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CN104140365A - Phloroglucinol derivative and use thereof in treatment of neurodegenerative diseases - Google Patents

Phloroglucinol derivative and use thereof in treatment of neurodegenerative diseases Download PDF

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Publication number
CN104140365A
CN104140365A CN201310166868.4A CN201310166868A CN104140365A CN 104140365 A CN104140365 A CN 104140365A CN 201310166868 A CN201310166868 A CN 201310166868A CN 104140365 A CN104140365 A CN 104140365A
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alkyl
straight
branched
phenyl
cooh
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Inventor
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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Institute of Materia Medica of CAMS and PUMC
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Institute of Materia Medica of CAMS and PUMC
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Priority to CN201310166868.4A priority Critical patent/CN104140365A/en
Priority to CN201480026162.0A priority patent/CN105189446B/en
Priority to PCT/CN2014/077029 priority patent/WO2014180321A1/en
Publication of CN104140365A publication Critical patent/CN104140365A/en
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Abstract

The invention discloses a phloroglucinol derivative and use thereof in treatment of neurodegenerative diseases, specifically discloses a phloroglucinol derivative as shown in formula I and pharmacodynamics acceptable salts thereof, pharmaceutical compositions containing the phloroglucinol derivative and pharmacodynamics acceptable salts thereof, and use of the compounds in preparing of drugs for treatment of neurodegenerative diseases. The neurodegenerative diseases includes Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia telangiectasia, bovine spongiform encephalopathy, Creutzfeldt-Jakob disease, Huntington's disease, spinocerebellar atrophy, primary lateral sclerosis, and spinal muscular atrophy.

Description

Phloroglucinol analog derivative and the purposes in treatment nerve degenerative diseases thereof
Technical field
The present invention relates to acceptable salt in a class Phloroglucinol analog derivative and pharmacodynamics thereof, the pharmaceutical composition that contains them and the application of this compounds in preparing the medicine of nerve degenerative diseases, belong to medical technical field.
Background technology
Nerve degenerative diseases (as Parkinson's disease, Alzheimer's disease, multiple sclerosis etc.) is a class disease of serious harm human health within the scope of the world today, and M & M is ascendant trend year by year.Such disease is by due to the neuronic damage of brain and spinal cord, passes in time and worsens, and causes the aspect dysfunctions such as motion or memory.Along with constantly increasing the weight of of world population aging, in the urgent need to effective medicine.
Recent study discovery, the generation of the interior neural inflammation of brain and multiple nerve degenerative diseases is closely related with development, and the pathology of its mediation is mainly caused by the activation of spongiocyte and the lymphocyte release neurotoxicity factor of periphery invasion.Microglia and astroglia cell are the intraparenchymatous inherent immunity cells of brain, under normal circumstances in quiescent condition, there is the effect of the normal stable state of the central nervous system of maintaining, under the pathological conditions such as brain infection or damage, these cells are activated, and start immune response and process of tissue reparation, remove foreign matter and pathology in brain, once infect or damage reply, these cells are got back to quiescent condition.In the process of nerve degenerative diseases, these cells are frequently activated, discharge a large amount of immune factors and cytotoxic factor, comprise arachidonic acid metabolite, cytokine, inflammatory chemokine, nitrogen protoxide, active oxygen radical and excitatory amino acid etc., cause neuronic damage, sex change even dead.And cell debris and biologically active substance that the neurone of degeneration necrosis etc. discharge also can activate microglia and astroglia cell again, thereby cause, in brain, there is continual Neuroinflammation, and then cause neuronic degeneration dead.Therefore, development and exploitation have the medicine that suppresses neural inflammatory activity, reduce the activation of spongiocyte and the overexpression of immune factor and inflammatory factor, significant for treatment nerve degenerative diseases.
Summary of the invention
The technical problem that will solve of the present invention is to provide hydrate or the prodrug of acceptable salt, salt in the compound of various situations described in general formula I and pharmacodynamics thereof.
The another technical problem that the present invention will solve is to provide a kind of pharmaceutical composition, and it comprises hydrate or prodrug and pharmaceutical carrier and/or the vehicle of acceptable salt, salt on the compound, its pharmacodynamics of various situations described at least one general formula I.
The technical problem again that the present invention will solve is to provide hydrate or the application of prodrug in preparing the medicine of nerve degenerative diseases of acceptable salt, salt on the compound, its pharmacodynamics of various situations described in general formula I.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
According to the present invention, compound is as shown in formula I:
Situation one, compound is to represent by general formula I A:
Wherein, R athe C of expression replacement or not substituted straight chain or side chain 1-10alkyl, benzyl ,-NO 2,-COR a1, wherein
Can be selected from-OH of substituting group ,-F ,-Cl ,-Br, alkoxyl group ,-SH, replacement or unsubstituted furazan base or-COOH, wherein
Substituting group can be selected from the C of straight or branched 1-10alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzenesulfonyl, wherein
The C of can be selected from-OH of the substituting group on phenyl and benzenesulfonyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R a1the optional C from replacement or unsubstituted straight or branched 2-10alkyl, wherein
Can be selected from-OH of substituting group on alkyl ,-F ,-Cl ,-Br, replacement or unsubstituted phenyl ,-COOH or-NH 2, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
According to the present invention, work as R athe C that represents unsubstituted straight or branched 1-10during alkyl, preferred R ylmethyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl etc., but be not limited to above group.
According to the present invention, work as R athe C that represents the straight or branched of replacement 1-10during alkyl, preferred R abase comprises, but is not limited to the group shown in general formula I Aa:
Wherein, n can represent 1-5
R a2can be selected from the C of straight or branched 1-10alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzenesulfonyl, wherein
The C of can be selected from-OH of the substituting group on phenyl and benzenesulfonyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
According to the present invention, the R that preferred general formula I Aa represents a2the compound of base comprises:
R a2independently be selected from respectively H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, replacement or unsubstituted phenyl, benzene substitution in ring or unsubstituted benzenesulfonyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Situation two, compound is to represent by general formula I B:
Wherein, R 3and R 5the C of respectively independent expression-H ,-OH, straight or branched 1-6alkyl ,-ONO 2,-OR cor-SR c, wherein
R cthe C of expression replacement or not substituted straight chain or side chain 1-10alkyl, benzyl,
Can be selected from-OH of described substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-NH 2,-COOH
R b1, R b2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR b1r b2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group
According to the present invention, the compound of the R base that preferred general formula I B represents comprises:
R 3and R 5independently be selected from respectively H ,-OH, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, alkoxyl group, benzyloxy.
R b1, R b2independently be selected from respectively H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, benzene substitution in ring or unsubstituted phenmethyl, styroyl, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Or-NR b1r b2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, can be selected from following heterocycle:
Wherein, can represent-OH of R ' ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl, alkoxyl group, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Situation three, compound is to represent by general formula I C:
Wherein, R d1, R d2and R d3the C of respectively independent expression-H, straight or branched 2-6alkyl, benzyl or-CF 3
N can be 2-10
R e1, R e2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR e1r e2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic (except morpholine ring), on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group
According to the present invention, the compound shown in preferred general formula I C comprises:
R d1, R d2and R d3independently be selected from respectively methyl, ethyl, propyl group, sec.-propyl, benzyl ,-CF 3
N represents 3-5
R e1, R e2independently be selected from respectively H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, benzene substitution in ring or unsubstituted phenmethyl, styroyl, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Or-NR e1r e2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, can be selected from following heterocycle:
Wherein, can represent-OH of R ' ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl, alkoxyl group, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
According to the present invention, the compound shown in preferred general formula I C comprises, but is not limited to the compound shown in general formula I Ca:
Wherein, R e1, R e2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR e1r e2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic (except morpholine ring), on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group
According to the present invention, the compound that preferred general formula I Ca represents comprises:
R e1, R e2independently be selected from respectively H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl, benzene substitution in ring or unsubstituted phenmethyl, styroyl, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Or-NR b1r b2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, can be selected from following heterocycle:
Wherein, can represent-OH of R ' ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl, alkoxyl group, replacement or unsubstituted phenyl, can be selected from-H of substituting group ,-OH ,-F ,-Cl ,-Br ,-COOH, C 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2, alkoxyl group ,-NH 2.
Situation four, compound is to represent by general formula I D:
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-6alkyl, benzyl or-CF 3,
R 2, R 4respectively independent expression-H ,-OH, alkoxyl group ,-OCF 3,-ONO 2,-F ,-Cl ,-Br ,-CN ,-NO 2, replace or the C of substituted straight chain or side chain not 1-10alkyl ,-CF 3,-COR g, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH,
R gthe C that can represent H ,-OH, straight or branched 1-10alkyl, replacement or unsubstituted phenyl, containing the C of ethylene linkage or acetylene bond 1-10unsaturated alkyl or-NR g1r g2, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R g1, R g2independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl, C 3-6cycloalkyl or-NR g1r g2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,
N can be 1-5
R 6can represent H, replacement or the C of substituted straight chain or side chain not 1-10alkyl, C 3-6cycloalkyl or and R 7, R 8and four-seven yuan of connected C atom and N atomic buildings containing 1-3 heteroatomic saturated heterocyclic, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2
R 7with R 8independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl or and R 6and four-seven yuan of connected C atom and N atomic buildings containing 1-3 heteroatomic saturated heterocyclic, condition is R 7with R 8can not be H, wherein simultaneously
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl
According to the present invention, the compound shown in preferred general formula I comprises, but is not limited to the compound shown in general formula I Da:
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-6alkyl, benzyl or-CF 3
R 6can represent H, replacement or the C of substituted straight chain or side chain not 1-10alkyl, C 3-6cycloalkyl, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2
R 7with R 8independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl, condition is R 7with R 8can not be H, wherein simultaneously
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl
According to the present invention, the compound shown in preferred general formula I Da comprises:
R f1, R f2, R f3be selected from methyl, ethyl, propyl group, sec.-propyl, benzyl ,-CF 3
R 6be selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and replacement or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2
R 7, R 8the two can not be simultaneously H to be independently selected from respectively H(), replacement or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, can be selected from-OH of substituting group ,-COOH ,-NH 2,-SH ,-SCH 3,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein the substituting group of phenyl can for-OH ,-F ,-Cl ,-Br ,-COOH, methyl, ethyl, sec.-propyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group, heterocyclic base can be selected from furyl, imidazolyl, pyrazolyl, pyridyl, thienyl, pyrryl, thiazolyl, pyrimidyl, indyl etc.
