CN102408395B - Novel piperazine and homopiperazine derivative and preparation method and use thereof - Google Patents
Novel piperazine and homopiperazine derivative and preparation method and use thereof Download PDFInfo
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- CN102408395B CN102408395B CN201110324535.0A CN201110324535A CN102408395B CN 102408395 B CN102408395 B CN 102408395B CN 201110324535 A CN201110324535 A CN 201110324535A CN 102408395 B CN102408395 B CN 102408395B
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- decenoyl
- piperazine
- acetoxyl group
- brometo
- amonio
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- RXQDHQWRTJDRJA-NSCUHMNNSA-N C/C=C/C(N1CCN(Cc(cc2)ccc2[N+]([O-])=O)CC1)=O Chemical compound C/C=C/C(N1CCN(Cc(cc2)ccc2[N+]([O-])=O)CC1)=O RXQDHQWRTJDRJA-NSCUHMNNSA-N 0.000 description 1
- MFRHMHBULJZZJW-UHFFFAOYSA-N CCC(N(CC)CCN(C)C)=O Chemical compound CCC(N(CC)CCN(C)C)=O MFRHMHBULJZZJW-UHFFFAOYSA-N 0.000 description 1
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N CCc1ccccc1 Chemical compound CCc1ccccc1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a compound of formula I or pharmaceutically acceptable salt and a preparation method thereof, as well as a drug composition containing the same. The compound of formula I is novel piperazine and homopiperazine derivative, which can be used for preparing cervical cancer-treating medicine, anti-acetylcholinesterase and butyrylcholinesterase medicine, and medicine for treating staphylococcus aureus infection.
Description
Technical field
The present invention relates to new piperazine and homopiperazine analog derivative or its pharmacologically acceptable salts, solvate, and preparation method thereof, and the pharmaceutical composition that contains above-mentioned substance.
Background technology
Piperazine claims again hexahydropyrazine, is in molecule, to contain the hexa-member heterocycle of two nitrogen-atoms, and its Enthalpies of Formation is high, Heat stability is good, is the ideal structure unit of azotic heterocyclic compound, is the important component part of a lot of medicines.Diethylenediamine compound is compared with traditional organic drug, has better nitrogen equilibrium symmetrical structure.In organic synthesis, introduce piperazine ring, as the synergy group of medicine, can improve the pharmacokinetic property of medicine, improve the biological activity of medicine.
On piperazine ring, introduce different substituting groups, difference due to substituted radical, position and mode of connection, piperazine compounds has shown various chemical structure and pharmacologically active widely, as cardiovascular in antibacterial, anti-oxidant, antitumor, antipsychotic, inhibition, anti-diabetic, treatment alzheimer's disease.In recent years, the research of relevant piperazine compounds report is more, and with speed increase, particularly relevant this nitrogen heterocycles medicine faster in application pharmaceutically.
The piperazine compounds of following structure be a kind of Comprecin (medicine vertical wave. Medical Molecular Biology experimental technique [M]. Beijing: People's Health Publisher, 2002, p.365 – is p.366.).It has broad-spectrum antibacterial action, inhibition to aerobic gram negative bacillus is best, the Diplococcus gonorrhoeae of most of bacterium of enterobacteriaceae, Penicillin-resistant, product enzyme hemophilus influenzae and Moraxella are had to good anti-microbial effect, all effective to gram-positive microorganism and Gram-negative bacteria.As sterilant, it is mainly by acting on DNA of bacteria gyrase, thereby suppresses the synthesizing of DNA, copy and cause bacterium dead.
The piperazine compounds of following structure is a kind of ACE-1 inhibitor, new compound (J.Med.Chem.2006,49 (14): 4275-4285.) of the most potential treatment AD.On piperazine ring, introduce hydroxyl side chain for 4, can significantly strengthen its inhibition to BACE-1 active, because 4 replacements can produce effectively and interact with the avtive spot of BACE-1 on piperazine ring, thereby it is active to the inhibition of BACE-1 to be conducive to improve compound.
The piperazine compounds of following structure is a kind of anti-allergy agent (Ann.Allergy1991,67 (4): 416-420; Allergy1994,49 (8): 598-604.), it is a kind of peripheral H1-receptor antagonist, can suppress transmission and the effect of histamine, reduce the movement of inflammatory cell, there is multiple anti-allergic effects.
The piperazine compounds of following structure is a kind of wide spectrum antipsychotic drug (new drug and clinical, 1982,1 (1): 25-27.) of dibenzo diazepine derivative.This medical instrument has quick sedative effect, can control rapidly patient's illusion vain hope behavior, regulates affective activity, and all kinds of acute and chronic schizophrenia is had to good curative effect.
The piperazine compounds of following structure is a kind of antidiabetic drug (Vasc.Health Risk Manag.2007,3 (2): 203-210; Bioorg.Med.Chem.Lett.2007,17 (12): 3373-3377.).The diabetes B patient that this medicine is applicable to tolerate other ofhypoglycemic medicines, can control blood sugar, realizes hypoglycemic up to standard, reaches protection cardiovascular, the effect of complication prevention.
Piperazines medicine mostly have effect rapid-action, side reaction is little, toxicity is low, without features such as habituation, be subject to liking of many researchers.Yet this class medicine is mostly water-soluble poor, limited it as the clinical application of oral medicine and medical injection.Therefore, increase the solubleness of such new compound in water, make it to become the new drug with DEVELOPMENT PROSPECT, be of great significance and value.Li Runtao etc. find in to the research of the antitumor drug of bis-piperazinium salts compounds, quaternary ammonium ion is to regulating oily – water dispenser ratio to play a role, the toxicity of this compounds and activity have obvious relation with oily – water dispenser ratio, the toxicity of compound increases (Acta Pharmaceutica Sinica with fat-soluble increase, 1995,30 (1): 63-69.).Therefore piperazine is carried out quaternizedly, explore dissimilar quaternary ammonium salt synthetic method, seek the quaternary ammonium salt of higher physiologically active, become current hot issue.
Sommers etc. show the correlation research of pharmaceutical activity and structure, with homopiperazine, replace after piperazine, and medicine marezine, the curosajin of synthesized obviously strengthen (J.Am.Chem.Soc.1954,76:5805-5805.) to antihistaminic activity.Ziegler etc. show the correlation research of pharmaceutical activity and structure, if contain homopiperazine group in compound, the activity of its medicine significantly improves (J.Med.Chem.1990,33 (1): 142-146.).Therefore, the research of homopiperazine series compound more and more comes into one's own.In China, homopiperazine is mainly used in pharmaceutical industry, and the medicinal efficacy of Foreign Epidemic exploitation homopiperazine derivative, as anti-inflammatory, analgesia, hypoglycemic etc.
At present, domestic nitrogen heterocyclic is mainly for the production of Comprecin, and this medicine is to produce anti-microbial effect (chemical intermediate, 2008, (9): 12-16.) by copying of anti-bacteria gyrase blocking dna.The medicines such as the quinoline that the homopiperazine of take is raw material modification and isoquinilone derivatives, Carbostyril derivative, thiazolidine hydroxy acid amide derivatives; with for the synthesis of pyridazinamines, water soluble azoles, containing the medicines such as benzyl amine derivative of nitroxyl; to Cardiovarscular, pneumocystis carinii pneumonia particularly to AIDS patient's pneumocystis carinii pneumonia, asthma, central nervous system disorders comprise dysthymia disorders and anxiety disorder etc. show good curative effect (Cai Liuqing. the synthetic and technological transformation [D] of homopiperazine. Shanxi: Northcentral University, 2009.).
Summary of the invention
The object of the invention is to provide new piperazine and homopiperazine analog derivative, or its pharmacologically acceptable salts, solvate, and preparation method thereof, with and in the application of preparing the aspect medicines such as acetylcholine esterase inhibition activity, inhibition tumor cell activity and bacteriostatic activity.
The invention provides the compound shown in formula I or its pharmaceutically acceptable salt.
Formula I
Wherein:
N is 1 or 2;
X
–independently selected from chlorion, bromide anion, iodide ion;
R
1, R
2for substituted radical that can be identical or different, independently selected from hydrogen, halogen, amino, nitro, itrile group, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl moiety are optionally replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl.
Preferred compound is R
1, R
2all can be selected from respectively methyl, ethyl, n-hexyl, allyl group, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Compound shown in typical formula I, comprising:
1,1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
2,1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
3,2-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
4,1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
5,1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
6,1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
7,1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
8,1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
9,1-methyl isophthalic acid-ethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
10,1-ethyl-1-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
11,1-ethyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
12,1-ethyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
13,1-ethyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
14,1-ethyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
15,1-ethyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
16,1-ethyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
17,1-methyl isophthalic acid-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
18,1-allyl group-1-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
19,1-n-hexyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
20,1-n-hexyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
21,1-n-hexyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
22,1-n-hexyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
23,1-n-hexyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
24,1-n-hexyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
25,1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium iodide;
26,1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
27,1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
28,1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
29,1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
30,1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
31,1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
32,1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium chloride.
The present invention also provides the preparation method of above-mentioned formula I compound, the method comprises: take E-10-hydroxy-2-decylenic acid as raw material, through esterification, there is respectively amination reaction with bridged piperazine derivatives, homopiperazine derivative, obtain corresponding intermediate, by quaterisation, synthesize corresponding piperazine, homopiperazine quaternary ammonium salt again, reaction formula is:
Wherein:
N is 1 or 2;
X
–independently selected from chlorion, bromide anion, iodide ion;
R
1, R
2for substituted radical that can be identical or different, independently selected from hydrogen, halogen, amino, nitro, itrile group, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Wherein each alkyl, thiazolinyl, alkynyl, cycloalkyl moiety are optionally replaced independently selected from following group by 1-5: hydroxyl, halogen, amino, nitro, trifluoromethyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, C
3-C
10cycloalkyl.
The preparation of 1.4-(10-acetoxyl group-2-decenoyl) piperazine quaternary ammonium salt, i.e. n=1.
(1) intermediate 10-acetoxyl group-2-decylenic acid is synthetic
(2) intermediate 1-alkyl-4-(10-acetoxyl group-2-decenoyl) piperazine is synthetic
(3) target product is synthetic
The preparation of 2.4-(10-acetoxyl group-2-decenoyl) homopiperazine quaternary ammonium salt, i.e. n=2.
