CN103058972B

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

Info

Publication number: CN103058972B
Application number: CN201310016846.XA
Authority: CN
Inventors: 赵桂龙; 王玉丽; 魏群超; 徐为人; 邹美香; 汤立达
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2013-01-17
Filing date: 2013-01-17
Publication date: 2014-12-10
Anticipated expiration: 2033-01-17
Also published as: CN103058972A

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

Phenyl C-glucoside derivative containing cyclohexane structure, preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, particularly relates to the field of medicines related to diabetes, and more particularly relates to a sodium glucose co-transporter type 2 (SGLT2) inhibitor containing a phenyl C-glucoside structure with a cyclohexane structure and having a treatment effect on diabetes, a preparation method thereof, and a pharmaceutical composition containing the same.

Background

Diabetic patients around the world currently have about 1.7 million, of which about the vast majority are type II (i.e., non-insulin dependent) diabetic patients. The antidiabetic drugs currently used in clinic mainly include metformin, sulfonylurea, insulin, thiazolidinedione, alpha-glucosidase inhibitor and dipeptidyl peptidase-IV inhibitor, which have good therapeutic effects, but have safety problems in long-term treatment, such as: liver toxicity, and some drugs have problems of weight gain and the like.

Sodium glucose co-transporter type 2 (SGLT2) is a new target discovered in recent years for the treatment of diabetes. SGLT2 is distributed mainly in the proximal tubule of the kidney and functions to absorb glucose in urine and return it to the blood, so that inhibition of SGLT2 lowers the blood glucose level by a different route from the past. When SGLT2 is functionally impaired, more glucose will be secreted in the urine, which will help the diabetic to maintain the correct blood glucose level. Since SGLT2 inhibitors do not intervene in glucose metabolism, it can be used as a supplement to the mainstream approach to glycemic control.

Chinese patent CN200610093189.9 discloses compounds of the following structure as SGLT2 inhibitors:

wherein A is O, S, NH, (CH)₂)_n，n=0-3。

Chinese patent CN200380110040.1 discloses compounds of the following structure as SGLT2 inhibitors:

wherein A is covalent bond, O, S, NH, (CH)₂)_n，n=1-3。

Chinese patent CN200480006761.2 discloses compounds of the following structure as SGLT2 inhibitors:

wherein X is a covalent bond or a lower alkylene group.

CN102146066 discloses the following compounds containing saturated ring structures as SGLT2 inhibitors:

wherein R is¹、R²Independently selected from H, F, Cl, Br, I, OR³，SR⁴，OCF₃，CF₃，CHF₂，CH₂F，C₁-C₃Alkyl of 3 to 5 carbon atoms, cycloalkyl, wherein R³And R⁴Is independently selected from C₁-C₃Each of which may be substituted with one or more F, Cl atoms; the definitions of X and Y are selected from the following cases: (1) x = Y = carbon atom; (2) x = Y = nitrogen atom; (3) x = nitrogen atom, Y = oxygen atom; (4) x = nitrogen atom and Y = carbon atom.

US20060025349 discloses the following saturated ring structure containing compounds as SGLT2 inhibitors:

wherein Cy represents saturated and monounsaturated five-and six-membered rings.

The invention discloses phenyl C-glucoside derivatives containing a cyclohexane structure as a novel SGLT2 inhibitor, and the compounds can be used for preparing medicines for treating diabetes, particularly type 2 diabetes.

Disclosure of Invention

It is an object of the present invention to overcome the disadvantages and drawbacks of the prior art and to provide a compound of formula I and pharmaceutically acceptable prodrug esters thereof with good activity.

It is another object of the present invention to provide a process for the preparation of compounds having the general formula I and pharmaceutically acceptable prodrug esters thereof.

It is a further object of the present invention to provide pharmaceutical compositions comprising a compound of formula I and pharmaceutically acceptable prodrug esters thereof as active ingredients, in combination with one or more pharmaceutically acceptable carriers, excipients or diluents, and the use thereof in the treatment of diabetes.

The present disclosure will now be described in detail for the purpose of the invention.

The compounds of the invention having the general formula (I) have the following structural formula:

wherein,

R¹selected from H, F, Cl, Br, I, N₃、NH₂SH, OPh, SPh and hydroxymethyl triazole;

R²is selected from C₁-C₅Alkyl of, CF₃And OCHF₂；

R³Is selected from C₁-C₅Alkyl group of (1).

