CN105732592A - Macrocyclic polyamine drug and preparation method thereof - Google Patents

Macrocyclic polyamine drug and preparation method thereof Download PDF

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Publication number
CN105732592A
CN105732592A CN201410731812.3A CN201410731812A CN105732592A CN 105732592 A CN105732592 A CN 105732592A CN 201410731812 A CN201410731812 A CN 201410731812A CN 105732592 A CN105732592 A CN 105732592A
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aryl
macrocyclic polyamine
compound
alkyl
medicine
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仝战旗
管文珍
马远程
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BEIJING RUIDU PHARMACEUTICAL Co Ltd
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BEIJING RUIDU PHARMACEUTICAL Co Ltd
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The present invention relates to a novel macrocyclic polyamine drug. Further, the invention relates to a pharmaceutical mixture using the macrocyclic polyamine drug as an active pharmaceutical ingredient, and one or more preferable pharmaceutical excipient or carrier, and a pharmaceutical composition for the treatment of AIDS, cancer and related diseases. In addition, the invention also relates to a preparation method of the macrocyclic polyamine drug.

Description

A kind of Macrocyclic polyamine medicine and preparation method thereof
Technical field
The present invention relates to a kind of Macrocyclic polyamine medicine, be specially the suberamide condensation substance that LBH589 generates with Plerixafor；The preparation method that the invention still further relates to this Macrocyclic polyamine medicine.
Background technology
Acquired immune deficiency syndrome (AIDS) is a kind of great infectious disease of hazardness, aids infection virus (inhibition of HIV) cause.HIV is a kind of virus that can attack human immune system.It as primary challenge target, this cell of considerable damage, makes human body lose immunologic function in T lymphocyte most important in human immune system, and therefore, human body is prone to infect various disease, and malignant tumor can occur, and case fatality rate is higher.
Cancer is the general designation of a big class malignant tumor.The feature of cancerous cell be unrestrictedly, hypertrophy without end, make nutrient substance in the patient be consumed in a large number；Cancerous cell discharges multiple toxin, makes human body produce series of symptoms；Cancerous cell also can be transferred to whole body growth and breeding everywhere, cause human body to be become thin, unable, anemia, inappetence, heating and serious organ function impaired etc..On the other side have benign tumor, benign tumor is then easily removed clean, generally do not shift, do not recur, to organ, tissue only extruding and blocking action, but cancer (malignant tumor) also can destroy the 26S Proteasome Structure and Function of tissue, organ, causing downright bad hemorrhage concurrent infection, patient is finally dead due to organ failure.
LBH589 (structural formula is as follows) is a kind of micromolecular histone deacetylase enzyme (HistoneDeacetylase, HDAC) inhibitor, cancer and the multiple pathology path relevant with cancer generation can be blocked, reduce the survival of cancerous cell, the apoptosis of induction cancerous cell, study on mechanism shows that hydroxamic acid is main avtive spot.Research simultaneously is it is also shown that use LBH589 can discharge in " thesaurus " that HIV (human immunodeficiency virus) is formed from DNA cell so that it is arrival cell surface.Virus is once come cell surface, and virus just can be killed by the natural immune system of human body when being excited by a kind of " vaccine ", so that human immune system forever removes inhibition of HIV and is possibly realized.
Plerixafor (structural formula is as follows) is CXCR4 inhibitors of chemokine receptors, it is possible to dramatically increase the quantity of leucocyte in human peripheral blood, improves body immunity.Research, it is also shown that Plerixafor can effectively break up the protective layer of pancreatic cancer cell appearance, allows the antibody T cell of human body self charge into attack cancerous issue, and its mechanism of action is unclear, and this medicine is possibly used for the treatment of other tumors and cancer.
