CN103788070B - The inhibitor class polymers of DPP 4 - Google Patents

The inhibitor class polymers of DPP 4 Download PDF

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CN103788070B
CN103788070B CN201210418156.2A CN201210418156A CN103788070B CN 103788070 B CN103788070 B CN 103788070B CN 201210418156 A CN201210418156 A CN 201210418156A CN 103788070 B CN103788070 B CN 103788070B
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acid
compound
dpp
anhydride
acids
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CN103788070A (en
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张孝清
宋志春
包金远
蒋玉伟
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Nanjing Huawe Medicine Technology Group Co Ltd
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Nanjing Huawe Medicine Technology Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention provides a kind of new dipeptidyl peptidase IV（DPP‑4）Inhibitor polymer formula（Ⅰ）And preparation method thereof.The compound and its salt of the present invention has the enzyme inhibitions of DPP 4, prevention and/or treatment available for treatment diabetes, particularly Non-Insulin Dependent Diabetes Mellitus, and other diseases related to DPP 4.Its formula of（Ⅰ）In each substituent definition it is identical with the definition in specification.

Description

DPP-4 inhibitor class polymers
Technical field
The invention belongs to organic synthesis field, and in particular to new dipeptidyl peptidase IV (DPP-4) inhibitor class poly Thing and preparation method thereof and for treating and preventing diabetes etc. and the purposes of DPP-4 relevant diseases.
Background technology
Diabetes be by inherent cause, immunologic function disorder, microorganism infection and its toxin, free radical toxin, spirit because Chronic metabolic diseases caused by the various virulence factor effects such as element, clinically using hyperglycaemia as main feature.1 type sugar can be divided into Urinate the glycosuria of sick (insulin-dependent), diabetes B (non-insulin-depending type), gestational diabetes mellitus and other specific types Disease.In diabetic, the ratio shared by diabetes B is about 95%.
OHA main at present has：Sulfonylureas (SU), biguanides, alpha-glucosidase restrainer, non-sulfonylureas Insulinotropic hormone excretion and insulin sensitizer：Thiazolidinediones.These medicines can not effectively control the development of diabetes, And tolerance is limited.With going deep into for research, occur in that it is a series of may act on novel targets and can continue control blood glucose water Flat antidiabetic thing.Of greatest concern in the recent period is glucagon-like-peptide-1 (GLP-1) and dipeptidyl peptidase IV (DPP-4).GLP-1 stimulates the biosynthesis and secretion of insulin, with glucose dependency, is a kind of more more preferable than insulin Control the activity in vivo material of blood glucose.But, DPP-4 can crack the proline of GLP-1 peptide chains N-terminal the 2nd rapidly in vivo Or alanine, cause GLP-1 inactivation.So, DPP-4 can increase GLP-1 half-life period and extend its advantageous effect；In pancreas islet Plain aspect, it can suppress the secretion of glicentin while β cells secrete insulins are stimulated, and this mechanism of action is With concentration of glucose dependence, thus the generation of hypoglycemia can be prevented to greatest extent；In addition, it can also suppress food Desire maincenter, thus can not put on weight while control blood glucose very well；It can also slightly suppress gastric emptying, delay sugared suction Receive and there are some cardioprotections.The DPP-4 developed based on secretin's mechanism is the type glycosuria for the treatment of 2 confirmed through clinic The novel targets of disease, the diabetes B new treatment as great prospect.
At present, the research of DPP-4 inhibitor has caused the concern of major drugmakers of the world, is controlled as diabetes B The research and development focus of medicine is treated, different types of small molecule DPP-4 inhibitor is continued to bring out (structure is shown below).
Most representational is that the vildagliptin (WO2000/034241) developed by Novartis Co., Ltd, Merck ＆ Co., Inc. develop Xi Gelieting (WO2003/04498) and the Egelieting (WO2005/095381) of military field pharmacy.In July, 2009, U.S. FDA batch The listing Shen of the new drug saxagliptin (WO2001/068603) of accurate AstraZeneca and Bristol-Myers Squibb Co.'s joint research and development Please.GlaxoSmithKline PLC company also have developed ground Na Lieting, and it is clinical to enter the second phase.The Rui Gelieting that permanent auspicious medicine is developed, is approved It is clinical that FDA enters the I phases.Patent of invention WO2008096841A1 discloses one kind and is prepared into phase by structural modification by Wella row spit of fland The carboxylic acid compound answered, then reacts with amino or alcohol compound, obtains the inventive method of corresponding dimer compound again, The compound possesses excellent DPP-4 enzyme inhibitions, can be used as the prevention and treatment medicine of diabetes.
The content of the invention
It is an object of the invention to provide a kind of new dipeptidyl peptidase IV (DPP-4) inhibitor class polymer.
It is a further object of the present invention to provide a kind of preparation method of above-claimed cpd.
Third object of the present invention is to provide above-claimed cpd applied to diabetes and other diseases related to DPP-4 The prevention and/or treatment of disease.
The purpose of the present invention can be reached by following measures：
One class DPP-4 inhibitor class polymers, it is the compound shown in formula (I) structure,
Wherein,
X or Y are separately the primary amine group or secondary amine group of the DPP-4 inhibitor containing amino or imino group, contained Have the DPP-4 inhibitor pharmaceutically acceptable salt of amino or imino group or the primary amine group or secondary amine group of optical isomer, The primary amine group or secondary amine group of DPP-4 inhibitor derivates containing amino or imino group, formula (II) group and contain formula (II) group of optical isomer or formula (III) group；
M is substituted or non-substituted alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl, alkynyl, ketone group, aryl or heteroaryl；Institute State substituent and be selected from Dai Ji selected from halogen, alkyl, haloalkyl, alkoxy, alkoxy carbonyl group, amino, alkylamino, hydroxyl, hydroxyl alkane Base, sulfydryl, cyano group, nitro, aryl or heteroaryl；
N is 1 or 0, and
When n is 1, Z is the primary amine group or secondary amine group of the DPP-4 inhibitor containing amino or imino group, contains ammonia The primary amine group or secondary amine group of the DPP-4 inhibitor pharmaceutically acceptable salt or optical isomer of base or imino group, contain The primary amine group or secondary amine group of the DPP-4 inhibitor derivates of amino or imino group, formula (II) group and contain formula (II) light Learn the group or formula (III) group of isomers；
When n is 0, Z is hydrogen, or substituted or non-substituted alkyl, cycloalkyl, Heterocyclylalkyl, alkenyl, alkynyl, ketone group, virtue Base or heteroaryl；The substituent be selected from halogen, alkyl, haloalkyl, alkoxy, alkoxy carbonyl group, amino, alkylamino, hydroxyl, Hydroxyalkyl, sulfydryl, cyano group, nitro, aryl or heteroaryl；
L is selected from CH2、S、CH2CH2、CHF、CF2Or CH2CHF, m are 0 or 1.
It is preferred that, the DPP-4 inhibitor containing amino or imino group is selected from Egelieting, Xi Gelieting, BI 1356, dimension Ge Lieting, saxagliptin, carmegliptin, melogliptin or Duloxetine.
It is preferred that, M is substituted or non-substituted C1~12Alkyl, C3~8Cycloalkyl, C2~8Alkenyl, phenyl, heteroaryl.
It is preferred that, M is substituted or non-substituted C2~10Alkyl, C5~6Cycloalkyl, C2~6Alkenyl, phenyl, pyridine radicals.
It is preferred that, M is substituted or non-substituted ethylidene, butylidene, decylene, cyclohexyl, phenyl, pyridine radicals.
It is preferred that, the substituent in M is selected from halogen, C1~4Alkyl, C1~4Haloalkyl, C1~4Alkoxy, cyano group, nitro or Phenyl.
