WO2014180321A1 - Phloroglucinol derivatives and application thereof in treatment of neurodegenerative disorder - Google Patents

Phloroglucinol derivatives and application thereof in treatment of neurodegenerative disorder Download PDF

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WO2014180321A1
WO2014180321A1 PCT/CN2014/077029 CN2014077029W WO2014180321A1 WO 2014180321 A1 WO2014180321 A1 WO 2014180321A1 CN 2014077029 W CN2014077029 W CN 2014077029W WO 2014180321 A1 WO2014180321 A1 WO 2014180321A1
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group
branched
linear
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substituent
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PCT/CN2014/077029
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庾石山
张丹
王亚丹
鲍秀琦
屈晶
徐嵩
泰文娇
武良玉
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中国医学科学院药物研究所
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Priority to CN201480026162.0A priority Critical patent/CN105189446B/en
Publication of WO2014180321A1 publication Critical patent/WO2014180321A1/en

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Definitions

  • the present invention relates to a class of phloroglucinol derivatives and pharmacologically acceptable salts thereof, to pharmaceutical compositions containing the same, and to the use of such compounds in the manufacture of a medicament for a neurodegenerative disease. Background technique
  • Neurodegenerative diseases are a type of disease that is seriously endangering human health in the world today, and morbidity and mortality are increasing year by year. These diseases are caused by damage to neurons in the brain and spinal cord, which deteriorate over time, leading to dysfunctions such as exercise or memory. As the world's population ages, there is an urgent need for effective treatments.
  • the mediated lesions are mainly caused by the activation of glial cells and the release of neurotoxic factors from peripherally invaded lymphocytes.
  • Microglia and astrocytes are innate immune cells in the brain parenchyma, which are normally in a resting state and have the function of maintaining the normal homeostasis of the central nervous system. Under pathological conditions such as brain infection or injury, these The cells are activated, initiate immune response and tissue repair processes, remove foreign bodies and lesions in the brain, and return to rest as soon as infection or damage is restored.
  • the technical problem to be solved by the present invention is to provide a compound of the formula Io, including racemates and optical isomers, and pharmacologically acceptable salts, hydrates or prodrugs thereof.
  • a further technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising at least one compound of the formula ⁇ , including racemates and optical isomers, pharmaceutically acceptable salts and salts thereof Hydrates or prodrugs and pharmaceutically acceptable carriers and/or excipients.
  • a further technical problem to be solved by the present invention is to provide a compound of the formula , ⁇ , including a racemate and an optical isomer, a pharmacologically acceptable salt thereof, a hydrate of a salt or a prodrug in the preparation of a nerve Application in drugs for degenerative diseases.
  • the technical solution adopted by the present invention is:
  • the compounds are of the formula I. Indicates:
  • the substituent may be selected from -0H, -F, -Cl, -Br, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or -COOH, substituted or unsubstituted Amine group, wherein
  • the substituent on the furfuryl group may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
  • the substituent on the phenyl group and the benzenesulfonyl group may be selected from -0H, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -0N0 2 or a linear or branched d. 6 anthracene group,
  • Substituted heterocyclyl selected from the -0H, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched, d. 6 an oxy group, a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -0H, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -0N0 2 , -NH 2 or linear or branched d. 6 ⁇ oxygen Base
  • R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
  • the substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
  • the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime;
  • R 2 and R 4 each independently represent -H, -OH, linear or branched d. 6 methoxy, benzyloxy, -OCF 3 , -ON0 2 , -F, -Cl, -Br, -CN, -N0 2 , a substituted or unsubstituted linear or branched dn) fluorenyl group, -CF 3 , a substituted or unsubstituted carbonyl group, wherein
  • the substituent on the fluorenyl group may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 , -SH,
  • the substituent on the carbonyl group may be selected from -OH, straight or branched. 1 () fluorenyl, substituted or unsubstituted phenyl, ethylenic or acetylenic CLH) unsaturated hydrocarbon group or substituted or unsubstituted Amine group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched. 10 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 methoxy group, the substituent on the amine group may be selected from a substituted or unsubstituted linear or branched dH) fluorenyl group, C 3 . 6 a cycloalkyl or a substituent and a N atom together form a five-, six- or seven-membered saturated heterocyclic ring having from 1 to 3 hetero atoms, wherein
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 ;
  • R 3 and R 5 each independently represent -H, -OH, a straight or branched d. 6 fluorenyl group, -ON0 2 , a substituted or unsubstituted linear or branched decyloxy group, a phenyl ring substituted or An unsubstituted benzyloxy group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -NH 2 , -COOH;
  • n 1-5
  • X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
  • Substituents selected from a straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with together with the N atom form a 5-, 1-3 heteroatoms unsaturated six-membered or seven-membered containing a heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
  • the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, C 3. 6 a fluorenyl, linear or branched decyloxy group, a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
  • the compounds are represented by the general formula I:
  • the substituent may be selected from -OH, -F, -Cl, -Br, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or -COOH, substituted or unsubstituted Amine group, wherein
  • the substituent on the furfuryl group may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
  • the substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 anthracene group,
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime;
  • R al selected from substituted or unsubstituted, straight-chain or branched C 2.
  • 1Q alkyl with, wherein The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
  • the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime;
  • R 3 and R 5 each independently represent -H, -OH, linear or branched d. 6 fluorenyl, -ON0 2 , substituted or unsubstituted straight or branched. 6 oxirane, phenyl ring a substituted or unsubstituted benzyloxy group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -NH 2 , -COOH;
  • n 1-5
  • X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
  • Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 cyclic alkyl with straight or branched chain group embankment, a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
  • the compound is represented by the formula IA:
  • R a represents a substituted or unsubstituted linear or branched dn) fluorenyl group, a benzyl group, -N0 2 , -COR al , wherein the substituent may be selected from the group consisting of -OH, -F, -Cl, -Br, a linear or branched d. 6 methoxy group, -SH, a substituted or unsubstituted furazyl group or -COOH, wherein
  • the substituent may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
  • the substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a straight chain or a branch Cw thiol of the chain, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d d. 6 oxime,
  • R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
  • the substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
  • the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched ⁇ . 6 oxime.
  • R a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Butyl, isopentyl, hexyl and the like are not limited to the above groups.
  • preferred groups include, but are not limited to, the group represented by the formula IAa: Where n can represent 1-5,
  • R a2 may be selected from a linear or branched du) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
  • the substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 oxime.
  • preferred compounds of the formula IAa include:
  • R a2 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, substituted or unsubstituted phenyl, benzene ring a substituted or unsubstituted benzenesulfonyl group, the substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, C 1-6 fluorenyl, -CHF 2 , -CF 3 , -CN , -N0 2 , -OCF 3 , -ON0 2 , linear or branched d. 6 methoxy, -NH 2 .
  • the compound is represented by the formula m:
  • R 3 and R 5 each independently represent -H, -OH, a linear or branched d. 6 fluorenyl group, -ON0 2 , -ORc or -SR C , wherein
  • Rc represents a substituted or unsubstituted linear or branched d.n) fluorenyl group, a benzyl group, wherein
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -NH 2 , -COOH;
  • Rbi 3 ⁇ 42 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cyclic alkyl with or -NR bl R b2 constitute containing 1-3 heteroatoms five-, six- or seven-membered of The saturated heterocyclic ring may have a substituent on the heterocyclic ring, wherein the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, C 3. 6 a fluorenyl, linear or branched decyloxy group, a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
  • preferred compounds of the formula m include:
  • R 3 and R 5 are each independently selected from H, -OH, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, linear or Branched d. 6 methoxy, benzyloxy,
  • R bl , 2 are each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH , d.
  • Or -NR bl R b2 constitute a saturated heterocycle containing 1-3 heteroatoms five-, six- or seven-membered, selected from Following heterocycle
  • R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d. 6 methoxy, -H 2 o
  • the compound is represented by the general formula IC:
  • Rd 3 ⁇ 4 2 and R d3 independently represent -H, a linear or branched C 2 . 6 fluorenyl group, a benzyl group or a —CF 3 , and n may be 2-5.
  • Rel, Re2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cycloalkyl or alkyl with -NRelRe2 configuration five-, six- or seven-membered having 1-3 heteroatoms saturated hetero a ring (except for the morpholine ring), which may have a substituent on the hetero ring, wherein
  • Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d.
  • 6 embankment group C 3.
  • 6 embankment cycloalkyl group a linear or branched d.
  • 6 embankment An oxy group a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
  • preferred compounds represented by the general formula IC include:
  • Rdi 2 and R d3 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 , and n is not 3-5.
  • Re ⁇ ReZ is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl, a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, d.
  • Or -NR ⁇ R ⁇ constitutes a five-, six- or seven-membered saturated heterocyclic ring containing 1-3 heteroatoms, which may be selected from
  • R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d.
  • preferred compounds of the formula IC include, but are not limited to, the compounds of the formula ICa: Wherein, Rel R e2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cycloalkyl or alkyl with -NRelRe2 configuration five-, six- or seven-membered containing 1-3 heteroatoms a saturated heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
  • Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d.
  • 6 embankment group C 3.
  • 6 embankment cycloalkyl group a linear or branched d.
  • 6 embankment An oxy group a substituted or unsubstituted phenyl group, wherein
  • the substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
  • preferred compounds of the general formula ICa include:
  • Re ⁇ Rez is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl, a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, d.
  • Or -NR bl R b2 constitutes a five-, six- or seven-membered saturated heterocyclic ring containing 1-3 heteroatoms, which may be selected from
  • R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d. 6 methoxy, -H 2 o
  • the compound is ID:
  • R fl , Re and 3 ⁇ 43 each independently represent -H, a linear or branched d. 6 fluorenyl group, a benzyl group or a -CF 3 ;
  • R 2 and R 4 each independently represent -H, -OH, a straight chain or a branch.
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 ,
  • R g may represent H, -OH, a linear or branched dn) fluorenyl group, a substituted or unsubstituted phenyl group, an ethylenic or acetylenic bond-containing CLH) unsaturated hydrocarbon group or -NR gl R g2 , wherein
  • the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched du) fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched ⁇ . 6 methoxy group,
  • R g i R g2 each independently represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3. 6 cyclic alkyl with or -NR gl R g2 configuration five-, six- or seven-membered containing 1 - a saturated heterocyclic ring of 3 hetero atoms, wherein
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 ; n may be 1-5,
  • Re may represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3. 6 cycloalkyl or alkyl with R 7, R 8 and C atoms and N atom constituting four - saturated heterocycle containing 1-3 heteroatoms seven-membered, wherein the substituents are selected from -OH, a straight or branched chain group d 6 embankment. , -F, -Cl, -Br, -COOH, - H 2 ;
  • R 7 and R 8 independently represent H, a substituted or unsubstituted linear or branched dn) fluorenyl group or a recombination of a C atom and an N atom to form a four-seven-membered saturation of 1-3 heteroatoms. a heterocyclic ring, the condition being that R 7 and not simultaneously H, wherein
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , ⁇ a substituted or unsubstituted phenyl and a aryl group, wherein
  • the substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 oxime,
  • R h represents a linear or branched CLH) fluorenyl group.
  • a preferred compound of the pass ID is a compound of the formula IDa: Wherein R fl , Re, 3 ⁇ 43 independently represent -H, linear or branched d. 6 fluorenyl, benzyl or -CF 3 Re may represent H, substituted or unsubstituted straight or branched du) ⁇ a C 3 .6 ring fluorenyl group, wherein the substituent may be selected from -OH, a linear or branched d.
  • R 7 and R 8 each independently represent H, a substituted or unsubstituted linear or branched dn) fluorenyl group, provided that H and 18 cannot simultaneously be H, wherein
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 ,
  • the substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched C 1-6 alkoxy group,
  • Rh represents a linear or branched CLH) fluorenyl group.
  • preferred compounds of the general formula IDa include: R fl , Rf 2 , Re are selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
  • Re is selected from the group consisting of H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentane a group, an isopentyl group, a hexyl group, the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -COOH, -NH 2 ,
  • R 7 and R 8 are each independently selected from H (both cannot be H at the same time), substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl , isopentyl, hexyl, the substituent may be selected from -OH, -COOH, -NH 2 , -SH, -SCH 3 , -CO H 2 , fluorenyl, substituted or unsubstituted phenyl and aryl, wherein The substituent of the phenyl group may be -OH, -F, -Cl, -Br, -COOH, methyl, ethyl, isopropyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched d.
  • the aryl group may be selected from furyl, imidazolyl, pyrazolyl, pyridyl, thienyl, pyrrolyl, thiazolyl, pyrimidinyl, anthracene ⁇ .
  • IDa a preferred compound represented by IDal:
  • R 7 represents a substituted or unsubstituted straight or branched du) fluorenyl group
  • the substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , ⁇ a substituted or unsubstituted phenyl and a aryl group, wherein
  • the substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched C 1-6 alkoxy group,
  • Rh represents a linear or branched CLK) sulfhydryl group.
  • preferred compounds of the general formula IDal include:
  • R fl , Rf 2 , Re are selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
  • R 7 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, and the substituent may be selected from - OH, -COOH, -NH 2 , -SH, -SCH 3 , -CO H 2 , fluorenyl, substituted or unsubstituted phenyl and aryl, wherein the substituent of the phenyl group may be -OH, -F, -Cl, -Br, -COOH, methyl, ethyl, isopropyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or straight or branched
  • the 6 methoxy group, the aryl group may be selected from the group consisting of furyl
  • R fl , Re, 3 ⁇ 43 respectively represent -H, a straight or branched di) fluorenyl group, a benzyl group or a -CF N atom and an ortho C atom together to form a 1-4 of a four-seven dollar A saturated heterocyclic ring of a hetero atom.
  • preferred compounds of the formula IDb include:
  • Rn Rf2 Re is selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
  • the decyloxy group means a linear or branched C1-6 decyloxy group, and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group and an isobutyl group.
  • Preferred compounds according to the invention include, but are not limited to, the following compounds:
  • the present invention also relates to a pharmaceutically effective amount of a compound as described in each of the formula I and pharmaceutically acceptable A pharmaceutical composition of the carrier.
  • the compound of the present invention may exist in the form of an isomer, and generally the “compound of the present invention” includes an isomer of the compound.
  • the compound of the present invention further includes a pharmacologically acceptable salt thereof, a hydrate of a salt or a prodrug.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as an active ingredient a compound of the invention and a conventional pharmaceutical excipient or adjuvant.
  • the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention.
  • the compound of the present invention is generally contained in a unit dosage form in an amount of from 0.1 to 100 mg, and the preferred unit dosage form contains from 4 to 50 mg.
  • compositions of the compounds of the invention can be prepared according to methods well known in the art.
  • the compounds of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage for use as a human or veterinary drug. form.
  • the compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.
  • the administration route of the compound of the present invention or a pharmaceutical composition containing the same can be administered by injection. Injection including intravenous injection Injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.
  • the dosage form can be a liquid dosage form or a solid dosage form.
  • the liquid dosage form may be a true solution type, a colloid type, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form.
  • Other dosage forms are, for example, tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders and the like.
  • the compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • a carrier for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid.
  • wetting agent and binder such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic, gelatin paste, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.
  • disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxygen Ethylene sorbitan fatty acid ester, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc.
  • disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.
  • absorption Promoters such as quaternary ammonium salts, sodium decyl sulfate, etc.
  • lubricants such as talc, silica
  • a carrier for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; Acacia gum, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrants, such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methyl cellulose, Ethyl cellulose and the like.
  • a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.
  • Acacia gum, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.
  • disintegrants such as agar powder, dried star
  • the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule.
  • the active ingredient of the compound of the present invention can also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or can be incorporated into a hard capsule or used for injection.
  • the compound of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs.
  • an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs.
  • the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fat, fatty acid ester, etc. .
  • an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the art.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the dosage of the pharmaceutical composition of the compound of the present invention depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, For therapeutic purposes, the therapeutic dose of the present invention can vary widely. In general, the dosage of the pharmaceutical ingredient of the present invention is well known to those skilled in the art.
  • the prophylactic or therapeutic purpose of the present invention can be accomplished by appropriately adjusting the amount of the actual drug contained in the final formulation of the compound composition of the present invention to achieve a therapeutically effective amount thereof.
  • Suitable daily dosage range for the compound of the present invention is used in an amount of 0.001 to 100 mg/kg body weight, preferably 0.1 to 60 mg/kg body weight, more preferably 1 to 30 mg/kg body weight, and most preferably 2 to 15 mg/ Kg weight.
  • the compound of the present invention administered by an adult patient is 10 to 500 mg, preferably 20 to 100 mg per day, and can be taken once or 2 to 3 times; the dosage for children is 5 to 30 mg per kg of body weight, preferably 10 to 20 mg/kg. body weight.
  • the above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the dosage regimen of the therapeutic means.
  • the compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the invention further relates to the use of a compound of the invention in the manufacture of a medicament for the prevention and treatment of neurodegenerative diseases.
  • the diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellum Atrophy, primary lateral sclerosis, spinal muscular atrophy.
  • Step 2 Preparation of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methylbutanone 2.1 g (10 mmol) 1-(2) obtained according to step 1. , 4,6-trihydroxyphenyl)-3-methyl-1-butanone was dissolved in 50 mL of dichloromethane, cooled at 0 ° C, and added to 3.65 mL (21 mmol) of dipropylethylamine. After stirring for 15 minutes, 1.6 mL (25 mmol) of chloromethyl methyl ether was dissolved in 20 mL of dichloromethane, and slowly added dropwise to the reaction solution. After completion, the reaction was carried out at 0 ° C for 15 minutes, and then at room temperature.
  • reaction solution was poured into 100 mL of water, extracted with 3 ⁇ 50 mL of chloroform, and the organic layer was combined, washed with 3 ⁇ 15 mL of saturated sodium chloride and dried over anhydrous sodium sulfate. Evaporate the solvent and perform silica gel column chromatography (petrole ether: ethyl acetate 15:1) 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone 1.40 g was obtained in a yield of 47%.
  • Step 3 Preparation of 1-[2-methoxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone 300 mg (1 mmol) obtained in Step 2 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone is dissolved in 20 mL of acetone, 276 mg (2 mmol) anhydrous Potassium carbonate was heated under reflux for 20 minutes, and 100 ⁇ M (2 mmol) of dimethyl sulfate was added to the reaction mixture, followed by reflux for 5 hours. The reaction mixture was evaporated to dryness.
  • the 3-chloromethyl-4-phenylfurazan 210 mg (1 mmol) obtained in the step 2 was dissolved in 20 mL of acetonitrile, and 210 mg (1 mmol) of 1-(2, 4,6-trihydroxyphenyl)-3-methyl-1-butanone, 207 mg (; 1.5 mmol;) anhydrous K 2 CO 3 and a small amount of KI, heated under reflux for 10 hours, and the reaction mixture was evaporated to dryness under pressure. 20 mL of water was added, and extracted with 3 ⁇ 25 mL of ethyl acetate. The organic layer was combined, washed with 3> ⁇ 10 mL of saturated sodium chloride and dried over anhydrous sodium sulfate.
  • Step 1 Preparation of benzyl p-toluenesulfonate
  • Step 3 Preparation of ( ⁇ )-1-[2-(epoxyethyl-2-yl)methoxy- 4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone
  • Step 4 ( ⁇ )-1-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1- Preparation of butanone hydrochloride
  • Step l (S)-l-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy-4,6--3-methyl-1-
  • butanone 3.00 g (7.5 mmol) of 1-(2-hydroxy-4,6-diphenylmethoxyphenyl) -3 -methyl-i-butanone obtained in Step 2 of Example 3 was dissolved in 20 mL of N , N -dimethylformamide, nitrogen gas, stirring for 5 minutes;
  • Step 3 (S)-l-[2-(2-Hydroxy-3-p-toluenesulfonyloxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1- Preparation of butanone
  • step 3 S iPO hydroxy-3-p-toluenesulfonyloxypropoxy) -4,6-diphenylmethoxyphenyl]-3-methyl-1- Butanone was placed in a thick-walled pressure-resistant tube, 3 mL (35 mmol) of isopropylamine was added, stirred well, and reacted at 70 ° C for 2 hours. After cooling, the reaction solution was evaporated to dryness under reduced pressure. Oil 100 mg.
  • Step 1 (R)-l-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy-4,6-diphenylmethoxyphenyl] Preparation of -3-methyl-1-butanone
  • Step 2 Preparation of ( ⁇ )-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone will be obtained according to step 1.
  • 1.04 g (5 mm0 l) of 1-(2-hydroxy-4-methoxyphenyl)-3-methyl-1-butanone was dissolved in 60 mL of N,N-dimethylformamide, and nitrogen was passed.
  • Step 3 Preparation of ( ⁇ )-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
  • Step 1 Preparation of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone as in Example 9 1.04 g (5 mmol) of 1-(2-hydroxy-4-methoxyphenyl;)-3-methyl-1-butanone obtained by the method of Step 1 was dissolved in 1.2 mL of N,N-dimethyl To a mixed solution of formamide and 1.8 mL of water, add 0.93 g (10 mmol) of ( )-2-chloromethyloxirane to the reaction solution and add 5 mL of an aqueous solution containing 0.40 g (10 mmol) of sodium hydroxide.
  • Step 1 Preparation of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone as in Example 10 Step 1 method using 1.04 g (5 mmol) of 1-P-hydroxy-4-methoxyphenyl)-3-methyl-1-butanone, 0.93 g (10 mmol) (S)-2-chloromethyl The reaction was carried out by the reaction of silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give (S)-l-[2-(epoxyethyl-2-) ;; methoxy-4-methoxyphenyl]-3-methyl-1-butanone 0.13 g, yield 9%.
  • Step 2 Preparation of ( ⁇ )-1-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
  • Step 2 in Example 9 According to the method of Step 2 in Example 9, 1.00 g (4.2 mmol) of 1-(hydroxy-4,6-dimethoxyphenyl)-3-methyl-1-butanone obtained in Step 1, 1.94 g (21 mmol) ( ⁇ ) 2-chloromethyloxime oxime and 0.10 g (4.2 mmol) of sodium hydride, obtained by silica gel column chromatography ( petroleum ether: ethyl acetate 30:1) —(Ethoxyethylene-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methylbutanone 0.9 g, yield 69%.
  • Step 1 Preparation of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
  • Step 2 in Example 10 150 mg (0.51 mmol) of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethyl obtained in Step 1 was used. Reaction of oxyphenyl]-3-methyl-1-butanone with 3 mL (35 mmol) of isopropylamine afforded solid (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy) -4,6-Dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 130 mg, yield 65%.
  • Step 1 Preparation of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
  • Step 2 Preparation of 4-(methylcyclohexylamine; )-1-(2,4,6-trihydroxyphenyl; ) 1-butanone hydrochloride. Dissolve 1.05 g of phloroglucinol (8.33 mmol). To 10 mL of nitrobenzene, 1.5 g of the oil obtained in Step 1 was added, and the dried HC1 gas was passed, and stirred at room temperature for 9 h. After the reaction solution was allowed to stand overnight, 15 mL of water was added, the aqueous layer was separated, and the organic layer was extracted with 2 ⁇ 15 mL of water, and the aqueous layer was combined and heated to reflux for 1 h.
  • Step 2 Preparation of 4-[4-(3-chlorophenyl)piperazin-1-yl]small (2,4,6-trihydroxyphenyl) 1-butanone hydrochloride 1.05 g of m-benzoic acid The phenol (8.33 mmol) was dissolved in 10 mL of nitrobenzene, and 3.00 g of the oil obtained in the step 1 was added, and the mixture was applied to dry HCl gas, and stirred at room temperature for 9 h. After the reaction solution was allowed to stand overnight, 15 mL of water was added, the aqueous layer was separated, and the organic layer was extracted with 2 ⁇ 15 mL of water, and the aqueous layer was combined and heated to reflux for 1 h.
  • Step 1 Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)propionic acid methyl ester
  • Step 1 Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-methyl-3-phenylpropionate
  • Step 1 Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropionic acid methyl ester
  • Step 1 Preparation of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1 ⁇ -imidazol-5-yl)propanoic acid methyl ester according to the method of Step 1 in Example 24.
  • Step 2 Preparation of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1 ⁇ -imidazol-5-yl)propionic acid according to the method of Step 2 in Example 24 After reacting 97 mg (0.28 mmol) of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1 ⁇ -imidazole-5-yl;) methyl propionate obtained in Step 1, Purified by preparative HPLC (YMC, 10% acetonitrile) to give (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1 ⁇ -imidazol-5-yl)propanoic acid 70 mg. The rate is 74%.
  • BV2 cells mouse microglia cell line
  • Lipopolysaccharide prepared in sterile PBS, at a final concentration of 300 ng / mL
  • BV2 cells were cultured in DMEM-F12 medium containing 10% newborn calf serum and grown at 37 ° C, 5 % C0 2 /95 % air, 100% relative humidity.
  • BV2 cells in logarithmic growth phase were inoculated into 96-well plates at 2 ⁇ 10 4 cells/well after digestion, and 24 hours later, different concentrations of test compound and positive control drug curcumin (10 ⁇ 5) were added. , 10 ⁇ 6 , 10 ⁇ 7 ⁇ ) , After 1 hour, LPS was added to a final concentration of 300 ng / mL, and the culture was continued for 24 hours, and the culture supernatant was collected.
  • IC 5 o indicates the concentration of the compound when the NO inhibition rate reaches 50%.
  • Lipopolysaccharide prepared in sterile PBS, at a final concentration of 100 ng / mL
  • Donepezil formulated in DMSO, at a final concentration of 5 x lO- 6 mol/L
  • Test compounds (Examples 1, 2, 26 and 28), formulated with DMSO, final concentration of 10 ⁇ 5, 10- 6, 10 "7 mol / L
  • the hippocampal neuron/glial mixed culture system showed an inflammatory reaction under ⁇ 25 . 35 ⁇ , and the release of IL- ⁇ , TNF- ⁇ and LDH in the medium increased significantly, and the latter showed neuronal damage.
  • the compounds represented by Examples 1, 2, 26 and 28 can significantly reduce the levels of these three factors, indicating that they have the effect of inhibiting neuroinflammation and protecting neurons, and at a concentration of 10 ⁇ 5 mol / L, the intensity of action and The positive control drug curcumin is equivalent.
  • Table 3 compounds inhibit the inhibition of neuroinflammation induced by A ⁇ 25-35
  • Cytarabine (Ara-C) is prepared by deionized water, filtered and sterilized to a final concentration of 4 m mol/L ⁇ 25 . 35 , prepared in sterile PBS, aged at 37 ° C for 7 days, and the final concentration is 2.5.
  • x lO— 5 mol/L donepezil prepared in DMSO, final concentration 5x lO- 6 mol/L
  • Test compounds (Examples 1, 2, 26 and 28), formulated with DMSO, final concentration of 10 ⁇ 5, 10- 6, 10 "7 mol / L
  • Test drug Compounds represented by Examples 1 and 28
  • L-DOPA Medoba (Dobasi), Shanghai Roche Pharmaceutical Co., Ltd.
  • MPTP Sigma product, batch number: 128kl549. .
  • DA and IP were purchased from Sigma.
  • mice were trained in advance by the Rotarod test for 3 days, and the mice with uncoordinated movements were excluded and randomly divided into groups of 15 each. Mice were intraperitoneally injected with MPTP (dissolved in physiological saline) 30 mg/kg once daily for 5 consecutive days.
  • MPTP dissolved in physiological saline
  • Examples 1 and 28 different dose groups and positive drug L-DOPA group. Examples 1 and 28 were administered with different doses and positive drugs 30 min after intraperitoneal injection of MPTP 30 mg/kg once daily for 5 consecutive days. MPTP continued to be administered after the injection was stopped, once a day for 7 consecutive days.
  • the normal control group was orally and intraperitoneally injected with the same dose of sterile double distilled water and normal saline, and the MPTP model group was orally administered the same dose of sterile double distilled water.
  • the stick stick instrument (developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences) is a horizontal rod with a diameter of 3cm and a length of about 50cm. It is divided into 5 sections by a partition to ensure that the animals are not affected by each other.
  • the speed of the stick is set to a constant speed of 14 rpm. Place the mouse on the rod, turn on the switch, start timing, record the time from the start of the stick to the time the mouse fell off the pole, and record it as the incubation period (ie the time of the first drop), in order to express its movement coordination ability. Each mouse was tested 3 times, with an interval of 1 h, and the average was taken. Mice were tested on the 5th, 9th and 16th day of the experiment.
  • the climbing rod method uses a smooth wooden rod with a diameter of 13mm and a height of 50cm, and a wooden ball with a diameter of 3cm at the top (developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences), placed vertically, and placed the mouse head down on the rod. On the top ball, let it climb down naturally along the pole to observe the animal's behavior during the climb. The behavior of the mice during the climbing process was scored according to the standard.
  • the scoring criteria were as follows: 5 points: Combined use of limbs, step by step Tune down to crawl; 4 points: Climb down step by step but have hindlimb glide behavior; 3 points: Climb over half the distance and then slide down, but can hold the bar; 2 points: Skid behavior occurs when you have not climbed halfway 1 point: After climbing half a distance, you can't grab the rod and drop it from the pole; 0 points: You can't grab the rod without climbing half a distance, and drop it from the rod. Each mouse was trained twice before the experiment. On the 6th, 10th, and 17th day of the experiment, the rod test was performed twice per mouse, and each time interval was 1 hour, and the score was averaged according to the above criteria. Striatum dopamine level detection: HPLC electrochemical detector detection. High Performance Liquid Chromatograph: Waters, Detector: 2465
  • Chromatographic conditions mobile phase: sodium acetate-citrate buffer, containing 85 mM citric acid, anhydrous sodium acetate 100 mM, EDTA-Na 2 0.2 mM, first formulated into 850 ml, then added 150 ml of methanol, three distilled water to a volume of 1 L, The pH was adjusted to 3.68, and after filtration, an appropriate amount of SOS (90 mg first, depending on the separation) and n-dibutylamine (15 ⁇ ) were added to completely separate the peak.
  • tissue homogenate sputum: Add 0.6% of perchloric acid solution to make the final concentration of ⁇ > 0.375 g/ml, and store at 4 °C.
  • Solution B Potassium citrate 20 mM, dipotassium hydrogen phosphate 300 mM, EDTA-Na 2 2 mM, stored at 4 °C.
  • Tissue sample processing is carried out under ice bath conditions, following the principle of fast temperature. Add liquid A, homogenate, centrifuge at 2000°g for 20 minutes at 4°C, absorb a certain amount of supernatant, add half volume of liquid B, ice bath for 30min, mix, let stand, 20,000g, centrifuge at 20°C for 20 minutes, pick up Clear, 20000g, centrifuge at 20 °C for 20 minutes, aspirate the supernatant, and store at 4 °C for testing.
  • Immunohistochemical detection of dopaminergic neurons in the substantia nigra After behavioral experiments, 5 mice were randomly selected from each group, and the brain was taken after perfusion fixation for immunohistochemistry. The changes of mouse TH neurons were observed under light microscope. Photographed under a 4x objective, the number of TH-positive neurons in the substantia nigra pars compacta was counted, and the brain slices of each mouse were averaged to the number of TH-positive neurons in the mouse.
  • mice's intraperitoneal injection of MPTP showed a significant decrease in the residence time on the rotating stick compared with the normal mice, indicating that the mice developed behavioral disorders.
  • Oral administration of Examples 1 and 28 improves the retention of mice on the stick There was a significant dose-response relationship, which was comparable to the positive control drug L-DOPA (20 mg/kg) at high dose levels (Figure 1, Table 5).
  • S Example Number Latency
  • mice Compared with normal mice, the crawler score of mice was significantly decreased after intraperitoneal injection of MPTP. Oral administration of Examples 1 and 28 increased the crawler score in mice in a dose-dependent manner, which improved the behavioral disorder and was comparable to L-DOPA at high dose levels (Figure 2, Table 6).
  • the number of TH-positive neurons in the substantia nigra pars compacta of the MPTP model group was significantly lower than that of normal mice. Examples 1 and 28 increased the number of TH-positive neurons in mice and there was a significant dose-effect relationship. The positive drug L-DOPA had no significant effect on the number of TH neurons in the model mice (Fig. 3).
  • Examples 1 and 28 can significantly improve the behavioral disorder of mice, significantly increase the number of dopaminergic neurons in the substantia nigra and the level of striatal dopamine. These two compounds are suggested to have the potential to be developed to treat PD drugs.
  • L-DOPA Medoba (Dobasi), Shanghai Roche Pharmaceutical Co., Ltd.
  • MPTP Sigma product, batch number: 128kl549. .
  • DA DOPAC
  • HVA HVA
  • P IP P IP
  • Rolling stick method The method is the same as in Example 33. Mice were tested for roller sticks at 0, 3, 5 and 7 weeks of dosing.
  • mice after screening showed a significant decrease in the residence time on the stick (compared to 0 weeks) compared with the normal mice.
  • the mice of the 20 mg/kg and 40 mg/kg groups of Example 1 were therapeutically administered, and the mice of the groups of 10 mg/kg and 20 mg/kg of Example 28 were administered, and stayed on the sticks at the 5th week and the 7th week.
  • the time was significantly longer than that of the model group, and there was a dose-effect relationship, and its efficacy was basically equivalent to that of the positive control drug L-DOPA (Table 8).
  • Table 8 Effects of Examples 1 and 28 on MPTP/p-induced behavior in mice with chronic PD model (" ⁇ SEM, n
  • mice developed significant stratum behavioral disorders.
  • the mice of the 20 mg/kg and 40 mg/kg groups of Example 1 were therapeutically administered, and the mice of the groups of 10 mg/kg and 20 mg/kg of Example 28 were administered, and the scores of the climbing rods were significantly higher at the 5th week and the 7th week.
  • the model group there was a dose-effect relationship, and its efficacy was basically equivalent to that of the positive control drug L-DOPA (Table 9).
  • Example 1 20 mg/kg had a tendency to increase the content of DA in the striatum of mice, but no Statistical differences, while 40 mg / kg can significantly increase the level of DA.
  • Example 2810 mg/kg had a tendency to increase DA content, but there was no statistical difference, while 20 mg/kg significantly increased the level of DA (Table 10). Table 10. Effects of Examples 1 and 28 on striatal dopamine content in MPTP/p-induced chronic PD model mice
  • the number of TH-positive neurons in the substantia nigra pars compacta of the MPTP/p model group was significantly lower than that of normal mice. Examples 1 and 28 increased the number of TH-positive neurons in mice and there was a significant dose-effect relationship. The positive drug L-DOPA had no significant effect on the number of TH neurons in the model mice (Fig. 4).
  • Examples 1 and 28 have a better effect on MPTP/p-induced behavioral disorders in chronic PD mouse models, which can increase the number of dopaminergic neurons in the substantia nigra and the level of striatal dopamine. These two compounds are expected to be developed as new drugs for the treatment of PD.
  • mice Male C57 mice weighing 22 ⁇ lg were purchased from Beijing Huakang Experimental Animal Technology Co., Ltd. Clean grade.
  • Test drug Compounds represented by Examples 1 and 28
  • mice were each administered to mice at a dose of 400 mg/kg once a day for 13 consecutive days. Blood samples were taken 13 days later to test blood biochemical indicators. 8 mice per group.
  • mice body weight mouse body weight, food intake and water intake, blood biochemistry (alkaline aminotransferase ALT, alkaline phosphatase ALP, creatinine Cre).
  • Example 1 and 28 400 mg/Kg in mice by gavage there was no significant change in body weight compared with the mice in the blank group (Table 11).
  • Example 28 had no significant effect on ALT, Cre and ALP, and was comparable to the blank group.
  • Example 1 caused ALP to be elevated compared with the blank group, but there was no statistical difference and had no significant effect on ALT and Cre (Table 14).
  • Table 14 Effects of Compounds 1 and 28 on Blood Biochemistry in Mice

Abstract

The present invention provides a class of phloroglucinol derivatives, a preparation method thereof, a pharmaceutical composition comprising the compounds, and an application of these compounds in preparing medicine for preventing and/or treating Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar ataxia, primary lateral sclerosis, and spinal muscular atrophy.

Description

间苯三酚类衍生物及其在治疗神经退行性疾病中的用途 技术领域  Pyrogallol derivatives and their use in the treatment of neurodegenerative diseases
本发明涉及一类间苯三酚类衍生物及其药效学上可接受的盐，含有它们的药 物组合物以及这类化合物在制备神经退行性疾病的药物中的应用。 背景技术  The present invention relates to a class of phloroglucinol derivatives and pharmacologically acceptable salts thereof, to pharmaceutical compositions containing the same, and to the use of such compounds in the manufacture of a medicament for a neurodegenerative disease. Background technique
神经退行性疾病 （如帕金森病、 阿尔茨海默症、 多发性硬化症等） 是当今世 界范围内严重危害人类健康的一类疾病， 发病率和死亡率呈逐年上升趋势。该类 疾病是由大脑和脊髓的神经元的损伤所致， 随时间推移而恶化， 导致运动或记忆 等方面功能障碍。 随着世界人口老龄化的不断加重， 迫切需要有效的治疗药物。  Neurodegenerative diseases (such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, etc.) are a type of disease that is seriously endangering human health in the world today, and morbidity and mortality are increasing year by year. These diseases are caused by damage to neurons in the brain and spinal cord, which deteriorate over time, leading to dysfunctions such as exercise or memory. As the world's population ages, there is an urgent need for effective treatments.
