CN107814788B - A kind of sulfamide derivative, preparation method and its application as NAMPT inhibitor - Google Patents
A kind of sulfamide derivative, preparation method and its application as NAMPT inhibitor Download PDFInfo
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- CN107814788B CN107814788B CN201711409215.9A CN201711409215A CN107814788B CN 107814788 B CN107814788 B CN 107814788B CN 201711409215 A CN201711409215 A CN 201711409215A CN 107814788 B CN107814788 B CN 107814788B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses a kind of sulfamide derivative formulas（Ⅰ）, formula（Ⅰ）For new construction, formula is also disclosed（Ⅰ）Preparation method and its application as NAMPT inhibitor in antitumor drug.Formula is measured in the activity experiment and mtt assay for inhibiting NAMPT（Ⅰ）To all showing good activity in the experiment of the inhibiting effect of different tumour cells.Formula（Ⅰ）Structure is, wherein R1、R2It is all H or is all CH3。
Description
Technical field
The present invention relates to a kind of sulfamide derivative, preparation method and its applications as NAMPT inhibitor.
Background technology
Nampt（Nicotinamide phosphoribosyl transferase, NAMPT) again
Name Nampt visfatin or pre-B cell clone enhancer PBEF regulates and controls required energy matter in mammalian cell
The level of NAD.Cancer cell has very high NAD consumption and metabolic rate, thus the rate-limiting enzyme NAMPT of NAD route of synthesis becomes
The new target drone for the treatment of of cancer, enzyme inhibitor FK866 and CHS-828 are typical NAMPT inhibitor, field of cancer treatment into
Extensive clinical research is gone.
FK866 ((E)-N- [4- (1- benzoyl piperidine -4- bases) butyl] -3- (pyridin-3-yl) acrylamide) exists
Inducing cell apoptosis in HepG2 cells, but do not have initial action to cellular energy metabolism.FK866 can be used for treatment and involve
The disease such as cancer of Apoptosis imbalance.The prior art is it was demonstrated that FK866 interferes the biology of nicotinamide adenine dinucleotide
Synthesize and apoptosis-induced cell death and without any DNA damage effect.FK866 inhibits NAMPT and exhausts the cell of NAD but do not draw
Cytotoxicity at once is played, this hint, for cancer cell of the anti-dependence niacinamide to synthesize NAD, FK866 is promising medicine
Object.In mouse mammary cancer model, FK866 also induces tumor growth delay and tumor radiosensitivity to enhance, along with NAD water
The dose dependent of flat, pH and energy state reduces.In THP-1 and K562 Leukemia Cell Lines, it has been observed that FK866 is fought
The chemical sensitization effect of the cell death of tumour medicine 1- methyl-3-nitro -1- nitrosoguanidines (MNNG)-induction.It is moved in xenogenesis
The effect of GMX1777 is evaluated in plant model and the medicine generation that GMX1778 is measured by liquid chromatography/mass spectrometry is distributed and its to nicotinoyl
The effect of amine adenine-dinucleotide cellular level.
The above shows that NAMPT inhibitor has good druggability, can be used for preparing by inhibiting niacinamide phosphoric acid
Phosphoribosynltransferase is come the drug for the disease prevented and/or treated, it can also be used to the diseases such as anti-curing cancers.Novel NAMPT inhibits
The exploitation of agent is also the hot spot of study of pharmacy.
Invention content
One of the objects of the present invention is to provide a kind of sulfamide derivatives.Its structural formula（Ⅰ）For
, wherein R1 、R2 It is all H or is all CH3。
Another object of the present invention is to provide the formulas（Ⅰ）Synthetic route：
。
Another object of the present invention is to provide the formulas（Ⅰ）Synthesis step：
（1）Pyrrolidines -3- phosgenes and 4,5- dihydro -1H- imidazoles -1- sulfonic acid chlorides react in toluene generates 1- ((4,5-
Dihydro -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides, it post-processes and is washed respectively with water and hydrochloric acid solution, then column
Chromatographic isolation obtains product；
（2）1- ((4,5- dihydro -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides and contain different substituents
It is reacted under primary amino-compound low temperature, is washed by the aqueous solution of water and salt, be finally recrystallized to give the derivative of amide.
Further, the concentration of hydrochloric acid solution used in the post-reaction treatment of sulfonic acid chloride is 1-5 mol/L, preferably 2-3 mol/
L, most preferably 2 mol/L.
