CN101684088B

CN101684088B - Cyanomethyl pyrrole derivative and preparation method and application thereof

Info

Publication number: CN101684088B
Application number: CN2008101515014A
Authority: CN
Inventors: 赵桂龙; 李袆亮; 徐为人; 王玉丽; 邹美香; 汤立达; 石玉; 战付旭; 张士俊
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2008-09-22
Filing date: 2008-09-22
Publication date: 2011-05-11
Anticipated expiration: 2028-09-22
Also published as: CN101684088A

Abstract

The invention relates to the field of diabetes associated medicaments, in particular to an N-cyanomethyl pyrrole derivative with a general formula I, a preparation method, a medical composition containing the same and application thereof in preparing diabetes medicaments, wherein all groups are as defined in the specification.

Description

Cyanomethyl pyrrole derivative, preparation method and application thereof

Technical Field

The invention relates to the field of diabetes-related medicines, in particular to a dipeptidyl peptidase-IV (DPP-IV) inhibitor containing an N-cyanomethylpyrrole structure and having a treatment effect on diabetes, a preparation method thereof and a pharmaceutical composition containing the DPP-IV inhibitor.

Background

According to the statistics of the world health organization, the diabetes patients around the world are about 1.7 hundred million, and about 90 percent of the diabetes patients are type II diabetes patients. The antidiabetic drugs currently used in clinic mainly include insulin, metformin, sulfonylurea drugs, and recently marketed thiazolidinedione drugs, α -glucosidase inhibitors, etc., which have good therapeutic effects, but have safety problems in long-term treatment, such as: it is easy to cause various problems such as hepatotoxicity and weight gain.

Dipeptidyl peptidase IV (DPP-IV) can effectively and rapidly degrade glucagon-like peptide 1 (GLP-1), wherein GLP-1 is one of the most effective stimulators for insulin production and secretion, so that the inhibition of DPP-IV can enhance the action of endogenous GLP-1, thereby increasing the level of insulin in blood (CN 200480017355.6). It has been medically established that DPP-IV Inhibitors are novel antidiabetic therapeutic agents (Deacon C.F., Holst J.J., Dipeptidyl Peptidase IV Inhibitors: A purifying New therapeutic Approach for the Management of Type 2 diabetes, the International journal of Biochemistry & Cell Biology, 2006, 38 (5-6): 831) 844). Clinical results show that the medicine has good hypoglycemic effect, and meanwhile, adverse reactions such as common weight gain, hypoglycemia and the like generated by other diabetes medicines are not found. The present invention has found novel DPP-IV inhibitors which are very effective in lowering plasma glucose levels, which compounds lay the foundation for the further discovery of drugs which can be used in the treatment of diabetes, particularly non-insulin dependent diabetes mellitus.

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 having the general formula I and pharmaceutically acceptable salts 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 salts thereof.

It is a further object of the present invention to provide pharmaceutical compositions containing a compound of formula I as an active ingredient, together with one or more pharmaceutically acceptable carriers, excipients or diluents, and their use in the treatment of diabetes.

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

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

wherein,

or

R’＝H，R₁，F，Cl，Br，I，NO₂，NR₂R₃，COOR₄，CONR₂R₃Or R₄CO, and combinations thereof di-or tri-substituted, wherein R₁Is C₁-C₈Alkyl of R₂，R₃And R4 is H or C₁-C₈Alkyl group of (1).

Preferred are compounds of the following general formula I or pharmaceutically acceptable salts thereof,

wherein,

or

R’＝H，R₁，F，Cl，Br，I，NO₂，NR₂R₃，CONR₂R₃Or R₄CO, and combinations thereof di-or tri-substituted, wherein R₁Is C₁-C₄Alkyl of R₂，R₃And R4 is H or C₁-C₄Alkyl group of (1).

