CN108069898A - The ester derivant of capsaicine containing niacin, preparation method and its usage - Google Patents
The ester derivant of capsaicine containing niacin, preparation method and its usage Download PDFInfo
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- CN108069898A CN108069898A CN201611008597.XA CN201611008597A CN108069898A CN 108069898 A CN108069898 A CN 108069898A CN 201611008597 A CN201611008597 A CN 201611008597A CN 108069898 A CN108069898 A CN 108069898A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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Abstract
The present invention provides a kind of ester derivants of capsaicine containing niacin with general structure I and its manufacturing method and this analog derivative to have analgesia, antitumor, anti-inflammatory, antiatherosclerosis, reducing blood lipid, promotion appetite, improvement digestion, antibacterial desinsection, anti-oxidant, anti-virus aspect purposes.
Description
Technical field
Have the present invention relates to a kind of ester derivant of capsaicine containing niacin and its manufacturing method and this analog derivative ease pain,
Antitumor, anti-inflammatory, antiatherosclerosis, reducing blood lipid promote appetite, improve digestion, antibacterial desinsection, anti-oxidant, antiviral side
The purposes in face.
Background technology
Capsaicine is a kind of main active in pepper fruit pungency component, such substance is in chemical industry at present
As being used widely in additive and medical industry.Capsaicine has analgesia, antitumor, anti-inflammatory, anti-atherogenic is hard
Change, reducing blood lipid promote appetite, improve digestion, antibacterial desinsection, anti-oxidant, antivirus action and have selectivity to neurotransmitter
Etc. a variety of pharmacological activity and pharmacological action.Capsaicine has good analgesic activity, but due to the poorly water-soluble of capsaicine, takes orally
It is difficult to absorb and irritation is big, limit its application.In addition, further investigation revealed that the activity of capsaicine in vivo is inadequate
High, absorption is less, metabolism is fast and bioavilability is low, further limits its application.
The content of the invention
The present invention provides the compound with general formula Ia or general formula Ib：
Or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein：
R1、R2、R3、R4It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl
Base C1-C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl,
Nitro C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8
Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl
Base C1-C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl,
Nitro C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8
Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R9It is or selected from C1-C25Alkyl, C1-C25Alkoxy, C1-C10Acyl group C1-C8Alkoxy, C2-C12Alkynyl, C2-C12Chain
Alkenyl, C3-C10Cycloalkyl, C7-C12Aralkyl, phenyl, cyano C1-C12Alkyl, nitro C1-C12Alkyl, carboxyl, halogenated C1-C12
Alkyl, single or multiple hydroxyl C1-C12Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyl-oxygen
Base C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group.
Preferably：
R1、R2、R3、R4It is or selected from hydrogen, halogen, hydroxyl, C independently1-C6Alkyl, C1-C6Alkoxy, C1-C6Acyl
Base C1-C6Alkoxy, C2-C6Alkynyl, C2-C6Alkenyl, C3-C6Cycloalkyl, C7-C8Aralkyl, phenyl, cyano C1-C6Alkyl, nitre
Base C1-C6Alkyl, carboxyl, halogenated C1-C6Alkyl, single or multiple hydroxyl C1-C6Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkane
Base sulphonyl C1-C6Alkyl, C1-C6Acyloxy C1-C6Alkyl, C1-C6Acyl group C1-C6Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C6Alkyl, C1-C6Alkoxy, C1-C6Acyl
Base C1-C6Alkoxy, C2-C6Alkynyl, C2-C6Alkenyl, C3-C6Cycloalkyl, C7-C8Aralkyl, phenyl, cyano C1-C6Alkyl, nitre
Base C1-C6Alkyl, carboxyl, halogenated C1-C6Alkyl, single or multiple hydroxyl C1-C6Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkane
Base sulphonyl C1-C6Alkyl, C1-C6Acyloxy C1-C6Alkyl, C1-C6Acyl group C1-C6Alkyl or sulfonic group；With
R9It is or selected from C1-C12Alkyl, C1-C12Alkoxy, C1-C6Acyl group C1-C6Alkoxy, C4-C10Alkynyl, C4-C10Chain
Alkenyl, C5-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C10Alkyl, nitro C1-C10Alkyl, carboxyl, halogenated C1-C10Alkane
Base, single or multiple hydroxyl C1-C10Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkyl sulfonyl C1-C6Alkyl, C1-C6Acyloxy
C1-C6Alkyl, C1-C6Acyl group C1-C6Alkyl or sulfonic group.
