Claims for Patent: 9,359,399

Summary for Patent: 9,359,399

Title:	Synthetic peptide amides
Abstract:	The invention relates to synthetic peptide amide 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 of formula I: ##STR00001## Pharmaceutical compositions containing these compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions. Such treatable pain includes visceral pain, neuropathic pain and hyperalgesia. Inflammation associated with conditions such as IBD and IBS, ocular and otic inflammation, other disorders and conditions such as pruritis, edema, hyponatremia, hypokalemia, ileus, tussis and glaucoma are treatable or preventable with the pharmaceutical compositions of the invention.
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; Robert Zhiyong (New City, NY)
Assignee:	Cara Therapeutics, Inc. (Shelton, CT)
Application Number:	14/585,438
Patent Claims:	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 pruritis, the method comprising administering to the mammal a composition comprising an effective amount of a synthetic peptide amide having the formula: ##STR00022## or a stereoisomer, mixture of stereoisomers, 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, and .beta.-(E)D-Ala, 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, and --CONH.sub.2, and wherein each (E) is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl; Xaa.sub.2 is selected from the group consisting of (A)(A')D-Phe, 3,4-dichloro-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, 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.-amidinopropionic acid, .alpha.-amino-4-piperidineacetic acid, cis-.alpha.,4-diaminocyclohexane acetic acid, trans-.alpha.,4-diaminocyclohexaneacetic acid, cis-.alpha.-amino-4-methylaminocyclo-hexane acetic acid, trans-.alpha.-amino-4-methylaminocyclohexane acetic acid, .alpha.-amino-1-amidino-4-piperidineacetic acid, cis-.alpha.-amino-4-guanidinocyclohexane acetic acid, and trans-.alpha.-amino-4-guanidinocyclohexane 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); 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, provided that Y is C; the moiety ##STR00023## 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.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 (i) R.sub.1 is selected from the group consisting of --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, IIe, Lys, Arg, Orn, Ser, Thr, --CN, --CONH.sub.2, --COR', --SO.sub.2R', --CONR'R'', --NHCOR', OR' and 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 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, --OH, --Cl, --F, --NH.sub.2, --NO.sub.2, --CN, --COOH and amidino; and R.sub.2 is selected from the group consisting of --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'' and --COOH; or (ii) 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 (iii) 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 (iv) 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 having a single ring heteroatom 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 having two ring heteroatoms, both Y and Z are N and W is null, then --(V).sub.eR.sub.1R.sub.2 is attached to a ring atom other than Z; and if e is zero, then R.sub.1 and R.sub.2 are not both --H; and lastly, provided that when Xaa.sub.3 is D-Nle, then Xaa.sub.4 is not (B).sub.2D-Arg, and when Xaa.sub.3 is D-Leu or (.alpha.Me)D-Leu, then Xaa.sub.4 is not .delta.-(B).sub.2.alpha.-(B')D-Orn. 2. The method of claim 1, wherein the moiety: ##STR00024## is selected from the group consisting of: ##STR00025## ##STR00026## 3. The method of claim 2, wherein Xaa.sub.1Xaa.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-Har, .zeta.-(B)D-Hlys, 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 method of claim 3 having the structure of Compound (2): ##STR00027## D-Phe-D-Phe-D-Leu-D-Lys-[.omega.(4-aminopiperidine-4-carboxylic acid)]-OH. 5. The method of claim 1, wherein the pruritis is selected from the group consisting of pruritis in atopic dermatitis, kidney dialysis-associated puritis, ocular pruritis, otitic pruritis, insect bite pruritis and opioid-induced pruritis. 6. The method of claim 4, wherein the pruritis is pruritis in atopic dermatitis. 7. The method of claim 4, wherein the pruritis is kidney-dialysis associated pruritis. 8. The method of claim 4, wherein the pruritis is uremic pruritis. 9. The method of claim 4, wherein the pruritis is ocular pruritis. 10. The method of claim 9, wherein the ocular pruritis is due to conjunctivitis. 11. The method of claim 4, wherein the pruritis is otic pruritis. 12. The method of claim 4, wherein the pruritis is insect bite pruritis. 13. The method of claim 4, wherein the pruritis is opioid-induced pruritis. 14. The method of claim 13, wherein the opioid-induced pruritis is morphine-induced pruritis. 15. The method of claim 4, wherein the pruritis is pruritis in cholestasis. 16. The method of claim 15, wherein the pruritis in cholestasis is selected from the group consisting of pruritis in primary biliary cirrhosis, pruritis in intrahepatic cholestasis of pregnancy and pruritis in chronic cholestatic liver disease. 17. The method of claim 4, wherein the pruritis is pruritis in malignant cholestasis. 18. The method of claim 4, wherein the pruritis is pruritis in anemia. 19. The method of claim 4, wherein the pruritis is associated with jaundice. 20. The method of claim 4, wherein the pruritis is pruritis associated with a condition selected from the group consisting of eczema, psoriasis, polycythemia vera, lichen planus, lichen simplex chronicus, pediculosis, thyrotoxicosis, tinea pedis, urticaria, scabies, vaginitis and hemorrhoids.