Claims for Patent: 7,713,937

Summary for Patent: 7,713,937

Title:	Synthetic peptide amides and dimeric forms thereof
Abstract:	The invention relates to synthetic peptide amides that are ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P.sub.450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure: ##STR00001## wherein Xaa is a D-amino acid and G is selected from the following three groups: ##STR00002## The compounds are useful in the prophylaxis and treatment of pain, pruritis and inflammation associated with a variety of diseases and conditions.
Inventor(s):	Schteingart; Claudio D. (San Diego, CA), Menzaghi; Frederique (Rye, NY), Jiang; Guangcheng (San Diego, CA), Alexander; Roberta Vezza (San Diego, CA), Sueiras-Diaz; Javier (La Jolla, CA), Spencer; Robert H. (New Hope, PA), Chalmers; Derek T. (Riverside, CT), Luo; Zhiyong (New City, NY)
Assignee:	Cara Therapeutics, Inc. (Shelton, CT)
Application Number:	12/119,311
Patent Claims:	1. A synthetic peptide amide having the formula: ##STR00181## or a stereoisomer, pharmaceutically acceptable salt, hydrate, acid salt hydrate, or N-oxide thereof, wherein Xaa.sub.1 is selected from the group consisting of (A)(A')D-Phe, (A)(A')(.alpha.-Me)D-Phe, D-Tyr, D-Tic, D-tert-leucine, D-neopentylglycine, D-phenylglycine, D-homophenylalanine, .beta.-(E)D-Ala and tert-butyl-D-Gly, wherein each (A) and each (A') are phenyl ring substituents independently selected from the group consisting of --H, --F, --Cl, --NO.sub.2, --CH.sub.3, --CF.sub.3, --CN, --CONH.sub.2, and wherein each (E) is independently selected from the group consisting of tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, pyridyl, thienyl, thiazolyl and benzothienyl; Xaa.sub.2 is selected from the group consisting of (A)(A')D-Phe, (A)(A')(.alpha.-Me)D-Phe, D-1Nal, D-2Nal, D-Tyr, (E)D-Ala, and D-Trp; Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (E)D-Ala, D-Leu, (.alpha.Me)D-Leu, D-Hle, D-Val, and D-Met; Xaa.sub.4 is selected from the group consisting of (B).sub.2D-Arg, (B).sub.2D-Nar, (B).sub.2D-Har, .zeta.-(B)D-Hlys, .beta.-amidino-D-Dap, .epsilon.-(B)D-Lys, .epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf, .gamma.-(B).sub.2D-Dbu, .delta.-(B).sub.2.alpha.-(B')D-Orn, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidyl)propionic acid, D-.alpha.-amino-.beta.-amidino-propionic acid, .alpha.-amino-4-piperidineacetic acid, cis-.alpha., 4-diaminocyclohexane acetic acid, trans-.alpha., 4-diaminocyclohexaneacetic acid, cis-.alpha.-amino-4-methyl-aminocyclo-hexane acetic acid, trans-.alpha.-amino-4-methylaminocyclohexane acetic acid, .alpha.-amino-1-amidino-4-piperidineacetic acid, cis-.alpha.-amino-4-guanidino-cyclohexane acetic acid, and trans-.alpha.-amino-4-guanidino-cyclohexane acetic acid, wherein each (B) is independently selected from the group consisting of --H and C.sub.1-C.sub.4 alkyl, and (B') is --H or (.alpha.-Me); wherein G is ##STR00182## wherein the moiety ##STR00183## 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.sub.2; provided that when such ring moiety is a 6-, 7- or 8-membered ring, Y and Z are separated by at least two ring atoms; and provided further that when such ring moiety is aromatic, then Y is carbon; wherein W is selected from the group consisting of: null, provided that when W is null, Y is N; --NH--(CH.sub.2).sub.b-- with b equal to zero, 1, 2, 3, 4, 5, or 6; and --NH--(CH.sub.2).sub.c--O-- with c equal to 2, or 3; wherein V is C.sub.1-C.sub.6 alkyl, and e is zero or 1, wherein when e is zero, then V is null and, R.sub.1 and