CN104910239A - Pentacyclic triterpene compound and its preparation method, its pharmaceutical composition and purpose thereof - Google Patents
Pentacyclic triterpene compound and its preparation method, its pharmaceutical composition and purpose thereof Download PDFInfo
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- 0 CC([C@](*)(CC1)C(C(CC2)[C@@](C)(CC3)C(C)(CC4)C2C2(C)C4C(C)(C)CCC2)C13C(OCc1ccccc1)=O)OC Chemical compound CC([C@](*)(CC1)C(C(CC2)[C@@](C)(CC3)C(C)(CC4)C2C2(C)C4C(C)(C)CCC2)C13C(OCc1ccccc1)=O)OC 0.000 description 5
- FELCJAPFJOPHSD-CHIKYJCJSA-N CC(C)(C(CC1)[C@](C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C([C@@H](CC3)C(C)=C)C13C=O)C2O Chemical compound CC(C)(C(CC1)[C@](C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C([C@@H](CC3)C(C)=C)C13C=O)C2O FELCJAPFJOPHSD-CHIKYJCJSA-N 0.000 description 1
- XNKSBKDFGVJZAV-UHFFFAOYSA-N CC(C)(C)CC(C)(C)C(C1N)SCC1N Chemical compound CC(C)(C)CC(C)(C)C(C1N)SCC1N XNKSBKDFGVJZAV-UHFFFAOYSA-N 0.000 description 1
- MIJYXULNPSFWEK-XCHAOHBRSA-N CC(C)(CC1)CC2C3=CC[C@H](C(C)(CC4)C(CC5)C(C)(C)C4O)C5(C)[C@]3(C)CC[C@@]12C(O)=O Chemical compound CC(C)(CC1)CC2C3=CC[C@H](C(C)(CC4)C(CC5)C(C)(C)C4O)C5(C)[C@]3(C)CC[C@@]12C(O)=O MIJYXULNPSFWEK-XCHAOHBRSA-N 0.000 description 1
- FDAMQLMUWHVOAK-AWRGFOENSA-N CC(C)([C@H](CC1)C(C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C(C(CC3)C(C)=O)C13C(OCC1=CC=CCC1)=O)[C@@H]2O Chemical compound CC(C)([C@H](CC1)C(C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C(C(CC3)C(C)=O)C13C(OCC1=CC=CCC1)=O)[C@@H]2O FDAMQLMUWHVOAK-AWRGFOENSA-N 0.000 description 1
- DSEHWDFPVDXKQM-UHFFFAOYSA-N CC(C)NC(C)=N Chemical compound CC(C)NC(C)=N DSEHWDFPVDXKQM-UHFFFAOYSA-N 0.000 description 1
- NJKLGKIQAGLPJC-YOGZGRLRSA-N CC(C)[C@H](CC1)[C@@](C)(C(CC2)[C@@](C)(CC3)[C@](C)(CC4)[C@H]2[C@@](C)(CC2)[C@@H]4C(C)(C)[C@H]2O)[C@]13C(O)=O Chemical compound CC(C)[C@H](CC1)[C@@](C)(C(CC2)[C@@](C)(CC3)[C@](C)(CC4)[C@H]2[C@@](C)(CC2)[C@@H]4C(C)(C)[C@H]2O)[C@]13C(O)=O NJKLGKIQAGLPJC-YOGZGRLRSA-N 0.000 description 1
- VYQXYZSSZXVMPB-UHFFFAOYSA-N CCC(C)(C)C(C1N)SCC1N Chemical compound CCC(C)(C)C(C1N)SCC1N VYQXYZSSZXVMPB-UHFFFAOYSA-N 0.000 description 1
- DUJYURPBUJBNOU-UYMPWHIGSA-N CCC(C)C(C(CC1)C(C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C(C(CC3)C(C)C)C13C(C)OCc1ccccc1)C2O Chemical compound CCC(C)C(C(CC1)C(C)(CC2)C(CC3)C1(C)[C@](C)(CC1)C3C(C(CC3)C(C)C)C13C(C)OCc1ccccc1)C2O DUJYURPBUJBNOU-UYMPWHIGSA-N 0.000 description 1
- NPBCMXATLRCCLF-RSSZJYSTSA-N CC[C@H]([C@H](C[C@@H](CC1)O)[C@@]1(C)C(C1)C2C(CC[C@@H]3[C@H](C)C[C@H](C)C(O)=O)[C@]3(C)[C@H]1O)[C@H]2O Chemical compound CC[C@H]([C@H](C[C@@H](CC1)O)[C@@]1(C)C(C1)C2C(CC[C@@H]3[C@H](C)C[C@H](C)C(O)=O)[C@]3(C)[C@H]1O)[C@H]2O NPBCMXATLRCCLF-RSSZJYSTSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention relates to a pentacyclic triterpene compound shown in a general formula (1) and its preparation method, its pharmaceutical composition containing the compound, a purpose of the compound in preparation of medicine for treating type 2 diebetes, and an application of the compound for treating type 2 diebetes.
Description
Technical field
The present invention relates to a class TGR5 (G-protein coupling cholic acid membrane receptor) agonist, in particular to a class pentacyclic triterpenoid, and preparation method thereof, and comprise the pharmaceutical composition of described compound, and described compounds can be used as TGR5 agonist.
Background technology
Diabetes cause islet beta cell function to go down by different pathogeny (as Yi passes Yin Su ﹑ immunologic function Wen Luan ﹑ infected by microbes and Du Su ﹑ Zi You Ji ﹑ mental element thereof etc.) and (or) body cell causes insulin resistant take blood sugar increasing as the metabolism disturbance syndrome of feature.According to IDF (International Diabetes Federation, IDF) statistics, have the diabetic subject of more than 4,300 ten thousand in China in 2010 crowd of 20 ~ 79 years old, morbidity reaches 4.5%.Diabetes have become the disease of harm humans safety and Health.
At present, the medicine for the treatment of diabetes mainly contains insulin secretion stimulators (sulphur acyl urea class ﹑ repaglinide) ﹑ euglycemic agent (two guanidine class ﹑ thiazolidinediones) and alpha-glucosidase inhibitor (acarbose), but they often have side effect in various degree, as Di Xue Tang ﹑ Ti heavy Zeng Jia ﹑ cardiovascular side effects etc.Developmental function avoids the antidiabetic thing of traditional antidiabetic medicine side effect very urgent in new Ba Dian ﹑.
TGR5 is a kind of g protein coupled receptor (GPCR) being expressed in brown adipose tissue and muscle.TGR5 was found to be the special receptor of bile acide endogenous metabolites in 2002, and before this, and it is considered to for a long time can the washing agent of dissolved fat Suan ﹑ liposoluble vitamin and cholesterol, and then impels their digestion to transport.Therefore it has only been endowed limited treatment use.Before TGR5 is found, orphan's farnesoid X receptor (FXR) is the uniquely known acceptor activated by cholic acid analogue.By the activation to TGR5, cholic acid can stimulate 2 types to take off the activation of iodine enzyme, thus causes mitochondrial function to increase and energy expenditure.Also, after having report to prove that TGR5 is activated by cholic acid, can cause secreting glucagon-like peptide 1 (GLP1) in the strain of mouse enteroendocrine cell.These data show that TGR5 is the important target spot for the treatment of diabetes and related metabolic disturbance.