It is preferred that, when n is 0, Z is hydrogen, C1~4Alkyl, C3~6Cycloalkyl, C3~6Heterocyclylalkyl, aryl or heteroaryl.
It is preferred that, L is selected from CH2Or CH2CH2。
A kind of preparation method of compound shown in formula (I) structure：It is characterized in that by containing amino or imino group DPP-4 inhibitor, DPP-4 inhibitor pharmaceutically acceptable salt or optical isomer containing amino or imino group, contain ammonia DPP-4 inhibitor derivates, formula (II) compound and formula (II) the compound light isomers or formula (III) of base or imino group are changed Compound, carries out acyl with omega-dicarboxylic acids compound, tricarboxylic acid compounds, diacid chloride class compound or three acyl chloride compounds respectively Aminating reaction is produced；Or by a kind of DPP-4 inhibitor containing amino or imino group, the DPP-4 containing amino or imino group Inhibitor pharmaceutically acceptable salt or optical isomer, the DPP-4 inhibitor derivates containing amino or imino group, formula (II) Compound and formula (II) compound light isomers or formula (III) compound, first enter reaction with dicarboxylic anhydride,
Again with the DPP-4 inhibitor containing amino or imino group, the DPP-4 inhibitor containing amino or imino group pharmaceutically Acceptable salt or optical isomer, the DPP-4 inhibitor derivates containing amino or imino group, formula (II) compound and formula (II) compound light isomers or formula (III) compound progress aminating reaction are produced.
Omega-dicarboxylic acids compound is the compound containing two carboxylic acid functionals (- COOH), it is preferred that omega-dicarboxylic acids chemical combination Thing is selected from substituted or non-substituted alkyl dicarboxylic aid, cycloalkyl dicarboxylic acids, Heterocyclylalkyl dicarboxylic acids, alkenyl dicarboxylic acids, alkynyl two Carboxylic acid, keto-dicarboxylic acids, aryl dicarboxylic acid or heteroaryl dicarboxylic acids.
It is preferred that, omega-dicarboxylic acids compound is selected to benzene dicarboxylic acid, pyridinedicarboxylic acid, C1~12Alkyl dicarboxylic aid.Further It is preferred that, omega-dicarboxylic acids compound is selected from hexanedioic acid, ethanedioic acid, malonic acid, glutaric acid, azelaic acid, 1,8- suberic acids, dodecane Diacid, pimelic acid, octadecane diacid, 22 dipropyl diacid, twenty diacid, decanedioic acid, isosebacic acid, nonadecandioic acid, 2- butyl Suberic acid, Beta-methyl glutaric acid, hexacosandiacid, (R) -3- methyl adipic acid, 1,1- cyclobutane ethanedioic acid, 3- butyl penta 2 Acid, anti-form-1,2- rings succinic acid, cis -1,2- pentamethylene dioctyl phthalate, trans- 1,2- cyclohexane cyclohexanedimethanodibasics, to cyclohexyl dicarboxylic acid, Octadecene dicarboxylic acid, hexadecadienedioic acid, diallyl malonic acid, tricosene diacid, undecyne diacid, trans-2-butene- Isosorbide-5-Nitrae-dioctyl phthalate, 1,3-butadiene-Isosorbide-5-Nitrae-dioctyl phthalate, maleic acid, 2,2- dimethylated pentanedioic acids, butanone diacid, α -one penta Diacid, β -one glutaric acid, 1,3-thiazoles alkane -2,4- dicarboxylic acids, bromosuccinic acid, 2- dimercaptosuccinic acids, his pyridine side chain diacid, 3- Thiophene malonic acid, the fluoro succinic acid of a chlorine three, 2 aminopentanedioic acid, DL- butanol diacid, 2,6- diaminopimelic acids, 2,6- bis- Diaminopimelic acid and dibromomalonic acid, L- butanol diacid, D- butanol diacid, hydroxymalonic acid, glucaric acid, DL- tartaric acid, L- Tartaric acid, D- tartaric acid, pyridine -3,4- dicarboxylic acids, 2,5- pyridinedicarboxylic acids, 5- bromopyridines -3,4- dicarboxylic acids, 2- chloropyridines - 3,4- dicarboxylic acids, terephthalic acids, phthalic acid, isophthalic acid, o-carboxyl phenylacetic acid, 2- bromo terephthalic acids, 4- methoxyl groups Phthalic acid, 2- amino terephthalic acid (TPA), four bromo terephthalic acids, four bromo terephthalic acids, four bromo terephthalic acids, 5- first Base isophthalic acid, oreinol diacid, 3- nitrophthalic acids, 4- nitros -1,3- phthalic acid, bromo- 1, the 3- benzene diformazans of 4- Acid, bromo- 1, the 3- phthalic acids of 4-, 5- Hydroxy M Phthalic Acids, 5- amino isophthalic acids, NDA, 2,2'- biphenyl Dioctyl phthalate, (S) -2- (4- (methylamino) benzamido) glutaric acid, 2,3- quinoline diacid, 2- (1,3- benzothiazole -2- sulphur) Any one in succinic acid, 2- benzyls succinic acid, S-2- benzyls butanedioic acid and (R)-(+) -2- phenylsuccinic acids.
Tricarboxylic acid compounds are selected from substituted or non-substituted alkyl tricarboxylic acids, cycloalkyl tricarboxylic acids, Heterocyclylalkyl tricarboxylic Acid, alkenyl tricarboxylic acids, alkynyl tricarboxylic acids, ketone group tricarboxylic acids, aryl tricarboxylic acids or heteroaryl tricarboxylic acids.
It is preferred that, tricarboxylic acid compounds are selected from tricarballylic acid, 2- phosphonobutanes -1,2,4- tricarboxylic acids, aurin tricarboxylic Acid, the third three acid, 2- hydroxy propane tricarboxylic acids, triphenylmenthanes -4,4,4- tricarboxylic acids, 1,2,4- benzenetricarboxylic acids, 1,2,3- benzenetricarboxylic acids, 1,3,5- equal benzene tricarbonic acid, 1,3,5- penta tricarboxylic acids, 1,2- ethane tricarboxylic acids, pyridine -2,3,4- tricarboxylic acids, 5- hydroxy benzenes -1, 2,4- tricarboxylic acids, 1,2,4- cyclohexanetricarboxylic acids, 1,3,5- hexamethylene tricarboxylic acids, 1- aminobenzenes -3,4,5- tricarboxylic acids, Benzophenone - 2,4,5- tricarboxylic acids, 3- carboxyls -2- amylenes -1,5- diacid or 3- amino -1,1,3- tricarballylic acids.
Diacid chloride class compound is the compound containing two acid chloride functional groups (- COCl), it is preferred that diacid chloride class chemical combination Thing is selected from substituted or non-substituted alkyl diacid chloride, cycloalkyl diacid chloride, Heterocyclylalkyl diacid chloride, alkenyl diacid chloride, alkynyl two Acyl chlorides, ketone group diacid chloride, aryl diacid chloride or heteroaryl diacid chloride.
It is preferred that, diacid chloride class compound be selected from the caprylyl chlorides of 1,8- bis-, 2,6- pyridines dimethyl chloride, malonyl chloride, to benzene Dimethyl chloride, m-phthaloyl chloride, ethyl malonyl chloride, fumaryl chloride, 4,4'- diacid chlorides diphenyl ether, succinyl chloride, oneself Diacid chloride, hexafluoro glutaryl chlorine, oxalyl dichloro, 1,7- pimeloyl chlorides, 3- methyl Adipoyl Chloride, sebacoyl chloride, azelaoyl chloride Or glutaryl dichloro.