近年来研究发现，脑内神经炎症与多种神经退行性疾病的发生与发展密切相 关，其介导的病变主要由胶质细胞的激活及外周入侵的淋巴细胞释放神经毒性因 子所引起。小胶质细胞和星形胶质细胞是脑实质内的固有免疫细胞， 在正常情况 下处于静息状态， 具有维持中枢神经***正常稳态的作用， 在脑感染或损伤等病 理条件下， 这些细胞被激活， 发动免疫反应及组织修复过程， 清除脑中的异物以 及病变， 一旦感染或损伤回复， 这些细胞则回到静息状态。在神经退行性疾病的 进程中， 这些细胞频繁被激活， 释放出大量的免疫因子和细胞毒因子， 包括花生 四烯酸代谢产物、 细胞因子、 炎性趋化因子、 一氧化氮、 活性氧自由基和兴奋性 氨基酸等， 导致神经元的损伤、变性甚至死亡。 而变性坏死的神经元等释放出的 细胞碎片以及生物活性物质也会再次激活小胶质细胞和星形胶质细胞，从而造成 脑中出现持续不断的神经炎症反应， 进而导致神经元的退行性死亡。 因此， 研制 和开发具有抑制神经炎症活性的药物，减少胶质细胞的激活和免疫因子及炎症因 子的过度表达， 对于治疗神经退行性疾病具有重要意义。 发明内容  In recent years, studies have found that neuroinflammation in the brain is closely related to the occurrence and development of various neurodegenerative diseases. The mediated lesions are mainly caused by the activation of glial cells and the release of neurotoxic factors from peripherally invaded lymphocytes. Microglia and astrocytes are innate immune cells in the brain parenchyma, which are normally in a resting state and have the function of maintaining the normal homeostasis of the central nervous system. Under pathological conditions such as brain infection or injury, these The cells are activated, initiate immune response and tissue repair processes, remove foreign bodies and lesions in the brain, and return to rest as soon as infection or damage is restored. In the course of neurodegenerative diseases, these cells are frequently activated, releasing a large number of immune and cytotoxic factors, including arachidonic acid metabolites, cytokines, inflammatory chemokines, nitric oxide, and reactive oxygen species. Base and excitatory amino acids, etc., cause damage, degeneration and even death of neurons. The cell debris and biologically active substances released by degeneration and necrosis neurons also activate microglia and astrocytes, resulting in a continuous neuroinflammatory reaction in the brain, which leads to neuronal degeneration. death. Therefore, the development and development of drugs that inhibit neuroinflammatory activity, reduction of glial cell activation and overexpression of immune factors and inflammatory factors are important for the treatment of neurodegenerative diseases. Summary of the invention
本发明的要解决的技术问题在于提供通式 Io所述的化合物，包括消旋体和光 学异构体， 及其药效学上可接受的盐、 盐的水合物或前体药物。 本发明要解决的又一技术问题在于提供一种药物组合物，其包括至少一个通 式 Ιο所述的化合物， 包括消旋体和光学异构体， 其药效学上可接受的盐、盐的水 合物或前体药物及药用载体和 /或赋形剂。 The technical problem to be solved by the present invention is to provide a compound of the formula Io, including racemates and optical isomers, and pharmacologically acceptable salts, hydrates or prodrugs thereof. A further technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising at least one compound of the formula 包括, including racemates and optical isomers, pharmaceutically acceptable salts and salts thereof Hydrates or prodrugs and pharmaceutically acceptable carriers and/or excipients.
本发明要解决的再一技术问题在于提供通式 Ιο所述的化合物，包括消旋体和 光学异构体，其药效学上可接受的盐、盐的水合物或前体药物在制备神经退行性 疾病的药物中的应用。 为解决上述技术问题， 本发明采用的技术方案为：  A further technical problem to be solved by the present invention is to provide a compound of the formula ,ο, including a racemate and an optical isomer, a pharmacologically acceptable salt thereof, a hydrate of a salt or a prodrug in the preparation of a nerve Application in drugs for degenerative diseases. In order to solve the above technical problems, the technical solution adopted by the present invention is:
根据本发明， 化合物通过通式 I。表示：  According to the invention, the compounds are of the formula I. Indicates:
Figure imgf000004_0001
Figure imgf000004_0001
其中， 表示 H、 -CF3、取代或未取代直链或支链的 d.n)垸基、苄基、 -N02 或 -CORal， 其中， Wherein, represents H, -CF 3 , substituted or unsubstituted linear or branched dn) fluorenyl, benzyl, -N0 2 or -COR al , wherein
取代基可选自 -0H、 -F、 -Cl、 -Br、 直链或支链的 d.6垸氧基、 -SH、 取代或 未取代的呋咱基或 -COOH、 取代或未取代的胺基， 其中， The substituent may be selected from -0H, -F, -Cl, -Br, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or -COOH, substituted or unsubstituted Amine group, wherein
呋咱基上的取代基可选自直链或支链的 d.H)垸基、 取代或未取代的苯基、 取代或未取代的苯磺酰基， 其中，  The substituent on the furfuryl group may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -0N02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -0H, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -0N0 2 or a linear or branched d. 6 anthracene group,
胺基上的取代基可选自直链或支链的 垸基， C3.6环垸基或取代基与 N原 子共同构成五元、六元或七元的含 1-3个杂原子的饱和杂环，杂环上可有取代基， 其中， Amino groups optionally substituted on the alkyl with from linear or branched, C 3. 6 cycloalkyl group or substituted alkyl with the N atom together form five-, six- or seven-membered containing 1-3 heteroatoms a saturated heterocyclic ring which may have a substituent, wherein
杂环上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 C3.6环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituted heterocyclyl selected from the -0H, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched, d. 6 an oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -0N02、 -NH2或直链或支链的 d.6垸氧 基； The substituent on the phenyl group may be selected from -0H, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -0N0 2 , -NH 2 or linear or branched d. 6垸 oxygen Base
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
垸基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 .6垸氧基； The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime;
R2和 R4分别独立表示 -H、 -OH、直链或支链的 d.6垸氧基、苄氧基、 -OCF3、 -ON02、 -F、 -Cl、 -Br、 -CN、 -N02、取代或未取代直链或支链的 d.n)垸基、 -CF3、 取代或未取代的羰基， 其中， R 2 and R 4 each independently represent -H, -OH, linear or branched d. 6 methoxy, benzyloxy, -OCF 3 , -ON0 2 , -F, -Cl, -Br, -CN, -N0 2 , a substituted or unsubstituted linear or branched dn) fluorenyl group, -CF 3 , a substituted or unsubstituted carbonyl group, wherein
d.n)垸基上的取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2、 -SH， Dn) The substituent on the fluorenyl group may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 , -SH,
羰基上的取代基可选自 -OH、直链或支链的 .1()垸基、取代或未取代的苯基、 含烯键或炔键的 CLH)不饱和烃基或取代或未取代的胺基， 其中， The substituent on the carbonyl group may be selected from -OH, straight or branched. 1 () fluorenyl, substituted or unsubstituted phenyl, ethylenic or acetylenic CLH) unsaturated hydrocarbon group or substituted or unsubstituted Amine group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 .10垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6垸氧基， 胺基上的取代基可选自取代或未取代的直链或支链的 d.H)垸基， C3.6环垸基 或取代基与 N原子共同构成五元、六元或七元的含 1-3个杂原子的饱和杂环，其 中， The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched. 10 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 methoxy group, the substituent on the amine group may be selected from a substituted or unsubstituted linear or branched dH) fluorenyl group, C 3 . 6 a cycloalkyl or a substituent and a N atom together form a five-, six- or seven-membered saturated heterocyclic ring having from 1 to 3 hetero atoms, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2;The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 ;
R3和 R5分别独立表示 -H、 -OH、 直链或支链的 d.6垸基、 -ON02、 取代或 未取代的直链或支链的 垸氧基、 苯环上取代或未取代的苄氧基， 其中， 所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、 -COOH; R 3 and R 5 each independently represent -H, -OH, a straight or branched d. 6 fluorenyl group, -ON0 2 , a substituted or unsubstituted linear or branched decyloxy group, a phenyl ring substituted or An unsubstituted benzyloxy group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -NH 2 , -COOH;
n可为 1-5，  n can be 1-5,
X表示 H、 直链或直链的 d.6垸基， 取代或未取代的胺基， 其中 X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
取代基可选自直链或支链的 d.6垸基， C3.6环垸基或取代基与 N原子共同构 成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上可 有取代基， 其中， Substituents selected from a straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with together with the N atom form a 5-, 1-3 heteroatoms unsaturated six-membered or seven-membered containing a heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 垸氧基、 取代或未取代的苯基， 其中， The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, C 3. 6 a fluorenyl, linear or branched decyloxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 根据本发明， 化合物通过通式 I表示: The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime. According to the invention, the compounds are represented by the general formula I:
Figure imgf000006_0001
Figure imgf000006_0001
其中， 表示 H、 -CF3、取代或未取代直链或支链的 d.n)垸基、苄基、 -N02 或 -CORal， 其中， Wherein, represents H, -CF 3 , substituted or unsubstituted linear or branched dn) fluorenyl, benzyl, -N0 2 or -COR al , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 直链或支链的 d.6垸氧基、 -SH、 取代或 未取代的呋咱基或 -COOH、 取代或未取代的胺基， 其中， The substituent may be selected from -OH, -F, -Cl, -Br, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or -COOH, substituted or unsubstituted Amine group, wherein
呋咱基上的取代基可选自直链或支链的 d.H)垸基、 取代或未取代的苯基、 取代或未取代的苯磺酰基， 其中，  The substituent on the furfuryl group may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 anthracene group,
胺基上的取代基可选自直链或支链的 垸基， C3.6环垸基或取代基与 N原 子共同构成五元、六元或七元的含 1-3个杂原子的饱和杂环，杂环上可有取代基， 其中， Amino groups optionally substituted on the alkyl with from linear or branched, C 3. 6 cycloalkyl group or substituted alkyl with the N atom together form five-, six- or seven-membered containing 1-3 heteroatoms a saturated heterocyclic ring which may have a substituent, wherein
杂环上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 C3.6环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， A substituted heterocyclic group selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched, d. 6 an oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基； The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime;
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 垸基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 .6垸氧基； The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime;
R3和 R5分别独立表示 -H、 -OH、 直链或支链的 d.6垸基、 -ON02、 取代或 未取代的直链或支链的 .6垸氧基、 苯环上取代或未取代的苄氧基， 其中， 所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、 -COOH; R 3 and R 5 each independently represent -H, -OH, linear or branched d. 6 fluorenyl, -ON0 2 , substituted or unsubstituted straight or branched. 6 oxirane, phenyl ring a substituted or unsubstituted benzyloxy group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -NH 2 , -COOH;
n可为 1-5，  n can be 1-5,
X表示 H、 直链或直链的 d.6垸基， 取代或未取代的胺基， 其中 X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
取代基可选自直链或支链的 垸基， C3.6环垸基或取代基与 N原子共同构 成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上可 有取代基， 其中， Group optionally substituted alkyl with from linear or branched, C 3. 6 cycloalkyl group or substituted alkyl with the N atom together form five-, six- or seven-membered saturated heterocyclic ring containing 1-3 heteroatom ( a morpholine ring, except that a heterocyclic ring may have a substituent, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 cyclic alkyl with straight or branched chain group embankment, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 根据本发明， 化合物是通过通式 IA表示: The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime. According to the invention, the compound is represented by the formula IA:
Figure imgf000007_0001
Figure imgf000007_0001
其中， Ra表示取代或未取代直链或支链的 d.n)垸基、 苄基、 -N02、 -CORal， 其中， 取代基可选自 -OH、 -F、 -Cl、 -Br, 直链或支链的 d.6垸氧基、 -SH、 取 代或未取代的呋咱基或 -COOH, 其中， Wherein R a represents a substituted or unsubstituted linear or branched dn) fluorenyl group, a benzyl group, -N0 2 , -COR al , wherein the substituent may be selected from the group consisting of -OH, -F, -Cl, -Br, a linear or branched d. 6 methoxy group, -SH, a substituted or unsubstituted furazyl group or -COOH, wherein
取代基可选自直链或支链的 d.H)垸基、 取代或未取代的苯基、 取代或未取 代的苯磺酰基， 其中，  The substituent may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a straight chain or a branch Cw thiol of the chain, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 oxime,
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
垸基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的^.6垸氧基。 根据本发明， 当 表示未取代的直链或支链的 CLH)垸基时， 优选的 Ra是甲 基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基、 戊基、 异戊基、 己基等， 但 不限定于以上基团。 根据本发明， 当 表示取代的直链或支链的 CLH)垸基时，优选的 基包括， 但不限定于通式 IAa所示的基团：
Figure imgf000008_0001
其中， n可表示 1-5， The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched ^. 6 oxime. According to the invention, when referring to an unsubstituted linear or branched CLH) fluorenyl group, preferred R a is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Butyl, isopentyl, hexyl and the like are not limited to the above groups. According to the present invention, when referring to a substituted linear or branched CLH) fluorenyl group, preferred groups include, but are not limited to, the group represented by the formula IAa:
Figure imgf000008_0001
Where n can represent 1-5,
Ra2可选自直链或支链的 d.u)垸基、 取代或未取代的苯基、 取代或未取代的 苯磺酰基， 其中， R a2 may be selected from a linear or branched du) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基。 根据本发明， 优选的通式 IAa表示的化合物包括 ： The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 oxime. According to the invention, preferred compounds of the formula IAa include:
Ra2选自 H、 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基、 戊基、 异戊基、 己基、 取代或未取代的的苯基、 苯环上取代或未取代的苯磺酰基， 取代 基可选自 -H、 -OH、 -F、 -Cl、 -Br、 -COOH、 C1-6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧基、 -NH2。 根据本发明， 化合物是通过通式 m 表示: R a2 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, substituted or unsubstituted phenyl, benzene ring a substituted or unsubstituted benzenesulfonyl group, the substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, C 1-6 fluorenyl, -CHF 2 , -CF 3 , -CN , -N0 2 , -OCF 3 , -ON0 2 , linear or branched d. 6 methoxy, -NH 2 . According to the invention, the compound is represented by the formula m:
Figure imgf000009_0001
其中， R3和 R5分别独立表示 -H、 -OH、直链或支链的 d.6垸基、 -ON02、 -ORc 或 -SRC， 其中，
Figure imgf000009_0001
Wherein R 3 and R 5 each independently represent -H, -OH, a linear or branched d. 6 fluorenyl group, -ON0 2 , -ORc or -SR C , wherein
Rc表示取代或未取代直链或支链的 d.n)垸基、 苄基， 其中，  Rc represents a substituted or unsubstituted linear or branched d.n) fluorenyl group, a benzyl group, wherein
所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、 -COOH; The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -NH 2 , -COOH;
Rbi ¾2分别独立表示 H、 直链或支链的 d.6垸基， C3.6环垸基或 -NRblRb2 构成五元、六元或七元的含 1-3个杂原子的饱和杂环，杂环上可有取代基，其中， 取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 垸氧基、 取代或未取代的苯基， 其中， Rbi ¾2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cyclic alkyl with or -NR bl R b2 constitute containing 1-3 heteroatoms five-, six- or seven-membered of The saturated heterocyclic ring may have a substituent on the heterocyclic ring, wherein the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, C 3. 6 a fluorenyl, linear or branched decyloxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 根据本发明， 优选的通式 m表示的化合物包括 ： The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime. According to the invention, preferred compounds of the formula m include:
R3和 R5分别独立选自 H、 -OH、 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁 基、 叔丁基、 戊基、 异戊基、 己基、 直链或支链的 d.6垸氧基、 苄氧基， R 3 and R 5 are each independently selected from H, -OH, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, linear or Branched d. 6 methoxy, benzyloxy,
Rbl、 2分别独立选自 H、 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔 丁基、 戊基、 异戊基、 己基、 环丙基、 环戊基、 环己基、 苯环上取代或未取代的 苯甲基、 苯乙基、 取代或未取代的苯基、 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br, -COOH、 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧基、 -NH2， R bl , 2 are each independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH , d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , linear or branched d. 6 methoxy, -NH 2 ,
或者 -NRblRb2构成五元、 六元或七元的含 1-3个杂原子的饱和杂环， 可选自 以下杂环
Figure imgf000010_0001
Or -NR bl R b2 constitute a saturated heterocycle containing 1-3 heteroatoms five-, six- or seven-membered, selected from Following heterocycle
Figure imgf000010_0001
其中， R'可表示 -OH、 -F、 -Cl、 -Br、 -COOH、 d.6垸基、直链或支链的 d.6 垸氧基、 取代或未取代的苯基， 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br、 -COOH、 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧 基、 - H2 o 根据本发明， 化合物是通过通式 IC 表示: Wherein R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d. 6 methoxy, -H 2 o According to the invention, the compound is represented by the general formula IC:
Figure imgf000010_0002
Figure imgf000010_0002
其中， Rd ¾2和 Rd3分别独立表示 -H、直链或支链的 C2.6垸基、苄基或 -CF3， n可为 2-5, Wherein, Rd 3⁄4 2 and R d3 independently represent -H, a linear or branched C 2 . 6 fluorenyl group, a benzyl group or a —CF 3 , and n may be 2-5.
Rel， Re2分别独立表示 H、 直链或支链的 d.6垸基， C3.6环垸基或 -NRelRe2 构成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上 可有取代基， 其中， Rel, Re2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cycloalkyl or alkyl with -NRelRe2 configuration five-, six- or seven-membered having 1-3 heteroatoms saturated hetero a ring (except for the morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched d. 6 embankment An oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 根据本发明， 优选的通式 IC 表示的化合物包括： The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime. According to the present invention, preferred compounds represented by the general formula IC include:
Rdi 2和 Rd3分别独立选自甲基、 乙基、 丙基、 异丙基、 苄基、 -CF3, n表不 3-5, Rdi 2 and R d3 are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 , and n is not 3-5.
Re^ ReZ分别独立选自 H、 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔 丁基、 戊基、 异戊基、 己基、 环丙基、 环戊基、 环己基、 苯环上取代或未取代的 苯甲基、 苯乙基、 取代或未取代的苯基、 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br, -COOH、 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 Cw垸氧基、 -NH2， Re^ ReZ is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl, a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , linear or branched Cw decyloxy, -NH 2 ,
或者 -NR^R^构成五元、 六元或七元的含 1-3个杂原子的饱和杂环， 可选自 以
Figure imgf000011_0001
Or -NR^R^ constitutes a five-, six- or seven-membered saturated heterocyclic ring containing 1-3 heteroatoms, which may be selected from
Figure imgf000011_0001
其中， R'可表示 -OH、 -F、 -Cl、 -Br、 -COOH、 d.6垸基、 直链或支链的 d.6 垸氧基、 取代或未取代的苯基， 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br、 -COOH、 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧 基、 - H2 o 根据本发明， 优选的通式 IC 所示的化合物包括， 但不限定于通式 ICa所示 的化合物：
Figure imgf000011_0002
其中， Rel Re2分别独立表示 H、直链或支链的 d.6垸基， C3.6环垸基或 -NRelRe2 构成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上 可有取代基， 其中， Wherein R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d. 6 methoxy, -H 2 o According to the invention, preferred compounds of the formula IC include, but are not limited to, the compounds of the formula ICa:
Figure imgf000011_0002
Wherein, Rel R e2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cycloalkyl or alkyl with -NRelRe2 configuration five-, six- or seven-membered containing 1-3 heteroatoms a saturated heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched d. 6 embankment An oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 根据本发明， 优选的通式 ICa表示的化合物包括 ： The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime. According to the invention, preferred compounds of the general formula ICa include:
Re^ Rez分别独立选自 H、 甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔 丁基、 戊基、 异戊基、 己基、 环丙基、 环戊基、 环己基、 苯环上取代或未取代的 苯甲基、 苯乙基、 取代或未取代的苯基、 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br, -COOH、 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧基、 -NH2。 Re^ Rez is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cyclopropyl, cyclopentyl, a cyclohexyl group, a substituted or unsubstituted benzyl group, a phenethyl group, a substituted or unsubstituted phenyl group, and a substituent may be selected from the group consisting of -H, -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , straight or branched d. 6 methoxy, -NH 2 .
或者 -NRblRb2构成五元、 六元或七元的含 1-3个杂原子的饱和杂环， 可选自 以
Figure imgf000012_0001
Or -NR bl R b2 constitutes a five-, six- or seven-membered saturated heterocyclic ring containing 1-3 heteroatoms, which may be selected from
Figure imgf000012_0001
其中， R'可表示 -OH、 -F、 -Cl、 -Br、 -COOH、 d.6垸基、直链或支链的 d.6 垸氧基、 取代或未取代的苯基， 取代基可选自 -H、 -OH、 -F、 -Cl、 -Br、 -COOH、 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 直链或支链的 d.6垸氧 基、 - H2 o 根据本发明， 化合物是 ID 表示: Wherein R' may represent -OH, -F, -Cl, -Br, -COOH, d. 6 fluorenyl, linear or branched d. 6 methoxy, substituted or unsubstituted phenyl, substituent selected from -H, -OH, -F, -Cl, -Br, -COOH, Cw alkyl with, -CHF 2, -CF 3, -CN , -N0 2, -OCF 3, -ON0 2, a straight-chain Or branched d. 6 methoxy, -H 2 o According to the invention, the compound is ID:
Figure imgf000012_0002
其中， Rfl、 Re、 ¾3分别独立表示 -H、直链或支链的 d.6垸基、苄基或 -CF3 ; R2、 R4分别独立表示 -H、 -OH、 直链或支链的 d.6垸氧基、 -OCF3、 -ON02、 -F、 -Cl、 -Br、 -CN、 -N02、取代或未取代直链或支链的 d.n)垸基、 -CF3、 -CORg， 其中，
Figure imgf000012_0002
Wherein R fl , Re and 3⁄43 each independently represent -H, a linear or branched d. 6 fluorenyl group, a benzyl group or a -CF 3 ; R 2 and R 4 each independently represent -H, -OH, a straight chain or a branch. Chain d. 6 methoxy, -OCF 3 , -ON0 2 , -F, -Cl, -Br, -CN, -N0 2 , substituted or unsubstituted linear or branched dn) fluorenyl, -CF 3 , -COR g , where,
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 ,
-SH， -SH,
Rg可表示 H、 -OH、 直链或支链的 d.n)垸基、 取代或未取代的苯基、 含烯 键或炔键的 CLH)不饱和烃基或 -NRglRg2， 其中， R g may represent H, -OH, a linear or branched dn) fluorenyl group, a substituted or unsubstituted phenyl group, an ethylenic or acetylenic bond-containing CLH) unsaturated hydrocarbon group or -NR gl R g2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.u)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的^.6垸氧基， The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched du) fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched ^. 6 methoxy group,
Rgi Rg2分别独立表示 H、 取代或未取代直链或支链的 d.u)垸基、 C3.6环垸 基或 -NRglRg2构成五元、 六元或七元的含 1-3个杂原子的饱和杂环， 其中， R g i R g2 each independently represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3. 6 cyclic alkyl with or -NR gl R g2 configuration five-, six- or seven-membered containing 1 - a saturated heterocyclic ring of 3 hetero atoms, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2; n可为 1-5， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 ; n may be 1-5,
Re可表示 H、 取代或未取代直链或支链的 d.u)垸基、 C3.6环垸基或与 R7、 R8及相连的 C原子和 N原子构成四-七元的含 1-3个杂原子的饱和杂环， 其中， 取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2;Re may represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3. 6 cycloalkyl or alkyl with R 7, R 8 and C atoms and N atom constituting four - saturated heterocycle containing 1-3 heteroatoms seven-membered, wherein the substituents are selected from -OH, a straight or branched chain group d 6 embankment. , -F, -Cl, -Br, -COOH, - H 2 ;
R7与 R8分别独立表示 H、 取代或未取代直链或支链的 d.n)垸基或与 Re及 相连的 C原子和 N原子构成四-七元的含 1-3个杂原子的饱和杂环， 条件是 R7 与 不能同时为 H， 其中， R 7 and R 8 independently represent H, a substituted or unsubstituted linear or branched dn) fluorenyl group or a recombination of a C atom and an N atom to form a four-seven-membered saturation of 1-3 heteroatoms. a heterocyclic ring, the condition being that R 7 and not simultaneously H, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、 -SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , 胍a substituted or unsubstituted phenyl and a aryl group, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 oxime,
Rh表示直链或支链的 CLH)垸基。 根据本发明， 优选的通 ID的化合物为通式 IDa所示的化合物:
Figure imgf000013_0001
其中， Rfl、 Re、 ¾3分别独立表示 -H、直链或支链的 d.6垸基、苄基或 -CF3 Re可表示 H、 取代或未取代直链或支链的 d.u)垸基、 C3.6环垸基， 其中， 取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2, R7与 R8分别独立表示 H、 取代或未取代直链或支链的 d.n)垸基， 条件是 与1 8不能同时为 H， 其中， R h represents a linear or branched CLH) fluorenyl group. According to the invention, a preferred compound of the pass ID is a compound of the formula IDa:
Figure imgf000013_0001
Wherein R fl , Re, 3⁄43 independently represent -H, linear or branched d. 6 fluorenyl, benzyl or -CF 3 Re may represent H, substituted or unsubstituted straight or branched du) 垸a C 3 .6 ring fluorenyl group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -COOH, -H 2 , R 7 and R 8 each independently represent H, a substituted or unsubstituted linear or branched dn) fluorenyl group, provided that H and 18 cannot simultaneously be H, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 ,
-SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， -SH, -SR h , -CO H 2 , fluorenyl, substituted or unsubstituted phenyl and aryl, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 C1-6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched C 1-6 alkoxy group,
Rh表示直链或支链的 CLH)垸基。 根据本发明， 优选的通式 IDa所示的化合物包括: Rfl、 Rf2、 Re选自甲基、 乙基、 丙基、 异丙基、 苄基、 -CF3， Rh represents a linear or branched CLH) fluorenyl group. According to the invention, preferred compounds of the general formula IDa include: R fl , Rf 2 , Re are selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
Re选自 H、 环丙基、 环丁基、 环戊基、 环己基以及取代或未取代的甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基、 戊基、 异戊基、 己基， 取代基可 选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2， Re is selected from the group consisting of H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentane a group, an isopentyl group, a hexyl group, the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -COOH, -NH 2 ,
R7、 R8分别独立选自 H (二者不能同时为 H)、取代或未取代的甲基、 乙基、 丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、 己基，取代基可选自 -OH、 -COOH、 -NH2、 -SH、 -SCH3、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中苯基的取代基可以为 -OH、 -F、 -Cl、 -Br、 -COOH、 甲基、 乙基、 异丙基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6垸氧基， 芳杂基 可选自呋喃基、 咪唑基、 吡唑基、 吡啶基、 噻吩基、 吡咯基、 噻唑基、 嘧啶基、 吲哚基等。 根据本发明， 优选的通 IDa所示的化合物为通式 IDal 所示的化合物: R 7 and R 8 are each independently selected from H (both cannot be H at the same time), substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl , isopentyl, hexyl, the substituent may be selected from -OH, -COOH, -NH 2 , -SH, -SCH 3 , -CO H 2 , fluorenyl, substituted or unsubstituted phenyl and aryl, wherein The substituent of the phenyl group may be -OH, -F, -Cl, -Br, -COOH, methyl, ethyl, isopropyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 methoxy group, the aryl group may be selected from furyl, imidazolyl, pyrazolyl, pyridyl, thienyl, pyrrolyl, thiazolyl, pyrimidinyl, anthracene哚基等. According to the present invention, a preferred compound represented by IDa is a compound of the formula IDal:
Figure imgf000014_0001
Figure imgf000014_0001
其中， R7表示取代或未取代直链或支链的 d.u)垸基， Wherein R 7 represents a substituted or unsubstituted straight or branched du) fluorenyl group,
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、 -SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , 胍a substituted or unsubstituted phenyl and a aryl group, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 C1-6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched C 1-6 alkoxy group,
Rh表示直链或支链的 CLK)垸基。 根据本发明， 优选的通式 IDal 所示的化合物包括：  Rh represents a linear or branched CLK) sulfhydryl group. According to the invention, preferred compounds of the general formula IDal include:
Rfl、 Rf2、 Re选自甲基、 乙基、 丙基、 异丙基、 苄基、 -CF3， R fl , Rf 2 , Re are selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
R7选自 H、 取代或未取代的甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基、戊基、异戊基、 己基， 取代基可选自 -OH、 -COOH、 -NH2、 -SH、 -SCH3、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中苯基的取代基可以为 -OH、 -F、 -Cl、 -Br、 -COOH、 甲基、 乙基、异丙基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 .6垸氧基， 芳杂基可选自呋喃基、 咪唑基、 吡唑基、 吡 口定基、 噻吩基、 吡咯基、 噻唑基、 嘧啶基、 吲哚基等。 根据本发明， 优选的通式 ID 所示的化合物包括通式 IDb 所示的化合物:
Figure imgf000015_0001
R 7 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, and the substituent may be selected from - OH, -COOH, -NH 2 , -SH, -SCH 3 , -CO H 2 , fluorenyl, substituted or unsubstituted phenyl and aryl, wherein the substituent of the phenyl group may be -OH, -F, -Cl, -Br, -COOH, methyl, ethyl, isopropyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or straight or branched The 6 methoxy group, the aryl group may be selected from the group consisting of furyl, imidazolyl, pyrazolyl, pyridyl, thienyl, pyrrolyl, thiazolyl, pyrimidinyl, fluorenyl and the like. According to the invention, preferred compounds of the general formula ID include the compounds of the formula IDb:
Figure imgf000015_0001
IDb  IDb
其中， Rfl、 Re、 ¾3分别独立表示 -H、 直链或支链的 d.u)垸基、 苄基或 -CF N原子与邻位 C原子共同参与构成四-七元的含 1-3个杂原子的饱和杂环。 根据本发明， 优选的通式 IDb 所示的化合物包括： Wherein, R fl , Re, 3⁄43 respectively represent -H, a straight or branched di) fluorenyl group, a benzyl group or a -CF N atom and an ortho C atom together to form a 1-4 of a four-seven dollar A saturated heterocyclic ring of a hetero atom. According to the present invention, preferred compounds of the formula IDb include:
Rn Rf2、 Re选自甲基、 乙基、 丙基、 异丙基、 苄基、 -CF3，
Figure imgf000015_0002
本发明中， 垸氧基是指直链或支链的 C1-6的垸氧基， 可举例甲氧基、 乙氧 基、 正丙氧基、 异丙氧基、 正丁氧基、 异丁氧基、 仲丁氧基、 叔丁氧基、 正戊氧 基、 异戊氧基、 正己氧基、 异己氧基等。 根据本发明， 优选的化合物包括， 但不仅限于以下化合物: Rn Rf2, Re is selected from the group consisting of methyl, ethyl, propyl, isopropyl, benzyl, -CF 3 ,
Figure imgf000015_0002
In the present invention, the decyloxy group means a linear or branched C1-6 decyloxy group, and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group and an isobutyl group. An oxy group, a sec-butoxy group, a tert-butoxy group, a n-pentyloxy group, an isopentyloxy group, a n-hexyloxy group, an isohexyloxy group or the like. Preferred compounds according to the invention include, but are not limited to, the following compounds:
1-(2-甲氧基 -4,6-二羟基苯基) -3-甲基 -1-丁酮  1-(2-methoxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone
1-(2-乙氧基 -4,6-二羟基苯基 )-3-甲基小丁酮  1-(2-ethoxy-4,6-dihydroxyphenyl)-3-methylbutanone
1-(2-异丙氧基 -4,6-二羟基苯基 )-3-甲基 -1-丁酮  1-(2-isopropoxy- 4,6-dihydroxyphenyl)-3-methyl-1-butanone
1-(2-丙酰氧基 -4,6-二羟基苯基 )-3-甲基 -1-丁酮 3-[3,5-二羟基 -2-(3-甲基丁酰基)苯氧基]甲基 -4-苯基呋咱 1-(2-propionyloxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone 3-[3,5-dihydroxy-2-(3-methylbutyryl)phenoxy]methyl-4-phenylfurazan
(±)-1-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 6-二羟基苯基] -3-甲基 -1-丁酮盐酸 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基 '-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐， (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 >-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 -甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 >-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 -甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 >-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 >-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐(±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy]-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (R)- 1-[2-(2-Hydroxy-3-isopropylaminopropoxy 6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (S)-l-[2-(2- Hydroxy-3-isopropylaminopropoxy '-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (±)-1-[2-(2-hydroxy-3- tert-Butylaminopropoxy '-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (R)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy) 6-Dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy]-4,6-dihydroxyphenyl] -3-methyl-1-butanone hydrochloride (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy]-4-methoxyphenyl]-3-methyl 1-butanone hydrochloride, (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy]-4-methoxyphenyl]-3-methyl-1-butane Ketone hydrochloride (S)-l-[2-(2-hydroxy-3-isopropylaminopropoxy-methoxyphenyl]-3-methyl-1-butanone hydrochloride (±)- 1-[2-(2-hydroxy-3-tert-butylaminopropoxy '-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride (R)-l-[2-( 2-hydroxy-3-tert-butylaminopropoxy>-4-methoxy Phenyl]-3-methyl-1-butanone hydrochloride (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy-methoxyphenyl]-3-methyl- 1-butanone hydrochloride (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy'-4,6-dimethoxyphenyl]-3-methyl-1- Butanone hydrochloride (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy]-4,6-dimethoxyphenyl]-3-methyl-1-butanone Hydrochloride (S)-l-[2-(2-hydroxy-3-isopropylaminopropoxy'-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Salt (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy '-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride (R )-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy]-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride
(S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 4- (哌啶 -1-基) -1-(2,4,6-三羟基苯基) -1-丁酮盐酸盐 (S)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy '-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 4- ( Piperidin-1-yl)-1-(2,4,6-trihydroxyphenyl)-1-butanone hydrochloride
4- (甲基环己基胺;) -1-(2,4,6-三羟基苯基; )-1-丁酮盐酸盐  4-(methylcyclohexylamine;)-1-(2,4,6-trihydroxyphenyl; )-1-butanone hydrochloride
4-[4-(3-氯苯基)哌嗪 -1-基] -1-(2,4,6-三羟基苯基) 1-丁酮盐酸盐 4-[4-(3-Chlorophenyl)piperazin-1-yl]-1-(2,4,6-trihydroxyphenyl) 1-butanone hydrochloride
(S)-2-(2,4,6-三羟基苯甲胺基)丙酸 (S)-2-(2,4,6-trihydroxybenzylamino)propionic acid
(S)-2-(2,4,6-三羟基苯甲胺基) -3-甲基丁酸 (S)-2-(2,4,6-trihydroxybenzylamino)-3-methylbutyric acid
(S)-2-(2,4,6-三羟基苯甲胺基) -4-甲基戊酸 (S)-2-(2,4,6-trihydroxybenzylamino)-4-methylpentanoic acid
(S)-2-(2,4,6-三羟基苯甲胺基) -3-甲基戊酸 (S)-2-(2,4,6-trihydroxybenzylamino)-3-methylpentanoic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -3-苯基丙酸 (S)-2-(2,4,6-trimethoxybenzylamino)-3-phenylpropionic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -3-(4-羟基苯基)丙酸 (S)-2-(2,4,6-trimethoxybenzylamino)-3-(4-hydroxyphenyl)propionic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基)戊二酸 (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸 (S)-2-(2,4,6-trimethoxybenzylamino)glutaric acid (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropionic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基)丁二酸  (S)-2-(2,4,6-trimethoxybenzylamino)succinic acid
(2S)-2-(2,4,6 -三甲氧基苯甲胺基 )-3-羟基丁酸  (2S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxybutyric acid
(R)-2-(2,4,6-三甲氧基苯甲胺基) -3-巯基丙酸  (R)-2-(2,4,6-trimethoxybenzylamino)-3-mercaptopropionic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -4-甲硫基丁酸  (S)-2-(2,4,6-trimethoxybenzylamino)-4-methylthiobutyric acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -6-氨基己酸  (S)-2-(2,4,6-trimethoxybenzylamino)-6-aminocaproic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基； )-5-胍基戊酸  (S)-2-(2,4,6-trimethoxybenzylamino);-5-mercaptovaleric acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -4-氨基 -4-氧丁酸  (S)-2-(2,4,6-trimethoxybenzylamino)-4-amino-4-oxobutanoic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -5-氨基 -5-氧戊酸  (S)-2-(2,4,6-trimethoxybenzylamino)-5-amino-5-oxovaleric acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -3 -0?H-咪唑 -5-基；)丙酸  (S)-2-(2,4,6-trimethoxybenzylamino)-3-0?H-imidazole-5-yl;)propionic acid
(S)-2-(2,4,6-三甲氧基苯甲胺基) -3-0?H-吲哚 -3-基)丙酸  (S)-2-(2,4,6-trimethoxybenzylamino)-3-0?H-indol-3-yl)propionic acid
(S)-l -(2,4,6-三甲氧基苯基)吡咯 -2-酸 本发明还涉及一种含有药物有效剂量的如通式 I各情况所述的化合物和药学 上可接受的载体的药物组合物。  (S)-l-(2,4,6-trimethoxyphenyl)pyrrole-2-acid The present invention also relates to a pharmaceutically effective amount of a compound as described in each of the formula I and pharmaceutically acceptable A pharmaceutical composition of the carrier.
