CN1939916B - Compound for treating AIDS - Google Patents
Compound for treating AIDS Download PDFInfo
- Publication number
- CN1939916B CN1939916B CN2006101516817A CN200610151681A CN1939916B CN 1939916 B CN1939916 B CN 1939916B CN 2006101516817 A CN2006101516817 A CN 2006101516817A CN 200610151681 A CN200610151681 A CN 200610151681A CN 1939916 B CN1939916 B CN 1939916B
- Authority
- CN
- China
- Prior art keywords
- compound
- hiv
- medicine
- ccr5
- carbobenzoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Compound for treating AIDS, its accepted salt and its use for inhibiting HIV virus are disclosed. It can inhibit HIV virus infect human-body cell and has less by-effects.
Description
Technical field
The present invention relates to a kind ofly have the active compound of anti-HIV-1, and pharmaceutical composition and purposes.
Background technology
CCR5 as one member of Chemokine Receptors family, its endogenous agonist has RANTES, MIP-1 α and MIP-1 β, and it is expressed in the dendritic cell in peripheral blood source, T lymphocyte, monocyte, scavenger cell and participation are kept the immunocyte and the inflammatory cell of long-term inflammatory reaction.Therefore, the function of regulating CCR5 may be regulated the T cell to the raising of inflammatory reaction injury region, thereby provides a new target spot for treatment inflammatory reaction and autoimmune disorder.
Have the activity of potential anti-HIV-1 although announced the CCR5 receptor antagonist, the CCR5 receptor antagonist differs and establishes a capital the activity of anti-HIV-1.According to the literature, external several drugmaker finds in the performance history of CCR5 antagonist, some compounds are the antagonizing CCR 5 acceptor efficiently, but but can not resist virus effectively enters [referring to 1.Kim, D.Discovery of human CCR5 antagonists containing hydantoins for the treatment ofHIV-1 infection.Bioorg.Med.Chem.Lett.2001,11,3099; 2.Hale, J.1,3,4-Trisubstitutedpyrrolidine CCR5 receptor antagonists.Part 2:lead optimization affording selective, orallybioavailable compounds with potent anti-HIV activity.Bioorg Med Chem Lett.2001 Oct22; 11 (20): 2741-5].The CCR5 antagonist that also has some companies after discovery, do not have always follow-up about bioactive report [referring to Wieslaw Kazmierski.Recent Progress in Discovery of Small-MoleculeCCR5 Chemokine Receptor Ligands as HIV-1 Inhibitors.Bioorganic ﹠amp; Medicinal Chemistry11 (2003) 2663-2676].
Yet, also lack the compound that effectively suppresses the HIV viral growth up to now.Therefore, this area presses for the compound that exploitation effectively suppresses or resist HIV virus (as HIV-1 virus).
Summary of the invention
Purpose of the present invention just provides compound and method for making and the purposes that a class can significantly suppress HIV virus (as HIV-1 virus).
In a first aspect of the present invention, the compound shown in a kind of general formula (I) is provided, or its pharmacy acceptable salt,
In the formula, R
1Be following groups unsubstituted or that replaced by 1-3 substituting group: benzyl, benzoyl, cyclohexyl formyl radical, cyclopentyl formyl radical, benzenesulfonyl or naphthoyl, described substituting group is selected from halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group;
R
3Be hydrogen, C
1-C
4Alkyl, phenyl or
Phenyl ring can be replaced by 1-3 substituting group that is selected from down group in the described group: halogen and C
1-C
4Alkyl;
R
6For to nitro carbobenzoxy-(Cbz), carbobenzoxy-(Cbz), to the halogen carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, to the methyl carbobenzoxy-(Cbz), to trifluoromethyl carbobenzoxy-(Cbz), N-phenyl formamide base, benzene oxygen ethanoyl, 3,4-dioxy methylene radical carbobenzoxy-(Cbz), to amino carbobenzoxy-(Cbz), benzenesulfonyl, to the Methyl benzenesulfonyl base.
In another preference, described compound is selected from down group:
Allyl group-and 1-[1-benzyl-4-hydroxyl-4-(4-fluorine) benzene pyrroles-3-methylene radical] piperidines-4-position } methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-benzyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-benzoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-[1-(2-iodine) benzoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical] piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-naphthoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-cyclohexyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide benzyl ester;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-methoxy benzyl ester;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-bromobenzyl ester;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position]-3-phenylurea;
Allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] ethanamide phenylate.
In another preference, described compound has structure shown in the following structural formula (II):
In the formula, R
1Be following groups unsubstituted or that replaced by 1-3 substituting group: benzyl, benzoyl, cyclohexyl formyl radical, cyclopentyl formyl radical, benzenesulfonyl or naphthoyl, described substituting group is selected from halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group;
R
6For to nitro carbobenzoxy-(Cbz), carbobenzoxy-(Cbz), to the halogen carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, to the methyl carbobenzoxy-(Cbz), to trifluoromethyl carbobenzoxy-(Cbz), N-phenyl formamide base, benzene oxygen ethanoyl, 3,4-dioxy methylene radical carbobenzoxy-(Cbz), to amino carbobenzoxy-(Cbz), benzenesulfonyl, to the Methyl benzenesulfonyl base.
In another preference, described compound is selected from down group:
Allyl group-[1-((3R, 4S)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-benzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-methoxy benzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-bromobenzyl ester.
In another preference, described compound is TD0232, and it has structure shown in the following structural formula (III):
In a second aspect of the present invention, a kind of pharmaceutical composition is provided, it contains the above-mentioned compound of safe and effective amount (as 0.0001-99.99wt%, more preferably 0.01-99wt%) the present invention or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable carrier.
In a third aspect of the present invention, the purposes of above-claimed cpd of the present invention is provided, they are used to prepare the medicine of anti HIV-1 virus.
The compounds of this invention also can be used for being selected from down the medicine of group:
(a) medicine of inhibition HIV virus infection people's peripheral blood lymphocytes;
(b) the bonded medicine of inhibition RANTES and CCR5;
(c) suppress the GTP γ S that RANTES, MIP-1 α or MIP-1 β cause and the bonded medicine of CCR5 cytolemma;
(d) suppress the medicine that CCR5 intracellular Ca2+ that RANTES causes discharges;
(e) suppress the medicine of the CCR5 cell chemotaxis motion that RANTES causes.
In another preference, described HIV virus is HIV-1 virus.
In another preference, described HIV-1 virus is A, B, C or O hypotype or multidrug resistant HIV virus strain.
Embodiment
The inventor has synthesized class CCR5 receptor antagonist efficiently through extensive and deep research.After having proved the CCR5 antagonistic action of such antagonist, furtherd investigate its antiviral activity again, be surprised to find that formula (I), (II) but or the entering of highly significant opposing HIV-1 virus in experiment in vitro of the CCR5 antagonist (III), and these compounds are not only all effective to multiple virus subtype, but also can act on the drug-fast multidrug resistant virus strain of various clinical medicine.
Term used herein " alkyl " refers to straight or branched aliphatic hydrocarbon group saturated, that contain 1-8 carbon atom (preferably 1-6 carbon atom); " alkenyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon-carbon double bond and 2-8 carbon atom (preferably 2-6 carbon atom); " alkynyl " comprises straight chain and the branched hydrocarbyl that contains at least one carbon carbon triple bond and 2-8 carbon atom (preferably 2-6 carbon atom).
Term used herein " aryl " refers to aromatic systems, can be monocycle or originally condensed or many aromatic rings of linking together, thereby at least a portion is condensed or the ring that connects forms conjugated virtue system.Aromatic yl group comprises (but being not restricted to): phenyl, naphthyl, tetralyl.
Term used herein " heterocycle " refers to stable 4-7 unit's monocycle or stable many rings heterocycle, this heterocycle can be saturated, part is undersaturated or undersaturated, and by carbon atom be selected from a following 1-4 heteroatoms and constitute: N, O and S atom.N and S atom can be oxidized.Heterocycle also can comprise any many rings, and wherein arbitrary above-mentioned heterocycle can condense in aromatic ring.
Term " aryl of replacement " or " heterocycle of replacement " refer to by 1-4 aryl that group replaced or heterocycle that is selected from down group: halogen, CN, OH, NO
2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxyl group, aryloxy, replacement alkoxyl group, alkyl-carbonyl, alkyl carboxyl, alkylamino or arylthio.Preferably, substituting group is halogen, C
1-C
4Alkyl.
" halogen " refers to F, Cl, Br or I.
Compound of the present invention can with by pharmaceutically or the acceptable acid of physiology or alkali deutero-salt form use.These salt include, but is not limited to the salt with following mineral acid formation: example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the salt that forms with organic acid, organic acid then refers to acetate, oxalic acid, Succinic Acid, tartrate, methylsulfonic acid and toxilic acid.Other salt comprise the salt that forms with basic metal or alkaline-earth metal (as sodium, potassium, calcium or magnesium), with the form (when with this form administration, can change into active part in vivo) of " prodrug " of ester, carbamate or other routines.
The present invention also comprises pharmaceutical composition and methods of treatment, and it comprises the formula I compound to the administration medicine effective quantity.Compound of the present invention can be used for treatment: HIV infection, asthma and local disorders (as locality dermatitis, local anaphylaxis), rheumatic arthritis, arteriosclerosis, psoriasis, meat shape knurl disease and other fibrotic disease, autoimmune disorder (as multiple sclerosis, inflammatory enteritis), chronic obstructive pulmonary disease (COPD).
