CN107814788A - 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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- CN107814788A CN107814788A CN201711409215.9A CN201711409215A CN107814788A CN 107814788 A CN107814788 A CN 107814788A CN 201711409215 A CN201711409215 A CN 201711409215A CN 107814788 A CN107814788 A CN 107814788A
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- 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
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Abstract
The invention discloses a kind of sulfamide derivative formula（Ⅰ）, formula（Ⅰ）For new construction, formula is also disclosed（Ⅰ）Preparation method and its application as NAMPT inhibitor in antineoplastic.Suppressing NAMPT activity experiment and mtt assay measure formula（Ⅰ）Good activity is all shown in experiment to the inhibitory action of different tumour cells.Formula（Ⅰ）Structure is, wherein R1、R2 It is all H or is all CH3。
Description
Technical field
The present invention relates to a kind of sulfamide derivative, preparation method and its application as NAMPT inhibitor.
Background technology
Nampt（Nicotinamide phosphoribosyl transferase, NAMPT) again
Name Nampt visfatin or PBEF PBEF, regulate and control required energy matter in mammalian cell
NAD level.Cancer cell has very high NAD consumption and metabolic rate, thus the rate-limiting enzyme NAMPT of NAD route of synthesis turns into
The new target drone for the treatment of of cancer, its enzyme inhibitor FK866 and CHS-828 are typical NAMPT inhibitor, are entered in field of cancer treatment
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.Prior art is it was demonstrated that the biology of FK866 interference NADHs
Synthesize and apoptosis-induced cell death and without any DNA damage effect.FK866 suppresses NAMPT and exhausts NAD cell but do not draw
Play cytotoxicity at once, this hint, synthesize NAD cancer cell for anti-dependence niacinamide for, FK866 is promising medicine
Thing.In mouse mammary cancer model, FK866 also induced tumor growth delay and tumor radiosensitivity enhancings, 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 resisted
The chemical sensitization effect of the cell death of tumour medicine 1- methyl-3-nitro -1- nitrosoguanidines (MNNG)-induction.Moved in xenogenesis
GMX1777 effect is evaluated in plant model and GMX1778 medicine generation distribution is measured and its to nicotinoyl by liquid chromatography/mass spectrometry
The effect of amine adenine-dinucleotide cellular level.
It is described above to show that NAMPT inhibitor has good druggability, available for preparation by suppressing niacinamide phosphoric acid
Phosphoribosynltransferase is come the medicine of disease that prevents and/or treat, it can also be used to the disease such as anti-curing cancers.New NAMPT suppresses
The exploitation of agent and the focus of study of pharmacy.
The content of the invention
An object of the present invention is to provide a kind of sulfamide derivative.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 formula（Ⅰ）Synthetic route：
。
Another object of the present invention is to provide the formula（Ⅰ）Synthesis step：
（1）Pyrrolidines -3- phosgenes and 4,5- dihydro -1H- imidazoles -1- sulfonic acid chlorides react generation 1- ((4,5- bis- in toluene
Hydrogen -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides, post-process and washed respectively with water and hydrochloric acid solution, then post 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
React under compound low temperature, washed by the aqueous solution of water and salt, be finally recrystallized to give the derivative of acid amides.
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 of amide derivatives generation, reaction temperature is -30-0 DEG C, preferably 0 DEG C；Wash organic phase
Salt include sodium acid carbonate, sodium carbonate, the aqueous solution of the salt such as saleratus, disodium hydrogen phosphate, preferably sodium acid carbonate and sodium carbonate,
Most preferably sodium acid carbonate；Recrystallization solvent used is ethyl acetate/n-hexane（1:5）.
Another object of the present invention is to provide the formula（Ⅰ）Purposes, as Nampt suppress
The application of agent.
Further, the formula（Ⅰ）Application in Nampt inhibitor medicaments are prepared.
Another object of the present invention is to provide the formula（Ⅰ）Another aspect purposes, in antineoplastic should
With.
Further, the formula（Ⅰ）Application in antineoplastic is prepared.Described tumor type includes lung cancer, liver
Cancer, stomach cancer, breast cancer, chronic myelogenous leukemia.
