CN109305957A - Phenylpyridine class compound and its application in DPP-4 enzyme inhibitor - Google Patents
Phenylpyridine class compound and its application in DPP-4 enzyme inhibitor Download PDFInfo
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- CN109305957A CN109305957A CN201710616507.3A CN201710616507A CN109305957A CN 109305957 A CN109305957 A CN 109305957A CN 201710616507 A CN201710616507 A CN 201710616507A CN 109305957 A CN109305957 A CN 109305957A
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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
- C07D401/02—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 two hetero rings
- C07D401/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
In the inhibitor that compound of the present invention is dipeptidyl peptidase-4.Furthermore, disclosure sets forth drug components and preparation comprising the compound, and the purposes of this kind of dipeptidyl peptidase-4 inhibitors, can single drug or with other compound drug combinations, for treat by dipeptidyl peptidase-4 mediate or dipeptidyl peptidase-4 rely on symptom.
Description
Technical field
The present invention relates to compound, the method for prepare compound, the pharmaceutical composition and medicament of compound, and by the change
Object is closed for controlling the relevant disease of dipeptidyl peptidase-4, imbalance or symptom.
Background technique
Dipeptidyl peptidase-4 (Dipeptidyl peptidase-4, abbreviation DPP-4 enzyme or DPP-4) is antidiabetic drug research
One important target spot in field, 2003 year determination its protein tridimensional knot isolated in rat liver for the first time in 1966
Structure.DPP-4 is with high specific serine protease existing for dimeric forms, its natural substrate is glucagon
Peptide -1 (GLP-1) and glucose pancreotropic hormone polypeptide (GIP) both have the function of promoting insulin secretion.Inhibit DPP-
4 can effectively improve internal GLP-1 and GIP level, and then by promoting insulin secretion to play blood sugar reducing function.DPP-4 inhibitor
Can effectively avoid hypoglycemia caused by traditional hypoglycemic medicine, weight gain, Instreptozotocin Induced damage etc. adverse reactions, with
There is significant advantage in terms of medicine safety, be generally considered a kind of very promising hypoglycemic medicine.
In recent years, the temperature of DPP-4 inhibitor research field does not subtract still, has emerged in large numbers many structure novels, potent Gao Xuan
" column spit of fland " class hypoglycemic medicine of selecting property, the phosphoric acid Xi Gelieting (1, Sitagliptin including Merck & Co., Inc.'s research and development
Phosphate, U.S.'s listing in 2006) and Ao Gelieting (Japan's listing in 2, Omarigliptin, 2015), Novartis Co., Ltd
Vildagliptin (3, Vildagliptin, 2007 Europe listing), Bristol-Myers Squibb Co. and AstraZeneca cooperative development
Saxagliptin (4, Saxagliptin, 2009 U.S. listing), Wu Tian company alogliptin benzoate (5,
Alogliptin benzoate, Japan's listing in 2010) and amber love song Ge Lieting (6, Trelagliptin
Succinate, Japan's listing in 2015), the Li Gelieting (beauty in 7, Linagliptin, 2011 of Boehringer Ingelheim company
State's listing), the teneligliptin (Japan's listing in 8, Teneligliptin, 2012) of Mitsubishi field side pharmacy exploitation, LG life section
My lattice of the gigue column spit of fland (Korean market in 9, Gemigliptin, 2012) of company, Japan three and chemistry institute arrange
Spit of fland (10, Anagliptin, 2012 Japan listing) and the research and development of East Asia drugmaker of South Korea Yi Gelieting (11,
Evogliptin, Korean market in 2015).
Currently, grinding a new direction of the DPP-4 inhibitor as hypoglycemic medicine exploitation containing aminomethyl biaryl.
Therefore, research structure novelty, aminomethyl phenyl yl pyridines class compound are of great significance to potential DPP-4 inhibitor is developed.
Summary of the invention
Compound of the present invention, pharmaceutical composition, medicament and method can be used for controlling and one or more dipeptides
The relevant disease of base peptase -4, imbalance or symptom.Method, compound, pharmaceutical composition and medicament set forth herein are by inhibiting one
A or multiple active inhibitor of dipeptidyl peptidase-4 are constituted.
In the first aspect of the present invention, a kind of compound of formula I or its pharmaceutically acceptable salt, solvate are provided
Or prodrug:
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol
[4,3- α] pyrazine -7- base.
In the second aspect of the present invention, II compound of formula, III compound of formula, IV compound of formula, V chemical combination of formula are provided
VII compound of object, VI compound of formula or formula:
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol
[4,3- α] pyrazine -7- base；
In the third aspect of the present invention, a kind of preparation method of compound of formula I is provided, the method includes the steps: it will
The cyano of compound ii carries out hydro-reduction reaction, obtains chemical compounds I.
In one example, it is described reaction carry out in a solvent, the solvent be one or both of alcohols and water with
On.
In one example, the catalyst of the reaction is Raney's nickel.
In one example, the temperature of the reaction is 20-60 DEG C.
In one example, the compound ii is prepared using following step: compound III and R1H replace anti-
It answers, obtains compound ii；
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol
[4,3- α] pyrazine -7- base.
In the fourth aspect of the present invention, a kind of preparation method of II compound of formula is provided, the method includes the steps:
Compound III and R1H carries out substitution reaction, obtains compound ii；
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol
[4,3- α] pyrazine -7- base.
In the fifth aspect of the invention, a kind of preparation method of III compound of formula is provided, the method includes the steps:
Compounds Ⅳ and mesyl chloride are subjected to acylation reaction, obtain compound III.
In the sixth aspect of the present invention, a kind of preparation method of IV compound of formula is provided, the method includes the steps:
Compound V carries out demethylating reaction, obtains compounds Ⅳ.
In the seventh aspect of the present invention, a kind of preparation method of V compound of formula is provided, the method includes the steps:
Compound VI carries out hydro-reduction reaction, obtains compound V.
In the eighth aspect of the present invention, a kind of preparation method of VI compound of formula is provided, the method includes the steps:
Compound VII carries out witting with methoxymethyl triphenylphosphonium bromide phosphine and reacts, and obtains compound VI.
In the ninth aspect of the present invention, a kind of preparation method of VII compound of formula is provided, the method includes the steps:
Compound VIII carries out oxidation reaction, obtains compound VII.
In the tenth aspect of the present invention, a kind of pharmaceutical composition is provided, which includes to mention present invention as described above
The type I compound and pharmaceutically acceptable carrier of confession.
In one example, the form of pharmaceutical composition be aqueous dispersion, liquid, Gel miles, syrup, elixir, medicine slurry,
Suspension, lotion, granule, aerosol, controlled release agent, quick-dissolving agent, effervescent agent, freeze-dried, tablet, pulvis, pill, dragee,
Capsule, suppository, injection, sustained release agent, extended release agent, pulse controlled release agent, multiparticulates agent release immediately agent.
In the eleventh aspect of the present invention, provides the pharmaceutical composition that one kind provides present invention as described above and making
Application in standby people's dipeptidyl peptidase-4 inhibitors.
In the twelveth aspect of the present invention, provides the pharmaceutical composition that one kind provides present invention as described above and making
The application made preparation for dropping in sugared pharmaceutical preparation.
In the thirteenth aspect of the present invention, provides the type I compound that one kind provides present invention as described above and preparing
Application in people's dipeptidyl peptidase-4 inhibitors.
In the fourteenth aspect of the present invention, provides the type I compound that one kind provides present invention as described above and preparing
Application in hypoglycemic medicine preparation.
Accordingly, the present invention provides a kind of phenylpyridine class compounds of structure novel inhibits to potential DPP-4 is developed
Agent.
Specific embodiment
Compound as described herein, can inhibit dipeptidyl peptidase-4.On the one hand, compound described herein is phenyl pyrazoline
Pyridine class compound.On the one hand, compound as described herein as dipeptidyl peptidase-4 inhibitors there is extensive treatment to make
With.
