CN103058972A - 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 PDFInfo
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- 0 *c1ccc(C(C(C2O)O)OC(CO)C2O)cc1CC1CCICC1 Chemical compound *c1ccc(C(C(C2O)O)OC(CO)C2O)cc1CC1CCICC1 0.000 description 6
- ZNOJKMMBFIMKMM-GMBBYAQNSA-N CCC[C@H]1CC[C@H](Cc2cc([C@@H](C(C3O)O)OC(COc4ccccc4)[C@H]3O)ccc2OC)CC1 Chemical compound CCC[C@H]1CC[C@H](Cc2cc([C@@H](C(C3O)O)OC(COc4ccccc4)[C@H]3O)ccc2OC)CC1 ZNOJKMMBFIMKMM-GMBBYAQNSA-N 0.000 description 1
- KFLMIZDEZOKJTP-WMGUDHAHSA-N COc(c(CC1CCCCC1)c1)ccc1OC(COC(CN)[C@H]1O)C1O Chemical compound COc(c(CC1CCCCC1)c1)ccc1OC(COC(CN)[C@H]1O)C1O KFLMIZDEZOKJTP-WMGUDHAHSA-N 0.000 description 1
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
Technical field
The invention belongs to medical technical field, be specifically related to the pharmaceutical field relevant with diabetes, more specifically, the present invention relates to the medicative 2 type sodium glucose that contain the phenyl C-glucoside structure of 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 is at present nearly about 1.7 hundred million, wherein about most II type (being non-insulin-depending type) diabetic subjects that are.Antidiabetic medicine in clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at present, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, some drugs still have 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 mainly is distributed in the kidney proximal tubule, and its effect is the glucose that absorbs in the urine, and it is turned back in the 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.When the SGLT2 function is obstructed, will secrete more glucose in the urine, this will help the diabetic subject to keep correct glucose level.Because the 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 the 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 the 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 the SGLT2 inhibitor:
Wherein, X is covalent linkage or low-grade alkylidene.
CN102146066 discloses the following compound that contains saturated structure of rings as the 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, contain 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, the Y=Sauerstoffatom; (4) X=nitrogen-atoms, the Y=carbon atom.
US20060025349 discloses the following compound that contains the saturated rings structure as the SGLT2 inhibitor:
Wherein, Cy represents five yuan and hexa-atomic saturated and cholesterol ring.
The invention discloses phenyl C-glucoside analog derivative that a class contains cyclohexane structure as novel SGLT2 inhibitor, these compounds can be used for preparing the particularly medicine of diabetes B for the treatment of diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound of general formula I and pharmaceutically can accept prodrug ester.
Another object of the present invention provides 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 provide the compound that contains general formula I and pharmaceutically the acceptable prodrug ester as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now in conjunction with purpose 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.
Preferred 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 usefulness 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 usefulness 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
3Compound 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; The 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
3Wherein, R
2And R
3Described as defined above, I-A and I-B belong to the compound with general formula I structure of the present invention.
Compound 4 uses halide reagent to process, and 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
3Described as defined above, I-C belongs to the compound with general formula I structure of the present invention.
Compound 7-1 (class in the compound 7, i.e. X=I) uses reductive agent to take off iodine, 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)
2Compound 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
3Described as defined 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 the Mitsunobu condition, obtains compound 9, and the reaction conditions of Mitsunobu is PPh
3And DEAD (ethyl azodicaboxylate) reacts or PPh in THF
3And DIAD (azo-2-carboxylic acid's di-isopropyl) reacts in THF, and wherein Y is selected from AcS, PhS and PhO; Compound 9 deacetylates obtain Compound I-E, and used condition 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
3Described as defined 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 used 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 and (6) K
2CO
3/ MeOH; Wherein, R
2And R
3Described as defined 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 a plurality of hydroxyl in the molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
Formula I compound of the present invention can be made 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 be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the 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 effective constituent for the preparation of the medicine of diabetes aspect.The activity of compound of Formula I of the present invention is by the glucose in urine modelling verification.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage of for example taking every day is divided into once or for several times administration in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: the person's of being treated physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment only is for explanation, and be not for restriction 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)-and 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 is dissolved among the DMF of 30mL drying, the ice-water bath cooling is lower stirs, and 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 stirred 5 hours.Reaction mixture is poured in the 200mL frozen water, stirs, and with 50mL * 3 extractions, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains 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 the 30mL pyridine, the ice-water bath cooling is lower stirs, and slowly drips the 15mL acetic anhydride, then adds 0.3g DMAP (DMAP) again.Reaction mixture at room temperature stirs and spends the night, and then is poured in the 200mL frozen water, stirs, and with 50mL * 3 extractions, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains 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 ℃, stirs 3 hours.After the compound of reaction cooling, be poured in the 200mL frozen water, stir, with 50mL * 3 extractions, merge extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 14.White solid.Fusing point 116-117 ℃.
