CN109627182A - A kind of kanochol hydroxylate, preparation method and applications - Google Patents
A kind of kanochol hydroxylate, preparation method and applications Download PDFInfo
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- CN109627182A CN109627182A CN201810660090.5A CN201810660090A CN109627182A CN 109627182 A CN109627182 A CN 109627182A CN 201810660090 A CN201810660090 A CN 201810660090A CN 109627182 A CN109627182 A CN 109627182A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Abstract
The present invention relates to kanochol hydroxylates, the kanochol hydroxylate can be by inhibiting RR enzyme that hepatitis B virus DNA is inhibited to replicate, the present invention also describes the preparation method of kanochol hydroxylate, helps to solve the still more rare technical problem of drug molecule inhibited to RR enzyme at present.
Description
Technical field
The present invention relates to kanochol hydroxylate, which has the following structure formula:
The invention further relates to the preparation of kanochol hydroxylate and its applications.
Background technique
Virus B hepatitis (hepatitis B) is still to seriously threaten one of Important Infectious Diseases of the health of our people, is to cause
The principal element of China's primary carcinoma of liver.Population of China HBsAg carrying rate nearly 7.2%, there are about 3.5 hundred million people by HBV in the whole world
Infection.It is existing research shows that inhibit HBV DNA duplication can prevent hepatitis B disease progression, slow down even reverse liver fibrosis
With cirrhosis and reduce the incidence of liver cancer.Nucleosides (acid) analogue treatment that world Anti-HBV activity treatment guidelines are recommended at present is still deposited
In more adverse reaction and higher resistant rate and virus variation defect.In addition, existing drug cannot fully erased Hepatitis B patients
Liver cell nuclear in cccDNA (covalently closed circular DNA), and cccDNA patient's body continue
In the presence of being the main reason for chronic HBV infection is difficult to obtain healing, in fact, the variation of HBV caused by nucleosides (acid) analog with
Drug resistance is the problem in global treating hepatitis B history, and captures the significant obstacle of hepatitis B.
Existing research at present is thought to directly act on viral medicine itself by the drug of target spot ratio of the albumen in host cell
The drug resistance incidence of object is substantially reduced, and can be similar to avoid nucleosides (acid) by drug target of the albumen in host cell
The mitochondrial toxicity of object.Therefore, virus-host cell interactions site is found in the hbv replication period as newly disease-resistant
Malicious target, so that it is current hepatitis B that exploitation, which can remove cccDNA but also reduce the new Anti-HBV activity therapeutic scheme of drug resistance incidence,
The critical issue for the treatment of and HBV-associated hepatocellular carcinoma prevention and treatment urgent need to resolve, has important clinical meaning and social effect.
Ribonucleotide reductase (Ribonucleotide reductase, RR) is human cell DNA's synthesis and repairs
Key enzyme, function is that ribonucleotide (Ribonucleotide triphosphates, NDPs) is reduced to deoxidation core
Ribotide (Deoxyribonucleotide triphosphates, dNDPs), the latter is further turned to by kinase phosphorylation
DNTPs provides raw material for DNA synthesis.Gene of the HBV itself without coding RR enzyme, and most of normal liver in adult liver
Cell remains static, and dNTPs concentration is very low.HBV (no RR gene) inhibits liver cell regulatory factor x1 by HBx albumen
(RFXl) in conjunction with the promoter of RRM2 or the Chk1-E2F1 approach of activation DNA damage access is to activating host hepatocytes
RR expression of enzymes and enzymatic activity can provide enough DNA synthesis materials by the RR enzyme of abnormal activation, guarantee hbv replication and liver cancer cells
It is proliferated the demand to DNA raw material, thus RR enzyme is the key factor albumen of hepatitis B and associated hepatocellular carcinoma occurrence and development, is anti-
The new target molecules of hepatitis B medicament.The supply of HBV DNA replication dna raw material, containment double-strand relaxation can be cut off in RR enzyme inhibitor
Ring molecule RcDNArcDNA (relaxed circular DNA) synthesis, can prevent HBV massive duplication in liver cell, be expected to
Effectively HBVcccDNA is inhibited to be formed from source, to mitigate hepatic tissue inflammatory damage, prevent hepatitis occurrence and development and to liver
Cancer transformation.