It is preferred that R2For hydroxyl, methoxy or ethoxy, remaining substituent group R1、R3And R4For hydrogen.R9For octyl, nonane
Any one of base, decyl, dodecyl, octenyl, nonenyl, decene base or dodecenyl succinic.Substituent R8For hydroxyl
Or acetoxyl group, remaining substituent R5、R6、R7For hydrogen.
It is preferred that R2For hydroxyl or methoxyl group.
Specifically, compound described above is selected from following one or more in these：
8- methyl-N- [(3- hydroxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 1)；
8- methyl-N- [(4- hydroxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 2)；
8- methyl-N- [(3- methoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 3)；
8- methyl-N- [(4- methoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 4)；
8- methyl-N- [(3- ethyoxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 5)；
8- methyl-N- [(4- ethyoxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 6)；
8- methyl-N- [(3- propoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 7)；
8- methyl-N- [(4- propoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 8)；
8- methyl-N- [(3- benzyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 9)；
8- methyl-N- [(4- benzyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 10)；
8- methyl-N- [(3- oxygroup in heptan -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 11)；
8- methyl-N- [(4- oxygroup in heptan -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 12)；
8- methyl-N- [(3- octyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 13)；
8- methyl-N- [(4- octyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 14)；
8- methyl-N- [(3- decyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 15)；
8- methyl-N- [(4- decyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 16)；
8- methyl-N- [(3- hydroxyls -4-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyl amide (compounds
17)；Or
8- methyl-N- [(4- hydroxyls -3-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyl amide (compounds
18)。
The present invention also provides general formula described above (Ia) or the preparation method of (Ib) compound, this method includes following step
Suddenly：
Step 1：The niacin of general formula (a) is reacted in a solvent with chlorinating agent or acyl chlorinating agent, and the cigarette of general formula (b) is made
Acyl chlorides：
Step 2：The nicotinoyl chlorine of general formula (b) is reacted in a solvent with the amide compound of general formula (c) or general formula (d),
General formula (Ia) or general formula (Ib) compound is made；
Or
Wherein：
R1、R2、R3、R4It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl
Base C1-C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl,
Nitro C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8
Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl
Base C1-C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl,
Nitro C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8
Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R9It is or selected from C1-C25Alkyl, C1-C25Alkoxy, C1-C10Acyl group C1-C8Alkoxy, C2-C12Alkynyl, C2-C12Chain
Alkenyl, C3-C10Cycloalkyl, C7-C12Aralkyl, phenyl, cyano C1-C12Alkyl, nitro C1-C12Alkyl, carboxyl, halogenated C1-C12
Alkyl, single or multiple hydroxyl C1-C12Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyl-oxygen
Base C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group.
It is preferred that the chlorinating agent or acyl chlorinating agent that use in step 1 are or are selected from：Phosphorus oxychloride, phosphorus trichloride, pentachloro-
Change phosphorus, thionyl chloride, sulfonic acid chloride, chlorine, chlorosulfuric acid SO2Cl2Or phosgene COCl2。
It is preferred that also using catalyst in step 1, which is in DMF, triethylamine, pyridine, potassium carbonate or sodium carbonate
One or more, preferably pyridine.
The present invention also provides general formula described above (Ia) or (Ib) compound or its pharmaceutically acceptable salt, hydrate,
Solvate, stereoisomer prepare treatment analgesia, antitumor, anti-inflammatory, antiatherosclerosis, reducing blood lipid, promotion appetite,
Improve the purposes in digestion, antibacterial desinsection, anti-oxidant, antivirus action drug.
The present invention also provides a kind of pharmaceutical compositions, it includes general formula (Ia) described above or (Ib) compound or its pharmacy
Upper acceptable salt, hydrate, solvate, stereoisomer and one or more of pharmaceutically acceptable auxiliary materials.
For the compound of general formula (c) or (d), product commercially can be used, it is of course also possible to which oneself is closed
Into：
Or
Alternatively, it is also possible to by esterification, from (c) or (d) prepare compound (Ia) or (Ib)：
Alternatively,
In the above-mentioned reaction mechanism mechanism of reaction, R2It can be hydroxyl.
For example, during the reaction of the compound of general formula (f) is prepared from general formula (e) compound, the benzaldehyde and formic acid of general formula (e)
Ammonium (HCO2NH4) reaction.Generally, react in water, for reaction temperature at 100-200 DEG C, the reaction time is 1~12h.And it adds in
Alkali (preferably KOH, NaOH, Ca (OH)2Any one of or a variety of, more preferable NaOH), be made general formula (f) aminomethyl phenyl.