Three acyl chloride compounds are the compound containing three acid chloride functional groups (- COCl), it is preferred that three acyl chloride chemical combination Thing is selected from the substituted or non-substituted acyl chlorides of alkyl three, the acyl chlorides of cycloalkyl three, the acyl chlorides of Heterocyclylalkyl three, the acyl chlorides of alkenyl three, alkynyl three Acyl chlorides, the acyl chlorides of ketone group three, the acyl chlorides of aryl three or the acyl chlorides of heteroaryl three；Most preferably 1, the formyl chloride of 3,5- benzene three.
Diacid compound anhydride preferably be selected from succinic anhydride and succinic anhydride derivative, glutaric anhydride and glutaric anhydride it is biological, One kind of adipic anhydride and adipic anhydride derivative, be, for example,：Succinic anhydride, glutaric anhydride, adipic anhydride, pyridine -3,4- bis- Carboxylic acid anhydrides, phthalic anhydride, diethylene-triamine pentaacetic acid dianhydride, methylendomethylenetetrahydrophthalic THPA, chlorendic anhydride, 4- (2,5- dioxies For tetrahydrofuran -3- bases) -1,2,3,4- naphthane -1,2- dicarboxylic acid anhydrides, NA acid anhydrides, 3,3,4,4- diphenyl sulfone tetrabasic carboxylic acids two Acid anhydrides, 1,8- naphthalic anhydrides, (S)-(-) -2- acetoxyl groups succinic anhydride, 2,3- dimethyl maleic anhydrides, 3- methylpents two Acid anhydrides, homophthalic acid acid anhydride, 2,3- pyridinedicarboxylic acids acid anhydride, S- acetyl mercaptos succinic anhydride, cis- 3- carboxyls glutaconic anhydride, 2, 2- dimethylated pentanedioic acids acid anhydride, tetrafluoro succinic anhydride, 2,2- dimethyl succinic anhydrides, methyl-maleic acid acid anhydride, dodecyl Succinic anhydride, hexahydrophthalic anhydride, iso-octadecyl succinic acid anhydrides, 4- phthalate bromines acid anhydride, pi-allyl succinic anhydride, 2- octenyls succinic anhydride, 2- itaconic anhydrides, dodecenylsuccinic acid acid anhydride, 3,3- tetramethylenes glutaric anhydride, methyl Succinic anhydride, octadecenyl succinic anhydride, 3- (4- chlorphenyls) glutaric anhydride, 3- ethyl -3- methylglutaric acid acid anhydrides, 2- phenyl penta Dicarboxylic anhydride, 2- (triphenyl phosphorous base) succinic anhydride, phenylsuccinic acid acid anhydride, 2,3- dichloromaleic anhydrides, maleic anhydride, 2- ten Dialkylene-succinic anhydride, 2- laurylene -1- bases succinic anhydride, 2- nonenyl succinic acids acid anhydride, 2- hexene -1- bases succinic anhydride, 2, 3- pyrazine diacids acid anhydride, N- (2,6- diethylbenzene aminocarbonyl methyl) iminodiacetic acid (salt) acid anhydrides, (R)-(+) -2- acetoxyl groups fourth two Acid anhydrides, 3,3- dimethylated pentanedioic acids acid anhydride, 4- nitro-1,8-naphthalic acids acid anhydride, N- decyls succinic anhydride, 1,2- naphthalenes dicarboxylic anhydride, β- (4- chlorphenyls) glutaric anhydride, N- last of the ten Heavenly stems enetutanedioic acid anhydride, D- camphoric acids, L- camphoric acids, DL- camphoric acids, 3- isobutyl groups penta 2 Acid anhydrides, 2- iso-octyl succinic anhydride, 3- tert-butyl group dimethylsilyloxies glutaric anhydride, hexafluoroglutaric anhydride, 1,8- naphthalic anhydrides, Homophthalic acid acid anhydride or anhydride maleique.Particularly preferably from succinic anhydride, glutaric anhydride, adipic anhydride, pyridine -3,4- dicarboxylic acids One kind in acid anhydride, hexafluoroglutaric anhydride, 2,2- dimethylated pentanedioic acids acid anhydride and tetrafluoro succinic anhydride.
The amidation process of compound shown in formula (I) structure, can be carried out in the presence of catalyst, wherein urging Agent is selected from 1,3- dicyclohexylcarbodiimides (DCC), N, N'- DICs (DIC), 1- (3- dimethylaminos third Base) -3- ethyl carbodiimides (EDC) and its hydrochloride, 1- (3- dimethyl aminopropyls) -3- ethylcarbonyl group diamines methiodide, N, N- Diisopropylethylamine (DIEA), I-hydroxybenzotriazole (HoBt), 2- (7- azos BTA)-N, N, N', N'- tetramethyls Urea hexafluorophosphoric acid ester (HATU), BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 6- chlorobenzenes and three nitrogen Azoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters (HCTU), 2- (1H- benzo trisazo- L-1- yls) -1,1,3,3- tetramethylurea Tetrafluoro boric acid ester (TBTU), 2- succinimidos -1,1,3,3- tetramethylurea tetrafluoro boric acid esters (TSTU), 5- ENBs - One or more combination in 2,3- dicarbapentaborane-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters (TNTU).
Present invention also offers the preparation method of formula (II), but it is not limited only to following method：
Boc- glycine and raw material 1 ' are dissolved, 0 DEG C is cooled to, stirring is lower to add condensation catalyst and the sour agent of Fu, room temperature Lower reaction generation amide product 2 '；Amide product 2 ' is dissolved, less than 5 DEG C addition trifluoroacetic acids add the sour agent of Fu, reaction life Into cyano group class compound 3 '；Cyano group class compound 3 ' is dissolved, trifluoroacetic acid is added at room temperature, Boc- protection groups are sloughed in reaction, Production (II) compound, wherein L with formula (II) L it is identical.
The illustrative of compound shown in formula (I) structure of the present invention, nonrestrictive instantiation is as follows：
Unless otherwise indicated, the following term being used in claims and specification has following implication.
DPP-4 inhibitor includes the existing various compounds inhibited to DPP-4.
DPP-4 inhibitor containing amino or imino group refers to contain-NH in such compound2Group or-NH- groups.
X, Y, Z be the DPP-4 inhibitor containing amino primary amine group or secondary amine group refer to X-H, Y-H, Z-H be containing - C (=O)-group in the DPP-4 inhibitor of amino or imino group, and formula (I) and amino or imino group on DPP-4 inhibitor In N be connected.
DPP-4 inhibitor derivates containing amino or imino group refer in the DPP-4 inhibitor containing amino or imino group Hydrogen atom or atomic group replaced and a derivative class compound with DPP-4 inhibitory action by other atoms or atomic group.
" alkyl " represents that the aliphatic group of the saturation of 1-20 carbon atom, including straight chain and branched group (are carried in this specification The digital scope arrived, such as " 1-20 ", refer to the group, are now alkyl, can contain 1 carbon atom, 2 carbon atoms, 3 carbon Atom etc., until including 20 carbon atoms).Alkyl in the present invention includes " alkylidene ".Alkyl containing 1-4 carbon atom claims For low alkyl group.When low alkyl group does not have substituent, unsubstituted low alkyl group is called.It is further preferred that alkyl is that have The medium sized alkyl of 1-10 carbon atom, such as methyl, ethyl, ethylidene, propyl group, propylidene, 2- propyl group, normal-butyl, Isobutyl group, butylidene, the tert-butyl group, amyl group etc..Preferably, alkyl is the low alkyl group for having 1-4 carbon atom, for example methyl, second Base, propyl group, 2- propyl group, normal-butyl, butylidene, isobutyl group or tert-butyl group etc..Alkyl can be substituted or unsubstituted.
" cycloalkyl " represents that (" fusion " ring means each ring in system with being for the ring of the monocyclic of all carbon or fusion Shared a pair of the carbon atoms adjoined of other rings in system) group, wherein one or more rings are without the pi-electron system being fully connected System, the example (being not limited to) of cycloalkyl is cyclopropane, cyclobutane, pentamethylene, cyclopentene, hexamethylene, adamantane, hexamethylene two Alkene, cycloheptane and cycloheptatriene.Cycloalkyl can be substitution and unsubstituted.