根据本发明， 本发明化合物可以异构体的形式存在， 而且通常所述的"本发 明化合物"包括该化合物的异构体。  According to the present invention, the compound of the present invention may exist in the form of an isomer, and generally the "compound of the present invention" includes an isomer of the compound.
根据本发明的实施方案， 所述的本发明化合物还包括其药效学上可接受的 盐、 盐的水合物或前体药物。  According to an embodiment of the present invention, the compound of the present invention further includes a pharmacologically acceptable salt thereof, a hydrate of a salt or a prodrug.
本发明还涉及含有作为活性成份的本发明化合物和常规药物赋形剂或辅剂 的药物组合物。 通常本发明药物组合物含有 0.1〜95重量％的本发明化合物。 在 单元剂型中本发明化合物一般含量为 0.1〜100mg， 优选的单元剂型含有 4〜 50mg。  The invention further relates to a pharmaceutical composition comprising as an active ingredient a compound of the invention and a conventional pharmaceutical excipient or adjuvant. Usually, the pharmaceutical composition of the present invention contains 0.1 to 95% by weight of the compound of the present invention. The compound of the present invention is generally contained in a unit dosage form in an amount of from 0.1 to 100 mg, and the preferred unit dosage form contains from 4 to 50 mg.
本发明化合物的药物组合物可根据本领域公知的方法制备。 用于此目的时， 如果需要， 可将本发明化合物与一种或多种固体或液体药物赋形剂和 /或辅剂结 合， 制成可作为人药或兽药使用的适当的施用形式或剂量形式。  Pharmaceutical compositions of the compounds of the invention can be prepared according to methods well known in the art. When used for this purpose, the compounds of the invention may be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if desired, in a suitable form or dosage for use as a human or veterinary drug. form.
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为 肠道或非肠道， 如口服、 肌肉、 皮下、 鼻腔、 口腔粘膜、 皮肤、 腹膜或直肠等。 本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注 射、 肌肉注射、 皮下注射、 皮内注射和穴位注射等。 The compound of the present invention or a pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as orally, muscle, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum. The administration route of the compound of the present invention or a pharmaceutical composition containing the same can be administered by injection. Injection including intravenous injection Injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection.
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、 微粒剂型、 乳剂剂型、 混悬剂型。 其他剂型例如片剂、 胶囊、 滴丸、 气雾剂、 丸 剂、 粉剂、 溶液剂、 混悬剂、 乳剂、 颗粒剂、 栓剂、 冻干粉针剂等。  The dosage form can be a liquid dosage form or a solid dosage form. For example, the liquid dosage form may be a true solution type, a colloid type, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms are, for example, tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders and the like.
本发明化合物可以制成普通制剂、 也可以是缓释制剂、控释制剂、靶向制剂及各 种微粒给药***。 The compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
例如为了将单位给药剂型制成片剂， 可以广泛使用本领域公知的各种载体。 关于载体的例子是， 例如稀释剂与吸收剂， 如淀粉、 糊精、 硫酸钙、 乳糖、 甘露 醇、 蔗糖、 氯化钠、 葡萄糖、 尿素、 碳酸钙、 白陶土、 微晶纤维素、 硅酸铝等； 湿润剂与粘合剂， 如水、 甘油、 聚乙二醇、 乙醇、 丙醇、 淀粉浆、 糊精、 糖浆、 蜂蜜、葡萄糖溶液、***胶浆、 明胶浆、羧甲基纤维素钠、紫胶、 甲基纤维素、 磷酸钾、 聚乙烯吡咯垸酮等； 崩解剂， 例如干燥淀粉、 海藻酸盐、 琼脂粉、 褐藻 淀粉、 碳酸氢钠与枸橼酸、 碳酸钙、 聚氧乙烯山梨糖醇脂肪酸酯、 十二垸基磺酸 钠、 甲基纤维素、 乙基纤维素等； 崩解抑制剂， 例如蔗糖、 三硬脂酸甘油酯、 可 可脂、 氢化油等； 吸收促进剂， 例如季铵盐、 十二垸基硫酸钠等； 润滑剂， 例如 滑石粉、 二氧化硅、 玉米淀粉、 硬脂酸盐、 硼酸、 液体石蜡、 聚乙二醇等。 还可 以将片剂进一步制成包衣片， 例如糖包衣片、 薄膜包衣片、 肠溶包衣片， 或双层 片和多层片。  For example, in order to prepare a unit dosage form into a tablet, various carriers known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid. Aluminum, etc.; wetting agent and binder, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic, gelatin paste, sodium carboxymethyl cellulose , shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and tannic acid, calcium carbonate, polyoxygen Ethylene sorbitan fatty acid ester, sodium dodecyl sulfonate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc.; absorption Promoters, such as quaternary ammonium salts, sodium decyl sulfate, etc.; lubricants such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol, etc.The tablets may also be further formed into coated tablets such as sugar-coated tablets, film-coated tablets, enteric coated tablets, or double-layered tablets and multi-layered tablets.
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于 载体的例子是， 例如稀释剂与吸收剂， 如葡萄糖、 乳糖、 淀粉、 可可脂、 氢化植 物油、 聚乙烯吡咯垸酮、 单硬脂酸甘油脂、 高岭土、 滑石粉等； 粘合剂， 如阿拉 伯胶、 黄蓍胶、 明胶、 乙醇、 蜂蜜、 液糖、 米糊或面糊等； 崩解剂， 如琼脂粉、 干燥淀粉、 海藻酸盐、 十二垸基磺酸钠、 甲基纤维素、 乙基纤维素等。  For example, in order to prepare a drug delivery unit into a pellet, various carriers known in the art can be widely used. Examples of the carrier are, for example, a diluent and an absorbent such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, glyceryl monostearate, kaolin, talc, etc.; Acacia gum, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter; etc.; disintegrants, such as agar powder, dried starch, alginate, sodium dodecyl sulfonate, methyl cellulose, Ethyl cellulose and the like.
例如为了将给药单元制成胶囊，将有效成分本发明化合物与上述的各种载体 混合， 并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本 发明化合物制成微囊剂， 混悬于水性介质中形成混悬剂， 亦可装入硬胶囊中或制 成注射剂应用。  For example, in order to encapsulate the administration unit, the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule. The active ingredient of the compound of the present invention can also be formulated into a microcapsule, suspended in an aqueous medium to form a suspension, or can be incorporated into a hard capsule or used for injection.
例如， 将本发明化合物制成注射用制剂， 如溶液剂、 混悬剂溶液剂、 乳剂、 冻干粉针剂， 这种制剂可以是含水或非水的， 可含一种和 /或多种药效学上可接 受的载体、 稀释剂、 粘合剂、 润滑剂、 防腐剂、 表面活性剂或分散剂。 如稀释剂 可选自水、 乙醇、 聚乙二醇、 1， 3-丙二醇、 乙氧基化的异硬脂醇、 多氧化的异 硬脂醇、 聚氧乙烯山梨醇脂、 肪酸酯等。 另外， 为了制备等渗注射液， 可以向注 射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、 缓冲剂、 pH调节剂等。 这些辅料是本领域常用的。 For example, the compound of the present invention is formulated into an injectable preparation such as a solution, a suspension solution, an emulsion, or a lyophilized powder injection, which may be aqueous or non-aqueous, and may contain one and/or more drugs. Efficiently connectable A carrier, diluent, binder, lubricant, preservative, surfactant or dispersant. For example, the diluent may be selected from the group consisting of water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fat, fatty acid ester, etc. . Further, in order to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin may be added to the preparation for injection, and a conventional cosolvent, a buffer, a pH adjuster or the like may be added. These excipients are commonly used in the art.
此外， 如需要， 也可以向药物制剂中添加着色剂、 防腐剂、 香料、 矫味剂、 甜味剂或其它材料。  In addition, coloring agents, preservatives, perfumes, flavoring agents, sweeteners or other materials may also be added to the pharmaceutical preparations as needed.
为达到用药目的，增强治疗效果， 本发明的药物或药物组合物可用任何公知 的给药方法给药。  The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
本发明化合物药物组合物的给药剂量取决于许多因素，例如所要预防或治疗 疾病的性质和严重程度， 患者或动物的性别、 年龄、 体重、 性格及个体反应， 给 药途径、 给药次数、 治疗目的， 因此本发明的治疗剂量可以有大范围的变化。一 般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发 明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整， 以达 到其治疗有效量的要求， 完成本发明的预防或治疗目的。本发明化合物的每天的 合适剂量范围： 本发明的化合物的用量为 0.001〜100mg/Kg体重， 优选为 0.1〜 60mg/Kg体重， 更优选为 l〜30mg/Kg体重， 最优选为 2〜15mg/Kg体重。 成人 患者服用的本发明化合物每日为 10〜500mg，优选为 20〜100mg，可一次服用或 分 2〜3次服用； 儿童服用的剂量按照每 kg体重 5〜30mg， 优选为 10〜20mg/kg 体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药， 这受限于给药医生的临床经验以及治疗手段的给药方案。本发明的化合物或组合 物可单独服用， 或与其他治疗药物或对症药物合并使用。  The dosage of the pharmaceutical composition of the compound of the present invention depends on a number of factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of administrations, For therapeutic purposes, the therapeutic dose of the present invention can vary widely. In general, the dosage of the pharmaceutical ingredient of the present invention is well known to those skilled in the art. The prophylactic or therapeutic purpose of the present invention can be accomplished by appropriately adjusting the amount of the actual drug contained in the final formulation of the compound composition of the present invention to achieve a therapeutically effective amount thereof. Suitable daily dosage range for the compound of the present invention: The compound of the present invention is used in an amount of 0.001 to 100 mg/kg body weight, preferably 0.1 to 60 mg/kg body weight, more preferably 1 to 30 mg/kg body weight, and most preferably 2 to 15 mg/ Kg weight. The compound of the present invention administered by an adult patient is 10 to 500 mg, preferably 20 to 100 mg per day, and can be taken once or 2 to 3 times; the dosage for children is 5 to 30 mg per kg of body weight, preferably 10 to 20 mg/kg. body weight. The above dosages may be administered in a single dosage form or divided into several, for example two, three or four dosage forms, which are limited by the clinical experience of the administering physician and the dosage regimen of the therapeutic means. The compounds or compositions of this invention may be administered alone or in combination with other therapeutic or symptomatic agents.
本发明还涉及本发明的化合物在制备防治神经退行性疾病药物中的应用。所 述疾病包括阿尔茨海默病、 帕金森病、 多发性硬化、 肌肉萎缩性侧索硬化症、 共 济失调毛血管扩张症、 牛海绵状脑病、 克雅二氏病、 亨廷顿氏病、 小脑萎缩症、 原发性侧索硬化症、 脊髓性肌萎缩症。 附图说明  The invention further relates to the use of a compound of the invention in the manufacture of a medicament for the prevention and treatment of neurodegenerative diseases. The diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellum Atrophy, primary lateral sclerosis, spinal muscular atrophy. DRAWINGS
图 1. 实施例 1 禾 B 28对小鼠转棍行为学的影响， **P<0.01 vs. Control 小鼠， #P<0.05, ##P<0.01 vs. MPTP模型小鼠 图 2. 实施例 1 和 28对小鼠爬杆行为学的影响， **P<0.01 vs. Control 小鼠， #P<0.05, ##P<0.01 vs. MPTP模型小鼠 图 3. 实施例 1和 28对 MPTP引起的亚急性 PD模型小鼠黑质中多巴胺神经元的 影响， **P<0.01 vs. Control小鼠， #P<0.05 , ##P<0.01 vs. MPTP模型小鼠， n=4~5 图 4. 实施例 1和 28对 MPTP/p引起的慢性 PD模型小鼠黑质中多巴胺神经元的 影响， *P<0.01 vs. Control小鼠， #P<0.05 , ##P<0.01 vs. MPTP/p模型小鼠， n=4~5 具体实施方式 Figure 1. Effect of Example 1 on the behavior of mouse roller sticks, **P<0.01 vs. Control mice, #P<0.05, ##P<0.01 vs. MPTP model mice Figure 2. Effect of Examples 1 and 28 on mouse crawler behavior, **P<0.01 vs. Control mice, #P<0.05, ##P<0.01 vs. MPTP model mice. Figure 3. Example Effects of 1 and 28 on MPTP-induced dopaminergic neurons in substantia nigra PD mice, **P<0.01 vs. Control mice, #P<0.05, ##P<0.01 vs. MPTP model mice, n=4~5 Figure 4. Effect of Examples 1 and 28 on dopaminergic neurons in the substantia nigra of chronic PD model mice induced by MPTP/p, *P<0.01 vs. Control mice, #P<0.05, ## P<0.01 vs. MPTP/p model mice, n=4~5
下面的实施例用来进一步说明本发明，但这并不意味着对本发明的任何限制。 实施例 1. 1-(2-甲氧基 -4,6-二 -3-甲基 -1-丁酮的制备
Figure imgf000020_0001
The following examples are intended to further illustrate the invention, but are not intended to limit the invention in any way. Example 1. Preparation of 1-(2-methoxy-4,6-bis-3-methyl-1-butanone
Figure imgf000020_0001
步骤 1 : 1-(2,4,6-三羟基苯基) -3-甲基 -1-丁酮的制备  Step 1: Preparation of 1-(2,4,6-trihydroxyphenyl)-3-methyl-1-butanone
将 5.00 g (40 mmol) 间苯三酚溶于 50 mL二硫化碳和 15 mL硝基苯的混合 溶液中， 加入 15.6 g (120 mmol) 无水三氯化铝， 室温搅拌 10 分钟； 向反应液 中缓慢滴加 20 mL含 4.82 g C40 mmoll) 异戊酰氯的二硫化碳溶液， 之后于 50°C 下加热回流 30 分钟；完毕后减压蒸干二硫化碳， 向残留物中滴入 10 mL盐酸和 20 mL冰水混合物， 用 3 x50 mL 乙酸乙酯萃取， 合并有机层， 用 3 x25 mL饱和 氯化钠溶液洗涤， 无水硫酸钠干燥； 减压蒸干溶剂后， 进行硅胶柱色谱 （氯仿： 甲醇 20: 1 ) 分离， 得到 1-(2,4,6-三羟基苯基) -3-甲基 -1-丁酮 6.5g， 收率 78%。  Dissolve 5.00 g (40 mmol) of phloroglucin in a mixture of 50 mL of carbon disulfide and 15 mL of nitrobenzene, add 15.6 g (120 mmol) of anhydrous aluminum chloride, and stir at room temperature for 10 minutes; 20 mL of a carbon disulfide solution containing 4.82 g of C40 mmoll of isovaleryl chloride was slowly added dropwise, followed by heating at 50 ° C for 30 minutes; after completion, the carbon disulfide was evaporated under reduced pressure, and 10 mL of hydrochloric acid and 20 mL of ice were added dropwise to the residue. The mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layer was washed with 3×25 mL of saturated sodium chloride solution and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, silica gel column chromatography (chloroform: methanol 20: 1) Separation gave 6.5 g of 1-(2,4,6-trihydroxyphenyl)-3-methyl-1-butanone in a yield of 78%.
步骤 2: 1-[2-羟基 -4,6-二 (甲氧基甲氧基)苯基] -3甲基小丁酮的制备 将按照步骤 1所得 2.1 g (10 mmol) 1-(2,4,6-三羟基苯基) -3-甲基 -1-丁酮溶于 50 mL二氯甲垸中， 于 0°C下冷却， 加入 3.65 mL (21 mmol)二丙基乙胺， 搅拌 15分钟，将 1.6 mL (25 mmol)氯甲基甲醚溶解于 20 mL二氯甲垸中， 缓慢滴加至 反应液， 完毕后于 0°C下反应 15分钟， 再于室温下反应 45分钟。 将反应液倾入 lOO mL水中， 用 3 x50 mL氯仿萃取， 合并有机层， 用 3 x 15 mL饱和氯化钠溶 液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色谱（石油醚:乙酸乙酯 15: 1 ) 分离得到 1-[2-羟基 -4,6-二 (甲氧基甲氧基)苯基] -3-甲基 -1-丁酮 1.40 g， 收率 47%。 步骤 3 : 1-[2-甲氧基 -4,6-二 (甲氧基甲氧基)苯基] -3甲基 -1-丁酮的制备 将步骤 2中所得的 300 mg (1 mmol) 1-[2-羟基 -4,6-二（甲氧基甲氧基)苯基] -3- 甲基 -1-丁酮溶于 20 mL丙酮中， 加入 276 mg (2 mmol)无水碳酸钾， 加热回流 20分钟， 向反应液中加入 100 μΐ (2 mmol)硫酸二甲酯， 继续回流 5小时。 减压 蒸干反应液， 残留物中加入 20 mL水， 用 3 x25 mL乙酸乙酯萃取， 合并有机层， 用 3 x 10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色 谱（石油醚:乙酸乙酯 30: 1 )分离得到 1-[2-甲氧基 -4,6-二 (甲氧基甲氧基)苯基] - 3- 甲基 -1-丁酮 250 mg, 收率 80%。 Step 2: Preparation of 1-[2-hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methylbutanone 2.1 g (10 mmol) 1-(2) obtained according to step 1. , 4,6-trihydroxyphenyl)-3-methyl-1-butanone was dissolved in 50 mL of dichloromethane, cooled at 0 ° C, and added to 3.65 mL (21 mmol) of dipropylethylamine. After stirring for 15 minutes, 1.6 mL (25 mmol) of chloromethyl methyl ether was dissolved in 20 mL of dichloromethane, and slowly added dropwise to the reaction solution. After completion, the reaction was carried out at 0 ° C for 15 minutes, and then at room temperature. minute. The reaction solution was poured into 100 mL of water, extracted with 3×50 mL of chloroform, and the organic layer was combined, washed with 3×15 mL of saturated sodium chloride and dried over anhydrous sodium sulfate. Evaporate the solvent and perform silica gel column chromatography (petrole ether: ethyl acetate 15:1) 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone 1.40 g was obtained in a yield of 47%. Step 3: Preparation of 1-[2-methoxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone 300 mg (1 mmol) obtained in Step 2 1-[2-Hydroxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone is dissolved in 20 mL of acetone, 276 mg (2 mmol) anhydrous Potassium carbonate was heated under reflux for 20 minutes, and 100 μM (2 mmol) of dimethyl sulfate was added to the reaction mixture, followed by reflux for 5 hours. The reaction mixture was evaporated to dryness. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (ethyl ether: ethyl acetate 30:1) to give 1-[2-methoxy-4,6-di(methoxymethoxy)phenyl]-3- 3- Keto-1-butanone 250 mg, yield 80%.
步骤 4: 1-(4-甲氧基 -2,6-二羟基苯基) -3-甲基 -1-丁酮的制备  Step 4: Preparation of 1-(4-methoxy-2,6-dihydroxyphenyl)-3-methyl-1-butanone
将步骤 3中所得的 250 mg (0.80 mmol) 1-[2-甲氧基 -4,6-二（甲氧基甲氧基)苯 基] - 3-甲基 -1-丁酮溶于 10 mL甲醇中， 加入 2mL 2N盐酸， 加热回流 1小时， 减 压蒸干反应液中的有机溶剂， 残留物中加入 20 mL水， 用 3 x25 mL乙酸乙酯萃 取， 合并有机层， 用 3 x 10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶 剂， 进行硅胶柱色谱 （石油醚:乙酸乙酯 20: 1 ) 分离得到 1-(4-甲氧基 -2,6-二羟基 苯基) -3-甲基 -1-丁酮 185 mg, 收率 83%。  250 mg (0.80 mmol) of 1-[2-methoxy-4,6-bis(methoxymethoxy)phenyl]-3-methyl-1-butanone obtained in Step 3 was dissolved in 10 To the methanol, 2 mL of 2N hydrochloric acid was added, and the mixture was heated under reflux for 1 hour. The organic solvent was evaporated to dryness under reduced pressure. 20 mL of water was added to the residue and extracted with 3×25 mL of ethyl acetate. The solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (ethyl ether: ethyl acetate 20:1) to give 1-(4-methoxy-2,6-dihydroxyphenyl)-3-methyl-1-butanone 185 Mg, yield 83%.
1H MR (500 MHz, d6-DMSO) δ 13.59 (br.s, OH-4 ' , OH-6 ' ), 5.94 (1H, s, H-5 ' ), 5.85 (1H, s, H-3 ' ), 3.80 (3H, s, OCH3 ), 2.77 (2H, d, J = 6.5 Hz, H-2), 2.07 (1H, m, H-3), 0.89 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, 1H MR (500 MHz, d 6 -DMSO) δ 13.59 (br.s, OH-4 ' , OH-6 ' ), 5.94 (1H, s, H-5 ' ), 5.85 (1H, s, H-3 ' ), 3.80 (3H, s, OCH 3 ), 2.77 (2H, d, J = 6.5 Hz, H-2), 2.07 (1H, m, H-3), 0.89 (6H, d, J = 6.5 Hz , CH 3 -4, CH 3 -5). 13 C NMR (125 MHz,
i¾-DMSO) δ 204.0, 165.7, 164.4, 162.4, 104.2, 95.3, 90.9, 55.3, 51.9, 24.5, 22.2. 22.2。 实施例 2. 3-[3,5-二羟基 -2-(3- -4-苯基呋咱的制备 I3⁄4-DMSO) δ 204.0, 165.7, 164.4, 162.4, 104.2, 95.3, 90.9, 55.3, 51.9, 24.5, 22.2. 22.2. Example 2. Preparation of 3-[3,5-dihydroxy-2-(3--4-phenylfurazan)
Figure imgf000021_0001
Figure imgf000021_0001
步骤 1 : 3-羟甲基 -4-苯基呋咱的制备 Step 1: Preparation of 3-hydroxymethyl-4-phenylfurazan
将 2.00 g (15 mmol)肉桂醇加入 3 mL冰醋酸中， 室温搅拌至其溶解， 冰浴冷 却下向反应液中滴加含 3.00 g (72 mmol) NaN02的饱和水溶液， 滴加完毕后室温 搅拌 5小时。 向反应液中加入 20 mL水， 用 3x50 mL乙酸乙酯萃取， 合并有机 层， 依次用 3χ 15 mL 5% NaOH溶液和 3x20 mL饱和氯化钠溶液洗涤， 无水硫酸 钠干燥， 减压蒸干得油状物 2.50 g。 Add 2.00 g (15 mmol) of cinnamyl alcohol to 3 mL of glacial acetic acid, stir at room temperature until it is dissolved, and ice-cold cold However, a saturated aqueous solution containing 3.00 g (72 mmol) of NaN0 2 was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 5 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with 3×50 mL of ethyl acetate. The organic layer was combined, washed successively with 3 χ 15 mL 5% NaOH solution and 3×20 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness An oil of 2.50 g was obtained.
步骤 2: 3-氯甲基 -4-苯基呋咱的制备 Step 2: Preparation of 3-chloromethyl-4-phenylfurazan
将步骤 1中所得的油状物 330 mg溶于 15 mL无水二氯甲垸中， 加入 0.32 mL (4 mmol)吡啶，冰浴冷却下向反应液中滴加 0.35 mL S0C12，室温搅拌 3小时。 将反应液依次用 3x15 mL冰水、 3x15 mL饱和 Na2C03溶液和 3x15 mL饱和氯 化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色谱 （石油醚:乙酸乙 酯 7:1) 分离得到 3-氯甲基 -4-苯基呋咱 280 mg， 收率 78%。 330 mg of the oil obtained in the step 1 was dissolved in 15 mL of anhydrous dichloromethane, 0.32 mL (4 mmol) of pyridine was added, and 0.35 mL of S0C1 2 was added dropwise to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 3 hours. . The reaction solution was washed with 3×15 mL of ice water, 3×15 mL of saturated Na 2 CO 3 3 and 3 ×15 mL of saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness, and then silica gel column chromatography ( petroleum ether: ethyl acetate: 7:1) to afford 3-chloromethyl-4-phenylfuran 280 mg, yield 78%.
步骤 3: 3-[3,5-二羟基 -2-(3-甲基丁酰基)苯氧基]甲基 -4-苯基呋咱的制备 Step 3: Preparation of 3-[3,5-dihydroxy-2-(3-methylbutanoyl)phenoxy]methyl-4-phenylfurazan
将步骤 2中所得的 3-氯甲基 -4-苯基呋咱 210 mg (1 mmol)溶于 20 mL乙腈， 加入 210 mg (1 mmol)按照实施例 1步骤 1所得的 1-(2,4,6-三羟基苯基) -3-甲基 -1- 丁酮， 207mg(；1.5mmol；)无水K2CO3和少量KI， 加热回流 10小时， 加压蒸干反 应液，残留物中加入 20 mL水，用 3x25 mL乙酸乙酯萃取，合并有机层，用 3><10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色谱（石油 醚： 乙酸乙酯 5:1)分离得到 3-[3,5-二羟基 -2-(3-甲基丁酰基)苯氧基]甲基 -4-苯基 呋咱 200 mg, 收率 53%。 The 3-chloromethyl-4-phenylfurazan 210 mg (1 mmol) obtained in the step 2 was dissolved in 20 mL of acetonitrile, and 210 mg (1 mmol) of 1-(2, 4,6-trihydroxyphenyl)-3-methyl-1-butanone, 207 mg (; 1.5 mmol;) anhydrous K 2 CO 3 and a small amount of KI, heated under reflux for 10 hours, and the reaction mixture was evaporated to dryness under pressure. 20 mL of water was added, and extracted with 3×25 mL of ethyl acetate. The organic layer was combined, washed with 3>< 10 mL of saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (ethyl ether: ethyl acetate 5:1) to give 3-[3,5-dihydroxy-2-(3-methylbutanoyl)phenoxy]methyl-4- Phenylfurazan 200 mg, yield 53%.
1H MR (500 MHz, i¾-DMSO) δ 13.43 (1Η, s, OH-6' ), 10.73 (1H, s,  1H MR (500 MHz, i3⁄4-DMSO) δ 13.43 (1Η, s, OH-6' ), 10.73 (1H, s,
OH-4 ' ), 7.79 (2H, d, J = 7.5 Hz, H-2' ' ' , H-6 ' ' ' ), 7.63 (2H, t, J = 7.5 Hz, H-3' ' ' ,H-5' ' ' ), 7.59 (1H, t, J = 7.5 Hz, H-4' ' ' ), 6.08 (1H, d, J = 1.5 Hz: H-3' ), 5.96(1H, d, J = 1.5 Hz, H-5' ), 5.24 (2H, s, H-l' ' ), 2.44 (2H, d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 0.66 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, 6-DMSO) δ 204.1, 165.7, 164.5, 160.2, 156.9, 131.8, 129.7, 129.7, 127.6, 127.6, 125.6, 112.3, 105.2, 96.9, 92.6, 59.1, 52.2, 24.5, 22.3, 22.3。 OH-4 ' ), 7.79 (2H, d, J = 7.5 Hz, H-2''' , H-6 ''' ), 7.63 (2H, t, J = 7.5 Hz, H-3''' , H-5''' ), 7.59 (1H, t, J = 7.5 Hz, H-4''' ), 6.08 (1H, d, J = 1.5 Hz: H-3' ), 5.96(1H, d, J = 1.5 Hz, H-5' ), 5.24 (2H, s, Hl'' ), 2.44 (2H, d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 0.66 (6H, d, J = 6.5 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, 6 -DMSO) δ 204.1, 165.7, 164.5, 160.2, 156.9, 131.8, 129.7, 129.7, 127.6, 127.6, 125.6, 112.3, 105.2, 96.9, 92.6, 59.1, 52.2, 24.5, 22.3, 22.3.
实施例 3. (±)-l-[2-(2-羟基 -3-异丙胺基丙氧基； )-4,6-二羟基苯基] -3-甲基 -1-丁酮盐 酸盐的制备
Figure imgf000023_0001
Example 3. (±)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy; )-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
Figure imgf000023_0001
步骤 1 : 对甲苯磺酸苄酯的制备  Step 1: Preparation of benzyl p-toluenesulfonate
将 10.49 g (97 mmol) 苯甲醇溶于 200 mL无水***中，加入 2.4 g (10 mmol) 氢化钠，加热回流 12小时，反应液低温冷却至 -30°C，缓慢滴入含 19.5 g (102 mmol) 对甲苯磺酰氯的无水***溶液 100 mL， 完毕后于 -20°C下反应 2小时， 再室温下 反应 1小时， 过滤， 滤液蒸干， 进行硅胶柱色谱（石油醚:乙酸乙酯 40: 1 )分离， 得对甲苯磺酸苄酯 9.8 g， 收率 37%。  10.49 g (97 mmol) of benzyl alcohol was dissolved in 200 mL of anhydrous diethyl ether, 2.4 g (10 mmol) of sodium hydride was added, and the mixture was heated under reflux for 12 hours. The reaction solution was cooled to -30 ° C, and slowly dropped into 19.5 g ( 102 mmol) 100 mL of p-toluenesulfonyl chloride in anhydrous diethyl ether. After completion, react at -20 ° C for 2 hours, then react at room temperature for 1 hour, filter, and evaporate the filtrate to carry out silica gel column chromatography (petroleum ether: acetic acid The ester 40: 1) was isolated to give 9.8 g of benzyl p-toluenesulfonate in a yield of 37%.
步骤 2: 1-(2-羟基 -4, 6-二苯甲氧基苯基;) -3-甲基 -1-丁酮的制备  Step 2: Preparation of 1-(2-hydroxy-4,6-diphenylmethoxyphenyl;)-3-methyl-1-butanone
将按照实施例 1步骤 1所得 3 g (14.3 mmol) 1-(2,4,6-三羟基苯基) -3-甲基 -1- 丁酮溶于 200 mL丙酮中， 加入步骤 1中所得 7.86 g (30 mmol) 对甲苯磺酸苄酯 和 25 g (181 mmol) 无水碳酸钾， 加热回流 3小时， 冷却后蒸干反应液， 残留物 用 150 mL水溶解， 用 3 x50 mL乙酸乙酯萃取， 合并有机层， 用 2x l5 mL饱和 氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色谱 （石油醚:乙酸 乙酯 30: 1 )分离得到 1-(2-羟基 -4, 6-二苯甲氧基苯基) -3-甲基 -1-丁酮 2.98 g，收率 53%。  3 g (14.3 mmol) of 1-(2,4,6-trihydroxyphenyl)-3-methyl-1-butanone obtained in the first step of Example 1 was dissolved in 200 mL of acetone and added to the step 1. 7.86 g (30 mmol) benzyl p-toluenesulfonate and 25 g (181 mmol) anhydrous potassium carbonate, heated under reflux for 3 hours, cooled and evaporated to dryness. The residue was dissolved in 150 mL of water, using 3 x 50 mL of ethyl acetate The ester was extracted, and the organic layer was combined, washed with 2×l 5 mL of saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness, and then purified to silica gel column chromatography (ethyl ether: ethyl acetate 30:1) to give 1-(2-hydroxy-4,6-diphenylmethoxyphenyl)-3-methyl-1-butanone 2.98 g, yield 53%.
步骤 3 : (±)-1-[2- (环氧乙 -2-基)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮的 制备  Step 3: Preparation of (±)-1-[2-(epoxyethyl-2-yl)methoxy- 4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone
将步骤 2所得的 1.00 g (2.5 mmol) 1-(2-羟基 -4, 6-二苯甲氧基苯基) -3-甲基 -1- 丁酮溶于 100 mL N,N-二甲基甲酰胺， 通入氮气， 搅拌 5分钟； 力口入 0.09 g (3.75 mmol)氢化钠， 于 40°C下反应 20分钟， 持续通入氮气； 加入 1.16 g (12.5 mmol) (±)-2-氯甲基环氧乙垸，于 90°C下反应 2小时；待反应液冷却至室温后，倾入 100 mL水中， 用 3 x50 mL乙酸乙酯萃取， 合并有机层， 用 3 >< 15 mL饱和氯化钠溶 液洗涤，无水硫酸钠干燥；减压蒸干溶剂，经硅胶柱色谱（石油醚：乙酸乙酯 20: 1 ) 分离得到 (±)-1-[2- (环氧乙 -2-基)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 0.90 g， 收率 81%。  1.00 g (2.5 mmol) of 1-(2-hydroxy-4,6-diphenylmethoxyphenyl)-3-methyl-1-butanone obtained in Step 2 was dissolved in 100 mL of N,N-dimethyl Base carboxamide, nitrogen was added, stirred for 5 minutes; 0.09 g (3.75 mmol) sodium hydride was added to the solution, and the reaction was carried out at 40 ° C for 20 minutes, and nitrogen gas was continuously introduced; 1.16 g (12.5 mmol) (±)-2 was added. -Chloromethyloxime oxime, reacted at 90 ° C for 2 hours; after the reaction solution was cooled to room temperature, pour into 100 mL of water, extract with 3 x 50 mL of ethyl acetate, and combine the organic layers with 3 > < 15 The mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness eluted to silica gel column ( petroleum ether: ethyl acetate 20:1) to give (±)-1-[2- (epoxy 2-yl)methoxy-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone 0.90 g, yield 81%.
步骤 4: (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二苯甲氧基苯基] -3-甲基 -1- 丁酮盐酸盐的制备 Step 4: (±)-1-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1- Preparation of butanone hydrochloride
将步骤 3中所得的 450 mg (l mmol) (±)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二苯甲 氧基苯基] -3-甲基 -1-丁酮置于厚壁耐压管中，加入 3 mL (35 mmol) 异丙胺，搅拌 均匀， 于 70°C下反应 2小时； 冷却后减压蒸干反应液， 残留物用 20 mL无水乙 醚溶解， 搅拌下滴加饱和氯化氢***溶液， 过滤， 得固体 (±)-1-[2-(2-羟基 -3-异丙 胺基丙氧基) -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 400 mg, 收率 74%。  450 mg (1 mmol) of (±)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-diphenylmethoxyphenyl]-3-methyl obtained in Step 3 Base 1-butanone was placed in a thick-walled pressure-resistant tube, 3 mL (35 mmol) of isopropylamine was added, stirred well, and reacted at 70 ° C for 2 hours; after cooling, the reaction solution was evaporated under reduced pressure, and the residue was used. Dissolve in anhydrous ethyl ether, add saturated hydrogen chloride ether solution with stirring, and filter to obtain solid (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4,6-diphenyl Oxyphenyl]-3-methyl-1-butanone hydrochloride 400 mg, yield 74%.
步骤 5 : (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基 )-4,6-二羟基苯基] -3-甲基 -1-丁酮 盐酸盐的制备  Step 5: (±)-1-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride Preparation
将步骤 4中所得的 170 mg (0.31 mmol) (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基） _4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮盐酸盐溶于 30 mL 甲醇中， 加入 100 mg 钯 碳和 2 mL盐酸， 在 3 atm的压力下进行催化氢化 12小时， 过滤， 滤液蒸干， 将 所得油状物进行制备 HPLC ( YMC柱， 22%乙腈）分离， 得到 (±)-1-[2-(2-羟基 -3- 异丙胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 50 mg, 收率 49%。  170 mg (0.31 mmol) of (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4,6-diphenylmethoxyphenyl]-3- obtained in the step 4 Methyl-1-butanone hydrochloride was dissolved in 30 mL of methanol, and 100 mg of palladium on carbon and 2 mL of hydrochloric acid were added thereto, and catalytic hydrogenation was carried out at a pressure of 3 atm for 12 hours, filtered, and the filtrate was evaporated to dryness. Preparative HPLC (YMC column, 22% acetonitrile) was isolated to give (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl Keto-1-butanone hydrochloride 50 mg, yield 49%.
