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US-12616732-B2 - Peptides for treatment of medical disorders

US12616732B2US 12616732 B2US12616732 B2US 12616732B2US-12616732-B2

Abstract

The present invention provides compounds which are selective kappa-opioid receptor agonist, method of preparation of these compounds, compositions that comprise these compounds, and methods for treating kappa-opiod receptor agonist related medical disorders.

Inventors

  • Subo Liao
  • Dali Liang
  • Rong Liu
  • Jun Yang
  • Jinliang Lv
  • Zongquan Liao
  • Hao Zhou
  • Jueyuan Gao
  • Tianpeng Xie
  • Quanli Yang
  • Yao He

Assignees

  • Yichang Humanwell Pharmaceutical Co., Ltd.

Dates

Publication Date
20260505
Application Date
20220711

Claims (12)

  1. 1 . A method of treating kappa-opioid receptor agonist-related disease or disorder, the method comprising administering a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 1 , R 2 , and R 3 are independently selected from a group consisting of H, CN, Cl, F, C 1 -C 8 unsubstituted alkyl, C 1 -C 8 substituted alkyl, C 3 -C 10 unsubstituted cycloalkyl, and C 3 -C 10 substituted cycloalkyl; R 4 is selected from a group consisting of C 1 -C 8 unsubstituted alkyl, C 1 -C 8 substituted alkyl, C 3 -C 10 unsubstituted cycloalkyl, and C 3 -C 10 substituted cycloalkyl; R 5 and R 6 are independently selected from a group consisting of H, C 1 -C 8 unsubstituted alkyl, C 1 -C 8 substituted alkyl, C 3 -C 10 unsubstituted cycloalkyl, C 3 -C 10 substituted cycloalkyl; unsubstituted aryl, substituted aryl, and substituted heterocyclic; R 7 is selected from a group consisting of H, C 1 -C 8 unsubstituted alkyl, C 1 -C 8 substituted alkyl, C 3 -C 10 unsubstituted cycloalkyl, and C 3 -C 10 substituted cycloalkyl; R 8 and R 9 are independently selected from a group consisting of H, C 1 -C 8 unsubstituted alkyl, C 1 -C 8 substituted alkyl, and O-substituted C 1 -C 8 alkyl; R 10 is R 11 is selected from a group consisting of OR 12 and NR 13 R 14 ; R 12 is selected from a group consisting of H, C 1 -C 24 unsubstituted alkyl, C 1 -C 24 substituted alkyl, O-substituted C 1 -C 24 alkyl, CH 3 O(CH 2 CH 2 ) n CH 2 CH 2 —, and HO(CH 2 CH 2 ) n CH 2 CH 2 —; R 13 and R 14 are independently selected from a group consisting of H, C 1 -C 24 unsubstituted alkyl, C 1 -C 24 substituted alkyl, O-substituted C 1 -C 24 alkyl, CH 3 O(CH 2 CH 2 ) n CH 2 CH 2 —, and HO(CH 2 CH 2 ) n CH 2 CH 2 —; and n is an integer from 0 to 100; wherein an unsubstituted alkyl, cycloalkyl, or aryl group comprises all carbon atoms, and a substituted alkyl, cycloalkyl, or aryl group comprises at least one nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom for at least one carbon atom; and wherein the kappa opioid receptor agonists-related disease or disorder is pain, pruritus, nausea, or both; to a subject in need thereof.
  2. 2 . The method of claim 1 , wherein the pharmaceutical composition is administered subcutaneous, intradermal, intravenous, intramuscular, orally, or intraperitoneal.
  3. 3 . The method of claim 1 , wherein the pharmaceutical composition comprising the compound of Formula (I) is administered at a dosage rate from about 0.0001 mg/kg to about 100.0 mg/kg.
  4. 4 . The method of claim 2 , wherein the pharmaceutical composition comprising the compound of Formula (I) is administered at a dosage rate from about 0.0001 mg/kg to about 10.0 mg/kg.
  5. 5 . The method of claim 1 , wherein the pharmaceutical composition comprising the compound of Formula (I) is administered at least once daily, as at least twice daily, at least thrice daily, or at multiple times each day.
  6. 6 . The method of claim 5 , wherein the pharmaceutical composition comprising the compound of Formula (I) is administered at least once daily.
  7. 7 . The method of claim 1 , wherein the subject is selected from a group consisting of a human, a livestock animal, a companion animal, a lab animal, and a zoological animal.
  8. 8 . The method of claim 7 , wherein the subject is a human.
  9. 9 . The method of claim 1 , wherein R 1 , R 2 , and R 3 are H or C 1 -C 4 alkyl; R 4 is methyl; R 5 is hydrogen; R 6 is phenyl; R 7 is isopropyl; R 10 is R 11 is selected from a group consisting of OR 12 ; R 12 is H or —CH 3 .
  10. 10 . The method of claim 9 , wherein the compound is:
  11. 11 . The method of claim 1 , wherein the pharmaceutical composition is administered subcutaneous or intravenous.
  12. 12 . The method of claim 1 , wherein the pharmaceutical composition comprising the compound of Formula (I) is administered at a dosage rate from about 0.01 mg/kg to about 50.0 mg/kg.