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 is dissolved in the methylene dichloride of 20mL drying, the ice-water bath cooling is lower stirs, and slowly drips 0.69g (6mmol) methylsulfonyl chloride.After dropwising, compound of reaction at room temperature stirred 3 hours, then was poured in the 100mL frozen water, stirred, and with 50mL * 3 extractions, merged extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains 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 among the DMF of 10mL drying, 100 ℃ of heating 5 hours.After compound of reaction is slightly cold, be poured in the 100mL frozen water, stir, with 50mL * 3 extractions, merge extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 16.White solid.Fusing point 132-134 ℃.
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 the 10mL anhydrous methanol, stirs under the room temperature, until all sodium dissolve fully.Add 0.56g (1mmol) compound 16, continue under the room temperature 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)-and 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 the 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)-and 6-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 of 30mL drying, stirs, and is cooled to-30 ℃.Slowly drip 1.61g (10mmol) DAST with syringe.After dropwising, reaction mixture at room temperature stirred 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 at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 17.White solid.ESI-MS,m/z=559([M+Na]
+)。
B.
0.2g sodium Metal 99.5 joins in the 10mL anhydrous methanol, stirs under the room temperature, until all sodium dissolve fully.Add 0.54g (1mmol) compound 17, continue under the room temperature 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)-and 6-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)-and 6-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 ℃.
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)-and 6-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 of 30mL drying, the ice-water bath cooling is lower stirs, and slowly adds 2.62g (10mmol) triphenylphosphine, continues under this temperature to stir half an hour.Slowly add again 2.72g (40mmol) imidazoles, continue to stir half an hour.Add 2.67g (5mmol) compound 14, stirred 5 hours under the room temperature.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 at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 20.White solid.Fusing point 161-163 ℃.
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 the 10mL anhydrous methanol, stirs under the room temperature, until all sodium dissolve fully.Add 0.64g (1mmol) compound 20, continue under the room temperature 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 of 30mL drying, stirs 3 hours under the room temperature in nitrogen atmosphere, and then temperature rising reflux is 3 hours.With the dilution of 200mL methylene dichloride, use the water washing of cold food salt, anhydrous sodium sulfate drying after the reaction mixture cooling.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains 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 the 10mL anhydrous methanol, stirs under the room temperature, until all sodium dissolve fully.Add 0.52g (1mmol) compound 21, continue under the room temperature 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 THF of 20mL drying, the ice-water bath cooling is lower stirs, and 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.Add at last 3.21g (6mmol) compound 14, stir under the reaction mixture room temperature and spend the night.Compound of reaction is poured in the 100mL frozen water, stirs, and with 50mL * 3 extractions, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 22.White solid.Fusing point 116-117 ℃.
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 the 10mL anhydrous methanol, stirs under the room temperature, until all sodium dissolve fully.Add 0.59g (1mmol) compound 22, continue under the room temperature 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 is dissolved among the 30mL DMF,
Stir under the room temperature.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 the 100mL frozen water, stirs, and with 50mL * 3 extractions, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains obtains sterling 25.White solid.Fusing point: 178-180 ℃.
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 the 20mL ethanol, stirs under the room temperature, adds the NaOH solution of 5mL50%, temperature rising reflux half an hour.Be poured in the 100mL frozen water after the compound of reaction cooling, concentrated hydrochloric acid is adjusted to pH=5, with 50mL * 3 extractions, merges extracted organic phase, with salt solution washing, anhydrous sodium sulfate drying.Suction filtration is removed siccative, and filtrate boils off solvent at Rotary Evaporators, and the resistates column chromatography purification that obtains 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
Operation steps with reference to embodiment 1 and 6-7 has prepared 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 is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in the 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 is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in the 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 in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, then join in the above-mentioned particle, encapsulated, and get 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 in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, then join in the above-mentioned particle, encapsulated, and get final product.
