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1. A method of treating, inhibiting or preventing a kappa opioid receptor-associated disease or condition in a mammal, wherein the kappa opioid receptor-associated disease or condition is pain, 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
Xaa1 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, —NO2, —CH3, —CF3, —CN, and —CONH2, and wherein each (E) is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl; Xaa2 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; Xaa3 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; Xaa4 is selected from the group consisting of (B)2D-Arg, (B)2D-Nar, (B)2D-Har, ζ-(B)D-Hlys, D-Dap, ε-(B)D-Lys, ε-(B)2-D-Lys, D-Amf, amidino-D-Amf, γ-(B)2D-Dbu, δ-(B)2α-(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-cyclohexaneacetic 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 C1-C4 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—(CH2)b— with b equal to zero, 1, 2, 3, 4, 5, or 6; and—NH—(CH2)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 C1-C6 alkyl, and e is zero or 1, wherein when e is zero, then V is null and R1 and R2 are directly bonded to the same or different ring atoms; wherein (i) R1 is selected from the group consisting of —H, —OH, halo, —CF3, —NH2, —COOH, C1-C6 alkyl, C1-C6 alkoxy, amidino, C1-C6 alkyl-substituted amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, —CN, —CONH2, —COR′, —SO2R′, —CONR′R″, —NHCOR′, OR′ and SO2NR′R″; wherein said optionally substituted heterocyclyl is optionally singly or doubly substituted with substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, oxo, —OH, —Cl, —F, —NH2, —NO2, —CN, —COOH, and amidino; wherein R′ and R″ are each independently —H, C1-C8 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 C1-C6 alkyl, —C1-C6 alkoxy, —OH, —Cl, —F, —NH2, —NO2, —CN, —COOH and amidino; and R2 is selected from the group consisting of —H, amidino, singly or doubly C1-C6 alkyl-substituted amidino, —CN, —CONH2, —CONR′R″, —NHCOR′, —SO2NR′R″ and —COOH; or
(ii) R1 and R2 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) R1 and R2 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) R1 and R2 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 R1 and R2 is optionally singly or doubly substituted with substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, optionally substituted phenyl, oxo, —OH, —Cl, —F, —NH2, —NO2, —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 R1 is not —OH, and R1 and R2 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)eR1R2 is attached to a ring atom other than Z; and if e is zero, then R1 and R2 are not both —H; and lastly, provided that when Xaa3 is D-Nle, then Xaa4 is not (B)2D-Arg, and when Xaa3 is D-Leu or (αMe)D-Leu, then Xaa4 is not δ-(B)2α-(B′)D-Orn. |
