CN103058972B - Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof - Google Patents

Phenyl C-glucoside derivatives containing cyclohexane structure as well as preparation method and application thereof Download PDF

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CN103058972B
CN103058972B CN201310016846.XA CN201310016846A CN103058972B CN 103058972 B CN103058972 B CN 103058972B CN 201310016846 A CN201310016846 A CN 201310016846A CN 103058972 B CN103058972 B CN 103058972B
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meoh
general formula
naoh
etoh
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CN103058972A (en
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赵桂龙
王玉丽
魏群超
徐为人
邹美香
汤立达
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention belongs to the technical field of medicines, particularly relates to the field of a medicine associated with diabetes mellitus, and more particularly relates to type II sodium galactose transporter (SGLT2) inhibitors of a phenyl C-glucoside structure containing a cyclohexane structure and a preparation method thereof as well as a medicinal composition containing medicines and application of the medicines on preparation of diabetes drugs, wherein R<1> is selected from H, F, Cl, Br, I, N3, NH2, SH, OPh, SPh and hydroxymethyl triazole; R<2> is selected from C1-C5 alkyl, CF3 and OCHF2; and R<3> is selected from C1-C5 alkyl.

Description

One class is containing phenyl C-glucoside derivative, the Preparation Method And The Use of cyclohexane structure
Technical field
The invention belongs to medical technical field, be specifically related to the pharmaceutical field relevant to diabetes, more specifically, the present invention relates to 2 type sodium glucose of the medicative phenyl C-glucoside structure containing cyclohexane structure of diabetes cotransport son (SGLT2) inhibitor and preparation method thereof and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject nearly 1.7 hundred million left and right at present, wherein approximately most is II type (being non-insulin-depending type) diabetic subject.At present mainly contain N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at the antidiabetic medicine of clinical use, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, some drugs still has the problems such as body weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes of discovered in recent years.SGLT2 is mainly distributed in kidney proximal tubule, and its effect is the glucose absorbing in urine, and returns it in blood, and that therefore suppresses SGLT2 just can reduce the concentration of glucose in blood, and this method has reduced glucose level from the past different approach.In the time that SGLT2 function is obstructed, in urine, will secrete more glucose, this will contribute to diabetic subject to keep correct glucose level.Because SGLT2 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The compound that Chinese patent CN200610093189.9 discloses time array structure is as SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH 2) n, n=0-3.
The compound that Chinese patent CN200380110040.1 discloses time array structure is as SGLT2 inhibitor:
Wherein, A is covalent linkage, O, S, NH, (CH 2) n, n=1-3.
The compound that Chinese patent CN200480006761.2 discloses time array structure is as SGLT2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
The compound that CN102146066 discloses the following structure containing saturated rings is as SGLT2 inhibitor:
Wherein, R 1, R 2independently be selected from H, F, Cl, Br, I, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2f, C 1-C 3alkyl, containing the cycloalkyl of 3-5 carbon atom, wherein R 3and R 4independently be selected from C 1-C 3alkyl, abovementioned alkyl or cycloalkyl all can be replaced by one or more F, Cl atom; The definition of X and Y is selected from following several situation: (1) X=Y=carbon atom; (2) X=Y=nitrogen-atoms; (3) X=nitrogen-atoms, Y=Sauerstoffatom; (4) X=nitrogen-atoms, Y=carbon atom.
US20060025349 discloses the following compound containing saturated rings structure as SGLT2 inhibitor:
Wherein, Cy represents five yuan and hexa-atomic saturated and cholesterol ring.
The invention discloses a class containing the phenyl C-glucoside analog derivative of cyclohexane structure as novel SGLT2 inhibitor, these compounds can be used for the particularly medicine of diabetes B of preparation treatment diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, provide one to there is 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 acceptable prodrug ester pharmaceutically thereof.
A further object of the present invention be to provide the compound that contains general formula I and pharmaceutically acceptable prodrug ester as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect diabetes in treatment.
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 1be selected from H, F, Cl, Br, I, N 3, NH 2, SH, OPh, SPh and methylol triazole;
R 2be selected from C 1-C 5alkyl, CF 3and OCHF 2;
R 3be selected from C 1-C 5alkyl.
Preferably following general formula (I) compound,
Wherein,
R 1be selected from H, F, N 3, NH 2, SH, OPh and SPh;
R 2be selected from C 1-C 3alkyl, CF 3and OCF 2;
R 3be selected from C 1-C 3alkyl.
