TOP > 外国特許検索 > Indole alkaloid derivatives having opioid receptor agonistic effect, and therapeutic compositions and methods relating to same

Indole alkaloid derivatives having opioid receptor agonistic effect, and therapeutic compositions and methods relating to same

外国特許コード F130007258
整理番号 P07-074US
掲載日 2013年4月3日
出願国 アメリカ合衆国
出願番号 26657908
公報番号 20090221623
公報番号 8247428
出願日 平成20年11月7日(2008.11.7)
公報発行日 平成21年9月3日(2009.9.3)
公報発行日 平成24年8月21日(2012.8.21)
優先権データ
  • 60/986,370P (2007.11.8) US
発明の名称 (英語) Indole alkaloid derivatives having opioid receptor agonistic effect, and therapeutic compositions and methods relating to same
発明の概要(英語) Indole alkaloid derivatives having an opioid receptor agonistic effect, their synthesis, and therapeutic compositions containing these derivatives, and methods of treating conditions with these compounds and therapeutic compositions, are provided.
従来技術、競合技術の概要(英語) BACKGROUND
For the clinical treatment of acute and chronic severe pain, morphine is utilized as a standard analgesic.
Morphine-related derivatives have been synthesized by simplification and introduction of substituents into the morphine structure in order to develop powerful analgesics without side effects (Corbett et al., 2006).
Analgesics such as fentanyl and buprenorphine have been consequently derived from morphine.
Most of them have mu -receptor agonist profiles and are used clinically.
Despite their profound utility in the management of pain, they have undesirable side effects such as constipation, respiratory, depression, and development of dependence.
It is known that h-opioids such as morphine induce not only potent antinociception but also undesired rewarding effects following chronic administration in mice.
The activation of dopaminergic systems after systemic administration of a mu -opioid agonist induces development of hyperlocomotion and place preference in mice (Matthes et al., 1999).
Inhibitory effects on gastrointestinal transit (IGIT), such as constipation, tend to be a significant problem during administration of a chronic opioid such as morphine.
The dose required for morphine's analgesic effect is much higher than that required for its constipating effect; thus, when morphine is used for analgesia, constipation is not a negligible issue (Megens et al., 1998).
The traditional Thai herbal medicine Mitragyna speciosa has long been used in Thailand for its opium- (Burkill, 1935) and coca-like effects and as a replacement for opium (Grewal, 1932; Suwanlert, 1975).
The leaves of Mitragyna speciosa have been used, and are effective when taken orally.
This medicinal herb contains many indole alkaloids (Takayama 2004).
Mitragynine, illustrated below, a main constituent of this plant, is an indole alkaloid and structurally different from morphine, also illustrated below.
Studies have been done on the pharmacological activities of mitragynine (Watanabe et al., 1997; Matsumoto et al., 2005) and related alkaloids (Yamamoto et al., 1999; Takayama et al., 2002; Takayama, 2004; Matsumoto et al., 2006a), which have found that these compounds have agonistic effects on opioid receptors.
Recently, studies have been done on the opioid agonistic effects of the constituents of Mitragyna speciosa using in vitro assays.
Among them, 7-hydroxymitragynine, illustrated below, which has a hydroxyl group at the C7 position of mitragynine, produced the most potent effect, suggesting that the opioid effect of Mitragyna speciosa is mostly based on the activity of 7-hydroxymitragynine (Horie et al., 2005).
7-Hydroxymitragynine induced a potent antinociceptive effect in mice, and its effect was more potent than those of morphine when subcutaneously or orally administered and mediated by the mu -opioid receptor mechanism (Matsumoto et al., 2004; Matsumoto et al., 2006).
Furthermore, 7-hydroxymitragynine inhibited gastrointestinal transit less potently than morphine at each equi-antinociceptive dose (Matsumoto et al., 2006).
The structural similarities between morphine and 7-hydroxymitragynine have been investigated using molecular modeling techniques (Matsumoto et al., 2005), but could not superimpose all three functional groups, i.e., a nitrogen atom, a benzene residue, and an oxygen atom on the benzene ring in the structures of morphine and 7-hydroxymitragynine.
These functional groups have been considered to play an important role in producing analgesic activity (Dhawan et al., 1996).
A need has been recognized and solved by the present inventors for developing unique and potent analgesic compounds that can provide pain relief and/or prevention with reduced side effects.

