Synthetic peptide amides

1. A method of treating a kappa opioid receptor-associated disease or condition in a mammal, wherein the kappa opioid receptor-associated disease or condition is a kappa opioid receptor-associated chronic kidney disease, the method comprising administering to the mammal a composition comprising an effective amount of a synthetic peptide amide having the formula:

or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, acid salt hydrate or N-oxide thereof;

wherein

Xaa 1 is selected from the group consisting of (A)(A′)D-Phe, (A)(A′)(α-Me)D-Phe, D-Tyr, D-Tic, D-tert-leucine, D-neopentylglycine, D-phenylglycine, D-homophenylalanine, and β-(E)D-Ala, wherein each (A) and each (A′) are phenyl ring substituents independently selected from the group consisting of —H, —F, —Cl, —NO 2 , —CH 3 , —CF 3 , —CN, and —CONH 2 , and wherein each (E) is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl;

Xaa 2 is selected from the group consisting of (A)(A′)D-Phe, 3,4-dichloro-D-Phe, (A)(A′)(α-Me) D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala and D-Trp;

Xaa 3 is selected from the group consisting of D-Nle, D-Phe, (E)D-Ala, D-Leu, (α-Me)D-Leu, D-Hle, D-Val, and D-Met;

Xaa 4 is selected from the group consisting of (B) 2 D-Arg, (B) 2 D-Nar, (B) 2 D-Har, ζ-(B)D-Hlys, D-Dap, ε-(B)D-Lys, ε-(B) 2 -D-Lys, D-Amf, amidino-D-Amf, γ-(B) 2 D-Dbu, δ-(B) 2 α-(B′)D-Orn, D-2-amino-3(4-piperidyl) propionic acid, D-2-amino-3(2-amino-pyrrolidyl)propionic acid, D-α-amino-β-amidinopropionic acid, α-amino-4-piperidineacetic acid, cis-α,4-diaminocyclohexane acetic acid, trans-α,4-diamino-cyclohexane acetic acid, cis-α-amino-4-methylaminocyclo-hexane acetic acid, trans-α-amino-4-methylaminocyclohexane acetic acid, α-amino-1-amidino-4-piperidineacetic acid, cis-α-amino-4-guanidinocyclohexane acetic acid, and trans-α-amino-4-guanidino cyclohexane acetic acid, wherein each (B) is independently selected from the group consisting of H and C 1 -C 4 alkyl, and (B′) is H or (α-Me);

W is selected from the group consisting of:

Null, provided that when W is null, Y is N;

—NH—(CH 2 ) b — with b equal to zero, 1, 2, 3, 4, 5, or 6; and

—NH—(CH 2 ) c —O— with c equal to 2, or 3, provided that Y is C;

the moiety

is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein all ring heteroatoms in said ring moiety are N; wherein Y and Z are each independently C or N; provided that when such ring moiety is a six, seven or eight-membered ring, Y and Z are separated by at least two ring atoms; and provided that when such ring moiety has a single ring heteroatom which is N, then such ring moiety is non-aromatic;

V is C 1 -C 6 alkyl, and e is zero or 1, wherein when e is zero, then V is null and R 1 and R 2 are directly bonded to the same or different ring atoms;

wherein (i) R 1 is selected from the group consisting of —H, —OH, halo, —CF 3 , —NH 2 , —COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amidino, C 1 -C 6 alkyl-substituted amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, —CN, —CONH 2 , —COR′, —SO 2 R′, —CONR′R″, —NHCOR′, OR′ and SO 2 NR′R″; wherein said optionally substituted heterocyclyl is optionally singly or doubly substituted with substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, oxo, —OH, —Cl, —F, —NH 2 , —NO 2 , —CN, —COOH, and amidino; wherein R′ and R″ are each independently —H, C 1 -C 8 alkyl, aryl, or heterocyclyl or R′ and R″ are combined to form a 4- to 8-membered ring, which ring is optionally singly or doubly substituted with substituents independently selected from the group consisting of C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, —OH, —Cl, —F, —NH 2 , —NO 2 , —CN, —COOH and amidino; and R 2 is selected from the group consisting of —H, amidino, singly or doubly C 1 -C 6 alkyl-substituted amidino, —CN, —CONH 2 , —CONR′R″, —NHCOR', —SO 2 NR′R″ and —COOH; or

