CN106810568A - DPP-4 inhibitor compounds, polymer and its preparation method and application - Google Patents

DPP-4 inhibitor compounds, polymer and its preparation method and application Download PDF

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CN106810568A
CN106810568A CN201510866369.5A CN201510866369A CN106810568A CN 106810568 A CN106810568 A CN 106810568A CN 201510866369 A CN201510866369 A CN 201510866369A CN 106810568 A CN106810568 A CN 106810568A
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alkyl
dpp
compound
amino
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张晓�
厉保秋
周俊
沈柯
路杨
杨东晖
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HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co Ltd
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HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co Ltd
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Priority to PCT/CN2015/098043 priority patent/WO2017092083A1/en
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala

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Abstract

The present invention relates to inhibitors of dipeptidyl IV drug field, and in particular to DPP-4 inhibitor compounds, polymer and preparation method and application.The compound structure is the group that X-R1-R2-Y, X and Y are respectively that the DPP-4 inhibitor containing amino or imino group or DPP-4 inhibitor analogues are formed；Or be the foregoing DPP-4 inhibitor containing amino or imino group or DPP-4 the inhibitor analogues group that pharmaceutically acceptable salt or optical isomer are formed；R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or for mercaptan carboxylic acid's compound group or be through the compound-modified peptide fragments of natural or alpha-non-natural amino acid containing 1-6 of mercaptan carboxylic acid.DPP-4 inhibitor compounds of the invention and polymer have the effect curves and lower clearance rate of longer time, while extending GLP-1 half-life period in vivo.

Description

DPP-4 inhibitor compounds, polymer and its preparation method and application
Technical field
The present invention relates to DPP IV (DPP-4) inhibitor medicaments field, and in particular to a class dipeptides Base peptase IV (DPP-4) inhibitor compound and polymer and its preparation method and application.
Background technology
Duodenin (incretin) is the help body carbon hydrate on the feed of small intestine endocrine cells secrete A kind of hormone of Postprandial insulin reaction is produced after thing, the effect of its insulin secretion accelerating accounts for Postprandial insulin The 60% of secretion total amount.So far it is separated go out 2 kinds of duodenins, i.e., glucose dependent insulin release Peptide (GIP) and glucagon-like-peptide-1 (GLP-1), and have the antidiabetic drug of the brand-new mechanism of action of two classes Listing, they are all by improving diabetes B (T2DM) patient GLP-1 levels so as to play hypoglycemic Effect.GLP-1 receptor stimulating agents can act on its acceptor instead of GLP-1, and avoid by dipeptidyl peptidase Enzyme -4 (DPP-4) is degraded, such as Exenatide, Liraglutide；And DPP-4 inhibitor then suppresses DPP-4 To the degradation of GLP-1, endogenous GLP-1 is set to accumulate in vivo and reach hypoglycemic effect, such as west Ge Lieting, vildagliptin etc..This two classes medicine has the functions such as protection islet cells, losing weight, while Seldom cause hypoglycemic reaction, clinical practice is increasingly extensive.
GLP-1 can be by dipeptidyl peptidase-4 (dipeptidyl peptidase-4, DPP-4) fast degradation (1~2min), is removed by kidney afterwards.DPP-4 inhibitor (row spit of fland class medicine) passes through competitive binding DPP-4 active sites, reduce the catalysis activity of enzyme, suppress GLP-1 degradeds, so as to lift GLP-1 exist Concentration in blood, obtaining improves glycemic control, the effect of protection β cell functions.
So far, 7 DPP-4 inhibitor have been listed in world wide：Xi Gelieting (sitagliptin), Vildagliptin (vildagliptin), BMS-477118 (saxagliptin), Egelieting (alogliptin), Li Gelieting (linagliptin), gigue row spit of fland (gemigliptin) and for Ge Lieting (teneligliptin). Wherein, Xi Gelieting, vildagliptin and BMS-477118 are listed in China, and Egelieting and Li Gelieting are Clinical application is proposed in China, gigue row spit of fland then authorizes double crane pharmacy to open in China by LG Life Sciences Hair.
DPP-4 inhibitor can correct alpha Cell of islet by improving the biological effect of endogenous GLP-1 The inappropriate secretion of glucagon caused by dysfunction.DPP-4 inhibitor reduces the mechanism of glucagon secretion Including：Elevated GLP-1 directly acts on alpha Cell of islet and suppresses glucagon secretion, by stimulating pancreas Island delta cell secretion growth hormone release inhibiting hormone plays indirectly-acting with insulin secretion is promoted.
The content of the invention
Problem of the prior art solved by the invention is：Existing DPP-4 inhibitor limitednumber, and And its half-life short in vivo, the continuous action time of medicine is shorter, and effect curative effect has to be strengthened.
In order to solve the above problems, the invention provides a kind of DPP-4 inhibitor compounds, polymer with And pharmaceutical composition and preparation method thereof, while present invention also offers DPP-4 inhibitor compounds or poly- Compound is being prepared treatment and/or prevention diabetes, subtracted by it as the pharmaceutical composition that active component is formed Fertilizer or other with DPP-4 relevant disease medicines in terms of purposes and for treat and/or prevent diabetes, Fat-reducing or other diseases related to DPP-4.
Specifically, the invention provides following technical scheme：
Technical scheme 1：
A kind of compound shown in formula (I) structure, X-R1-R2-Y (I)
Wherein,
It is similar that X is respectively DPP-4 inhibitor or DPP-4 inhibitor containing amino or imino group with Y The group that thing is formed, or be that the foregoing DPP-4 inhibitor containing amino or imino group or DPP-4 press down The formulation analogous group that pharmaceutically acceptable salt or optical isomer are formed；Wherein X is identical with Y Or it is different；
R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or are sulfydryl Carboxylic acid compound group or be that 1-6 is natural or non-natural ammonia through mercaptan carboxylic acid's compound-modified containing The peptide fragments of base acid, wherein, R1 and R2 are identical or different.
