Synthetic peptide amides and dimers thereof

1. 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 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, —NO 2 , —CH 3 , —CF 3 , —CN, —CONH 2 , and wherein each (E) is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl;

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

when G is (i) then Xaa 3 -Xaa 4 - is selected from the group consisting of D-Nle-(B) 2 D-Arg-, D-Leu-δ-(B) 2 α-(B′)D-Orn-, and (α-Me)D-Leu-δ(B) 2 -α(B′)D-Orn-, wherein each (B) is independently selected from the group consisting of —H and C 1 -C 4 alkyl;

when G is (ii) then Xaa 3 is D-Nle, D-Leu, (α-Me)D-Leu, D-Hle or D-Val; and Xaa 4 is (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, 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);

p is 1;

G is selected from one of the following moieties:

(i) G is

the moiety

is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein all ring hetero atoms 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 heteroatom which is N, then such ring moiety is non-aromatic; and

(ii) G is

and the moiety

is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein Y is C or N and Z is C, N, O, S, SO, or SO 2 ; 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; provided that when such ring moiety is non-aromatic and Z is C or N then such ring moiety comprises at least one S or O ring heteroatom; 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—(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;

wherein 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 (a) —R 1 is —H, —OH, halo, CF 3 , —NH 2 , —COOH, C 1 -C 6 alkyl, amidino, C 1 -C 6 alkyl-substituted amidino, aryl, optionally substituted 5- or 6-membered 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′, or 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, —F, —NH 2 , —NO 2 , —CN, —COOH, and amidino; wherein R′ and R″ are each independently —H, C 1 -C 8 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 C 1 -C 6 alkyl, —C 1 -C 6 alkoxy, —OH, —F, —NH 2 , —NO 2 , —CN, —COOH and amidino; and R 2 is H, amidino, singly or doubly C 1 -C 6 alkyl-substituted amidino, —CN, —CONH 2 , —CONR′R″, —NHCOR′, —SO 2 NR′R″, or —COOH; or

(b) 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

(c) 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

(d) 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- to 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, —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 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 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 comprising two ring heteroatoms, both Y and Z are N, W is null, and —V e (R 1 )(R 2 ) is attached to Z, then —V e (R 1 )(R 2 ) is selected from the group consisting of amidino, C 1 -C 6 alkyl-substituted amidino, dihydroimidazole, —CH 2 COOH, and —H 2 C(O)NH 2 ; 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, R 1 and R 2 are not both —H.

2. The synthetic peptide amide of claim 1 wherein W is null, Y is N and Z is C.

3. The synthetic peptide amide of claim 1 wherein the Y and Z-containing ring moiety is a six-membered saturated ring comprising a single ring heteroatom.

4. The synthetic peptide amide of claim 1 wherein Y and Z are both N and are the only ring heteroatoms in the Y and Z-containing ring moiety.

5. The synthetic peptide amide of claim 1 wherein R 1 is H, OH, —NH 2 , —COOH, —CH 2 COOH, C 1 -C 3 alkyl, amidino, C 1 -C 3 alkyl-substituted amidino, dihydroimidazole, D-Pro, D-Pro amide, or CONH 2 and wherein R 2 is H, —COOH, or C 1 -C 3 alkyl.

6. The synthetic peptide amide of claim 1 wherein the moiety:

is selected from the group consisting of:

7. The synthetic peptide amide of claim 1 wherein the moiety:

is selected from the group consisting of:

8. The peptide amide of claim 1 , wherein the moiety

is an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein Y is carbon or nitrogen and Z is carbon, nitrogen, oxygen, sulfur, sulfoxide, or sulfonyl.