Preference is given to compounds of the general formula (I),

wherein,

R¹selected from H, F, N₃、NH₂SH, OPh and SPh;

R²is selected from C₁-C₃Alkyl of, CF₃And OCF₂；

R³Is selected from C₁-C₃Alkyl group of (1).

More preferably the compound of formula (I) has the structure,

the compound of the general formula (I) is synthesized by the following route:

protecting the compound 1 with TBDMSCl, TBDPSCl and TIPSCl to obtain compound 2, PG₁Selected from TBDMS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl) and TIPS (triisopropylsilyl); acetylating the compound 2 to convert the compound 3, wherein the acetylating agent is selected from acetic anhydride and acetyl chloride; compound 3 deprotection group PG₁Obtaining a compound 4, wherein the used reagents comprise tetra-n-butylammonium fluoride, pyridine hydrogen fluoride and acetic acid; compound 4 is converted to compound 5, PG, with methanesulfonyl chloride, trifluoromethanesulfonyl chloride and p-toluenesulfonyl chloride₂Selected from the group consisting of methylsulfonyl, trifluoromethylsulfonyl and p-toluenesulfonyl; converting compound 5 into compound 6 by using NaN as reagent₃(ii) a Compound 6 is deacetylated to give compound I-A using a reagent selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H2O, (3) NaOH/EtOH/H2O, (4) KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O and (6) K₂CO₃(ii) MeOH; and reducing the I-A into I-B under the condition selected from: (1) h₂,Pd/C、(2)Zn/NH₄Cl and (3) PPh₃(ii) a Wherein R is²And R³As defined above, I-A and I-B belong to the compounds of the present invention having the structure of formula I.

Compound 4 is treated with a halogenating agent to obtainCompound 7, wherein X is selected from F, Cl, Br and I, and the halogenating agent is selected from DAST (diethylaminosulfur trifluoride), PCl₃、PCl₅、PBr₃、PBr₅And I₂/PPh₃Imidazole; deacetylation of compound 7 to compound I-C using MeONa/MeOH as the reagent; wherein R is²And R³As defined above, I-C belongs to the compounds of the present invention having the structure of formula I.

Compound 7-1 (one class of compound 7, i.e., X = I) is deiodinated using a reducing agent selected from: (1) n-Bu₃SnH/AIBN、(2)H₂Pd/C and (3) H₂,Pd(OH)₂(ii) a Compound 8 is deacetylated to give compounds I-D using reagents selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O and (6) K₂CO₃(ii) MeOH; wherein R is²And R³As defined above, I-D pertains to the compounds of the present invention having the structure of formula I.

The compound 4 reacts with AcSH, PhSH and PhOH under the Mitsunobu condition to obtain a compound 9, and the reaction condition of Mitsunobu is PPh₃And DEAD (Ethylazodicarboxylate) in THF or PPh₃And DIAD (diisopropyl azodicarboxylate) in THF, wherein Y is selected from AcS, PhS and PhO; deacetylation of compound 9 to give compounds I-E under conditions selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H2O, (3) NaOH/EtOH/H2O, (4) KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O and (6) K₂CO₃(ii) MeOH, wherein Z is selected from SH, PhS and PhO; wherein,R²and R³As defined above, I-E pertains to the compounds of the present invention having the structure of formula I.

Reacting the compound 6 with propargyl alcohol under the catalysis of Cu (I) to obtain a compound 10; compound 10 is deacetylated to give compounds I-F under conditions selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O and (6) K₂CO₃(ii) MeOH; wherein R is²And R³As defined above, I-F are compounds of the present invention having the structure of formula I.

The pharmaceutically acceptable prodrug ester of the compound of the formula I comprises ester formed by any one or more hydroxyl groups in a molecule and acetyl, pivaloyl, various phosphoryl groups, carbamoyl, alkoxy formyl and the like.

The compound of formula I can be prepared into a pharmaceutical composition together with one or more pharmaceutically acceptable carriers, excipients or diluents. The pharmaceutical composition can be made into solid oral preparation, liquid oral preparation, injection, etc. The solid and liquid oral formulations comprise: tablet, dispersible tablet, sugar-coated preparation, granule, dry powder, capsule and solution. The injection comprises: small needle, large infusion solution, lyophilized powder for injection, etc.

The composition of the invention, the pharmaceutically or dietetically acceptable auxiliary materials are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, or other excipients.