1H MR (500 MHz, d6-DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, H-l ' ' a), 3.92 (1H, overlap, H-l ' ' b), 3.88 (1H, m, H-2 ' ' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' a), 2.77 (1H, m, H-5 ' ' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a), 2.60 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 0.99 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.88 (3H, d, J = 6.5 Hz, CH3-5)。 13C NMR (125 MHz , 6-DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7: 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 4. (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 )-4,6-二羟基苯基] -3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, d 6 -DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, Hl '' a), 3.92 (1H, overlap, Hl '' b), 3.88 (1H, m, H-2 '' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' a), 2.77 (1H, m, H-5 '' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a ), 2.60 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH 3 -6 '' ), 0.99 (3H, d, J = 6.0 Hz, CH 3 -7 '' ), 0.90 (3H, d, J = 6.5 Hz, CH 3 -4), 0.88 (3H, d, J = 6.5 Hz, CH 3 - 5) 13 C NMR (125 MHz, 6 -DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7 : 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6. Example 4. (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride preparation
Figure imgf000024_0001
Figure imgf000024_0001
步骤 l : (S)-l-[2- (2,2-二甲基 -1,3-二氧戊环 -4-基)甲氧基 -4,6- -3-甲基 -1-丁酮的制备 将实施例 3中步骤 2所得的 3.00 g (7.5 mmol) 1 -(2-羟基 -4,6-二苯甲氧基苯 基 )-3-甲基- i -丁酮溶于 20 mL N,N-二甲基甲酰胺， 通入氮气， 搅拌 5分钟； 加入Step l : (S)-l-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy-4,6--3-methyl-1- Preparation of butanone 3.00 g (7.5 mmol) of 1-(2-hydroxy-4,6-diphenylmethoxyphenyl) -3 -methyl-i-butanone obtained in Step 2 of Example 3 was dissolved in 20 mL of N , N -dimethylformamide, nitrogen gas, stirring for 5 minutes;
0.27 g (11.3 mmol)氢化钠， 于 40°C下反应 20分钟， 持续通入氮气； 加入 3.39 g (22.5mmol) (R)-4-氯甲基 -2,2-二甲基 -1,3-二氧戊环，于 90°C下反应 24小时；待反 应液冷却至室温后， 倾入 50 mL水中， 用 3 x50 mL乙酸乙酯萃取， 合并有机层， 用 3 x 15 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥； 减压蒸干溶剂， 经硅胶柱 色谱 （石油醚： 乙酸乙酯 30: 1 ) 分离得到 (S)-l-[2- (2,2-二甲基 -1,3-二氧戊环 -4- 基)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 0.90 g， 收率 23%。 0.27 g (11.3 mmol) of sodium hydride was reacted at 40 ° C for 20 minutes, and nitrogen gas was continuously introduced; 3.39 g (22.5 mmol) of (R)-4-chloromethyl-2,2-dimethyl-1 was added. 3-Dioxolane, reacted at 90 ° C for 24 hours; after the reaction solution was cooled to room temperature, poured into 50 mL of water, extracted with 3 x 50 mL of ethyl acetate, combined with organic layer, with 3 x 15 mL of saturated chlorine The solution was washed with sodium chloride and dried over anhydrous sodium sulfate. The solvent was evaporated to dryness. Methyl-1,3-dioxolan-4-yl)methoxy-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone 0.90 g, yield 23%.
步骤 2: (R)-l-[2-(2,3-二羟基丙氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮的 制备  Step 2: Preparation of (R)-l-[2-(2,3-dihydroxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone
将步骤 1中得到的 900 mg (1.86 mmol) (S)-l-[2- (2,2-二甲基 -1,3-二氧戊环 -4- 基;)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮溶于 20 mL四氢呋喃中， 缓慢滴 加 4%硫酸 10 mL，室温下反应 8小时，减压蒸掉有机溶剂，剩余溶液用 3 x30 mL 乙酸乙酯萃取， 合并有机层， 用饱和碳酸氢钠溶液洗至中性， 再用 3 x 15 mL饱 和氯化钠溶液洗涤， 无水硫酸钠干燥， 减压蒸干有机层， 得 (R)-l-[2-(2,3-二羟基 丙氧基）-4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 840 mg， 收率 98%。  900 mg (1.86 mmol) of (S)-l-[2-(2,2-dimethyl-1,3-dioxolan-4-yl;)methoxy-4 obtained in the first step, 6-Diphenylmethoxyphenyl]-3-methyl-1-butanone was dissolved in 20 mL of tetrahydrofuran, and 10 mL of 4% sulfuric acid was slowly added dropwise. The reaction was carried out for 8 hours at room temperature, and the organic solvent was evaporated under reduced pressure. The solution was extracted with 3 x 30 mL of ethyl acetate. The organic layer was combined, washed with saturated sodium hydrogen carbonate solution to neutral, washed with 3 x 15 mL of saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated , (R)-l-[2-(2,3-dihydroxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone 840 mg, yield 98%.
步骤 3 : (S)-l-[2-(2-羟基 -3-对甲苯磺酰氧基丙氧基） -4,6-二苯甲氧基苯基] -3- 甲基 -1-丁酮的制备  Step 3: (S)-l-[2-(2-Hydroxy-3-p-toluenesulfonyloxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1- Preparation of butanone
将步骤 2中得到的 800 mg (1.76 mmol) (R)-l-[2-(2,3-二羟基丙氧基） -4,6-二苯 甲氧基苯基] -3-甲基 -1-丁酮溶于 20 mL干燥二氯甲垸中，加入少量吡啶， 向反应 液中缓慢滴加含 336 mg (1.76 mmol) 对甲苯磺酰氯的二氯甲垸溶液 10 mL,室温 下反应 48小时， 减压蒸干反应液， 经硅胶柱色谱（石油醚:酸乙酯 15 : 1 )分离得 (S)-l-[2-(2-羟基 -3-对甲苯磺酰氧基丙氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 320 mg, 收率 29%。  800 mg (1.76 mmol) of (R)-l-[2-(2,3-dihydroxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl group obtained in step 2 1-butanone was dissolved in 20 mL of dry dichloromethane, a small amount of pyridine was added, and 10 mL of a solution of 336 mg (1.76 mmol) of p-toluenesulfonyl chloride in dichloromethane was slowly added dropwise to the reaction solution, and the reaction was carried out at room temperature. After 48 hours, the reaction mixture was evaporated to dryness (mjjjjjjjjjjj Oxy)) 4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone 320 mg, yield 29%.
步骤 4: (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮 盐酸盐的制备  Step 4: (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride Preparation
将步骤 3中所得的 160 mg (0.26 mmol) (S i-P-O羟基 -3-对甲苯磺酰氧基丙 氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮置于厚壁耐压管中， 加入 3 mL (35 mmol)异丙胺， 搅拌均匀， 于 70°C下反应 2小时； 冷却后减压蒸干反应液， 得 油状物 100 mg。将该油状物溶于 30 mL 甲醇中，加入 50 mg钯碳和 1 mL盐酸， 在 3 atm的压力下进行催化氢化 12小时， 过滤， 滤液蒸干， 将所得油状物进行 制备 HPLC ( YMC柱， 22%乙腈） 分离， 得到 (R)-l-[2-(2-羟基 -3-异丙胺基丙氧 基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 30 mg, 收率 32%。 160 mg (0.26 mmol) of the obtained step 3 (S iPO hydroxy-3-p-toluenesulfonyloxypropoxy) -4,6-diphenylmethoxyphenyl]-3-methyl-1- Butanone was placed in a thick-walled pressure-resistant tube, 3 mL (35 mmol) of isopropylamine was added, stirred well, and reacted at 70 ° C for 2 hours. After cooling, the reaction solution was evaporated to dryness under reduced pressure. Oil 100 mg. The oil was dissolved in 30 mL of methanol, 50 mg of palladium on carbon and 1 mL of hydrochloric acid were added, and catalytic hydrogenation was carried out under a pressure of 3 atm for 12 hours, filtered, and the filtrate was evaporated to dryness, and the obtained oil was subjected to preparative HPLC (YMC column, Separation of 22% acetonitrile afforded (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone Hydrochloride 30 mg, yield 32%.
1H MR (500 MHz, d6-DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, H-l ' ' a), 3.92 (1H, overlap, H-l ' ' b), 3.88 (1H, m, H-2 ' ' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' a), 2.77 (1H, m, H-5 ' ' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a), 2.72 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 0.99 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.88 (3H, d, J = 6.5 Hz, CH3-5)。 13C NMR (125 MHz, i¾-DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7, 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 5. (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, d 6 -DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, Hl '' a), 3.92 (1H, overlap, Hl '' b), 3.88 (1H, m, H-2 '' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' a), 2.77 (1H, m, H-5 '' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a ), 2.72 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH 3 -6 '' ), 0.99 (3H, d, J = 6.0 Hz, CH 3 -7 '' ), 0.90 (3H, d, J = 6.5 Hz, CH 3 -4), 0.88 (3H, d, J = 6.5 Hz, CH 3 - 5) 13 C NMR (125 MHz, i3⁄4-DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7, 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6. Example 5. (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride preparation
Figure imgf000026_0001
Figure imgf000026_0001
步骤 1 : (R)-l-[2-(2,2-二甲基 -1,3-二氧戊环 -4-基)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮的制备  Step 1: (R)-l-[2-(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy-4,6-diphenylmethoxyphenyl] Preparation of -3-methyl-1-butanone
按照实施例 4中步骤 1的方法， 采用 3.00 g (7.5 mmol) 1 -(2-羟基 -4,6-二苯甲 氧基苯基) -3-甲基 -1-丁酮、 0.27 g (11.3 mmol)氢化钠和 3.39 g (22.5mmol) (S)-4-氯 甲基 -2,2-二甲基 -1,3-二氧戊环反应后， 经硅胶柱色谱 （石油醚:乙酸乙酯 30: 1 ) 分离得到 (R)-l-[2-(2,2-二甲基 -1,3-二氧戊环 -4-基)甲氧基 -4,6-二苯甲氧基苯基] -3- 甲基 -1-丁酮 1.20 g， 收率 31%。  3.00 g (7.5 mmol) of 1-(2-hydroxy-4,6-diphenylmethoxyphenyl)-3-methyl-1-butanone, 0.27 g (using the procedure of Step 1 in Example 4) 11.3 mmol) sodium hydride and 3.39 g (22.5 mmol) of (S)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane, after silica gel column chromatography (petroleum ether: acetic acid Ethyl ester 30: 1) isolated (R)-l-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy-4,6-diphenyl Oxyphenyl]-3-methyl-1-butanone 1.20 g, yield 31%.
步骤 2: (S)-l-[2-(2,3-二羟基丙氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮的 制备  Step 2: Preparation of (S)-l-[2-(2,3-dihydroxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone
按照实施例 4中步骤 2的方法，采用 1.20 g (2.38 mmol) (R)-l-[2- (2,2-二甲基 -1,3-二氧戊环 -4-基)甲氧基 -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮得到 (S)-l-[2-(2, 3-二羟基丙氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 1.06 g， 收率 96%。 Following the procedure of Step 2 in Example 4, 1.20 g (2.38 mmol) of (R)-l-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy Benzyl-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone gives (S)-l-[2-(2, 3-Dihydroxypropoxy) -4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone 1.06 g, yield 96%.
步骤 3 : (R)-l-[2-(2-羟基 -3-对甲苯磺酰氧基丙氧基) -4,6-二苯甲氧基苯基] -3- 甲基 -1-丁酮的制备  Step 3: (R)-l-[2-(2-Hydroxy-3-p-toluenesulfonyloxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1- Preparation of butanone
按照实施例 4中步骤 3的方法， 采用步骤 2中得到的 1.06 g (2.28 mmol) According to the method of Step 3 in Example 4, 1.06 g (2.28 mmol) obtained in Step 2 was used.
(S)-l-[2-(2,3-二羟基丙氧基） -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮和 434 mg (2.28 mmol)对甲苯磺酰氯反应后， 经硅胶柱色谱 （石油醚:乙酸乙酯 15 : 1 ) 分离得(S)-l-[2-(2,3-Dihydroxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone and 434 mg (2.28 mmol) After reacting with toluenesulfonyl chloride, it was separated by silica gel column chromatography (petrole ether: ethyl acetate 15:1).
(R)-l-[2-(2-羟基 -3-对甲苯磺酰氧基丙氧基) -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮(R)-l-[2-(2-Hydroxy-3-p-toluenesulfonyloxypropoxy)-4,6-diphenylmethoxyphenyl]-3-methyl-1-butanone
400 mg, 收率 37%。 400 mg, yield 37%.
步骤 4: (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮 盐酸盐的制备  Step 4: (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride Preparation
按照实施例 4中步骤 4的方法， 采用步骤 3中所得的 200 mg (0.33 mmol) (R)-l-[2-(2-羟基 -3-对甲苯磺酰氧基丙氧基) -4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮 禾口 3 mL C35 mmol) 异丙胺反应， 得油状物 120 mg。 该油状物催化氢化后， 经制 备 HPLC ( YMC柱， 22%乙腈）分离，得到 (S)-l-[2 2-羟基 -3-异丙胺基丙氧基) -4,6- 二羟基苯基] -3-甲基 -1-丁酮盐酸盐 45 mg, 收率 38%。  200 mg (0.33 mmol) of (R)-l-[2-(2-hydroxy-3-p-toluenesulfonyloxypropoxy)-4 obtained in Step 3 was used according to the method of Step 4 in Example 4. ,6-Diphenylmethoxyphenyl]-3-methyl-1-butanone and 3 mL C35 mmol) isopropylamine to give an oil 120 mg. After the oil was catalytically hydrogenated, it was separated by preparative HPLC (YMC column, 22% acetonitrile) to give (S)-l-[2 2-hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxybenzene. Benzyl]-3-methyl-1-butanone hydrochloride 45 mg, yield 38%.
1H MR (500 MHz, d6-DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, H-l ' ' a), 3.92 (1H, overlap, H-l ' ' b), 3.88 (1H, m, H-2 ' ' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' a), 2.77 (1H, m, H-5 ' ' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a), 2.72 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 0.99 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.88 (3H, d, J = 6.5 Hz, CH3-5)。 13C NMR (125 MHz, 6-DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7, 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 6. (±)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, d 6 -DMSO) δ 5.90 (1Η, s, H-3 ' ), 5.89 (1H, s, H-5 ' ), 3.99 (1H, dd, J = 3.5, 8.0 Hz, Hl '' a), 3.92 (1H, overlap, Hl '' b), 3.88 (1H, m, H-2 '' X 2.93 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.84 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' a), 2.77 (1H, m, H-5 '' ), 2.72 (1H, dd, J = 6.5, 13.5 Hz, H-2a ), 2.72 (1H, dd, J = 7.0, 13.5 Hz, H-2b), 2.13 (1H, m, H-3), 1.00 (3H, d, J = 6.0 Hz, CH 3 -6 '' ), 0.99 (3H, d, J = 6.0 Hz, CH 3 -7 '' ), 0.90 (3H, d, J = 6.5 Hz, CH 3 -4), 0.88 (3H, d, J = 6.5 Hz, CH 3 - 5) 13 C NMR (125 MHz, 6 -DMSO) δ 204.7, 166.2, 165.5, 162.3, 104.7, 95.9, 92.2, 71.6, 68.2, 52.3, 49.9, 48.5, 24.5, 22.7, 22.7, 22.6, 22.6. Example 6. Preparation of (±)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000027_0001
按照实施例 3中步骤 1-4， 用 450 mg (1 mmol) (±)-1 -[2- (环氧乙 -2-基)甲氧基 4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (26.8 mmol) 叔丁基胺反应得到固体 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 )-4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 450 mg, 收率 81%。
Figure imgf000027_0001
According to steps 1-4 of Example 3, 450 mg (1 mmol) of (±)-1 -[2-(epoxyethyl-2-yl)methoxy 4,6-diphenylmethoxyphenyl] Reaction of -3-methyl-1-butanone with 3 mL (26.8 mmol) of tert-butylamine gave solid (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6 -Diphenylmethoxyphenyl]-3-methyl-1-butanone hydrochloride 450 mg, yield 81%.
按照实施例 3中步骤 5， 将 150 mg (0.27 mmol) (±)-1-[2-(2-羟基 -3-叔丁胺基 丙氧基 )-4,6-二苯甲氧基苯基] -3-甲基 -1-丁酮盐酸盐进行催化氢化后， 经制备 HPLC (YMC柱， 22%乙腈）分离， 得到 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6- 二羟基苯基] -3-甲基 -1-丁酮盐酸盐 59 mg, 收率 64%。  150 mg (0.27 mmol) of (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-diphenylmethoxyphenyl] according to Step 5 in Example 3. After catalytic hydrogenation of -3-methyl-1-butanone hydrochloride, it was separated by preparative HPLC (YMC column, 22% acetonitrile) to give (±)-1-[2-(2-hydroxy-3-tert-butylamino) Propyl) -4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride 59 mg, yield 64%.
1H MR (500 MHz, 6-DMSO) δ 5.89 (1Η, br.s, H-3 ' ), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, H-l ' ' a), 3.89 (1H, overlap, H-l ' ' b), 3.84 (1H, m, H-2 ' ' X 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.89 (3H, d, J = 6.5 Hz, CH3-5)。 13C NMR (125 MHz, i¾-DMSO) δ 204.4, 166.3, 166.2, 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45.4. 28.6, 28.6, 28.6, 24.6, 22.7, 22.6 实施例 7. (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-羟基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, 6 -DMSO) δ 5.89 (1Η, br.s, H-3 '), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, Hl '' a), 3.89 (1H, overlap, Hl '' b), 3.84 (1H, m, H-2 '' X 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH 3 -6 '' , CH 3 -7 '' , CH 3 -8 '' ), 0.90 (3H, d, J = 6.5 Hz, CH 3 -4), 0.89 (3H, d, J = 6.5 Hz, CH 3 -5). 13 C NMR (125 MHz, i3⁄4-DMSO) δ 204.4, 166.3, 166.2 , 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45.4. 28.6, 28.6, 28.6, 24.6, 22.7, 22.6 Example 7. (R)-l-[2-(2-hydroxy-3- Preparation of tert-butylaminopropoxy)-4,6-hydroxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000028_0001
Figure imgf000028_0001
按照实施例 4中步骤 4的方法， 采用实施例 3中步骤 3所得的 216 mg (0.26 mmol) CS l-P-O羟基 -3-对甲苯磺酰氧基丙氧基;) -4,6-二苯甲氧基苯基] -3-甲基 -1 -丁酮和 3 mL (26.8 mmol) 叔丁胺反应，得油状物 110 mg。该油状物催化氢化后， 经制备 HPLC (YMC柱， 22%乙腈） 分离， 得到 (R)-l-[2-(2-羟基 -3-叔丁胺基丙 氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 42 mg, 收率 43%。  216 mg (0.26 mmol) of CS lPO hydroxy-3-p-toluenesulfonyloxypropoxy group obtained in Step 3 of Example 3 was used according to the method of Step 4 in Example 4; -4,6-diphenyl Reaction of oxyphenyl]-3-methyl-1-butanone with 3 mL (26.8 mmol) of tert-butylamine afforded 110 mg of oil. After the oil was catalytically hydrogenated, it was separated by preparative HPLC (YMC column, 22% acetonitrile) to give (R)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dihydroxy Phenyl]-3-methyl-1-butanone hydrochloride 42 mg, yield 43%.
1H MR (500 MHz, 6-DMSO) δ 5.89 (1Η, br.s, H-3 ' ), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, H-l ' ' a), 3.89 (1H, overlap, H-l ' ' b), 3.84 (1H, m, H-2 ' ' ), 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.89 (3H, d, J = 6.5 Hz, CH3-5)。 13C MR (125 MHz, i¾-DMSO) δ 204.4, 166.3, 166.2, 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45Λ 28.6, 28.6, 28.6, 24.6, 22.7, 22.6 实施例 8. (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, 6 -DMSO) δ 5.89 (1Η, br.s, H-3 '), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, Hl '' a), 3.89 (1H, overlap, Hl '' b), 3.84 (1H, m, H-2 '' ), 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH 3 -6 '' , CH 3 -7 '' , CH 3 -8 '' ), 0.90 (3H, d, J = 6.5 Hz, CH 3 -4), 0.89 (3H, d, J = 6.5 Hz, CH 3 -5). 13 C MR (125 MHz, i3⁄4-DMSO) δ 204.4, 166.3, 166.2, 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45Λ 28.6, 28.6, 28.6, 24.6, 22.7, 22.6 Example 8. Preparation of (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000029_0001
按照实施例 4中步骤 4的方法， 采用实施例 5中步骤 3所得的 200 mg (0.26 mmol) CR)-l-[2-C2-羟基 -3-对甲苯磺酰氧基丙氧基) -4,6-二苯甲氧基苯基] -3-甲基 -1 -丁酮和 3 mL (26.8 mmol) 叔丁胺反应，得油状物 130 mg。该油状物催化氢化后， 经制备 HPLC ( YMC柱， 22%乙腈）分离， 得到 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧 基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 40 mg, 收率 41%。
Figure imgf000029_0001
200 mg (0.26 mmol) of CR)-l-[2-C2-hydroxy-3-p-toluenesulfonyloxypropoxyl) obtained in Step 3 of Example 5 was used according to the procedure of Step 4 in Example 4. 4,6-Diphenylmethoxyphenyl]-3-methyl-1-butanone was reacted with 3 mL (26.8 mmol) of tert-butylamine to give an oil of 130 mg. After the oil was catalytically hydrogenated, it was separated by preparative HPLC (YMC column, 22% acetonitrile) to give (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dihydroxy Phenyl]-3-methyl-1-butanone hydrochloride 40 mg, yield 41%.
1H MR (500 MHz, 6-DMSO) δ 5.89 (1Η, br.s, H-3 ' ), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, H-l ' ' a), 3.89 (1H, overlap, H-l ' ' b), 3.84 (1H, m, H-2 ' ' X 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 ' ' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.90 (3H, d, J = 6.5 Hz, CH3-4), 0.89 (3H, d, J = 6.5 Hz, CH3-5)。 13C NMR (125 MHz, i¾-DMSO) δ 204.4, 166.3, 166.2, 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45.4. 28.6, 28.6, 28.6, 24.6, 22.7, 22.6. 1H MR (500 MHz, 6 -DMSO) δ 5.89 (1Η, br.s, H-3 '), 5.81 (1H, br.s, H-5 ' ). 4.01 (1H, dd, J = 4.0, 9.5 Hz, Hl '' a), 3.89 (1H, overlap, Hl '' b), 3.84 (1H, m, H-2 '' X 2.94 (1H, dd, J = 7.0, 16.0 Hz, H-3 '' a), 2.85 (1H, dd, J = 6.5, 16.0 Hz, H-3 '' b), 2.69 (1H, dd, J = 5.0, 12.0 Hz, H-2a), 2.62 (1H, dd, J = 6.0, 12.0 Hz, H-2b), 2.13 (1H, m, H-3), 1.05 (9H, s, CH3-6'' , CH 3 -7 '' , CH3-8 '' ), 0.90 (3H , d, J = 6.5 Hz, CH3-4), 0.89 (3H, d, J = 6.5 Hz, CH 3 -5). 13 C NMR (125 MHz, i¾-DMSO) δ 204.4, 166.3, 166.2, 162.3, 104.6, 95.9, 92.3, 71.5, 68.7, 52.3, 50.2, 45.4. 28.6, 28.6, 28.6, 24.6, 22.7, 22.6.
实施例 9. (±)-l-[2-(2-羟基 -3-异丙胺基丙氧基 )-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸 盐的制备 Example 9. (±)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
Figure imgf000030_0001
Figure imgf000030_0001
步骤 1: 1-(2-羟基 -4-甲氧基苯基) -3-甲基 -1-丁酮的制备  Step 1: Preparation of 1-(2-hydroxy-4-methoxyphenyl)-3-methyl-1-butanone
将 1.24 g (10 mmol) 3-甲氧基苯酚溶于 30 mL三氟化硼***溶液中， 加入 1.21g(10mmol) 异戊酰氯， 之后于 80°C下加热反应 2小时， 待反应液冷却后倾 入 50 mL 5%的醋酸钾溶液中， 用 3x30mL 乙酸乙酯萃取， 合并有机层， 用饱和 碳酸氢钠溶液洗涤至中性， 再用 3x10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干 燥；减压蒸干溶剂后，进行硅胶柱色谱（石油醚:乙酸乙酯 30:1)分离，得到 1-(2- 羟基 -4-甲氧基苯基) -3-甲基 -1-丁酮 1.95 g， 收率 94%。  1.24 g (10 mmol) of 3-methoxyphenol was dissolved in 30 mL of boron trifluoride diethyl ether solution, and 1.21 g (10 mmol) of isovaleryl chloride was added, followed by heating at 80 ° C for 2 hours, and the reaction liquid was cooled. After pouring into 50 mL of 5% potassium acetate solution, extract with 3×30 mL of ethyl acetate, combine the organic layers, wash with neutral sodium hydrogen carbonate solution to neutral, and then wash with 3×10 mL of saturated sodium chloride solution, anhydrous sodium sulfate Drying; evaporation of the solvent under reduced pressure and then silica gel column chromatography (ethyl ether: ethyl acetate 30:1) to give 1-(2-hydroxy-4-methoxyphenyl)-3-methyl-1- Butanone 1.95 g, yield 94%.
步骤 2: (±)-1-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮的制备 将按照步骤 1得到的 1.04 g (5 mm0l)l-(2-羟基 -4-甲氧基苯基) -3-甲基 -1-丁酮 溶于 60mLN,N-二甲基甲酰胺中， 通入氮气， 搅拌 5分钟； 加入 0.12 g (5 mmol) 氢化钠， 于 40°C下反应 20分钟， 持续通入氮气； 加入 2.31gC25mmoi; ±;)2-氯 甲基环氧乙垸， 于 90°C下反应 2小时； 待反应液冷却至室温后， 倾入 lOOmL水 中， 用 3x50 mL乙酸乙酯萃取， 合并有机层， 用 3xl5mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥； 减压蒸干溶剂， 经硅胶柱色谱 （石油醚： 乙酸乙酯 10:1) 分 离得到 (±)-1-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮 0.80 g， 收率 61%。 Step 2: Preparation of (±)-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone will be obtained according to step 1. 1.04 g (5 mm0 l) of 1-(2-hydroxy-4-methoxyphenyl)-3-methyl-1-butanone was dissolved in 60 mL of N,N-dimethylformamide, and nitrogen was passed. Stir for 5 minutes; add 0.12 g (5 mmol) of sodium hydride, react at 40 ° C for 20 minutes, continue to pass nitrogen; add 2.31g of C25mmoi; ±;) 2-chloromethyl epoxide, at 90 ° C After the reaction mixture was cooled to room temperature, it was poured into 100 mL of water, and extracted with 3×50 mL of ethyl acetate. The organic layer was combined, washed with 3×1 5 mL of saturated sodium chloride solution and dried over anhydrous sodium sulfate. Separation of (±)-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3- by silica gel column chromatography ( petroleum ether: ethyl acetate 10:1) Methyl-1-butanone 0.80 g, yield 61%.
步骤 3: (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐制备  Step 3: Preparation of (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
将步骤 2中所得的 264 mg (1 mmol) (±)-1 -[2- (环氧乙 -2-基)甲氧基 -4-甲氧基 苯基] -3-甲基 -1-丁酮置于厚壁耐压管中，加入 3 mL (35 mmol) 异丙胺，搅拌均匀， 于 70°C下反应 2小时；冷却后减压蒸干反应液，残留物用 20 mL无水***溶解， 搅拌下滴加饱和氯化氢***溶液， 过滤， 得固体 (±)-1-[2-(2-羟基 -3-异丙胺基丙氧 基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 70 mg, 收率 19%。  264 mg (1 mmol) of (±)-1 -[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1- obtained in Step 2 Butanone was placed in a thick-walled pressure-resistant tube, 3 mL (35 mmol) of isopropylamine was added, stirred well, and reacted at 70 ° C for 2 hours. After cooling, the reaction solution was evaporated to dryness under reduced pressure. Dissolved, saturated aqueous hydrogen chloride solution was added dropwise with stirring, and filtered to give a solid (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3- Methyl-1-butanone hydrochloride 70 mg, yield 19%.
1H MR (500 MHz, D20) δ 7.61 (1Η, d, J =8.5 Hz, H-6 ' ), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H, d, J =1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 ' ' ), 4.06 (2H d, J = 4.5 Hz, H-l ' ' X 3.74 (3H, s, OCH3), 3.39 (1H, m, H-5 ' ' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd, J = 3.5, 12.0 Hz, H-2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 1.22 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C MR (125 MHz, D20) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6。 实施例 10. (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮的 制备 1H MR (500 MHz, D 2 0) δ 7.61 (1Η, d, J = 8.5 Hz, H-6 '), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H, d, J = 1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 '' ), 4.06 (2H d, J = 4.5 Hz , Hl '' X 3.74 (3H, s, OCH 3 ), 3.39 (1H, m, H-5 '' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H-3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 '' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd, J = 3.5, 12.0 Hz , H-2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J = 6.0 Hz, CH 3 -6 '' ), 1.22 (3H, d, J = 6.0 Hz, CH 3 - 7 '' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH 3 -5) 13 C MR (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6. Example 10. (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy) Preparation of -4-methoxyphenyl]-3-methyl-1-butanone
Figure imgf000031_0001
Figure imgf000031_0001
步骤 1 : (R)-l-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮的制备 将按照实施例 9中步骤 1的方法得到的 1.04 g (5 mmol)l-(2-羟基 -4-甲氧基苯 基;) -3-甲基 -1-丁酮溶于 1.2 mL N,N-二甲基甲酰胺和 1.8 mL水的混合溶液中， 加 入 0.93 g (10 mmol) ( )-2-氯甲基环氧乙垸向反应液滴加含 0.40 g (10 mmol) 氢氧 化钠的水溶液 5 mL,于室温下搅拌反应 48小时。反应液用 3 x25 mL乙酸乙酯萃 取， 合并有机层， 用 3 x 15 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥； 减压蒸 干溶剂， 经硅胶柱色谱（石油醚:乙酸乙酯 10: 1 )分离得到 (R)-l-[2- (环氧乙 -2-基；) 甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮 0.11 g， 收率 8%。  Step 1: Preparation of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone as in Example 9 1.04 g (5 mmol) of 1-(2-hydroxy-4-methoxyphenyl;)-3-methyl-1-butanone obtained by the method of Step 1 was dissolved in 1.2 mL of N,N-dimethyl To a mixed solution of formamide and 1.8 mL of water, add 0.93 g (10 mmol) of ( )-2-chloromethyloxirane to the reaction solution and add 5 mL of an aqueous solution containing 0.40 g (10 mmol) of sodium hydroxide. The reaction was stirred at room temperature for 48 hours. The reaction mixture was extracted with EtOAc (3 mL, EtOAc (EtOAc) 10: 1) Isolated (R)-l-[2-(epoxyethyl-2-yl;)methoxy-4-methoxyphenyl]-3-methyl-1-butanone 0.11 g, The yield was 8%.
步骤 2: (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐制备  Step 2: Preparation of (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
按照实施例 9中步骤 3的方法， 用步骤 1中所得的 60 mg (0.23 mmol) (R)-l-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (35 mmol) 异 丙胺反应， 得固体 (R)-l-[2 2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1- 丁酮盐酸盐 40 mg， 收率 48%。  60 mg (0.23 mmol) of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxybenzene obtained in Step 1 was used according to the procedure of Step 3 in Example 9. Reaction of 3-methyl-1-butanone with 3 mL (35 mmol) of isopropylamine afforded solid (R)-l-[2 2-hydroxy-3-isopropylaminopropoxy)-4-methyl Oxyphenyl]-3-methyl-1-butanone hydrochloride 40 mg, yield 48%.
1H MR (500 MHz, D20) δ 7.61 (1Η, d, J =8.5 Hz, H-6 ' ), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H, d, J =1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 ' ' ), 4.06 (2H d, J = 4.5 Hz, H-l ' ' ), 3.74 (3H, s, OCH3), 3.39 (1H, m, H-5 ' ' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd, J = 3.5, 12.0 Hz, H-2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 1.22 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C MR (125 MHz, D20) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6。 实施例 11. (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, D 2 0) δ 7.61 (1Η, d, J = 8.5 Hz, H-6 ' ), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H , d, J = 1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 '' ), 4.06 (2H d, J = 4.5 Hz, Hl '' ), 3.74 (3H, s, OCH 3 ), 3.39 (1H, m, H-5 '' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H- 3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 '' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd , J = 3.5, 12.0 Hz, H-2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J = 6.0 Hz, CH 3 -6 '' ), 1.22 (3H, d, J = 6.0 Hz, CH 3 -7 '' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH 3 -5). 13 C MR (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6. Example 11. (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride preparation
Figure imgf000032_0001
Figure imgf000032_0001
步骤 1 : (S)-l-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮的制备 按照实施例 10中步骤 1的方法，用 1.04 g (5 mmol) 1-P-羟基 -4-甲氧基苯基) -3 甲基 -1-丁酮， 0.93 g (10 mmol) (S)-2-氯甲基环氧乙垸及 0.40 g (10 mmol) 氢氧化 钠反应， 经硅胶柱色谱（石油醚:乙酸乙酯 10: 1 )分离得到 (S)-l-[2- (环氧乙 -2-基；) 甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮 0.13 g， 收率 9%。  Step 1: Preparation of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl-1-butanone as in Example 10 Step 1 method using 1.04 g (5 mmol) of 1-P-hydroxy-4-methoxyphenyl)-3-methyl-1-butanone, 0.93 g (10 mmol) (S)-2-chloromethyl The reaction was carried out by the reaction of silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give (S)-l-[2-(epoxyethyl-2-) ;; methoxy-4-methoxyphenyl]-3-methyl-1-butanone 0.13 g, yield 9%.
步骤 2: (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐的制备  Step 2: Preparation of (S)-l-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
按照实施例 9中步骤 3的方法， 用步骤 1中所得的 60 mg (0.23 mmol) (S)-l-[2- (环氧乙 -2-基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (35 mmol) 异 丙胺反应， 得固体 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1- 丁酮盐酸盐 35 mg， 收率 42%。  60 mg (0.23 mmol) of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4-methoxybenzene obtained in Step 1 according to the method of Step 3 in Example 9. Reaction of 3-methyl-1-butanone with 3 mL (35 mmol) of isopropylamine afforded solid (S)-l-[2-(2-hydroxy-3-isopropylaminopropoxy) -4 -Methoxyphenyl]-3-methyl-1-butanone hydrochloride 35 mg, yield 42%.
1H MR (500 MHz, D20) δ 7.61 (1Η, d, J =8.5 Hz, H-6 ' ), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H, d, J =1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 ' ' ), 4.06 (2H d, J = 4.5 Hz, H-l ' ' X 3.74 (3H, s, OCH3), 3.39 (1H, m, H-5 ' ' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd, J = 3.5, 12.0 Hz, H-2b), 1.93 (1H, m, H-3), 1.24 (3H, d, J = 6.0 Hz, CH3-6 ' ' ), 1.22 (3H, d, J = 6.0 Hz, CH3-7 ' ' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 "C MR (125 MHz, D20) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6。 实施例 12. (±)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, D 2 0) δ 7.61 (1Η, d, J = 8.5 Hz, H-6 ' ), 6.54 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.47 (1H , d, J = 1.5 Hz, H-3 ' ), 4.23 (1H, m, H-2 '' ), 4.06 (2H d, J = 4.5 Hz, Hl '' X 3.74 (3H, s, OCH 3 ) , 3.39 (1H, m, H-5 '' ), 3.22 (1H, dd, J = 3.5, 13.0 Hz, H-3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H- 3 '' b), 2.71 (1H, dd, J = 3.5, 12.0 Hz, H-2a), 2.65 (1H, dd, J = 3.5, 12.0 Hz, H-2b), 1.93 (1H, m, H- 3), 1.24 (3H, d, J = 6.0 Hz, CH3-6 ''), 1.22 (3H, d, J = 6.0 Hz, CH 3 -7 '' ), 0.77 (6H, d, J = 6.5 Hz, CH3-4, CH 3 -5). "C MR (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 132.3, 114.0, 106.8, 100.7, 71.8, 69.2, 55.6, 52.7, 49.5, 45.4, 24.5, 22.8, 22.8, 22.6, 22.6. 12. Preparation of (±)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000033_0001
Figure imgf000033_0001
按照实施例 9中步骤 2-3的方法， 用 264 mg (1 mmol) (±)-1-[2-(环氧乙-2- 基)甲氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (28.6 mmol)叔丁基胺反应， 得 到固体 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 80 mg, 收率 21%。  According to the procedure of Step 2-3 in Example 9, 264 mg (1 mmol) of (±)-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]- 3-methyl-1-butanone is reacted with 3 mL (28.6 mmol) of t-butylamine to give a solid (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4-methyl Oxyphenyl]-3-methyl-1-butanone hydrochloride 80 mg, yield 21%.