Summary of the invention
It is right although having now been found that RR enzyme is the key factor albumen of hepatitis B and associated hepatocellular carcinoma occurrence and development
The inhibited drug molecule of RR enzyme is still more rare, and the present invention provides a kind of pair of RR enzyme thus, and there is inhibition to make
Drug molecule, the molecule are kanochol hydroxylate, and structural formula is as follows:
It is a discovery of the invention that the molecule using SimBioSys company molecular docking software eHiTS (Version 12.0,
SimBioSys Inc., Canada) analysis shows that, (log (the Kd) (dissociation that eHiTS_Score correspondence is of eHiTS_Score value
Constant takes logarithm), value is more negative, and the binding ability for representing small molecule compound is stronger, such as -6 is equivalent to μM, -9 are equivalent to nM；Number
Value difference is 1, and binding ability differs 10 times) it is -3.807.
In addition, kanochol hydroxylate also has the function of extremely strong inhibition hepatitis B virus DNA duplication, so as to
It is used to prepare the drug for the treatment of hepatitis B, specifically, the kanochol hydroxylate (C4) is used to prepare prevention and treatment hepatitis (especially
It is hepatitis B) drug.
The drug can be prepared into the dosage form for adapting to various form of medication.
The present invention also provides a kind of methods for preparing kanochol hydroxylate, this method comprises:
A, the step of intermediate being dissolved, and catalyst is added, forming the first mixture；
B, the first hydrogenation mixture reacts the step of generating kanochol hydroxylate completely；
The catalyst is one of palladium carbon, Raney Ni, tin tetrachloride, ferric trichloride, the intermediate are as follows:
The reaction yield of usual b step is up to 80% or more.The a step dissolves intermediate, and catalyst is added,
Selected solvent can dissolve intermediate, generally methylene chloride, methanol, ethyl alcohol, the tert-butyl alcohol, second in usual a step
Nitrile, tetrahydrofuran, dioxane, preferably methanol.
The various specifications of the catalyst are used equally for the hydrogenation reaction to intermediate, the catalyst generally preferably palladium
Carbon.The reaction temperature of the b step is controlled at 0 DEG C -50 DEG C.
Those skilled in the art can use various synthetic route synthetic intermediates, but in the present invention, the intermediate
It is generated by compound A and compound B reaction, the compound A are as follows:
The compound B are as follows:
Wherein X is Cl, Br or I.
For compound A and compound B, those skilled in the art can voluntarily consult technological document synthesis, and the present invention is no longer
Narration.
The synthesis step of the intermediate includes:
C, the step of compound A and compound B mixed dissolution, the second mixture of formation；
D, the second mixture reacts the step of generating intermediate completely.
The reaction yield of usual Step d is up to 70% or more, and selected solvent is nonpolar solvent in step c, no
Alcohols isopolarity solvent can be used.The nonpolar solvent can be methylene chloride, dichloroethanes, tetrahydrofuran, acetonitrile, two
At least one of six ring of oxygen, preferably methylene chloride, tetrahydrofuran.
The step c further includes mixing during compound A and compound B are mixed into the second mixture to second
The cooling step of object, to inhibit the formation of by-product.It is described cooling to the second mixture in section Example of the invention
The step of the temperature of the second mixture can be made to be maintained at -15 DEG C~35 DEG C, preferably -15 DEG C~15 DEG C.
To enable compound A smoothly to react with compound B, the step c further includes being free of to the addition of the second mixture
The step of organic base of hydrogen, in this step still cools down the second mixture, so that adding the of the organic base
The temperature of two mixtures is controlled at 15 DEG C hereinafter, to reduce the generation of by-product as far as possible while keeping reaction efficiency.?
In section Example of the invention, the organic base is triethylamine, n,N-diisopropylethylamine, pyridine, 4- dimethylamino pyrrole
Pyridine, preferably triethylamine.
In general, the molar feed ratio of compound A, compound B and organic base are 1: 1-3: 1-3, preferably 1: 1-2: 1-
2。
Theoretically, those skilled in the art can synthesize oxybenzene bigcatkin willow of the present invention using other synthetic routes
Amine hydroxylate, but synthetic method provided by the present invention has significant technical effect:
1, raw material is cheap, low in cost, purchases very convenient, the raw material of synthesis compound A and compound B, technical staff
Can refer to technological document selects commercial product as initial feed.
2, the reaction of b step and Step d very sufficiently, by-product do not allow it is easily generated, in fact, b step and Step d
Reaction yield is 70% or more.
3, gained by-product all has certain water solubility, can make intermediate and institute by simply washing extraction
It states kanochol hydroxylate to be purified, reduced purifying cost.
Detailed description of the invention
Fig. 1 is the LC/MS spectrogram of intermediate in embodiment 1；
Fig. 2 is the nuclear magnetic spectrogram of kanochol hydroxylate in embodiment 5；
Fig. 3 is the LC/MS spectrogram of kanochol hydroxylate in embodiment 5；
Fig. 4 is the HPLC spectrogram of kanochol hydroxylate in embodiment 5；
Fig. 5 is RRM23D structure chart described in embodiment 10；
Fig. 6 is influence chart of each drug to HBVDNA described in embodiment 11.