Technical scheme 2：
In the formula (I) structural formula,
It is similar that X is respectively DPP-4 inhibitor or DPP-4 inhibitor containing amino or imino group with Y Secondary amine or tertiary amine group that thing is formed, or for the foregoing DPP-4 inhibitor containing amino or imino group or Person DPP-4 inhibitor analogues secondary amine or tertiary amine that pharmaceutically acceptable salt or optical isomer are formed Group；Wherein X and Y are identical or different；
R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or are sulfydryl Carboxylic acid compound group or be that 1-6 is natural or non-natural ammonia through mercaptan carboxylic acid's compound-modified containing Base acid peptide fragments, wherein, R1 is identical with R2, between R1 and R2 formed CO-NH, S-S or CO-S keys, preferably S -- S.
Technical scheme 3：
The DPP-4 inhibitor containing amino or imino group or DPP-4 inhibitor analogues are selected from west Ge Lieting and the like, Egelieting and the like, Li Gelieting and the like, BMS-477118 and Its analog, vildagliptin and the like, song Ge Lieting and the like, Ao Gelieting and the like Or melogliptin and the like.
Technical scheme 4：
In the formula (I) structural formula,
X and Y are respectively selected from Xi Gelieting, Egelieting, Li Gelieting, BMS-477118, Wei Gelie The secondary amine or tertiary amine group in spit of fland, song Ge Lieting, Ao Gelieting or melogliptin；R1 is identical with R2, is Mercaptan carboxylic acid, forms S-S, CO-NH or CO-S key between R1 and R2.
Technical scheme 5：
The X is identical with Y, be selected from Xi Gelieting, Egelieting, Li Gelieting, BMS-477118, The secondary amine or tertiary amine group of vildagliptin, song Ge Lieting, Ao Gelieting or melogliptin；The R1 and R2 It is identical, it is mercaptan carboxylic acid's group that carbon number is 1-6, preferably mercaptopropionic acid group.
Technical scheme 6：
Xi Gelieting analog general structures are as follows：
Formula (1)
In formula (1), Ar is for phenyl or respectively by halogen, alkyl, the carbon number that carbon number is 1-6 For the phenyl that the alkoxy or cyano group of 1-6 replace；X is N atoms and-CR2；R1And R2Independently of one another Selected from the one kind in following group：H, cyano group is unsubstituted or respectively by 1-5 halogen, cyano group, hydroxyl Or the carbon number of carboxyl substitution is alkyl, phenyl, five yuan or the hexa-member heterocycle of 1-10；The Ar is preferred It is halogen substituted phenyl, also preferably fluorine or chlorine or bromine substituted-phenyl, more preferably three halogen substituted phenyls, More preferably three fluorine atoms or chlorine substituted-phenyl；The R1Preferably 1-3 halogen-substituted alkyl, More preferably three halogen substituent methyls；Wherein, the Xi Gelieting analogs do not include Xi Gelieting itself；
The general structure of wherein Egelieting analog is as follows：
Formula (2)
In formula (2), M is nitrogen-atoms or-CR4, and R2, R3And R4It is independently selected from following base One kind in group：It is non-substituted or respectively by the carbon number of amino, cyano group, carboxylic acid-substituted for 1-10 Straight or branched alkyl, carbon number are the cyclic alkyl of 3-12, carbon number is 3-12 containing hetero atom Cyclic alkyl or carbon number are the one kind in the aromatic ring alkyl of 1-10；Wherein, R3Preferably amino substitution Carbon number for 3-12 alkyl containing heteroatomic ring, the hetero atom be selected from nitrogen or oxygen or sulphur, more preferably For the carbon number of amino substitution is the nitrogen atom cycloalkyl of 3-12, even more preferably for amino replaces Piperidyl；Wherein L is selected from the 1-3 bridge chain of N atoms, C atoms, O atom or S atom, The preferably bridge chain of C atoms, S atom；X is selected from the one kind in following group：It is non-substituted or respectively by Amino, cyano group, the carbon number of carboxylic acid-substituted are the straight chained alkyl of 1-10, and carbon number is the ring of 3-12 Shape alkyl, carbon number is the aromatic ring alkyl of 1-10, and preferably amino, the carbon number of cyano group substitution are The aromatic ring alkyl of 6-10；Wherein, the Egelieting analog does not include Egelieting itself；
The analog general structure of wherein Li Gelieting is as follows：
Formula (3)
In formula (3), R1For naphthyl or respectively by the naphthalene of methyl, methoxyl group, nitro or methylamino substitution Base；2- styryls；Connect phenyl；Cyclohexyl-carbonyl；Benzothienyl or quinolyl；R1Preferably naphthyl Or respectively by methyl, the naphthyl of methoxy substitution；R2It is methyl, isopropyl, 2- acrylic, phenyl, cyanogen Methyl or methoxy carbonvlmethyl, preferably methyl, phenyl, cyanogen methyl；R3It is 2- cyano-phenyls, 2,6- Dicyano phenyl, 2- methyl -2- acrylic, 2- chloro-2-propenes base, bromo- 2 acrylic of 3-, 2- cyclobutenyls, 3- Methyl-2-butene base, 2,3- dimethyl -2- acrylic, 2- butynyls, 1- ring penten methyl or 2- Furfuryl, preferably 2- butynyls, 2- cyclobutenyls, more preferably 2- methyl -2- acrylic, 2- butynyls； Wherein, the Li Gelieting analogs do not include Li Gelieting itself；
The analog general structure of wherein BMS-477118 is as follows：
Formula (4)
In formula (4), x is that 1, y is that 0 or x is that 0, y is that 1, n is 0 or 1, X are H or cyanogen Base, R1, R2, R3And R4It is each independently selected from the one kind in following group：H, it is non-substituted or point Not by halogen, straight or branched alkyl, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, Alkenyl, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl, it is excellent Elect as straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, Aralkyl, heterocyclic aryl, more preferably straight or branched alkyl, alkenyl, alkynyl, cycloalkyl；Wherein, The BMS-477118 analog does not include BMS-477118 itself；
The analog general structure of wherein vildagliptin is as follows：
Formula (5)
In formula (5), R1And R2Separately selected from the one kind in following group：H, cyano group is non-to take Generation or respectively by halogen, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, alkenyl, Alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1Preferably cyano group, straight or branched alkyl, cycloalkanes non-substituted or replaced by cyano group, hydroxyl respectively Base, aralkyl, R2Cycloalkyl, aralkyl preferably non-substituted or replaced by cyano group, hydroxyl respectively； Wherein, the vildagliptin analog does not include vildagliptin itself；
The analog general structure of wherein song Ge Lieting is as follows：
Formula (6)
In formula (6), R1And R2Separately selected from the one kind in following group：H, it is non-substituted or Respectively by halogen, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, alkenyl, alkynyl, Cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1It is preferred that It is non-substituted or halogen, cycloalkyl, the aralkyl of cyano group substitution, more preferably halogen or cyano group replaces Aralkyl；R2Preferably straight or branched alkyl, more preferably methyl, ethyl, propyl group；Wherein, institute Stating bent Ge Lieting analogs does not include song Ge Lieting itself；
The analog general structure of wherein Ao Gelieting is as follows：
Formula (7)
In formula (7), R1And R2Separately selected from the one kind in following group：H, it is non-substituted or Straight or branched alkyl, alkenyl, alkynyl, the ring for being replaced by halogen, nitro, cyano group, hydroxy amino respectively Alkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1Preferably Non-substituted or halogen, cycloalkyl, the aralkyl of cyano group substitution, the more preferably 1-3 virtue of halogen substitution Alkyl；R2Cycloalkyl, aralkyl preferably non-substituted or replaced by cyano group, hydroxyl respectively；Wherein, The Ao Gelieting analogs do not include Ao Gelieting itself；
The analog general structure of wherein melogliptin is as follows：
Formula (8)
In formula (8), R1、R2And R3Separately selected from the one kind in following group：H, cyano group, Straight or branched alkyl, alkene non-substituted or replaced by halogen, nitro, cyano group, amino or hydroxyl respectively Base, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein R1Preferably cyano group, cycloalkyl, aralkyl non-substituted or replaced by cyano group, halogen respectively, R2It is excellent Elect the aralkyl of halogen or cyano group substitution, R as3The heterocyclic aryl that preferably Heterocyclylalkyl or halogen replace, The heterocyclic aryl that more preferably halogen replaces；Wherein, the melogliptin analog does not include melogliptin certainly Body.
