CN107513083A - The preparation method of glycosyl naphthoyl imide compounds and application - Google Patents
The preparation method of glycosyl naphthoyl imide compounds and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
Abstract
The present invention relates to a kind of preparation method of glycosyl naphthoyl imide compounds and application, with pharmaceutical chemistry principle, the general structure such as I of a series of new glycosyl naphthalimide derivative has been designed and synthesized, and inhibitory activity of this analog derivative for mankind's GH20 and GH84 β N acetylhexosamine enzymes is tested and evaluated.Test result shows：The glycosyl naphthalimide compound of present invention design synthesis, shows inhibitory activity, part of compounds shows efficient activity and selectivity to the β N acetylhexosamine enzymes of mankind Liang Ge families.Therefore, compound of the present invention or its pharmaceutically acceptable salt have wide practical use in the medicine for being used for treating the disease related to mankind's β N acetylhexosamine enzymes is prepared.
Description
Technical field
The present invention relates to the screening of the selective depressant to mankind β-N-acetylmuramic glycanchydrolase, specifically discloses a kind of sugar
The preparation method of base naphthoyl imide compounds and purposes (application as mankind β-N-acetylmuramic glycanchydrolase inhibitor).
Background technology
β-N-acetylmuramic glycanchydrolase (EC 3.2.1.52) is a kind of hydrolysis saccharide complex end of being responsible for β -1,4- glycosidic bonds
The N-Acetyl-D-glucosamine of connection or the glycosyl hydrolase of N- acetylgalactosamines.Two are primarily present in the mankind and mammalian body
β-N-acetylmuramic glycanchydrolase of type, it is to belong to the Hex of the family of glycosyl hydrolase 20 and belong to glycosyl hydrolase 84 respectively
The OGA of race, both enzymes are for maintaining all to play vital effect in organism normal growth and development
β-N-acetylmuramic glycanchydrolase (OGA) of 84 families is mainly responsible for distinctive one in hydrolyzed cellular matter and Nuclear extract
Kind betides the O-GlcNAc posttranslational modifications on serine or threonine, participates in intracellular a variety of physiological and biochemical procedures, including
The transcription and translation of gene, signal transduction, protein stability etc..The exception of O-GlcNAc level of glycosylation also with many diseases
As type ii diabetes, Alzheimer's disease are related to cancer.β-N-acetylmuramic glycanchydrolase (Hex) of 20 families be primarily present in people and
In the lysosome of mammal, it is responsible for hydrolysis release glycoprotein, glycolipid and GlcNAc or GalNAc in proteoglycans, participates in life
A variety of important physiology and pathologic process in object.Hex exception can cause gangliosides in neuronal cell lysosome
Accumulation, causes serious gangliosidosis, such as Tay-Sachs diseases and Sandhoff diseases.
Therefore, research of the micromolecular inhibitor for relevant disease for the design of both enzymes and treatment have important
Application prospect.In view of both enzymes have identical catalytic mechanism and similar substrate binding site, selective suppression
The exploitation and initiative of agent are also very important.
The content of the invention
It is an object of the invention to provide a kind of glycosyl naphthalimide compound or its pharmaceutically acceptable salt.The present invention's
Glycosyl naphthalimide derivative shows good inhibitory activity to mankind β-N-acetylmuramic glycanchydrolase, and part of compounds is shown
To the selectivity of two kinds of enzymes.
Shown in glycosyl naphthalimide compound CAUS provided by the present invention structural formula such as formula (I),
Wherein m and n is respectively 0~6 integer, and R bases are imide, triazolyl, acid imide and triazolyl, such as formula
(II), shown in formula (III), formula (IV), CAUS-A, CAUS-B, CAUS-C are designated as respectively：
In formula, a=1,2；B=0,2,3,4；C=1,2,3,4,5,6；D=2,3,4,5,6.
The present invention also aims to provide the preparation method of above-mentioned glycosyl naphthalimide compound.