Term
If being used for the present patent application without other explanation, including the term in specification and claims, definition is such as
Under.It has to be noticed that in the specification and the appended claims, if nothing clearly dictates otherwise in text, singular " one
It is a " it include plural references.If using mass spectrum, nuclear-magnetism, HPLC, protein chemistry, biochemistry, recombinant DNA without other explanation
The conventional method of technology and pharmacology.In this application, if referring to "and/or" using "or" or "and" without other explanation.
" formula (I) compound " refers to that structural formula is the compound of (I).
If the term " aryl " used herein refers to aromatic rings, wherein each atom for forming ring is carbon atom.Aryl
By five, six, seven, eight, nine or more form ring.Aryl is optionally substituted.On the one hand, aryl is phenyl
Or naphthalene.According to structure, aryl can be single free radical or diradical (such as arlydene).On the one hand, aryl is C6-C10Virtue
Base.
In certain specific embodiments, the compound has one or more stereocenters, and each center is with R or S
Type is individually present.Compound includes all diastereomeric bodily forms as mentioned herein, and the mapping bodily form is poor suitable with theirs to the structure bodily form
Work as mixture.Stereoisomer can be obtained by method of such as chiral chromatographic column to Enantiomer separation.
Method described herein and molecular formula include using N- oxide (if appropriate), and crystal form is (also referred to as more
Crystal form) or formula (I) structural compounds pharmaceutically acceptable salt, with the active generation with identical these active compounds
Thank to object.In some cases, compound may exist as tautomer.All tautomers include mentioning herein
Within the scope of the compound arrived.In some specific embodiment, the compound exists with solvation form, pharmaceutically may be used
The solvent of receiving such as water, ethyl alcohol etc..In other specific embodiments, the compound exists with nonsolvated forms.
Term " acceptable " refers to that a prescription component or active constituent are good for general treatment target as used herein
The inexcessive adverse effect of health.
Term " subject " or " patient " include mammal and nonmammalian.Mammal includes but is not limited to feed
Newborn class: people, non-human primates such as orangutan, ape and monkey class；Agricultural animal such as ox, horse, goat, sheep, pig；Domestic animal such as rabbit, dog；
Experimental animal includes rodent, such as rat, mouse and cavy.Non-mammalian animal includes but is not limited to bird, fish etc..One
In preference, selected mammal is people.
Term " treatment ", " therapeutic process " or " therapy " as used herein, including mitigation, inhibition or improve disease disease
Shape or situation；Inhibit the generation of complication；Improve or prevent potential metabolic syndrome；Inhibit the generation of disease or symptom, such as controls
The development of disease or situation processed；Mitigate disease or symptom；Disease or symptom is set to decline；Mitigate as caused by disease or symptom simultaneously
Send out disease, or prevention or the treatment sign as caused by disease or symptom.
As used herein, a certain compound or pharmaceutical composition after administration, can be such that a certain disease, symptom or situation obtains
To improvement, espespecially its severity is improved, delayed onset, slows down disease progression, or reduce the state of an illness duration.It is no matter solid
Fixed administration or interim administration are administered continuously or interrupted continuous administration, can be attributed to or the situation related with administration.
As used herein, " room temperature " refers to environment temperature, is 10 DEG C -30 DEG C.
Compound
In one aspect of the invention, provide a kind of compound of formula I or its pharmaceutically acceptable salt, solvate or
Prodrug:
Wherein,
R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3-
α] pyrazine -7- base.
Formula (I) compound includes but is not limited to the explanation in table 1.
Table 1.
| Compound number | R1 |
| I-1 | 1,2,4- triazole -1- base |
| I-2 | Imidazoles -1- base |
| I-3 | 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3- α] pyrazine -7- base |
The further form of compound
In some specific embodiment, (one kind is pharmaceutically according to pharmaceutically acceptable acid-addition salts for formula (I) compound
Acceptable salt) prepare, pass through compound free alkali form and pharmaceutically acceptable inorganic or organic acid reaction, packet
Include but be not limited to inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, phosphoric acid hydrogen, hydrogen sulfate etc.；Organic acid such as formic acid,
Acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, octanoic acid, capric acid, adipic acid, ethanedioic acid, malonic acid, succinic acid, trifluoroacetic acid, apple
Acid, maleic acid, fumaric acid, succinic acid, benzoic acid, methanesulfonic acid, benzene sulfonic acid, tartaric acid, phenylacetic acid, phthalic acid, to benzene two
Formic acid, stearic acid, palmitic acid, acrylic acid etc..
The salt of phenylpyridine class compound as described above is by phenylpyridine class compound and sour acid-base reaction
The salt of formation.Its acid-base reaction is known by this field conventional technique personnel.
" pharmaceutically acceptable " herein refers to a kind of substance, such as carrier or dilution, will not make compound bioactivity or
Property disappears, and relative nontoxic e.g. gives individual something, will not cause undesired biotic influence or in harmful manner
It interacts with any component that it contains.
Term " pharmaceutically acceptable salt " refers to that a kind of existence form of compound, the form will not cause to have administration
The important stimulation of body, and the bioactivity of compound and property will not be made to disappear.In certain specific aspects, pharmaceutically may be used
The salt of receiving is to react acquisition, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, second with acid by formula (I) compound
Sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc..
It should be understood that the reference of pharmaceutically acceptable salt includes solvent addition form or crystal form, especially solvation
Object or polymorphic.Solvate contains stoichiometry or non-stoichiometric solvent, and be with pharmaceutically acceptable solvent such as
Water, ethyl alcohol etc. are selectively formed in crystallisation procedure.Hydrate, or the shape when solvent is ethyl alcohol are formed when solvent is water
At alcoholates.The solvate of formula (I) compound is very easily made or is formed according to method described herein.It illustrates
Bright, the hydrate of formula (I) compound is recrystallized from water/organic solvent in the mixed solvent and is easily made, and what is used is organic
Solvent includes but is not limited to dioxane, tetrahydrofuran, ethyl alcohol or methanol.In addition, compound can as mentioned herein
Exist with non-solvated and solvation form.In short, for the purpose of for Compounds and methods for provided herein, solvation form
It is considered being equivalent to nonsolvated forms.
In other specific embodiments, formula (I) compound is prepared to different forms, including but not limited to, without fixed
Shape crushes shape and millimicro-granularity form.In addition, formula (I) compound includes crystal type, polymorphic can also be used as.Polymorphic
The different crystalline lattice arrangement of identical element composition including compound.Polymorphic usually has different x-ray diffraction patterns, infrared light
Spectrum, fusing point, density, hardness, crystal form, the property of light and electricity, stability and dissolubility.Different factors such as recrystallization solvent, knot
It is leading that brilliant rate and storage temperature, which may cause single crystal form,.
In certain specific embodiments, formula (I) compound is prepared as prodrug." prodrug " refers to a reagent in vivo
It is converted into prototype medicine.Prodrug is usually useful, because under certain conditions, they may administration easier than prototype medicine.They
Can be with, for example, be administered orally and can be with biological utilisation, but prototype medicine is not all right.Prodrug can also improve on pharmaceutical composition
The dissolubility of prototype medicine.For example, there is no limit prodrug is formula (I) compound, is unfavorable for the feelings by cell membrane in water solubility
Under condition, prodrug makes to be easier by cell membrane as ester administration, is then hydrolyzed into carboxylic acid by metabolism, active entities once into
Enter into cell, it is water-soluble just highly beneficial.Further example, prodrug can be small peptide (polyaminoacid) connection
To an acid groups, peptide shows active fragment after being metabolized.
