WO2017092083A1

WO2017092083A1 - Dpp-4 inhibitor compound, polymer and preparation method and use of same

Info

Publication number: WO2017092083A1
Application number: PCT/CN2015/098043
Authority: WO
Inventors: 张晓�; 厉保秋; 周俊; 沈柯; 杨东晖; 路杨
Original assignee: 杭州阿诺生物医药科技股份有限公司
Priority date: 2015-12-01
Filing date: 2015-12-21
Publication date: 2017-06-08
Also published as: CN106810568A

Abstract

Disclosed are a DPP-4 inhibitor compound, a polymer and a preparation method and use. The structure of said compound is X-R1-R2-Y, X and Y respectively being a group formed of a DPP-4 inhibitor or a DPP-4 inhibitor analogue containing an amino or imino group,, or being a group formed of a pharmaceutically acceptable salt or an optical isomer of the above mentioned DPP-4 inhibitor or DPP-4 inhibitor analogue containing an amino or imino group; and R1 and R2 respectively being a peptide chain fragment containing 1-6 natural or non-natural amino acid(s), or being a mercaptocarboxylic acid compound group or being a mercaptocarboxylic acid compound modified peptide chain fragment containing 1-6 natural or non-natural amino acid(s). Said DPP-4 inhibitor compound and polymer have an action curve of longer time and a lower clearance rate, and at the same time prolong the half-life period of the GLP-1 in vivo.

Description

DPP-4 inhibitor compound, polymer and preparation method and application thereof

Technical field

The present invention relates to the field of dipeptidyl peptidase IV (DPP-4) inhibitor drugs, and in particular to a class of dipeptidyl peptidase IV (DPP-4) inhibitor compounds and polymers, and a preparation method and application thereof.

Background technique

Incretin is a hormone secreted by small intestinal endocrine cells to help the body produce postprandial insulin response after eating carbohydrates. Its insulin-promoting effect accounts for about 60% of the total postprandial insulin secretion. Two kinds of incretins, glucose-dependent insulin-releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1), have been isolated so far, and two new mechanisms of action have been put on the market for hypoglycemic agents. Both of them play a hypoglycemic effect by increasing the level of GLP-1 in patients with type 2 diabetes (T2DM). GLP-1 receptor agonists can act on their receptors in place of GLP-1 and avoid degradation by dipeptidyl peptidase-4 (DPP-4), such as exenatide, liraglutide, etc.; and DPP- 4 inhibitors inhibit the degradation of GLP-1 by DPP-4, so that endogenous GLP-1 accumulates in the body to achieve hypoglycemic effects, such as sitagliptin, vildagliptin and so on. These two drugs have functions such as protecting islet cells, reducing body weight, and rarely cause hypoglycemia, and are increasingly used in clinical applications.

GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) (1 to 2 min) and then cleared by the kidneys. DPP-4 inhibitor (statin) competitively binds to the DPP-4 activation site, reduces the catalytic activity of the enzyme, inhibits the degradation of GLP-1, thereby increasing the concentration of GLP-1 in the blood, and improving glycemic control and protection. The effect of beta cell function.

To date, seven DPP-4 inhibitors have been marketed worldwide: sitagliptin, vildagliptin, saxagliptin, alogliptin, gligle Linagliptin, gemigliptin and teneligliptin. Among them, sitagliptin, vildagliptin and saxagliptin have been listed in China, alogliptin and linagliptin have been applied in China, and gigliptin is licensed by LG Life Sciences in China. Pharmaceutical development.

DPP-4 inhibitors can correct the inappropriate secretion of glucagon caused by abnormal islet α cell function by increasing the biological effect of endogenous GLP-1. Mechanism of DPP-4 inhibitors reducing glucagon secretion Including: elevated GLP-1 directly acts on islet α cells to inhibit glucagon secretion, and exerts an indirect effect by stimulating islet delta cells to secrete somatostatin and promote insulin secretion.

Summary of the invention

The prior art problem solved by the present invention is that the existing DPP-4 inhibitor has a limited variety, and its half-life in the body is short, the sustained action time of the drug is short, and the therapeutic effect needs to be strengthened.

In order to solve the above problems, the present invention provides a DPP-4 inhibitor compound, a polymer, and a pharmaceutical composition, and a preparation method thereof, and the present invention also provides a DPP-4 inhibitor compound or polymer as an active group thereof. The use of a divided pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of diabetes, weight loss or other diseases associated with DPP-4, and for the treatment and/or prevention of diabetes, weight loss or other diseases associated with DPP-4.

Specifically, the present invention provides the following technical solutions:

Technical solution 1:

A compound of the formula (I), X-R1-R2-Y(I)

among them,

X and Y are respectively a group formed by a DPP-4 inhibitor or a DPP-4 inhibitor analog containing an amino group or an imino group, or a DPP-4 inhibitor or a DPP-4 inhibitor similar to the aforementioned amino group or imino group. a pharmaceutically acceptable salt or optical isomer forming a group; wherein X and Y are the same or different;

R1 and R2 are respectively a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound group, or a peptide containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound. A fragment of a chain in which R1 and R2 are the same or different.

Technical Solution 2:

The compound according to the first aspect, wherein in the structural formula of the formula (I),

X and Y are a secondary or tertiary amine group formed by a DPP-4 inhibitor or a DPP-4 inhibitor analog containing an amino group or an imino group, respectively, or a DPP-4 inhibitor or DPP containing the above amino group or imino group. a secondary or tertiary amine group formed by a pharmaceutically acceptable salt or optical isomer of the -4 inhibitor analog; wherein X and Y are the same or different;

R1 and R2 are respectively a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound group, or a peptide containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound. A chain fragment in which R1 and R2 are the same, and a CO-NH, SS or CO-S bond is formed between R1 and R2, preferably an SS bond.

Technical solution 3:

The compound according to

claim

1 or 2, wherein the amino group or imino group-containing DPP-4 inhibitor or DPP-4 inhibitor analog is selected from the group consisting of sitagliptin and the like, alogliptin and the same Analogs, linagliptin and its analogues, saxagliptin and its analogues, vildagliptin and its analogues, tricretin and its analogues, alogliptin and its analogues or Meg Lenin and its analogues.