(1) formula (II) compound CAUS-A preparation method, comprises the steps：
1) reagent V and reagent amine are reacted to obtain compound shown in Formula IV；
2) compound shown in Formula IV and chloro acyl chloride reaction are obtained into compound shown in Formula VII；
3) compound shown in compound shown in Formula VII and Formula VIII is reacted to obtain compound shown in Formula IX；
4) compound shown in Formula IX is reacted in methanolic ammonia solution and obtains Formula II；
Specifically, prepared for described above in compound CAUS-A method shown in the formula (II)：The reagent V
It is 1 with reagent amine mol ratio：1.5~2.5；Compound shown in VI is 1 with chloro acyl chlorides mol ratio：1~2；Compound shown in VII
It is 1 with compound mole ratio shown in Formula VIII：1~2；
Specifically, prepared for described above in compound CAUS-A method shown in the formula (II)：
In step 1), for the reagent used for absolute ethyl alcohol, the time of the reaction is 16~24h；In step 2), use
Reagent is at least one of dichloromethane, triethylamine, acyl chlorides G；The temperature of the reaction is room temperature, and the time is 4~6h；Step
3) in, the reagent used is at least one of potassium carbonate, acetone, dichloromethane；The temperature of the reaction is room temperature, and the time is
16~24h；In step 4), the temperature of the reaction is room temperature, and the time is 35~45h；In each step, in addition to extract, be dry
The step of dry, rotary evaporation, recrystallization and column chromatography.
(2) formula (III) compound CAUS-B preparation method, comprises the steps：
1) reagent V and reagent propargylamine are reacted to obtain compound shown in Formula X；
2) compound shown in Formula VIII and dihalo thing are reacted to obtain compound shown in Formula X I；
3) compound shown in Formula X I and Sodium azide are reacted to obtain compound shown in Formula X II；
4) compound shown in compound shown in Formula X II and Formula X is reacted to obtain compound shown in Formula X III；
5) compound shown in Formula X III is reacted in methanolic ammonia solution and obtains formula III；
R is Cl, Br in Formula X I.
Specifically, in compound CAUS-B method shown in formula (III) described above：Reagent V and reagent alkynes third
Amine mol ratio is 1:1.5~2.5；Compound shown in Formula VIII is 1 with dihalo thing mol ratio:6~10；Compound shown in Formula X I
It is 1 with Sodium azide mol ratio:3~5；Compound shown in Formula X II is 1 with compound mole ratio shown in Formula X:1~2；
Specifically, in compound CAUS-B method shown in formula (III) described above：
In step 1), for the reagent used for dichloromethane, the reaction temperature is room temperature, and the time is 16~24h；Step 2)
In, the reagent used is Sodium azide, acetone and dichloromethane；The time of the reaction is 20~30h；In step 3), use
Reagent is at least one of potassium carbonate, acetone, dichloromethane, and the temperature of the reaction is room temperature, and the time is 16~24h；Step
It is rapid 4) in, for the reagent used at least one of THF, sodium ascorbate and copper sulphate, the temperature of the reaction is room temperature, when
Between be 16~24h；In step 5), the temperature of the reaction is room temperature, and the time is 35~45h；In each step, in addition to extraction
Take, dry, rotary evaporation, recrystallization and the step of column chromatography.
(3) formula (IV) compound CAUS-C preparation method, comprises the steps：
1) will react to obtain compound shown in Formula X V again with compound shown in Formula VIII after chloracetyl chloride and propargylamine reaction；
2) compound shown in compound shown in Formula X V and Formula X IV is reacted to obtain compound shown in Formula X VI；
3) by compound reaction equation IV in methanolic ammonia solution shown in Formula X VI；
Specifically, in compound CAUS-C method shown in formula (IV) described above：Chloracetyl chloride and propargylamine
Mol ratio is 1:1.5~2.5, its product is 1 with compound mole ratio shown in Formula VIII:1；Compound shown in Formula X V and Formula X IV
Shown compound mole ratio is 1:1~2；
Specifically, in compound CAUS-C method shown in formula (IV) described above：
In step 1), at least one of potassium carbonate, acetone and dichloromethane, the reaction temperature is the reagent used
Room temperature, time are 16~24h；In step 2), the reagent used is at least one of THF, sodium ascorbate and copper sulphate, institute
The temperature for stating reaction is room temperature, and the time is 16~24h；In step 3), the temperature of the reaction is room temperature, and the time is 35~45h；
In each step, in addition to the step of extraction, drying, rotary evaporation, recrystallization and column chromatography.
It is another object of the present invention to protect a kind of people β-N-acetylmuramic glycanchydrolase inhibitor, the activity of the inhibitor
Composition is the glycosyl naphthalimide derivative or its pharmaceutically acceptable salt as shown in formula (II), formula (III), formula (IV).
It is another object of the present invention to a kind of purposes for disclosing above-mentioned glycosyl naphthalimide derivative, i.e., institute of the present invention
Application of the glycosyl naphthalimide derivative of offer as mankind β-N-acetylmuramic glycanchydrolase inhibitor, it is of the invention in other words to be carried
The glycosyl naphthalimide derivative of confession should as research and treatment and the medicine of mankind β-N-acetylmuramic glycanchydrolase relevant disease
With.
