CN104497069A - Amido phenyl S-glucoside derivative, preparation method and use thereof - Google Patents
Amido phenyl S-glucoside derivative, preparation method and use thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000003368 amide group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 43
- 239000011734 sodium Substances 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229940002612 prodrug Drugs 0.000 claims description 5
- 239000000651 prodrug Substances 0.000 claims description 5
- -1 sodium alkoxide Chemical class 0.000 claims description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000006196 deacetylation Effects 0.000 claims description 2
- 238000003381 deacetylation reaction Methods 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 235000001727 glucose Nutrition 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000003729 cation exchange resin Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 2
- 0 CSC(*)=C(C#N)C#N Chemical compound CSC(*)=C(C#N)C#N 0.000 description 2
- 241000699802 Cricetulus griseus Species 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 229940126902 Phlorizin Drugs 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Chemical class 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical class CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- IOUVKUPGCMBWBT-UHFFFAOYSA-N phloridzosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-UHFFFAOYSA-N 0.000 description 1
- IOUVKUPGCMBWBT-GHRYLNIYSA-N phlorizin Chemical compound O[C@@H]1[C@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-GHRYLNIYSA-N 0.000 description 1
- 235000019139 phlorizin Nutrition 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- 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
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the medicine field related to the diabetes. Specifically, the sodium-glucose co-transporter-2 (SGLT2) inhibitor of the amido phenyl S-glucoside structure, the preparation method and the application thereof for preparing the diabetes drug are provided. R is amido.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes B.Specifically, the present invention relates to 2 type sodium dependent glucose transhipment (SGLT2) inhibitor, the Preparation method and uses to the medicative class aminocarbonyl phenyl S-glucoside structure of diabetes B.
Background technology
Whole world diabetic subject presents the trend increased gradually, and wherein about the overwhelming majority is diabetes B patient.Sulfonylurea, N1,N1-Dimethylbiguanide class, thiazolidinediones, alpha-glucosidase inhibitor class, dipeptidyl peptidase-iv inhibitor class and trypsin class medicine is mainly contained at present at the antidiabetic medicine of Clinical practice.These medicines have good therapeutic action, but long-term treatment exists comparatively severe side effect; And owing to there is resistance, in some cases in time drug combination be all difficult to the blood sugar controlling patient.
2 type sodium dependent glucoses transhipment (SGLT2) are the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in renal proximal tubules, and its effect absorbs the glucose in urine, and returns it in blood, therefore suppresses that SGLT2's just can reduce the concentration of glucose in blood.When SGLT2 function is suppressed, more glucose will be secreted from urine, this glucose level that will contribute to diabetic subject and keep correct.
Chinese patent CN200610093189.9 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH
2)
n, n=0-3.
Chinese patent CN200380110040.1 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, A is covalent linkage, O, S, NH, (CH
2)
n, n=1-3.
The invention discloses a class amido benzene S-glucoside analog derivative as novel SGLT2 inhibitor, these compounds can be used for the medicine preparing treatment diabetes particularly diabetes B.
Summary of the invention
An object of the present invention is the shortcoming and defect overcoming prior art, provide one to have excellent activity, there is the compound of general formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable prodrug ester thereof.Another object of the present invention is to provide the compound containing general formula I and and is treating the application in diabetes.Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R is amido.
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention is synthesized by following route:
Compound II per is according to literature method synthesis (SCI, 1996,17,236).Compound II per and compound III are obtained by reacting IV; Compound IV and V are obtained by reacting VI in the presence of a base; VI deacetylate obtains I; Described alkali is selected from various mineral alkali and organic bases; The reagent of described deacetylation is selected from NH
3, mineral alkali and sodium alkoxide; The definition of R as previously mentioned.
The pharmaceutically acceptable prodrug ester of formula I of the present invention, comprises the ester that any one or more hydroxyl in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. are formed.
