CN102408395A - 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 PDF

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CN102408395A
CN102408395A CN2011103245350A CN201110324535A CN102408395A CN 102408395 A CN102408395 A CN 102408395A CN 2011103245350 A CN2011103245350 A CN 2011103245350A CN 201110324535 A CN201110324535 A CN 201110324535A CN 102408395 A CN102408395 A CN 102408395A
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piperazine
decenoyl
acetoxyl group
brometo
amonio
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CN102408395B (en
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苏桂发
郑志兵
农娟
李松
***
覃江克
潘成学
唐煌
邓业成
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Guangxi Normal University
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Abstract

The invention relates to a compound of formula I or pharmaceutically acceptable salt and solvate thereof, 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 anti-tumor drug, in particular drug for treating malignant tumors such as solid tumor, acute leukemia and the like, and preparing anti-acetylcholinesterase drug for treating diseases such as Alzheimer disease and cerebral vascular dementia and the like, and preparing drug for treating gram-positive bacterium and negative bacterium infection.

Description

New piperazine and high piperazine derivative
Technical field
The present invention relates to new piperazine and high piperazine derivative or its pharmacologically acceptable salts, solvolyte, and preparation method thereof, and the pharmaceutical composition that contains above-mentioned substance.
Background technology
Piperazine is claimed hexahydropyrazine again, is the hexa-member heterocycle that contains two nitrogen-atoms in the molecule, and its Enthalpies of Formation is high, Heat stability is good, is the ideal structure unit of rich nitrogen heterocyclic, is the important component part of a lot of medicines.Diethylenediamine compound is compared with traditional organic drug, has better nitrogen equilibrium symplex structure.In organic synthesis, introduce piperazine ring,, can improve the pharmacokinetic property of medicine, improve the biological activity of medicine as the synergy group of medicine.
On piperazine ring, introduce different substituting groups; Because the difference of substituted radical, position and mode of connection; Piperazine compounds has shown various chemical structure and pharmacologically active widely,, anti-diabetic cardiovascular like antibiotic, anti-oxidant, antitumor, psychosis, inhibition, treatment alzheimer's disease.In recent years, the research of relevant piperazine compounds report is more, and increases progressively with fast speeds, and particularly relevant this nitrogen heterocycles medicine is in pharmaceutically application.
The piperazine compounds of following structure be a kind of Comprecin (the medicine vertical wave. Medical Molecular Biology experimental technique [M]. Beijing: the People's Health Publisher, 2002, p. 365 – p. 366.).It has broad-spectrum antibacterial action; Inhibition effect to aerobic gram negative bacillus is best; The drug-fast NEISSERIA GONORRHOEAE of most of bacterium, penicillium mould, product enzyme hemophilus influenzae and Moraxella to enterobacteriaceae have good anti-microbial effect, and be all effective to gram-positive microorganism and Gram-negative bacteria.As sterilant, it is mainly through acting on the DNA of bacteria gyrase, thereby suppresses the synthesizing of DNA, duplicate and cause bacterial death.
Figure 2011103245350100002DEST_PATH_IMAGE001
The piperazine compounds of following structure is a kind of ACE-1 suppressor factor, the new compound of the most potential treatment AD ( J. Med. Chem. 2006, 49(14): 4275-4285.).On piperazine ring, introduce the hydroxyl side chain for 4, it is active significantly to strengthen its inhibition to BACE-1, because 4 replacements can produce effectively interaction with the avtive spot of BACE-1 on the piperazine ring, thereby it is active to the inhibition of BACE-1 to help improving compound.
 
Figure 832943DEST_PATH_IMAGE002
The piperazine compounds of following structure be a kind of anti-allergy agent ( Ann. Allergy 1991, 67(4): 416-420; Allergy 1994, 49(8): 598-604.), it is a kind of peripheral H1-receptor antagonist, can suppress the transmission and the effect of histamine, reduces moving of inflammatory cell, has multiple anti-allergic effects.
Figure 2011103245350100002DEST_PATH_IMAGE003
The piperazine compounds of following structure be a kind of dibenzo diazepine verivate the wide spectrum psychotroptic drug ( New drug and clinical, 1982, 1(1): 25-27.).This medical instrument has quick sedative effect, can control patient's illusion vain hope behavior rapidly, regulates affective activity, and all kinds of acute and chronic schizophrenia are all had better curative effect.
The piperazine compounds of following structure be a kind of antidiabetic drug ( Vasc. Health Risk Manag. 2007, 3(2): 203-210; Bioorg. Med. Chem. Lett. 2007, 17(12): 3373-3377.).This medicine is applicable to the diabetes B patient that can not tolerate other ofhypoglycemic medicines, and the ability controlling blood sugar realizes that hypoglycemic is up to standard, and it is cardiovascular to reach protection, the effect of complication prevention.
The piperazines medicine has rapid-action, the characteristics such as side reaction is little, toxicity is low, no habituation property of effect mostly, receives liking of many researchers.Yet this type medicine is mostly water-soluble relatively poor, has limited its clinical application as oral medicine and medical injection.Therefore, increase the solubleness of such new compound in water, make it to become new drug, be of great significance and value with DEVELOPMENT PROSPECT.Li Runtao etc. find in the research to the antitumor drug of two piperazine bi-quaternary ammonium salt compounds; Quaternary ammonium ion is to regulating oily – water dispenser compared with to certain function; The toxicity of this compounds has tangible relation with active with oily – water dispenser ratio, the toxicity of compound with fat-soluble increase increase ( Acta Pharmaceutica Sinica, 1995, 30(1): 63-69.).Therefore piperazine is carried out quaternizedly, explore dissimilar quaternary ammonium salt compound methods, seek the quaternary ammonium salt of higher physiologically active, become current hot issue.
Sommers etc. show the correlation research of pharmaceutical activity and structure, replace piperazine with high piperazine after, institute's synthetic medicine marezine, curosajin to antihistaminic activity obviously strengthen ( J. Am. Chem. Soc. 1954, 76: 5805-5805.).Ziegler etc. show the correlation research of pharmaceutical activity and structure, if contain high piperazine group in the compound, the activity of its medicine significantly improve ( J. Med. Chem. 1990, 33(1): 142-146.).Therefore, the research of high piperazine series compound more and more comes into one's own.In China, high piperazine is mainly used in pharmaceutical industry, and the medicinal efficacy of the high bridged piperazine derivatives of external popular exploitation is like anti-inflammatory, analgesia, hypoglycemic etc.
At present, domestic nitrogen heterocyclic is mainly used in the production Comprecin, this medicine be through suppress duplicating of bacterium gyrase blocking dna produce anti-microbial effect ( Chemical intermediate, 2008, (9): 12-16.).With high piperazine is quinoline and the isoquinilone derivatives that raw material is modified; Carbostyril derivative; Medicines such as thiazolidine hydroxy acid amide derivatives; Be used for synthetic pyridazine amine; Water soluble azoles; The medicines such as benzyl amine derivative that contain nitroxyl; To the treatment cardiovascular disorder; Pneumocystis carinii pneumonia is particularly to AIDS patient's pneumocystis carinii pneumonia; Asthma; Central nervous system disorders comprise dysthymia disorders and anxiety etc. show good curative effect (Cai Liuqing. the synthetic and technological transformation [D] of high piperazine. Shanxi: Northcentral University 2009.).
Summary of the invention
The object of the invention provides new piperazine and high piperazine derivative; Or its pharmacologically acceptable salts, solvolyte; And preparation method thereof, with and at the preparation acetylcholine esterase inhibition activity, suppress the application of aspect medicines such as activity of tumor cells and bacteriostatic activity.
The present invention provides the compound shown in the formula I or its pharmacologically acceptable salts, solvolyte.
 
Figure 2011103245350100002DEST_PATH_IMAGE005
The formula I
Wherein:
N is 1 or 2;
X –Be independently selected from cl ions, bromide anion, iodide ion, sulfate ion, phosphate anion, nitrate ion, perchlorate, fumarate ion, acetate ion, propionate ion, succinate ion, oxyacetic acid radical ion, formate ion, lactate ion, maleate ion, tartrate anion ion, citrate ion, malonate ion;
R 1, R 2Be substituted radical that can be identical or different, be 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 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl;
Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical part randomly are independently selected from following group replacement by 1-5: hydroxyl, halogen, amino, nitro, trifluoromethyl, C 1-C 10Alkyl, C 2-C L0Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl;
Preferred compound is R 1, R 2All can be selected from methyl, ethyl, n-hexyl, allyl group, benzyl respectively, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl;
Compound shown in the typical formula I comprises:
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) high piperazine-1-ammonium iodide;
26,1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
27,1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
28,1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
29,1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
30,1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
31,1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
32,1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-ammonium chloride.