TGR5 agonist known at present mainly comprises two large classes.One class is chemosynthesis small molecules.Although this compounds agonist activity is mostly very strong, some even has the EC lower than 10nM
50value, but TGR5 acceptor on the strong activation gall-bladder caused due to this compounds thus cause smooth muscle loosening, promote that gall-bladder fills, so there is the side effect of serious increase gall-bladder volume.Another kind of natural product quasi-molecule, comprising steroid and other types natural product, although active, synthetic molecules is more weak relatively, and due to its structural advantage, this compounds can overcome the gall-bladder toxicity of chemosynthesis molecule.Wherein the most noticeablely surely belong to INT-777 (.J.Med.Chem.2009 such as Pellicciari, R., 52,7958-7961), this is the derivative of cholic acid, and reaching EC50 to the agonist activity of TGR5 is 0.82nM, enters clinical stage at present.But Compound I NT777 has the shortcoming of preparation difficulty, and take cholic acid as starting point, synthetic route reaches 12 steps, and repeatedly use very harsh reaction conditions.Contriver is devoted for years in the structure of modification based on Compound I NT777, to expect to find that activity is better, the Novel diabetes medicine that toxicity is lower.The invention discloses a class pentacyclic triterpenoid, its principal feature is the reversion of 3 hydroxyls, after being reversed to α type hydroxyl by the β type hydroxyl of natural product Betulinic acid etc., its TGR5 agonist activity obviously increases, and along with the transformation in these other sites of series compound, it is also different that the activity after hydroxyl reversion improves degree.The invention discloses the affecting laws of this structure to activity, and obtain the compound of a series of excellent performance, compared with INT777, not only synthesize easy, and the agonist activity of its TGR5 is obviously better than INT777, be expected to become the newtype drug of the treatment type-II diabetes acting on this target spot.
Summary of the invention
The object of the invention is to the pentacyclic triterpenoid that Design and synthesis has general formula (I) described structure.
Another object of the present invention is to the preparation method that described compound is provided.
An also object of the present invention is to provide a kind of containing the pharmaceutical composition of described compound as activeconstituents.
Another object of the present invention is to provide the application of compound of the present invention in the medicine of preparation treatment type-II diabetes.
Another object of the present invention is to provide the application of compound of the present invention in treatment diabetes.
The invention provides a kind of pentacyclic triterpenoid, it has the structure shown in following general formula (I):
Wherein:
R
1for hydrogen, hydroxyl, halogen or C
1-C
6alkyl;
R
2for hydrogen, hydroxyl, halogen, oxo group (=O) ,=N-OH, C
1-C
6alkyl-carbonyl oxygen groups, 3 to 8 ring alkyl-carbonyl oxygen groups, C
1-C
6alkyl, 3 to 8 yuan of cycloalkyl or
wherein, Rc is C
1-C
6alkyl or hydrogen;
R
3and R
8be hydrogen independently of one another; Hydroxyl; Halogen; By C
1-C
6the amino C that alkyl replaces
1-C
6alkyl; The C not replacing or replace
1-C
6alkyl, wherein, the C of replacement
1-C
6substituting group in alkyl is selected from hydroxyl, halogen, oxo group (=O) ,=N-OH, propylene oxide base, amino and hydroxyl C
1-C
6more than one substituting group in alkylamino; Do not replace or replace C
1-C
6alkenyl, wherein, the C of replacement
1-C
6alkenyl comprises and is selected from hydroxyl, halogen, oxo group (=O) ,=N-OH, amino and hydroxyl C
1-C
6more than one substituting group in alkylamino;
Wherein, R
9for H, C
1-C
6alkyl, C
1-C
6alkoxyl group, hydroxyl, hydroxyl C
1-C
6alkyl ,-CH
2oC (O) R
10,-CH
2oC (O) OR
11,-CH
2oC (O) CH
2oR
12;
R
10, R
11and R
12be substituted or unsubstituted 5 to 8 yuan of aryl independently of one another; Substituted or unsubstituted 3 to 8 yuan of cycloalkyl; 5 to 8 yuan of arylaminos; Comprise at least one heteroatomic 5 to the 8 yuan of heteroaryl in N, S or O; C
1-C
6alkyl, halo C
1-C
6alkyl; Hydroxyl C
1-C
6alkyl;
bocNH (CH
2)
mo (CH
2)
n-, wherein, each m and n is identical or different, and is the integer of 1 to 6 independently of one another; Wherein, the substituting group in 5 to 8 yuan of aryl of replacement or 3 to 8 yuan of cycloalkyl of replacement is selected from hydroxyl, halogen, C
1-C
6alkyl, C
1-C
6more than one substituting group in alkoxyl group;
R
4for hydrogen, hydroxyl, halogen or C
1-C
6alkyl;
R
5independently selected from hydrogen; Hydroxyl; Hydroxyl C
1-C
6alkyl; Halogen; C
1-C
6alkyl;-C (O) R
13;-C (O) O (CH
2cH
2o)
ocH
2cH
2r
14;-C (O) NH (CH
2cH
2o)
pcH
2cH
2r
15; Or-C (O) NH (CH
2)
qc (O) OH; Wherein, o and p is separately 0,1,2 or 3; And q is the integer of 3 to 8;
R
13for hydrogen; Hydroxycarbonyl group C
1-C
8alkylamino; Hydroxyl; Unsubstituted or by C
1-C
6the piperazinyl that alkyl replaces; Benzyl oxygen groups; C
1-C
6alkoxyl group; Tert-butoxycarbonyl C
1-C
6alkyl oxy; Or hydroxycarbonyl group C
1-C
6alkylamino;
R
14and R
15be independently hydrogen; Amino; 5-(2-oxo six hydrogen-1H-thieno-[3,4-d] imidazol-4 yl) valeryl amido; C
1-C
6amide group; Tert.-butoxy formamido-; Or C
1-C
6alkoxyl group;
R
6and R
7be hydrogen, hydroxyl, halogen, hydroxycarbonyl group or C independently of one another
1-C
6alkoxy carbonyl;
R
aand R
bbe hydrogen, hydroxyl, halogen, C independently of one another
1-C
6alkyl or hydroxyl C
1-C
6alkyl;
Z is methylene radical or direct key;
represent singly-bound or double bond.
Further preferably, R
3and R
8be independently of one another hydrogen, hydroxyl, methyl, ethyl,
In the present invention unless otherwise noted,
represent connection site;
Preferably, R
5for methyl, carboxaldehyde radicals ,-COOH, methoxycarbonyl,
In a preferred embodiment of the invention, further preferably, general formula of the present invention (I) has the structure shown in following general formula (II):
Each substituent definition in general formula (II) is identical with the definition in general formula (I).
Further preferably, general formula of the present invention (I) has following general formula (III) or the structure shown in (IV):
Wherein, in general formula (III) or (IV), each substituent definition is identical with the definition in general formula (I).
In the description, term " C
1-C
6alkyl " can be straight or branched C
1-C
6alkyl especially, can be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, neo-pentyl or hexyl; Be preferably straight or branched C
1-C
3alkyl.
In the description, term " 5 to 8 yuan of aryl " is the group with aromaticity of 5 to 8 rings, is preferably phenyl;
In the description, term " 5 to 8 yuan of cycloalkyl " for having the cycloalkyl of 5 to 8 rings, particularly, Ke Yiwei, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group;
The pentacyclic triterpenoid of general formula of the present invention (I) structure is specially:
According on the other hand, the invention provides the preparation method of the compound shown in general formula (I).
Described preparation method comprises following syntheti c route:
Route one:
Route two:
Route three:
Specifically, Dess-Martin oxidizing reaction is there is in compound 2 in methylene dichloride, obtain compound 16, then in the tetrahydrofuran (THF) of drying, under the catalysis of (S)-CBS, be obtained by reacting with borine the compound 17 that 3-OH reverses, final compound 17 catalytic hydrogenation in methyl alcohol is sloughed benzyl and is obtained compound 1 ', compound 1 ' is obtained by reacting compound 2 ' with alcohol or amine, and compound 2 ' obtains compound 3 ' with acid or acyl chloride reaction;
Route four:
Wherein, R
16and R
17be respectively hydrogen, C
1-C
6alkyl or hydroxyl C
1-C
6alkyl;
R
18for C
1-C
6alkyl; All the other substituting groups are identical with the definition in general formula (I).