When compound is used for such use; they can with one or more pharmaceutically acceptable carrier or mixed with excipients; as solvent, thinner etc.; and can be with following form oral administration: tablet, capsule, dispersible powder, particle or suspension (containing 0.05-5% suspension agent according to appointment), syrup (containing 10-50% sugar according to appointment) and elixir (containing the 20-50% ethanol of having an appointment), perhaps carry out the parenteral administration with sterile injectable solution or form of suspension (containing the 0.05-5% suspension agent of having an appointment in the medium waiting to ooze).For example, these pharmaceutical preparations can contain and the about 25-90% of carrier blended, are about the activeconstituents of 25-60% (weight) usually.
The effective dose of used activeconstituents can change with the severity of the pattern of used compound, administration and disease to be treated.Yet, when compound of the present invention every day gives with the dosage of about 0.5-500mg/kg the weight of animals, can obtain gratifying effect usually, preferably give with the dosage that separates for 2-4 time every day, or with the slowly-releasing form administration.For most of large mammal, the total dose of every day is about 1-100mg, preferably is about 2-80mg.Be applicable to dosage form for oral administration, comprise active compound with the intimately mixed about 0.5-500mg of solid-state or liquid pharmaceutically acceptable carrier.Can regulate this dosage replys so that optimal treatment to be provided.For example, by an urgent demand of treatment situation, but give the dosage that several times separate every day, or dosage is reduced pari passu.
These active compounds can be by oral and intravenously, intramuscular or administration such as subcutaneous.Solid-state carrier comprises: starch, lactose, Lin Suanergai, Microcrystalline Cellulose, sucrose and white bole, and liquid carrier comprises: sterilized water, polyoxyethylene glycol, nonionic surface active agent and edible oil (as Semen Maydis oil, peanut oil and sesame oil), as long as be fit to the characteristic of activeconstituents and required specific administration mode.Normally used adjuvant also can advantageously be comprised in pharmaceutical compositions, for example seasonings, pigment, sanitas and antioxidant such as vitamin-E, vitamins C, BHT and BHA.
From being easy to prepare the position with administration, preferred pharmaceutical composition is a solid-state composition, and especially tablet and solid are filled or the capsule of liquid filling.The oral administration of compound is preferred.
But these active compounds are parenteral or intraperitoneal administration also.The solution or the suspension that also can in the water that suitably is mixed with tensio-active agent (as hydroxypropylcellulose), prepare these active compounds (as free alkali or pharmacy acceptable salt).Also can in glycerine, liquid, polyoxyethylene glycol and the mixture in oil thereof, prepare dispersion liquid.Under routine storage and working conditions, contain sanitas in these preparations to prevent microbial growth.
The medicament forms that is adapted to inject comprises: aseptic aqueous solution or dispersion liquid and aseptic powder (being used for preparing aseptic injectable solution or dispersion liquid) temporarily.In all situations, these forms must be aseptic and must be that fluid is discharged fluid to be easy to syringe.Under manufacturing and condition of storage must be stable, and must be able to prevent the pollution effect of microorganism (as bacterium and fungi).Carrier can be solvent or dispersion medium, wherein contains just like water, alcohol (as glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetables oil.
The inventor has carried out deep anti-HIV-1 activity research at the numerous compounds that comprise formula (I) compound, find some preferably have anti-HIV-1 active compound, especially formula (I), (II) and (III) shown in compound.
A kind of particularly preferred compound is allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxy-4-phenyl tetramethyleneimine-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester (hereinafter referred TD0232) or its pharmacy acceptable salt.TD0232 is the specific antagonist of CCR5, also shows the biological activity of anti-efficiently R5 preferendum HIV-1 simultaneously in experiment in vitro.
The experimental study result shows, TD0232 can suppress the peripheral blood lymphocytes (PBMC) of different HIV-1 virus strain infected person significantly, proved that this compound has an anti-HIV-1 effect efficiently external.In test to the B hypotype HIV-1 virus strain of three kinds of R5 preferendums, TD0232 has obviously suppressed the infection of HIV-1 to human PBMC's cell, the scope of its IC50 value at 2.6nM between the 18.1nM, compare with the specific antagonists SCH-C of a kind of CCR5 that reported in the past, TD0232 has suitable with it antiviral activity at least on the virus strain of being tested, on some virus strain even be better than SCH-C.
For further proving conclusively the antiviral activity of TD0232, carried out antivirus test with the PBMC cell that derives from three Different Individual, the result proves that TD0232 has the activity of anti-HIV-1 virus really.Simultaneously, for the HIV-1 virus strain of utilizing another co-receptor CXCR4 (being the virus strain of X4 preferendum), HIV-1NL4-3, TD0232 can not effectively suppress its infection to human PBMC's cell, and TD0232 antagonism R5 preferendum HIV-1 virus strain specifically is described.
For further proving conclusively TD0232 is the specific entry inhibitor of a kind of R5, and the inventor utilizes the U87.CD4 cell of expressing CCR5 or CXCR4 acceptor that TD0232 has been carried out virus and enters experiment.Result of study shows that again TD0232 has the restraining effect of entering for the B hypotype strain JR-FL and the ADA of R5 preferendum, and the B hypotype strain HXB2 or the amphotropic AmLV of in contrast X4 preferendum then do not had the restraining effect of entering.What the restraining effect that this result has proved conclusively this medicine occurred in virus enters the stage, and has verified the specificity of TD0232 effect from mechanism.
To multiple hypotype (A, B, C and O hypotype) the antiviral experiment of HIV-1 virus strain in, TD0232 has suppressed the infection of virus to human PBMC's cell significantly, proved that TD0232 is wide to the HIV-1 antiviral spectrum of R5 preferendum, had the activity of the R5 preferendum HIV-1 virus strain of anti-multiple hypotype (A, B, C and O hypotype) widely.
At the resistance phenomenon that present anti-AIDS drug occurs clinically, the inventor has selected for use a kind of HIV-1 multidrug resistant strain J18 of B hypotype to carry out antiviral experiment, and this virus strain is to widely used clinically multiple antiviral resistance at present.The result shows that TD0232 can efficiently suppress the infection of J18 virus strain to human PBMC's cell, illustrates that TD0232 has the ability of the multidrug resistant virus strain of anti-R5 preferendum.
The inventor finds that also the cytotoxicity of TD0232 is little, and the MTT experimental result shows that TD0232 is to the Cytotoxic medium lethal dose (CC of CHO/CCR5, Jurkat and people's liver cell L02
50) all greater than 10 μ M.
Compound of the present invention can be prepared with flow process shown in following:
Flow process I:
Methyl esters on β-Beta Alanine compound 1 refluxes in methyl alcohol and thionyl chloride is made the amino compound 2 that gets of protection in the alkali acetonitrile with two molecule benzyl bromines at salt of wormwood again.The Beta-alanine ester 2 and the keto ester 3 of protection carry out the Aldol condensation and obtain two groups of enantiomers 4.
Pass five membered lactams rings obtained two groups of cis-trans-isomers 5 after the condensation product catalytic hydrogenation that obtains was fallen a benzyl.Next using the methyl esters in highly basic (sodium hydroxide or potassium hydroxide) the saponification molecule is trans acids 6.
Acid 6 gets ketone compound 7 with the condensation of hydration piperidone hydrochloride in the presence of condensation reagent, Li-Al hydrogen reduce alkylol cpd 8, Swern oxidation alcohol is ketone compound 9, gets compound 10 with allylamine condensation in the presence of the acetic acid sodium borohydride again, at last and R
6The Cl reaction obtains compound 11.
Flow process II:
The compound 8 usefulness ethyl esters that obtain among the flow process I protect compound 12, catalytic hydrogenation is fallen the benzyl in the molecule, obtains compound 13, again with R
1Cl react compound 14, the protecting group that compound 14 is sloughed in salt of wormwood methyl alcohol on the secondary alcohol obtains compound 15, Swern oxidation secondary alcohol is ketone 16, gets compound 17 with allylamine condensation in the presence of the acetic acid sodium borohydride again, last and R
6The Cl reaction obtains compound 18.
Flow process III:
Flow process IV:
When R1 is the cyclopentyl formyl radical,
Flow process V:
When R1 is the cyclopentyl formyl radical,
Flow process VI:
When R1 is the cyclopentyl formyl radical,
Major advantage of the present invention is:
(a) The compounds of this invention can suppress the HIV virus infection effectively and enter human body cell.
(b) The compounds of this invention is effective for multiple hypotype and multidrug resistant strain.
(c) toxic side effect of The compounds of this invention is little.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.
Embodiment 1 compound III-a-a: allyl group-[1-(1-benzyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
N, N-dibenzyl Beta-alanine methyl esters
According to flow process I, under the ice bath with SOCl
2(10ml) splash into temperature rising reflux 3h behind methyl alcohol (40ml) solution of Beta-alanine hydrochloride (7.05g), be spin-dried for solvent after the cooling, drain, add K
2CO
3(38g) with 150ml second cyanogen solution stirring, add 22ml benzyl bromine stirring at room 20h, add water salt of wormwood is dissolved, ethyl acetate extraction twice, salt washing, Na
2SO
4Drying, filtering and concentrating, column chromatography obtains N, N-dibenzyl Beta-alanine methyl esters (14.9g), yield 93.6%.
1H?NMR(CDCl
3，300MHz)δ7.27(m，10H)，3.56(s，3H)，3.51(s，4H)，2.74(t，J＝6.9Hz，2H)，2.45(t，2H).