Prodrug is usually the precursor of medicine, and next administration and absorption are converted into active material, or pass through some processes
Become the stronger type of activity, is such as converted by metabolic pathway.The chemical group that some prodrugs have make its activity it is lower and/
Or the dissolubility or some other properties of comparison prototype medicine.Once the chemical group of prodrug is removed and/or modifies it, obtain
To active drug.Prodrug be usually it is useful, in some cases, their administrations easier than prototype medicine.In certain specific embodiment
In, prodrug compound as described herein is administered orally and can be with biological utilisation, but prototype medicine is not all right.Moreover, in certain tools
In body embodiment, prodrug as described herein can also improve the dissolubility of prototype medicine on pharmaceutical composition.
In other specific embodiments, prodrug is designed as reversible medicaments derivative, as modifier come using with
Tissue of the enhancing medicament transport to specific location.At specific aspect, it is that water is that the purpose of prodrug design, which is for target area,
It is effectively water-soluble can to increase it for the therapeutic compounds of primary solvent.Fedorak et al., Am.J.Physiol., 269:
G210-218(1995)；McLoed et al., Gastroenterol, 106:405-413 (1994)；Hochhaus et
Al., Biomed.Chrom., 6:283-286 (1992)；J.Larsen and H.Bundgaard, Int.J.Pharmaceutics,
37,87 (1987)；J.Larsen et al., Int.J. Pharmaceutics, 47,103 (1988)；Sinkula et al.,
J.Pharm.Sci., (1975) 64:181-210；T.Higuchi and V.Stella, Prodrugs as Novel Delivery
Systems, Vol.14of the A.C.S. Symposium Series；With Edward B.Roche, Bioreversible
Carriers in Drug Design, American Pharmaceutical AssocItion and Pergamon
Press, 1987.
In certain specific embodiments, the aromatic moieties of formula (I) compound are very sensitive to different metabolic responses.Therefore exist
Substituent group appropriate will be incorporated in aromatic ring structure to be reduced, this metabolic pathway is reduced or eliminated.In the particular embodiment, suitably
Substituent group to increase or eliminate aromatic ring to the sensibility of metabolic response, for example, halogen or alkyl.
In another specific embodiment, compound as described herein has isotope labelling (e.g., radioisotope)
Or by other methods, including but not limited to, using chromophore or fluorescence segment, feel cold signal or chemiluminescent labeling.
In a certain specific embodiment, compound exists as geometric isomer provided herein.Chemical combination provided herein
Object and method include all cis-, trans-, E formula, and Z formula isomers properly mixes object with they.In certain specific aspects, originally
Compound described in text exists as tautomer.Within the scope of all tautomers molecular structural formula as described herein.
The another aspect of Compounds and methods for provided herein, from single preparation step (in conjunction with or interconversion) obtained enantiomer and/
Or the mixture of diastereomer is expected.
The synthesis of compound
The side combined in the synthetic technology or well known technology and text of the usable standard of formula (I) compound described above
Method synthesizes.In addition, solvent, temperature and other reaction conditions can change as mentioned herein.
The starting material of synthesis for formula (I) compound can be obtained by synthesizing or from commercial source, e.g., but not
It is limited to Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.).
The conventional method of compound preparation can introduce not isoplastic item by using reagent appropriate and provided herein in molecular formula
Part changes.For example, reaction dissolvent is chosen by reaction type, and the temperature reacted can pass through reaction classification and reaction
Used solvent is chosen, and the material proportion of reaction can also be according to reaction type and to all kinds of materials and reagent cost
The considerations of come suitably choose, in addition, reaction carry out degree and the reaction time confirmation can also by routine chromatography side
Method (such as gas phase, liquid phase and thin-layer chromatography are chosen).
But in order to further illustrate the preparation side of phenylpyridine class compound or its salt present invention as described above
Method, below with regard to the part of compounds in general formula for, carry out more detailed description.
The preparation method of phenylpyridine class compound is the following steps are included: in solvent shown in formula I provided by the invention
In, under reduction system effect, the cyano of compound ii is subjected to hydro-reduction reaction, obtains chemical compounds I；
Wherein, the R in compound I1With the R in compound ii1Definition and range are identical, and in above-mentioned chemical compounds I
R1Definition and range are identical.
Preferably, in the method for prepare compound I, the solvent is one of alcohols solvent and water or a variety of；
The reduction system is Raney's nickel/hydrogen (composite reagent of Raney's nickel and hydrogen, Raney Ni/H2)；The reduction is anti-
The temperature answered is 20 DEG C -60 DEG C.
The preparation method of phenylpyridine class compound present invention as described above, ordinary skill in the art personnel can
The experiment just specifically optimized or reaction condition can carry out conventional selection according to common sense.For example, reaction dissolvent passes through reaction class
Type is chosen, and the temperature reacted can be by reaction classification and solvent used by reacting is chosen, and the material of reaction is matched
Than can also be according to reaction type and to all kinds of materials and reagent cost the considerations of come suitably choose, in addition, react carry out degree
And the confirmation in reaction time can also by conventional chromatography method (such as gas phase, liquid phase and thin-layer chromatography are chosen).
But in order to further illustrate the preparation method of phenylpyridine class compound present invention as described above, below
For the part of compounds in general formula, more detailed description is carried out.
It is following methods that the present invention, which provides the preparation method of phenylpyridine class compound as shown in formula I:
Include the following steps: in a solvent, under reduction system effect, it is anti-that the cyano of compound ii is subjected to hydro-reduction
It answers, obtains chemical compounds I；
Wherein, the R in compound ii1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro -
[1,2,4] triazol [4,3- α] pyrazine -7- base.
The method of prepare compound I can be the conventional method of such reduction reaction in this field, especially excellent in the present invention
It selects following reaction method and condition: in enclosed system, compound ii being mixed with the solution of ammonia, under raney ni catalysis, with
Hydrogen carries out reduction reaction.
In the method for prepare compound I, the preferred alcohols solvent of solvent used in the solution of the ammonia and/or
Water；The preferred C of the alcohols solvent1-C4Alcoholic solvent；The C1-C4The preferred methanol of alcoholic solvent or ethyl alcohol.The ammonia
The ethanol solution of the preferred ammonia of the solution of gas or the methanol solution of ammonia.The molar concentration of the solution of the ammonia is preferred
1mol/L-10mol/L, further preferred 2mol/L-5mol/L.When the molar concentration refers to 10 DEG C -30 DEG C, ammonia
The ratio of the volume of the solution of mole and ammonia.
In the method for prepare compound I, the preferred conventional commercial Raney's nickel reagent of the Raney's nickel, further preferably
Mass percent is the Raney's nickel reagent of 50%-95%, and it is total that the mass percent refers to that the quality of nickel accounts for Raney's nickel reagent
The percentage of quality.
In the method for prepare compound I, preferably 20 DEG C -60 DEG C of the temperature of the reduction reaction, further preferred 20
℃-35℃。
In the method for prepare compound I, the preferred 0.1MPa-1MPa of the pressure of the reduction reaction, further preferably
0.3MPa-0.6MPa。
In the method for prepare compound I, the time of the reduction reaction preferred 1h-20h, further preferred 2h-
12h。
The method of prepare compound I preferably includes following post-processing step: after reaction, filtering, concentration, through column layer
Analysis purifying.The method and condition of the column chromatography is selected according to the method and condition that the column of this field routine chromatographs
It selects.
In the method for prepare compound I, the compound ii is prepared using following methods:
Include the following steps: in a solvent, under the action of alkali, compound III and R1H carries out substitution reaction, obtains chemical combination
Object II；
Wherein, the R in compound ii1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro -
[1,2,4] triazol [4,3- α] pyrazine -7- base；According still further to the method for prepare compound I, chemical compounds I is made.
The method of prepare compound II can be the conventional method of such substitution reaction in this field, in the present invention especially
It is preferred that following reaction method and condition: in a solvent, under the action of alkali, elimination reaction occurs first for compound III, then again with
R1H carries out substitution reaction.