Technical scheme 7：
It is described containing mercaptan carboxylic acid's compound be carbon number for 1-8 mercaptan carboxylic acid, be preferably mercaptopropionic acid, TGA or mercaptobutyric acid, more preferably 3- mercaptopropionic acids；It is described compound-modified through mercaptan carboxylic acid Containing 1-6, the peptide fragments of natural or alpha-non-natural amino acid are for the mercaptan carboxylic acid of 1-8 repaiies through carbon number The peptide fragments of the or alpha-non-natural amino acid natural containing 1-6 of decorations, preferably mercapto is for Propionylglycine, mercapto For acetoglycocoll or mercapto for butyryl glycine, more preferably 3- mercapto-propionyl-glycins.
Technical scheme 8：
Formd between X and R1 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S, preferably CO-NH, CO-S or S-S；
Formd between Y and R2 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S, preferably CO-NH, CO-S or S-S；
Formd between R1 and R2 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S, preferably CO-NH, CO-S or S-S.
Technical scheme 9：
C-N, C-O, C-S or S -- S are formed between X and R1；Between Y and R2 formed C-N, C-O, C-S or S -- S；CO-NH, CO-S or S -- S are formed between R1 and R2.
Technical scheme 10：
C=N, C=C or CO-NH key are formed between X and R1；C=N, C=C are formed between Y and R2 Or CO-NH keys；CO-NH, CO-S or S -- S are formed between R1 and R2.
Technical scheme 11：
CO-NH keys are formed between X and R1；CO-NH keys are formed between Y and R2；R1 and R2 it Between formed S-S, CO-S or CO-NH key.
Technical scheme 12：
Invention also provides a kind of polymer, made using any described compounds of technical scheme 1-11 It is constitutional repeating unit, its formula is expressed as [X-R1-R2-Y]n, wherein n is 2~10 integer.
Technical scheme 13：
Between the constitutional repeating unit using selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, A kind of chemical bond in CO-NH, CO-S, preferably CO-NH, CO-S or S -- S.
Technical scheme 14：
Invention also provides the preparation method of compound described in any of the above, comprise the following steps：
By the DPP-4 inhibitor containing amino or imino group or the DPP-4 containing amino or imino group Inhibitor analogue or the DPP-4 inhibitor pharmaceutically acceptable salt containing amino or imino group or Optical isomer respectively with peptide fragments or the mercaptan carboxylic acid of the natural or alpha-non-natural amino acid containing 1-6 Compound or through the compound-modified peptide chain of natural or alpha-non-natural amino acid containing 1-6 of mercaptan carboxylic acid Fragment mixes, and is reacted in the presence of coupling agent.
Technical scheme 15：
The coupling agent is selected from 1,3- dicyclohexylcarbodiimides, N, N '-DIC, 1- (3- dimethylamino-propyls) -3- ethylcarbonyl group diamines methiodide, DIPEA, N- methylmorphines Quinoline, I-hydroxybenzotriazole, 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluoro Phosphate, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, 6- Chloro-Benzotriazoles - 1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, 2- (1H- benzo trisazo- L-1- yls) -1,1,3,3- tetramethylureas Tetrafluoro boric acid ester, 5- ENB -2,3- dicarbapentaborane-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, It is more than one or more in hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus.
Technical scheme 16：
Present invention also offers a kind of pharmaceutical composition, it is characterised in that the pharmaceutical composition has comprising treatment Compound or technical scheme described in the free form of effect amount or the technical scheme 1-11 of pharmaceutical acceptable salt Polymer described in 12-13 is used as active component；With one or more medicinal carrier substance and/or diluent.
Technical scheme 17：
Any described compounds of technical scheme 1-11 or any described polymer of technical scheme 12-13 Or the pharmaceutical composition described in technical scheme 16 is preparing treatment and/or prevention diabetes, is losing weight or other With the purposes in terms of the medicine of DPP-4 relevant diseases.
Technical scheme 18：
Any described compounds of technical scheme 1-11 or any described polymer of technical scheme 12-13 Or the pharmaceutical composition described in technical scheme 16 be used for treat and/or prevent diabetes, fat-reducing or other with DPP-4 related disease.
It should be noted that the cycloalkyl that the present invention is mentioned, refers to a cycloalkyl for ring.