特許請求の範囲(英語) [claim1]
1. A C10-halogenated indole alkaloid compound having opioid receptor agonistic effect, wherein the C10-halogenated indole alkaloid compound having the formulae:

wherein R is a halogen atom, R1 and R2 independently are hydrogen, hydroxy, alkoxy, aryloxy, alkyl, aryl, aralkyl, alkaryl, alkyl amide, amino, alkylamino, halogen, fluorinated alkyl, fluorinated alkoxy, nitro group, or cyano group, and R3 represents an ester group or carboxyl group.
[claim2]
2. The C10-halogenated indole alkaloid compound of claim 1 selected from the formulae:

wherein R is fluorine, chlorine, bromine, or iodine.
[claim3]
3. The C10-halogenated indole alkaloid compound of claim 1, wherein C10-halogenated indole alkaloid compound is C10-halogenated mitragynine, 7-hydroxy-C10-halogenatedmitragynine, C10-halogenated 2,3-dimethylindole, C10-halogenated tetrahydrocarbazole, C10-halogenated indoloquinolizidine corynantheol, C10-halogenated dihydrocorynantheol, or C10-halogenated yohimbine, singly or in any combination thereof.
[claim4]
4. The C10-halogenated indole alkaloid compound of claim 1, wherein said compound is 10-halomitragynine.
[claim5]
5. The C10-halogenated indole alkaloid compound of claim 1, wherein said compound is 7-hydroxy-10-halomitragynine.
[claim6]
6. An indole alkaloid compound having an opioid receptor agonistic effect having the formula:

where X is hydrogen or a halogen atom, R1 and R2 independently are hydrogen, hydroxy, alkoxy, aryloxy, alkyl, aryl, aralkyl, alkaryl, alkyl amide, amino, alkylamino, halogen, fluorinated alkyl, fluorinated alkoxy, nitro group, or cyano group, and R3 represents an ester group or carboxyl group.
[claim7]
7. The indole alkaloid compound of claim 6 having the formula:
[claim8]
8. A pharmaceutical composition comprising a therapeutic amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
[claim9]
9. A pharmaceutical composition comprising a therapeutic amount of a compound of claim 6 or a pharmaceutically acceptable salt thereof.
[claim10]
10. A method for eliciting a therapeutic effect in a patient in need thereof, comprising the step of administering to said patient an effective dose of an indole alkaloid compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutic effect is an analgesic effect.
[claim11]
11. The method of claim 10 wherein said step of administering is performed by a delivery route selected from the group consisting of oral, transdermal, inhalation, injection, infusion, and suppository.
[claim12]
12. The method of claim 10 wherein said patient is an animal.
[claim13]
13. The method of claim 10 wherein said patient is a mammal.
[claim14]
14. The method of claim 10 wherein said patient is a human.
[claim15]
15. The method of claim 10 wherein patient is a human and the therapeutic effect is pain treatment, where an effective total daily dosage of said compound ranges from about 0.1 mg to about 1,000 mg active compound/kg body weight of said patient.
[claim16]
16. A method for making a C10-halogenated indole alkaloid derivative compound, comprising the steps of: reacting a Corynanthe-type indole alkaloid with hypervalent iodine in the presence of ethylene glycol effective to provide a 2,3-ethylene glycol bridged indoline adduct, effective to mask a 2,3-pi bond of an indole nucleus of said adduct;
introducing a halogen atom at a C10 position of the adduct via electrophilic aromatic substitution, providing a C10-halogenated adduct derivative;
converting said C10-halogenated adduct derivative into a corresponding C10-halogenated mitragynine derivative by reduction reaction effective to eliminate the ethylene glycol bridge;
optionally, converting said C10-halogenated mitragynine derivative into a corresponding 7-hydroxy-10-halomitragynine derivative by oxidation reaction, and optionally isolating or otherwise concentrating said derivative,
wherein the C10-halogenated indole alkaloid compound having the formulae:

wherein R is a halogen atom, R1 and R2 independently are hydrogen, hydroxy, alkoxy, aryloxy, alkyl, aryl, aralkyl, alkaryl, alkyl amide, amino, alkylamino, halogen, fluorinated alkyl, fluorinated alkoxy, nitro group, or cyano group, and R3 represents an ester group or carboxyl group.
[claim17]
17. A method for making an indole alkaloid compound comprising reacting 7-hydroxymitragynine and/or 7-hydroxy-10-halomitragynine with a reducing agent to yield a compound according to claim 6, and optionally isolating or otherwise concentrating said compound.
[claim18]
18. The method of claim 17, wherein said reducing agent comprises NaBH4 in MeOH.
[claim19]
19. A method for eliciting a therapeutic effect in a patient in need thereof, comprising the step of administering to said patient an effective dose of an indole alkaloid compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein said therapeutic effect is an analgesic effect.
  • 発明者/出願人(英語)
  • TAKAYAMA HIROMITSU
  • KITAJIMA MARIKO
  • MATSUMOTO KENJIRO
  • HORIE SYUNJI
  • CHIBA UNIVERSITY
  • JOSAI UNIVERSITY
国際特許分類(IPC)
米国特許分類/主・副
  • 514/285
  • 546/70

PAGE TOP

close
close
close
close
close
close