Specific embodiment
With reference to the accompanying drawing to implementation further detailed description of the invention.
A, the preparation process in relation to kanochol hydroxylate
In this part, compound B is
1, about the preparation of intermediate
Embodiment 1
At room temperature, methylene chloride (20L) is added in a kettle, by compound A (5.00kg, 16.37mol, 1.0eq),
Compound B (8.08kg, 32.75mol, 2.0eq) is added sequentially in reaction kettle, is cooled to 0~5 DEG C, and 4- dimethylamino is added dropwise
The dichloromethane solution of pyridine (4.00kg, 32.75mol, 2.0eq), after being added dropwise, insulation reaction 1h, middle control has been reacted
Entirely, water (10L) is added into reaction solution, methylene chloride extraction is directly concentrated, obtains yellow oil 7.85kg, molar yield
93%, products obtained therefrom does not have to purifying, is directly used in next step.
EI-MS [M+1]=516.3, is shown in Fig. 1.
Embodiment 2
At room temperature, in a kettle be added tetrahydrofuran (400mL), by compound A (100.00g, 0.33 mol,
1.0eq), compound B (162.81g, 0.66mol, 2.0eq), is added sequentially in reaction kettle, is cooled to 0~5 DEG C, is added dropwise three
The dichloromethane solution of ethamine (66.66g, 0.66mol, 2.0eq), after being added dropwise, insulation reaction 2h, middle control fully reacting,
Water (200ml) is added into reaction solution, concentration, methylene chloride extraction is concentrated again, obtains yellow oil 147.91g, rub
That yield 87.6%, products obtained therefrom do not have to purifying, are directly used in next step.
Embodiment 3
At room temperature, acetonitrile (400mL) is added in a kettle, compound A (100.00g, 0.33mol, 1.0eq) changes
It closes object B (162.81g, 0.66mol, 2.0eq), is added sequentially in reaction kettle, be cooled to 0~5 DEG C, N, N- diisopropyl is added dropwise
The dichloromethane solution of base ethamine (128.0g, 0.99mol, 3.0eq), after being added dropwise, insulation reaction 2h, middle control has been reacted
Entirely, water (200ml) being added into reaction solution, concentration, methylene chloride extraction is concentrated again, obtains yellow oil 151.77g,
Molar yield 89.2%, products obtained therefrom do not have to purifying, are directly used in next step.
Embodiment 4
At room temperature, in a kettle be added methylene chloride (1200mL), by compound A (100.00g, 0.33 mol,
1.0eq), compound B (162.81g, 0.66mol, 3.0eq), is added sequentially in reaction kettle, is cooled to 0~5 DEG C, and 4- is added dropwise
The dichloromethane solution of dimethylamino naphthyridine (120.95g, 0.99mol, 3.0eq), after being added dropwise, insulation reaction 2h, middle control
Water (200ml) is added into reaction solution in fully reacting, and methylene chloride extraction is concentrated again, obtains yellow oil
148.35g, molar yield 87.2%, products obtained therefrom do not have to purifying, are directly used in next step.
2, the preparation about kanochol hydroxylate
Embodiment 5
At room temperature, methanol (1L) is added in reaction kettle, then sequentially adds the resulting intermediate of embodiment 1-4
(7.85kg, 15.22mol, 1.0eq), palladium carbon (785g, 10%) are filled with hydrogen, keep 0.2MPa pressure, react at room temperature 10h,
After completion of the reaction, it filters, filtrate is concentrated to dryness, and obtains pink solid 3.20kg, molar yield 85.6%.
1HNMR (DMSO), 6Hppm:11.861 (s, 1H), 7.894-7.912 (d, J=7.2Hz, 1H), 7.587-
7.609 (d, J=8.8Hz, 2H), 7.250-7.287 (t, J=7.2,8.4Hz, 1H), 6.997-7.019 (d, J=8.8Hz,
2H), 6.849-6.870 (d, J=8.4Hz, 1H), 6.682-6.720 (t, J=7.6,7.6Hz, 1H), 4.828-4.847 (d,
J=7.6Hz, 1H), 3.477-3.502 (d, J=10.0Hz, 1H), 3.163-3.194 (m, 4H).See Fig. 2.
EI-MS [M+1]=246.3, is shown in Fig. 3.
The HPLC of kanochol hydroxylate, is shown in Fig. 4.