1H MR (500 MHz, D20) δ 7.62 (1Η, d, J =8.5 Hz, H-6 ' ), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.45 (1H, d, J =1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 ' ' ), 4.11 (2H d, J = 4.5 Hz, H-l ' ' X 3.65 (3H, s, OCH3), 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ),, 0.73 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, D20) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 实施例 13. (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 )-4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, D 2 0) δ 7.62 (1Η, d, J = 8.5 Hz, H-6 '), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 '), 6.45 (1H , d, J = 1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 '' ), 4.11 (2H d, J = 4.5 Hz, Hl '' X 3.65 (3H, s, OCH 3 ) , 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 '' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH3-6 '' , CH3-7 '' , CH3-8 '' ),, 0.73 (6H, d, J = 6.5 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, D 2 0) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 Example 13. (R)-l-[2- Preparation of (2-hydroxy-3-tert-butylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000033_0002
Figure imgf000033_0002
按照实施例 10的方法，用 50 mg (0.19 mmol) (R)- 1 -[2- (环氧乙 -2-基)甲氧基 -4- 甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (26.8 mmol) 叔丁基胺反应， 得固体 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 25 mg， 收率 35%。 According to the method of Example 10, 50 mg (0.19 mmol) of (R)-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl- 1-butanone reacts with 3 mL (26.8 mmol) of t-butylamine to give a solid (R)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride 25 mg, yield 35 %.
1H MR (500 MHz, D20) δ 7.62 (1Η, d, J =8.5 Hz, H-6 ' ), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.45 (1H, d, J =1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 ' ' ), 4.11 (2H d, J = 4.5 Hz, H-l ' ' X 3.65 (3H, s, OCH3), 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ),, 0.73 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, D20) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 实施例 14. (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐 酸盐的制备 1H MR (500 MHz, D 2 0) δ 7.62 (1Η, d, J = 8.5 Hz, H-6 '), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 '), 6.45 (1H , d, J = 1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 '' ), 4.11 (2H d, J = 4.5 Hz, Hl '' X 3.65 (3H, s, OCH 3 ) , 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 '' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH 3 -6 '' , CH 3 -7 '' , CH3-8 '' ),, 0.73 (6H, d, J = 6.5 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, D 2 0 ) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 Example 14. (S)-l-[ Preparation of 2-(2-hydroxy-3-tert-butylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride
Figure imgf000034_0001
Figure imgf000034_0001
按照实施例 11的方法，用 60 mg (0.23 mmol) (S)- 1 -[2- (环氧乙 -2-基)甲氧基 -4- 甲氧基苯基] -3-甲基 -1-丁酮和 3 mL (26.8 mmol) 叔丁基胺反应， 得固体  According to the method of Example 11, 60 mg (0.23 mmol) of (S)-1-[2-(epoxyethyl-2-yl)methoxy-4-methoxyphenyl]-3-methyl- 1-butanone reacts with 3 mL (26.8 mmol) of t-butylamine to give a solid
(S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 30 mg, 收率 34%。 (S)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride 30 mg, yield 34 %.
1H MR (500 MHz, D20) δ 7.62 (1Η, d, J =8.5 Hz, H-6 ' ), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 ' ), 6.45 (1H, d, J =1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 ' ' ), 4.11 (2H, d, J = 4.5 Hz, H-l ' ' X 3.65 (3H, s, OCH3), 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 ' ' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 ' ' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ),, 0.73 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, D20) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 实施例 15. (±)-l-[2-(2-羟基 -3-异丙胺基丙氧基； )-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 7.62 (1Η, d, J = 8.5 Hz, H-6 '), 6.53 (1H, dd, J = 8.5, 1.5 Hz, H-5 '), 6.45 (1H , d, J = 1.5 Hz, H-3 ' ), 4.27 (1H, m, H-2 '' ), 4.11 (2H, d, J = 4.5 Hz, Hl '' X 3.65 (3H, s, OCH 3 ), 3.30 (1H, dd, J = 3.5, 13.0 Hz, H-3 '' a), 3.11 (1H, dd, J = 8.0, 13.5 Hz, H-3 '' b), 2.69 (1H, dd, J = 3.5, 11.5 Hz, H-2a), 2.60 (1H, dd, J = 3.5, 11.5 Hz, H-2b), 1.90 (1H, m, H-3), 1.42 (9H, s, CH3-6 '' , CH3-7 '' , CH3-8 '' ),, 0.73 (6H, d, J = 6.5 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, D 2 0) δ 205.0, 166.3, 164.5, 131.7, 112.3, 105.7, 99.9, 72.4, 69.5, 55.6, 52.3, 50.4, 45.4, 28.6, 28.6, 28.6, 24.6, 22.6, 22.6 Example 15. (±)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy; )-4,6-dimethoxyphenyl]-3-methyl-1-butanone Preparation of hydrochloride
Figure imgf000035_0001
Figure imgf000035_0001
步骤 1 : 1-(2-羟基 -4,6-二甲氧基苯基 )-3-甲基 -1-丁酮的制备  Step 1: Preparation of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-methyl-1-butanone
将 1.54 g (10 mmol) 3,5-二甲氧基苯酚溶于 20 mL三氟化硼***溶液中， 力口 入 1.21g (10 mmol) 异戊酰氯，之后于 80°C下加热反应 2小时， 待反应液冷却后 倾入 50 mL 5%的醋酸钾溶液中， 用 3 x30 mL 乙酸乙酯萃取， 合并有机层， 用饱 和碳酸氢钠溶液洗涤至中性， 再用 3 x 10 mL饱和氯化钠溶液洗涤， 无水硫酸钠 干燥； 减压蒸干溶剂后， 进行硅胶柱色谱 （石油醚:乙酸乙酯 30: 1 ) 分离， 得到 1-(2-羟基 -4,6-二甲氧基苯基 )-3-甲基 -1-丁酮 1.7g， 收率 71%。  1.54 g (10 mmol) of 3,5-dimethoxyphenol was dissolved in 20 mL of boron trifluoride diethyl ether solution, and 1.21 g (10 mmol) of isovaleryl chloride was added thereto, followed by heating at 80 ° C. After the reaction solution is cooled, pour into 50 mL of 5% potassium acetate solution, extract with 3 x 30 mL of ethyl acetate, combine the organic layers, wash with saturated sodium bicarbonate solution until neutral, and then saturate with 3 x 10 mL. The solution was washed with a sodium chloride solution and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, silica gel column chromatography ( petroleum ether: ethyl acetate 30:1) to give 1-(2-hydroxy-4,6-dimethyl Ethoxyphenyl)-3-methyl-1-butanone 1.7 g, yield 71%.
步骤 2: (±)-1-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮的制 备  Step 2: Preparation of (±)-1-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
按照实施例 9中步骤 2的方法， 用步骤 1中得到的 1.00 g (4.2 mmol) 1-( 羟 基 -4,6-二甲氧基苯基 )-3-甲基 -1-丁酮， 1.94 g (21 mmol) (±)2-氯甲基环氧乙垸及 0.10 g (4.2 mmol) 氢化钠反应， 经硅胶柱色谱 （石油醚:乙酸乙酯 30: 1 ) 得到 (士)小 [2— (环氧乙—2—基)甲氧基—4,6-二甲氧基苯基 ]-3-甲基小丁酮 0.9 g， 收率 69%。  According to the method of Step 2 in Example 9, 1.00 g (4.2 mmol) of 1-(hydroxy-4,6-dimethoxyphenyl)-3-methyl-1-butanone obtained in Step 1, 1.94 g (21 mmol) (±) 2-chloromethyloxime oxime and 0.10 g (4.2 mmol) of sodium hydride, obtained by silica gel column chromatography ( petroleum ether: ethyl acetate 30:1) —(Ethoxyethylene-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methylbutanone 0.9 g, yield 69%.
步骤 3 : (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁 酮盐酸盐的制备  Step 3: (±)-1-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
按照实施例 9中步骤 3的方法， 用步骤 2中所得的 294 mg (1 mmol)  According to the method of Step 3 in Example 9, the 294 mg (1 mmol) obtained in Step 2 was used.
(士)小 [2— (环氧乙 -2—基)甲氧基—4,6-二甲氧基苯基 ]-3-甲基小丁酮和 3 mL (35 mmol) 异丙胺反应， 得固体 (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲 基 -1-丁酮盐酸盐 110 mg， 收率 28%。 (士)小 [2-(epoxyethyl-2-yl)methoxy- 4,6-dimethoxyphenyl]-3-methylbutanone and 3 mL (35 mmol) of isopropylamine, Obtained solid (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 110 mg, yield 28%.
1H MR (500 MHz, D20) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 ' ), 4.10 (1H, m, H-2 ' ' ), 3.92 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.67 (3H, s, OCH3), 3.62 (3H, s, OCH3), 3.33 (1H, m, H-5 ' ' ), 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.56 (2H, br.d, J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH3-6 ' ' ), 1.17 (3H, d, J = 6.5 Hz, CH3-7 ' ' ), 0.72 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C雇 R (125 MHz, D20) δ 205.0, 165.7, 165.3, 162.7: 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 16. (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基； )-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 '), 4.10 (1H, m, H-2 '' ), 3.92 (2H, d, J = 4.5 Hz, Hl '' ), 3.67 (3H, s, OCH 3 ), 3.62 (3H, s, OCH 3 ), 3.33 (1H, m, H-5 '' ) , 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.56 (2H, br.d , J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH 3 -6 '' ), 1.17 (3H, d, J = 6.5 Hz, CH 3 -7 '' ), 0.72 (6H, d, J = 6.5 Hz, CH 3 -4, CH 3 -5). 13 Cemployed R (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 162.7 : 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6 . Example 16. (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy; )-4,6-dimethoxyphenyl]-3-methyl-1-butanone Preparation of hydrochloride
Figure imgf000036_0001
Figure imgf000036_0001
步骤 1 : (R)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮的制 备  Step 1: Preparation of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
按照实施例 10中步骤 1的方法，用实施例 15步骤 1中得到的 1.00 g (4.2 mmol) 1-(2-羟基 -4,6-二甲氧基苯基 )-3-甲基小丁酮， 1.94 g (21 mmol) (R)-2-氯甲基环氧 乙垸及 0.10 g (4.2 mmol) 氢氧化钠反应，经硅胶柱色谱（石油醚:乙酸乙酯 30: 1 ) 得到 (R)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 0.30 g， 收率 24%。  Using the procedure of Step 1 in Example 10, 1.00 g (4.2 mmol) of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-methyldibutylate obtained in Step 1 of Example 15 Ketone, 1.94 g (21 mmol) of (R)-2-chloromethyloxime oxime and 0.10 g (4.2 mmol) of sodium hydroxide, obtained by silica gel column chromatography ( petroleum ether: ethyl acetate 30:1) R)-l-[2-(Ethoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone 0.30 g, yield 24%.
步骤 2: (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁 酮盐酸盐的制备  Step 2: (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
按照实施例 10中步骤 2的方法， 用步骤 1中所得的 150 mg (0.51 mmol) (R)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮和 3 mL (35 mmol) 异丙胺反应， 得固体 (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲 基 -1-丁酮盐酸盐 130 mg, 收率 65%。  According to the method of Step 2 in Example 10, 150 mg (0.51 mmol) of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethyl obtained in Step 1 was used. Reaction of oxyphenyl]-3-methyl-1-butanone with 3 mL (35 mmol) of isopropylamine afforded solid (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy) -4,6-Dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 130 mg, yield 65%.
1H MR (500 MHz, D20) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 ' ), 4.10 (1H, m, H-2 ' ' ), 3.92 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.67 (3H, s, OCH3), 3.62 (3H, s, OCH3), 3.33 (1H, m, H-5 ' ' ), 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.56 (2H, br.d, J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH3-6 ' ' ), 1.17 (3H, d, J = 6.5 Hz, CH3-7 ' ' ), 0.72 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C雇 R (125 MHz, D20) δ 205.0, 165.7, 165.3, 162.7, 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 17. (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 )-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 '), 4.10 (1H, m, H-2 '' ), 3.92 (2H, d, J = 4.5 Hz, Hl '' ), 3.67 (3H, s, OCH 3 ), 3.62 (3H, s, OCH3), 3.33 (1H, m, H-5 '' ), 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.56 (2H, br.d, J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH3-6 '' ), 1.17 (3H, d, J = 6.5 Hz, CH 3 -7 '' ), 0.72 (6H, d, J = 6.5 Hz, CH3-4, CH 3 -5). 13 Cemployment R (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 162.7, 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6 . Example 17. (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone salt Preparation of acid salt
Figure imgf000037_0001
Figure imgf000037_0001
步骤 1 : (S)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮的制 备  Step 1: Preparation of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone
按照实施例 11中步骤 1的方法，用实施例 15中步骤 1得到的 1.00 g (4.2 mmol) 1-(2-羟基 -4,6-二甲氧基苯基 )-3-甲基小丁酮， 1.94 g (21 mmol) (R)-2-氯甲基环氧 乙垸及 0.10 g (4.2 mmol) 氢氧化钠反应，经硅胶柱色谱（石油醚：乙酸乙酯 30: 1 ) 得到 (S)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 0.27 g， 收率 22%。  1.00 g (4.2 mmol) of 1-(2-hydroxy-4,6-dimethoxyphenyl)-3-methyldibutylate obtained in Step 1 of Example 15 according to the procedure of Step 1 in Example 11. Ketone, 1.94 g (21 mmol) of (R)-2-chloromethyloxime oxime and 0.10 g (4.2 mmol) of sodium hydroxide, obtained by silica gel column chromatography ( petroleum ether: ethyl acetate 30:1) S)-l-[2-(Ethoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone 0.27 g, yield 22%.
步骤 2: (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁 酮盐酸盐的制备  Step 2: (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
按照实施例 11中步骤 2的方法， 用步骤 1中所得的 130 mg (0.44 mmol) (S)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮和 3 mL (35 mmol) 异丙胺反应， 得固体 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲 基 -1-丁酮盐酸盐 100 mg, 收率 58%。  According to the method of Step 2 in Example 11, 130 mg (0.44 mmol) of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethyl was obtained in Step 1. Reaction of oxyphenyl]-3-methyl-1-butanone with 3 mL (35 mmol) of isopropylamine afforded solid (S)-l-[2-(2-hydroxy-3-isopropylaminopropoxy) -4,6-Dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 100 mg, yield 58%.
1H MR (500 MHz, D20) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 ' ), 4.10 (1H, m, H-2 ' ' ), 3.92 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.67 (3H, s, OCH3), 3.62 (3H, s, OCH3), 3.33 (1H, m, H-5 ' ' ), 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.56 (2H, br.d, J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH3-6 ' ' ), 1.17 (3H, d, J = 6.5 Hz, CH3-7 ' ' ), 0.72 (6H, d, J = 6.5 Hz, CH3-4, CH3-5)。 13C雇 R (125 MHz, D20) δ 205.0, 165.7, 165.3, 162.7, 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6。 实施例 18. (±)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备
Figure imgf000038_0001
1H MR (500 MHz, D 2 0) δ 6.15 (1Η, br.s, H-5 ' ), 6.09 (1H, br.s, H-3 '), 4.10 (1H, m, H-2 '' ), 3.92 (2H, d, J = 4.5 Hz, Hl '' ), 3.67 (3H, s, OCH 3 ), 3.62 (3H, s, OCH 3 ), 3.33 (1H, m, H-5 '' ) , 3.08 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.56 (2H, br.d , J = 7.0 Hz, H-2), 1.86 (1H, m, H-3), 1.18 (3H, d, J = 6.5 Hz, CH3-6 '' ), 1.17 (3H, d, J = 6.5 Hz , CH 3 -7 '' ), 0.72 (6H, d, J = 6.5 Hz, CH3-4, CH 3 -5). 13 Cemployment R (125 MHz, D 2 0) δ 205.0, 165.7, 165.3, 162.7, 105.8, 92.9, 90.8, 71.8, 69.2, 56.0, 55.9, 52.7, 49.5, 48.7, 24.5, 22.7, 22.7, 22.6, 22.6 . Example 18. (±)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
Figure imgf000038_0001
按照实施例 15的方法，用 294 mg (1 mmol) (±)-1-[2- (环氧乙 -2-基)甲氧基 -4,6- 二甲氧基苯基 ]-3-甲基 -1-丁酮和 3 mL (26.8 mmol)叔丁基胺反应， 得固体  According to the method of Example 15, 294 mg (1 mmol) of (±)-1-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3- Methyl-1-butanone reacts with 3 mL (26.8 mmol) of t-butylamine to give a solid
(±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 200 mg, 收率 49%。 (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 200 mg, The yield was 49%.
1H MR (500 MHz, D20) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 ' ), 4.11 (1H, m, H-2 ' ' ), 3.99 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.73 (3H, s, OCH3), 3.68 (3H, s: OCH3), 3.33 (1H, m, H-5 ' ' ), 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.63 (1H, br.d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.76 (6H, d, J = 7.0 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, D20) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6。 实施例 19. (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 '), 4.11 (1H, m, H-2 '' ), 3.99 (2H, d, J = 4.5 Hz, Hl '' ), 3.73 (3H, s, OCH 3 ), 3.68 (3H, s : OCH 3 ), 3.33 (1H, m, H-5 '' ) , 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.63 (1H, br.d , J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6 '' , CH3-7 '' , CH3-8 '' ), 0.76 (6H , d, J = 7.0 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, D 2 0) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6. Example 19. (R)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
Figure imgf000038_0002
按照实施例 16的方法， 用 150 mg (0.51 mmol) (R)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮和 3 mL (26.8 mmol) 叔丁基胺反应， 得固体 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 128 mg, 收率 62%。
Figure imgf000038_0002
According to the method of Example 16, 150 mg (0.51 mmol) of (R)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3- Reaction of methyl-1-butanone with 3 mL (26.8 mmol) of tert-butylamine afforded solid (R)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4-methoxy Phenyl]-3-methyl-1-butanone hydrochloride 128 mg, yield 62%.
1H MR (500 MHz, D20) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 ' ), 4.11 (1H, m, H-2 ' ' ), 3.99 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.73 (3H, s, OCH3), 3.68 (3H, s: OCH3), 3.33 (1H, m, H-5 ' ' ), 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.63 (1H, br.d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.76 (6H, d, J = 7.0 Hz, CH3-4, CH3-5)。 13C MR (125 MHz, D20) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6。 实施例 20. (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 )-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮 盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 '), 4.11 (1H, m, H-2 '' ), 3.99 (2H, d, J = 4.5 Hz, Hl '' ), 3.73 (3H, s, OCH 3 ), 3.68 (3H, s : OCH3), 3.33 (1H, m, H-5 '' ), 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, Dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.63 (1H, br.d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH 3 -6 '' , CH3-7 '' , CH3-8 '' ), 0.76 (6H, d, J = 7.0 Hz, CH 3 -4, CH 3 -5). 13 C MR (125 MHz, D 2 0) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6. Example 20. (S)-l-[2-(2-Hydroxy-3-tert-butylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride Preparation of salt
Figure imgf000039_0001
按照实施例 17的方法， 用 130 mg (0.44 mmol) (S)-l-[2- (环氧乙 -2-基)甲氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮和 3 mL (26.8 mmol) 叔丁基胺反应， 得固体 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 135mg， 收率 76%。
Figure imgf000039_0001
According to the method of Example 17, 130 mg (0.44 mmol) of (S)-l-[2-(epoxyethyl-2-yl)methoxy-4,6-dimethoxyphenyl]-3- Reaction of methyl-1-butanone with 3 mL (26.8 mmol) of tert-butylamine gave solid (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4-methoxy Phenyl]-3-methyl-1-butanone hydrochloride 135 mg, yield 76%.
1H MR (500 MHz, D20) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 ' ), 4.11 (1H, m, H-2 ' ' ), 3.99 (2H, d, J = 4.5 Hz, H-l ' ' ), 3.73 (3H, s, OCH3), 3.68 (3H, s: OCH3), 3.33 (1H, m, H-5 ' ' ), 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 ' ' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 ' ' b), 2.63 (1H, br.d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6 ' ' , CH3-7 ' ' , CH3-8 ' ' ), 0.76 (6H, d, J = 7.0 Hz, CH3-4, CH3-5)。 13C NMR (125 MHz, D20) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6。 实施例 21. 4- (哌啶 -1-基) -l-(2,4,6-三羟基苯基) -1-丁酮盐酸盐的制备 1H MR (500 MHz, D 2 0) δ 6.23 (1Η, br.s, H-5 ' ), 6.16 (1H, br.s, H-3 '), 4.11 (1H, m, H-2 '' ), 3.99 (2H, d, J = 4.5 Hz, Hl '' ), 3.73 (3H, s, OCH 3 ), 3.68 (3H, s : OCH3), 3.33 (1H, m, H-5 '' ), 3.13 (1H, dd, J = 3.0, 13.0 Hz, H-3 '' a), 2.96 (1H, dd, J = 9.0, 13.0 Hz, H-3 '' b), 2.63 (1H, br.d, J = 7.0 Hz, H-2), 1.91 (1H, m, H-3), 1.41 (9H, s, CH3-6 '' , CH3-7 '' , CH3-8 '' ), 0.76 (6H, d, J = 7.0 Hz, CH 3 -4, CH 3 -5). 13 C NMR (125 MHz, D 2 0) 5 205.1, 165.5, 165.4, 162.3, 104.9, 93.0, 90.5, 72.8, 68.7, 55.8, 55.6, 52.8, 50.8, 45.4, 28.7, 28.7, 28.7, 24.6, 22.6, 22.6. Example 21. Preparation of 4-(piperidin-1-yl)-1 -(2,4,6-trihydroxyphenyl)-1-butanone hydrochloride
Figure imgf000039_0002
Figure imgf000039_0002
步骤 1 : 4- (哌啶 -1-基)丁腈的制备  Step 1: Preparation of 4-(piperidin-1-yl)butyronitrile
将 2.58 g (25 mmol ) 4-氯丁腈溶于 5 mL 乙腈， 加入 3.5 g (25 mmol )无水 碳酸钾和少量碘化钠， 缓慢滴入 2.13 g(25 mmol) 哌啶， 室温下搅拌 20 h。 减压 蒸干溶剂， 残余物中加入 10 mL水溶解， 用 3x15 mL乙酸乙酯萃取， 合并有机 层， 用 2x10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 得油状液 #3.30 2.58 g (25 mmol) of 4-chlorobutyronitrile was dissolved in 5 mL of acetonitrile and 3.5 g (25 mmol) of anhydrous Potassium carbonate and a small amount of sodium iodide were slowly added dropwise to 2.13 g (25 mmol) of piperidine, and stirred at room temperature for 20 h. The solvent was evaporated to dryness. EtOAc m. Evaporate the solvent to obtain an oily liquid #3.30
步骤 2: 4- (哌啶 -1-基) -1-(2,4,6-三羟基苯基) -1-丁酮盐酸盐的制备  Step 2: Preparation of 4-(piperidin-1-yl)-1-(2,4,6-trihydroxyphenyl)-1-butanone hydrochloride
将 1.33 g 间苯三酚（10.5 mmol)溶于 10 mL硝基苯中， 加入步骤 1中所得 油状物 1.60 g，通入干燥 HC1气体， 于室温下搅拌 12 h。反应液放置过夜， 过滤， 将固体溶于 10mL水中， 加热回流 l h 。冷却， 过滤， 所得固体用乙醇-水（4:1) 重结晶， 得 4- (哌啶 -1-基) -1-(2,4,6-三羟基苯基) -1-丁酮盐酸盐 0.67 g， 收率 20%。  1.33 g of phloroglucinol (10.5 mmol) was dissolved in 10 mL of nitrobenzene, and 1.60 g of the oil obtained in the step 1 was added thereto, and the mixture was passed through a dry HCl gas and stirred at room temperature for 12 hr. The reaction solution was allowed to stand overnight, filtered, and the solid was dissolved in water (10 mL) and heated to reflux for 1 h. After cooling, filtration, the obtained solid was recrystallized from ethanol-water (4:1) to give 4-(piperidin-1-yl)-1-(2,4,6-trihydroxyphenyl)-1-butanone salt. The acid salt was 0.67 g, and the yield was 20%.
1H MR (500 MHz, d6-OMSO) δ 12.23 (2Η, s, OH-2' , OH-6' ), 10.45 (1H, s, OH-4' ), 5.81 (2H, s, H-3 ' ,H-5' ), 3.43 (2H, br.d, J =11.5 Hz, H-2' ' a, H-6 ' ' a), 3.08 (2H, t, J = 6.5 Hz, H-2), 3.05 (2H, overlap, H-4), 2.86 (2H, m, H-2 ' ' b, H-6' ' b), 1.94 (2H, m, H-3), 1.79 (2H, br.d, J =14.0 Hz, H-3 ' ' a, H-5 ' ' a), 1.65 (2H, overlap, H-3' ' b, H-5 ' ' b), 1.60 (1H, m, H-4' ' a,), 1.38 (1H, m, H-4' ' b)。 13C MR (125 MHz, 6-DMSO) δ 202.8, 164.5, 163.9, 163.9, 103.4, 94.3, 94.3, 55.2, 51.8, 51.8, 38.7, 22.3, 22.3, 21.0, 17.9。 实施例 22.4- (甲基环己 -l-(2,4,6-三羟基苯基； )1-丁酮盐酸盐的制备
Figure imgf000040_0001
1H MR (500 MHz, d 6 -OMSO) δ 12.23 (2Η, s, OH-2', OH-6'), 10.45 (1H, s, OH-4'), 5.81 (2H, s, H-3 ',H-5' ), 3.43 (2H, br.d, J =11.5 Hz, H-2'' a, H-6 '' a), 3.08 (2H, t, J = 6.5 Hz, H-2 ), 3.05 (2H, overlap, H-4), 2.86 (2H, m, H-2 '' b, H-6'' b), 1.94 (2H, m, H-3), 1.79 (2H, br .d, J =14.0 Hz, H-3 '' a, H-5 '' a), 1.65 (2H, overlap, H-3'' b, H-5 '' b), 1.60 (1H, m, H-4'' a,), 1.38 (1H, m, H-4'' b). 13 C MR (125 MHz, 6 -DMSO) δ 202.8, 164.5, 163.9, 163.9, 103.4, 94.3, 94.3, 55.2, 51.8, 51.8, 38.7, 22.3, 22.3, 21.0, 17.9. Example 22.4-Preparation of (methylcyclohexyl-l-(2,4,6-trihydroxyphenyl; ) 1-butanone hydrochloride
Figure imgf000040_0001
步骤 1: 4- (甲基环己基胺；)丁腈的制备  Step 1: Preparation of 4-(methylcyclohexylamine;) butyronitrile
按照实施例 21中步骤 1的方法， 用 1.98 g (19.2 mmol) 4-氯丁腈， 2.56 g (19.2 mmol) 无水碳酸钾和少量 Nal， 以及 2.17 g (19.2 mmol) 甲基环己基胺反 应后得油状液体 4.00  According to the procedure of Step 1 in Example 21, 1.98 g (19.2 mmol) of 4-chlorobutyronitrile, 2.56 g (19.2 mmol) of anhydrous potassium carbonate and a small amount of Nal, and 2.17 g (19.2 mmol) of methylcyclohexylamine were reacted. After the oily liquid 4.00
步骤 2: 4- (甲基环己基胺; )-1-(2,4,6-三羟基苯基； )1-丁酮盐酸盐的制备 将 1.05 g 间苯三酚（8.33 mmol)溶于 10 mL硝基苯中， 加入步骤 1中所得 油状物 1.5 g ， 通入干燥 HC1气体， 于室温下搅拌 9 h。 反应液放置过夜后， 加 入 15mL水， 分出水层， 有机层用 2x15 mL水萃取， 合并水层， 加热回流 1 h 。 冷却， 过滤， 所得固体用乙醇-水 （4:1) 重结晶， 得 4- (甲基环己基胺; )- -(2,4,6- 三羟基苯基) 1-丁酮盐酸盐 0.30 g， 收率 11%。 Step 2: Preparation of 4-(methylcyclohexylamine; )-1-(2,4,6-trihydroxyphenyl; ) 1-butanone hydrochloride. Dissolve 1.05 g of phloroglucinol (8.33 mmol). To 10 mL of nitrobenzene, 1.5 g of the oil obtained in Step 1 was added, and the dried HC1 gas was passed, and stirred at room temperature for 9 h. After the reaction solution was allowed to stand overnight, 15 mL of water was added, the aqueous layer was separated, and the organic layer was extracted with 2×15 mL of water, and the aqueous layer was combined and heated to reflux for 1 h. After cooling, filtration, the obtained solid was recrystallized from ethanol-water (4:1) to give 4-(methylcyclohexylamine; )--(2,4,6- Trihydroxyphenyl) 1-butanone hydrochloride 0.30 g, yield 11%.
1H MR (500 MHz, d6-OMSO) δ 5.81 (2Η, s, H-3 ' , H-5 ' ), 2.98 (2H, t, J = 7.0 Hz, H-2), 2.44 (2H, t, J = 7.0 Hz, H-4), 2.35 (1H, m, H-l ' ' ),2.18 (3H, s, NCH3), 1.74 (2H, overlap, H-3), 1.73 (2H, overlap, H-2' ' a, H-6' ' a), 1.71 (2H, m, H-2' ' b, H-6 ' ' b), 1.54 (1H, br.d, J =12.5 Hz, H-4 ' ' a), 1.16 (2H, m, H-3' ' a, H-5' ' a), 1.12 (2H, m, H-3' ' b, H-5 ' ' b), 1.04 (1H, m, H-4' ' b)。 13C NMR (125 MHz, 6-DMSO) δ 204.9, 164.8, 164.7, 164.7, 104.4, 94.7, 94.7, 62.1, 52.3, 40.3, 37.0, 27.8, 27.8, 25.9, 25.4, 25.4, 22.6。 实施例 23.4-[4-(3-氯 -1-基]小(2,4,6-三羟基苯基； )1-丁酮盐酸盐的制备 1H MR (500 MHz, d 6 -OMSO) δ 5.81 (2Η, s, H-3 ' , H-5 ' ), 2.98 (2H, t, J = 7.0 Hz, H-2), 2.44 (2H, t , J = 7.0 Hz, H-4), 2.35 (1H, m, Hl '' ), 2.18 (3H, s, NCH 3 ), 1.74 (2H, overlap, H-3), 1.73 (2H, overlap, H -2'' a, H-6'' a), 1.71 (2H, m, H-2'' b, H-6 '' b), 1.54 (1H, br.d, J =12.5 Hz, H- 4 '' a), 1.16 (2H, m, H-3'' a, H-5'' a), 1.12 (2H, m, H-3'' b, H-5 '' b), 1.04 ( 1H, m, H-4''b). 13 C NMR (125 MHz, 6 -DMSO) δ 204.9, 164.8, 164.7, 164.7, 104.4, 94.7, 94.7, 62.1, 52.3, 40.3, 37.0, 27.8, 27.8, 25.9, 25.4, 25.4, 22.6. Example 23.4 Preparation of [4-(3-Chloro-1-yl)small (2,4,6-trihydroxyphenyl; ) 1-butanone hydrochloride
Figure imgf000041_0001
Figure imgf000041_0001
步骤 1: 4-[4-(3-氯苯基)哌嗪 -1-基]丁腈的制备 Step 1: Preparation of 4-[4-(3-chlorophenyl)piperazin-1-yl]butyronitrile
按照实施例 21中步骤 1的方法， 用 1.35 g (13 mmoi;>4-氯丁腈， 1.80 g (15 mmol)无水碳酸钾和少量 Nal， 以及 2.90 g (15 mmol) 4-(3-氯苯基；)哌嗪反应后得 油状液体 4.00 go  Following the procedure of Step 1 in Example 21, 1.35 g (13 mm oi; >4-chlorobutyronitrile, 1.80 g (15 mmol) anhydrous potassium carbonate and a small amount of Nal, and 2.90 g (15 mmol) 4-(3- Chlorophenyl;) piperazine reaction oily liquid 4.00 go
步骤 2: 4-[4-(3-氯苯基)哌嗪 -1-基]小(2,4,6-三羟基苯基) 1-丁酮盐酸盐的制备 将 1.05 g 间苯三酚（8.33 mmol)溶于 10 mL硝基苯中， 加入步骤 1中所得 油状物 3.00 g ， 通入干燥 HC1气体， 于室温下搅拌 9 h。 反应液放置过夜后， 加 入 15mL水， 分出水层， 有机层用 2x15 mL水萃取， 合并水层， 加热回流 1 h 。 冷却， 过滤， 所得固体用乙醇-水 （5:1) 重结晶， 得 4- (甲基环己基胺； )-1-(2,4,6- 三羟基苯基) 1-丁酮盐酸盐 0.45 g， 收率 13%。 Step 2: Preparation of 4-[4-(3-chlorophenyl)piperazin-1-yl]small (2,4,6-trihydroxyphenyl) 1-butanone hydrochloride 1.05 g of m-benzoic acid The phenol (8.33 mmol) was dissolved in 10 mL of nitrobenzene, and 3.00 g of the oil obtained in the step 1 was added, and the mixture was applied to dry HCl gas, and stirred at room temperature for 9 h. After the reaction solution was allowed to stand overnight, 15 mL of water was added, the aqueous layer was separated, and the organic layer was extracted with 2×15 mL of water, and the aqueous layer was combined and heated to reflux for 1 h. After cooling, filtration, the obtained solid was recrystallized from ethanol-water (5:1) to give 4-(methylcyclohexylamine;)-1-(2,4,6-trihydroxyphenyl) 1-butanone hydrochloride Salt 0.45 g, yield 13%.
1H MR (500 MHz, 6-DMSO) δ 12.21 (2Η, s, OH-2' , OH-6' ), 10.43 (1H, s, OH-4' ), 7.26 (1H, t, J = 8.0 Hz, H-5' ' ' ), 7.05 (1H, br.s, H- H-2' ' ' ), 6.96 (1H, br.d, J = 8.0 Hz, H- H-4' ' ' ), 6.87 (1H, br.d, J = 8.0 Hz, H-6 ' ' ' ), 5.82 (2H, s, H-3 ' , H-5' ), 3.90 (2H, br.d, J =12.5 Hz, H-2' ' a, H-6' ' a), 3.59 (2H, br.d, J = 11.5 Hz, H-3' ' a, H-5' ' a), 3.19 (2H, overlap, H-2' ' b, H-6' ' b), 3.16 (2H, overlap, H-3' ' b, H-5 ' ' b), 3.10 (2H, t, J = 6.5 Hz, H-2), 3.01 (2H, t, J = 11.5 Hz, H-4), 1.99 (2H, m, H-3)。 "C MR (125 MHz, i¾-DMSO) δ 203.0, 164.8 164.1, 164.1, 150.7, 133.9, 130.6, 119.2, 115.2, 114.1, 103.6, 94.6, 94.6, 55.1, 50.5, 50.5, 44.9, 44.9, 38.9, 18.2。 实施例 24. (S)-2-(2,4,6-三甲 1H MR (500 MHz, 6 -DMSO) δ 12.21 (2Η, s, OH-2', OH-6'), 10.43 (1H, s, OH-4'), 7.26 (1H, t, J = 8.0 Hz , H-5''' ), 7.05 (1H, br.s, H- H-2''' ), 6.96 (1H, br.d, J = 8.0 Hz, H- H-4''' ), 6.87 (1H, br.d, J = 8.0 Hz, H-6 ''' ), 5.82 (2H, s, H-3 ' , H-5' ), 3.90 (2H, br.d, J =12.5 Hz , H-2'' a, H-6'' a), 3.59 (2H, br.d, J = 11.5 Hz, H-3'' a, H-5'' a), 3.19 (2H, overlap, H-2'' b, H-6'' b), 3.16 (2H, overlap, H-3'' b, H-5 '' b), 3.10 (2H, t, J = 6.5 Hz, H-2 ), 3.01 (2H, t, J = 11.5 Hz, H-4), 1.99 (2H, m, H-3). "C MR (125 MHz, i3⁄4-DMSO) δ 203.0, 164.8 164.1, 164.1, 150.7, 133.9, 130.6, 119.2, 115.2, 114.1, 103.6, 94.6, 94.6, 55.1, 50.5, 50.5, 44.9, 44.9, 38.9, 18.2 Example 24. (S)-2-(2,4,6-Third
Figure imgf000042_0001
Figure imgf000042_0001
步骤 1 : (S)-2-(2,4,6-三甲氧基苯甲胺基)丙酸甲酯的制备  Step 1: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)propionic acid methyl ester
将 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛溶于 10 mL甲醇中， 加入 76 mg (1.2 mmol) NaBH3CN和 280 mg (2 mmol)丙氨酸甲酯盐酸盐， 氩气保护， 室温下 搅拌 3h。 向反应液中加入 20 mL水， 用 3 x25 mL乙酸乙酯萃取， 合并有机层， 用 3 x 10 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥。 蒸干溶剂， 进行硅胶柱色 谱（石油醚:乙酸乙酯 4: 1 )分离得到 (S)-2-(2,4,6-三甲氧基苯甲胺基)丙酸甲酯 118 mg, 收率 42%。 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde was dissolved in 10 mL of methanol, and 76 mg (1.2 mmol) of NaBH 3 CN and 280 mg (2 mmol) of alanine methyl ester hydrochloride were added. , argon protection, stirring at room temperature for 3 h. 20 mL of water was added to the reaction mixture, and the mixture was extracted with 3×25 mL of ethyl acetate. The solvent was evaporated to dryness and purified by silica gel column chromatography (ethyl ether: ethyl acetate 4:1) to afford (S)-2-(2,4,6-trimethoxybenzylamino)propanoic acid methyl ester 118 mg. The rate is 42%.