(1) intermediate 10-acetoxyl group-2-decylenic acid is synthetic
(2) intermediate 1-alkyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine is synthetic
(3) target product is synthetic
C in the present invention
1-C
10alkyl, alkyl refer to the straight or branched alkyl with 1-10 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl, heptyl, octyl group etc.Preferred alkyl is C
1-C
6alkyl.Preferred alkyl is C
1-C
3alkyl;
C
2-C
l0thiazolinyl refers to the thiazolinyl with the two keys of 2-10 carbon atom and at least one, and comprise vinyl, propenyl, 1-fourth-3-thiazolinyl, 1-penta-3-thiazolinyl, 1-oneself-5-thiazolinyl etc.The low-grade alkenyl more preferably with 3-5 carbon atom;
C
2-C
l0refer to the alkyl with 2-10 carbon atom and at least one three key, and comprise ethynyl, proyl, butynyl, pentyne-2-base etc.The alkynyl more preferably with 3-5 carbon atom;
Halogen refers to fluorine, chlorine, bromine and iodine atom;
Aryl refer to there is monocycle (as phenyl), many rings (as xenyl) or wherein at least one ring be that a plurality of fused rings of aromaticity are (as 1,2,3,4-tetralyl, naphthyl) aromatic carbocyclyl groups, it is optionally replaced by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Heteroaryl refers to one or more aromatics ring systems of 5,6 or 7 rings, and what it comprised 5-10 atom condenses ring system (wherein at least one ring is aromaticity), and described ring system contains at least one and maximum four heteroatomss that are selected from nitrogen, oxygen or sulphur.The example of heteroaryl is pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrole ring, quinoline ring, isoquinoline 99.9 ring, indole ring, benzoglyoxaline, cumarone ring, thionaphthene ring, benzothiazole ring, pyridazine ring etc.It is optionally replaced by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Carbocyclic ring, carbocylic radical, cycloalkyl, C
3-C
10cycloalkyl refers to the saturated carbon ring group with 3-10 carbon atom.This cycloalkyl can be that monocycle or many rings condense system, and can condense on aromatic ring.The example of these groups comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Ring a heatable brick bed base herein can be unsubstituted or as describe in detail, in one or more commutable positions, by various groups, replaced.For example, these cycloalkyl can optionally be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6halogenated alkoxy;
Heterocycle or heterocyclic radical refer to one or more carbocyclic ring ring system of 5,6 or 7 rings, it comprises the ring system that condenses of 4-10 atom, described ring system contains at least one and maximum four heteroatomss that are selected from nitrogen, oxygen or sulphur, and condition is that the ring of this group does not contain two adjacent O or S atom.Condensing ring system can be the heterocycle condensing on virtue group group.Preferred heterocycle includes but not limited to pyrrolidyl, tetrahydrofuran base, dihydrofuran base, tetramethylene sulfide, piperidyl, morpholine ring, hexamethylene ring, piperazine ring etc., and they can be replaced by following group: C
1-C
6alkyl, C
1-C
6alkoxyl group, itrile group, halogen, hydroxyl, amino, nitro, list (C
1-C
6) alkylamino, two (C
1-C
6) alkylamino, C
2-C
6thiazolinyl, C
2-C
6alkynyl, C
1-C
6haloalkyl, C
1-C
6halogenated alkoxy;
Arylalkyl refers to (as defined above) alkyl being replaced by one or more (as defined above) aryl.Preferred arylalkyl is aryl-C
l-C
3alkyl.Example comprises benzyl, phenylethyl etc.;
Heteroarylalkyl refers to (as defined above) alkyl being replaced by (as defined above) heteroaryl.Preferred heteroarylalkyl is 5-or the heteroaryl-C of 6-unit
1-C
3-alkyl.Example comprises pyridyl ethyl etc.;
Heterocyclic radical alkyl refers to (as defined above) alkyl being replaced by (as defined above) heterocyclic radical.Preferred heterocyclic radical alkyl is 5 or 6 yuan of heterocyclic radical-C
l-C
3-alkyl.Example comprises tetrahydropyrans ylmethyl;
Cycloalkylalkyl refers to by (as defined above) alkyl of (as defined above) cycloalkyl substituted.Preferred heterocyclic radical is 5 or 6 yuan of cycloalkyl-C
l-C
3-alkyl.Example comprises cyclopropyl methyl;
Compound of the present invention also can be used with the form of its pharmacy acceptable salt or solvate.On the physiology of formula I compound, receivable salt comprises the conventional salt that formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, flutters the salt of acid, propanedioic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, fumaric acid, toluenesulphonic acids, methylsulfonic acid, naphthalene-2-sulfonic acid, Phenylsulfonic acid, hydroxynaphthoic acid, hydroiodic acid HI, oxysuccinic acid, steroic, tannic acid etc.Other acid, as oxalic acid, although itself is not pharmaceutically acceptable, can be for the preparation of the salt as intermediate, to obtain the compounds of this invention and pharmacy acceptable salt thereof.The example more specifically of suitable alkali salt comprises sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, choline, diethanolamine, quadrol, N-METHYL-ALPHA-L-GLUCOSAMINE and procaine salt.
The present invention also comprises the prodrug of the compounds of this invention, and this prodrug, once administration, carries out chemical conversion by metabolic process, becomes afterwards the activated medicine of tool.Conventionally, this class prodrug is the functional derivatives of formula I compound of the present invention, and it easily changes into required formula I compound in vivo.For example, H Bund Saard has described the ordinary method of selecting and prepare suitable prodrug derivant in " Design of Prodrugs " (Elsevier press, 1985).
The present invention also comprises the active metabolite of the compounds of this invention.
Another aspect of the present invention relates to pharmaceutical composition, the raceme that it contains the compounds of this invention or optically active isomer and at least one pharmaceutically acceptable carrier, and it can be used for interior therapeutic and has biocompatibility.Described pharmaceutical composition can be prepared into various forms according to different way of administration.The mentioned compound of the present invention also can be prepared to various pharmacologically acceptable salts.
Pharmaceutical composition of the present invention comprises formula I compound or pharmaceutically acceptable salt thereof of the present invention or hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein is as human serum albumin, and buffer substance is as phosphoric acid salt, glycerine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloided silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, lanolin.
The pharmaceutical composition of the compounds of this invention can be made into injection, oral acceptable preparation, local application's preparation, sprays or drops etc.Can use with any-mode below: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.
When oral medication, the compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet is used generally comprises lactose and W-Gum, also can add in addition lubricant as Magnesium Stearate.The thinner that capsule preparations is used generally comprises lactose and dried corn starch.Aqueous suspension preparation normally mixes use by activeconstituents with suitable emulsifying agent and suspension agent.If need, also can add some sweeting agents, perfume compound or tinting material in above oral preparations form.
When local application, particularly treat local external application easy to reach and suffer from face or organ, during as eyes, skin or lower intestinal tract nervous system disease, can the compounds of this invention be made to different local application's dosage forms according to different trouble faces or organ, be described as follows:
When eye topical application, the compounds of this invention can be mixed with the dosage form of a kind of micronization suspension or solution, the carrier that uses for waiting Sterile Saline of the certain pH ooze, wherein can add also not adding preservative agent as zephiran chloride alkoxide.For eye use, also compound can be made to paste form as vaseline paste.
When topical application, the compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, and sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
The all right aseptic injection preparation form medication of the compounds of this invention, comprises aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.
The invention provides new piperazine and homopiperazine analog derivative, or its pharmacologically acceptable salts, solvate comprise in the application of preparing the aspect medicines such as acetylcholine esterase inhibition activity, inhibition tumor cell activity and bacteriostatic activity:
In the application of preparing aspect antitumor drug.The particularly application aspect preparation treatment solid tumor, acute leukemia medicine; The specifically application aspect preparation treatment cervical cancer medicine.
Application aspect the anti-acetylcholinesterasemedicine medicine of the diseases such as preparation treatment alzheimer's disease and cerebrovascular dementia; Specifically in the application of preparing aspect anti-acetylcholinesterase and butyrylcholine esterase medicine.
And the application aspect the medicine for the preparation for the treatment of gram-positive microorganism and negative bacterium infection.The specifically application aspect the medicine for the preparation for the treatment of infection of staphylococcus aureus.
Embodiment
The following examples are the preferred illustrative preferred versions of the present invention, and the present invention is not constituted any limitation.
The preparation of intermediate:
The preparation of embodiment 1:1-methyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 1)
Step 1: the preparation of 10-acetoxyl group-2-decylenic acid
Under agitation condition, successively by 10-HAD (9.30g, 50mmol), aceticanhydride (9.43mL, 100mmol) joins in the round-bottomed flask that 50mL is dry, by said mixture reflux 1h in 100 ℃ of oil baths.Concentrating under reduced pressure reaction solution, gained thick silica gel column chromatography (eluent: V for product
acetone: V
sherwood oil=1:20) separating-purifying obtains 9.51g pale yellow oily liquid body, productive rate 83.4%.
Step 2: the preparation of 1-methyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 1)
By 10-acetoxyl group-2-decylenic acid (2.28g, 10mmol), methylene dichloride (30mL) joins in 50mL round-bottomed flask, under agitation condition, dropwise adds SOCl
2(1.46mL, 20mmol), stirring at room reaction 10h.Reaction solution is cooled to 0 ℃, dropwise adds methylpiperazine (20mmol), 0 ℃ of stirring reaction 1h.30mL chloroform dilution for reaction solution, then use 10%NaOH regulator solution pH=13, organic phase is washed with saturated sodium-chloride water solution, and anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, gained thick silica gel column chromatography (eluent: V for product
methyl alcohol: V
ethyl acetate=1:20) separating-purifying, obtains pale yellow oily liquid body 5.50g, productive rate 88.6%.
1H?NMR(DMSO-d
6,500MHz)δ:6.68～6.62(m,1H,CH=CHCO),6.44(d,J=15.0Hz,1H,CH=CHCO),3.98(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.56～3.44(m,4H,(CH
2)
2NCH
3),2.30～2.20(m,4H,CON(CH
2)
2),2.20～2.12(m,5H,NCH
3and?OCH
2–(CH
2)
5–CH
2),1.99(s,3H,CH
3CO
2),1.58～1.23(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(DMSO-d
6,125MHz)δ:170.8,164.8,145.8,121.0,64.2,55.5,54.8,46.1,45.3,41.7,32.1,29.0,28.9,28.6,28.3,25.8,21.2;APCI-MS?m/z:311.24(M+1)
+;IR(KBr,cm
–1)ν:1737(C=O),1657(C=O),1619(C=C),1243(C–O–C),1039(C–O–C).