In addition, in the reaction for preparing general formula (c) compound from general formula (f) compound, the aminomethyl phenyl and R of general formula (f)9
Substituted acyl chlorides (R9- COCl) it is reacted.It is preferred that it is reacted in anhydrous ether, 0-100 DEG C of reaction temperature, the reaction time 1
The amide compound of general formula (c) is made in~6h.
In the reaction of general formula (c) amide compound and general formula (b) compound, general formula (c) amide compound and general formula (b)
(solvent is preferably any one of thionyl chloride, DMF, acetone or a variety of to nicotinic acid compounds, and more preferable dichloro is sub- in a solvent
Sulfone), catalyst (preferably any one of pyridine, triethylamine or a variety of, more preferable pyridine) is added in, is reacted.Generally, instead
Answering temperature, the reaction time is 1~48h for 0-100 DEG C.So as to which general formula Ia compounds be made.
The present invention also provides general formula (Ia) or the salt of the compound of (Ib).The salt be by above-claimed cpd and alkali (preferably
KOH、NaOH、Ca(OH)2Any one of or a variety of, more preferable NaOH) reacted and obtained.5-85 DEG C of reaction temperature.
The present invention also provides the compounds or its pharmaceutically acceptable salt of above-mentioned general formula (Ia) or (Ib), hydrate, molten
Agent compound, stereoisomer prepare treatment analgesia, antitumor, anti-inflammatory, antiatherosclerosis, reducing blood lipid, promotion appetite, change
Application in kind digestion, antibacterial desinsection, anti-oxidant, antivirus action drug.
The present invention also provides a kind of pharmaceutical composition, compound including above-mentioned general formula (Ia) or (Ib) or its pharmaceutically
Acceptable salt, hydrate, solvate, stereoisomer and one or more of pharmaceutically acceptable auxiliary materials.
Pharmacological evaluation is carried out to the compound of the present invention：
Ease pain：Using female small white mouse, the analgesic activity of compound of Formula I is determined with hot plate method.Injection applies
0.005-0.50mg/kg compounds of formula I is smeared, pain reaction time lengthening after administration shows that it makees with good analgesia
With.
In terms of reducing blood lipid：Using ApoE knock-out mice Atherosclerosis Models, with the full-automatic bioids of HITACHI7060
Credit analyzer enzyme process (Zhang C, et al.J Lipid Res.2006；47(9):2055-63) determine compounds of formula I
Effect for reducing blood fat and study of anti-atherogenic effect.It takes orally 20mg/Kg/ days (being mixed into feed), successive administration 10 weeks can be shown
Writing reduces blood plasma LDL-C, TC level, also has certain reduction to act on to TG；Meanwhile also raise the effect of HDL-C, efficiency
It is suitable with Lovastatin；And substantially inhibit atherosclerosis plaque forming.
Anti-tumor aspect：Including in vitro and in vivo experiments.Wherein experiment in vitro system mtt assay is with srb assay detection general formula I's
Compound has significant cytotoxicity, IC50It is worth for 0.03~30.0nM.What experiment in vivo was performed such：To lotus
Lewis lung knurls mouse peritoneal injects compounds of formula I, continuous 10 days, can significantly inhibit the growth of Lewis lung knurls, inhibiting rate
For 93.1%.If 0.3-30mg/kg compounds of formula I is injected intraperitoneally, the S-180 of ICR-Jc1 mouse hypodermic inoculations can inhibit
Knurl is grown, and half inhibiting rate is 0.05-15mg/kg.
In terms of promoting digestion：Experiment mice is randomly divided into control group and compound of Formula I various dose group.It is real to observe each group
Test Intestinal propulsive rate, pepsin activity, gastric juice and the pepsinia situation of animal.The results show that compound of Formula I agent
Amount group has mouse small intestine propulsion facilitation, and with the increase of dosage, acts on gradually enhancing；Compound of Formula I difference agent
Amount group can promote the secretion of gastric juice and pepsin.Illustrate that compound of Formula I plays an important role of to promote to digest and assimilate.
Antibiosis：Compounds of formula I has significant antibacterial action, and MIC is 0.0012-20.32 μ g/ml.