The composition of the invention, and the pharmaceutically or dietetically acceptable auxiliary materials. The filler is one or more of lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, and microcrystalline cellulose; the adhesive comprises one or a combination of more of sucrose, starch, polyvidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene glycol, medicinal ethanol and water; the disintegrating agent comprises one or more of starch, cross-linked polyvidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, and effervescent disintegrating agent.

The compound of the general formula I has the inhibiting effect of SGLT2, and can be used as an effective component for preparing a medicament for treating diabetes. The activity of the compounds of the general formula I according to the invention is verified by a urine glucose model.

The compounds of formula I of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 1mg to about 1000mg per person, divided into one or more administrations. The actual dosage of the compounds of formula I to be administered according to the invention can be determined by the physician in the light of the relevant circumstances. These include: the physical state of the subject, the route of administration, the age, body weight, individual response to the drug, severity of the symptoms, and the like.

Detailed Description

The present invention will be further described with reference to the following examples. It should be noted that the following examples are only for illustration and are not intended to limit the present invention. Variations of the teachings of the present invention may be made by those skilled in the art without departing from the scope of the claims of the present application.

Example 1

(1S) -6-Azide-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-1)

A.

4.09g (10mmol) of Compound 11 and 2.72g (40mmol) of imidazole were dissolved in 30mL of dry DMF, and a solution of 1.81g (12mmol) of TBDMSCl (tert-butyldimethylsilylchloride) in 2mL of dry DMF was slowly dropped while stirring with cooling in an ice-water bath. After the addition was complete, the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 200mL of ice water, stirred, extracted with 50 mL. times.3, and the organic phases of the extracts were combined, washed with brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 12. White foamy solid.¹HNMR(DMSO-d₆,400MHz),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-d₆,100MHz),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) of Compound 12 are dissolved in 30mL of pyridine, stirred with cooling in an ice-water bath, and 15mL of acetic anhydride are slowly added dropwise, followed by addition of 0.3g of DMAP (4-dimethylaminopyridine). The reaction mixture was stirred at room temperature overnight, and then poured onto 200mL of ice water, stirred, extracted with 50 mL. times.3, and the organic phases were combined, washed with brine, and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 13. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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) of Compound 13 was dissolved in 30mL of 90% aqueous acetic acid, and the mixture was stirred at 50 ℃ for 3 hours. After the reaction mixture was cooled, it was poured into 200mL of ice water, stirred, and extracted with 50 mL. times.3, and the organic phases of the extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 14. A white solid. Melting point 116-.¹H NMR(DMSO-d₆,400MHz),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-d₆,400MHz),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) of Compound 14 and 2.53g (25mmol) of triethylamine were dissolved in 20mL of dry dichloromethane, stirred with cooling in an ice-water bath, and 0.69g (6mmol) of methanesulfonyl chloride was slowly dropped. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hoursThen, the mixture was poured into 100mL of ice water, stirred, extracted with 50 mL. times.3, and the organic phases of the extracts were combined, washed with brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 15. A white solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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) of Compound 15 and 1.95g (30mmol) of NaN₃Dissolved in 10mL of dry DMF and heated at 100 ℃ for 5 hours. After the reaction mixture was cooled slightly, it was poured into 100mL of ice water, stirred, and extracted with 50 mL. times.3, and the organic phases of the extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 16. A white solid. Melting point 132-.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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 of metallic sodium was added to 10mL of anhydrous methanol, and stirred at room temperature until all the sodium was completely dissolved. 0.56g (1mmol) of Compound 16 was added and stirring was continued at room temperature for 3 hours. 2g of a strongly acidic cation exchange resin was added thereto, and the mixture was stirred overnight. The resin is removed by suction filtration, the filtrate is evaporated to dryness on a rotary evaporator, and the residue is dried on an oil pump to obtain the product I-1. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 2

(1S) -6-amino-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-2)

0.43g (1mmol) of Compound I-1 was dissolved in 5mL of methanol, 0.1g of 10% Pd/C was added thereto, followed by stirring,

hydrogenation was carried out at room temperature and pressure overnight. And (4) filtering to remove the catalyst, evaporating the filtrate on a rotary evaporator, and drying the residue on an oil pump to obtain a product I-2. White foamy solid, ESI-MS, M/z =430([ M + Na)]⁺)。

Example 3

(1S) -6-fluoro-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-3)

A.

2.67g (5mmol) of Compound 14 are dissolved in 30mL of dry dichloromethane, stirred and cooled to-30 ℃. 1.61g (10mmol) of DAST was slowly dropped using a syringe. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, diluted with 100mL of dichloromethane, washed with cold brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 17. A white solid. ESI-MS, M/z =559([ M + Na ]]⁺)。

B.