The preparation of embodiment 2:1-ethyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 2)
Method, with intermediate embodiment 1, substitutes methylpiperazine by ethyl piperazidine, obtains pale yellow oily liquid body 5.56g, productive rate 85.8%.
1H?NMR(CD
3OD,500MHz)δ:6.86～6.70(m,1H,CH=CHCO),6.45(d,J=14.9Hz,1H,CH=CHCO),4.07(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.68(t,J=5.0Hz,4H,(CH
2)
2NC
2H
5),2.55～2.45(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.30～2.24(m,2H,OCH
2–(CH
2)
5–CH
2),2.05(s,3H,CH
3CO
2),1.68～1.35(m,10H,OCH
2–(CH
2)
5–CH
2),1.14(t,J=7.2Hz,3H,NCH
2CH
3);
13CNMR(CD
3OD,125MHz)δ:171.6,166.3,146.8,119.9,64.3,52.7,52.1,51.8,45.2,41.5,32.1,28.8,28.7,28.6,28.3,25.6,19.7,10.7;ESI-MS?m/z:325.23(M+1)
+;IR(KBr,cm
–1)ν:1738(C=O),1659(C=O),1622(C=C),1243(C–O–C).
The preparation of embodiment 3:1-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 3)
Method is with intermediate embodiment 1, and hexyl piperazine is substituted to methylpiperazine, gained thick silica gel column chromatography (eluent: V for product
methyl alcohol: V
ethyl acetate=1:2) separating-purifying, obtains pale yellow oily liquid body 5.92g, productive rate 77.8%.
1H?NMR(DMSO-d
6,500MHz)δ:6.69～6.10(m,1H,CH=CHCO),6.44(d,J=15.0Hz,1H,CH=CHCO),4.06(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.55～3.45(m,4H,(CH
2)
2N(CH
2)
5CH
3),2.35～2.23(m,6H,CON(CH
2)
2and?NCH
2–(CH
2)
4–CH
3),2.21～2.14(m,2H,OCH
2–(CH
2)
5–CH
2),2.00(s,3H,CH
3CO
2),1.60～1.22(m,18H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.87(t,J=6.5Hz,3H,NCH
2–(CH
2)
4–CH
3);
13C?NMR(DMSO-d
6,125MHz)δ:170.8,164.8,145.6,121.1,64.2,64.1,58.2,53.7,53.0,45.5,32.0,31.7,30.4,28.9,28.8,28.6,28.3,27.8,27.0,26.6,25.8,22.5,21.2,14.3;ESI-MS?m/z:381.22(M+1)
+;IR(KBr,cm
–1)ν:1739(C=O),1659(C=O),1621(C=C),1244(C–O–C).
The preparation of embodiment 4:1-methyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine (compound 4)
Under agitation condition, by 10-acetoxyl group-2-decylenic acid (2.28g, 10mmol), methylene dichloride (30mL), 1-methyl homopiperazine (1.67mL, 13mmol) joins in 50mL round-bottomed flask, stirring at room 1h.30mL chloroform dilution for reaction solution, organic phase is used saturated ammonium chloride (3 * 60mL), saturated sodium-chloride water solution (1 * 60mL) washing, anhydrous magnesium sulfate drying successively.Filter, remove solvent under reduced pressure, gained thick silica gel column chromatography (eluent: V for product
methyl alcohol: V
ethyl acetate=1:2, V
ethanol: V
acetone=5:1) separating-purifying, obtains pale yellow oily liquid body 1.62g, productive rate 50.0%.
1H?NMR(CD
3Cl,500MHz)δ:6.90～6.83(m,1H,CH=CHCO),6.22～6.13(m,1H,CH=CHCO),4.10～4.00(m,2H,OCH
2–(CH
2)
5–CH
2),3.74～3.50(m,4H,CON(CH
2)
2),2.72～2.60(m,2H,(CH
2)
2NCH
3),2.58～2.50(m,2H,(CH
2)
2NCH
3),2.36(s,3H,NCH
3),2.21～2.11(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),2.02～1.90(m,2H,NCH
2CH
2CH
2N),1.68～1.22(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:171.1,166.6,146.5,120.4,64.5,59.0,58.1,57.1,56.7,47.3,47.0,46.6,46.4,45.0,45.0,32.4,29.0,29.0,28.6,28.3,28.0,27.0,20.9;APCI-MS?m/z:325.02(M+1)
+;IR(KBr,cm
–1)ν:1738(C=O),1658(C=O),1616(C=C),1246(C–O–C),1048(C–O–C).
The preparation of target substance:
Embodiment 1:1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide
Under agitation condition, by compound 1 (2mmol), 30mL chloroform, raw material methyl iodide (4mmol) joins in 50mL round-bottomed flask, and 65 ℃ of reactions, with TLC monitoring reaction (developping agent: V
methyl alcohol: V
chloroform=1:10), after having reacted, by reaction solution concentrating under reduced pressure, gained thick silica gel column chromatography (eluent: V for product
methyl alcohol: V
ethyl acetate=1:10) separating-purifying obtains pale yellow oily liquid body 0.64g, productive rate 71.1%.
1H?NMR(CD
3OD,500MHz)δ:6.95～6.88(m,1H,CH=CHCO),6.51(d,J=15.1Hz,1H,CH=CHCO),4.12～4.00(m,6H,(CH
2)
2NCH
3and?OCH
2–(CH
2)
5–CH
2),3.60～3.50(m,4H,CON(CH
2)
2),3.38～3.27(m,6H,CH
2N(CH
3)
2),2.35～2.26(m,2H,OCH
2–(CH
2)
5–CH
2),2.08～2.00(m,J=1.7Hz,3H,CH
3CO
2),1.70～1.34(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CD
3OD,125MHz)δ:171.7,166.6,148.7,118.9,64.3,61.0,48.1,32.1,28.7,28.6,28.2,27.9,25.5,19.5;ESI-MS?m/z:325.25(M–I)
+;IR(KBr,cm
–1)ν:1730(C=O),1658(C=O),1615(C=C),1245(C–O–C),1034(C–O–C).
Embodiment 2:1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by raw material allyl bromide 98 alternative materials methyl iodide, obtains pale yellow oily liquid body 0.41g, productive rate 47.5%.
1H?NMR(D
2O,500MHz)δ:6.91～6.83(m,1H,CH=CHCO),6.41(d,J=15.2Hz,1H,CH=CHCO),6.10～6.01(m,1H,CH
2CH=CH
2),5.82～5.71(m,2H,CH
2CH=CH
2),4.21～4.05(m,6H,(CH
2)
2NCH
2CH?and?OCH
2–(CH
2)
5–CH
2),4.00～3.74(m,2H,CH
2CH=CH
2),3.58～3.45(m,4H,CON(CH
2)
2),3.17(s,3H,NCH
3),2.30～2.22(m,2H,OCH
2–(CH
2)
5–CH
2),2.07(s,3H,CH
3CO
2),1.67～1.58(m,2H,OCH
2–(CH
2)
5–CH
2),1.51～1.42(m,2H,OCH
2–(CH
2)
5–CH
2),1.34～1.26(m,6H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.8,168.5,150.4,130.2,123.5,118.9,66.8,65.9,59.0,47.0,39.8,36.1,32.1,28.4,28.3,27.9,27.5,25.2,20.7;ESI-MS?m/z:351.18(M–Br)
+;IR(KBr,cm
–1)ν:1737(C=O),1656(C=O),1611(C=C),1251(C–O–C).
Embodiment 3:1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by raw material bromotoluene alternative materials methyl iodide, obtains white solid 0.88g, productive rate 91.6%.
1H?NMR(D
2O,500MHz)δ:7.66～7.44(m,5H,ArH),6.88～6.79(m,1H,CH=CHCO),6.37(d,J=15.2Hz,1H,CH=CHCO),4.61(s,2H,ArCH
2),4.36～4.24(m,2H,(CH
2)
2NCH
2Ar),4.04(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2)3.93～3.59(m,2H,(CH
2)
2NCH
2Ar),3.50～3.33(m,4H,CON(CH
2)
2),3.40(s,3H,NCH
3),2.30～2.10(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.65～1.23(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.9,168.5,150.5,143.5,133.3,133.3,131.2,129.4,129.4,126.2,118.7,69.2,65.8,58.9,45.8,39.8,36.1,32.0,29.2,28.2,28.1,27.8,27.4,25.1,20.6;ESI-MS?m/z:401.19(M–Br)
+;IR(KBr,cm
–1)ν:1736(C=O),1655(C=O),1613(C=C),1247(C–O–C).
Embodiment 4:1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, to nitro bromobenzyl alternative materials methyl iodide, obtains faint yellow solid 0.82g, productive rate 78.3% by raw material.
1H?NMR(D
2O,500MHz)δ:8.34(d,J=8.7Hz,2H,ArH),7.79(d,J=8.6Hz,2H,ArH),6.88～6.80(m,1H,CH=CHCO),6.38(d,J=15.2Hz,1H,CH=CHCO),4.76(s,2H,ArCH
2),4.40～4.18(m,2H,(CH
2)
2NCH
2Ar),4.05(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.93～3.84(m,1H,(CH
2)
2NCH
2Ar),3.70～3.50(m,5H,(CH
2)
2NCH
2Ar?and?CON(CH
2)
2),3.16(s,3H,NCH
3),2.25～2.18(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.63～1.39(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.9,168.5,150.6,149.3,134.6,134.6,133.1,124.4,124.4,118.7,67.9,65.8,59.4,45.9,39.8,36.1,32.0,28.2,28.1,27.8,27.4,25.1,20.6;ESI-MS?m/z:446.21(M–Br)
+;IR(KBr,cm
–1)ν:1731(C=O),1656(C=O),1614(C=C),1526(Ar–NO
2),1350(Ar–NO
2),1245(C–O–C).
Embodiment 5:1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, to bromine bromobenzyl alternative materials methyl iodide, obtains white solid 1.05g, productive rate 93.8% by raw material.