In the method for prepare compound II, the preferred ether solvent of the solvent, nitrile solvents, amide solvent and
One of sulfoxide type solvents are a variety of；The preferred tetrahydrofuran of the ether solvent；The preferred acetonitrile of the nitrile solvents；
The preferred N,N-dimethylformamide of the amide solvent；The preferred dimethyl sulfoxide of the sulfoxide type solvents.
In the method for prepare compound II, the volume mass of the solvent and the compound III is than preferred
1mL/g-40mL/g, further preferred 10mL/g-25mL/g.
In the method for prepare compound II, the preferred potassium carbonate of the alkali, cesium carbonate, triethylamine, diisopropylethylamine
With one or more, further preferred potassium carbonate and/or the diisopropylethylamine of pyridine.
In the method for prepare compound II, the preferred 1:1-10:1 of molar ratio of the alkali and the compound III,
Further preferred 1:1-4:1.
In the method for prepare compound II, the R1The preferred 1:1-10:1 of molar ratio of H and the compound III,
Further preferred 1.5:1-4:1.
In the method for prepare compound II, preferably 10 DEG C -100 DEG C of the temperature of the substitution reaction, further preferably
45℃-90℃。
In the method for prepare compound II, the process of the substitution reaction can be surveyed by the routine in this field
Method for testing (such as TLC or HPLC) is monitored, and as terminal is reacted to obtain when generally being disappeared using compound III, the reaction time is preferred
1h-10h, further preferred 2h-6h.
The method of prepare compound II preferably includes following any post-processing step: working as R1Selected from imidazole radicals or 1,2,4-
When triazolyl, it is preferred to use method (1).Work as R1Selected from 3- (trifluoromethyl) -5,6,7,8- tetrahydro-[1,2,4] triazol [4,
3- α] pyrazine -7- base when, it is preferred to use method (2).
Method (1) includes the following steps: after reaction, to filter, concentration, through column chromatographic purifying.Wherein, described
Column chromatography method and condition according to this field routine column chromatography method and condition selected.
Method (2) includes the following steps: that after reaction water is added in reaction solution, and water phase is extracted with organic solvent, dry,
It filters, concentration, through column chromatographic purifying.Wherein, the preferred esters solvent of organic solvent for extraction.Described
Esters solvent ethyl acetate.The method that the method and condition of the described column chromatography is chromatographed according to the column of this field routine with
Condition is selected.
In the method for prepare compound II, the compound III is prepared using following methods: in a solvent, alkali
Under effect, compounds Ⅳ and mesyl chloride carry out acylation reaction, obtain compound III；
According still further to the method for prepare compound II, compound ii is made.
The method of prepare compound III can be the conventional method of such acylation reaction in this field, in the present invention especially
It is preferred that following reaction method and condition: at 0 DEG C -10 DEG C, sulfonylation agent being instilled what compounds Ⅳ, alkali and solvent were formed
In solution, sulfonylation is carried out.
In the method for prepare compound III, the preferred halogenated hydrocarbon solvent of the solvent, ether solvent and nitrile solvents
One of or it is a variety of；Further preferred ether solvent.The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, further
It is preferred that methylene chloride.The preferred tetrahydrofuran of the ether solvent.The preferred acetonitrile of the nitrile solvents.
In the method for prepare compound III, the volume mass of the solvent and the compounds Ⅳ is than preferred
1mL/g-40mL/g, further preferred 5mL/g-20mL/g.
In the method for prepare compound III, the preferred triethylamine of the alkali, diisopropylethylamine and pyridine one kind or
It is a variety of；Further preferred triethylamine.
In the method for prepare compound III, the preferred 1:1-3:1 of molar ratio of the alkali and the compounds Ⅳ,
Further preferred 1:1-2:1.
In the method for prepare compound III, the molar ratio preferably 1 of the mesyl chloride and the compounds Ⅳ:
1-2:1, further preferred 1:1-1.5:1.
In the method for prepare compound III, preferably 0 DEG C -40 DEG C of the temperature of the acylation reaction, further preferred 10
℃-30℃。
In the method for prepare compound III, the process of the acylation reaction can be surveyed by the routine in this field
Method for testing (such as TLC or HPLC) is monitored, and as terminal is reacted to obtain when generally being disappeared using compounds Ⅳ, the reaction time is preferred
0.25h-3h, further preferred 0.5h-2h.
Following post-processing step is preferably included in the method for prepare compound III: after reaction, water is added in reaction solution
In, stirring, water phase is extracted with organic solvent, dry, suction filtration, concentration, through column chromatographic purifying.Wherein, described to be used for
The preferred esters solvent of the organic solvent of extraction.The esters solvent ethyl acetate.The method and item of the column chromatography
Part is selected according to the method and condition that the column of this field routine chromatographs.
In the method for prepare compound III, the compounds Ⅳ is prepared using following methods: in a solvent, piptonychia
Under the action of base reagent, compound V carries out demethylating reaction, obtains compounds Ⅳ；
According still further to the method for prepare compound III, compound III is made.
The method of prepare compound IV can be the conventional method of such demethylating reaction in this field, spy in the present invention
Preferably not following reaction method and condition: at -5 DEG C -5 DEG C, by demethylation reagent instill compound V formed with solvent it is molten
In liquid, demethylating reaction is carried out.
In the method for prepare compound IV, the preferred halogenated hydrocarbon solvent of the solvent, ether solvent and nitrile solvents
One of or it is a variety of；Further preferred halogenated hydrocarbon solvent.The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent, into
The preferred methylene chloride of one step.The preferred tetrahydrofuran of the ether solvent.The preferred acetonitrile of the nitrile solvents.
In the method for prepare compound IV, the volume mass of the solvent and the compound V is than preferred
1mL/g-40mL/g, further preferred 5mL/g-20mL/g.
In the method for prepare compound IV, the preferred boron chloride of the demethylation reagent, Boron tribromide and triiodide
One or more, the further preferred Boron tribromide of boron.
In the method for prepare compound IV, the molar ratio of the demethylation reagent and the compound V is preferred
1:1-5:1, further preferred 1.5:1-3:1.
In the method for prepare compound IV, preferably 0 DEG C -40 DEG C of the temperature of the demethylating reaction, further preferably
5℃-30℃。
In the method for prepare compound IV, the process of the demethylating reaction can pass through the routine in this field
Test method (such as TLC or HPLC) is monitored, and as terminal is reacted to obtain when generally being disappeared using compound V, the reaction time is excellent
Select 0.5h-5h, further preferred 1h-3h.
Following post-processing step is preferably included in the method for prepare compound IV: after reaction, ice water is added in reaction solution
In, with lye pH adjustment to neutrality, water phase is extracted with organic solvent, dry, suction filtration, concentration, through column chromatographic purifying.Its
In, the preferred molar concentration of the lye is 2mol/L sodium hydroxide solution.The preferred chlorine of organic solvent for extraction
For hydrocarbon solvent, further preferred methylene chloride.The method and condition of the column chromatography is chromatographed according to the column of this field routine
Method and condition selected.
In the method for prepare compound IV, the compound V is prepared using following methods: in a solvent, reduction
Under the action of system, the double bond of compound VI is subjected to hydro-reduction reaction, obtains compound V；
According still further to the method for prepare compound IV, compounds Ⅳ is made.
The method of prepare compound V can be the conventional method of such reduction reaction in this field, in the present invention especially
It is preferred that following reaction method and condition: in enclosed system, compound VI being mixed with solvent, under raney ni catalysis, with hydrogen
Carry out reduction reaction.
In the method for prepare compound V, the preferred alcohols solvent of the solvent and/or water, further preferred alcohols
Solvent.The preferred C of the alcohols solvent1-C4Alcoholic solvent.The C1-C4The preferred methanol of alcoholic solvent or ethyl alcohol.