More preferred compounds of the invention having the general formula I are shown in the following table:

(Code)	name of Compound
		I-1	(S) -2- { { [2- (benzylamino) acetyl]Amino } methyl } -1-cyanomethyl pyrrole
I-2	(S) -1-cyanomethyl-2- { {2- { [ (4-fluorophenyl) methyl]Amino } acetyl } amino } methyl } pyrrole
		I-3	(S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole
I-4	(S) -2- { {2- { [ (2-chloro-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole
		I-5	(S) -2- { {2- { [ (4-bromo-2-formyl-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole
I-6	(S) -1-cyanomethyl-2- { {2- { [ (6-methyl-1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole
		I-7	(S) -2- { { [2- (benzylamino) acetyl]Amino } methyl } -1-cyanomethyl pyrrole trifluoroacetate salt

I-8	(S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole acetate salt

The compound of the general formula I is synthesized by the following steps:

reacting the protected glycine PG-Gly-OH II with a compound III in the presence of a condensing agent to obtain a compound IV, wherein PG-Gly-OH II is protected glycine, and PG is a protecting group (such as Boc, Cbz and the like).

And deprotecting the compound IV by a deprotection method corresponding to the protecting group PG to obtain a compound V.

Compounds VI and V in inorganic bases, e.g. Na₂CO₃And K₂CO₃In the presence of a catalyst to obtain the compound I. The compound I reacts with acid HA at room temperature to obtain a compound I-s. Wherein R is as defined above.

Wherein the compound III in the above route is synthesized by the following route:

the starting material is L-proline. L-proline is subjected to LiAlH₄And reducing to obtain a compound VII. Compound VII with bromoacetonitrile in an inorganic base, e.g. Na₂CO₃And K₂CO₃And reacting in the presence of the catalyst to obtain the compound VIII. The compound VIII is reacted with methanesulfonyl chloride MsCl in the presence of an organic base such as triethylamine and the like to obtain a compound IX. Compounds IX and NaN₃Heating and reflecting in an aprotic dipolar solvent to obtain a compound X. And catalytically hydrogenating the compound X at normal pressure to obtain a compound III.

The pharmaceutically acceptable salts of the compounds of formula I of the present invention include, but are not limited to, pharmaceutically acceptable salts formed with various inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids, such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, amino acids, and the like.

The compound of formula I or the pharmaceutically acceptable salt thereof 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 or the salt thereof has the DPP-IV inhibiting effect and can be used as an active ingredient for preparing a medicament for treating diabetes. The activity of the compound of the general formula I is verified by an in vivo hypoglycemic 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.

Instruments and reagents unless otherwise specified, were commercially available analytical grade pure reagents and infrared spectroscopy was performed by a Fourier transform infrared spectrometer (KBr pellet or pure film method) of ThermoNicolet AVATAR FT370 USA.

Example 1

Synthesis of (S) -2- { {2- [ (t-butoxycarbonyl) amino ] acetyl } amino } methyl-1-cyanomethylpyrrole (IV-a)

A100 mL round-bottomed flask was charged with 1.75g (10mmol) of Boc-protected glycine II-a, dissolved in 20mL anhydrous THF, followed by addition of 2.06g (10mmol) of DCC, stirring at room temperature for 1 hour, followed by addition of 1.39g (10mmol) of Compound III, and the resulting system was stirred at room temperature overnight. The reaction mixture was filtered to remove solidsThe solvent was evaporated from the filtrate on a rotary evaporator to give a residue, which was subjected to column chromatography to give the product IV-a, 2.66g, yield 90%, as a colorless oily liquid. IR (thin film), 3321, 3217, 2228, 1690, 1684cm^-1.

The compound II-a is one of the compounds II having the general formula, and in this case IV-a is also one of the compounds having the general formula IV. The protective group PG is then Boc (t-Butoxycarbonyl) as tert-butyloxycarbonyl.

Example 2

Synthesis of (S) -2- { [2- (amino) acetyl ] amino } methyl-1-cyanomethylpyrrole (V)

A100 mL reaction flask was charged with 2.96g (10mmol) of Compound IV-a as 20mL CH₂Cl₂Dissolve, add 1mL of trifluoroacetic acid (TFA) with stirring at room temperature, and then continue stirring at room temperature for 2 hours. The reaction system was poured with 100mL of 2% Na₂CO₃In solution, stir, use 50mL × 3 CH₂Cl₂Extracting, mixing the organic phases, washing with saturated saline solution, and drying (Na)₂SO₄) The solvent was evaporated on a rotary evaporator to give pure compound V as a colorless oily liquid, 1.90g, 97% yield IR (thin film), 3321, 3313, 2226, 1686cm^-1.