Further, in the reaction that amide derivatives generate, reaction temperature is -30-0 DEG C, preferably 0 DEG C；Wash organic phase
Salt include sodium bicarbonate, sodium carbonate, saleratus, the aqueous solution of the salt such as disodium hydrogen phosphate, preferably sodium bicarbonate and sodium carbonate,
Most preferably sodium bicarbonate；Recrystallization solvent used is ethyl acetate/n-hexane（1:5）.
Another object of the present invention is to provide the formulas（Ⅰ）Purposes, as Nampt inhibit
The application of agent.
Further, the formula（Ⅰ）Application in preparing Nampt inhibitor medicaments.
Another object of the present invention is to provide the formulas（Ⅰ）Another aspect purposes, answering in antitumor drug
With.
Further, the formula（Ⅰ）Application in preparation of anti-tumor drugs.The tumor type includes lung cancer, liver
Cancer, gastric cancer, breast cancer, chronic myelogenous leukemia.
Formula according to the present invention（Ⅰ）It is real in the activity for inhibiting Nampt for new construction
It tests and measures formula with mtt assay（Ⅰ）To all showing good activity in the experiment of the inhibiting effect of different tumour cells.
Obviously, the above according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Specific implementation mode
Embodiment 1：1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）The synthesis of pyrrolidines -3- dicarbonyl chlorides
By pyrrolidines -3- phosgenes（16.8ml 0.2mol）In dry toluene（40ml）In solution be added drop-wise to 4,5- bis-
Hydrogen -1H- imidazoles -1- sulfonic acid chlorides（33.72g 0.2mol）In toluene（30ml）In it is cold（-10℃）In solution so that internal temperature
Degree is no more than -5 °C.Once addition is completed, mixture is stirred 30 minutes at -5 DEG C, then adds water（50ml）.Layering, has
Machine layer HCl（2mol/l, 50ml）Washing, with anhydrous MgSO4Dry, vacuum evaporation obtains clear oily matter（9.6g）.The oil
It is required sulfonamides chlorine and 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）The 2 of pyrrolidines -3- dicarbonyl chlorides:1 mixture.
Pillar layer separation obtains 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）Pyrrolidines -3- dicarbonyl chloride 42.4g, yield 80%.1H-NMR (400 MHz, CDCl3) δ:1.77(m,1H), 2.07(m, 1H), 2.80(m, 1H), 3.55-3.64(m,
4H), 3.73(m, 1H), 3.84(m, 1H), 3.95-3.98(t, 2H), 7.98(s, 1H).13C-NMR (125 MHz,
CDCl3) δ: 31.92,43.81, 45.34, 46.45, 50.02, 55.87, 136.36, 174.48.LC-MS(ESI,
pos, ion) m/z: 266[M+1].
Embodiment 2：1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（Pyridin-4-yl）Pyrrolidines -3- carbonyl acyls
The synthesis of amine
By 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）Pyrrolidines -3- dicarbonyl chlorides（53.14g 0.2mol）In nothing
Water CH2Cl2（36mL）In solution be carefully added to 4-aminopyridine at 0 DEG C（18.82g 0.2mol）And triethylamine（27mL）
Anhydrous CH2Cl2（90mL）Solution）.Reaction mixture is stirred 1 hour in ice bath, is then warmed to room temperature and stirred
Night.Cold water is added（100mL）, and CH is detached from aqueous solution2Cl2Layer.Organic phase saturation NaHCO3Solution（2×40mL）With
Water washing, with anhydrous MgSO4It is dried, filtered and concentrated, obtains crude product, by it from ethyl acetate/n-hexane（1:5）Middle heavy knot
Crystalline substance obtains white spicule 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（Pyridin-4-yl）Pyrrolidines -3- carbonyl acyls
Amine, yield：55g（85%）1H-NMR (400 MHz, CDCl3) δ: 1.77(m,1H), 2.01(m, 1H), 2.78(t,
2H), 3.60(t, 2H), 3.64-3.77(m, 2H), 3.80-3.92(m, 2H),3.98-4.06(t, 2H), 7.78
(s, 1H), 8.18(s, 1H), 8.31(d, 2H), 8.56(d, 2H). 13C-NMR (125 MHz, CDCl3) δ:
31.21, 43.24, 43.81, 45.14, 45.34, 55.87, 119.13, 136.36, 145.70, 149.33,
173.83.LC-MS(ESI, pos, ion) m/z: 324[M+1].