The present invention also provides the preparation method of above-mentioned formula I compound; This method comprises: with the E-10-hydroxy-2-decylenic acid is raw material, through esterification, with N-METHYL PIPERAZINE, ethyl piperazidine, hexyl piperazine, the high piperazine of methyl amination reaction takes place respectively; Obtain corresponding intermediates; Through quaterisation, synthesize corresponding piperazine, high piperazine quaternary ammonium salt again, reaction formula is:
Figure 841405DEST_PATH_IMAGE006
1. the preparation of 4-(10-acetoxyl group-2-decenoyl) piperazine quaternary ammonium salt, i.e. n=1.
(1) midbody 10-acetoxyl group-2-decylenic acid is synthetic
Figure 2011103245350100002DEST_PATH_IMAGE007
(2) midbody 1-alkyl-4-(10-acetoxyl group-2-decenoyl) piperazine is synthetic
Figure 613446DEST_PATH_IMAGE008
(3) title product is synthetic
Figure 2011103245350100002DEST_PATH_IMAGE009
2. the preparation of the high piperazine quaternary ammonium salt of 4-(10-acetoxyl group-2-decenoyl), i.e. n=2.
(1) midbody 10-acetoxyl group-2-decylenic acid is synthetic
Figure 365501DEST_PATH_IMAGE010
(2) the high piperazine of midbody 1-alkyl-4-(10-acetoxyl group-2-decenoyl) is synthetic
Figure 2011103245350100002DEST_PATH_IMAGE011
(3) title product is synthetic
C among the present invention 1-C 10Alkyl, alkyl are meant the straight or branched alkyl with 1-10 carbon atom, for example 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 is meant 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 that more preferably has 3-5 carbon atom;
C 2-C L0Be meant alkyl, and comprise ethynyl, proyl, butynyl, pentyne-2-base etc. with 2-10 carbon atom and at least one three key.The alkynyl that more preferably has 3-5 carbon atom;
Halogen is meant fluorine, chlorine, bromine and iodine atom;
Aryl be meant have monocycle (like phenyl), many rings (like 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 optional to be replaced by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three.
Heteroaryl is meant one or more aromatics ring systems of 5,6 or 7 yuan of rings, and what it comprised 5-10 atom condenses ring system (wherein at least one ring is an aromaticity), and said ring system contains at least one and maximum four heteroatomss that are selected from nitrogen, oxygen or sulphur.The instance 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 optional by for example halogen, low alkyl group, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxyl list, two or three replacements.
Carbocyclic ring, carbocylic radical, naphthenic base, C 3-C 10Naphthenic base is meant the saturated carbon ring group with 3-10 carbon atom.This naphthenic base can be that monocycle or many rings condense system, and can condense on aromatic ring.These examples of groups comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.The ring a heatable brick bed base of this paper can be unsubstituted or as specify, replaced by various groups in one or more commutable positions.For example, these naphthenic base can be chosen wantonly by following group and replace: 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 are meant one or more carbocyclic ring ring system of 5,6 or 7 yuan of rings; It comprises the ring system that condenses of 4-10 atom; Said 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 that condenses on virtue group group.Preferred heterocycle includes but not limited to pyrrolidyl, tetrahydrofuran base, dihydrofuran-base, THTP, 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 is meant by one or more (as above defining) aryl substituted (as above defining) alkyl.Preferred arylalkyl is aryl-C l-C 3Alkyl.Instance comprises benzyl, phenylethyl etc.;
Heteroarylalkyl is meant (as above being defined) heteroaryl substituted (as above defining) alkyl.Preferred heteroarylalkyl is 5-or the heteroaryl-C of 6-unit 1-C 3-alkyl.Instance comprises pyridyl ethyl etc.;
The heterocyclic radical alkyl is meant (as above being defined) heterocyclic radical substituted (as above defining) alkyl.Preferred heterocyclic radical alkyl is 5 or 6 yuan of heterocyclic radical-C l-C 3-alkyl.Instance comprises the tetrahydropyrans ylmethyl;
Cycloalkylalkyl is meant (as above defining) alkyl of (as above being defined) cycloalkyl substituted.Preferred heterocyclic radical is 5 or 6 yuan of naphthenic base-C l-C 3-alkyl.Instance comprises the cyclopropyl methyl;
Compound of the present invention also can use with its pharmacy acceptable salt or solvate forms.Receivable salt comprises the salt of the routine that is formed by pharmaceutically acceptable mineral acid or organic acid or mineral alkali or organic bases and the acid salt of quaternary ammonium on the physiology of formula I compound.The example more specifically of suitable hydrochlorate comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetate, propionic acid, succsinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, Hydrocerol A, pounces on 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 like oxalic acid, though itself be not pharmaceutically acceptable, can be used to prepare the salt as midbody, 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, diethylolamine, quadrol, N-NMG and procaine salt.
The present invention also comprises the prodrug of The compounds of this invention, and this prodrug promptly carries out chemical conversion through metabolic process once administration, becomes afterwards to have active medicine.Usually, this type prodrug is a formula I compound functions property verivate of the present invention, and it changes into required formula I compound in vivo easily.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, and it contains raceme or the optically active isomer and at least a pharmaceutically acceptable carrier of The compounds of this invention, and it can be used for interior therapeutic and has biocompatibility.Said 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 the hydrate and one or more suitable pharmaceutically acceptable carrier of effective dose.The pharmaceutical carrier here includes but not limited to: ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as rHSA, buffer substance such as phosphoric acid salt; Glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid, water; Salt or ionogen, like protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloided silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, yolk.
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 following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication; Local application, non-enterally administer, as subcutaneous, vein, intramuscular; Intraperitoneal, in the sheath, in the ventricle, breastbone interior 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 medicine for oral use, 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 uses generally comprises lactose and W-Gum, also can add lubricant such as Magnesium Stearate in addition.The thinner that capsule preparations uses generally comprises lactose and dried corn starch.Aqueous suspension preparation then normally mixes use with activeconstituents with examples of suitable emulsifiers and suspension agent.If desired, also can add some sweeting agents, perfume compound or tinting material in the above oral prepns form.
During the Where topical medication; Particularly treat local external application easy to reach and suffer from face or organ; During like eyes, skin or lower intestinal tract nervous system disease, can The compounds of this invention be processed different local application's dosage forms, specify as follows according to different trouble faces or organ:
When the eye topical application, The compounds of this invention can be mixed with the dosage form of a kind of micronization suspension-s or solution, and the carrier that uses is the Sterile Saline of isoosmotic certain pH, wherein can add also not adding preservative agent such as zephiran chloride alkoxide.For eye usefulness, also can compound be processed paste form such 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: MO, Albolene, white vaseline, Ucar 35, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: MO, and sorbitan monostearate, polysorbate60, the 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 sterilization also can be used as solvent or suspension medium, like direactive glyceride or two glyceryl ester.
The present invention provides new piperazine and high piperazine derivative, or its pharmacologically acceptable salts, solvolyte comprise in preparation acetylcholine esterase inhibition activity, the application that suppresses aspect medicines such as activity of tumor cells and bacteriostatic activity:
Application aspect the preparation antitumor drug.The particularly application aspect preparation treatment solid tumor, acute leukemia medicine;
Application aspect the anti-acetylcholinesterasemedicine medicine of diseases such as preparation treatment alzheimer's disease and cerebrovascular dementia;
And be used to treat the application aspect the medicine that gram-positive microorganism and negative bacterium infect in preparation.
Embodiment
Following embodiment is the preferred illustrative preferred version of the present invention, and the present invention is not constituted any limitation.
 
The preparation of midbody:
Embodiment 1:1-methyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 1) preparation
Step 1: the preparation of 10-acetoxyl group-2-decylenic acid
Figure 2011103245350100002DEST_PATH_IMAGE013
Under agitation condition, successively with 10-hydroxyl-2-decylenic acid (9.30 g, 50 mmol), aceticanhydride (9.43 mL, 100 mmol) joins in the 50 mL exsiccant round-bottomed flasks, with said mixture 100 °Reflux 1 h in the C oil bath.The concentrating under reduced pressure reaction solution, the thick product of gained with silica gel column chromatography (eluent: V Acetone: V Sherwood oil=1:20) separate purify 9.51 g pale yellow oily liquid bodies, productive rate 83.4 %.
Step 2: 1-methyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 1) preparation
Figure 2011103245350100002DEST_PATH_IMAGE015
1
With 10-acetoxyl group-2-decylenic acid (2.28 g, 10 mmol), methylene dichloride (30 mL) joins in the 50 mL round-bottomed flasks, under the agitation condition, dropwise adds SOCl 2(1.46 mL, 20 mmol), stirring at room is reacted 10 h.Reaction solution is cooled to 0 °C dropwise adds N-METHYL PIPERAZINE (20 mmol), 0 °C stirring reaction 1 h.Reaction solution dilutes with 30 mL chloroforms, uses 10 % NaOH regulator solution pH=13 again, and organic phase is washed with saturated sodium-chloride water solution, and anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure, the thick product of gained with silica gel column chromatography (eluent: V Methyl alcohol: V ETHYLE ACETATE=1:20) separate purification, get pale yellow oily liquid body 5.50 g, productive rate 88.6 %. 1H?NMR?(DMSO- d 6,?500?MHz)? δ:?6.68~6.62?(m,?1H,?C H =CHCO),?6.44?(d,? J=15.0?Hz,?1H,?CH=C H CO),?3.98?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.56~3.44?(m,?4H,?(C H 2) 2NCH 3),?2.30~2.20?(m,?4H,?CON(C H 2) 2),?2.20~2.12?(m,?5H,?NC H 3?and?OCH 2–(CH 2) 5–C H 2),?1.99?(s,?3H,?C H 3CO 2),?1.58~1.23?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(DMSO- d 6,?125?MHz)? 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).