Embodiment 6
At room temperature, tetrahydrofuran (800mL) is added in reaction kettle, then sequentially adds the resulting intermediate of embodiment 1-4
(100g, 0.19mol, 1.0eq), Raney Ni (5g, 5%) are filled with hydrogen, keep 0.2MPa pressure, and 50 DEG C of reactions for 24 hours, are reacted
After, filtering, filtrate is concentrated to dryness, and obtains pink solid 38.67g, molar yield 81.3%.
Embodiment 7
At room temperature, in reaction kettle be added methanol (1L), then sequentially add the resulting intermediate of embodiment 1-4 (100g,
0.19mol, 1.0eq), palladium carbon (10g, 10%) is filled with hydrogen, keeps 0.2MPa pressure, 5h is reacted at room temperature, after completion of the reaction,
Filtering, filtrate are concentrated to dryness, and obtain pink solid 39.14g, molar yield 82.3%.
Embodiment 8
At room temperature, the tert-butyl alcohol (300mL) is added in reaction kettle, then sequentially adds the resulting intermediate of embodiment 1-4
(100g, 0.19mol, 1.0eq), palladium carbon (1g, 1%) are filled with hydrogen, keep 0.2MPa pressure, react at room temperature 10h, have reacted
Bi Hou, filtering, filtrate are concentrated to dryness, and obtain pink solid 36.48g, molar yield 78.3%.
Embodiment 9
At room temperature, in reaction kettle be added methanol (1L), then sequentially add the resulting intermediate of embodiment 1-4 (100g,
0.19mol, 1.0eq), palladium carbon (10g, 10%) is filled with hydrogen, keeps 0.2MPa pressure, 5h is reacted at room temperature, after completion of the reaction,
Filtering, filtrate are concentrated to dryness, and obtain pink solid 39.14g, molar yield 82.3%
B, the effect in relation to kanochol hydroxylate in terms of inhibiting RR enzyme and hepatitis B virus DNA duplication
1, effect of the kanochol hydroxylate in terms of inhibiting RR enzyme
Embodiment 10
Kanochol and its derivative molecular docking calculate
(1) by the molecular docking software eHiTS of SimBioSys company (Version 12.0, SimBioSys Inc.,
Canada), 4 compounds and target RRM2 binding ability size are predicted.
4 compounds are as follows:
(2) molecular docking method
The preparation of small molecule: 2D small molecule is converted into 3D structure using OpenBabel 2.3.0, to carry out molecular docking
Research.
Target and active pocket definition: the crystal structure of RRM2 is to obtain from the library PDB (PDB code:3OLJ), is lived
The definition of property pocket is published in the article on Biochemical Pharmacology referring to Xia Liu et al., i.e., by F244,
The region D271, R330 and E334 is defined as active site.
Molecular docking method: molecular Docking Study is carried out using the eHiTS software from Wiley.EHiTS it is a it is accurate,
Quick flexible docking software.EHiTS can pre-process automatically target；And the small molecule docked need to be only 3D
Structure, it is not necessary to be minimum energy conformation.Accuracy parameter-accuracy when docking is set as 6, i.e., highest accuracy into
Row molecular docking.Kanochol and its derivative are docked to this site to assess with itself and RRM2 binding ability respectively
It is strong and weak.
(3) the binding ability marking of compound
The docking marking of 4 small molecules is as follows, and is sorted according to binding ability power:
| Name | eHiTS-Score |
| OH-1.mol | -3.807 |
| laf.mol | -2.885 |
| OH-2.mol | -2.424 |
| HU.mol | -2.289 |
Note: eHiTS software evaluates the binding ability size of small molecule compound and target by eHiTS_Score.
The log (Kd) (dissociation constant takes logarithm) that eHiTS_Score correspondence is, the more negative binding ability for representing small molecule compound of value
It is stronger, it such as -6 is equivalent to μM, -9 are equivalent to nM；Numerical value difference is 1, and binding ability differs 10 times.
2, effect of the kanochol hydroxylate in terms of inhibiting hepatitis B virus DNA duplication
Embodiment 11
The external Anti-HBV effect experiment of kanochol hydroxylate.
1. experimental material
(1) cell strain: HepG2.2.15 cell (stable transfection HBV gene, can stablize carry out HBV gene group duplication and
Expression, this laboratory preservation.
