CN103159650B - The preparation of aromatic heterocycle sulfamide compound and application thereof - Google Patents
The preparation of aromatic heterocycle sulfamide compound and application thereof Download PDFInfo
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- CN103159650B CN103159650B CN201210589448.2A CN201210589448A CN103159650B CN 103159650 B CN103159650 B CN 103159650B CN 201210589448 A CN201210589448 A CN 201210589448A CN 103159650 B CN103159650 B CN 103159650B
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- -1 aromatic heterocycle sulfamide compound Chemical class 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims abstract description 5
- 239000012188 paraffin wax Substances 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000004083 survival effect Effects 0.000 abstract description 5
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Abstract
The present invention relates to preparation and the application thereof of aromatic heterocycle sulfamide compound, provide in particular aromatic heterocycle sulfamide compound, have the structure shown in following general formula (I), this compounds can suppress the survival and growth of SUM-159, HCC-1954 and MCF-7 cell effectively:
wherein, n=0,1,2 or 3; R is selected from C
1-C
4straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, 3-pyridyl, 2-pyridyl ethyl group,
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to aromatic heterocycle sulfamide compound and preparation method thereof and purposes.
Background technology
Mammary cancer (mammarycarcinoma) is the modal a kind of malignant tumour of the mankind is also one of women's major malignant tumor.The malignant tumour overwhelming majority system of breast comes from the epithelium (breast cancer) of mammary gland, and the various non-epithelium (various sarcoma) that minority can be derived from 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 tumour of women's whole body.
Univ Michigan-Ann Arbor USA researchist MaxS.Wicha in 2010 etc. identify the new effect of a kind of acceptor, CXCR1, are positioned at mammary cancer cancer stem cell surface, under tissue damaged or the stimulation of inflammatory reaction, have the ability exciting cancer stem cell to grow.CXCR1 is the acceptor of interleukin 8 (IL-8), and IL-8 is everlasting in chronic inflammatory diseases and tissue-damaging process and produces.After patient with breast cancer accepts chemotherapy, dead cancer cell can produce IL-8, and this will promote the self-replacation of cancer stem cell.If add relative medicine and block CXCR1 in Breast Cancer Patients Treated process, will effectively help to kill breast carcinoma stem cell.
Reparixin (N-[(R)-2-(4-isobutylphenyl) propionyl]-methanesulfonamide) is a kind of benzyl propionate derivant, interleukin 8 albumen can be suppressed to be combined with acceptor CXCR1, thus block breast carcinoma stem cell FAK/AKT/ beta-catenin path, accurately hit cancer stem cell.Researchist with the experimental mouse of et al. Ke breast cancer cell for object carries out studying rear discovery, accept simultaneously chemotherapy and repertaxin treatment experimental mouse body in cancer stem cell quantity far below the experimental mouse only accepting chemotherapy, further, the probability adding the mouse generation Nasopharyngeal neoplasms of repertaxin treatment also reduces.Interim for suppressing the medicine Reparixin (Repertaxin) of organ naltrindole can kill breast carcinoma stem cell and stop the diffusion of tumour in clinical trial 2 at present.
Up to the present, do not have a kind of medicine fundamentally to suppress or to eliminate breast carcinoma stem cell, reach the effect of thoroughly curing.Therefore, urgently find a kind of better efficacy, toxic side effect is little, the medicine of the treatment mammary cancer of high specificity.
Summary of the invention
The structure of the present invention to Reparixin is optimized, and has newly synthesized a compounds, and replacing the phenyl ring in Reparixin with oxazole ring, is aromatic heterocycle sulfamide compound.Pharmacologically active result shows, this compounds has growth-inhibiting effect effectively to SUM-159, HCC-1954 and MCF-7 cell, and it may be used for prevention or treatment mammary cancer.
The invention provides sulfamide compound, there is general formula (I):
Wherein, R is selected from C
1-C
4straight chain or branched paraffin, phenyl, cyclohexyl, o-tolyl, 3-pyridyl, 2-pyridyl ethyl group,
N=0,1,2 or 3.
In a particular embodiment, described sulfamide compound has general formula (I), wherein R be selected from phenyl,
n=0 or R is selected from methyl, n=2.
