CN103159650A - Preparation and application of aromatic heterocyclic sulfonamide compound - Google Patents
Preparation and application of aromatic heterocyclic sulfonamide compound Download PDFInfo
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- CN103159650A CN103159650A CN2012105894482A CN201210589448A CN103159650A CN 103159650 A CN103159650 A CN 103159650A CN 2012105894482 A CN2012105894482 A CN 2012105894482A CN 201210589448 A CN201210589448 A CN 201210589448A CN 103159650 A CN103159650 A CN 103159650A
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- PYUNKICBPYUVLP-UHFFFAOYSA-N CC(C(NS(c1ccccc1)(=O)=O)=O)c1ccc(-c2ccccc2)c(F)c1 Chemical compound CC(C(NS(c1ccccc1)(=O)=O)=O)c1ccc(-c2ccccc2)c(F)c1 PYUNKICBPYUVLP-UHFFFAOYSA-N 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N CC(C(O)=O)c1ccc(-c2ccccc2)c(F)c1 Chemical compound CC(C(O)=O)c1ccc(-c2ccccc2)c(F)c1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to preparation and application of an aromatic heterocyclic sulfonamide compound, and in particular provides the aromatic heterocyclic sulfonamide compound. The compound is in a structure of the following general formula (I), the compound can effectively suppress survival and growth of SUM-159, HCC-1954 and MCF-7 cells, wherein n=0. 1, 2 or 3, and R is selected from C1-C4 straight chain or branched paraffin, phenyl, cyclohexyl, o-methylphenyl, 3- pyridyl and 2- pyridyl ethyl.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, in particular to aromatic heterocycle sulfamide compound and preparation method thereof and purposes.
Background technology
Mammary cancer (mammary carcinoma) is that the modal a kind of malignant tumour of the mankind is also one of women's major malignant tumor.The most systems of the malignant tumour of breast come from the epithelium (breast cancer) of mammary gland, and minority can be derived from the various non-epithelium (various sarcoma) of breast occasionally can see blended sarcocarcinoma.The sickness rate of mammary cancer rises year by year, and crowd's morbidity is 23,/10 ten thousand; Account for 7～10% of the various malignant tumours of women's whole body.
Univ Michigan-Ann Arbor USA researchist Max S.Wicha in 2010 etc. have identified the effect that a kind of acceptor is new, and CXCR1 is positioned at the mammary cancer cancer stem cell surperficial, has the ability that excites the cancer stem cell growth under tissue damaged or the stimulation of inflammatory reaction.CXCR1 is the acceptor of interleukin 8 (IL-8), and IL-8 is everlasting and produces in chronic inflammatory diseases and tissue injury process.After the patient with breast cancer accepted chemotherapy, dead cancer cell can produce IL-8, and this will promote the self-replacation of cancer stem cell.If, add relative medicine blocking-up CXCR1 in the Breast Cancer Patients Treated process, will effectively help to kill breast carcinoma stem cell.
Reparixin (N-[(R)-2-(4-isobutylphenyl) propionyl]-methanesulfonamide) be a kind of benzyl propionate derivant, can suppress interleukin 8 albumen is combined with acceptor CXCR1, thereby blocking-up breast carcinoma stem cell FAK/AKT/ beta-catenin path accurately hits cancer stem cell.The researchist is implanted into breast cancer cell take body experimental mouse is studied rear discovery as object, accept simultaneously chemotherapy and repertaxin the treatment the experimental mouse body in cancer stem cell quantity far below the experimental mouse of only accepting chemotherapy, and the transcellular probability of mouse Cancer that adds the repertaxin treatment has also reduced.At present can kill breast carcinoma stem cell and stop the diffusion of tumour at the interim medicine Reparixin (Repertaxin) for suppressing the organ naltrindole of clinical trial 2.
Up to the present, do not have a kind of medicine can fundamentally suppress or eliminate breast carcinoma stem cell, reach the effect of thorough healing.Therefore, demand finding a kind of better efficacy urgently, toxic side effect is little, the medicine of the treatment mammary cancer of high specificity.
Summary of the invention
The present invention is optimized the structure of Reparixin, has newly synthesized a compounds, and the phenyl ring with in oxazole ring replacement Reparixin is the aromatic heterocycle sulfamide compound.The pharmacologically active result shows, this compounds has growth-inhibiting effect effectively to SUM-159, HCC-1954 and MCF-7 cell, and it can be used for prevention or treatment mammary cancer.
The invention provides sulfamide compound, have general formula (I):
Wherein, R is selected from C
1-C
4Straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, the 3-pyridyl, 2-pyridyl ethyl group,
N=0,1,2 or 3.