According to the present invention, the compound shown in preferred general formula I Da comprises, but is not limited to the compound shown in general formula I Da1:
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-10alkyl, benzyl or-CF 3
R 7the C of expression replacement or not substituted straight chain or side chain 1-10alkyl
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl
According to the present invention, the compound shown in preferred general formula I Da1 comprises:
R f1, R f2, R f3be selected from methyl, ethyl, propyl group, sec.-propyl, benzyl ,-CF 3
R 7be selected from H, replacement or unsubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl, can be selected from-OH of substituting group ,-COOH ,-NH 2,-SH ,-SCH 3,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein the substituting group of phenyl can for-OH ,-F ,-Cl ,-Br ,-COOH, methyl, ethyl, sec.-propyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group, heterocyclic base can be selected from furyl, imidazolyl, pyrazolyl, pyridyl, thienyl, pyrryl, thiazolyl, pyrimidyl, indyl etc.
According to the present invention, the compound shown in preferred general formula I D comprises, but is not limited to the compound shown in general formula I Db:
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-10alkyl, benzyl or-CF 3
N atom and ortho position C atom participate in forming 1-3 the heteroatomic saturated heterocyclic that contain of four-seven yuan jointly
According to the present invention, the compound shown in preferred general formula I Db comprises:
R f1, R f2, R f3be selected from methyl, ethyl, propyl group, sec.-propyl, benzyl ,-CF 3
M ring is selected from
In the present invention, alkoxyl group refers to the alkoxyl group of the C1-6 of straight or branched, the methoxyl group of can giving an example, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, positive hexyloxy, different hexyloxy etc.
According to the present invention, preferred compound include but not limited to following compound:
1.1-(2-methoxyl group-4,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
2.1-(2-oxyethyl group-4,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
3.1-(2-isopropoxy-4,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
4.1-(2-propionyloxy-4,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
5.3-[3,5-dihydroxyl-2-(3-methylbutyryl base) phenoxy group] methyl 4-phenyl furazan
6. (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride
7. (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride
8. (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride
9. (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride
10. (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloric acid
11. (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride
12. (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride,
13. (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride
14. (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride
15. (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride
16. (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride
17. (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride
18. (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
19. (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
20. (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
21. (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
22. (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
23. (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride
24.4-(piperidin-1-yl)-1-(2,4,6-trihydroxy-phenyl)-1-butanone hydrochloride
25.4-(methylcyclohexyl amine)-1-(2,4,6-trihydroxy-phenyl)-1-butanone hydrochloride
26.4-[4-(3-chloro-phenyl-) piperazine-1-yl]-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride
27. (S)-2-(2,4,6-trihydroxybenzene methylamino) propionic acid
28. (S)-2-(2,4,6-trihydroxybenzene methylamino)-3 Methylbutanoic acid
29. (S)-2-(2,4,6-trihydroxybenzene methylamino)-4-methylvaleric acid
30. (S)-2-(2,4,6-trihydroxybenzene methylamino)-3 methylvaleric acid
31. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid
32. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-(4-hydroxy phenyl) propionic acid
33. (S)-2-(2,4,6-trimethoxy-benzene methylamino) pentanedioic acid
34. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy-propionic acid
35. (S)-2-(2,4,6-trimethoxy-benzene methylamino) succinic acid
36. (2S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxybutyrate
37. (R)-2-(2,4,6-trimethoxy-benzene methylamino)-3-thiohydracrylic acid
38. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-4-methylmercapto butyric acid
39. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-6-aminocaprolc acid
40. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-5-guanidine radicals valeric acid
41. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-4-amino-4-oxy butyrate
42. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-5-amino-5-oxy pentanoic acid
43. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-(1H-imidazoles-5-yl) propionic acid
44. (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-(1H-indol-3-yl) propionic acid
45. (S)-1-(2,4,6-trimethoxyphenyl) pyrroles-2-acid
The invention still further relates to a kind of compound as described in each situation of general formula I of medicine effective dose and pharmaceutical composition of pharmaceutically acceptable carrier of containing.
According to the present invention, the form that the compounds of this invention can isomer exists, and described " the compounds of this invention " comprises the isomer of this compound conventionally.
According to embodiment of the present invention, described the compounds of this invention also comprises hydrate or the prodrug of acceptable salt, salt in its pharmacodynamics.
The invention still further relates to and contain as the compounds of this invention of active ingredient and the pharmaceutical composition of conventional medicine vehicle or assistant agent.Conventionally the compounds of this invention that pharmaceutical composition of the present invention contains 0.1～95 % by weight.In unit dosage form, the general content of the compounds of this invention is 0.1～100mg, and preferred unit dosage form contains 4～50mg.
The pharmaceutical composition of the compounds of this invention can be according to method preparation well known in the art.When this object, if needed, the compounds of this invention and one or more solids or liquid medicine vehicle and/or assistant agent can be combined, make the suitable administration form or the dosage form that can be used as people's medicine or veterinary drug use.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, and route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.The route of administration of the compounds of this invention or the pharmaceutical composition that contains it can be drug administration by injection.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage.If liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder etc.The compounds of this invention can be made ordinary preparation, also can be sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For example, for unit form of administration is made to tablet, can be widely used various carrier well known in the art.Example about carrier is, for example thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, for example sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For example, for pill is made in administration unit, can be widely used various carrier well known in the art.Example about carrier is, for example thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, single stearic acid glycerine lipoprotein, kaolin, talcum powder etc.; Tackiness agent, as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.
For example, for capsule is made in administration unit, effective constituent the compounds of this invention is mixed with above-mentioned various carriers, and the mixture obtaining is thus placed in to hard gelatine capsule or soft capsule.Also effective constituent the compounds of this invention can be made to microcapsule, be suspended in aqueous medium and form suspensoid, also can pack in hard capsule or make injection application.
For example, the compounds of this invention is made to injection preparation, as solution, suspensoid solution, emulsion, lyophilized injectable powder, this preparation can be moisture or non-water, can be containing acceptable carrier, thinner, tackiness agent, lubricant, sanitas, tensio-active agent or dispersion agent in a kind of and/or multiple pharmacodynamics.As thinner can be selected from the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, isooctadecanol of polyoxy, polyoxyethylene sorbitol fat, fat acid esters etc.In addition, in order preparing etc., to ooze injection liquid, can in injection preparation, to add appropriate sodium-chlor, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH adjusting agent etc.These auxiliary materials are that this area is conventional.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition depends on many factors, for example to prevent or treat character and the severity of disease, the sex of patient or animal, age, body weight, personality and individual reaction, route of administration, administration number of times, therapeutic purpose, therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.Can be according to actual drug quantity contained in preparation last in the compounds of this invention composition, in addition suitable adjustment, to reach the requirement of its treatment significant quantity, completes prevention of the present invention or therapeutic purpose.The appropriate dose scope of the every day of the compounds of this invention: the consumption of compound of the present invention is 0.001～100mg/Kg body weight, is preferably 0.1～60mg/Kg body weight, and more preferably 1～30mg/Kg body weight, most preferably is 2～15mg/Kg body weight.Be 10～500mg the compounds of this invention every day that adult patient is taken, and is preferably 20～100mg, can once take or minute take for 2～3 times; The dosage of children taking, according to every kg body weight 5～30mg, is preferably 10～20mg/kg body weight.Above-mentioned dosage can single dose form or be divided into several, for example two, three or four dosage form administrations, this is limited to administration doctor's clinical experience and the dosage regimen for the treatment of means.Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.
The invention still further relates to the application of compound of the present invention in preparation control nerve degenerative diseases medicine.Described disease comprises alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia hair and blood enlargement of pipe disease, mad cow disease, gram refined Er Shi disease, Huntington's disease, cerebellar atrophy disease, primary lateral sclerosis, spinal muscular atrophy.
Embodiment
The following examples are used for further illustrating the present invention, but this and do not mean that any limitation of the invention.
The preparation of embodiment 1 1-(2-methoxyl group-4,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
The preparation of step 1:1-(2,4,6-trihydroxy-phenyl)-3-methyl isophthalic acid-butanone
5.00g (40mmol) Phloroglucinol is dissolved in the mixing solutions of 50mL dithiocarbonic anhydride and 15mL oil of mirbane, adds 15.6g (120mmol) aluminum trichloride (anhydrous), stirring at room 10 minutes; To slowly dripping 20mL in reaction solution containing the dithiocarbonic anhydride solution of 4.82g (40mmoll) isoveryl chloride, reflux 30 minutes at 50 ℃ afterwards; After evaporated under reduced pressure dithiocarbonic anhydride, in residue, splash into 10mL hydrochloric acid and 20mL mixture of ice and water, with 3 * 50mL ethyl acetate extraction, merge organic layer, with 3 * 25mL saturated nacl aqueous solution, wash anhydrous sodium sulfate drying; After evaporated under reduced pressure solvent, carry out silica gel column chromatography (chloroform: methyl alcohol 20:1) separation, obtains 1-(2,4,6-trihydroxy-phenyl)-3-methyl isophthalic acid-butanone 6.5g, yield 78%.
Step 2:1-[2-hydroxyl-4,6-bis-(methoxymethoxy) phenyl] preparation of-3 methyl isophthalic acids-butanone
Will be according to step 1 gained 2.1g (10mmol) 1-(2,4,6-trihydroxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in 50mL methylene dichloride, cooling at 0 ℃, add 3.65mL (21mmol) dipropyl ethamine, stir 15 minutes, 1.6mL (25mmol) chloromethyl methyl ether is dissolved in 20mL methylene dichloride, slowly drop to reaction solution, after at 0 ℃, react 15 minutes, then under room temperature, react 45 minutes.By in reaction solution impouring 100mL water, with 3 * 50mL chloroform extraction, merge organic layer, with the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carry out silica gel column chromatography (sherwood oil: ethyl acetate 15:1) separation obtains 1-[2-hydroxyl-4,6-bis-(methoxymethoxy) phenyl]-3-methyl isophthalic acid-butanone 1.40g, yield 47%.
Step 3:1-[2-methoxyl group-4,6-bis-(methoxymethoxy) phenyl] preparation of-3 methyl isophthalic acids-butanone
By the 300mg of gained in step 2 (1mmol) 1-[2-hydroxyl-4,6-bis-(methoxymethoxy) phenyl]-3-methyl isophthalic acid-butanone is dissolved in 20mL acetone, add 276mg (2mmol) Anhydrous potassium carbonate, reflux 20 minutes, in reaction solution, add 100 μ l (2mmol) methyl-sulfates, continue to reflux 5 hours.Evaporated under reduced pressure reaction solution, adds 20mL water in residue, with the extraction of 3 * 25mL ethyl acetate, merge organic layer, with the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carry out silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation obtains 1-[2-methoxyl group-4,6-bis-(methoxymethoxy) phenyl]-3-methyl isophthalic acid-butanone 250mg, yield 80%.
