CN107383146A - Oxime ester compound of lithocholic acid 3 and its preparation method and application - Google Patents
Oxime ester compound of lithocholic acid 3 and its preparation method and application Download PDFInfo
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- CN107383146A CN107383146A CN201710416767.6A CN201710416767A CN107383146A CN 107383146 A CN107383146 A CN 107383146A CN 201710416767 A CN201710416767 A CN 201710416767A CN 107383146 A CN107383146 A CN 107383146A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
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Abstract
The invention discloses oxime ester compound of lithocholic acid 3 shown in a kind of formula (I) and preparation method thereof, first substituted cinnamic acid and thionyl chloride are reacted to obtain substituted cinnamoyl chloride, then it is condensed to yield logical formula (I) compound with the oxime of lithocholic acid 3 in the presence of acid binding agent, gained compound has to PTP 1B (PTP1B) inhibitory activity, available for preparing antidiabetic medicine.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of lithocholic acid -3- oxime ester compounds and preparation method thereof,
As well as PTP 1B (PTP1B) application and prepare treat type ii diabetes medicine in apply.
Background technology
Diabetes are one of major diseases of serious threat human health.Because the origin cause of formation is different, diabetes can be divided into four classes,
I.e.：I type, II type, gestational diabetes mellitus and other types.Wherein type II diabetes is also referred to as non-insulin-depending type, accounts for sugar
Urinate more than the 90% of patient.Instantly diversified trend is presented in Remedies for diabetes and its action target, wherein to pancreas islet
The regulation and control of plain signal path are one of these medicine important function mechanism.Research show in insulin signaling pathway one it is crucial
Regulatory mechanism is the protein-tyrosine to insulin receptor (IR), IRS (IRS) and other downstream molecules
Phosphorylation carries out reversible regulation.PTP 1B (PTP1B) is turned into by the dephosphorylation effect to IR and IRS
In vivo lower insulin signaling main path, so as to find with develop the micromolecular compound with PTP1B inhibitory activity into
For the important research direction of hypoglycemic medicine.
Published PTP1B inhibitor includes the compound and its derivative in synthesized micromolecule compound and natural products source
Thing, such as thiazolidine dione compounds, DF ester type compound.Cinnamic acid derivative is also proved to be effective
PTP1B inhibitor, such as Moran reports three peptides cinnamic acid derivatives (J.Am.Chem.Soc.1995,117,10787-
10788)：
Research finds that natural steroid class compound lithocholic acid (LCA) is another effective PTP1B inhibitor, its IC50Reach
12.7μM(Bioorg.Med.Chem.Lett.2012,22,7237)：
Based on the imagination of active group splicing, it is contemplated that the 3- positions that cinnamic acid structure fragment is incorporated into lithocholic acid are formed
New PTP1B inhibitor, to further enhance the latent effect of its activity and treatment anti-diabetic.
The content of the invention
The present invention on the basis of existing technology, proposes a kind of new lithocholic acid -3- oxime ester compounds and its preparation side
Method.The present invention to the 3- positions of lithocholic acid by introducing substitution cinnamoyl oxime to strengthen inhibitory action of the compound to PTP1B.
Lithocholic acid -3- oxime ester compounds of the present invention, shown in its structure such as formula (I)：
In formula (I), R H, 2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me, 3-OMe, 3-F, 3-Cl, 3-Br, 4-Me,
4-OMe、4-F、4-Cl、4-Br、2,4-Cl2、2,3-Cl2Or 3,4-Cl2；
The invention also provides the preparation method of the lithocholic acid -3- oxime ester compounds as shown in formula (I), its feature exists
In, with substituted cinnamic acid (II) for raw material, in the dichloromethane solution of thionyl chloride reaction obtain acyl chlorides (III), then with stone
Cholic acid -3- oximes (IV) are condensed to yield the compound shown in formula (I), and the reaction equation of the preparation method is as follows：
Wherein R is H, 2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me, 3-OMe, 3-F, 3-Cl, 3-Br, 4-Me, 4-
OMe、4-F、4-Cl、4-Br、2,4-Cl2、2,3-Cl2Or 3,4-Cl2；
Wherein the condensation of compound (III) and compound (IV) is in dichloromethane, 1,2- dichloroethanes, chloroform, tetrahydrochysene furan
Mutter, carried out in DMF or DMSO；And the condensation of compound (III) and compound (IV) is in acid binding agent triethylamine, pyridine, methyl pyrrole
Carried out in the presence of pyridine, N-methylmorpholine or diisopropylethylamine.