" aryl " represent 6 to 12 carbon atoms full carbon is monocyclic or fused polycycle group, the pi-electron system with total conjugated System.The non-limiting examples of aryl have phenyl, naphthyl and anthryl.Aryl can be substituted or unsubstituted.When substituted, Substituent is preferably one or more, more preferably one, two or three, and then is more preferably one or two, independently Selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulphur For acyl group, O- carbamoyls, N- carbamoyls, O- thiocarbamoyls, N- thiocarbamoyls, C- acylamino-s, N- acylamino-s, nitro, N- sulfonamidos, S- sulfonamidos.
" heteroaryl " represents the monocyclic or fused ring group of 5 to 12 annular atoms, contains one, two, three or four Ring hetero atom selected from N, O or S, remaining annular atom is C, in addition the pi-electron system with total conjugated.Unsubstituted heteroaryl Ground non-limiting examples have pyrroles, furans, thiophene, imidazoles, oxazoles, thiazole, pyrazoles, pyrimidine, quinoline, isoquinolin, purine, four Azoles, triazine and carbazole.Heteroaryl can be substituted or unsubstituted.When substituted, substituent is preferably one or more, More preferably one, two or three, and then be more highly preferred to one or two.
" heterocyclic radical " represents the saturated cyclic group of 3 to 8 annular atoms, and wherein one or two annular atom is to be selected from N, O Or S (O)mThe hetero atom of (wherein m is 0 to 2 integer), remaining annular atom is C, and wherein one or two C atom can be with optional Ground is replaced by carbonyl.More specifically, term heterocyclic radical includes but is not limited to THP trtrahydropyranyl, 2,2- dimethyl -1,3- dioxy penta It is ring, piperidino, N- methyl piperidine -3- bases, Piperazino, N- methylpyrrolidin- 3- bases, pyrrolidinyl, morpholino base, thio Morpholino base, thiomorpholine generation -1- oxides, thiomorpholine generation -1,1- dioxide, 4- ethoxycarbonylpiperazines subbase, 3- oxygen For Piperazino, 2- imidazolones, 2-Pyrrolidone, tetrahydropyrimidin-2-ones and its derivative.Wherein heteroalicyclyl is non-limiting Example has pyrrolidinyl, piperidino, Piperazino etc..
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl).Representative example is included but not It is limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine, chlorine or bromine.
" amino " expression-NH2Group.
" nitro " expression-NO2Group.
" sulfydryl " expression-SH groups.
" hydroxyl " expression-OH groups.
" haloalkyl " expression alkyl, low alkyl group preferably as defined above, it is by one or more identical or different Halogen atom substitution, such as-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3Deng.
" pharmaceutically acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of property.This kind of salt Including：
(1) obtained, inorganic acid example by the reaction of the free alkali and inorganic acid or organic acid of parent compound into salt with acid Such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acids as (but Be not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxyl Butyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid, ethyl sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, water Poplar acid, tartaric acid, citric acid, lactic acid, mandelic acid, butanedioic acid or malonic acid etc..
(2) it is present in the acid proton in parent compound to be replaced or given birth to organic base ligand compound by metal ion Into salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example monoethanolamine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
" optical isomer " refer to the present invention molecular structure of compounds it is identical, physicochemical properties are close, but rotation The different material of photosensitiveness.
" Pharmaceutical composition " refers to one or more compounds described here or theirs is pharmaceutically acceptable Salt and prodrug and other chemical compositions, the mixture of such as pharmaceutically acceptable carrier and excipient.Pharmaceutical composition Purpose is to promote the administration of compound on organism body.
" pharmaceutically acceptable carrier " refers to not causing obvious excitant to organism and does not disturb giving The bioactivity of compound and the carrier of property or diluent.
" excipient " is referred to being added in Pharmaceutical composition with the further convenient inert substance for giving compound.Assign The example of shape agent including (without limitation) calcium carbonate, calcium phosphate, various saccharides and polytype starch, cellulose derivative, Gelatin, vegetable oil and polyethylene glycol.
The structure-activity relationship of DPP-4 inhibitor of the inventor to having listed at present has carried out repeatedly conscientious research, selects It is DPP-4 inhibitor and its derivative, the pharmaceutically acceptable salt of the effective functional group of DPP-4 inhibitor and DPP-4 inhibitor, different Structure body, prodrug, derivative and its derivative of effective functional group, by the amino active function groups in compound respectively with dicarboxylic acids Class compound, tricarboxylic acid compounds, diacid chloride class compound or three acyl chloride compounds carry out amidation process, obtain structure New poly species DPP-4 inhibitor；DPP-4 inhibitor and its derivative, the effective functional group of DPP-4 inhibitor are selected simultaneously With the pharmaceutically acceptable salt of DPP-4 inhibitor, isomers, prodrug, derivative and its derivative of effective functional group, first will Amino active function groups in compound react with diacid compound anhydride, obtain corresponding dicarbapentaborane class carboxylic acid derivates, so Carry out amidation process, new many of preparation structure with the amino active function groups in DPP-4 inhibitor and its derivative again afterwards Polymers class DPP-4 inhibitor.So as to complete the present invention.The compound of the present invention can be applied to treat and/or prevent diabetes Medicine or other and DPP-4 relevant diseases medicine aspect.
Embodiment
Following examples further describe the present invention, still, and these embodiments are only for the explanation present invention, rather than right The limitation of the scope of the invention.
Following examples part of compounds is referred to as follows：DMF:DMF；DMSO:Dimethyl sulfoxide；MeOH: Methanol；DCM:Dichloromethane；EA:Ethyl acetate；DCC：1,3- dicyclohexylcarbodiimide；HoBt：I-hydroxybenzotriazole； HBTU:BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester.
Embodiment 1
Chemical equation：
Egelieting 0.5g (1.1mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then will be right Phthalic acid 90mg (0.54mmol), HoBt0.30g (2.17mmol), DCC 0.45g (2.17mmol) are added in reaction solution, It is stirred at room temperature, all dissolving adds 5ml triethylamines to question response, reaction 4h, TLC detection is stirred at room temperature, raw material fundamental reaction is complete Entirely, by reacting liquid filtering, then filtrate is slowly poured into the water of 10 times of filtrate volumes, there are a large amount of white solids to separate out, stirs 20min is mixed, filters, obtains faint yellow solid, dries, obtains 0.35g compounds 1.Solvent is：CHCl3：MeOH:NH3.H2O =40:1:0.01.
MSm/z(ESI):807.3(M-1)。
1H-NMR (500MHz, deuterated DMSO):δ 8.09 (m, 4H), 7.8 (d, 2H), 7.61 (t, 2H), 7.44 (m, 2H), 7.23 (d, 2H), 5.37 (s, 2H), 5.19 (ABq, 4H), 3.28 (d, 2H), 3.14 (m, 2H), 3.08 (s, 6H), 2.93 (d, 2H), 2.73 (s, 4H), 1.93 (m, 2H), 1.76 (m, 2H), 1.48 (m, 4H).
Embodiment 2
Chemical equation：
Egelieting 0.5g (1.1mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then by 2, 5- pyridinedicarboxylic acids 90mg (0.54mmol), HoBt0.30g (2.17mmol), DCC 0.45g (2.17mmol) are added to reaction In liquid, it is stirred at room temperature, all dissolving adds 5ml triethylamines to question response, reaction 4h, TLC detection is stirred at room temperature, raw material is substantially anti- Should be complete, then filtrate slowly poured into the water of 10 times of filtrate volumes by reacting liquid filtering, there are a large amount of white solids to analyse Go out, stir 20min, filtering obtains faint yellow solid, dries, obtain 0.4g compounds 2.Solvent is：CHCl3：MeOH: NH3.H2O=40:1:0.01.