In the method for prepare compound V, the preferred conventional commercial Raney's nickel reagent of the Raney's nickel, further preferably
Mass percent is the Raney's nickel reagent of 50%-95%, and it is total that the mass percent refers to that the quality of nickel accounts for Raney's nickel reagent
The percentage of quality.
In the method for prepare compound V, preferably 20 DEG C -60 DEG C of the temperature of the reduction reaction, further preferably
20℃-35℃。
In the method for prepare compound V, the preferred 0.1MPa-0.5MPa of the pressure of the reduction reaction, further
It is preferred that 0.1MPa-0.3MPa.
In the method for prepare compound V, the time of the reduction reaction preferred 1h-20h, further preferred 3h-
10h。
The method of prepare compound V preferably includes following post-processing step: after reaction, filtering, concentration, through column layer
Analysis purifying.The method and condition of the column chromatography is selected according to the method and condition that the column of this field routine chromatographs
It selects.
In the method for prepare compound V, the compound VI is prepared using following methods: in a solvent, alkali
Under effect, compound VII carries out witting with methoxymethyl triphenylphosphonium bromide phosphine and reacts, and obtains compound VI；
According still further to the method for prepare compound V, compound V is made.
The method of prepare compound VI can be the conventional method of such witting reaction in this field, spy in the present invention
Preferably not following reaction method and condition: under gas shield, at 0 DEG C -10 DEG C, the solution that compound VII and solvent are formed is dripped
In the mixed liquor for entering alkali and methoxymethyl triphenylphosphonium bromide phosphine, witting reaction is carried out.
In the method for prepare compound VI, in the preferred nitrogen of gas, argon gas and the helium in " gas shield "
It is one or more.
In the method for prepare compound VI, the preferred sulfoxide type solvents of the solvent, ether solvent and amide solvent
One of or it is a variety of；Further preferred ether solvent.The preferred dimethyl sulfoxide of sulfoxide hydrocarbon solvent.The ether
The preferred tetrahydrofuran of class solvent.The preferred N,N-dimethylformamide of the amide solvent.
In the method for prepare compound VI, the volume mass of the solvent and the compound VII is than preferred
10mL/g-40mL/g, further preferred 15mL/g-35mL/g.
In the method for prepare compound VI, one of the preferred sodium hydrogen of the alkali, n-BuLi and potassium tert-butoxide or
It is a variety of, further preferred potassium tert-butoxide.
In the method for prepare compound VI, the preferred 1:1-3:1 of molar ratio of the alkali and the compound VII,
Further preferred 1:1-2:1.
In the method for prepare compound VI, the methoxymethyl triphenylphosphonium bromide phosphine and the compound VII
Molar ratio preferred 1:1-3:1, further preferred 1:1-2:1.
In the method for prepare compound VI, preferably -10 DEG C -35 DEG C of the temperature of the witting reaction, further
It is preferred that 0 DEG C -20 DEG C.
In the method for prepare compound VI, the process of the witting reaction can pass through the routine in this field
Test method (such as TLC or HPLC) is monitored, and as the terminal of reaction when generally being disappeared using compound VII, the reaction time is excellent
Select 1h-6h, further preferred 2h-5h.
The method of preparation VI preferably includes following post-processing step: after reaction, reaction solution is added to the water, You Jirong
Agent extraction, dry, suction filtration, concentration, through column chromatographic purifying.Wherein, the preferred esters solvent of the organic solvent, esters
Solvent ethyl acetate.The method and condition that the method and condition of the column chromatography is chromatographed according to the column of this field routine
It is selected.
In the method for prepare compound VI, the compound VII is prepared using following methods: in a solvent, oxidation
Under the action of agent, compound VIII carries out oxidation reaction, obtains compound VII；
According still further to the method for prepare compound VI, compound VI is made.
The method of prepare compound VII can be the conventional method of such oxidation reaction in this field, in the present invention especially
It is preferred that following reaction method and condition: compound VIII being mixed with solvent, oxidant, carries out oxidation reaction.
In the method for prepare compound VII, the preferred halogenated hydrocarbon solvent of the solvent, ether solvent and amides are molten
One of agent is a variety of；Further preferred halogenated hydrocarbon solvent.The preferred chlorinated hydrocarbon solvent of the halogenated hydrocarbon solvent,
Further preferred methylene chloride.The preferred tetrahydrofuran of the ether solvent.The preferred N of the amide solvent, N- dimethyl
Formamide.
In the method for prepare compound VII, the volume mass of the solvent and the compound VIII is than preferred
1mL/g-40mL/g, further preferred 5mL/g-20mL/g.
In the method for prepare compound VII, the preferred manganese dioxide of the oxidant, pyridinium chloro-chromate and dioxy
Change one or more, the further preferred pyridinium chloro-chromate of selenium.
In the method for prepare compound VII, the preferred 1:1- of molar ratio of the oxidant and the compound VIII
5:1, further preferred 1.5:1-3:1.
In the method for prepare compound VII, preferably 0 DEG C -40 DEG C of the temperature of the oxidation reaction, further preferred 5
℃-30℃。
In the method for prepare compound VII, the process of the oxidation reaction can be surveyed by the routine in this field
Method for testing (such as TLC or HPLC) is monitored, and as terminal is reacted to obtain when generally being disappeared using compound VIII, the reaction time is preferred
2h-10h, further preferred 4h-8h.
Following post-processing step is preferably included in the method for prepare compound VII: after reaction, reaction solution concentration, warp
Column chromatographic purifying.Wherein, the method that the method and condition of the described column chromatography is chromatographed according to the column of this field routine with
Condition is selected.
What the compound VIII described in the method for prepare compound VII can be reported according to patent 201610139626.X
Method preparation, i.e., following route one:
Route one
The compound 1 and 2 described in the method for prepare compound VIII can be with bibliography Chemistry of
Heterocyclic Compounds.2016,52 (8), the method preparation p.564-569 reported.
The present invention also provides the intermediate for synthesizing the phenylpyridine class compound as shown in formula I, compound ii,
Compound III, compounds Ⅳ, compound V, compound VI or compound VII, structural formula is as follows:
R in II1Selected from imidazole radicals, 1,2,4- triazol radical or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] three
Azoles simultaneously [4,3- α] pyrazine -7- base.
The synthesis of formula (I) compound is summarized in embodiment.
Purposes
The purposes of compound is to prepare preparation or pharmaceutical composition in the present invention, comprising: directly uses compound or is making
Any ingredient obtained during standby uses；For being used to preventing or treating glycosuria for screening verification in in-vitro screening experiment
The ingredient of disease or hyperglycemia shape.
On the other hand, formula (I) compound is used in screening experiment, specifically by formula (I) compound or its pharmaceutically
The derivative thing liquid of acceptable salt or solvent, or hydrolysate physiologically, solubilized derivative or solid phase, in screening experiment
Candidate compound is verified, these candidate compounds can be used for treating diabetes or related symptoms.Preferably, the change in the present invention
Closing object can be used for confirming the ability that candidate compound inhibits dipeptidyl peptidase-4.
Pharmaceutical composition prepared by the present invention includes phenylpyridine class compound or its salt and one kind shown in formula I
Or a variety of pharmaceutically acceptable carriers.
Medicine group can be made with pharmaceutically various typical additives (such as diluent and excipient) in the compound of the present invention
Close object.According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as aqueous dispersion, liquid
Body, Gel miles, syrup, elixir, medicine slurry, suspension, lotion, granule, aerosol, controlled release agent, quick-dissolving agent, effervescent agent, freeze-drying
Agent, tablet, pulvis, pill, dragee, capsule, suppository, injection, sustained release agent, extended release agent, pulse controlled release agent are more
Fine granule releases immediately agent etc..