1H?NMR(D
2O,500MHz)δ:7.66(d,J=8.4Hz,2H,ArH),7.40(d,J=8.4Hz,2H,ArH),6.84～6.77(m,1H,CH=CHCO),6.34(d,J=15.2Hz,1H,CH=CHCO),4.56(s,2H,ArCH
2),4.32～4.12(m,2H,(CH
2)
2NCH
2Ar),4.02(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.88～3.56(m,2H,(CH
2)
2NCH
2Ar),3.54～3.40(m,4H,CON(CH
2)
2),3.07(s,3H,NCH
3),2.24～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.00(s,3H,CH
3CO
2),1.60～1.53(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.9,168.6,150.6,143.4,134.9,134.9,132.6,132.6,125.3,118.7,68.5,65.9,59.0,45.8,39.8,36.1,32.0,29.1,28.2,28.1,27.8,27.4,25.1,20.6;ESI-MS?m/z:479.14(M–Br)
+;IR(KBr,cm
–1)ν:1738(C=O),1656(C=O),1616(C=C),1245(C–O–C).
Embodiment 6:1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, to fluorine bromobenzyl alternative materials methyl iodide, obtains white solid 0.77g, productive rate 77.3% by raw material.
1H?NMR(D
2O,500MHz)δ:7.63～7.57(m,2H,ArH),7.30～7.27(m,2H,ArH),6.92～6.85(m,1H,CH=CHCO),6.42(d,J=15.2Hz,1H,CH=CHCO),4.65(s,2H,ArCH
2),4.40～4.33(m,1H,(CH
2)
2NCH
2Ar),4.27～4.20(m,1H,(CH
2)
2NCH
2Ar),4.10(t,J=6.63Hz,2H,OCH
2–(CH
2)
5–CH
2),3.96～3.88(m,1H,(CH
2)
2NCH
2Ar),3.72～3.64(m,1H,(CH
2)
2NCH
2Ar),3.63～3.47(m,4H,CON(CH
2)
2),3.15(s,3H,NCH
3),2.30～2.23(m,2H,OCH
2–(CH
2)
5–CH
2),2.08(s,3H,CH
3CO
2),1.67～1.30(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.9,168.6,165.3,163.3,150.5,135.6,135.5,122.4,118.8,116.6,116.4,68.5,65.9,58.9,45.7,39.8,36.1,32.0,28.3,28.2,27.9,27.4,25.1,20.7;ESI-MS?m/z:419.20(M–Br)
+;IR(KBr,cm
–1)ν:1737(C=O),1656(C=O),1608(C=C),1232(C–O–C),1033(C–O–C).
Embodiment 7:1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, to methyl bromobenzyl alternative materials methyl iodide, obtains white solid 0.75g, productive rate 75.6% by raw material.
1H?NMR(D
2O,500MHz)δ:7.41(d,J=7.9Hz,2H,ArH),7.35(d,J=7.9Hz,2H,ArH),6.87～6.79(m,1H,CH=CHCO),6.37(d,J=15.2Hz,1H,CH=CHCO),4.58(s,2H,ArCH
2),4.36～4.14(m,2H,(CH
2)
2NCH
2Ar),4.04(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.92～3.59(m,2H,(CH
2)
2NCH
2Ar),3.56～3.41(m,4H,CON(CH
2)
2),3.10(s,3H,NCH
3),2.36(s,3H,ArCH
3),2.25～2.18(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.60～1.54(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.8,168.4,150.4,142.0,133.2,133.2,130.0,130.0,123.1,118.8,69.1,65.8,58.7,45.9,39.8,36.1,32.0,28.3,28.2,27.9,27.4,25.1,20.7,20.6;ESI-MS?m/z:415.23(M–Br)
+;IR(KBr,cm
–1)ν:1738(C=O),1656(C=O),1615(C=C),1246(C–O–C),1030(C–O–C).
Embodiment 8:1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride
Method, with embodiment 1, to methoxyl group benzyl chloride alternative materials methyl iodide, obtains white solid 0.57g, productive rate 61.4% by raw material.
1H?NMR(D
2O,500MHz)δ:7.46(d,J=8.7Hz,2H,ArH),7.06(d,J=8.7Hz,2H,ArH),6.85～6.77(m,1H,CH=CHCO),6.36(d,J=15.2Hz,1H,CH=CHCO),4.55(s,2H,ArCH
2),4.36～4.13(m,2H,(CH
2)
2NCH
2Ar),4.02(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.90～3.80(m,4H,(CH
2)
2NCH
2Ar?and?ArOCH
3),3.66～3.56(m,1H,(CH
2)
2NCH
2Ar),3.51～3.39(m,4H,CON(CH
2)
2),3.10(s,3H,NCH
3),2.23～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.02(s,3H,CH
3CO
2),1.60～1.52(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.7,168.3,161.2,150.3,150.3,134.9,134.9,118.8,118.6,114.9,69.1,65.8,58.5,55.8,45.8,39.8,36.1,32.0,28.3,28.2,27.9,27.5,25.2,20.6;ESI-MS?m/z:431.20(M–Cl)
+;IR(KBr,cm
–1)ν:1737(C=O),1657(C=O),1612(C=C),1253(C–O–C),1030(Ar–O–C).
Embodiment 9:1-methyl isophthalic acid-ethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide
Method, with embodiment 1, by compound 2 alternative compounds 1, obtains yellow oily liquid 0.41g, productive rate 43.6%.
1H?NMR(D
2O,500MHz)δ:7.00～6.92(m,1H,CH=CHCO),6.49(d,J=15.2Hz,1H,CH=CHCO),4.19(t,J=6.4Hz,4H,(CH
2)
2NC
2H
5),4.08～3.84(m,2H,OCH
2–(CH
2)
5–CH
2),3.67～3.53(m,6H,CON(CH
2)
2and(CH
2)
2NCH
2Ar),3.25(s,3H,NCH
3),2.39～2.31(m,2H,OCH
2–(CH
2)
5–CH
2),2.17(s,3H,CH
3CO
2),1.76～1.52(m,4H,OCH
2–(CH
2)
5–CH
2),1.48(t,J=7.1Hz,3H,NCH
2CH
3),1.46～1.38(m,6H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.4.168.1,149.9,118.3,65.4,59.9,58.5,45.9,39.3,35.6,31.5,27.8,27.7,27.4,26.9,24.6,20.2,6.4;ESI-MS?m/z:339.16(M–I)
+;IR(KBr,cm
–1)ν:1739(C=O),1655(C=O),1604(C=C),1248(C–O–C),1037(C–O–C).
Embodiment 10:1-ethyl-1-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 2 alternative compounds 1, by raw material allyl bromide 98 alternative materials methyl iodide, obtains white solid 0.70g, productive rate 78.6%.
1H?NMR(DMSO-d
6,500MHz)δ:6.75～6.68(m,1H,CH=CHCO),6.48(d,J=15.0Hz,1H,CH=CHCO),6.05～5.95(m,1H,CH
2CH=CH
2),5.69(d,J=16.1Hz,1H,CH
2CH=CH
2),5.61(d,J=10.2Hz,1H,CH
2CH=CH
2),4.10(d,J=7.2Hz,2H,CH
2CH=CH
2),3.95(t,J=6.7Hz,4H,(CH
2)
2NCH
2CH),3.86～3.77(m,2H,OCH
2–(CH
2)
5–CH
2),3.46～3.36(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.20～2.13(m,2H,OCH
2–(CH
2)
5–CH
2),1.96(s,3H,CH
3CO
2),1.56～1.48(m,4H,OCH
2–(CH
2)
5–CH
2),1.29～1.19(m,9H,NCH
2CH
3and?OCH
2–(CH
2)
5–CH
2);
13C?NMR(DMSO-d
6,125MHz)δ:170.9,165.2,147.4,128.1,125.5,120.3,64.2,59.4,57.1,56.8,54.0,39.0,35.4,32.1,29.0,28.9,28.6,28.2,25.7,21.2,7.4;ESI-MS?m/z:365.16(M–Br)
+;IR(KBr,cm
–1)ν:1735(C=O),1656(C=O),1615(C=C),1246(C–O–C),1038(C–O–C).
Embodiment 11:1-ethyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Shape liquid 0.76g, productive rate 77.0%.
1H?NMR(D
2O,500MHz)δ:7.61～7.49(m,5H,ArH),6.86～6.77(m,1H,CH=CHCO),6.37(d,J=15.2Hz,1H,CH=CHCO),4.61(s,2H,ArCH
2),4.29～4.11(m,2H,(CH
2)
2NCH
2Ar),4.03(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.98～3.85(m,1H,(CH
2)
2NCH
2Ar),3.73～3.63(m,1H,(CH
2)
2NCH
2Ar),3.58～3.37(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.50～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.60～1.55(m,2H,OCH
2–(CH
2)
5–CH
2),1.49(t,J=7.1Hz,3H,NCH
2CH
3),1.44～1.23(m,8H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.6,168.3,150.2,133.2,133.2,131.2,129.6,129.6,126.3,118.9,65.7,63.9,56.1,52.7,39.6,35.9,32.1,28.4,28.3,28.0,27.8,27.6,25.3,20.7,7.1;ESI-MS?m/z:415.29(M–Br)
+;IR(KBr,cm
–1)ν:1731(C=O),1658(C=O),1621(C=C),1249(C–O–C),1036(C–O–C).
Embodiment 12:1-ethyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 2 alternative compounds 1, to nitro bromobenzyl alternative materials methyl iodide, obtains faint yellow solid 0.82g, productive rate 76.0% by raw material.
1H?NMR(D
2O,500MHz)δ:8.30(d,J=8.7Hz,2H,ArH),7.75(d,J=8.7Hz,2H,ArH),6.83～6.76(m,1H,CH=CHCO),6.34(d,J=15.2Hz,1H,CH=CHCO),4.72(s,2H,ArCH
2),4.31～4.11(m,2H,(CH
2)
2NCH
2Ar),4.02(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.94～3.64(m,2H,(CH
2)
2NCH
2Ar),3.60～3.43(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.22～2.15(m,2H,OCH
2–(CH
2)
5–CH
2),2.01(s,3H,CH
3CO
2),1.60～1.52(m,2H,OCH
2–(CH
2)
5–CH
2),1.48(t,J=7.2Hz,3H,NCH
2CH
3),1.43～1.20(m,8H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.4,168.0,150.0,148.8,133.9,133.9,132.8,123.9,123.9,118.2,65.3,62.0,56.1,52.4,39.0,35.4,31.5,27.7,27.6,27.3,26.9,24.6,20.1,6.5;ESI-MS?m/z:460.18(M–Br)
+;IR(KBr,cm
–1)ν:1736(C=O),1659(C=O),1614(C=C),1524(Ar–NO
2),1349(Ar–NO
2),1253(C–O–C),1243(C–O–C).