Embodiment 2:1-ethyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 2) preparation
Figure 641947DEST_PATH_IMAGE016
2
Method substitutes N-METHYL PIPERAZINE with midbody embodiment 1 with ethyl piperazidine, gets pale yellow oily liquid body 5.56 g, productive rate 85.8 %. 1H?NMR?(CD 3OD,?500?MHz)? δ:?6.86~6.70?(m,?1H,?C H =CHCO),?6.45?(d,? J=14.9?Hz,?1H,?CH=C H CO),?4.07?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.68?(t,? J=5.0?Hz,?4H,?(C H 2) 2NC 2H 5),?2.55~2.45?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.30~2.24?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.05?(s,?3H,?C H 3CO 2),?1.68~1.35?(m,?10H,?OCH 2–(C H 2) 5–CH 2),?1.14?(t,? J=7.2?Hz,?3H,?NCH 2C H 3);? 13C?NMR?(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).
Embodiment 3:1-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine (compound 3) preparation
Figure 2011103245350100002DEST_PATH_IMAGE017
3
Method is with midbody embodiment 1, and the hexyl piperazine is substituted N-METHYL PIPERAZINE, the thick product of gained with silica gel column chromatography (eluent: V Methyl alcohol: V ETHYLE ACETATE=1:2) separate purification, get pale yellow oily liquid body 5.92 g, productive rate 77.8 %. 1H?NMR?(DMSO- d 6,?500?MHz)? δ:?6.69~6.10?(m,?1H,?C H =CHCO),?6.44?(d,? J=15.0?Hz,?1H,?CH=C H CO),?4.06?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.55~3.45?(m,?4H,?(C H 2) 2N(CH 2) 5CH 3),?2.35~2.23?(m,?6H,?CON(C H 2) 2?and?NC H 2–(CH 2) 4–CH 3),?2.21~2.14?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.00?(s,?3H,?C H 3CO 2),?1.60~1.22?(m,?18H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.87?(t,? J=6.5?Hz,?3H,?NCH 2–(CH 2) 4–C H 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).
High piperazine (the compound of embodiment 4:1-methyl-4-(10-acetoxyl group-2-decenoyl) 4) preparation
Figure 211819DEST_PATH_IMAGE018
4
Under the agitation condition, with 10-acetoxyl group-2-decylenic acid (2.28 g, 10 mmol), methylene dichloride (30 mL), the high piperazine of 1-methyl (1.67 mL, 13 mmol) joins in the 50 mL round-bottomed flasks stirring at room 1 h.Reaction solution dilutes with 30 mL chloroforms, and organic phase is used saturated ammonium chloride (3 * 60 mL), saturated sodium-chloride water solution (1 * 60 mL) washing, anhydrous magnesium sulfate drying successively.Filter, remove solvent under reduced pressure, the thick product of gained with silica gel column chromatography (eluent: V Methyl alcohol: V ETHYLE ACETATE=1:2, V Ethanol: V Acetone=5:1) separate purification, get pale yellow oily liquid body 1.62 g, productive rate 50.0 %. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?6.90~6.83?(m,?1H,?C H =CHCO),?6.22~6.13?(m,?1H,?CH=C H CO),?4.10~4.00?(m,?2H,?OC H 2–(CH 2) 5–CH 2),?3.74~3.50?(m,?4H,?CON(C H 2) 2),?2.72~2.60?(m,?2H,?(C H 2) 2NCH 3),?2.58~2.50?(m,?2H,?(C H 2) 2NCH 3),?2.36?(s,?3H,?NC H 3),?2.21~2.11?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?2.02~1.90?(m,?2H,?NCH 2C H 2CH 2N),?1.68~1.22?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE019
Under the agitation condition, with compound 1(2 mmol), 30 mL chloroforms, raw material methyl iodide (4 mmol) joins in the 50 mL round-bottomed flasks, and 65 °C reaction, with the TLC monitoring reaction (developping agent: V Methyl alcohol: V Chloroform=1:10), after reaction is accomplished, with the reaction solution concentrating under reduced pressure, the thick product of gained with silica gel column chromatography (eluent: V Methyl alcohol: V ETHYLE ACETATE=1:10) separate purify pale yellow oily liquid body 0.64 g, productive rate 71.1 %. 1H?NMR?(CD 3OD,?500?MHz)? δ:?6.95~6.88?(m,?1H,?C H= CHCO),?6.51?(d,? J=15.1?Hz,?1H,?CH=C H CO),?4.12~4.00?(m,?6H,?(C H 2) 2NCH 3?and?OC H 2–(CH 2) 5–CH 2),?3.60~3.50?(m,?4H,?CON(C H 2) 2),?3.38~3.27?(m,?6H,?CH 2N(C H 3) 2),?2.35~2.26?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.08~2.00?(m,? J=1.7?Hz,?3H,?C H 3CO 2),?1.70~1.34?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CD 3OD,125?MHz)? 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
Figure 818381DEST_PATH_IMAGE020
Method with raw material allyl bromide 98 alternative materials methyl iodide, gets pale yellow oily liquid body 0.41 g, productive rate 47.5 % with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?6.91~6.83(m,?1H,?C H =CHCO),?6.41?(d,? J=15.2?Hz,?1H,?CH=C H CO),?6.10~6.01?(m,?1H,?CH 2C H =CH 2),?5.82~5.71?(m,?2H,?CH 2CH=C H 2),?4.21~4.05?(m,?6H,?(C H 2) 2NCH 2CH?and?OC H 2–(CH 2) 5–CH 2),?4.00~3.74?(m,?2H,?C H 2CH=CH 2),?3.58~3.45?(m,?4H,?CON(C H 2) 2),?3.17?(s,?3H,?NC H 3),?2.30~2.22?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.07?(s,?3H,?C H 3CO 2),?1.67~1.58?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.51~1.42?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.34~1.26?(m,?6H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,?125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE021
Method with raw material bromotoluene alternative materials methyl iodide, gets white solid 0.88 g, productive rate 91.6 % with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?7.66~7.44?(m,?5H,?Ar H ),?6.88~6.79?(m,?1H,?C H= CHCO),?6.37?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.61?(s,?2H,?ArC H 2),?4.36~4.24?(m,?2H,?(C H 2) 2NCH 2Ar),?4.04?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2)?3.93~3.59?(m,?2H,?(C H 2) 2NCH 2Ar),?3.50~3.33?(m,?4H,?CON(C H 2) 2),?3.40?(s,?3H,?NC H 3),?2.30~2.10?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.65~1.23?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 687111DEST_PATH_IMAGE022
Method to nitro bromobenzyl alternative materials methyl iodide, gets faint yellow solid 0.82 g, productive rate 78.3 % with raw material with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?8.34?(d,? J=8.7?Hz,?2H,?Ar H ),?7.79?(d,? J=8.6?Hz,?2H,?Ar H ),?6.88~6.80?(m,?1H,?C H =CHCO),?6.38?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.76?(s,?2H,?ArC H 2),?4.40~4.18?(m,?2H,?(C H 2) 2NCH 2Ar),?4.05?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.93~3.84?(m,?1H,?(C H 2) 2NCH 2Ar),?3.70~3.50?(m,?5H,?(C H 2) 2NCH 2Arand?CON(C H 2) 2),?3.16?(s,?3H,?NC H 3),?2.25~2.18?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.63~1.39?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE023
Method to bromine bromobenzyl alternative materials methyl iodide, gets white solid 1.05 g, productive rate 93.8 % with raw material with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?7.66?(d,? J=8.4?Hz,?2H,?Ar H ),?7.40?(d,? J=8.4?Hz,?2H,?Ar H ),?6.84~6.77?(m,?1H,?C H =CHCO),?6.34?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.56?(s,?2H,?ArC H 2),?4.32~4.12?(m,?2H,?(C H 2) 2NCH 2Ar),?4.02?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.88~3.56?(m,?2H,?(C H 2) 2NCH 2Ar),?3.54~3.40?(m,?4H,?CON(C H 2) 2),?3.07?(s,?3H,?NC H 3),?2.24~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.00?(s,?3H,?C H 3CO 2),?1.60~1.53?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 815342DEST_PATH_IMAGE024
Method to fluorine bromobenzyl alternative materials methyl iodide, gets white solid 0.77 g, productive rate 77.3 % with raw material with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?7.63~7.57?(m,?2H,?Ar H ),?7.30~7.27?(m,?2H,?Ar H ),?6.92~6.85?(m,?1H,?C H =CHCO),?6.42?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.65?(s,?2H,?ArC H 2),?4.40~4.33?(m,?1H,?(C H 2) 2NCH 2Ar),?4.27~4.20?(m,?1H,?(C H 2) 2NCH 2Ar),?4.10?(t,? J=6.63?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.96~3.88?(m,?1H,?(C H 2) 2NCH 2Ar),?3.72~3.64?(m,?1H,?(C H 2) 2NCH 2Ar),?3.63~3.47?(m,?4H,?CON(C H 2) 2),?3.15?(s,?3H,?NC H 3),?2.30~2.23?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.08?(s,?3H,?C H 3CO 2),?1.67~1.30?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE025
Method to methyl bromobenzyl alternative materials methyl iodide, gets white solid 0.75 g, productive rate 75.6 % with raw material with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?7.41?(d,? J=7.9?Hz,?2H,?Ar H ),?7.35?(d,? J=7.9?Hz,?2H,?Ar H ),?6.87~6.79?(m,?1H,?C H =CHCO),?6.37?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.58?(s,?2H,?ArC H 2),?4.36~4.14?(m,?2H,?(C H 2) 2NCH 2Ar),?4.04?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.92~3.59?(m,?2H,?(C H 2) 2NCH 2Ar),?3.56~3.41?(m,?4H,?CON(C H 2) 2),?3.10?(s,?3H,?NC H 3),?2.36?(s,?3H,?ArC H 3),?2.25~2.18?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.60~1.54?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE027