Anti-inflammatory aspect：Ear stimulus method is applied using small white mouse-croton oil, takes orally 0.01-0.50mg/kg compound of Formula I
Mice ear degree is significantly lower than blank control group (p<0.01), show that its anti-inflammatory effect is good.
Anti-virus aspect：Compounds of formula I can significantly inhibit the growth and breeding of HIV-1 viruses.
Acute toxicity testing：Mice lavage compounds of formula I is given with 1 heavy dose, small white mouse behavior is observed continuously
The indexs such as activity and toxic reaction degree, and put to death small white mouse at the end of experiment and analysed, to obtain compounds of formula I
Toxicity data.It is observed continuously 15 days, small white mouse is abnormal without evident act, does not also occur death, tests the maximum dose level of setting
1000mg/kg and its following dosage are to small white mouse without overt toxicity.
It is proved by more than pharmacological evaluation, the compound of the present invention eases pain with different degrees of, is antitumor, is anti-inflammatory, dropping
Blood fat, antibacterial, antivirus action.And toxicity is relatively low.
The compound of the present invention can be applied to patient in need for the treatment of in the form of compositions, and described composition includes controlling
A effective amount of the compound of the present invention and its salt and pharmaceutically acceptable carrier are treated, described carrier includes diluent, such as
Water, filler such as starch, wetting agent, such as glycerine, adhesive, such as cellulose derivative, and are made in a manner well
Standby piece agent, capsule, pill, granule, syrup, emulsion, suspension and solution, are routinely administered, preferential to be administered orally.Agent
It measures as 0.005~20mg/kg weight.
Compared with prior art, the present invention has the following advantages：
1st, a kind of new ester derivant of capsaicine containing niacin and its salt provided by the invention can prepare treatment analgesia, resist
Tumour, anti-inflammatory, antiatherosclerosis, reducing blood lipid, promotion appetite, improvement digestion, antibacterial desinsection, anti-oxidant, antivirus action
Drug, and toxicity is relatively low.
2nd, niacin group is introduced into capsaicin compound by the present invention, is obtained a kind of new ester of capsaicine containing niacin and is spread out
Biology, the present invention also provides the preparation methods of the above-mentioned ester derivant of capsaicine containing niacin, can improve capsaicin compound
Bioactivity and improve irritation, to meet the needs of clinical application.
3rd, analgesic activity is measured using hot plate method, measuring reducing blood lipid using ApoE knock-out mices Atherosclerosis Model makees
With, and determine the cytotoxicity (inhibiting tumor cell effect) of the compounds of this invention, promote digestion, antibacterial action, anti-inflammatory work
With, the results show, the compound of the present invention and its salt, which have, different degrees of to ease pain, is antitumor, is anti-inflammatory, is reducing blood lipid, anti-
Bacterium, antivirus action, and toxicity is relatively low.
In conclusion the compound of the present invention and its salt have it is excellent ease pain, be antitumor, is anti-inflammatory, reducing blood lipid, antibacterial,
Antivirus action, and toxicity is smaller, and preparation method is easy, convenient for industrialized production, disclosure satisfy that the needs of field of medicaments.This
The compound of invention has curative effect height, low toxin.
Specific embodiment
Embodiment 1
8- methyl-N- [(3- hydroxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 1, i.e. generation
Number 1) with 8- methyl-N- [(4- hydroxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 2, i.e. code name
2) preparation：
By 0.1mol 8- methyl-N- [(3,4- dihydroxy phenyls)-methyl]-(anti-) -6- nonenyls amide in 100ml bis-
In chlorine sulfoxide at 80 DEG C with 0.15mol niacin reaction 10 it is small when, pour into ice-water bath, be extracted with ethyl acetate 3 times, anhydrous sulphur
Sour sodium drying, then uses ethyl acetate：Petroleum ether=1：2~1:5 column chromatographies, acquisition target product 8- methyl-N- [(3- hydroxyls-
4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyl amides, yield 48.8%；And 8- methyl-N- [(4- hydroxyl -3- niacin
Ester phenyl)-methyl]-(anti-) -6- nonenyl amides, yield 44.3%.Related data is as follows：
8- methyl-N- [(3- hydroxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 1) MS
(EI,70ev)m/z:370；Anal.Calcd.for C21H26O4N2:C,68.21,H,7.03,N 7.57；Found C,
68.19,H,6.99,N 7.53.
8- methyl-N- [(4- hydroxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 2) MS
(EI,70ev)m/z:370；Anal.Calcd.for C21H26O4N2:C,68.21,H,7.03,N 7.57；Found C,
68.19,H,6.99,N 7.53.