4-benzene-1-benzyl-4-hydroxyl-5-oxygen base pyrroles-3-carboxylic acid
Earlier with the reaction system waterless operation, nitrogen protection following 0 ℃ to 1.09ml (iPr)
2Drip the butyllithium hexane solution of 4.5ml 1.6M in the 7ml THF solution of NH, stir 10min and be chilled to-78 ℃, drip N, N-dibenzyl Beta-alanine methyl esters (1.00g, 3.53mmol) 40ml THF solution after stir 1h, the 5ml THF solution of dropwise reaction thing benzoylformic acid ethyl ester again ,-78 ℃ of reaction 4h.Use saturated NH
4The cancellation of the Cl aqueous solution, with (60 * 2) ethyl acetate extraction, washing, salt washing, Na
2SO
4Drying, column chromatography after the filtering and concentrating is with (ethyl acetate: sherwood oil=1: 13) cross post and get a solid chemical compound (0.654g) and a fluid cpds (0.653g), total recovery 73.3%.Fluid cpds (3.197g) is dissolved among the 250ml MeOH, add 0.32g Pd/C, air pressure hydrogen of room temperature is reaction 3h down, filter, be spin-dried for methyl alcohol, earlier with (ethyl acetate: sherwood oil=1: 4) cross unreacted raw material 1.065g down, use (ethyl acetate: sherwood oil=1: 2) cross post and obtain white solid 0.935g, transformation efficiency 59.8% again.
Add the NaOH aqueous solution of 1.4 equivalent 1N in the methanol solution of the methyl compound that obtains upward, room temperature reaction disappears to raw material, is spin-dried for methyl alcohol, add water and be neutralized to pH=3 with the HCl aqueous solution of 1N, with ethyl acetate extraction twice, washing, salt solution is washed till neutrality, Na
2SO
4Drying, filtering and concentrating obtains solid chemical compound.
IR(KBr)3267，2887，1713，1688，1501，1487，1254，1299cm
-1；
1H?NMR(DMSO?d
6，300MHz)δ12.45(s，1H)7.41-7.30(m，5H)，6.94-6.86(m，3H)，6.44(s，1H)，4.46(d，J
AB＝15.3Hz，1H)，4.44(d，J
AB＝15.0Hz，1H)，3.58(m，1H)，3.37(m，2H)。
Allyl group-[1-(1-benzyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
4-benzene-1-benzyl-4-hydroxyl-5-oxygen base pyrroles-3-carboxylic acid the intermediate of aforementioned acquisition and DCC (1.1eq) and HOSu (1.1eq) are dissolved in the tetrahydrofuran (THF), 6 hours after-filtration of room temperature reaction add triethylamine (2.0eq) and hydration piperidone hydrochloride (1.1eq) and stirring is spent the night.Add water and ethyl acetate concussion separatory after being spin-dried for tetrahydrofuran (THF), organic phase is washed after drying with salt, filters and is spin-dried for solvent and obtain white solid.
Be dissolved in solid in the tetrahydrofuran (THF) and add Li-Al hydrogen (8eq), temperature rising reflux with 10% sodium hydroxide cancellation, filtered and is spin-dried for solvent and obtain solid foam secondary alcohol compound after 24 hours.
Under-78 ℃, the dichloromethane solution of oxalyl chloride (1.3eq) is added drop-wise in the dichloromethane solution of methyl-sulphoxide and stirred 10 minutes, the dichloromethane solution of top white foam compound (1eq) added reaction added triethylamine (3eq) and is warmed up to room temperature after 30 minutes in the above-mentioned system, add water and ethyl acetate concussion separatory, organic phase is washed after drying with salt, and column chromatography obtains ketone compound.
Ketone compound upward (1eq) and NaBH (OAc)
3Add 1 in the mixture (1.5eq), the 2-ethylene dichloride, in system, add allylamine (1eq) and acetic acid (1eq) again, after spending the night, reaction adds saturated sodium bicarbonate aqueous solution, merge organic phase with twice back of ethyl acetate extraction, salt washing after drying, filtration is spin-dried for solvent and obtains the white foam compound.
Top solid foam is dissolved in methylene dichloride, added triethylamine (1.5eq) and p-nitrophenyl oxygen carbonyl chlorine (1.2eq) and room temperature reaction 4 hours, washing separatory after drying obtains compound III-a-a behind the column chromatography.
IR(kBr)2938，2806，1751，1710，1608，1523，1496，1448，1378，1348，1261cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.27-8.22(m，2H)，7.55-7.25(m，12H)，5.97-5.82(m，1H)，5.36-5.07(m，4H)，4.39(m，1H)，3.68(m，2H)，3.25(m，2H)，2.80-2.22(m，6H)，1.79(m，4H)；
ESI-MS?m/z?585(M
++1)；
HRMS calculated value: C
34H
41N
4O
5(M
++ 1) 585.3071, observed value 585.3070.
Embodiment 2 compound III-a-b: allyl group-[1-(1-benzoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
According to flow process II, the intermediate secondary alcohol compound (1eq) that obtains during with preparation compound III-a-a is dissolved in the methylene dichloride, the DMAP (0.1eq) that in system, adds catalytic amount, triethylamine (5.0eq) and vinegar are done (3.0eq), the zero degree reaction adds water concussion separatory after 2 hours, organic phase obtains solid foam with salt washing and dry behind the column chromatography.
Above solid foam be dissolved in the methyl alcohol, add Pd/C hydrogenation under a normal atmosphere hydrogen of 5% and spend the night, filtration catalizer also is spin-dried for solvent and obtains the foamed compound.Product is dissolved in the methylene dichloride and adds triethylamine (1.5eq) and Benzoyl chloride (1.2eq) stirred 2 hours, and washing and dry back column chromatography obtain the foamed compound.
The compound that obtains (1eq) is dissolved in methyl alcohol: water is in 5: 1 solvents, add salt of wormwood (2.0eq) and stir after 4 hours and be spin-dried for methyl alcohol, merge organic phase with twice of ethyl acetate extraction back, the salt washing, dry after-filtration also is spin-dried for solvent and obtains the white foam compound.
Under-78 ℃, the dichloromethane solution of oxalyl chloride (1.3eq) is added drop-wise in the dichloromethane solution of methyl-sulphoxide and stirred 10 minutes, the dichloromethane solution of top white foam compound (1eq) added reaction added triethylamine (3eq) and is warmed up to room temperature after 30 minutes in the above-mentioned system, add water and ethyl acetate concussion separatory, organic phase is washed after drying with salt, and column chromatography obtains ketone compound.
Ketone compound upward (1eq) and NaBH (OAc)
3Add 1 in the mixture (1.5eq), the 2-ethylene dichloride, in system, add allylamine (1eq) and acetic acid (1eq) again, after spending the night, reaction adds saturated sodium bicarbonate aqueous solution, merge organic phase with twice back of ethyl acetate extraction, salt washing after drying, filtration is spin-dried for solvent and obtains the white foam compound.
The foamed compound (1eq) that obtains above is dissolved in the methylene dichloride, adds triethylamine (2eq) and nitro Carbobenzoxy Chloride (1.5eq) back was stirred 2 hours.Add water and ethyl acetate concussion back separatory, organic phase is washed after drying with salt, filters the back column chromatography and obtains compound III-a-b.
IR(KBr)3375，3063，2943，1701，1627，1608，1577，1522，1496，1421，1346，1250cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.24-8.19(m，2H)，7.61-7.21(m，12H)，5.82-5.77(m，1H)，5.22-5.11(m，4H)，4.14-3.61(m，8H)，3.17-3.07(m，1H)，2.98-2.40(m，4H)，2.20(m，1H)，1.82-1.50(m，4H)；
ESI-MS?m/z?599(M
++1)；
HRMS calculated value: C
34H
39N
4O
6(M
++ 1) 599.2864, observed value 599.2879.
Embodiment 3 compound III-a-c: allyl group-[1-[1-(2-iodine) benzoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical] piperidines-4-position] methane amide-4-nitrobenzyl ester
According to preparing the identical method of compound III-a-b, change Benzoyl chloride into adjacent iodobenzene formyl chloride and promptly can obtain compound III-a-c.
IR(KBr)3375，2941，1701，1637，1522，1467，1421，1345，1249cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.24-8.20(m，2H)，7.86-7.80(m，1H)，7.55-7.06(m，10H)，5.95-5.76(m，1H)，5.23-5.12(m，4H)，4.16-4.04(m，2H)，3.96-3.85(m，3H)，3.70-3.13(m，3H)，3.03(m，1H)，2.80(m，2H)，2.57(m，1H)，2.18-2.02(m，2H)，1.87-1.64(m，4H)；
ESI-MS?m/z?725(M
++1)；
HRMS calculated value: C
34H
38N
4O
6I (M
++ 1) 725.1831, observed value 725.1833.
Embodiment 4 III-a-d: allyl group-[1-(1-naphthoyl-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
According to preparing the identical method of compound III-a-b, change Benzoyl chloride into the 1-naphthoyl chloride and promptly can obtain compound III-a-d.
IR(KBr)3381，3060，2943，1701，1633，1522，1465，1428，1384，1346，1249cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.23-8.18(m，2H)，7.96-7.82(m，3H)，7.58-7.21(m，11H)，5.95-5.76(m，1H)，5.21-5.11(m，4H)，4.20-3.96(m，3H)，3.94-3.58(m，3H)，3.52-3.21(m，2H)，3.10(m，1H)，2.82-2.52(m，4H)，2.25-2.06(m，1H)，1.74-1.39(m，4H)；
ESI-MS?m/z?649(M
++1)；
HRMS calculated value: C
38H
41N
4O
6(M
++ 1) 649.3021, observed value 649.3016.
