CN105237415A - Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy - Google Patents
Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy Download PDFInfo
- Publication number
- CN105237415A CN105237415A CN201510253240.7A CN201510253240A CN105237415A CN 105237415 A CN105237415 A CN 105237415A CN 201510253240 A CN201510253240 A CN 201510253240A CN 105237415 A CN105237415 A CN 105237415A
- Authority
- CN
- China
- Prior art keywords
- acid
- cancer
- compound
- alkyl
- yuan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ONLUBKZFFYYJGM-UHFFFAOYSA-N CC(C)=CC(ON)=O Chemical compound CC(C)=CC(ON)=O ONLUBKZFFYYJGM-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention provides Vibsanin B derivatives represented by a formula (I), pharmaceutically acceptable salts thereof, a preparation method thereof, pharmaceutical compositions with the Vibsanin B derivative or salt thereof as an effective component, and their applications in preparing medicines used for treating or preventing cancers such as liver cancer, leukemia, colon cancer, breast cancer and lung cancer. The Vibsanin B derivatives provided by the invention have a half inhibitory concentration (IC50) of 2.64-3.46muM against the growth of the above tumor strains. Through the change of C18-site hydrogen bond interaction, the anti-tumor activity of Vibsanin B can be substantially improved.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals, particularly, relate to Vibsane type diterpene-kind compound VibsaninB derivative and organic and inorganic acid salt thereof, the pharmaceutical composition being effective ingredient with it, its preparation method and they preparation treatment or preventing cancer medicine in application.
Background technology:
The centuries history of mankind's Exploration & stu dy cancer confirms that cancer causes (Hanahan, D., Weinberg, R.A., Cell by multiple factors, 2000,100,57) (Hanahan, D., Weinberg, R.A., Cell, 2011,144,646).So far, cancer is still annoying global scientist, according to statistics, the patient that the developed countries such as the U.S. die from cancer every year accounts for 13% of sum, and China about newly-increased 1,600,000 cancer patientss every year, and have 1,300,000 cancer death, visible cancer is current harm humans the most serious healthy a kind of disease simultaneously.And chemotherapy is the important means of Therapeutic cancer, but to any one chemotherapeutics, unavoidably face resistance and toxicity problem.Therefore cancer therapy drug and the anticancer ancillary drug of finding high-efficiency low-toxicity are the important contents that Current cancer is studied.
Natural product is not only a very large structure diversity storehouse, is also the compound resources bank of a diverse in function simultaneously.The natural product skeleton going through 10000000 year Natural Selection and thousands of years human administration's history is introduced medicinal design, not only can improve the potential safety hazard of hitting probability but also medicine later development can be reduced to a great extent.VibsaninB (VB) derivative is the chemical synthetic derivative coming from natural product VibsaninB.Research shows that VB has cytotoxic activity (Minami, the H. of low micromolar level to KB cell; Anzaki, S.; Kubo, M.; Kodama, M.; Kawazu, K.; Fukuyama, Y., Chem.Pharm.Bull., 1998,46 (8), 1194).At present, prior art is there are no the report of VB derivative and activity thereof.
Summary of the invention:
The object of the invention is to: diterpene compound VibsaninB derivative is provided, and the salt utilizing organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) to make; Its pharmaceutical composition formed with pharmaceutically acceptable carrier or vehicle as effective constituent; And VibsaninB derivative and pharmaceutical salts thereof the purposes in the medicine of preparation prevention or Hepatoma therapy, leukemia, colorectal carcinoma, mammary cancer and lung cancer.