R.sub.2 are directly bonded to the same or different ring atoms; wherein (a) R.sub.1 is --H, --OH, halo, CF.sub.3, --NH.sub.2, --COOH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, amidino, C.sub.1-C.sub.6 alkyl-substituted amidino, aryl, optionally substituted heterocyclyl, Pro-amide, Pro, Gly, Ala, Val, Leu, Ile, Lys, Arg, Orn, Ser, Thr, CN, CONH.sub.2, COR', SO.sub.2R', CONR'R'', NHCOR', OR', or SO.sub.2NR'R''; wherein said optionally substituted heterocyclyl is optionally singly or doubly substituted with substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy, oxo, --OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN, --COOH, and amidino; wherein R' and R'' are each independently --H, C.sub.1-C.sub.8 alkyl, aryl, or 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.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy, --OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN, --COOH and amidino; and R.sub.2 is H, amidino, singly or doubly C.sub.1-C.sub.6 alkyl-substituted amidino, --CN, --CONH.sub.2, --CONR'R'', --NHCOR', --SO.sub.2NR'R'', or --COOH; or (b) R.sub.1 and R.sub.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.sub.1 and R.sub.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.sub.1 and R.sub.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.sub.1 and R.sub.2 is optionally singly or doubly substituted with substituents independently selected from the group consisting of C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy, optionally substituted phenyl, oxo, --OH, --Cl, --F, --NH.sub.2, --NO.sub.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 wherein such heteroatom is N, and e is zero, then R.sub.1 is not --OH, and R.sub.1 and R.sub.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.sub.e(R.sub.1)(R.sub.2) is attached to Z, then -V.sub.e(R.sub.1)(R.sub.2) is selected from the group consisting of amidino, C.sub.1-C.sub.6 alkyl-substituted amidino, dihydroimidazole, --CH.sub.2COOH, and --CH.sub.2C(O)NH.sub.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.sub.1 and R.sub.2 are not both --H. 2. The synthetic peptide amide of claim 1, wherein Xaa.sub.1 is selected from the group consisting of (A)D-Phe, (.alpha.-Me)D-Phe, D-Tyr, D-Tic, (tert-butyl)D-Gly, and .beta.-(E)D-Ala, wherein (A) is selected from the group consisting of --H, --F, --Cl, --NO.sub.2, and --CH.sub.3, and (E) is selected from the group consisting of tert-butyl, cyclopentyl and thienyl; Xaa.sub.2 is selected from the group consisting of (A)(A')D-Phe, D-1Nal, D-2Nal, D-Tyr, and D-Trp, wherein (A') is H or Cl; Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu, (.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met; and Xaa.sub.4 is selected from the group consisting of D-Arg, (ethyl).sub.2D-Arg, D-Nar, D-Har, (ethyl).sub.2D-Har, .epsilon.-(isopropyl)D-Lys, D-Lys, D-Amf, amidino-D-Amf, .beta.-amidino-D-Dap, D-Dbu, D-Orn, .alpha.-(methyl)D-Orn and .delta.-(isopropyl)D-Orn. 3. The synthetic peptide amide of claim 1, wherein Xaa.sub.1-Xaa.sub.2 is D-Phe-D-Phe, Xaa.sub.3 is D-Leu or D-Nle and Xaa.sub.4 is selected from the group consisting of (B).sub.2D-Arg, D-Lys, (B).sub.2D-Nar, (B).sub.2D-Har, .zeta.-(B)D-Hlys, D-Dap, .beta.-amidino-D-Dap, .epsilon.-(B)D-Lys, .epsilon.-(B).sub.2-D-Lys, D-Amf, amidino-D-Amf, .gamma.-(B).sub.2D-Dbu and .delta.-(B).sub.2.alpha.-(B')D-Orn. 4. The synthetic peptide amide of claim 3, wherein Xaa.sub.4 is selected from the group consisting of D-Lys, (B).sub.2D-Har, .epsilon.(B)-D-Lys, .delta.(B).sub.2-.alpha.(B')D-Orn and .epsilon.