The preparation of step 4:1-(4-methoxyl group-2,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone
By the 250mg of gained in step 3 (0.80mmol) 1-[2-methoxyl group-4,6-bis-(methoxymethoxy) phenyl]-3-methyl isophthalic acid-butanone is dissolved in 10mL methyl alcohol, add 2mL2N hydrochloric acid, reflux 1 hour, the organic solvent in evaporated under reduced pressure reaction solution, adds 20mL water in residue, by 3 * 25mL ethyl acetate, extract, merge organic layer, with the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carries out silica gel column chromatography (sherwood oil: ethyl acetate 20:1) separation obtains 1-(4-methoxyl group-2,6-dihydroxy phenyl)-3-methyl isophthalic acid-butanone 185mg, yield 83%.
1H?NMR(500MHz,d 6-DMSO)δ13.59(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=6.5Hz,H-2),2.07(1H,m,H-3),0.89(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.0,165.7,164.4,162.4,104.2,95.3,90.9,55.3,51.9,24.5,22.2,22.2。
Embodiment 2 3-[3,5-dihydroxyl-2-(3-methylbutyryl base) phenoxy group] preparation of methyl 4-phenyl furazan
The preparation of step 1:3-methylol-4-phenyl furazan
2.00g (15mmol) styryl carbinol is added in 3mL Glacial acetic acid, and stirring at room is dissolved to it, in the cooling downhill reaction liquid of ice bath, drips containing 3.00g (72mmol) NaNO 2saturated aqueous solution, dropwise rear stirring at room 5 hours.In reaction solution, add 20mL water, with the extraction of 3 * 50mL ethyl acetate, merge organic layer, use successively 3 * 15mL5%NaOH solution and the washing of 3 * 20mL saturated nacl aqueous solution, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains oily matter 2.50g.
The preparation of step 2:3-chloromethyl-4-phenyl furazan
The oily matter 330mg of gained in step 1 is dissolved in 15mL anhydrous methylene chloride, adds 0.32mL (4mmol) pyridine, in the cooling downhill reaction liquid of ice bath, drip 0.35mL SOCl 2, stirring at room 3 hours.Reaction solution is used to 3 * 15mL frozen water, the saturated Na of 3 * 15mL successively 2cO 3solution and the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carries out silica gel column chromatography (sherwood oil: ethyl acetate 7:1) separation obtains 3-chloromethyl-4-phenyl furazan 280mg, yield 78%.
Step 3:3-[3,5-dihydroxyl-2-(3-methylbutyryl base) phenoxy group] preparation of methyl 4-phenyl furazan
3-chloromethyl-4-phenyl furazan 210mg (1mmol) of gained in step 2 is dissolved in to 20mL acetonitrile, add 210mg (1mmol) according to the 1-(2 of embodiment 1 step 1 gained, 4,6-trihydroxy-phenyl)-3-methyl isophthalic acid-butanone, 207mg (1.5mmol) anhydrous K 2cO 3with a small amount of KI, reflux 10 hours, pressurization evaporate to dryness reaction solution, adds 20mL water in residue, with the extraction of 3 * 25mL ethyl acetate, merge organic layer, with the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carry out silica gel column chromatography (sherwood oil: ethyl acetate 5:1) separation obtains 3-[3,5-dihydroxyl-2-(3-methylbutyryl base) phenoxy group] methyl 4-phenyl furazan 200mg, yield 53%.
1H?NMR(500MHz,d 6-DMSO)δ13.43(1H,s,OH-6′),10.73(1H,s,OH-4′),7.79(2H,d,J=7.5Hz,H-2′′′,H-6′′′),7.63(2H,t,J=7.5Hz,H-3′′′,H-5′′′),7.59(1H,t,J=7.5Hz,H-4′′′),6.08(1H,d,J=1.5Hz,H-3′),5.96(1H,d,J=1.5Hz,H-5′),5.24(2H,s,H-1′′),2.44(2H,d,J=7.0Hz,H-2),1.91(1H,m,H-3),0.66(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.1,165.7,164.5,160.2,156.9,131.8,129.7,129.7,127.6,127.6,125.6,112.3,105.2,96.9,92.6,59.1,52.2,24.5,22.3,22.3。
Embodiment 3 (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1: the preparation of tosic acid benzyl ester
10.49g (97mmol) phenylcarbinol is dissolved in 200mL anhydrous diethyl ether, add 2.4g (10mmol) sodium hydride, reflux 12 hours, reaction solution subcooling is to-30 ℃, slowly splash into the anhydrous ether solution 100mL containing 19.5g (102mmol) Tosyl chloride, after at-20 ℃, react 2 hours, under room temperature, react again 1 hour, filter, filtrate evaporate to dryness, carry out silica gel column chromatography (sherwood oil: ethyl acetate 40:1) separation, obtains tosic acid benzyl ester 9.8g, yield 37%.
The preparation of step 2:1-(2-hydroxyl-4,6-hexichol p-methoxy-phenyl)-3-methyl isophthalic acid-butanone
Will be according to embodiment 1 step 1 gained 3g (14.3mmol) 1-(2,4,6-trihydroxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in 200mL acetone, adds gained 7.86g (30mmol) tosic acid benzyl ester and 25g (181mmol) Anhydrous potassium carbonate in step 1, reflux 3 hours, cooling rear evaporate to dryness reaction solution, residue 150mL water dissolution, with the extraction of 3 * 50mL ethyl acetate, merges organic layer, with the washing of 2 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carries out silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation obtains 1-(2-hydroxyl-4,6-hexichol p-methoxy-phenyl)-3-methyl isophthalic acid-butanone 2.98g, yield 53%.
Step 3:(±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
The 1.00g of step 2 gained (2.5mmol) 1-(2-hydroxyl-4,6-hexichol p-methoxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in to 100mL DMF, passes into nitrogen, stir 5 minutes; Add 0.09g (3.75mmol) sodium hydride, at 40 ℃, react 20 minutes, continue to pass into nitrogen; Add 1.16g (12.5mmol) (±)-2-chloromethyloxirane, at 90 ℃, react 2 hours; Question response liquid is cooled to after room temperature, in impouring 100mL water, with the extraction of 3 * 50mL ethyl acetate, merges organic layer, with the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; Evaporated under reduced pressure solvent, through silica gel column chromatography (sherwood oil: ethyl acetate 20:1) separation obtains (±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 0.90g, yield 81%.
Step 4:(±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
By the 450mg of gained in step 3 (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone is placed in heavy wall pressure piping, add 3mL (35mmol) Isopropylamine, stir, at 70 ℃, react 2 hours; Cooling rear evaporated under reduced pressure reaction solution, residue dissolves with 20mL anhydrous diethyl ether, stir the lower saturated ether solution of hydrogen chloride that drips, filter, obtain solid (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 400mg, yield 74%.
Step 5:(±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
By the 170mg of gained in step 4 (0.31mmol) (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride is dissolved in 30mL methyl alcohol, add 100mg palladium carbon and 2mL hydrochloric acid, under the pressure of 3atm, carry out catalytic hydrogenation 12 hours, filter, filtrate evaporate to dryness, gained oily matter is prepared to HPLC(YMC post, 22% acetonitrile) separation, obtain (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 50mg, yield 49%.
1H?NMR(500MHz,d 6-DMSO)δ5.90(1H,s,H-3′),5.89(1H,s,H-5′),3.99(1H,dd,J=3.5,8.0Hz,H-1′′a),3.92(1H,overlap,H-1′′b),3.88(1H,m,H-2′′),2.93(1H,dd,J=7.0,16.0Hz,H-3′′a),2.84(1H,dd,J=6.5,16.0Hz,H-3′′a),2.77(1H,m,H-5′′),2.72(1H,dd,J=6.5,13.5Hz,H-2a),2.60(1H,dd,J=7.0,13.5Hz,H-2b),2.13(1H,m,H-3),1.00(3H,d,J=6.0Hz,CH 3-6′′),0.99(3H,d,J=6.0Hz,CH 3-7′′),0.90(3H,d,J=6.5Hz,CH 3-4),0.88(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9,92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 4 (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1:(S)-1-[2-(2,2-dimethyl-DOX-4-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
3.00g (7.5mmol) 1-of step 2 gained in embodiment 3 (2-hydroxyl-4,6-hexichol p-methoxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in to 20mL DMF, passes into nitrogen, stir 5 minutes; Add 0.27g (11.3mmol) sodium hydride, at 40 ℃, react 20 minutes, continue to pass into nitrogen; Add 3.39g (22.5mmol) (R)-4-chloromethyl-2,2-dimethyl-DOX reacts 24 hours at 90 ℃; Question response liquid is cooled to after room temperature, in impouring 50mL water, with the extraction of 3 * 50mL ethyl acetate, merges organic layer, with the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; Evaporated under reduced pressure solvent, through silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation obtains (S)-1-[2-(2,2-dimethyl-DOX-4-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 0.90g, yield 23%.
Step 2:(R)-1-[2-(2,3-dihydroxyl propoxy-)-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
By the 900mg obtaining in step 1 (1.86mmol) (S)-1-[2-(2, 2-dimethyl-1, 3-dioxolane-4-yl) methoxyl group-4, 6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone is dissolved in 20mL tetrahydrofuran (THF), slowly drip 4% sulfuric acid 10mL, under room temperature, react 8 hours, decompression evaporates organic solvent, surplus solution extracts by 3 * 30mL ethyl acetate, merge organic layer, with saturated sodium bicarbonate solution, be washed till neutrality, use again the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying, evaporated under reduced pressure organic layer, obtain (R)-1-[2-(2, 3-dihydroxyl propoxy-)-4, 6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 840mg, yield 98%.
Step 3:(S)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
By the 800mg obtaining in step 2 (1.76mmol) (R)-1-[2-(2, 3-dihydroxyl propoxy-)-4, 6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone is dissolved in 20mL dry methylene chloride, add a small amount of pyridine, in reaction solution, slowly drip the dichloromethane solution 10mL containing 336mg (1.76mmol) Tosyl chloride, under room temperature, react 48 hours, evaporated under reduced pressure reaction solution, through silica gel column chromatography (sherwood oil: acetoacetic ester 15:1) separated (the S)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4 that obtains, 6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 320mg, yield 29%.
