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A-B-C-D-E (Formula I) O00 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/181408 A2 17 November 2016 (17.11.2016) P O P CT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/07 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/IN20 16/000 120 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, May 2016 (09.05.2016) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 1849/MUM/2015 11 May 2015 ( 11.05.2015) IN (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: CADILA HEALTHCARE LIMITED GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [IN/IN]; Zydus Tower, Satellite Cross Roads, Ahmedabad TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 380015, Gujarat (IN). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: DESAI, Ranjit; Cadila Healthcare Limited, Zy LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, dus Tower, Satellite Cross Roads, Ahmedabad 380015, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Gujarat (IN). BAHEKAR, Rajesh; Cadila Healthcare Lim GW, KM, ML, MR, NE, SN, TD, TG). ited, Zydus Tower, Satellite Cross Roads, Ahmedabad 380015, Gujarat (IN). PRAJAPATI, Vijay; Cadila Health Declarations under Rule 4.17 : care Limited, Zydus Tower, Satellite Cross Roads, — as to applicant's entitlement to applyfor and be granted a Ahmedabad 380015, Gujarat (IN). CHOPADE, Rajendra; patent (Rule 4.1 7(H)) Cadila Healthcare Limited, Zydus Tower, Satellite Cross Roads, Ahmedabad 380015, Gujarat (IN). Published: (74) Agent: SUBRAMANIAM, Hariharan; Subramaniam & — without international search report and to be republished Associates, Central Square, Suite 328, Plaza III, 20 Mano- upon receipt of that report (Rule 48.2(g)) harlal Khurana Marg, Bara Hindu Rao (off Rani Jhansi Road), Delhi 110006 (IN). (54) Title: NOVEL SHORT-CHAIN PEPTIDES AS KAPPA (κ) OPIOID RECEPTORS (KOR) AGONIST A-B-C-D-E (Formula I) o00 00 (57) Abstract: The present invention relates to novel short-chain peptides of the general formula (I), which are selective and peri - pherally acting KOR agonist, their tautomeric forms, their enantiomers, their diastereoisomers, their stereoisomers, their pharmaceut - ically accepted salts, or prodrugs thereof which are useful in the treatment or prevention of diseases in which the Kappa (κ) opioid receptors (KOR) are involved, such as treatment or prevention of visceral pain, hyperalgesia, rheumatoid arthritic inflammation, os - teoarthritic inflammation, IBD inflammation, IBS inflammation, ocular inflammation, otitic inflammation or autoimmune inflamma- tion. The invention also relates to process for the manufacture of said short-chain peptides, and pharmaceutical compositions con - S taining them and their use. NOVEL SHORT-CHAIN PEPTIDES AS KAPPA (κ) OPIOID RECEPTORS (KOR) AGONIST FIELD OF INVENTION The present invention relates to novel short-chain peptides of the general formula (I), which are selective and peripherally acting KOR agonist, their tautomeric forms, their enantiomers, their diastereo isomers, their stereoisomers, their pharmaceutically accepted salts, or prodrugs thereof which are useful in the treatment or prevention of diseases in which the Kappa ( ) opioid receptors (KOR) are involved, such as treatment or prevention of visceral pain, hyperalgesia, rheumatoid arthritic inflammation, osteoarthritic inflammation, IBD inflammation, IBS inflammation, ocular inflammation, otitic inflammation or autoimmune inflammation. The invention also relates to process for the manufacture of said compounds, and pharmaceutical compositions containing them and their use. BACKGROUND OF THE INVENTION There are three types of opioid receptors (Mu (µ), Kappa (κ) and Delta (δ)), found to be expressed in both the CNS and in the periphery and the available opioid analgesics mediate their effects through these opioid receptors (Evans, C , Keith, J.D., Morrison, H., Magendzo, K and Edwards, R., Science, 258, 1952-1955, 1992; Cox, B. M., Mol. Pharmacol., 83, 723-728, 2013; Chen, Y., Mestek, A., Liu, J., Hurley, J and Yu, L., Mol. Pharmacol., 44, 8-12, 1993; Meng, F., Xie, G.X., Thompson, R., Mansour, A., Goldstein, A., Watson, S.J and Akil, H., Proc. Natl. Acad. Sci., U.S.A., 90, 9954-9958, 1993; Simonin, F., Gaveriaux, R. C , Befort, K., Matthes, H., Lannes, B., Micheletti, G., Mattei, M . G., Charron, G., Bloch, B and Kieffer, B., Proc. Natl. Acad. Sci., U.S.A., 92, 7006-7010, 1995; Stein, C , Anesth. Analg., 76, 182-191, 1993). Most of the opioid analgesics at present, for example, morphine, act by binding to the µ-opioid receptor, and their analgesic activity are associated with a spectrum of undesirable side effects, such as physical