CN108017614A - DPP-4 inhibitor and its application in treatment diabetes B medicine is prepared - Google Patents
DPP-4 inhibitor and its application in treatment diabetes B medicine is prepared Download PDFInfo
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Abstract
Application the present invention relates to three kinds of new 4 inhibitor of DPP and in treatment diabetes B drug field, affiliated 4 inhibitor of DPP with it is more than one or both of following three kinds of compounds for active ingredient, the structure of three kinds of compounds：The compound has preferable therapeutic effect by suppressing the level of the activity of dipeptidyl peptidase 4, increase incretin sample peptide 1 and glucose dependent insulin release peptide for diabetes B.
Description
Technical field
The present invention relates to biological medicine, aromatic derivatives 2- { [6- [(3R) -3- ammonia of specifically three kinds marine sources
Base -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzene first
Nitrile (1), 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyl) -2,4- dioxos -1
(2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (2), 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4-
Dimethoxy-benzyl) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (3) and its pharmacological activity, pharmacy use
On the way.Above compound and its derivative can be used for treating diabetes B as DPP-4 inhibitor.
Background technology
Diabetes are a kind of metabolic disorder diseases, at present number of patients rapid growth.International Diabetes Federation it is newest
Data is shown, is ended to 2017, there are about 4.25 hundred million maturity-onset diabetes patients in the world, it was predicted that to 2045, this numeral
7.00 hundred million will be risen to.The treatment of diabetes seems particularly urgent.
Dipeptidyl peptidase IV (DPP-4) is also referred to as CD26, is a kind of multi-functional transmembrane serine protease, mainly passes through drop
Solve incretin sample peptide -1 (GLP-1) and glucose dependent insulin release peptide (GIP) adjusts glucose metabolism.Oral
Dipeptidy peptidase in inhibitors can extend the half-life period of GLP-1 and GIP in vivo by suppressing the activity of dipeptidyl peptidase IV,
The level of GLP-1 and GIP, extends its blood sugar reducing function time, and glucagon suppression is secreted, and extends GLP-1 to insulin
The stimulus duration of secretion, plays blood sugar reducing function.DPP-4 inhibitor is stably controlled blood glucose, improves β cell functions, and
The increase of patient's weight will not be caused, risk of hypoglycemia is avoided, there is significant advantage in terms of drug safety, be generally considered
The novel targets of most promising treatment diabetes B.
The natural products of marine source is always the important sources of hypoglycemic medicine.From subtropical and tropical zones red algae
Phenyl substitution class compound (aromatic ring substitution class compound) isolated Laurencia similis, hypoglycemic activity IC50For
2.66 (Wang L J etc., Rsc Advances.5 (2015), 48822)；From seaweed Rhodomela confervoides ethanol
Isolated fragrant cyclics in extract, it may have significant hypoglycemic activity (Shi D.Y. etc., China
J.Chin.Mater.Med.33(2008),2238).Accordingly, we have synthesized living with notable DPP-4 suppression for marine source
Aromatic derivatives 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxies of property
- 1 (2H)-pyrimidine radicals of generation] methyl } -4- fluorobenzonitriles (1), 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3-
(3,5- dimethyl benzyl) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (2), 2- { [6- [(3R) -3- ammonia
Base -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorine
Benzonitrile (3).
The content of the invention
Present invention aims at three kinds of new DPP-4 inhibitor are provided, three kinds of compounds are by suppressing the work of DPP-4
Property, extend the action time of GLP-1 and GIP, achieve the purpose that to reduce blood glucose, available for treating diabetes B.
To achieve the above object, the technical solution adopted by the present invention is as follows：
DPP-4 inhibitor, it is with one or two or more kinds of for active ingredient in following three kinds of compounds, three kinds of compounds
Structural formula it is as follows：
That is 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1
(2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (1), 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5-
Dimethyl benzyl) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (2), 2- { [6- [(3R) -3- amino -1-
Piperidyl] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzene first
Nitrile (3).
Aromatic derivatives the object of the present invention is to provide 3 kinds of marine sources are in diabetes B medicine preparation is treated
Using.
It is a further object of the present invention to provide with one or both of compound 1~3 compound or its can pharmaceutically connect
The salt received is used to prepare or prevents the pharmaceutical composition of diabetes B as active ingredient.
Above-mentioned pharmaceutical composition (i.e. DPP-4 inhibitor), it is formed in the compound 1~3 containing therapeutically effective amount
One or two kinds of or its pharmaceutically acceptable salt, described compound can be used alone in pharmaceutical composition, can also
It is used cooperatively with other drugs.The pharmaceutical composition contains 0.1~99%, is preferably 0.5~90% the compounds of this invention, its
It is remaining for pharmaceutically acceptable pharmaceutical carrier and/or excipient.
The pharmaceutical carrier or excipient is one or more solids, semisolid and liquid diluent, filler and medicine
Tetramune assistant agent.The pharmaceutical composition of the present invention is used in the form of per weight dose.The medicine of the present invention can be through note
Penetrate (intravenous, intramuscular injection), oral and three kinds of form administrations of external application.
Compound is by suppressing the activity of dipeptidyl peptidase-4, increase incretin sample peptide -1 and glucose dependency pancreas
The level of island element release peptide, has preferable therapeutic effect for diabetes B.
The invention has the advantages that：
The target compound is the compound for having notable DPP-4 enzyme inhibition activities, is that the treatment of diabetes B is new
Medicine；Present invention introduces the aromatic derivatives of marine source, aboundresources, low toxicity, has preferable hypoglycemic activity, realizes mesh
The synthesis of compound in high yield, inexpensive is marked, and technological operation is simple, has good industrialization production prospect.
Brief description of the drawings
Fig. 1 is the dose dependent figure that compound 1 suppresses DPP-4.
Fig. 2 is the dose dependent figure that compound 2 suppresses DPP-4.
Fig. 3 is the dose dependent figure that compound 3 suppresses DPP-4.
1. the synthesis and structure identification of compound
Using 6- chlorouracils and 2- cyano group -5- fluorine bromobenzyls as starting material, using substitution reaction synthetic intermediate；Then with
Aromatic derivatives substitution occurs on 1 nitrogen of hybar X for three kinds of different aromatic derivatives bromobenzyls, and generation aromatic derivatives take
For intermediate；Reacted again in hybar X 6 and (R) -3- (Boc- amino) piperidines, finally slough tertiary butyloxycarbonyl with trifluoroacetic acid
Base obtains crude product, then makees eluant, eluent with chloroform-methanol-triethylamine system, silica gel column chromatography is refining to obtain white solid.Through wave spectrum number
According to wait Structural Identification for compound 2- [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,
4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (1), 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- bis-
Hydrogen -3- (3,5- dimethyl benzyl) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles (2), 2- { [6-
[(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals]
Methyl } -4- fluorobenzonitriles (3)；English name is respectively:2-[6-(3(R)-aminopiperidin-1-yl)-3-(3,5-
difluorobenzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-
fluorobenzonitrile(1),2-[6-(3(R)-aminopiperidin-1-y l)-3-(3,5-dimethyl)-2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobe nzonitrile(2),2-[6-(3
(R)-aminopiperidin-1-yl)-3-(3,4-dimethoxybenzyl)-2,4-diox o-3,4-dihydro-2H-
pyrimidin-1-ylmethyl]-4-fluorobenzonitrile(3).
2. 4 inhibitory activity of dipeptidyl peptidase measures
DPP-4 inhibitor activities are screened with the new small molecule fluorescence probe of aggregation-induced emission characteristic.Should
Small-molecule fluorescent probe itself does not fluoresce in the reaction system, after the N-terminal dipeptides of DPP-4 cut-out fluorescence probes, residue water
Dissolubility reduces, and aggregation occurs and produces fluorescence.This method has higher sensitivity and specificity to the Activity determination of DPP-4.
Embodiment
To better understand the essence of the present invention, it will illustrate this five kinds of compounds with the embodiment of the present invention below
Pharmacological action with this embodiment as a result, but do not limit the present invention.
The synthetic route of compound is specific as follows shown：
(a) 2- cyano group -5- fluorine bromobenzyl and 6 molar ratio of compound are 1:1~1:1.5, diisopropylethylamine, solvent N, N-
Dimethylformamide, room temperature；(b) compound 18 (or 19, or 20) with 7 molar ratio of compound be 1:1~1:1.5, potassium carbonate, iodine
Change potassium, room temperature；(c) (R) -3- (Boc- amino) piperidines and compound 21 (or 22, or 23) molar ratio is 1:1~1:1.5, carbonic acid
Potassium, solvent are n,N-Dimethylformamide, inert gas shielding, 80~100 DEG C；(d) trifluoroacetic acid, solvent are dichloromethane,
Room temperature；
" 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- the difluorobenzyls) -2,4- two of embodiment 1
Oxo -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles (compound 1) " chemical fully synthetic and Structural Identification
(1) the chemistry conjunction of 2- { [chloro- 3,4- dihydros -2,4- dioxos -1 (the 2H)-pyrimidine radicals of 6-] methyl } -4- fluorobenzonitriles
Into and Structural Identification
It is stirred at room temperature down, to 80mL dissolved with being added in the n,N-Dimethylformamide solution of 10 grams of 6- chlorouracils
13.53mL diisopropylethylamine, is added dropwise Ns of the 20mL dissolved with 16 grams of 2- cyano group -5- fluorine bromobenzyls (mass concentration 15~20%),
Dinethylformamide solution, persistently stir under the conditions of lucifuge 24 it is small when after, TLC detections, raw material point is reacted after disappearing to be terminated, to
In reaction solution plus 10 times are measured distilled water, there is Precipitation, and 20min is added, and persistently stirs 15min, and precipitation is filtered, frozen water washing
Precipitation, drains to obtain white solid, mixture is recrystallized with absolute ethyl alcohol, obtains 14.78 grams of white solid.By Spectrum Analysis, really
It is 2- { [chloro- 3,4- dihydros -2,4- dioxos -1 (the 2H)-pyrimidine radicals of 6-] methyl } -4- fluorobenzonitriles to demonstrate,prove the compound；
(2) 2- { [6- chloro- 3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -
The chemical synthesis of 4- fluorobenzonitriles
Under room temperature, to 5mL dissolved with 1 gram of 2- { [chloro- 3,4- dihydros -2,4- dioxo -1 (the 2H)-pyrimidine radicals of 6-] first
Base } -4- fluorobenzonitriles n,N-Dimethylformamide solution in add 0.59 gram of Anhydrous potassium carbonate, 0.10 gram of potassium iodide, dropwise
N,N-Dimethylformamide solution of the 5mL dissolved with 0.82 gram of 3,5-, bis- fluorobenzyl bromide is added, when reaction 24 is small under lucifuge, TLC detections,
After raw material point disappears, into reaction solution plus 10 times of amount distilled water, ethyl acetate extract 3 times, merge organic phase, and use mass concentration
20% salt is washed 3 times, and organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure.Column chromatography chromatogram separates, petroleum ether：Ethyl acetate
10:1.09 grams of white solid is obtained after 1 elution.By Spectrum Analysis, confirm the compound for 2- [chloro- 3, the 4- dihydros -3- of 6- (3,
5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles.
(3) 2- { [6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- two
Oxo -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
In 50mL three-necked bottles, 0.51 gram of Anhydrous potassium carbonate, 0.55 gram of (R) -3- (Boc- amino) piperidines are added to 15mL
Dissolved with 1 gram of 2- { [6- chloro- 3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorine
In the n,N-Dimethylformamide solution of benzonitrile, argon gas is protected, 3 hours of 90 DEG C of back flow reactions, TLC detections, and raw material point disappears
After mistake, cooling reaction solution to room temperature.Add 10 times of amount distilled water, ethyl acetate extracts 3 times, merges organic phase, and use mass concentration
20% salt is washed 3 times, and organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram, petroleum ether：
Ethyl acetate 4:1 elution, obtains 1.2 grams of white solid.By Spectrum Analysis, it is 2- { [6- [(3R) -3-Boc- to confirm the compound
Amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzene
Formonitrile HCN；
(4) 2- [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -
1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
Under 0 DEG C of stirring, 4.5mL is added into 5mL dissolved with 0.5 gram of 2- dissolved with the dichloromethane solution of 0.9mL trifluoroacetic acids
{ [6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-phonetic
Piperidinyl] methyl -4- fluorobenzonitriles dichloromethane solution in, TLC detections, after raw material point disappears, water on the rocks quenching reaction, is used
The NaOH solution tune PH of mass concentration 10% adds 30mL dichloromethane and extracts 3 times, merge organic phase, mass concentration to alkalescence
20% salt water washing 3 times, organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram, dichloromethane
Alkane-methanol-triethylamine system elutions, obtains 0.35 gram of white solid.By Spectrum Analysis, it is 2- { [6- to confirm the compound
[(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] first
Base } -4- fluorobenzonitriles, it is referred to as compound 1.
The compound physicochemical property is as follows：White solid, 70-72 DEG C of fusing point；Nuclear magnetic resonance spectroscopy：1H NMR(500MHz,
CDCl3) δ 7.65 (dd, J=8.5,5.3Hz, 1H), 7.12-7.02 (m, 1H), 6.99-6.85 (m, 1H), 6.84 (s, 1H),
6.82 (s, 1H), 6.65 (t, J=9.0Hz, 1H), 5.40 (s, 1H), 5.23 (t, J=10.0Hz, 2H), 4.99 (s, 2H),
3.98 (s, 1H), 3.29-3.17 (m, 2H), 2.94 (d, J=12.0Hz, 1H), 2.70 (s, 2H), 2.03 (d, J=13.0Hz,
1H), 1.82 (s, 1H), 1.66-1.59 (m, 1H), 1.45 (d, J=25.0Hz, 1H), 1.26 (d, J=8.0Hz, 1H) nuclear-magnetisms
Resonate carbon spectrum：13C NMR(126MHz,CDCl3) δ 165.2 (d, J=12.7Hz), 163.8 (d, J=12.7Hz), 162.5,
161.9 (d, J=12.4Hz), 159.7,152.1,143.9 (d, J=8.7Hz), 140.2 (d, J=8.9Hz), 135.6 (d, J
=9.5Hz), 116.5,115.9 (d, J=22.7Hz), 115.4 (d, J=22.7Hz), 111.3 (dd, J=19.7,6.0Hz),
106.6 (d, J=3.2Hz), 103.1 (dd, J=25.2,26.5Hz), 90.2,56.1,51.8,47.2,46.6,43.6,
30.4,29.7.
" 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- the dimethyl benzyls) -2,4- of embodiment 2
Dioxo -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles (compound 2) " chemical fully synthetic and Structural Identification
(1) 2- { [6- chloro- 3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] first
Base } -4- fluorobenzonitriles chemical synthesis
Under room temperature, to 5mL dissolved with 1 gram of 2- { [chloro- 3,4- dihydros -2,4- dioxo -1 (the 2H)-pyrimidine radicals of 6-] first
Base } -4- fluorobenzonitriles n,N-Dimethylformamide solution in add 0.59 gram of Anhydrous potassium carbonate, 0.10 gram of potassium iodide, dropwise
N,N-Dimethylformamide solution of the 5mL dissolved with 0.79 gram of 3,5- dimethylbenzyl bromine is added, when reaction 24 is small under lucifuge, TLC inspections
Survey, after raw material point disappears, into reaction solution plus 10 times of amount distilled water, ethyl acetate extract 3 times, merge organic phase, and use quality
20% salt of concentration is washed 3 times, and organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure.Column chromatography chromatogram separates, petroleum ether：Acetic acid
Ethyl ester 8:1.15 grams of white solid is obtained after 1 elution.By Spectrum Analysis, it is 2- { [chloro- 3, the 4- dihydros -3- of 6- to confirm the compound
(3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles.
(2) 2- { [6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4-
Dioxo -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
In 50mL three-necked bottles, 0.49 gram of Anhydrous potassium carbonate, 0.52 gram of (R) -3- (Boc- amino) piperidines are added to 15mL
Dissolved with 1 gram of 2- { [6- chloro- 3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4-
In the n,N-Dimethylformamide solution of fluorobenzonitrile, argon gas protection, 4 hours of 90 DEG C of back flow reactions, TLC detections, raw material point
After disappearance, cooling reaction solution to room temperature.Add 10 times of amount distilled water, ethyl acetate extracts 3 times, merges organic phase, and dense with quality
Spend 20% salt to wash 3 times, organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram, oil
Ether：Ethyl acetate 3:1 elution, obtains 1.18 grams of white solid.By Spectrum Analysis, it is 2- { [6- [(3R) -3- to confirm the compound
Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -
4- fluorobenzonitriles；
(3) 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxies
Generation -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
Under 0 DEG C of stirring, 4.5mL is added into 5mL dissolved with 0.5 gram of 2- dissolved with the dichloromethane solution of 0.9mL trifluoroacetic acids
[6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H) -
Pyrimidine radicals] methyl -4- fluorobenzonitriles dichloromethane solution in, TLC detections, after raw material point disappears, water on the rocks quenching reaction,
With the NaOH solution tune PH of mass concentration 10% to alkalescence, add 30mL dichloromethane and extract 3 times, merge organic phase, quality is dense
20% salt water washing 3 times are spent, organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram, dichloro
Methane-methanol-triethylamine system elutions, obtains 0.34 gram of white solid.By Spectrum Analysis, it is 2- { [6- to confirm the compound
[(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] first
Base } -4- fluorobenzonitriles, it is referred to as compound 2.
The compound physicochemical property is as follows：White solid, 115~117 DEG C of fusing point；Nuclear magnetic resonance spectroscopy：1H NMR
(500MHz,CDCl3) δ 7.63 (dd, J=8.5,5.3Hz, 1H), 7.03 (t, J=7.0Hz, 1H), 6.90 (s, 1H), 6.90
(s,1H),6.88(s,1H),6.84(s,1H),5.44(s,1H),5.24–5.16(m,2H),4.94(s,2H),3.43(s,
1H), 3.41 (s, 1H), 3.38 (s, 1H), 2.92 (s, 1H), 2.86 (d, J=11.5Hz, 1H), 2.65 (s, 1H), 2.22 (s,
6H), 2.10 (s, 1H), 1.79 (s, 1H), 1.66-1.56 (m, 2H), 1.27-1.23 (m, 1H) carbon-13 nmr spectras：13C NMR
(126MHz,CDCl3) δ 165.1 (d, J=259.56Hz), 163.0,159.2,152.1,144.2 (d, J=8.82Hz),
137.9,136.4,135.6 (d, J=10.8Hz), 129.3,126.0,116.7,115.8 (d, J=23.94Hz), 115.5 (d,
), J=25.2Hz 106.6,90.6,54.0,53.4,51.8,47.3,46.6,44.4,28.6,21.2.
Embodiment 3 " 2- [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,
4- dioxos -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles (compound 3) " chemical fully synthetic and Structural Identification
(1) 2- { [6- chloro- 3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] first
Base } -4- fluorobenzonitriles chemical synthesis
Under room temperature, to 5mL dissolved with 1 gram of 2- { [chloro- 3,4- dihydros -2,4- dioxo -1 (the 2H)-pyrimidine radicals of 6-] first
Base } -4- fluorobenzonitriles n,N-Dimethylformamide solution in add 0.54 gram of Anhydrous potassium carbonate, 0.10 gram of potassium iodide, dropwise
Add n,N-Dimethylformamide solution of the 5mL dissolved with 0.75 gram of 3,4- dimethoxybenzyl bromide, when reaction 24 is small under lucifuge, TLC
Detection, after raw material point disappears, into reaction solution plus 10 times of amount distilled water, ethyl acetate extract 3 times, merge organic phase, and use matter
Measure 20% salt of concentration to wash 3 times, organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure.Column chromatography chromatogram separates, petroleum ether：Second
Acetoacetic ester 3:1.15 grams of white solid is obtained after 1 elution.By Spectrum Analysis, confirm the compound for 2- [chloro- 3, the 4- dihydros of 6--
3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzonitriles.
(2) 2- [6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,
4- dioxos -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
In 50mL three-necked bottles, by 0.62 gram of Anhydrous potassium carbonate, that 0.6 gram of (R) -3- (Boc- amino) piperidines is added to 15mL is molten
Have 1.28 grams of 2- { [6- chloro- 3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -
In the n,N-Dimethylformamide solution of 4- fluorobenzonitriles, argon gas protection, 3 hours of 90 DEG C of back flow reactions, TLC detections, raw material
After point disappears, cooling reaction solution to room temperature.Add 10 times of amount distilled water, ethyl acetate extracts 3 times, merges organic phase, and use quality
20% salt of concentration is washed 3 times, and organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram, oil
Ether：Ethyl acetate 3:2 elutions, obtain 1.16 grams of white solid.By Spectrum Analysis, it is 2- { [6- [(3R) -3- to confirm the compound
Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] first
Base } -4- fluorobenzonitriles；
(3) 2- { [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- two
Oxo -1 (2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles chemical synthesis
Under 0 DEG C of stirring, 4.5mL is added into 5mL dissolved with 0.55 gram of 2- dissolved with the dichloromethane solution of 0.9mL trifluoroacetic acids
{ [6- [(3R) -3-Boc- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1
(2H)-pyrimidine radicals] methyl -4- fluorobenzonitriles dichloromethane solution in, TLC detections, after raw material point disappears, water on the rocks quenching
Reaction, with the NaOH solution tune PH of mass concentration 10% to alkalescence, adds 30mL dichloromethane and extracts 3 times, merge organic phase, matter
Measure 20% salt water washing of concentration 3 times, organic phase is dried with anhydrous magnesium sulfate, is concentrated under reduced pressure, and mixture is separated through column chromatography chromatogram,
Methylene chloride-methanol-triethylamine system elutions, obtains 0.39 gram of white solid.By Spectrum Analysis, it is 2- to confirm the compound
{ [6- [(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-phonetic
Piperidinyl] methyl } -4- fluorobenzonitriles, it is referred to as compound 3.
The compound physicochemical property is as follows：White solid, 75~77 DEG C of fusing point；Nuclear magnetic resonance spectroscopy：1H NMR
(500MHz,CDCl3) δ 7.67 (dd, J=8.5,5.3Hz, 1H), 7.07 (dd, J=8.0,2.1Hz, 1H), 7.05 (s, 1H),
7.03 (d, J=8.0Hz, 1H), 6.80 (d, J=2.0Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 5.37 (s, 1H), 5.25
(s, 2H), 5.02 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.00 (d, J=11.0Hz, 1H), 2.91 (d, J=4.5Hz,
1H), 2.90 (s, 1H), 2.59 (s, 1H), 2.39 (s, 1H), 1.93 (d, J=9.5Hz, 1H), 1.76 (dd, J=10.0,
3.9Hz, 1H), 1.60 (dd, J=10.5,3.4Hz, 1H), 1.50 (s, 2H), 1.24 (d, J=5.0Hz, 1H) nuclear magnetic resonance carbon
Spectrum：13C NMR(126MHz,CDCl3) δ 165.2 (d, J=259.6Hz), 162.6,159.4,152.5,148.7,148.5,
144.4 (d, J=8.7Hz), 135.5 (d, J=9.6Hz), 129.4,121.8,116.3,115.6 (d, J=22.7Hz),
114.5 (d, J=24.0Hz), 112.6,110.8,106.7,90.8,59.4,55.8,53.4,51.8,47.3,46.2,44. 2,
33.3,23.2.
4 dipeptidyl peptidase-4 inhibitory activity of embodiment measures
Testing compound 1~3 is dissolved with DMSO respectively, HEPES buffer solution dilutes the test sample for being configured to various concentrations
Solution.Experiment is divided into sample sets and (contains 10 μm of olL-1Small-molecule fluorescent probe tetraphenylethylene, 5UL-1DPP-4 solution, 10 μ
L testing compound solutions), sample controls group (contain 10 μm of olL-1Small-molecule fluorescent probe tetraphenylethylene, 25mgL-1Treat
Survey compound solution), control group (contain 10 μm of olL-1Small-molecule fluorescent probe tetraphenylethylene, 5UL-1DPP-4 solution),
Blank group (10 μm of olL-1Small-molecule fluorescent probe tetraphenylethylene), reaction dissolvent is HEPES buffer solution (0.5mmolL-1, PH 7.0), total reaction volume is 100 μ L.Positive control drug is Sitagliptin.After 37 DEG C are incubated 30 minutes, microplate reader inspection
Each group fluorescence intensity (λ ex=320nm, λ em=450nm) is surveyed, inhibiting rate of each component to DPP-4, wherein I tables is calculated as follows
Show fluorescence intensity.Experimental result is usedRepresent.
1 dipeptidyl peptidase-4 inhibiting rate (%) of table
As shown in Figs. 1-3.
Result of the test shows：Above compound shows dipeptidyl peptidase-4 significant inhibitory action, has potential
Anti- diabetes B potential applicability in clinical practice.
Embodiment 5：The preparation of 1~3 parenteral solution of compound
With a small amount of DMSO, (weight ratio is compound 1~3 respectively：1：0.1-1：0.5, it is herein 1：0.4) after dissolving, press
Conventional plus water for injection (weight ratio 1:20-1:200, it is herein 1:200) parenteral solution is made in, refined filtration, embedding sterilizing.
Embodiment 6：The preparation of 1~3 powder-injection of compound
With a small amount of DMSO, (weight ratio is compound 1~3 respectively：1：0.1-1：0.5, it is herein 1：0.5), will after dissolving
It is dissolved in sterile water for injection, and (weight ratio is：1：20-1：60, it is herein 1:60) in, it is stirred to dissolve, with sterile suction funnel
Filtering, then sterile refined filtration, are sub-packed in ampoule, sterile after frozen drying to seal to obtain powder-injection.
Embodiment 7：The preparation of 1~3 pulvis of compound
Compound 1~3 is respectively 9 by itself and excipient weight ratio:1 ratio adds excipient (weight ratio, Tween 80:
Propane diols:Cyclodextrin:Lactose=1:2:4:12) pulvis, is made.
Embodiment 8：The preparation of 1~3 tablet of compound
Compound 1~3 presses itself and excipient (weight ratio, hypromellose E5 respectively：Microcrystalline cellulose MCC102:
Magnesium stearate:(8% PVP K30)=15:15:2:0.1) weight ratio is 5:1 ratio adds excipient, pelletizing press sheet.
Embodiment 9：The preparation of 1~3 oral liquid of compound
Compound 1~3 is added separately in the distilled water containing 20% simple syrup of mass concentration and 0.1% sodium benzoate, is pressed
It is 15 μ g/mL oral liquids that concentration, which is made, in traditional oral liquid preparation method.
Embodiment 10：The preparation of 1~3 capsule of compound
Compound 1~3 presses itself and excipient (weight ratio, medical starch respectively:Glucose:Gelatin hydrolysate:Glycine=
30:10:1:1) weight ratio is 5:1 ratio mixing, is made capsule.
Embodiment 11：The preparation of 1~3 pill of compound
Compound 1~3 presses itself and excipient (weight ratio, PEG2000 respectively:PEG6000=4:1) weight ratio is 1:10
Ratio mixes, and pill is made.
Claims (10)
1.DPP-4 inhibitor, it is characterised in that：It is with following three kinds of compounds or the corresponding medicine of following three kinds of compounds
More than one or both of acceptable salt it is active ingredient on, three kinds of structural formula of compound difference are as follows：
2. according to DPP-4 inhibitor described in claim 1, it is characterised in that：
Compound 1:Wherein 1 nitrogen of hybar X and 3,5- difluorobenzyl are connected, and chemical name Chinese is：2-{[6-[(3R)-3-
Amino -1- piperidyls] -3,4- dihydros -3- (3,5- difluorobenzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4- fluorobenzene
Formonitrile HCN；English is：2-[6-(3(R)-aminopiperidin-1-yl)-3-(3,5-difluorobenzyl)-2,4-dioxo-
3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile；
Compound 2：Wherein 1 nitrogen of hybar X and 3,5- dimethyl benzyl are connected, and chemical name Chinese is：2-{[6-[(3R)-
3- amino -1- piperidyls] -3,4- dihydros -3- (3,5- dimethyl benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals] methyl } -4-
Fluorobenzonitrile；English is：2-[6-(3(R)-aminopiperidin-1-yl)-3-(3,5-dimethyl)-2,4-dioxo-3,
4-dihydro-2H-pyr imidin-1-ylmethyl]-4-fluorobenzonitrile；
Compound 3：Wherein 1 nitrogen of hybar X and 3,4- dimethoxy-benzyl are connected, and chemical name Chinese is：2-{[6-
[(3R) -3- amino -1- piperidyls] -3,4- dihydros -3- (3,4- dimethoxy-benzyls) -2,4- dioxos -1 (2H)-pyrimidine radicals]
Methyl } -4- fluorobenzonitriles；English is：2-[6-(3(R)-aminopiperidin-1-yl)-3-(3,4-
dimethoxybenzyl)-2,4-dioxo-3,4-dihydr o-2H-pyrimidin-1-ylmethyl]-4-
fluorobenzonitrile；
One kind or two kinds of mixing in the compound 1~3 have DPP-4 inhibitory activity, and signified compound 1~3 can herein
For one kind in the chemical equivalents such as the pharmaceutically acceptable salt of compound 1~3 itself and compound 1~3, but not office
It is limited to above chemical equivalent.
3. DPP-4 inhibitor according to claim 1 or claim 2, it is characterised in that
The DPP-4 inhibitor includes pharmaceutically acceptable excipient substance or carrier.
4. DPP-4 inhibitor according to claim 3, it is characterised in that
The DPP-4 inhibitor include diluent, wetting agent, adhesive, disintegrant, lubricant, conditioning agent and other pharmaceutically
Or the one or more in bromatology in acceptable auxiliary material.
5. according to the DPP-4 inhibitor of claim 3 or 4, it is characterised in that
The compound 1~3 or one kind in their corresponding pharmaceutically acceptable salt or two kinds of mixing can be with doctors
Acceptable excipient substance or carrier mixing can be made into tablet, capsule, oral liquid, granule, the ball for the treatment of relevant disease on medicine
Agent or injection, but it is not limited to above formulation.
6. according to the DPP-4 inhibitor of claim 3 or 4, it is characterised in that
The single dose of described pharmaceutical composition contains one or both of active compound component 1~3 or its is pharmaceutically acceptable
Effective content of the salt in pharmaceutical composition be 1~95%.
7. application of any DPP-4 inhibitor of claim 1-6 in diabetes B medicine is treated, it is characterised in that：
The DPP-4 inhibitor is corresponding pharmaceutically acceptable with following three kinds of compounds or following three kinds of compounds
More than one or both of salt it is active ingredient, three kinds of structural formula of compound difference are as follows：
The diabetes B includes the diabetes as caused by the generation of insulin resistance or as caused by defect of insulin secretion
Diabetes.
8. application according to claim 7, it is characterised in that
The medicine includes pharmaceutically acceptable excipient substance.
9. application according to claim 4, it is characterised in that
The medicine include diluent, wetting agent, adhesive, disintegrant, lubricant, conditioning agent and other pharmaceutically or food
Acceptable auxiliary material on；
One kind or two kinds of mixing in the compound 1~3 can mix with pharmaceutically acceptable pharmaceutical carrier and can be made into treatment
Tablet, capsule, oral liquid, granule, pill or the injection of relevant disease, but it is not limited to above formulation.
10. the application according to claim 4 or 9, it is characterised in that
The single dose of described pharmaceutical composition is containing one kind in active compound component 1~3 or their pharmaceutically acceptable salts
Or the two or more effective mass contents in pharmaceutical composition are 1~95%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558836A (en) * | 2018-05-14 | 2018-09-21 | 东南大学 | One kind has the DPP-4 inhibitor and application thereof of double action mechanism |
| CN109369782A (en) * | 2018-08-31 | 2019-02-22 | 华南理工大学 | A kind of decapeptide improving diabetes and senile dementia |
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| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| WO2007112368A1 (en) * | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Preparation of (r)-3-aminopiperidine dihydrochloride |
| CN102134230A (en) * | 2004-03-15 | 2011-07-27 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CN104109417A (en) * | 2014-07-21 | 2014-10-22 | 常熟市协新冶金材料有限公司 | Environmental-friendly oil-based ink for ball-point pens |
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2018
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1926128A (en) * | 2004-03-15 | 2007-03-07 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| CN102134230A (en) * | 2004-03-15 | 2011-07-27 | 武田药品工业株式会社 | Dipeptidyl peptidase inhibitors |
| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| WO2007112368A1 (en) * | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Preparation of (r)-3-aminopiperidine dihydrochloride |
| CN104109417A (en) * | 2014-07-21 | 2014-10-22 | 常熟市协新冶金材料有限公司 | Environmental-friendly oil-based ink for ball-point pens |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108558836A (en) * | 2018-05-14 | 2018-09-21 | 东南大学 | One kind has the DPP-4 inhibitor and application thereof of double action mechanism |
| CN109369782A (en) * | 2018-08-31 | 2019-02-22 | 华南理工大学 | A kind of decapeptide improving diabetes and senile dementia |
| CN109369782B (en) * | 2018-08-31 | 2021-09-21 | 华南理工大学 | Decapeptide for improving diabetes and senile dementia |
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