Brief description of the drawings
Fig. 1 compounds CAUS-A-3 hydrogen nuclear magnetic resonance spectrogram；
Fig. 2 compounds CAUS-A-3 carbon-13 nmr spectra figure；
Fig. 3 compounds CAUS-B-2 hydrogen nuclear magnetic resonance spectrogram；
Fig. 4 compounds CAUS-B-2 carbon-13 nmr spectra figure；
Fig. 5 compounds CAUS-C-1 hydrogen nuclear magnetic resonance spectrogram；
Fig. 6 compounds CAUS-C-1 hydrogen nuclear magnetic resonance spectrogram.
Embodiment
Below by specific embodiment, the present invention will be described.It should be noted that description given here and embodiment
Just for the sake of the embodiment of the description present invention, technical staff is set to be easier to understand the present invention, they are not intended to limit
Determine the scope of the present invention.
Experimental method described in following embodiments, it is conventional method unless otherwise specified；The reagent and material, such as
Without specified otherwise, commercially obtain.
Embodiment 1
Compound CAUS-A preparation
Compound CAUS-A-3, a=1, b=3 are prepared according to following reaction scheme, are comprised the following steps that：
(1) in 500mL round-bottomed flasks, 1,8- naphthalic anhydrides (10.0g, 50.5mmol), ethanol 200mL is added, is stirred
Lower addition 1,3- propane diamine (8.4mL, 100.9mmol) is mixed, temperature rising reflux reaction 4h, TLC detection reaction is complete；Filter while hot,
Refrigerator freezing is placed in after filtrate cooling to stay overnight, separates out faint yellow solid, and obtains 10.3g white solids with ethyl alcohol recrystallization, is produced
Rate 81.1%.
Structural identification data is as follows：1H NMR(300MHz,CDCl3) δ 8.63 (d, J=7.3Hz, 2H, Ar-H), 8.24 (d,
J=7.9Hz, 2H, Ar-H), 7.77 (m, 2H, Ar-H), 4.31 (t, J=6.9Hz, 2H, CH2), 2.79 (t, J=6.6Hz, 2H,
CH2),1.99–1.87(m,2H,CH2).
(2) take products therefrom (1.0g, 3.9mmol) in (1) to be added in dry methylene chloride 30mL, add triethylamine
(0.83mL, 5.9mmol), and chloracetyl chloride (0.47mL, 5.9mmol) is slowly added dropwise under conditions of nitrogen protection, room temperature is anti-
It should stay overnight, TLC detection reactions are complete；Add 1mL methanol and reaction is quenched, add water and dichloromethane to extract, organic phase is successively with full
With sodium bicarbonate solution, water, saturated common salt water washing, dry, rotation with recrystallizing methanol obtains target chemical combination after removing organic solvent
Thing 1.1g, yield 85.3%.
Structural identification data is as follows：1H NMR (300MHz, DMSO) δ 8.39 (dd, J=10.8,7.7Hz, 4H, Ar-H),
8.24 (t, J=5.2Hz, 1H, NH), 7.80 (t, J=7.8Hz, 2H, Ar-H), 4.13-3.96 (m, 4H, 2CH2),3.18(dd,
J=13.2,6.9Hz, 2H, CH2), 1.82 (dd, J=14.3,7.2Hz, 2H, CH2).
(3) products therefrom (0.50g, 1.5mmol) in (2), compound (0.55g, 1.5mmol), carbon shown in Formula VIII are taken
Sour potassium (0.25g, 1.8mmol) is dissolved in acetone 30mL, water 15mL in the mixed solvent, and overnight, TLC detections have been reacted for room temperature reaction
Entirely；Rotation removes acetone, adds dichloromethane and water extraction, organic phase washing, dries, after rotation removes organic solvent, column chromatography purifies
To white solid 0.81g, yield 82.7%.
Structural identification data is as follows：1H NMR(300MHz,DMSO)δ8.49–8.36(m,4H,ArH),8.05–7.93(m,
2H, 2NH), 7.82 (dd, J=8.2,7.4Hz, 2H, ArH), 5.11 (t, J=9.7Hz, 1H, H-3), 4.89 (t, J=9.7Hz,
1H, H-4), 4.79 (d, J=10.4Hz, 1H, H-1), 4.17 (dd, J=12.4,4.8Hz, 1H, H-6b), 4.09-3.98 (m,
3H,CH2Ar,H-6b),3.98–3.89(m,1H,H-2),3.89–3.80(m,1H,H-5),3.34–3.19(m,2H,S CH2),
3.15 (dd, J=13.4,6.7Hz, 2H, CH2),1.97,1.96,1.92(3s,9H,3OAc),1.76(s,3H,NHAc),
1.85–1.71(m,2H,CH2).