In order to shape the pharmaceutical composition of tablet form, it can be used this field any of and widely used tax
Shape agent.For example, carrier, such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, avicel cellulose
With silicic acid etc.；Adhesive, such as water, ethyl alcohol, propyl alcohol, common syrup, glucose solution, starch solution, penetrating judgment solution, carboxymethyl
Cellulose, lac, methylcellulose and potassium phosphate, polyvinylpyrrolidone etc.；Disintegrating agent, such as dried starch, mosanom, agar
Powder and Kelp Powder, sodium bicarbonate, calcium carbonate, the aliphatic ester of polyethylene sorbitan, lauryl sodium sulfate, stearic acid
Monoglyceride, starch and lactose etc.；Disintegration inhibitor, such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil and fat；Absorption promotees
Into agent, such as quaternary amine alkali and lauryl sodium sulfate；Wetting agent, such as glycerol, starch；Adsorbent, such as starch, lactose, kaolinite
Soil, bentonite and colloid silicic acid etc.；And lubricant, such as pure talcum, stearate, boric acid powder and polyethylene glycol etc..Such as
If fruit needs, common coated material can also be used to make tablet as sugar coated tablet, apply gelatin film tablet, enteric coated tablets, painting
Diaphragm agent, duplicature tablet and multilayer tablet.
In order to shape the pharmaceutical composition of pill, it can be used this field any of and widely used tax
Property agent, for example, carrier, such as lactose, starch, coconut oil, hardened vegetable oils, kaolin and talcum etc.；Adhesive, it is such as Arabic
Gum powder, Huang write rubber powder, gelatin and ethyl alcohol etc.；Disintegrating agent, such as agar and Kelp Powder.
In order to shape the pharmaceutical composition of suppository form, it can be used this field any known and widely used inborn nature
Agent, for example, polyethylene glycol, coconut oil, higher alcohol, the ester of higher alcohol, gelatin and semi-synthetic glyceride etc..
, can be by solution and suspension liquid disinfectant in order to prepare the pharmaceutical composition of injection form, and it is preferably added suitable chlorine
Change sodium, glucose or glycerol etc. are made and the isotonic injection of blood.When preparing injection, it is possible to use in the art any
Common carrier.For example, water, ethyl alcohol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol and polyethylene of polyoxy
The aliphatic ester etc. of anhydro sorbitol.In addition, common lytic agent, buffer and analgesic etc. can also be added.As needed,
During treating schizophrenia, colorant, preservative, fragrance, flavoring agent, sweetening agent and other medicines etc. can also be added.
The content of compound and its pharmaceutically acceptable salt shown in formula I of the invention in pharmaceutical composition without
It is specifically limited, it can be selected in a wide range, generally can be mass percent 1-90%, preferably quality percentage
Compare 1-30%.
In the present invention, the medication of the pharmaceutical composition is not particularly limited.It can be according to patient age, gender
With other conditions and symptom, the preparation of various dosage forms is selected to be administered.For example, tablet, pill, solution, suspension, lotion, particle
Agent and capsule are oral administrations；Injection can be administered alone, or convey liquid (such as glucose solution and amino acid with injection
Solution) it is mixed into row vein injection, muscle can be carried out with injection merely if necessary, inject in intradermal, subcutaneous or abdomen；Bolt
Agent is to be administered into rectum.
In the present invention, it can be properly selected according to method of administration, patient age, gender and other conditions and symptom
Dosage.
The present invention also provides the medicine groups comprising the phenylpyridine class compound or its salt shown in formula I
It closes object and is preparing the application in dipeptidyl peptidase-4 inhibitors, especially people's dipeptidyl peptidase-4 inhibitors.
Inhibit DPP-4 that can effectively improve internal GLP-1 and GIP horizontal, and then by promoting insulin secretion to play hypoglycemic
Effect.Therefore, the present invention also provides the drugs comprising the phenylpyridine class compound or its salt shown in formula I
Composition is preparing the application in hypoglycemic medicine preparation.
Show phenylpyridine class compound and its salt the compound of the present invention of the invention through active testing experimental data
With good DPP-4 enzyme inhibition activity, and activity is better than the inhibitory effect of marketed drug Xi Gelieting；For DPP-4 inhibitor
Research and development provide a new direction, have the good prospect of marketing.
All features (including any claim and abstract) being described in the present specification, and/or it is any
All steps involved in method or process, it is possible that existing with any one combination, unless certain features or step are same
It is excluded each other in one combination.
These embodiments do not limit the scope of the claims provided herein only for the purpose of illustrations.
It summarizes.1H-NMR spectrum uses Bruker-AV400 Nuclear Magnetic Resonance, and the unit of chemical shift is hundred a ten thousandths,
Internal standard is tetramethylsilane.Coupling constant (J) is close to 0.1Hz.The abbreviation used is as described below: s, singlet；D, it is dual
Peak；T, triplet；Q, quartet；Qu, quintet；M, multiplet；Br, spectrum.Mass spectrum uses Agilent 6210TOF mass spectrum
Instrument.
Agents useful for same and raw material are commercially available in embodiment.
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited the present invention to described
Among scope of embodiments.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or presses
It is selected according to commercial specification.
In the examples below, undefined abbreviation has its generally accepted meaning, unless stated otherwise.Table 2, table 3
With table 4 be respectively compound I-1~I-3 physicochemical data,1HNMR data and the external inhibitory activity data of I-1~I-3.
Synthetic example 1
2- (2,4 dichloro benzene base) -3- aminomethyl -4- (2- (1,2,4- triazol-1-yl) ethyl) -6- picoline (I-1)
2- (2,4- dichlorophenyl) -3- cyano -4- mesylethyl -6- picoline (compound III, 0.5g,
1.3mmol), 1,2,4- triazoles (0.18g, 2.6mmol) are dissolved in 10ml acetonitrile, are added potassium carbonate (0.22g, 1.6mmol),
50 DEG C of stirring 3h are warming up to after 1h is stirred at room temperature.It filters, reaction solution is concentrated to give yellow oil crude product, and column chromatographs (dichloromethane
Alkane: methanol) obtain light yellow oil 0.406g, yield 87.5%.1H-NMR(CDCl3),δ(ppm):8.02(s,1H),7.92
(s, 1H), 7.58-7.57 (d, 1H, J=2.0Hz), 7.44-7.41 (d, 1H, J=2.0Hz 8.4Hz), 7.39-7.37 (d,
1H, J=8.4Hz), 6.92 (s, 1H), 4.60-4.57 (t, 2H, J=6.8Hz), 3.50-3.47 (t, 2H, J=6.8Hz),
2.60(s,3H).
Above-mentioned grease (0.5g, 1.4mmol), Raney Ni (0.1g 1.0ml) and 25ml are saturated NH3/ EtOH is molten
Liquid is placed in hydrogenation reaction cauldron, is passed through hydrogen, and pressure 0.4MPa reacts at room temperature 4h.It filters, mother liquor concentrations, column chromatographs (dichloro
Methane: methanol) obtain faint yellow solid 0.086g, yield 17.2%.
The synthetic method of I-2 is identical as I-1.