Embodiment 2
8- methyl-N- [(3- methoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 3)
It prepares：
By the 8- methyl-N- of 0.2mol iodomethane and 0.1mol [(3- methoxyl group -4- hydroxy phenyls)-methyl]-(anti-) -6-
Nonenyl amide is dissolved in 300ml acetone, adds in 12 grams of catalyst K2CO3, with 0.15mol niacin when 80 DEG C of reactions 3 are small,
Obtain target product 8- methyl-N- [(3- methoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data
It is as follows：
MS(EI,70ev)m/z:384；Anal.Calcd.for C22H28O4N2:C,68.75,H,7.29,N 7.29；
Found C,68.70,H,7.25,N 7.24.
Embodiment 3
8- methyl-N- [(4- methoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 4)
It prepares
According to the operation of embodiment 2, simply using 8- methyl-N- [(4- methoxyl group -3- hydroxy phenyls)-methyl]-(anti-) -
6- nonenyls amide replaces 8- methyl-N- [(3- methoxyl group -4- hydroxy phenyls)-methyl]-(anti-) -6- nonenyl amides, obtains
Compound 8- methyl-N- [(4- methoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:384；Anal.Calcd.for C22H28O4N2:C,68.75,H,7.29,N 7.29；
Found C,68.70,H,7.25,N 7.24.
Embodiment 4
8- methyl-N- [(3- ethyoxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 5)
It prepares
Iodomethane is replaced with bromoethane, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- ethyoxyls -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:398；Anal.Calcd.for C23H30O4N2:C,69.35,H,7.54,N 7.04；
Found C,69.31,H,7.49,N 7.01.
Embodiment 5
8- methyl-N- [(4- ethyoxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 6)
It prepares
Embodiment 4 is repeated, simply using 8- methyl-N- [(4- methoxyl group -3- hydroxy phenyls)-methyl]-(anti-) -6- nonenes
Base amide replaces 8- methyl-N- [(3- methoxyl group -4- hydroxy phenyls)-methyl]-(anti-) -6- nonenyl amides, obtains compound
8- methyl-N- [(4- ethyoxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:398；Anal.Calcd.for C23H30O4N2:C,69.35,H,7.54,N 7.04；
Found C,69.31,H,7.49,N 7.01.
Embodiment 6
8- methyl-N- [(3- propoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 7)
It prepares
Iodomethane is replaced with N-Propyl Bromide, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- propoxyl group -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:412；Anal.Calcd.for C24H32O4N2:C,69.90,H,7.77,N 6.80；
Found C,69.87,H,7.75,N 6.79.
Embodiment 7
8- methyl-N- [(4- propoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 8)
It prepares
Iodomethane is replaced with N-Propyl Bromide, according to the operation of embodiment 3, obtains compound 8- methyl-N- [(4- propoxyl group -3-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:412；Anal.Calcd.for C24H32O4N2:C,69.90,H,7.77,N 6.80；
Found C,69.87,H,7.75,N 6.79.
Embodiment 8
8- methyl-N- [(3- benzyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 9)
It prepares
Iodomethane is replaced with bromobenzyl alkane, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- benzyloxies -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:488；Anal.Calcd.for C30H36O4N2:C73.77,H,7.38,N 5.73；
Found C,73.75,H,7.37,N 5.70.
Embodiment 9
8- methyl-N- [(4- benzyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 10)
It prepares
Iodomethane is replaced with bromobenzyl alkane, according to the operation of embodiment 3, obtains compound 8- methyl-N- [(4- benzyloxies -3-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:488；Anal.Calcd.for C30H36O4N2:C73.77,H,7.38,N 5.73；
Found C,73.75,H,7.37,N 5.70.
Embodiment 10
8- methyl-N- [(3- oxygroup in heptan -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 11)
It prepares
Iodomethane is replaced with heptyl bromide, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- oxygroups in heptan -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:468；Anal.Calcd.for C28H40O4N2:C,71.79,H,8.55,N 5.98；
Found C,71.78,H,8.52,N 5.97.
Embodiment 11
8- methyl-N- [(4- oxygroup in heptan -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 12)
It prepares
Iodomethane is replaced with heptyl bromide, according to the operation of embodiment 3, obtains compound 8- methyl-N- [(4- oxygroups in heptan -3-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:468；Anal.Calcd.for C28H40O4N2:C,71.79,H,8.55,N 5.98；
Found C,71.78,H,8.52,N 5.97.