(4) take products therefrom (0.50g, 0.76mmol) in (3) to be added in methanol 20mL, add the methanol of 4mL saturations
Ammonia solution, reacts at room temperature 24h, and TLC detection reactions are complete；Concentration, column chromatography purify to obtain faint yellow solid, yield 92.3%.
Structural identification data is as follows：1H NMR(300MHz,DMSO-d6)δ8.41–8.30(m,4H,ArH),7.93(t,J
=5.7Hz, 1H, NHCH2),7.83–7.73(m,3H,2ArH,NHAc),5.08(br s,2H,2OH),4.61(br s,1H,
), OH 4.48 (d, J=10.3Hz, 1H, H-1), 4.07-3.96 (m, 2H, H-3, H-4), 3.71 (d, J=11.4Hz, 1H, H-
6b),3.64–3.48(m,2H,H-2,H-6a),3.42–3.37(m,1H,H-5),3.33–3.25(m,2H,CH2),3.20–
3.08(m,4H,2CH2),1.80(s,3H,NAc),1.78–1.71(m,2H,CH2).13C NMR(75MHz,DMSO-d6)δ
169.42,169.14,163.48,134.33,131.27,130.75,127.32,127.21,121.97,83.80,81.22,
75.45,70.70,61.44,54.61,37.88,37.10,33.12,28.00,23.11.
Other formulas are that CAUS-A series compound is prepared according to the method described above.Their compound number,
A, b is shown in Table 1 for corresponding carbon atom number, physicochemical data, and the proton nmr spectra of Structural Identification, mass spectrometric data are shown in Table 2.
The formula of table 1 is the numbering and physicochemical data of CAUS-A series compounds
The CAUS-A episode compounds proton nmr spectra of table 2, mass spectrometric data
(Pos：The positive ion mode of mass spectroscopy；Neg：The negative ion mode of mass spectroscopy)
Embodiment 2
Compound CAUS-B preparation
Compound CAUS-B-2, c=2, prepare, comprise the following steps that according to following reaction scheme：
(1) in 250mL round-bottomed flasks, compound (2.0g, 5.5mmol), 1,2- Bromofumes shown in Formula VIII are added
(3.8mL, 44.0mmol), potassium carbonate (0.91g, 6.6mmol), acetone 40mL, water 20mL, overnight, TLC detections are anti-for room temperature reaction
Should be complete；Rotation removes reaction dissolvent, adds dichloromethane, water extraction, washes, dry, rotation removes organic solvent, and column chromatography purifies to obtain
White solid 2.1g, yield 81.1%.
Structural identification data is as follows：1H NMR(300MHz,CDCl3) δ 5.55 (d, J=9.6Hz, 1H, NH), 5.17-5.07
(m, 2H, H-3, H-4), 4.67 (d, J=10.3Hz, 1H, H-1), 4.17 (d, J=4.0Hz, 2H, H-6a, H-6b), 4.08
(td, J=10.1,9.1Hz, 1H, H-2), 3.72 (dt, J=9.8,4.0Hz, 1H, H-5), 3.66-3.48 (m, 2H, CH2Br),
3.25-2.94(m,2H,SCH2),2.12,2.04,2.03(3s,9H,3OAc),1.96(s,3H,NHAc).
(2) products therefrom (1g, 2.1mmol) in (1), Sodium azide (0.55g, 8.4mmol) is taken to be added in reaction bulb, then
Acetone 30mL, water 15mL are added, back flow reaction is overnight, and TLC detection reactions are complete；Rotation removes the acetone in reaction system, adds two
Chloromethanes and water extraction, wash, dry, rotation obtains white solid 0.81g, yield except organic solvent rear pillar chromatographic purifying
89.0%.
Structural identification data is as follows：1H NMR(300MHz,CDCl3) δ 5.87 (d, J=9.3Hz, 1H, NH), 5.27-5.16
(m, 1H, H-3), 5.08 (t, J=9.7Hz, 1H, H-4), 4.70 (d, J=10.4Hz, 1H, H-1), 4.22 (dd, J=12.4,
5.0Hz, 1H, H-6b), 4.15 (dd, J=9.9,2.4Hz, 1H, H-6a), 4.12-4.02 (m, 1H, H-2), 3.74 (ddd, J=
9.9,5.0,2.6Hz, 1H, H-5), 3.52 (dt, J=12.0,6.8Hz, 2H, CH2N3),3.04-2.74(m,2H,SCH2),
2.09,2.04,2.03(3s,9H,3OAc),1.96(s,3H,NHAc).