Example 3

(S) -2- { { [2- (benzylamino) acetyl ] amino } methyl } -1-cyanomethylpyrrole (1-1)

A100 mL round-bottomed flask was charged with 1.71g (10mmol) of Compound VI-1, 1.96g (10mmol) of Compound V and 1.06g (10mmol) of solid Na₂CO₃To do soThen add 10mL MeOH and 10mL CH₂Cl₂. The system was stirred at room temperature overnight. The solid present in the reaction system was removed by filtration, the solvent was evaporated from the filtrate on a rotary evaporator, and the obtained residue was purified by column chromatography to give the product I-1 as a colorless oil, 2.55g, in 89% yield. IR (thin film), 3030, 3332, 3251, 2229, 1687cm^-1.

Compound VI-1 is one of the compounds having the general formula VI.

Examples 4 to 7

The same procedure as in example 3, except that VI in the following table was used in place of VI-1 in example 3, and the other procedure was the same as in example 3, gave the compounds I-2 to I-5 in the following table.

Example number

Yield/%)

VI

I

4	90	4-Fluorobenzyl Bromide	I-2: (S) -1-cyanomethyl-2- { {2- { [ (4-fluorophenyl) methyl]Amino } acetyl } amino } methyl } pyrrole
				5	89	(1, 2-dihydroquinolin-2-one-4-yl) methyl bromide	I-3: (S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole
6	87	2-chloro-3-methylbenzyl bromide	I-4: (S) -2- { {2- { [ (2-chloro-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole
				7	90	4-bromo-2-formyl-3-methylphenylbenzyl bromide	I-5: (S) -2- { {2- { [ (4-bromo-2-formyl-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole
8	88	(6-methyl-1, 2-	I-6: (S) -1-cyanomethyl-2- { {2- { [ (6-methyl-1, 2-dihydro

Dihydroquinolin-2-one-4-yl) methyl bromide

Quinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole

The characterization data for compound I in the table above are as follows:

i-2: (S) -1-cyanomethyl-2- { {2- { [ (4-fluorophenyl) methyl]Amino } acetyl } amino } methyl } pyrrole, colourless oil, IR (thin film), 3033, 3335, 3253, 2229, 1688cm^-1.

I-3: (S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole, colourless oil, IR (thin film), 3031, 3329, 3251, 2228, 1684, 1663cm^-1.

I-4: (S) -2- { {2- { [ (2-chloro-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole, colorless oil, IR (thin film), 3035, 3322, 3253, 2229, 1682cm^-1.

I-5: (S) -2- { {2- { [ (4-bromo-2-formyl-3-methylphenyl) methyl]Amino } acetyl } amino } methyl } -1-cyanomethyl pyrrole, colorless oil, IR (thin film), 3039, 3324, 3255, 2227, 1702, 1686cm^-1.

I-6: (S) -1-cyanomethyl-2- { {2- { [ (6-methyl-1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } amino } methyl } pyrrole, colourless oil, IR (thin film), 3039, 3324, 3255, 2227, 1702, 1686, 1655cm^-1.

Example 9

Synthesis of (S) -2-hydroxymethylpyrrole (VII)

A500 mL round bottom flask was charged with 11.5g (0.1mol) of solid L-proline and 200mL of dry THF, followed by 7.6g (0.2mol) of solid LiAlH in portions with ice-cooling₄And then stirred at room temperature overnight. Slowly dropwise adding 50mL of anhydrous methanol, stirring for half an hour, suction-filtering to remove solids, evaporating the solvent from the filtrate on a rotary evaporator to obtain an oil which is the compound VII, 8.6g, 85% yield IR (thin film), 3451, 3325cm^-1.

Example 10

Synthesis of (S) -1-cyanomethyl-2-hydroxymethylpyrrole (VIII)

A250 mL round bottom flask was charged with 10.1g (0.1mol), 12.0g (0.1mol) and 10.6g (0.1mol) of solid Na₂CO₃Then, 100mL of anhydrous MeOH was added and the reaction was stirred at room temperature overnight. The solid was removed by suction filtration and the filtrate was freed of solvent on a rotary evaporator to give product VIII as a colourless oil, 12.0g, 0.86%. IR (thin film), 3454, 2229cm^-1.