The invention provides a kind of method preparing sulfamide compound, comprise the following steps:
Make formula (II) compound
After reacting with condensing agent generation activated carboxylic in aprotic solvent at 0 DEG C and with formula (III) compound
There is condensation reaction production (I) compound in the basic conditions,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, described condensing agent is selected from N, N '-carbonyl dimidazoles (CDI), and described alkali is 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, 3-pyridyl, 2-pyridyl ethyl group,
The invention provides the method that one prepares general formula (I) sulfamide compound, comprising:
Make formula (II) compound
After reacting with condensing agent generation activated carboxylic in aprotic solvent at 0 DEG C and with formula (III) compound
There is condensation reaction production (I) compound in the basic conditions,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, described condensing agent is selected from N, N '-carbonyl dimidazoles (CDI), and described alkali is selected from 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU).
In a particular embodiment, prepare R in general formula (I) be phenyl,
n=0 or R is methyl, and the method for the sulfamide compound of n=2, comprising:
Make formula (II) compound
After reacting with condensing agent generation activated carboxylic in aprotic solvent at 0 DEG C and with formula (III) compound
There is condensation reaction production (I) compound in the basic conditions,
Wherein, described aprotic solvent is selected from methylene dichloride, tetrahydrofuran (THF), preferred methylene dichloride, described condensing agent is selected from N, N '-carbonyl dimidazoles (CDI), and described alkali is selected from 1,8-diazabicylo-dicyclo (5,4,0)-7-hendecene (DBU);
Wherein, the R in formula (III) be phenyl,
n=0 or R is methyl, n=2.
Present invention also offers described sulfamide compound prevent in preparation or treat the application in the medicine of 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 was methyl, n=2, the sulfamide compound of different configuration, at 72 hours suppression IC to SUM-159, HCC-1954 and MCF-7 cell
50value sees the following form.
Thus the medicine that this compounds can be mixed with for prevention or treatment mammary cancer.
Aromatic heterocycle sulfamide compound of the present invention can be mixed to form pharmaceutical preparation according to conventional medicine compounding process and pharmaceutical carrier or vehicle (such as pharmaceutically acceptable carrier and vehicle).Can described sulfinyl amine compounds be blended in any conventional oral dosage form as activeconstituents, described oral dosage form comprises tablet, capsule and liquid preparation (such as elixir and suspensoid), wherein contains the material of toner, correctives, stablizer and taste masking.For mixing oral dosage form, described sulfinyl amine compounds can mix with various conventional tablet material (such as starch, calcium carbonate, lactose, sucrose and Si Liaodengji dicalcium phosphate feed grade) to help compressing tablet as activeconstituents and incapsulate.Can dissolve in described sulfinyl amine compounds pharmaceutically acceptable sterile liquid carrier such as sterilized water, sterile organic solvent or both mixtures or suspendible.Liquid vehicle can be the carrier of applicable injection, such as physiological saline, propylene glycol or Aqueous Solutions of Polyethylene Glycol.In other cases, can also micronized activeconstituents be dispersed in the aqueous solution of starch or Xylo-Mucine or be dispersed in suitable oil (such as peanut oil) and obtain.Liquid pharmaceutical formulation (referring to sterile solution or suspensoid) may be used for intravenous injection, intramuscular injection, peritoneal injection or subcutaneous injection.
Present invention also offers a kind of pharmaceutical composition, this pharmaceutical composition comprises the of the present invention aromatic heterocycle sulfamide compound of at least one as activeconstituents.In addition, described pharmaceutical composition can also comprise that one or more are inorganic or organic, the pharmaceutically acceptable carrier of solid or liquid or vehicle.Term " pharmaceutically acceptable " refers to and when being administered to animal such as Mammals (such as the mankind), physiology can to tolerate and usually can not produce additive or the composition of irritated or similar untoward reaction (such as dizzy etc.).Pharmaceutical carrier and vehicle can include but not limited to thinner, such as lactose, glucose, seminose and/or glycerine; Lubricant; Polyoxyethylene glycol; Tackiness agent, such as magnesium aluminum silicate, starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone; Further, if necessary, also comprise disintegrating agent, such as starch, agar, Lalgine or its salt are as sodium alginate; And/or sorbent material, tinting material, sanitas, stablizer, correctives and sweeting agent.
Embodiment
Be further described with feature to various aspects of the present invention below.