(3) products therefrom (0.50g, 1.2mmol) in (2), compound (0.28g, 1.2mmol) shown in Formula X is taken to be added to
In reaction bulb, tetrahydrofuran 20mL, water 10mL dissolving are added, adds cupric sulfate pentahydrate (25mg, 0.1mmol), sodium ascorbate
(30mg, 0.15mmol), overnight, TLC detection reactions are complete for room temperature reaction；Rotation removes reaction dissolvent, and column chromatography purifies to obtain white
Solid 0.67g, yield 83.8%.
Structural identification data is as follows：1H NMR(300MHz,DMSO)δ8.50–8.37(m,4H,ArH),8.04(s,1H,
), ArH 7.99 (d, J=9.5Hz, 1H, NHAc), 7.88-7.79 (m, 2H, ArH), 5.29 (s, 2H, ArCH2Ar),5.06(t,J
=9.7Hz, 1H, H-3), 4.88 (t, J=9.7Hz, 1H, H-4), 4.76 (d, J=10.4Hz, 1H, H-1), 4.53 (t, J=
6.9Hz,2H,CH2),4.20–3.99(m,2H,H-6b,H-6a),3.98–3.83(m,2H,H-2,H-5),3.23–2.89(m,
2H,SCH2),1.98,1.93,1.91(3s,9H,3OAc),1.71(s,3H,NAc).
(4) take products therefrom (0.50g, 0.75mmol) in (3) to be added in methanol 20mL, add the methanol of 4mL saturations
Ammonia solution, reacts at room temperature 24h, and TLC detection reactions are complete；Concentration, column chromatography purify to obtain white solid 0.38g, yield
93.6%.
Structural identification data is as follows：1H NMR(300MHz,DMSO)δ8.46–8.34(m,4H,ArH),8.04(s,1H,
), ArH 7.85-7.76 (m, 2H, ArH), 7.72 (d, J=9.3Hz, 1H, NHAc), 5.27 (s, 2H, ArCH2Ar),5.07(d,J
=4.8Hz, 1H, OH), 5.03 (d, J=5.3Hz, 1H, OH), 4.63-4.49 (m, 3H, H-3, H-4, OH), 4.41 (d, J=
10.3Hz, 1H, H-1), 3.69 (dd, J=10.8,5.5Hz, 1H, H-6b), 3.54 (dd, J=19.5,9.8Hz, 1H, H-2),
3.48–3.43(m,1H,H-6a),3.34–3.22(m,1H,H-5),3.21–3.06(m,3H,CH2,SCH2), 2.97 (dd, J=
14.0,7.0Hz,1H,SCH2),1.76(s,3H,NAc).13C NMR(75MHz,DMSO)δ169.28,163.20,142.79,
134.58,131.35,130.98,127.41,127.29,123.86,121.90,84.60,81.25,75.53,70.58,
61.34,54.46,49.84,35.33,29.91,23.08.
Other formulas are that CAUS-B series compound is prepared according to the method described above.Their compound number, c
3 are shown in Table for corresponding carbon atom number, physicochemical data, the proton nmr spectra of Structural Identification, mass spectrometric data are shown in Table 4.
The formula of table 3 is the numbering and physicochemical data of CAUS-B series compounds
The CAUS-B episode compounds proton nmr spectra of table 4, mass spectrometric data
(Pos：The positive ion mode of mass spectroscopy；Neg：The negative ion mode of mass spectroscopy)
Embodiment 3
Compound CAUS-C preparation
Compound CAUS-C-1, d=2, prepare, comprise the following steps that according to following reaction scheme
(1) in 250mL round-bottomed flasks, compound (2.0g, 5.5mmol), the chloro- N- propargyls of 2- shown in Formula VIII are added
Acetamide (0.72g, 5.5mmol), potassium carbonate (0.91g, 6.6mmol), acetone 50mL, water 25mL, room temperature reaction are stayed overnight, TLC
Detection reaction is complete；Rotation removes reaction dissolvent, adds dichloromethane, water extraction, washes, dry, rotation removes organic solvent, and column chromatography is pure
Change obtains white solid 2.2g, yield 88.0%.
