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

Foreign code F130007258
File No. P07-074US
Posted date Apr 3, 2013
Country United States of America
Application number 26657908
Gazette No. 20090221623
Gazette No. 8247428
Date of filing Nov 7, 2008
Gazette Date Sep 3, 2009
Gazette Date Aug 21, 2012
Priority data
  • 2007US-60986370 (Nov 8, 2007) US
Title Indole alkaloid derivatives having opioid receptor agonistic effect, and therapeutic compositions and methods relating to same
Abstract (US8247428)
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.
Scope of claims [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.
  • Inventor, and Inventor/Applicant
  • TAKAYAMA HIROMITSU
  • KITAJIMA MARIKO
  • MATSUMOTO KENJIRO
  • HORIE SYUNJI
  • CHIBA UNIVERSITY
  • JOSAI UNIVERSITY
IPC(International Patent Classification)
U.S. Cl./(Sub)
  • C07D459/00
  • C07D471/04
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