Step 4:(R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
By the 160mg of gained in step 3 (0.26mmol) (S)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone is placed in heavy wall pressure piping, add 3mL (35mmol) Isopropylamine, stir, at 70 ℃, react 2 hours; Cooling rear evaporated under reduced pressure reaction solution, obtains oily matter 100mg.This oily matter is dissolved in 30mL methyl alcohol, add 50mg palladium carbon and 1mL hydrochloric acid, under the pressure of 3atm, carry out catalytic hydrogenation 12 hours, filter, filtrate evaporate to dryness, is prepared HPLC(YMC post by gained oily matter, 22% acetonitrile) separation, obtain (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 30mg, yield 32%.
1H?NMR(500MHz,d 6-DMSO)δ5.90(1H,s,H-3′),5.89(1H,s,H-5′),3.99(1H,dd,J=3.5,8.0Hz,H-1′′a),3.92(1H,overlap,H-1′′b),3.88(1H,m,H-2′′),2.93(1H,dd,J=7.0,16.0Hz,H-3′′a),2.84(1H,dd,J=6.5,16.0Hz,H-3′′a),2.77(1H,m,H-5′′),2.72(1H,dd,J=6.5,13.5Hz,H-2a),2.72(1H,dd,J=7.0,13.5Hz,H-2b),2.13(1H,m,H-3),1.00(3H,d,J=6.0Hz,CH 3-6′′),0.99(3H,d,J=6.0Hz,CH 3-7′′),0.90(3H,d,J=6.5Hz,CH 3-4),0.88(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9,92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 5 (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1:(R)-1-[2-(2,2-dimethyl-DOX-4-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 1 in embodiment 4, adopt 3.00g (7.5mmol) 1-(2-hydroxyl-4,6-hexichol p-methoxy-phenyl)-3-methyl isophthalic acid-butanone, 0.27g (11.3mmol) sodium hydride and 3.39g (22.5mmol) (S)-4-chloromethyl-2,2-dimethyl-1, after the reaction of 3-dioxolane, through silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation obtains (R)-1-[2-(2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 1.20g, yield 31%.
Step 2:(S)-1-[2-(2,3-dihydroxyl propoxy-)-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 2 in embodiment 4, adopt 1.20g (2.38mmol) (R)-1-[2-(2,2-dimethyl-1,3-dioxolane-4-yl) methoxyl group-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone obtains (S)-1-[2-(2,3-dihydroxyl propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 1.06g, yield 96%.
Step 3:(R)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 3 in embodiment 4, adopt the 1.06g (2.28mmol) that obtains in step 2 (S)-1-[2-(2,3-dihydroxyl propoxy-)-4,6-hexichol p-methoxy-phenyl] after the reaction of-3-methyl isophthalic acid-butanone and 434mg (2.28mmol) Tosyl chloride, through silica gel column chromatography (sherwood oil: ethyl acetate 15:1) separated (the R)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4 that obtains, 6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 400mg, yield 37%.
Step 4:(S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 4 in embodiment 4, the 200mg (0.33mmol) that adopts gained in step 3 (R)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain oily matter 120mg.After this oily matter catalytic hydrogenation, through preparative HPLC (YMC post, 22% acetonitrile) separation, obtain (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 45mg, yield 38%.
1H?NMR(500MHz,d 6-DMSO)δ5.90(1H,s,H-3′),5.89(1H,s,H-5′),3.99(1H,dd,J=3.5,8.0Hz,H-1′′a),3.92(1H,overlap,H-1′′b),3.88(1H,m,H-2′′),2.93(1H,dd,J=7.0,16.0Hz,H-3′′a),2.84(1H,dd,J=6.5,16.0Hz,H-3′′a),2.77(1H,m,H-5′′),2.72(1H,dd,J=6.5,13.5Hz,H-2a),2.72(1H,dd,J=7.0,13.5Hz,H-2b),2.13(1H,m,H-3),1.00(3H,d,J=6.0Hz,CH 3-6′′),0.99(3H,d,J=6.0Hz,CH 3-7′′),0.90(3H,d,J=6.5Hz,CH 3-4),0.88(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.7,166.2,165.5,162.3,104.7,95.9,92.2,71.6,68.2,52.3,49.9,48.5,24.5,22.7,22.7,22.6,22.6。
Embodiment 6 (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to step 1-4 in embodiment 3, with 450mg (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group 4,6-hexichol p-methoxy-phenyl] reaction of-3-methyl isophthalic acid-butanone and 3mL (26.8mmol) tert-butylamine obtains solid (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 450mg, yield 81%.
According to step 5 in embodiment 3, by 150mg (0.27mmol) (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride carries out after catalytic hydrogenation, through preparative HPLC (YMC post, 22% acetonitrile) separation, obtain (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 59mg, yield 64%.
1H?NMR(500MHz,d 6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H,dd,J=4.0,9.5Hz,H-1′′a),3.89(1H,overlap,H-1′′b),3.84(1H,m,H-2′′),2.94(1H,dd,J=7.0,16.0Hz,H-3′′a),2.85(1H,dd,J=6.5,16.0Hz,H-3′′b),2.69(1H,dd,J=5.0,12.0Hz,H-2a),2.62(1H,dd,J=6.0,12.0Hz,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=6.5Hz,CH 3-4),0.89(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6,28.6,24.6,22.7,22.6
Embodiment 7 (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-hydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 4 in embodiment 4, the 216mg (0.26mmol) that adopts step 3 gained in embodiment 3 (S)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (26.8mmol) TERTIARY BUTYL AMINE, obtain oily matter 110mg.After this oily matter catalytic hydrogenation, through preparative HPLC (YMC post, 22% acetonitrile) separation, obtain (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 42mg, yield 43%.
1H?NMR(500MHz,d 6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H,dd,J=4.0,9.5Hz,H-1′′a),3.89(1H,overlap,H-1′′b),3.84(1H,m,H-2′′),2.94(1H,dd,J=7.0,16.0Hz,H-3′′a),2.85(1H,dd,J=6.5,16.0Hz,H-3′′b),2.69(1H,dd,J=5.0,12.0Hz,H-2a),2.62(1H,dd,J=6.0,12.0Hz,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=6.5Hz,CH 3-4),0.89(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6,28.6,24.6,22.7,22.6
Embodiment 8 (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 4 in embodiment 4, the 200mg (0.26mmol) that adopts step 3 gained in embodiment 5 (R)-1-[2-(2-hydroxyl-3-tolysulfonyl oxygen base propoxy-)-4,6-hexichol p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (26.8mmol) TERTIARY BUTYL AMINE, obtain oily matter 130mg.After this oily matter catalytic hydrogenation, through preparative HPLC (YMC post, 22% acetonitrile) separation, obtain (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-dihydroxy phenyl]-3-methyl isophthalic acid-butanone hydrochloride 40mg, yield 41%.
1H?NMR(500MHz,d 6-DMSO)δ5.89(1H,br.s,H-3′),5.81(1H,br.s,H-5′),4.01(1H,dd,J=4.0,9.5Hz,H-1′′a),3.89(1H,overlap,H-1′′b),3.84(1H,m,H-2′′),2.94(1H,dd,J=7.0,16.0Hz,H-3′′a),2.85(1H,dd,J=6.5,16.0Hz,H-3′′b),2.69(1H,dd,J=5.0,12.0Hz,H-2a),2.62(1H,dd,J=6.0,12.0Hz,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=6.5Hz,CH 3-4),0.89(3H,d,J=6.5Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ204.4,166.3,166.2,162.3,104.6,95.9,92.3,71.5,68.7,52.3,50.2,45.4,28.6,28.6,28.6,24.6,22.7,22.6.
Embodiment 9 (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
The preparation of step 1:1-(2-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-butanone
1.24g (10mmol) 3-methoxyphenol is dissolved in 30mL boron trifluoride ether solution, add 1.21g (10mmol) isoveryl chloride, reacting by heating 2 hours at 80 ℃ afterwards, after question response liquid cooling but in the liquor kalii acetici of impouring 50mL5%, with the extraction of 3 * 30mL ethyl acetate, merge organic layer, extremely neutral with saturated sodium bicarbonate solution washing, use again the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; After evaporated under reduced pressure solvent, carry out silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation, obtains 1-(2-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-butanone 1.95g, yield 94%.
Step 2:(±)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
The 1.04g obtaining according to step 1 (5mmol) 1-(2-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in 60mL DMF, passes into nitrogen, stir 5 minutes; Add 0.12g (5mmol) sodium hydride, at 40 ℃, react 20 minutes, continue to pass into nitrogen; Add 2.31g (25mmol) (±) 2-chloromethyloxirane, at 90 ℃, react 2 hours; Question response liquid is cooled to after room temperature, in impouring 100mL water, with the extraction of 3 * 50mL ethyl acetate, merges organic layer, with the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; Evaporated under reduced pressure solvent, through silica gel column chromatography (sherwood oil: ethyl acetate 10:1) separation obtains (±)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 0.80g, yield 61%.
Step 3:(±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
By the 264mg of gained in step 2 (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone is placed in heavy wall pressure piping, add 3mL (35mmol) Isopropylamine, stir, at 70 ℃, react 2 hours; Cooling rear evaporated under reduced pressure reaction solution, residue dissolves with 20mL anhydrous diethyl ether, stirs the lower saturated ether solution of hydrogen chloride that drips, and filters, obtain solid (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 70mg, yield 19%.
1H?NMR(500MHz,D 2O)δ7.61(1H,d,J=8.5Hz,H-6′),6.54(1H,dd,J=8.5,1.5Hz,H-5′),6.47(1H,d,J=1.5Hz,H-3′),4.23(1H,m,H-2′′),4.06(2H,d,J=4.5Hz,H-1′′),3.74(3H,s,OCH 3),3.39(1H,m,H-5′′),3.22(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.71(1H,dd,J=3.5,12.0Hz,H-2a),2.65(1H,dd,J=3.5,12.0Hz,H-2b),1.93(1H,m,H-3),1.24(3H,d,J=6.0Hz,CH 3-6′′),1.22(3H,d,J=6.0Hz,CH 3-7′′),0.77(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,132.3,114.0,106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 10 (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
Step 1:(R)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
1.04g (5mmol) 1-obtaining according to the method for step 1 in embodiment 9 (2-hydroxyl-4-p-methoxy-phenyl)-3-methyl isophthalic acid-butanone is dissolved in to 1.2mL N, in the mixing solutions of dinethylformamide and 1.8mL water, add 0.93g (10mmol) (R)-2-chloromethyloxirane drips the aqueous solution 5mL containing 0.40g (10mmol) sodium hydroxide to reaction solution, under room temperature, stirring reaction is 48 hours.3 * 25mL ethyl acetate extraction for reaction solution, merges organic layer, with the washing of 3 * 15mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; Evaporated under reduced pressure solvent, through silica gel column chromatography (sherwood oil: ethyl acetate 10:1) separation obtains (R)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 0.11g, yield 8%.