Structural identification data is as follows：1H NMR (300MHz, DMSO) δ 8.36 (t, J=5.3Hz, 1H, NH), 8.01 (d, J
=9.5Hz, 1H, NH), 5.06 (t, J=9.7Hz, 1H, H-3), 4.87 (t, J=9.7Hz, 1H, H-4), 4.74 (d, J=
10.4Hz, 1H, H-1), 4.17 (dd, J=12.2,4.7Hz, 1H, H-6b), 4.10-3.89 (m, 2H, H-6a, H-2), 3.85
(dd, J=5.3,2.4Hz, 2H, ≡ CCH2),3.83–3.75(m,1H,H-5),3.41–3.18(m,2H,SCH2),3.11(t,J
=2.5Hz, 1H, ≡ CH), 2.02,1.96,1.91,1.77 (3s, 9H, 3OAc), 1.77 (s, 3H, NHAc)
(2) products therefrom (1.0g, 2.2mmol) in (1), compound (0.59g, 2.2mmol) shown in Formula X V is taken to be added to
In reaction bulb, tetrahydrofuran 40mL, water 20mL dissolving are added, adds cupric sulfate pentahydrate (50mg, 0.2mmol), sodium ascorbate
(60mg, 0.30mmol), overnight, TLC detection reactions are complete for room temperature reaction；Rotation removes reaction dissolvent, and column chromatography purifies to obtain white
Solid 1.3g, yield 81.3%.
Structural identification data is as follows：1H NMR(300MHz,CDCl3) δ 8.51-8.29 (m, 5H, ArH), 8.03 (d, J=
8.7Hz, 2H, 2NH), 7.89-7.73 (m, 2H, ArH), 5.08 (t, J=9.7Hz, 1H, H-3), 4.88 (t, J=9.7Hz, 1H,
), H-4 4.78 (d, J=10.4Hz, 1H, H-1), 4.67 (t, J=5.9Hz, 2H, CH2), 4.45 (t, J=5.9Hz, 2H, CH2),
4.37–4.21(m,2H,CH2), 4.15 (dd, J=12.5,4.6Hz, 1H, H-6b), 4.01-3.84 (m, 2H, H-6a, H-2),
3.84–3.74(m,1H,H-5),3.35–3.20(m,2H,CH2),1.99,1.96,1.91(3s,9H,3OAc),1.77(s,3H,
NAc).
(3) take products therefrom (0.50g, 0.69mmol) in (2) to be added in methanol 20mL, add the methanol of 4mL saturations
Ammonia solution, reacts at room temperature 48h, and TLC detection reactions are complete；Concentration, column chromatography purify to obtain white solid 0.37g, yield
90.2%.
Structural identification data is as follows：1H NMR(300MHz,DMSO)δ8.47–8.31(m,5H,4ArH,CONHCH2),8.00
(s,1H,ArH),7.89–7.76(m,3H,2ArH,NH), Ac 4.66 (t, J=5.6Hz, 2H, CH2),4.54–4.38(m,3H,
H-1, H-3, H-4), 4.26 (d, J=5.0Hz, 2H, CH2), 3.68 (d, J=11.4Hz, 1H, H-6b), 3.56 (dd, J=
18.9,9.3Hz, 1H, H-2), 3.44 (d, J=9.1Hz, 1H, H-6a), 3.38-3.20 (m, 3H, H-5, CH2),3.14–3.07
(m,2H,CH2),1.80(s,3H,NAc).13C NMR(75MHz,DMSO)δ169.40,169.10,163.36,144.68,
134.55,131.34,130.92,127.45,127.28,123.54,121.79,83.97,81.23,75.42,70.66,
61.38,54.58,48.74,47.11,34.58,33.00,23.11.
Other formulas are that CAUS-C series compound is prepared according to the method described above.Their compound number, d
5 are shown in Table for corresponding carbon atom number, physicochemical data, the proton nmr spectra of Structural Identification, mass spectrometric data are shown in Table 6.
The formula of table 5 is the numbering and physicochemical data of CAUS-C series compounds
The CAUS-C episode compounds proton nmr spectra of table 6, mass spectrometric data
(Pos：The positive ion mode of mass spectroscopy；Neg：The negative ion mode of mass spectroscopy)
Embodiment 4
Test of the compound provided by the invention to GH20 β-N-acetylmuramic glycanchydrolase (hsHex) inhibitory activity of people：
Enzyme：HsHex is that the present inventor is prepared by recombinant expression method.