Embodiment 13:1-ethyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 2 alternative compounds 1, to bromine bromobenzyl alternative materials methyl iodide, obtains white solid 1.03g, productive rate 89.8% by raw material.
1H?NMR(D
2O,500MHz)δ:7.69(d,J=8.4Hz,2H,ArH),7.42(d,J=8.4Hz,2H,ArH),6.87～6.79(m,1H,CH=CHCO),6.36(d,J=15.2Hz,1H,CH=CHCO),4.58(s,2H,ArCH
2),4.29～4.12(m,2H,(CH
2)
2NCH
2Ar),4.05(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.94～3.86(m,1H,(CH
2)
2NCH
2Ar),3.74～3.65(m,1H,(CH
2)
2NCH
2Ar),3.56～3.40(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.26～2.19(m,2H,OCH
2–(CH
2)
5–CH
2),2.05(s,3H,CH
3CO
2),1.63～1.56(m,2H,OCH
2–(CH
2)
5–CH
2),1.50～1.37(m,5H,NCH
2CH
3and?OCH
2–(CH
2)
5–CH
2),1.34～1.22(m,6H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.9,168.6,150.5,134.7,134.7,132.7,132.7,125.4,125.2,118.8,65.9,63.1,56.2,52.6,39.6,35.9,32.0,28.2,28.1,27.8,27.4,25.1,20.7,7.0;ESI-MS?m/z:493.11(M–Br)
+;IR(KBr,cm
–1)ν:1731(C=O),1656(C=O),1614(C=C),1246(C–O–C).
Embodiment 14:1-ethyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 2 alternative compounds 1, to fluorine bromobenzyl alternative materials methyl iodide, obtains white solid 0.62g, productive rate 60.9% by raw material.
1H?NMR(D
2O,500MHz)δ:7.58～7.50(m,2H,ArH),7.28～7.20(m,2H,ArH),6.87～6.77(m,1H,CH=CHCO),6.36(d,J=15.2Hz,1H,CH=CHCO),4.60(s,2H,ArCH
2),4.30～4.11(m,2H,(CH
2)
2NCH
2Ar),4.04(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.94～3.63(m,2H,(CH
2)
2NCH
2Ar),3.57～3.37(m,6H,CON(CH
2)
2and?NCH
2CH
3),2.25～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.63～1.53(m,2H,OCH
2–(CH
2)
5–CH
2),1.50～1.37(m,5H,NCH
2CH
3and?OCH
2–(CH
2)
5–CH
2),1.30～1.21(m,6H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:174.8,168.5,165.1,163.2,150.4,135.4,135.3,122.4,118.8,116.7,116.5,65.8,63.1,56.1,52.5,39.6,35.9,32.0,28.3,28.2,27.9,27.5,25.2,20.7,7.0;ESI-MS?m/z:433.27(M–Br)
+;IR(KBr,cm
–1)ν:1733(C=O),1657(C=O),1607(C=C),1240(C–O–C),1038(C–O–C).
Embodiment 15:1-ethyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 2 alternative compounds 1, to methyl bromobenzyl alternative materials methyl iodide, obtains white transparent oily liquid 0.73g, productive rate 71.7% by raw material.
1H?NMR(D
2O,500MHz)δ:7.36(d,J=7.9Hz,2H,ArH),7.30(d,J=7.7Hz,2H,ArH),6.80～6.73(m,1H,CH=CHCO),6.32(d,J=15.2Hz,1H,CH=CHCO),4.51(s,2H,ArCH
2),4.24～4.04(m,2H,(CH
2)
2NCH
2Ar),3.98(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.89～3.57(m,2H,(CH
2)
2NCH
2Ar),3.51～3.30(m,6H,CON(CH
2)
2andNCH
2CH
3),2.30(s,3H,ArCH
3),2.21～2.10(m,2H,OCH
2–(CH
2)
5–CH
2),1.99(s,3H,CH
3CO
2),1.57～1.48(m,2H,OCH
2–(CH
2)
5–CH
2),1.43(t,J=7.1Hz,3H,NCH
2CH
3),1.40～1.15(m,8H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz);
13C?NMR(D
2O,125MHz)δ:175.3,168.9,150.9,142.5,133.6,133.6,130.7,130.7,123.8,119.4,66.3,64.3,56.5,53.3,40.2,36.5,32.6,28.9,28.9,28.5,28.1,25.8,21.3,21.2,7.7;ESI-MS?m/z:429.20(M–Br)
+;IR(KBr,cm
–1)ν:1737(C=O),1656(C=O),1612(C=C),1245(C–O–C),1039(C–O–C).
Embodiment 16:1-ethyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride
Method, with embodiment 1, by compound 2 alternative compounds 1, to methoxyl group benzyl chloride alternative materials methyl iodide, obtains faint yellow solid 0.54g, productive rate 56.3% by raw material.
1H?NMR(D
2O,500MHz)δ:7.43(d,J=8.4Hz,2H,ArH),7.02(d,J=8.3Hz,2H,ArH),6.81～6.72(m,1H,CH=CHCO),6.33(d,J=15.2Hz,1H,CH=CHCO),4.52(s,2H,ArCH
2),4.28～4.07(m,2H,(CH
2)
2NCH
2Ar),3.97(t,J=6.5Hz,2H,OCH
2–(CH
2)
5–CH
2),3.90～3.76(m,4H,ArOCH
3and(CH
2)
2NCH
2Ar),3.66～3.56(m,1H,(CH
2)
2NCH
2Ar),3.49(t,J=6.5Hz,4H,CON(CH
2)
2),3.39～3.26(m,2H,NCH
2CH
3),2.19～2.10(m,2H,OCH
2–(CH
2)
5–CH
2),2.00(s,3H,CH
3CO
2),1.56～1.48(m,2H,OCH
2–(CH
2)
5–CH
2),1.45(t,J=6.9Hz,3H,NCH
2CH
3),1.39～1.14(m,8H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(D
2O,125MHz)δ:175.1,168.7,161.7,150.7,135.4,135.4,119.5,119.1,115.6,115.6,66.3,64.4,56.4,56.3,53.3,40.1,36.5,32.7,29.0,29.0,28.6,28.2,25.9,21.3,7.7;ESI-MS?m/z:445.21(M–Cl)
+;IR(KBr,cm
–1)ν:1731(C=O),1655(C=O),1611(C=C),1255(C–O–C),1032(Ar–O–C).
Embodiment 17:1-methyl isophthalic acid-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide
Method, with embodiment 1, by compound 3 alternative compounds 1, obtains yellow oily liquid 0.73g, productive rate 70.1%.
1H?NMR(D
2O,500MHz)δ:6.85～6.78(m,1H,CH=CHCO),6.34(d,J=15.3Hz,1H,CH=CHCO),4.03(t,J=6.7Hz,4H,(CH
2)
2NCH
3),3.93～3.72(m,2H,OCH
2–(CH
2)
5–CH
2),3.48～3.35(m,6H,CON(CH
2)
2and?NCH
2–(CH
2)
4–CH
3),3.11(s,3H,NCH
3),2.23～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.01(s,3H,CH
3CO
2),1.78～1.69(m,2H,NCH
2–(CH
2)
4–CH
3),1.60～1.53(m,2H,OCH
2–(CH
2)
5–CH
2),1.45～1.36(m,2H,OCH
2–(CH
2)
5–CH
2),1.35～1.19(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.81(t,J=7.1Hz,3H,NCH
2–(CH
2)
4–CH
3);
13CNMR(D
2O,125MHz)δ:175.0,168.6,150.5,150.5,118.8,65.9,64.7,59.4,47.1,39.8,36.1,32.0,30.5,28.2,28.1,27.8,27.4,25.3,25.1,21.8,21.2,20.7,13.3;ESI-MS?m/z:395.22(M–I)
+;IR(KBr,cm
–1)ν:1729(C=O),1656(C=O),1615(C=C),1252(C–O–C),1035(C–O–C).
Embodiment 18:1-allyl group-1-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, by raw material allyl bromide 98 alternative materials methyl iodide, obtains white solid 0.78g, productive rate 78.4%.
1H?NMR(D
2O,500MHz)δ:6.86～6.77(m,1H,CH=CHCO),6.34(d,J=15.2Hz,1H,CH=CHCO),5.99～5.88(m,1H,CH
2CH=CH
2),5.71～5.63(m,2H,CH
2CH=CH
2),4.05～3.81(m,8H,CH
2CH=CH
2,(CH
2)
2NCH
2CH?and?OCH
2–(CH
2)
5–CH
2),3.50～3.41(m,4H,CON(CH
2)
2),3.44(t,J=8.5Hz,2H,NCH
2–(CH
2)
4–CH
3),2.23～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.01(s,3H,CH
3CO
2),1.76～1.68(m,2H,NCH
2–(CH
2)
4–CH
3),1.60～1.53(m,2H,OCH
2–(CH
2)
5–CH
2),1.44～1.36(m,2H,OCH
2–(CH
2)
5–CH
2),1.34～1.20(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.80(t,J=7.0Hz,3H,NCH
2–(CH
2)
4–CH
3);
13CNMR(D
2O,125MHz)δ:174.9,168.6,150.4,129.5,123.4,118.8,65.8,61.3,58.8,57.2,39.5,35.9,32.0,30.5,28.3,28.2,27.8,27.4,25.2,25.1,21.8,20.9,20.7,13.3;ESI-MS?m/z:421.26(M–Br)
+;IR(KBr,cm
–1)ν:1739(C=O),1658(C=O),1614(C=C),1243(C–O–C),1039(C–O–C).
Embodiment 19:1-n-hexyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, by raw material bromobenzyl alternative materials methyl iodide, obtains pale yellow oily liquid body 0.85g, productive rate 77.6%.