Shortenings used herein is generally well-known to those skilled in the art, or can be understandable according to rudimentary knowledge.
The starting raw material adopted in the preparation of the compounds of this invention is known, that can prepare according to currently known methods or commercially available acquisition.
The invention still further relates to new intermediate and/or starting raw material.Particularly preferably with those the identical or similar reaction conditionss mentioned in embodiment and new intermediate.
Intermediate and end product can carry out aftertreatment and/or purifying according to conventional methods, and described ordinary method comprises and 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 various method known in the art or methods described herein.
The following example only for illustrating the present invention, limits the invention never in any form.
The preparation of embodiment 12-(the fluoro-4-biphenyl of 2-)-N-(benzenesulfonyl) propionic acid amide
Get 50ml round-bottomed flask, inside dichloromethane solution CDI (0.41g, 2.52mmol) being added to the drying of 2-(the fluoro-4-biphenyl of 2-) propionic acid (0.61g, 2.52mmol), mixing solutions stirs 2 hours at 0-5 DEG C.Stirred at ambient temperature 6 hours after adding benzsulfamide (0.39g, 2.52mmol) and DBU (0.3ml), TLC follows the tracks of reaction, after reaction terminates.Organic phase NaH
2pO
4(2*5ml), saturated aqueous common salt (2*5ml) is washed.With anhydrous sodium sulfate drying, solvent is removed.With silica gel column chromatography separation, (sherwood oil: ethyl acetate=5: 1) obtain target compound (0.62g), productive rate is 79%.
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 22-(the fluoro-4-biphenyl of 2-)-N-((4-hydroxyphenyl) alkylsulfonyl) propionic acid amide
Get 50ml round-bottomed flask, inside dichloromethane solution CDI (0.41g, 2.52mmol) being added to the drying of 2-(the fluoro-4-biphenyl of 2-) propionic acid (0.61g, 2.52mmol), mixing solutions stirs 2 hours at 0-5 DEG C.Stirred at ambient temperature 6 hours after adding 4-hydroxyphenyl sulphonamide (0.44g, 2.52mmol) and DBU (0.3ml), TLC follows the tracks of reaction, after reaction terminates.Organic phase NaH
2pO
4(2*5ml), saturated aqueous common salt (2*5ml) is washed.With anhydrous sodium sulfate drying, solvent is removed.(sherwood oil: ethyl acetate=5: 1) obtain target compound (0.62g productive rate 79%) is separated 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 32-(the fluoro-4-biphenyl of 2-)-N-(2-(methylsulfonyl) ethyl) propionic acid amide
Get 50ml round-bottomed flask, inside dichloromethane solution CDI (0.41g, 2.52mmol) being added to the drying of 2-(the fluoro-4-biphenyl of 2-) propionic acid (0.61g, 2.52mmol), mixing solutions stirs 2 hours at 0-5 DEG C.Add Toluidrin ethamine (0.31g, 2.52mmol), (sherwood oil: ethyl acetate=2: 1) obtain target compound (0.70g), productive rate is 77% in 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).
pharmacologically active part
The present invention adopts MTT colorimetric method for determining cytoactive.
MTT colorimetry is a kind of method detecting cell survival and growth.Its Cleaning Principle is that the succinodehydrogenase in 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.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, can indirectly reflect viable cell quantity.Within the scope of certain cell count, the amount that the crystallization of first a ceremonial jade-ladle, used in libation is formed is directly proportional to cell count.
MTT full name is 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, chemistry 3-(4 by name, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, commodity are called tetrazolium bromide, are a kind of dyestuffs of yellow color.
MTT powder is bought in Sigma company, and during use, phosphoric acid buffer (PBS) is mixed with the solution that concentration is 5mg/ml, with 0.22 μm of membrane filtration to remove the bacterium in solution, then keeps in Dark Place at 4 DEG C.
MTT colorimetric method for determining cytoactive comprises several step below:
Step 1): dosing spreads 96 orifice plates with SUM-159, HCC-1954 and MCF-7 cell (purchased from gold amethyst bio tech ltd, Beijing) noon before that day.Collect SUM-159, HCC-1954 and MCF-7 cell of logarithmic phase, after viable count, adjust cell concn to 2.5 × 10
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 2500cells/ hole.Surrounding marginal pore not inoculating cell, only add 100 μ L cell culture mediums (cell culture medium used in this experiment is modified form RPMI-1640 (Hyclone) basic medium, adds the foetal calf serum (Hyclone) of 10%).5%CO
2, 37 DEG C of overnight incubation, to make cell fully adherent.