More preferably the compound of general formula (I) has following structure,
General formula of the present invention (I) compound is synthetic by following route:
Compound 1 use TBDMSCl, TBDPSCl, TIPSCl protection obtain compound 2, PG 1be selected from TBDMS (t-Butyldimethylsilyl), TBDPS (tert-butyl diphenyl is silica-based) and TIPS (triisopropylsilyl); Compound 2 acetylizes are converted into compound 3, and acetylation reagent is selected from diacetyl oxide and Acetyl Chloride 98Min.; Compound 3 is sloughed protecting group PG 1obtain compound 4, agents useful for same comprises tetra-n-butyl Neutral ammonium fluoride, hydrogen fluoride pyridine and acetic acid; Compound 4 use methylsulfonyl chlorides, trifluoromethanesulfchloride chloride and Tosyl chloride are converted into compound 5, wherein PG 2be selected from methylsulfonyl, trifyl and p-toluenesulfonyl; Compound 5 is converted into compound 6, and agents useful for same is NaN 3; Compound 6 deacetylates obtain Compound I-A, and agents useful for same is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H2O, (3) NaOH/EtOH/H2O, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o and (6) K 2cO 3/ MeOH; I-A reduction is converted into I-B, and reductive condition is selected from: (1) H 2, Pd/C, (2) Zn/NH 4cl and (3) PPh 3; Wherein, R 2and R 3definition described above, I-A and I-B belong to the compound with general formula I structure of the present invention.
Compound 4 uses halide reagent processing, obtains compound 7, and wherein X is selected from F, Cl, Br and I, and halide reagent is selected from DAST (diethylin sulfur trifluoride), PCl 3, PCl 5, PBr 3, PBr 5and I 2/ PPh 3/ imidazoles; Compound 7 deacetylates are converted into Compound I-C, and agents useful for same is MeONa/MeOH; Wherein, R 2and R 3definition described above, I-C belongs to the compound with general formula I structure of the present invention.
Compound 7-1 (class in compound 7, i.e. X=I) uses the de-iodine of reductive agent, obtains compound 8, and reductive agent is selected from: (1) n-Bu 3snH/AIBN, (2) H 2, Pd/C and (3) H 2, Pd (OH) 2; Compound 8 deacetylates obtain Compound I-D, and agents useful for same is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o and (6) K 2cO 3/ MeOH; Wherein, R 2and R 3definition described above, I-D belongs to the compound with general formula I structure of the present invention.
Compound 4 reacts with AcSH, PhSH and PhOH respectively under Mitsunobu condition, obtains compound 9, and the reaction conditions of Mitsunobu is PPh 3and DEAD (ethyl azodicaboxylate) reacts or PPh in THF 3with DIAD (azo-2-carboxylic acid's di-isopropyl) reacts in THF, wherein Y is selected from AcS, PhS and PhO; Compound 9 deacetylates obtain Compound I-E, and condition used is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H2O, (3) NaOH/EtOH/H2O, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o and (6) K 2cO 3/ MeOH, wherein Z is selected from SH, PhS and PhO; Wherein, R 2and R 3definition described above, I-E belongs to the compound with general formula I structure of the present invention.
Compound 6 reacts under Cu (I) catalysis with propargyl alcohol, obtains compound 10; Compound 10 deacetylates obtain Compound I-F, and condition used is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o and (6) K 2cO 3/ MeOH; Wherein, R 2and R 3definition described above, I-F belongs to the compound with general formula I structure of the present invention.
The pharmaceutically acceptable prodrug ester of formula I compound of the present invention, comprises the ester that any one or more hydroxyls in molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
Formula I compound of the present invention, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention, can accept auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle in described pharmacy or bromatology.
Composition of the present invention, can accept auxiliary material in described pharmacy or bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, calcium carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
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 by glucose in urine modelling verification.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that take for example every day, within the scope of 1mg-1000mg/ people, is divided into once or administration for several times.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, individual reaction to medicine, the severity of symptom etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
embodiment 1
(1S)-6-nitrine-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-1)
A.
4.09g (10mmol) compound 11 and 2.72g (40mmol) imidazoles are dissolved in the DMF that 30mL is dry, the cooling lower stirring of ice-water bath, slowly drips 1.81g (12mmol) TBDMSCl (t butyldimethylsilyl chloride) and is dissolved in the solution that the dry DMF of 2mL makes.After dropwising, reaction mixture at room temperature stirs 5 hours.Reaction mixture is poured in 200mL frozen water, stirs, and with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 12.White foam shape solid. 1HNMR(DMSO-d 6,400MHz),7.06(dd,1H,J=2.0Hz?and8.4Hz),7.01(d,1H,J=1.6Hz),6.83(d,1H,J=8.4Hz),4.87-4.88(m,2H),4.64(d,1H,J=6.0Hz),3.90(d,1H,J=9.2Hz),3.84(d,1H,J=11.2Hz),3.73(s,3H),3.68(dd,1H,J=3.8Hz?and11.4Hz),3.20-3.24(m,3H),3.05-3.11(m,1H),2.37-2.40(m,2H),1.60-1.66(m,4H),1.39-1.41(m,1H),1.22-1.28(m,2H),1.06-1.17(m,3H),0.75-0.95(m,17H),-0.01(s,3H),-0.06(s,3H)。 13C?NMR(DMSO-d 6,100MHz),156.47,131.74,129.46,127.81,126.45,109.57,81.06,80.65,78.50,74.72,69.78,63.13,55.24,39.18,38.13,37.38,36.84,32.79,32.66,32.59,25.78,25.75,19.38,18.00,14.16。
B.
