, —Cl, —Br, —I, —N 3 , —CN, —NR7R8, —OH, —NO 2 , alkyl, aryl, arylalkyl, —O-alkyl, —O-aryl, and —O-arylalkyl;

R4 is hydrogen;

R5 is a radical

a) selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —CO-alkyl, —CO-cycloalkyl, —CO-cycloalkylalkyl, —CO-aryl, and —CO-arylalkyl, wherein said radical from (a) is optionally substituted by up to 3 substituents independently selected from the group consisting of halogen, —F, —Cl, —Br, —I, —N 3 , —CN, —OH, —NO 2 , alkyl, aryl, arylalkyl, —O-alkyl, —O-aryl, and —O-arylalkyl; or

b) selected from the group consisting of —CO-heteroaryl, —CO-heteroarylalkyl, —CO-heterocyclyl, —CO-heterocyclylalkyl, wherein said radical from (b) is optionally substituted by up to 3 substituents independently selected from the group consisting of halogen, —F, —Cl, —Br, —I, —N 3 , —CN, —NR7R8, —OH, —NO 2 , alkyl, aryl, arylalkyl, —O-alkyl, —O-aryl, and —O-arylalkyl;

R6 is hydrogen;

R7 and R8 are independently of one another selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, and cycloalkylalkyl; and

m is 0;

wherein * designates a carbon atom of R or S configuration when chiral.

2. The method of claim 1 , where R3 is selected from the group consisting of -alkyl-CO-aryl, -alkyl-CO-arylalkyl, -alkyl-CO-heteroaryl, -alkyl-CO-heteroarylalkyl, -alkyl-CO-heterocyclyl, alkyl-CO-heterocyclylalkyl, -alkyl-C(O)O-aryl, -alkyl-C(O)O-arylalkyl, -alkyl-C(O)O-heteroaryl, -alkyl-C(O)O-heteroarylalkyl, -alkyl-C(O)O-heterocyclyl, -alkyl-C(O)O-heterocyclylalkyl, -alkyl-CO—NH 2 , -alkyl-CO—OH, -alkyl-NH—C(NH)—NH 2 , alkyl-S-alkyl, and alkyl-S—H.

3. The method of claim 1 , wherein

R5 is selected from the group consisting of —CO-heteroaryl, —CO-heteroarylalkyl, —CO-heterocyclyl, and —CO-heterocyclylalkyl;

with the proviso that if R5 is —CO-heteroarylalkyl, then heteroaryl is not imidazole; and

with the proviso that if R5 is —CO-heterocyclyl and heterocyclyl contains only nitrogen atoms as heteroatoms, that at least two nitrogen atoms are contained in heterocyclyl; and

with the proviso that if R5 is —CO-heterocyclylalkyl and heterocyclyl contains only nitrogen atoms as heteroatoms that in the case that one or two nitrogen atoms are contained in heterocyclyl then no nitrogen atom is positioned at position 1 of heterocyclyl that is the atom directly linking heterocyclyl to the carbonyl group —CO—;

wherein —CO-heteroaryl, —CO-heteroarylalkyl, —CO-heterocyclyl, and/or —CO-heterocyclylalkyl are optionally substituted by up to 3 substituents independently selected from the group consisting of halogen, —F, —Cl, —Br, —I, —N 3 , —CN, —NR7R8, —OH, —NO 2 , alkyl, aryl, arylalkyl, —O-alkyl, —O-aryl, and —O-arylalkyl.