0.2g of metallic sodium was added to 10mL of anhydrous methanol, and stirred at room temperature until all the sodium was completely dissolved. 0.54g (1mmol) of Compound 17 was added and stirring was continued at room temperature for 3 hours. 2g of a strongly acidic cation exchange resin was added thereto, and the mixture was stirred overnight. The resin is removed by suction filtration, the filtrate is evaporated to dryness on a rotary evaporator, and the residue is dried on an oil pump to obtain the product I-3. White foamy solid. ESI-MS, M/z =433([ M + Na ]]⁺)。

Example 4

(1S) -6-chloro-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-4)

Following the procedure of example 3, with PCl₃In place of DAST, Compound I-4 was obtained. White foamy solid, ESI-MS, M/z =449([ M + Na)]⁺)。

Example 5

(1S) -6-bromo-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-5)

Following the procedure of example 3, with PBr₃In place of DAST, Compound I-5 was obtained. White solid, ESI-MS, melting point 160-.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 6

(1S) -6-iodo-1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-6)

A.

2.54g (10mmol) iodine was dissolved in 30mL of dry methylene chloride, stirred with cooling in an ice-water bath, and 2.62g (10mmol) triphenylphosphine was slowly added and stirring continued at this temperature for half an hour. Then 2.72g (40mmol) of imidazole was slowly added and stirring was continued for half an hour. 2.67g (5mmol) of Compound 14 was added, and the mixture was stirred at room temperature for 5 hours. Diluted with 100mL of dichloromethane, washed with cold brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 20. A white solid. Melting point 161-.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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 of metallic sodium was added to 10mL of anhydrous methanol, and stirred at room temperature until all the sodium was completely dissolved. 0.64g (1mmol) of Compound 20 was added and stirring was continued at room temperature for 3 hours. 2g of a strongly acidic cation exchange resin was added thereto, and the mixture was stirred overnight. The resin was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator and the residue was dried on an oil pump to give product I-6. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 7

(1S) -1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-7)

A.

3.22g (5mmol) of Compound 20, 2.91g (10mmol) of n-Bu₃SnH and 0.82g (5mmol) of AIBN (azobisisobutyronitrile) were dissolved in 30mL of dry benzene, stirred at room temperature for 3 hours under a nitrogen atmosphere, and then heated to reflux for 3 hours. The reaction mixture was cooled, diluted with 200mL of dichloromethane, washed with cold brine, and dried over anhydrous sodium sulfate. And (3) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 21. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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 of metallic sodium was added to 10mL of anhydrous methanol, and stirred at room temperature until all the sodium was completely dissolved. 0.52g (1mmol) of Compound 21 is added and stirring is continued at room temperature for 3 hours. 2g of a strongly acidic cation exchange resin was added thereto, and the mixture was stirred overnight. Suction filtrationThe resin was removed, the filtrate evaporated to dryness on a rotary evaporator and the residue dried on an oil pump to give product I-7. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 8

(1S) -1, 6-dideoxy-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -6-mercapto-D-glucose (I-8)

A.

2.62g (1mmol) of triphenylphosphine were dissolved in 20mL of dry THF, stirred with cooling in an ice-water bath, 1.74g (1mmol) of DEAD was slowly added, and stirring was continued for half an hour. Then 0.76g (1mol) of AcSH are slowly added and stirring is continued for half an hour. Finally 3.21g (6mmol) of compound 14 are added and the reaction mixture is stirred at room temperature overnight. The reaction mixture was poured into 100mL of ice water, stirred, extracted with 50 mL. times.3, and the organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 22. A white solid. Melting point 116-.¹H NMR(DMSO-d₆,400MHz),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-d₆,400MHz),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 of metallic sodium was added to 10mL of anhydrous methanol, and stirred at room temperature until all the sodium was completely dissolved. 0.59g (1mmol) of Compound 22 was added and stirring was continued at room temperature for 3 hours. 2g of a strongly acidic cation exchange resin was added thereto, and the mixture was stirred overnight. The resin was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator and the residue was dried on an oil pump to give product I-8. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 9

(1S) -1, 6-dideoxy-6-phenylthio-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-9)

Using the procedure of example 8, replacing AcSH with PhSH, product I-9 was obtained. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 10

(1S) -1-deoxy-6-O-phenyl-1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-10)

Using the procedure of example 8, replacing AcSH with PhOH, the product I-10 was obtained. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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-d₆,100MHz),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。

Example 11

(1S) -1, 6-dideoxy-6- (4-hydroxymethyl-1, 2, 3-triazol-1-yl) -1- [ 4-methoxy-3- (trans-4-n-propylcyclohexyl) methylphenyl ] -D-glucose (I-11)

A.