4.18g (8mmol) compound 12 is dissolved in 30mL pyridine, and the cooling lower stirring of ice-water bath, slowly drips 15mL acetic anhydride, then adds 0.3g DMAP (DMAP) again.Reaction mixture at room temperature stirs and spends the night, and is then poured in 200mL frozen water, stirs, and with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 13.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.08(dd,1H,J=1.8and8.2Hz),7.01(d,1H,J=1.6Hz),6.87(d,1H,J=8.4Hz),5.28(t,1H,J=9.4Hz),5.09(t,1H,J=9.8Hz),4.87(t,1H,J=9.6Hz),4.52(d,1H,J=9.6Hz),3.79-3.81(m,1H),3.73(s,3H),3.69-3.72(m,1H),3.63(dd,1H,J=4.2Hz?and11.8Hz),2.32-2.44(m,2H),2.00(s,3H),1.91(s,3H),1.73(s,3H),1.63-1.66(m,2H),1.53-1.56(m,2H),1.39-1.41(m,1H),1.22-1.28(m,2H),1.08-1.11(m,3H),0.77-0.91(m,19H),0.00(s,3H),-0.06(s,3H)。 13C?NMR(DMSO-d 6,100MHz),169.61,168.94,168.35,157.06,129.14,128.38,128.18,125.95,109.97,77.91,77.15,73.94,72.51,68.19,61.71,55.22,39.14,37.84,37.21,36.81,32.62,32.48,25.64,20.40,20.29,20.06,19.38,17.88,14.16。
C.
3.89g (6mmol) compound 13 is dissolved in the aqueous acetic acid of 30mL90%, is warming up to 50 DEG C, stirs 3 hours.After compound of reaction is cooling, be poured in 200mL frozen water, stir, with 50mL × 3 extraction, merge extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 14.White solid.Fusing point 116-117 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.09-7.11(m,1H),6.95(d,1H,J=2.0Hz),6.87(d,1H,J=8.4Hz),5.68(d,1H,J=6.0Hz),5.06(t,1H,J=9.2Hz),4.83(t,1H,J=9.8Hz),4.43(d,1H,J=10.0Hz),4.33-4.37(m,1H),4.03-4.08(m,1H),3.68-3.84(m,4H),3.52-3.58(m,1H),2.38-2.39(m,2H),2.00(s,3H),1.96(s,3H),1.69(s,3H),1.63-1.65(m,2H),1.53(s,2H),1.35-1.40(m,1H),1.21-1.30(m,2H),1.08-1.19(m,3H),0.82-0.94(m,7H)。 13C?NMR(DMSO-d 6,400MHz),170.19,169.68,168.40,157.04,129.58,128.60,128.00,125.97,110.21,78.01,77.35,76.28,72.72,68.02,63.54,55.24,39.16,37.80,37.18,36.83,32.61,32.57,32.53,20.64,20.57,20.51,20.08,19.41,14.18。
D.
2.67g (5mmol) compound 14 and 2.53g (25mmol) triethylamine are dissolved in the methylene dichloride that 20mL is dry, and the cooling lower stirring of ice-water bath slowly drips 0.69g (6mmol) methylsulfonyl chloride.After dropwising, compound of reaction at room temperature stirs 3 hours, is then poured in 100mL frozen water, stirs, and with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 15.White solid. 1H?NMR(DMSO-d 6,400MHz),7.14-7.16(m,1H),7.02(s,1H),6.89(d,1H,J=8.4Hz),5.33(t,1H,J=9.4Hz),5.07(t,1H,J=9.8Hz),5.03(t,1H,J=9.8Hz),4.60(d,1H,J=9.6Hz),4.27-4.29(m,2H),4.12-4.14(m,1H),3.74(s,3H),3.11(s,3H),2.38-2.40(m,2H),2.03(s,3H),1.92(s,3H),1.72(s,3H),1.64(s,2H),1.50-1.56(m,2H),1.41(s,1H),1.23-1.28(m,2H),1.08-1.11(m,3H),0.78-0.91(m,7H)。 13C?NMR(DMSO-d 6,100MHz),169.58,169.32,168.28,157.23,129.64,128.19,127.85,126.15,110.28,78.04,74.18,73.56,72.04,68.38,68.13,55.25,39.16,37.72,37.19,36.81,32.59,20.45,20.25,20.01,19.40,14.18。
E.
1.84g (3mmol) compound 15 and 1.95g (30mmol) NaN 3be dissolved in the DMF that 10mL is dry, 100 DEG C of heating 5 hours.After compound of reaction is slightly cold, be poured in 100mL frozen water, stir, with 50mL × 3 extraction, merge extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 16.White solid.Fusing point 132-134 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.13(dd,1H,J=2.0Hz?and8.4Hz),7.14(d,1H,J=2.0Hz),6.88(d,1H,J=8.4Hz),5.31(t,1H,J=9.4Hz),5.04(t,1H,J=9.6Hz),4.95(t,1H,J=9.6Hz),4.61(d,1H,J=9.6Hz),4.01-4.05(m,1H),3.73(s,3H),3.52(dd,1H,J=2.4Hz?and13.6Hz),3.28-3.33(m,1H),2.37-2.40(m,2H),2.00(s,3H),1.92(s,3H),1.74(s,3H),1.63(s,2H),1.54(s,2H),1.39-1.41(m,1H),1.22-1.28(m,2H),1.08-1.11(m,3H),0.80-0.94(m,7H)。 13CNMR(DMSO-d 6,100MHz),169.56,169.28,168.31,157.14,129.30,128.18,128.03,125.76,110.18,77.85,75.60,73.53,72.32,68.97,55.23,50.19,39.16,37.71,37.23,36.82,32.60,32.53,20.42,20.25,20.04,19.40,14.18。IR(KBr),2107(s),2096(s),1747(s),1612(w),1504(s),1373(s),1251(s),1230(s)。
F.