Present invention also offers a kind of pharmaceutical composition for the treatment of type-II diabetes, said composition comprises in the pentacyclic triterpenoid shown in one or more general formulas of the present invention (I) as activeconstituents.Described composition also can comprise pharmaceutically conventional assistant agent, such as dispersion agent, vehicle, disintegrating agent, antioxidant, sweeting agent, Drug coating etc. further.
According to a further aspect in the invention, the application of the compound shown in general formula (I) in the medicine of preparation treatment type-II diabetes is provided.
According to another aspect of the invention, the application of the compound shown in general formula (I) as TGR5 agonist is provided.
In accordance with a further aspect of the present invention, the application of the compound shown in general formula (I) in treatment diabetes is provided.
Beneficial effect
The pentacyclic triterpenoid that Design and synthesis of the present invention one class is novel, can effective exciting TGR5, and have the medicine for making treatment type-II diabetes, overcome the defects such as the gall-bladder toxicity existing for existing chemosynthesis small molecules class TGR5 agonist, and have more easy synthetic method and more gentle reaction conditions relative to positive control INT777.The raw material of pentacyclic triterpenoid of the present invention, at occurring in nature abundance, has the structural advantage of natural product.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to these embodiments.
Compound prepares embodiment
In following preparation embodiment, the Mercury-Vx 300M Instrument measuring that NMR produces with Varian, NMR calibrates: δ H 7.26ppm (CDCl
3), 2.50ppm (DMSO-d
6); Mass spectrum Agilent 1200 Quadrupole LC/MS LC-MS instrument or SHIMADZU GCMS-QP5050A measure; Reagent provides primarily of Solution on Chemical Reagents in Shanghai company; TLC tlc silica gel plate is produced by Yantai, Shandong fellow member of an association or organization's silica gel development corporation, Ltd., model HSGF 254; The normal phase column chromatography silica gel that compound purifying uses is the production of Qingdao subsidiary factory of marine chemical industry factory, model zcx-11,200-300 order.
Preparation embodiment one (compound number: C33)
(1) Betulinic acid benzyl ester
By raw material Betulinic acid (4g under room temperature, 8.76mmol) (purchased from Hao Xuan bio tech ltd, Xi'an) is dissolved in DMF (50mL), add Anhydrous potassium carbonate (2.4g, 17.37mmol), slowly drip under stirring and after Benzyl Chloride (1.2mL, 10.52mmol) dropwises, reaction solution is moved to 50 DEG C of stirrings and spend the night.Next day, mixture is cooled to room temperature, add deionized water 100mL to dilute, extract by ethyl acetate (2 × 100mL), the organic layer of merging is used respectively deionized water and saturated common salt water washing, after dried over sodium sulfate, also underpressure distillation obtains required compound as white solid Betulinic acid benzyl ester (4.62g), molar yield: 97%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 4.75 (s, 1H), 4.62 (s, 1H), 3.21-3.15 (m, 1H), 2.92-2.80 (m, 1H), 2.10-1.90 (m, 2H), 1.87-1.69 (m, 2H), 1.64 (s, 3H), 1.64-0.96 (m, other cycloaliphatic ring proton), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 569.4 (M+Na)
+(C
37h
54o
3theoretical value: 546.41).
(2) 3-carbonyl Betulinic acid benzyl ester
Under ice-water bath, upper step product (4.62g, 8.64mmol) is dissolved in methylene dichloride (100mL), adds Dess-Martin oxygenant (4.3g, 10.15mmol) in batches, slowly rise to rt while stirring overnight.Next day, be spin-dried for after being filtered by reaction mixture, carrying out column chromatography for separation by the eluent system that petrol ether/ethyl acetate is 20:1, obtain compound 3-carbonyl Betulinic acid benzyl ester (4.39g), is white solid, molar yield: 95%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 4.75 (s, 1H), 4.62 (s, 1H), 2.92-2.80 (m, 1H), 2.49-2.39 (m, 2H), 2.10-2.04 (m, 2H), 1.92-1.80 (m, 2H), 1.78-1.68 (m, 2H), 1.65 (s, 3H), 1.50-1.16 (m, other cycloaliphatic ring proton), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 567.3 (M+Na)
+(C
37h
52o
3theoretical value: 544.39).
(3) 3-Alpha-hydroxy Betulinic acid benzyl ester
In the round-bottomed flask that 100mL is dried, add upper step product (1.58g, 2.90mmol) and S-(-)-2-methyl oxazaborolidine (80mg, 0.29mmol), and add the THF (50mL) of fresh sodium silk process.Slowly drip the borine-tetrahydrofuran solution (0.32mL) of 10M under room temperature, control rate of addition, add, stirred at ambient temperature ten minutes in ten minutes, TLC monitoring display reaction completes.Reaction flask is moved to ice-water bath, slowly drip methyl alcohol cancellation reaction, solvent is spin-dried for after no longer including bubble formation, column chromatography for separation is carried out by the eluent system that petrol ether/ethyl acetate is 20:1, obtain compound 3-Alpha-hydroxy Betulinic acid benzyl ester (790mg), for white solid, molar yield: 50%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 4.73 (s, 1H), 4.60 (s, 1H), 3.39 (s, 1H), 3.02-2.96 (m, 1H), 2.28-2.16 (m, 2H), 1.98-1.95 (m, 2H), 1.68 (s, 3H), 1.64-0.96 (m, other cycloaliphatic ring proton), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 569.4 (M+Na)
+(C
37h
54o
3theoretical value: 546.41).
(4) 3-Alpha-hydroxy Betulinic acid
Upper step product (100mg, 0.18mmol) is dissolved in methyl alcohol (8mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen, it is that the eluent system of 10:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, and obtaining Compound C 33 (78mg), is white solid, molar yield: 94%.
1h NMR (300MHz, CDCl
3) δ 4.73 (s, 1H), 4.60 (s, 1H), 3.39 (s, 1H), 3.02-2.96 (m, 1H), 2.28-2.16 (m, 2H), 1.98-1.95 (m, 2H), 1.68 (s, 3H), 1.64-0.96 (m, other cycloaliphatic ring proton), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 479.3 (M+Na)
+(C
30h
48o
3theoretical value: 456.36).
Preparation embodiment two (compound number: C34)
Betulinic acid (1.2g, 2.63mmol) is dissolved in methanol/ethyl acetate (40mL/10mL), adds the Pd/C of catalytic amount after changing nitrogen, then changes hydrogen after changing nitrogen, and stirring at room temperature 2 days, TLC detection reaction is complete.Change filtering reacting liquid after nitrogen, with sherwood oil after being spin-dried for: ethyl acetate is that the polarity of 10:1 carries out column chromatography for separation.Obtaining product C 34 is white solid (1.04g, 2.27mmol), and molar yield is 86%.
1h NMR (300MHz, CDCl
3) δ 3.13 (t, 1H, J=9.0,6.9Hz), 2.28-2.16 (m, 2H), 1.98-1.78 (m, 4H), 1.64-0.96 (m, other cycloaliphatic ring proton), 0.96 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.78 (s, 3H); ESI-MS (m/z): 481.3 (M+Na)
+(C
30h
50o
3theoretical value: 458.38).