Embodiment 12
8- methyl-N- [(3- octyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 13)
It prepares
Iodomethane is replaced with bromooctane, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- octyloxies -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:482；Anal.Calcd.for C29H42O4N2:C,72.20,H,8.71,N 5.81；
Found C,72.17,H,8.68,N 5.79.
Embodiment 13
8- methyl-N- [(4- octyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 14)
It prepares
Iodomethane is replaced with bromooctane, according to the operation of embodiment 3, obtains compound 8- methyl-N- [(4- octyloxies -3-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:482；Anal.Calcd.forC29H42O4N2:C,72.20,H,8.71,N 5.81；
Found C,72.17,H,8.68,N 5.79.
Embodiment 14
8- methyl-N- [(3- decyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 15)
It prepares
Iodomethane is replaced with bromo-decane, according to the operation of embodiment 2, obtains compound 8- methyl-N- [(3- decyloxies -4-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70ev)m/z:510；Anal.Calcd.for C31H46O4N2:C,72.94,H,9.02,N 5.49；
Found C,72.91,H,9.01,N 5.48.
Embodiment 15
8- methyl-N- [(4- decyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 16)
It prepares
Iodomethane is replaced with bromo-decane, according to the operation of embodiment 3, obtains compound 8- methyl-N- [(4- decyloxies -3-
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyl amides.Related data is as follows：
MS(EI,70evm/z:510；Anal.Calcd.for C31H46O4N2:C,72.94,H,9.02,N 5.49；
Found C,72.91,H,9.01,N 5.48.
Embodiment 16
8- methyl-N- [(3- hydroxyls -4-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyl amide (compounds
17) with 8- methyl-N- [(4- hydroxyls -3-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 18)
It prepares
Niacin is replaced with 2- chlorine apellagrins, the operation of embodiment 1 is repeated, obtains compound 8- methyl-N- [(3- hydroxyls -4-
2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 17) and 8- methyl-N- [(4- hydroxyls -3-2 '-chlorine
Nicotinate phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 18).Related data is as follows：
8- methyl-N- [(3- hydroxyls -4-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyl amide (compounds
17)
MS(EI,70evm/z:404.5；Anal.Calcd.for C21H25O4N2Cl:C,62.30,H,6.18,N
6.98,Cl,8.78；Found C,62.29,H,6.19,N 6.90,Cl,8.79.
8- methyl-N- [(4- hydroxyls -3-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyl amide (compounds
18)
MS(EI,70evm/z:404.5；Anal.Calcd.for C21H25O4N2Cl:C,62.30,H,6.18,N
6.98,Cl,8.78；Found C,62.29,H,6.19,N 6.90,Cl,8.79.
Embodiment 17 (experiment)
The six kinds of compounds compound of embodiment 16 (embodiment 1-3) of synthesized logical formula (I) are determined using hot plate method
Analgesic activity, the results are shown in Table 1.Using female small white mouse, injection or smearing 0.01mg/kg compounds of formula I, pain after administration
Reaction time extends, and shows it with good analgesic activity.
Improve percentage in six kinds of compound threshold of pains that 1 mouse of the table injection present invention synthesizes
Embodiment 18
Using ApoE knock-out mice Atherosclerosis Models, using the full-automatic biochemical analyzing equipments of HITACHI7060
Enzyme process (Zhang C, et al.J Lipid Res.2006；47(9):2055-63) determine compound of Formula I (embodiment 1-
2nd, the compound of embodiment 15-16) effect for reducing blood fat and study of anti-atherogenic effect.Some obtained the results are shown in Table 2.Mouthful
It takes 20mg/Kg/ days (being mixed into feed), successive administration 10 weeks, the results showed that compound of Formula I can significantly reduce blood plasma LDL-
C, TC is horizontal, also has certain reduction to act on to TG；Meanwhile the effect of HDL-C is also raised, efficiency is suitable with Lovastatin；
And substantially inhibit atherosclerosis plaque forming.
Table 2 leads to the influence of four kinds of compounds of formula (I) to atherosclerosis mouse (ApoE-/-) blood fat
TC=T-CHOLs；TG=triacylglycerols；LDL-C=low density lipoprotein cholesterol；
DL-C=low hdl cholesterol；*,p<0.05；**,p<0.01vs model groups
Embodiment 19
With reference to the method (Mosman, T.J.Immunol Methods.1983,65,55) of Mosman, pass through MTT colorimetric methods
Determine the cytotoxicity of the compounds of this invention, IC50It is worth for 0.03~30.0nM.It the results are shown in Table 3.