步骤 2: (S)-2-(2,4,6-三甲氧基苯甲胺基)丙酸的制备  Step 2: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)propionic acid
将步骤 1得到的 100 mg (0.35 mmol) (S)-2-(2,4,6-三甲氧基苯甲胺基)丙酸甲 酯溶解于 20 mL 5% KOH 乙醇水 （EtOH: ¾0 = 1 : 1 ) 溶液中， 室温下搅拌 2h， 加入 Amberlite 120 H+树脂，搅拌至溶液 pH = 7, 过滤，滤液浓缩，经制备 HPLC ( YMC, 20%乙腈）纯化， 得到 (S)-2-(2,4,6-三甲氧基苯甲胺基)丙酸 85 mg， 收率 90%。 100 mg (0.35 mmol) of methyl (S)-2-(2,4,6-trimethoxybenzylamino)propanoate obtained in Step 1 was dissolved in 20 mL of 5% KOH ethanol water (EtOH: 3⁄40 = 1 : 1 ) In a solution, stir at room temperature for 2 h, add Amberlite 120 H + resin, stir until the solution pH = 7, filter, concentrate the filtrate, and purify by preparative HPLC (YMC, 20% acetonitrile) to give (S)-2- (2,4,6-Trimethoxybenzylamino)propionic acid 85 mg, yield 90%.
1H MR (500 MHz, d6-DMSO) δ 6.27 (2Η, s, H-3 ' , H-5 ' ), 4.07 (2H, br.s, H-l), 3.80 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.79 (3H, s, OCH3-4 ' ), 3.36 (1H, m, H-3), 1.44 (3H, d, J = 6.0 Hz, CH3-5)。 13C NMR (125 MHz, i¾-DMSO) δ 170.8, 162.5, 159.7, 159.7, 99.3, 90.7, 90.7, 55.9, 55.9, 55.6, 54.0, 37.7, 15.2。 实施例 25. (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-苯基丙酸的制备
Figure imgf000043_0001
1H MR (500 MHz, d 6 -DMSO) δ 6.27 (2Η, s, H-3 ' , H-5 ' ), 4.07 (2H, br.s, Hl), 3.80 (6H, s, OCH 3 -2 ' , OCH 3 -6 ' ), 3.79 (3H, s, OCH 3 -4 ' ), 3.36 (1H, m, H-3), 1.44 (3H, d, J = 6.0 Hz, CH 3 -5). 13 C NMR (125 MHz, i3⁄4-DMSO) δ 170.8, 162.5, 159.7, 159.7, 99.3, 90.7, 90.7, 55.9, 55.9, 55.6, 54.0, 37.7, 15.2. Example 25. Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-3-phenylpropionic acid
Figure imgf000043_0001
步骤 1 : (S)-2-(2,4,6-三甲氧基苯甲胺基； )-3-苯基丙酸甲酯的制备  Step 1 : Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-methyl-3-phenylpropionate
按照实施例 24中步骤 1的方法，用 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛， Following the procedure of Step 1 in Example 24, 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde,
76 mg (1.2 mmol) NaBH3CN和 520 mg (2 mmol)苯丙氨酸甲酯盐酸盐反应后， 经 硅胶柱色谱（石油醚:乙酸乙酯 10: 1 )分离得到 (S)-2-(2,4,6-三甲氧基苯甲胺基) -3- 苯基丙酸甲酯 136mg， 收率 38%。 步骤 2: (S)-2-(2,4,6-三甲氧基苯甲胺基； )-3-苯基丙酸的制备 After reacting 76 mg (1.2 mmol) of NaBH 3 CN with 520 mg (2 mmol) of phenylalanine methyl ester hydrochloride, it was separated by silica gel column chromatography ( petroleum ether: ethyl acetate 10:1) to obtain (S)-2 -(2,4,6-Trimethoxybenzylamino)methyl-3-phenylpropanoate 136 mg, yield 38%. Step 2: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino);-3-phenylpropionic acid
按照实施例 24中步骤 2的方法， 用步骤 1得到的 100 mg (0.28 mmol) (S)-2- (2,4,6-三甲氧基苯甲胺基) -3-苯基丙酸甲酯反应后， 经制备 HPLC ( YMC, 30%乙 腈） 纯化， 得到 (S 2-(2,4,6-三甲氧基苯甲胺基； )-3-苯基丙酸 85 mg， 收率 88%。  100 mg (0.28 mmol) of (S)-2-(2,4,6-trimethoxybenzylamino)-3-phenylpropanoate obtained in step 1 according to the method of Step 2 in Example 24. After the ester reaction, it was purified by preparative HPLC (YMC, 30% acetonitrile) to give (S2-(2,4,6-trimethoxybenzylamino) -3-phenylpropanoic acid 85 mg, yield 88 %.
1H MR (500 MHz, d6-DMSO) δ 7.32 (2Η, t, J = 7.5 Hz, H-3 ' ' , H-5 ' ' ), 7.26 (1H, t, J = 8.0 Hz, H-4 ' ' ), 7.22 (2H, d, J = 7.5 Hz, H-2 ' ' , H-6 ' ' ), 6.27 (2H, s, H-3 ' , H-5 ' ), 4.07 (2H, br.s, H-l), 3.91 (1H, br.s, H-3), 3.80 (3H, s, 1H MR (500 MHz, d 6 -DMSO) δ 7.32 (2Η, t, J = 7.5 Hz, H-3 '' , H-5 '' ), 7.26 (1H, t, J = 8.0 Hz, H-4 '' ), 7.22 (2H, d, J = 7.5 Hz, H-2 '' , H-6 '' ), 6.27 (2H, s, H-3 ' , H-5 ' ), 4.07 (2H, br .s, Hl), 3.91 (1H, br.s, H-3), 3.80 (3H, s,
OCH3-4 ' ), 3.78 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.32 (1H, dd, J = 13.5, 4.5 Hz, H-5a), 3.09 (1H, dd, J = 13.5, 8.0 Hz, H-5b) 13C NMR (125 MHz, 6-DMSO) δ 169.2, 162.4, 159.6, 159.6, 134.8, 129.3, 129.3, 128.4, 128.4, 127.1, 98.8, 90.6, 90.6, 59.3, 55.8, 55.8, 55.4, 38.3, 34.9。 实施例 26. (S)-2-(2,4,6-三 -5-氨基 -5-氧戊酸的制备 OCH3-4 ' ), 3.78 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.32 (1H, dd, J = 13.5, 4.5 Hz, H-5a), 3.09 (1H, dd, J = 13.5 , 8.0 Hz, H-5b) 13 C NMR (125 MHz, 6 -DMSO) δ 169.2, 162.4, 159.6, 159.6, 134.8, 129.3, 129.3, 128.4, 128.4, 127.1, 98.8, 90.6, 90.6, 59.3, 55.8, 55.8, 55.4, 38.3, 34.9. Example 26. Preparation of (S)-2-(2,4,6-tri-5-amino-5-oxovaleric acid
Figure imgf000043_0002
Figure imgf000043_0002
步骤 1 : (S)-2-(2,4,6-三甲氧基苯甲胺基)戊二酸二甲酯的制备  Step 1: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino) glutaric acid dimethyl ester
按照实施例 24中步骤 1的方法，用 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛， Following the procedure of Step 1 in Example 24, 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde,
76 mg (1.2 mmol) NaBH3CN禾 P 410 mg (2 mmol)谷氨酸二甲酯盐酸盐反应后， 经 硅胶柱色谱 （石油醚:乙酸乙酯 1 : 1 ) 分离得到 (S)-2-(2,4,6-三甲氧基苯甲胺基； )-4- 氨基 -4-氧丁酸甲酯 165mg， 收率 50%。 步骤 2: (S)-2-(2,4,6-三甲氧基苯甲胺基)戊二酸的制备 After the reaction of 76 mg (1.2 mmol) of NaBH 3 CN and P 410 mg (2 mmol) of dimethyl glutamate hydrochloride, it was separated by silica gel column chromatography ( petroleum ether: ethyl acetate 1: 1 ) to give (S)- 2-(2,4,6-Trimethoxybenzylamino); methyl 4-amino-4-oxobutanoate 165 mg, yield 50%. Step 2: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)glutaric acid
按照实施例 24中步骤 2的方法，用步骤 1得到的 100 mg (0.31 mmol) (S)-2- (2,4,6-三甲氧基苯甲胺基； )-5-氨基 -5-氧丁酸甲酯反应后， 经制备 HPLC ( YMC, 13%乙腈） 纯化， 得到 (S)-2-(2,4,6-三甲氧基苯甲胺基)戊二酸 91 mg， 收率 95%。  100 mg (0.31 mmol) of (S)-2-(2,4,6-trimethoxybenzylamino)--5-amino-5- obtained in Step 1 according to the procedure of Step 2 in Example 24. After reacting methyl oxybutyrate, it was purified by preparative HPLC (YMC, 13% acetonitrile) to give (S)-2-(2,4,6-trimethoxybenzylamino) glutaric acid 91 mg, yield 95%.
1H MR (500 MHz, d6-DMSO) δ 6.26 (2Η, s, H-3 ' , H-5 ' ), 4.03 (1H, d, J = 13.0 Hz, H-la), 3.97 (1H, d, J = 13.0Hz, H-lb), 3.79 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.78 (3H, s, OCH3-4 ' ), 3.44 (1H, t, J = 6.5Hz, H-3), 2.41 (1H, m, H-5a), 2.32(1H, m: H-5b), 2.01 (1H, m, H-6a), 1.94 (1H, m, H-6b)。 13C NMR (125 MHz, 6-DMSO) δ 173.7, 169.9, 162.3, 159.6, 159.6, 99.8, 90.7, 90.7, 58.8, 55.9, 55.9, 55.5, 38.5, 30.3, 24.9。 实施例 27. (S)-2-(2,4,6-三 二酸的制备 1H MR (500 MHz, d 6 -DMSO) δ 6.26 (2Η, s, H-3 ' , H-5 ' ), 4.03 (1H, d, J = 13.0 Hz, H-la), 3.97 (1H, d , J = 13.0 Hz, H-lb), 3.79 (6H, s, OCH 3 -2 ' , OCH 3 -6 ' ), 3.78 (3H, s, OCH 3 -4 ' ), 3.44 (1H, t, J = 6.5 Hz, H-3), 2.41 (1H, m, H-5a), 2.32 (1H, m : H-5b), 2.01 (1H, m, H-6a), 1.94 (1H, m, H- 6b). 13 C NMR (125 MHz, 6 -DMSO) δ 173.7, 169.9, 162.3, 159.6, 159.6, 99.8, 90.7, 90.7, 58.8, 55.9, 55.9, 55.5, 38.5, 30.3, 24.9. Example 27. Preparation of (S)-2-(2,4,6-trisuccinic acid
Figure imgf000044_0001
Figure imgf000044_0001
步骤 1 : (S)-2-(2,4,6-三甲氧基苯甲胺基)丁二酸二甲酯的制备  Step 1: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino) dimethyl succinate
按照实施例 24中步骤 1的方法，用 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛， Following the procedure of Step 1 in Example 24, 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde,
76 mg (1.2 mmol) NaBH3CN和 420 mg (2 mmol)天冬氨酸二甲酯盐酸盐反应后， 经硅胶柱色谱 （石油醚:乙酸乙酯 5 : 1 ) 分离得到 (S)-2-(2,4,6-三甲氧基苯甲胺基) 丁二酸二甲酯 155mg， 收率 46%。 步骤 2: (S)-2-(2,4,6-三甲氧基苯甲胺基)丁二酸的制备 After reacting 76 mg (1.2 mmol) of NaBH 3 CN with 420 mg (2 mmol) of dimethyl aspartate hydrochloride, it was separated by silica gel column chromatography ( petroleum ether: ethyl acetate 5:1) to give (S)- 2-(2,4,6-Trimethoxybenzylamino) dimethyl succinate 155 mg, yield 46%. Step 2: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)succinic acid
按照实施例 24中步骤 2的方法，用步骤 1得到的 100 mg (0.29 mmol) (S)-2- (2,4,6-三甲氧基苯甲胺基)丁二酸二甲酯反应后， 经制备 HPLC ( YMC, 9%乙腈） 纯化， 得到 (S)-2-(2,4,6-三甲氧基苯甲胺基)丁二酸 75 mg， 收率 85%。  After reacting 100 mg (0.29 mmol) of (S)-2-(2,4,6-trimethoxybenzylamino) succinate according to the procedure of Step 2 in Example 24, Purified by preparative HPLC (YMC, 9% acetonitrile) afforded (S)-2-(2,4,6-trimethoxybenzylamino) succinic acid 75 mg, yield 85%.
1H MR (500 MHz, 6-DMSO) δ 6.28 (2Η, s, H-3 ' , H-5 ' ), 4.17 (1H, d, J = 13.0 Hz, H-la), 4.13 (1H, d, J = 13.0 Hz, H-lb), 3.99 (1H, t, J = 6.0 Hz, H-3), 3.80 (3H, s, OCH3-4 ' ), 3.79 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 2.84 (2H, br.s, H-5)。 13C NMR (125 MHz, 6-DMSO) δ 171.1, 169.2, 162.5, 159.6, 159.6, 99.2, 90.8, 90.8, 56.0, 56.0, 55.5, 54.7, 39.0, 34.0。 实施例 28. (S)-2-(2,4,6-三 -3-羟基丙酸的制备 1H MR (500 MHz, 6 -DMSO) δ 6.28 (2Η, s, H-3 ' , H-5 ' ), 4.17 (1H, d, J = 13.0 Hz, H-la), 4.13 (1H, d, J = 13.0 Hz, H-lb), 3.99 (1H, t, J = 6.0 Hz, H-3), 3.80 (3H, s, OCH3-4 '), 3.79 (6H, s, OCH 3 -2 ' , OCH 3 -6 ' ), 2.84 (2H, br.s, H-5). 13 C NMR (125 MHz, 6 -DMSO) δ 171.1, 169.2, 162.5, 159.6, 159.6, 99.2, 90.8, 90.8, 56.0, 56.0, 55.5, 54.7, 39.0, 34.0. Example 28. Preparation of (S)-2-(2,4,6-tri-3-hydroxypropionic acid
Figure imgf000045_0001
Figure imgf000045_0001
步骤 1 : (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸甲酯的制备  Step 1 : Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropionic acid methyl ester
按照实施例 24中步骤 1的方法，用 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛， 76 mg (1.2 mmol) NaBH3CN禾 P 310 mg (2 mmol)丝氨酸甲酯盐酸盐反应后， 经硅 胶柱色谱 （石油醚:乙酸乙酯 1 : 1 ) 分离得到 (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟 基丙酸甲酯 110mg， 收率 37%。 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde, 76 mg (1.2 mmol) of NaBH 3 CN and P 310 mg (2 mmol) of serine methyl ester salt according to the procedure of Step 1 in Example 24. After the acid salt reaction, (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropanoic acid was isolated by silica gel column chromatography ( petroleum ether: ethyl acetate: 1 : 1 ). The ester was 110 mg in a yield of 37%.
步骤 2: (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸的制备  Step 2: Preparation of (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropionic acid
按照实施例 24中步骤 2的方法， 用步骤 1得到的 100 mg (0.33 mmol) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸甲酯反应后， 经制备 HPLC ( YMC, 13%乙腈） 纯化， 得到 (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸 86 mg， 收率 92%。  100 mg (0.33 mmol) of (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropanoic acid methyl ester obtained in Step 1 according to the procedure in Step 2 in Example After the reaction, it was purified by preparative HPLC (YMC, 13% acetonitrile) to give (S)-2-(2,4,6-trimethoxybenzylamino)-3-hydroxypropanoic acid 86 mg, yield 92% .
1H MR (500 MHz, d6-DMSO) δ 6.27 (2Η, s, H-3 ' , H-5 ' ), 4.10 (2H, br.s, H-1), 3.85 (IH, overlap, H-5a), 3.85 (IH, overlap, H-5b), 3.79 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.78 (3H, s, OCH3-4 ' ), 3.48 (IH, br.s, H-3) 0 13C NMR (125 MHz, i¾-DMSO) δ 168.4, 162.3, 159.7, 159.7, 99.4, 90.8, 90.8, 60.8, 59.3, 56.0, 56.0, 55.5, 38.7。 实施例 29. (S)-2-(2,4,6-三羟基苯甲胺基 -3-(1Η-咪唑 -5-基)丙酸的制备 1H MR (500 MHz, d 6 -DMSO) δ 6.27 (2Η, s, H-3 ' , H-5 ' ), 4.10 (2H, br.s, H-1), 3.85 (IH, overlap, H- 5a), 3.85 (IH, overlap, H-5b), 3.79 (6H, s, OCH 3 -2 ' , OCH 3 -6 ' ), 3.78 (3H, s, OCH3-4 ' ), 3.48 (IH, br .s, H-3) 0 13 C NMR (125 MHz, i3⁄4-DMSO) δ 168.4, 162.3, 159.7, 159.7, 99.4, 90.8, 90.8, 60.8, 59.3, 56.0, 56.0, 55.5, 38.7. Example 29. Preparation of (S)-2-(2,4,6-trihydroxybenzylamino-3-(1Η-imidazol-5-yl)propionic acid
Figure imgf000045_0002
Figure imgf000045_0002
步骤 1 : (S)-2-(2,4,6-三羟基苯甲胺基) -3-(1Η-咪唑 -5-基)丙酸甲酯的制备 按照实施例 24中步骤 1的方法，用 196 mg (1 mmol) 2,4,6-三甲氧基苯甲醛， 76 mg (1.2 mmol) NaBH3CN禾 P 411 mg (2 mmol) 组氨酸甲酯盐酸盐反应后， 经硅 胶柱色谱 （二氯甲垸:甲醇 10: 1 ) 分离得到 (S)-2 2,4,6-三羟基苯甲胺基) -3-GH- 咪唑 -5-基)丙酸甲酯 97mg， 收率 28%。 Step 1: Preparation of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1Η-imidazol-5-yl)propanoic acid methyl ester according to the method of Step 1 in Example 24. Using 196 mg (1 mmol) of 2,4,6-trimethoxybenzaldehyde, 76 mg (1.2 mmol) of NaBH 3 CN and P 411 mg (2 mmol) of histidine methyl ester hydrochloride, Glue column chromatography (dichloromethane:methanol 10:1) isolated (S)-2 2,4,6-trihydroxybenzylamino) -3-GH-imidazol-5-yl)methyl propionate 97mg , yield 28%.
步骤 2: (S)-2-(2,4,6-三羟基苯甲胺基) -3-(1Η-咪唑 -5-基)丙酸的制备 按照实施例 24中步骤 2的方法， 用步骤 1得到的 97 mg (0.28 mmol) (S)-2- (2,4,6-三羟基苯甲胺基) -3-(1Η-咪唑 -5-基;)丙酸甲酯反应后， 经制备 HPLC (YMC, 10%乙腈）纯化， 得到 (S)-2-(2,4,6-三羟基苯甲胺基) -3-(1Η-咪唑 -5-基)丙酸 70mg， 收率 74%。  Step 2: Preparation of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1Η-imidazol-5-yl)propionic acid according to the method of Step 2 in Example 24 After reacting 97 mg (0.28 mmol) of (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1Η-imidazole-5-yl;) methyl propionate obtained in Step 1, Purified by preparative HPLC (YMC, 10% acetonitrile) to give (S)-2-(2,4,6-trihydroxybenzylamino)-3-(1Η-imidazol-5-yl)propanoic acid 70 mg. The rate is 74%.
1H MR (500 MHz, i¾-DMSO) δ 7.95 (1Η, s, H-3 ' ' ), 7.47 (1H, s, H-5 ' ' ), 6.29 (2H, s, H-3 ' , H-5 ' ), 4.13 (1H, d, J = 13.5 Hz, H-la), 4.07 (1H, d, J = 13.5 Hz, H-lb), 3.91 (1H, br.s, H-3), 3.79 (3H, s, OCH3-4 ' ), 3.80 (6H, s, OCH3 -2 ' , OCH3 -6 ' ), 3.32 (1H, dd, J = 15.5, 6.0 Hz, H-5a), 3.24 (1H, dd, J = 15.5, 8.0 Hz, H-5b) 13C NMR (125 MHz, 6-DMSO) δ 168.9, 162.6, 159.8, 159.8, 134.5, 127.6, 117.8, 99.1, 90.8, 90.8, 57.4, 55.9, 55.9, 55.6, 38.5, 24.8。 药理实验 1H MR (500 MHz, i3⁄4-DMSO) δ 7.95 (1Η, s, H-3 '' ), 7.47 (1H, s, H-5 '' ), 6.29 (2H, s, H-3 ' , H- 5 ' ), 4.13 (1H, d, J = 13.5 Hz, H-la), 4.07 (1H, d, J = 13.5 Hz, H-lb), 3.91 (1H, br.s, H-3), 3.79 (3H, s, OCH 3 -4 ' ), 3.80 (6H, s, OCH 3 -2 ' , OCH 3 -6 ' ), 3.32 (1H, dd, J = 15.5, 6.0 Hz, H-5a), 3.24 (1H, dd, J = 15.5, 8.0 Hz, H-5b) 13 C NMR (125 MHz, 6 -DMSO) δ 168.9, 162.6, 159.8, 159.8, 134.5, 127.6, 117.8, 99.1, 90.8, 90.8, 57.4, 55.9, 55.9, 55.6, 38.5, 24.8. Pharmacological experiment
1. 实验例 1 (化合物体外对 LPS引起的 NO释放的抑制作用） 1. Experimental Example 1 (Inhibition of NO release by LPS in vitro)
(一）材料和方法：  (1) Materials and methods:
材料： BV2细胞 （小鼠小胶质细胞系） Materials: BV2 cells (mouse microglia cell line)
Griess试剂： 以蒸熘水配制 0.1%萘乙二胺， 以 5%磷酸配制 1%对氨基苯 磺酸， 两者在临用前以 1 : 1等体积混合 姜黄素， 用 DMSO配制， 终浓度为 10-5,10-6, 10-7mol/L Griess reagent: 0.1% naphthylethylenediamine in distilled water, 1% p-aminobenzenesulfonic acid in 5% phosphoric acid, the two are mixed with curcumin in an equal volume of 1:1 before use, in DMSO, final concentration 10 - 5 , 10 - 6 , 10- 7 mol/L
脂多糖， 用无菌 PBS配制， 终浓度为 300 ng / mL  Lipopolysaccharide, prepared in sterile PBS, at a final concentration of 300 ng / mL
受试化合物， 用 DMSO配制， 终浓度为 10-5,10-6, 10-7mol/L Test compound prepared in DMSO, final concentration of 10- 5, 10- 6, 10- 7 mol / L
方法： Method:
1) BV2细胞于含 10%新生牛血清的 DMEM-F12培养基中培养， 于 37 °C， 5 % C02/95 %空气， 100 %相对湿度下生长。 1) BV2 cells were cultured in DMEM-F12 medium containing 10% newborn calf serum and grown at 37 ° C, 5 % C0 2 /95 % air, 100% relative humidity.
2) 对数生长期的 BV2细胞，经消化计数后，以 2 X 104个 /孔接种到 96孔板中， 24小时后加入不同浓度的受试化合物和阳性对照药姜黄素（10·5, 10·6, 10·7Μ) , 1小时后加入 LPS , 终浓度为 300ng / mL， 继续培养 24小时， 收集培养基 上清液。 2) BV2 cells in logarithmic growth phase were inoculated into 96-well plates at 2×10 4 cells/well after digestion, and 24 hours later, different concentrations of test compound and positive control drug curcumin (10· 5) were added. , 10· 6 , 10· 7 Μ) , After 1 hour, LPS was added to a final concentration of 300 ng / mL, and the culture was continued for 24 hours, and the culture supernatant was collected.
3) 取细胞培养液上液清 100 μί， 加入等体积 Griess试剂， 室温静置 20min， 蒸 熘水调零， 于酶标仪上在 540nm处测定 OD值， 同时以硝酸钠为标准品， 测 定 OD值， 计算待测样品中 Ν02·的浓度反映 NO的浓度。 3) Take 100 μί of the supernatant from the cell culture medium, add an equal volume of Griess reagent, let stand at room temperature for 20 min, distill the distilled water to zero, measure the OD value at 540 nm on the microplate reader, and measure with sodium nitrate as the standard. The OD value is calculated by calculating the concentration of Ν0 2 · in the sample to be tested.
, 样品组 OD值 -空白组 OD值 、 抑制率 （％) = ( 1 χ 100%  , sample group OD value - blank group OD value, inhibition rate (%) = ( 1 χ 100%
模型组 OD值 - 空白组 OD值 )  Model group OD value - blank group OD value)
(二） 结果 多个受试化合物均表现出了良好的抑制小胶质细胞的活性 (l x lO—5 mol/L浓 度下， 抑制率 >50%)， 其中实施例 1， 2， 26， 28表示的化合物的活性与阳性对 照药物姜黄素相当 （表 1和图 1 )。 (II) Results A plurality of test compounds showed good activity of inhibiting microglia (inhibition rate >50% at a concentration of lx lO- 5 mol/L), wherein Examples 1, 2, 26, 28 The activity of the indicated compound was comparable to that of the positive control drug curcumin (Table 1 and Figure 1).
表 1： 实施例中化合物的 IC5。值 Table 1: IC 5 of the compounds in the examples. value
化合物实施 化合物实施 Compound implementation compound implementation
IC50 (μΜ) IC50 (μΜ) IC 50 (μΜ) IC 50 (μΜ)
例号 例号  Case number
1 5.82 16 13.35  1 5.82 16 13.35
2 6.36 17 24.45  2 6.36 17 24.45
3 16.69 18 12.21  3 16.69 18 12.21
4 19.40 19 9.27  4 19.40 19 9.27
5 13.07 20 48.04  5 13.07 20 48.04
6 14.50 21 34.90  6 14.50 21 34.90
7 16.99 22 28.76  7 16.99 22 28.76
8 15.41 23 77.02  8 15.41 23 77.02
9 一 24 16.36  9 a 24 16.36
10 1 1.82 25 22.12  10 1 1.82 25 22.12
11 14.58 26 8.58  11 14.58 26 8.58
12 12.19 27 14.95  12 12.19 27 14.95
13 14.77 28 6.86  13 14.77 28 6.86
14 16.38 29 一  14 16.38 29 one
15 19.31 姜黄素 3.75  15 19.31 Curcumin 3.75
注： "IC5o"表示化合物对 NO抑制率达到 50%时的浓度 Note: "IC 5 o" indicates the concentration of the compound when the NO inhibition rate reaches 50%.
"一"表示化合物在最大浓度 lx lO—5 mol L下对 NO抑制率低于 50% 2. 实验例 2 (化合物体外对 LPS及 Αβ25.35引发的神经炎症的抑制作用）"One" means that the compound has a NO inhibition rate of less than 50% at a maximum concentration of lx lO- 5 mol L 2 (Inhibitory Effect of compounds on LPS and Αβ 25. 35 induced neuroinflammation) 2. Experimental Example
(一） 材料和方法： (i) Materials and methods:
材料： 孕 18d的 SD大鼠胚胎 Materials: SD rat embryos at 18 days of gestation
脂多糖， 用无菌 PBS配制， 终浓度为 lOO ng / mL  Lipopolysaccharide, prepared in sterile PBS, at a final concentration of 100 ng / mL
Αβ25.35， 用无菌 PBS配制， 37°C下老化 7天， 终浓度为 2.5χ 10·5 mol/L 姜黄素， 用 DMSO配制， 终浓度为 10—5mol/L Αβ 25 . 35 , prepared in sterile PBS, aged at 37 ° C for 7 days, final concentration of 2.5 χ 10 · 5 mol / L curcumin, prepared in DMSO, the final concentration of 10 - 5 mol / L
多奈哌齐， 用 DMSO配制， 终浓度为 5 x lO—6 mol/L Donepezil, formulated in DMSO, at a final concentration of 5 x lO- 6 mol/L
受试化合物（实施例 1、 2、 26和 28 ), 用 DMSO配制，终浓度为 10·5, 10—6， 10"7 mol/L Test compounds (Examples 1, 2, 26 and 28), formulated with DMSO, final concentration of 10 · 5, 10- 6, 10 "7 mol / L
ELISA试剂盒 （R&D公司）  ELISA kit (R&D)
LDH检测试剂 （南京建成生物试剂公司）  LDH detection reagent (Nanjing Built Bioreagent Company)
方法： Method:
1) 原代海马神经元 /胶质细胞混合培养体系的建立： 孕 18d的 SD大鼠胚胎， 在 解剖镜下分离海马， 用移液管进行吹打， 直至看不到组织块为止， 过滤后接 种于 24孔板中。  1) Establishment of a primary hippocampal neuron/glial mixed culture system: SD rat embryos at 18 days of gestation, the hippocampus were separated under a dissecting microscope, and pipetted with a pipette until the tissue block was not visible. In a 24-well plate.
2) 细胞给药处理： 上述原代细胞培养 7d后， 分别与受试化合物 （10·5, 10·6, 10·7 mol/L)或阳性对照药姜黄素（10—5 mol/L)、多奈哌齐（5χ 10·6 mol/L)共孵育， 3h后加入剌激剂 LPS 100 ng / mL或 Ap25.35 2.5 x l(T5 mol/L， 5h后取培养基测 IL-Ιβ和 TNF-α 。 2) cells treated administration: After the above-described primary cell cultures 7d, respectively, with a test compound (10 · 5, 10 · 6 , 10 · 7 mol / L) or a positive control drug curcumin (10- 5 mol / L) And donepezil (5χ 10· 6 mol/L) were co-incubated. After 3 h, add sputum LPS 100 ng / mL or Ap 25 . 35 2.5 xl (T 5 mol/L. After 5 h, the medium was taken to measure IL-Ιβ and TNF. -α.
3) 细胞经药物处理 7d后， 收集培养基检测 LDH。  3) After the cells were treated with the drug for 7 days, the culture medium was collected to detect LDH.
(二） 结果 (ii) Results
1 ) 海马神经元 /胶质细胞混合培养体系在 LPS 剌激下出现炎症反应， 培养基中 IL-Ιβ, TNF-α和 LDH的释放量明显增加， 后者表明神经元出现损伤。 而实 施例 1、 2、 26和 28表示的化合物可明显降低这三种因子的水平， 说明其具 有抑制神经炎症， 保护神经元的作用， 且在 10·5 mol/L浓度下， 作用强度与 阳性对照药姜黄素相当 （见表 2)。 表 2: 化合物对 LPS引起的神经炎症的抑制作用 剂量 IL-Ιβ TNF-α LDH 1) The hippocampal neuron/glial mixed culture system showed an inflammatory reaction under LPS stimulation, and the release of IL-Ιβ, TNF-α and LDH in the culture medium was significantly increased, and the latter showed neuronal damage. The compounds represented by Examples 1, 2, 26 and 28 can significantly reduce the levels of these three factors, indicating that they have the effect of inhibiting neuroinflammation and protecting neurons, and at a concentration of 10 · 5 mol / L, the intensity of action and The positive control drug curcumin was comparable (see Table 2). Table 2: Inhibition of LPS-induced neuroinflammation by compounds Dose IL-Ιβ TNF-α LDH
实施例号  Example number
(mol/L) (pg / mL ) (pg / mL ) (pg / mL )  (mol/L) (pg / mL ) (pg / mL ) (pg / mL )
10 90.45 77.03 279.72  10 90.45 77.03 279.72
-6  -6
10 127.26 123.84 485.89  10 127.26 123.84 485.89
-7  -7
10 144.90 168.59 591.10  10 144.90 168.59 591.10
10 88.60 83.33 193.11  10 88.60 83.33 193.11
-6  -6
10 138.60 145.78 511.19  10 138.60 145.78 511.19
-7  -7
10 186.08 186.48 635.10  10 186.08 186.48 635.10
10 102.05 92.10 326.59  10 102.05 92.10 326.59
-6  -6
26 10 136.92 153.33 555.71  26 10 136.92 153.33 555.71
-7  -7
10 173.05 199.77 684.84  10 173.05 199.77 684.84
10 113.06 89.40 220.85  10 113.06 89.40 220.85
-6  -6
28 10 171.79 142.02 539.45  28 10 171.79 142.02 539.45
-7  -7
10 212.54 171.18 660.93  10 212.54 171.18 660.93
10 82.45 79.12 198.56 模型组 （LPS) 197.76 210.39 703.97  10 82.45 79.12 198.56 Model group (LPS) 197.76 210.39 703.97
空白组 0 0 47.00  Blank group 0 0 47.00
2)海马神经元 /胶质细胞混合培养体系在 Αβ25.35剌激下出现炎症反应， 培养基中 IL-Ιβ, TNF-α和 LDH的释放量明显增加， 后者表明神经元出现损伤。 而实 施例 1、 2、 26和 28表示的化合物可明显降低这三种因子的水平， 说明其具 有抑制神经炎症， 保护神经元的作用， 且在 10·5 mol/L浓度下， 作用强度与 阳性对照药姜黄素相当。 表 3化合物对 Αβ25-35引起的神经炎症的抑制作用 2) The hippocampal neuron/glial mixed culture system showed an inflammatory reaction under Αβ 25 . 35剌, and the release of IL-Ιβ, TNF-α and LDH in the medium increased significantly, and the latter showed neuronal damage. The compounds represented by Examples 1, 2, 26 and 28 can significantly reduce the levels of these three factors, indicating that they have the effect of inhibiting neuroinflammation and protecting neurons, and at a concentration of 10 · 5 mol / L, the intensity of action and The positive control drug curcumin is equivalent. Table 3 compounds inhibit the inhibition of neuroinflammation induced by Aβ 25-35
剂量 TNF-a LDH 实施例号  Dosage TNF-a LDH Example Number
(mol/L) (pg / mL ) (pg / mL )  (mol/L) (pg / mL ) (pg / mL )
43.48 37.63 279.72  43.48 37.63 279.72
1 Ι χ ΙΟ"6 54.82 53.27 485.89 1 Ι χ ΙΟ" 6 54.82 53.27 485.89
Ι χ ΙΟ"7 81.54 85.99 591.10 10 38.18 44.43 193.11 Ι χ ΙΟ" 7 81.54 85.99 591.10 10 38.18 44.43 193.11
-6  -6
10 58.26 63.43 511.19  10 58.26 63.43 511.19
-7  -7
10 90.78 88.61 635.10 10 52.70 48.00 326.59  10 90.78 88.61 635.10 10 52.70 48.00 326.59
-6  -6
26 10 63.80 59.39 555.71  26 10 63.80 59.39 555.71
-7  -7
10 81.88 94.39 684.84  10 81.88 94.39 684.84
10 51.32 50.74 220.85  10 51.32 50.74 220.85
-6  -6
28 10 61.54 61.62 539.45  28 10 61.54 61.62 539.45
-7  -7
10 79.44 86.51 660.93 10 37.26 42.41 198.56 模型组  10 79.44 86.51 660.93 10 37.26 42.41 198.56 Model group
85.79 99.32 703.97 (Αβ25-35) 85.79 99.32 703.97 (Αβ 25-35 )
空白组 47.00  Blank group 47.00
3. 实验例 3 (化合物体外对 Αβ25.35引起的神经元损伤的影响） 3.3 (Effect of the compound on the in vitro neuronal damage caused by Αβ 25. 35) of Experimental Example
(一） 材料和方法：  (i) Materials and methods:
材料： 新生 SD大鼠 Material: Newborn SD Rat
阿糖胞苷 （Ara-C) 用去离子水配制， 过滤除菌， 终浓度为 4 m mol/L Αβ25.35， 用无菌 PBS配制， 37°C下老化 7天， 终浓度为 2.5x lO—5 mol/L 多奈哌齐， 用 DMSO配制， 终浓度为 5x lO—6 mol/L Cytarabine (Ara-C) is prepared by deionized water, filtered and sterilized to a final concentration of 4 m mol/L Αβ 25 . 35 , prepared in sterile PBS, aged at 37 ° C for 7 days, and the final concentration is 2.5. x lO— 5 mol/L donepezil, prepared in DMSO, final concentration 5x lO- 6 mol/L
受试化合物（实施例 1、 2、 26和 28), 用 DMSO配制，终浓度为 10·5, 10—6， 10"7 mol/L Test compounds (Examples 1, 2, 26 and 28), formulated with DMSO, final concentration of 10 · 5, 10- 6, 10 "7 mol / L
方法： Method:
1 ) 原代单纯海马神经元培养体系的建立： 新生 SD大鼠， 解剖镜下分离海马， 加胰蛋白酶消化，终止消化后，用移液管进行吹打，直至看不到组织块为止， 过滤， 离心后接种于 96孔板中。 48h后加入 Ara-C， 抑制胶质细胞生长。 1) Establishment of primary hippocampal neuron culture system: Newborn SD rats, hippocampus were dissected under anatomical microscope, trypsinized, and after digestion, pipetting was performed until the tissue block was not visible, and filtered. After centrifugation, it was inoculated into a 96-well plate. After 48 hours, Ara-C was added to inhibit the growth of glial cells.