Embodiment 5 III-a-e: allyl group-[1-(1-cyclopentyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
According to preparing the identical method of compound III-a-b, change Benzoyl chloride into the cyclopentyl formyl chloride and promptly can obtain compound III-a-e:
IR(KBr)3375，2948，1700，1637，1523，1467，1345，1249cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.23(d，2H)，7.54-7.23(m，8H)，5.83-5.77(m，1H)，5.23-5.12(m，4H)，4.10-3.67(m，7H)，3.58-3.40(m，1H)，3.06-2.60(m，4H)，2.59-2.40(m，1H)，2.14-2.03(m，1H)，2.00-1.48(m，13H)；
ESI-MS?m/z?591(M
++1)；
HRMS calculated value: C
33H
43N
4O
6(M
++ 1) 591.3177, observed value 591.3168.
Embodiment 6 compound III-a-f: allyl group-[1-(1-cyclohexyl formyl radical-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester
According to preparing the identical method of compound III-a-b, change Benzoyl chloride into the cyclohexyl formyl chloride and promptly can obtain compound III-a-f.
IR(KBr)3375，2933，2855，1701，1638，1523，1450，1346，1250cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.22(d，J＝7.8Hz)，7.60-7.52(m，3H)，7.42-7.11(m，4H)，5.92-5.76(m，1H)，5.22(s，2H)，5.16-5.10(m，2H)，4.15-3.62(m，7H)，3.58-3.37(m，1H)，3.11-2.60(m，4H)，2.58-2.00(m，2H)，2.00-1.44(m，15H)；
ESI-MS?m/z?605(M
++1)；
HRMS calculated value: C
34H
45N
4O
6(M
++ 1) 605.3334, observed value 605.3333.
Embodiment 7 compound III-a-g: allyl group-1-[1-benzyl-4-hydroxyl-4-(4-fluorine) benzene pyrroles-3-methylene radical] and piperidines-4-position } methane amide-4-nitrobenzyl ester
According to preparing the identical method of compound III-a-a, change intermediate 4-phenyl-1-benzyl-4-hydroxyl-5-oxygen base pyrroles-3-carboxylic acid into 4-(4-fluorine) phenyl-1-benzyl-4-hydroxyl-5-oxygen base pyrroles-3-carboxylic acid and promptly can obtain compound III-a-g.
IR(KBr)
1H?NMR(CDCl
3，300MHz)δ8.21(m，2H)，7.64-7.47(m，3H)，7.40-7.20(m，6H)，7.05-6.96(m，2H)，5.89(m，1H)，5.18-5.06(m，4H)，3.68(m，3H)，3.28-3.21(m，3H)，2.95(d，1H)，2.86-2.74(m，3H)，2.60(m，1H)，2.53-2.25(m，5H)，1.85-1.75(m，4H).
ESI-MS?m/z(M
++1)603；
HRMS calculated value: C
34H
39N
4O
5F (M
++ 1) 625.2797, observed value 625.2808.
Embodiment 8: compound III-a-h
According to preparing the identical method of compound III-a-e, will be changed to Carbobenzoxy Chloride to the nitro Carbobenzoxy Chloride, obtain compound III-a-h:
1H?NMR(CDCl
3，300MHz)7.52-7.26(m，10H)，5.85-5.77(m，1H)，5.21-5.08(m，4H)，4.05-3.88(m，1H)3.87-3.64(m，6H)，3.01-2.39(m，7H)，2.38-2.14(m，1H)，1.87-1.48(m，12H)；
ESI-MS?m/z?546.4(M
++1)；
Embodiment 9: compound III-a-i
According to preparing the identical method of compound III-a-e, will be changed to methoxyl group benzyloxy carbonyl chlorine the nitro Carbobenzoxy Chloride, obtain compound III-a-i:
1H?NMR(CDCl
3，300MHz)δ7.52-7.24(m，7H)，6.95-6.82(d，2H)，5.92-5.68(m，1H)，5.26-5.02(m，4H)，4.21-3.63(m，10H)，3.22-2.34(m，7H)，2.02-1.51(m，13H)；
Embodiment 10: compound III-a-j
According to preparing the identical method of compound III-a-e, will be changed to bromo-benzyloxycarbonyl chlorine the nitro Carbobenzoxy Chloride, obtain compound III-a-j:
1H?NMR(CDCl
3，300MHz)δ7.55-7.15(m，9H)，5.86-5.67(m，1H)，5.30-5.00(m，4H)，4.17-3.62(m，7H)，3.06-2.35(m，6H)，2.22-2.02(m，2H)，1.86-1.53(m，12H)；
Embodiment 11: compound III-a-k
According to preparing the identical method of compound III-a-e, will be changed to the phenyl carbimide to the nitro Carbobenzoxy Chloride, obtain compound III-a-k:
1H?NMR(CDCl
3，300MHz)δ7.58-7.26(m，8H)，7.08-6.98(m，2H)，6.60-6.52(d，1H)，6.00-5.86(m，1H)，5.48-5.32(m，2H)，4.44-4.32(m，1H)，3.91-3.50(m，5H)，3.11-2.02(m，9H)，1.96-1.49(m，12H)；
ESI-MS?m/z?531(M
++1)；
Embodiment 12: compound III-a-l
According to preparing the identical method of compound III-a-e, will be changed to phenoxyacetyl chloride to the nitro Carbobenzoxy Chloride, obtain compound III-a-l:
1H?NMR(CDCl
3，300MHz)7.52-7.26(m，7H)，7.00-6.89(m，3H)5.86-5.77(m，1H)，5.30-5.21(m，2H)，4.70-4.66(d，2H)，4.58-4.40(m，1H)，4.00-3.69(m，6H)，3.02-2.38(m，6H)，2.38-2.05(m，2H)，1.87-1.45(m，12H)；
ESI-MS?m/z?546.5(M
++1)；
Each prepared compound of the foregoing description is summarized in the table 1:
Table 1 compound
Embodiment 13: the preparation of rotational isomerism compound
Referring to flow process III.
Compound 19
Add NaOH and the isopyknic THF of 2N in the ethyl benzoylformate, stirring reaction is 4 hours under the room temperature; The point plate; Add the hydrochloric acid cancellation after reacting completely; Be spin-dried for THF; Ethyl acetate extraction; Washing; Dry.Obtain colourless sticky solid, promptly compound 19.
Compound 20
The sour methyl esters of raw material propylene is dissolved in the amount of methanol, stirs adding 1.2 normal (R)-Alpha-Methyl benzylamines down, reaction system stirred 20 hours at normal temperatures, and decompression (0.1Mpa,＜60 ℃) boils off methyl alcohol, gets faint yellow thick product, and promptly compound 20.Need not further purification and can directly do reaction downwards.
Compound 21
Compound 19 and compound 20 are pressed the equivalent mixed dissolution in an amount of methylene dichloride, add HOBt and DCC under the ice bath successively inward, reaction system rose to room temperature reaction two days naturally.Filter, water, saturated common salt water washing successively obtains faint yellow solid with re-crystallizing in ethyl acetate after being spin-dried for solvent, and promptly compound 21.
Compound 22
Under the anhydrous and oxygen-free condition, compound 21 is dissolved in an amount of anhydrous tetrahydro furan ,-78 ℃ slowly drip 1.2 normal LDA down, and reaction is 8 hours under this temperature; The point plate is followed the tracks of; Reacted back acetate cancellation; Be spin-dried for; Dichloromethane extraction; Dry; Concentrate and promptly get compound 22.
Method for splitting:
Add in the concentrated solution of gained while hot and left standstill crystallization at least 12 hours after an amount of ethyl acetate is mixed stirring, filter, 60 ℃ of oven dry promptly get a white crystal, turn out to be the simplification compound 22 with absolute configuration through the monocrystalline X-ray diffraction ".
Above-mentioned mother liquor continues secondary crystal can obtain another flaxen crystal again in 12 hours, behind polarimetry with above-mentioned compound 4 " the specific rotation contrast, be defined as compound 4 " enantiomer, be decided to be compound 22 '.
Compound 23
With 14g compound 22 " be dissolved in the amount of methanol; add the NaOH solution of 2 normal 2N under the violent stirring; reaction system at room temperature stirred 6 hours; after adding the entry dilution; boil off methyl alcohol under the decompression (0.1Mpa;＜60 ℃), with hydrochloric acid (36.5% the hydrochloric acid preparation) regulation system of 3N to acid (pH=4), filter crude product.Add an amount of ethyl acetate and sherwood oil in the crude product again, be heated to 50 ℃ of stirred for several hour, filtered while hot obtains white filter cake, obtains white powder 12g after the oven dry, and promptly compound 23 ".Productive rate 87%.
Compound 24
With compound 23 " (12g) and HOSu (5.1g) be dissolved among the exsiccant THF; ice bath is cooled to 0 ℃ with the temperature of system; the anhydrous THF solution that slowly adds DCC (9.12g) then in the reaction system stirred after 1 hour, slowly rose to room temperature, and at room temperature restir is about 24 hours.Filter, filter cake washs fast with the THF that does, merging filtrate, and in filtrate, add 3 normal triethylamines (15mL), and reaction system is cooled to 0 ℃, in reaction system, slowly add the hydrochloride (6.24g) of 1.1 normal piperidone again, finished in about 30 minutes, slowly be raised to room temperature, stir after 20 hours, filter, be spin-dried for filtrate, add 50mL ethyl acetate and the extraction of 20mL water in the solid that obtains, the salt solution washing is left standstill a few hours after dry the concentrating, filter, 50 ℃ of normal pressure oven dry obtain white powder 11g, and promptly compound 24, productive rate 73.3%.