Compound of Formula I of the present invention has the restraining effect of SGLT2, can be used as the medicine of effective constituent for the preparation of diabetes aspect.The activity of compound of Formula I of the present invention is verified by receptor binding assays.Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-700mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
The preparation of embodiment 1 I-1
3.41g (20mmol) Compound II per and 2.80g (20mmol) compound III-1 are dissolved in the toluene of 30mL drying, and under stirring in nitrogen atmosphere, temperature rising reflux spends the night, and TLC shows reaction to be completed.Be poured into after reaction mixture is slightly cold in 200mL frozen water, stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains IV-1, white solid, ESI-MS, m/z=263 [M+H]
+.
2.62g (10mmol) compound IV-1 and 6.17g (15mmol) compound V are dissolved in 30mL chloroform, stir, add 3.18g (30mmol) solid Na
2cO
3, 1mL water and 0.5g benzyl triethyl ammonium bromide, vigorous stirring overnight under room temperature.TLC shows reaction to be completed.Reaction mixture is poured in 200mL frozen water, and stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains VI-1, white solid, ESI-MS, m/z=593 [M+H]
+.
2.96g (5mmol) compound VI-1 is dissolved in the methyl alcohol containing 0.3g MeONa, stirred at ambient temperature 5 hours, and TLC shows reaction to be completed.Add 5g storng-acid cation exchange resin in reaction system, stir until the pH=7 of system.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and residue vacuum is dry, obtains I-1, white solid, ESI-MS, m/z=425 [M+H]
+.
The preparation of embodiment 2 I-2
3.41g (20mmol) Compound II per and 3.08g (20mmol) compound III-2 are dissolved in the toluene of 30mL drying, and under stirring in nitrogen atmosphere, temperature rising reflux spends the night, and TLC shows reaction to be completed.Be poured into after reaction mixture is slightly cold in 200mL frozen water, stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains IV-2, white solid, ESI-MS, m/z=277 [M+H]
+.
2.76g (10mmol) compound IV-2 and 6.17g (15mmol) compound V are dissolved in 30mL chloroform, stir, add 3.18g (30mmol) solid Na
2cO
3, 1mL water and 0.5g benzyl triethyl ammonium bromide, vigorous stirring overnight under room temperature.TLC shows reaction to be completed.Reaction mixture is poured in 200mL frozen water, and stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains VI-2, white solid, ESI-MS, m/z=607 [M+H]
+.
3.03g (5mmol) compound VI-2 is dissolved in the methyl alcohol containing 0.3g MeONa, stirred at ambient temperature 5 hours, and TLC shows reaction to be completed.Add 5g storng-acid cation exchange resin in reaction system, stir until the pH=7 of system.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and residue vacuum is dry, obtains I-2, white solid, ESI-MS, m/z=439 [M+H]
+.
Embodiment 3-6
With reference to embodiment 1,2 operation steps, prepare compound listed in Table.
The preparation of embodiment 7 reference compound
In order to further illustrate the drug effect of the compounds of this invention, this invention describes not yet open and being all the Compound D-1 of the applicant's design.
Its preparation method is as follows:
3.41g (20mmol) Compound II per and 2.50g (20mmol) compound III-7 are dissolved in the toluene of 30mL drying, and under stirring in nitrogen atmosphere, temperature rising reflux spends the night, and TLC shows reaction to be completed.Be poured into after reaction mixture is slightly cold in 200mL frozen water, stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains IV-7, white solid, ESI-MS, m/z=248 [M+H]
+.
2.47g (10mmol) compound IV-7 and 6.17g (15mmol) compound V are dissolved in 30mL chloroform, stir, add 3.18g (30mmol) solid Na
2cO
3, 1mL water and 0.5g benzyl triethyl ammonium bromide, vigorous stirring overnight under room temperature.TLC shows reaction to be completed.Reaction mixture is poured in 200mL frozen water, and stir, 100mL × 3 dichloromethane extraction, brine It, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, resistates column chromatography purification obtains VI-7, white solid, ESI-MS, m/z=578 [M+H]
+.