4. The method of claim 1 , where

R1 is selected from the group consisting of hydrogen, methyl, (2-methoxyphenyl)-methyl, (3-methoxyphenyl)-methyl, (4-methoxyphenyl)-methyl, (3-methoxyphenyl)-ethyl, (4-methoxyphenyl)-ethyl, phenyl, phenyl-methyl, phenyl-ethyl, (4-ethylphenyl)-methyl, (4-methylphenyl)-methyl, (4-fluorophenyl)-methyl, (4-bromophenyl)-methyl, (2,4-dimethoxyphenyl)-methyl, (3,5-dimethoxyphenyl)-methyl, 2,2-diphenyl-ethyl, naphthaline-1-yl-methyl, 1H-indole-3-yl-methyl, 2-(1H-indole-3-yl)-ethyl, 3-(1H-indole-3-yl)-propyl, 4-methyl-phenyl, 4-ethyl-phenyl, n-hexyl, (3,4-dichlorophenyl)-methyl, (4-nitro-phenyl)-methyl, (pyridine-2-yl)-methyl, (pyridine-3-yl)-methyl, (pyridine-4-yl)-methyl, (thiophene-2-yl)-methyl, (thiophene-3-yl)-methyl, (furan-2-yl)-methyl, (furan-3-yl)-methyl; and

R2 is selected from the group consisting of methyl, 1H-indole-3-yl-methyl, 2-(1H-indole-3-yl)-ethyl, 3-(1H-indole-3-yl)-propyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl, 4-methoxy-phenylmethyl, 2-methoxy-phenylethyl, 3-methoxy-phenylethyl, and 4-methoxy-phenylethyl;

R3 is selected from the group consisting of methyl, propan-2-yl, 2-methyl-propan-1-yl, butan-2-yl, butan-1-yl, —CH 2 —SH, —(CH 2 ) 2 —S—CH 3 , 1H-indole-3-yl-methyl, phenyl-methyl, 2-phenyl-ethyl, —CH 2 —O—CH 2 -phenyl, —CH 2 —CO—CH 2 -phenyl, —(CH 2 ) 2 —CO—CH 2 -phenyl, —CH 2 —C(O)O-phenyl, —(CH 2 ) 2 —C(O)O-phenyl, hydroxy-methyl, 1-hydroxy-ethan-1-yl, —CH 2 —CO—NH 2 , —(CH 2 ) 2 —CO—NH 2 , (1-hydroxy-benzene-4-yl)-methyl, —CH 2 —CO—OH, —(CH 2 ) 2 —CO—OH, —(CH 2 ) 4 —NH 2 , (1H-imidazol-5-yl)-methyl, —(CH 2 ) 3 —NH—C(NH)—NH 2 , —(CH 2 ) 3 —NH 2 , and —(CH 2 ) 3 —NH—CO—NH 2 ;

R5 is selected from the group consisting of —CO-(pyrrolidine-2-yl), 4-carbonyl-1H-piperidine, 3-carbonyl-1H-piperidine, R-(3-carbonyl-1H-piperidine), S-(3-carbonyl-1H-piperidine), 2-carbonyl-1H-piperidine, R-(2-carbonyl-1H-piperidine), S-(2-carbonyl-1H-piperidine), 2-acetyl-pyridine, 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, 2-carbonyl-1H-imidazole, 2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-amino-3-carbonyl-pyridine, 2-carbonyl-pyrazine, 2-carbonyl-4-hydroxy-1H-pyrrolidine, 4-carbonyl-1H,3H-diazacyclohexane, 2-carbonyl-2,5-dihydro-1H-pyrrole, 2-carbonyl-piperazine, 2-carbonyl-1H-pyrrolidine, 2-carbonyl-pyrazine, 3-carbonyl-pyrazine, and 4-carbonyl-oxacyclohexane.

5. The method of claim 4 , where R3 is selected from the group consisting of —CH 2 —CO—CH 2 -phenyl, —(CH 2 ) 2 —CO—CH 2 -phenyl, —CH 2 —CO—NH 2 , —(CH 2 ) 2 —CO—NH 2 , —CH 2 —CO—OH, —(CH 2 ) 2 —CO—OH, —(CH 2 ) 3 —NH—C(NH)—NH 2 , —CH 2 —SH, and —(CH 2 ) 2 —S—CH 3 .