5.60g (10mmol) of compound 16 and 0.56g (10mmol) of propargyl alcohol are dissolved in 30mL of DMF,

stirring at room temperature. 10 drops of 1mL0.5M CuSO are added dropwise₄And 1ml of a 0.5M ascorbic acid mixture. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 100mL of ice water, stirred, extracted with 50 mL. times.3, and the organic phases were combined, washed with brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product 25. A white solid. Melting point: 178 ℃ and 180 ℃.¹H NMR(DMSO-d₆,400MHz),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) of Compound 25 was dissolved in 20mL of ethanol, stirred at room temperature, added with 5mL of 50% NaOH solution, and refluxed at elevated temperature for half an hour. The reaction mixture was cooled and poured into 100mL of ice water, and the pH was adjusted to 5 with concentrated hydrochloric acid, 50mL × 3 extraction, combined organic phases, washed with brine and dried over anhydrous sodium sulfate. And (4) removing the drying agent by suction filtration, evaporating the solvent from the filtrate on a rotary evaporator, and purifying the obtained residue by column chromatography to obtain a pure product I-11. White foamy solid.¹H NMR(DMSO-d₆,400MHz),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)。

Examples 12 to 19

Referring to the procedure of examples 1 and 6-7, the following compounds were prepared.

TABLE 1 Compounds of examples 12-19

Example 20

Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft mass, sieving, making wet granule, drying at 50-60 deg.C, sieving carboxymethyl starch sodium salt, magnesium stearate and pulvis Talci, adding into the above granule, and tabletting.

Example 21

Example 22

Sieving active ingredients, pregelatinized starch and microcrystalline cellulose, mixing, adding polyvinylpyrrolidone solution, mixing, making soft material, sieving, making wet granule, drying at 50-60 deg.C, sieving magnesium stearate and pulvis Talci, adding into the above granule, and making into capsule.

Example 23

Example 24

Adding distilled water and citric acid into distilled water, stirring for dissolving, adding sample, slightly heating for dissolving, adjusting pH to 4.0-5.0, adding 0.2g of activated carbon, stirring at room temperature for 20 min, filtering, measuring solution concentration by central control, packaging at 5ml per ampoule, and sterilizing at high temperature for 30 min to obtain injection.

Example 25

Example 26

The preparation process comprises the following steps: taking 80ml of water for injection, adding the main drug, mannitol, lactose and poloxamer, stirring to dissolve, adding 1mol/L citric acid to adjust the pH value to 7.0-9.0, and adding water to 100 ml. Adding 0.5g of activated carbon, stirring at 30 ℃ for 20 minutes, decarburizing, filtering with a microporous filter membrane for sterilization, subpackaging the filtrate with 1ml per piece, pre-freezing for 2 hours, freezing, drying under reduced pressure for 12 hours until the temperature of the sample reaches room temperature, drying for 5 hours again to obtain white loose blocks, and sealing to obtain the product.

Example 27

The preparation process comprises the following steps: the main drug and the auxiliary materials are respectively sieved by a 100-mesh sieve, fully mixed, and then the auxiliary materials with the prescription amount are weighed and fully mixed with the main drug. Adding adhesive to make soft material, granulating with 14 mesh sieve, drying at 55 deg.C, grading with 12 mesh sieve, measuring bag weight, and packaging.

Example 28

After normal SD rats are fed with high fat and high sugar for one month, a small dose of streptozotocin is injected into the abdominal cavity for molding (type 2 diabetes model) for multiple times, and the blood sugar content before and after molding is measured. After the molding was successful, the molded rats were randomly assigned (8 rats/group) according to the 24-hour urine glucose amount and body weight, and were a group of blank group (given an equal volume of 0.5% CMC sodium solution) and several test compound groups (10mg/kg), respectively. Rats in each group were fasted for 16 hours prior to the experiment. Test rats were gavaged with test compound for 0.5h, followed by gavage with glucose (2 g/kg). Urine was collected for a period of 0-12h after administration and the glucose value was determined for this period by the glucose oxidase method (results are shown in table 2 below).