Above-mentioned purpose of the present invention is achieved by the following technical solutions:
VibsaninB derivative shown in formula (I),
In formula, lowercase a-d represents independently double bond or singly-bound, uses
represent
Wherein R
1for-CH
2oH ,-CH
2nH
2,-CHO ,-COOH ,-CH
2x (X=F, Cl, Br) ,-CH=NOR ' ,-CH
2nHOR ' ,-CH
2oC=SSR ' (R ' be H or C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl) ,-CH
2oR " ,-CH
2oC=OR " ,-CH
2(R " is C to NHC=OR " ,-C=OOR "
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls) ,-C=ONR " '
2,-CH
2nR " '
2(R " ' be C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls; Identical and different C
1-10alkyl),
(wherein n=1 – 10, X is CH
2or the heteroatoms such as O, N, S, P, Si, heteroatoms position changeable and can by C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10replace containing heteroatomic ring alkyl, 6 yuan of aryl, 5 to 6 yuan of heteroaryls);
When a is double bond, R
2for O, N, N-OH or N-OMe, S; When a is singly-bound, R
2for H ,-OH, C
1-10alkyl, C
1-10ester group, halogen (F, Cl, Br);
When c is double bond, R
3do not exist; When c is singly-bound, R
3for-OH, halogen (F, Cl, Br), C
1-3alkoxyl group, C
1-10ester group;
When d is double bond, R
4for O, S; When d is singly-bound, R
4for H ,-OH, halogen (F, Cl, Br), C
1-10alkyl amine group, C
1-10ester group, C
1-10unsaturated ester group or containing 6 yuan of aryl ester groups, C
1-10amide group, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls, identical from different C
1-10dialkyl amino, C
1-10alkyl, C
1-3alkoxyl group;
Wherein said C
1-10alkyl, C
1-10alkoxyl group, C
3-C
10cycloalkyl, 5,6 yuan of aryl or heteroaryl are optionally by 1 ~ 3 halogen (F, Cl, Br), hydroxyl, C
1-10alkoxyl group replaces.
Such as formula the diterpene VibsaninB derivative shown in (I), be selected from formula (II), the diterpene VibsaninB derivative shown in formula (III),
Wherein R
1for-CH
2oH ,-CH
2nH
2,-CHO ,-COOH ,-CH
2x (X=F, Cl, Br) ,-CH=NOR ' ,-CH
2nHOR ' ,-CH
2oC=SSR ' (R ' be H or C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl) ,-CH
2oR " ,-CH
2oC=OR " ,-CH
2(R " is C to NHC=OR " ,-C=OOR "
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls) ,-C=ONR " '
2,-CH
2nR " '
2(R " ' be C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls; Identical and different C
1-10alkyl),
(wherein n=1 – 10, X is CH
2or the heteroatoms such as O, N, S, P, Si, heteroatoms position changeable and can by C
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls replace);
R
4for H ,-OH, halogen (F, Cl, Br), C
1-10alkyl amine group, C
1-10ester group, C
1-10unsaturated ester group or containing 6 yuan of aryl ester groups, C
1-10amide group, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls, identical from different C
1-10dialkyl amino, C
1-10alkyl, C
1-3alkoxyl group.
Such as formula the VibsaninB derivative shown in (II) and formula (III), be preferably as follows compound:
Pharmaceutical salts of the present invention, refer to pharmacy acceptable salt, the salt mainly formed with organic acid, described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, sulfocyanic acid, tosilate and undecane hydrochlorate.
Present invention also offers the preparation method of formula (I), formula (II), the VibsaninB derivative shown in formula (III), one of comprise the following steps:
(1) by compound vibsaninB acetylize, compound 1 is obtained; By compound vibsaninB chloro, obtain compound 11, then change into compound 2-8 by 11:
(2) by compound vibsaninB DAST process, compound 9 is obtained:
(3) by compound vibsaninB and NaH/CS
2/ MeI is obtained by reacting compound 10:
(4) the C18 position TBS of compound vibsaninB is protected, then use SOCl
2process, then slough TBS protection obtain compound 12:
(5) DAST and CCl is used respectively by compound 12
3cN process obtains compound 13 and 14:
(6) compound 12 is used NaBH
4reduction, then use MnO
2oxidation, then from different secondary amine generation reduction aminations, finally obtains compound 15 with the oxidation of TEMPO/PIDA system:
Pharmaceutical composition, wherein containing above-mentioned VibsaninB derivative or its pharmaceutical salts, and at least one pharmaceutically acceptable carrier and/or vehicle.