Synthetic example 2
2- (2,4 dichloro benzene base) -3- aminomethyl -4- (2- (3- (trifluoromethyl) -5,6,7,8- tetrahydro-[1,2,4] triazole
And [4,3- α] pyrazine) ethyl) -6- picoline (I-3)
2- (2,4- dichlorophenyl) -3- cyano -4- mesylethyl -6- picoline (compound III, 0.53g,
1.38mmol), DIPEA (0.53g, 4.14mmol) is dissolved in 10ml DMF, and 3- (trifluoro is added after being warming up to 60 DEG C of stirring 2.5h
Methyl) -5,6,7,8- tetrahydros-[1,2,4] triazol [4,3- α] pyrazine (0.53g, 2.76mmol) is warming up to 90 DEG C of stirrings
5h.20ml water is added in reaction solution, with EA (10ml × 2) extraction, merges organic phase, anhydrous sodium sulfate is dry, filters, concentrated
Column (CH2Cl2/ MeOH) obtain light yellow oil 0.47g, yield 71%.1H-NMR(CDCl3),δ(ppm):7.55-7.54(d,
1H, J=1.6Hz), 7.42-7.40 (d, 1H, J=1.6Hz 8.0Hz), 7.39-7.37 (d, 1H, J=8.0Hz), 7.24 (s,
1H), 4.21-4.19 (t, 2H, J=5.2Hz), 3.97 (s, 2H), 3.15-3.11 (t, 2H, J=6.8Hz), 3.11-3.09
(t, 2H, J=5.2Hz), 3.04-3.01 (t, 2H, J=6.8Hz), 2.68 (s, 3H)
Above-mentioned grease (0.47g, 0.98mmol), Raney Ni (0.12g 1.2ml), 15mlEtOH and 5ml are saturated
NH3/ EtOH solution is placed in hydrogenation reaction cauldron, is passed through hydrogen, and pressure 0.4MPa reacts at room temperature 4h.It filters, mother liquor concentrations, column
It chromatographs (methylene chloride/methanol) and obtains weak yellow foam shape solid 0.075g, yield 16.0%.
Synthetic example 3
2- (2,4 dichloro benzene base) -3- cyano -4- mesylethyl -6- picoline (III)
2- (2,4- dichlorophenyl) -3- cyano -4- ethoxy -6- picoline (compounds Ⅳ, 1.8g, 5.88mmol),
TEA (1.19g, 11.76mmol) is dissolved in 20ml THF, and ice-water bath is cooling, temperature control at 0-5 DEG C, be added dropwise MsCl (0.81g,
7.06mmol), it finishes and removes ice bath reaction 30min.10ml H is added in reaction solution2In O, with EA (10ml × 2) extraction water
Phase merges organic phase, and anhydrous magnesium sulfate is dry, filters, and is concentrated to give brown oil crude product, and column chromatographs (methylene chloride: methanol)
Light yellow solid 1.85g, yield 81.5%, m.p:97-99 DEG C.1H-NMR(CDCl3),δ(ppm):7.58-7.57(d,1H,
), J=1.6Hz 7.44-7.41 (d, 1H, J=1.6Hz 8.0Hz), 7.41-7.39 (d, 1H, J=8.0Hz), 7.30 (s,
1H), 4.60-4.57 (t, 2H, J=6.4Hz), 3.36-3.32 (t, 2H, J=6.4Hz), 3.05 (s, 3H), 2.71 (s, 3H)
Synthetic example 4
2- (2,4 dichloro benzene base) -3- cyano -4- ethoxy -6- picoline (IV)
2- (2,4- dichlorophenyl) -3- cyano -4- methoxy ethyl -6- picoline (compound V, 1.0g,
It 3.13mmol) is dissolved in 20ml DCM, ice-water bath is cooling, and temperature control is added dropwise Boron tribromide (1.96g, 7.81mmol), adds at 0-5 DEG C
Finish and removes ice bath reaction 2h.Reaction solution is added in 20ml ice water, with 2N NaOH solution tune pH to neutrality, with CH2Cl2(20ml
× 3) aqueous phase extracted merges organic phase, and anhydrous sodium sulfate is dry, filters, and is concentrated to give brownish foam crude product, and column chromatographs (dichloro
Methane: methanol) obtain light brown oily substance 0.64g, yield 66.8%.1H-NMR(CDCl3),δ(ppm):7.56(m,1H),
7.40-7.39 (m, 2H), 7.30 (s, 1H), 4.03-4.00 (t, 2H, J=6.4Hz), 3.15-3.11 (t, 2H, J=
6.4Hz),2.68(s,3H).
Synthetic example 5
2- (2,4 dichloro benzene base) -3- cyano -4- methoxy ethyl -6- picoline (V)
2- (2,4- dichlorophenyl) -3- cyano -4- (2- methoxyl group) vinyl -6- picoline (compound VI, 2.3g,
7.23mmol), Raney Ni (0.46g 4.6ml) and 45ml EtOH is mixed, and hydrogen is passed through under normal pressure, reacts at room temperature 7h.It takes out
Filter, mother liquor concentrations, column chromatograph (methylene chloride: methanol) and obtain light yellow oil 1.37g, yield 59.6%.1H-NMR
(CDCl3), δ (ppm): 7.54 (s, 1H), 7.38-7.37 (m, 2H), 7.26 (s, 1H), 3.75-3.72 (t, 2H, J=
6.0Hz), 3.37 (s, 3H), 3.14-3.11 (t, 2H, J=6.0Hz), 2.66 (s, 3H)
Synthetic example 6
2- (2,4 dichloro benzene base) -3- cyano -4- (2- methoxyl group) vinyl -6- picoline (VI)
Methoxymethyl triphenylphosphonium bromide phosphine (6.0g, 15.5mmol) is mixed with 60ml THF, ice-water bath is cooling, control
THF (30ml) solution of t-BuOK (1.74g, 15.5mmol) is added dropwise in temperature under 0-5 DEG C, nitrogen protection, finishes and removes ice bath room
Temperature is lower to react 1.5h, and reaction solution is in Chinese red suspension shape.Ice-water bath cooling, is added dropwise 2- (2,4- dichlorophenyl) -3- cyano -4-
THF (10ml) solution of formoxyl -6- picoline (compound VII, 3.0g, 10.3mmol), finishes that remove ice bath room temperature anti-
Answer 2h.100ml H is added in reaction solution2In O, with EA (50ml × 3) aqueous phase extracted, merge organic phase, anhydrous magnesium sulfate is dry
It is dry, it filters, is concentrated to give sepia grease crude product, column chromatographs (PE:EA=10:1) and obtains yellow oil 2.13g, yield
65.2%.1H-NMR(CDCl3),δ(ppm):7.95(s,0.4H),7.57-7.53(m,1.6H),7.42-7.37(m,2H),
7.25 (s, 0.6H), 6.60-6.58 (d, 1H, J=7.2Hz), 6.10-6.07 (d, 1H, J=12.8Hz), 5.67-5.66 (d,
1H, J=7.2Hz), 3.98 (s, 1.2H), 3.84 (s, 1.8H), 2.66 (s, 1.2H), 2.64 (s, 1.8H)
Synthetic example 7
2- (2,4 dichloro benzene base) -3- cyano -4- formoxyl -6- picoline (VII)
2- (2,4- dichlorophenyl) -3- cyano -4- methylol -6- picoline (compound VIII, 10.65g,
36.35mmol), PCC (15.63g, 72.70mmol) and 250ml CH2Cl2Mixing, is stirred at room temperature 6h.Reaction solution is concentrated to give light
Yellow oil, column chromatograph (methylene chloride) faint yellow solid 8.72g, yield 82.4%, m.p:135-137 DEG C.1H-NMR
(CDCl3), δ (ppm): 10.42 (s, 1H), 7.78 (s, 1H), 7.60-7.59 (d, 1H, J=2.0Hz), 7.47-7.44 (dd,
1H, J=8.0Hz 2.0Hz), 7.43-7.41 (d, 1H, J=8.0Hz), 2.82 (s, 3H)
2 compound I-1~I-3 physicochemical data of table
A: cyano reduction yield
3 compound I-1~I-3's of table1HNMR data
Active testing embodiment 8
Part phenylpyridine class compound has carried out external DPP-4 enzyme and has inhibited test
DPP-4 enzyme activity determination method is with glycyl proline paranitroanilinum (Gly-Pro-p-nitroanilide)
For the color development method of substrate.DPP-4 substrate for enzymatic activity Gly-Pro-p-nitroanilide is hydrolyzed under alkaline condition, is generated sweet
The paranitroanilinum of aminoacyl proline and yellow, paranitroanilinum have characteristic absorption peak at wavelength 405nm, pass through enzyme mark
How much the absorption value size that instrument measures at 405nm i.e. chromophoric group PNA production quantity reflects that enzymatic activity height, reaction equation are as follows.