Step 2:(R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 3 in embodiment 9, with the 60mg (0.23mmol) of gained in step 1 (R)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain solid (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 40mg, yield 48%.
1H?NMR(500MHz,D 2O)δ7.61(1H,d,J=8.5Hz,H-6′),6.54(1H,dd,J=8.5,1.5Hz,H-5′),6.47(1H,d,J=1.5Hz,H-3′),4.23(1H,m,H-2′′),4.06(2H,d,J=4.5Hz,H-1′′),3.74(3H,s,OCH 3),3.39(1H,m,H-5′′),3.22(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.71(1H,dd,J=3.5,12.0Hz,H-2a),2.65(1H,dd,J=3.5,12.0Hz,H-2b),1.93(1H,m,H-3),1.24(3H,d,J=6.0Hz,CH 3-6′′),1.22(3H,d,J=6.0Hz,CH 3-7′′),0.77(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,132.3,114.0,106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 11 (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1:(S)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 1 in embodiment 10, with 1.04g (5mmol) 1-(2-hydroxyl-4-p-methoxy-phenyl)-3 methyl isophthalic acids-butanone, 0.93g (10mmol) (S)-reaction of 2-chloromethyloxirane and 0.40g (10mmol) sodium hydroxide, through silica gel column chromatography (sherwood oil: ethyl acetate 10:1) separation obtains (S)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone 0.13g, yield 9%.
Step 2:(S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 3 in embodiment 9, with the 60mg (0.23mmol) of gained in step 1 (S)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain solid (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 35mg, yield 42%.
1H?NMR(500MHz,D 2O)δ7.61(1H,d,J=8.5Hz,H-6′),6.54(1H,dd,J=8.5,1.5Hz,H-5′),6.47(1H,d,J=1.5Hz,H-3′),4.23(1H,m,H-2′′),4.06(2H,d,J=4.5Hz,H-1′′),3.74(3H,s,OCH 3),3.39(1H,m,H-5′′),3.22(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.71(1H,dd,J=3.5,12.0Hz,H-2a),2.65(1H,dd,J=3.5,12.0Hz,H-2b),1.93(1H,m,H-3),1.24(3H,d,J=6.0Hz,CH 3-6′′),1.22(3H,d,J=6.0Hz,CH 3-7′′),0.77(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,132.3,114.0,106.8,100.7,71.8,69.2,55.6,52.7,49.5,45.4,24.5,22.8,22.8,22.6,22.6。
Embodiment 12 (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 2-3 in embodiment 9, with 264mg (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (28.6mmol) tert-butylamine, obtain solid (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 80mg, yield 21%.
1H?NMR(500MHz,D 2O)δ7.62(1H,d,J=8.5Hz,H-6′),6.53(1H,dd,J=8.5,1.5Hz,H-5′),6.45(1H,d,J=1.5Hz,H-3′),4.27(1H,m,H-2′′),4.11(2H,d,J=4.5Hz,H-1′′),3.65(3H,s,OCH 3),3.30(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.69(1H,dd,J=3.5,11.5Hz,H-2a),2.60(1H,dd,J=3.5,11.5Hz,H-2b),1.90(1H,m,H-3),1.42(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),,0.73(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,166.3,164.5,131.7,112.3,105.7,99.9,72.4,69.5,55.6,52.3,50.4,45.4,28.6,28.6,28.6,24.6,22.6,22.6
Embodiment 13 (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for embodiment 10, with 50mg (0.19mmol) (R)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl] reaction of-3-methyl isophthalic acid-butanone and 3mL (26.8mmol) tert-butylamine, obtain solid (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 25mg, yield 35%.
1H?NMR(500MHz,D 2O)δ7.62(1H,d,J=8.5Hz,H-6′),6.53(1H,dd,J=8.5,1.5Hz,H-5′),6.45(1H,d,J=1.5Hz,H-3′),4.27(1H,m,H-2′′),4.11(2H,d,J=4.5Hz,H-1′′),3.65(3H,s,OCH 3),3.30(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.69(1H,dd,J=3.5,11.5Hz,H-2a),2.60(1H,dd,J=3.5,11.5Hz,H-2b),1.90(1H,m,H-3),1.42(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),,0.73(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,166.3,164.5,131.7,112.3,105.7,99.9,72.4,69.5,55.6,52.3,50.4,45.4,28.6,28.6,28.6,24.6,22.6,22.6
Embodiment 14 (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for embodiment 11, with 60mg (0.23mmol) (S)-1-[2-(epoxy second-2-yl) methoxyl group-4-p-methoxy-phenyl] reaction of-3-methyl isophthalic acid-butanone and 3mL (26.8mmol) tert-butylamine, obtain solid (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 30mg, yield 34%.
1H?NMR(500MHz,D 2O)δ7.62(1H,d,J=8.5Hz,H-6′),6.53(1H,dd,J=8.5,1.5Hz,H-5′),6.45(1H,d,J=1.5Hz,H-3′),4.27(1H,m,H-2′′),4.11(2H,d,J=4.5Hz,H-1′′),3.65(3H,s,OCH 3),3.30(1H,dd,J=3.5,13.0Hz,H-3′′a),3.11(1H,dd,J=8.0,13.5Hz,H-3′′b),2.69(1H,dd,J=3.5,11.5Hz,H-2a),2.60(1H,dd,J=3.5,11.5Hz,H-2b),1.90(1H,m,H-3),1.42(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),,0.73(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13c NMR (125MHz, D 2o) δ 205.0,166.3, and 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 embodiment 15 (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
The preparation of step 1:1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-methyl isophthalic acid-butanone
By 1.54g (10mmol) 3,5-syringol is dissolved in 20mL boron trifluoride ether solution, add 1.21g (10mmol) isoveryl chloride, reacting by heating 2 hours at 80 ℃, in the liquor kalii acetici of impouring 50mL5%, extracts by 3 * 30mL ethyl acetate after question response liquid cooling but afterwards, merge organic layer, extremely neutral with saturated sodium bicarbonate solution washing, then use the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying; After evaporated under reduced pressure solvent, carry out silica gel column chromatography (sherwood oil: ethyl acetate 30:1) separation, obtains 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-methyl isophthalic acid-butanone 1.7g, yield 71%.
Step 2:(±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 2 in embodiment 9, with the 1.00g obtaining in step 1 (4.2mmol) 1-(2-hydroxyl-4,6-Dimethoxyphenyl)-3-methyl isophthalic acid-butanone, 1.94g (21mmol) (±) 2-chloromethyloxirane and the reaction of 0.10g (4.2mmol) sodium hydride, through silica gel column chromatography (sherwood oil: ethyl acetate 30:1) obtain (±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone 0.9g, yield 69%.
Step 3:(±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 3 in embodiment 9,294mg (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group-4 with gained in step 2,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain solid (±)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride 110mg, yield 28%.
1H?NMR(500MHz,D 2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H-2′′),3.92(2H,d,J=4.5Hz,H-1′′),3.67(3H,s,OCH 3),3.62(3H,s,OCH 3),3.33(1H,m,H-5′′),3.08(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.56(2H,br.d,J=7.0Hz,H-2),1.86(1H,m,H-3),1.18(3H,d,J=6.5Hz,CH 3-6′′),1.17(3H,d,J=6.5Hz,CH 3-7′′),0.72(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6,22.6。
Embodiment 16 (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1:(R)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 1 in embodiment 10, with 1.00g (4.2mmol) 1-(2-hydroxyl-4 that obtain in embodiment 15 steps 1,6-Dimethoxyphenyl)-3-methyl isophthalic acid-butanone, 1.94g (21mmol) (R)-reaction of 2-chloromethyloxirane and 0.10g (4.2mmol) sodium hydroxide, through silica gel column chromatography (sherwood oil: ethyl acetate 30:1) obtain (R)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone 0.30g, yield 24%.
Step 2:(R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 2 in embodiment 10, with the 150mg (0.51mmol) of gained in step 1 (R)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain solid (R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride 130mg, yield 65%.
1H?NMR(500MHz,D 2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H-2′′),3.92(2H,d,J=4.5Hz,H-1′′),3.67(3H,s,OCH 3),3.62(3H,s,OCH 3),3.33(1H,m,H-5′′),3.08(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.56(2H,br.d,J=7.0Hz,H-2),1.86(1H,m,H-3),1.18(3H,d,J=6.5Hz,CH 3-6′′),1.17(3H,d,J=6.5Hz,CH 3-7′′),0.72(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6,22.6。
Embodiment 17 (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
Step 1:(S)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone
According to the method for step 1 in embodiment 11, with 1.00g (4.2mmol) 1-(2-hydroxyl-4 that in embodiment 15, step 1 obtains, 6-Dimethoxyphenyl)-3-methyl isophthalic acid-butanone, 1.94g (21mmol) (R)-reaction of 2-chloromethyloxirane and 0.10g (4.2mmol) sodium hydroxide, through silica gel column chromatography (sherwood oil: ethyl acetate 30:1) obtain (S)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone 0.27g, yield 22%.
Step 2:(R)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for step 2 in embodiment 11, with the 130mg (0.44mmol) of gained in step 1 (S)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (35mmol) Isopropylamine, obtain solid (S)-1-[2-(2-hydroxyl-3-isopropylamine base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride 100mg, yield 58%.
1H?NMR(500MHz,D 2O)δ6.15(1H,br.s,H-5′),6.09(1H,br.s,H-3′),4.10(1H,m,H-2′′),3.92(2H,d,J=4.5Hz,H-1′′),3.67(3H,s,OCH 3),3.62(3H,s,OCH 3),3.33(1H,m,H-5′′),3.08(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.56(2H,br.d,J=7.0Hz,H-2),1.86(1H,m,H-3),1.18(3H,d,J=6.5Hz,CH 3-6′′),1.17(3H,d,J=6.5Hz,CH 3-7′′),0.72(6H,d,J=6.5Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.0,165.7,165.3,162.7,105.8,92.9,90.8,71.8,69.2,56.0,55.9,52.7,49.5,48.7,24.5,22.7,22.7,22.6,22.6。
Embodiment 18 (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for embodiment 15, with 294mg (1mmol) (±)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (26.8mmol) tert-butylamine, obtain solid (±)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone hydrochloride 200mg, yield 49%.
1H?NMR(500MHz,D 2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H-2′′),3.99(2H,d,J=4.5Hz,H-1′′),3.73(3H,s,OCH 3),3.68(3H,s,OCH 3),3.33(1H,m,H-5′′),3.13(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.63(1H,br.d,J=7.0Hz,H-2),1.91(1H,m,H-3),1.41(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),0.76(6H,d,J=7.0Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5,72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
Embodiment 19 (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for embodiment 16, with 150mg (0.51mmol) (R)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (26.8mmol) tert-butylamine, obtain solid (R)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 128mg, yield 62%.