In specific embodiment, described sulfamide compound has general formula (I), wherein R be selected from phenyl,
N=0 or R are selected from methyl, n=2.
The invention provides a kind of method for preparing sulfamide compound, comprise the following steps:
Make formula (II) compound
Under 0 ℃ in aprotic solvent with condensing agent generation activated carboxylic reaction after and with formula (III) compound
Condensation reaction production (I) compound occurs under alkaline condition,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, and described condensing agent is selected from N, and N '-carbonyl dimidazoles (CDI), described alkali are selected from 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU);
Wherein, n=0,1,2 or 3; Formula (III) compound R is selected from C
2-C
4Straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, the 3-pyridyl, 2-pyridyl ethyl group,
The invention provides a kind of method for preparing general formula (I) sulfamide compound, comprising:
Make formula (II) compound
Under 0 ℃ in aprotic solvent with condensing agent generation activated carboxylic reaction after and with formula (III) compound
Condensation reaction production (I) compound occurs under alkaline condition,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, and described condensing agent is selected from N, and N '-carbonyl dimidazoles (CDI), described alkali are selected from 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU).
In specific embodiment, in preparation general formula (I) R be phenyl,
N=0 or R are methyl, and the method for the sulfamide compound of n=2 comprises:
Make formula (II) compound
Under 0 ℃ in aprotic solvent with condensing agent generation activated carboxylic reaction after and with formula (III) compound
Condensation reaction production (I) compound occurs under alkaline condition,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, and described condensing agent is selected from N, and N '-carbonyl dimidazoles (CDI), described alkali are selected from 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU);
Wherein, the R in formula (III) be phenyl,
N=0 or R are methyl, n=2.
The present invention also provides the application of described sulfamide compound in the medicine of preparation prevention or treatment mammary cancer.This compounds can suppress the survival and growth of SUM-159, HCC-1954 and MCF-7 cell.Especially in general formula (I) R be phenyl,
N=0 or R are methyl, n=2, and the sulfamide compound of isomorphism type not was at 72 hours inhibition IC to SUM-159, HCC-1954 and MCF-7 cell
50Value sees the following form.
Thereby this compounds can be mixed with to prevent or treat the medicine of mammary cancer.
Aromatic heterocycle sulfamide compound of the present invention can become pharmaceutical preparation with pharmaceutical carrier or vehicle (for example pharmaceutically acceptable carrier and vehicle) mixed-shaped according to the conventional medicine compounding process.Described sulfinyl amine compounds can be blended in any oral dosage form commonly used as activeconstituents, described oral dosage form comprises tablet, capsule and liquid preparation (for example elixir and suspensoid), wherein comprises the material of tinting material, correctives, stablizer and taste masking.For mixing oral dosage form, described sulfinyl amine compounds can mix with various conventional tablet materials (for example starch, calcium carbonate, lactose, sucrose and Si Liaodengji dicalcium phosphate feed grade) to help compressing tablet and incapsulate as activeconstituents.Can be with described sulfinyl amine compounds for example dissolving or suspendible in sterilized water, aseptic organic solvent or both mixtures of acceptable sterile liquid carrier pharmaceutically.Liquid vehicle can be the carrier that is fit to injection, such as physiological saline, propylene glycol or Aqueous Solutions of Polyethylene Glycol.In other cases, micronized activeconstituents can also be dispersed in the aqueous solution of starch or Xylo-Mucine or be dispersed in suitable oil (for example peanut oil) and make.Liquid pharmaceutical formulation (referring to sterile solution or suspensoid) can be used for intravenous injection, intramuscular injection, peritoneal injection or subcutaneous injection.
The present invention also provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises at least a aromatic heterocycle sulfamide compound of the present invention as activeconstituents.In addition, described pharmaceutical composition can also comprise that one or more are inorganic or organic, pharmaceutically acceptable carrier or the vehicle of solid or liquid.Term " pharmaceutically acceptable " refers to can to tolerate on physiology and usually can not produce additive or the composition of allergy or similarly untoward reaction (such as dizziness etc.) when being administered to animal such as Mammals (such as the mankind).Pharmaceutical carrier and vehicle can include but not limited to thinner, for example lactose, glucose, seminose and/or glycerine; Lubricant; Polyoxyethylene glycol; Tackiness agent, for example magnesium aluminum silicate, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; And, if necessary, also comprise disintegrating agent, for example starch, agar, Lalgine or its salt such as sodium alginate; And/or sorbent material, tinting material, sanitas, stablizer, correctives and sweeting agent.