DPP-4 enzyme amount needed for the Gly-Pro-p-nitroanilide of the 1 μm of ol of hydrolysis in one minute is defined as 1U,
(substrate 0.4mM, DPP-4 enzyme is appropriate, buffer 50mM Tris-HCl, pH8.3) is added different in DPP-4 enzyme activity determination system
The various inhibitor of concentration, 37 DEG C reaction one hour after by microplate reader measure 405nm light absorption value, further according to Beer-
Bouguer law is converted into the production quantity of p-nitroaniline with the light absorption value measured at 405nm.For certain inhibitor
For, the amount of inhibitor needed for inhibiting 1U enzyme activity is defined as a unit inhibitory activity, evaluates various inhibitor with this
Activity.
The screening of inhibitor is that enzyme activity determination system is formed with a certain amount of enzyme, be added different amounts of various inhibitor and
Blank control, data are shown in Table 4, wherein compound I-4 is the compound recorded in patent CN104610262B, the following institute of structure
Show.
IC of the 4 compound I-1~I-4 of table to DPP-4 enzyme50Value
| Number | IC50(nM) | Number | IC50(nM) |
| I-1 | 6.4 | I-2 | 8.1 |
| I-3 | 3.2 | I-4 | 2781.0 |
| Xi Gelieting | 15 |
The result shows that all compounds in the present invention have good DPP-4 enzyme inhibition activity, part of compounds is excellent
In marketed drug Xi Gelieting (IC50=15nM).The DPP-4 enzyme inhibitor and structure of modification of Future Development brand new are risen
Directive function is arrived.
Embodiment described herein is served only for explanation (illustratively), the various modifications or change that technical staff is done
It should include in the spirit and scope of patent application and within accessory claim scope.
Claims (19)
1. a kind of compound of formula I or its pharmaceutically acceptable salt, solvate or prodrug:
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3-
α] pyrazine -7- base.
2. II compound of formula, III compound of formula, IV compound of formula, VII compound of V compound of formula, VI compound of formula or formula:
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3-
α] pyrazine -7- base；
3. a kind of preparation method of compound of formula I, which is characterized in that the method includes the steps: by the cyano of compound ii into
The reaction of row hydro-reduction, obtains chemical compounds I.
4. preparation method as claimed in claim 3, which is characterized in that the reaction carries out in a solvent, and the solvent is alcohol
One or more of class and water.
5. preparation method as claimed in claim 3, which is characterized in that the catalyst of the reaction is Raney's nickel.
6. preparation method as claimed in claim 3, which is characterized in that the temperature of the reaction is 20-60 DEG C.
7. preparation method as claimed in claim 3, which is characterized in that the compound ii is prepared using following step:
Compound III and R1H carries out substitution reaction, obtains compound ii；
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3-
α] pyrazine -7- base.
8. a kind of preparation method of II compound of formula, which is characterized in that the method includes the steps: compound III and R1H is taken
Generation reaction, obtains compound ii；
Wherein R1Selected from imidazole radicals, 1,2,4- triazolyl or 3- trifluoromethyl -5,6,7,8- tetrahydro-[1,2,4] triazol [4,3-
α] pyrazine -7- base.
9. a kind of preparation method of III compound of formula, which is characterized in that the method includes the steps: by compounds Ⅳ and methylsulfonyl
Chlorine carries out acylation reaction, obtains compound III.
10. a kind of preparation method of IV compound of formula, which is characterized in that the method includes the steps: compound V carries out piptonychia
Base reaction, obtains compounds Ⅳ.
11. a kind of preparation method of V compound of formula, which is characterized in that the method includes the steps: compound VI is hydrogenated
Reduction reaction obtains compound V.
12. a kind of preparation method of VI compound of formula, which is characterized in that the method includes the steps: compound VII and methoxyl group
Methyltriphenylphosphonium bromide carries out witting reaction, obtains compound VI.
13. a kind of preparation method of VII compound of formula, which is characterized in that the method includes the steps: compound VIII is aoxidized
Reaction, obtains compound VII.
14. a kind of pharmaceutical composition, which includes compound as described in claim 1 and pharmaceutically acceptable carrier.
15. pharmaceutical composition as claimed in claim 14, wherein the form of pharmaceutical composition is aqueous dispersion, liquid, Gel
Mile, syrup, elixir, medicine slurry, suspension, lotion, granule, aerosol, controlled release agent, quick-dissolving agent, effervescent agent, freeze-dried, piece
Agent, pulvis, pill, dragee, capsule, suppository, injection, sustained release agent, extended release agent, pulse controlled release agent, multiparticulates agent,
Or release immediately agent.
16. a kind of pharmaceutical composition as described in claims 14 or 15 answering in preparation people's dipeptidyl peptidase-4 inhibitors
With.
17. a kind of pharmaceutical composition as described in claims 14 or 15 is preparing the application in hypoglycemic medicine preparation.
18. a kind of application of compound as described in claim 1 in preparation people's dipeptidyl peptidase-4 inhibitors.
19. a kind of compound as described in claim 1 is preparing the application in hypoglycemic medicine preparation.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1886376A (en) * | 2003-10-31 | 2006-12-27 | 武田药品工业株式会社 | Pyridine compounds as inhibitors of dipeptidyl peptidase iv |
| CN101166725A (en) * | 2005-02-25 | 2008-04-23 | 武田药品工业株式会社 | Pyridylacetic acid compound |
| WO2012101013A1 (en) * | 2011-01-28 | 2012-08-02 | Boehringer Ingelheim International Gmbh | Substituted pyridinyl-pyrimidines and their use as medicaments |
| CN104610262A (en) * | 2013-11-01 | 2015-05-13 | 上海医药工业研究院 | Biphenyl compound, intermediate, preparation method, pharmaceutical composition, and applications of biphenyl compound and pharmaceutical composition |
-
2017
- 2017-07-26 CN CN201710616507.3A patent/CN109305957B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1886376A (en) * | 2003-10-31 | 2006-12-27 | 武田药品工业株式会社 | Pyridine compounds as inhibitors of dipeptidyl peptidase iv |
| CN101166725A (en) * | 2005-02-25 | 2008-04-23 | 武田药品工业株式会社 | Pyridylacetic acid compound |
| WO2012101013A1 (en) * | 2011-01-28 | 2012-08-02 | Boehringer Ingelheim International Gmbh | Substituted pyridinyl-pyrimidines and their use as medicaments |
| CN104610262A (en) * | 2013-11-01 | 2015-05-13 | 上海医药工业研究院 | Biphenyl compound, intermediate, preparation method, pharmaceutical composition, and applications of biphenyl compound and pharmaceutical composition |
Non-Patent Citations (4)
| Title |
|---|
| GUO-LIANG GU等: "《Application of Wittig Reaction in Synthesis of Novel Pyridine Dicarboxylic Acid Derivatives with High Ligand Activity》", 《SYNTHETIC COMMUNICATIONS 》 * |
| JOSÉ MANUEL BARTOLOMÉ-NEBREDA等: "《Identification of a Novel Orally Bioavailable Phosphodiesterase 10A (PDE10A) Inhibitor with Efficacy in Animal Models of Schizophrenia》", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| YAN ZHU等: "《Alkylation of 2-(2,4-dichlorophenyl)-3-cyano-6-methyl -4-(1H-1,2,4-triazol-1-yl)methylpyridine at the methylene group》", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
| YAN ZHU等: "《Synthesis of phenylpyridine derivatives and their biological evaluation toward dipeptidyl peptidase-4》", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
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| CN109305957B (en) | 2021-08-03 |
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