1H?NMR(500MHz,D 2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H-2′′),3.99(2H,d,J=4.5Hz,H-1′′),3.73(3H,s,OCH 3),3.68(3H,s,OCH 3),3.33(1H,m,H-5′′),3.13(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.63(1H,br.d,J=7.0Hz,H-2),1.91(1H,m,H-3),1.41(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),0.76(6H,d,J=7.0Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5,72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
Embodiment 20 (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4,6-Dimethoxyphenyl] preparation of-3-methyl isophthalic acid-butanone hydrochloride
According to the method for embodiment 17, with 130mg (0.44mmol) (S)-1-[2-(epoxy second-2-yl) methoxyl group-4,6-Dimethoxyphenyl]-3-methyl isophthalic acid-butanone and the reaction of 3mL (26.8mmol) tert-butylamine, obtain solid (S)-1-[2-(2-hydroxyl-3-TERTIARY BUTYL AMINE base propoxy-)-4-p-methoxy-phenyl]-3-methyl isophthalic acid-butanone hydrochloride 135mg, yield 76%.
1H?NMR(500MHz,D 2O)δ6.23(1H,br.s,H-5′),6.16(1H,br.s,H-3′),4.11(1H,m,H-2′′),3.99(2H,d,J=4.5Hz,H-1′′),3.73(3H,s,OCH 3),3.68(3H,s,OCH 3),3.33(1H,m,H-5′′),3.13(1H,dd,J=3.0,13.0Hz,H-3′′a),2.96(1H,dd,J=9.0,13.0Hz,H-3′′b),2.63(1H,br.d,J=7.0Hz,H-2),1.91(1H,m,H-3),1.41(9H,s,CH 3-6′′,CH 3-7′′,CH 3-8′′),0.76(6H,d,J=7.0Hz,CH 3-4,CH 3-5)。 13C?NMR(125MHz,D 2O)δ205.1,165.5,165.4,162.3,104.9,93.0,90.5,72.8,68.7,55.8,55.6,52.8,50.8,45.4,28.7,28.7,28.7,24.6,22.6,22.6。
The preparation of embodiment 21 4-(piperidin-1-yl)-1-(2,4,6-trihydroxy-phenyl)-1-butanone hydrochloride
The preparation of step 1:4-(piperidin-1-yl) butyronitrile
By 2.58g(25mmol) 4-chlorobutyronitrile is dissolved in 5mL acetonitrile, adds 3.5g(25mmol) Anhydrous potassium carbonate and a small amount of sodium iodide, slowly splash into 2.13g (25mmol) piperidines, under room temperature, stir 20h.Evaporated under reduced pressure solvent, adds 10mL water dissolution in resistates, with the extraction of 3 * 15mL ethyl acetate, merge organic layer, with the washing of 2 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, obtains oily liquids 3.30g.
The preparation of step 2:4-(piperidin-1-yl)-1-(2,4,6-trihydroxy-phenyl)-1-butanone hydrochloride
1.33g Phloroglucinol (10.5mmol) is dissolved in 10mL oil of mirbane, adds gained oily matter 1.60g in step 1, pass into dry HCl gas, under room temperature, stir 12h.Reaction solution is placed and is spent the night, and filters, and solid is dissolved in 10mL water to reflux 1h.Cooling, filter, gained is alcohol-water (4:1) recrystallization for solid, obtains 4-(piperidin-1-yl)-1-(2,4,6-trihydroxy-phenyl)-1-butanone hydrochloride 0.67g, yield 20%.
1H?NMR(500MHz,d 6-DMSO)δ12.23(2H,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=11.5Hz,H-2′′a,H-6′′a),3.08(2H,t,J=6.5Hz,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=14.0Hz,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?NMR(125MHz,d 6-DMSO)δ202.8,164.5,163.9,163.9,103.4,94.3,94.3,55.2,51.8,51.8,38.7,22.3,22.3,21.0,17.9。
The preparation of embodiment 22 4-(methylcyclohexyl amine)-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride
The preparation of step 1:4-(methylcyclohexyl amine) butyronitrile
According to the method for step 1 in embodiment 21, with 1.98g(19.2mmol) 4-chlorobutyronitrile, 2.56g(19.2mmol) Anhydrous potassium carbonate and a small amount of NaI, and obtain oily liquids 4.00g after the reaction of 2.17g (19.2mmol) methylcyclohexyl amine.
The preparation of step 2:4-(methylcyclohexyl amine)-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride
1.05g Phloroglucinol (8.33mmol) is dissolved in 10mL oil of mirbane, adds gained oily matter 1.5g in step 1, pass into dry HCl gas, under room temperature, stir 9h.Reaction solution adds 15mL water after placing and spending the night, minute water-yielding stratum, 2 * 15mL water extraction for organic layer, combining water layer, reflux 1h.Cooling, filter, gained is alcohol-water (4:1) recrystallization for solid, obtains 4-(methylcyclohexyl amine)-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride 0.30g, yield 11%.
1H?NMR(500MHz,d 6-DMSO)δ5.81(2H,s,H-3′,H-5′),2.98(2H,t,J=7.0Hz,H-2),2.44(2H,t,J=7.0Hz,H-4),2.35(1H,m,H-1′′),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=12.5Hz,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(125MHz,d 6-DMSO)δ204.9,164.8,164.7,164.7,104.4,94.7,94.7,62.1,52.3,40.3,37.0,27.8,27.8,25.9,25.4,25.4,22.6。
Embodiment 23 4-[4-(3-chloro-phenyl-) piperazine-1-yl] preparation of-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride
Step 1:4-[4-(3-chloro-phenyl-) piperazine-1-yl] preparation of butyronitrile
According to the method for step 1 in embodiment 21, with 1.35g (13mmol) 4-chlorobutyronitrile, 1.80g (15mmol) Anhydrous potassium carbonate and a small amount of NaI, and obtain oily liquids 4.00g after the reaction of 2.90g (15mmol) 4-(3-chloro-phenyl-) piperazine.
Step 2:4-[4-(3-chloro-phenyl-) piperazine-1-yl] preparation of-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride
1.05g Phloroglucinol (8.33mmol) is dissolved in 10mL oil of mirbane, adds gained oily matter 3.00g in step 1, pass into dry HCl gas, under room temperature, stir 9h.Reaction solution adds 15mL water after placing and spending the night, minute water-yielding stratum, 2 * 15mL water extraction for organic layer, combining water layer, reflux 1h.Cooling, filter, gained is alcohol-water (5:1) recrystallization for solid, obtains 4-(methylcyclohexyl amine)-1-(2,4,6-trihydroxy-phenyl) 1-butanone hydrochloride 0.45g, yield 13%.
1H?NMR(500MHz,d 6-DMSO)δ12.21(2H,s,OH-2′,OH-6′),10.43(1H,s,OH-4′),7.26(1H,t,J=8.0Hz,H-5′′′),7.05(1H,br.s,H-H-2′′′),6.96(1H,br.d,J=8.0Hz,H-H-4′′′),6.87(1H,br.d,J=8.0Hz,H-6′′′),5.82(2H,s,H-3′,H-5′),3.90(2H,br.d,J=12.5Hz,H-2′′a,H-6′′a),3.59(2H,br.d,J=11.5Hz,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=6.5Hz,H-2),3.01(2H,t,J=11.5Hz,H-4),1.99(2H,m,H-3)。 13C?NMR(125MHz,d 6-DMSO)δ203.0,164.8,164.1,164.1,150.7,133.9,130.6,119.2,115.2,114.1,103.6,94.6,94.6,55.1,50.5,50.5,44.9,44.9,38.9,18.2。
The preparation of embodiment 24 (S)-2-(2,4,6-trimethoxy-benzene methylamino) propionic acid
The preparation of step 1:(S)-2-(2,4,6-trimethoxy-benzene methylamino) methyl propionate
By 196mg (1mmol) 2,4,6-TMB is dissolved in 10mL methyl alcohol, adds 76mg (1.2mmol) NaBH 3cN and 280mg (2mmol) alanine methyl ester hydrochloride, argon shield, stirs 3h under room temperature.In reaction solution, add 20mL water, with the extraction of 3 * 25mL ethyl acetate, merge organic layer, with the washing of 3 * 10mL saturated nacl aqueous solution, anhydrous sodium sulfate drying.Solvent evaporated, carries out silica gel column chromatography (sherwood oil: ethyl acetate 4:1) separation obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino) methyl propionate 118mg, yield 42%.
The preparation of step 2:(S)-2-(2,4,6-trimethoxy-benzene methylamino) propionic acid
The 100mg that step 1 is obtained (0.35mmol) (S)-2-(2,4,6-trimethoxy-benzene methylamino) methyl propionate is dissolved in 20mL5%KOH ethanol water (EtOH:H 2o=1:1) in solution, under room temperature, stir 2h, add Amberlite120H +resin, is stirred to pH value of solution=7, filters, and filtrate is concentrated, through preparative HPLC (YMC, 20% acetonitrile) purifying, obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino) propionic acid 85mg, yield 90%.
1H?NMR(500MHz,d 6-DMSO)δ6.27(2H,s,H-3′,H-5′),4.07(2H,br.s,H-1),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=6.0Hz,CH 3-5)。 13C?NMR(125MHz,d 6-DMSO)δ170.8,162.5,159.7,159.7,99.3,90.7,90.7,55.9,55.9,55.6,54.0,37.7,15.2。
The preparation of embodiment 25 (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid
The preparation of step 1:(S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid methyl esters
According to the method for step 1 in embodiment 24, with 196mg (1mmol) 2,4,6-TMB, 76mg (1.2mmol) NaBH 3after the reaction of CN and 520mg (2mmol) phenylalanine methyl ester hydrochloride, through silica gel column chromatography (sherwood oil: ethyl acetate 10:1) separation obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid methyl esters 136mg, yield 38%.
The preparation of step 2:(S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid
According to the method for step 2 in embodiment 24, the 100mg obtaining by step 1 (0.28mmol) (S)-2-(2,4,6-trimethoxy-benzene methylamino) after-3-phenylpropionic acid methyl esters reaction, through preparative HPLC (YMC, 30% acetonitrile) purifying, obtain (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-phenylpropionic acid 85mg, yield 88%.