Eight kinds of different DPP-4 inhibitor and the like are entered with the peptide fragments containing 1-6 amino acid Row chemical bonding, or enter with through the compound-modified peptide fragments containing 1-6 amino acid of mercaptan carboxylic acid Row chemical bonding, or directly with mercaptan carboxylic acid's compound react, prepare DPP-4 inhibitor chemical combination Thing, at the same can also using the compound for preparing as constitutional repeating unit, then by other chemical bonds, Especially the mode of disulfide bond, acyl sulfide linkage or amido link bonding forms DPP-4 inhibitor dimerization or polymer.
Inventor has carried out substantial amounts of screening to the DPP-4 inhibitor for having listed at present, from different DPP-4 inhibitor and the like, the effective functional group of DPP-4 inhibitor and DPP-4 inhibitor pharmaceutically may be used The derivative of the salt of receiving, isomers, prodrug, derivative and its effective functional group, by the ammonia in compound Base or imino group active function groups are carried out with 1-6 amino acid or small peptide containing mercaptan carboxylic acid's compound respectively Amidation process, the peptide chain after the modification of DPP-4 inhibitor is carried out by disulfide bond or simple other chemical bonds Dimerization or poly, prepare the DPP-4 inhibitor polymers of structure novel, so as to complete the present invention. Compound of the invention is further illustrated by zoopery simultaneously to can be applied to prepare treatment and/or prevention sugar Urine medicine or other and DPP-4 relevant diseases medicine aspect.
If carry out bridging by disulfide bond between R1 and R2, can be carried out in the presence of oxidant, wherein Oxidant is selected from the one kind in iodine, bromine, hydrogen peroxide, Peracetic acid, carbamide peroxide.Certainly, also may be used With the direct compound by being commercially available bridging between the R1 and R2 that have prepared.
The beneficial effects of the present invention are：DPP-4 inhibitor or its analog are directly modified to one section 1 Dimerization or many is then carried out on to the peptide fragments of 6 natural, alpha-non-natural amino acids or mercaptan carboxylic acid's compound It is poly-, DPP-4 inhibitor compounds or polymer are obtained, such condensate suppresses there is provided a kind of DPP-4 The homologous or heterodimer or polymer of agent, it is longer with the DPP-4 inhibitor class medicines than having listed The effect curves of time and lower clearance rate, such compound is with by suppressing DPP-4 for GLP-1 Degrading activity, be embodied in blocking DPP-4 for GLP-1 or GLP-1 analogs amino end The fast degradation of two amino acids is held, so as to extend GLP-1 half-life period in vivo.
Brief description of the drawings
Fig. 1 is the mass spectrogram of the target compound that the embodiment of the present invention one is prepared.
Fig. 2 is the mass spectrogram of the target compound that the embodiment of the present invention two is prepared.
Specific embodiment
As described above, it is an object of the invention to：A kind of DPP-4 inhibitor compounds, polymer are provided And pharmaceutical composition, their preparation method and purposes.
Specifically, the invention provides the compound shown in a kind of formula (I) structure, X-R1-R2-Y (I)
Wherein,
It is similar that X is respectively DPP-4 inhibitor or DPP-4 inhibitor containing amino or imino group with Y The group that thing is formed, or be that the foregoing DPP-4 inhibitor containing amino or imino group or DPP-4 press down The formulation analogous group that pharmaceutically acceptable salt or optical isomer are formed；Wherein X is identical with Y Or it is different；
R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or are sulfydryl Carboxylic acid compound group or be that 1-6 is natural or non-natural ammonia through mercaptan carboxylic acid's compound-modified containing The peptide fragments of base acid, wherein, R1 and R2 are identical or different.
Wherein, DPP-4 inhibitor is selected from Xi Gelieting, Egelieting, BI 1356, BMS-477118, dimension Ge Lieting, song Ge Lieting, Ao Gelieting or melogliptin.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be Xi Gelieting or foregoing Secondary amine or tertiary amine group that the Xi Gelieting analogs that formula (1) is represented are formed, most preferably Xi Gelieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be Egelieting or foregoing Secondary amine or tertiary amine group that the Egelieting analog that formula (1) is represented is formed, most preferably Egelieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be Li Gelieting or foregoing Secondary amine or tertiary amine group that the Li Gelieting analogs that formula (1) is represented are formed, most preferably Li Gelieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be BMS-477118 or foregoing Secondary amine or tertiary amine group that the BMS-477118 analog that formula (1) is represented is formed, most preferably BMS-477118 are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be vildagliptin or foregoing Secondary amine or tertiary amine group that the vildagliptin analog that formula (1) is represented is formed, most preferably vildagliptin are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be bent Ge Lieting or foregoing Secondary amine or tertiary amine group that the bent Ge Lieting analogs that formula (1) is represented are formed, optimal selected songs Ge Lieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be Ao Gelieting or foregoing Secondary amine or tertiary amine group that the Ao Gelieting analogs that formula (1) is represented are formed, most preferably Ao Gelieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be melogliptin or foregoing Secondary amine or tertiary amine group that the melogliptin analog that formula (1) is represented is formed, most preferably melogliptin are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is mercaptan carboxylic acid's group, and more preferably carbon is former Subnumber is mercaptan carboxylic acid's group of 1-6, most preferably mercaptopropionic acid group；Shape between wherein R1 and R2 Into S-S, CO-NH or CO-S key.
Wherein, in the preferred embodiment of the present invention, the invention provides a kind of formula (I) structure Shown compound, X-R1-R2-Y (I), wherein, X is identical with Y to be Xi Gelieting or foregoing Secondary amine or tertiary amine group that the Xi Gelieting analogs that formula (1) is represented are formed, most preferably Xi Gelieting are formed Secondary amine or tertiary amine group；Wherein, R1 is identical with R2, is that mercaptan carboxylic acid is compound-modified to be contained 1-6 natural or alpha-non-natural amino acid peptide fragments, more preferably carbon number is the mercaptan carboxylic acid of 1-6 The peptide fragments of compound-modified or alpha-non-natural amino acid natural containing 1-6, most preferably mercaptopropionyl Glycine group；S-S, CO-NH or CO-S key are formed between wherein R1 and R2.
Make further detailed description to the present invention with specific embodiment below in conjunction with the accompanying drawings.But, this A little embodiments are only for the explanation present invention, without limiting the scope of the present invention.