Use the same method, respectively with different natural products or compound for raw material (raw material Oleanolic Acid: C2, raw material ursolic acid: C7, raw material glycyrrhetinic acid: C107, raw material trochol: C29, raw material: C34), according to preparing the identical method of embodiment one, synthesize following compound or intermediate:
Preparation embodiment three 3-α-acetoxyl group Betulinic acid (compound number: C97)
(1) 3-α-acetoxyl group Betulinic acid benzyl ester
3-Alpha-hydroxy Betulinic acid benzyl ester (107mg, 0.20mmol) and the DMAP (10mg of catalytic amount, 0.08mmol) be dissolved in methylene dichloride (10mL), add triethylamine (82mL, 0.60mmol), diacetyl oxide (42mL, 0.60mmol) is instilled under ice-water bath, room temperature reaction 12 hours, TLC display reaction is complete.Concentrated except after desolventizing, after diluted ethyl acetate, respectively with after water and saturated sodium-chloride water solution washing, organic phase drying is concentrated, gained resistates is obtain compound 3-α-acetoxyl group Betulinic acid benzyl ester white solid (77mg after the eluent column chromatography purification of 20:1 with petrol ether/ethyl acetate, 0.13mmol), molar yield: 65%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 4.62 (s, 1H), 2.84-2.20 (m, 4H), 2.08 (s, 3H), 1.98-1.15 (m, other cycloaliphatic ring proton), 1.01 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.76 (s, 3H), 0.74 (s, 3H); ESI-MS (m/z): 611.4 (M+Na)
+(C
39h
56o
4theoretical value: 588.42).
(2) 3-α-acetoxyl group Betulinic acid
Upper step product (77mg, 0.13mmol) is dissolved in methyl alcohol (8mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen, it is that the eluent system of 10:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, obtains compound 3-α-acetoxyl group Betulinic acid (60mg, 0.12mmol), for white solid, molar yield: 92%.
1h NMR (300MHz, CDCl
3) δ 4.62 (s, 1H), 2.84-2.20 (m, 4H), 2.08 (s, 3H), 1.98-1.15 (m, other cycloaliphatic ring proton), 1.01 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.76 (s, 3H), 0.74 (s, 3H); ESI-MS (m/z): 521.3 (M+Na)
+(C
32h
50o
4theoretical value: 498.37).
The method same by embodiment three and different acid anhydrides synthesize following compound:
Preparation embodiment four (compound number C46)
(1) 3-alpha-hydroxy-2 0,21-epoxy Betulinic acid benzyl ester
Intermediate 3-Alpha-hydroxy Betulinic acid benzyl ester (90mg, 0.17mmol) be dissolved in phosgene (10mL), metachloroperbenzoic acid (71mg is slowly added under ice-water bath, 0.34mmol) stirring at room temperature 3h afterwards, TLC detection reaction is complete, add S-WAT saturated solution cancellation reaction, wash organic phase with water, dry concentrated gained resistates petrol ether/ethyl acetate is that the eluent system of 6:1 carries out column chromatography for separation, obtain compound 3-alpha-hydroxy-2 0,21-epoxy Betulinic acid benzyl ester 74mg is white solid, molar yield: 80.4%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 3.40 (s, 1H), 2.64 (t, 2H), 2.25 (m, 2H), 2.14 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.76-1.32 (m, other cycloaliphatic ring proton), 1.28 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H); ESI-MS (m/z): 585.4 (M+Na)
+(C
37h
54o
4theoretical value: 562.40).
(2) 3-alpha-hydroxy-2 0,21-epoxy Betulinic acid
Upper step product (74mg, 0.14mmol) is dissolved in methyl alcohol (8mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen, it is that the eluent system of 6:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, obtains compound 3-alpha-hydroxy-2 0,21-epoxy Betulinic acid (38mg, 0.08mmol), be white solid, molar yield: 58%.
1h NMR (300MHz, CDCl
3) δ 3.40 (s, 1H), 2.64 (t, 2H), 2.25 (m, 2H), 2.14 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.76-1.32 (m, other cycloaliphatic ring proton), 1.28 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H); ESI-MS (m/z): 495.3 (M+Na)
+(C
30h
48o
4theoretical value: 472.36).
The method same by embodiment four synthesizes C36:
Preparation embodiment five (compound number: C48)
(1) 3-alpha-hydroxy-2 0-formyl radical Betulinic acid benzyl ester
Intermediate 3-alpha-hydroxy-2 0; 21-epoxy Betulinic acid benzyl ester (68mg; 0.12mmol) be dissolved in carbon trichloride (10mL); instill two concentrated hydrochloric acids, backflow 1h, TLC detection reaction is complete; it is that the eluent system of 4:1 carries out column chromatography for separation that convection drying concentrates gained resistates petrol ether/ethyl acetate; obtaining compound 3-alpha-hydroxy-2 0-formyl radical Betulinic acid benzyl ester 50mg, is white solid, molar yield: 73.6%.
1h NMR (300MHz, CDCl
3) δ 9.84 (s, 1H), 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 3.39 (s, 1H), 3.33 (d, 1H, J=4.2Hz), 2.40 (td, 1H, J=11.7,2.7Hz), 2.28 (td, 1H, J=11.7,2.7Hz), 2.30-2.18 (m, 2H), 1.98-1.84 (m, 2H), 1.69-0.96 (m, other cycloaliphatic ring proton), 1.11 (s, 3H), 0.93 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.78 (s, 3H); ESI-MS (m/z): 585.4 (M+Na)
+(C
37h
54o
4theoretical value: 562.40).
(2) 3-alpha-hydroxy-2 0-formyl radical Betulinic acid
Upper step product (50mg, 0.088mmol) is dissolved in methyl alcohol (5mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen; it is that the eluent system of 2:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, obtains compound 3-alpha-hydroxy-2 0-formyl radical Betulinic acid (36.7mg, 0.078mmol); for white solid, molar yield: 87.3%.
1h NMR (300MHz, CDCl
3) δ 9.84 (s, 1H), 3.39 (s, 1H), 3.33 (d, 1H, J=4.2Hz), 2.58 (m, 1H), 2.40 (m, 1H), 2.23 (m, 2H), 1.98-1.84 (m, 2H), 1.69-0.96 (m, other cycloaliphatic ring proton), 1.12 (d, 3H, J=9.0Hz), 0.96 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H); ESI-MS (m/z): 495.2 (M+Na)
+(C
30h
48o
4theoretical value: 472.36).
Preparation embodiment six (compound number: C53)
(1) 3-alpha-hydroxy-2 0-(2 '-aminoethyle alcohol base) Betulinic acid benzyl ester
Intermediate 3-alpha-hydroxy-2 0-formyl radical Betulinic acid benzyl ester (20mg, 0.036mmol) with sodium cyanoborohydride (11mg, 0.018mmol) in stirred at ambient temperature 2h, instill thanomin (11 μ L afterwards, 0.18mmol) stirred overnight at room temperature, TLC detection reaction is complete, saturated sodium bicarbonate solution cancellation is reacted, extraction into ethyl acetate twice after thin up, after saturated common salt water washing, organic phase drying is concentrated, gained resistates chloroform/methanol is that the eluent system of 20:1 carries out column chromatography for separation, obtain compound 3-alpha-hydroxy-2 0-(2 '-aminoethyle alcohol base) Betulinic acid benzyl ester 12mg, for white solid, molar yield: 60%.
1h NMR (300MHz, CDCl
3+ CD
3oD) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 3.49 (t, 2H, J=4.5Hz), 3.00 (s, 1H), 2.75 (t, 2H, J=4.5Hz), 2.57-2.46 (m, 2H), 2.10-1.85 (m, 4H), 1.55-0.90 (m, other cycloaliphatic ring proton), 0.93 (s, 3H), 0.66 (s, 3H), 0.62 (d, 3H, J=6.0Hz), 0.58 (s, 3H), 0.52 (s, 3H), 0.48 (s, 3H); ESI-MS (m/z): 608.5 (M+H)
+(C
38h
59nO
4theoretical value: 607.91).