Table 3
Embodiment 20
(Zhang Juntian is edited reference literature, modern pharmacology experimental method.) various dose compounds of formula I is studied to thin
Bacterium, the effect of fungi.Its MIC is 0.0012-20.32 μ g/ml.The result is shown in tables 4.
Table 4
Embodiment 21
The tablet of compound (such as compound 1) containing logical formula (I), can be prepared by method well known in the art.
Embodiment 22
The capsule of compound containing logical formula (I) can be prepared by method well known in the art.
Claims (10)
1. the compound with general formula Ia or general formula Ib：
Or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, wherein：
R1、R2、R3、R4It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl group C1-
C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl, nitro
C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl
Sulphonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl group C1-
C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl, nitro
C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl
Sulphonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R9It is or selected from C1-C25Alkyl, C1-C25Alkoxy, C1-C10Acyl group C1-C8Alkoxy, C2-C12Alkynyl, C2-C12Alkene
Base, C3-C10Cycloalkyl, C7-C12Aralkyl, phenyl, cyano C1-C12Alkyl, nitro C1-C12Alkyl, carboxyl, halogenated C1-C12Alkane
Base, single or multiple hydroxyl C1-C12Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy
C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group.
2. compound according to claim 1, which is characterized in that R1、R2、R3、R4It is or selected from hydrogen, halogen independently
Element, hydroxyl, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Acyl group C1-C6Alkoxy, C2-C6Alkynyl, C2-C6Alkenyl, C3-C6Cycloalkanes
Base, C7-C8Aralkyl, phenyl, cyano C1-C6Alkyl, nitro C1-C6Alkyl, carboxyl, halogenated C1-C6Alkyl, single or multiple hydroxyl C1-
C6Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkyl sulfonyl C1-C6Alkyl, C1-C6Acyloxy C1-C6Alkyl, C1-C6Acyl
Base C1-C6Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C6Alkyl, C1-C6Alkoxy, C1-C6Acyl group C1-
C6Alkoxy, C2-C6Alkynyl, C2-C6Alkenyl, C3-C6Cycloalkyl, C7-C8Aralkyl, phenyl, cyano C1-C6Alkyl, nitro C1-
C6Alkyl, carboxyl, halogenated C1-C6Alkyl, single or multiple hydroxyl C1-C6Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkyl sulphur
Acyl C1-C6Alkyl, C1-C6Acyloxy C1-C6Alkyl, C1-C6Acyl group C1-C6Alkyl or sulfonic group；
R9It is or selected from C1-C12Alkyl, C1-C12Alkoxy, C1-C6Acyl group C1-C6Alkoxy, C4-C10Alkynyl, C4-C10Alkenyl,
C5-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C10Alkyl, nitro C1-C10Alkyl, carboxyl, halogenated C1-C10Alkyl, list
Or polyhydroxy C1-C10Alkyl, C1-C6Alkylthio C1-C6Alkyl, C1-C6Alkyl sulfonyl C1-C6Alkyl, C1-C6Acyloxy C1-C6
Alkyl, C1-C6Acyl group C1-C6Alkyl or sulfonic group.
3. compound according to claim 1 or 2, which is characterized in that R2For hydroxyl, methoxy or ethoxy, remaining substitution
Group R1、R3And R4For hydrogen；R9For octyl, nonyl, decyl, dodecyl, octenyl, nonenyl, decene base or 12
Any one of carbene base；Substituent R8For hydroxyl or acetoxyl group, remaining substituent R5、R6、R7For hydrogen.
4. compound according to claim 3, which is characterized in that R2For hydroxyl or methoxyl group.