Method to methoxyl group benzyl chloride alternative materials methyl iodide, gets white solid 0.57 g, productive rate 61.4 % with raw material with embodiment 1. 1H?NMR?(D 2O,?500?MHz)? δ:?7.46?(d,? J=8.7?Hz,?2H,?Ar H ),?7.06?(d,? J=8.7?Hz,?2H,?Ar H ),?6.85~6.77?(m,?1H,?C H =CHCO),?6.36?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.55?(s,?2H,?ArC H 2),?4.36~4.13?(m,?2H,?(C H 2) 2NCH 2Ar),?4.02?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.90~3.80?(m,?4H,?(C H 2) 2NCH 2Ar?and?ArOC H 3),?3.66~3.56?(m,?1H,?(C H 2) 2NCH 2Ar),?3.51~3.39?(m,?4H,?CON(C H 2) 2),?3.10?(s,?3H,?NC H 3),?2.23~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.02?(s,?3H,?C H 3CO 2),?1.60~1.52?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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 is with embodiment 1, with compound 2Alternative compounds 1, get yellow oily liquid 0.41 g, productive rate 43.6 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.00~6.92?(m,?1H,?C H =CHCO),?6.49?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.19?(t,? J=6.4?Hz,?4H,?(C H 2) 2NC 2H 5),?4.08~3.84?(m,?2H,?OC H 2–(CH 2) 5–CH 2),?3.67~3.53?(m,?6H,?CON(C H 2) 2?and?(C H 2) 2NCH 2Ar),?3.25?(s,?3H,?NC H 3),?2.39~2.31?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.17?(s,?3H,?C H 3CO 2),?1.76~1.52?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.48?(t,? J=7.1?Hz,?3H,?NCH 2C H 3),1.46~1.38?(m,?6H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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).
Figure 390253DEST_PATH_IMAGE030
Embodiment 10:1-ethyl-1-allyl group-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method is with embodiment 1, with compound 2Alternative compounds 1,, get white solid 0.70 g, productive rate 78.6 % with raw material allyl bromide 98 alternative materials methyl iodide. 1H?NMR?(DMSO- d 6,?500?MHz)? δ:?6.75~6.68?(m,?1H,?C H =CHCO),?6.48?(d,? J=15.0?Hz,?1H,?CH=C H CO),?6.05~5.95?(m,?1H,?CH 2C H =CH 2),?5.69?(d,? J=16.1?Hz,?1H,?CH 2CH=C H 2),?5.61?(d,? J=10.2?Hz,?1H,?CH 2CH=C H 2),?4.10?(d,? J=7.2?Hz,?2H,?C H 2CH=CH 2),?3.95?(t,? J=6.7?Hz,?4H,?(C H 2) 2NCH 2CH),?3.86~3.77?(m,?2H,?OC H 2–(CH 2) 5–CH 2),?3.46~3.36?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.20~2.13?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?1.96?(s,?3H,?C H 3CO 2),?1.56~1.48?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.29~1.19?(m,?9H,?NCH 2C H 3?and?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(DMSO- d 6,125?MHz)? 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
Figure 757780DEST_PATH_IMAGE032
Method is with embodiment 1,, with compound 2Alternative compounds 1,, get pale yellow oily liquid body 0.76 g, productive rate 77.0 % with raw material benzyl bromine alternative materials methyl iodide. 1H?NMR?(D 2O,?500?MHz)? δ:?7.61~7.49?(m,?5H,?Ar H ),?6.86~6.77?(m,?1H,?C H =CHCO),?6.37?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.61?(s,?2H,?ArC H 2),?4.29~4.11?(m,?2H,?(C H 2) 2NCH 2Ar),?4.03?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.98~3.85?(m,?1H,?(C H 2) 2NCH 2Ar),?3.73~3.63?(m,?1H,?(C H 2) 2NCH 2Ar),?3.58~3.37?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.50~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.60~1.55?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.49?(t,? J=7.1?Hz,?3H,?NCH 2C H 3),?1.44~1.23?(m,?8H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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).
Figure 937089DEST_PATH_IMAGE034
embodiment 12:1-ethyl-1-is to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio
Method is with embodiment 1, with compound 2Alternative compounds 1, raw material to nitro bromobenzyl alternative materials methyl iodide, is got faint yellow solid 0.82 g, productive rate 76.0 %. 1H?NMR?(D 2O,?500?MHz)? δ:?8.30?(d,? J=8.7?Hz,?2H,?Ar H ),?7.75?(d,? J=8.7?Hz,?2H,?Ar H ),?6.83~6.76?(m,?1H,?C H =CHCO),?6.34?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.72?(s,?2H,?ArC H 2),?4.31~4.11?(m,?2H,?(C H 2) 2NCH 2Ar),?4.02?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.94~3.64?(m,?2H,?(C H 2) 2NCH 2Ar),?3.60~3.43?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.22~2.15?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.01?(s,?3H,?C H 3CO 2),?1.60~1.52?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.48?(t,? J=7.2?Hz,?3H,?NCH 2C H 3),?1.43~1.20?(m,?8H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,?125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE035
Method is with embodiment 1, with compound 2Alternative compounds 1, raw material to bromine bromobenzyl alternative materials methyl iodide, is got white solid 1.03 g, productive rate 89.8 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.69?(d,? J=8.4?Hz,?2H,?Ar H ),?7.42?(d,? J=8.4?Hz,?2H,?Ar H ),?6.87~6.79?(m,?1H,?C H =CHCO),?6.36?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.58?(s,?2H,?ArC H 2),?4.29~4.12?(m,?2H,?(C H 2) 2NCH 2Ar),?4.05?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.94~3.86?(m,?1H,?(C H 2) 2NCH 2Ar),?3.74~3.65?(m,?1H,?(C H 2) 2NCH 2Ar),?3.56~3.40?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.26~2.19?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.05?(s,?3H,?C H 3CO 2),?1.63~1.56?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.50~1.37?(m,?5H,?NCH 2C H 3?and?OCH 2–(C H 2) 5–CH 2),?1.34~1.22?(m,?6H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz)? 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 is with embodiment 1, with compound 2Alternative compounds 1, raw material to fluorine bromobenzyl alternative materials methyl iodide, is got white solid 0.62 g, productive rate 60.9 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.58~7.50?(m,?2H,?Ar H ),?7.28~7.20?(m,?2H,?Ar H ),?6.87~6.77?(m,?1H,?C H =CHCO),?6.36?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.60?(s,?2H,?ArC H 2),?4.30~4.11?(m,?2H,?(C H 2) 2NCH 2Ar),?4.04?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.94~3.63?(m,?2H,?(C H 2) 2NCH 2Ar),?3.57~3.37?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.25~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.63~1.53?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.50~1.37?(m,?5H,?NCH 2C H 3?and?OCH 2–(C H 2) 5–CH 2),?1.30~1.21?(m,?6H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,?125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE037
Method is with embodiment 1, with compound 2Alternative compounds 1, raw material to methyl bromobenzyl alternative materials methyl iodide, is got white transparent oily liquid 0.73 g, productive rate 71.7 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.36?(d,? J=7.9?Hz,?2H,?Ar H ),?7.30?(d,? J=7.7?Hz,?2H,?Ar H ),?6.80~6.73?(m,?1H,?C H =CHCO),?6.32?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.51?(s,?2H,?ArC H 2),?4.24~4.04?(m,?2H,?(C H 2) 2NCH 2Ar),?3.98?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.89~3.57?(m,?2H,?(C H 2) 2NCH 2Ar),?3.51~3.30?(m,?6H,?CON(C H 2) 2?and?NC H 2CH 3),?2.30?(s,?3H,?ArC H 3),?2.21~2.10?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?1.99?(s,?3H,?C H 3CO 2),?1.57~1.48?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.43?(t,? J=7.1?Hz,?3H,?NCH 2C H 3),?1.40~1.15?(m,?8H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,125?MHz);? 13C?NMR?(D 2O,?125?MHz)? 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
Figure 167268DEST_PATH_IMAGE038
Method is with embodiment 1, with compound 2Alternative compounds 1, raw material to methoxyl group benzyl chloride alternative materials methyl iodide, is got faint yellow solid 0.54 g, productive rate 56.3 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.43?(d,? J=8.4?Hz,?2H,?Ar H ),?7.02?(d,? J=8.3?Hz,?2H,?Ar H ),?6.81~6.72?(m,?1H,?C H =CHCO),?6.33?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.52?(s,?2H,?ArC H 2),?4.28~4.07?(m,?2H,?(C H 2) 2NCH 2Ar),?3.97?(t,? J=6.5?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.90~3.76?(m,?4H,?ArOC H 3?and?(C H 2) 2NCH 2Ar),?3.66~3.56?(m,?1H,?(C H 2) 2NCH 2Ar),?3.49?(t,? J=6.5?Hz,?4H,?CON(C H 2) 2),?3.39~3.26?(m,?2H,?NC H 2CH 3),?2.19~2.10?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.00?(s,?3H,?C H 3CO 2),?1.56~1.48?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.45?(t,? J=6.9?Hz,?3H,?NCH 2C H 3),?1.39~1.14?(m,?8H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(D 2O,?125?MHz)? 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).