Embodiment 3：1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（3,5- lutidines -4- bases）Pyrrole
Cough up the synthesis of -3- formamides
By 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）Pyrrolidines -3- dicarbonyl chlorides（53.14g 0.2mol）In nothing
Water CH2Cl2（36mL）In solution 3,5- dimethyl -4-aminopyridine is carefully added at 0 DEG C（24.43g 0.2mol）With
Triethylamine（27mL）Anhydrous CH2Cl2（90mL）Solution）.Reaction mixture is stirred 1 hour in ice bath, is then warmed to room
Temperature is simultaneously stirred overnight.Cold water is added（100mL）, and CH is detached from aqueous solution2Cl2Layer.Organic phase saturation NaHCO3Solution（2
×40mL）And water washing, with anhydrous MgSO4It is dried, filtered and concentrated, obtains crude product, by it from ethyl acetate/n-hexane（1:
5）Middle recrystallization obtains white spicule 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（3,5- lutidines-
4- bases）Pyrrole-3-carboxamide 60.45g, yield 86%.1H-NMR (400 MHz, CDCl3) δ: 1.77(m,1H),
1.96(s, 6H), 2.07(m, 1H), 2.87(t, 2H), 3.25-3.36(m, 2H), 3.52(d, 1H), 3.60(t,
2H), 3.76-3.94(m, 3H), 7.32(s, 1H), 7.72(s, 1H), 8.37(s, 2H). 13C-NMR (125
MHz, CDCl3) δ: 15.68, 31.21, 43.24, 43.81, 45.14, 45.34, 55.87, 126.88,
136.36, 140.93, 149.40, 173.33.LC-MS(ESI, pos, ion) m/z: 352[M+1].
Effect example 1：Formula（Ⅰ）Inhibit the activity of Nampt
1, the preparation of enzyme：There are BL21 (DE3) plysS cell inoculations of recombinant plasmid (Nampt-pET28a+) in 2 conversion
In × YT culture mediums (37ug/ml chloramphenicol and 75ug/ml kanamycins), 37 DEG C of shakings are stayed overnight, with 20 times after collection thalline
The fresh culture of original volume is resuspended, and 37 DEG C of cultures induce 5h to OD600 about 0.6 under the conditions of 0.3mM IPTG, 28 DEG C.From
The heart collects thalline, and is resuspended in lysis buffer (20mM Tris-HCl pH8.0,300mM NaCl), and 200W ultrasounds are split
Cell is solved, the ultrasonic gaps 1s 9s carries out 30min altogether.By lysate in 12500rpm, 4 DEG C of centrifugation 50min Aspirate supernatants.It should
Shaking is incubated 1h to supernatant on ice with Ni-NTA columns (being purchased from QIAGEN companies), then uses binding buffer (5mM successively
Imidazole, 0.5M NaCl, 20mMTris-Hcl, pH=7.5), wash buffer (40mM imidazole, 0.5M
NaCl, 20mM Tris-HCl, pH=7.5) foreign protein is washed away successively, finally use Elution buffer (200mM
Imidazole, 0.5MNaCl, 20mM Tris-Hcl, pH=7.5) elution destination protein, and carry out SDS-PAGE detections.It will wash
De- destination protein is transferred in bag filter, with Tris-HCl (20mM pH=7.5) dialysis 4~5 of sterilizing in 4 DEG C of refrigerators
It is secondary, after 20%PEG20000 concentrations, albumen concentration is measured with Bradford methods.
2, enzyme reaction system is 25 μ l, wherein various components is a concentration of：50mM Tris-HCl (pH7.5), 0.02%
BSA, 12mM MgCl2,2mM ATP, 0.4mM PRPP, 2mM DTT, 2 μ g/mlNampt, 0.2 μM of NAM, 2%DMSO and multiple proportions
Diluted compound.The DMSO solution of the various concentration of 0.5 μ l compounds is first added on 96 orifice plates, it is mixed to add 20 μ l enzyme reactions
Solution (the enzyme reaction component in addition to substrate) is closed, after 37 DEG C of preincubate 5min, it is anti-to start that 4.5 μ l substrate NAM solution are added
It answers, heating 1min in 95 DEG C after 37 DEG C of reaction 15min terminates enzyme reaction.
