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US-12617790-B2 - Mitragynine analogs and uses thereof

US12617790B2US 12617790 B2US12617790 B2US 12617790B2US-12617790-B2

Abstract

Described herein are compounds of Formulae (I′)-(II′), compounds of Formulae (I)-(II) and pharmaceutically acceptable salts thereof. Compounds of the present invention are useful for modulating opioid receptor activity. The provided compounds may have both agonistic and antagonistic effect on one or more opioid receptors. Methods of using the compounds for treating or managing pain are also described.

Inventors

  • Gavril Pasternak
  • Susruta Majumdar
  • Rashad Karimov
  • Andras Varadi

Assignees

  • MEMORIAL SLOAN-KETTERING CANCER CENTER

Dates

Publication Date
20260505
Application Date
20210624

Claims (20)

  1. 1 . A compound of the formula: or a pharmaceutically acceptable salt or tautomer thereof, wherein: is a single bond or double bond; each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —SeR A , —C(═O)R C , —C(═O)OR A , —C(═O)N(R B ) 2 , —OC(═O)R C , —OC(═O)N(R B ) 2 , —NR B C(═O)R C , —NR B C(═O)OR A , —NR B C(═O)N(R B ) 2 , —S(═O)R C , —SO 2 R C , —NR B SO 2 R C , and —SO 2 N(R B ) 2 ; R 5 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R C , —C(═O)OR A , —C(═O)N(R B ) 2 , —S(═O)R C , —SO 2 R C , —SO 2 N(R B ) 2 , or a nitrogen protecting group; R 6 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , —SR A , —C(═O)R C , —C(═O)OR A , —C(═O)N(R B ) 2 , —OC(═O)R C , —OC(═O)N(R B ) 2 , —NR B C(═O)R C , —NR B C(═O)OR A , —NR B C(═O)N(R B ) 2 , —S(═O)R C , —SO 2 R C , —NR B SO 2 R C , or —SO 2 N(R B ) 2 ; or R 5 and R 6 are absent and is a double bond; provided that (i) R 2 is optionally substituted heteroaryl, and R 7 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A , —OC(═O)R C , —C(═O)R C , —C(═O)OR A , —OC(═O)N(R B ) 2 , —C(═O)N(R B ) 2 , —S(═O)R C , —SO 2 R C , or —SO 2 N(R B ) 2 ; or (ii) at least one of R 1 , R 2 , R 3 , and R 4 is independently optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted, monocyclic or bicyclic heterocyclyl, or optionally substituted heteroaryl, and R 7 is —OH; each of R 10 , R 11 , R 12 , and R 13 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , and —SR A ; or R 12 and R 13 are taken together to form an optionally substituted alkenyl moiety; R 14 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; each of R 15 and R 16 is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —CN, —N 3 , —OR A , —N(R B ) 2 , and —SR A ; each of R 17 and R 18 is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —OR A , —N(R B ) 2 , and —SR A ; or R 17 and R 18 are taken together to form each instance of R A is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to oxygen, a sulfur protecting group when attached to sulfur, or a selenium protecting group when attached to selenium; each instance of R B is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R B groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and each instance of R C is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.
  2. 2 . The compound of claim 1 , wherein the compound is of Formula (I): or a pharmaceutically acceptable salt or tautomer thereof.
  3. 3 . The compound of claim 1 , wherein the compound is of Formula (I-a): or a pharmaceutically acceptable salt or tautomer thereof.
  4. 4 . A compound of one of the following formulae: or a pharmaceutically acceptable salt or tautomer thereof.
  5. 5 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, and optionally a pharmaceutically acceptable carrier.
  6. 6 . The compound of claim 1 , wherein the compound is of Formula (I-b): or a pharmaceutically acceptable salt or tautomer thereof.
  7. 7 . The compound of claim 1 , wherein the compound is of Formula (I-c): or a pharmaceutically acceptable salt or tautomer thereof.
  8. 8 . The compound of claim 1 , wherein the compound is of Formula (I-d): or a pharmaceutically acceptable salt thereof.
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 1 is optionally substituted heteroaryl.
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 2 is optionally substituted five-membered heteroaryl.
  11. 11 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 3 is hydrogen.
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 4 is optionally substituted heteroaryl.
  13. 13 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein is a single bond, and R 5 is hydrogen or optionally substituted alkyl.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein is a single bond, and R 6 is hydrogen or optionally substituted alkyl.
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein is a single bond, and R 7 is hydrogen or —OR A .
  16. 16 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein is a single bond, and R 7 is optionally substituted, monocyclic or bicyclic heterocyclyl.
  17. 17 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein is a double bond, and R 5 and R 6 are absent.
  18. 18 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 10 is hydrogen.
  19. 19 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 11 is optionally substituted alkyl.
  20. 20 . The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein R 12 and R 13 are taken together to form an optionally substituted alkenyl moiety.