Wherein, manufacturer's model of reagent used in embodiment and instrument is as follows：
Xi Gelieting, Egelieting, Li Gelieting, vildagliptin, BMS-477118, melogliptin, Qu Ge Row spit of fland, Ao Gelieting is purchased from peace profit medical sci-tech (Suzhou) Co., Ltd；
3,3 '-dithiodipropionic acid, purchased from Aladdin；
Dimethylformamide, purchased from Jiangshan Chemical Co Ltd, Zhejiang；
Hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus (PyBop), give birth to purchased from Suzhou sky sail Thing Science and Technology Ltd.；
N, N '-diisopropylethylamine (DIEA), purchased from Suzhou Wu Fan bio tech ltd；
Mass spectrograph, model MALDI-TOF 4700, vendor A B SCIEX；
BP211D Sarorius electronic balances, manufacturer：German Sartorius AG；
BA-90 Biochemical Analyzers, model HL-YQ-4, manufacturer：Shenzhen steps auspicious；
High performance liquid chromatograph, model Ultimate-U3000, manufacturer DIONEX；
The testing conditions of HPLC wherein used in embodiment are：
It is filler with octadecylsilane chemically bonded silica (5 μm, 250 × 4.6mm)；With 0.1%TFA Solution is mobile phase A, with acetonitrile as Mobile phase B, carries out gradient elution；Flow velocity is 1.0ml per minute； Detection wavelength is 220nm；30 DEG C of column temperature.The μ l of need testing solution 20 are taken, liquid chromatograph, record is injected Chromatogram.
(1) experiment of synthetic chemistry
Embodiment one
Chemical equation
Xi Gelieting 1.01mmol are added in 50ml round-bottomed flasks, using 10ml dimethylformamides (DMF) dissolved, then by 3,3 '-dithiodipropionic acid 0.50mmol, hexafluorophosphoric acid BTA -1- Base-epoxide tripyrrole alkyl phosphorus (PyBop) 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) It is added in reaction solution, reaction 2h is stirred at room temperature, detects that raw material reaction is complete by HPLC, by reaction solution Slowly pour into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stir 20min, mistake Filter, obtains off-white powder, dries, and obtains target compound 0.37g.Mass-to-charge ratio is detected by mass spectrograph For MSm/z:991.225 (M+H), its mass spectrogram is as shown in Figure 1.
Embodiment two
Chemical equation
Egelieting 1.01mmol is added in 50ml round-bottomed flasks, is dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.33g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:853.806 (M+H), its mass spectrogram is as shown in Figure 2.
Embodiment three
Chemical equation
Li Gelieting 1.01mmol are added in 50ml round-bottomed flasks, are dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.47g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:1119.476(M+H).
Example IV
Chemical equation
Vildagliptin 1.01mmol is added in 50ml round-bottomed flasks, is dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.29g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:781.375(M+H).
Embodiment five
Chemical equation
BMS-477118 1.01mmol is added in 50ml round-bottomed flasks, is dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.31g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:835.485(M+H).
Embodiment six
Chemical equation
Melogliptin 1.01mmol is added in 50ml round-bottomed flasks, is dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.34g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:815.297(M+H).
Embodiment seven
Chemical equation
Bent Ge Lieting 1.01mmol are added in 50ml round-bottomed flasks, are dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.28g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:889.352(M+H).
Embodiment eight
Chemical equation
Ao Gelieting 1.01mmol are added in 50ml round-bottomed flasks, are dissolved using 10mlDMF, Again by 3,3 '-dithiodipropionic acid 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) is added in reaction solution, and reaction 2h is stirred at room temperature, and treats that HPLC detection raw material reactions are complete, Reaction solution is slowly poured into 10 times of water of reaction solution volume, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains off-white powder, dries, and obtains target compound 0.35g.Examined by mass spectrograph Surveying mass-to-charge ratio is, MSm/z:971.258(M+H).
Embodiment nine
Chemical equation
Xi Gelieting 1.01mmol are added in 50ml round-bottomed flasks, using 10ml dimethylformamides (DMF) dissolved, then by 3,3 '-dithio dipropyl aminoacyl Diglycocol 0.50mmol, PyBop 0.79g (1.52mmol), DIEA 0.50ml (3.04mmol) are added in reaction solution, and reaction 2h is stirred at room temperature, Treat that HPLC detection raw material reactions are complete, reaction solution is slowly poured into 10 times of water of reaction solution volume, have A large amount of white solids are separated out, and stir 20min, and filtering obtains off-white powder, dries, and obtains targeted Compound 0.32g.Detect that mass-to-charge ratio is by mass spectrograph, MSm/z:1103.260(M+H).
(2) zoopery
Following method is to set up rat diabetes model using intraperitoneal injection streptozotocin (STZ), is passed through The DPP-4 inhibitor compounds that hypodermic injection embodiment one to nine is prepared evaluate they hypoglycemic make With so as to make further screening.
1. material
1.1 test samples and compound method
Uviol lamp carries out disinfection sterilizing preparation area irradiation 30min before preparing, and 1.04mg is then weighed respectively The DPP-4 inhibitor compounds that embodiment one is prepared to embodiment nine, are separately added into 10.4ml solvents, It is configured to the need testing solution that concentration is 100ug/ml.
Wherein, the compound method of solvent is as follows：Take Na2HPO4·2H2O 0.71g add 450ml distilled water Dissolving, adds 7.0g propane diols and 2.75g phenol, and it is 7.7 to adjust PH with 1mol/LNaOH solution, Distilled water is settled to 500ml mixings.
1.2 modeling medications and compound method
Title：Streptozotocin (STZ)
Purity：>=98% (HPLC)
Specification：1.0g/ bottles
Lot number：WXBB7151V
Proterties：White or off-white color or light yellow crystalline powder
Preservation condition：-20℃
Production unit：Sigma-Aldrich
Compound method：Prepare preceding uviol lamp and preparation area is irradiated into 30min, weigh STZ and add 0.1mol/L Sodium citrate-citric acid buffer solution (PH=4.2), (lucifuge is matched somebody with somebody in ice bath to be configured to the solution of 10mg/ml System).
1.3 experimental animals and feeding and management
Wistar rats 20, male, 180~220g of body weight is purchased from Shandong Shandong Pharmaceuticals Ltd, Credit number：SCXK (Shandong) 20130001.
Animal enters the room and quarantines 3 days, 20~26 DEG C of temperature, humidity 40~70%, rate of ventilation：10~15 times / h, illuminates 12h daily.