Technical solution 4:

The compound according to

claim

1 or 2, wherein in the structural formula of the formula (I),

X and Y are secondary amines selected from the group consisting of sitagliptin, alogliptin, linagliptin, saxagliptin, vildagliptin, troigliptin, alogliptin or megliptin, respectively. a tertiary amine group; R1 and R2 are the same, both are mercaptocarboxylic acids, and SS, CO-NH or CO-S bonds are formed between R1 and R2.

Technical solution 5:

The compound according to claim 4, wherein the X and Y are the same, and are selected from the group consisting of sitagliptin, alogliptin, linagliptin, saxagliptin, vildagliptin, trozastatin, A secondary or tertiary amine group of alogliptin or meglitin; wherein R1 and R2 are the same, both are a fluorenylcarboxylic acid group having from 1 to 6 carbon atoms, preferably a mercaptopropionic acid group.

Technical solution 6:

The compound according to claim 3, wherein the structural formula of the sitagliptin analog is as follows:

Formula 1)

In the formula (1), Ar is a phenyl group or a phenyl group substituted by a halogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a cyano group; X is an N atom and -CR ² ; R ¹ and R ² are each independently selected from one of the following groups: H, cyano, unsubstituted or substituted by 1 to 5 halogen, cyano, hydroxy or carboxy, respectively. An alkyl, phenyl, five- or six-membered heterocyclic ring of 1-10; said Ar is preferably a halogen-substituted phenyl group, further preferably a fluorine or chlorine or bromine-substituted phenyl group, more preferably three halogen-substituted phenyl groups, Further preferably, three fluorine atoms or chlorine-substituted phenyl groups; the R ¹ is preferably 1-3 halogen-substituted alkyl groups, more preferably three halogen-substituted methyl groups; wherein the sitagliptin analog does not include Sitagliptin itself;

The structural formula of the alogliptin analog is as follows:

Formula (2)

In the formula (2), M is a nitrogen atom or -CR ⁴ , and R ² , R ³ and R ⁴ are each independently selected from one of the following groups: unsubstituted or substituted by an amino group, a cyano group or a carboxylic acid, respectively. a linear or branched alkyl group having 1 to 10 carbon atoms, a cyclic alkyl group having 3 to 12 carbon atoms, a hetero atom-containing cyclic alkyl group having 3 to 12 carbon atoms or a carbon atom a 1-10 alkylcycloalkyl group; wherein R ³ is preferably an amino-substituted carbon atom-containing cycloalkyl group having 3 to 12 carbon atoms, the hetero atom being selected from nitrogen or oxygen or sulfur, more Preferred is an amino-substituted cycloalkyl group having 3 to 12 carbon atoms, more preferably an amino-substituted azacyclohexyl group; wherein L is selected from 1 to 3 N atoms, C atoms, O atoms or S The bridge of an atom, preferably a bridge of a C atom or an S atom; X is selected from one of the following groups: unsubstituted or substituted by amino, cyano, carboxylic acid, respectively, having a carbon number of 1-10 An alkyl group, a cyclic alkyl group having 3 to 12 carbon atoms, an aromatic cycloalkyl group having 1 to 10 carbon atoms, preferably an amino group, an aryl group having 6 to 10 carbon atoms substituted by a cyano group The alogliptin Alogliptin itself was not included;

The structural formula of the analog of linagliptin is as follows:

Formula (3)

In the formula (3), R ¹ is a naphthyl group or a naphthyl group each substituted by a methyl group, a methoxy group, a nitro group or a methylamino group; a 2-styryl group; a phenyl group; a cyclohexylcarbonyl group; a benzothienyl group; Or quinolyl; R ¹ is preferably naphthyl or naphthyl substituted by methyl or methoxy, respectively; R ² is methyl, isopropyl, 2-propenyl, phenyl, cyanomethyl or methoxy Carbonylmethyl, preferably methyl, phenyl, cyanomethyl; R ³ is 2-cyanophenyl, 2,6-dicyanophenyl, 2-methyl-2-propenyl, 2-chloro- 2-propenyl, 3-bromo-2-propenyl, 2-butenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-propenyl, 2-butynyl, 1 a cyclopentaethylenehexaminemethyl or 2-furanmethyl group, preferably 2-butynyl, 2-butenyl, 2-methyl-2-propenyl, more preferably 2-butynyl; Wherein the linagliptin analog does not include linagliptin itself;

The structural formula of the analog of saxagliptin is as follows:

Formula (4)

In the formula (4), x is 1, y is 0 or x is 0, y is 1, n is 0 or 1, X is H or a cyano group, and R ¹ , R ² , R ³ and R ⁴ are each independently selected. From one of the following groups: H, unsubstituted or straight or branched alkyl, alkenyl, alkynyl substituted by halogen, straight or branched alkyl, nitro, cyano, amino or hydroxy, respectively , cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl, preferably straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicyclic An alkyl group, a tricycloalkyl group, a hydroxyalkyl group, an aralkyl group, a heterocyclic aryl group, more preferably a linear or branched alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group; wherein the saxagliptin Analogs do not include saxagliptin itself;

The structural formula of the analog of vildagliptin is as follows:

Formula (5)

In formula (5), R ¹ and R ² are each independently selected from one of the group consisting of H, cyano, unsubstituted or straight-chain substituted by halogen, nitro, cyano, amino or hydroxy, respectively. a branched alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R ¹ is preferably cyano, unsubstituted or a linear or branched alkyl group, a cycloalkyl group or an aralkyl group substituted by a cyano group or a hydroxy group, respectively, and R ² is preferably a cycloalkyl group or an aralkyl group which is unsubstituted or substituted by a cyano group or a hydroxy group, respectively; Said vildagliptin analogue does not include vildagliptin itself;

The structural formula of the analog of troglitazone is as follows:

Formula (6)

In the formula (6), R ¹ and R ² are each independently selected from one of the group consisting of H, unsubstituted or a straight or branched alkane substituted by a halogen, a nitro group, a cyano group, an amino group or a hydroxyl group, respectively. a base, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R ¹ is preferably unsubstituted or halogen, cyano substituted a cycloalkyl group, an aralkyl group, more preferably a halogen or a cyano substituted aralkyl group; R ² is preferably a linear or branched alkyl group, more preferably a methyl group, an ethyl group, a propyl group; The gliptin analogue does not include troglitazone itself;