Description

RELATED APPLICATIONS This application is a division of U.S. patent application Ser. No. 15/570,308, filed Oct. 27, 2017, which is a national stage filing under 35 U.S.C. § 371 of International PCT Application, PCT/US2016/030305, filed on Apr. 29, 2016, which claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S. Ser. No. 62/155,248, filed Apr. 30, 2015, each of which is incorporated herein by reference. REFERENCE TO A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB The application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 13, 2021, is named S171570017US02-SEQ-WWZ and is 1,367 bytes in size. BACKGROUND OF THE INVENTION Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The opioid receptors are categorized into three subsets, μ (MOR), δ (DOR) and κ (KOR) receptors. Opioid receptors are found throughout the central and peripheral nervous system of many mammalian species, including humans. Modulation of the respective receptors can elicit numerous, albeit different, biological effects (Riviere et al., Drug Development, 2000, 203-238). A couple of biological effects identified for opioid modulators have led to many useful medicinal agents. Most significant are the many centrally acting MOR agonistic modulators, marketed as analgesic agents, to attenuate pain (e.g., morphine), as well as peripherally acting MOR agonists to regulate motility (e.g., loperamide). Mitragynine, an indole alkaloid, is the most abundant active alkaloid in the plant Mitragyna speciosa, commonly known as Kratom (Jansen, J. Ethnopharmacol., 1988, 23 (1), 115-119). The pharmacological activities of mitragynine and related alkaloids have been found to have agonistic effects on opioid receptors (Watanabe et al., Life Sci., 1997, 60, 933-942; Takayama et al., J. Med. Chem., 2002, 45, 1949-1956). Studies have been carried out on the opioid agonistic effects of the constituents of Mitragyna speciosa using in vitro assays. 7-Hydroxymitragynine and mitragynine pseudoindoxyl have been found to be more active as opioid agonists than mitragynine, and 7-Hydroxymitragynine and mitragynine pseudoindoxyl are more potent than morphine (Takayama et al., Chem. Pharm. Bull. 52 (8): 916-928 (2004); see also Kim et al., Chem Sci., 2012, 3(9): 2849-2852). Opioid modulators produce a diverse spectrum of centrally- and peripherally-mediated side effects, including respiratory depression, nausea, sedation, euphoria or dysphoria, decreased gastrointestinal motility, and itching (Inturrisi, Clin. J. Pain, 2002, 18(4 Suppl): S3-S13.). Long-term use of opioids can also be problematic due to the rapid development of profound tolerance to the analgesic effects coupled with slow development of untoward side effects. It is the inability to tolerate these undesirable side effects that eventually limits dose escalations and analgesic efficacy (Dumas et al., AAPS J., 2008, 10(4): 537-551). Therefore, there is a need to develop new therapeutic agents for pain treatment with improved pharmacological profiles. SUMMARY OF THE INVENTION Mitragynine and 7-hydroxymitragynine, and mitragynine pseudoindoxyl (FIG. 1) are indole alkaloids isolated from the plant Mitragyna speciose (Takayama et al., Chem. Pharm. Bull. 52 (8): 916-928 (2004); see also Kim et al., Chem Sci., 2012, 3(9): 2849-2852). Mitragynine pseudoindoxyl has been reported to be a microbial transformation product of mitragynine. (Zarembo et. al., Journal of Pharmaceutical Sciences 1974, 63, 1407-15). Oxidation of the indole nucleus of mitragynine produces 7-hydroxymitragynine, which can undergo a base/acid-induced rearrangement to the isomeric metabolite mitragynine pseudoindoxyl. 7-Hydroxymitragynine and mitragynine pseudoindoxyl are more active as opioid agonists than the parent indole mitragynine, and 7-hydroxymitragynine and mitragynine pseudoindoxyl are more potent than the well-known opioid morphine. These indole alkaloids present a class of useful therapeutics for pain treatment and modulating activities of opioid receptors with reduced side effects compared to the prior alkaloid analgesics, such as morphine and morphine derivatives. The present invention provides compounds of Formulae (I′)-(II′), pharmaceutical compositions thereof, and kits including the compounds and compositions described herein useful in pain management/treatment or modulating the activities of opioid receptors. The present invention provides compounds of Formulae (I)-(II), pharmaceutical compositions thereof, and kits including the compounds and compositions described herein useful in pain management/treatment or modulating the activities of opioid receptors. The present invention further provides methods of using the inventive compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isot