6. The method of claim 4 , where R5 is selected from the group consisting of 2-carbonyl-pyridine, 3-carbonyl-pyridine, 4-carbonyl-pyridine, 2-acetyl-pyridine, 3-acetyl-pyridine, 4-acetyl-pyridine, 2-propionyl-pyridine, 3-propionyl-pyridine, 4-propionyl-pyridine, 2-amino-3-carbonyl-pyridine, 2-carbonyl-1H-imidazole, 2-carbonyl-pyrazine, and 4-carbonyl-1H,3H-diazacyclohexane.

7. The method of claim 1 , wherein the compound according to formula (I) that increases or decreases growth hormone level and is selected from the group consisting of

Compound 31: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,

Compound 44: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide,

Compound 64: (R)—N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,

Compound 71: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,

Compound 90: (R)—N—((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide.

8. The method of claim 1 , wherein the compound according to formula (I) decreases food intake and is selected from the group consisting of

Compound 38: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminobenzamide,

Compound 47: (R)—N—((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide,

Compound 49: (R)—N—((R)-1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-2-carboxamide,

Compound 64: (R)—N-(1-(4-(2,4-dimethoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,

Compound 71: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrazine-2-carboxamide,

Compound 72: (R)—N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide,

Compound 80: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)picolinamide,

Compound 81: (R)—N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide, and

Compound 90: (R)—N—((R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)pyrrolidine-2-carboxamide.

9. The method of claim 8 , wherein the mammal is a human and is in need of treatment for adiposity, for obesity, or for body weight gain.

10. The method of claim 1 , comprising administering a compound according to formula (I) that increases food intake selected from the group consisting of

Compound 44: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide, and

Compound 83: (R)—N-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperazine-2-carboxamide.

11. The method of claim 10 , wherein the subject is in need of treatment for anorexia.

12. The method of claim 1 , wherein the compound according to formula (I) is (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)piperidine-4-carboxamide (compound 44) that increases food intake and binds to the Motilin Receptor.

13. The method of claim 12 , wherein the subject is in need of treatment for cachexia.

14. The method of claim 1 , further comprising administering at least one other pharmacologically active substance.

15. The method of claim 1 , wherein the compound of formula (I) is administered before, during or after administration of the at least one other pharmacologically active substance.

16. A method for increasing or decreasing growth hormone-levels in a mammal comprising administering to a mammal in need of treatment a compound selected from the group consisting of:

Compound 1: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 9: (R)—N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 12: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 20: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 22: (R)—N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 39: (R)—N-(1-(5-benzyl-4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 50: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide, and

Compound 74: (R)-1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethanamine.

17. A method for decreasing food intake in a mammal comprising:

administering to a mammal in need of treatment a compound selected from the group consisting of:

Compound 9: (R)—N-(1-(5-(3-(1H-indol-3-yl)propyl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 13: (R)—N-(1-(4-(4-methoxybenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 17: (R)—N-(1-(4,5-bis(2-(1H-indol-3-yl)ethyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 24: (R)—N-(1-(4-(2-(1H-indol-3-yl)ethyl)-5-(3-(1H-indol-3-yl)propyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide,

Compound 30: (R)—N-(1-(4-(4-fluorobenzyl)-5-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, and

Compound 50: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide.

18. The method of claim 17 , wherein the mammal is a human and is in need of treatment for adiposity, for obesity, or for body weight gain.

19. A method for decreasing food intake in a mammal receiving hexarelin comprising:

administering to a mammal in need of treatment a compound selected from the group consisting of:

Compound 1: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(2,4-dimethoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide

Compound 12: (R)—N-(1-(5-(2-(1H-indol-3-yl)ethyl)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide

Compound 20: (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide, and

Compound 22: (R)—N-(1-(4-(4-methoxybenzyl)-5-(3-phenylpropyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-amino-2-methylpropanamide.

20. The method of claim 17 , wherein the subject is in need of treatment of obesity or growth retardation associated with obesity, wherein the compound of formula (I) is (R)—N-(1-(4-(4-methoxybenzyl)-5-phenethyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl)-2-aminoacetamide (compound 50).