CN104530149A - Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof - Google Patents

Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof Download PDF

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Publication number
CN104530149A
CN104530149A CN201510019615.3A CN201510019615A CN104530149A CN 104530149 A CN104530149 A CN 104530149A CN 201510019615 A CN201510019615 A CN 201510019615A CN 104530149 A CN104530149 A CN 104530149A
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compound
halogen
preparation
meoh
application
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蔡子洋
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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Foshan Saiweisi Pharmaceutical Technology Co Ltd
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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
    • C07H15/20—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

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

The invention relates to the field of drugs relates to diabetes, in particular to a 2-type sodium dependency glucose transporter (SGTL2) inhibitor containing a halogen-substituted phenyl group double-O-glucoside structure, a preparing method of the inhibitor and an application of the inhibitor to preparation of the diabetes drugs. Please see the formula in the specification, wherein R is selected from a halogen-substituted group.

Description

Halogenophenyl two O-glucoside derivative, Preparation Method And The Use
Technical field
The present invention relates to the pharmaceutical field relevant to diabetes B.Specifically, the present invention relates to medicative 2 type sodium dependent glucose transhipment (SGLT2) inhibitor, preparation method and the purposes in pharmacy containing the two O-glucoside structure of halogenophenyl 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.
Chinese patent CN200480006761.2 discloses the compound of having structure as SGLT2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
The invention discloses a class containing the two O-glucoside analog derivative of halogenophenyl as novel SGLT2 inhibitor, these compounds can be used for preparing the medicine for the treatment of 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 selected from halogenic substituent.
Preferred following general formula (I) compound,
General formula of the present invention (I) compound is synthesized by following route:
Compound II per and III react in the presence of a base and obtain IV, and the ratio of III and II is 2:1-10:1; Compound IV deacetylate obtains I; Described alkali is selected from mineral alkali; Described deacetylated condition is selected from: 1) NH 3/ MeOH; 2) NaOH/MeOH/H 2o; 3) KOH/MeOH/H 2o; 4) MeONa/MeOH.
Wherein, 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-300mg/ 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.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
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.
Embodiment 1
1.44g (10mmol) Compound II per-1 and 8.22g (20mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-1, white solid, ESI-MS, m/z=805 ([M+H] +).
4.02g (5mmol) compound IV-1 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I-1, white solid, ESI-MS, m/z=469 ([M+H] +).
Embodiment 2
1.28g (10mmol) Compound II per-2 and 20.55g (50mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-2, white solid, ESI-MS, m/z=789 ([M+H] +).
3.94g (5mmol) compound IV-2 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I-2, white solid, ESI-MS, m/z=453 ([M+H] +).
Embodiment 3
1.89g (10mmol) Compound II per-3 and 41.11g (100mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-3, white solid, ESI-MS, m/z=850 ([M+H] +).
4.25g (5mmol) compound IV-3 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I-3, white solid, ESI-MS, m/z=514 ([M+H] +).
Embodiment 4
2.35g (10mmol) Compound II per-4 and 12.33g (30mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-4, white solid, ESI-MS, m/z=897 ([M+H] +).
4.98g (5mmol) compound IV-4 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains I-4, white solid, ESI-MS, m/z=561 ([M+H] +).
The preparation of embodiment 5 reference compound D1
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:
1.10g (10mmol) Compound II per-5 and 8.22g (20mmol) compound III are dissolved in 10mL methylene dichloride, stirred at ambient temperature, add the solution configured by 0.8g (20mmol) NaOH and 3mL water, add 0.5g tetra-n-butyl ammonium bromide again, vigorous stirring 48 hours under room temperature.TLC shows reaction to be completed.Compound of reaction pours in 100mL frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, the resistates column chromatography purification obtained after evaporate to dryness on a rotary evaporator, obtains product IV-5, white solid, ESI-MS, m/z=771 ([M+H] +).
3.85g (5mmol) compound IV-5 is dissolved in the 20mlMeOH containing 0.31g (5mmol) MeONa, stirred at ambient temperature 3 hours, and now TLC display reaction completes.Add 3g storng-acid cation exchange resin in the reactive mixture, room temperature for overnight, pH value of solution=7.Suction filtration removing resin, filtrate boils off solvent on a rotary evaporator, and the resistates obtained is dry in vacuum oil pump, obtains D-1, white solid, ESI-MS, m/z=435 ([M+H] +).
The IC that embodiment 6 compound suppresses SGLT2 50
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)
Compound I-1 2.6
Compound I-2 3.2
Compound I-3 5.0
Compound I-4 8.7
Reference compound D-1 10.4
Above-mentioned IC 50measurement result show, compound of the present invention is strong SGLT2 inhibitor.

Claims (4)

1. there is compound and the pharmaceutically acceptable prodrug ester thereof of general formula I,
Wherein, R is selected from halogenic substituent.
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 III react in the presence of a base and obtain IV, and the ratio of III and II is 2:1-10:1; Compound IV deacetylate obtains I; Described alkali is selected from mineral alkali; Described deacetylated condition is selected from: 1) NH 3/ MeOH; 2) NaOH/MeOH/H 2o; 3) KOH/MeOH/H 2o; 4) MeONa/MeOH; Wherein R as arbitrary in claim 1-2 shown in.
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.
CN201510019615.3A 2015-01-14 2015-01-14 Halogen-substituted phenyl group double-O-glucoside derivant, and preparation method and application thereof Pending CN104530149A (en)

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Cited By (1)

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CN106831904A (en) * 2017-01-24 2017-06-13 昆药集团股份有限公司 A kind of compound and preparation method thereof, preparation and application

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CN1802366A (en) * 2003-03-14 2006-07-12 安斯泰来制药有限公司 C-glycoside derivatives and salts thereof
CN100391963C (en) * 2003-01-03 2008-06-04 布里斯托尔-迈尔斯斯奎布公司 Methods of producing C-aryl glucoside SGLT2 inhibitors
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CN104230866A (en) * 2002-05-20 2014-12-24 阿斯利康有限公司 C-aryl glucoside sglt2 inhibitors and method
CN100391963C (en) * 2003-01-03 2008-06-04 布里斯托尔-迈尔斯斯奎布公司 Methods of producing C-aryl glucoside SGLT2 inhibitors
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831904A (en) * 2017-01-24 2017-06-13 昆药集团股份有限公司 A kind of compound and preparation method thereof, preparation and application
CN106831904B (en) * 2017-01-24 2019-09-20 昆药集团股份有限公司 A kind of compound and preparation method thereof, preparation and application

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