0.2g sodium Metal 99.5 joins in 10mL anhydrous methanol, stirs, until all sodium dissolves completely under room temperature.Add 0.56g (1mmol) compound 16, under room temperature, continue to stir 3 hours.Add storng-acid cation exchange resin 2g, continue to stir and spend the night.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-1.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.10(dd,1H,J=2.0Hz?and8.4Hz),7.02(d,1H,J=2.0Hz),6.85(d,1H,J=8.4Hz),5.15(d,1H,J=4.8Hz),4.97(d,1H,J=4.8Hz),4.76(d,1H,J=5.6Hz),4.01(d,1H,J=9.6Hz),3.73(s,3H),3.52(dd,1H,J=2.0Hz?and13.2Hz),3.42-3.44(m,1H),3.21-3.37(m,3H),3.11-3.13(m,1H),2.38-2.39(m,2H),1.59-1.66(m,4H),1.40(bs,1H),1.23-1.28(m,2H),1.08-1.11(m,3H),0.74-0.92(m,7H)。 13C?NMR(DMSO-d 6,100MHz),156.57,131.36,129.56,127.84,126.09,109.79,94.81,81.08,78.76,78.06,74.69,70.70,55.29,51.21,39.20,37.97,37.43,36.85,32.66,19.42,14.20。
embodiment 2
(1S)-6-amino-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-2)
0.43g (1mmol) Compound I-1 is dissolved in 5mL methyl alcohol, adds 0.1g 10% Pd/C, stir,
Depressing hydrogenation at Room spends the night.Suction filtration is removed catalyzer, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-2.White foam shape solid, ESI-MS, m/z=430 ([M+Na] +).
embodiment 3
(1S)-6-is fluoro-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-3)
A.
2.67g (5mmol) compound 14 is dissolved in the methylene dichloride that 30mL is dry, stirs, and is cooled to-30 DEG C.Slowly drip 1.61g (10mmol) DAST with syringe.After dropwising, reaction mixture at room temperature stirs 1 hour, with the dilution of 100mL methylene dichloride, with the water washing of cold food salt, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 17.White solid.ESI-MS,m/z=559([M+Na] +)。
B.
0.2g sodium Metal 99.5 joins in 10mL anhydrous methanol, stirs, until all sodium dissolves completely under room temperature.Add 0.54g (1mmol) compound 17, under room temperature, continue to stir 3 hours.Add storng-acid cation exchange resin 2g, continue to stir and spend the night.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-3.White foam shape solid.ESI-MS,m/z=433([M+Na] +)。
embodiment 4
(1S)-6-is chloro-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-4)
According to the step of embodiment 3, with PCl 3replace DAST, obtain Compound I-4.White foam shape solid, ESI-MS, m/z=449 ([M+Na] +).
embodiment 5
(1S)-6-is bromo-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-5)
According to the step of embodiment 3, with PBr 3replace DAST, obtain Compound I-5.White solid, ESI-MS, fusing point 160-161 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.12-7.15(m,1H),6.99(s,1H),6.90(d,1H,J=8.4Hz),5.33(t,1H,J=9.4Hz),5.02(t,1H,J=9.6Hz),4.97(t,1H,J=9.6Hz),4.62(d,1H,J=9.6Hz),4.04-4.07(m,1H),3.70-3.74(m,4H),5.53(dd,1H,J=5.6Hz?and11.2Hz),2.39-2.40(m,2H),2.03(s,3H),1.91(s,3H),1.72(s,3H),1.64(s,2H),1.52-1.57(s,2H),1.41(s,1H),1.23-1.28(m,2H),1.08-1.12(m,3H),0.80-0.95(m,7H)。 13C?NMR(DMSO-d 6,100MHz),169.54,169.22,168.29,157.19,129.54,128.11,128.04,125.96,110.32,77.68,75.01,73.43,72.22,70.30,55.25,39.15,37.71,37.16,36.81,32.93,32.60,32.56,32.51,20.47,20.24,20.01,19.40,14.17。
embodiment 6
(1S)-6-is iodo-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-6)
A.