We are analyzing on the basis of structure activity relationship and mechanism of action, design and synthesize a series of compound, in vitro, in vivo test has been investigated pharmacologically active and the toxicity of these compounds, and compare with LBH589, result is surprisingly found out that, after being administered 4 weeks, the CWR22 prostate gland cancer cell of nude mice model is completely removed, this is likely to relevant with the synergism of Macrocyclic polyamine end and hydroxamic acid end, newly synthesized macrocyclic polyamine compound shows the activity more significantly higher than LBH589, is expected to become the medicine of more potent low toxicity.
Summary of the invention
It is an object of the invention to provide a kind of high activity Macrocyclic polyamine medicine and preparation method thereof.
In order to realize object above, the macrocyclic polyamine compound of a kind of below formula of the present invention and pharmaceutically acceptable salt thereof:
Wherein, alkyl, aryl, aralkyl, alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, alkoxyl, the one or more hydrogen in R can be replaced by amino.
" alkyl " refers to have one to specifying number the direct-connected of carbon atom or branched saturated hydrocarbon group.Such as methyl, ethyl, isopropyl, n-pro-pyl, normal-butyl, n-pentyl, n-heptyl, dodecyl, octadecyl etc..
" aryl " refers to remove, from aromatic hydrocarbon, the organic group that one or more hydrogen atoms are derived.Preferred aryl has 6-12 carbon atom as ring carbon atom in aromatic hydrocarbons.
" aralkyl " refers to the organic group derived from aryl alkane, and wherein alkyl hydrogen atom is replaced by aryl defined above.
Especially, R is double; two carbonyl structures, is structured with:
Wherein R ' be alkyl, aryl, aralkyl, alkylamino.
More particularly, R ' is hexyl, and structural formula is as follows:
。
The preparation method of above-mentioned Macrocyclic polyamine; it is characterized in that: in the solution of suberoyl chlorine, slowly at the uniform velocity and the Plerixafor of constant speed dropping p-toluenesulfonyl protection and the solution of LBH589, through purification by silica gel column chromatography after having reacted; use HBr-HAc solution deprotection, obtain target compound.
Using above-mentioned macrocyclic polyamine compound as active drug composition, it is preferable that the mixture of one or more excipient or carrier, for treating the pharmaceutical composition of acquired immune deficiency syndrome (AIDS), tumor and relevant disease.
The macrocyclic polyamine compound of the present invention, has following significant advantage compared with LBH589:
(1) anti AIDS virus cell culture test shows, has significantly higher antiviral efficacy and selectivity index；
(2) antitumor cell culture experiment shows, its antitumor action is apparently higher than LBH589；
(3) acute toxicity test in mice shows, its toxicity is significantly less than LBH589；
(4) anti-tumor in vivo test shows, is surprisingly found out that interior tumor cell is eliminated after being administered 4 weeks.
Detailed description of the invention
Below by way of detailed description of the invention, one Macrocyclic polyamine medicine of the present invention and preparation method thereof is described in further detail.
One Macrocyclic polyamine of the present invention and preparation method thereof, its general formula compound structural formula is:
Embodiment 1N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } suberamide
(1) synthesis of the Plerixafor of p-toluenesulfonyl protection
Take 50.2g(0.1mmol) Plerixafor, add 400mL toluene and 160mL(2.0mol) 50%NaOH solution, reactant liquor is cooled to 10 DEG C, in 45min, drips 152.52g(0.8mol) it is dissolved in the solution of 250mL toluene, after dropwising, reactant mixture is heated to 25 DEG C, keep 90min, be subsequently adding 1000mL water and 1500mL n-butyl alcohol, regulate pH to 8-12 with concentrated hydrochloric acid, separate organic layer, using 500mL water washing, evaporated under reduced pressure, through silica gel column chromatography (MeOH/CH2Cl2Gradient elution, 10:90 → 40:60), collect the flow point containing pure compound, evaporated under reduced pressure, to obtain final product；
(2) coupling
Take 10.5g(50mmol) suberoyl chlorine, it is dissolved in 100mLN, dinethylformamide (DMF), adds pyridine 20mL, put and stir under room temperature；
Separately take 63.7g(50mmol) step (1) obtain p-toluenesulfonyl protection Plerixafor, be dissolved in 50mLDMF, as solution 1.；
Separately take 17.5g(50mmol) LBH589, in solution 50mLDMF, as solution 2.；
Do not stop under stirring, 1. with solution 2., 4h is stirred at room temperature after dropwising, has reacted rear sucking filtration with phase same rate (about 1/2 seconds) from left and right two Dropping funnels to dropping solution above-mentioned reactant liquor, wash with DMF, obtain off-white color solid.Take solid, after dissolving with methanol, by silica gel column chromatography (MeOH/CH2Cl2Gradient elution, 5:95 → 20:80), to obtain final product；