(B).sub.2-D-Lys. 5. The synthetic peptide amide of claim 2, wherein Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu and (.alpha.-Me)D-Leu. 6. The synthetic peptide amide of claim 3, wherein Xaa.sub.4 is selected from the group consisting of D-Arg, D-Lys, D-Nar, D-Har, .epsilon.-Me-D-Lys, .epsilon.-iPr-D-Lys, .beta.-amidino-D-Dap, D-Dbu, .delta.-iPr-D-Orn, .delta.-Me-D-Orn and D-Orn. 7. The synthetic peptide amide of claim 1, wherein Xaa.sub.1 and Xaa.sub.2 are each independently selected from the group consisting of (A)(A')D-Phe and (A)(A')(.alpha.-Me)D-Phe. 8. The synthetic peptide amide of claim 7, wherein Xaa.sub.1Xaa.sub.2 is D-Phe-D-Phe. 9. The synthetic peptide amide of claim 7, wherein Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu, (.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met. 10. The synthetic peptide amide of claim 9, wherein Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu, (.alpha.-Me)D-Leu. 11. The synthetic peptide amide of claim 10, wherein Xaa.sub.3 is selected from the group consisting of D-Nle and D-Leu. 12. The synthetic peptide amide of claim 7, wherein Xaa.sub.4 is selected from the group consisting of D-Arg, (ethyl).sub.2D-Arg, D-Nar, D-Har, (ethyl).sub.2D-Har, .epsilon.-(isopropyl)D-Lys, D-Lys, D-Amf, amidino-D-Amf, .beta.-amidino-D-Dap, D-Dbu, D-Orn, .alpha.-(methyl)D-Orn and .delta.-(isopropyl)D-Orn. 13. The synthetic peptide amide of claim 12, wherein Xaa.sub.4 is selected from the group consisting of D-Arg, D-Lys, D-Nar, D-Har, .epsilon.-Me-D-Lys, .epsilon.-iPr-D-Lys, .beta.-amidino-D-Dap, D-Dbu, .delta.-(isopropyl)D-Orn, .delta.-Me-D-Orn and D-Orn. 14. The synthetic peptide amide of claim 13, wherein Xaa.sub.4 is selected from the group consisting of D-Arg, D-Nar, .beta.-amidino-D-Dap, D-Lys, .delta.-iPr-D-Orn, .alpha.-Me-D-Orn and D-Orn. 15. The synthetic peptide amide of claim 1, wherein W is null, Y is N. 16. The synthetic peptide amide of claim 15, wherein Xaa.sub.1 and Xaa.sub.2 are each independently selected from the group consisting of (A)(A')D-Phe and (A) (A')(.alpha.-Me)D-Phe; Xaa.sub.3 is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu, (.alpha.-Me)D-Leu, D-Hle, D-Val, and D-Met; and Xaa.sub.4 is selected from the group consisting of D-Arg, (ethyl).sub.2D-Arg, D-Nar, D-Har, (ethyl).sub.2D-Har, .epsilon.-(isopropyl)D-Lys, D-Lys, D-Amf, amidino-D-Amf, .beta.-amidino-D-Dap, D-Dbu, D-Orn, .alpha.-(methyl)D-Orn and .delta.-(isopropyl)D-Orn. 17. The synthetic peptide amide of claim 15, wherein the Y and Z-containing ring moiety is a five-membered saturated ring. 18. The synthetic peptide amide of claim 17, wherein G is an optionally substituted proline radical. 19. The synthetic peptide amide of claim 15, wherein the Y and Z-containing ring moiety is a six-membered saturated ring. 20. The synthetic peptide amide of claim 19, wherein the Y and Z-containing ring moiety comprises a single heteroatom. 21. The synthetic peptide amide of claim 20, wherein e is zero and R.sub.1 and R.sub.2 taken together, or with one or two ring atoms of the Y and Z-containing ring moiety comprise an optionally substituted monocyclic or bicyclic 4-9 membered heterocyclic ring moiety. 22. The synthetic peptide amide of claim 21, wherein R.sub.1 and R.sub.2 taken together with one ring atom of the Y and Z-containing ring moiety comprises a 5-membered heterocyclic ring moiety having heteroatoms selected from the group consisting of N and O, which heterocyclic ring moiety with the Y and Z-containing ring moiety forms a spiro structure. 