Formula involved in the present invention（Ⅰ）It is real in the activity for suppressing Nampt for new construction
Test and determine formula with mtt assay（Ⅰ）Good activity is all shown in experiment to the inhibitory action of different tumour cells.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and means of this area, this hair is not being departed from
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Embodiment
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- dihydros-
1H- imidazoles -1- sulfonic acid chlorides（33.72g 0.2mol）In toluene（30ml）In it is cold（-10℃）In solution so that internal temperature is not
More than -5 °C.Once addition is completed, mixture is stirred 30 minutes at -5 DEG C, then adds water（50ml）.Layering, organic layer
Use HCl（2mol/l, 50ml）Washing, with anhydrous MgSO4Dry, vacuum evaporation obtains clear oily matter（9.6g）.The oil is institute
Need sulfonamides chlorine and 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）The 2 of pyrrolidines -3- dicarbonyl chlorides:1 mixture.Post color
Compose isolated 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 acid amides
Synthesis
By 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）Pyrrolidines -3- dicarbonyl chlorides（53.14g 0.2mol）Anhydrous
CH2Cl2（36mL）In solution be carefully added to 4-aminopyridine at 0 DEG C（18.82g 0.2mol）And triethylamine（27mL）'s
Anhydrous CH2Cl2（90mL）Solution）.Reactant mixture is stirred 1 hour in ice bath, then warms to room temperature and is stirred overnight.
Add cold water（100mL）, and CH is separated from the aqueous solution2Cl2Layer.Organic phase saturation NaHCO3Solution（2×40mL）And washing
Wash, with anhydrous MgSO4It is dried, filtered and concentrated, obtains crude product, by it from ethyl acetate/n-hexane（1:5）Middle recrystallization, is obtained
To white spicule 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（Pyridin-4-yl）Pyrrolidines -3- carbonyl acid amides, production
Rate：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）Pyrroles -3-
The synthesis of formamide
By 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）Pyrrolidines -3- dicarbonyl chlorides（53.14g 0.2mol）Anhydrous
CH2Cl2（36mL）In solution 3,5- dimethyl -4-aminopyridine is carefully added at 0 DEG C（24.43g 0.2mol）With three
Ethamine（27mL）Anhydrous CH2Cl2（90mL）Solution）.Reactant mixture is stirred 1 hour in ice bath, then warmed to room temperature
And it is stirred overnight.Add cold water（100mL）, and CH is separated from the 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, obtain white spicule 1-（（4,5- dihydro -1H- imidazoles -1- bases）Sulfonyl）-N-（3,5- lutidines -4-
Base）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）Suppress the activity of Nampt
1st, the preparation of enzyme：BL21 (DE3) plysS cells that conversion has recombinant plasmid (Nampt-pET28a+) are inoculated in 2 × YT
In culture medium (37ug/ml chloramphenicol and 75ug/ml kanamycins), 37 DEG C of shakings are stayed overnight, with 20 times of substances after collection thalline
Long-pending fresh culture 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.Centrifugation is received
Collect thalline, and be resuspended in lysis buffer (20mM Tris-HCl pH8.0,300mM NaCl), 200W ultrasonic degradations are thin
Born of the same parents, ultrasonic 1s gaps 9s, carry out 30min altogether.By lysate in 12500rpm, 4 DEG C of centrifugation 50min Aspirate supernatants.The supernatant
Liquid is incubated 1h with Ni-NTA posts (being purchased from QIAGEN companies) in shaking on ice, 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 with 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, protein concentration is determined with Bradford methods.
2nd, enzyme reaction system is 25 μ l, wherein the concentration of various components is：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
The compound of dilution.The DMSO solution of the various concentrations of 0.5 μ l compounds is first added on 96 orifice plates, 20 μ l enzyme reactions is added and mixes
Solution (the enzyme reaction component in addition to substrate) is closed, after 37 DEG C of preincubate 5min, it is anti-to start to add 4.5 μ l substrate NAM solution
Should, 37 DEG C of reaction 15min heat 1min after 95 DEG C and terminate enzyme reaction.