The invention also provides application of the lithocholic acid -3- oxime ester compounds as PTP1B inhibitor shown in formula (I).This
Invention also proposed lithocholic acid -3- oxime ester compounds shown in formula (I) and prepare the application in treating type II diabetes medicine, its
In, lithocholic acid -3- oxime ester compounds shown in formula (I) suppress PTP1B activity.
Brief description of the drawings
Fig. 1 is that compound tests 96 orifice plate examples to PTP1B inhibitory activity.
Embodiment
With reference to specific examples below, the present invention is described in further detail, and of the invention protects content not limit to
In following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and excellent
Point is all included in the present invention, and using appended claims as protection domain.Implement the present invention process, condition,
Reagent, experimental method etc., it is the universal knowledege and common knowledge of this area in addition to the following content specially referred to, this hair
It is bright that content is not particularly limited.
Intermediate lithocholic acid -3- oximes (IV) are to synthesize to obtain according to the method for document using lithocholic acid as initiation material.
Embodiment 1 prepares the compounds of this invention I-1 (R=H)
Cinnamic acid (II-1,5mmol) is dissolved in dichloroethanes (10mL), adds thionyl chloride (15mmol) and DMF (1
Drop), it is warming up to back flow reaction and stays overnight, reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride (III-1).
III-1 (5mmol) and intermediate compound IV (5mmol) are dissolved in dichloromethane (20mL), under ice-water bath cooling, to solution
In pyridine (10mmol) is slowly added dropwise, be stirred overnight at room temperature after dripping off, next day, add dchloromethane reaction solution after.Add
After frozen water stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography (PE with after saturated common salt water washing：
EA=10：1) product I-1 is obtained.1H NMR(400MHz,CDCl3) δ 7.74 (d, J=15.8Hz, 1H), 7.45-7.49 (m, 2H),
7.27-7.33 (m, 3H), 6.44 (d, J=15.9HZ, 1H), 3.01 (d, J=13.3Hz, 0.5H), 2.83 (d, J=
13.2Hz, 0.5H), 2.57 (t, J=13.9Hz, 0.5H), 0.91 (s, 3H), 0.86 (d, J=4.6Hz, 3H), 0.60 (s,
3H).
Embodiment 2 prepares the compounds of this invention I-2 (R=2-Me)
2- methyl cinnamic acids (II-2,5mmol) are dissolved in dichloroethanes (10mL), add thionyl chloride (15mmol) and
DMF (1 drop), is warming up to back flow reaction and stays overnight, and reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride
(III-2)。
III-2 (5mmol) and intermediate compound IV (5mmol) are dissolved in DMSO (20mL), under ice-water bath cooling, delayed into solution
It is slow that triethylamine (10mmol) is added dropwise, it is stirred overnight at room temperature after dripping off, next day, after adding ethyl acetate dilute reaction solution.Add frozen water
After stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography (PE with after saturated common salt water washing：EA=
10：1) product I-2 is obtained.1H NMR(400MHz,CDCl3) δ 8.08 (d, J=15.8Hz, 1H), 7.58 (s, 3H), 7.21-7.29
(m, 3H), 6.43 (dd, J=15.6HZ, J=5.7Hz, 1H), 3.08 (d, J=13.0Hz, 0.5H), 2.91 (d, J=
13.0Hz, 0.5H), 2.65 (t, J=14.2Hz, 0.5H), 2.45 (s, 3H), 0.99 (s, 3H), 0.92 (d, J=4.5Hz,
3H),0.68(s,3H).