3,10 μ l, 20% acetophenones and 2M KOH are sequentially added after enzyme reaction solution cools down on ice, on vortex mixed instrument
2min is acted in 0 DEG C after mixing, 45 μ l88% formic acid, 70 DEG C of heating 5min, cooled on ice is added.
4, the fluorescent value at excitation wavelength 382nm, launch wavelength 445nm is measured using microplate reader.
5, according to formula：E=R/ (1+ (C/IC50)S) (wherein E is enzymatic activity to+B, and C is compound concentration, R, IC50、S、B
For parameter to be fitted), enzymatic activity is fitted the curve of compound concentration in origin softwares, finds out formula（Ⅰ）'s
IC50。
1 formula of table（Ⅰ）The IC that NAMPT inhibits50Value
| IC50（nM） | |
| Embodiment 2 | 6.34±0.47 |
| Embodiment 3 | 6.72±0.38 |
It therefore deduces that, formula disclosed in this invention（Ⅰ）It, can with the activity for inhibiting Nampt
As Nampt inhibitor, can be used for the treatment of Nampt relevant disease.
Effect example 2：MTT（Tetrazolium bromide）Method measures formula（Ⅰ）To the inhibiting effect of different tumour cells
1, used tumour cell is：Human lung cancer cell A549, human liver cancer cells Hep G2, human liver cancer cell
Bel-7402, human gastric adenocarcinoma SGC-7901, human breast cancer cell line Bcap-37, people's chronic myelogenous leukemia cell K562.
2, experimental procedure
1. the cell of logarithmic growth phase, trypsin digestion, 1640 cell culture fluid tune concentration of cell suspension of RPMI are
6×104A/mL.Add 100 μ L of cell suspension per hole in 96 well culture plates, sets 37 DEG C, 5% CO2It is cultivated in incubator for 24 hours, carefully
Born of the same parents are adherent.
2. removing 1640 cell culture fluids of RPMI, 1640 cell culture fluids of RPMI of the drug to be measured of concentration gradient are added
100 μ L, each concentration set 6 parallel holes.96 orifice plates after dosing are placed in 37 DEG C, 5% CO248h is cultivated in incubator, is inverted
The function and effect of microscopically observation drug.
Culture solution is discarded after the centrifugation of 3.96 orifice plates, after carefully being rushed 2 ~ 3 times with PBS, adds the RPMI containing 0.5% MTT
1640 cell culture fluid, 100 μ L continue to cultivate 4h.
4. removing supernatant, 150 μ L dimethyl sulfoxide (DMSO)s are added per hole, sets low-speed oscillation 10min on shaking table, formazan is made to tie
Brilliant fully dissolving.
5. measuring the optical density in each hole at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values are indicated with mean ± SD, inhibiting rate formula is calculated：[(ODControl group-ODBlank group)-(ODDrug study group-
ODBlank group)]/(ODControl group-ODBlank group)*100%。
7. using 5 data processing softwares of GraphPad Prism, by drawing amount effect curve calculation of half inhibitory concentration
（IC50）.
2 formula of table（Ⅰ）Human tumor cells IC50Value
It therefore deduces that, formula disclosed in this invention（Ⅰ）It is inhibited to six kinds of human tumor cells, it can conduct
Cancer prevention and/or the drug candidate for the treatment of carry out more deep research and development, have prompted formula disclosed in this invention（Ⅰ）It can use
In preparing antitumor drug.
Claims (5)
1. a kind of sulfamide derivative, which is characterized in that its structural formula is
, wherein R1 、R2 It is all H or is all CH3。
2. the preparation method of sulfamide derivative as described in claim 1, which is characterized in that synthetic route is
。
3. preparation method as claimed in claim 2, which is characterized in that its synthesis step is：
（1）Pyrrolidines -3- phosgenes and 4,5- dihydro -1H- imidazoles -1- sulfonic acid chlorides react in toluene generates 1- ((4,5- bis-
Hydrogen -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides, it post-processes and is washed respectively with water and hydrochloric acid solution, then column color
Compose isolated product；
（2）1- ((4,5- dihydro -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides and the primary amine containing different substituents
It is reacted under compound low temperature, is washed by the aqueous solution of water and salt, be finally recrystallized to give the derivative of amide.
4. sulfamide derivative as described in claim 1 is in the application for preparing Nampt inhibitor.
5. sulfamide derivative application in preparation of anti-tumor drugs as described in claim 1.
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