MSm/z(ESI):832.3(M+Na)。
1H-NMR (500MHz, deuterated DMSO):δ 9.71 (m, 1H), δ 8.78 (m, 1H), δ 8.60 (m, 1H), 7.81 (d, 2H), 7.62 (t, 2H), 7.43 (m, 2H), 7.21 (d, 2H), 5.35 (s, 2H), 5.18 (ABq, 4H), 3.26 (d, 2H), 3.13 (m, 2H), 3.09 (s, 6H), 2.91 (d, 2H), 2.74 (s, 4H), 1.95 (m, 2H), 1.75 (m, 2H), 1.46 (m, 4H).
Embodiment 3
Chemical equation：
Egelieting 0.5g (1.1mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then by oneself Diacid 80mg (0.54mmol), HoBt 0.30g (2.17mmol), DCC 0.45g (2.17mmol) are added in reaction solution, room Temperature is stirred, and all dissolving adds 5ml triethylamines to question response, and reaction 4h, TLC detection is stirred at room temperature, and raw material fundamental reaction is complete, By reacting liquid filtering, then filtrate is slowly poured into the water of 10 times of filtrate volumes, there are a large amount of white solids to separate out, stirring 20min, filtering, obtains faint yellow solid, dries, obtains 0.38g compounds 3.Solvent is：CHCl3：MeOH:NH3.H2O= 40:1:0.01。
MSm/z(ESI):789.0(M+H)。
1H-NMR (500MHz, deuterated DMSO):δ 7.82 (d, 2H), 7.60 (t, 2H), 7.45 (m, 2H), 7.23 (d, 2H), 5.36 (s, 2H), 5.20 (ABq, 4H), 3.26 (d, 2H), 3.14 (m, 2H), 3.10 (s, 6H), 2.90 (d, 2H), 2.75 (s, 4H), 2.16 (t, 4H), 1.94 (m, 2H), 1.77 (m, 2H), 1.55 (t, 4H), 1.47 (m, 4H).
Embodiment 4
Chemical equation：
Egelieting 0.5g (1.1mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then by fourth Diacid 80mg (0.54mmol), HBTU 1.24g (3.3mmol), DIEA0.60g (4.34mmol) is added in reaction solution, room temperature Stirring, is stirred at room temperature reaction 2h, TLC detection, and completely, then reacting liquid filtering slowly topples over filtrate for raw material fundamental reaction In the water for entering 10 times of filtrate volumes, there are a large amount of white solids to separate out, stir 20min, filtering obtains faint yellow solid, dries, obtain To 0.45g compounds 4.Solvent is：CHCl3：MeOH:NH3.H2O=40:1:0.01.
MSm/z(ESI):759.2(M-H)。
1H-NMR (500MHz, deuterated DMSO):δ 7.80 (d, 2H), 7.61 (t, 2H), 7.44 (m, 2H), 7.21 (d, 2H), 5.35 (s, 2H), 5.20 (ABq, 4H), 3.25 (d, 2H), 3.15 (m, 2H), 3.11 (s, 6H), 2.91 (d, 2H), 2.74 (s, 4H), 2.46 (t, 4H), 1.95 (m, 2H), 1.76 (m, 2H), 1.47 (m, 4H).
Embodiment 5
Chemical equation：
Sitagliptin 0.5g (1.23mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then will Terephthalic acid (TPA) 100mg (0.61mmol), HBTU 1.39g (3.69mmol), DIEA 0.64g (4.92mmol) are added to reaction In liquid, it is stirred at room temperature, reaction 2h, TLC detection is stirred at room temperature, raw material fundamental reaction is complete, by reacting liquid filtering, then by filtrate In the NaOH aqueous solution for slowly pouring into 10 times of filtrate volumes, there are a large amount of white solids to separate out, stir 20min, filtering obtains class White solid, dries, obtains 0.45g compounds 5.Solvent is：CHCl3：MeOH:NH3.H2O=15:1:0.01.
MSm/z(ESI):982.9(M+K)。
1H-NMR (500MHz, deuterated DMSO):δ 8.09 (m, 4H), 7.31~7.38 (m, 2H), 7.13~7.22 (M, 2H), 5.07~5.27 (m, 4H), 4.01~4.15 (m, 2H), 3.53~3.60 (m, 4H), 2.80~2.91 (m, 4H), 2.59 ~2.72 (m, 4H).
Embodiment 6
Chemical equation：
Sitagliptin 0.5g (1.23mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then will 2,5 pyridinedicarboxylic acid 100mg (0.61mmol), HBTU 1.39g (3.69mmol), DIEA 0.64g (4.92mmol) are added to In reaction solution, it is stirred at room temperature, reaction 2h, TLC detection is stirred at room temperature, completely, then reacting liquid filtering will for raw material fundamental reaction Filtrate is slowly poured into the NaOH aqueous solution of 10 times of filtrate volumes, has a large amount of white solids to separate out, and stirs 20min, and filtering is obtained To off-white powder, dry, obtain 0.42g compounds 6.Solvent is：CHCl3：MeOH:NH3.H2O=15:1:0.01.
MSm/z(ESI):944.0(M+H)。
1H-NMR (500MHz, deuterated DMSO):δ 9.71 (m, 1H), δ 8.78 (m, 1H), δ 8.60 (m, 1H), 7.31~ (7.38 m, 2H), 7.13~7.22 (m, 2,5.07~5.27 (m, 4H), 4.01~4.15 (m, 2H), 3.53~3.60 (m, 4H), 2.80~2.91 (m.4H), 2.59~2.72 (m, 4H).
Embodiment 7
Chemical equation：
Sitagliptin 0.5g (1.23mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then will Adipic acid 100mg (0.61mmol), HBTU 1.39g (3.69mmol), DIEA 0.64g (4.92mmol) are added to reaction solution In, it is stirred at room temperature, reaction 2h, TLC detection is stirred at room temperature, raw material fundamental reaction is completely, then slow by filtrate by reacting liquid filtering Slowly pour into the NaOH aqueous solution of 10 times of filtrate volumes, EA is extracted three times, merge organic phase, anhydrous sodium sulfate drying, decompression Concentration, obtains 0.36g faint yellow solids, as compound 7.Solvent is：CHCl3：MeOH:NH3.H2O=10:1:0.01.
MSm/z(ESI):923.0(M-H)。
1H-NMR (500MHz, deuterated DMSO):δ 9.71 (m, 1H), δ 8.78 (m, 1H), δ 8.60 (m, 1H), 7.31~ 7.38 (m, 2H), 7.13~7.22 (m, 2H), 5.07~5.27 (m.4H), 4.01~4.15 (m, 2H), 3.53~3.60 (m, 4H), 2.80~2.91 (m.4H), 2.59~2.72 (m, 4H), 2.16 (t, 4H), 1.55 (t, 4H).
Embodiment 8
Chemical equation：
DCM50ml is added in there-necked flask, succinic anhydride 0.5g (4.92mmol) is weighed and is added in reaction solution, treat it All dissolvings, sitagliptin 2.0g (4.92mmol) is added drop-wise in reaction with DCM50ml dissolvings, reacts at room temperature 1.5h, TLC inspections Survey raw material to have reacted completely, stop reaction, reaction solution is concentrated under reduced pressure and is evaporated, white solid is obtained.By white obtained above Solid weighs 0.5g (0.98mmol), and BI 1356 0.46g (0.98mmol) is added in 100ml round-bottomed flasks, uses 20mlDMF is dissolved, then by HBTU 0.74g (2.0mmol), DIEA 0.25g (2.0mmol) are added in reaction solution, room Temperature stirring, is stirred at room temperature reaction 2h, TLC detection, and completely, then reacting liquid filtering slowly inclines filtrate for raw material fundamental reaction In the NaOH aqueous solution for pouring into 10 times of filtrate volumes, there are a large amount of white solids to separate out, filter, dry, obtain 0.70g compounds 8. Solvent is：CHCl3：MeOH:NH3.H2O=10:1:0.01.