23. The synthetic peptide amide of claim 19, wherein the Y and Z-containing ring moiety comprises two heteroatoms. 24. The synthetic peptide amide of claim 23, wherein the two heteroatoms of the Y and Z-containing ring moiety are both N. 25. The synthetic peptide amide of claim 24, wherein e is zero, R.sub.2 is H and the Y and Z-containing ring moiety is 3-substituted with R.sub.1. 26. The synthetic peptide amide of claim 23, wherein the two heteroatoms of the Y and Z-containing ring moiety are N and O. 27. The synthetic peptide amide of claim 26, wherein the Y and Z-containing ring moiety is 3-substituted with R.sub.1, e is zero and R.sub.2 is H. 28. The synthetic peptide amide of claim 23, wherein the two heteroatoms of the Y and Z-containing ring moiety are N and S. 29. The synthetic peptide amide of claim 28, wherein the Y and Z-containing ring moiety is 3-substituted with R.sub.1, e is zero and R.sub.2 is H. 30. The synthetic peptide amide of claim 15, wherein the Y and Z-containing ring moiety is a seven-membered saturated ring comprising two heteroatoms. 31. The synthetic peptide amide of claim 30, wherein Y and Z are both N and the moiety V.sub.eR.sub.1R.sub.2 is attached to Z. 32. The synthetic peptide amide of claim 30, wherein Y is N and the second heteroatom of the Y and Z-containing ring moiety is selected from the group consisting of S and O. 33. The synthetic peptide amide of claim 1, wherein W is --NH.sub.2--(CH.sub.2).sub.b-- and b is zero, 1, 2, or 3. 34. The synthetic peptide amide of claim 33, wherein the Y and Z-containing ring moiety is a five-membered saturated ring. 35. The synthetic peptide amide of claim 34, wherein the Y and Z-containing ring moiety is an optionally substituted proline radical. 36. The synthetic peptide amide of claim 33, wherein the Y and Z-containing ring moiety is a six-membered saturated ring. 37. The synthetic peptide amide of claim 36, wherein Y is C and Z is N. 38. The synthetic peptide amide of claim 36, wherein Y is N and Z is N. 39. The synthetic peptide of claim 1, wherein G is selected from the group consisting of substituted piperidinyl, piperidinyl forming a spiro structure with an optionally substituted heterocycle, piperidinyl fused with an optionally substituted heterocycle, substituted piperazinyl, 4-sulfonamidyl piperazinyl, 3-substituted piperazinyl, substituted homopiperazinyl, optionally substituted homomorpholinyl, optionally substituted homothiomorpholinyl, 3-substituted morpholinyl, 3-substituted thiomorpholinyl, 4-4 dioxo thiomorpholinyl, and optionally substituted proline, and W is null, or W is --NH.sub.2--(CH.sub.2).sub.b-- and b is zero, 1, 2, or 3 and the moiety ##STR00184## is selected from the group consisting of substituted pyrazinyl, substituted pyridinyl, substituted piperazinyl, optionally substituted pyrimidinyl, substituted "reverse" piperidinyl, optionally substituted heterocyclic bicycle, optionally substituted proline, optionally substituted thiazolyl, optionally substituted dioxolanyl, and optionally substituted tetrahydropyranyl. 40. The synthetic peptide amide of claim 39 wherein G is selected from the group consisting of substituted piperidinyl, piperidinyl forming a spiro structure with an optionally substituted heterocycle, and piperidinyl fused with an optionally substituted heterocycle. 41. The synthetic peptide amide of claim 39, wherein G is selected from the group consisting of substituted piperazinyl, 4-sulfonamidyl piperazinyl, 3-substituted piperazinyl, and substituted homopiperazinyl. 