(2) main agents: kanochol hydroxylate (LAF04, Hangzhou nucleic chemical technology Co., Ltd), oxybenzene
Salicylamine (Osalmid, Beijing lark prestige Science and Technology Ltd.), Lamivudine (3-TC, the limited public affairs of Beijing lark prestige science and technology
Department), hydroxycarbamide (HU, Beijing lark prestige Science and Technology Ltd.) hbv nucleic acid quantitative determination reagent kit (sage Hunan, Hunan
Biotechnology Co., Ltd)
(3) key instrument: carbon dioxide incubator (Thermo Forma company, the U.S.), real-time fluorescence quantitative PCR instrument
(American AB I company 7500Fast)
2. experimental method:
(1) cell culture:
HepG2.2.15 and A64 cell culture is in DMEM high glucose medium (10% fetal calf serum of addition, 1% green strepto-
The G418 of element, 400 μ g/ml, 2mmol/L glutamine), it is placed in cell incubator in 37 DEG C, 5%CO2It is cultivated under environment.
When cell grows into 70%~80%, with the pancreatin had digestive transfer culture containing EDTA.
(2) inhibiting effect of the measurement drug to HBV DNA in HepG2.2.15 cells and supernatant:
Kanochol hydroxylate is configured to HepG2.2.15 cell with the DMEM culture medium of removal G418 with 5*
104A/mL density spreads 24 orifice plates, and every hole adds 500uL cell suspension.Set CO2After 37 DEG C of incubator cultures for 24 hours, cell is adherent and raw
It is long good, culture solution is absorbed, 500 hole μ L/ of pastille culture medium, 3 multiple holes of each concentration are added.It was collected in culture the 4th, 6,8 day
Culture medium supernatant detects HBV DNA content.It takes 5uL cells and supernatant that 5uL sample releasing agent is added, mixes well rear room temperature
38uL reaction solution, 2uL enzyme mixation, 0.2uL internal standard is added after being incubated for 10min, is expanded by the following conditions: 50 DEG C of 2min,
After 94 DEG C of 5min initial denaturations 94 DEG C of 15s, 57 DEG C of 30s and acquire signal repeat 40 circulation.By in the ratio of standard items Ct value
Instrument calculates HBV DNA quantitative result automatically.
3. statistical analysis:
Experimental data with 13.0 software of SPSS handle, as a result withIt indicates, the comparison of multiple sample averages is using single
Factor variance (One-wayANOVA) analysis, p < 0.05 are that statistical difference is significant.
4. experimental result:
Compared with blank group control group, kanochol hydroxylate 10uM dosage after dosing the 4th, 6,8 day it is right
HBV copy number has obvious inhibiting effect (P < 0.01), and enhances with the extension of action time.Its inhibiting effect is better than prototype
Kanochol is lower than Lamivudine.
Each drug of table 1 to HepG2.2.15 cells and supernatant HBV DNA influence (n=3,)
Compared with the control group, * * P < 0.01, * * * P < 0.001, * * * * P < 0.0001
Above is only a specific embodiment of the present invention, the not limitation to this case design, all designs according to this case are closed
The equivalent variations that key is done each falls within the protection scope of this case.
Claims (9)
1. a kind of kanochol hydroxylate, structural formula are as follows:
2. a kind of method for preparing kanochol hydroxylate described in claim 1, comprising:
A, the step of intermediate being dissolved, and catalyst is added, forming the first mixture；
B, the first hydrogenation mixture reacts the step of generating kanochol hydroxylate completely；
The catalyst is one of palladium carbon, Raney Ni, tin tetrachloride, ferric trichloride, the intermediate are as follows:
3. according to the method described in claim 2, it is characterized in that this method further includes the synthesis step of intermediate, the centre
The synthesis step of body includes:
C, the step of compound A and compound B mixed dissolution, the second mixture of formation；
D, the second mixture reacts the step of generating intermediate completely.
The compound A are as follows:
The compound B are as follows:
Wherein X is Cl, Br or I.
4. according to the method in claim 2 or 3, it is characterised in that the reaction temperature in b step is 0 DEG C -50 DEG C.
5. according to the method described in claim 3, it is characterized in that the step c further include:
E, the step that the second mixture is cooling；
F, the step of adding not hydrogeneous organic base to the second mixture.
6. according to the method described in claim 5, it is characterized in that the temperature of the second mixture is controlled at 15 DEG C in the f step
Below.
7. method according to claim 5 or 6, it is characterised in that in second mixture compound A, compound B with
And the molar ratio of organic base is 1: 1-3: 1-3.
8. application of the kanochol hydroxylate described in claim 1 in terms of inhibiting ribonucleotide reductase activity.
9. application of the kanochol hydroxylate described in claim 1 in terms of inhibiting hepatitis B virus DNA duplication.
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| CN109627182B (en) | 2021-04-02 |
| CN112724037B (en) | 2022-03-11 |
| CN112724037A (en) | 2021-04-30 |
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