(3) deprotection
Taking step (2) product 36.7g, add 30%HBr-HAc solution 400mL, 60 DEG C are stirred at room temperature 72h, after having reacted, 80 DEG C of evaporated under reduced pressure, add that ether 400mL is ultrasonic makes suspendible, sucking filtration, uses ether drip washing, adds dichloromethane 300mL and water 300mL in filter cake, it is stirred to dissolve, regulate pH to 12, separate dichloromethane layer with 2NNaOH, dry with anhydrous sodium sulfate, evaporated under reduced pressure, obtains target compound.Mass spectrum (MALDI-TOF, m/z): 991.38 [M+H]+；1H-NMR(DMSO-d6,600MHz):δ1.26(m,4H),1.48(m,2H),1.56(m,2H),1.87(br,4H),1.93(t,2H),2.14(br,4H),2.28(t,2H),2.30(s,3H),2.81-3.36(m,36H),3.89(s,4H),4.01(s,2H),6.49(d,H),6.90(t,H),6.96(t,H),7.21(d,H),7.37(d,H),7.41(s,4H),7.42-7.46(m,3H),7.54(d,2H),10.80(s,H)；13C-NMR(DMSO-d6,150MHz):δ11.1,22.3,24.6,25.1,27.4,28.4,32.3,36.4,47.6,49.3,50.3,50.4,52.1,52.3,53.8,55.6,57.6,106.2,110.5,117.0,118.1,119.3,120.1,127.2,128.1,129.7,132.2,133.4,134.4,135.1,137.1,137.3,137.5,162.7。
Embodiment 2N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } to dibenzamide
Prepare with embodiment 1, suberoyl chlorine is replaced with dibenzoyl chlorine, obtains target compound.Mass spectrum (MALDI-TOF, m/z): 1011.35 [M+H]+。
Embodiment 3N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } octadecylamine
Preparing with embodiment 1, suberoyl chlorine replaces with 1,18-bis-bromo-octadecane, the reaction temperature of (2nd) step is 80 DEG C of stirring reaction 12h.Obtain target compound.Mass spectrum (MALDI-TOF, m/z): 1103.65 [M+H]+。
Below by test example, the activity of macrocyclic polyamine compound provided by the invention, selectivity index, toxicity are made further comparative descriptions.
Test example 1
Extracorporeal antivirus effect is evaluated
After MT4 cell infection HIV, the effect of Syncytium formation is suppressed to investigate HIV (human immunodeficiency virus)-resistant activity by each compound.By 3 × 105The need testing solution (DMSO is as solvent) of MT4 cell and 100 μ L variable concentrations carries out preculture together, dilutes with phosphate buffered saline subsequently, cultivates 1 hour at 37 DEG C.Then in mixture, add 100 μ L viral dilution liquid, then cultivate 1 hour at 37 DEG C.After washing three times, cell is suspended in again in the culture medium of presence or absence test sample.At 5%CO at 37 DEG C2Middle cultivation 7 days, gives containing after infection or does not contain the culture medium of test sample on the 3rd day again.Each cultivation repetition twice.Inverted light microscope is used to see whether there is syncytium every day.Generally, the viral dilution liquid used in this mensuration forms syncytium on the 5th day after infection.The inhibition concentration of test sample is expressed as the concentration (EC that cell does not have the 50% of direct toxicity suppress Syncytium formation50).Investigate the test sample cytotoxic concentration to non-infected cells by trypan exclusion stain, be expressed as causing the concentration (CC of 50% cell death50).
Pass through EC50And CC50Calculate selectivity index, selectivity index (SI)=EC50/CC50
Result is as shown in table 1.In table, " ACC-072 " represents N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl prepared by embodiment 1 } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } suberamide；" ACC-064 " represents N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl prepared by embodiment 2 } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } to dibenzamide；" ACC-035 " represents N-{5-[1,4,8,11-tetraazacyclododecane tetradecane base] methyl prepared by embodiment 3 } phenyl)-1,4,8,11-tetraazacyclododecane tetradecane base]-N '-{ 4-([2-(2-methyl isophthalic acidH-indol-3-yl) ethyl]-(2E)-N-hydroxyl-allylamine-phenyl-methyl-amino) } octadecylamine.
The antiviral evaluation of each compound of table 1
It is shown that Macrocyclic polyamine medicine has significantly higher antiviral efficacy and selectivity index than LBH589 or Plerixafor, more taller several times than positive control zidovudine.
Test example 2
Extracorporeal anti-tumor function is evaluated
Cell is cultivated: by 4 kinds of man-machine systems: human colon cancer cell strain (LS174-T), cervical cancer cell lines (Hela229), hepatoma cell strain (SMMC-7721), lung cancer cell line (A549) and Human normal hepatocyte (HL-7702), it is inoculated in containing in the 10% RPMI1640 culture fluid inactivateing calf serum, at 37 DEG C, 5%CO2, cultivate under saturated humidity, every 2～3d changes liquid 1 time, and the cell of trophophase of taking the logarithm is tested.