2.54g (10mmol) iodine is dissolved in the methylene dichloride that 30mL is dry, and the cooling lower stirring of ice-water bath slowly adds 2.62g (10mmol) triphenylphosphine, continues to stir half an hour at this temperature.Slowly add again 2.72g (40mmol) imidazoles, continue to stir half an hour.Add 2.67g (5mmol) compound 14, under room temperature, stir 5 hours.With the dilution of 100mL methylene dichloride, with the water washing of cold food salt, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 20.White solid.Fusing point 161-163 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.14(dd,1H,J=2.0Hz?and8.4Hz),7.00(d,1H,J=2.4Hz),6.90(d,1H,J=8.8Hz),5.34(t,1H,J=9.6Hz),4.90-4.96(m,2H),4.63(d,1H,J=9.6Hz),3.74(s,1H),3.67-3.72(m,1H),3.49(dd,1H,J=2.8Hz?and11.2Hz),3.25(dd,1H,J=6.0Hz?and11.2Hz),2.39-2.41(m,2H),2.03(s,3H),1.91(s,3H),1.73(s,3H),1.63-1.65(m,2H),1.53-1.57(m,2H),1.39-1.41(m,1H),1.21-1.28(m,2H),1.07-1.12(m,3H),0.84-0.95(m,7H)。 13C?NMR(DMSO-d 6,100MHz),169.54,169.22,168.34,157.17,129.50,128.15,128.10,125.89,110.32,77.50,74.54,73.18,72.36,71.85,55.26,39.16,37.68,37.19,36.82,32.62,32.57,20.49,20.25,20.04,19.41,14.19,7.03。
B.
0.2g sodium Metal 99.5 joins in 10mL anhydrous methanol, stirs, until all sodium dissolves completely under room temperature.Add 0.64g (1mmol) compound 20, under room temperature, continue to stir 3 hours.Add storng-acid cation exchange resin 2g, continue to stir and spend the night.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-6.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.11(dd,1H,J=2.0Hz?and8.4Hz),7.02(d,1H,J=2.0Hz),6.87(d,1H,J=8.4Hz),5.16(bs,1H),4.78(bs,2H),4.04(d,1H,J=9.2Hz),3.74(s,3H),3.52(dd,1H,J=2.6Hz?and10.6Hz),3.39(dd,1H,J=5.2Hz?and10.4Hz),3.31(t,1H,J=8.8Hz),3.08-3.15(m,2H),2.95-2.99(m,1H),2.34-2.46(m,2H),1.64-1.67(m,4H),1.41(s,1H),1.21-1.30(m,2H),1.07-1.12(m,3H),0.83-0.97(m,7H)。 13C?NMR(DMSO-d 6,100MHz),156.61,131.54,129.93,127.73,126.09,109.90,80.70,77.54,77.32,74.71,73.63,55.31,39.20,37.94,37.38,36.85,32.70,19.42,14.20,10.61。
embodiment 7
(1S)-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-7)
A.
3.22g (5mmol) compound 20,2.91g (10mmol) n-Bu 3snH and 0.82g (5mmol) AIBN (azo-bis-isobutyl cyanide) is dissolved in the benzene that 30mL is dry, stirs 3 hours, then temperature rising reflux 3 hours in nitrogen atmosphere under room temperature.After reaction mixture is cooling, with the dilution of 200mL methylene dichloride, use the water washing of cold food salt, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 21.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.13(dd,1H,J=2.0Hz?and8.4Hz),6.98(d,1H,J=2.0Hz),6.87(d,1H,J=8.4Hz),5.24(t,1H,J=9.6Hz),4.99(t.1H.J=9.6Hz),4.81(t,1H,J=9.6Hz),4.48(d,1H,J=10.0Hz),3.81(dd,1H,J=6.4Hz?and9.6Hz),3.73(s,3H),2.38-2.40(m,2H),2.03(s,3H),1.92(s,3H),1.70(s,3H),1.64-1.66(m,2H),1.51-1.57(m,2H),1.38-1.45(m,1H),1.23-1.28(m,3H),1.08-1.12(m,6H),0.76-0.91(m,8H)。
B.
0.2g sodium Metal 99.5 joins in 10mL anhydrous methanol, stirs, until all sodium dissolves completely under room temperature.Add 0.52g (1mmol) compound 21, under room temperature, continue to stir 3 hours.Add storng-acid cation exchange resin 2g, continue to stir and spend the night.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-7.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.07(dd,1H,J=2.0Hz?and8.4Hz),6.97(d,1H,J=2.0Hz),6.84(d,1H,J=8.4Hz),4.91(d,1H,J=5.6Hz),4.84(d,1H,J=4.4Hz),4.62(d,1H,J=5.2Hz),3.91(d,1H,J=9.2Hz),3.73(s,3H),3.12-3.28(m,3H),2.89-2.94(m,1H),2.44(dd,1H,J=6.8Hz?and12.8Hz),2.35(dd,1H,J=7.2Hz?and12.8Hz),1.59-1.67(m,4H),1.39(s,1H),1.23-1.29(m,3H),1.07-1.15(m,5H),0.88-0.96(m,7H)。 13C?NMR(DMSO-d 6,100MHz),156.54,131.81,129.98,127.77,126.25,109.89,81.21,78.20,75.64,74.77,55.30,39.19,38.09,37.40,36.85,32.71,32.67,32.61,19.42,18.24,14.19。
embodiment 8
(1S)-1,6-dideoxy-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-6-sulfydryl-D-Glucose (I-8)
A.