1H?NMR(D
2O,500MHz)δ:7.60～7.46(m,5H,ArH),6.87～6.78(m,1H,CH=CHCO),6.35(d,J=15.2Hz,1H,CH=CHCO),4.61(s,2H,ArCH2),4.29～4.10(m,2H,(CH
2)
2NCH
2Ar),4.05(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),3.92～3.83(m,1H,(CH
2)
2NCH
2Ar),3.72～3.64(m,1H,(CH
2)
2NCH
2Ar),3.55～3.42(m,4H,CON(CH
2)
2),3.30(t,J=8.5Hz,2H,NCH
2–(CH
2)
4–CH
3),2.26～2.18(m,2H,OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.91～1.82(m,2H,NCH
2–(CH
2)
4–CH
3),1.62～1.55(m,2H,OCH
2–(CH
2)
5–CH
2),1.46～1.39(m,2H,OCH
2–(CH
2)
5–CH
2),1.36～1.23(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.85(t,J=6.9Hz,3H,NCH
2–(CH
2)
4–CH
3);
13C?NMR(D
2O,125MHz)δ:174.9,168.6,150.5,132.9,132.9,131.2,129.6,129.6,126.3,118.7,65.9,64.4,56.9,56.8,39.6,36.0,32.0,30.6,28.2,28.1,27.8,27.4,25.2,25.1,21.9,21.2,20.6,13.3;ESI-MS?m/z:471.31(M–Br)
+;IR(KBr,cm
–1)ν:1736(C=O),1656(C=O),1615(C=C),1245(C–O–C),1033(C–O–C).
Embodiment 20:1-n-hexyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, to nitro bromobenzyl alternative materials methyl iodide, obtains pale yellow oily liquid body 0.87g, productive rate 73.4% by raw material.
1H?NMR(CD
3OD,500MHz)δ:8.40(d,J=8.6Hz,2H,ArH),7.88(d,J=8.5Hz,2H,ArH),6.94～6.84(m,1H,CH=CHCO),6.49(d,J=15.1Hz,1H,CH=CHCO),4.91(s,2H,ArCH
2),4.43～4.22(m,2H,(CH
2)
2NCH
2Ar),4.07(t,J=6.7Hz,2H,OCH
2–(CH
2)
5–CH
2),4.03～3.73(m,2H,(CH
2)
2NCH
2Ar),3.69～3.52(m,4H,CON(CH
2)
2),3.46(t,J=8.2Hz,2H,NCH
2–(CH
2)
4–CH
3),2.33～2.23(m,2H,OCH
2–(CH
2)
5–CH
2),2.04(s,3H,CH
3CO
2),2.02～1.94(m,2H,NCH
2–(CH
2)
4–CH
3),1.71～1.59(m,2H,OCH
2–(CH
2)
5–CH
2),1.54～1.33(m,14H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.97(t,J=7.0Hz,3H,NCH
2–(CH
2)
4–CH
3);
13CNMR(CD
3OD,125MHz)δ:172.3,167.2,150.0,149.1,134.9,134.9,134.1,124.5,124.5,119.6,64.9,63.1,57.9,57.6,39.6,36.0,32.6,31.6,29.3,29.2,28.9,28.5,26.1,26.1,22.7,22.1,20.1,13.5;ESI-MS?m/z:516.31(M–Br)
+;IR(KBr,cm
–1)ν:1731(C=O),1656(C=O),1609(C=C),1526(Ar–NO2),1349(Ar–NO2),1249(C–O–C),1040(C–O–C).
Embodiment 21:1-n-hexyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, to bromine bromobenzyl alternative materials methyl iodide, obtains white solid 0.93g, productive rate 73.7% by raw material.
1H?NMR(CD
3OD,500MHz)δ:7.74(d,J=8.2Hz,2H,ArH),7.52(d,J=8.1Hz,2H,ArH),6.92～6.85(m,1H,CH=CHCO),6.49(d,J=15.1Hz,1H,CH=CHCO),4.75(s,2H,ArCH
2),4.41～4.21(m,2H,(CH
2)
2NCH
2Ar),4.07(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),4.03～3.89(m,1H,(CH
2)
2NCH
2Ar),3.83～3.71(m,1H,(CH
2)
2NCH
2Ar),3.64～3.47(m,4H,CON(CH
2)
2),3.39(t,J=8.3Hz,2H,NCH
2–(CH
2)
4–CH
3),2.33～2.24(m,2H,OCH
2–(CH
2)
5–CH
2),2.04(s,3H,CH
3CO
2),1.98～1.90(m,2H,NCH
2–(CH
2)
4–CH
3),1.70～1.49(m,4H,OCH
2–(CH
2)
5–CH
2),1.49～1.33(m,12H,OCH
2–(CH
2)
5–CH
2andNCH
2–(CH
2)
4–CH
3),0.97(t,J=6.7Hz,3H,NCH
2–(CH
2)
4–CH
3);
13CNMR(CD
3OD,125MHz)δ:171.6,166.6,148.5,134.5,134.5,132.4,132.4,125.8,125.2,119.0,64.3,63.1,57.0,56.7,39.1,35.4,32.0,31.0,28.7,28.6,28.3,27.9,25.5,25.5,22.1,21.4,19.5,12.8;ESI-MSm/z:551.21(M–Br)
+;IR(KBr,cm
–1)ν:1733(C=O),1656(C=O),1612(C=C),1246(C–O–C),1040(C–O–C).
Embodiment 22:1-n-hexyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, to fluorine bromobenzyl alternative materials methyl iodide, obtains white solid 0.95g, productive rate 83.6% by raw material.
1HNMR(D
2O,500MHz)δ:7.60～7.56(m,2H,ArH),7.37～7.32(m,2H,ArH),6.70～6.55(m,1H,CH=CHCO),6.45(d,J=15.0Hz,1H,CH=CHCO),4.71(s,2H,ArCH
2),4.12～4.10(m,2H,(CH
2)
2NCH
2Ar),3.96(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.92～3.42(m,2H,(CH
2)
2NCH
2Ar),3.41～3.29(m,4H,CON(CH
2)
2),2.18～2.14(m,2H,OCH
2–(CH
2)
5–CH
2),1.97(s,3H,CH
3CO
2),1.79～1.77(m,2H,NCH
2–(CH
2)
4–CH
3),1.55～1.29(m,4H,OCH
2–(CH
2)
5–CH
2),1.30～1.20(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.86(t,J=7.0Hz,3H,NCH
2–(CH
2)
4–CH
3)
; 13CNMR(DMSO-d
6,125MHz)δ:170.9,165.3,164.7,162.7,147.3,135.8,135.8,124.1,120.3,116.6,116.5,64.2,62.5,57.0,56.0,39.1,35.6,32.1,31.1,28.9,28.8,28.6,28.2,25.8,25.7,22.3,21.4,21.2,14.2;ESI-MSm/z:489.29(M–Br)
+;IR(KBr,cm
–1)ν:1732(C=O),1656(C=O),1606(C=C),1235(C–O–C),1036(C–O–C).
Embodiment 23:1-n-hexyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method, with embodiment 1, by compound 3 alternative compounds 1, to methyl bromobenzyl alternative materials methyl iodide, obtains white solid 0.85g, productive rate 75.4% by raw material.
1HNMR(CD
3OD,500MHz)δ:7.45(d,J=8.0Hz,2H,ArH),7.38(d,J=7.9Hz,2H,ArH),6.93～6.86(m,1H,CH=CHCO),6.49(d,J=15.0Hz,1H,CH=CHCO),4.70(s,2H，ArCH
2)，4.38～4.20(m，2H，(CH
2)
2NCH
2Ar)，4.07(t，J=6.4Hz，2H，OCH
2-(CH
2)
5CH
2)，4.02～3.71(m,2H,(CH
2)
2NCH
2Ar),3.61～3.47(m,4H,CON(CH
2)
2),3.38～3.31(m,2H,NCH
2–(CH
2)
4–CH
3),2.43(s,3H,ArCH
3),2.33～2.26(m,2H,OCH
2–(CH
2)
5–CH
2),2.04(s,3H,CH
3CO
2),1.99～1.89(m,2H,NCH
2–(CH
2)
4–CH
3),1.70～1.48(m,4H,OCH
2–(CH
2)
5–CH
2),1.45～1.34(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.97(t,J=6.9Hz,3H,NCH
2–(CH
2)
4–CH
3);
13C?NMR(CD
3OD,125MHz)δ:171.6,166.6,148.5,141.4,132.5,132.5,129.8,129.8,123.6,119.0,64.2,63.7,56.9,56.5,39.1,35.6,32.0,31.0,28.7,28.6,28.2,27.9,25.5,25.5,22.1,21.4,19.9,19.4,12.8;ESI-MS?m/z:485.29(M–Br)
+;IR(KBr,cm
–1)ν:1735(C=O),1657(C=O),1615(C=C),1245(C–O–C),1038(C–O–C).
Embodiment 24:1-n-hexyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride
Method, with embodiment 1, by compound 3 alternative compounds 1, to methoxyl group benzyl chloride alternative materials methyl iodide, obtains white solid 0.89g, productive rate 83.8% by raw material.
1H?NMR(D
2O,500MHz)δ:7.42(d,J=8.5Hz,2H,ArH),7.06(d,J=7.06Hz,2H,ArH),6.85～6.77(m,1H,CH=CHCO),6.35(d,J=15.2Hz,1H,CH=CHCO),4.54(s,2H,ArCH
2),4.29～4.08(m,2H,(CH
2)
2NCH
2Ar),4.03(t,J=6.6Hz,2H,OCH
2–(CH
2)
5–CH
2),3.91～3.78(m,4H,ArOCH
3and(CH
2)
2NCH
2Ar),3.70～3.60(m,1H,(CH
2)
2NCH
2Ar),3.54～3.36(m,4H,CON(CH
2)
2),3.31～3.23(m,2H,NCH
2–(CH
2)
4–CH
3),2.24～2.17(m,2H,OCH
2–(CH
2)
5–CH
2),2.02(s,3H,CH
3CO
2),1.89～1.78(m,2H,NCH
2–(CH
2)
4–CH
3),1.61～1.37(m,4H,OCH
2–(CH
2)
5–CH
2),1.36～1.21(m,12H,OCH
2–(CH
2)
5–CH
2and?NCH
2–(CH
2)
4–CH
3),0.84(t,J=6.9Hz,3H,NCH
2–(CH
2)
4–CH
3);
13C?NMR(D
2O,125MHz)δ:175.4,169.1,161.7,151.1,135.1,135.1,119.4,119.2,115.6,115.6,66.4,64.9,57.1,56.3,40.2,36.6,32.6,31.2,28.8,28.7,28.4,28.3,28.0,25.8,25.7,22.5,21.8,21.2,13.9;ESI-MS?m/z:501.30(M–Cl)
+;IR(KBr,cm
–1)ν:1731(C=O),1655(C=O),1612(C=C),1255(C–O–C),1032(Ar–O–C).