TABLE 2 determination of the urine glucose value by the glucose oxidase method for a period of 0-12h

From the above results, it can be seen that the compounds disclosed in the present invention have a better urine glucose inducing effect than the comparative compounds shown in the left column of the table.

Claims

1. A compound having a structure of the general formula (I),

wherein,

R¹selected from H, F, Cl, Br, I, N₃、NH₂、SH；

R²＝Me；

R³＝n-Pr。

2. The compound of claim 1 having the structure of formula (I),

wherein,

R¹selected from H, F, N₃、NH₂、SH；

R²＝Me；

R³＝n-Pr。

3. The compound of claim 2 having the structure of formula (I) selected from the group consisting of,

4. a process for the synthesis of compounds I-a and I-B having the general structure (I) as defined in any one of claims 1-2:

protecting the hydroxyl group of the compound 1 to obtain a compound 2, wherein PG is₁Selected from TBDMS, TBDPS or TIPS; acetylating compound 2 to compound 3 with an acetylating agent selected from acetic anhydride or acetyl chloride; compound 3 deprotection group PG₁Obtaining a compound 4, wherein the protecting group removing reagent comprises tetra-n-butylammonium fluoride, pyridine hydrogen fluoride or acetic acid; conversion of Compound 4 to Compound 5, wherein PG₂Selected from methylsulfonyl, trifluoromethylsulfonyl or p-toluenesulfonyl; converting compound 5 into compound 6 by using NaN as reagent₃(ii) a Deacetylation of compound 6 to give compound I-a under deacetylation conditions selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O or (6) K₂CO₃(ii) MeOH; the I-A is reduced and converted into I-B, and the reduction stripThe component is selected from: (1) h₂,Pd/C、(2)Zn/NH₄Cl or (3) PPh₃(ii) a Wherein R is²And R³Is as defined in claim 1.

5. A process for the synthesis of compounds I-C having the general structure (I) as defined in any one of claims 1-2:

treating compound 4 with halogenating agent to obtain compound 7, wherein X is selected from F, Cl, Br or I, and the halogenating agent is selected from DAST and PCl₃、PCl₅、PBr₃、PBr₅Or I₂/PPh₃Imidazole; deacetylation of compound 7 to compound I-C using MeONa/MeOH as the reagent; wherein R is²And R³Is as defined in claim 1.

6. A process for the synthesis of compounds I-D having the general structure (I) as defined in any one of claims 1 to 3:

compound 7-1 is deiodinated using a reducing agent selected from the group consisting of: (1) n-Bu₃SnH/AIBN、(2)H₂Pd/C or (3) H₂,Pd(OH)₂(ii) a Compound 8 is deacetylated to give compounds I-D using reagents selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O or (6) K₂CO₃(ii) MeOH; wherein R is²And R³Is as defined in claim 1.

7. A process for the synthesis of compounds I-E having the general structure (I) as defined in any one of claims 1-2:

compound 4 is reacted with AcSH, PhSH or PhOH under Mitsunobu conditions selected from the group consisting of: (1) PPh₃DEAD/THF or (2) PPh₃/DIAD/THF, wherein Y is selected from AcS, PhS or PhO; deacetylation of compound 9 to give compounds I-E under conditions selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O or (6) K₂CO₃(ii) MeOH, wherein Z is selected from SH, PhS or PhO; r²And R³Is as defined in claim 1.

8. A process for the synthesis of compounds I-F having the general structure (I) as defined in any one of claims 1-2:

reacting the compound 6 with propargyl alcohol under the catalysis of Cu (I) to obtain a compound 10; compound 10 is deacetylated to give compounds I-F under conditions selected from: (1) MeONa/MeOH, (2) NaOH/MeOH/H₂O、(3)NaOH/EtOH/H₂O、(4)KOH/MeOH/H₂O、(5)KOH/EtOH/H₂O or (6) K₂CO₃(ii) MeOH; wherein R is²And R³Is as defined in claim 1.

9. Use of a compound having the structure of formula (I) as defined in any one of claims 1 to 3 for the manufacture of a medicament for the treatment of diabetes.

10. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 3, together with a suitable carrier or excipient.

11. The pharmaceutical composition of claim 10, wherein the composition is a solid oral formulation, a liquid oral formulation or an injection.

12. The pharmaceutical composition of claim 11, wherein the solid oral dosage form comprises: dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, and granule; the liquid oral preparation is an oral solution; the injection preparation comprises water injection for injection, freeze-dried powder injection for injection, large transfusion and small transfusion.