The structural formula of the analogue of alogliptin is as follows:

Formula (7)

In the formula (7), R ¹ and R ² are each independently selected from one of the group consisting of H, unsubstituted or a straight or branched alkyl group substituted by a halogen, a nitro group, a cyano group or an aminohydroxy group, respectively. , alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R ¹ is preferably unsubstituted or halogen, cyano substituted ring An alkyl group, an aralkyl group, more preferably 1 to 3 halogen-substituted aralkyl groups; R ² is preferably a cycloalkyl group or an aralkyl group which is unsubstituted or substituted by a cyano group or a hydroxy group, respectively; The statin analogue does not include alogliptin itself;

The structural formula of the analog of meglitin is as follows:

Formula (8)

In the formula (8), R ¹ , R ² and R ³ are each independently selected from one of the following groups: H, cyano, unsubstituted or substituted by halogen, nitro, cyano, amino or hydroxy, respectively. a linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R ¹ is preferably cyano, non Substituted or substituted by cyano, halogen substituted cycloalkyl, aralkyl, R ² is preferably halogen or cyano substituted aralkyl, R ³ is preferably heterocycloalkyl or halogen substituted heteroaryl, Preferred is a halogen-substituted heterocyclic aryl group; wherein the meglitinine analog does not include meglitin itself.

Technical solution 7:

The compound according to any one of claims 1 to 6, wherein the mercaptocarboxylic acid-containing compound is a mercaptocarboxylic acid having 1 to 8 carbon atoms, preferably mercaptopropionic acid, mercaptoacetic acid or mercaptobutyric acid, more preferably Is a 3-mercaptopropionic acid; the peptide chain fragment containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound is modified to have 1 to 6 carbonic acid carboxylic acids having 1 to 8 carbon atoms The peptide chain fragment of the natural or unnatural amino acid is preferably deuterated propionylglycine, deuterated acetylglycine or deuterated butyrylglycine, more preferably 3-mercaptopropionylglycine.

Technical solution 8:

The compound according to claim 1, 3 or 6, wherein X and R1 are formed between CN, CO, C=N, CC, C=C, CS, SS, CO-NH, CO-S. a chemical bond, preferably CO-NH, CO-S or SS;

A chemical bond selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, CO-S is formed between Y and R2, preferably CO-NH, CO-S or SS;

A chemical bond selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, CO-S is formed between R1 and R2, preferably CO-NH, CO-S or SS.

Technical solution 9:

The compound according to claim 8, wherein a CN, CO, CS or SS bond is formed between X and R1; a CN, CO, CS or SS bond is formed between Y and R2; and CO-NH is formed between R1 and R2, CO-S or SS key.

Technical solution 10:

The compound according to claim 8, wherein a C=N, C=C or CO-NH bond is formed between X and R1; a C=N, C=C or CO-NH bond is formed between Y and R2; R1 and A CO-NH, CO-S or SS bond is formed between R2.

Technical Solution 11:

The compound according to claim 8, wherein a CO-NH bond is formed between X and R1; a CO-NH bond is formed between Y and R2; and an S-S, CO-S or CO-NH bond is formed between R1 and R2.

Technical Solution 12:

The present invention also provides a polymer using the compound according to any one of claims 1 to 11 as a repeating structural unit, wherein the formula is represented by [X-R1-R2-Y] _n , wherein n is 2 to 10 Integer.

Technical Solution 13:

The polymer according to claim 12, wherein one of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, CO-S is used between the repeating structural units. A chemical bond, preferably a CO-NH, CO-S or SS bond.

Technical Solution 14:

The invention also provides a preparation method of any of the above compounds, comprising the following steps:

A DPP-4 inhibitor containing an amino group or an imino group, or a DPP-4 inhibitor analog containing an amino group or an imino group, or a pharmaceutically acceptable salt or optical isomer of a DPP-4 inhibitor containing an amino group or an imino group The body is mixed with a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound, or a peptide chain fragment containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound, respectively. The reaction is carried out by the action of a crosslinking agent.

Technical Solution 15:

The preparation method according to claim 14, wherein the coupling agent is selected from the group consisting of 1,3-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-di) Methylaminopropyl)-3-ethylcarbonyldiaminemethyl iodide, N,N-diisopropylethylamine, N-methylmorpholine, 1-hydroxybenzotriazole, 2-(7-azobenzene and Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate,6 -Chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate, 2-(1H-benzotriazolyl-1-yl)-1,1,3,3- Tetramethyluronium tetrafluoroborate, 5-norbornene-2,3-dicarbonyl-N,N,N',N'-tetramethyluronium tetrafluoroborate, benzotriazole hexafluorophosphate One or more of 1--1-yl-tripyrrolidinylphosphonium.

Technical Solution 16:

The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any of the formulas 1-11 in free form or in a pharmaceutically acceptable salt form or in accordance with claims 12-13 a polymer as an active ingredient; and one or more pharmaceutically acceptable carrier materials and/or diluents.

Technical Solution 17:

The compound of any one of claims 1 to 11 or the polymer of any one of claims 12 to 13 or the pharmaceutical composition of claim 16 for the preparation of a therapeutic and/or prophylactic diabetes, weight loss or other with DPP-4 The use of drugs for related diseases.

Technical Solution 18:

The compound of any one of claims 1 to 11 or the polymer of any one of claims 12 to 13 or the pharmaceutical composition of claim 16 for use in the treatment and/or prevention of diabetes, weight loss or other with DPP-4 Related diseases.

It should be noted that the cycloalkyl group referred to in the present invention means a cycloalkyl group having one ring.

Chemically bonding eight different DPP-4 inhibitors and their analogs to a peptide chain fragment containing 1-6 amino acids or a peptide chain fragment containing 1-6 amino acids modified with a mercaptocarboxylic acid compound The DPP-4 inhibitor compound can be prepared by directly reacting with a mercaptocarboxylic acid compound, and the prepared compound can also be used as a repeating structural unit, and then through other chemical bonds, especially a disulfide bond, an acid sulfur bond or an amide bond. The DPP-4 inhibitor dimer or polymer is formed by bonding.