5. according to the compound any one of claim 1-4, wherein the compound be selected from it is following in these one
Kind is a variety of：
8- methyl-N- [(3- hydroxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 1)；
8- methyl-N- [(4- hydroxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 2)；
8- methyl-N- [(3- methoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 3)；
8- methyl-N- [(4- methoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 4)；
8- methyl-N- [(3- ethyoxyl -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 5)；
8- methyl-N- [(4- ethyoxyl -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 6)；
8- methyl-N- [(3- propoxyl group -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 7)；
8- methyl-N- [(4- propoxyl group -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 8)；
8- methyl-N- [(3- benzyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 9)；
8- methyl-N- [(4- benzyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 10)；
8- methyl-N- [(3- oxygroup in heptan -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 11)；
8- methyl-N- [(4- oxygroup in heptan -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 12)；
8- methyl-N- [(3- octyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 13)；
8- methyl-N- [(4- octyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 14)；
8- methyl-N- [(3- decyloxy -4- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 15)；
8- methyl-N- [(4- decyloxy -3- nicotinates phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 16)；
8- methyl-N- [(3- hydroxyls -4-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 17)；Or
8- methyl-N- [(4- hydroxyls -3-2 '-chlorine apellagrin ester phenyl)-methyl]-(anti-) -6- nonenyls amide (compound 18).
6. according to the preparation method of compound any one of claim 1-5, this method comprises the following steps：
Step 1：The niacin of below general formula (a) is reacted in a solvent with chlorinating agent or acyl chlorinating agent,
The nicotinoyl chlorine of below general formula (b) is made：
Step 2：The nicotinoyl chlorine of general formula (b) is reacted in a solvent with the amide compound of below general formula (c) or general formula (d),
General formula (Ia) or general formula (Ib) compound is made：
Or
Wherein：
R1、R2、R3、R4It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl group C1-
C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl, nitro
C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl
Sulphonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R5、R6、R7、R8It is or selected from hydrogen, halogen, hydroxyl, C independently1-C8Alkyl, C1-C8Alkoxy, C1-C8Acyl group C1-
C8Alkoxy, C2-C8Alkynyl, C2-C8Alkenyl, C3-C8Cycloalkyl, C7-C10Aralkyl, phenyl, cyano C1-C8Alkyl, nitro
C1-C8Alkyl, carboxyl, halogenated C1-C8Alkyl, single or multiple hydroxyl C1-C8Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl
Sulphonyl C1-C8Alkyl, C1-C8Acyloxy C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group；
R9It is or selected from C1-C25Alkyl, C1-C25Alkoxy, C1-C10Acyl group C1-C8Alkoxy, C2-C12Alkynyl, C2-C12Alkene
Base, C3-C10Cycloalkyl, C7-C12Aralkyl, phenyl, cyano C1-C12Alkyl, nitro C1-C12Alkyl, carboxyl, halogenated C1-C12Alkane
Base, single or multiple hydroxyl C1-C12Alkyl, C1-C8Alkylthio C1-C8Alkyl, C1-C8Alkyl sulfonyl C1-C8Alkyl, C1-C8Acyloxy
C1-C8Alkyl, C1-C8Acyl group C1-C8Alkyl or sulfonic group.
7. according to the method described in claim 6, it is characterized in that the chlorinating agent or acyl chlorinating agent that are used in step 1 are or are selected from
In：Phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, sulfonic acid chloride, chlorine, chlorosulfuric acid SO2Cl2Or phosgene COCl2。
8. the method according to claim 6 or 7, it is characterised in that also using catalyst in step 1, the catalyst be DMF,
One or more in triethylamine or pyridine, preferably pyridine.
9. compound or its pharmaceutically acceptable salt, hydrate, solvation according to any one of claim 1-5
Object, stereoisomer disappear in preparation treatment analgesia, antitumor, anti-inflammatory, antiatherosclerosis, reducing blood lipid, promotion appetite, improvement
Purposes in change, antibacterial desinsection, anti-oxidant, antivirus action drug.
10. a kind of pharmaceutical composition, it includes compound any one of claim 1-5 or its is pharmaceutically acceptable
Salt, hydrate, solvate, stereoisomer and one or more of pharmaceutically acceptable auxiliary materials.
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| CN103992269A (en) * | 2014-05-26 | 2014-08-20 | 中国人民解放军第三军医大学 | Capsaicine derivatives and preparation method thereof |
| US20160145225A1 (en) * | 2014-11-25 | 2016-05-26 | Concentric Analgesics, Inc. | Prodrugs of phenolic trpv1 agonists |
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| CN101774938A (en) * | 2010-01-20 | 2010-07-14 | 中国药科大学 | Type of capsaicine derivative, preparation method thereof and medical use thereof |
| CN103992269A (en) * | 2014-05-26 | 2014-08-20 | 中国人民解放军第三军医大学 | Capsaicine derivatives and preparation method thereof |
| US20160145225A1 (en) * | 2014-11-25 | 2016-05-26 | Concentric Analgesics, Inc. | Prodrugs of phenolic trpv1 agonists |
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