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CN-121990920-A - Rhododendron toxin VI derivative with analgesic activity, and preparation method and application thereof

CN121990920ACN 121990920 ACN121990920 ACN 121990920ACN-121990920-A

Abstract

The invention belongs to the technical field of medicines, and discloses application of an rhodotoxin VI derivative in analgesia. Specifically discloses derivatives shown as a formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the derivatives and the pharmaceutically acceptable salts thereof, and application of the compounds in preparing medicines for preventing or treating pain and acute toxicity research of the compounds.

Inventors

  • YU SHISHAN
  • SONG YANG
  • Shi Qinyan
  • Yong Jinyao
  • GUO PIYU
  • WANG HAIQIANG

Assignees

  • 中国医学科学院药物研究所

Dates

Publication Date
20260508
Application Date
20241101

Claims (11)

  1. 1. A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein n is 0 or 1;R 1 、R 2 、R 3 each independently selected from-H, -COR A . R A is selected from-CHR a R b 、-L 1 R c 、-CH＝CHR d 、-NHR e R a 、R b is each independently selected from-H, straight or branched saturated C 1-8 alkyl; L 1 is selected from none or C 1-5 alkylene; R c is selected from 3-8 membered saturated cycloalkyl and phenyl; R d is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 . R e is selected from the group consisting of phenyl, benzyl, phenethyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms, indole, benzothiazole, substituted with one or more substituents selected from the group consisting of-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 .
  2. 2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by formula IA: Wherein n is 0 or 1;R 1a is selected from-CHR a1 R b1 、-L 1a R c1 、-CH＝CHR d1 、-NHR e1 . R a1 、R b1 is each independently selected from-H, straight or branched saturated C 1-8 alkyl L 1a is selected from none or C 1-5 alkylene; R c1 is selected from 3-8 membered saturated cycloalkyl and phenyl; R d1 is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 . R e1 is selected from the group consisting of phenyl, benzyl, phenethyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms, indole, benzothiazole, substituted with one or more substituents selected from the group consisting of-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 .
  3. 3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the general formula IB: wherein R 2a is selected from-CHR a2 R b2 、-L 2a R c2 、-CH＝CHR d2 、-NHR e2 . R a2 、R b2 is each independently selected from-H, straight or branched saturated C 1-8 alkyl L 2a is selected from none or C 1-5 alkylene; r c2 is selected from 3-8 membered saturated cycloalkyl and phenyl; R d2 is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 . R e2 is selected from the group consisting of phenyl, benzyl, phenethyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms, indole, thiazole substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 .
  4. 4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the general formula IC: Wherein R 3a is selected from-CHR a3 R b3 、-L 3a R c3 、-CH＝CHR d3 、-NHR e3 . R a3 、R b3 is each independently selected from-H, straight or branched saturated C 1-8 alkyl L 3a is selected from none or C 1-5 alkylene; R c3 is selected from 3-8 membered saturated cycloalkyl and phenyl; R d3 is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 . R e3 is selected from the group consisting of phenyl, benzyl, phenethyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms, indole, benzothiazole, substituted with one or more substituents selected from the group consisting of-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO 2 、-CF 3 、-COCH 3 、-COPh、-OPh、-SO 2 CH 3 、-NH 2 、-N(CH 3 ) 2 .