9. The synthetic peptide amide according to claim 1 , selected from the group consisting of:

D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-aminoethyl)-1-carboxymethyl-piperazine]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[4-carboxymethyl-piperidine]-OH,

D-Phe-D-Phe-D-Nle-D-Arg-D-Pro-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[(2S,4R)-4-amino-pyrrolidine-2-carboxylic acid]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[(2S,4S)-4-amino-pyrrolidine-2-carboxylic acid]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[ω(4-aminopiperidine-4-carboxylic acid)]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[ω(D/L-2-amino-3-(4-N-piperidinyl)propionic acid)]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[ω(D/L-4-piperazine-2-carboxylic acid)]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[Isonipecotic acid]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-proline]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[homopiperazine amide],

D-Phe-D-Phe-D-Leu-D-Orn-[4-(4-piperidinyl)-butanoic acid]-OH,

D-Phe-D-Phe-D-Leu-D-Orn-[4-(2-aminoethyl)-1-carboxymethyl-piperazine]-NH 2 ,

D-Phe-D-Phe-D-Leu-D-Orn-[N-(4-piperidinyl)-L-proline]-NH 2 ,

D-Phe-D-Phe-D-Leu-D-Orn-[4-amino-1-carboxymethyl-piperidine]-NH 2 ,

D-Phe-D-Phe-D-Leu-D-Orn-[4-amidinohomopiperazine amide],

D-Phe-D-Phe-D-Leu-D-Orn-[4-(4,5-dihydro-1H-imidazol-2-yl)homopiperazine amide],

D-Phe-D-Phe-D-Leu-D-Orn-[4-ethylhomopiperazine amide],

D-Phe-D-Phe-D-Leu-D-Orn-[4-(N-methyl)amidino-homopiperazine amide],

D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[ω(4-aminopiperidine-4-carboxylic acid)]-OH,

D-Phe-D-Phe-D-Leu-(δ-Me)D-Orn-[4-amidinohomopiperazine amide],

D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[4-amidinohomopiperazine amide],

D-Phe-D-Phe-D-Leu-(δ-Me)D-Orn-[homopiperazine amide],

D-Phe-D-Phe-D-Leu-(δ-iPr)D-Orn-[homopiperazine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[1,3-dioxolan-2-yl)methanamine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazin-1-yl)pyrimidine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazin-1-yl)pyrazine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[1-(pyridin-2-yl)piperazine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[2-(piperazin-1-yl)thiazole amide],

D-Phe-D-Phe-D-Leu-D-Lys-[N,N-dimethylpiperazine-1-sulfonamide amide],

D-Phe-D-Phe-D-Leu-D-Lys-[1-(methylsulfonyl)piperazine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[1-(phenylsulfonyl)piperazine amide],

D-Phe-D-Phe-D-Leu-D-Lys-[phenyl(piperazin-1-yl)methanone amide],

D-Phe-D-Phe-D-Leu-D-Lys-[thiolmorpholine-1,1-dioxide amide],

D-Phe-D-Phe-D-Leu-D-Lys-[6-trifluoromethyl-3-aminomethylpyridine amide],

D-Phe-D-Phe-D-Leu-D-Lys-N-methyl-1-(tetrahydro-2H-pyran-4-yl)methanamine amide; and

H-D-Phe-D-Phe-D-Leu-D-Lys-[5-(aminomethyl)-1H-benzo[d]imidazol-2(3H)one-amide].

10. The synthetic peptide amide according to claim 9 , having an EC 50 of less than about 500 nM for a kappa opioid receptor.

11. The synthetic peptide amide according to claim 9 , which at an effective concentration exhibits no more than about 50% inhibition of any of P 450 CYP1A2, CYP2C9, CYP2C19 or CYP 2D6 by the synthetic peptide amide at a concentration of 10 uM after 60 minutes incubation with human liver microsomes.

12. The synthetic peptide amide according to claim 9 , which at a dose of about 3 mg/kg in rat reaches a peak plasma concentration of the synthetic peptide amide and exhibits at least about a five fold lower concentration in brain than such peak plasma concentration.

13. The synthetic peptide amide according to claim 9 , having an ED 50 for a sedative effect in a locomotion-reduction assay in a mouse at least about ten times the ED 50 of the synthetic peptide amide for an analgesic effect in a writhing assay in a mouse.

14. The synthetic peptide amide according to claim 9 , having at least about 50% of maximum efficacy at about 3 hours post administration of a dose of about 3 mg/kg of the synthetic peptide amide in a rat.