Embodiment 3 prepares the compounds of this invention I-3 (R=4-Cl)
4- chloro-cinnamic acids (II-3,5mmol) are dissolved in dichloroethanes (10mL), add thionyl chloride (15mmol) and DMF
(1 drop), is warming up to back flow reaction and stays overnight, and reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride (III-
3)。
III-3 (5mmol) and intermediate compound IV (5mmol) are dissolved in tetrahydrofuran (20mL), under ice-water bath cooling, to solution
In 2- picolines (10mmol) are slowly added dropwise, be stirred overnight at room temperature after dripping off, next day, after adding ethyl acetate dilute reaction solution.
After adding frozen water stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography with after saturated common salt water washing
(PE：EA=10：1) product I-3 is obtained.1H NMR(400MHz,DMSO-d6)δ12.0(brs,1H),7.79 -7.81(m,2H),
7.72 (d, J=16.1Hz, 1H), 7.50 (d, J=8.4Hz, 2H), 6.78 (dd, J1=16.1Hz, J2=7.2 Hz, 1H),
2.96 (d, J=13.9Hz, 0.5H), 2.82 (d, J=11.1Hz, 0.5H), 2.71 (t, J=13.6Hz, 0.5H), 2.42 (t,
J=13.9Hz, 0.5H), 0.94 (s, 3H), 0.87 (d, J=6.3Hz, 3H), 0.63 (s, 3H)
Embodiment 4 prepares the compounds of this invention I-4 (R=4-OMe)
4- methoxy cinnamic acids (II-4,5mmol) are dissolved in dichloroethanes (10mL), add thionyl chloride (15mmol)
With DMF (1 drop), it is warming up to back flow reaction and stays overnight, reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride
(III-4)。
III-4 (5mmol) and intermediate compound IV (5mmol) are dissolved in dichloromethane (20mL), under ice-water bath cooling, to solution
In N-methylmorpholine (10mmol) is slowly added dropwise, be stirred overnight at room temperature after dripping off, next day, after the dilute reaction solution that adds methylene chloride.
After adding frozen water stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography with after saturated common salt water washing
(PE：EA=10：1) product I-4 is obtained.1H NMR(400MHz,CDCl3) δ 7.75 (d, J=15.9Hz, 1H), 7.51 (d, J=
7.6Hz, 2H), 6.91 (d, J=8.1Hz, 2H), 6.38 (dd, J1=15.8Hz, J2=5.6Hz, 1H), 3.85 (s, 3H),
3.08 (d, J=13.6Hz, 0.5H), 2.92 (d, J=12.1Hz, 0.5H), 2.64 (t, J=13.5Hz, 0.5H), 0.99 (s,
3H), 0.92 (d, J=4.5Hz, 3H), 0.67 (s, 3H)
Embodiment 5 prepares the compounds of this invention I-5 (R=4-F)
4- fluoro cinnamic acids (II-5,5mmol) are dissolved in dichloroethanes (10mL), add thionyl chloride (15mmol) and DMF
(1 drop), is warming up to back flow reaction and stays overnight, and reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride (III-
5)。
III-5 (5mmol) and intermediate compound IV (5mmol) are dissolved in dichloroethanes (20mL), under ice-water bath cooling, to solution
In 3- picolines (10mmol) are slowly added dropwise, be stirred overnight at room temperature after dripping off, next day, after adding dichloroethanes dilute reaction solution.
After adding frozen water stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography with after saturated common salt water washing
(PE：EA=10：1) product I-5 is obtained.1H NMR(400MHz,CDCl3)δ7.70-7.78(m,1H),7.51-7.56 (m,2H),
7.07-7.11 (m, 2H), 6.34-6.47 (m, 1H), 3.07 (d, J=13.8Hz, 0.5H), 2.90 (d, J=11.8Hz,
0.5H), 2.64 (t, J=13.5Hz, 0.5H), 0.99 (s, 3H), 0.93 (d, J=5.1Hz, 3H), 0.68 (s, 3H)
Embodiment 6 prepares the compounds of this invention I-6 (R=2,4-Cl2)
4- fluoro cinnamic acids (II-6,5mmol) are dissolved in dichloroethanes (10mL), add thionyl chloride (15mmol) and DMF
(1 drop), is warming up to back flow reaction and stays overnight, and reaction solution is concentrated under reduced pressure into dry by next day, obtains oily intermediate cinnamoyl chloride (III-
6)。
III-6 (5mmol) and intermediate compound IV (5mmol) are dissolved in tetrahydrofuran (20mL), under ice-water bath cooling, to solution
In 4- picolines (10mmol) are slowly added dropwise, be stirred overnight at room temperature after dripping off, next day, after adding dichloroethanes dilute reaction solution.