  5. 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: 1) 6-O-pentanoyl rhododendron toxin VI 2) 6-O- (3-methylbutyryl) rhodotoxin VI 3) 6-O- (4-methylpentanoyl) rhodotoxin VI 4) 6-O- (3-cyclopropyl propionyl) azalea toxin VI 5) 6-O- (3-Cyclohexylpropionyl) Rhododendron toxin VI 6) 6-O- (3-phenylpropionyl) rhodotoxin VI 7) 6-O- ((E) -3- (4-fluorophenyl) acryloyl) rhodotoxin VI 8) 6-O- ((E) -3- (4- (trifluoromethyl) phenyl) acryloyl) rhodotoxin VI 9) 6-O- ((E) -3- (4-cyanophenyl) acryloyl) rhodotoxin VI 10 6-O- ((E) -3- (4-isopropylphenyl) acryloyl) rhodotoxin VI 11 6-O- ((E) -3- (4-methoxyphenyl) acryloyl) rhodotoxin VI 12 2-O- (N-benzylcarbamoyl) rhodotoxin VI 13 2-O- (N- (4-fluorophenyl) carbamoyl) rhodotoxin VI 14 2-O- (N- (4- (trifluoromethyl) phenyl) carbamoyl) rhodotoxin VI 15 2-O- (N- (4-bromophenyl) carbamoyl) rhodotoxin VI 16 2-O- (N- (3-fluorophenyl) carbamoyl) rhodotoxin VI 17 2-O- (N- (2-fluorophenyl) carbamoyl) rhodotoxin VI 18 2-O- (N- (4-fluorobenzyl) carbamoyl) rhodotoxin VI 19 2-O- (N- (4-methoxyphenyl) carbamoyl) rhodotoxin VI 20 2-O- (N- (4-benzoylphenyl) carbamoyl) rhodotoxin VI 21 2-O- (N- (1-methyl-1H-indol-6-yl) carbamoyl) rhodotoxin VI 22 3-O- (N- (4-fluorophenyl) carbamoyl) rhodotoxin VI 23 3-O- (N- (3-fluorophenyl) carbamoyl) rhodotoxin VI 24 3-O- (N- (2-fluorophenyl) carbamoyl) rhodotoxin VI 25 3-O- (N- (4-bromophenyl) carbamoyl) rhodotoxin VI 26 3-O- (N- (4- (trifluoromethyl) phenyl) carbamoyl) rhodotoxin VI 27 3-O- (N- (4-methoxyphenyl) carbamoyl) rhodotoxin VI 28 3-O- (N-benzylcarbamoyl) rhodotoxin VI 29 3-O- (N- (4-fluorobenzyl) carbamoyl) rhodotoxin VI 30 6-O- (N- (3-fluorophenyl) carbamoyl) rhodotoxin VI 31 6-O- (N- (2-fluorophenyl) carbamoyl) rhodotoxin VI 32 6-O- (N- (4- (trifluoromethyl) phenyl) carbamoyl) rhodotoxin VI 33 6-O- (N- (4-bromophenyl) carbamoyl) rhodotoxin VI 34 6-O- (N- (4-fluorobenzyl) carbamoyl) rhodotoxin VI 35 6-O- (N- (4-benzoylphenyl) carbamoyl) rhodotoxin VI 36 2-O- (N-phenylcarbamoylmethyl) rhodotoxin VI 37 2-O- (N- (4-fluorophenyl) carbamoylmethyl) rhodotoxin VI 38 2-O- (N- (4-fluorobenzyl) carbamoylmethyl) rhodotoxin VI 39 2-O- (N- (4-fluorophenylethyl) carbamoylmethyl) rhodotoxin VI 40 2-O- (N- (3-fluorophenyl) carbamoylmethyl) rhodotoxin VI 41 2-O- (N- (2-fluorophenyl) carbamoylmethyl) rhodotoxin VI 42 2-O- (N- (3- (trifluoromethyl) phenyl) carbamoylmethyl) rhodotoxin VI 43 2-O- (N- (4- (trifluoromethyl) phenyl) carbamoylmethyl) rhodotoxin VI 44 2-O- (N- (4-methylsulfonylphenyl) carbamoylmethyl) rhodotoxin VI 45 2-O- (N- (3-methylsulfonylphenyl) carbamoylmethyl) rhodotoxin VI 46 2-O- (N- (4-nitrophenyl) carbamoylmethyl) rhodotoxin VI 47 2-O- (N- (4-methoxyphenyl) carbamoylmethyl) rhodotoxin VI 48 2-O- (N- (4-methylphenyl) carbamoylmethyl) rhodotoxin VI 49 2-O- (N- (4-acetylphenyl) carbamoylmethyl) rhodotoxin VI 50 2-O- (N- (4- (dimethylamino) phenyl) carbamoylmethyl) rhodotoxin VI 51 2-O- (N- (thiazol-2-yl) carbamoylmethyl) rhodotoxin VI 52 2-O- (N- (3, 4-difluorophenyl) carbamoylmethyl) rhodotoxin VI 53 2-O- (N- (2, 4-difluorophenyl) carbamoylmethyl) rhodotoxin VI 54 2-O- (N- (3, 5-difluorophenyl) carbamoylmethyl) rhodotoxin VI 55 2-O- (N- (4-fluoro-3- (trifluoromethyl) phenyl) carbamoylmethyl) rhodotoxin VI 56 2-O- (N- (4-fluoro-3-nitrophenyl) carbamoylmethyl) rhodotoxin VI 57 2-O- (N- (3-chloro-4-fluorophenyl) carbamoylmethyl) rhodotoxin VI 58 2-O- (N- (4-benzoylphenyl) carbamoylmethyl) rhodotoxin VI 59 2-O- (N- (3-benzoylphenyl) carbamoylmethyl) rhodotoxin VI 60 2-O- (N- (4-phenoxyphenyl) carbamoylmethyl) rhodotoxin VI 61 2-O- (N- (2-methylbenzo [ d ] thiazol-5-yl) carbamoylmethyl) rhodotoxin VI.
  6. 6. A pharmaceutical composition comprising any one of the compounds of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  7. 7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is selected from the group consisting of tablets, capsules, pills, injections, sustained release formulations, controlled release formulations and various particulate delivery systems.
  8. 8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of pain.
  9. 9. The use according to claim 8, wherein the pain is associated with the central nervous system or the peripheral nervous system.
  10. 10. Use according to claim 9, characterized in that said pain is selected from acute pain or chronic pain.
  11. 11. The use according to claim 10, wherein the pain is somatic pain, visceral pain or neuropathic pain.