Step 2): dosing in morning next day.First dilute medicine, prepare corresponding drug concentration gradient.Add the medicine of the corresponding concentration of 100 μ L in the cell of 96 orifice plates completed to the day before yesterday, be provided with 8 concentration gradients in this experiment, system Chinese traditional medicine final concentration gradient is: 30 μMs, 27 μMs, 24 μMs, 21 μMs, 18 μMs, 15 μMs, 12 μMs, 9 μMs.Each concentration arranges 5 repetitions.The hole simultaneously arranging not dosing only inoculating cell is control group, and control group not dosing, adds the cell culture medium of 100 μ L; The hole that non-inoculating cell only adds substratum is set and is set to blank well, also add 100 μ L cell culture mediums.5%CO
2, 37 DEG C of incubators hatch X (X=24,48,72,96) hour.
Step 3): after X hour, every hole adds 20 μ LMTT solution (5mg/ml, MTT) again, continues cultivation 4 hours.If medicine and MTT can react, can first centrifugal after discard nutrient solution, carefully with PBS rinse 2-3 all over after, then add the nutrient solution containing MTT.
Step 4): stop after 4 hours cultivating, carefully suck liquid in hole.Every hole adds 150 μ L dimethyl sulfoxide (DMSO), and 37 DEG C of incubators hatch 10 minutes.Enzyme-linked immunosorbent assay instrument MULTISKANFC (Thermoscientific) is adopted to measure the light absorption value in each hole, 490nm place, using blank well as zeroing hole during measurement.
Step 5): processing data.First following formulae discovery inhibiting rate is adopted:
Inhibiting rate=1-dosing group OD value/control group OD value
Then with LogC (drug level logarithm) for X-coordinate, inhibiting rate is ordinate zou, carry out probit weighted regression method (Bliss method) with data processing software SPSS software (IBM Corporation) and carry out data processing, mapping, obtains IC
50value.
According to above-mentioned testing method, record embodiment 1-3 compound at 72 hours suppression 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, the survival and growth that the compounds of this invention effectively can suppress SUM159, HCC-1954 cell can be understood, slightly poor to the survival and growth restraining effect of MCF-7 cell.The compounds of this invention may be used for prevention or treatment mammary cancer, is expected to substitute the Reparixin easily producing resistance.
In order to clear and understandable object, explanation and embodiment describe in detail foregoing invention by way of example.Can carry out changing and revising in the scope of subsidiary claim, this be clearly to one skilled in the art.Therefore, the specification sheets being appreciated that above be intended to for illustration of instead of for restriction.Therefore, scope of the present invention should not determined with reference to above-mentioned specification sheets, and should determine with reference to the determined four corner of doctrine of equivalents that claims and these claims are enjoyed below.
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, 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 is selected from methyl, n=2.
3. prepare the method for aromatic heterocycle sulfamide compound according to claim 1, comprise the following steps:
Make formula (II) compound
After reacting with condensing agent generation activated carboxylic in aprotic solvent at 0 DEG C and with formula (III) compound
There is condensation reaction production (I) compound in the basic conditions,
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, 3-pyridyl, 2-pyridyl ethyl group,
4. prepare the method for aromatic heterocycle sulfamide compound according to claim 2, comprising: make formula (II) compound
After reacting with condensing agent generation activated carboxylic in aprotic solvent at 0 DEG C and with formula (III) compound
There is condensation reaction production (I) compound in the basic conditions,
Wherein, R be selected from phenyl,
n=0, or R is selected from methyl, n=2.
5. aromatic heterocycle sulfamide compound according to claim 1 prevents in preparation or treats the application in the medicine of mammary cancer.
6. a pharmaceutical composition, this pharmaceutical composition comprises the according to claim 1 aromatic heterocycle sulfamide compound of at least one as activeconstituents.
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| 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 aminopyrimidine derivatives and their applications |
| CN102272599A (en) * | 2008-11-11 | 2011-12-07 | 密执安大学评议会 | Anti-CXCR1 compositions and methods |
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| 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 aminopyrimidine derivatives and their applications |
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