After adding frozen water stirring 1h, divide and go aqueous phase, organic phase is dried, filtered, is concentrated under reduced pressure, column chromatography with after saturated common salt water washing
(PE：EA=10：1) product I-6 is obtained.1H NMR(400MHz,CDCl3) δ 8.09 (d, J=16.0Hz, 1H), 7.57-7.60 (m,
1H),7.46(s,1H),7.28(s,1H),6.49(dd,J1=16.0Hz, J2=5.7Hz, 1H), 3.06 (d, J=13.6Hz,
0.5H), 2.89 (d, J=12.1Hz, 0.5H), 2.64 (t, J=13.5Hz, 0.5H), 0.99 (s, 3H), 0.93 (d, J=
4.5Hz,3H),0.68(s,3H).
The compounds of this invention I PTP1B inhibitory activity test on the molecular level of embodiment 7
PTP1B enzymes for screening are the gst fusion proteins from expression in escherichia coli and purifying.PTP1B hydrolyzes substrate
The product that the phosphide of 4-NPP (pNPP) obtains has very strong light absorbs at 405nm, thus can pass through inspection
Survey the effect of the activity and compound of absorbance test reaction enzyme at 405nm to enzyme.
Material and instrument
The substrate p-nitrophenylphosphate (pNPP) used during test purchased from Calbiochem (San Diego,
CA, USA)；The automatic sample-adding system used is available from Beckman (Fullerton, CA, the U.S.A.) Hes of Biomek 2000
Purchased from Robbins Scientific Hydra96；The 96- holes polypropylene ELISA Plate used and 96 orifice plates it is ultraviolet/vis spectroscopy
Photometer SpectraMAX 340 and Flexstation II 384 respectively purchased from Greiner (Epsom, Surrey KT199AP,
) and Molecular Devices (Sunnyvale, CA, U.S.A.) UK.
Preparation of samples
1mg samples are dissolved in 200mL DMSO, liquid storage of the obtained solution as 5g/mL.20 are taken from the liquid storage
ML is into the A2-H11 sample wells of 96 hole polypropylene boards, then adds 80mL DMSO thereto, is well mixed, as 1 g/mL
Sample motherboard (Figure 26).The automatic sample-adding systems of Biomek 2000 shift 2mL samples to 96 hole polyphenyl second from the motherboard
In alkene plate, the sample daughter board as screening
As shown in Figure 1
The high flux screening of PTP1B inhibitor
With Na3VO4The aqueous solution as positive control, into sample well plus 2mLDMSO, but be not added with other any reagents or
Sample, as blank control, detected according to the method described above.
After detection, the average value of 8 blank control enzyme reaction initial velocity is calculated, as full activity, is then calculated
The relative activity of various kinds sample wells enzyme reaction, last complete active (100%) subtract relative activity and obtain suppression percentage.By
After the data processing that Excel softwares are carried out, the result finally shown is the suppression percentage of each sample well.Afterwards, from primary dcreening operation
As a result the middle sample for choosing inhibiting rate 50%, carries out follow-up secondary screening.
Secondary screening and IC50Measure
Take 2mL into 96 orifice plates (in the final concentration of 20g/mL of reaction system) from the daughter board that concentration is 1mg/mL, and
Two multiple holes are set to each compound, again the inhibitory activity of detection compound, the same primary dcreening operation of detection method of secondary screening.Finally with
Relative activity is mapped to compound concentration, is fitted through Graphpad softwares, IC is calculated50Value.