42. The synthetic peptide amide of claim 39, wherein G is selected from the group consisting of optionally substituted homomorpholinyl, optionally substituted homothiomorpholinyl, 3-substituted morpholinyl, 3-substituted thiomorpholinyl, and 4-4-dioxo thiomorpholinyl. 43. The synthetic peptide amide of claim 39, wherein G is optionally substituted proline. 44. The synthetic peptide amide of claim 39, wherein W is --NH.sub.2--(CH.sub.2).sub.b--, b is zero, 1, 2, or 3 and the moiety ##STR00185## is selected from the group consisting of optionally substituted thiazolyl, optionally substituted dioxolanyl, and optionally substituted tetrahydropyranyl. 45. The synthetic peptide amide of claim 39, wherein W is --NH.sub.2--(CH.sub.2).sub.b--, b is zero, 1, 2, or 3 and the moiety ##STR00186## is selected from the group consisting of substituted pyrazinyl, substituted pyridinyl, optionally substituted pyrimidinyl, and optionally substituted heterocyclic bicycle. 46. The synthetic peptide amide of claim 39, wherein W is --NH.sub.2--(CH.sub.2).sub.b--, b is zero, 1, 2, or 3 and the moiety ##STR00187## is selected from the group consisting of substituted piperazinyl and 4-substituted piperidinyl. 47. The synthetic peptide amide of claim 39, wherein W is --NH.sub.2--(CH.sub.2).sub.b--, b is zero, 1, 2, or 3 and the moiety ##STR00188## is optionally substituted proline. 48. The synthetic peptide amide of claim 1, wherein e is zero and R.sub.1 and R.sub.2 are bonded directly to the same ring atom. 49. The synthetic peptide amide of claim 48, wherein R.sub.1 is H, OH, --NH.sub.2, --COOH, --CH.sub.2COOH, C.sub.1-C.sub.3 alkyl, amidino, C.sub.1-C.sub.3 alkyl-substituted amidino, dihydroimidazole, D-Pro, D-Pro amide, or CONH.sub.2 and wherein R.sub.2 is H, --COOH, or C.sub.1-C.sub.3 alkyl. 50. The synthetic peptide amide of claim 1, wherein the moiety: ##STR00189## is selected from the group consisting of: ##STR00190## ##STR00191## ##STR00192## ##STR00193## 51. A pharmaceutical composition comprising the synthetic peptide amide according to claim 1, and a pharmaceutically acceptable excipient or carrier. 52. A method of 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 pain, pancreatitis, or pruritis. 53. The method according to claim 52, wherein the pain is chronic pain or acute pain. 54. The method according to claim 52, wherein the pain is selected from the group consisting of neuropathic pain, somatic pain, visceral pain, cutaneous pain, and ocular pain. 55. The method according to claim 52, wherein the pain is post injury pain or postoperative pain. 56. The method according to claim 52, wherein the pain is post-surgical pain. 57. The method according to claim 56 wherein the post-surgical pain arises from a surgical procedure selected from the group consisting of appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonic resection, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparoscopy, tubal ligation, hysterectomy, vasectomy and cholecystecomy. 58. The method according to claim 52, wherein the pain is post medical procedure pain. 59. The method according to claim 58 wherein the post medical procedure pain arises from a medical procedure selected from the group consisting of colonoscopy, cystoscopy, hysteroscopy, cervical and endometrial biopsy. 60. The method according to claim 52, wherein the pruritis is selected from the group consisting of atopic pruritis, pruritis associated with kidney dialysis, ocular pruritis, otic pruritis, insect-bite pruritis and opioid-induced pruritis.