Above-mentioned VibsaninB derivative or the application of its pharmaceutical salts in preparation treatment or preventing cancer medicine.Described application, wherein said cancer is mammary cancer, lung cancer, small cell lung cancer, nonsmall-cell lung cancer, bronchial adenoma and pleura pulmonary blastoma, brain stem and hypothalamus neurospongioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma, schwann's sheath cancer, neuroderm and Pinealoma, prostate cancer, carcinoma of testis, carcinoma of endometrium, carcinoma of uterine body, cervical cancer, ovarian cancer, carcinoma of vagina, carcinoma vulvae, sarcoma of uterus, anus cancer, colorectal carcinoma, esophagus cancer, carcinoma of gallbladder, cancer of the stomach, duodenal cancer, carcinoma of the pancreas, the rectum cancer, carcinoma of small intestine, tongue cancer, glandula cancer, bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter and urethral carcinoma, cancer eye, liver cancer, cholangiocarcinoma, Combination liver cell cholangiocarcinoma, skin carcinoma, head and neck cancer, vascular tumor, bone tumor, lymphoma, vascular fibroma, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, leiomyosarcoma and rhabdosarcoma, jaw knurl, leukemia, thyroid carcinoma, parathyroid carcinoma.
Except as otherwise noted, the term " alkyl " that the present invention uses refers to the saturated monovalent hydrocarbon of straight chain or side chain, and wherein alkyl can optionally be replaced by one or more substituting group.Term " alkyl " also comprises straight chain and branched-chain alkyl, unless otherwise mentioned.In some embodiments, alkyl has 1 to 20 (C
1-20), 1 to 15 (C
1-15), 1 to 12 (C
1-12), 1 to 10 (C
1-10) or 1 to 6 (C
1-6) monovalent hydrocarbon that the straight chain of individual carbon atom is saturated, or there are 3 to 20 (C
3-20), 3 to 15 (C
3-15), 3 to 12 (C
3-12), 3 to 10 (C
3-10) or 3 to 6 (C
3-6) the saturated monovalent hydrocarbon of side chain of individual carbon atom.The straight chain C that the present invention uses
1-6with side chain C
3-6alkyl is also referred to as " low alkyl group ".The embodiment of alkyl includes but not limited to methyl, ethyl, propyl group (comprising all isomeric forms), n-propyl group, sec.-propyl, butyl (comprising all isomeric forms), n-butyl, isobutyl-, t-butyl, amyl group (comprising all isomeric forms) and hexyl (comprising all isomeric forms).Such as, C
1-6alkyl refers to have the saturated monovalent hydrocarbon of straight chain of 1 to 6 carbon atoms or has the saturated monovalent hydrocarbon of side chain of 3 to 6 carbon atoms.
Unless otherwise mentioned, the term " thiazolinyl " that the present invention uses refers to the straight chain or side chain monovalent hydrocarbon that comprise one or more carbon-carbon double bond (in one embodiment 1 to 5).Thiazolinyl can optionally be replaced by one or more substituting group.Term " thiazolinyl " also comprises the group of " cis (cis) " and " trans (trans) " structure, or " E " and " Z " formula structure that those of ordinary skill in the art understand.Unless otherwise mentioned, the term " thiazolinyl " that the present invention uses comprises straight chain and branched-chain alkenyl.Such as, C
2-6thiazolinyl refers to the unsaturated monovalent hydrocarbon of side chain of the unsaturated monovalent hydrocarbon of the straight chain of 2 to 6 carbon atoms or 3 to 6 carbon atoms.In some embodiments, thiazolinyl is 2 to 20 (C
2-20), 2 to 15 (C
2-15), 2 to 12 (C
2-12), 2 to 10 (C
2-10) or 2 to 6 (C
2-6) the straight chain monovalent hydrocarbon of individual carbon atom, or 3 to 20 (C
3-20), 3 to 15 (C
3-15), 3 to 12 (C
3-12), 3 to 10 (C
3-10) or 3 to 6 (C
3-6) the side chain monovalent hydrocarbon of individual carbon atom.The embodiment of thiazolinyl includes but not limited to vinyl, propylene-1-base, propylene-2-base, allyl group, butenyl and 4-methyl butene base.