2.62g (1mmol) triphenylphosphine dissolved is in the dry THF of 20mL, and the cooling lower stirring of ice-water bath, slowly adds 1.74g (1mmol) DEAD, continues to stir half an hour.Then slowly add 0.76g (1mol) AcSH, continue to stir half an hour.Finally add 3.21g (6mmol) compound 14, under reaction mixture room temperature, stir and spend the night.Compound of reaction is poured in 100mL frozen water, stirs, and with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 22.White solid.Fusing point 116-117 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.09(dd,1H,J=2.0Hz?and8.4Hz),6.95(d,1H,J=2.0Hz),6.88(d,1H,J=8.8Hz),5.28(t,1H,J=9.6Hz),4.91-5.00(m,2H),4.54(d,1H,J=9.6Hz),3.94-3.98(m,1H),3.19(dd,1H,J=3.0Hz?and14.2Hz),3.03(dd,1H,J=6.4Hz?and14.4Hz),2.38-2.40(d,2H,J=6.8Hz),2.31(s,3H),2.03(s,3H),1.91(s,3H),1.64(s,2H),1.51-1.57(m,2H),1.40(s,1H),1.18-1.28(m,3H),1.03-1.12(m,3H),0.75-0.94(m,6H)。 13C?NMR(DMSO-d 6,400MHz),194.26,169.53,169.29,168.28,157.16,129.43,128.12,128.07,125.87,110.27,77.86,75.22,73.43,72.29,70.47,55.24,39.16,37.73,37.17,36.83,32.62,32.56,32.53,30.27,29.67,20.40,20.24,20.01,19.41,14.17。
B.
0.2g sodium Metal 99.5 joins in 10mL anhydrous methanol, stirs, until all sodium dissolves completely under room temperature.Add 0.59g (1mmol) compound 22, under room temperature, continue to stir 3 hours.Add storng-acid cation exchange resin 2g, continue to stir and spend the night.Suction filtration is removed resin, and filtrate is evaporate to dryness on Rotary Evaporators, and resistates is dry on oil pump, obtains product I-8.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.10(dd,1H,J=1.8Hz?and8.2Hz),7.00(d,1H,J=1.6Hz),6.86(d,1H,J=7.6Hz),5.06(d,1H,J=5.2Hz),4.92(d,1H,J=4.0Hz),4.70(d,1H,J=6.0Hz),3.96(d,1H,J=9.6Hz),3.11-3.29(m,4H),2.85-2.91(m,1H),2.56-2.63(m,1H),2.34-2.47(m,2H),2.00(t,1H,J=7.6Hz),1.61-1.67(m,4H),1.38-1.42(m,1H),1.21-1.30(m,2H),1.07-1.18(m,3H),0.76-0.98(m,7H)。 13C?NMR(DMSO-d 6,100MHz),156.61,131.58,129.96,127.77,126.15,109.93,81.02,79.79,78.01,74.66,72.02,55.31,39.19,38.00,37.38,36.85,32.69,26.13,19.42,14.20。
embodiment 9
(1S)-1,6-dideoxy-6-thiophenyl-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-9)
Use the method for embodiment 8, replace AcSH with PhSH, obtain product I-9.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.31(d,2H,J=7.6Hz),7.25(t,2H,J=7.6Hz),7.13(t,1H,J=7.2Hz),7.05(dd,1H,J=1.6Hz?and8.4Hz),6.97(d,1H,J=1.6Hz),6.84(d,1H,J=8.4Hz),5.21(d,1H,J=4.4Hz),4.96(s,1H),4.72(d,1H,J=5.6Hz),3.95(d,1H,J=9.6Hz),3.73(s,3H),3.42-3.45(m,2H),3.22-3.24(m,2H),3.11-3.17(m,1H),3.02(dd,1H,J=8.0Hz?and14.0Hz),2.44(dd,1H,J=6.8Hzand12.8Hz),2.33(dd,1H,J=7.0Hz?and13.0Hz),1.60-1.67(m,4H),1.39(s,1H),1.21-1.30(m,3H),1.07-1.12(m,3H),0.81-0.96(6H)。 13C?NMR(DMSO-d 6,100MHz),156.58,137.46,131.47,129.81,128.78,127.75,127.53,126.15,125.13,109.84,81.19,78.86,78.05,74.67,72.89,55.30,39.19,38.01,37.37,36.84,35.12,32.72,32.67,19.42,14.20。
embodiment 10
(1S)-1-deoxidation-6-O-phenyl-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-10)
Use the method for embodiment 8, replace AcSH with PhOH, obtain product I-10.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.23-7.27(m,2H),7.09(dd,1H,J=2.0Hz?and8.4Hz),6.98(d,1H,J=2.0Hz),6.84-6.93(m,4H),5.18(d,1H,J=4.8Hz),4.98(d,1H,J=4.0Hz),4.72(d,1H,J=5.6Hz),4.25(d,1H,J=10.0Hz),3.98-4.04(m,2H),3.72(s,3H),3.55-3.59(m,1H),3.27-3.32(m,3H),3.15-3.21(m,1H),2.44(dd,1H,J=6.8Hz?and12.8Hz),2.34(dd,1H,J=7.0Hz?and13.0Hz),1.59-1.66(m,4H),1.39(s,1H),1.21-1.28(m,2H),1.06-1.11(m,3H),0.78-0.96(m,7H)。 13C?NMR(DMSO-d 6,100MHz),158.69,156.63,131.51,129.96,129.35,127.83,126.27,120.40,114.47,109.91,81.13,78.57,78.32,74.54,70.34,68.22,55.31,39.18,38.06,37.36,36.83,32.71,32.65,19.41,14.19。
embodiment 11
(1S)-1,6-dideoxy-6-(4-methylol-1,2,3-triazoles-1-yl)-1-[4-methoxyl group-3-(trans-4-n-propyl cyclohexyl) aminomethyl phenyl]-D-Glucose (I-11)
A.