The inventors screened a large number of DPP-4 inhibitors currently on the market, using different DPP-4 inhibitors and their analogs, DPP-4 inhibitor effective functional groups and pharmaceutically acceptable salts of DPP-4 inhibitors. a derivative of an isomer, a prodrug, a derivative, and an effective functional group thereof, and amidating the amino or imino reactive functional group in the compound with a 1-6 amino acid or a short peptide containing a mercaptocarboxylic acid compound, DPP The -4 inhibitor-modified peptide chain is dimerized or polymerized by a disulfide bond or a simple other chemical bond to prepare a novel DPP-4 inhibitor polymer, thereby completing the present invention. At the same time, it is further illustrated by animal experiments that the compounds of the present invention are useful for the preparation of a medicament for the treatment and/or prevention of diabetes or other diseases associated with DPP-4.

When R1 and R2 are bridged by a disulfide bond, it can be carried out under the action of an oxidizing agent selected from the group consisting of iodine, bromine, hydrogen peroxide, peracetic acid, and urea peroxide. Of course, it is also possible to obtain, by purchase, a compound which has been bridged between R1 and R2 which has been prepared.

The invention has the beneficial effects of directly modifying a DPP-4 inhibitor or an analog thereof to a peptide chain fragment of a 1 to 6 natural, unnatural amino acid or mercaptocarboxylic acid compound, followed by dimerization or polymerization to obtain DPP. a -4 inhibitor compound or polymer that provides a homologous or heterodimer or multimer of a DPP-4 inhibitor that is longer than a marketed DPP-4 inhibitor Time course of action and lower clearance, such compounds by inhibiting the degradation activity of DPP-4 for GLP-1, specifically by blocking DPP-4 for the amino terminal two of GLP-1 or GLP-1 analogues Rapid degradation of amino acids, thereby prolonging the half-life of GLP-1 in vivo.

DRAWINGS

Figure 1 is a mass spectrum of a target compound prepared according to Example 1 of the present invention.

2 is a mass spectrum of a target compound prepared in Example 2 of the present invention.

detailed description

As described above, it is an object of the present invention to provide a DPP-4 inhibitor compound, a polymer, and a pharmaceutical composition, a process for the preparation thereof, and use thereof.

In particular, the present invention provides a compound of the formula (I), X-R1-R2-Y(I)

among them,

Wherein, the DPP-4 inhibitor is selected from the group consisting of sitagliptin, alogliptin, linagliptin, saxagliptin, vildagliptin, troglitazone, alogliptin or megliptin.

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same a secondary or tertiary amine group formed by the sitagliptin analog represented by the above formula (1), and most preferably a secondary or tertiary amine group formed by sitagliptin; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same a secondary or tertiary amine group formed by the alogliptin analog represented by the above formula (1), and most preferably a secondary or tertiary amine group formed by alogliptin; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same a secondary or tertiary amine group formed by the linagliptin analog represented by the above formula (1), and most preferably a secondary or tertiary amine group formed by linagliptin; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same a secondary or tertiary amine group formed by the saxagliptin analog represented by the above formula (1), most preferably a secondary or tertiary amine group formed by saxagliptin; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same The secondary or tertiary amine group formed by the statin analog represented by the above formula (1), most preferably vildagliptin is formed. a secondary or tertiary amine group; wherein R1 and R2 are the same, both are a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having from 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; Wherein an SS, CO-NH or CO-S bond is formed between R1 and R2.

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are the same as the grid a secondary or tertiary amine group formed by the statin analog represented by the above formula (1), and most preferably a secondary or tertiary amine group formed by troglitazone; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same The secondary or tertiary amine group formed by the alogliptin analog represented by the above formula (1) is most preferably a secondary or tertiary amine group formed by alogliptin; wherein R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are the same as Meg. a secondary or tertiary amine group formed by the statin analog represented by the above formula (1), most preferably a secondary or tertiary amine group formed by meglitin; wherein, R1 and R2 are the same, More preferably a mercaptocarboxylic acid group, more preferably a mercaptocarboxylic acid group having 1 to 6 carbon atoms, most preferably a mercaptopropionic acid group; wherein SS, CO-NH or CO-S bond is formed between R1 and R2 .

Wherein, in a preferred embodiment of the present invention, the present invention provides a compound of the formula (I), X-R1-R2-Y(I), wherein X and Y are both the same a secondary or tertiary amine group formed by the sitagliptin analog represented by the above formula (1), and most preferably a secondary or tertiary amine group formed by sitagliptin; wherein R1 and R2 are the same, a peptide chain fragment containing 1-6 natural or unnatural amino acids modified for a mercaptocarboxylic acid compound, more preferably a mercaptocarboxylic acid compound having 1 to 6 carbon atoms modified with 1-6 natural or unnatural amino acids The peptide chain fragment is most preferably a mercaptopropionylglycine group; wherein an SS, CO-NH or CO-S bond is formed between R1 and R2.

The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. However, the examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.

Among them, the manufacturer models of the reagents and instruments used in the examples are as follows:

Sitagliptin, alogliptin, linagliptin, vildagliptin, saxagliptin, meglitin, troglitazone, alogliptin, all purchased from Anrun Medical Technology (Suzhou) Limited company;

3,3'-dithiodipropionic acid, purchased from Aladdin;

Dimethylformamide, purchased from Zhejiang Jiangshan Chemical Co., Ltd.;

Benzotriazole-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBop), purchased from Suzhou Haofan Biotechnology Co., Ltd.;

N,N'-diisopropylethylamine (DIEA), purchased from Suzhou Wufan Biotechnology Co., Ltd.;

Mass spectrometer, model MALDI-TOF 4700, manufacturer AB SCIEX;

BP211D Sarorius electronic balance, manufacturer: Germany Sartorius Co., Ltd.;

BA-90 biochemical analyzer, model HL-YQ-4, manufacturer: Shenzhen Mindray;

High performance liquid chromatography, model Ultimate-U3000, manufacturer DIONEX;

The HPLC conditions used in the examples were as follows:

Using octadecylsilane bonded silica gel (5 μm, 250 × 4.6 mm) as a filler; 0.1% TFA solution as mobile phase A, acetonitrile as mobile phase B, gradient elution; flow rate of 1.0 ml per minute; The detection wavelength was 220 nm; the column temperature was 30 °C. Take 20 μl of the test solution and inject it into the liquid chromatograph to record the chromatogram.