(2) 3-alpha-hydroxy-2 0-(2 '-aminoethyle alcohol base) Betulinic acid
Upper step product (12mg, 0.020mmol) is dissolved in methyl alcohol (2mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen, it is that the eluent system of 4:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, obtain compound 3-alpha-hydroxy-2 0-(2 '-aminoethyle alcohol base) Betulinic acid (9.3mg, 0.018mmol), for white solid, molar yield: 91%.
1h NMR (300MHz, CDCl
3+ CD
3oD) δ 3.49 (t, 2H, J=4.5Hz), 3.00 (s, 1H), 2.75 (t, 2H, J=4.5Hz), 2.57-2.46 (m, 2H), 2.10-1.85 (m, 4H), 1.55-0.90 (m, other cycloaliphatic ring proton), 0.93 (s, 3H), 0.66 (s, 3H), 0.62 (d, 3H, J=6.0Hz), 0.58 (s, 3H), 0.52 (s, 3H), 0.48 (s, 3H); ESI-MS (m/z): 518.4 (M+H)
+(C
32h
55nO
4theoretical value: 517.41).
Preparation embodiment seven (compound number: C47)
(1) 3-alpha-hydroxy-2 2-hydroxyl Betulinic acid benzyl ester
Tin anhydride (22mg, 0.22mmol) with tertbutyl peroxide (165 μ L, the tetrahydrofuran solution of 5.5M) be dissolved in dry methylene dichloride (20mL), acetic acid (the 6 μ L of catalytic amount are dripped under ice-water bath, 0.1eq.), stir at this temperature after ten minutes, slowly drip intermediate 3-Alpha-hydroxy Betulinic acid benzyl ester (242mg, dichloromethane solution (5mL) 0.44mmol), slowly be warming up to rt while stirring overnight, TLC detection reaction is complete, add S-WAT saturated solution cancellation reaction, dichloromethane extraction also washes organic phase with water, dry concentrated gained resistates directly throws next step.Crude product is dissolved in methyl alcohol (20mL), add sodium borohydride (25mg under ice-water bath in batches, 0.66mmol), react after one hour, TLC detection reaction is complete, drip ammonium chloride saturated solution cancellation reaction, extraction into ethyl acetate also uses saturated common salt water washing, the concentrated rear petrol ether/ethyl acetate of organic phase drying is that the eluent system of 2:1 carries out column chromatography for separation, obtain compound 3-alpha-hydroxy-2 2-hydroxyl Betulinic acid benzyl ester 197mg, for white solid, molar yield: 79.2%.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (d, 1H, J=11.7Hz), 5.17 (d, 1H, J=11.7Hz), 4.97 (s, 1H), 4.92 (s, 1H), 4.12 (m, 2H), 3.39 (s, 1H), 2.88 (td, 1H, J=12.0,3.0Hz), 2.32-2.26 (m, 2H), 2.21-2.10 (m, 2H), 1.98-1.77 (m, 2H), 1.64-0.96 (m, other cycloaliphatic ring proton), 0.99 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 585.4 (M+Na)
+(C
37h
54o
4theoretical value: 562.40).
(2) 3-alpha-hydroxy-2 2-hydroxyl Betulinic acid
Upper step product (197mg, 0.35mmol) is dissolved in methyl alcohol (10mL) and a small amount of ethyl acetate, after changing nitrogen, adds rapidly the Pd/C of 10%, then changes hydrogen after changing nitrogen, stirring at room temperature.After one hour, TLC detection reaction is complete.Change elimination Pd/C after nitrogen, it is that the eluent system of 2:1 carries out column chromatography for separation that reaction solution is spin-dried for rear petrol ether/ethyl acetate, obtains compound 3-alpha-hydroxy-2 2-hydroxyl Betulinic acid (140mg, 0.30mmol), for white solid, molar yield: 85%.
1h NMR (300MHz, CDCl
3) δ 4.97 (s, 1H), 4.92 (s, 1H), 4.12 (m, 2H), 3.39 (s, 1H), 2.88 (td, 1H, J=12.0,3.0Hz), 2.32-2.26 (m, 2H), 2.21-2.10 (m, 2H), 1.98-1.77 (m, 2H), 1.64-0.96 (m, other cycloaliphatic ring proton), 0.99 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 495.3 (M+Na)
+(C
30h
48o
4theoretical value: 472.36).
Preparation embodiment eight (compound number C111)
Trochol (250mg, 0.56mmol), in methylene dichloride (20mL), slowly adds Dess-Martin oxygenant (718mg, 4.5mmol) under room temperature, and back flow reaction 4h, TLC detection reaction is complete.Be spin-dried for after being filtered by reaction mixture, carry out column chromatography for separation by the eluent system that petrol ether/ethyl acetate is 10:1, obtaining compound 3-carbonyl-white birch lipidal (145mg), is white solid, molar yield: 58.7%.
1h NMR (300MHz, CDCl
3) δ 9.66 (s, 1H), 4.75 (s, 1H), 4.62 (s, 1H), 2.92-2.80 (m, 1H), 2.49-2.39 (m, 2H), 2.10-2.04 (m, 2H), 1.92-1.80 (m, 2H), 1.78-1.68 (m, 2H), 1.65 (s, 3H), 1.50-1.16 (m, other cycloaliphatic ring proton), 1.04 (s, 3H), 1.00 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H); ESI-MS (m/z): 456.3 (M+Na)
+(C
30h
46o
2theoretical value: 438.35).
Preparation embodiment nine (compound number C37)
Betulinic acid (41mg, 0.09mmol), in the tetrahydrofuran (THF) (5mL) of drying, instills BH under ice-water bath
3-Me
2the tetrahydrofuran solution (2M) of S, stirs and moves to room temperature after one hour.Next day, reaction solution is moved to ice-water bath, add ethanol (280 μ L) successively, saturated acetic acid sodium solution (200 μ L), the superoxol (140 μ L) of 30%.Room temperature for overnight, TLC detection reaction is complete.Thin up, saturated common salt water washing after extraction into ethyl acetate.The concentrated rear chloroform/methanol of organic phase drying is that the eluent system of 50:1 carries out column chromatography for separation, and obtaining compound 20 (29)-reduction-29-hydroxyl Betulinic acid 19mg, is white solid, molar yield: 45.3%.
1h NMR (300MHz, CD
3oD) δ 3.73 (dd, 1H, J=9.0,3.0Hz), 3.34 (s, 1H), 3.13 (dd, 1H, J=9.0,6.0Hz), 2.36-2.12 (m, 4H), 1.83-1.08 (m, other cycloaliphatic ring proton), 0.99 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.87 (s, 3H), 0.75 (s, 3H); ESI-MS (m/z): 497.3 (M+Na)
+(C
30h
50o
4theoretical value: 474.37).
Preparation embodiment ten (compound number C115)
20 (29)-reduction Betulinic acid (37mg, 0.08mmol) with EDCI (21mg, 0.12mmol) in DMF (2mL), add triethylamine (15 μ L), HOBt (15mg, 0.12mmol) with N-Boc-2-(2-aminoethoxy) ethylamine (15mg, 0.08mmol), 50 DEG C of stirrings are spent the night.Next day, TLC detection reaction was complete, and reaction solution thin up, is extracted with ethyl acetate rear saturated common salt water washing.The concentrated rear chloroform/methanol of organic phase drying is that the eluent system of 80:1 carries out column chromatography for separation, and obtaining target compound 45mg, is white solid, molar yield: 86.5%.