5.60g (10mmol) compound 16 and 0.56g (10mmol) propargyl alcohol are dissolved in 30mL DMF,
Under room temperature, stir.Drip 10 CuSO by 1mL0.5M 4cu (I) solution with the xitix compositions of mixtures of 1mL0.5M.After dropwising, compound of reaction at room temperature continues stirring and spends the night.Compound of reaction is poured in 100mL frozen water, stirs, and with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling 25.White solid.Fusing point: 178-180 DEG C. 1H?NMR(DMSO-d 6,400MHz),7.76(s,1H),7.10(dd,1H,J=1.8Hz?and8.2Hz),6.96(d,1H,J=2.0Hz),6.87(d,1H,J=8.4Hz),5.32(t,1H,J=9.4Hz),5.12(t,1H,J=5.6Hz),4.87-4.95(m,2H),4.46-4.62(m,4H),4.21-4.29(m,2H),3.73(s,3H),2.37-2.40(m,2H),2.04(s,3H),1.90(s,3H),1.72(s,3H),1.63-1.65(m,2H),1.50-1.56(m,2H),1.36-1.39(m,1H),1.23-1.28(m,3H),1.08-1.12(m,3H),0.75-0.92(m,6H)。
B.
3.08g (5mmol) compound 25 is dissolved in 20mL ethanol, under room temperature, stirs, and adds the NaOH solution of 5mL50%, temperature rising reflux half an hour.After compound of reaction is cooling, be poured in 100mL frozen water, concentrated hydrochloric acid is adjusted to pH=5, with 50mL × 3 extraction, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent on Rotary Evaporators, and the resistates column chromatography purification obtaining, obtains sterling I-11.White foam shape solid. 1H?NMR(DMSO-d 6,400MHz),7.71(s,1H),7,04-7.07(m,1H),6.95(s,1H),6.84(d,1H,J=8.4Hz),5.34(d,1H,J=5.2Hz),5.09(t,1H,J=5.6Hz),5.02(d,1H,J=4.8Hz),4.77(d,1H,J=6.0Hz),4.69(d,1H,J=12.0Hz),4.45-4.46(m,2H),4.46(d,2H,J=5.6Hz),3.95(d,1H,J=9.6Hz),3.73(s,3H),3.59-3.62(m,1H),3.03-3.09(m,2H),1.58-1.67(m,4H),1.39(s,1H),1,23-1,29(m,2H),1.09-1.12(m,3H),0.76-0.93(m,7H)。
embodiment 12-19
With reference to the operation steps of embodiment 1 and 6-7, prepare following compounds.
Table 1 embodiment 12-19 compound
embodiment 20
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, in 50-60 DEG C dry, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
embodiment 21
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix softwood processed, sieve, wet granular processed, in 50-60 DEG C dry, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
embodiment 22
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 DEG C, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, to obtain final product.
embodiment 23
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mix, add polyvinylpyrrolidonesolution solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 DEG C, Magnesium Stearate and talcum powder are sieved in advance, then join in above-mentioned particle, encapsulated, to obtain final product.
embodiment 24
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
embodiment 25
In distilled water, first add distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes to dissolve again, and adjust pH is 4.0-5.0, add 0.2 gram of activated carbon, under room temperature, stir 20 minutes, filter filtrate, strength of solution is determined in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes, obtains injection liquid.
embodiment 26
Preparation technology: get water for injection 80ml, after adding main ingredient, N.F,USP MANNITOL, lactose, poloxamer and being stirred to dissolve, the Citric Acid that adds 1mol/L regulates PH to 7.0-9.0, mends and adds water to 100ml.Add 0.5g gac, stir 20 minutes at 30 DEG C, de-charcoal, adopts filtering with microporous membrane degerming, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing lower drying under reduced pressure 12 hours, to sample temperature after room temperature, dry 5 hours again, make white loose block, seal and get final product.
embodiment 27
Preparation technology: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, and 55 DEG C dry, and the whole grain of 12 mesh sieves is measured heavily packaging of bag.
embodiment 28
The high sugar of the high fat of normal SD rats was fed after one month, with the repeatedly abdominal injection modeling of streptozocin low dose (diabetes B model), and blood-sugar content before and after mensuration modeling.After modeling success, modeling rat is measured and body weight random packet (8/group) according to twenty-four-hour urine sugar, be respectively one group of blank group (giving equal-volume 0.5%CMC sodium solution) and some testing compound groups (10mg/kg).Fasting 16 hours before each group rat experiment.Gavage gives after experimental rat testing compound 0.5h, then gavage gives glucose (2g/kg).The urine of 0-12h time period after collection administration, with the urine sugar value (the results are shown in following table 2) of this time period of determination of glucose oxidase.