Figure 440117DEST_PATH_IMAGE040
embodiment 17:1-methyl isophthalic acid-n-hexyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-ammonium iodide
Method is with embodiment 1, with compound 3Alternative compounds 1, get yellow oily liquid 0.73 g, productive rate 70.1 %. 1H?NMR?(D 2O,?500?MHz)? δ:?6.85~6.78?(m,?1H,?C H =CHCO),?6.34?(d,? J=15.3?Hz,?1H,?CH=C H CO),?4.03?(t,? J=6.7?Hz,?4H,?(C H 2) 2NCH 3),?3.93~3.72?(m,?2H,?OC H 2–(CH 2) 5–CH 2),?3.48~3.35?(m,?6H,?CON(C H 2) 2?and?NC H 2–(CH 2) 4–CH 3),?3.11?(s,?3H,?NC H 3),?2.23~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.01?(s,?3H,?C H 3CO 2),?1.78~1.69?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.60~1.53?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.45~1.36?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.35~1.19?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.81?(t,? J=7.1?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 106722DEST_PATH_IMAGE042
Method is with embodiment 1, with compound 3Alternative compounds 1,, get white solid 0.78 g, productive rate 78.4 % with raw material allyl bromide 98 alternative materials methyl iodide. 1H?NMR?(D 2O,?500?MHz)? δ:?6.86~6.77?(m,?1H,?C H =CHCO),?6.34?(d,? J=15.2?Hz,?1H,?CH=C H CO),?5.99~5.88?(m,?1H,?CH 2C H =CH 2),?5.71~5.63?(m,?2H,?CH 2CH=C H 2),?4.05~3.81?(m,?8H,?C H 2CH=CH 2,?(C H 2) 2NCH 2CH?and?OC H 2–(CH 2) 5–CH 2),?3.50~3.41?(m,?4H,?CON(C H 2) 2),?3.44?(t,? J=8.5?Hz,?2H,?NC H 2–(CH 2) 4–CH 3),?2.23~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.01?(s,?3H,?C H 3CO 2),?1.76~1.68?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.60~1.53?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.44~1.36?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.34~1.20?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.80?(t,? J=7.0?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 2011103245350100002DEST_PATH_IMAGE043
Method is with embodiment 1, with compound 3Alternative compounds 1,, get pale yellow oily liquid body 0.85 g, productive rate 77.6 % with raw material bromobenzyl alternative materials methyl iodide. 1H?NMR?(D 2O,?500?MHz)? δ:?7.60~7.46?(m,?5H,?Ar H ),?6.87~6.78?(m,?1H,?C H =CHCO),?6.35?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.61?(s,?2H,?ArC H 2),?4.29~4.10?(m,?2H,?(C H 2) 2NCH 2Ar),?4.05?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.92~3.83?(m,?1H,?(C H 2) 2NCH 2Ar),?3.72~3.64?(m,?1H,?(C H 2) 2NCH 2Ar),?3.55~3.42?(m,?4H,?CON(C H 2) 2),?3.30?(t,? J=8.5?Hz,?2H,?NC H 2–(CH 2) 4–CH 3),?2.26~2.18?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.91~1.82?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.62~1.55?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.46~1.39?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.36~1.23?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.85?(t,? J=6.9?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(D 2O,125?MHz)? 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
Figure 618825DEST_PATH_IMAGE044
Method is with embodiment 1, with compound 3Alternative compounds 1, raw material to nitro bromobenzyl alternative materials methyl iodide, is got pale yellow oily liquid body 0.87 g, productive rate 73.4 %. 1H?NMR?(CD 3OD,?500?MHz)? δ:?8.40?(d,? J=8.6?Hz,?2H,?Ar H ),?7.88?(d,? J=8.5?Hz,?2H,?Ar H ),?6.94~6.84?(m,?1H,?C H =CHCO),?6.49?(d,? J=15.1?Hz,?1H,?CH=C H CO),?4.91?(s,?2H,?ArC H 2),?4.43~4.22?(m,?2H,?(C H 2) 2NCH 2Ar),?4.07?(t,? J=6.7?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?4.03~3.73?(m,?2H,?(C H 2) 2NCH 2Ar),?3.69~3.52?(m,?4H,?CON(C H 2) 2),?3.46?(t,? J=8.2?Hz,?2H,?NC H 2–(CH 2) 4–CH 3),?2.33~2.23?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.04?(s,?3H,?C H 3CO 2),?2.02~1.94?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.71~1.59?(m,?2H,?OCH 2–(C H 2) 5–CH 2),?1.54~1.33?(m,?14H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.97?(t,? J=7.0?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(CD 3OD,125?MHz)? 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–NO 2),?1349?(Ar–NO 2),?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
Figure 2011103245350100002DEST_PATH_IMAGE045
Method is with embodiment 1, with compound 3Alternative compounds 1, raw material to bromine bromobenzyl alternative materials methyl iodide, is got white solid 0.93 g, productive rate 73.7 %. 1H?NMR?(CD 3OD,?500?MHz)? δ:?7.74?(d,? J=8.2?Hz,?2H,?Ar H ),?7.52?(d,? J=8.1?Hz,?2H,?Ar H ),?6.92~6.85?(m,?1H,?C H =CHCO),?6.49?(d,? J=15.1?Hz,?1H,?CH=C H CO),?4.75?(s,?2H,?ArC H 2),?4.41~4.21?(m,?2H,?(C H 2) 2NCH 2Ar),?4.07?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?4.03~3.89?(m,?1H,?(C H 2) 2NCH 2Ar),?3.83~3.71?(m,?1H,?(C H 2) 2NCH 2Ar),?3.64~3.47?(m,?4H,?CON(C H 2) 2),?3.39?(t,? J=8.3?Hz,?2H,?NC H 2–(CH 2) 4–CH 3),?2.33~2.24?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.04?(s,?3H,?C H 3CO 2),?1.98~1.90?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.70~1.49?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.49~1.33?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.97?(t,? J=6.7?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(CD 3OD,125?MHz)? 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-MS? m/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
Figure 2011103245350100002DEST_PATH_IMAGE047
Method is with embodiment 1, with compound 3Alternative compounds 1, raw material to fluorine bromobenzyl alternative materials methyl iodide, is got white solid 0.95 g, productive rate 83.6 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.60~7.56?(m,?2H,?Ar H ),?7.37~7.32?(m,?2H,?Ar H ),?6.70~6.55?(m,?1H,?C H =CHCO),?6.45?(d,? J=15.0?Hz,?1H,?CH=C H CO),?4.71?(s,?2H,?ArC H 2),?4.12~4.10?(m,?2H,?(C H 2) 2NCH 2Ar),?3.96?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.92~3.42?(m,?2H,?(C H 2) 2NCH 2Ar),?3.41~3.29?(m,?4H,?CON(C H 2) 2),?2.18~2.14?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?1.97?(s,?3H,?C H 3CO 2),?1.79~1.77?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.55~1.29?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.30~1.20?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.86?(t,? J=7.0?Hz,?3H,?NCH 2–(CH 2) 4–C H 3) ; 13C?NMR?(DMSO- d 6,125?MHz)? 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-MS? m/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
Figure 992169DEST_PATH_IMAGE048