(1) Chemical synthesis experiment

Embodiment 1

Chemical reaction

Add 1.01 mmol of sitagliptin to a 50 ml round bottom flask, dissolve it with 10 ml of dimethylformamide (DMF), and then add 0.50 mmol of 3,3'-dithiodipropionic acid to benzohexafluorophosphate. Triazol-1-yl-oxytripyrrolidinylphosphoryl (PyBop) 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) was added to the reaction solution, stirred at room temperature for 2h, and the reaction was confirmed by HPLC. The reaction solution was poured into a water solution of 10 times the volume of the reaction solution, and a large amount of a white solid was precipitated, stirred for 20 min, and filtered to give an off-white solid. The mass-to-charge ratio was measured by a mass spectrometer to be MSm/z: 991.225 (M+H), and the mass spectrum thereof is shown in Fig. 1.

Embodiment 2

Chemical reaction

Add alogliptin 1.01 mmol to a 50 ml round bottom flask, dissolve it with 10 ml of DMF, then add 0.50 mmol of 3,3'-dithiodipropionic acid, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04 Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.33 g. The mass-to-charge ratio was measured by a mass spectrometer to be MSm/z: 853.806 (M+H), and the mass spectrum thereof is shown in Fig. 2.

Embodiment 3

Chemical reaction

Add 1.03 mmol of linagliptin to a 50 ml round bottom flask, dissolve it with 10 ml of DMF, then add 0.50 mmol of 3,3'-dithiodipropionate, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04 Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.47 g. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 1119.476 (M+H).

Embodiment 4

Chemical reaction

1.01 mmol of vildagliptin was added to a 50 ml round bottom flask, which was dissolved in 10 ml of DMF, and then 0.50 mmol of 3,3'-dithiodipropionic acid, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04) Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.29 g. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 781.375 (M+H).

Embodiment 5

Chemical reaction

Add 1.01 mmol of saxagliptin to a 50 ml round bottom flask, dissolve it with 10 ml of DMF, and then add 0.50 mmol of 3,3'-dithiodipropionic acid, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04 Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.31 g. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 835.485 (M+H).

Embodiment 6

Chemical reaction

1.01 mmol of meglietti was added to a 50 ml round bottom flask, which was dissolved in 10 ml of DMF, and then 0.50 mmol of 3,3'-dithiodipropionate, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04 Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.34 g. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 815.297 (M+H).

Example 7

Chemical reaction

Add 1.01 mmol of troglitazone to a 50 ml round bottom flask, dissolve it with 10 ml of DMF, and then add 0.50 mmol of 3,3'-dithiodipropionate, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04 Methyl) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid. A large amount of white solid was precipitated, stirred for 20 min, and filtered to give a white solid. Dry to give the target compound 0.28 g. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 889.352 (M+H).

Example eight

Chemical reaction

1.01 mmol of alogliptin was added to a 50 ml round bottom flask, which was dissolved in 10 ml of DMF, and then 0.50 mmol of 3,3'-dithiodipropionic acid, PyBop 0.79 g (1.52 mmol), DIEA 0.50 ml (3.04) Ment) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. The reaction solution was poured into water of 10 times the volume of the reaction solution, and a large amount of white solid was precipitated, stirred for 20 min, and filtered to give an off-white solid. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 971.258 (M+H).

Example nine

Chemical reaction

Add 1.01 mmol of sitagliptin to a 50 ml round bottom flask, dissolve it with 10 ml of dimethylformamide (DMF), and then add 0.50 mmol of 3,3'-dithiodialanyl diglycine, PyBop 0.79. g (1.52 mmol), DIEA 0.50 ml (3.04 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 2 h. After the reaction of the HPLC was completed, the reaction solution was slowly poured into 10 times the volume of the reaction liquid, and a large amount of white solid was obtained. The mixture was stirred, stirred for 20 min, and filtered to give a white solid. The mass-to-charge ratio was measured by mass spectrometry to be MSm/z: 1103.260 (M+H).

(2) Animal experiment

The following method is to establish a rat model of diabetes by intraperitoneal injection of streptozotocin (STZ), and the DPP-4 inhibitor compounds prepared by subcutaneous injection of Examples 1 to 9 are used to evaluate their hypoglycemic effects for further screening. .

Material

1.1 Test samples and preparation methods

The preparation of the front UV lamp irradiated the preparation area for 30 minutes for sterilization, and then weighed 1.04 mg of the DPP-4 inhibitor compound prepared in the first to the ninth steps, respectively, and added 10.4 ml of the solvent to prepare a concentration of 100 ug/ml. Test solution.

The preparation method of the solvent is as follows: 0.71 g of Na ₂ HPO ₄ · 2H ₂ O is added and dissolved in 450 ml of distilled water, 7.0 g of propylene glycol and 2.75 g of phenol are added, the pH is adjusted to 7.7 with 1 mol/L NaOH solution, and the volume is adjusted to 500 ml with distilled water. Just fine.

1.2 modeling drugs and preparation methods

Name: Streptozotocin (STZ)

Purity: ≥98% (HPLC)

Specification: 1.0g / bottle

Batch number: WXBB7151V

Traits: white or off-white or light yellow crystalline powder

Storage conditions: -20 ° C

Production unit: Sigma-Aldrich

Preparation method: Before preparation, irradiate the preparation area with ultraviolet light for 30 minutes, weigh STZ and add 0.1mol/L sodium citrate-citrate buffer (pH=4.2) to prepare 10mg/ml solution (in the ice bath, protected from light) ).

1.3 experimental animals and feeding management

Twenty Wistar rats, male, weighing 180-220 g, were purchased from Shandong Lukang Pharmaceutical Co., Ltd., license number: SCXK (Lu) 20130001.