Compound 25
In reaction flask, add 2g Lithium Aluminium Hydride and an amount of THF respectively, be cooled to 0 ℃ in the ice bath.Then compound 24 (10g) is dissolved in an amount of tetrahydrofuran (THF), this solution is divided into slowly is added drop-wise to respectively after two parts in the above-mentioned reaction flask, dripped in about about 1 hour and to finish.Reaction system slowly is warming up to tetrahydrofuran (THF) and begins to reflux, and keeps reflux state 72 hours, reaction system is cooled to 0 ℃ once more, in each reaction flask, slowly drip about 2mL water respectively successively, the NaOH solution of 2mL15% and 2mL water, stirring at normal temperature is spent the night approximately, filters.Filter cake washs with tetrahydrofuran (THF), merges organic phase, concentrate colourless viscous liquid 9.38g, promptly compound 25, crude product yield 100%.This compound need not be further purified and can be directly used in next step reaction.
Compound 26
The intermediate secondary alcohol compound 25 (1eq) that obtains is dissolved in an amount of methylene dichloride, the DMAP (0.1eq) that in system, adds catalytic amount, triethylamine (5.0eq) and vinegar are done (3.0eq), add water concussion separatory behind the reaction 2h down at 0 ℃, organic phase is also dry with the salt washing, obtain solid foam behind the column chromatography, promptly compound 26.
Compound 27
Top solid foam compound 26 is dissolved in the amount of methanol, adds Pd/C hydrogenation under a normal atmosphere hydrogen of 5% and spend the night, filtration catalizer also is spin-dried for solvent and obtains the colourless foam compound, and promptly compound 27.
Compound 28
Above-claimed cpd 27 is dissolved in the methylene dichloride and adds triethylamine (1.5eq) and ring penta formyl chloride (1.2eq) stirring 4h, and washing and dry back column chromatography obtain the weak yellow foam compound, and promptly compound 28.
Compound 29
The above-claimed cpd 28 (1eq) that obtains is dissolved in methyl alcohol: in water=5: 1 solvent, be spin-dried for methyl alcohol after adding salt of wormwood (2.0eq) and stirring 4h, merge organic phase with twice back of ethyl acetate extraction, the salt washing, dry after-filtration also is spin-dried for solvent and obtains the white foam compound, and promptly compound 29.
Compound 30
Under-78 ℃, the dichloromethane solution of oxalyl chloride (1.3eq) is added drop-wise in the dichloromethane solution of methyl-sulphoxide and stirred 10 minutes, the dichloromethane solution of top white foam compound 29 (1eq) is added in the above-mentioned system reaction to add triethylamine (3eq) after 30 minutes and is warmed up to room temperature and continue to stir 20 minutes, add water and ethyl acetate concussion separatory, organic phase is washed after drying with salt, column chromatography obtains ketone compound, and promptly compound 30.
Compound 31
Ketone compound 30 (1eq) upward and NaBH (OAc)
3Add 1 in the mixture (1.5eq), the 2-ethylene dichloride, in system, add allylamine (1eq) and acetic acid sodium borohydride (1eq) again, after spending the night, reaction adds saturated sodium bicarbonate aqueous solution, merge organic phase with twice back of ethyl acetate extraction, salt washing after drying, filtration is spin-dried for solvent and obtains the white foam compound, and promptly compound 31.
Compound 32
The foamed compound 31 (1eq) that obtains above is dissolved in the methylene dichloride, adds triethylamine (2eq) and nitro Carbobenzoxy Chloride (1.5eq) back was stirred 4 hours.Add water and ethyl acetate concussion back separatory, organic phase is washed after drying with salt, filters the back column chromatography and obtains compound 32, be i.e. TD0232, weak yellow foam.The TD0232 structural characterization:
IR(KBr)3375，2948，1700，1637，1523，1467，1345，1249cm
-1；
1H?NMR(CDCl
3，300MHz)δ8.23-8.20(d，2H)，7.52-7.27(m，8H)，5.85-5.77(m，1H)，5.22-5.11(m，4H)，4.04-3.66(m，8H)，3.06-2.83(m，1H)，2.82-2.60(m，3H)，2.59-2.40(m，2H)，2.30-2.03(m，2H)，2.00-1.48(m，13H)；
13C?NMR(CDCl
3，300MHz)δ175.3，175.1，147.5，144.1，143.4，128.4，128.3，128.0，127.3，127.2，125.1，125.0，123.7，82.1，65.6，61.3，55.8，55.4，55.2，54.6，54.0，47.7，46.3，44.3，42.7，42.5，29.9，29.7，26.1，26.0；
ESI-MS?m/z?591(M
++1)；
HRMS calculated value: C
33H
43N
4O
6(M
++ 1) 591.3177, observed value 591.3168.
Its absolute configuration is confirmed indirectly by the monocrystalline X-ray diffraction spectrogram of midbody compound 29.
According to the method for flow process III, prepare TD0231 equally, its synthetic route is from splitting the same TD0232 in back.
According to flow process IV, compound 31 is dissolved in CH
2Cl
2: H
2O=1: in 1 the solution, be chilled to 0 ℃, the NaOH of 1.2eq slowly adds, and begins to drip Carbobenzoxy Chloride then.NaOH with 1N carefully keeps pH=10, stirs 2 hours.Dilute with water, dichloromethane extraction, the saturated common salt washing, anhydrous sodium sulfate drying, column chromatography obtains white solid, called after compound TD0237:
1H?NMR(CDCl
3，300MHz)7.52-7.26(m，10H)，5.85-5.77(m，1H)，5.21-5.08(m，4H)，4.05-3.88(m，1H)3.87-3.64(m，6H)，3.01-2.39(m，7H)，2.38-2.14(m，1H)，1.87-1.48(m，12H)；
ESI-MS?m/z?546.4(M
++1).
According to flow process V, solid phosgene is dissolved in the anhydrous diethyl ether, N
2Protection, cryosel are bathed down and are dripped the pure and mild N of bromobenzyl, and the anhydrous ether solution of accelerine stirred 1 hour, filter, and cryoconcentration, the ether washing, cryoconcentration obtains white crystal again.
Compound 31 is dissolved in the methylene dichloride, adds the DMAP of catalytic amount and the triethylamine of 1.5eq, in the ice bath, N
2Protection drips the dichloromethane solution of above-mentioned white crystal down.Naturally rising to room temperature reaction spends the night.Add shrend and go out, dichloromethane extraction, the saturated common salt washing, anhydrous sodium sulfate drying concentrates, and column chromatography obtains the solid TD0245 of white:
1H?NMR(CDCl
3，300MHz)δ7.55-7.15(m，9H)，5.86-5.67(m，1H)，5.30-5.00(m，4H)，4.17-3.62(m，7H)，3.06-2.35(m，6H)，2.22-2.02(m，2H)，1.86-1.53(m，12H)
According to flow process VI, experimental implementation obtains compound TD0240 with compound TD0245:
1H?NMR(CDCl
3，300MHz)δ7.52-7.24(m，7H)，6.95-6.82(d，2H)，5.92-5.68(m，1H)，5.26-5.02(m，4H)，4.21-3.63(m，10H)，3.22-2.34(m，7H)，2.02-1.51(m，13H)；
Each rotational isomerism compound that table 2 the foregoing description is prepared
The external anti-HIV-1 activity research of embodiment 14 each compound
1. test materials
Cell: human PBMC's cell, available from blood station, center, Wuhan City, respectively from 3 healthy people.
HIV-1 strain: HIV-1JR-FL, HIV-120678 and HIV-1NL4-3, available from NIH AIDS Research andReference Reagent Program, HIV-1HNz2 is available from the modern viral research centre of Wuhan University.
The P24 test kit: HIV-1 p24 Antigen EIA, available from Beckman Coulter company.
Solution with RPMI1640 preparation different concns.TD0232 according to required prepared at concentrations, is respectively 600nM, 200nM, 66.7nM, 22.2nM, 7.4nM, 2.5nM, 0.8nM.
The dilution of virus: be used for the virus strain of medicine body outer suppressioning experiment, generally select 100TCID for use
50/ hole.Be diluted to 100TCID with nutrient solution
50/ 50ul/ hole.
Carry and a few days ago from human blood, prepare PBMC (peripheral blood lymphocytes), and in the substratum that contains PHA and IL-2, cultivate.
Test the same day:
1. extract PBMC and with 10
5The every hole of individual cell places 96 orifice plates to cultivate every hole 100ul.
2. gradient dilution medicine
3. every hole adds (diluting) medicine of 50ul
4. every hole adds virus 5 0ul, final concentration 100TCID
50Every hole.
First day:
1 usefulness ordinary culture medium cleans infected cell three times;
2. after last the cleaning, add newly join contain medicine growth medium 200ul;
The 7th day: collect viral supernatant, carry out p24 and detect
Result: can utilize calculation formula to calculate this medicine and suppress viral rate according to the p24 detected result.