1h NMR (300MHz, CDCl
3) δ 5.93 (t, 1H, J=5.1Hz), 4.84 (brs, 1H), 3.48 (m, 4H), 3.13 (dd, 1H, J=9.0,6.0Hz), 3.30 (m, 4H), 2.40 (td, 1H, J=12.0,3.0Hz), 2.23 (td, 1H, J=12.0,3.0Hz), 1.44 (s, 9H), 1.96-1.09 (m, other cycloaliphatic ring proton), 0.96 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H), 0.78 (s, 3H); ESI-MS (m/z): 667.5 (M+Na)
+(C
39h
68n
2o
5theoretical value: 644.51).
The method same by embodiment ten and different amine synthesize following compound:
Preparation embodiment 11 (compound number C39)
Intermediate 3-carbonyl-20 (29)-reduction Betulinic acid (82mg, 0.18mmol), oxammonium hydrochloride (25mg, 0.37mmol) with pyridine (37 μ L, 0.46mmol) in dehydrated alcohol (5mL), stirred overnight at room temperature, next day, TLC detection reaction was complete.Direct concentrated rear petrol ether/ethyl acetate is that the eluent system of 10:1 carries out column chromatography for separation, and obtaining target compound 77mg, is white solid, molar yield: 91.2%.
1h NMR (300MHz, CDCl
3) ClR (300MHz: slough benzyl simultaneously by reduction, obtain 0.92 (s, 3H), 0.90 (s, 3 other cycloaliphatic ring protons), 0.94 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.88 (s, 3H), 0.85 (s, 3H), 0.84 (s, 3H), 0.76 (s, 3H); ESI-MS (m/z): 494.3 (M+Na)
+(C
30h
49nO
3theoretical value: 471.37).
Preparation embodiment 12 (compound number C119)
molecular sieve and dry methylene dichloride (10mL) are placed in dry 50mL round-bottomed flask, tetra isopropyl oxygen titanium (the 1 μ L heavily steamed is instilled respectively at-20 DEG C, 0.0037mmol) with D-(-)-DIPT (1 μ L, 0.0056eq). stir THF solution (the 10 μ L adding the TBHP of 5.5M after 15 minutes, 0.056mmol), stir 30 minutes.The dichloromethane solution (2mL) of the benzyl ester (21mg, 0.037mmol) of instillation preparation embodiment seven products therefrom, is placed in-20 DEG C of refrigerator overnight again.Next day, reaction solution is warming up to zero degree, add the saturated common salt aqueous solution (50 μ L) of 5N sodium hydroxide, stir after one hour and excessively filter molecular sieve, it is that the eluent system of 2:1 carries out column chromatography for separation that filtrate is spin-dried for rear petrol ether/ethyl acetate, obtaining target compound 16mg, is white solid, molar yield: 76.2%.It is that S is configured as main product that NMR proves C-17.
1h NMR (300MHz, CDCl
3) δ 7.34 (m, 5H), 5.09 (s, 2H), 3.80-3.64 (m, 2H), 3.40 (s, 1H), (2.92 d, 1H, J=4.5Hz), (2.63 d, 1H, J=4.5Hz), 2.35-2.24 (m, 2H), 2.01-1.92 (m, 4H), 1.86-1.75 (m, 4H), 1.57-1.28 (m, other cycloaliphatic ring proton), 0.97 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H).Product directly sloughs benzyl by step above under the catalysis of palladium carbon, obtains 12mg target product, is white solid, molar yield: 89.2%.
1h NMR (300MHz, CDCl
3) δ 3.76 (d, 1H, J=12.0Hz), 3.67 (d, 1H, J=12.0Hz), 3.40 (s, 1H), (2.91 d, 1H, J=6.0Hz), (2.62 d, 1H, J=6.0Hz), 2.35-2.24 (m, 2H), 2.01-1.92 (m, 4H), 1.86-1.75 (m, 4H), 1.57-1.28 (m, other cycloaliphatic ring proton), 0.97 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H); ESI-MS (m/z): 511.3 (M+Na)
+(C
30h
48o
5theoretical value: 488.35).
Following compound is synthesized by the method that embodiment 12 is same:
Preparation embodiment 13 (compound number C75)
Benzyl ester (the 16mg of preparation embodiment 12 products therefrom, 0.028mmol) with DMAP (1mg, 0.1eq) in methylene dichloride (5ml), TEA (6 μ L are dripped successively under ice-water bath, 0.04mmol) with Acetyl Chloride 98Min. (3 μ L, 0.04mmol), stirred overnight at room temperature.Next day, TLC detection reaction was complete.Direct concentrated rear petrol ether/ethyl acetate is that the eluent system of 2:1 carries out column chromatography for separation, and obtaining target compound 14mg, is white solid, molar yield: 82.3%.Product directly sloughs benzyl by step above under the catalysis of palladium carbon, obtains 6mg target product, is white solid, molar yield: 50%.
1h NMR (300MHz, CDCl
3) δ 4.35 (d, 1H, J=12.0Hz), 4.04 (d, 1H, J=12.0Hz), 3.40 (s, 1H), 2.76 (d, 1H, J=6.0Hz), 2.66 (d, 1H, J=6.0Hz), 2.35-2.24 (m, 2H), 2.09 (s, 3H), 2.01-1.92 (m, 4H), 1.86-1.75 (m, 4H), 1.57-1.28 (m, other cycloaliphatic ring proton), 0.97 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H); ESI-MS (m/z): 553.3 (M+Na)
+(C
32h
50o
6theoretical value: 530.36).
The method same by embodiment 13 and different acyl chlorides synthesize following compound:
Preparation embodiment 14: the synthesis of Compound C 94
Compd A 2 (2mL, 19.9mmol) and triethylamine (2.8mL, 19.9mmol) in methylene dichloride (40mL), slowly drip chloroformic acid benzyl alcohol ester (2.72mL under ice-water bath, 19.9mmol), stirred at ambient temperature reaction is spent the night.Next day, TLC detection reaction is complete, and reaction system concentrating under reduced pressure, gained residue by silicagel column chromatography purification (chloroform/methanol=40/1, V/V), obtains intermediate S29 (4.45g, yield 93.1%), colorless oil.
1H NMR(300MHz,CDCl
3)δ7.36-7.26(m,5H),5.29(brs,1H),5.10(s,2H),3.71(t,2H,J＝4.8Hz),3.54(m,4H),3.40(t,2H,J＝5.1Hz),2.31(brs,1H)。
Gained intermediate S29 (1.49g, 6.23mmol) be dissolved in acetonitrile/water (10mL/5mL) mixed solvent, iodobenzene diacetate (6g is added respectively under ice-water bath, 18.68mmol) with tetramethyl piperidine (TEMPO, 292mg, 1.87mmol), stirred at ambient temperature reaction is spent the night.Next day, TLC detection reaction is complete, adds saturated sodium bisulfite solution and stirs 10min, pH=5 is adjusted to 1N hydrochloric acid soln, dichloromethane extraction, merges organic phase saturated common salt water washing, and organic phase is dry, concentrating under reduced pressure, gained residue by silicagel column chromatography purification (chloroform/methanol=20/1, V/V), obtains intermediate S30 (1.23g, yield 77.8%), yellow oil.
1H NMR(300MHz,CDCl
3)δ7.36-7.26(m,5H),5.42(brs,1H),5.10(s,2H),4.12(s,2H),3.64(t,2H,J＝4.8Hz),3.43(t,2H,J＝5.1Hz)。
By intermediate S14 (31mg, 0.054mmol) ﹑ S30 (27mg, 0.107mmol) ﹑ EDCI (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride) (20mg, 0.107mmol) with DMAP (DMAP) (7mg, 0.054mmol) in DMF (N, dinethylformamide) room temperature reaction spends the night in (5mL), second day reaction solution thin up, extraction into ethyl acetate, organic phases washed with water twice, saturated common salt is washed, anhydrous sodium sulfate drying, filter, residue by silicagel column chromatography purification (ethyl acetate/petroleum ether=1/2) after filtrate is concentrated, obtain intermediate S31 (33mg, yield 76.7%), white solid.