Unless otherwise mentioned, the term " cycloalkyl " that the present invention uses refers to the monovalent hydrocarbon of the saturated bridge of ring-type and/or non-bridge, and it can optionally be replaced by one or more substituting group of the present invention.In some embodiments, cycloalkyl has from 3 to 20 (C
3-20), from 3 to 15 (C
3-15), from 3 to 12 (C
3-12), from 3 to 10 (C
3-10) or from 3 to 7 (C
3-7) individual carbon atom.The embodiment of cycloalkyl group includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, decahydro naphthyl and adamantyl.
Unless otherwise mentioned, the term " heteroatoms " that the present invention uses refers to other any atoms except carbon or hydrogen.In some embodiments, term " heteroatoms " refers to N, O, S, Si or P.In other embodiments, term " heteroatoms " refers to N, O or S.
Unless otherwise mentioned, the term " aryl " that the present invention uses refers to monocyclic aryl and/or comprises the polycyclic monovalent aryl of at least one aromatic hydrocarbon ring.In some embodiments, aryl has from 6 to 20 (C
6-20), from 6 to 15 (C
6-15) or from 6 to 10 (C
6-10) individual annular atoms.The embodiment of aryl includes but not limited to phenyl, naphthyl, fluorenyl, Azulene base (azulenyl), anthryl, phenanthryl, pyrenyl, xenyl and terphenyl.Aryl also refers to that one of them ring is aromatic and other rings can be saturated, the carbocyclic ring of part undersaturated or aromatic two rings or three rings, such as dihydro naphthyl, indenyl, dihydro indenyl or tetralyl (tetralin base (tetralinyl)).In some embodiments, aryl also can optionally be replaced by one or more substituting group.
Unless otherwise mentioned, the term " pharmacy acceptable salt " that the present invention uses refers to the salt be prepared from by pharmaceutically acceptable nontoxic acid, mainly organic acid.Described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, sulfocyanic acid, tosilate and undecane hydrochlorate.
Composition of the present invention can be any suitable form, such as solid, semi-solid, liquid or aerosol form.Generally, medicine contains compound of the present invention or extract as activeconstituents, with applicable outside, enteron aisle, or the organic or inorganic carrier of administered parenterally or mixed with excipients.Activeconstituents can be compound, such as, can accept carrier and/or vehicle make tablet, piller, capsule, suppository, vaginal suppository, solution, emulsion, suspension and be applicable to other forms of using with conventional non-toxic pharmaceutical.The pharmaceutical acceptable carrier used in the composition comprises, such as, water, glucose, lactose, gum arabic, gelatin, mannitol, starch, Magnesium Trisilicate, talcum, W-Gum, Keratin sulfate, colloidal silica, yam starch, and be adapted at preparing other carriers used in the preparation of solid, semisolid, liquid or aerosol form.Composition can contain stablizer, thickening material in addition, and/or tinting material and spices.
Utilize the additive method previously used for low-solubility drug also can prepare composition of the present invention.Such as, compound of the present invention can be mixed with emulsion with vitamin-E or its PEGization derivative.Typically, compound dissolution, in the aqueous solution containing ethanol (being preferably less than 1%w/v), then adds vitamin-E or PEGization vitamin-E.Then remove ethanol, emulsion before being formed, it can be mixed with for intravenously or oral administration.Or compound of the present invention can make capsule in liposome.
In some embodiments, composition of the present invention can contain polymkeric substance, biological example polymkeric substance or physiologically acceptable (synthesis or naturally occurring) polymkeric substance.Bioavailable polymer can be categorized as biodegradable and not biodegradable.Biodegradable polymers degradation in vivo is chemical composition, preparation method, and/or the function of implant structure.The example of the detailed description of synthetic polymer comprises, such as, and polyanhydrides, polyhydroxy acid class, such as poly(lactic acid), polyglycolic acid and multipolymer thereof, polyester, polyamide-based, poly-former ester class and some poly phosphazene classes.The example of the detailed description of naturally occurring polymkeric substance comprises protein and polysaccharide, such as collagen, hyaluronic acid, albumin and gelatin.
In other embodiments, compound of the present invention can with enhancing water miscible polymkeric substance coupling.The representative example of the polymkeric substance of this object be applicable to comprises polyoxyethylene glycol, poly-(d-L-glutamic acid), poly-(1-L-glutamic acid), poly-(d-aspartic acid), poly-(1-aspartic acid), and their multipolymer.