Formula: medicine inhibiting rate=((control wells-detection hole)/control wells) * 100%
The result shows that compound TD0232 and positive control drug SHC-C all can obviously suppress the infection of three kinds of B hypotype R5 preferendum HIV-1 strains to the human PBMC, the IC of TD0232
50To between the 18.1nM, its antiviral activity is better than positive control drug SHC-C to the value scope slightly at 2.6nM.At the antiviral activity of the enterprising step card of the PBMC of three Different Individual cell TD0232, the result shows that TD0232 can be in the infection of external remarkable opposing HIV-1 to the PBMC cell.In the experiment to B hypotype X4 preferendum HIV-1 strain NL4-3, TD0232 and positive control drug SHC-C do not show tangible antivirus action, illustrate that TD0232 has the activity of specific anti-R5 preferendum HIV-1.The results are shown in Table 3.
Each compound of table 3. and SCH-C suppress B hypotype R5 preferendum HIV-1 virus strain
The IC that in the human PBMC, duplicates
50(IC
90) and to the CC of PBMC
50Value
The The specificity of the external anti-HIV-1 effect of embodiment 15 TD0232
1. experiment material
Cell: express the U87.CD4 cell of CCR5 or CXCR4 acceptor, available from NIH AIDS Research andReference Reagent Program.
Strain: HIV-1JR-FL, HIV-1ADA, HIV-1HXB2 and HIV-1Amlv are available from NIH AIDSResearch and Reference Reagent Program.
Luciferase detection kit: Promega company
Luminoscope: DYNEX Technologies, Inc company
2. experimental technique and evaluation
A. with the drug solution of TD0232 with DMEM substratum preparation different concns.Press the required prepared at concentrations of drug test, the experiment final concentration is 600nM, 200nM, 66.7nM, 22.2nM, 7.4nM, 2.5nM, 0.8nM.
B. Bing Du dilution
The virus strain that is used for the medicine body outer suppressioning experiment is generally selected 100TCID for use
50/ hole.
Be diluted to the 100TCID50/50ul/ hole with the DMEM nutrient solution
C. experimental arrangement:
Carry the day before yesterday:
Prepare U87.CD4.CCR5 and U87.CD4.CXCR4 (source), and in 96 orifice plates, with the DMEM culture medium culturing that contains 10%FBS.Cell number is 4 * 10
4/ hole.
Test the same day:
1. gradient dilution medicine
2. every hole adds (diluting) medicine of 50ul
3. every hole adds virus 5 0ul, and final concentration is the virus that is equivalent to the p24 value in the every hole of 10ng/
After 72 hours:
Collect infected cells, with the test kit detection fluorescein value of Promega company, microplate reader is DYNEXTechnologies, and Inc company produces.
Result: can utilize calculation formula to calculate this medicine and suppress viral rate according to the detected result of fluorescein.
Formula: medicine inhibiting rate=((control wells-detection hole)/control wells) * 100%
CCR5 and CXCR4 are two kinds of co-receptors that the present HIV-1 that has found enters cell, and mainly mediation R5 preferendum HIV-1 virus enters the PBMC cell to the CCR5 acceptor infecting in early days, and the CXCR4 acceptor mainly mediates entering of X4 preferendum HIV-1 virus at later period of infection.Experimental result shows that TD0232 has the restraining effect of entering for the B hypotype strain JR-FL and the ADA of R5 preferendum, and the B hypotype strain HXB2 or the amphotropic AmLV of in contrast X4 preferendum then do not had the restraining effect of entering.Simultaneously, this experiment has verified that also TD0232 is in the stage that enters of virus performance restraining effect, and auxiliary receptor CCR 5 is had the selectivity of height.
The activity research of the R5 preferendum HIV-1 virus strain of the anti-multiple hypotype of embodiment 16.TD0232
1. experiment material
Cell: human PBMC's cell, available from blood station, center, Wuhan City, respectively from 3 healthy people
The HIV-1 strain: the original HIV-1 virus strain of three hypotypes (A, C and O) R5 preferendum, available from NIH AIDSResearch and Reference Reagent Program.
2. experimental technique and evaluation
A. with the solution of TD0232 with RPMI1640 preparation different concns.Press the required prepared at concentrations of drug test, the experiment final concentration is 600nM, 200nM, 66.7nM, 22.2nM, 7.4nM, 2.5nM, 0.8nM.
B. Bing Du dilution
The virus strain that is used for the medicine body outer suppressioning experiment is generally selected 100TCID for use
50/ hole.
Be diluted to 100TCID with nutrient solution
50/ 50ul/ hole
C. experimental arrangement:
Carry a few days ago:
From human blood, prepare PBMC (peripheral blood lymphocytes), and in the substratum that contains PHA and IL-2, cultivate.
Test the same day:
1. extract PBMC and with 10
5The every hole of individual cell places 96 orifice plates to cultivate every hole 100ul.
2. gradient dilution medicine
3. every hole adds (diluting) medicine of 50ul
4. every hole adds virus 5 0ul, final concentration 100TCID
50Every hole.
First day:
1 usefulness ordinary culture medium cleans infected cell three times;
2. after last the cleaning, add newly join contain medicine growth medium 200ul;
The 7th day: collect viral supernatant, carry out p24 and detect
Result: can utilize calculation formula to calculate this medicine and suppress viral rate according to the p24 detected result.
Formula: medicine inhibiting rate=((control wells-detection hole)/control wells) * 100%
Experimental result sees Table 4.Compound TD0232 can effectively suppress the R5 preferendum human PBMC's of virus strain infection of 4 kinds of hypotypes effect, illustrates that TD0232 has the activity of the R5 preferendum HIV-1 virus strain of anti-multiple hypotype (A, B, C and O) widely.
The IC that the R5 preferendum HIV-1 strain of table 4.TD0232 inhibition A, C and O hypotype duplicates in the human PBMC
50(IC
90) value
The ability of the multidrug resistant virus strain of the anti-R5 preferendum of embodiment 17 TD0232
1. experiment material
Cell: human PBMC's cell, available from blood station, center, Wuhan City, respectively from 3 healthy people
The HIV-1 strain: R5 preferendum multidrug resistant strain HIV-1J18, available from U.S. Rockefeller University Aaron Diamond acquired immune deficiency syndrome (AIDS) research centre
2. experimental technique and evaluation
A. with the solution of TD023 with RPMI1640 preparation different concns.Press the required prepared at concentrations of drug test, the experiment final concentration is 600nM, 200nM, 66.7nM, 22.2nM, 7.4nM, 2.5nM, 0.8nM.
B. Bing Du dilution
The virus strain that is used for the medicine body outer suppressioning experiment is generally selected the 100TCID50/ hole for use.
Be diluted to the 100TCID50/50ul/ hole with nutrient solution.
C. experimental arrangement:
Carry a few days ago:
From human blood, prepare PBMC (peripheral blood lymphocytes), and in the substratum that contains PHA and IL-2, cultivate.
Test the same day:
1. extract PBMC and with 10
5The every hole of individual cell places 96 orifice plates to cultivate every hole 100ul.
2. gradient dilution medicine
3. every hole adds (diluting) medicine of 50ul
4. every hole adds virus 5 0ul, the every hole of final concentration 100TCID50.
First day:
1. clean infected cell three times with ordinary culture medium;
2. after last the cleaning, add newly join contain medicine growth medium 200ul;
The 7th day: collect viral supernatant, carry out p24 and detect
The result:
Can utilize calculation formula to calculate this medicine and suppress viral rate according to the p24 detected result.
Formula: medicine inhibiting rate=((control wells-detection hole)/control wells) * 100%
J18 is the multidrug resistant HIV-1 virus strain of a kind of known R5 preferendum B hypotype, to multiple protein enzyme inhibitors and several reverse transcriptase inhibitors resistances.The result shows that compound TD0232 has significantly suppressed the infection of HIV-1J18 to human PBMC's cell in experiment in vitro, have the activity of anti-efficiently multidrug resistant virus strain, sees Table 5.
Table 5.TD0232 suppresses HIV-1
J18The IC that persister duplicates in PBMC
50(IC
90) value
The cytotoxicity of embodiment 18 TD0232 on the PBMC cell
1. experiment material
Cell: human PBMC's cell, available from blood station, center, Wuhan City, respectively from 3 healthy people
2. experimental technique and evaluation
A. with the solution of TD0232 with RPMI1640 preparation different concns.Press the required prepared at concentrations of drug test, the experiment final concentration is 100uM, 20uM, 4uM.
B. experimental arrangement
The 0th day: on cell, add the dilution medicine
The 3rd day: use Vi-CELL from Beckman Courter
TMCell Viability Analyzer detects cell survival rate.The monitoring of the survival rate of the cell under the same concentrations medicine has repeated 3 times, tests the cell of two culture hole of duplicate detection at every turn, so acquisition is a mean value.
Experimental result sees Table 6, and visible compound TD0232 is lower to human PBMC's cytotoxicity.
Table 6.TD0232 is to human PBMC's cytotoxic effect
The Study on mechanism of embodiment 19 TD0232---TD0232 with [
125I]-RANTES is competitively in conjunction with CCR5
Experimental technique is as follows:
A. use Trisodium Citrate Digestive system (15mM Na
3Citrate, 134mM KCl) peptic cell, add 1ml0.2%BSA-PBS solution, blow and beat repeatedly 30 times with the rifle of 1ml, form single cell suspension.1,200rpm, centrifugal 4min abandons supernatant.
B. add 4ml 0.2%BSA-PBS solution, dispel, 1,200rpm, centrifugal 4min abandons supernatant.
C. add 500 μ l lysis buffers (5mM Tris-Cl, 5mM EDTA, 5mM EGTA, pH7.5), fully blow even, 12,000rpm, 4 ℃ of centrifugal 15min abandon supernatant.