1h NMR (300MHz, CDCl
3) δ 7.36-7.26 (m, 5H), 5.45 (brs, 1H), 5.10 (m, 2H), 4.43 (d, 1H, J=12.0Hz), 4.20 (s, 1H), 4.13 (s, 2H), 3.61 (t, 2H, J=5.1Hz), 3.41 (t, 2H, J=5.1Hz), 3.39 (s, 1H), 2.63 (dd, 2H, J=8.7, 4.8Hz), 2.30 (m, 2H), 2.10 (m, 2H), 1.90 (m, 4H), 1.82 (m, 4H), 1.76-1.32 (m, all the other aliphatic acyclic hydrocarbon protons), 0.90 (s, 3H), 0.87 (s, 3H), 0.84 (s, 3H), 0.81 (s, 3H), 0.73 (s, 3H).
Gained intermediate S31 is dissolved in methyl alcohol, and there is lower catalytic hydrogenolysis in Pd-C under normal pressure, the benzyl simultaneously sloughing benzyloxycarbonyl and C-20 obtains intermediate S32, not purified, directly carries out the next step.By intermediate S32 (30mg, 0.05mmol), active ester Biotin-OSu (17mg, 0.05mmol) be dissolved in dry DMF (2mL) solvent with triethylamine (200 μ L), at being heated to 50 DEG C, stirring reaction spends the night.After being as cold as room temperature, reaction system use water (20mL) dilutes, extraction into ethyl acetate, washes, anhydrous Na after merging organic phase with saturated common salt
2sO
4drying, after filtering and concentrating, gained crude on silica gel column chromatography purification obtains Compound C 82 (yield 60%), white solid.
1h NMR (300MHz, CDCl
3) δ 6.75 (brs, 1H), 5.33 (brs, 1H), 5.23 (brs, 1H), 4.63 (d, 1H, J=12.0Hz), 4.50 (t, 1H, J=6.0Hz), 4.31 (t, 1H, J=6.0Hz), 4.10 (m, 2H+2H), 3.94 (d, 1H, J=12.0Hz), 3.65 (m, 2H), 3.48 (m, 2H), 3.39 (s, 1H), 3.19 (m, 1H), 2.90 (m, 1H), 2.72 (d, 1H, J=6.0Hz), 2.67 (d, 1H, J=6.0Hz), 2.25 (m, 4H), 1.95 (m, 4H), 1.78-1.09 (m, all the other aliphatic acyclic hydrocarbon protons), 0.95 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H), 0.83 (s, 3H), 0.81 (s, 3H).
Test example 1
TGR5 Agonist Assay embodiment
TGR5 agonistic assay embodiment one compound is by activating the accumulation of cyclic monophosphate 3'-5'-cyclic monophosphate (cAMP) in TGR5 mediated cell
1, test objective
The HEK293 cell compound turning TGR5 wink is utilized to stimulate, then homogeneous phase time discrimination fluorescence (Homogeneous Time-Resolved Fluorescence is used, HTRF) detect, object detects these compounds and whether mediates by TGR5 the accumulation improving cAMP in cell.
2, test principle
G
α sthe Farnesoid X receptor TGR5 of albumen coupling is combined rear its and can changes by recurring structure with agonist, thus adenosine cyclase of acid (AC), further catalysis ATP generates cAMP, cAMP is degraded into AMP further again under phosphodiesterase (PDE) effect simultaneously, and IBMX can suppress the activity of PDE, thus cAMP is suppressed to be degraded into AMP.Therefore can detect the cAMP amount of accumulation by adding IBMX in an experiment, and the amount of cAMP directly can reflect that compound is activation to the AC that GPCR mediates or suppresses.The antigen binding site of the anti-cAMP antibody of Immune competition is carried out between the cAMP that the HEK293 cell turning TGR5 wink produces and the cAMP that marked d2 that test kit provides.When having larger signal after the cAMP combination that the monoclonal antibody that marked europium or terbium marks with d2, along with the cAMP produced in cell increases, signal reduces gradually, thus causes fluorescence reading to decline.Therefore the impact of compound of reaction on the accumulation of cAMP in cell can be carried out by fluorescence reading.
3, laboratory sample
Before test, compound is dissolved in DMSO, preparation mother liquor, is diluted to desired concn with nutrient solution during use, and establishes INT-777 and lithocholic acid (Lithocholic Acid) as the positive control of test, detects the whether normal of each test reaction.
4, experimental technique
4.1, testing compound 1xPBS is made into 2 times of final concentration. wherein final concentration is 100 μMs, 10 μMs, 1 μM, 100nM, 10nM, 1nM, 0.1nM, DMSO (DMSO of 1% is contained in each hole).
4.2, cell process:
4.2.1, with trypsin digestion cell, then suspend with serum-free medium.
4.2.2, cell density is determined. and in serum-free medium, add IBMX (final concentration is 500 μMs) simultaneously, cell count is 2000/5 μ l/ hole.
4.2.3, add 5 μ l testing compound & 5 μ l and mix containing the cell suspension of IBMX, 384 orifice plates are closed by masking foil, and the reaction of room temperature lucifuge is no more than 30 minutes.
4.3. detection substrate configuration
4.3.1,1 μ l cAMP-d2 cAMP & cGMP conjugates & lysis buffer is diluted to 20 μ l
4.3.2,1 μ l anti-cAMP-Cryptate cAMP & cGMP conjugates & lysis buffer is diluted to 20 μ l
4.3.3, after 30 minutes, add 5 μ l (1.3.1)+5 μ l (1.3.2), 384 orifice plates are closed by masking foil, the reaction minute of room temperature lucifuge.
4.4, after 60 minutes, Envision2101 multi-functional microwell plate microplate reader (PerkinElmer) reading.
5, experimental result: (with 14 compounds such as C29, C33, C40, C98 for example, but being not limited to these compounds)
Table 1 compound TGR5 agonist activity testing experiment
Note: EC
50for example pharmaceuticals is to the evaluation of TGR5 agonist activity, half 50% effective concentration.NR represents do not have activity under the concentration of 100 μMs.
6, result and discussion:
These compounds can improve intracellular cAMP in the HEK293 cell of expressing TGR5 to be accumulated, and it is active in dose-dependence, EC
50value is in table one.And in the HEK293 cell of not expressing TGR5, these compounds then can not cause the accumulation of cAMP.Result further illustrates the agonist that these compounds are TGR5 acceptors.And in table, show 3-α configuration be significantly improved than the TGR5 agonist activity of 3-beta comfiguration.
Test example two:
Compound can not activate the reporter gene expression that nuclear receptor FXR mediates
1, test objective
Utilize the HEK293 cell compound turning expression plasmid pBind-FXR and reporter plasmid pGL4.31 wink in a twinkle to stimulate, then use Steady-
stable Luciferase Assay System detects, and object detects whether these compounds improve intracellular luciferase expression level by FXR.