Embodiment
The below is further described with characteristics to various aspects of the present invention.
Shortenings used herein is generally well-known to those skilled in the art, can be perhaps understandable according to rudimentary knowledge.
The starting raw material that adopts in the preparation of the compounds of this invention be known, can be according to currently known methods preparation or commercially available acquisition.
The invention still further relates to new intermediate and/or starting raw material.Particularly preferably with embodiment in those identical or similar reaction conditionss and the new intermediate mentioned.
Intermediate and end product can carry out aftertreatment and/or purifying according to conventional methods, and described ordinary method comprises regulates pH, extraction, filtration, drying, concentrated, chromatography, grinding, crystallization etc.
In addition, the compounds of this invention can also be prepared by the alternative of the whole bag of tricks known in the art or methods described herein.
The following example only is used for illustrating the present invention, limits the invention never in any form.
The preparation of embodiment 1 2-(2-fluoro-4-biphenyl)-N-(benzenesulfonyl) propionic acid amide
Get the 50ml round-bottomed flask, CDI (0.41g, 2.52mmol) is added to the dichloromethane solution the inside of the drying of 2-(2-fluoro-4-biphenyl) propionic acid (0.61g, 2.52mmol), mixing solutions stirred 2 hours under 0-5 ℃.Add benzsulfamide (0.39g, 2.52mmol) and DBU (0.3ml) and stirred about 6 hours under room temperature afterwards, TLC follows the tracks of reaction, after reaction finishes.Organic phase NaH
2PO
4(2*5ml), saturated aqueous common salt (2*5ml) is washed.Use anhydrous sodium sulfate drying, solvent is removed.(sherwood oil: ethyl acetate=5: 1) obtain target compound (0.62g), productive rate is 79% with the silica gel column chromatography separation.
This compound MS:[M+H]
+384.15;
1H-NMR (400MHz, CDCl
3) δ 7.86 (d, 4H), 7.72 (m, 2H), 7.62 (t, 2H), 7.52 (m, 4H), 7.12 (d, 1H), 6.89 (S, 1H), 3.62 (q, 1H, J=6.8Hz), 1.46 (d, 3H, J=6.4Hz).
The preparation of embodiment 2 2-(2-fluoro-4-biphenyl)-N-((4-hydroxyphenyl) alkylsulfonyl) propionic acid amide
Get the 50ml round-bottomed flask, CDI (0.41g, 2.52mmol) is added to the dichloromethane solution the inside of the drying of 2-(2-fluoro-4-biphenyl) propionic acid (0.61g, 2.52mmol), mixing solutions stirred 2 hours under 0-5 ℃.Add 4-hydroxyphenyl sulphonamide (0.44g, 2.52mmol) and DBU (0.3ml) and stirred about 6 hours under room temperature afterwards, TLC follows the tracks of reaction, after reaction finishes.Organic phase NaH
2PO
4(2*5ml), saturated aqueous common salt (2*5ml) is washed.Use anhydrous sodium sulfate drying, solvent is removed.Separate (sherwood oil: ethyl acetate=5: 1) obtain target compound (0.62g productive rate 79%) with silica gel column chromatography.
This compound MS:[M+H]
+400.05;
1H-NMR (400MHz, DMSO) δ 12.09 (s, 1H), 10.59 (s, 1H), 7.69 (d, 2H, J=8.4Hz), (7.51 m, 6H), 7.06 (t, 2H, J=9.2Hz), 6.88 (d, 2H, J=8.4Hz), 3.74 (q, 1H), (1.27 d, 3H, J=6.8Hz).
The preparation of embodiment 3 2-(2-fluoro-4-biphenyl)-N-(2-(methylsulfonyl) ethyl) propionic acid amide
Get the 50ml round-bottomed flask, CDI (0.41g, 2.52mmol) is added to the dichloromethane solution the inside of the drying of 2-(2-fluoro-4-biphenyl) propionic acid (0.61g, 2.52mmol), mixing solutions stirred 2 hours under 0-5 ℃.Add Toluidrin ethamine (0.31g, 2.52mmol), (sherwood oil: ethyl acetate=2: 1) obtain target compound (0.70g), productive rate is 77% in the silica gel column chromatography separation.
The MS:[M+H of this compound]
+350.31;
1H-NMR (400MHz, CDCl
3) δ 7.54 (t, 2H), 7.46 (m, 4H), 7.16 (m, 2H), 6.21 (s, 1H, CONH), 3.79 (q, 2H), 3.60 (q, 1H), 3.23 (t, 2H, J=5.6Hz), 2.92 (s, 3H), 1.58 (d, 3H, J=7.0Hz).