D. add 1ml binding buffer liquid (50mM HEPES, 125mM NaCl, 1mM CaCl
2, 5mM MgCl
2, 0.2%BSA, pH7.4) suspension cell film, fully mixing is stand-by.
E. add 79 μ l cytolemma suspensions in every 5ml centrifuge tube, every group parallel does 2 centrifuge tubes.The drug solution or the DMSO that add 1 μ l, 4 ℃ of operations, fully mixing.
F. in above-mentioned system, add 0.5nM[
125I]-RANTES 10 μ l, fully mixing was placed 45 minutes for 25 ℃.Add the Wheatgerm Agglutinin SPA Beads that 10 μ l 30mg/ml suspend, abundant mixing, every pipe experimental system cumulative volume is 100 μ l, 25 ℃ were reacted 15 minutes.
G. take out pipe, centrifugal 10 minutes of 2000 rev/mins of room temperatures are measured the cpm value with liquid scintillation instrument.
H.[
125I]-RANTS bonded amount calculates as follows:
% is untreated=100% * (cpm
Compound/ cpm
Nocompound), use the Sigmaplot8.0 software data processing, calculate IC
50Value.
The results are shown in Table 7, visible TD0232 effectively suppresses [1
25I]-RANTES combines with CCR5's, and presents concentration dependent, the IC of TD0232
50Be 1.4nM, illustrate that TD0232 combines with CCR5 with higher avidity.
Table 7.TD0232 inhibition [
125I]-situation that combines of RANTES and CCR5
| The concentration of TD0232 (Log, M) | [ 125I]-RANTES is in conjunction with per-cent (%) |
| -12 | 97.5±1.2 |
| -11 | 100.3±3.4 |
| -10 | 96.1±4.5 |
| -9.5 | 92.1±5.5 |
| -9 | 66.2±6.7 |
| -8.5 | 42.9±2.2 |
| -8 | 33.0±5.7 |
| -7 | 27.4±7.7 |
| -6 | 22.0±3.3 |
| -5 | 18.6±3.2 |
The Study on mechanism of embodiment 20 TD0232---the proteic activation of G of the CCR5 mediation that TD0232 inhibition RANTES, MIP-1 α and MIP-1 β cause
Experimental technique is as follows:
A. take out cell from incubator, incline and train liquid, (PBS) washes twice with phosphate buffered saline buffer, adds 0.04%EDTA-PBS room temperature effect 5 minutes, and add 1ml PBS and put into the 1.5ml centrifuge tube, 3, centrifugal 2 minutes of 000rpm abandons supernatant.
B. use 600 μ l lysate damping fluids (5mM EGTA PH7.5), and inhales with insulin syringe and to make a call to 6 times for 5mM Tris-Cl, 5mM EDTA, 12,000rpm, 4 ℃ of centrifugal 15min abandon supernatant.
C. according to precipitation capacity, with reaction solution (50mM Tris-Cl, the 5mM MgCl of proper volume
2, 1mM EGTA, 100mM NaCl, PH7.5) resuspended, inhale repeatedly with insulin syringe and to make a call to 6 times to forming uniform cytolemma suspension.
D. in 4 1.5ml centrifuge tubes, add reaction solution 5 μ l respectively, the standard protein liquid (1.0 μ gBSA/ μ l) that adds 2,4,6 and 8 μ l more respectively, get a new 1.5ml centrifuge tube again, add 5 μ l film suspension to be measured, in 5 eppendorf pipes, add 800 μ l Xylene Brilliant Cyanine G solution respectively, shake up.According to colour contrast, estimate the protein concentration of film suspension, transfer to 0.2 μ g/ μ l.
E. reaction system is 100 μ l in every 5ml centrifuge tube, contains 0.5nM[in the system
35S]-GTP γ S (1,200Ci/mmol) GDP, the 0.01%BSA of (available from Amersham), 40 μ M, protein concentration are the cytolemma suspension of 0.1 μ g/ μ l, the agonist of 10nM (RANTES (available from Peprotech EC Ltd), MIP-1 α or MIP-1 β (available from Peprotech ECLtd)), the TD0232 under each reaction density (being dissolved in DMSO).Mixing, 30 ℃ were reacted 1 hour.
F. glass fibre membrane (GF/C film) is put on the suction filter, added 4ml PBS in reaction system, be poured on the GF/C film, repeated washing once again.
G. open the vacuum filtration pump, the suction filtration that boosts when treating that moisture is taken away fully, unscrews the knob on the suction filter, opens suction filter, closes suction filter pump.
H. the GF/C film that suction filtration is finished is put into baking oven dries, and puts into the 1.5ml centrifuge tube, adds 1ml liquid and dodges liquid, puts into liquid scintillation instrument and measures.
I. data processing: the system that will not add agonist is as background bonded sample (basal), testing sample is designated as sample, the sample that not only adds agonist but also add testing compound is designated as compound, will adds agonist and do not have the sample of testing compound to be designated as agonist, then [
35S]-per-cent (%ofuntreated) that GTP γ S bonded amount accounts for maximal stimulation calculates by following formula: 100% * (cpm
Compound-cpm
Basal)/(cpm
Agonist-cpm
Basal), use the Sigmaplot8.0 software data processing, calculate IC
50Value.
The results are shown in Table 8, visible TD0232 efficiently antagonism RANTES, MIP-1 α or MIP-1 β cause [
35S]-GTP γ S combines with the CHO-CCR5 cytolemma, and its IC50 is respectively 2.9nM, 0.6nM and 0.7nM.
Table 8.TD0232 suppress that RANTES, MIP-1 α or MIP-1 β cause [
35S]-situation that combines of GTP γ S and CHO-CCR5 cytolemma
| -8.5 | 42.8±5.5 | 12.5±4.9 | ND |
| -8 | 11.6±2.9 | 3.3±1.7 | ND |
| -7.5 | 3.5±2.2 | 4.0±0.7 | 11.3±12.4 |
| -7 | 3.2±2.5 | 4.2±2.2 | 0.7±1.1 |
| -6 | 1.1±0.3 | 0.0±0.0 | 0.0±0.0 |
Note: ND is the data of not surveying.
The G albumen that the Study on mechanism of embodiment 21 TD0232---TD0232 can not be suppressed at CCR1, CCR2b under the corresponding agonist effect, CCR3, CCR4, CXCR1, CXCR2, CXCR3 or CXCR4 mediation activates
Experimental technique is with embodiment 22.
The results are shown in Table 9, the TD0232 of 1pM to 10 μ M all can not be reduced in corresponding agonist (RANTES (available from Peprotech EC Ltd), MCP-1 (available from Peprotech EC Ltd), Eotaxin (available from Peprotech EC Ltd), MDC (available from Peprotech EC Ltd) and SDF-1 (available from Peprotech EC Ltd)) effect down [
35S]-level that combines of GTP γ S and Chinese hamster ovary celI film, illustrate compound TD0232 can't antagonism acceptor CCR1, the function of CCR2b, CCR3, CCR4, CXCR1, CXCR2, CXCR3 and CXCR4 coupling activated G protein.But the function that this compound but can antagonizing CCR 5 illustrates that this compound is the specific antagonists of CCR5.
Table 9.TD0232 is to the selectivity research of acceptor
| -7.5 | 99.7±3.01 | 103.8±7.22 | 101.26±9.53 | 98.3±5.3 |
| -7 | 111.6±4.87 | 98.8±2.2 | 99.0±10 | 103.8±6.1 |
| -6 | 94.29±3.01 | 108.99±4.15 | 102.9±7.5 | 105.0±5.6 |
The Study on mechanism of embodiment 22 TD0232-TD0232 suppresses the CHO/CCR5 intracellular Ca2+ release that RANTES causes
Experimental technique is as follows:
A.CHO/CCR5 or CHO/CXCR4 cell are with 0.6 * 10
6The concentration kind of individual/ml is in 96 orifice plates, and 5%CO is put in 100 μ l/ holes behind the mixing
2The incubator incubated overnight.
B. take out Assay Buffer (component B, ready to use) and dyestuff (component A) in the FLEXstationTM Calcium Plus Assay Kit, equilibrate to room temperature.
C. take by weighing the Probenecid (Sigma) of 14.27mg, add among the component A, add 10mlAssayBuffer again, component A and Probenecid are thoroughly dissolved.
D. from incubator, take out 96 porocyte culture plates of incubated overnight, add above-mentioned solution, put into incubator and hatched 1 hour by 100 μ l/ holes.
E. take out 96 orifice plates of hatching, put into FlexStation II (Molecular Devices), set 37 ℃, add testing compound, read once in per 1.6 seconds, read 100 seconds.Add 25 μ l micromolecular compounds earlier, add the 25nMRANTES of 25 μ l again, the final concentration of DMSO is 0.1% in the system.
Represent the variation of intracellular calcium concentration with the maximum difference (RFUchange) that adds test agent front and back relative fluorescence units (Relative Fluorescence Units).Use the Sigmaplot8.0 software data processing, calculate the IC50 value.
The results are shown in Table 10, TD0232 can suppress the release that 5nM RANTES activates the CHO/CCR5 intracellular calcium, its IC
50Be 78.9 ± 9.9nM.0.01 the release of the calcium ion that μ M TD0232 causes RANTES is influence not, the TD0232 of 1 μ M can suppress the release of the CHO/CCR5 intracellular calcium that 5nMRANTES causes fully.The result shows can be on the second messenger's level efficient antagonizing CCR 5 acceptor of compound TD0232.