2. experimental technique
2.1 models are set up
Body weight will be determined after experimental rat fasting 8h, and be randomly divided into blank control group and model group, wherein Model group rats intraperitoneal injection STZ (60mg/kg), the isometric sodium citrate of blank control group intraperitoneal injection- Citrate buffer solution；Period, observation rats eating situation, urine volume and changes of weight, and in blood sampling after 4d Survey fasting blood-glucose.If many drinks, many food, diuresis occur, becoming thin, blood sugar is modeling more than 16.7mmol/L Success.
2.2 experiment packets and administration
Normal rat and diabetes rat are taken respectively, Normal group and administration group are respectively defined as, wherein Rats in normal control group according to 1ml/kg amount, hypodermic injection solvent；Administration group according to 100ug/kg amount Hypodermic injection need testing solution.
3. observation index and blood sugar detection
Minute：3-7d after administration
Number of cases：Full example
Inspection method：Orbital vein is taken a blood sample, and routinely prepares serum, is entered using BA-90 blood biochemistry analyzers Row determines blood glucose value.
4. statistical procedures
Typing and statistical analysis are carried out to data using EXCEL2013 and SPSS13.0 softwares.Result is such as Shown in table 1.
Screening and assessment of the table 1DPP-4 inhibitor compounds to diabetes rat blood sugar reducing function
±S；*p<0.05,**p<0.01 compares with each administration group with before administration；★★p<Administration group after 0.01 administration Compare with Normal group.
5. experimental result
Results of animal data are shown in Table 1, from the results shown in Table 1：
Blood sugar no significant difference (P compared with before medicine after Normal group medicine>0.05), illustrate of the invention used Solvent will not bring the change of any blood glucose value to rat in itself；And blood-sugar level measuring result table after being administered Bright, administration group has notable difference (P compared with Normal group<0.01).
Wherein, administration group blood glucose value declines compared with before administration after embodiment one is acted on 7 days, and shows Significant difference (P<0.01), administration group blood glucose value no significant difference compared with Normal group after administration (P>0.05).Measurement result shows that the medicine that experimental example one is prepared shows good hypoglycemic effect, It can make rat blood sugar be reduced to normal value within the time for determining, and show good hypoglycemic effect, Simultaneously because medicine act on 7 days after its blood glucose value and normal value almost without difference, it can be seen that prepare synthesis Compound have the effect curves of longer time, medicine can further be studied and be applied to prepare glycosuria Disease or the disease related to blood sugar.
Example IV act on 7 days after and embodiment six effect 5 days after administration group blood glucose value compared with before administration under Drop, there is notable difference (P<0.05, P<0.01), after administration administration group blood glucose value compared with Normal group There is notable difference (P<0.01), although showing within the time for determining, although blood glucose value is not lowered to just Constant value, but medicine prepared by example IV and embodiment six still shows good hypoglycemic effect, makes me Have reason to believe equally can by medicinal application in prepare diabetes or the disease related to blood sugar.
Embodiment two act on 3 days after, embodiment three act on 3 days after, embodiment five act on 3 days after, implement Example seven act on 7 days after, embodiment eight act on 3 days after and embodiment nine act on 5 days after administration group blood glucose value with Compared to simultaneously no significant difference (P before administration>0.05), after administration administration group blood glucose value compared with Normal group There is notable difference (P<0.01).Measurement result shows, although the medicine that above example is prepared is being surveyed In the fixed time, obvious hypoglycemic effect is not shown, but embodiment two, embodiment seven and real Apply example nine blood glucose value compare administration before still show as downward trend.This points out the medicine that we prepare Thing is more likely used for treating diabetes or the disease related to blood sugar.Due to the error of experimental data detection, Blood glucose value slightly has fluctuation rising compared with before administration after embodiment three, embodiment five, the administration of embodiment eight, and The structure of the compound that theoretically analysis embodiment three, five, eight is prepared and the like, not seldom To go out these compound presence can block DPP-4 enzyme digestion GLP-1, so as to lift GLP-1 in blood Concentration, obtaining improves glycemic control, the Potential feasibility of the effect of protection β cell functions.So even being Embodiment three, embodiment five, the experimental result of embodiment eight are not ideal, but due to Li Gelieting, sand Ge Lieting, Ao Gelieting patent medicine in itself, in combination with the experimental result of other embodiment, equally make me Have reason to believe that the compound that embodiment three, five, eight is prepared is likewise supplied with druggability.
Finally illustrate, embodiment described above is only presently preferred embodiments of the present invention, be only used to illustrate this The technical scheme of invention, is not used to the limitation present invention, although by above preferred embodiment to this hair It is bright to be described in detail, it is to be understood by those skilled in the art that all in the spirit and principles in the present invention Within modification, equivalent and the improvement made etc., be all contained within protection scope of the present invention.

Claims (18)

1. the compound shown in a kind of formula (I) structure, X-R1-R2-Y (I)
Wherein,
It is similar that X is respectively DPP-4 inhibitor or DPP-4 inhibitor containing amino or imino group with Y The group that thing is formed, or be that the foregoing DPP-4 inhibitor containing amino or imino group or DPP-4 press down The formulation analogous group that pharmaceutically acceptable salt or optical isomer are formed；Wherein X is identical with Y Or it is different；
R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or are sulfydryl Carboxylic acid compound group or be that 1-6 is natural or non-natural ammonia through mercaptan carboxylic acid's compound-modified containing The peptide fragments of base acid, wherein, R1 and R2 are identical or different.
2. compound according to claim 1, it is characterised in that in the formula (I) structural formula,
It is similar that X is respectively DPP-4 inhibitor or DPP-4 inhibitor containing amino or imino group with Y Secondary amine or tertiary amine group that thing is formed, or for the foregoing DPP-4 inhibitor containing amino or imino group or Person DPP-4 inhibitor analogues secondary amine or tertiary amine that pharmaceutically acceptable salt or optical isomer are formed Group；Wherein X and Y are identical or different；
R1 and R2 are respectively the peptide fragments of or alpha-non-natural amino acid natural containing 1-6 or are sulfydryl Carboxylic acid compound group or be that 1-6 is natural or non-natural ammonia through mercaptan carboxylic acid's compound-modified containing Base acid peptide fragments, wherein, R1 is identical with R2, between R1 and R2 formed CO-NH, S-S or CO-S keys, preferably S -- S.