The animals were quarantined for 3 days, the temperature was 20 ~ 26 ° C, the humidity was 40 ~ 70%, the number of air changes: 10 ~ 15 times / h, lighting 12h per day.

2. Experimental methods

2.1 Model establishment

The rats were fasted for 8 hours, and the body weights were determined and randomly divided into blank control group and model group. The model group rats were intraperitoneally injected with STZ (60 mg/kg), and the blank control group was intraperitoneally injected with an equal volume of sodium citrate-citric acid buffer. During the period, the rats were observed for changes in feeding, urine output and body weight, and blood was taken 4 days later to measure fasting blood glucose. If there is polydipsia, polyphagia, polyuria, weight loss, blood sugar greater than 16.7mmol / L is successful modeling.

2.2 Experimental grouping and administration

Normal rats and diabetic rats were respectively divided into a normal control group and a drug-administered group. The rats in the normal control group were injected subcutaneously in a dose of 1 ml/kg; the drug-administered group was subcutaneously injected at a dose of 100 ug/kg. Sample solution.

3. Observation indicators and blood glucose determination

Measurement time: 3-7d after administration

Number of cases: full case

Examination method: blood was collected from the orbital vein, serum was routinely prepared, and blood glucose level was measured using a BA-90 blood biochemical analyzer.

4. Statistical processing

The data was entered and statistically analyzed using EXCEL2013 and SPSS13.0 software. The results are shown in Table 1.

Table 1 Screening and evaluation of DPP-4 inhibitor compounds on hypoglycemic effect in diabetic rats

±S; *p<0.05, **p<0.01 compared with each administration group before administration; ^★★ p<0.01 After administration, the administration group was compared with the normal control group.

5. Experimental results

The results of animal experiment results are shown in Table 1. From the results in Table 1, it can be seen that:

There was no significant difference in post-medication blood glucose between the normal control group and the pre-dose (P>0.05), indicating that the vehicle used in the present invention does not bring any change in blood glucose level to the rats; There was a significant difference between the drug group and the normal control group (P<0.01).

Among them, after 7 days of the first embodiment, the blood glucose level of the administration group decreased compared with that before administration, and showed significant difference (P<0.01). There was no significant difference between the blood glucose level of the administration group and the normal control group after administration. (P>0.05). The results of the measurement showed that the drug prepared in the first experiment showed good hypoglycemic effect, and it can reduce the blood sugar of the rat to a normal value during the measurement time, and showed a good hypoglycemic effect, and 7 days after the drug action There is almost no difference between the blood glucose level and the normal value. It can be seen that the preparation of the synthesized compound has a longer action curve, and the drug can be further studied and applied to the preparation of diabetes or blood sugar-related diseases.

After the effect of the fourth embodiment, the blood glucose level of the administration group decreased after 7 days and the effect of the sixth embodiment for 5 days, there was a significant difference (P<0.05, P<0.01), and the blood glucose level of the administration group after administration was compared with the normal control. There was a significant difference between the groups (P<0.01), indicating that although the blood glucose level did not decrease to the normal value during the measurement time, the drugs prepared in Example 4 and Example 6 still showed good hypoglycemic effect. We have reason to believe that drugs can also be used to prepare diabetes or blood sugar-related diseases.

The blood glucose level of the drug-administered group after 3 days of action, 3 days after the action of Example 3, 3 days after the action of Example 5, 7 days after the action of Example 7, 3 days after the action of Example 8 and 5 days after the effect of Example 9 There was no significant difference (P>0.05), and the blood glucose level of the drug-administered group was significantly different from that of the normal control group (P<0.01). The results of the measurement showed that although the drugs prepared in the above examples did not show significant hypoglycemic effects during the measurement time, the blood glucose levels of Example 2, Example 7 and Example 9 were compared before administration. For a downward trend. This suggests that the drugs we prepare are likely to be used to treat diabetes or blood sugar-related diseases. Due to the error of the experimental data detection, the blood glucose values of Example 3, Example 5, and Example 8 were slightly increased after administration, and the compounds prepared in Examples 3, 5, and 8 were theoretically analyzed. And the structure of its analogues, it is not difficult to conclude that the presence of these compounds can block the digestion of GLP-1 by DPP-4 enzyme, thereby increasing the GLP-1 in the blood. At the concentration, the potential for improving blood sugar control and protecting the function of β-cells is obtained. Therefore, even the experimental results in the third embodiment, the fifth embodiment, and the eighth embodiment are not ideal, but since linagliptin, saxagliptin, and alogliptin are already prepared by the drug, and combined with the experimental results of other examples, It is also reasonable for us to believe that the compounds prepared in Examples III, V and VIII are also of a medicinal property.

It is to be understood that the above-described embodiments are merely preferred embodiments of the present invention, and are merely used to illustrate the technical solutions of the present invention, and are not intended to limit the present invention, although the present invention has been described in detail by the preferred embodiments described above. It is to be understood that modifications, equivalents, and improvements made within the spirit and scope of the invention are intended to be included within the scope of the present invention.

Claims

A compound of the formula (I), X-R1-R2-Y (I)

among them,

X and Y are respectively a group formed by a DPP-4 inhibitor or a DPP-4 inhibitor analog containing an amino group or an imino group, or a DPP-4 inhibitor or a DPP-4 inhibitor similar to the aforementioned amino group or imino group. a pharmaceutically acceptable salt or optical isomer forming a group; wherein X and Y are the same or different;

R1 and R2 are respectively a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound group, or a peptide containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound. A fragment of a chain in which R1 and R2 are the same or different.
The compound according to claim 1, wherein in the structural formula of the formula (I),

X and Y are a secondary or tertiary amine group formed by a DPP-4 inhibitor or a DPP-4 inhibitor analog containing an amino group or an imino group, respectively, or a DPP-4 inhibitor or DPP containing the above amino group or imino group. a secondary or tertiary amine group formed by a pharmaceutically acceptable salt or optical isomer of the -4 inhibitor analog; wherein X and Y are the same or different;