2) 细胞给药处理： 上述原代细胞培养 7d后， 分别与受试化合物（10·5, 10·6, 10·7 mol/L )或阳性对照药多奈哌齐（ 5 X 10·6 mol/L )共孵育， 3h后加入剌激剂 Αβ25.35 2.5χ 10"5 mol/L。 3) 细胞经药物处理 7d后， 吸出培养液， 加入无血清的培养基配制的 MTT， 终 浓度为 0.5mg/mL， 37°C继续培养 4h后， 加 150 二甲亚砜溶解 MTT， 在 570 nm处读取吸收值。 以对照组细胞存活率为 100%， 计算不同处理组细 胞的存活率。 2) Cell administration: After the primary cells were cultured for 7 days, they were tested with the test compound (10· 5 , 10.6 , 10· 7 mol/L) or the positive control drug donepezil (5 X 10· 6 mol/L). Co-incubation, 3 h after the addition of stimulating agent Αβ 25 . 35 2.5 χ 10" 5 mol / L. 3) After the cells were treated with the drug for 7 days, the culture solution was aspirated, MTT was added to the serum-free medium, and the final concentration was 0.5 mg/mL. After further incubation at 37 °C for 4 hours, 150 dimethyl sulfoxide was added to dissolve MTT. The absorption value is read at nm. The survival rate of cells in different treatment groups was calculated by the cell survival rate of the control group being 100%.
(二） 结果 (ii) Results
单纯海马原代培养的神经元在 Αβ25.35的剌激下， 神经元存活率明显降低， 实 施例 1、 2、 26和 28表示的化合物可显着提高神经元的存活率， 说明其对神经元 具有直接的保护作用，且在 10—5mol/L浓度下，效果优于阳性药多奈哌齐（表 4)。 表 4: 化合物对 Αβ25— 35引起神经元损伤的保护作用 Simple primary neural hippocampal cultured under stimulation element Αβ 25. 35, the neuron viability decreased, Examples 1, 2, 26 and 28 represented by the compound can significantly increase the survival of neurons, its description neurons have direct protective effect, and in / L concentration of 10- 5 mol, better than positive drug donepezil (table 4). Table 4: Protective effects of compounds on neuronal damage induced by Αβ 25 — 35
实施例号 剂量 （mol/L) 神经元存活率 （％)  Example No. Dosage (mol/L) Neuron survival rate (%)
Figure imgf000051_0001
Figure imgf000051_0001
lxlO"7 49.59 lxlO" 7 49.59
lxlO"5 88.17 lxlO" 5 88.17
26 lxlO"6 64.24 26 lxlO" 6 64.24
lxlO—7 55.65 lxlO— 7 55.65
lxlO"5 78.81 lxlO" 5 78.81
28 lxlO"6 56.47 28 lxlO" 6 56.47
lxlO"7 46.57 lxlO" 7 46.57
多奈哌齐 5χ1(Τ6 75.21 Donepezil 5χ1 (Τ 6 75.21
模型组 （LPS) 47.34  Model Group (LPS) 47.34
空白组 100  Blank group 100
4. 实验例 4 (化合物体内对 MPTP诱发的亚急性 PD模型的影响) (一） 材料和方法 4. Experimental Example 4 (Influence of compounds on MPTP-induced subacute PD model) (i) Materials and methods
材料： 动物： 雄性 C57小鼠， 体重 22±lg， 购自北京华阜康实验动物技术有限公 司。 清洁级。 词养条件： 屏障级动物房词养， 许可证号： Materials: Animals: Male C57 mice weighing 22 ± lg were purchased from Beijing Huakang Experimental Animal Technology Co., Ltd. Clean grade. Word cultivation conditions: barrier-level animal room words, license number:
SYXK (；京 )2009-0004， 标准词养盒内词养， 每盒 5只。  SYXK (; Jing) 2009-0004, the word in the standard word box, 5 per box.
受试药物： 实施例 1和 28表示的化合物  Test drug: Compounds represented by Examples 1 and 28
L-DOPA: 美多芭 （多巴丝肼片）， 上海罗氏制药有限公司， 国药准字 L-DOPA: Medoba (Dobasi), Shanghai Roche Pharmaceutical Co., Ltd.
H10930198, 批号： SH0895。 H10930198, Lot number: SH0895.
MPTP: Sigma公司产品， 批号： 128kl549。。  MPTP: Sigma product, batch number: 128kl549. .
DA和 IP购自 Sigma公司。  DA and IP were purchased from Sigma.
方法： Method:
1 ) 模型建立： 小鼠采用转棍法 （Rotarod test) 提前训练 3天， 将运动不协调的 小鼠剔除， 随机分组， 每组 15只。小鼠每天腹腔注射 MPTP (溶于生理盐水） 30mg/kg—次， 连续 5天。  1) Model establishment: The mice were trained in advance by the Rotarod test for 3 days, and the mice with uncoordinated movements were excluded and randomly divided into groups of 15 each. Mice were intraperitoneally injected with MPTP (dissolved in physiological saline) 30 mg/kg once daily for 5 consecutive days.
2) 分组给药： 分为正常对照组、 MPTP模型组、 实施例 1不同剂量组、 实施例  2) Group administration: divided into normal control group, MPTP model group, Example 1 different dose group, example
28不同剂量组和阳性药 L-DOPA组。 实施例 1和 28不同剂量及阳性药给药 后 30min腹腔注射 MPTP 30mg/kg, 每天一次， 连续 5天。 MPTP停止注射后 继续给药， 每天一次， 连续 7天。 正常对照组口服和腹腔注射相同剂量的无 菌双蒸水和生理盐水， MPTP模型组口服给予相同剂量的无菌双蒸水。  28 different dose groups and positive drug L-DOPA group. Examples 1 and 28 were administered with different doses and positive drugs 30 min after intraperitoneal injection of MPTP 30 mg/kg once daily for 5 consecutive days. MPTP continued to be administered after the injection was stopped, once a day for 7 consecutive days. The normal control group was orally and intraperitoneally injected with the same dose of sterile double distilled water and normal saline, and the MPTP model group was orally administered the same dose of sterile double distilled water.
3 ) 行为学检测： 采用转棍法和爬杆法 （Pole test) 来评价小鼠的运动协调能力。 3) Behavioral testing: The roller coordination method and the Pole test were used to evaluate the motor coordination ability of the mice.
① 转棍法： 转棍仪 （中国医学科学院药物研究所研制） 为直径 3cm， 长约为 50cm, 用隔板分隔为 5段的水平杆， 保证动物彼此不受影响。 转棍仪转速设 为恒速 14转 /min。 将小鼠置于杆上， 打开开关， 开始计时， 记录从开始转棍 到小鼠从杆上掉下的时间， 记为潜伏期（即第一次掉落的时间）， 以此表示其 运动协调能力。 每只小鼠测试 3次， 每次间隔 lh， 取平均值。 小鼠于实验的 第 5天， 9天和 16天转棍测试。 1 Rolling stick method: The stick stick instrument (developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences) is a horizontal rod with a diameter of 3cm and a length of about 50cm. It is divided into 5 sections by a partition to ensure that the animals are not affected by each other. The speed of the stick is set to a constant speed of 14 rpm. Place the mouse on the rod, turn on the switch, start timing, record the time from the start of the stick to the time the mouse fell off the pole, and record it as the incubation period (ie the time of the first drop), in order to express its movement coordination ability. Each mouse was tested 3 times, with an interval of 1 h, and the average was taken. Mice were tested on the 5th, 9th and 16th day of the experiment.
② 爬杆法： 爬杆法用一直径 13mm， 高 50cm， 顶部有一直径 3cm的木球的光 滑木杆（中国医学科学院药物研究所研制）， 垂直放置， 将小鼠头向下放置在 杆的顶部球上， 让其沿杆自然爬下， 观察动物在爬下过程中的行为。 小鼠爬 下过程中的行为按标准记分， 评分标准如下： 5分： 四肢并用， 一步一步协 调向下爬行； 4分： 一步一步向下爬行但兼有后肢滑行行为； 3分： 爬过一半 距离后向下滑行， 但可抱紧杆; 2分： 未爬过一半距离即出现滑行行为； 1分： 爬过一半距离后不能抓杆从杆上掉落； 0分： 未爬过一半距离即不能抓杆， 从杆上掉落。 实验前每只小鼠训练两次。 于实验第 6， 10， 17天爬杆测试， 每只小鼠测试 2次， 每次间隔 lh， 按照上述标准进行评分， 取平均值。) 纹状体多巴胺水平检测： HPLC电化学检测器检测。高效液相色谱仪： Waters, 检测器： 2465 2 Climbing method: The climbing rod method uses a smooth wooden rod with a diameter of 13mm and a height of 50cm, and a wooden ball with a diameter of 3cm at the top (developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences), placed vertically, and placed the mouse head down on the rod. On the top ball, let it climb down naturally along the pole to observe the animal's behavior during the climb. The behavior of the mice during the climbing process was scored according to the standard. The scoring criteria were as follows: 5 points: Combined use of limbs, step by step Tune down to crawl; 4 points: Climb down step by step but have hindlimb glide behavior; 3 points: Climb over half the distance and then slide down, but can hold the bar; 2 points: Skid behavior occurs when you have not climbed halfway 1 point: After climbing half a distance, you can't grab the rod and drop it from the pole; 0 points: You can't grab the rod without climbing half a distance, and drop it from the rod. Each mouse was trained twice before the experiment. On the 6th, 10th, and 17th day of the experiment, the rod test was performed twice per mouse, and each time interval was 1 hour, and the score was averaged according to the above criteria. Striatum dopamine level detection: HPLC electrochemical detector detection. High Performance Liquid Chromatograph: Waters, Detector: 2465
色谱条件： 流动相： 乙酸钠一柠檬酸缓冲液， 含柠檬酸 85mM， 无水乙酸钠 lOOmM, EDTA- Na2 0.2mM, 先配成 850ml， 之后加入 150ml甲醇， 三蒸水 定容至 1L， 调节 pH为 3.68， 抽滤后加入适量 SOS (先加 90mg， 再根据分 离情况而定）、 正二丁胺 （先加 15μί) 使峰完全分离。 Chromatographic conditions: mobile phase: sodium acetate-citrate buffer, containing 85 mM citric acid, anhydrous sodium acetate 100 mM, EDTA-Na 2 0.2 mM, first formulated into 850 ml, then added 150 ml of methanol, three distilled water to a volume of 1 L, The pH was adjusted to 3.68, and after filtration, an appropriate amount of SOS (90 mg first, depending on the separation) and n-dibutylamine (15 μί) were added to completely separate the peak.
组织匀浆液的配制： Α液： 0.6mol/L的高氯酸溶液中加入 IP， 使 Π>的终浓度 为 0.375 g/ml， 4°C保存。 B液： 含柠檬酸钾 20mM， 磷酸氢二钾 300mM， EDTA-Na2 2mM, 4°C保存。 Preparation of tissue homogenate: sputum: Add 0.6% of perchloric acid solution to make the final concentration of Π> 0.375 g/ml, and store at 4 °C. Solution B: Potassium citrate 20 mM, dipotassium hydrogen phosphate 300 mM, EDTA-Na 2 2 mM, stored at 4 °C.
样品处理： 组织样品处理过程均在冰浴条件下进行， 遵循低温快速的原则。 加入 A液， 匀浆， 4°C， 20000g离心 20分钟， 吸取一定量上清， 加入半体 积的 B液， 冰浴 30min， 混匀， 静置， 20000g， 4°C离心 20分钟， 吸取上清， 20000g, 4°C离心 20分钟， 吸取上清， 4°C保存待测。 Sample processing: Tissue sample processing is carried out under ice bath conditions, following the principle of fast temperature. Add liquid A, homogenate, centrifuge at 2000°g for 20 minutes at 4°C, absorb a certain amount of supernatant, add half volume of liquid B, ice bath for 30min, mix, let stand, 20,000g, centrifuge at 20°C for 20 minutes, pick up Clear, 20000g, centrifuge at 20 °C for 20 minutes, aspirate the supernatant, and store at 4 °C for testing.
) 免疫组化检测黑质多巴胺神经元： 行为学实验后， 每组随机取 5只小鼠， 灌 流固定后取脑， 用于免疫组织化学检测。 光镜下观察小鼠 TH神经元的变化。 在 4倍物镜下拍照， 计数黑质致密部 TH阳性神经元数目， 将每只小鼠的脑 片取平均值为最后该小鼠 TH阳性神经元数目。Immunohistochemical detection of dopaminergic neurons in the substantia nigra: After behavioral experiments, 5 mice were randomly selected from each group, and the brain was taken after perfusion fixation for immunohistochemistry. The changes of mouse TH neurons were observed under light microscope. Photographed under a 4x objective, the number of TH-positive neurons in the substantia nigra pars compacta was counted, and the brain slices of each mouse were averaged to the number of TH-positive neurons in the mouse.
) 统计学分析： 用 SPSS13.0进行统计分析。 不同组间的变化用方差分析， 然 后用 LSD-S K检验。 Ρ<0.05为具有统计学差异。 Statistical analysis: Statistical analysis was performed using SPSS 13.0. Changes between the different groups were analyzed by analysis of variance and then examined by LSD-S K. Ρ<0.05 was considered statistically significant.
(二） 结果(ii) Results
) 实施例 1和 28代表的化合物对小鼠行为学的改善作用 The improvement of mouse behavior by the compounds represented by Examples 1 and 28
① 小鼠腹腔注射 MPTP后与正常小鼠相比在转棍上停留时间明显降低，表明 小鼠出现行为学障碍。 口服给予实施例 1 和 28可提高小鼠在转棍上停留时 间， 并存在明显的剂量效应关系， 其在高剂量水平与阳性对照药 L-DOPA (20mg/kg) 的效果基本相当 （图 1， 表 5 )。 表 5. 化合物 1和 28对小鼠转棍行为学的影响 ( "《±SEM n=15) 实施例号 潜伏期 （S) 1 The mice's intraperitoneal injection of MPTP showed a significant decrease in the residence time on the rotating stick compared with the normal mice, indicating that the mice developed behavioral disorders. Oral administration of Examples 1 and 28 improves the retention of mice on the stick There was a significant dose-response relationship, which was comparable to the positive control drug L-DOPA (20 mg/kg) at high dose levels (Figure 1, Table 5). Table 5. Effect of Compounds 1 and 28 on Mouse Roll Behavior ("±SEM n=15) Example Number Latency (S)
10 46.40±7.46 10 46.40±7.46
1 20 65.30±7.06# 1 20 65.30±7.06 #
40 75.79±8.30## 40 75.79±8.30 ##
5 60.70±4.37  5 60.70±4.37
28 10 67.93±6.66# 28 10 67.93±6.66 #
20 74.20±6.48## 20 74.20±6.48 ##
L-DOPA 20 80.46±7.78## L-DOPA 20 80.46±7.78 ##
模型组 （MPTP) 44.07±6.28** Model Group (MPTP) 44.07±6.28**
空白组 100.67±4.95  Blank group 100.67±4.95
"P<0.01 vs. Control小鼠， *P<0.05, ##P<0.01 vs. MPTP模型小鼠 "P<0.01 vs. Control mice, *P<0.05, ## P<0.01 vs. MPTP model mice
② 小鼠腹腔注射 MPTP后与正常小鼠相比爬杆评分明显降低。口服给予实施 例 1 和 28可剂量依赖性的提高小鼠的爬杆评分， 对其行为障碍具有改善作 用， 且在高剂量水平与 L-DOPA的效果基本相当 （图 2， 表 6)。 2 Compared with normal mice, the crawler score of mice was significantly decreased after intraperitoneal injection of MPTP. Oral administration of Examples 1 and 28 increased the crawler score in mice in a dose-dependent manner, which improved the behavioral disorder and was comparable to L-DOPA at high dose levels (Figure 2, Table 6).
表 6. 化合物 1和 28对小鼠爬杆行为学的影响 ( "《±SEM n=15) 实施例号 潜伏期 （s) Table 6. Effects of Compounds 1 and 28 on the behavior of rod-climbing in mice ("±SEM n=15) Example No. Incubation period (s)
(mg/Kg)  (mg/Kg)
10 3.37±0.16  10 3.37±0.16
1 20 3.87±0.15*  1 20 3.87±0.15*
40 4.21±0.14*  40 4.21±0.14*
3.83±0.18  3.83±0.18
28 10 4.03±0.11*  28 10 4.03±0.11*
20 4.03±0.11*  20 4.03±0.11*
L-DOPA 20 4.60±0.11#' 模型组 （MPTP) 3.32±0.15** 空白组 4.83±0.06 L-DOPA 20 4.60±0.11 # ' Model Group (MPTP) 3.32±0.15** Blank Group 4.83±0.06
"P<0.01 vs. Control小鼠， *P<0.05, ##P<0.01 vs. MPTP模型小鼠 "P<0.01 vs. Control mice, *P<0.05, ## P<0.01 vs. MPTP model mice
2 ) 实施例 1和 28代表的化合物对小鼠纹状体多巴胺的影响 2) Effects of the compounds represented by Examples 1 and 28 on mouse striatal dopamine
实施例 1和 28代表的化合物可剂量依赖性提高小鼠纹状体中 DA的水平，且 高剂量水平下效果与阳性对照药 L-DOPA相当 （表 7)。 表 7. 实施例 1和 28对小鼠纹状体多巴胺含量的影响  The compounds represented by Examples 1 and 28 dose-dependently increased the level of DA in the mouse striatum, and the effect at the high dose level was comparable to the positive control drug L-DOPA (Table 7). Table 7. Effect of Examples 1 and 28 on dopamine content in mouse striatum
剂量 DA含量  Dose DA content
实施例号  Example number
(mg/Kg) ( g/g wet tissue)  (mg/Kg) ( g/g wet tissue)
10 27.12±6.03  10 27.12±6.03
1 20 33.50±11.78# 1 20 33.50±11.78 #
40 40.82±5.99## 40 40.82±5.99 ##
5 28.12±6.95  5 28.12±6.95
28 10 37.64±4.39## 28 10 37.64±4.39 ##
20 44.48±2.39## 20 44.48±2.39 ##
L-DOPA 20 46.00±4.45## L-DOPA 20 46.00±4.45 ##
模型组 （MPTP) 22.70±2.97** Model Group (MPTP) 22.70±2.97**
空白组 69.06±5.23  Blank group 69.06±5.23
*P<0.01 vs. Control小鼠， ^^.OS^PO.Ol vs. MPTP模型小鼠  *P<0.01 vs. Control mice, ^^.OS^PO.Ol vs. MPTP model mice
3 ) 实施例 1和 28代表的化合物对小鼠多巴能神经元的影响 3) Effects of the compounds represented by Examples 1 and 28 on dopaergic neurons in mice
MPTP 模型组小鼠黑质致密部 TH 阳性神经元数目较正常小鼠数量明显降 低。 实施例 1和 28可提高小鼠 TH阳性神经元数量， 且存在明显的剂量效应关 系。 阳性药 L-DOPA对模型小鼠 TH神经元数量无明显影响 （图 3 )。  The number of TH-positive neurons in the substantia nigra pars compacta of the MPTP model group was significantly lower than that of normal mice. Examples 1 and 28 increased the number of TH-positive neurons in mice and there was a significant dose-effect relationship. The positive drug L-DOPA had no significant effect on the number of TH neurons in the model mice (Fig. 3).
结论： 在 MPTP引起的小鼠亚急性 PD模型中， 实施例 1和 28代表的化合 物能明显改善小鼠行为学障碍，显着提高黑质多巴胺能神经元的数量和纹状体多 巴胺的水平， 提示这两种化合物具有开发成为治疗 PD药物的潜能。  Conclusion: In the sub-acute PD model of mice induced by MPTP, the compounds represented by Examples 1 and 28 can significantly improve the behavioral disorder of mice, significantly increase the number of dopaminergic neurons in the substantia nigra and the level of striatal dopamine. These two compounds are suggested to have the potential to be developed to treat PD drugs.
5. 实验例 5 (化合物体内对 MPTP+丙磺舒诱发的慢性 PD模型的影响） (一） 材料和方法 5. Experimental Example 5 (Influence of compound in vivo on MPTP + probenecid-induced chronic PD model) (i) Materials and methods
材料： 动物： 雄性 C57小鼠， 体重 22±lg， 购自北京华阜康实验动物技术有限公 司。 词养条件： 屏障级动物房词养， 标准词养盒内词养， 每盒 5只。 受试药物： 实施例 1和 28表示的化合物 Materials: Animals: Male C57 mice weighing 22 ± lg were purchased from Beijing Huakang Experimental Animal Technology Co., Ltd. The wording conditions: the barrier-level animal room words, the standard word raising box words, 5 per box. Test drug: Compounds represented by Examples 1 and 28
L-DOPA: 美多芭 （多巴丝肼片）， 上海罗氏制药有限公司， 国药准字 L-DOPA: Medoba (Dobasi), Shanghai Roche Pharmaceutical Co., Ltd.
H10930198, 批号： SH0895。 H10930198, Lot number: SH0895.
MPTP: Sigma公司产品， 批号： 128kl549。。  MPTP: Sigma product, batch number: 128kl549. .
丙磺舒： 北京百灵威科技有限公司， 批号： 10139442。  Probenecid: Beijing Bailingwei Technology Co., Ltd., batch number: 10139442.
DA， DOPAC, HVA禾 P IP购自 Sigma公司。  DA, DOPAC, HVA and P IP were purchased from Sigma.
方法： Method:
1 ) 模型建立： 小鼠采用转棍法提前训练 3天， 将运动不协调的小鼠剔除。 腹腔 注射丙磺舒 250mg/kg (溶于 DMSO)， 30min后皮下注射 MPTP 25mg/kg (溶 于生理盐水）， 一周两次 （3.5天间隔）， 共注射 10次 （5周）， 7周时进行行 为学测试（转棍法和爬杆法），转棍潜伏期或爬杆评分降低有显着差异的小鼠 视为造模成功， 随机分组 （n=15 )， 进行后续药物治疗性实验。  1) Model establishment: The mice were trained for 3 days in advance using the walking stick method, and the mice with uncoordinated movement were excluded. Intraperitoneal injection of probenecid 250mg/kg (dissolved in DMSO), 30 minutes after subcutaneous injection of MPTP 25mg/kg (dissolved in normal saline), twice a week (3.5 days interval), a total of 10 injections (5 weeks), 7 weeks Mice with behavioral tests (rolling and climbing), significant differences in walking stick latency or climbing scores were considered successful modeling, randomized (n=15), and follow-up pharmacotherapeutic experiments.
2) 分组给药： 分为正常对照组、 MPTP+丙磺舒模型组、 实施例 1不同剂量组、 实施例 28不同剂量组和阳性对照 L-DOPA组。 小鼠每天灌胃实施例 1和 28 代表的化合物或 L-DOPA—次， 连续 7周。 正常对照组灌胃和腹腔注射相同 剂量的无菌双蒸水和生理盐水， MPTP+丙磺舒模型组灌胃给予相同剂量的无 菌双蒸水。  2) Group administration: divided into normal control group, MPTP+ probenecid model group, Example 1 different dose group, Example 28 different dose group and positive control L-DOPA group. Mice were orally administered with the compounds represented by Examples 1 and 28 or L-DOPA once daily for 7 weeks. The normal control group was intragastrically and intraperitoneally injected with the same dose of sterile double distilled water and normal saline. The MPTP + probenecid model group was intragastrically administered with the same dose of sterile double distilled water.
3 ) 行为学检测： 采用转棍法和爬杆法 （Pole test) 来评价小鼠的运动协调能力。 3) Behavioral testing: The roller coordination method and the Pole test were used to evaluate the motor coordination ability of the mice.
① 转棍法： 方法同实施例 33。 小鼠于给药第 0， 3， 5和 7 周进行转棍测试。1 Rolling stick method: The method is the same as in Example 33. Mice were tested for roller sticks at 0, 3, 5 and 7 weeks of dosing.
② 爬杆法： 方法同实施例 33。 小鼠于给药第 0， 3， 5和 7 周进行爬杆测试。2 Climbing method: The method is the same as in Example 33. The mice were subjected to a climbing rod test at 0, 3, 5 and 7 weeks of administration.
4) 纹状体多巴胺水平检测： 方法同实施例 33。 4) Striatum dopamine level detection: The same procedure as in Example 33.
5 ) 免疫组化检测黑质多巴胺神经元： 方法同实施例 33。  5) Immunohistochemical detection of substantia nigra dopamine neurons: The same procedure as in Example 33.
7) 统计学分析： 用 SPSS13.0进行统计分析。 数据以 ± S表示。 不同组间的变 化用方差分析， 然后用 LSD-S K检验。 Ρ<0.05为具有统计学差异。 7) Statistical analysis: Statistical analysis was performed using SPSS 13.0. The data is expressed in ± S. Variances between groups were analyzed by analysis of variance followed by LSD-S K test. Ρ<0.05 was considered statistically significant.
(二） 结果 1 ) 实施例 1和 28代表的化合物对小鼠行为学的改善作用 (ii) Results 1) The effects of the compounds represented by Examples 1 and 28 on the behavior of mice
① 筛选后的模型小鼠与正常小鼠相比在转棍仪上停留时间明显降低（此时记 为 0周）。 治疗性给予实施例 1 20mg/kg和 40mg/kg组的小鼠， 以及给予实施 例 28 10mg/kg和 20mg/kg组的小鼠， 在第 5周和第 7周时在转棍仪上停留时 间均明显长于模型组小鼠， 且存在剂量效应关系， 其药效与阳性对照药 L-DOPA基本相当 （表 8)。 表 8. 实施例 1 和 28对 MPTP/p引起的慢性 PD模型小鼠转棍行为学的影响 (；"《±SEM， n  1 The model mice after screening showed a significant decrease in the residence time on the stick (compared to 0 weeks) compared with the normal mice. The mice of the 20 mg/kg and 40 mg/kg groups of Example 1 were therapeutically administered, and the mice of the groups of 10 mg/kg and 20 mg/kg of Example 28 were administered, and stayed on the sticks at the 5th week and the 7th week. The time was significantly longer than that of the model group, and there was a dose-effect relationship, and its efficacy was basically equivalent to that of the positive control drug L-DOPA (Table 8). Table 8. Effects of Examples 1 and 28 on MPTP/p-induced behavior in mice with chronic PD model ("±SEM, n
剂量 潜伏期 （s)  Dose latency (s)
实施例号  Example number
0周 3周 5周 7周 0 weeks 3 weeks 5 weeks 7 weeks
10 40.00±5.69 39.97±4.43 38.97±5.26 37.53±3.6010 40.00±5.69 39.97±4.43 38.97±5.26 37.53±3.60
1 20 39.80±4.86 42.63±6.35 50.67±1.54# 53.70±6.73# 1 20 39.80±4.86 42.63±6.35 50.67±1.54 # 53.70±6.73 #
40 40.87±3.97 44.53±6.80 55.53±5.73# 57.63±6.24# 40 40.87±3.97 44.53±6.80 55.53±5.73 # 57.63±6.24 #
2.5 39.63±4.88 40.97±4.43 40.63±4.99 40.23±5.762.5 39.63±4.88 40.97±4.43 40.63±4.99 40.23±5.76
5 41.70±6.60 43.67±5.57 47.67±2.55 54.23±7.195 41.70±6.60 43.67±5.57 47.67±2.55 54.23±7.19
28 28
10 42.20±5.01 44.53±5.65 57.33±5.50# 57.93±8.05# 10 42.20±5.01 44.53±5.65 57.33±5.50 # 57.93±8.05 #
20 41.47±7.05 44.07±6.07 57.90±6.95# 60.60±5.02## 20 41.47±7.05 44.07±6.07 57.90±6.95 # 60.60±5.02 ##
L-DOPA 20 39.60±5.58 57.80±9.23# 62.53±8.13# 64.33±6.56## 模型组 L-DOPA 20 39.60±5.58 57.80±9.23 # 62.53±8.13 # 64.33±6.56 ##模型组
41.43±6.25 37.83±4.82** 38.97±5.26** 37.53±3.60" (MPTP/p)  41.43±6.25 37.83±4.82** 38.97±5.26** 37.53±3.60" (MPTP/p)
空白组 75.60±6.78 79.20±7.12 77.70±5.50 76.17±6.27 Blank group 75.60±6.78 79.20±7.12 77.70±5.50 76.17±6.27
"P<0.01 vs. Control小鼠， *P<0.05, ##P<0.01 v s. MPTP/p模型小鼠 "P<0.01 vs. Control mice, *P<0.05, ## P<0.01 v s. MPTP/p model mice
② MPTP/p 损伤的小鼠出现明显爬杆行为学障碍。 治疗性给予实施例 1 20mg/kg和 40mg/kg组的小鼠， 以及给予实施例 28 10mg/kg和 20mg/kg组的 小鼠， 在第 5周和第 7周时爬杆评分均明显高于模型组小鼠， 且存在量效关 系， 其药效与阳性对照药 L-DOPA基本相当 （表 9)。 表 9. 实施例 1 和 28对 MPTP/p弓 I起的慢性 PD模型小鼠爬杆行为学的影响 (； x ±SEM , n=15) 实施例号 ~~ ¾5 潜伏期 （s ) 2 MPTP/p-injured mice developed significant stratum behavioral disorders. The mice of the 20 mg/kg and 40 mg/kg groups of Example 1 were therapeutically administered, and the mice of the groups of 10 mg/kg and 20 mg/kg of Example 28 were administered, and the scores of the climbing rods were significantly higher at the 5th week and the 7th week. In the model group, there was a dose-effect relationship, and its efficacy was basically equivalent to that of the positive control drug L-DOPA (Table 9). Table 9. Effect of Examples 1 and 28 on the crawling behavior of mice with chronic PD model from MPTP/p-I ( x ± SEM, n=15) Example No. ~~3⁄45 Latency (s)
(mg/Kg) 0周 3 5 7周 (mg/Kg) 0 weeks 3 5 7 weeks
1 10 2.60±0.21 3.17±0.16 3.70±0.10 4.03±0.20 20 2.63±0.21 3.20±0.16 4.00±0. 17# 4.50±0.13## 1 10 2.60±0.21 3.17±0.16 3.70±0.10 4.03±0.20 20 2.63±0.21 3.20±0.16 4.00±0. 17 # 4.50±0.13 ##
40 2.63±0. 19 3.50±0.17 4.37±0.18## 4.63±0. 11## 40 2.63±0. 19 3.50±0.17 4.37±0.18 ## 4.63±0. 11 ##
2.5 2.70±0. 19 3.57±0.1 1 3.58±0.18 3.63±0. 172.5 2.70±0. 19 3.57±0.1 1 3.58±0.18 3.63±0. 17
5 2.63±0.20 3.73±0.19 3.97±0.18 4.13±0.19# 5 2.63±0.20 3.73±0.19 3.97±0.18 4.13±0.19 #
28 28
10 2.65±0.20 3.83±0.15 4. 17±0. 17# 4.47±0.17## 10 2.65±0.20 3.83±0.15 4. 17±0. 17 # 4.47±0.17 ##
20 2.60±0.21 4.13±0.14 4.37±0.17## 4.67±0.10## 20 2.60±0.21 4.13±0.14 4.37±0.17 ## 4.67±0.10 ##
L-DOPA 20 2.60±0.21 4.27±0.13# 4.70±0.10## 4.87±0.06## 模型组 L-DOPA 20 2.60±0.21 4.27±0.13 # 4.70±0.10 ## 4.87±0.06 ##模型组
2.77±0. 18 3.03±0.22** 3.43±0.19 3.50±0.21 (MPTP/p)  2.77±0. 18 3.03±0.22** 3.43±0.19 3.50±0.21 (MPTP/p)
空白组 4.40±0. 17 4.47±0.1 1 4.77±0.10 4.93±0.06 Blank group 4.40±0. 17 4.47±0.1 1 4.77±0.10 4.93±0.06
"P<0.01 vs. Control小鼠， *P<0.05, ##P<0.01 v s. MPTP/p模型小鼠 "P<0.01 vs. Control mice, *P<0.05, ## P<0.01 v s. MPTP/p model mice
2 ) 实施例 1和 28代表的化合物对小鼠纹状体多巴胺的影响 2) Effects of the compounds represented by Examples 1 and 28 on mouse striatal dopamine
MPTP/p损伤的小鼠纹状体 DA的含量明显下降， 采用实施例 1和 28代表的 化合物治疗 7周后， 实施例 1 20mg/kg有提高小鼠纹状体 DA含量的趋势， 但无 统计学差异， 而 40mg/kg可明显提高 DA的水平。 实施例 2810mg/kg有提高 DA 含量的趋势， 但无统计学差异， 而 20mg/kg可明显提高 DA的水平 （表 10)。 表 10. 实施例 1和 28对 MPTP/p诱导的慢性 PD模型小鼠纹状体多巴胺含量的影响  The content of DA in the striatum of MPTP/p-injured mice was significantly decreased. After 7 weeks of treatment with the compounds represented by Examples 1 and 28, Example 1 20 mg/kg had a tendency to increase the content of DA in the striatum of mice, but no Statistical differences, while 40 mg / kg can significantly increase the level of DA. Example 2810 mg/kg had a tendency to increase DA content, but there was no statistical difference, while 20 mg/kg significantly increased the level of DA (Table 10). Table 10. Effects of Examples 1 and 28 on striatal dopamine content in MPTP/p-induced chronic PD model mice
DA含量  DA content
实施例号  Example number
( g/g wet tissue)  ( g/g wet tissue)
10 48.41±3.59  10 48.41±3.59
1 20 56.14±4. 11  1 20 56.14±4. 11
40 58.43±6.30# 40 58.43±6.30 #
2.5 44.86±4.36  2.5 44.86±4.36
5 48.79±4.34  5 48.79±4.34
28  28
10 54.30± 1.41  10 54.30± 1.41
20 60.60±5.97# 20 60.60±5.97 # #
L-DOPA 20 66.21±4.24## L-DOPA 20 66.21±4.24 ##
模型组 46.27±4.75** (MPTP/p) Model group 46.27±4.75** (MPTP/p)
空白组 72.83±9.20  Blank group 72.83±9.20
"P<0.01 vs. Control小鼠， ^Ο.ί^,^ΡΟ.ΟΙ vs. MPTp/p模型小鼠 "P<0.01 vs. Control mice, ^Ο. ί^, ^ΡΟ.ΟΙ vs. MPTp/p model mice
3 ) 实施例 1和 28代表的化合物对小鼠多巴能神经元的影响 3) Effects of the compounds represented by Examples 1 and 28 on dopaergic neurons in mice
MPTP/p模型组小鼠黑质致密部 TH阳性神经元数目较正常小鼠数量明显降 低。 实施例 1和 28可提高小鼠 TH阳性神经元数量， 且存在明显的剂量效应关 系。 阳性药 L-DOPA对模型小鼠 TH神经元数量无明显影响 （图 4)。  The number of TH-positive neurons in the substantia nigra pars compacta of the MPTP/p model group was significantly lower than that of normal mice. Examples 1 and 28 increased the number of TH-positive neurons in mice and there was a significant dose-effect relationship. The positive drug L-DOPA had no significant effect on the number of TH neurons in the model mice (Fig. 4).
结论： 实施例 1和 28代表的化合物对 MPTP/p引起的慢性 PD小鼠模型行为 学障碍有较好的改善作用，可提高黑质多巴胺能神经元的数量和纹状体多巴胺的 水平， 表明这两种化合物有望开发成为治疗 PD的新药。  Conclusion: The compounds represented by Examples 1 and 28 have a better effect on MPTP/p-induced behavioral disorders in chronic PD mouse models, which can increase the number of dopaminergic neurons in the substantia nigra and the level of striatal dopamine. These two compounds are expected to be developed as new drugs for the treatment of PD.
6. 实验例 6 (亚急性毒性试验） 6. Experimental Example 6 (Subacute Toxicity Test)
(一）材料和方法  (1) Materials and methods
材料： 动物： 雄性 C57小鼠， 体重 22± lg， 购自北京华阜康实验动物技术有限公 司。 清洁级。 Materials: Animals: Male C57 mice weighing 22 ± lg were purchased from Beijing Huakang Experimental Animal Technology Co., Ltd. Clean grade.