PTP1B inhibitory activity (the IC of the compound of table 150)
Claims (5)
1. a kind of lithocholic acid -3- oxime ester compounds, it is characterised in that shown in the compound structure such as formula (I)：
In formula (I), R H, 2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me, 3-OMe, 3-F, 3-Cl, 3-Br, 4-Me, 4-
OMe、4-F、4-Cl、4-Br、2,4-Cl2、2,3-Cl2Or 3,4-Cl2。
2. the preparation method of the lithocholic acid -3- oxime ester compounds shown in formula (I) as claimed in claim 1, it is characterised in that to take
Be raw material for cinnamic acid (II), in the dichloromethane solution of thionyl chloride reaction obtain acyl chlorides (III), then with lithocholic acid -3-
Oxime (IV) is condensed to yield the compound shown in formula (I), and the reaction equation of the preparation method is as follows：
Wherein R is H, 2-Me, 2-OMe, 2-F, 2-Cl, 2-Br, 3-Me, 3-OMe, 3-F, 3-Cl, 3-Br, 4-Me, 4-OMe, 4-
F、4-Cl、4-Br、2,4-Cl2、2,3-Cl2Or 3,4-Cl2。
3. preparation method as claimed in claim 2, it is characterised in that the condensation of compound (III) and compound (IV) is molten
Carried out in agent dichloromethane, 1,2- dichloroethanes, chloroform, tetrahydrofuran, DMF or DMSO；And compound (III) and compound
(IV) condensation is carried out in the presence of acid binding agent triethylamine, pyridine, picoline, N-methylmorpholine or diisopropylethylamine.
4. lithocholic acid -3- oxime ester compounds shown in formula (I) as claimed in claim 1 are in treatment type II diabetes medicine is prepared
Using, it is characterised in that it is living that lithocholic acid -3- oxime ester compounds shown in formula (I) suppress PTP 1B (PTP1B)
Property.
5. lithocholic acid -3- oxime ester compounds are as PTP 1B shown in formula (I) as claimed in claim 1
(PTP1B) application of inhibitor.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB996256A (en) * | 1964-04-07 | 1965-06-23 | Searle & Co | Steroid compounds |
| US3211756A (en) * | 1963-07-23 | 1965-10-12 | Searle & Co | 3-hydroxyimino-17alpha-(lower alkyl)-5alpha-androstan-17beta-ols and the optionally substituted 3-acyloxyimino and 3-alkoxyimino derivatives corresponding |
| US3299107A (en) * | 1965-02-12 | 1967-01-17 | Searle & Co | 17-(unsaturated hydrocarbon-substituted)-3-hydroxyimino-5alpha-androstan-17beta-ols,alkyl and acyl derivatives thereof |
| US3409609A (en) * | 1964-12-24 | 1968-11-05 | Sterling Drug Inc | Adrostano-pyridines and their preparation |
| US3415818A (en) * | 1965-07-08 | 1968-12-10 | Sterling Drug Inc | Dioximidoandrostanes and cyclized n-oxides derived therefrom |
-
2017
- 2017-06-06 CN CN201710416767.6A patent/CN107383146A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3211756A (en) * | 1963-07-23 | 1965-10-12 | Searle & Co | 3-hydroxyimino-17alpha-(lower alkyl)-5alpha-androstan-17beta-ols and the optionally substituted 3-acyloxyimino and 3-alkoxyimino derivatives corresponding |
| GB996256A (en) * | 1964-04-07 | 1965-06-23 | Searle & Co | Steroid compounds |
| US3409609A (en) * | 1964-12-24 | 1968-11-05 | Sterling Drug Inc | Adrostano-pyridines and their preparation |
| US3299107A (en) * | 1965-02-12 | 1967-01-17 | Searle & Co | 17-(unsaturated hydrocarbon-substituted)-3-hydroxyimino-5alpha-androstan-17beta-ols,alkyl and acyl derivatives thereof |
| US3415818A (en) * | 1965-07-08 | 1968-12-10 | Sterling Drug Inc | Dioximidoandrostanes and cyclized n-oxides derived therefrom |
Non-Patent Citations (3)
| Title |
|---|
| EDMUND J. MORAN ET AL: "Radio Frequency Tag Encoded Combinatorial", 《J. AM. CHEM. SOC.》 * |
| HAI-BING HE ET AL: "Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 刘华文 等: "新型苦参碱肟酯类化合物的合成", 《合成化学》 * |
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