Compound VibsaninB derivative of the present invention or its salt can per os or without mouth administration, dosage is had nothing in common with each other because medicine is different, and concerning adult, every day, 1-1000mg was proper.
During oral administration administration, first make compound mix as vehicle, disintegrating agent, tamanori, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc. with conventional medicinal adjuvant, be made into the form administrations such as granule, capsule, tablet; Can the form administration such as injection liquid, infusion solution or suppository during non-oral administration.When preparing above-mentioned preparation, conventional preparation technique can be used.
The present invention finds that VB derivative all has comparatively strong inhibitory activity (see table 1) to different human body tumor cell line.In addition VB derivative had not reported similar application, and therefore VB derivative has high using value.
Embodiment:
Test example below, embodiment and example of formulations can illustrate in greater detail the present invention, but do not limit the present invention in any form.
Test example 1:
The compounds of this invention VibsaninB derivative has obvious anti-tumor activity, experimental technique and result as follows:
One, materials and methods:
1. sample and preparation:
Sample is colourless or faint yellow, and dimethyl sulfoxide (DMSO) (DMSO) is dissolved the stock solution being formulated as 10mg/ml concentration and kept in Dark Place for subsequent use.
2. cell strain:
MCF-7, Breast cancer lines
SMMC7721, human hepatoma cell strain
HL-60, human leukemia cell line
SW-480, human colon cancer cell strain
A549, human lung carcinoma cell line
3. experimental technique:
(1). inoculating cell: be made into individual cells suspension with the nutrient solution (DMEM or RMPI1640) containing 10% foetal calf serum, 96 orifice plates are inoculated into every hole 10000-20000 cell, every pore volume 100ul, attached cell shifts to an earlier date 12 hours inoculation culture.
(2). add testing compound solution (compound monomer fixed concentration 40uM primary dcreening operation, crude extract 100ug/ml primary dcreening operation, suppress the compound near 50% to establish 5 concentration to enter gradient in this concentration to growth of tumour cell to sieve again), every hole final volume 200ul, 3 multiple holes are all established in often kind of process.
(3). colour developing: cultivate after 48 hours for 37 degrees Celsius, every hole adds MTT solution 20ul.Continue to hatch 4 hours, stop cultivating, in careful absorption hole, culture supernatant 100ul is to avoid cell loss, and every hole adds the SDS100ul of 20%, and night incubation (temperature 37 DEG C), makes crystallisate fully melt.
(4). colorimetric: select 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad680) reads each hole absorbance value, record result, take concentration as X-coordinate, cell survival rate is that ordinate zou draws cell growth curve, the IC50 value of application two-point method (ReedandMuench method) computerized compound.
(5). positive control: cis-platinum
Two, result:
Half-inhibition concentration (the IC that table 1.VibsaninB derivative grows human tumor cell line
50, μM)
Three, conclusion:
Under this experiment condition, compound VibsaninB derivative is to comprising Breast cancer lines (SK-BR-3) above, human hepatoma cell strain (SMMC7721), human leukemia cell line (HL-60), human colon cancer cell strain (SW480), the half-inhibition concentration (IC50) that human lung carcinoma cell line (A549) grows is between 0.064-2.94 μM, and VibsaninB to the half-inhibition concentration (IC50) of the growth of above tumor line between 2.64-3.46 μM, by the variation at C18 position hydrogen bond action, the anti-tumor activity of VibsaninB can be significantly improved.
According to Chinese Journal of Pharmaceuticals 1993,24:455-457, the improvement mtt assay of the evaluation antitumorigenic substance activity that Zhou Jianjun etc. propose is reached a conclusion: the effect of obvious suppression cancer of above-mentioned data presentation.
Embodiment 1
The preparation of compound 1:
In 10mL round-bottomed bottle, add the DCM of vibsaninB (0.2g, 0.48mmol) and 5mL drying, add TEA (200 μ L, 1.44mmol), Ac
2o (100 μ L, 0.96mmol) and DMAP (6mg, 0.048mmol), this reaction system is at room temperature stirred 4h, adds 1mL water quencher reaction, then add 5mLDCM, organic layer saturated common salt washing (10mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and residuum obtains compound 1 for colorless gum through silica gel column chromatography (PE/EA=10:1) purifying.