受试药物： 实施例 1和 28表示的化合物  Test drug: Compounds represented by Examples 1 and 28
方法： Method:
实施例 1和 28代表的化合物各以 400 mg/Kg的剂量灌胃给予小鼠， 每天 一次， 连续 13天。 13天后取血检验血生化指标。 每组小鼠 8只。  The compounds represented by Examples 1 and 28 were each administered to mice at a dose of 400 mg/kg once a day for 13 consecutive days. Blood samples were taken 13 days later to test blood biochemical indicators. 8 mice per group.
观察指标： 小鼠体重， 进食量和进水量、 血生化 （谷丙转氨酶 ALT , 碱 性磷酸酶 ALP， 肌酐 Cre)。  Observation indicators: mouse body weight, food intake and water intake, blood biochemistry (alkaline aminotransferase ALT, alkaline phosphatase ALP, creatinine Cre).
(二） 结果  (ii) Results
1 ) 实施例 1和 28代表的化合物对小鼠体重的影响  1) Effects of the compounds represented by Examples 1 and 28 on the body weight of mice
结果显示， 小鼠灌胃给予实施例 1和 28 400 mg/Kg后， 与空白组的小鼠相 比体重无明显变化 （表 11 )。 表 11. 化合物 1和 28对小鼠体重的影响 （g, ±S, n=8) 实施例号 0d 2d 5d 8d 13d  The results showed that after administration of Example 1 and 28 400 mg/Kg in mice by gavage, there was no significant change in body weight compared with the mice in the blank group (Table 11). Table 11. Effect of Compounds 1 and 28 on body weight of mice (g, ±S, n=8) Example No. 0d 2d 5d 8d 13d
1 22.88±0.65 26.23±0.84 29.53±1.49 3 1.02±2.05 33.90±2.47 28 23.04±0.70 25.88±0.99 28.91±1.88 29.85±1.86 33.10±2.69 空白 22.94±0.88 25.65±0.79 28.49±0.80 29.83±0.85 32.69±0.94 1 22.88±0.65 26.23±0.84 29.53±1.49 3 1.02±2.05 33.90±2.47 28 23.04±0.70 25.88±0.99 28.91±1.88 29.85±1.86 33.10±2.69 blank 22.94±0.88 25.65±0.79 28.49±0.80 29.83±0.85 32.69±0.94
2) 实施例 1和 28代表的化合物对小鼠进食和进水的影响 2) Effects of the compounds represented by Examples 1 and 28 on feeding and water in mice
结果显示， 小鼠灌胃给予实施例 1和 28 400 mg/Kg后， 与空白组的小鼠相比 进食量和进水量无明显差异 （表 12和表 13 )。 表 12. 化合物 1和 28对小鼠进食的影响 （g )  The results showed that there was no significant difference in food intake and water intake between the mice treated with Example 1 and 28 400 mg/Kg by intragastric administration (Table 12 and Table 13). Table 12. Effects of Compounds 1 and 28 on Eating in Mice (g)
实施例号 2d 5d 8d 13d 平均 Example No. 2d 5d 8d 13d Average
1 78 119 113 186 35.5 1 78 119 113 186 35.5
28 75 117 115 184 34.9 空白 75 114 120 189 35.6 表 13. 化合物 1和 28对小鼠进水的影响 （mL) 28 75 117 115 184 34.9 Blank 75 114 120 189 35.6 Table 13. Effect of Compounds 1 and 28 on Influent of Mice (mL)
实施例号 2d 5d 8d 13d 平均 Example No. 2d 5d 8d 13d Average
1 112 163 174 178 44.8 1 112 163 174 178 44.8
28 102 160 164 150 41.1 空白 102 155 165 190 43.7 28 102 160 164 150 41.1 Blank 102 155 165 190 43.7
3 ) 实施例 1和 28代表的化合物对小鼠血生化指标的影响 3) Effects of the compounds represented by Examples 1 and 28 on blood biochemical parameters in mice
结果显示， 实施例 28对 ALT、 Cre及 ALP无明显影响， 与空白组相当。 实 施例 1引起 ALP较空白组升高，但无统计学差异，对 ALT和 Cre无明显影响（表 14)。 表 14. 化合物 1和 28对小鼠血生化的影响  The results showed that Example 28 had no significant effect on ALT, Cre and ALP, and was comparable to the blank group. Example 1 caused ALP to be elevated compared with the blank group, but there was no statistical difference and had no significant effect on ALT and Cre (Table 14). Table 14. Effects of Compounds 1 and 28 on Blood Biochemistry in Mice
实施例号 ALT (U/L) ALP (U/L) Cre Oumol/L)  Example Number ALT (U/L) ALP (U/L) Cre Oumol/L)
1 47.71±9.19 118.86±17.49 31.57±2.94  1 47.71±9.19 118.86±17.49 31.57±2.94
28 47.00±10.74 140.25±29.62 30.13±1.89  28 47.00±10.74 140.25±29.62 30.13±1.89
空白 39.13±7.81 127.00±22.93 31.00±2.20 结论： 实施例 1和 28代表的化合物在 400 mg/Kg 的剂量下对小鼠没有表现 出毒性。  Blank 39.13±7.81 127.00±22.93 31.00±2.20 Conclusion: The compounds represented by Examples 1 and 28 showed no toxicity to mice at a dose of 400 mg/Kg.

Claims

权 利 要 求 书 Claim
1. 由通式 Io 表示的化合物， 包括消旋体和光学异构体， 及其药学上可接受的  1. A compound represented by the formula Io, including racemates and optical isomers, and pharmaceutically acceptable thereof
Figure imgf000061_0001
Figure imgf000061_0001
其中， 表示 H、 -CF3、取代或未取代直链或支链的 d.n)垸基、苄基、 -N02 或 -CORal， 其中， Wherein, represents H, -CF 3 , substituted or unsubstituted linear or branched dn) fluorenyl, benzyl, -N0 2 or -COR al , wherein
取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸氧基、 -SH、 取代或未取代的呋咱基或取代或未取代的胺基， 其中， The substituent may be selected from -0H, -F, -Cl, -Br, -COOH, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or substituted or unsubstituted Amine group, wherein
呋咱基上的取代基可选自直链或支链的 CLH)垸基、 取代或未取代的苯基、 取代或未取代的苯磺酰基， 其中，  The substituent on the furyl group may be selected from a linear or branched CLH) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -0N02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -0H, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -0N0 2 or a linear or branched d. 6 anthracene group,
胺基上的取代基可选自直链或支链的 d.6垸基， C3.6环垸基或取代基与 N原 子共同构成五元、六元或七元的含 1-3个杂原子的饱和杂环，杂环上可有取代基， 其中， Substituents on the amine selected from straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with the N atom together form five-, six- or seven-membered containing 1-3 a saturated heterocyclic ring of a hetero atom, which may have a substituent on the hetero ring, wherein
杂环上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 C3.6环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituted heterocyclyl selected from the -0H, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched, d. 6 an oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -0N02、 -NH2或直链或支链的 d.6垸氧 基； The substituent on the phenyl group may be selected from -0H, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -0N0 2 , -NH 2 or a linear or branched d. 6 anthracene;
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
垸基上的取代基可选自 -0H、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， The substituent on the fluorenyl group may be selected from -0H, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -0H、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -0N02或直链或支链的 .6垸氧基； R2和 R4分别独立表示 -H、 -OH、直链或支链的 d.6垸氧基、苄氧基、 -OCF3、 -ON02、 -F、 -Cl、 -Br、 -CN、 -N02、取代或未取代直链或支链的 d.n)垸基、 -CF3、 取代或未取代的羰基， 其中， The substituent may be selected from -0H, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -0N0 2 or linear or branched. 6 oxime; R 2 and R 4 each independently represent -H, -OH, linear or branched d. 6 methoxy, benzyloxy, -OCF 3 , -ON0 2 , -F, -Cl, -Br, -CN, -N0 2 , a substituted or unsubstituted linear or branched dn) fluorenyl group, -CF 3 , a substituted or unsubstituted carbonyl group, wherein
d.n)垸基上的取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2、 -SH， Dn) The substituent on the fluorenyl group may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 , -SH,
羰基上的取代基可选自 -OH、直链或支链的 .1()垸基、取代或未取代的苯基、 含烯键或炔键的 CLH)不饱和烃基或取代或未取代的胺基， 其中， The substituent on the carbonyl group may be selected from -OH, straight or branched. 1 () fluorenyl, substituted or unsubstituted phenyl, ethylenic or acetylenic CLH) unsaturated hydrocarbon group or substituted or unsubstituted Amine group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 .10垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6垸氧基， 胺基上的取代基可选自取代或未取代的直链或支链的 d.H)垸基， C3.6环垸基 或取代基与 N原子共同构成五元、六元或七元的含 1-3个杂原子的饱和杂环，其 中， The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched. 10 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 methoxy group, the substituent on the amine group may be selected from a substituted or unsubstituted linear or branched dH) fluorenyl group, C 3 . 6 a cycloalkyl or a substituent and a N atom together form a five-, six- or seven-membered saturated heterocyclic ring having from 1 to 3 hetero atoms, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2;The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -H 2 ;
R3和 R5分别独立表示 -H、 -OH、 直链或支链的 d.6垸基、 -ON02、 取代或 未取代的直链或支链的 垸氧基、 苯环上取代或未取代的苄氧基， 其中， 所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、 -COOH; R 3 and R 5 each independently represent -H, -OH, a straight or branched d. 6 fluorenyl group, -ON0 2 , a substituted or unsubstituted linear or branched decyloxy group, a phenyl ring substituted or An unsubstituted benzyloxy group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -NH 2 , -COOH;
n可为 1-5，  n can be 1-5,
X表示 H、 直链或直链的 d.6垸基， 取代或未取代的胺基， 其中 X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
取代基可选自直链或支链的 d.6垸基， C3.6环垸基或取代基与 N原子共同构 成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上可 有取代基， 其中， Substituents selected from a straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with together with the N atom form a 5-, 1-3 heteroatoms unsaturated six-membered or seven-membered containing a heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched d. 6 embankment An oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
2. 根据权利要求 1的化合物， 其特征在于， 所述的化合物是通过通式 I表示的 化合物， 包括消旋体和光学异构体， 及其药学上可接受的盐: 2. A compound according to claim 1 wherein said compound is represented by formula I Compounds, including racemates and optical isomers, and pharmaceutically acceptable salts thereof:
Figure imgf000063_0001
Figure imgf000063_0001
其中， 表示 H、 -CF3、取代或未取代直链或支链的 d.n)垸基、苄基、 -N02 或 -CORal， 其中， Wherein, represents H, -CF 3 , substituted or unsubstituted linear or branched dn) fluorenyl, benzyl, -N0 2 or -COR al , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 直链或支链的 d.6垸氧基、 -SH、 取代或 未取代的呋咱基或 -COOH、 取代或未取代的胺基， 其中， The substituent may be selected from -OH, -F, -Cl, -Br, linear or branched d. 6 methoxy, -SH, substituted or unsubstituted furazyl or -COOH, substituted or unsubstituted Amine group, wherein
呋咱基上的取代基可选自直链或支链的 CLH)垸基、 取代或未取代的苯基、 取代或未取代的苯磺酰基， 其中，  The substituent on the furyl group may be selected from a linear or branched CLH) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 anthracene group,
胺基上的取代基可选自直链或支链的 d.6垸基， C3.6环垸基或取代基与 N原 子共同构成五元、六元或七元的含 1 -3个杂原子的饱和杂环，杂环上可有取代基， 其中， Substituents on the amine selected from straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with the N atom together form five-, six- or seven-membered having from 1 to 3 a saturated heterocyclic ring of a hetero atom, which may have a substituent on the hetero ring, wherein
杂环上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 C3.6环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， A substituted heterocyclic group selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched, d. 6 an oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基； The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime;
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein
垸基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 .6垸氧基； The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime;
R3和 R5分别独立表示 -H、 -OH、 直链或支链的 d.6垸基、 -ON02、 取代或 未取代的直链或支链的 垸氧基、 苯环上取代或未取代的苄氧基， 其中， 所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、R 3 and R 5 each independently represent -H, -OH, linear or branched d. 6 fluorenyl, -ON0 2 , substituted or An unsubstituted linear or branched decyloxy group, a substituted or unsubstituted benzyloxy group on the phenyl ring, wherein the substituent may be selected from -OH, a linear or branched d. 6 an oxy group, -F, -Cl, -Br, -NH 2 ,
-COOH; -COOH;
n可为 1-5，  n can be 1-5,
X表示 H、 直链或直链的 d.6垸基， 取代或未取代的胺基， 其中 X represents H, a linear or linear d. 6 fluorenyl group, a substituted or unsubstituted amine group, wherein
取代基可选自直链或支链的 d.6垸基， C3.6环垸基或取代基与 N原子共同构 成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上可 有取代基， 其中， Substituents selected from a straight-chain or branched alkyl with d.6, C 3. 6 cycloalkyl group or substituted alkyl with together with the N atom form a 5-, 1-3 heteroatoms unsaturated six-membered or seven-membered containing a heterocyclic ring (except a morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched d. 6 embankment An oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or linear or branched d. 6垸 oxygen
3. 根据权利要求 2的化合物， 其特征在于， 所述化合物是通过通式 IA表示的 化合物， 包括消旋体和光学异构体， 及其药学上可接受的盐： The compound according to claim 2, wherein the compound is a compound represented by the formula IA, including a racemate and an optical isomer, and a pharmaceutically acceptable salt thereof:
Figure imgf000064_0001
其中， Ra表示取代或未取代直链或支链的 d.n)垸基、苄基、 -N02、 -CORal， 其中， 取代基可选自 -OH、 -F、 -Cl、 -Br, 直链或支链的 d.6垸氧基、 -SH、 取代 或未取代的呋咱基或 -COOH, 其中，
Figure imgf000064_0001
Wherein R a represents a substituted or unsubstituted linear or branched dn) fluorenyl group, a benzyl group, -N0 2 , -COR al , wherein the substituent may be selected from the group consisting of -OH, -F, -Cl, -Br, a linear or branched d. 6 methoxy group, -SH, a substituted or unsubstituted furazyl group or -COOH, wherein
取代基可选自直链或支链的 d.H)垸基、 取代或未取代的苯基、 取代或未取 代的苯磺酰基， 其中，  The substituent may be selected from a linear or branched d.H) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 anthracene group,
Ral可选自取代或未取代的直链或支链的 C2.1Q垸基， 其中 垸基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 取代或未取代的苯基、 -COOH 或 -NH2， 其中， R al selected from substituted or unsubstituted, straight-chain or branched C 2. 1Q alkyl with, wherein The substituent on the fluorenyl group may be selected from -OH, -F, -Cl, -Br, a substituted or unsubstituted phenyl group, -COOH or -NH 2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.6垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 .6垸氧基。 The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched. 6 oxime.
4. 根据权利要求 3的化合物， 其特征在于， Ra表示未取代的 d.u)垸基。 4. A compound according to claim 3, characterized in that R a represents an unsubstituted du) fluorenyl group.
5. 根据权利要求 4的化合物， 其特征在于， Ra选自甲基、 乙基、 丙基、 异丙基、 丁基、 异丁基、 叔丁基、 戊基、 异戊基、 己基。 5. A compound according to claim 4, wherein, R a is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl group.
6. 根据权利要求 2的化合物， 其特征在于， Ra表示以下通式 IAa
Figure imgf000065_0001
The compound according to claim 2, wherein R a represents the following formula IAa
Figure imgf000065_0001
其中， n可表示 1-5， Where n can represent 1-5,
Ra2可选自直链或支链的 d.u)垸基、 取代或未取代的苯基、 取代或未取代的 苯磺酰基， 其中， R a2 may be selected from a linear or branched du) fluorenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzenesulfonyl group, wherein
苯基和苯磺酰基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支 链的 Cw垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基。 The substituent on the phenyl group and the benzenesulfonyl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched Cw fluorenyl group, -CHF 2 , -CF 3 , -CN, - N0 2 , -OCF 3 , -ON0 2 or a linear or branched d. 6 oxime.
7. 根据权利要求 2的化合物， 其特征在于， 所述化合物是通过通式 m 表示的 化合物， 包括消旋体和光 受的盐： The compound according to claim 2, wherein the compound is a compound represented by the formula m, including a racemate and a light-receiving salt:
Figure imgf000065_0002
Figure imgf000065_0002
其中， R3和 R5分别独立表示 -H、 -OH、直链或支链的 d.6垸基、 -ON02、 -ORc -SRC, 其中， Rc表示取代或未取代直链或支链的 d.n)垸基、 苄基， 其中， 所述取代基可选自 -OH、 直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br, -NH2、 -COOH; Wherein R 3 and R 5 each independently represent -H, -OH, a linear or branched d. 6 fluorenyl group, -ON0 2 , -ORc -SR C , wherein Rc represents a substituted or unsubstituted linear or branched dn) fluorenyl group, benzyl group, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl , -Br, -NH 2 , -COOH;
Rbi ¾2分别独立表示 H、 直链或支链的 d.6垸基， C3.6环垸基或 -NRblRb2 构成五元、六元或七元的含 1-3个杂原子的饱和杂环，杂环上可有取代基，其中， 取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 垸氧基、 取代或未取代的苯基， 其中， Rbi ¾2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cyclic alkyl with or -NR bl R b2 constitute containing 1-3 heteroatoms five-, six- or seven-membered of The saturated heterocyclic ring may have a substituent on the heterocyclic ring, wherein the substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, C 3. 6 a fluorenyl, linear or branched decyloxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
8. 根据权利要求 2的化合物， 其特征在于， 所述化合物是通过通式 IC 表示的 化合物， 包括消旋体和光学异构体， 及其药学上可接受的盐： The compound according to claim 2, wherein the compound is a compound represented by the general formula IC, including a racemate and an optical isomer, and a pharmaceutically acceptable salt thereof:
Figure imgf000066_0001
Figure imgf000066_0001
其中， Rd ¾2和 Rd3分别独立表示 -H、直链或支链的 C2.6垸基、苄基或 -CF3， n可为 2-5, Wherein, Rd 3⁄4 2 and R d3 independently represent -H, a linear or branched C 2 . 6 fluorenyl group, a benzyl group or a —CF 3 , and n may be 2-5.
Rel， Re2分别独立表示 H、 直链或支链的 d.6垸基， C3.6环垸基或 -NRelRe2 构成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上 可有取代基， 其中， Rel, Re2 each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cycloalkyl or alkyl with -NRelRe2 configuration five-, six- or seven-membered having 1-3 heteroatoms saturated hetero a ring (except for the morpholine ring), which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 d.6垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 embankment cycloalkyl group, a linear or branched d. 6 embankment An oxy group, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH, 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
9. 根据权利要求 8的化合物， 其特征在于， 所述的化合物是通式 ICa所示的化 合物， 包括消旋体和光学异构体， 及其药学上可接受的盐：
Figure imgf000067_0001
The compound according to claim 8, wherein the compound is a compound represented by the formula ICa, including a racemate and an optical isomer, and a pharmaceutically acceptable salt thereof:
Figure imgf000067_0001
ICa  ICa
其中， Re R^分别独立表示 H、直链或支链的 d.6垸基， C3.6环垸基或 -NR^R^ 构成五元、 六元或七元的含 1-3个杂原子的饱和杂环 （***啉环除外）， 杂环上 可有取代基， 其中， Wherein, Re R ^ each independently represent H, linear or branched d. 6 embankment group, C 3. 6 cyclic alkyl with or -NR ^ R ^ constitute a five-, six- or seven-membered containing 1-3 a saturated heterocyclic ring (except a morpholine ring) of a hetero atom, which may have a substituent on the hetero ring, wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸基、 C3.6 环垸基、 直链或支链的 垸氧基、 取代或未取代的苯基， 其中， Substituents selected from -OH, -F, -Cl, -Br, -COOH, straight-chain or branched d. 6 embankment group, C 3. 6 cyclic alkyl with straight or branched chain group embankment, a substituted or unsubstituted phenyl group, wherein
苯基上的取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、 直链或支链的 d.6垸 基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02、 -NH2或直链或支链的 d.6垸氧 基。 The substituent on the phenyl group may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched d. 6 fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 , -NH 2 or a linear or branched d. 6 oxime.
10.由通式 ID 表示的化合物， 包括消旋体和光学异构体， 及其药学上可接受的 10. A compound represented by the general formula ID, including a racemate and an optical isomer, and a pharmaceutically acceptable thereof
Figure imgf000067_0002
Figure imgf000067_0002
ID  ID
其中， Rfl、 Re、 ¾3分别独立表示 -H、直链或支链的 d.6垸基、苄基或 -CF3 ; R2、 R4分别独立表示 -H、 -OH、 直链或支链的 d.6垸氧基、 -OCF3、 -ON02、 -F、 -Cl、 -Br、 -CN、 -N02、取代或未取代直链或支链的 d.n)垸基、 -CF3、 -CORg， 其中， Wherein R fl , Re and 3⁄43 each independently represent -H, a linear or branched d. 6 fluorenyl group, a benzyl group or a -CF 3 ; R 2 and R 4 each independently represent -H, -OH, a straight chain or a branch. Chain d. 6 methoxy, -OCF 3 , -ON0 2 , -F, -Cl, -Br, -CN, -N0 2 , substituted or unsubstituted linear or branched dn) fluorenyl, -CF 3 , -COR g , where,
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 ,
-SH， -SH,
Rg可表示 H、 -OH、 直链或支链的 d.n)垸基、 取代或未取代的苯基、 含烯 键或炔键的 CLH)不饱和烃基或 -NRGLRG2， 其中， R g may represent H, -OH, a linear or branched dn) fluorenyl group, a substituted or unsubstituted phenyl group, an ethylenic or acetylenic bond-containing CLH) unsaturated hydrocarbon group or -NR GL R G2 , wherein
取代基可选自 -OH、 -F、 -Cl、 -Br、 -COOH、直链或支链的 d.u)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的^.6垸氧基， The substituent may be selected from -OH, -F, -Cl, -Br, -COOH, linear or branched du) fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or a linear or branched ^. 6 methoxy group,
Rgi Rg2分别独立表示 H、 取代或未取代直链或支链的 d.u)垸基、 C3.6环垸 基或 -NRglRg2构成五元、 六元或七元的含 1-3个杂原子的饱和杂环， 其中， 取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2; n可为 1-5， R g i R g2 each independently represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3. 6 cycloalkyl embankment Group or -NR gl R g2 constitutes a saturated heterocycle containing 1-3 heteroatoms five-, six- or seven-membered, wherein the substituents are selected from -OH, a straight-chain or branched d. 6 oxygen embankment Base, -F, -Cl, -Br, -COOH, - H 2 ; n can be 1-5,
Re可表示 H、 取代或未取代直链或支链的 d.u)垸基、 C3.6环垸基或与 R7、 R8及相连的 C原子和 N原子构成四-七元的含 1-3个杂原子的饱和杂环， 其中， 取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2;Re may represent H, substituted or unsubstituted, linear or branched du) embankment group, C 3 6 cycloalkyl group or the embankment with R 7, R 8, and C atoms and N atom constituting four - Seven-membered containing 1 a saturated heterocyclic ring of 3 hetero atoms, wherein the substituent may be selected from -OH, a linear or branched d. 6 methoxy group, -F, -Cl, -Br, -COOH, -H 2 ;
R7与 R8分别独立表示 H、 取代或未取代直链或支链的 d.n)垸基或与 Re及 相连的 C原子和 N原子构成四-七元的含 1-3个杂原子的饱和杂环， 条件是 R7 与 不能同时为 H， 其中， R 7 and R 8 independently represent H, a substituted or unsubstituted linear or branched dn) fluorenyl group or a recombination of a C atom and an N atom to form a four-seven-membered saturation of 1-3 heteroatoms. a heterocyclic ring, the condition being that R 7 and not simultaneously H, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、 -SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , 胍a substituted or unsubstituted phenyl and a aryl group, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 oxime,
Rh表示直链或支链的 CLH)垸基。 R h represents a linear or branched CLH) fluorenyl group.
1 1.根据权利要求 10的化合物， 其特征在于， 所述的化合物是通式 IDa所示的 化合物， 包括消旋体和 可接受的盐：
Figure imgf000068_0001
其中， Rfl、 ¾2、 Re分别独立表示 -H、直链或支链的 d.6垸基、苄基或 -CF3 1 1. A compound according to claim 10, characterized in that the compound is a compound of the formula IDa, including a racemate and an acceptable salt:
Figure imgf000068_0001
Wherein R fl , 3⁄42, Re independently represent -H, linear or branched d. 6 fluorenyl, benzyl or -CF 3
R6可表示 H、 取代或未取代直链或支链的 d.H)垸基、 C3.6环垸基， 其中， 取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 - H2,R6 may represent H, substituted or unsubstituted, linear or branched, dH) embankment group, C 3. 6 embankment cycloalkyl group, wherein the substituent selected from -OH, a straight-chain or branched d. 6 embankment group , -F, -Cl, -Br, -COOH, - H 2 ,
R7与 R8分别独立表示 H、 取代或未取代直链或支链的 d.u)垸基， 条件是 与 不能同时为 H， 其中， R 7 and R 8 each independently represent H, a substituted or unsubstituted straight or branched du) fluorenyl group, provided that it is not simultaneously H, wherein
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、 -SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , 胍a substituted or unsubstituted phenyl and a aryl group, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, straight or branched chain CH) fluorenyl, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 decyloxy,
RH表示直链或支链的 CLH)垸基。 R H represents a linear or branched CLH) fluorenyl group.
12.根据权利要求 11的化合物， 其特征在于， 所述的化合物是通式 IDal 所示的 化合物， 包括消旋体和光 ， 及其药学上可接受的盐： The compound according to claim 11, wherein the compound is a compound represented by the formula IDal, including a racemate and light, and a pharmaceutically acceptable salt thereof:
Figure imgf000069_0001
Figure imgf000069_0001
其中， R7表示取代或未取代直链或支链的 d.u)垸基， Wherein R 7 represents a substituted or unsubstituted straight or branched du) fluorenyl group,
取代基可选自 -OH、直链或支链的 d.6垸氧基、 -F、 -Cl、 -Br、 -COOH、 -NH2、 -SH、 -SRh、 -CO H2、 胍基、 取代或未取代的苯基及芳杂基， 其中， The substituent may be selected from -OH, linear or branched d. 6 methoxy, -F, -Cl, -Br, -COOH, -NH 2 , -SH, -SR h , -CO H 2 , 胍a substituted or unsubstituted phenyl and a aryl group, wherein
苯基及芳杂基上的取代基可选自 -OH、 -F、 -Cl、 -Br, -COOH、 直链或支链 的 C H)垸基、 -CHF2、 -CF3、 -CN、 -N02、 -OCF3、 -ON02或直链或支链的 d.6 垸氧基， The substituent on the phenyl group and the aryl group may be selected from -OH, -F, -Cl, -Br, -COOH, a linear or branched CH) fluorenyl group, -CHF 2 , -CF 3 , -CN, -N0 2 , -OCF 3 , -ON0 2 or linear or branched d. 6 oxime,
Rh表示直链或支链的 垸基。 R h represents a linear or branched fluorenyl group.
13.根据权利要求 10的化合物， 其特征在于， 所述的化合物是通式 IDb所示的 化合物， 包括消旋体和光学异构体， 及其药学上可接受的盐：
Figure imgf000069_0002
其中， Rfl、 、 Re分别独立表示 -H、 直链或支链的 Cwo垸基、 苄基或 -CF N原子与邻位 C原子共同参与构成四-七元的含 1-3个杂原子的饱和杂环。 The compound according to claim 10, wherein the compound is a compound represented by the formula IDb, including a racemate and an optical isomer, and a pharmaceutically acceptable salt thereof:
Figure imgf000069_0002
Wherein, R fl , and Re respectively represent -H, a linear or branched Cwo fluorenyl group, a benzyl group or a -CF N atom and an ortho C atom together to form a four- to seven-membered 1-3 hetero atom Saturated heterocycle.
14.根据权利要求 1-13中任一项的化合物， 其特征在于， 所述的化合物选自：The compound according to any one of claims 1 to 13, wherein the compound is selected from the group consisting of:
1) 1-(2-甲氧基 -4,6-二羟基苯基) -3-甲基 -1-丁酮 1) 1-(2-methoxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone
2) 1-(2-乙氧基 -4,6-二羟基苯基) -3-甲基 -1-丁酮 3) l-(2-异丙氧基 -4,6-二羟基苯基) -3-甲基 -1-丁酮 2) 1-(2-Ethoxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone 3) l-(2-Isopropoxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone
4) 1-(2-丙酰氧基 -4,6-二羟基苯基) -3-甲基 -1-丁酮  4) 1-(2-propionyloxy-4,6-dihydroxyphenyl)-3-methyl-1-butanone
5) 3-[3,5-二羟基 -2-(3-甲基丁酰基)苯氧基]甲基 -4-苯基呋咱  5) 3-[3,5-Dihydroxy-2-(3-methylbutyryl)phenoxy]methyl-4-phenylfurazan
6) (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 6) (±)-1-[2-(2-Hydroxy-3-isopropylaminopropoxy)-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
7) (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐7) (R)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy]-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
8) (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐8) (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy- 4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
9) (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 -4,6-二羟基苯基] -3-甲基 -1-丁酮盐酸盐9) (±)-1-[2-(2-hydroxy-3-tert-butylaminopropoxy]-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (R) -l-[2-(2-Hydroxy-3-tert-butylaminopropoxy'-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride (S)-l-[2-( 2-hydroxy-3-tert-butylaminopropoxy-4,6-dihydroxyphenyl]-3-methyl-1-butanone hydrochloride
(±)-1-[2-(2-羟基 -3-异丙胺基丙氧基) -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐，(±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy)-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride,
(R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 '-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 -4-甲氧基苯基] -3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-异丙胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-异丙胺基丙氧基 4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸 (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy '-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride (S)-l -[2-(2-hydroxy-3-isopropylaminopropoxy-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride (±)-1-[2-(2 -hydroxy-3-tert-butylaminopropoxy '-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride (R)-l-[2-(2-hydroxy-3-tert-butylamine Propyloxy '-4-methoxyphenyl]-3-methyl-1-butanone hydrochloride (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy-4 -Methoxyphenyl]-3-methyl-1-butanone hydrochloride (±)-1-[2-(2-hydroxy-3-isopropylaminopropoxy]-4,6-dimethyl Oxyphenyl]-3-methyl-1-butanone hydrochloride (R)-l-[2-(2-hydroxy-3-isopropylaminopropoxy 4,6-dimethoxyphenyl) ]-3-methyl-1-butanone hydrochloride
(S)-l-[2-(2-羟基 -3-异丙胺基丙氧基 -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (±)-1-[2-(2-羟基 -3-叔丁胺基丙氧基 '-4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 (R)-l-[2-(2-羟基 -3-叔丁胺基丙氧基 4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸 (S)-l-[2-(2-Hydroxy-3-isopropylaminopropoxy-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride (±) 1-[2-(2-hydroxy-3-tert-butylaminopropoxy'-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride (R)-l- [2-(2-Hydroxy-3-tert-butylaminopropoxy 4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride
(S)-l-[2-(2-羟基 -3-叔丁胺基丙氧基) -4,6-二甲氧基苯基 ]-3-甲基 -1-丁酮盐酸盐 4- (哌啶 -1-基) -1 -(2,4,6-三羟基苯基) -1-丁酮盐酸盐 (S)-l-[2-(2-hydroxy-3-tert-butylaminopropoxy)-4,6-dimethoxyphenyl]-3-methyl-1-butanone hydrochloride 4- ( Piperidin-1-yl)-1 -(2,4,6-trihydroxyphenyl)-1-butanone hydrochloride
4- (甲基环己基胺;) -1-(2,4,6-三羟基苯基； )-1-丁酮盐酸盐  4-(methylcyclohexylamine;)-1-(2,4,6-trihydroxyphenyl; )-1-butanone hydrochloride
4-[4-(3-氯苯基)哌嗪 -1-基] -1-(2,4,6-三羟基苯基) 1-丁酮盐酸盐  4-[4-(3-Chlorophenyl)piperazin-1-yl]-1-(2,4,6-trihydroxyphenyl) 1-butanone hydrochloride
(S)-2-(2,4,6-三羟基苯甲胺基)丙酸  (S)-2-(2,4,6-trihydroxybenzylamino)propionic acid
(S)-2-(2,4,6-三羟基苯甲胺基) -3-甲基丁酸  (S)-2-(2,4,6-trihydroxybenzylamino)-3-methylbutyric acid
(S)-2-(2,4,6-三羟基苯甲胺基) -4-甲基戊酸 30) (S)-2-(2,4,6-三羟基苯甲胺基) -3-甲基戊酸 (S)-2-(2,4,6-trihydroxybenzylamino)-4-methylpentanoic acid 30) (S)-2-(2,4,6-Trihydroxybenzylamino)-3-methylpentanoic acid
31) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-苯基丙酸  31) (S)-2-(2,4,6-Trimethoxybenzylamino)-3-phenylpropionic acid
32) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-(4-羟基苯基)丙酸  32) (S)-2-(2,4,6-Trimethoxybenzylamino)-3-(4-hydroxyphenyl)propionic acid
33) (S)-2-(2,4,6-三甲氧基苯甲胺基)戊二酸  33) (S)-2-(2,4,6-Trimethoxybenzylamino)glutaric acid
34) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-羟基丙酸  34) (S)-2-(2,4,6-Trimethoxybenzylamino)-3-hydroxypropionic acid
35) (S)-2-(2,4,6-三甲氧基苯甲胺基)丁二酸  35) (S)-2-(2,4,6-Trimethoxybenzylamino)succinic acid
36) (2S)-2-(2,4,e >-三甲氧基苯甲胺基) -3-轻基丁酸  36) (2S)-2-(2,4,e >-trimethoxybenzylamino)-3-carbobutyric acid
37) (R)-2-(2,4,6-三甲氧基苯甲胺基) -3-巯基丙酸  37) (R)-2-(2,4,6-Trimethoxybenzylamino)-3-mercaptopropionic acid
38) (S)-2-(2,4,6-三甲氧基苯甲胺基) -4-甲硫基丁酸  38) (S)-2-(2,4,6-Trimethoxybenzylamino)-4-methylthiobutyric acid
39) (S)-2-(2,4,6-三甲氧基苯甲胺基) -6-氨基己酸  39) (S)-2-(2,4,6-Trimethoxybenzylamino)-6-aminocaproic acid
40) (S)-2-(2,4,6-三甲氧基苯甲胺基) -5-胍基戊酸  40) (S)-2-(2,4,6-Trimethoxybenzylamino)-5-mercaptovaleric acid
41) (S)-2-(2,4,6-三甲氧基苯甲胺基) -4-氨基 -4-氧丁酸  41) (S)-2-(2,4,6-Trimethoxybenzylamino)-4-amino-4-oxobutanoic acid
42) (S)-2-(2,4,6-三甲氧基苯甲胺基) -5-氨基 -5-氧戊酸  42) (S)-2-(2,4,6-Trimethoxybenzylamino)-5-amino-5-oxovaleric acid
43) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-(JH-咪唑 -5-基)丙酸  43) (S)-2-(2,4,6-Trimethoxybenzylamino)-3-(JH-imidazole-5-yl)propionic acid
44) (S)-2-(2,4,6-三甲氧基苯甲胺基) -3-(JH-吲哚 -3-基;)丙酸  44) (S)-2-(2,4,6-Trimethoxybenzylamino)-3-(JH-indol-3-yl;)propionic acid
45) (S)-l-(2,4,6-三甲氧基苯基)吡咯 -2-酸。  45) (S)-l-(2,4,6-Trimethoxyphenyl)pyrrole-2-acid.
15.一种药物组合物， 其特征在于， 含有有效剂量的如权利要求 1-14中任一项所 述的任一化合物和药学上可接受的载体。 A pharmaceutical composition comprising an effective amount of any one of the compounds according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier.
16.根据权利要求 15的药物组合物， 其特征在于， 所述的药物组合物选自片剂、 胶囊、 丸剂、 注射剂、 缓释制剂、 控释制剂及各种微粒给药***。  The pharmaceutical composition according to claim 15, wherein the pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, an injection, a sustained release preparation, a controlled release preparation, and various microparticle delivery systems.
17.如权利要求 1-14中任一项所述的化合物在制备防治神经退行性疾病药物中的 应用。 17. Use of a compound according to any one of claims 1 to 14 for the manufacture of a medicament for the prevention and treatment of neurodegenerative diseases.
18.如权利要求 17所述的应用，其特征在于所述的疾病是阿尔茨海默病、帕金森 病、 多发性硬化、 肌肉萎缩性侧索硬化症、 共济失调毛血管扩张症、 牛海绵 状脑病、 克雅二氏病、 亨廷顿氏病、 小脑萎缩症、 原发性侧索硬化症、 脊髓 性肌萎缩症。 18. The use according to claim 17, wherein the disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia telangiectasia, cow Spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, primary lateral sclerosis, spinal muscular atrophy.
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