Substrate：4-methyl umbelliferone β-N-Acetyl-D-glucosamine (4-methylumbelliferyl N-acetyl- β-D-
Glucosaminide, MU-GlcNAc), purchased from Sigma-Aldrich companies.
Enzyme activity determination method：By enzyme with surveying buffer solution (Britton-Robinson buffer solutions, pH 4.0) living in 96 orifice plates
It is 90 μ L inside to mix to final volume, adds 10 μ L, 500 μM of MU-GlcNAc initial actions, 30 DEG C of incubation 20min, adds 100 μ L
0.5M sodium carbonate terminating reactions, measure fluorescence (366nm is excited, 445nm transmittings).
Compound inhibitory activity assay method：By the inhibitor of enzyme and various concentrations (to be made in the embodiment of the present invention 1 and 2
Standby obtained compound, specific as shown in table 7) in incubation at room temperature 10min, method described above measure enzyme activity.Compound is to people
HsHex inhibitory activity is as shown in table 7 below.
Inhibitory activity of the compounds of this invention of table 7 to hsHex
It was found from the inhibitory activity test result of table 7, the compounds of this invention has inhibitory activity, wherein chemical combination to hsHex
Thing CAUS-C-5 shows good inhibition, in 20 μM of inhibitory activity more than 50%.
Embodiment 5
Test of the compound provided by the invention to GH84 β-N-acetylmuramic glycanchydrolase (hOGA) inhibitory activity of people：
Enzyme：HOGA is that the present inventor is prepared by recombinant expression method, and specific method is referring to document " Synthesis of
NAM-thiazoline derivatives as novel O-GlcNAcase inhibitors”。
Substrate：4-methyl umbelliferone β-N-Acetyl-D-glucosamine (4-methylumbelliferyl N-acetyl- β-D-
Glucosaminide, MU-GlcNAc), purchased from Sigma-Aldrich companies.
Enzyme activity determination method：By enzyme with surveying buffer solution (Britton-Robinson buffer solutions, pH 6.0) living in 96 orifice plates
It is 90 μ L inside to mix to final volume, adds 10 μ L, 500 μM of MU-GlcNAc initial actions, 30 DEG C of incubation 20min, adds 100 μ L
0.5M sodium carbonate terminating reactions, measure fluorescence (366nm is excited, 445nm transmittings).
Compound inhibitory activity assay method：By the inhibitor of enzyme and various concentrations (to be made in the embodiment of the present invention 1 and 2
Standby obtained compound, specific as shown in table 8) in incubation at room temperature 10min, method described above measure enzyme activity.Compound is to people
HOGA inhibitory activity is as shown in table 8 below.
Inhibitory activity of the compounds of this invention of table 8 to hOGA
It was found from the inhibitory activity test result of table 8, the compounds of this invention shows inhibitory activity, partization to hOGA
Compound such as CAUS-A-3 has efficient inhibition, in 20 μM of inhibitory activity more than 80%.
Claims (9)
1. a kind of glycosyl naphthalimide derivative or its pharmaceutically acceptable salt, it is characterised in that：The glycosyl naphthalimide
Shown in derivative CAUS structural formula such as formula (I)：
Wherein m and n is respectively 0~6 integer, and R bases are imide, triazolyl, acid imide and triazolyl, such as formula (II), formula
(III), shown in formula (IV)：
In formula, a 1,2；B is 0,2,3,4；C is 1,2,3,4,5,6；D is 2,3,4,5,6.
2. the preparation method of compound shown in formula (II) as described in the appended claim 1, it is characterised in that：Comprise the following steps：
1) compound shown in Formula V and reagent amine are reacted to obtain compound shown in Formula IV；Reagent V is 1 with reagent amine mol ratio:
1.5~2.5；
2) compound shown in Formula IV and chloro acyl chloride reaction are obtained into compound shown in Formula VII；Compound shown in VI and chloro acyl
Cl molar ratio is 1：1~2；
3) compound shown in compound shown in Formula VII and Formula VIII is reacted to obtain compound shown in Formula IX；Compound shown in VII
It is 1 with compound mole ratio shown in Formula VIII:1~2；
4) compound shown in Formula IX is reacted in methanolic ammonia solution and obtains compound shown in Formula II；
3. preparation method according to claim 2, it is characterised in that：The method for preparing compound shown in the formula (II)
In：
In step 1), for the reagent used for absolute ethyl alcohol, the time of the reaction is 16~24h；In step 2), the reagent of use
For at least one of dichloromethane, triethylamine, acyl chlorides G；The temperature of the reaction is room temperature, and the time is 4~6h；Step 3)
In, the reagent used is at least one of potassium carbonate, acetone, dichloromethane；The temperature of the reaction is room temperature, the time 16
~24h；In step 4), the temperature of the reaction is room temperature, and the time is 35~45h；In each step, in addition to extract, dry,
The step of rotary evaporation, recrystallization and column chromatography.