MSm/z(ESI):962.5(M-H)。
1H-NMR (deuterated DMSO):δ 8.01~8.04 (m, 1H), 7.82~7.85 (m, 2H), 7.31~7.38 (m, 1H), 7.13~7.22 (m, 1H), 5.07~5.27 (m.2H), 4.01~4.15 (m, 2H), 3.53~3.60 (m, 2H), 3.24 (s.2H), 2.60~2.94 (m.13H), 2.35 (s, 6H), 2.15~2.20 (m, 4H), 1.55 (t, 4H).
Embodiment 9
Chemical equation：
Sitagliptin 0.5g (1.23mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then will Dodecanedioic acid 140mg (0.61mmol), HBTU 0.93g (2.0mmol), DIEA 0.32g (2.0mmol) are added to reaction solution In, it is stirred at room temperature, reaction 2h, TLC detection is stirred at room temperature, raw material fundamental reaction is completely, then slow by filtrate by reacting liquid filtering Slowly pour into the NaOH aqueous solution of 10 times of filtrate volumes, there are a large amount of white solids to separate out, filtering, then wash two with isopropyl ether It is secondary, dry, obtain white solid 0.35g, as compound 9.Solvent is：CHCl3：MeOH:NH3.H2O=10:1:0.01.
MSm/z(ESI):1009.3(M+H)。
1H-NMR (500MHz, deuterated DMSO):δ 9.71 (m, 1H), δ 8.78 (m, 1H), δ 8.60 (m, 1H), 7.31~ (7.38 m, 2H), 7.13~7.22 (m, 2H), 5.07~5.27 (m.4H), 4.01~4.15 (m, 2H), 3.53~3.60 (m, 2H), 2.80~2.91 (m.4H), 2.59~2.72 (m, 4H), 2.22 (t, 4H), 1.55 (t, 4H), 1.29 (m, 16H).
Embodiment 10
Chemical equation：
BI 1356 0.5g (1.1mmol) is added in 100ml round-bottomed flasks, dissolved with 20mlDMF, then by ten Two docosandioic acid 120mg (0.53mmol), HBTU 0.80g (2.0mmol), DIEA 0.41g (3.0mmol) are added to reaction solution In, it is stirred at room temperature, reaction 2h, TLC detection is stirred at room temperature, raw material fundamental reaction is completely, then slow by filtrate by reacting liquid filtering Slowly pour into the NaOH aqueous solution of 10 times of filtrate volumes, there are a large amount of white solids to separate out, filter, dry, obtain white solid 0.40g, as compound 10.Solvent is：CHCl3：MeOH:NH3.H2O=10:1:0.01.
MSm/z(ESI):1139.5(M-H)。
1H-NMR (deuterated DMSO):δ 8.01~8.04 (m, 2H), 7.82~7.85 (m, 4H), 4.40 (s, 4H), 4.09~ 4.14 (m, 4H), 3.53~3.60 (m, 2H), 3.24 (s.4H), 2.59~2.72 (m, 4H), 2.65~2.70 (m, 10H), 2.35 (s, 6H), 2.20 (m, 4H), 1.25~1.45 (m, 16H).
Embodiment 11
Chemical equation：
The preparation of the first step [2- (2- carbamyls-pyrrolidin-1-yl) -2- oxo-ethyls]-t-butyl carbamate
Boc- glycine 2.5g (14.28mmol) and L- prolineamides 1.62g (14.25mmol) are dissolved in 50mlDMF, 0 DEG C is cooled to, stirring is lower to add HOBt 5.9g (43.6mmol), DIC 5.65g (28.5mmol), triethylamine 6.0ml, nature Room temperature is warming up to, is stirred overnight, TLC detections, raw material reacts, is concentrated under reduced pressure completely, and remaining grease is extracted with ethyl acetate (200ml*3), merges organic phase, then is washed with saturated sodium-chloride, and organic phase anhydrous sodium sulfate drying is concentrated under reduced pressure, obtained Target compound 3.7g.Solvent is：CHCl3：MeOH:NH3.H2O=20:1:0.01.
MSm/z(ESI):272.5(M+H)。
The preparation of second step [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-t-butyl carbamate
[2- (2- carbamyls-pyrrolidin-1-yl) -2- oxo-ethyls]-t-butyl carbamate 3.7g is added to In 100ml round-bottomed flasks, 0 DEG C is then cooled to, 4.0ml TFAAs are added in reaction solution, the three of 3.0ml are added Ethamine, keeps 0 DEG C of reaction 1h, TLC detection, and raw material reacts completely, 100ml ethyl acetate is added into reaction solution, organic phase is used Washing three times, organic phase anhydrous sodium sulfate drying is concentrated under reduced pressure, and obtains target compound 3.0g.Solvent is：CHCl3： MeOH:NH3.H2O=20:1:0.01.MSm/z(ESI):254.5(M+H).
The preparation of the 3rd step [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-amino
[2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-t-butyl carbamate 3.0g is dissolved in 16mlDCM In 100ml round-bottomed flasks, 4ml trifluoroacetic acids are added in reaction solution, reaction 1h is stirred at room temperature, reaction terminates, reaction solution is subtracted Pressure concentration, remaining grease adjusts pH to 8.0 with the NaOH aqueous solution, is extracted with ethyl acetate three times (100ml*3), merges organic Phase, anhydrous sodium sulfate drying is concentrated under reduced pressure, and obtains grease 1.5g.Solvent is：CHCl3：
MeOH:NH3.H2O=20:1:0.01.
MSm/z(ESI):154.5(M+H)。
Embodiment 12
Chemical equation：
0.8g [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-amino is dissolved in 100ml round bottoms with 50mlDCM In flask, 5ml triethylamines are added in reaction solution, are stirred at room temperature, then the dichloromethane of 0.16g paraphthaloyl chloride is molten Liquid 10ml is added drop-wise in reaction solution, and reaction 2.5 hours is stirred at room temperature, and occurs insoluble matter in reaction solution, and TLC monitoring reactions terminate, Filtering, is dried, it is compound 12 to obtain 0.7g white solids.Solvent is：CHCl3：MeOH:NH3.H2O=10:1:0.01.
MSm/z(ESI):437.2(M+H)
1H-NMR (deuterated DMSO):δ 8.09 (m, 4H), 4.71~4.73 (m, 2H), 4.05~4.10 (m, 4H), 3.35~ 3.59 (m.4H), 1.90~2.36 (m, 8H).
Embodiment 13
Chemical equation：
0.75g [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-amino is dissolved in 50ml round bottoms with 50mlDCM In flask, 5ml triethylamines are added in reaction solution, are stirred at room temperature, then by the dichloromethane solution of 0.17g Adipoyl Chloride 10ml is added drop-wise in reaction solution, and reaction 2.5 hours is stirred at room temperature, and occurs insoluble matter in reaction solution, and TLC monitoring reactions terminate, mistake Filter, dries, obtains white solid 0.5g, as target compound.Solvent is：CHCl3：MeOH:NH3.H2O=10:1: 0.01。
MSm/z(ESI):439.2(M+Na)
1H-NMR (deuterated DMSO):δ 4.71~4.73 (m, 2H), 4.05~4.10 (m, 4H), 3.35~3.59 (m.4H), 1.90~2.36 (m, 12H), 1.55 (t, 4H).