1HNMR(500MHz,CDCl
3)δ6.46(d,J＝16.4Hz,1H),6.04(dd,J＝20.0,12.9Hz,2H),5.78(s,1H),5.63(d,J＝16.1Hz,1H),5.36(d,J＝9.2Hz,1H),5.19(dd,J＝16.2,9.2Hz,1H),5.09(s,1H),4.85(d,J＝12.1Hz,1H),4.58(d,J＝12.3Hz,1H),3.68(s,1H),2.20(s,3H),2.05(s,3H),1.93(s,3H),1.89–1.82(m,2H),1.80(s,2H),1.67(s,3H),1.58(s,3H),1.36(s,3H),1.03(s,3H).
13CNMR(120MHz,CDCl
3)δ200.21,167.31,154.81,145.30,138.40,131.69(s),128.35(s),124.03,123.35,115.16,81.91,74.17,66.10,44.52,40.52,38.81,27.51,25.55,23.06,22.84,20.74,20.42,18.43；MSESI(m/z):481[M+Na]
+。
Embodiment 2:
The preparation of compound 11 and 2:
50mgvibsaninB is dissolved in 4mL methylene dichloride, adds the CCl of 2eq.
3cN, stirs a moment, adds the PPh of 2eq.
3stirring at room temperature 0.5h, removes solvent under reduced pressure, obtains yellow oil, and this yellow oil obtains compound 11 for weak yellow foam shape solid through silica gel column chromatography (sherwood oil: ethyl acetate=20:1).
1HNMR(400MHz,CDCl
3)δ6.59(d,J＝16.4Hz,1H),6.16–6.01(m,2H),5.78(d,J＝5.6Hz,1H),5.65(d,J＝16.1Hz,1H),5.40(d,J＝9.1Hz,1H),5.21(dd,J＝16.1,9.2Hz,1H),5.09(t,J＝7.7Hz,1H),4.46(d,J＝11.6Hz,1H),4.05(d,J＝11.2Hz,1H),2.19(s,3H),1.93(s,3H),1.68(s,3H),1.58(s,3H),1.38(s,3H),1.04(s,3H).
13CNMR(100MHz,CDCl
3)δ199.69,167.15,159.41,154.94,145.07,139.57,132.03,128.45,124.02,123.59,115.25,81.38,74.24,53.41,46.56,45.95,44.69,40.71,38.78,29.66,27.58,25.64,23.09,22.85,20.48,18.43,17.64；MSESI(m/z):457[M+Na]
+。
Compound 11 (20mg) is dissolved in 2mL tetrahydrofuran (THF), slowly adds the THF mixed solution 2mL of 2eq dimethylamine hydrochloride and 2eq sodium acetate at 0 DEG C, 0 DEG C is stirred 15min, stirring at room temperature 12h, removes solvent under reduced pressure, obtain yellow oil.This oily matter obtains compound 2 for pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=3:1 ~ 1:1).
1HNMR(600MHz,CDCl
3)δ6.51(d,J＝16.4Hz,1H),6.07(d,J＝16.4Hz,1H),6.02(d,J＝8.6Hz,1H),5.78(d,J＝6.2Hz,1H),5.68(d,J＝16.1Hz,1H),5.38(d,J＝9.1Hz,1H),5.20(dd,J＝16.2,9.1Hz,1H),5.11(t,J＝7.0Hz,1H),5.05(s,1H),3.44(d,J＝13.5Hz,1H),3.06–2.98(m,1H),2.37(s,6H),2.20(s,overlaped,5H),2.10–2.03(m,overlaped,2H),1.94(s,3H),1.81(dd,J＝12.7,6.4Hz,2H),1.68(s,3H),1.59(s,3H),1.38(s,3H),1.03(s,3H).