Method is with embodiment 1, with compound 3Alternative compounds 1, raw material to methyl bromobenzyl alternative materials methyl iodide, is got white solid 0.85 g, productive rate 75.4 %. 1H?NMR?(CD 3OD,?500?MHz)? δ:?7.45?(d,? J=8.0?Hz,?2H,?Ar H ),?7.38?(d,? J=7.9?Hz,?2H,?Ar H ),?6.93~6.86?(m,?1H,?C H =CHCO),?6.49?(d,? J=15.0?Hz,?1H,?CH=C H CO),?4.70?(s,?2H,?ArC H 2),?4.38~4.20?(m,?2H,?(C H 2) 2NCH 2Ar),?4.07?(t,? J=6.4?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?4.02~3.71?(m,?2H,?(C H 2) 2NCH 2Ar),?3.61~3.47?(m,?4H,?CON(C H 2) 2),?3.38~3.31?(m,?2H,?NC H 2–(CH 2) 4–CH 3),?2.43?(s,?3H,?ArC H 3),?2.33~2.26?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.04?(s,?3H,?C H 3CO 2),?1.99~1.89?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.70~1.48?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.45~1.34?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.97?(t,? J=6.9?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(CD 3OD,125?MHz)? 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 is with embodiment 1, with compound 3Alternative compounds 1, raw material to methoxyl group benzyl chloride alternative materials methyl iodide, is got white solid 0.89 g, productive rate 83.8 %. 1H?NMR?(D 2O,?500?MHz)? δ:?7.42?(d,? J=8.5?Hz,?2H,?Ar H ),?7.06?(d,? J=7.06?Hz,?2H,?Ar H ),?6.85~6.77?(m,?1H,?C H =CHCO),?6.35?(d,? J=15.2?Hz,?1H,?CH=C H CO),?4.54?(s,?2H,?ArC H 2),?4.29~4.08?(m,?2H,?(C H 2) 2NCH 2Ar),?4.03?(t,? J=6.6?Hz,?2H,?OC H 2–(CH 2) 5–CH 2),?3.91~3.78?(m,?4H,?ArOCH 3?and?(C H 2) 2NCH 2Ar),?3.70~3.60?(m,?1H,?(C H 2) 2NCH 2Ar),?3.54~3.36?(m,?4H,?CON(C H 2) 2),?3.31~3.23?(m,?2H,?NC H 2–(CH 2) 4–CH 3),?2.24~2.17?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.02?(s,?3H,?C H 3CO 2),?1.89~1.78?(m,?2H,?NCH 2–(C H 2) 4–CH 3),?1.61~1.37?(m,?4H,?OCH 2–(C H 2) 5–CH 2),?1.36~1.21?(m,?12H,?OCH 2–(C H 2) 5–CH 2?and?NCH 2–(C H 2) 4–CH 3),?0.84?(t,? J=6.9?Hz,?3H,?NCH 2–(CH 2) 4–C H 3);? 13C?NMR?(D 2O,125?MHz)? 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) high piperazine-1-ammonium iodide
Figure 2011103245350100002DEST_PATH_IMAGE051
Under the agitation condition, with compound 4(2 mmol), 30 mL acetonitriles, raw material methyl iodide (4 mmol) joins in the 50 mL round-bottomed flasks successively, and 85 °C reaction, with the TLC monitoring reaction (developping agent: V Methyl alcohol: V Chloroform=1:10), after reaction is accomplished, with the reaction solution concentrating under reduced pressure, the thick product of gained with silica gel column chromatography (eluent: V Methyl alcohol: V Chloroform=1:30) separate purify pale yellow oily liquid body 0.72 g, productive rate 77.7 %. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?6.95~6.88?(m,?1H,?C H =CHCO),?6.23?(d,? J=15.0?Hz,?1H,?CH=C H CO),?4.12~4.05?(m,?4H,?OC H 2–(CH 2) 5–CH 2?and?CON(C H 2) 2),?3.98~3.86?(m,?5H,?CON(C H 2) 2?and?(C H 2) 2NCH 3),?3.58?(s,?6H,?CH 2N(C H 3) 2),?2.62~2.50?(m,?1H,?(C H 2) 2NCH 3),?2.49~2.15?(m,?4H,?NCH 2C H 2CH 2N?and?OCH 2–(CH 2) 5–C H 2),?2.05?(s,?3H,?C H 3CO 2),?1.65~1.21?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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-MS? m/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) high piperazine-1-brometo de amonio
Figure 13083DEST_PATH_IMAGE052
Method with raw material allyl bromide 98 alternative materials methyl iodide, gets white transparent oily liquid 0.72 g, productive rate 81.3 % with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?6.97~6.90?(m,?1H,?C H =CHCO),?6.21?(d,? J=15.7?Hz,?1H,?CH=C H CO),?6.18~6.02?(m,?1H,?CH 2C H =CH 2),?5.89?(d,? J=16.8?Hz,?1H,?CH 2CH=C H 2),?5.75?(d,? J=10.1?Hz,?1H,?CH 2CH=C H 2),?4.58~4.31?(m,?6H,?OC H 2–(CH 2) 5–CH 2,?CON(C H 2) 2),?4.03?(t,?4H,? J=6.7?Hz,?(C H 2) 2NCH 2CH),?3.94~3.62?(m,?5H,?NC H 3?and?C H 2CH=CH 2),?2.42~2.30?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.27~2.13?(m,?2H,?NCH 2C H 2CH 2N),?2.04?(s,?3H,?C H 3CO 2),?1.65~1.27?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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) high piperazine-1-brometo de amonio
Figure 901405DEST_PATH_IMAGE054
Method with raw material bromobenzyl alternative materials methyl iodide, gets faint yellow transparent oily liquid 0.97g, productive rate 97.8 % with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?7.65?(d,? J=6.9?Hz,?2H,?Ar H ),?7.48~7.37?(m,?3H,?Ar H ),?6.92~6.84?(m,?1H,?C H =CHCO),?6.17?(d,? J=14.8?Hz,?1H,?CH=C H CO),?5.39~5.08?(m,?2H,?ArC H 2),?4.11~3.79?(m,?8H,?OC H 2–(CH 2) 5–CH 2,?CON(C H 2) 2,?and?(C H 2) 2NCH 2Ar),?3.72~3.55?(m,?2H,?(C H 2) 2NCH 2Ar),?3.26?(s,?3H,?NC H 3),?2.50~2.11?(m,?4H,?NCH 2C H 2CH 2N?and?OCH 2–(CH 2) 5–C H 2),?2.02?(s,?3H,?C H 3CO 2),?1.62~1.24?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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) high piperazine-1-brometo de amonio
Figure 2011103245350100002DEST_PATH_IMAGE055
Method to nitro bromobenzyl alternative materials methyl iodide, gets white solid 0.50 g, productive rate 46.4 % with raw material with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?8.36?(d,? J=6.8?Hz,?2H,?Ar H ),?7.87?(d,? J=7.5?Hz,?2H,?Ar H ),?6.91~6.78?(m,?1H,?C H =CHCO),?6.42?(d,? J=15.0?Hz,?1H,?CH=C H CO),?4.21~3.98?(m,?3H,?OC H 2–(CH 2) 5–CH 2?and?CON(C H 2) 2),?3.94~3.55?(m,?7H,?CON(C H 2) 2,?and?(C H 2) 2NCH 2Ar),?3.14?(s,?3H,?NC H 3),?2.52~2.23?(m,?4H,?NCH 2C H 2CH 2N?and?OCH 2–(CH 2) 5–C H 2),?2.03?(s,?3H,?C H 3CO 2),?1.63~1.25?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CD 3OD,125?MHz)? 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) high piperazine-1-brometo de amonio
Figure 223058DEST_PATH_IMAGE056
Method to bromine bromobenzyl alternative materials methyl iodide, gets pale yellow oily liquid body 1.09 g, productive rate 95.6 % with raw material with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?7.60~7.52?(m,?4H,?Ar H ),?6.92~6.84?(m,?1H,?C H =CHCO),?6.16?(d,? J=15.0?Hz,?1H,?CH=C H CO),?5.44~5.12?(m,?2H,?ArC H 2),?4.12~3.79?(m,?8H,?OC H 2–(CH 2) 5–CH 2,?CON(C H 2) 2,?and?(C H 2) 2NCH 2Ar),?3.75~3.58?(m,?1H,?(C H 2) 2NCH 2Ar),?3.30?(s,?3H,?NC H 3),?2.72~2.54?(m,?3H,?NCH 2C H 2CH 2N?and?(C H 2) 2NCH 2Ar),?2.23~2.16?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.04?(s,?3H,?C H 3CO 2),?1.66~1.24?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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) high piperazine-1-brometo de amonio
Figure 513225DEST_PATH_IMAGE058
Method to fluorine bromobenzyl alternative materials methyl iodide, gets yellow oily liquid 1.00 g, productive rate 98.0 % with raw material with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?7.74~7.67?(m,?2H,?Ar H ),?7.13~7.08?(m,?2H,?Ar H ),?6.92~6.84?(m,?1H,?C H =CHCO),?6.17?(d,? J=15.1?Hz,?1H,?CH=C H CO),?5.38~5.09?(m,?2H,?ArC H 2),?4.15~3.77?(m,?8H,?OC H 2–(CH 2) 5–CH 2,?CON(C H 2) 2?and?(C H 2) 2NCH 2Ar),?3.30?(s,?3H,?NC H 3),?2.42~2.30?(m,?4H,?NCH 2C H 2CH 2N?and?(C H 2) 2NCH 2Ar),?2.30~2.12?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.06?(s,?3H,?C H 3CO 2),?1.66~1.26?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? δ:?171.2,?167.0,?165.1,?163.1,?148.8,?135.7,?135.7,?123.0,?119.4,?116.6,?116.4,?67.3,?64.5,?63.0,?62.3,?48.1,?45.4,?38.7,?32.6,?29.7,?29.1,?29.0,?28.5,?28.2,?25.8,?23.2,?21.0;?ESI-MS? m/z:?433.33?(M–Br) +;?IR?(KBr,?cm –1)?ν:?1734?(C=O),?1655?(C=O),?1606?(C=C),?1231?(C–O–C),?1038?(C–O–C).
