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1. A method of treating, inhibiting or preventing kappa opioid receptor associated pain, or of inhibiting or treating kappa opioid receptor associated pancreatitis or pruritis in a mammal, 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 each Xaa1 is independently 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; each Xaa2 is independently selected from the group consisting of (A)(A′)D-Phe, (A)(A′)(α-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala, and D-Trp; each Xaa3 is independently 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; each Xaa4 is independently selected from the group consisting of (B)2D-Arg, (B)2D-Nar, (B)2D-Har, ξ-(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-aminopyrrolidyl)propionic acid, D-α-amino-β-amidino-propionic acid, α-amino-4-piperidineacetic acid, cis-α,4-diaminocyclohexane acetic acid, trans-α,4-diaminocyclohexaneacetic acid, cis-α-amino-4-methyl-aminocyclo-hexane acetic acid, trans-α-amino-4-methylaminocyclohexane acetic acid, α-amino-1-amidino-4-piperidineacetic acid, cis-α-amino-4-guanidino-cyclohexane acetic acid, and trans-α-amino-4-guanidinocyclohexane 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), and p is zero or 1; G is selected from one of the following moieties:
(i) G is wherein
q is zero or 1;r is zero or 1;s is zero or 1;p and t are each independently zero or 1, provided that at least one of q, r, s and t is 1; and wherein either A. (i) L is a linker selected from the group consisting of ε-D-Lys, ε-Lys, δ-D-Orn, ε-Orn, γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine and (D-Lys-GlyLactam)2, and
(ii) the moieties Xaa1-Xaa2-Xaa3-(Xaa4)p and (Xaa1)q-(Xaa2)r-(Xaa3)s-(Xaa4)t are different from one another, or B. L is a linker selected from the group consisting of γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine and (D-Lys-Gly Lactam)2,
and(ii) G is wherein p is 1;andthe moiety is an optionally substituted 6 or 7-membered heterocyclic ring moiety wherein Y is C or N and Z is C, N, O, S, SO, or SO2; provided that Y and Z are separated by at least two ring atoms; and provided further that when such ring moiety is aromatic, then Y is C; wherein 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; wherein 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
(a) R1 is —H, —OH, halo, CF3, —NH2, —COOH, C1-C6 alkyl, 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′, or 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, heterocyclyl or R′ and R″ are combined to form a 4- to 8-membered ring, which ring is optionally substituted singly or doubly 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 H, amidino, singly or doubly C1-C6 alkyl-substituted amidino, —CN, —CONH2, —CONR′R″, —NHCOR′, —SO2NR′R″, or —COOH; or(b) 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(c) 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(d) 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- to 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 comprising a single ring heteroatom and when one of Y and Z is C and the other of Y and Z is N, 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 comprising two ring heteroatoms, both Y and Z are N, W is null, and —Ve(R1)(R2) is attached to Z, then —Ve(R1)(R2) is selected from the group consisting of amidino, C1-C6 alkyl-substituted amidino, dihydroimidazole, —CH2COOH, and —CH2C(O)NH2; and lastly, provided that if the Y and Z-containing ring moiety is a six membered ring comprising an S or O ring heteroatom, or if the Y and Z-containing ring moiety is a six membered ring comprising two ring heteroatoms, wherein both Y and Z are N and W is null, or if the Y and Z-containing ring moiety is a six membered aromatic ring comprising a single ring heteroatom, which heteroatom is N, then, when e is zero, R1 and R2 are not both —H. |