Embodiment 25:1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium iodide
Under agitation condition, by compound 4 (2mmol), 30mL acetonitrile, raw material methyl iodide (4mmol) joins in 50mL round-bottomed flask successively, and 85 ℃ of reactions, with TLC monitoring reaction (developping agent: V
methyl alcohol: V
chloroform=1:10), after having reacted, by reaction solution concentrating under reduced pressure, gained thick silica gel column chromatography (eluent: V for product
methyl alcohol: V
chloroform=1:30) separating-purifying obtains pale yellow oily liquid body 0.72g, productive rate 77.7%.
1H?NMR(CD
3Cl,500MHz)δ:6.95～6.88(m,1H,CH=CHCO),6.23(d,J=15.0Hz,1H,CH=CHCO),4.12～4.05(m,4H,OCH
2–(CH
2)
5–CH
2and?CON(CH
2)
2),3.98～3.86(m,5H,CON(CH
2)
2and(CH
2)
2NCH
3),3.58(s,6H,CH
2N(CH
3)
2),2.62～2.50(m,1H,(CH
2)
2NCH
3),2.49～2.15(m,4H,NCH
2CH
2CH
2N?and?OCH
2–(CH
2)
5–CH
2),2.05(s,3H,CH
3CO
2),1.65～1.21(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:171.2,167.2,148.8,120.0,66.1,65.1,65.0,53.8,45.3,39.3,32.6,29.7,29.1,29.0,28.5,28.2,25.8,23.5,21.0;ESI-MSm/z:339.27(M–I)
+;IR(KBr,cm
–1)ν:1725(C=O),1654(C=O),1604(C=C),1250(C–O–C),998(C–O–C).
Embodiment 26:1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Method, with embodiment 25, by raw material allyl bromide 98 alternative materials methyl iodide, obtains white transparent oily liquid 0.72g, productive rate 81.3%.
1H?NMR(CD
3Cl,500MHz)δ:6.97～6.90(m,1H,CH=CHCO),6.21(d,J=15.7Hz,1H,CH=CHCO),6.18～6.02(m,1H,CH
2CH=CH
2),5.89(d,J=16.8Hz,1H,CH
2CH=CH
2),5.75(d,J=10.1Hz,1H,CH
2CH=CH
2),4.58～4.31(m,6H,OCH
2–(CH
2)
5–CH
2,CON(CH
2)
2),4.03(t,4H,J=6.7Hz,(CH
2)
2NCH
2CH),3.94～3.62(m,5H,NCH
3and?CH
2CH=CH
2),2.42～2.30(m,2H,OCH
2–(CH
2)
5–CH
2),2.27～2.13(m,2H,NCH
2CH
2CH
2N),2.04(s,3H,CH
3CO
2),1.65～1.27(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:171.2,167.4,149.1,130.4,124.5,119.5,67.0,64.5,63.6,62.0,49.8,45.7,39.2,32.6,29.6,29.0,28.5,28.1,28.0,25.8,23.0,21.0;ESI-MS?m/z:365.29(M–Br)
+;IR(KBr,cm
–1)ν:1739(C=O),1654(C=O),1602(C=C),1245(C–O–C),1042(C–O–C).
Embodiment 27:1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Method, with embodiment 25, by raw material bromobenzyl alternative materials methyl iodide, obtains faint yellow transparent oily liquid 0.97g, productive rate 97.8%.
1H?NMR(CD
3Cl,500MHz)δ:7.65(d,J=6.9Hz,2H,ArH),7.48～7.37(m,3H,ArH),6.92～6.84(m,1H,CH=CHCO),6.17(d,J=14.8Hz,1H,CH=CHCO),5.39～5.08(m,2H,ArCH
2),4.11～3.79(m,8H,OCH
2–(CH
2)
5–CH
2,CON(CH
2)
2,and(CH
2)
2NCH
2Ar),3.72～3.55(m,2H,(CH
2)
2NCH
2Ar),3.26(s,3H,NCH
3),2.50～2.11(m,4H,NCH
2CH
2CH
2N?and?OCH
2–(CH
2)
5–CH
2),2.02(s,3H,CH
3CO
2),1.62～1.24(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:166.4,148.5,148.0,133.0,133.0,130.3,128.8,128.8,126.5,119.0,67.7,64.0,62.4,62.0,47.6,44.8,38.2,32.0,29.1,28.8,28.5,28.4,28.0,27.7,25.2,22.7,20.5;ESI-MS?m/z:415.32(M–Br)
+;IR(KBr,cm
–1)ν:1735(C=O),1657(C=O),1614(C=C),1245(C–O–C),1040(C–O–C).
Embodiment 28:1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Method, with embodiment 25, to nitro bromobenzyl alternative materials methyl iodide, obtains white solid 0.50g, productive rate 46.4% by raw material.
1H?NMR(CD
3Cl,500MHz)δ:8.36(d,J=6.8Hz,2H,ArH),7.87(d,J=7.5Hz,2H,ArH),6.91～6.78(m,1H,CH=CHCO),6.42(d,J=15.0Hz,1H,CH=CHCO),4.21～3.98(m,3H,OCH
2–(CH
2)
5–CH
2and?CON(CH
2)
2),3.94～3.55(m,7H,CON(CH
2)
2,and(CH
2)
2NCH
2Ar),3.14(s,3H,NCH
3),2.52～2.23(m,4H,NCH
2CH
2CH
2N?and?OCH
2–(CH
2)
5–CH
2),2.03(s,3H,CH
3CO
2),1.63～1.25(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CD
3OD,125MHz)δ:175.6,171.8,153.4,152.1,138.5,138.5,137.7,127.7,127.7,123.8,71.3,68.2,68.1,66.8,49.4,47.1,44.3,41.7,36.0,32.6,32.6,32.2,32.0,29.5,25.6,23.4;ESI-MS?m/z:460.31(M–Br)
+;IR(KBr,cm
–1)ν:1733(C=O),1651(C=O),1612(C=C),1526(Ar–NO
2),1350(Ar–NO
2),1248(C–O–C),1046(C–O–C).
Embodiment 29:1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Method, with embodiment 25, to bromine bromobenzyl alternative materials methyl iodide, obtains pale yellow oily liquid body 1.09g, productive rate 95.6% by raw material.
1H?NMR(CD
3Cl,500MHz)δ:7.60～7.52(m,4H,ArH),6.92～6.84(m,1H,CH=CHCO),6.16(d,J=15.0Hz,1H,CH=CHCO),5.44～5.12(m,2H,ArCH
2),4.12～3.79(m,8H,OCH
2–(CH
2)
5–CH
2,CON(CH
2)
2,and(CH
2)
2NCH
2Ar),3.75～3.58(m,1H,(CH
2)
2NCH
2Ar),3.30(s,3H,NCH
3),2.72～2.54(m,3H,NCH
2CH
2CH
2N?and(CH
2)
2NCH
2Ar),2.23～2.16(m,2H,OCH
2–(CH
2)
5–CH
2),2.04(s,3H,CH
3CO
2),1.66～1.24(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:171.2,167.0,148.8,135.1,135.1,132.6,132.6,126.0,125.8,119.4,67.2,64.5,63.3,62.3,48.3,45.4,38.7,32.6,30.0,29.1,29.0,28.5,28.2,25.8,23.1,21.1;ESI-MS?m/z:493.26(M–Br)
+;IR(KBr,cm
–1)ν:1738(C=O),1656(C=O),1615(C=C),1248(C–O–C),1046(C–O–C).
Embodiment 30:1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Embodiment 31:1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio
Method, with embodiment 25, to methyl bromobenzyl alternative materials methyl iodide, obtains white transparent oily liquid 0.73g, productive rate 71.8% by raw material.
1H?NMR(CD
3Cl,500MHz)δ:7.47(d,J=7.3Hz,2H,ArH),7.15(d,J=7.5Hz,2H,ArH),6.87～6.83(m,1H,CH=CHCO),6.13(d,J=15.0Hz,1H,CH=CHCO),5.15～4.92(m,2H,ArCH
2),4.00(t,J=6.6Hz,4H,OCH
2–(CH
2)
5–CH
2and?CON(CH
2)
2),3.95～3.70(m,6H,CON(CH
2)
2and(CH
2)
2NCH
2Ar),3.26(s,3H,NCH
3),2.45～2.28(m,5H,NCH
2CH
2CH
2N?and?ArCH
3),2.21～2.09(m,2H,OCH
2–(CH
2)
5–CH
2),2.00(s,3H,CH
3CO
2),1.68～1.18(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:170.6,166.6,148.1,140.4,132.8,132.8,129.3,129.3,123.5,119.0,67.8,63.9,62.7,61.2,47.6,45.0,38.2,35.0,32.0,28.6,28.4,28.0,27.6,25.2,20.8,20.4;ESI-MS?m/z:429.33(M–Br)
+;IR(KBr,cm
–1)ν:1737(C=O),1656(C=O),1615(C=C),1243(C–O–C),1036(C–O–C).
Embodiment 32:1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium chloride
Method, with embodiment 25, to methoxyl group bromobenzyl alternative materials methyl iodide, obtains white transparent oily liquid 0.87g, productive rate 90.2% by raw material.
1H?NMR(CD
3Cl,500MHz)δ:7.58～7.50(m,2H,ArH),7.00～6.85(m,3H,ArH?and?CH=CHCO),6.15(d,J=15.0Hz,1H,CH=CHCO),5.27～4.92(m,2H,ArCH
2),4.10～3.92(m,4H,OCH
2–(CH
2)
5–CH
2and(CH
2)
2NCH
2Ar),3.91～3.68(m,9H,ArOCH
3,CON(CH
2)
2and(CH
2)
2NCH
2Ar),3.25(s,3H,NCH
3),2.50～2.31(m,2H,NCH
2CH
2CH
2N),2.23～2.14(m,2H,OCH
2–(CH
2)
5–CH
2),2.05(s,3H,CH
3CO
2),1.65～1.27(m,10H,OCH
2–(CH
2)
5–CH
2);
13C?NMR(CDCl
3,125MHz)δ:171.2,167.0,161.3,148.8,135.0,135.0,119.4,119.0,114.6,114.6,68.6,64.5,62.8,61.8,55.4,47.9,45.6,38.8,32.6,29.7,29.1,29.0,28.5,28.1,25.8,23.1,20.9;ESI-MS?m/z:445.33(M–Cl)
+;IR(KBr,cm
–1)ν:1734(C=O),1652(C=O),1611(C=C),1251(C–O–C),1033(Ar–O–C).