Embodiment 31:1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio
Figure 2011103245350100002DEST_PATH_IMAGE059
Method to methyl bromobenzyl alternative materials methyl iodide, gets white transparent oily liquid 0.73 g, productive rate 71.8 % with raw material with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?7.47?(d,? J=7.3?Hz,?2H,?Ar H ),?7.15?(d,? J=7.5?Hz,?2H,?Ar H ),?6.87~6.83?(m,?1H,?C H =CHCO),?6.13?(d,? J=15.0?Hz,?1H,?CH=C H CO),?5.15~4.92?(m,?2H,?ArC H 2),?4.00?(t,? J=6.6?Hz,?4H,?OC H 2–(CH 2) 5–CH 2?and?CON(C H 2) 2),?3.95~3.70?(m,?6H,?CON(C H 2) 2?and?(C H 2) 2NCH 2Ar),?3.26?(s,?3H,?NC H 3),?2.45~2.28?(m,?5H,?NCH 2C H 2CH 2N?and?ArC H 3),?2.21~2.09?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.00?(s,?3H,?C H 3CO 2),?1.68~1.18?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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) high piperazine-1-ammonium chloride
Figure 331140DEST_PATH_IMAGE060
Method to methoxyl group bromobenzyl alternative materials methyl iodide, gets white transparent oily liquid 0.87 g, productive rate 90.2 % with raw material with embodiment 25. 1H?NMR?(CD 3Cl,?500?MHz)? δ:?7.58~7.50?(m,?2H,?Ar H ),?7.00~6.85?(m,?3H,?Ar H ?and?C H =CHCO),?6.15?(d,? J=15.0?Hz,?1H,?CH=C H CO),?5.27~4.92?(m,?2H,?ArC H 2),?4.10~3.92?(m,?4H,?OC H 2–(CH 2) 5–CH 2?and?(C H 2) 2NCH 2Ar),?3.91~3.68?(m,?9H,?ArOC H 3,?CON(C H 2) 2?and?(C H 2) 2NCH 2Ar),?3.25?(s,?3H,?NC H 3),?2.50~2.31?(m,?2H,?NCH 2C H 2CH 2N),?2.23~2.14?(m,?2H,?OCH 2–(CH 2) 5–C H 2),?2.05?(s,?3H,?C H 3CO 2),?1.65~1.27?(m,?10H,?OCH 2–(C H 2) 5–CH 2);? 13C?NMR?(CDCl 3,125?MHz)? 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).
Use:
Embodiment 1: the anti-tumor activity test of compound
The present invention uses the anti tumor activity in vitro that classical mtt assay has been investigated part of compounds.
One, materials and methods
1. cell strain
The transfection cervical cancer cell, the 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 dose groups of 0.3,1,3,10,30,100,300 μ M; The blank group is set simultaneously; Solvent control group.
4. experimental technique
The transfection Hela cell of cultivating grows to nearly fusion state, with 0.25 % tryptic digestion, 2 min, with nutrient solution (1640+10 % FBS+1 mg/mL G418) preparation single cell suspension, adjustment cell concn to 3 * 10 4Individual/mL, be inoculated in 96 well culture plates, 100 μ l/ holes, 37 °C 5 % CO 2Under cultivate and add the full substratum in 80 μ l/ holes behind 24 h earlier, add the test-compound 20 μ L/ holes of different concns again, 3 repetitions, 37 are established in every kind of processing °C 5 % CO 2After 72 h were cultivated in following continuation, every hole sucking-off supernatant 100 μ L added tetrazolium bromide (MTT) the solution 10 μ L of 5 mg/mL, 37 again °C continues to hatch 4 h, and last every hole adds the SDS of 100 μ L, 10 %, 37 °C 5 % CO 2Under hatch 24 h, the MTT crystallization is dissolved fully.Enzyme-linked immunosorbent assay instrument 570 nm wavelength are measured every hole absorbancy.By formula:
Inhibiting rate (%)=(1 – receives the average OD value in prospect hole OD value/solvent control hole) ' 100 %
Calculate inhibiting rate, and be X-coordinate with the logarithm of test-compound concentration, cell inhibitory rate MV is that ordinate zou is drawn dose effect curve, and asks half cytostatics value (IC with the Origin analysis software 50).The result representes with
Figure 2011103245350100002DEST_PATH_IMAGE061
SD.
 
Two, the anti-tumor activity result of part of compounds
Table 1Part embodiment is to the IC of Bcl-2 empty carrier and Bcl-2 high expression level Hela cell 50(μ M)
Compd. Hela BCL-2-is empty Hela BCL-2-3 Hela BCL-2-4
Embodiment 19 57.70±13.39 149.94±60.67 156.10±105.20
Embodiment 20 134.14±25.94 >;300 258.88±7.14
Embodiment 21 230.72±15.78 >;300 >;300
Embodiment 24 154.58±12.15 >;300 >;300
Can know that from table 1 cell proliferation has certain restraining effect to embodiment to Hela, at the cell strain experimental result basically identical of Hela-Bcl-2-3, this 2 strain of Hela-Bcl-2-4 Bcl-2 high expression level.
 
Embodiment 2: the activity of cholinesterase test of compound
The present invention use Ellman ( Biochemical Pharmacology 1961,7, the IC that method test compounds 88-95.) suppresses Pseudocholinesterase 50Value.All tests all are with Microplate reader ELX808 TMType ELIASA (U.S. BioTek company) is 37 °Measure under the C condition.DAS uses Origin software to carry out data processing, uses Galanthamine as reference substance.
One, materials and methods
1. the preparation of suppressor factor storing solution
The suppressor factor of being tested is made into the DMSO solution of 10 mM.
2. the preparation of enzyme storing solution
E.C. 3.1.1.7 (from electric eel, extracting) and butyrylcholine esterase (from the blood plasma of horse, extracting) are available from Sigma company; Phosphate buffered saline buffer with pH=8.0 is made into 0.1 mg/mL respectively, 2 mg/mL.
3. the preparation of substrate storing solution
Acetyl mercapto choline (E.C. 3.1.1.7 substrate) and butyryl sulfydryl choline (butyrylcholine esterase substrate) are available from Sigma company; Phosphate buffered saline buffer with pH=8.0 is made into 2 mg/mL respectively, 4 mg/mL.
4. the preparation of developer storing solution
Developer DTNB is available from Sigma company; Phosphate buffered saline buffer with pH=8.0 is made into 4 mg/mL (test E.C. 3.1.1.7) and 8 mg/mL (test butyrylcholine esterase) respectively.
5. test
The volume of each test all is 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 15 μ L different concns inhibitor solutions (with pH=8.0 phosphate buffer soln dilution suppressor factor storing solution) more respectively; With pH=8.0 phosphate buffer soln polishing to 139 μ L, add 5 μ L enzyme storing solutions then, insulation 12 min in the ELIASA of 37 C; Add 6 μ L substrate storing solutions immediately, survey immediately behind the mixing its λThe one minute absorbancy in=405 nm places changes (slope).Reference liquid is pH=8.0 phosphate buffer solns.
6. the result judges
Do not change (slope) as 100 unit of activity to add the measured absorbancy of sample; Relative enzyme activity=(absorbancy that adds suppressor factor changes the absorbancy variation (slope) that (slope)/not adds suppressor factor) * 100, the concentration of the suppressor factor when the relative vigor of enzyme is 50 is the IC of suppressor factor 50Value.