3rd, the acetophenones of 10 μ l 20% and 2M KOH are sequentially added after enzyme reaction solution after cooled on ice, on vortex mixed instrument
Mix and act on 2min after 0 DEG C, add 45 μ l88% formic acid, 70 DEG C of heating 5min, cooled on ice.
4th, the fluorescent value at excitation wavelength 382nm, launch wavelength 445nm is determined using ELIASA.
5th, 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 to the curve of compound concentration in origin softwares, obtains formula（Ⅰ）'s
IC50。
The formula of table 1（Ⅰ）The IC that NAMPT suppresses50Value
| IC50（nM） | |
| Embodiment 2 | 6.34±0.47 |
| Embodiment 3 | 6.72±0.38 |
Therefore deduce that, formula disclosed in this invention（Ⅰ）With the activity for suppressing Nampt, Ke Yizuo
For Nampt inhibitor, it can be used for the treatment of Nampt relevant disease.
Effect example 2：MTT（Tetrazolium bromide）Method determines formula（Ⅰ）To the inhibitory action of different tumour cells
1st, 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.
2nd, experimental procedure
1. the cell in growth period of taking the logarithm, Trypsin Induced, the cell culture fluids of RPMI 1640 adjust concentration of cell suspension be 6 ×
104Individual/mL.Add the μ L of cell suspension 100 per hole in 96 well culture plates, put 37 DEG C, 5% CO224h, cell patch are cultivated in incubator
Wall.
2. removing the cell culture fluids of RPMI 1640, the cell culture fluids of RPMI 1640 of the medicine 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 action effect of micro- Microscopic observation medicine.
Nutrient 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
The μ L of 1640 cell culture fluid 100, continue to cultivate 4h.
4. removing supernatant, 150 μ L dimethyl sulfoxide (DMSO)s are added per hole, low-speed oscillation 10min on shaking table is put, ties formazan
Brilliant fully dissolving.
5. the optical density in each hole is measured at enzyme-linked immunosorbent assay instrument 490nm（OD values）.
6. parallel hole OD values are represented with mean ± SD, inhibiting rate formula is calculated：[(ODControl group-ODBlank group)-(ODDrug study group-
ODBlank group)]/(ODControl group-ODBlank group)*100%。
7. using the data processing softwares of GraphPad Prism 5, by drawing amount effect curve calculation of half inhibitory concentration
（IC50）.
The formula of table 2（Ⅰ）Human tumor cells IC50Value
Therefore deduce that, formula disclosed in this invention（Ⅰ）It is inhibited to six kinds of human tumor cells, cancer can be used as
The drug candidate of prevention and/or treatment carries out more deep research and development, has prompted formula disclosed in this invention（Ⅰ）It can be used for making
Standby antineoplastic.
Claims (5)
1. a kind of sulfamide derivative, preparation method and its application as NAMPT inhibitor, its structural formula（Ⅰ）For
, wherein R1 、R2 It is all H or is all CH3。
2. formula as claimed in claim 1（Ⅰ）, synthetic route is
。
3. formula as claimed in claim 2（Ⅰ）Synthetic route, its synthesis step is：
（1）Pyrrolidines -3- phosgenes and 4,5- dihydro -1H- imidazoles -1- sulfonic acid chlorides react generation 1- ((4,5- bis- in toluene
Hydrogen -1H- imidazoles -1- bases) sulfonyl) pyrrolidines -3- dicarbonyl chlorides, post-process and washed respectively with water and hydrochloric acid solution, then post 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
React under compound low temperature, washed by the aqueous solution of water and salt, be finally recrystallized to give the derivative of acid amides.
4. formula as claimed in claim 1（Ⅰ）, the application as Nampt inhibitor.
5. formula as claimed in claim 1（Ⅰ）, the application in antineoplastic.
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| WO2023070878A1 (en) * | 2021-10-29 | 2023-05-04 | 深圳先进技术研究院 | Bioluminescence nampt enzyme activity detection composition, kit and detection method |
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