Embodiment 14
Chemical equation：
1.5g [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-amino is dissolved in 100ml round bottoms with 50mlDCM In flask, 5ml triethylamines are added in reaction solution, are stirred at room temperature, then by the dichloromethane of the 2 of 0.36g, 5 pyridine dimethyl chlorides Alkane solution 10ml is added drop-wise in reaction solution, and reaction 2.5 hours is stirred at room temperature, and occurs insoluble matter, TLC monitoring reaction knots in reaction solution Beam, is filtered, and is dried, is obtained 1.4g white solids i.e. target compound 14.Solvent is：CHCl3：MeOH:NH3.H2O=10:1: 0.01。
MSm/z(ESI):438.2(M+H)
1H-NMR (deuterated DMSO):δ 9.71 (m, 1H), 8.78 (m, 1H), 8.60 (m, 1H), 4.71~4.73 (m, 2H), 4.05~4.10 (m, 4H), 3.35~3.59 (m.4H), 1.90~2.36 (m, 8H).
Embodiment 15
Chemical equation：
0.75g (4.9mmol) [2- (2 cyano-pyrolidin -1- bases) -2- oxo-ethyls]-amino is dissolved in 50mlDMF In 50ml round-bottomed flasks, then by 1,3,5- tri- benzoic acid (1.02g, 4.9mmol), HBTU 13.7g (29.4.0mmol), DIEA 4.72g (29.4mmol) are added in reaction solution, are stirred at room temperature, and reaction 2h, TLC detection is stirred at room temperature, and raw material is substantially anti- Should be complete, by reacting liquid filtering, in the NaOH aqueous solution that then filtrate slowly poured into 10 times of filtrate volumes, there are a large amount of whites Solid is separated out, filtering, then is washed twice with isopropyl ether, is dried, is obtained white solid 0.85g, i.e. compound 15.Solvent is： CHCl3：MeOH:NH3.H2O=10:1:0.01
MSm/z(ESI):614.3(M+H)
1H-NMR (deuterated DMSO):δ 8.60~8.78 (m, 3H), 4.71~4.73 (m, 2H), 4.05~4.10 (m, 4H), 3.35~3.59 (m.4H), 1.90~2.36 (m, 8H).
Embodiment 16
Chemical equation：
The chemical synthesis process of embodiment 16 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 5.
MSm/z(ESI):767.3(M+H)
1H-NMR (deuterated DMSO):δ 4.40~4.51 (m, 2H), 3.50~3.55 (m, 2H), 2.25~2.35 (m, 6H), 1.60~1.70 (m.8H), 1.00~1.50 (m, 30H), 0.50~1.00 (m, 6H).
Embodiment 17
Chemical equation：
The chemical synthesis process of embodiment 17 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 5.
MSm/z(ESI):731.3(M+H)
1H-NMR (deuterated DMSO):δ 8.10~8.20 (m, 1H), 7.60~7.70 (m, 2H), 7.10~7.50 (m, 8H), 6.50~7.00 (m.6H), 1.00~1.50 (m, 15H), 0.50~1.00 (m, 3H).
Embodiment 18
Chemical equation：
The chemical synthesis process of embodiment 18 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 1.
MSm/z(ESI):885.3(M+H)
1H-NMR (deuterated DMSO):δ 8.10~8.20 (m, 4H), 6.50~6.70 (m, 4H), 4.00~4.30 (m, 6H), 3.75 (s.12H), 3.40~3.50 (m, 4H), 2.50~3.00 (m, 10H), 2.00~2.50 (m, 14H).
Embodiment 19
Chemical equation：
The chemical synthesis process of embodiment 19 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 1.
MSm/z(ESI):772.3(M+H)
1H-NMR (deuterated DMSO):δ 9.40~9.50 (m, 1H), 8.60~8.80 (m, 2H), 8.00~8.30 (m, 4H), 3.60~4.00 (m, 18H), 2.50~3.00 (m, 10H), 1.40~2.20 (m, 18H).
Embodiment 20
Chemical equation：
The chemical synthesis process of embodiment 20 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 5.
MSm/z(ESI):803.3(M+H)
1H-NMR (deuterated DMSO):δ 4.40~4.51 (m, 2H), 3.50~3.55 (m, 4H), 2.25~2.45 (m, 6H), 1.60~1.85 (m.4H), 1.00~1.50 (m, 30H), 0.50~1.00 (m, 6H).
Embodiment 21
Chemical equation：
The chemical synthesis process of embodiment 21 is similar to the chemical synthesis process of embodiment 5, and specific experiment process is for reference Embodiment 1.
MSm/z(ESI):787.4(M+H)。
1H-NMR (500MHz, deuterated DMSO):δ 7.82 (d, 2H), 7.60 (t, 2H), 7.45 (m, 2H), 7.23 (d, 2H), 5.80~5.90 (m, 2H), 5.36 (s, 2H), 5.20 (ABq, 4H), 3.26 (d, 2H), 3.14 (m, 2H), 3.10 (s, 6H), 2.90 (d, 2H), 2.75 (s, 4H), 2.16 (t, 4H), 1.94 (m, 2H), 1.77 (m, 2H), 1.47 (m, 4H).
Test case：
Biological assessment
Following method is the DPP-4 inhibitory activity for determining the compounds of this invention.It has detected chemical combination in the present invention Thing suppresses the rejection ability of DPP-4 enzymatic activitys.The inhibiting rate of each compound is the enzyme mixing testing compound with fixed amount Determine.
The measure of DPP-4 inhibitory activity
1st, material
A, dimethyl sulfoxide (DMSO) (DMSO)
B, white 384 orifice plate (BMG)
C, buffer solution (25mM Tris-HCl, pH 8.0)
D, DPP-4 enzyme (supplier：Enzo Biochem)
E, fluorescein detection reagent：Gly-Pro-AMC (suppliers：Enzo Biochem)
F, KR-62436 (supplier Sigma)
G, BI 1356, sitagliptin, Egelieting
2nd, method of testing：
Weigh the compound 1-14 in embodiment and the KR-62436 of purchase, BI 1356, sitagliptin, Egelieting pair DMSO is dissolved in respectively according to product, is configured to the solution that concentration is 2.5mg/mL.All compound solutions are placed on subzero 20 DEG C Cord blood is standby.Solution is further diluted with buffer solution, DMSO contents are not higher than 2% in dilute solution.Operating procedure is such as Under：
A, with buffer solution dilute each test sample and reference substance.
B, with buffer solution dilute DPP-4 enzymes, concentration be 0.5 μ g/ml.
C, each testing sample and substrate after dilution be transferred on flat board, sample concentration is respectively 0.5mg/L, respectively Add same amount of DPP-4 enzymes.
D, orifice plate is sealed with sealer, at room temperature preculture ten minutes.
E, addition Gly-Pro-AMC substrates (concentration is 10 μM), are reacted.
F, the data for recording multi-function microplate reader.
G, inhibiting rate definition：(1- sample activities/enzyme is entirely active) × 100%
Enzyme is entirely active：Activity measured by DPP-4 enzymes/buffer solution/Gly-Pro-AMC hybrid reactions.