 
Two, the active result of the anticholinesterase of compound
Table 2Part of compounds is active to the inhibition of cholinesterase
Compd. IC 5 0 (μM) for AChe IC 50 (μM)for BuChe
Embodiment 9 72.32±0.50 >;100
Embodiment 10 52.78±1.89 >;100
Embodiment 11 32.83±0.28 13.74±0.10
Embodiment 12 44.89±1.07 76.05±1.74
Embodiment 13 29.17±1.30 22.83±0.86
Embodiment 14 41.97±1.19 9.68±0.55
Embodiment 15 34.68±0.91 42.75±1.05
Embodiment 16 47.89±0.68 56.96±0.10
Embodiment 17 53.54±1.46 78.89±2.24
Embodiment 18 44.05±1.04 25.08±0.07
Embodiment 19 4.23±0.12 3.66±0.03
Embodiment 20 20.99±1.17 12.2±0.50
Embodiment 21 15.34±0.73 2.81±0.01
Embodiment 22 16.51±0.23 6.48±0.06
Embodiment 23 13.44±0.49 3.55±0.20
Embodiment 24 19.15±0.50 4.08±0.15
Can know that from table 2 majority of compounds shows AChE and the stronger inhibition ability of BuChE, it is the strongest that 19 couples of AChE of embodiment suppress ability, its IC 50Be 4.23 μ M, the inhibition effect 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 use coating method tested compound compound divide real to streptococcus aureus ( Staphylococcus aureus) minimum inhibitory concentration.
One, experimental technique
1. spawn culture
With the streptococcus aureus streak inoculation on beef-protein medium, 37 °Enlarged culturing is subsequent use under the C.
2. initial soup preparation
Take by weighing 5 mg samples and be dissolved in the 5 mL acetone, all the dissolving back moves in the volumetric flask of 10 mL, dilutes constant volume with 5 mL sterilized waters then, be mixed with concentration and be 0.5 g/L subsequent use medicine (solvent: V Acetone: V Sterilized water=1:1), blank liquid is made into 0.5 mL acetone and 0.5 mL sterilized water, establishes a blank, each concentration do three parallel.
3. the preparation of band medicine substratum
Under the aseptic condition, (control group is used to draw 1 mL soup V Acetone: V Sterilized water=1:1 replaces) with the sterilising medium mixing of 9 mL hot melts, pour in the glass culture dish that diameter is 9 cm, process thin and thick and be with the medicine plate culture medium subsequent use uniformly.This moment, liquor strength was diluted 10 times, and the soup ultimate density is 0.05 g/L.
4. try bacterium in the sterilized water of 10 mL with a small amount of cultured confession of transfering loop picking, process concentration about 10 6~ 10 7The bacteria suspension of cfu/mL.Draw on 100 μ L bacteria suspensions to contrast and the band medicine plate culture medium; Spreading rod with sterilization is even with the coating of bacterium liquid, and 3 repetitions are established in each processing, place 37 C constant incubators to cultivate at last; Respectively at 24 h and 48 h observationss, experimental result is listed in table 3.
 
Two, the bacteriostatic activity result of compound
Table 3Part of compounds of the present invention is to aureus with inhibition
Figure 2011103245350100002DEST_PATH_IMAGE063
Annotate: ++ ++ represent strong bacteriostasis, almost not growth, +++represent very small portion growth ,+number more multilist shows that bacteriostasis is strong more, – representes there is not bacteriostasis.
Experimental result shows that most of embodiment compound has bacteriostatic action, and embodiment 19 is the strongest with embodiment 21 bacteriostatic action, and its minimum inhibitory concentration is 0.04 g/L.

Claims (10)

1. the compound shown in the formula I or its pharmacologically acceptable salts, solvolyte,
?
Figure 2011103245350100001DEST_PATH_IMAGE002
The formula I
Wherein:
N is 1 or 2;
X –Be independently selected from cl ions, bromide anion, iodide ion, sulfate ion, phosphate anion, nitrate ion, perchlorate, fumarate ion, acetate ion, propionate ion, succinate ion, oxyacetic acid radical ion, formate ion, lactate ion, maleate ion, tartrate anion ion, citrate ion, malonate ion;
R 1, R 2Be substituted radical that can be identical or different, be 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 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl;
Wherein each alkyl, thiazolinyl, alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical part randomly are independently selected from following group replacement by 1-5: hydroxyl, halogen, amino, nitro, trifluoromethyl, C 1-C 10Alkyl, C 2-C L0Thiazolinyl, C 2-C 10Alkynyl, C 3-C 10Naphthenic base, C 3-C 10Cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, heterocyclic radical alkyl.
2. compound as claimed in claim 1, wherein R 1, R 2All can be selected from methyl, ethyl, n-hexyl, allyl group, benzyl respectively, to nitrobenzyl, to bromobenzyl, to luorobenzyl, to methyl-benzyl, to methoxy-benzyl.
3. like the described compound of claim 1 Chinese style I, 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;
The 1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) piperazine-1-brometo de amonio;
The 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) high piperazine-1-ammonium iodide;
1-methyl isophthalic acid-allyl group-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
1-methyl isophthalic acid-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to nitrobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to bromobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to luorobenzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to methyl-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-brometo de amonio;
The 1-methyl isophthalic acid-to methoxy-benzyl-4-(10-acetoxyl group-2-decenoyl) high piperazine-1-ammonium chloride.
4. the method for preparing each said compound of claim 1-2; Comprise: with the E-10-hydroxy-2-decylenic acid is raw material, through esterification, with N-METHYL PIPERAZINE, ethyl piperazidine, hexyl piperazine, the high piperazine of methyl amination reaction takes place respectively; Obtain corresponding intermediates; Through quaterisation, synthesize corresponding piperazine, high piperazine quaternary ammonium salt again, reaction formula is:
Figure 2011103245350100001DEST_PATH_IMAGE004
。
5. pharmaceutical composition comprises at least a pharmaceutically acceptable carrier and like the defined formula I compound of claim 1 or its pharmacologically acceptable salts, solvolyte.
Like the defined formula I compound of claim 1 or its pharmacologically acceptable salts, solvolyte in the application aspect the preparation antitumor drug.
Like the defined formula I compound of claim 1 or its pharmacologically acceptable salts, solvolyte in the application aspect preparation treatment solid tumor, the acute leukemia medicine.
Like the defined formula I compound of claim 1 or pharmacologically acceptable salts, solvolyte in the application aspect the anti-acetylcholinesterasemedicine medicine of diseases such as preparation treatment alzheimer's disease and cerebrovascular dementia.
9. be used to treat the application aspect the medicine that gram-positive microorganism and negative bacterium infect like the defined formula I compound of claim 1 or pharmacologically acceptable salts, solvolyte in preparation.
10. contain the injection of the compound shown in the said formula I of claim 1 or its pharmacologically acceptable salts, solvolyte, oral acceptable preparation, local application's preparation, sprays or drops.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10004711B2 (en) 2014-05-08 2018-06-26 Dsm Ip Assets B.V. Methods and compositions comprising 10-hydroxy-2-decenoic acid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4873331A (en) * 1988-12-09 1989-10-10 American Home Products Corporation Noradamantyl-carboxylic acid piperazinoalkyl esters
EP0988292B1 (en) * 1997-06-12 2003-02-12 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
CN101565409A (en) * 2009-03-20 2009-10-28 深圳市湘雅生物医药研究院 Piperazidine or homopiperazine oxalyl hydrazine class compound, preparation and use thereof
CN102036666A (en) * 2008-03-20 2011-04-27 森林实验室控股有限公司 Novel piperazine derivatives as inhibitors of stearoyl-coA desaturase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4873331A (en) * 1988-12-09 1989-10-10 American Home Products Corporation Noradamantyl-carboxylic acid piperazinoalkyl esters
EP0988292B1 (en) * 1997-06-12 2003-02-12 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
CN102036666A (en) * 2008-03-20 2011-04-27 森林实验室控股有限公司 Novel piperazine derivatives as inhibitors of stearoyl-coA desaturase
CN101565409A (en) * 2009-03-20 2009-10-28 深圳市湘雅生物医药研究院 Piperazidine or homopiperazine oxalyl hydrazine class compound, preparation and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HANS H. MAURER，等: "Chemistry, Pharmacology, Toxicology, and Hepatic Metabolism of Designer Drugs of the Amphetamine (Ecstasy), Piperazine, and Pyrrolidinophenone Types A Synopsis", 《THER DRUG MONIT》 *
胡国强，等: "非对称双杂环取代均***并噻二唑哌嗪衍生物的合成及抗菌活性", 《应用化学》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10004711B2 (en) 2014-05-08 2018-06-26 Dsm Ip Assets B.V. Methods and compositions comprising 10-hydroxy-2-decenoic acid

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