Description

CROSS REFERENCE TO RELATED APPLICATIONS The present application is a continuation in part of U.S. application Ser. No. 16/911,701, filed on Jun. 25, 2020, entitled, “PEPTIDES FOR TREATMENT OF MEDICAL DISORDERS,” which is hereby incorporated by reference. FIELD OF THE INVENTION The present disclosure generally relates to compounds which are selective kappa-opioid receptor agonist, method of preparation of these compounds, compositions that comprise these compounds, and methods for treating kappa-opioid receptor agonist related medical disorders. BACKGROUND OF THE INVENTION Opioid kappa receptors (KORs) are expressed in many parts of the body such as brain, spinal cord, and on central and peripheral terminals. KORs play an important role in signal transduction to maintain many physiological functions of the body. Like opioid mu receptors (MORs) and delta receptors (DORs), activation of KORs by agonist ligands leads to the inhibition of adenylyl cyclase and calcium channel activity while stimulation of the potassium channel activities (Law P Y, Wong Y H, Loh H H. Molecular mechanisms and regulation of opioid receptor signaling. Annu Rev Pharmacol Toxicol 2000; 40: 389-430). Many physiological processes are related to the activation of KORs including analgesia, anti-pruritic actives (Inan S, Cowan A. Kappa opioid agonists suppress chloroquine-induced scratching in mice. Eur J. Pharmacol 2004; 502, 233-7), diuresis (Barber A, Gottschlich R. Novel developments with selective non-peptidic kappa-opioid receptor agonists. Exp Opinion Investigational drugs. 1997; 6: 1351-68; DeHaven-Hudkins D L, Dolls R E. Peripherally restricted opioid agonists are novel analgesic agents (Curr Pharm Des 2004; 10:743-57), inflammation agents, immune system modulation agents, etc. The agonists offer great potentials for KORs selective ligands to treat various medical disorder such as pain, depression, autoimmune disorders and neurological diseases. (Tyler C. Beck, Matthew A. Hapstack, Kyle R. Beck, and Thomas A. Dix. “Therapeutic Potential of Kappa Opioid Agonists”, Pharmaceuticals (Basel). 2019 June; 12(2): 95). Many KORs selective agonists were synthesized and evaluated as potential analgesics which are in avoid of side effects associated with traditional opioid analgesics like respiratory depression, dependence, addiction, and constipation; a few of them had already been tested in clinical trial but failed due to side effects like diuresis, sedation, and dysphoria, et al or lack of efficacy; examples include spiradoline mesylate (U62,066E) (Wadenberg M L, A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist. CNS Drug Rev. 2003, Summer, 9(2): 187-98), enadoline for potential analgesics (Walsh S L., Strain E C, Abreu M. E. Bigelow G. E. Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans. Psychopharmacology 2001, 157, 151-162) and ADL-10-0101 et al. TRK-820 (Nalfurafine) was originally developed as potential analgesics but achieved success as anti-pruritic reagents and got regulatorily approved in Japan with brand name Remitch. Highly opioid kappa-receptor selective and potent D-amino acids tetrapeptide agonists were reported by Ferring BV (US005965701A) and were further developed by Cara therapeutics. The lead tetrapeptide compound, CR-845, is currently under development by Cara therapeutics in the clinical trials as analgesics and anti-pruritic agents (Hesselink, J. M. K. CR845 (Difelikefalin), A Kappa Receptors Agonist in Phase III by CARA Therapeutics: A Case of ‘Spin’ in Scientific Writing? J. Pharm.& clinical Res. 2017 2(3), 001). Encouraged by the progress of CR-845 in clinical trial, several pharmaceutical companies also actively engaged in the discovery of peptide-based KORs selective agonist ligands via modifying molecular structure of CR-845 with hope to find new analgesics and potential anti-pruritus agents without conventional side effects of morphinan analgesics (CN107098871, WO2017211272A1, WO2018103624A1, WO2017210668A1, WO2018059331A1). In addition, KORs agonists are also developed for other indications; for example, both fedotozine and asimadoline were tested as potential therapeutics for irritable bowel syndrome and dyspepsia. What is needed is a novel kappa-opiate agonist that treats a variety of medical disorders. FIGURES FIG. 1 is a chemical reaction scheme useful to prepare the compound comprising Formula (I) in accordance with embodiments of the disclosure. FIG. 2 is a bar graph representing the efficacy of the compounds of Formula (I) in formalin model inhibited formalin-induced nociceptive response. Data was presented as mean±SEM, n=10/group. *p<0.05, **p<0.01, ***p<0.001 vs. Vehicle group by one way ANOVA followed by Dunnett's Multiple Comparison Test. MPE % is defined as 100%−((total motion counts in each group-total motion counts in naïve group)/(total motion counts in vehicle group-total motion counts in naïve gro