R1 and R2 are respectively a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound group, or a peptide containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound. A chain fragment in which R1 and R2 are the same, and a CO-NH, SS or CO-S bond is formed between R1 and R2, preferably an SS bond.
The compound according to claim 1 or 2, wherein the amino group or imino group-containing DPP-4 inhibitor or DPP-4 inhibitor analog is selected from the group consisting of sitagliptin and the like, Agre. Ting and its analogues, linagliptin and its analogues, saxagliptin and its analogues, vildagliptin and its analogues, troglitazone and its analogues, alogliptin and analogues thereof Or meglitin and its analogues.
The compound according to claim 1 or 2, wherein in the structural formula of the formula (I),

X and Y are secondary amines selected from the group consisting of sitagliptin, alogliptin, linagliptin, saxagliptin, vildagliptin, troigliptin, alogliptin or megliptin, respectively. a tertiary amine group; R1 and R2 are the same, both are mercaptocarboxylic acids, and SS, CO-NH or CO-S bonds are formed between R1 and R2.
The compound according to claim 4, wherein said X and Y are the same, each selected from the group consisting of sitagliptin, alogliptin, linagliptin, saxagliptin, vildagliptin, and quarantine. a secondary or tertiary amine group of statin, alogliptin or meglitin; said R1 and R2 being the same, each being a fluorenylcarboxylic acid group having 1 to 6 carbon atoms, preferably a mercaptopropionic acid group group.
The compound according to claim 3, characterized in that

Among them, the structural formula of sitagliptin analogs is as follows:

In the formula (1), Ar is a phenyl group or a phenyl group substituted by a halogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a cyano group; X is an N atom and -CR 2 ; R 1 and R 2 are each independently selected from one of the following groups: H, cyano, unsubstituted or substituted by 1 to 5 halogen, cyano, hydroxy or carboxy, respectively. An alkyl, phenyl, five- or six-membered heterocyclic ring of 1-10; said Ar is preferably a halogen-substituted phenyl group, further preferably a fluorine or chlorine or bromine-substituted phenyl group, more preferably three halogen-substituted phenyl groups, Further preferably, three fluorine atoms or chlorine-substituted phenyl groups; the R 1 is preferably 1-3 halogen-substituted alkyl groups, more preferably three halogen-substituted methyl groups; wherein the sitagliptin analog does not include Sitagliptin itself;

The structural formula of the alogliptin analog is as follows:

In the formula (2), M is a nitrogen atom or -CR 4 , and R 2 , R 3 and R 4 are each independently selected from one of the following groups: unsubstituted or substituted by an amino group, a cyano group or a carboxylic acid, respectively. a linear or branched alkyl group having 1 to 10 carbon atoms, a cyclic alkyl group having 3 to 12 carbon atoms, a hetero atom-containing cyclic alkyl group having 3 to 12 carbon atoms or a carbon atom a 1-10 alkylcycloalkyl group; wherein R 3 is preferably an amino-substituted carbon atom-containing cycloalkyl group having 3 to 12 carbon atoms, the hetero atom being selected from nitrogen or oxygen or sulfur, more Preferred is an amino-substituted cycloalkyl group having 3 to 12 carbon atoms, more preferably an amino-substituted azacyclohexyl group; wherein L is selected from 1 to 3 N atoms, C atoms, O atoms or S The bridge of an atom, preferably a bridge of a C atom or an S atom; X is selected from one of the following groups: unsubstituted or substituted by amino, cyano, carboxylic acid, respectively, having a carbon number of 1-10 An alkyl group, a cyclic alkyl group having 3 to 12 carbon atoms, an aromatic cycloalkyl group having 1 to 10 carbon atoms, preferably an amino group, an aryl group having 6 to 10 carbon atoms substituted by a cyano group The alogliptin Alogliptin itself was not included;

The structural formula of the analog of linagliptin is as follows:

In the formula (3), R 1 is a naphthyl group or a naphthyl group each substituted by a methyl group, a methoxy group, a nitro group or a methylamino group; a 2-styryl group; a phenyl group; a cyclohexylcarbonyl group; a benzothienyl group; Or quinolyl; R 1 is preferably naphthyl or naphthyl substituted by methyl or methoxy, respectively; R 2 is methyl, isopropyl, 2-propenyl, phenyl, cyanomethyl or methoxy Carbonylmethyl, preferably methyl, phenyl, cyanomethyl; R 3 is 2-cyanophenyl, 2,6-dicyanophenyl, 2-methyl-2-propenyl, 2-chloro- 2-propenyl, 3-bromo-2-propenyl, 2-butenyl, 3-methyl-2-butenyl, 2,3-dimethyl-2-propenyl, 2-butynyl, 1 a cyclopentaethylenehexaminemethyl or 2-furanmethyl group, preferably 2-butynyl, 2-butenyl, 2-methyl-2-propenyl, more preferably 2-butynyl; Wherein the linagliptin analog does not include linagliptin itself;

The structural formula of the analog of saxagliptin is as follows:

In the formula (4), x is 1, y is 0 or x is 0, y is 1, n is 0 or 1, X is H or a cyano group, and R 1 , R 2 , R 3 and R 4 are each independently selected. From one of the following groups: H, unsubstituted or straight or branched alkyl, alkenyl, alkynyl substituted by halogen, straight or branched alkyl, nitro, cyano, amino or hydroxy, respectively , cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl, preferably straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicyclic An alkyl group, a tricycloalkyl group, a hydroxyalkyl group, an aralkyl group, a heterocyclic aryl group, more preferably a linear or branched alkyl group, an alkenyl group, an alkynyl group or a cycloalkyl group; wherein the saxagliptin Analogs do not include saxagliptin itself;

The structural formula of the analog of vildagliptin is as follows:

In formula (5), R 1 and R 2 are each independently selected from one of the group consisting of H, cyano, unsubstituted or straight-chain substituted by halogen, nitro, cyano, amino or hydroxy, respectively. Branched alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R 1 is preferably cyano, unsubstituted or a linear or branched alkyl group, a cycloalkyl group or an aralkyl group substituted by a cyano group or a hydroxy group, respectively, and R 2 is preferably a cycloalkyl group or an aralkyl group which is unsubstituted or substituted by a cyano group or a hydroxy group, respectively; Said vildagliptin analogue does not include vildagliptin itself;

The structural formula of the analog of troglitazone is as follows:

In the formula (6), R 1 and R 2 are each independently selected from one of the group consisting of H, unsubstituted or a straight or branched alkane substituted by a halogen, a nitro group, a cyano group, an amino group or a hydroxyl group, respectively. a base, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R 1 is preferably unsubstituted or halogen, cyano substituted a cycloalkyl group, an aralkyl group, more preferably a halogen or a cyano substituted aralkyl group; R 2 is preferably a linear or branched alkyl group, more preferably a methyl group, an ethyl group, a propyl group; The gliptin analogue does not include troglitazone itself;

The structural formula of the analogue of alogliptin is as follows:

In the formula (7), R 1 and R 2 are each independently selected from one of the group consisting of H, unsubstituted or a straight or branched alkyl group substituted by a halogen, a nitro group, a cyano group or an aminohydroxy group, respectively. , alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R 1 is preferably unsubstituted or halogen, cyano substituted ring An alkyl group, an aralkyl group, more preferably 1 to 3 halogen-substituted aralkyl groups; R 2 is preferably a cycloalkyl group or an aralkyl group which is unsubstituted or substituted by a cyano group or a hydroxy group, respectively; The statin analogue does not include alogliptin itself;

The structural formula of the analog of meglitin is as follows:

In the formula (8), R 1 , R 2 and R 3 are each independently selected from one of the following groups: H, cyano, unsubstituted or substituted by halogen, nitro, cyano, amino or hydroxy, respectively. a linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicycloalkyl, tricycloalkyl, hydroxyalkyl, aralkyl, heterocyclic aryl; wherein R 1 is preferably cyano, non Substituted or substituted by cyano, halogen substituted cycloalkyl, aralkyl, R 2 is preferably halogen or cyano substituted aralkyl, R 3 is preferably heterocycloalkyl or halogen substituted heteroaryl, Preferred is a halogen-substituted heterocyclic aryl group; wherein the meglitinine analog does not include meglitin itself.
The compound according to any one of claims 1 to 6, wherein the mercaptocarboxylic acid-containing compound is a mercaptocarboxylic acid having 1 to 8 carbon atoms, preferably mercaptopropionic acid, mercaptoacetic acid or mercaptobutyric acid. More preferably, it is 3-mercaptopropionic acid; the peptide chain fragment containing 1-6 natural or unnatural amino acids modified by the mercaptocarboxylic acid compound is modified by a mercaptocarboxylic acid having 1-8 carbon atoms; A peptide chain fragment of -6 natural or unnatural amino acids, preferably deuterated propionylglycine, deuterated acetylglycine or deuterated butyrylglycine, more preferably 3-mercaptopropionylglycine.
The compound according to claim 1, 3 or 6, wherein

A chemical bond selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, and CO-S bonds is formed between X and R1, preferably CO-NH, CO-S Or SS;

A chemical bond selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, and CO-S bonds is formed between Y and R2, preferably CO-NH, CO-S Or SS;

A chemical bond selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, and CO-S bonds is formed between R1 and R2, preferably CO-NH, CO-S Or SS.
The compound according to claim 8, wherein a CN, CO, CS or SS bond is formed between X and R1; a CN, CO, CS or SS bond is formed between Y and R2; and a CO is formed between R1 and R2 -NH, CO-S or SS.
The compound according to claim 8, wherein a C=N, C=C or CO-NH bond is formed between X and R1; and a C=N, C=C or CO-NH bond is formed between Y and R2. ; form a CO-NH, CO-S bond or SS bond between R1 and R2.
The compound according to claim 8, wherein a CO-NH bond is formed between X and R1; a CO-NH bond is formed between Y and R2; and an SS, CO-S bond or CO- is formed between R1 and R2. NH bond.
A polymer characterized by using the compound according to any one of claims 1 to 11 as a repeating structural unit represented by the formula [X-R1-R2-Y] n wherein n is 2 to 10 Integer.
The polymer according to claim 12, wherein said repeating structural unit is selected from the group consisting of CN, CO, C=N, CC, C=C, CS, SS, CO-NH, CO-S. A chemical bond, preferably a CO-NH, CO-S or SS bond.
A method of preparing a compound according to any one of claims 1-11, comprising the steps of:

A DPP-4 inhibitor containing an amino group or an imino group, or a DPP-4 inhibitor analog containing an amino group or an imino group, or a pharmaceutically acceptable salt or optical isomer of a DPP-4 inhibitor containing an amino group or an imino group The body is mixed with a peptide chain fragment containing 1-6 natural or unnatural amino acids, or a mercaptocarboxylic acid compound, or a peptide chain fragment containing 1-6 natural or unnatural amino acids modified with a mercaptocarboxylic acid compound, respectively. The reaction is carried out by the action of a crosslinking agent.
The preparation method according to claim 14, wherein the coupling agent is selected from the group consisting of 1,3-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-( 3-dimethylaminopropyl)-3-ethylcarbonyldiamine methyl iodide, N,N-diisopropylethylamine, N-methylmorpholine, 1-hydroxybenzotriazole, 2-(7- Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-N,N,N',N'-tetramethylurea hexafluoro Phosphate, 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate, 2-(1H-benzotriazolyl-1-yl)-1,1, 3,3-tetramethyluronium tetrafluoroborate, 5-norbornene-2,3-dicarbonyl-N,N,N',N'-tetramethyluronium tetrafluoroborate, hexafluorophosphate One or more of benzotriazol-1-yl-oxytripyrrolidinylphosphonium.
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1-11 or a polymer of claims 12-13 as a therapeutically effective amount in free form or in a pharmaceutically acceptable salt form An ingredient; and one or more pharmaceutically acceptable carrier materials and/or diluents.
A compound according to any one of claims 1 to 11 or a polymer according to any one of claims 12 to 13 or a pharmaceutical composition according to claim 16 for the preparation of a medicament for the treatment and/or prevention of diabetes, weight loss or other with DPP -4 The use of drugs for related diseases.
A compound according to any one of claims 1 to 11 or a polymer according to any one of claims 12 to 13 or a pharmaceutical composition according to claim 16 for use in the treatment and/or prevention of diabetes, weight loss or other with DPP -4 related diseases.