Embodiment 24
In distilled water, add first distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes dissolving again, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes namely gets injection liquid.
Embodiment 25
In distilled water, add first distilled water and citric acid, stirring and dissolving and after, add sample, low-grade fever makes dissolving again, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every ampulla, high-temperature sterilization 30 minutes namely gets injection liquid.
Embodiment 26
Preparation technology: get water for injection 80ml, add main ingredient, N.F,USP MANNITOL, lactose, poloxamer stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100ml.Add the 0.5g gac, 30 ℃ of lower stirrings 20 minutes, take off charcoal, adopt the 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 the white loose block, seal and get final product.
Embodiment 27
Preparation technology: main ingredient and auxiliary material are crossed respectively 100 mesh sieves, fully mix, then take by weighing the recipe quantity auxiliary material and fully mix with main ingredient.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 28
The high sugar of the high fat of normal SD rats was fed after one month, with repeatedly abdominal injection modeling of streptozocin low dose (diabetes B model), and blood-sugar content before and after the mensuration modeling.After the modeling success modeling rat is measured according to twenty-four-hour urine sugar and body weight random packet (8/group), be respectively one group of blank group (giving equal-volume 0.5%CMC sodium solution) and some testing compound groups (10mg/kg).Each organizes the front fasting of rat experiment 16 hours.After gavage gave experimental rat testing compound 0.5h, gavage gave glucose (2g/kg) again.Collect the urine of 0-12h time period after the administration, with determination of glucose oxidase should the time period urine sugar value (the results are shown in following table 2).
The urine sugar value of table 2 determination of glucose oxidase 0-12h time period
Can find out that from the above results compound disclosed by the invention has to have than the control compounds shown in one hurdle, the left side in the table better induces the glucose in urine effect.
Claims (12)
2. according to claim 1 have the compound of general formula (I) structure and an acceptable prodrug ester pharmaceutically thereof,
Wherein,
R
1Be selected from H, F, N
3, NH
2, SH, OPh or SPh;
R
2Be selected from C
1-C
3Alkyl, CF
3Or OCF
2
R
3Be selected from C
1-C
3Alkyl.
Synthetic claim 1-2 each definedly have the Compound I-A of general formula (I) structure and the method for I-B:
Compound 1 hydroxyl protection is obtained 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, the described protecting group reagent of sloughing comprises 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
3Compound 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; The 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
3Wherein, R
2And R
3Definition as claimed in claim 1.
5. synthesize each defined method with Compound I-C of general formula (I) structure of claim 1-2:
Compound 4 uses halide reagent to process, and 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. synthesize each defined method with Compound I-D of general formula (I) structure of claim 1-3:
Compound 7-1 uses reductive agent to take off iodine, 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)
2Compound 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. synthesize each defined method with Compound I-E of general formula (I) structure of claim 1-2:
Compound 4 reacts with AcSH, PhSH or PhOH under the 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 used 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, wherein Z is selected from SH, PhS or PhO; R
2And R
3Definition as claimed in claim 1.
8. synthesize each defined method with Compound I-F of general formula (I) structure of claim 1-2:
Compound 6 reacts under Cu (I) catalysis with propargyl alcohol, obtains compound 10; Compound 10 deacetylates obtain Compound I-F, and used 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; Wherein, R
2And R
3Definition as claimed in claim 1.
9. one of claim 1-3 is defined has the compound of general formula (I) structure and the pharmaceutically application of acceptable prodrug ester aspect preparation treatment diabetes medicament thereof.
10. pharmaceutical composition contains general formula (I) compound of one of claim 1-3 and acceptable prodrug ester pharmaceutically thereof, and suitable carrier or vehicle.
11. pharmaceutical composition claimed in claim 10, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
12. the described pharmaceutical composition of claim 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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CN104861002A (en) * | 2014-02-26 | 2015-08-26 | 天津药物研究院 | 3,6-anhydroglucose structure-containing phenyl C-glucoside derivatives and their preparation method and use |
CN114426538A (en) * | 2022-01-27 | 2022-05-03 | 怀化学院 | Berberine canagliflozin derivative and preparation method and application thereof |
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