Inhibiting rate and IC50As a result it is as shown in the table：

Claims (12)

  1. The compound shown in formula 1. (I) structure,
    Wherein,
    X or Y are separately the primary amine group or secondary amine group of the DPP-4 inhibitor containing amino or imino group, contain ammonia The primary amine group or secondary amine group of the DPP-4 inhibitor pharmaceutically acceptable salt or optical isomer of base or imino group, formula (II) group of group or formula (II) optical isomer；The DPP-4 inhibitor containing amino or imino group is selected from A Gelie Spit of fland, Xi Gelieting, BI 1356, vildagliptin, saxagliptin, carmegliptin, melogliptin or Duloxetine；
    M is substituted or non-substituted C1~12Alkyl, C3~8Cycloalkyl, C2~8Alkenyl, phenyl or pyridine radicals, the substituent are selected from halogen Element, C1~4Alkyl, C1~4Haloalkyl, C1~4Alkoxy, cyano group, nitro or phenyl；
    N is 1 or 0, and
    When n is 1, Z for the primary amine group or secondary amine group of the DPP-4 inhibitor containing amino or imino group, containing amino or The DPP-4 inhibitor pharmaceutically acceptable salt of imino group or the primary amine group or secondary amine group of optical isomer, formula (II) base Group or the group containing formula (II) optical isomer；The DPP-4 inhibitor containing amino or imino group be selected from Egelieting, Xi Gelieting, BI 1356, vildagliptin, saxagliptin, carmegliptin, melogliptin or Duloxetine；
    When n is 0, Z is hydrogen, C1~4Alkyl, C3~6Cycloalkyl, C3~6Heterocyclylalkyl or phenyl；
    L is selected from CH2、S、CH2CH2、CHF、CF2Or CH2CHF。
  2. 2. compound according to claim 1, wherein the M is substituted or non-substituted C2~10Alkyl, C5~6Cycloalkyl, C2~6Alkenyl, phenyl, pyridine radicals, the substituent are selected from halogen, C1~4Alkyl, C1~4Haloalkyl, C1~4Alkoxy, cyano group, nitre Base or phenyl.
  3. 3. compound according to claim 2, wherein the M is substituted or non-substituted ethylidene, butylidene, the sub- last of the ten Heavenly stems Base, cyclohexyl, phenyl or pyridine radicals, the substituent are selected from halogen, C1~4Alkyl, C1~4Haloalkyl, C1~4Alkoxy, cyanogen Base, nitro or phenyl.
  4. 4. compound according to claim 1, wherein L are selected from-CH2- or-CH2CH2-。
  5. 5. compound according to claim 1, wherein being selected from：
  6. 6. the preparation method of compound described in claim 1 (I), it is characterised in that press down the DPP-4 containing amino or imino group Preparation, DPP-4 inhibitor pharmaceutically acceptable salt or optical isomer containing amino or imino group, formula (II) compound or Formula (II) compound light isomers, respectively with omega-dicarboxylic acids compound, tricarboxylic acid compounds, diacid chloride class compound or three Acyl chloride compound carries out amidation process and produced；
    Or by a kind of DPP-4 inhibitor containing amino or imino group, the DPP-4 inhibitor pharmacy containing amino or imino group Upper acceptable salt or optical isomer, formula (II) compound or formula (II) compound light isomers, are first carried out with dicarboxylic anhydride Reaction, then pharmaceutically may be used with the DPP-4 inhibitor containing amino or imino group, the DPP-4 inhibitor containing amino or imino group The salt or optical isomer of receiving, formula (II) compound or formula (II) compound light isomers carry out aminating reaction and produced；
    The DPP-4 inhibitor containing amino or imino group be selected from Egelieting, Xi Gelieting, BI 1356, vildagliptin, Saxagliptin, carmegliptin, melogliptin or Duloxetine；Formula (II) compound has following structure：
    L is selected from CH2、S、CH2CH2、CHF、CF2Or CH2CHF。
  7. 7. method according to claim 6, it is characterised in that the omega-dicarboxylic acids compound is selected from substituted or non-substituted Alkyl dicarboxylic aid, cycloalkyl dicarboxylic acids, alkenyl dicarboxylic acids, aryl dicarboxylic acid or heteroaryl dicarboxylic acids；
    The tricarboxylic acid compounds are selected from substituted or non-substituted alkyl tricarboxylic acids, cycloalkyl tricarboxylic acids, alkenyl tricarboxylic acids, virtue Base tricarboxylic acids or heteroaryl tricarboxylic acids；
    The diacid chloride class compound is selected from substituted or non-substituted alkyl diacid chloride, cycloalkyl diacid chloride, alkenyl diacid chloride, virtue Base diacid chloride or heteroaryl diacid chloride；
    Three acyl chloride compound be selected from the substituted or non-substituted acyl chlorides of alkyl three, the acyl chlorides of cycloalkyl three, the acyl chlorides of aryl three or The acyl chlorides of heteroaryl three；
    The dicarboxylic anhydride be selected from succinic anhydride, succinic anhydride derivative, glutaric anhydride, glutaric anhydride derivative, adipic anhydride or Adipic anhydride derivative.
  8. 8. method according to claim 7, it is characterised in that the omega-dicarboxylic acids compound is selected to benzene dicarboxylic acid, pyridine Dicarboxylic acids, C1~12Alkyl dicarboxylic aid；
    The tricarboxylic acid compounds are selected from tricarballylic acid, 1,2,4- benzenetricarboxylic acids, 1,2,3- benzenetricarboxylic acids, 1,3,5- equal benzene Tricarboxylic acids, 1,3,5- penta tricarboxylic acids, pyridine -2,3,4- tricarboxylic acids, 1,2,4- cyclohexanetricarboxylic acids or 1,3,5- hexamethylene tricarboxylic acids； The diacid chloride class compound be selected from the caprylyl chlorides of 1,8- bis-, 2,6- pyridines dimethyl chloride, malonyl chloride, paraphthaloyl chloride, Phthalyl chloride, ethyl malonyl chloride, fumaryl chloride, succinyl chloride, Adipoyl Chloride, hexafluoro glutaryl chlorine, oxalyl two Chlorine, 1,7- pimeloyl chlorides, 3- methyl Adipoyl Chloride, sebacoyl chloride, azelaoyl chloride or glutaryl dichloro；
    Three acyl chloride compound is selected from the formyl chloride of 1,3,5- benzene three；
    The dicarboxylic anhydride be selected from succinic anhydride, glutaric anhydride, adipic anhydride, 2,2- dimethylated pentanedioic acids acid anhydride, tetrafluoro succinic anhydride, 2,2- dimethyl succinic anhydrides, dimethyl succinic acid acid anhydride, 3- ethyl -3- methylglutaric acid acid anhydrides, 3,3- dimethylated pentanedioic acids acid anhydride, 3- are different Butyl glutaric anhydride or 2- iso-octyl succinic anhydrides.
  9. 9. method according to claim 8, it is characterised in that the dicarboxylic anhydride be selected from succinic anhydride, glutaric anhydride, oneself two Acid anhydrides, hexafluoroglutaric anhydride, 2,2- dimethylated pentanedioic acids acid anhydride or tetrafluoro succinic anhydride.
  10. 10. method according to claim 6, it is characterised in that catalyst is added during the amidation process, described Catalyst is selected from 1,3- dicyclohexylcarbodiimides, N, N'- DICs, 1- (3- dimethylamino-propyls) -3- second Base carbodiimide and its hydrochloride, 1- (3- dimethyl aminopropyls) -3- ethylcarbonyl group diamines methiodide, DIPEA, I-hydroxybenzotriazole, 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, BTA- N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester, 6- Chloro-Benzotriazoles -1,1,3,3- tetramethylurea hexafluorophosphoric acid esters, 2- (1H- Benzo trisazo- L-1- yls) -1,1,3,3- tetramethylurea tetrafluoro boric acid ester, 2- succinimidos -1,1,3,3- tetramethylureas One or more of groups in tetrafluoro boric acid ester, 5- ENB -2,3- dicarbapentaborane-N, N, N', N'- tetramethylurea tetrafluoro boric acid esters Close.
  11. 11. the power of a kind of pharmaceutical composition, free form of the pharmaceutical composition comprising therapeutically effective amount or pharmaceutical acceptable salt Profit requires compound defined in 1 as active component, and one or more medicinal carrier substances and/or diluent.
  12. 12. the compound described in claim 1 is preparing treatment and/or prevention diabetes medicament or other diseases related to DPP-4 Purposes in terms of medicine.
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