1H?NMR(500MHz,d 6-DMSO)δ7.32(2H,t,J=7.5Hz,H-3′′,H-5′′),7.26(1H,t,J=8.0Hz,H-4′′),7.22(2H,d,J=7.5Hz,H-2′′,H-6′′),6.27(2H,s,H-3′,H-5′),4.07(2H,br.s,H-1),3.91(1H,br.s,H-3),3.80(3H,s,OCH3-4′),3.78(6H,s,OCH 3-2′,OCH 3-6′),3.32(1H,dd,J=13.5,4.5Hz,H-5a),3.09(1H,dd,J=13.5,8.0Hz,H-5b) 13C?NMR(125MHz,d 6-DMSO)δ169.2,162.4,159.6,159.6,134.8,129.3,129.3,128.4,128.4,127.1,98.8,90.6,90.6,59.3,55.8,55.8,55.4,38.3,34.9。
The preparation of embodiment 26 (S)-2-(2,4,6-trimethoxy-benzene methylamino)-5-amino-5-oxy pentanoic acid
The preparation of step 1:(S)-2-(2,4,6-trimethoxy-benzene methylamino) Methyl glutarate
According to the method for step 1 in embodiment 24, with 196mg (1mmol) 2,4,6-TMB, 76mg (1.2mmol) NaBH 3after the reaction of CN and 410mg (2mmol) glutamic acid dimethyl ester hydrochloride, through silica gel column chromatography (sherwood oil: ethyl acetate 1:1) separation obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino)-4-amino-4-oxy butyrate methyl esters 165mg, yield 50%.
The preparation of step 2:(S)-2-(2,4,6-trimethoxy-benzene methylamino) pentanedioic acid
According to the method for step 2 in embodiment 24, the 100mg obtaining by step 1 (0.31mmol) (S)-2-(2,4,6-trimethoxy-benzene methylamino) after the reaction of-5-amino-5-oxy butyrate methyl esters, through preparative HPLC (YMC, 13% acetonitrile) purifying, obtain (S)-2-(2,4,6-trimethoxy-benzene methylamino) pentanedioic acid 91mg, yield 95%.
1H?NMR(500MHz,d 6-DMSO)δ6.26(2H,s,H-3′,H-5′),4.03(1H,d,J=13.0Hz,H-1a),3.97(1H,d,J=13.0Hz,H-1b),3.79(6H,s,OCH 3-2′,OCH 3-6′),3.78(3H,s,OCH 3-4′),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(125MHz,d 6-DMSO)δ173.7,169.9,162.3,159.6,159.6,99.8,90.7,90.7,58.8,55.9,55.9,55.5,38.5,30.3,24.9。
The preparation of embodiment 27 (S)-2-(2,4,6-trimethoxy-benzene methylamino) succinic acid
The preparation of step 1:(S)-2-(2,4,6-trimethoxy-benzene methylamino) dimethyl succinate
According to the method for step 1 in embodiment 24, with 196mg (1mmol) 2,4,6-TMB, 76mg (1.2mmol) NaBH 3after the reaction of CN and 420mg (2mmol) aspartic acid dimethyl ester hydrochloride, through silica gel column chromatography (sherwood oil: ethyl acetate 5:1) separation obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino) dimethyl succinate 155mg, yield 46%.
The preparation of step 2:(S)-2-(2,4,6-trimethoxy-benzene methylamino) succinic acid
According to the method for step 2 in embodiment 24, the 100mg obtaining by step 1 (0.29mmol) (S)-2-(2,4,6-trimethoxy-benzene methylamino) after dimethyl succinate reaction, through preparative HPLC (YMC, 9% acetonitrile) purifying, obtain (S)-2-(2,4,6-trimethoxy-benzene methylamino) succinic acid 75mg, yield 85%.
1H?NMR(500MHz,d 6-DMSO)δ6.28(2H,s,H-3′,H-5′),4.17(1H,d,J=13.0Hz,H-1a),4.13(1H,d,J=13.0Hz,H-1b),3.99(1H,t,J=6.0Hz,H-3),3.80(3H,s,OCH 3-4′),3.79(6H,s,OCH 3-2′,OCH 3-6′),2.84(2H,br.s,H-5)。 13C?NMR(125MHz,d 6-DMSO)δ171.1,169.2,162.5,159.6,159.6,99.2,90.8,90.8,56.0,56.0,55.5,54.7,39.0,34.0。
The preparation of embodiment 28 (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy-propionic acid
The preparation of step 1:(S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy methyl propionate
According to the method for step 1 in embodiment 24, with 196mg (1mmol) 2,4,6-TMB, 76mg (1.2mmol) NaBH 3after the reaction of CN and 310mg (2mmol) serine methyl ester hydrochloride, through silica gel column chromatography (sherwood oil: ethyl acetate 1:1) separation obtains (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy methyl propionate 110mg, yield 37%.
The preparation of step 2:(S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy-propionic acid
According to the method for step 2 in embodiment 24, the 100mg obtaining by step 1 (0.33mmol) (S)-2-(2,4,6-trimethoxy-benzene methylamino) after-3-hydroxy methyl propionate reaction, through preparative HPLC (YMC, 13% acetonitrile) purifying, obtain (S)-2-(2,4,6-trimethoxy-benzene methylamino)-3-hydroxy-propionic acid 86mg, yield 92%.
1H?NMR(500MHz,d 6-DMSO)δ6.27(2H,s,H-3′,H-5′),4.10(2H,br.s,H-1),3.85(1H,overlap,H-5a),3.85(1H,overlap,H-5b),3.79(6H,s,OCH 3-2′,OCH 3-6′),3.78(3H,s,OCH 3-4′),3.48(1H,br.s,H-3)。 13C?NMR(125MHz,d 6-DMSO)δ168.4,162.3,159.7,159.7,99.4,90.8,90.8,60.8,59.3,56.0,56.0,55.5,38.7。
The preparation of embodiment 29 (S)-2-(2,4,6-trihydroxybenzene methylamino)-3-(1H-imidazoles-5-yl) propionic acid
The preparation of step 1:(S)-2-(2,4,6-trihydroxybenzene methylamino)-3-(1H-imidazoles-5-yl) methyl propionate
According to the method for step 1 in embodiment 24, with 196mg (1mmol) 2,4,6-TMB, 76mg (1.2mmol) NaBH 3after the reaction of CN and 411mg (2mmol) Histidine methyl ester hydrochloride, through silica gel column chromatography (methylene dichloride: methyl alcohol 10:1) separation obtains (S)-2-(2,4,6-trihydroxybenzene methylamino)-3-(1H-imidazoles-5-yl) methyl propionate 97mg, yield 28%.
The preparation of step 2:(S)-2-(2,4,6-trihydroxybenzene methylamino)-3-(1H-imidazoles-5-yl) propionic acid
According to the method for step 2 in embodiment 24, the 97mg obtaining by step 1 (0.28mmol) (S)-2-(2,4,6-trihydroxybenzene methylamino) after the reaction of-3-(1H-imidazoles-5-yl) methyl propionate, through preparative HPLC (YMC, 10% acetonitrile) purifying, obtain (S)-2-(2,4,6-trihydroxybenzene methylamino)-3-(1H-imidazoles-5-yl) propionic acid 70mg, yield 74%.
1H?NMR(500MHz,d 6-DMSO)δ7.95(1H,s,H-3′′),7.47(1H,s,H-5′′),6.29(2H,s,H-3′,H-5′),4.13(1H,d,J=13.5Hz,H-1a),4.07(1H,d,J=13.5Hz,H-1b),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=15.5,6.0Hz,H-5a),3.24(1H,dd,J=15.5,8.0Hz,H-5b) 13C?NMR(125MHz,d 6-DMSO)δ168.9,162.6,159.8,159.8,134.5,127.6,117.8,99.1,90.8,90.8,57.4,55.9,55.9,55.6,38.5,24.8。
Pharmacological evaluation
Experimental example 1
(1) materials and methods:
Material: BV2 cell (mouse microglia system)
Griess reagent: prepare 0.1% naphthodiamide with distilled water, prepare 1% Sulphanilic Acid with 5% phosphoric acid, both are mixing with 1:1 equal-volume before use
Curcumine, with DMSO preparation, final concentration is 10 -5, 10 -6, 10 -7mol/L
Lipopolysaccharides, with aseptic PBS preparation, final concentration is 300ng/mL
Test-compound, with DMSO preparation, final concentration is 10 -5, 10 -6, 10 -7mol/L
Method:
1) BV2 cell is in cultivating containing in the DMEM-F12 substratum of 10% new-born calf serum, in 37 ° of C, 5%CO 2/ 95% air, grows under 100% relative humidity.
2) the BV2 cell of logarithmic phase, after digestion counting, with 2 * 10 4individual/hole is inoculated in 96 orifice plates, adds test-compound and the positive control drug curcumine (10 of different concns after 24 hours -5, 10 -6, 10 -7m), after 1 hour, add LPS, final concentration is 300ng/mL, continues to cultivate 24 hours, collects medium supernatant.
3) get the clear 100 μ L of liquid on cell culture fluid, add equal-volume Griess reagent, the standing 20min of room temperature, OD value is measured in distilled water zeroing in microplate reader at 540nm place, take SODIUMNITRATE as standard substance simultaneously, measures OD value, calculates NO in testing sample 2 -the concentration of concentration reflection NO.
(2) result (table 1)
Table 1
Conclusion: a plurality of test-compounds have all shown the activity (1 * 10 of good inhibition microglia -5under mol/L concentration, inhibiting rate >50%), wherein embodiment 1,2, and the activity of 26,28 compounds that represent is suitable with positive control medicine curcumine.
Experimental example 2
(1) materials and methods:
Material: the SD rat embryo of pregnant 18d
Lipopolysaccharides, with aseptic PBS preparation, final concentration is 100ng/mL
A β 25-35, with aseptic PBS preparation, at 37 ℃ aging 7 days, final concentration was 2.5 * 10 -5mol/L
Curcumine, with DMSO preparation, final concentration is 10 -5mol/L
E2020, with DMSO preparation, final concentration is 5 * 10 -6mol/L
Test-compound (embodiment 6,27,45,47), with DMSO preparation, final concentration is 10 -5, 10 -6, 10 -7mol/L
ELISA test kit (R & D company)
LDH detection reagent (biological reagent company is built up in Nanjing)
Method:
1) foundation of primary hippocampal neurons/spongiocyte co-culture system: the SD rat embryo of pregnant 18d, separated hippocampus, blows and beats with transfer pipet under anatomical lens, until can't see tissue block, is inoculated in 24 orifice plates after filtration.
2) cell administration is processed: after above-mentioned primary cell culture 7d, respectively with test-compound (10 -5, 10 -6, 10 -7mol/L) or positive control drug curcumine (10 -5mol/L), E2020 (5 * 10 -6mol/L) hatch altogether, after 3h, add stimulant LPS100ng/mL or A β 25-352.5 * 10 -5mol/L, gets substratum and surveys IL-1 β and TNF-α after 5h.