Description

Rhododendron toxin VI derivative with analgesic activity, and preparation method and application thereof Technical Field The invention belongs to the technical field of medicines, and particularly relates to an rhodotoxin VI derivative with analgesic activity, and a preparation method and application thereof. Background Analgesic drugs are widely used clinically, and have very large usage amounts both in prescription drugs and over-the-counter drugs. At present, the traditional analgesic drugs applied clinically are mainly non-steroidal drugs such as aspirin, acetaminophen, ibuprofen and the like, and opioid drugs such as morphine, pethidine, fentanyl and the like. However, nonsteroidal analgesic drugs have gastrointestinal side effects, while opioid analgesic drugs have higher addiction and cause adverse reactions to the blood system, cardiovascular system and the like, which seriously affect the safety of the administration of patients and greatly limit the clinical use of the drugs. Therefore, searching for safe and effective analgesic drugs becomes a primary task for analgesic treatment. The resveratrol diterpenoid compound has various pharmacological activities, is one of the hot research fields of natural products, and has remarkable analgesic activity. Studies have found that rhodotoxin VI exhibits a better analgesic effect in a variety of acute or chronic pain models, and does not act on opioid receptors, but rather modulates analgesia, perhaps by inhibiting the interaction of N-ethylmaleimide-sensitive fusion protein (NSF) with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid receptor (AMPAR) subunit GluA2, thereby blocking neuronal Ca 2+ ion entry, resulting in reduced neuronal excitability. Has the advantages of high analgesic effect, no dependence, no addiction, etc. However, the toxicity is large, and the safety range is narrow, so that the further patent medicine of the rhodotoxin VI is limited. Therefore, development of the rhodotoxin VI derivatives with low toxicity and high analgesic activity is a new direction for searching safe and effective analgesic drugs. Disclosure of Invention The invention aims to provide a low-toxicity and high-analgesic-activity rhodotoxin VI derivative or pharmaceutically acceptable salt, hydrate of the salt and a precursor compound thereof. The second technical problem to be solved by the invention is to provide a pharmaceutical composition which comprises compounds in various conditions as shown in the general formula I or pharmaceutically acceptable salts, hydrates of the salts, prodrugs and pharmaceutical carriers thereof. The third technical problem to be solved by the invention is to provide the application of the rhodotoxin VI derivative with low toxicity and high analgesic activity or the pharmaceutically acceptable salt, the hydrate of the salt and the precursor compound thereof in preparing the medicine for preventing or treating the pain. Further, the half lethal dose of the low toxicity rhodotoxin VI derivative is higher than the half lethal dose of rhodotoxin VI. In order to solve the problems, the invention adopts the following technical scheme: according to the invention, the compounds have the general formula: 1) A compound of formula I or a pharmaceutically acceptable salt thereof: Wherein n is 0 or 1;R 1、R2、R3 each independently selected from-H, -COR A. R A is selected from the group consisting of-CHR aRb、-L1Rc、-CH＝CHRd、-NHReRa、Rb each independently selected from the group consisting of-H, straight or branched saturated C 1-8 alkyl; L 1 is selected from none or C 1-5 alkylene; R c is selected from 3-8 membered saturated cycloalkyl and phenyl; R d is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selected from-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO2、-CF3、-COCH3、-COPh、-OPh、-SO2CH3、-NH2、-N(CH3)2. R e is selected from the group consisting of phenyl, benzyl, phenethyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms, indole, benzothiazole, substituted with one or more substituents selected from the group consisting of-H, linear or branched C 1-6 alkyl, linear or branched C 1-6 alkoxy 、-F、-Cl、-Br、-I、-CN、-NO2、-CF3、-COCH3、-COPh、-OPh、-SO2CH3、-NH2、-N(CH3)2. In case one, the compound or pharmaceutically acceptable salt thereof is represented by formula IA: Wherein n is 0 or 1;R 1a is selected from-CHR a1Rb1、-L1aRc1、-CH＝CHRd1、-NHRe1. R a1、Rb1 is each independently selected from-H, straight or branched saturated C 1-8 alkyl L 1a is selected from none or C 1-5 alkylene; R c1 is selected from 3-8 membered saturated cycloalkyl and phenyl; R d1 is selected from the group consisting of phenyl, five-or six-membered saturated or unsaturated heterocyclic ring containing 1-3 heteroatoms substituted with one or more substituents selec