The urine sugar value of table 2 determination of glucose oxidase 0-12h time period
Can find out from the above results, compound disclosed by the invention has than the control compounds shown in one hurdle, the left side in table and has the effect of better induction glucose in urine.

Claims (12)

1. there is the compound of general formula (I) structure,
Wherein,
R 1be selected from H, F, Cl, Br, I, N 3, NH 2, SH;
R 2=Me;
R 3=n-Pr。
2. the compound with general formula (I) structure according to claim 1,
Wherein,
R 1be selected from H, F, N 3, NH 2, SH;
R 2=Me;
R 3=n-Pr。
3. the compound with general formula (I) structure according to claim 2, is selected from following compounds,
4. synthetic claim 1-2 any one is defined has the Compound I-A of general formula (I) structure and a method of I-B:
Compound 1 hydroxyl protection is obtained to compound 2, wherein PG 1be selected from TBDMS, TBDPS or TIPS; Compound 2 acetylizes are converted into compound 3, and described acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.; Compound 3 is sloughed protecting group PG 1obtain compound 4, described in slough protecting group reagent and comprise tetra-n-butyl Neutral ammonium fluoride, hydrogen fluoride pyridine or acetic acid; Compound 4 is converted into compound 5, wherein PG 2be selected from methylsulfonyl, trifyl or p-toluenesulfonyl; Compound 5 is converted into compound 6, and agents useful for same is NaN 3; Compound 6 deacetylates obtain Compound I-A, and described deacetylate condition is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o or (6) K 2cO 3/ MeOH; I-A reduction is converted into I-B, and described reductive condition is selected from: (1) H 2, Pd/C, (2) Zn/NH 4cl or (3) PPh 3; Wherein, R 2and R 3definition as claimed in claim 1.
5. the method for the synthetic defined Compound I-C with general formula (I) structure of claim 1-2 any one:
Compound 4 uses halide reagent processing, obtains compound 7, and wherein X is selected from F, Cl, Br or I, and described halide reagent is selected from DAST, PCl 3, PCl 5, PBr 3, PBr 5or I 2/ PPh 3/ imidazoles; Compound 7 deacetylates are converted into Compound I-C, and agents useful for same is MeONa/MeOH; Wherein, R 2and R 3definition as claimed in claim 1.
6. the method for the synthetic defined Compound I-D with general formula (I) structure of claim 1-3 any one:
Compound 7-1 uses the de-iodine of reductive agent, obtains compound 8, and described reductive agent is selected from: (1) n-Bu 3snH/AIBN, (2) H 2, Pd/C or (3) H 2, Pd (OH) 2; Compound 8 deacetylates obtain Compound I-D, and agents useful for same is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o or (6) K 2cO 3/ MeOH; Wherein, R 2and R 3definition as claimed in claim 1.
7. the method for the synthetic defined Compound I-E with general formula (I) structure of claim 1-2 any one:
Compound 4 reacts with AcSH, PhSH or PhOH under Mitsunobu condition, obtains compound 9, and the reaction conditions of described Mitsunobu is selected from: (1) PPh 3/ DEAD/THF or (2) PPh 3/ DIAD/THF, wherein Y is selected from AcS, PhS or PhO; Compound 9 deacetylates obtain Compound I-E, and condition used is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o or (6) K 2cO 3/ MeOH, wherein Z is selected from SH, PhS or PhO; R 2and R 3definition as claimed in claim 1.
8. the method for the synthetic defined Compound I-F with general formula (I) structure of claim 1-2 any one:
Compound 6 reacts under Cu (I) catalysis with propargyl alcohol, obtains compound 10; Compound 10 deacetylates obtain Compound I-F, and condition used is selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H 2o, (3) NaOH/EtOH/H 2o, (4) KOH/MeOH/H 2o, (5) KOH/EtOH/H 2o or (6) K 2cO 3/ MeOH; Wherein, R 2and R 3definition as claimed in claim 1.
9. the application of the defined compound with general formula (I) structure of one of claim 1-3 aspect preparation treatment diabetes medicament.
10. a pharmaceutical composition, the general formula that contains one of claim 1-3 (I) compound, and suitable carrier or vehicle.
11. pharmaceutical compositions claimed in claim 10, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
Pharmaceutical composition described in 12. claims 11, described solid orally ingestible comprises: dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule; Described liquid oral medicine is oral solution; Described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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CN104761523B (en) * 2014-01-06 2017-03-15 天津药物研究院有限公司 Phenyl C glucoside derivatives, Preparation Method And The Use containing 3 oxo glucose structures
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