3) cell, after drug treating 7d, is collected substratum and is detected LDH.
(2) result
1) restraining effect (table 2) of the neural inflammation that compound causes LPS
Table 2
Conclusion: embodiment 1,2,26 and 28 compounds that represent can obviously suppress the inflammatory reaction that hippocampal neuron/spongiocyte co-culture system occurs under LPS stimulates, and reduce the level of IL-1 β, two kinds of cytokines of TNF-α in substratum, 10 -5under mol/L concentration, suitable with positive control drug curcumine to the inhibition degree of inflammation.
2) compound is to A β 25-35the restraining effect (table 3) of the neural inflammation causing
Table 3
Conclusion: embodiment 1,2,26 and 28 compounds that represent can obviously suppress hippocampal neuron/spongiocyte co-culture system at A β 25-35stimulate the lower inflammatory reaction occurring, reduce the level of IL-1 β, two kinds of cytokines of TNF-α in substratum, 10 -5under mol/L concentration, suitable with positive control drug curcumine to the inhibition degree of inflammation.
3) provide protection (table 4) of the neuronal damage that compound causes LPS
(table 4)
Conclusion: hippocampal neuron/spongiocyte co-culture system is under the stimulation of LPS, and the burst size of LDH obviously increases, shows that damage appears in neurone.And embodiment 1,2,26 and 28 compounds that represent can obviously suppress the release of LDH, neurone is had to provide protection, 10 -5under mol/L concentration, the inhibition degree that LDH is discharged is suitable with positive control drug curcumine.
4) compound is to A β 25-35the provide protection (table 5) of the neuronal damage causing
(table 5)
Conclusion: hippocampal neuron/spongiocyte co-culture system is at A β 25-35stimulation under, the burst size of LDH obviously increases, and shows that damage appears in neurone.And embodiment 1,2,26 and 28 compounds that represent can obviously suppress the release of LDH, neurone is had to provide protection, 10 -5under mol/L concentration, the inhibition degree that LDH is discharged is suitable with positive control drug E2020.
Experimental example 3
(1) materials and methods:
Material: newborn SD rat
Deionized water preparation for cytosine arabinoside (Ara-C), filtration sterilization, final concentration is 4m mol/L
A β 25-35, with aseptic PBS preparation, at 37 ℃ aging 7 days, final concentration was 2.5 * 10 -5mol/L
E2020, with DMSO preparation, final concentration is 5 * 10 -6mol/L
Test-compound (embodiment 6,27,45,47), with DMSO preparation, final concentration is 10 -5, 10 -6, 10 -7mol/L
Method:
1) foundation of primary simple hippocampal neuron culture system: newborn SD rat, under anatomical lens, separated hippocampus, adds tryptic digestion, stops, after digestion, blowing and beating with transfer pipet, until can't see tissue block, filters, and is inoculated in 96 orifice plates after centrifugal.After 48h, add Ara-C, suppress spongiocyte growth.
4) cell administration is processed: after above-mentioned primary cell culture 7d, respectively with test-compound (10 -5, 10 -6, 10 -7mol/L) or positive control drug E2020 (5 * 10 -6mol/L) hatch altogether, after 3h, add stimulant A β 25-352.5 * 10 -5mol/L.
5) cell is after drug treating 7d, and sucking-off nutrient solution adds the MTT of the substratum preparation of serum-free, and final concentration is 0.5mg/mL, and 37 ℃ are continued to cultivate after 4h, add 150 μ L methyl-sulphoxides and dissolve MTT, at 570nm place, read absorption value.Take cellular control unit survival rate as 100%, calculate the survival rate of different treatment group cell.
(2) result
Compound is to A β 25-35cause the provide protection (table 6) of neuronal damage
Table 6
Conclusion: the neurone of the simple former culture of hippocampus is at A β 25-35stimulation under, neuron survival rate obviously reduces, the compounds that embodiment 1,2,26 and 28 represents can obviously improve neuronic survival rate, 10 -5under mol/L concentration, cell survival rate raising degree is better than to positive control drug E2020.

Claims (11)

1. represented compound, its pharmacy acceptable salt of formula I:
It is characterized in that,
1) described compound is the compound representing by general formula I A, and pharmacy acceptable salt,
Wherein, R athe C of expression replacement or not substituted straight chain or side chain 1-10alkyl, benzyl ,-NO 2,-COR a1,
Be selected from-OH of substituting group ,-F ,-Cl ,-Br, alkoxyl group ,-SH, replacement or unsubstituted furazan base or-COOH, wherein
Substituting group is selected from the C of straight or branched 1-10alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzenesulfonyl, wherein
The C of can be selected from-OH of the substituting group on phenyl and benzenesulfonyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R a1the optional C from replacement or unsubstituted straight or branched 2-10alkyl, wherein
Can be selected from-OH of substituting group on alkyl ,-F ,-Cl ,-Br, replacement or unsubstituted phenyl ,-COOH or-NH 2, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group;
Or
2), described compound is the compound representing by general formula I B, and pharmacy acceptable salt:
Wherein, R 3and R 5the C of respectively independent expression-H ,-OH, straight or branched 1-6alkyl ,-ONO 2,-OR cor-SR c, wherein
R cthe C of expression replacement or not substituted straight chain or side chain 1-10alkyl, benzyl,
Can be selected from-OH of described substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-NH 2,-COOH
R b1, R b2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR b1r b2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group;
Or
3), described compound is the compound representing by general formula I C, and pharmacy acceptable salt:
Wherein, R d1, R d2and R d3the C of respectively independent expression-H, straight or branched 2-6alkyl, benzyl or-CF 3
N can be 2-5
R e1, R e2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR e1r e2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic (except morpholine ring), on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group;
Or
4), described compound is the compound representing by general formula I D, and pharmacy acceptable salt:
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-6alkyl, benzyl or-CF 3,
R 2, R 4respectively independent expression-H ,-OH, alkoxyl group ,-OCF 3,-ONO 2,-F ,-Cl ,-Br ,-CN ,-NO 2, replace or the C of substituted straight chain or side chain not 1-10alkyl ,-CF 3,-COR g, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH,
R gthe C that can represent H ,-OH, straight or branched 1-10alkyl, replacement or unsubstituted phenyl, containing the C of ethylene linkage or acetylene bond 1-10unsaturated alkyl or-NR g1r g2, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R g1, R g2independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl, C 3-6cycloalkyl or-NR g1r g2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,
N can be the integer of 1-5;
R 6can represent H, replacement or the C of substituted straight chain or side chain not 1-10alkyl, C 3-6cycloalkyl or and R 7, R 8and four-seven yuan of connected C atom and N atomic buildings containing 1-3 heteroatomic saturated heterocyclic, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2
R 7with R 8independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl or and R 6and four-seven yuan of connected C atom and N atomic buildings containing 1-3 heteroatomic saturated heterocyclic, condition is R 7with R 8can not be H, wherein simultaneously
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl.
2. according to the compound of claim 1, and pharmacy acceptable salt: it is characterized in that described R aunsubstituted C in definition 1-10alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl.
3. according to the compound of claim 1, and pharmacy acceptable salt: it is characterized in that R arepresent following general formula I Aa
Wherein, n is selected from the integer of 1-5;
R a2can be selected from the C of straight or branched 1-10alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzenesulfonyl, wherein
The C of can be selected from-OH of the substituting group on phenyl and benzenesulfonyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group.
4. according to the compound of claim 1, and pharmacy acceptable salt: it is characterized in that, described compound as shown in general formula I Ca,
Wherein, R e1, R e2independently represent respectively the C of H, straight or branched 1-6alkyl, C 3-6cycloalkyl or-NR e1r e2form five yuan, hexa-atomic or seven yuan containing 1-3 heteroatomic saturated heterocyclic (except morpholine ring), on heterocycle, can have substituting group, wherein
The C of can be selected from-OH of substituting group ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl, C 3-6cycloalkyl, alkoxyl group, replacement or unsubstituted phenyl, wherein
The C of can be selected from-OH of the substituting group on phenyl ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-6alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2,-NH 2or alkoxyl group.
5. according to the compound of claim 1, and pharmacy acceptable salt: it is characterized in that, described compound is shown in general formula I Da
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-6alkyl, benzyl or-CF 3
R 6can represent H, replacement or the C of substituted straight chain or side chain not 1-10alkyl, C 3-6cycloalkyl, wherein
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2
R 7with R 8independent H, replacement or the C of substituted straight chain or side chain not of representing respectively 1-10alkyl, condition is R 7with R 8can not be H, wherein simultaneously
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl.
6. according to the compound of claim 5, and pharmacy acceptable salt: it is characterized in that, described compound is as shown in general formula I Da1:
Wherein, R 7the C of expression replacement or not substituted straight chain or side chain 1-10alkyl
Can be selected from-OH of substituting group, alkoxyl group ,-F ,-Cl ,-Br ,-COOH ,-NH 2,-SH ,-SR h,-CONH 2, guanidine radicals, replacement or unsubstituted phenyl and heterocyclic base, wherein
The C of can be selected from-OH of the substituting group on phenyl and heterocyclic base ,-F ,-Cl ,-Br ,-COOH, straight or branched 1-10alkyl ,-CHF 2,-CF 3,-CN ,-NO 2,-OCF 3,-ONO 2or alkoxyl group
R hthe C that represents straight or branched 1-10alkyl.
7. according to the compound of claim 1, and pharmacy acceptable salt: it is characterized in that, described compound is as shown in general formula I Db
Wherein, R f1, R f2, R f3the C of respectively independent expression-H, straight or branched 1-10alkyl, benzyl or-CF 3
N atom and ortho position C atom participate in forming 1-3 the heteroatomic saturated heterocyclic that contain of four-seven yuan jointly.
8. a pharmaceutical composition, is characterized in that, the arbitrary compound as described in claim 1-7 and the pharmaceutically acceptable carrier that contain effective dose.
9. pharmaceutical composition according to Claim 8, is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
10. the application of the compound as described in claim 1-7 in preparation control nerve degenerative diseases medicine.
11. application as claimed in claim 10, is characterized in that described nerve degenerative diseases is selected from alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, ataxia hair and blood enlargement of pipe disease, mad cow disease, gram refined Er Shi disease, Huntington's disease, cerebellar atrophy disease, primary lateral sclerosis, spinal muscular atrophy.
CN201310166868.4A 2013-05-08 2013-05-08 Phloroglucinol derivative and use thereof in treatment of neurodegenerative diseases Pending CN104140365A (en)

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