2, test principle
Mammalian cell list acrobatics art (Mammalian one-hybrid) is also referred to as GAL4 Chimerical receptor gene tester (GAL4chimera receptor assay), this technology grew up in recent years and was mainly used in a kind of new technology of nuclear receptor (Nuclear receptor, NR) function and part physiologically active screening and evaluation thereof.This technology mechanism make use of the yeast cell transcription factor GAL4 main domains similar with all having 2 in the molecular structure of mammalian cell nuclear receptor: ligand binding domains (LBD) and DNA binding domains (DBD), the ligand binding domains (LBD) of nuclear receptor and the DNA binding domains (DBD) of yeast cell transcription factor GAL4 are fused into chimeric protein expression plasmid, again with the reporter plasmid cotransfection zooblast containing the special response element of GAL4, by measuring the expression level of reporter gene thus evaluating the excitement of nuclear receptor ligands or antagonistic activity.
3, laboratory sample
Before test, compound is dissolved in DMSO, preparation mother liquor, is diluted to desired concn with nutrient solution during use, and establishes GW4604 as the positive control of test, detects the whether normal of each test reaction.
4, experimental technique
4.1, wink turns: turn expression plasmid pBind-FXR and reporter plasmid pGL4.31 to HEK293 cell wink in a twinkle, then 384 orifice plates are seeded to by 10000 cells/well cell densities, at 10%FBS DMEM in high glucose, 37 DEG C, cultivate 12 hours under 5%CO2 condition.
4.2, add compound: in agonist test, agonist positive control and diluted chemical compound to 10 × final concentration are directly added Tissue Culture Plate, volume is 5 μ l, continue 37 DEG C, cultivate 24 hours under 5%CO2 condition.
4.3, detect: dosing, after 24 hours, uses Steady-
stable Luciferase Assay System detects.Every hole sucks 25 μ L substratum, adds 25 μ L luciferase assays reagent, vibration 5min.Finally detect chemoluminescence count value in the multi-functional microwell plate microplate reader of Envision2101.
5, experimental result: (with 14 compounds such as C29, C33, C40, C98 for example, but being not limited to these compounds)
Table 2 compound F 17-hydroxy-corticosterone XR agonist activity testing experiment
Note: EC
50for example pharmaceuticals is to the evaluation of TGR5 agonist activity, half 50% effective concentration.NR represents do not have activity under the concentration of 100 μMs.
6, result and discussion
Turning in wink in nuclear receptor FXR, GW4604 can activate FXR, improves the expression of intracellular luciferase by activating FXR, and it is active in dose-dependence.But these compounds do not improve the expression of intracellular luciferase by activating FXR.Result illustrates that these compounds can not be played a role by nuclear receptor FXR, further illustrates these compounds and has certain selection specificity.
Claims (10)
1. there is a compound for structure shown in general formula (I),
Wherein, R
1for hydrogen, hydroxyl, halogen or C
1-C
6alkyl;
R
2for hydrogen; Hydroxyl; Halogen; Oxo group (=O);=N-OH; C
1-C
6alkyl-carbonyl oxygen groups; 3 to 8 ring alkyl-carbonyl oxygen groups; C
1-C
6alkyl; 3 to 8 yuan of cycloalkyl; Or
wherein, R
cfor C
1-C
6alkyl or hydrogen;
R
3and R
8be independently of one another: hydrogen; Hydroxyl; Halogen; By C
1-C
6the amino C that alkyl replaces
1-C
6alkyl; The C not replacing or replace
1-C
6alkyl, wherein, the C of replacement
1-C
6substituting group in alkyl is selected from hydroxyl, halogen, oxo group (=O) ,=N-OH, propylene oxide base, amino or hydroxyl C
1-C
6alkylamino; Do not replace or replace C
1-C
6alkenyl, wherein, the C of replacement
1-C
6substituting group in alkenyl is selected from hydroxyl, halogen, oxo group (=O) ,=N-OH, amino or hydroxyl C
1-C
6alkylamino;
wherein, R
9for H, C
1-C
6alkyl, C
1-C
6alkoxyl group, hydroxyl, hydroxyl C
1-C
6alkyl ,-CH
2oC (O) R
10,-CH
2oC (O) OR
11,-CH
2oC (O) CH
2oR
12;
Wherein, R
10, R
11and R
12be substituted or unsubstituted 5 to 8 yuan of aryl independently of one another; Substituted or unsubstituted 3 to 8 yuan of cycloalkyl; 5 to 8 yuan of arylaminos; Comprise at least one heteroatomic 5 to the 8 yuan of heteroaryl in N, S or O; C
1-C
6alkyl; Halo C
1-C
6alkyl; Hydroxyl C
1-C
6alkyl;
bocNH (CH
2)
mo (CH
2)
n-, wherein, each m and n is identical or different, and is the integer of 1 to 6 independently of one another; Wherein, the substituting group in 5 to 8 yuan of aryl of replacement or 3 to 8 yuan of cycloalkyl of replacement is selected from hydroxyl, halogen, C
1-C
6alkyl or C
1-C
6alkoxyl group;
R
4for hydrogen, hydroxyl, halogen or C
1-C
6alkyl;
R
5independently selected from hydrogen; Hydroxyl; Hydroxyl C
1-C
6alkyl; Halogen; C
1-C
6alkyl;-C (O) R
13;-C (O) O (CH
2cH
2o)
ocH
2cH
2r
14;-C (O) NH (CH
2cH
2o)
pcH
2cH
2r
15; Wherein, o and p is separately 0,1,2 or 3; Or-C (O) NH (CH
2)
qc (O) OH, q are the integer of 3 to 8;
R
13for hydrogen; Hydroxycarbonyl group C
1-C
8alkylamino; Hydroxyl; Unsubstituted or by C
1-C
6the piperazinyl that alkyl replaces; Benzyl oxygen groups; C
1-C
6alkoxyl group; Tert-butoxycarbonyl C
1-C
6alkyl oxy; Or hydroxycarbonyl group C
1-C
6alkylamino;
R
14and R
15be independently hydrogen; Amino; 5-(2-oxo six hydrogen-1H-thieno-[3,4-d] imidazol-4 yl) valeryl amido; C
1-C
6amide group; Tert.-butoxy formamido-; Or C
1-C
6alkoxyl group;
R
6and R
7be hydrogen, hydroxyl, halogen, hydroxycarbonyl group or C independently of one another
1-C
6alkoxy carbonyl;
R
aand R
bbe hydrogen, hydroxyl, halogen, C independently of one another
1-C
6alkyl or hydroxyl C
1-C
6alkyl;
Z is methylene radical or direct key;
represent singly-bound or double bond.
2. compound according to claim 1, wherein, R
3and R
8be independently of one another hydrogen, hydroxyl, methyl, ethyl,
3. compound according to claim 1, wherein, R
5for methyl, carboxaldehyde radicals ,-COOH, methoxycarbonyl,
4. compound according to claim 1, wherein, described compound has the structure shown in following general formula (II):
Wherein, the definition of each substituent definition as is in claim 1 identical.
5. compound according to claim 1, wherein, described compound has the structure of following general formula (III) or (IV):
Wherein, the definition of each substituent definition as is in claim 1 identical.
6. compound according to claim 1, wherein, described compound has following structure:
7. a preparation method for compound according to claim 1, it comprises following syntheti c route:
Wherein, R
16and R
17be respectively hydrogen, C
1-C
6alkyl or hydroxyl C
1-C
6alkyl;
R
18for C
1-C
6alkyl; All the other substituting groups are identical with the definition in claim 1.
8. a pharmaceutical composition, it comprises compound according to any one of claim 1 to 6 as activeconstituents.
9. the application of compound according to any one of claim 1 to 6 in the medicine of preparation treatment type-II diabetes.
10. compound according to any one of claim 1 to 6 is as the application of TGR5 agonist.
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| CN112694514A (en) * | 2019-10-23 | 2021-04-23 | 中国科学院上海药物研究所 | Pentacyclic triterpenoid TGR5 receptor agonist, and preparation method and application thereof |
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