2.89g (5mmol) compound VI-7 is dissolved in the methyl alcohol containing 0.3g MeONa, stirred at ambient temperature 5 hours, and TLC shows reaction to be completed.Add 5g storng-acid cation exchange resin in reaction system, stir until the pH=7 of system.Suction filtration, filtrate is evaporate to dryness on a rotary evaporator, and residue vacuum is dry, obtains Compound D-1, white solid, ESI-MS, m/z=410 [M+H]
+.
Embodiment 8
The IC that compound of the present invention and related compound suppress SGLT2
50be worth the similar method recorded according to document and measure (Meng, W.et al, J.Med.Chem., 2008,51,1145-1149).
The carrier using the Chinese hamster ovary celI of stably express humanization SGLT2 to analyze as transhipment, uses the substrate that [14C]-α-D-methyl glucoside ([14C]-AMG) analyzes as transhipment.By stably express, the Chinese hamster ovary celI of humanization SGLT2 is inoculated on 96 orifice plates, and 12 hours are hatched at 37 DEG C, every hole by the KRH-Na+ washing lotion of 200 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES and 1mM Tris (pH=7.4)) wash 3 times, then the KRH-Na+ washing lotion containing testing compound or blank is added in every hole, each testing compound arranges 10 concentration, and last each hole adds the washing lotion that 100 μ L contain [14C]-AMG (10 μ Ci/mL).96 orifice plates hatch 1 hour subsequently at 37 DEG C, then every hole adds the ice-cold stop buffer of 100 μ L (containing 120mM NaCl, 4.7mM KCl, 1.2mM MgCl2,2.2mM CaCl2,10mM HEPES, 1mM Tris and 10mM phlorizin (pH=7.4)), 5 times are washed again subsequently, each every hole 100 μ L with this stop buffer.Every Kong Zhongzai adds the ice-cold cytolysate (100mM NaOH) of 20 μ L, then shakes 5 minutes with the speed of 600rpm, and then Microscint 40 liquid adding 80 μ L in every hole dodges liquid, then shakes 5 minutes with the speed of 600rpm.Finally, this 96 orifice plate is at the upper counting of MicroBeta Trilux liquid scintillation counter (PerkinElmer).Response curve use experience four parameter model measures 503nhibiting concentration, is expressed as IC50.Shown in the following list of result.
Part of compounds of the present invention is to the IC of SGLT2
50value
| Compound | IC 50(hSGLT2,nM) |
| I-1 | 11.6 |
| I-2 | 17.2 |
| I-3 | 16.1 |
| I-4 | 24.7 |
| I-5 | 13.8 |
| I-6 | 28.4 |
| Reference compound D-1 | 18.5 |
Above-mentioned IC
50measurement result show, compound of the present invention is strong SGLT2 inhibitor, can be used for prepare treatment diabetes B medicine.
Claims (4)
1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
Wherein, R is amido.
2. the compound of Formula I that defines of claim 1, is selected from following compounds,
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per and compound III are obtained by reacting IV; Compound IV and V are obtained by reacting VI in the presence of a base; VI deacetylate obtains I; Described alkali is selected from various mineral alkali and organic bases; The reagent of described deacetylation is selected from NH
3, mineral alkali, sodium alkoxide; As described in the definition of R is as arbitrary in claim 1-2.
4. the compound of Formula I that defines of one of claim 1-2 and pharmaceutically acceptable salt and the application of prodrug ester in preparation treatment diabetes medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510020837.7A CN104497069A (en) | 2015-01-15 | 2015-01-15 | Amido phenyl S-glucoside derivative, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510020837.7A CN104497069A (en) | 2015-01-15 | 2015-01-15 | Amido phenyl S-glucoside derivative, preparation method and use thereof |
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| Publication Number | Publication Date |
|---|---|
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|---|---|---|---|
| CN201510020837.7A Pending CN104497069A (en) | 2015-01-15 | 2015-01-15 | Amido phenyl S-glucoside derivative, preparation method and use thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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