The pharmacologically active part
The present invention adopts MTT colorimetric method for determining cytoactive.
The MTT colorimetry is a kind of method that detects cell survival and growth.Its detection principle is that the succinodehydrogenase in the viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.The first a ceremonial jade-ladle, used in libation of dimethyl sulfoxide (DMSO) (DMSO) in can dissolved cell measured its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, can indirectly reflect viable cell quantity.In certain cell count scope, the amount that the crystallization of first a ceremonial jade-ladle, used in libation forms is directly proportional to cell count.
The MTT full name is 3-(4,5)-dimethylthiahiazo (z-y1)-3,5-di-phenytetrazoliumromide, chemistry 3-(4,5-dimethylthiazole-2)-2 by name, 5-phenylbenzene tetrazole bromine salt, commodity are called tetrazolium bromide, are a kind of dyestuffs of yellow color.
The MTT powder is bought the company in Sigma, is mixed with concentration with phosphoric acid buffer (PBS) when using and is the solution of 5mg/ml,, then keeps in Dark Place under 4 ℃ to remove the bacterium in solution with 0.22 μ m membrane filtration.
MTT colorimetric method for determining cytoactive comprises following several step:
Step 1): dosing spreads 96 orifice plates with SUM-159, HCC-1954 and MCF-7 cell (available from Beijing gold amethyst bio tech ltd) noon before that day.Collect SUM-159, HCC-1954 and the MCF-7 cell of logarithmic phase, adjust cell concn to 2.5 * 10 after viable count
4Cells/mL.Inoculating cell in 96 orifice plates, every hole adds 100 μ L cell suspension bed boards, and final cell to be measured is the 2500cells/ hole.The surrounding marginal pore is inoculating cell not, only adds 100 μ L cell culture mediums (cell culture medium that uses in this experiment is modified form RPMI-1640 (Hyclone) basic medium, adds 10% foetal calf serum (Hyclone)).5%CO
2, 37 ℃ of overnight incubation are so that cell is fully adherent.
Step 2): dosing in morning next day.At first dilute medicine, prepare corresponding drug level gradient.Add the medicine of the 100 corresponding concentration of μ L in the cell of 96 orifice plates of completing to the day before yesterday, be provided with 8 concentration gradients in this experiment, system Chinese traditional medicine final concentration gradient is: 30 μ M, 27 μ M, 24 μ M, 21 μ M, 18 μ M, 15 μ M, 12 μ M, 9 μ M.Each concentration arranges 5 repetitions.Arrange simultaneously not dosing only the hole of inoculating cell be control group, not dosing of control group, the cell culture medium of adding 100 μ L gets final product; The hole that inoculating cell not only adds substratum is set is made as blank well, also add 100 μ L cell culture mediums.5%CO
2, 37 ℃ of incubators were hatched X (X=24,48,72,96) hour.
Step 3): after X hour, every hole adds 20 μ LMTT solution (5mg/ml, MTT) again, continues to cultivate 4 hours.If medicine and MTT can react, discard nutrient solution after can be first centrifugal, carefully with PBS rinse 2-3 all over after, then add the nutrient solution that contains MTT.
Step 4): stop after 4 hours cultivating, carefully suck liquid in the hole.Every hole adds 150 μ L dimethyl sulfoxide (DMSO), and 37 ℃ of incubators were hatched 10 minutes.Adopt enzyme-linked immunosorbent assay instrument MULTISKAN FC (Thermo scientific) to measure the light absorption value in each hole, 490nm place, during measurement with blank well as the zeroing hole.
Step 5): processing data.At first adopt following formula to calculate inhibiting rate:
Inhibiting rate=1-dosing group OD value/control group OD value
Then take Log C (drug level logarithm) as X-coordinate, inhibiting rate is ordinate zou, carries out probit weighted regression method (Bliss method) with data processing software SPSS software (IBM Corporation) and carries out data processing, and mapping obtains IC
50Value.
According to above-mentioned testing method, record embodiment 1-3 compound at 72 hours inhibition IC to SUM-159, HCC-1954 and MCF-7 cell
50Value is respectively
| ? | SUM-159 | HCC-1954 | MCF-7 |
| Embodiment 1 | 17.677μM | 16.654μM | 24.235μM |
| Embodiment 2 | 14.621μM | 14.654μM | 24.231μM |
| Embodiment 3 | 11.612μM | 14.213μM | 24.237μM |
According to foregoing, can understand the survival and growth that the compounds of this invention can effectively suppress SUM159, HCC-1954 cell, slightly poor to the survival and growth restraining effect of MCF-7 cell.The compounds of this invention can be used for prevention or treatment mammary cancer, is expected to substitute the Reparixin of easy generation resistance.