Application:
Embodiment 1: the anti-tumor activity test of compound
The present invention applies the anti tumor activity in vitro that classical mtt assay has been investigated part of compounds.
One, materials and methods
1. cell strain
Transfection cervical cancer cell, Hela-bcl-2-empty carrier, Hela-bcl-2-3, Hela-bcl-2-4 is provided by Beijing Military Medical Science Institute.
2. reagent
RPMI – 1640, foetal calf serum (FBS), G418, trypsinase, MTT, SDS.
3. dosage and grouping
Compound is seven dosage groups of 0.3,1,3,10,30,100,300 μ M; Blank group is set simultaneously; Solvent control group.
4. experimental technique
The transfection Hela Growth of Cells of cultivating, to nearly fusion state, with 0.25% tryptic digestion 2min, is prepared single cell suspension with nutrient solution (1640+10%FBS+1mg/mL G418), adjusts cell concn to 3 * 10
4individual/mL, is inoculated in 96 well culture plates, 100 μ l/ holes, 37 ℃ of 5%CO
2after lower cultivation 24h, first add the 80 full substratum in μ l/ hole, then add the test-compound 20 μ L/ holes of different concns, 3 repetitions are established in every kind of processing, 37 ℃ of 5%CO
2lower continuation is cultivated after 72h, every hole sucking-off supernatant 100 μ L, then add tetrazolium bromide (MTT) the solution 10 μ L of 5mg/mL, and 37 ℃ are continued to hatch 4h, and last every hole adds the SDS of 100 μ L10%, 37 ℃ of 5%CO
2under hatch 24h, MTT crystallization is dissolved completely.Enzyme-linked immunosorbent assay instrument 570nm wavelength is measured every hole absorbancy.Press formula:
Inhibiting rate (%)=(1 – is subject to the average OD value in prospect hole OD value/solvent control hole) * 100%
Calculate inhibiting rate, and to take the logarithm of test-compound concentration be X-coordinate, cell inhibitory rate mean value is that ordinate zou is drawn dose effect curve, and asks half cytostatics value (IC with Origin analysis software
50).Result with
represent.
Two, the anti-tumor activity result of part of compounds
The IC of table 1 part embodiment to Bcl-2 empty carrier and Bcl-2 high expression level Hela cell
50(μ M)
As known from Table 1, to Hela, cell proliferation has certain restraining effect to embodiment, basically identical in the cell strain experimental result of this 2 strain of Hela-Bcl-2-3, Hela-Bcl-2-4 Bcl-2 high expression level.
Embodiment 2: the activity of cholinesterase test of compound
The present invention's application Ellman (Biochemical Pharmacology1961,7, the IC that method test compounds 88-95.) suppresses Pseudocholinesterase
50value.All tests are all with Microplate reader ELX808
tMtype microplate reader (U.S. BioTek company) is measured under 37 ℃ of conditions.Data analysis software is used Origin software to carry out data processing, uses Galanthamine product in contrast.
One, materials and methods
1. the preparation of inhibitor storing solution
The inhibitor of testing is made into the DMSO solution of 10mM.
2. the preparation of enzyme storing solution
Acetylcholinesterase (extracting from electric eel) and butyrylcholine esterase (from the blood plasma of horse, extracting) are purchased from Sigma company; With the phosphate buffered saline buffer of pH=8.0, be made into respectively 0.1mg/mL, 2mg/mL.
3. the preparation of substrate storing solution
Acetyl mercapto choline (acetylcholinesterase substrate) and butyryl sulfydryl choline (butyrylcholine esterase substrate) are purchased from Sigma company; With the phosphate buffered saline buffer of pH=8.0, be made into respectively 2mg/mL, 4mg/mL.
4. the preparation of developer storing solution
Developer DTNB is purchased from Sigma company; With the phosphate buffered saline buffer of pH=8.0, be made into respectively 4mg/mL (test acetylcholinesterase) and 8mg/mL (test butyrylcholine esterase).
5. test
The volume of each test is all the phosphate buffered saline buffer of the pH=8.0 of 150 μ L.In 96 hole enzyme plates, add 6 μ L developer storing solutions, add respectively again 15 μ L different concns inhibitor solutions (with pH=8.0 phosphate buffer soln dilution inhibitor storing solution), with pH=8.0 phosphate buffer soln polishing to 139 μ L, then add 5 μ L enzyme storing solutions, in the microplate reader of 37 ℃, be incubated 12min, add immediately 6 μ L substrate storing solutions, one minute absorbancy changes (slope) at λ=405nm place after mixing, to survey immediately it.Reference liquid is pH=8.0 phosphate buffer soln.
6. result judgement
Using and do not add the measured absorbancy variation (slope) of sample as 100 unit of activity; Enzyme activity=(adding the absorbancy of inhibitor to change (slope)/do not add the absorbancy of inhibitor to change (slope)) * 100, the concentration of the inhibitor when the relative activity of enzyme is 50 is the IC of inhibitor
50value.
Two, the active result of the anticholinesterase of compound
Table 2 part of compounds is active to the inhibition of cholinesterase
As known from Table 2, majority of compounds shows AChE and the stronger inhibition ability of BuChE, and it is the strongest that 19 couples of AChE of embodiment suppress ability, its IC
50be 4.23 μ M, the inhibition of 21 couples of BuChE of embodiment is best, its IC
50be 2.81 μ M.
Embodiment 3: the bacteriostatic activity test of compound
The present invention's application coating method has been tested the minimum inhibitory concentration of compound to streptococcus aureus (Staphylococcus aureus).
One, experimental technique
1. spawn culture
By streptococcus aureus streak inoculation, on beef-protein medium, at 37 ℃, enlarged culturing is standby.
2. initial liquid preparation
Take 5mg sample and be dissolved in 5mL acetone, after all dissolving, move in the volumetric flask of 10mL, then, with 5mL sterilized water dilution constant volume, being mixed with concentration is the standby medicine (solvent: V of 0.5g/L
acetone: V
sterilized water=1:1), blank liquid is made into 0.5mL acetone and 0.5mL sterilized water, establishes a blank, each concentration do three parallel.
3. with the preparation of medicine substratum
Under aseptic condition, draw 1mL liquid (control group V
acetone: V
sterilized water=1:1 replaces) mix with the sterilising medium of 9mL hot melt, pour in the glass culture dish that diameter is 9cm, make thin and thick and be with uniformly medicine plate culture medium standby.Now liquor strength has been diluted 10 times, and liquid ultimate density is 0.05g/L.
4. a small amount of cultured for trying bacterium in the sterilized water of 10mL with transfering loop picking, make concentration approximately 10
6～10
7the bacteria suspension of cfu/mL.Draw 100 μ L bacteria suspensions to contrast and band medicine plate culture medium, with the spreading rod of sterilizing, bacterium liquid is coated with evenly, 3 repetitions are established in each processing, are finally placed in 37 ℃ of constant incubators and cultivate, and respectively at 24h and 48h observations, experimental result is listed in table 3.
Two, the bacteriostatic activity result of compound
The restraining effect of table 3 part of compounds of the present invention to streptococcus aureus
Note: ++++represent strong bacteriostasis, almost not growth, +++ represent very small portion growth ,+number more multilist shows that bacteriostasis is stronger, – represents there is no bacteriostasis.
Experimental result shows, most of embodiment compound has bacteriostatic action, and embodiment 19 and embodiment 21 bacteriostatic action are the strongest, and its minimum inhibitory concentration is 0.04g/L.
Claims (9)
1. the compound shown in formula I or its pharmaceutically acceptable salt,
?
Formula I
Wherein:
N is 1 or 2;
X
–independently selected from chlorion, bromide anion, iodide ion;
R
1, R
2for substituted radical that can be identical or different, independently selected from hydrogen, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Wherein each alkyl, thiazolinyl, alkynyl part are optionally replaced independently selected from following group by 1-5: hydroxyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl.
2. material as claimed in claim 1, wherein R
1, R
2be selected from respectively methyl, ethyl, n-hexyl, allyl group, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl.
3. as the material in claim 1, be selected from:
1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
1-methyl isophthalic acid-ethyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
1-ethyl-1-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-ethyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
1-methyl isophthalic acid-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide;
1-allyl group-1-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-is to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-is to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-is to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
1-n-hexyl-1-is to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium chloride;
1,1-dimethyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium iodide;
1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-brometo de amonio;
1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) homopiperazine-1-ammonium chloride.
4. the method for preparing compound described in claim 1, comprising: take E-10-hydroxy-2-decylenic acid as raw material, through esterification, there is respectively amination reaction with bridged piperazine derivatives, homopiperazine derivative, obtain corresponding intermediate, then pass through quaterisation, synthetic corresponding piperazine, homopiperazine quaternary ammonium salt, reaction formula is:
，
Wherein:
N is 1 or 2;
X
–independently selected from chlorion, bromide anion, iodide ion;
R
1, R
2for substituted radical that can be identical or different, independently selected from hydrogen, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl, benzyl, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Wherein each alkyl, thiazolinyl, alkynyl part are optionally replaced independently selected from following group by 1-5: hydroxyl, C
1-C
10alkyl, C
2-C
l0thiazolinyl, C
2-C
10alkynyl.
5. a pharmaceutical composition, comprises at least one pharmaceutically acceptable carrier and material as defined in claim 1.
6. the application of material as defined in claim 1 aspect preparation treatment cervical cancer medicine.
7. material as defined in claim 1 is in the application of preparing aspect anti-acetylcholinesterase and butyrylcholine esterase medicine.
8. the application of material as defined in claim 1 aspect the medicine for the preparation for the treatment of infection of staphylococcus aureus.
9. the injection, oral acceptable preparation, local application's preparation, sprays or the drops that contain the material shown in formula I described in claim 1.
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