Example 11

Synthesis of (S) -1-cyanomethyl-2-methanesulfonyloxymethylpyrrole (IX)

14.0g (0.1mol) of Compound VIII was dissolved in 50mL of ethyl acetate, 11.1g (0.1mol) of triethylamine was added thereto, the mixture was stirred at room temperature, 11.5g (0.1mol) of methanesulfonyl chloride was slowly dropped, and after completion of the dropping, the reaction system was stirred at room temperature overnight. The reaction mixture was washed once with saturated brine in a separatory funnel and dried (Na)₂SO₄) The solvent was evaporated on a rotary evaporator to give the residue product IX as a colorless oily liquid, 20.3g, 93% yield. IR (thinfilm), 2228cm^-1.

Example 12

Synthesis of (S) -2-azidomethyl-1-cyanomethylpyrrole (IX)

21.8g (0.1mol) of Compound IX are dissolved in 60mL of dry DMF, 19.5g (0.3mol) of solid NaN are added₃The reaction was stirred at 80 ℃ overnight. The system was poured into 500mL of water and 70mL of 3 CH was used₂Cl₂Extracting, mixing the organic phases, washing with saturated saline solution, and drying (Na)₂SO₄) The solvent was evaporated on a rotary evaporator to give Compound X as a colorless oily liquid, 13.9g, 84% yield IR (thin film), 2241, 2226cm^-1.

Example 13

Synthesis of (S) -2-aminomethyl-1-cyanomethylpyrrole (III)

16.5g (0.1mol) of Compound X were dissolved in 60mL of anhydrous methanol, and 1.0g of 5% Pd/C was added, followed by hydrogenation overnight according to a standard hydrogenation method. The catalyst was removed by suction filtration and the filtrate was freed of solvent on a rotary evaporator to give product III as a colourless oil, 11.8g, 85% yield. IR (thin film), 3323, 3312, 2229cm^-1.

Example 14

Synthesis of (S) -2- { { [2- (benzylamino) acetyl ] amino } methyl } -1-cyanomethylpyrrole trifluoroacetate (I-7)

2.86g (10mmol) of Compound I-1 were dissolved in 20mL of dry ethyl acetate, followed by addition of 1.14g (10mmol) of trifluoroacetic acid and stirring at room temperature for 1 hour. The crystals were collected by filtration and dried to give the product I-7 as colorless crystals, 3.60g, 90% yield. IR (KBr), 3030, 2543, 2226, 1683cm^-1。

Example 15

Synthesis of (S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl ] amino } acetyl } amino } methyl } pyrrole acetate (I-8)

The same operation as in example 14, except for replacing I-1 in example 14 with I-3 and replacing trifluoroacetic acid in example 14 with acetic acid, was carried out in the same manner as in example 14 to obtain compound I-8.

I-8: (S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl]Amino } acetyl } aminoMethyl pyrrole acetate, colorless crystals, 91% yield, IR (KBr), 3031, 2551, 2228, 1683, 1664cm^-1。

Example 16

Dosage/tablet

Example 5 sample (I-3) 100mg

Microcrystalline cellulose 80mg

Pregelatinized starch 70mg

Polyvinylpyrrolidone 6mg

Carboxymethyl starch sodium salt 5mg

Magnesium stearate 2mg

Talcum powder 2mg

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 17

A pellet was obtained in the same manner as in example 16 except that the sample (I-1) obtained in example 3 was used in place of I-3 in example 16 in the procedure of example 16.

Example 18

Dosage/granule

EXAMPLE 6 sample (I-4) 50mg

Microcrystalline cellulose 30mg

Pregelatinized starch 20mg

Polyvinylpyrrolidone 3mg

Magnesium stearate 2mg

Talcum powder 1mg

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 19

Referring to the procedure of example 18, a capsule was obtained in the same manner as in example 18 except that I-4 in example 18 was replaced with the sample (I-2) of example 4.

Example 20

The dosage is 50ml

Example 15 sample 50mg

Citric acid 100mg

Appropriate amount of NaOH (adjusting pH4.0-5.0)

50ml of distilled water

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 0.2 g of activated carbon, stirring at room temperature for 20 min, filtering, measuring solution concentration by central control, packaging at 5 ml per ampoule, and sterilizing at high temperature for 30 min to obtain injection.