Test method: tetrazolium bromide (MTT) reducing process detection inhibitory rate of cell growth, above-mentioned each cell of trophophase of taking the logarithm, adjusting cell concentration is 2 × 105/ ml, is sub-packed in the culture bottle of several 25ml by cell, and every bottle of 3ml is separately added into each compound, and making final concentration respectively 10 μ g/ml(is 100 μ g/ml except 5-fluorouracil).Taking 96 orifice plates several, every hole adds above-mentioned cell suspension 100 μ l, and each concentration of every kind of medicine is one group, and often group sets 3 parallel holes.Often group cell takes out after cultivating 48h from incubator, then every hole adds MTT (5mg/ml) 10 μ l, take out after continuing cultivation 4～6h, sucking supernatant after centrifugal, every hole adds DMSO100 μ l, then by culture plate shaken well about 5min, after basis of microscopic observation colored particles disappears, with 570nm for test wavelength in 20min, 630nm is reference wavelength, reads absorbance (A) value.Inhibitory rate of cell growth is calculated according to equation below:
Inhibitory rate of cell growth=(control group A value-experimental group A value)/control group A value × 100%.
The inhibitory action (suppression ratio, %) of each compound on tumor cell of table 2
It is shown that the Macrocyclic polyamine medicine of the present invention has obvious antitumor action, and the toxicity of Human normal hepatocyte is less, potential carry out further anti-tumor in vivo screening and assessment widely, to investigate the internal antitumor action to various tumors.
Test example 3
Acute Toxicity is evaluated
By CD-1 mice random packet, often group 3, blank solvent was given at first day, 100,300,500,700,1000,1500 and each compound of 2000mg/kg, to observe 7 days subsequently, observe the toxic action of each compound, result is in Table 3.NOAEL=does not observe untoward reaction level.
The acute toxicity of each compound of table 3
It is shown that ACC-072 toxicity is significantly less than other each compounds, it does not have the death of laboratory animal occur, and the untoward reaction that maximal dose occurs dies down upon administration.
Test example 4
Anticancer effect in vivo is evaluated
To nude mice model CWR22 prostate gland cancer cell, random packet, often group 5, the tumor volume size often organizing nude mice is similar, is approximately 5 × 5mm.It is orally administered to each compound (dissolving with DMSO) of 50mg/kg, successive administration 21 days respectively.Matched group is only given the DMSO solution of same volume, and administration volume is 1ml/g.Body weight nominal during testing assesses the issuable toxicity of medicine for 3 times, and tumor volume calculates 1 time after within every 2 weeks, measuring tumor footpath with slide gauge.Tumor volume is calculated by two dimension tumor footpath, and computing formula is: long × (width)2×1/2。
The antitumor action of each compound of table 4
Result is it has surprisingly been found that cases of complete remission after giving ACC-072 and ACC-064, and the toxicity observed during administration is less than LBH589 group, and the compound of the present invention is expected to become a kind of new anti-tumor medicine.
The present invention can be made into various preparation, such as preparation example 1～4.
Preparation example 1
Hard capsule
No. 3 gelatine capsules that these powder load 250mg, after 60 mesh sieves, are made capsule by mixing 100mgACC-072,75mg microcrystalline Cellulose, 50mg hydroxypropyl cellulose and 20mg crospovidone and 5mg magnesium stearate.
Preparation example 2
Tablet
Mixing 100mgACC-072,13mg sodium carboxymethyl cellulose, 15mg crospovidone, 20mg hydroxypropyl cellulose, 50mg microcrystalline Cellulose, 1mg micropowder silica gel and 1mg magnesium stearate, by tabletting machine, make the tablet of 1 200mg.
This tablet can be carried out coating as required.
Preparation example 3
Solution
Take 100mgACC-072, sucrose 12mg, sodium benzoate 0.2mg, add water for injection 5ml, through 0.22 μm of membrane filtration, load vial, 121 DEG C of autoclaving 10min, to obtain final product.
Preparation example 4
Injection
Take 100mgACC-072, add normal saline 2ml, with 0.1N salt acid for adjusting pH to about 6-7, through 0.22 μm of membrane filtration, load cillin bottle, 121 DEG C of autoclaving 15min, to obtain final product.

Claims (6)

1. Macrocyclic polyamine medicine and a pharmaceutically acceptable salt thereof, its structural formula of compound is:
Wherein, R is alkyl, aryl, aralkyl, alkyl-carbonyl, aryl carbonyl, aromatic alkyl carbonyl, alkoxyl, and the one or more hydrogen in R can be replaced by amino.
2. Macrocyclic polyamine medicine and a pharmaceutically acceptable salt thereof, its structural formula of compound is:
Wherein R ' be alkyl, aryl, aralkyl, alkylamino.
3. the lorcaserin derivant described in claim 1 or 2, " alkyl " refers to have one to specifying number the direct-connected of carbon atom or branched saturated hydrocarbon group, for instance methyl, ethyl, isopropyl, n-pro-pyl, normal-butyl, n-pentyl, n-heptyl, dodecyl, octadecyl etc.；" aryl " refers to remove, from aromatic hydrocarbon, the organic group that one or more hydrogen atoms are derived, it is preferred that aryl has 6-12 carbon atom as ring carbon atom in aromatic hydrocarbons；" aralkyl " refers to the organic group derived from aryl alkane, and wherein alkyl hydrogen atom is replaced by aryl defined above.
4. Macrocyclic polyamine medicine and a pharmaceutically acceptable salt thereof, its structural formula of compound is:
。
5. Macrocyclic polyamine medicine according to claim 4, is characterized in that: using macrocyclic polyamine compound as active drug composition, it is preferable that the mixture of one or more excipient or carrier, for treating the pharmaceutical composition of acquired immune deficiency syndrome (AIDS), tumor and relevant disease.
6. the preparation method of Macrocyclic polyamine described in a claim 4; it is characterized in that: in the solution of suberoyl chlorine; slowly at the uniform velocity and the solution of the Plerixafor of constant speed dropping p-toluenesulfonyl protection and LBH589; through purification by silica gel column chromatography after having reacted; use HBr-HAc solution deprotection, obtain target compound.
CN201410731812.3A 2014-12-06 2014-12-06 Macrocyclic polyamine drug and preparation method thereof Pending CN105732592A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011147330A1 (en) * 2010-05-27 2011-12-01 中国医学科学院药物研究所 Chemical synthesis and anti-tumor and anti-metastatic effects of dual functional conjugate
WO2014189648A1 (en) * 2013-05-24 2014-11-27 Cooper Human Systems Llc Methods and compositions for treatment of hiv infection

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011147330A1 (en) * 2010-05-27 2011-12-01 中国医学科学院药物研究所 Chemical synthesis and anti-tumor and anti-metastatic effects of dual functional conjugate
WO2014189648A1 (en) * 2013-05-24 2014-11-27 Cooper Human Systems Llc Methods and compositions for treatment of hiv infection

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘敏等: "拼合原理及其在新药设计中的应用", 《化学试剂》 *

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Application publication date: 20160706