For clear and understandable purpose, explanation and embodiment have described foregoing invention in detail by way of example.Can change and revise in the scope of subsidiary claim, this be clearly to one skilled in the art.Therefore, be appreciated that top specification sheets is intended to for explanation rather than for restriction.Therefore, scope of the present invention should not determine with reference to above-mentioned specification sheets, and should determine with reference to the determined four corner of doctrine of equivalents that following claims and these claims are enjoyed.
Claims (6)
1. aromatic heterocycle sulfamide compound has general formula (I):
Wherein, n=0,1,2 or 3;
R is selected from C
1-C
4Straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, the 3-pyridyl, 2-pyridyl ethyl group,
2. aromatic heterocycle sulfamide compound according to claim 1, wherein, R be selected from phenyl,
N=0 or R are selected from methyl, n=2.
3. prepare the method for aromatic heterocycle sulfamide compound claimed in claim 1, comprise the following steps:
Make formula (II) compound
Under 0 ℃ in aprotic solvent with condensing agent generation activated carboxylic reaction after and with formula (III) compound
Condensation reaction production (I) compound occurs under alkaline condition,
Wherein, n=0,1,2 or 3; In formula (III), R is selected from C
1-C
4Straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, the 3-pyridyl, 2-pyridyl ethyl group,
4. prepare the method for aromatic heterocycle sulfamide compound according to claim 2, comprising:
Make formula (II) compound
Under 0 ℃ in aprotic solvent with condensing agent generation activated carboxylic reaction after and with formula (III) compound
Condensation reaction production (I) compound occurs under alkaline condition,
Wherein, R be selected from phenyl,
N=0 or R are selected from methyl, n=2.
5. the application of aromatic heterocycle sulfamide compound claimed in claim 1 in the medicine of preparation prevention or treatment mammary cancer.
6. pharmaceutical composition, this pharmaceutical composition comprises at least a aromatic heterocycle sulfamide compound according to claim 1 as activeconstituents.
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| CN201210589448.2A CN103159650B (en) | 2011-12-19 | 2012-12-19 | The preparation of aromatic heterocycle sulfamide compound and application thereof |
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| CN201110428978.4 | 2011-12-19 | ||
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| CN201210589448.2A CN103159650B (en) | 2011-12-19 | 2012-12-19 | The preparation of aromatic heterocycle sulfamide compound and application thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030216392A1 (en) * | 1998-10-23 | 2003-11-20 | Dompe S.P.A. | N - ( 2 - aryl - propionyl ) - sulfonamides and pharmaceutical preparations containing them |
| CN1514824A (en) * | 2001-06-06 | 2004-07-21 | Benzoylsulfonamides and sulfonylbenzamidines for use as antitumour agents | |
| WO2005049594A1 (en) * | 2003-11-13 | 2005-06-02 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
| WO2005090295A2 (en) * | 2004-03-23 | 2005-09-29 | Dompe' Pha.R.Ma S.P.A. | 2-phenylpropionic acid derivatives and pharmaceutical compositions containing them |
| CN101857572A (en) * | 2010-06-08 | 2010-10-13 | 东南大学 | 4-aromatic amino pyrimidine derivative and application thereof |
| CN102272599A (en) * | 2008-11-11 | 2011-12-07 | 密执安大学评议会 | Anti-cxcr1 compositions and methods |
-
2012
- 2012-12-19 CN CN201210589448.2A patent/CN103159650B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030216392A1 (en) * | 1998-10-23 | 2003-11-20 | Dompe S.P.A. | N - ( 2 - aryl - propionyl ) - sulfonamides and pharmaceutical preparations containing them |
| CN1514824A (en) * | 2001-06-06 | 2004-07-21 | Benzoylsulfonamides and sulfonylbenzamidines for use as antitumour agents | |
| WO2005049594A1 (en) * | 2003-11-13 | 2005-06-02 | Abbott Laboratories | N-acylsulfonamide apoptosis promoters |
| WO2005090295A2 (en) * | 2004-03-23 | 2005-09-29 | Dompe' Pha.R.Ma S.P.A. | 2-phenylpropionic acid derivatives and pharmaceutical compositions containing them |
| CN102272599A (en) * | 2008-11-11 | 2011-12-07 | 密执安大学评议会 | Anti-cxcr1 compositions and methods |
| CN101857572A (en) * | 2010-06-08 | 2010-10-13 | 东南大学 | 4-aromatic amino pyrimidine derivative and application thereof |
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