(ii) R 1 and R 2 taken together can form an optionally substituted 4- to 9-membered heterocyclic monocyclic or bicyclic ring moiety which is bonded to a single ring atom of the Y and Z-containing ring moiety; or

(iii) R 1 and R 2 taken together with a single ring atom of the Y and Z-containing ring moiety can form an optionally substituted 4- to 8-membered heterocyclic ring moiety to form a spiro structure; or

(iv) R 1 and R 2 taken together with two or more adjacent ring atoms of the Y and Z-containing ring moiety can form an optionally substituted 4- to 9-membered heterocyclic monocyclic or bicyclic ring moiety fused to the Y and Z-containing ring moiety;

wherein each of said optionally substituted 4-, 5-, 6,-, 7-, 8- and 9-membered heterocyclic ring moieties comprising R 1 and R 2 is optionally singly or doubly substituted with substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 —C 6 alkoxy, optionally substituted phenyl, oxo, —OH, —Cl, —F, —NH 2 , —NO 2 , —CN, —COOH, and amidino;

provided that when the Y and Z-containing ring moiety is a six or seven membered ring having a single ring heteroatom and e is zero, then R 1 is not —OH, and R 1 and R 2 are not both —H;

provided further that when the Y and Z-containing ring moiety is a six membered ring having two ring heteroatoms, both Y and Z are N and W is null, then —(V) e R 1 R 2 is attached to a ring atom other than Z; and if e is zero, then R 1 and R 2 are not both —H; and

lastly, provided that when Xaa 3 is D-Nle, then Xaa 4 is not (B) 2 D-Arg, and when Xaa 3 is D-Leu or (αMe)D-Leu, then Xaa 4 is not δ—(B) 2 α—(B′)D-Orn.

2. The method according to claim 1 , wherein the chronic kidney disease is end-stage renal disease.

3. The method according to claim 1 , wherein the chronic kidney disease is being treated by dialysis.

4. The method according to claim 3 , wherein the chronic kidney disease is being treated by dialysis and the dialysis is hemodialysis.

5. The method according to claim 1 , wherein the mammal is a human patient.

6. The method according to claim 5 , wherein the synthetic peptide amide has the structure of the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or a pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof.

7. The method according to claim 6 , wherein the synthetic peptide amide having the structure of the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or a pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered intravenously.

8. The method according to claim 7 , wherein the synthetic peptide amide having the structure of the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or a pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered intravenously as a bolus.

9. The method according to claim 7 , wherein the human patient is undergoing dialysis treatment for the chronic kidney disease and the synthetic peptide amide having the structure of the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or a pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered post dialysis.

10. The method according to claim 9 , wherein the chronic kidney disease is end-stage renal disease.

11. The method according to claim 5 , wherein the human patient is undergoing dialysis treatment for the chronic kidney disease and the synthetic peptide amide having the structure of the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or a pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered post dialysis.

12. The method according to claim 11 , wherein the chronic kidney disease is end-stage renal disease.

13. The method according to claim 11 , wherein the synthetic peptide amide having the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or the pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered orally.

14. The method according to claim 13 , wherein the synthetic peptide amide having the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or the pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered in a tablet.

15. The method according to claim 13 , wherein the synthetic peptide amide having the formula:

D-Phe-D-Phe-D-Leu-D-Lys-[ω(4-aminopiperidine-4-carboxylic acid)]—OH or the pharmaceutically acceptable salt, hydrate or acid salt hydrate thereof is administered in a solution or a suspension.