15. A pharmaceutical composition comprising the synthetic peptide amide according to claim 1 and a pharmaceutically acceptable excipient or carrier.

16. A method of treating, inhibiting or preventing pain, or for treating or inhibiting a kappa opioid receptor-associated disease or condition in a mammal, the method comprising administering to the mammal a composition comprising an effective amount of a synthetic peptide amide according to claim 1 , wherein the kappa opioid receptor-associated disease or condition is selected from the group consisting of pain, pancreatitis and pruritis.

17. The synthetic peptide amide according to claim 1 , wherein Xaa 1 Xaa 2 is D-Phe-D-Phe; Xaa 3 is selected from the group consisting of D-Nle, D-Leu, D-Leu-(δ-Me) and D-Leu-(δ-iPr); and Xaa 4 is selected from the group consisting of D-Lys, D-Dap-(amidino), D-Arg, D-Orn, D-Orn(Me) and D-Orn-(iPr).

18. The synthetic peptide amide according to claim 17 , wherein Xaa 3 Xaa 4 is selected from the group consisting of D-Leu-D-Lys, D-Leu-D-Dap-(amidino), D-Nle-D-Dap-(amidino), D-Leu-D-Arg, D-Leu-D-Orn, D-Leu-(δ-Me)D-Orn and D-Leu-D-Orn-(iPr).

19. The synthetic peptide amide according to claim 17 , wherein the moiety:

is selected from the group consisting of:

20. 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 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, wherein each (A) and each (A′) are phenyl ring substituents independently selected from the group consisting of —F, —Cl, —NO 2 , —CH 3 , —CF 3 , —CN, —CONH 2 ;

Xaa 2 is independently selected from the group consisting of (A)(A′)D-Phe, (A)(A′)(α-Me)D-Phe;

when G is (i) then Xaa 3 -Xaa 4 - is selected from the group consisting of D-Nle-(B) 2 D-Arg-, D-Leu-δ-(B) 2 α-(B′)D-Orn-, and (α-Me)D-Leu-δ(B) 2 -α(B′)D-Orn-, wherein each (B) is independently selected from the group consisting of —H and C 1 -C 4 alkyl;

when G is (ii) Xaa 3 is D-Nle, D-Leu, (α-Me)D-Leu, D-Hle or D-Val; and Xaa 4 is (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, 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);

and p is 1;

G is selected from one of the following moieties:

(i) G is

the moiety

is an optionally substituted 5-, 6, or 7-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 heteroatom which is N, then such ring moiety is non-aromatic;

and

(ii) G is

the moiety

is an optionally substituted 5-, 6, or 7-membered heterocyclic ring moiety wherein Y is C or N and Z is C, N, O, S, SO, or SO 2 ; 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; provided that when such ring moiety is non-aromatic and Z is C or N then such ring moiety comprises at least one S or O ring heteroatom; 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—(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;

wherein 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 R 1 is —H, —OH, halo, CF 3 , —NH 2 , —COOH, C 1 -C 6 alkyl, amidino, C 1 -C 6 alkyl-substituted amidino, aryl, optionally substituted 5- or 6-membered 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′, or 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, 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 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 H, amidino, singly or doubly C 1 -C 6 alkyl-substituted amidino, —CN, —CONH 2 , —CONR′R″, —NHCOR′, —SO 2 NR′R″, or —COOH; wherein each of said optionally substituted 5- or 6-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 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 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 comprising two ring heteroatoms, both Y and Z are N, W is null, and —V e (R 1 )(R 2 ) is attached to Z, then —V e (R 1 )(R 2 ) is selected from the group consisting of amidino, C 1 -C 6 alkyl-substituted amidino, dihydroimidazole, —CH 2 COOH, and —H 2 C(O)NH 2 ; 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, R 1 and R 2 are not both —H.

21. The method according to claim 16 , for the treatment, inhibition or prevention of pain.

22. The method according to claim 16 , for the treatment or inhibition of pancreatitis or pruritis.

23. The synthetic peptide amide of claim 1 wherein the moiety:

is selected from the group consisting of: