CN106632130B - Furodiazole compound and its application in preparation prevention and/or treatment diabetes B drug - Google Patents
Furodiazole compound and its application in preparation prevention and/or treatment diabetes B drug Download PDFInfo
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- CN106632130B CN106632130B CN201611175726.4A CN201611175726A CN106632130B CN 106632130 B CN106632130 B CN 106632130B CN 201611175726 A CN201611175726 A CN 201611175726A CN 106632130 B CN106632130 B CN 106632130B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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Abstract
The present invention relates to the chemical total synthesis method of a kind of novel furodiazole Protein tyrosine phosphatase 1B (PTP1B) and its application in treatment diabetes B drug, the furodiazole structural formula of compound are as follows:
Description
Technical field
The present invention relates to a new class of furodiazole PTP1B inhibitor and its synthetic methods, pharmacological activity and pharmaceutical use.
For the analog derivative by inhibiting PTP1B activity, enhancing insulin receptor sensibility plays insulin physiological function normally, into
And regulating and controlling blood sugar, reach the therapeutic efficiency to insulin resistance class diabetes B.
Background technique
Diabetes are reduced by the sensibility of hypoinsulinism or target tissue to insulin, caused by chronic metabolic
Property disease.The World Health Organization (WHO) shows that global diabetic is up to 3.47 in the data that in November, 2014 announces
Hundred million.Diabetes are divided into insulin-dependent (1 type) and insulin-resistant (2 type), and wherein type 2 diabetic patient accounts for diabetes disease
90% or more of example.Mainly there is alpha-glucosidase inhibitor for treating the oral drugs of diabetes B currently on the market, promote pancreas islet
The types antidiabetic drug such as plain secrete pharmaceutical, biguanides and thiazolidinedione.Due to they both for illness rather than cause of disease target spot
Design medicine, there are hypoglycemia, lactic acidosis and the sudden medium various disadvantages of heart.Find safe and efficient targeting type new drug
Urgent need as treating diabetes.
Insulin resistance is the important clinical indication of diabetes B.As the negative regulatory factor of insulin signaling pathway,
The overexpression of PTP1B can block the transmitting of insulin signaling, inhibit the synthesis of glycogen.It knocks out PTP1B gene or inhibits PTP1B
Enzyme can significantly improve test mice to the sensibility of insulin, insulin resistance is effectively relieved.Therefore, targeting is designed and developed
The micromolecular inhibitor of PTP1B, it is considered to be treat the new way of diabetes B.
PTP1B starts late as the research for the treatment of diabetes B drug novel targets, there is no facing for this target spot at present
Bed drug listing.Type of compounds in conceptual phase is varied, mainly there is difluoro methylene phosphonic acid ester, salicylic acid
Class, heterocyclic carboxylic acid class, sulfamic acid class, N- oxamides benzoic acid derivative.Due to these compounds include mostly phosphoric acid or
Carboxylic acid group, higher hydrophily and electronegativity cause its permeability cell and bioavilability too low.Researcher thinks,
The research and development of PTP1B inhibitor need the compound of electroneutral.
Therefore, the bromo marine natural products that we have found from seaweed is guide, and design has synthesized a series of electroneutral
And the furodiazole compound with PTP1B inhibitory activity.
Summary of the invention
One of the objects of the present invention is to provide a kind of furodiazole compounds, such compound is by inhibiting PTP1B's
Activity enhances insulin receptor sensibility, can be used for treating insulin resistance class diabetes B.
The compound has following structures:
Wherein:
R is selected from-CH2Ph-R1,-CH2COOPh-R2,-CH2COPh-R3。R1,R2,R3Selected from F, the saturation alkane of Br, C1~C6
Base, the saturation alkoxy of C1~C6.R1,R2,R3Quantity be 0,1,2.
Furodiazole compound of the invention the preparation method is as follows:
3,4-Dihydroxybenzoic acid (1) is esterified in dehydrated alcohol, obtains 3,4-Dihydroxybenzoic acid ethyl ester (2), then pass through
Hydrazinolysis, two step of cyclization are crossed, synthesis obtains oxadiazoles intermediate (3).Compound 3 respectively with replace benzyl chloride (4), chloracetyl ester (5),
The compound condensations such as alpha-brominated acetophenone (6) can be obtained target product of the invention (7,8,9).
To the compound obtained by the above method, we have detected their PTP1B rejection ability by multiple means.
The result shows that the above-mentioned compound with new construction of the invention has efficient PTP1B inhibitory activity, negative regulation can be passed through
Insulin signaling pathway enhances insulin receptor sensibility, plays insulin physiological function normally, and then regulates and controls blood
Sugar reaches the therapeutic efficiency to insulin resistance class diabetes B.
Based on this, the present invention points out that above-mentioned furodiazole compound can be used for preparing PTP1B inhibitor, and further uses
In preparing anti-diabetes B drug.The PTP1B inhibitor or corresponding anti-diabetes B drug, can be compound
Simple substance dosage form is also possible to the combination preparation that a effective amount of furodiazole compound and suitable medicinal adjuvant are mixed to form.
Furodiazole compound of the present invention, by competitive binding and antagonism PTP1B, thus enhance insulin by
Body sensibility, and then regulating and controlling blood sugar realize its application as anti-diabetes B drug.
Detailed description of the invention
Fig. 1 .Western blot method detects the phosphorylation level schematic diagram of protein I R β, IRS1 and Akt.NC is blank pair
According to PC is positive control, and compound concentration is 10 μM, 1 μM, 0.1 μM.
Specific embodiment
Following non-limiting embodiments can with a person of ordinary skill in the art will more fully understand the present invention, but not with
Any mode limits the present invention.
The synthesis of embodiment 1:4- (5- (benzylthio) -1,3,4- oxadiazoles -2- substitution) benzene -1,2- hydroxyl and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
The solvent of 80% volume is diluted with 30mL ethyl acetate and 25mL water, and water layer is extracted with 300mL ethyl acetate, merges organic layer,
With saturation NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4- dihydroxy benzenes
Ethyl formate 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.Cooling, decompression boils off 80% volume
Solvent, add 100mL water, after solid precipitation after, filtering washing, dehydrated alcohol recrystallization, obtain 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off the solvent of 80% volume, and the dilute salt of mass fraction 10% is added dropwise
Acid is precipitated a large amount of solids, filters, 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles to pH=6
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that 120 μ L benzyl chlorides are added dropwise of stirring, after dripping off, normal-temperature reaction 30 minutes, filters, washes, dry,
Obtain 4- (5- (benzylthio) -1,3,4- oxadiazoles -2- substitution) benzene -1,2- hydroxyl 152mg.
Structural characterization: M.p.213.2-214.5 DEG C, TOF MS (EI+):C15H12N2O3S,(m/z):calcd for
300.0569,found 300.0328.
1H NMR (500MHz, DMSO-d6) δ 9.79 (s, 1H), 9.52 (s, 1H), 7.43 (d, J=7.4Hz, 2H),
7.36-7.29 (m, 3H), 7.25 (dd, J=17.4,8.3Hz, 2H), 6.86 (d, J=8.2Hz, 1H), 4.51 (s, 2H)
13C NMR(126MHz,DMSO-d6)δ165.95(s),162.36(s),149.79(s),146.30(s),137.08
(s),129.43(s),129.01(s),128.17(s),119.09(s),116.63(s),114.30(s),113.71(s),
36.39(s).
DEPT(135°)δ129.43(CH),129.01(CH),128.17(CH),119.09(CH),116.63(CH),
113.70(CH),36.38(negative peak,CH2).
DEPT(90°)δ129.43(CH),129.01(CH),128.17(CH),119.09(CH),116.63(CH),
113.70(CH).
Embodiment 2:p- tolyl -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- substitution) sulfydryl) acetic acid
The synthesis of ester and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
80% solvent is diluted with 30mL ethyl acetate and 25mL water, and aqueous layer with ethyl acetate extraction merges organic layer, with saturation
NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4-Dihydroxybenzoic acid second
Ester 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.It is cooling, decompression boil off 80% it is molten
Agent adds 100mL water, and after solid precipitation, filtering washing, 200mL dehydrated alcohol recrystallization obtains 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off 80% solvent, and 10% dilute hydrochloric acid of mass fraction is added dropwise extremely
A large amount of solids are precipitated in pH=6, filtering, and 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that 130 μ L p- tolyl -2- ethyl chloroacetates are added dropwise of stirring, after dripping off, normal-temperature reaction 30 is divided
Clock filters, and washes, dry, obtains p- tolyl -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- replace) sulfydryl)
Acetic acid esters.
Structural characterization: M.p.206.4-207.8 DEG C, TOF MS (EI+):C17H14N2O5S,(m/z):calcd for
358.0674,found 358.0265.
1H NMR (500MHz, DMSO-d6) δ 9.87 (s, 1H), 9.59 (s, 1H), 7.32 (d, J=1.7Hz, 1H), 7.25
(dd, J=8.2,1.7Hz, 1H), 7.19 (d, J=8.2Hz, 2H), 6.97 (d, J=8.3Hz, 2H), 6.87 (d, J=8.2Hz,
1H),4.46(s,2H),2.26(s,3H).
13C NMR(126MHz,DMSO-d6)δ167.49(s),166.13(s),161.99(s),149.87(s),148.58
(s),146.32(s),135.91(s),130.42(s),121.50(s),119.18(s),116.64(s),114.16(s),
113.72(s),34.42(s),20.80(s).
DEPT(135°)δ130.41(CH),121.50(CH),119.18(CH),116.63(CH),113.72(CH),
34.42(negative peak,CH2),20.80(CH3).
DEPT(90°)δ130.42(CH),121.50(CH),119.18(CH),116.64(CH),113.72(CH).
Embodiment 3:3- ethoxybenzene 2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- substitution) sulfydryl) second
The synthesis of acid esters and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
80% solvent is diluted with 30mL ethyl acetate and 25mL water, and water layer is extracted with 300mL ethyl acetate, merges organic layer, with full
And NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4-Dihydroxybenzoic acid
Ethyl ester 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.It is cooling, decompression boil off 80% it is molten
Agent adds 100mL water, and after solid precipitation, filtering washing, 200mL dehydrated alcohol recrystallization obtains 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off 80% solvent, and 10% dilute hydrochloric acid of mass fraction is added dropwise extremely
A large amount of solids are precipitated in pH=6, filtering, and 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that 214mg 3- ethoxy benzene 2- chloracetate is added dropwise of stirring, after dripping off, normal-temperature reaction 30 minutes, mistake
Filter is washed, dry, obtains 3- ethoxybenzene 2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- replace) sulfydryl) acetic acid
Ester.
Structural characterization: M.p.238.2-239.4 DEG C, TOF MS (EI+):C18H16N2O6S,(m/z):calcd for
388.0729,found 388.0136.
1H NMR (500MHz, DMSO-d6) δ 9.84 (s, 1H), 9.56 (s, 1H), 7.34 (d, J=1.5Hz, 1H), 7.25
(dd, J=8.3,1.5Hz, 1H), 7.00 (d, J=8.9Hz, 2H), 6.90 (m, 3H), 4.46 (s, 2H), 3.97 (q, J=
6.9Hz, 2H), 1.28 (t, J=6.9Hz, 3H)
13C NMR(126MHz,DMSO-d6)δ167.65(s),166.13(s),161.97(s),156.79(s),149.89
(s),146.34(s),144.06(s),122.63(s),119.15(s),116.66(s),115.44(s),114.18(s),
113.76(s),63.83(s),34.42(s),15.03(s).
DEPT(135°)δ122.63(CH),119.14(CH),116.66(CH),115.44(CH),113.76(CH),
63.83(negative peak,CH2),34.42(negative peak,CH2),15.03(CH3).
DEPT(90°)δ122.63(CH),119.15(CH),116.66(CH),115.44(CH),113.76(CH).
Embodiment 4:1- (2- bromophenyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- substitution) sulfydryl)
The synthesis of ethyl ketone and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
80% solvent is diluted with 30mL ethyl acetate and 25mL water, and water layer is extracted with 300mL ethyl acetate, merges organic layer, with full
And NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4-Dihydroxybenzoic acid
Ethyl ester 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.It is cooling, decompression boil off 80% it is molten
Agent adds 100mL water, and after solid precipitation, filtering washing, 200mL dehydrated alcohol recrystallization obtains 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off 80% solvent, and 10% dilute hydrochloric acid of mass fraction is added dropwise extremely
A large amount of solids are precipitated in pH=6, filtering, and 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that the bromo- 1- of 276mg 2- (2- bromophenyl) ethyl ketone is added dropwise of stirring, after dripping off, normal-temperature reaction 30 is divided
Clock filters, and washes, dry, obtains 1- (2- bromophenyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- replace)
Sulfydryl) ethyl ketone.
Structural characterization: M.p.278.6-279.5 DEG C, TOF MS (EI+):C16H11BrN2O4S,(m/z):calcd for
406.0623,found 406.0328.
1H NMR (500MHz, DMSO-d6) δ 8.14 (s, 1H), 8.00 (d, J=7.7Hz, 1H), 7.86 (d, J=
7.8Hz, 1H), 7.51 (t, J=7.9Hz, 1H), 7.26 (s, 1H), 7.18 (d, J=7.9Hz, 1H), 6.82 (d, J=7.5Hz,
1H),5.03(s,2H).
13C NMR(126MHz,DMSO-d6)δ192.31(s),137.42(s),136.97(s),131.60(s),131.33
(s),127.88(s),122.65(s),119.15(s),116.54(s),40.51(s).
DEPT(135°)δ136.97(CH),131.60(CH),131.33(CH),127.88(CH),119.15(CH),
116.54(CH),109.99(CH),40.50(negative peak,CH2).
DEPT(90°)δ136.97(CH),131.60(CH),131.33(CH),127.88(CH),119.15(CH),
116.54(CH).
Embodiment 5:1- (3,4- difluorophenyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- substitution)
Sulfydryl) ethyl ketone synthesis and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
80% solvent is diluted with 30mL ethyl acetate and 25mL water, and water layer is extracted with 300mL ethyl acetate, merges organic layer, with full
And NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4-Dihydroxybenzoic acid
Ethyl ester 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.It is cooling, decompression boil off 80% it is molten
Agent adds 100mL water, and after solid precipitation, filtering washing, 200mL dehydrated alcohol recrystallization obtains 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off 80% solvent, and 10% dilute hydrochloric acid of mass fraction is added dropwise extremely
A large amount of solids are precipitated in pH=6, filtering, and 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that the bromo- 1- of 234mg 2- (3,4- difluorophenyl) ethyl ketone is added dropwise of stirring, after dripping off, normal-temperature reaction 30
Minute, it filters, washes, it is dry, obtain 1- (3,4- difluorophenyl) -2- ((- 1,3,4- oxadiazoles -2- of 5- (3,4- dihydroxy phenyl)
Replace) sulfydryl) ethyl ketone.
Structural characterization: M.p.239.1-240.2 DEG C, TOF MS (EI+):C16H10F2N2O4S,(m/z):calcd for
364.0329,found 364.0323.
1H NMR (500MHz, DMSO-d6) δ 9.80 (s, 1H), 9.54 (s, 1H), 8.11 (t, J=12Hz, 1H), 7.94
(s, 1H), 7.64 (dd, J=18.4,8.5Hz, 1H), 7.28 (s, 1H), 7.21 (dd, J=8.2,1.7Hz, 1H), 6.85 (d, J
=8.2Hz, 1H), 5.07 (s, 2H)
13C NMR(126MHz,DMSO-d6)δ191.26(s),165.93(s),162.16(s),149.81(s),146.30
(s),132.99(s),126.96(s),119.10(s),118.72(s),118.58(s),118.44(s),118.30(s),
116.60(s),114.23(s),113.70(s),40.54(s).
DEPT(135°)δ126.96(CH),119.10(CH),118.72(CH),118.58(CH),118.44(CH),
118.30(CH),116.60(CH),113.70(CH).40.54(negative peak,CH2)
DEPT(90°)δ126.90(CH),119.09(CH),118.72(CH),118.58(CH),118.44(CH),
118.30(CH),116.60(CH),113.70(CH).
Embodiment 6:1- (4- tolyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- substitution) sulfydryl)
The synthesis of ethyl ketone and Structural Identification
15.4g (0.1mol) 3,4-Dihydroxybenzoic acid and 200mL dehydrated alcohol are added in 500mL flask, not
The concentrated sulfuric acid of 5mL mass fraction 98% is slowly added dropwise under disconnected stirring.Mixture is heated to reflux, and TLC tracking reaction, decompression boils off
80% solvent is diluted with 30mL ethyl acetate and 25mL water, and water layer is extracted with 300mL ethyl acetate, merges organic layer, with full
And NaHCO3Aqueous solution, saturated common salt water washing, anhydrous Na2SO4It dries, filters, depressurizes precipitation, obtain 3,4-Dihydroxybenzoic acid
Ethyl ester 15.8g, yield 86.8%.
Step solid 3,4-Dihydroxybenzoic acid ethyl ester 15.8g is taken, is added in 100mL dehydrated alcohol, heats 60 DEG C, stirring
Under the hydrazine hydrate of 37.5g (0.6mol) mass fraction 80% is slowly added dropwise, drop finishes, and flow back 6h.It is cooling, decompression boil off 80% it is molten
Agent adds 100mL water, and after solid precipitation, filtering washing, 200mL dehydrated alcohol recrystallization obtains 3,4- dihydroxybenzoyl hydrazine
12g, yield 88.9%.
Once be added 12g 3 in 500mL flask, 4- dihydroxybenzoyl hydrazine, the 200mL dehydrated alcohol of 4g KOH and
12g CS2, agitating and heating reflux 4h.After reaction, decompression boils off 80% solvent, and 10% dilute hydrochloric acid of mass fraction is added dropwise extremely
A large amount of solids are precipitated in pH=6, filtering, and 200mL dehydrated alcohol recrystallization obtains 5- phenyl -2- sulfydryl -1,3,4- oxadiazoles
10.3g, yield 69.1%.
210mg (1mmol) 5- phenyl -2- sulfydryl -1,3 is taken, 4- oxadiazoles, 56mg (1mmol) KOH are added in 10mL water,
The lower 20mL ethanol solution that the bromo- 1- of 212mg 2- (4- tolyl) ethyl ketone is added dropwise of stirring, after dripping off, normal-temperature reaction 30 is divided
Clock filters, and washes, dry, obtains 1- (4- tolyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- replace)
Sulfydryl) ethyl ketone.
Structural characterization: M.p.242.3-242.4 DEG C, TOF MS (EI+):C17H14N2O4S,(m/z):calcd for
342.01297,found 342.0328.
1H NMR (500MHz, DMSO-d6) δ 8.04 (d, J=8.6Hz, 2H), 7.29 (s, 1H), 7.25 (d, J=
8.3Hz, 2H), 7.20 (d, J=8.2Hz, 1H), 7.02 (d, J=6.9Hz, 4H), 6.85 (d, J=8.2Hz, 1H), 5.04 (s,
2H),2.30(s,3H).
13C NMR(126MHz,DMSO-d6)δ191.61(s),165.84(s),162.79(s),162.41(s),152.77
(s),149.78(s),146.30(s),134.70(s),131.57(s),131.19(s),129.91(s),128.91(s),
120.63(s),119.07(s),117.23(s),116.60(s),114.28(s),113.70(s),40.67(s),20.80
(s).
DEPT(135°)δ131.56(CH),131.19(CH),128.91(CH),120.63(CH),119.07(CH),
117.22(CH),116.59(CH),113.69(CH),40.66(negative peak,CH2),20.80(CH3).
DEPT(90°)δ131.57(CH),131.19(CH),129.34(CH),120.63(CH),119.07(CH),
117.23(CH),116.60(CH),113.69(CH).
Embodiment 7: Protein tyrosine phosphatase 1B inhibitory activity measurement
Using molecular biology method, hGST-PTP1B-BL21E.Coli mankind's PTP1B engineering of genetic recombination is constructed
Bacterium utilizes the polypeptide para-Nitrophenyl containing phosphoric acid with GST affinity chromatography column purification hGST-PTP1B protein
Phosphate (pNPP) is fallen the product pNP after a phosphoric acid by PTP1B enzymatic hydrolysis the principle of absorption peak at wavelength 405nm, with
The amount that pNP is generated after PTP1B effect indicates the inhibition situation of PTP1B Enzyme activities and compound to enzymatic activity, calculatingization
Close object PTP1B enzyme activity inhibiting rate.
By the compound in embodiment, respectively with DMSO be configured to 0.1 μM, 1 μM, 10 μM, 100 μM various concentration for examination
Product solution takes the test solution of 1 μ L various concentration to be added separately to live body system (the 50mM Tris-HCl, pH of 99 μ L standards
6.5,2mM pNPP, 30nM hGST-PTP1B), negative control: DMSO, positive control: the DMSO solution (concentration of sodium vanadate
0.1 μM, 1 μM, 10 μM, 100 μM, the same test solution of test condition), reaction temperature is 37 DEG C, and it is 405nm that dynamic, which measures wavelength,
The light absorption at place, the time 30 minutes.First calculate the enzyme initial velocity phase in unit time optical absorption intensity increment (unit:
MO.D./min), the initial velocity of enzyme is represented with this, then according to formula %Inhibition=(VDMSO- VSample)/VDMSO×
100% calculates sample to the inhibiting rate (%Inhibition) of enzymatic activity, wherein VSampleIndicate the initial velocity of dosing group, VDMSO
Indicate the initial velocity of DMSO group (i.e. not dosing group).
It is vertical sit with the inhibiting rate (%Inhibition) of enzymatic activity using test sample compound molar concentration as abscissa
Mark, can obtain PTP1B enzyme suppression curve.According to formula %Inhibition=Bottom+ (Top-Bottom)/(1+10(lgIC50 -X)*h) curve is fitted, compound is calculated to the inhibitory activity IC of PTP1B50Value, i.e. inhibitor inhibit enzymatic activity
Required compound concentration when 50%.Wherein, %Inhibition, that is, inhibition of enzyme activity rate, Bottom are suppression curve bottom
Value, Top are value at the top of suppression curve, and X is test sample compound concentration, and h is hill coefficient.
The PTP1B inhibitory activity of 1 furodiazole compound of table
Table 1PTP1B Inhibitory of oxadiazol compounds
Test result shows: the above compound especially shows significantly to inhibit to make to protein tyrosine phosphatase 1B
With with good anti-diabetes B potential applicability in clinical practice.
Embodiment 8: ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- takes compound 1- (4- tolyl) -2-
Generation) sulfydryl) ethyl ketone cytoactive detection
With every hole 4 × 10 after the C2C12 cell for covering with bottom of bottle area 90% in culture bottle is resuspended5A cell is taped against 6
In orifice plate, and in the incubator (37 DEG C, 95% air of volume and 5%CO2) with the height of 10%FBS containing mass concentration (fetal calf serum)
Sugared DMEM cultivates C2C12 cell, after its cell is adherent cover with after with the DMEM in high glucose of the horse serum containing volumetric concentration 10% by 4
Its induction removes culture medium later and addition does not add DMEM starved cells 24 hours of FBS, then sop up the training in every hole at myotube
Base is supported, every hole is rejoined into the DMEM that 2mL does not add FBS, and compound is pressed into the concentration of 1uM, 0.5uM and 0.25uM with every hole
The amount of 2ul is added to test hole, and wherein the DMSO of same volume, after 7.5 hours, pancreas islet is added in negative control hole and insulin hole
Plain hole, which is added the insulin of 2uL10mM and is put into incubator, continues to cultivate.
6 orifice plates are taken out after 30 minutes and outwell culture medium, and 4 DEG C of PBS cleaning of every hole addition 1mL pre-cooling is residual to remove twice
Later every hole is added in the lysate of 150uL PMSF containing 1mM by the culture medium stayed, and standing 5 minutes on ice splits cell sufficiently
Cell, is then collected in 1.5mL EP pipe by solution, is placed in 12000 turns of 4 DEG C of centrifuges centrifugations and collects on 110uL after ten minutes
Clear liquid is in new EP pipe.4uL protein sample is added after taking clean 96 orifice plate, every hole that 16uLPBS is added, sample is diluted
5 times, 200uLBCA working solution is added in each hole later, in 37 DEG C of placement 20min, A562 is measured with microplate reader, later according to standard
Curve calculates the protein concentration of sample and the applied sample amount of 10ug albumen.The loading buffer that 26.5uL is added in every pipe is mixed
It is put into 95 DEG C of metal baths and heats 10 minutes, be put into -20 DEG C of storages, detect albumen in each processing sample with western blot method
The difference of expression.
Such as Fig. 1, compound 1- (4- tolyl) -2- ((5- (3,4- dihydroxy phenyl) -1,3,4- oxadiazoles -2- replace)
Sulfydryl) ethyl ketone can raise the phosphorylation level of insulin signaling pathway key protein IR β, IRS1 and Akt and present certain
Concentration dependent, such as Fig. 1, the expression of pIRS1 with 0.1 μM of compound concentration, 1 μM, 10 μM of raising and successively increase.It should
Compound can activate insulin signaling pathway, and promoting sugar to absorb reduces blood glucose level, therefore the compound has certain drop
Sugared potentiality are simultaneously of great significance for the exploitation of newly-developed hypoglycemic agent.
Claims (5)
1. a kind of furodiazole compound, general formula of molecular structure are as follows:
Wherein:
R is selected from-CH2COOPh-R2Or-CH2COPh-R3； R2 、R3It is respectively selected from F, the saturated alkyl of Br, C1 ~ C6, C1 ~ C6's
It is saturated one of alkoxy or two kinds；The upper R of R2Or R3Quantity be 1 or 2.
2. furodiazole compound as described in claim 1, it is characterised in that: the saturated alkyl of C1 ~ C6 is selected from methyl, different
The saturation alkoxy of one of propyl or two kinds, C1 ~ C6 is selected from one of methoxyl group, ethyoxyl or two kinds.
3. furodiazole compound described in claim 1 is in preparation prevention and/or treats answering in anti-2- patients with type Ⅰ DM drug
With.
4. application as claimed in claim 3, it is characterised in that: the furodiazole compound can inhibit the activity of PTP1B,
Enhance insulin receptor sensibility, plays insulin physiological function normally, and then regulating and controlling blood sugar, reach to insulin resistance class
The therapeutic efficiency of 2 patients with type Ⅰ DM.
5. according to the application of claim 3 or 4, it is characterised in that: one of described furodiazole compound or two kinds with
It is upper to be mixed and made into the tablet of prevention and/or the anti-2- patients with type Ⅰ DM for the treatment of with pharmaceutically acceptable pharmaceutical carrier, capsule, take orally
Liquid, granule, pill or injection.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001328357A (en) * | 2000-01-31 | 2001-11-27 | Mitsubishi Paper Mills Ltd | Direct thermal recording material |
| CN104892590A (en) * | 2014-03-05 | 2015-09-09 | 华东师范大学 | Benzheterocycle substituted 1,3,4-oxadiazole compound, preparation method and applications thereof |
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2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001328357A (en) * | 2000-01-31 | 2001-11-27 | Mitsubishi Paper Mills Ltd | Direct thermal recording material |
| CN104892590A (en) * | 2014-03-05 | 2015-09-09 | 华东师范大学 | Benzheterocycle substituted 1,3,4-oxadiazole compound, preparation method and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| Design and Synthesis of 2, 5-disubstituted Oxadiazole as Novel PTP1B Inhibitors;Chandrashekhar L.Athare，等;《Int.J.Pharm.Phytopharmacol.Res》;20141231;第3卷(第5期);第383-386页 * |
| Design, synthesis and biological evaluation of novel arylidinemalononitrile derivatives as non-carboxylic inhibitors of protein tyrosine phosphatase 1B;Girdhar Singh Deora，等;《MEDICINAL CHEMISTRY RESEARCH》;20130219;第22卷(第11期);第5347页表1 * |
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