4. the preparation method of compound shown in formula (III) as described in the appended claim 1, it is characterised in that：Comprise the following steps：
1) reagent V and reagent propargylamine are reacted to obtain compound shown in Formula X；Reagent V is 1 with reagent propargylamine mol ratio:1.5
~2.5；
2) compound shown in Formula VIII and dihalo thing are reacted to obtain compound shown in Formula X I；Compound shown in Formula VIII and two
Halides mol ratio is 1:6~10；
3) compound shown in Formula X I and Sodium azide are reacted to obtain compound shown in Formula X II；Compound and Sodium azide shown in Formula X I
Mol ratio is 1:3~5；
4) compound shown in compound shown in Formula X II and Formula X is reacted to obtain compound shown in Formula X III；Chemical combination shown in Formula X II
Thing is 1 with compound mole ratio shown in Formula X:1~2；
5) compound shown in Formula X III is reacted in methanolic ammonia solution and obtains compound shown in formula III；
R=Cl, Br in Formula X I.
5. preparation method according to claim 4, it is characterised in that：The method for preparing compound shown in the formula (III)
In：
In step 1), for the reagent used for dichloromethane, the reaction temperature is room temperature, and the time is 16~24h；In step 2),
The reagent used is Sodium azide, acetone and dichloromethane；The time of the reaction is 20~30h；In step 3), the reagent of use
For at least one of potassium carbonate, acetone, dichloromethane, the temperature of the reaction is room temperature, and the time is 16~24h；Step 4)
In, for the reagent used at least one of THF, sodium ascorbate and copper sulphate, the temperature of the reaction is room temperature, and the time is
16~24h；In step 5), the temperature of the reaction is room temperature, and the time is 35~45h；In each step, in addition to extract, be dry
The step of dry, rotary evaporation, recrystallization and column chromatography.
6. the preparation method of compound shown in formula (IV) as described in the appended claim 1, it is characterised in that：Comprise the following steps：
1) will react to obtain compound shown in Formula X V again with compound shown in Formula VIII after chloracetyl chloride and propargylamine reaction；Chloroethene
Acyl chlorides is 1 with propargylamine mol ratio:1~2, its product is 1 with compound mole ratio shown in Formula VIII:1~2；
2) compound shown in compound shown in Formula X V and Formula X IV is reacted to obtain compound shown in Formula X VI；Compound shown in Formula X V
It is 1 with compound mole ratio shown in Formula X IV:1~2；
3) by compound shown in Formula X VI in methanolic ammonia solution compound shown in reaction equation IV.
7. preparation method according to claim 6, it is characterised in that：The method for preparing compound shown in the formula (IV)
In：
In step 1), for the reagent used at least one of potassium carbonate, acetone and dichloromethane, the reaction temperature is room
Temperature, time are 16~24h；In step 2), the reagent used is described at least one of THF, sodium ascorbate and copper sulphate
The temperature of reaction is room temperature, and the time is 16~24h；In step 3), the temperature of the reaction is room temperature, and the time is 35~45h；Respectively
In individual step, in addition to the step of extraction, drying, rotary evaporation, recrystallization and column chromatography.
A kind of 8. people β-N-acetylmuramic glycanchydrolase inhibitor, it is characterised in that：The active component of the inhibitor is claim 1 institute
State glycosyl naphthalimide derivative or its pharmaceutically acceptable salt.
9. prepared by the glycosyl naphthalimide derivative or its pharmaceutically acceptable salt as described in any one in claim 1
The application in medicine for treating the disease related to mankind β-N-acetylmuramic glycanchydrolase.
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| US20080182805A1 (en) * | 2007-01-18 | 2008-07-31 | The Gov. Of The U.S.A., As Represented By The Secretary, Dept Of Health And Human Services | O-GlcNAcase-specific inhibitor and substrate engineered by the extension of the N-Acetyl moiety |
| CN102911117A (en) * | 2012-11-01 | 2013-02-06 | 华东理工大学 | Naphthylamine derivative and purpose thereof |
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| CN114524854A (en) * | 2022-02-25 | 2022-05-24 | 中国农业大学 | Glycosyl aromatic cyclic carbon glycoside derivative and preparation method and application thereof |
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