Example 21

The samples were prepared as a 5mg/ml suspension in 1% sodium carboxymethylcellulose in a dose capacity of 0.4ml/20g body weight, corresponding to a 100mg/kg dose. Damekang is administered in a dose of about 80mg/kg, formulated with 1% sodium carboxymethylcellulose to a concentration of about 4mg/ml, and administered in a volume of about 0.4ml/20g of body weight. The alloxan is prepared into 15mg/ml with fresh physiological saline when being injected. 0.1ml/20g body weight, corresponding to 75 mg/kg.

Healthy ICR mice, each half of male and female, weigh 20-24 g, and meet the first-class standard. Animals were fasted for 16 hours and then injected tail vein with alloxan. After fasting for 6 hours after 48 hours, blood was taken from the retrobulbar venous plexus of mice by capillary, and serum was separated by centrifugation and the glucose content of serum was measured by glucose oxidase method. Selecting mice with blood glucose value higher than 300mg/dl, and dividing into 4 groups according to the measured blood glucose content, wherein the groups are respectively a model group, a positive group (80 mg/kg of Dameikang) group and an administration group. The administration is carried out for 3 days, fasting is carried out for 24 hours, blood is taken 1 hour after the last administration, and the blood sugar content is determined. The results are shown in the table

Influence on blood sugar content of mice model hyperglycemic by alloxan

Note: p <0.01 in comparison to model group

Claims

1. A compound having the general formula I:

wherein,

R′＝H，R₁f, Cl, wherein R₁Is C₁-C₈Alkyl group of (1).

2. A compound of the general formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof, wherein, preferably,

R′＝H，R₁f, Cl, wherein R₁Is C₁-C₄Alkyl group of (1).

3. A compound of general formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, selected from:

(S) -2- { { [2- (benzylamino) acetyl ] amino } methyl } -1-cyanomethylpyrrolidine

(S) -1-cyanomethyl-2- { {2- { [ (4-fluorophenyl) methyl ] amino } acetyl } amino } methyl } pyrrolidine

(S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl ] amino } acetyl } amino } methyl } pyrrolidine

(S) -1-cyanomethyl-2- { {2- { [ (6-methyl-1, 2-dihydroquinolin-2-one-4-yl) methyl ] amino } acetyl } amino } methyl } pyrrolidine

(S) -2- { { [2- (benzylamino) acetyl ] amino } methyl } -1-cyanomethylpyrrolidine trifluoroacetate salt

(S) -1-cyanomethyl-2- { {2- { [ (1, 2-dihydroquinolin-2-one-4-yl) methyl ] amino } acetyl } amino } methyl } pyrrolidine acetate.

4. A compound, or a pharmaceutically acceptable salt thereof, selected from: (S) -2- { {2- { [ (2-chloro-3-methylphenyl) methyl ] amino } acetyl } amino } methyl } -1-cyanomethyl-pyrrolidine

(S) -2- { {2- { [ (4-bromo-2-formyl-3-methylphenyl) methyl ] amino } acetyl } amino } methyl } -1-cyanomethylpyrrolidine.

5. A method of synthesizing a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting compound II with compound III in the presence of a condensing agent to obtain compound IV, wherein compound IIPG-Gly-OH is protected glycine, and PG is protecting groups Boc and Cbz;

deprotecting the compound IV by a deprotection method corresponding to the protecting group PG to obtain a compound V;

reacting the compound VI with the compound V in the presence of inorganic base to obtain a compound I; the compound I reacts with acid HA at room temperature to obtain a compound I-s.

6. The process of claim 5, wherein compound VI and compound V are reacted in the presence of an inorganic base selected from Na to obtain compound I₂CO₃、K₂CO₃Any one of them.

7. The method of claim 5 or 6, wherein III is synthesized by the following route:

the starting material is L-proline; reducing the L-proline by LiAlH4 to obtain a compound VII; reacting the compound VII with bromoacetonitrile in the presence of inorganic base to obtain a compound VIII; reacting the compound VIII with methanesulfonyl chloride MsCl in the presence of organic base triethylamine to obtain a compound IX; compounds IX and NaN₃Heating and reacting in an aprotic dipolar solvent to obtain a compound X; and catalytically hydrogenating the compound X at normal pressure to obtain a compound III.

8. The process of claim 7, wherein compound VII is reacted with bromoacetonitrile in the presence of an inorganic base selected from Na to obtain compound VIII₂CO₃、K₂CO₃Any one of them.

9. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of diabetes.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a suitable carrier.

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