Table 10.TD0232 suppresses the release conditions of CHO/CCR5 intracellular calcium
| The concentration of TD0232 (Log, M) | The relative fluorescence unit change |
| -9 | 17016.3±572.3 |
| -8 | 16210.2±1015.9 |
| -7.5 | 16512.1±778.3 |
| -7 | 5274.0±1601.4 |
| -6.5 | 2129.3±490.3 |
| -6 | 1720.7±463.3 |
| -5 | 729.5±190.7 |
The Study on mechanism of embodiment 23 TD0232-TD0232 suppresses the CHO/CCR5 cell chemotaxis motion that RANTES causes
Experimental technique is as follows:
A. the Fibronectin with 3.3 μ g/ml soaks polycarbonate chemotactic film (NeuroProbe), and 4 ℃ are spent the night, and taking-up is dried.
B. after CHO/CXCR4 or CHO/CCR5 cell being digested with 0.02%EDTA-pancreatin solution, add chemotactic damping fluid (the serum-free MEM-α that contains 0.1%BSA), centrifugal 2 minutes of 500rmp, abandon supernatant, repeat again to wash twice, with counting behind the chemotactic damping fluid re-suspended cell, cell concn is transferred to 1 * 10
6Individual/ml, certain density testing compound and cell were hatched 15 minutes.
C. get the cell that 26 μ l agonists or chemotactic damping fluid add the lower plywood of 48 hole chemotactic plates (NeuroProbe), top plate adds 50 μ l cell suspensions, puts into incubator, hatches 4 hours.
D. take off film with tweezers, film is placed on fixes in 4% Paraformaldehyde 96 more than 2 hours, the film that fixes is placed on dyeing 2-6 hour (room temperature) or spend the night (4 ℃) in 0.5% Viola crystallina.Dye good film and wash 5 times, dry on glass then with clear water.
E. on scanner, scan out image, use the gray-scale value of the border circular areas of ScionImage system statistics and cells contacting to calculate.
F. data statistical approach is: treat that gray-scale value that gray-scale value that gaging hole passes the cell of chemotactic film is defined as this border circular areas deducts the gray-scale value (G) of the blank space of onesize area.When measuring compound to the influencing of the cell chemotaxis effect of agonist induction, compound is represented with the per-cent of chemotactic index the influence of chemotactic index, by calculating with following formula: 100% * (G
Compound-G
Control)/(G
Agonist-G
Control).Use the Sigmaplot8.0 software data processing, calculate IC
50Value.
The results are shown in Table 11, but the CHO/CCR5 cell chemotaxis effect that TD0232 antagonism RANTES causes, and be dose-dependently.TD0232 can suppress the chemotactic of cell fully under 100nM concentration, and IC50 is 3.0nM.But the function of experimental result proof compound TD0232 antagonizing CCR 5 acceptor on cell levels.
Table 11.TD0232 suppresses the situation of CHO/CCR5 cell chemotaxis motion
| The concentration of TD0232 (Log, M) | Cell chemotaxis exponential per-cent |
| -11 | 100±0.0 |
| -10 | 91.8±2.7 |
| -9 | 66.3±11.7 |
| -8.5 | 54.2±9.9 |
| -8 | 21.7±2.4 |
| -7.5 | 7.1±4.3 |
| -7 | 3.8±3.8 |
| -6 | 2.0±2.3 |
The Study on mechanism of embodiment 24 TD0232---TD0232 suppresses the endocytosis of CCR5 but does not suppress the endocytosis of CXCR4
Experimental technique is as follows:
A.0.02%EDTA-pancreatin solution digestion CHO/CCR5 or CHO/CXCR4 cell add serum-free MEM-α collecting cell, and centrifugal 2 minutes of 500rmp abandons supernatant, repeat to wash once again, with serum-free MEM-α re-suspended cell, cell density are transferred to 1 * 10
6Individual/ml, 80 μ l/ pipes are sub-packed in the 5ml centrifuge tube.
B. add 10 μ l testing compounds in cell suspension, hatched 15 minutes for 37 ℃, the final concentration of DMSO is 0.1%.In CHO/CCR5 or CHO/CXCR4 cell, add 2 * 10 respectively
-6The agonist of M (SDF-1 or RANTES) or serum-free MEM-α 10 μ l were hatched 1 hour for 37 ℃.
C. be put in stopped reaction on ice, add ice-cold 0.1%BSA-PBS, 4 ℃, 1200rpm, centrifugal 4min abandons supernatant.Repeated washing once.
D. add the antibody 10 μ l of 10 μ g/ml CCR5 or CXCR4, mixing is hatched 40min for 4 ℃.
E. add ice-cold 0.1%BSA-PBS, 4 ℃, 1200rpm, centrifugal 4min abandons supernatant.Repeated washing once.
F. add the two anti-100 μ l of the goat-anti mouse of the FITC mark that dilutes at 1: 100, mixing is hatched 40min for 4 ℃.
G. add 0.1%BSA-PBS, 4 ℃, 1200rpm, centrifugal 4min abandons supernatant.Repeated washing once.
H. add 300 μ lPBS re-suspended cells, be put on ice, flow cytometer detects.
I. the average fluorescent strength of the cell that will hatch with testing compound or agonist is Mean
Compound, the average fluorescent strength that does not add a cell that resists is Mean
Control, add one anti-but average fluorescent strength cell that do not hatch with compound or agonist is Mean
No compound, the expression amount of cell surface receptor calculates by following formula: 100% * (Mean
Compound-Mean
Control)/(Mean
No compound-Mean
Control).Use the Sigmaplot8.0 software data processing.
The situation of TD0232 antagonizing CCR 5 or CXCR4 endocytosis sees Table 12.TD0232 can not induce the endocytosis of CCR5 or CXCR4 separately, can not suppress the endocytosis that SDF-1 causes CXCR4, but can suppress the endocytosis of the CCR5 that RANTES causes, and presents dose-dependently.0.01 the TD0232 of μ M is to the not influence of the endocytosis of RANTES inductive CCR5, the TD0232 of 0.1 μ M partly suppresses the endocytosis of CCR5, and the TD0232 of 1 μ M then can suppress the endocytosis of the CCR5 that RANTES causes fully.This experimental result shows that compound TD0232 has the characteristic of CCR5 antagonist, but not the antagonist of CXCR4.
The situation of table 12.TD0232 antagonizing CCR 5 or CXCR4 endocytosis
| Sample | The CCR5 expression amount |
| Contrast (control) | 100±0 |
| RANTES | 24.5±2.8 |
| TD0232 | 113.1±8.5 |
| RANTES+TD0232(-6) | 108.4±6.2 |
| RANTES+TD0232(-7) | 50.4±14.5 |
| RANTES+TD0232(-8) | 27.6±1.6 |
| Sample | The CXCR4 expression amount |
| Contrast (control) | 100±0 |
| SDF-1 | 16.7±2.5 |
| TD0232 | 90.1±3.2 |
| RANTES+TD0232(-6) | 16.5±3.5 |
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (8)
1. the compound shown in the general formula (II), or its pharmacy acceptable salt,
In the formula, R
1Be following groups unsubstituted or that replaced by 1-3 substituting group: benzyl, benzoyl, cyclohexyl formyl radical, cyclopentyl formyl radical, benzenesulfonyl or naphthoyl, described substituting group is selected from halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group;
R
6For to nitro carbobenzoxy-(Cbz), carbobenzoxy-(Cbz), to the halogen carbobenzoxy-(Cbz), to methoxyl group benzyloxy carbonyl, to the methyl carbobenzoxy-(Cbz), to trifluoromethyl carbobenzoxy-(Cbz), N-phenyl formamide base, benzene oxygen ethanoyl, 3,4-dioxy methylene radical carbobenzoxy-(Cbz), to amino carbobenzoxy-(Cbz), benzenesulfonyl, to the Methyl benzenesulfonyl base.
2. compound according to claim 1 is characterized in that, is selected from down group:
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-nitrobenzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-benzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-methoxy benzyl ester;
Allyl group-[1-((3S, 4R)-1-(cyclopentyl formyl radical)-4-hydroxyl-4-benzene pyrroles-3-methylene radical) piperidines-4-position] methane amide-4-bromobenzyl ester.
3. compound according to claim 1 is characterized in that, described compound has structure shown in the following structural formula (III):
4. pharmaceutical composition contains among the claim 1-3 arbitrary described compound or its pharmacy acceptable salt as activeconstituents, and pharmaceutically acceptable carrier.
5. as the purposes of the arbitrary described compound of claim 1-3, it is characterized in that, can be used for preparing the medicine of anti HIV-1 virus.
6. as the purposes of the arbitrary described compound of claim 1-3, it is characterized in that can be used for preparing medicine, described medicine is selected from down group:
(a) medicine of inhibition HIV virus infection people's peripheral blood lymphocytes;
(b) the bonded medicine of inhibition RANTES and CCR5;
(c) suppress the GTP γ S that RANTES, MIP-1 α or MIP-1 β cause and the bonded medicine of CCR5 cytolemma;
(d) suppress the medicine that CCR5 intracellular Ca2+ that RANTES causes discharges;
(e) suppress the medicine of the CCR5 cell chemotaxis motion that RANTES causes.
7. purposes as claimed in claim 6 is characterized in that, described HIV virus is HIV-1 virus.
8. purposes as claimed in claim 7 is characterized in that, described HIV-1 virus is A, B, C or O hypotype.
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| CN101885721A (en) * | 2010-06-11 | 2010-11-17 | 银杏树药业(苏州)有限公司 | Pyrrole derivatives serving as CCR5 antagonists, method for preparing same and application thereof |
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