3. compound according to claim 1 and 2, it is characterised in that described containing amino or Asia The DPP-4 inhibitor or DPP-4 inhibitor analogues of amino be selected from Xi Gelieting and the like, Ah Ge Lieting and the like, Li Gelieting and the like, BMS-477118 and the like, vildagliptin and Its analog, song Ge Lieting and the like, Ao Gelieting and the like or melogliptin and the like.
4. compound according to claim 1 and 2, it is characterised in that in the formula (I) structure In formula,
X and Y are respectively selected from Xi Gelieting, Egelieting, Li Gelieting, BMS-477118, Wei Gelie The secondary amine or tertiary amine group in spit of fland, song Ge Lieting, Ao Gelieting or melogliptin；R1 is identical with R2, is Mercaptan carboxylic acid, forms S-S, CO-NH or CO-S key between R1 and R2.
5. compound according to claim 4, it is characterised in that the X is identical with Y, selects Ge Lieting, Egelieting, Li Gelieting, BMS-477118, vildagliptin, song Ge Lieting, Ao Gelie westerly Spit of fland or the secondary amine or tertiary amine group of melogliptin；The R1 is identical with R2, is carbon number for 1-6 Mercaptan carboxylic acid's group, preferably mercaptopropionic acid group.
6. compound according to claim 3, it is characterised in that
Wherein, Xi Gelieting analogs general structure is as follows：
In formula (1), Ar is for phenyl or respectively by halogen, alkyl, the carbon number that carbon number is 1-6 For the phenyl that the alkoxy or cyano group of 1-6 replace；X is N atoms and-CR2；R1And R2Independently of one another Selected from the one kind in following group：H, cyano group is unsubstituted or respectively by 1-5 halogen, cyano group, hydroxyl Or the carbon number of carboxyl substitution is alkyl, phenyl, five yuan or the hexa-member heterocycle of 1-10；The Ar is preferred It is halogen substituted phenyl, also preferably fluorine or chlorine or bromine substituted-phenyl, more preferably three halogen substituted phenyls, More preferably three fluorine atoms or chlorine substituted-phenyl；The R1Preferably 1-3 halogen-substituted alkyl, More preferably three halogen substituent methyls；Wherein, the Xi Gelieting analogs do not include Xi Gelieting itself；
The general structure of wherein Egelieting analog is as follows：
In formula (2), M is nitrogen-atoms or-CR4, and R2, R3And R4It is independently selected from following base One kind in group：It is non-substituted or respectively by the carbon number of amino, cyano group, carboxylic acid-substituted for 1-10 Straight or branched alkyl, carbon number are the cyclic alkyl of 3-12, carbon number is 3-12 containing hetero atom Cyclic alkyl or carbon number are the one kind in the aromatic ring alkyl of 1-10；Wherein, R3Preferably amino substitution Carbon number for 3-12 alkyl containing heteroatomic ring, the hetero atom be selected from nitrogen or oxygen or sulphur, more preferably For the carbon number of amino substitution is the nitrogen atom cycloalkyl of 3-12, even more preferably for amino replaces Piperidyl；Wherein L is selected from the 1-3 bridge chain of N atoms, C atoms, O atom or S atom, The preferably bridge chain of C atoms, S atom；X is selected from the one kind in following group：It is non-substituted or respectively by Amino, cyano group, the carbon number of carboxylic acid-substituted are the straight chained alkyl of 1-10, and carbon number is the ring of 3-12 Shape alkyl, carbon number is the aromatic ring alkyl of 1-10, and preferably amino, the carbon number of cyano group substitution are The aromatic ring alkyl of 6-10；Wherein, the Egelieting analog does not include Egelieting itself；
The analog general structure of wherein Li Gelieting is as follows：
In formula (3), R1For naphthyl or respectively by the naphthalene of methyl, methoxyl group, nitro or methylamino substitution Base；2- styryls；Connect phenyl；Cyclohexyl-carbonyl；Benzothienyl or quinolyl；R1Preferably naphthyl Or respectively by methyl, the naphthyl of methoxy substitution；R2It is methyl, isopropyl, 2- acrylic, phenyl, cyanogen Methyl or methoxy carbonvlmethyl, preferably methyl, phenyl, cyanogen methyl；R3It is 2- cyano-phenyls, 2,6- Dicyano phenyl, 2- methyl -2- acrylic, 2- chloro-2-propenes base, bromo- 2 acrylic of 3-, 2- cyclobutenyls, 3- Methyl-2-butene base, 2,3- dimethyl -2- acrylic, 2- butynyls, 1- ring penten methyl or 2- Furfuryl, preferably 2- butynyls, 2- cyclobutenyls, more preferably 2- methyl -2- acrylic, 2- butynyls； Wherein, the Li Gelieting analogs do not include Li Gelieting itself；
The analog general structure of wherein BMS-477118 is as follows：
In formula (4), x is that 1, y is that 0 or x is that 0, y is that 1, n is 0 or 1, X are H or cyanogen Base, R1, R2, R3And R4It is each independently selected from the one kind in following group：H, it is non-substituted or point Not by halogen, straight or branched alkyl, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, Alkenyl, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl, it is excellent Elect as straight or branched alkyl, alkenyl, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, Aralkyl, heterocyclic aryl, more preferably straight or branched alkyl, alkenyl, alkynyl, cycloalkyl；Wherein, The BMS-477118 analog does not include BMS-477118 itself；
The analog general structure of wherein vildagliptin is as follows：
In formula (5), R1And R2Separately selected from the one kind in following group：H, cyano group is non-to take Generation or respectively by halogen, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, alkenyl, Alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1Preferably cyano group, straight or branched alkyl, cycloalkanes non-substituted or replaced by cyano group, hydroxyl respectively Base, aralkyl, R2Cycloalkyl, aralkyl preferably non-substituted or replaced by cyano group, hydroxyl respectively； Wherein, the vildagliptin analog does not include vildagliptin itself；
The analog general structure of wherein song Ge Lieting is as follows：
In formula (6), R1And R2Separately selected from the one kind in following group：H, it is non-substituted or Respectively by halogen, nitro, cyano group, amino or hydroxyl replace straight or branched alkyl, alkenyl, alkynyl, Cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1It is preferred that It is non-substituted or halogen, cycloalkyl, the aralkyl of cyano group substitution, more preferably halogen or cyano group replaces Aralkyl；R2Preferably straight or branched alkyl, more preferably methyl, ethyl, propyl group；Wherein, institute Stating bent Ge Lieting analogs does not include song Ge Lieting itself；
The analog general structure of wherein Ao Gelieting is as follows：
In formula (7), R1And R2Separately selected from the one kind in following group：H, it is non-substituted or Straight or branched alkyl, alkenyl, alkynyl, the ring for being replaced by halogen, nitro, cyano group, hydroxy amino respectively Alkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein, R1Preferably Non-substituted or halogen, cycloalkyl, the aralkyl of cyano group substitution, the more preferably 1-3 virtue of halogen substitution Alkyl；R2Cycloalkyl, aralkyl preferably non-substituted or replaced by cyano group, hydroxyl respectively；Wherein, The Ao Gelieting analogs do not include Ao Gelieting itself；
The analog general structure of wherein melogliptin is as follows：
In formula (8), R1、R2And R3Separately selected from the one kind in following group：H, cyano group, Straight or branched alkyl, alkene non-substituted or replaced by halogen, nitro, cyano group, amino or hydroxyl respectively Base, alkynyl, cycloalkyl, bicyclic alkyl, tricyclic alkyl, hydroxyalkyl, aralkyl, heterocyclic aryl；Wherein R1Preferably cyano group, cycloalkyl, aralkyl non-substituted or replaced by cyano group, halogen respectively, R2It is excellent Elect the aralkyl of halogen or cyano group substitution, R as3The heterocyclic aryl that preferably Heterocyclylalkyl or halogen replace, The heterocyclic aryl that more preferably halogen replaces；Wherein, the melogliptin analog does not include melogliptin certainly Body.