dependence, respiratory depression, urinary retention, constipation, euphoria/dysphoria and constipation (Pasternak, G.W., Clin. Neuropharmacol., 16, 1-18, 1993). In recent years, considerable attention has been focused on the development o f receptor selective K-agonists as potent and efficacious analgesics devoid of the undesirable side effects of the µ analgesics (Barber, A and Gottschlich, R., Med. Res. Rev., 12, 525-562, 1992). Unlike agonist at δ and µ receptors, agonist at κ-opioid receptors does not elicit constipation and euphoria. The - opioid receptors are members of the superfamily of G protein-coupled receptors (GPCRs). Agonist binding to the κ-receptors, activates the intracellular associated Gi protein, which decreases Ca2+ channel conductance or inhibits adenylyl cyclase (AC) (Prather, P. L., McGinn, T. M., Claude, P. A., Liu-Chen, L. Y., Loh, H. H and Law, P.Y., Mol. Brain. Res., 29, 336-346, 1995). K-opioid agonists have been suggested to have potential for treatment of incisional/inflammatory pain, burn injury pain (Field, M. J., Carnell, A.J., Gonzalez, M.I., McCleary, S., Oles, R.J., Smith, R., Hughes, J and Singh, L., Pain, 80, 383-389, 1999) neuropathic pain (Catheline, G., Guilbaud, G and Kayser, V., Eur. J. Pharmacol., 357, 171-178, 1998), visceral pain including dysmenorrhea or gastrointestinal pain (Delgado Aros S., Chial H.J., Camilleri M., Szarka L.A., Weber F.T., Jacob, J., Ferber, I., McKinzie, S., Burton, D.D and Zinsmeister, A.R., Am. J. Physiol. Gastrointest. Liver Phsyiol., 284, G558-G566, 2002), Irritable bowel syndrome (IBS) (Dapoigny, M., Abitbol, J.L., Fraitag, B., Digest. Dis. ScL, 40, 2244-2249, 1995; Mangel, A.W., Bornstein, J.D., Hamm, L.R., Buda, J., Wang, J., Irish, W., Urso, D., Pharmacol. Ther., 28, 239- 249, 2008), rheumatoid arthritis (Endoh, T., Tajima, A., Suzuki, T., amei, J., Suzuki, T., Narita, M., Tseng, L and Nagase, H., Eur. J. Pharmacol. 387, 133-140, 2000) and anti-pruritis effects (Peters, G and Gaylor, S., Clin. Pharmacol. Ther., 51, PPF-5, 1989). Walker et al., (Walker, J.S., Adv. Exp. Med. Biol., 521, 148-60, 2003) appraised the anti-inflammatory properties of kappa agonists for treatment of osteoarthritis, rheumatoid arthritis, inflammatory bowel disease and eczema. Bileviciute-Ljungar et al., (Bileviciute-Ljungar, T. Saxne, and M. Spetea, Rheumatology, 45, 295-302, 2006) describe the reduction of pain and degeneration in Freund's adjuvant-induced arthritis by the kappa agonist U-50,488. Thus, the κ-receptors represent important therapeutic targets (Pan, Z.Z., Tershner, S.A., Fields, H.L., Nature, 389, 382-385, 1997; Chavkin, C , Neuropsychopharmacology, 36, 369-370, 201 1). K-opioid receptors exist extensively in the central nervous system (CNS) arid play important roles in many physiological and pathological functions. Inspite of such potential applications, clinical studies have shown that κ-receptor agonist elicit severe centrally mediated side effects generally described as "dysphoric actions" (Pfeiffer, A., Brantl, V., Herz, A and Emrich, H.M., Science, 233, 774-776, 1986), water diuresis (Dykstra, L.A., Gmerek, D.E., Winger, G and Woods, J.H., J. Pharmacol. Exp. Ther., 242, 413-420, 1987) and psychotomimetic effects (Rimoy, G.H., Wright, D.M., Bhaskar, N. ., Rubin, P. C, Eur. J. Clin. Pharmacol. 46 (3), 203- 207, 1994). These side effects have apparently halted further clinical development for this class of compounds. Many studies have shown that opiates have peripheral analgesic effects, especially under inflammatory or hyperalgesic conditions (Barber, A and Gottschlich, R., Med. Res. Rev., 12, 525-562, 1992). Agonist at κ-opioid receptors have been shown to produce analgesia and decrease inflammation in models of rheumatoid arthritis after local administration (Wilson, J. L., Nayanar, V and Walker, J.S., Br. J. Pharmacol., 1 8, 1754-1760, 1996). Restricted CNS penetration is a common strategy to reduce central side effects of drugs with beneficial peripheral actions. Attempts have been made to develop peripherally restricted κ-opioid agonists, such as ICI204448 (Shaw, J.S., Carroll, J.A., Alcoc, P and Main, B.G., Br. J. Pharmacol., 96, 986-992, 1989), GR94839 (Rogers, H., Birch, P.J., Harrison, S.M., Palmer, E., Manchee, G.R., Judd, D.B., Naylor, A., Scopes, D.I.C and Hayes, A.G., Br. J. Pharmacol., 106, 783-789, 1992), Cadila Healthcare Ltd., Novel Heterocyclic compounds as Kappa Opioid Agonist (WO20 15/1 19660) and EMD61753/ Asimadoline (Barber, A., Bartoszyk, G.D., Bender, H.M., Gottschlich, R., Greiner, H.E., Harting, J., Mauler, F., Minck, K.O., Murray, R.D., Simon, M and Seyfried, C.A., Br.
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