7. the compound according to claim any one of 1-6, it is characterised in that described to contain sulfydryl carboxylic Acid compound is that carbon number is the mercaptan carboxylic acid of 1-8, preferably mercaptopropionic acid, TGA or sulfydryl Butyric acid, more preferably 3- mercaptopropionic acids；It is described through mercaptan carboxylic acid it is compound-modified containing 1-6 it is natural or The peptide fragments of alpha-non-natural amino acid are to contain 1-6 day for what the mercaptan carboxylic acid of 1-8 modified through carbon number So or alpha-non-natural amino acid peptide fragments, preferably mercapto for Propionylglycine, mercapto for acetoglycocoll or Mercapto is for butyryl glycine, more preferably 3- mercapto-propionyl-glycins.
8. the compound according to claim 1,3 or 6, it is characterised in that
Formd between X and R1 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S keys, preferably CO-NH, CO-S or S-S；
Formd between Y and R2 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S keys, preferably CO-NH, CO-S or S-S；
Formd between R1 and R2 selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, A kind of chemical bond in CO-S keys, preferably CO-NH, CO-S or S-S.
9. compound according to claim 8, it is characterised in that formed between X and R1 C-N, C-O, C-S or S -- S；C-N, C-O, C-S or S -- S are formed between Y and R2；R1 and R2 Between formed CO-NH, CO-S key or S -- S.
10. compound according to claim 8, it is characterised in that formed between X and R1 C=N, C=C or CO-NH keys；C=N, C=C or CO-NH key are formed between Y and R2；R1 and R2 it Between formed CO-NH, CO-S key or S -- S.
11. compounds according to claim 8, it is characterised in that CO-NH is formed between X and R1 Key；CO-NH keys are formed between Y and R2；S-S, CO-S key or CO-NH are formed between R1 and R2 Key.
12. a kind of polymer, it is characterised in that using the compound described in claim any one of 1-11 Used as constitutional repeating unit, its formula is expressed as [X-R1-R2-Y]n, wherein n is 2~10 integer.
13. polymer according to claim 12, it is characterised in that the constitutional repeating unit it Between using selected from C-N, C-O, C=N, C-C, C=C, C-S, S-S, CO-NH, CO-S Plant chemical bond, preferably CO-NH, CO-S or S -- S.
The preparation method of compound described in 14. claim any one of 1-11, it is characterised in that including as follows Step：
By the DPP-4 inhibitor containing amino or imino group or the DPP-4 containing amino or imino group Inhibitor analogue or the DPP-4 inhibitor pharmaceutically acceptable salt containing amino or imino group or Optical isomer respectively with peptide fragments or the mercaptan carboxylic acid of the natural or alpha-non-natural amino acid containing 1-6 Compound or through the compound-modified peptide chain of natural or alpha-non-natural amino acid containing 1-6 of mercaptan carboxylic acid Fragment mixes, and is reacted in the presence of coupling agent.
15. preparation methods according to claim 14, it is characterised in that the coupling agent is selected from 1,3- Dicyclohexylcarbodiimide, N, N '-DIC, 1- (3- dimethylamino-propyls) -3- ethyls Carbonyl diamide methiodide, DIPEA, N- methylmorpholines, I-hydroxybenzotriazole, 2- (7- Azo BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester, 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester, 2- (1H- benzo trisazo- L-1- yls) -1,1,3,3- tetramethylurea tetrafluoro boric acids ester, 5- ENBs -2,3- two Carbonyl-N, N, N ', N '-tetramethylurea tetrafluoro boric acid ester, the hexafluorophosphoric acid BTA -1- bases-pyrrole of epoxide three Cough up more than one or more in alkyl phosphorus.
16. a kind of pharmaceutical compositions, it is characterised in that the pharmaceutical composition is free comprising therapeutically effective amount Described in compound or claim 12-13 described in the claim 1-11 of form or pharmaceutical acceptable salt Polymer as active component；With one or more medicinal carrier substance and/or diluent.
Described in compound or claim any one of 12-13 described in 17. claim any one of 1-11 Pharmaceutical composition described in polymer or claim 16 is preparing treatment and/or prevention diabetes, fat-reducing Or the purposes in terms of other medicines with DPP-4 relevant diseases.
Described in compound or claim any one of 12-13 described in 18. claim any one of 1-11 Pharmaceutical composition described in polymer or claim 16 is used to treating and/or prevent diabetes, fat-reducing or Other diseases related to DPP-4.
CN201510866369.5A 2015-12-01 2015-12-01 DPP-4 inhibitor compounds, polymer and its preparation method and application Pending CN106810568A (en)

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