13CNMR(150MHz,CDCl
3)δ201.91,167.42,159.65,154.10,145.74,131.99,128.73,124.43,123.62,115.52,81.90,74.40,65.80,63.13,45.30,44.94,40.90,39.12,29.92,27.87,25.91,23.39,23.12,20.72,18.68,17.93；MSESI(m/z):444[M+H]
+。
Embodiment 3:
The preparation of compound 3
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq. diethylamine and be warming up to stirring at room temperature 12h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=3:1 ~ 1:1).
1HNMR(600MHz,CDCl
3)δ6.42(d,J＝16.4Hz,1H),6.04(d,J＝16.4Hz,1H),5.83(dd,J＝12.8,3.6Hz,1H),5.79(s,2H),5.64(d,J＝16.2Hz,1H),5.61(s,1H),5.34(d,J＝9.1Hz,1H),5.19(dd,J＝16.2,9.1Hz,1H),5.12(t,J＝6.9Hz,1H),3.46(d,J＝14.3Hz,1H),2.92(d,J＝14.7Hz,1H),2.62(dq,J＝14.3,7.2Hz,3H),2.44(td,J＝13.8,6.9Hz,4H),2.20(s,overlaped,7H),2.03(d,J＝14.5Hz,2H),1.94(s,overlaped,8H),1.69(s,3H),1.59(s,3H),1.39(s,6H),1.05–0.98(m,overlaped,18H).
13CNMR(150MHz,CDCl
3)δ203.09,167.33,159.42,153.88,145.92,142.34,131.93,129.06,124.46,123.39,115.56,81.92,74.34,68.14,63.38,57.76,53.03,46.97,46.82,44.89,40.65,39.09,29.87,27.81,25.82,23.32,23.04,20.65,18.70,17.84,11.96,8.24；MSESI(m/z):472[M+H]
+。
Embodiment 4:
The preparation of compound 4
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq. diisopropylamine and be warming up to stirring at room temperature 12h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=3:1 ~ 1:1).
1HNMR(600MHz,CDCl
3)δ6.41(d,J＝16.3Hz,1H),6.05(t,J＝13.6Hz,1H),5.86(t,J＝15.1Hz,1H),5.80(dd,J＝10.0,8.8Hz,2H),5.61(d,J＝16.0Hz,1H),5.37–5.29(m,1H),5.21–5.15(m,1H),5.15–5.10(m,1H),3.43(t,J＝29.5Hz,3H),3.14–2.98(m,overlaped,6H),2.23–2.16(m,overlaped,7H),2.05–1.96(m,overlaped,4H),1.94(s,6H),1.92–1.86(m,3H),1.85(s,1H),1.84–1.75(m,3H),1.69(d,J＝9.1Hz,overlaped,5H),1.63(d,J＝4.2Hz,1H),1.60(d,J＝7.4Hz,overlaped,5H),1.40–1.37(m,overlaped,5H),1.05–0.94(m,overlaped,10H).
13CNMR(150MHz,CDCl
3)δ203.88,167.55,159.68,153.83,146.21,131.97,129.20,124.53,123.10,115.52,82.23,74.51,49.12,47.89,47.65,44.67,40.67,39.10,27.87,25.91,23.34,23.09,21.95,20.69,19.77,18.77,17.87；MSESI(m/z):500[M+H]
+。
Embodiment 5
The preparation of compound 5:
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq. morpholine and be warming up to stirring at room temperature 6h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=4:1 ~ 1:1).
1HNMR(500MHz,CDCl
3)δ6.39(d,J＝16.4Hz,1H),6.02(d,J＝16.4Hz,1H),5.78(s,2H),5.62(d,J＝16.1Hz,1H),5.32(d,J＝9.1Hz,1H),5.17(dd,J＝16.2,9.1Hz,1H),5.10(t,J＝6.9Hz,1H),3.31(d,J＝13.9Hz,1H),2.83(d,J＝13.9Hz,1H),2.48(s,2H),2.34(s,4H),2.19(s,5H),2.01(s,2H),1.96(d,J＝5.4Hz,2H),1.93(s,6H),1.87–1.80(m,3H),1.68(s,3H),1.55(s,4H),1.45–1.39(m,4H),1.37(s,4H),1.01(s,3H).；MSESI(m/z):484[M+H]
+。
Embodiment 6:
The preparation of compound 6
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq. piperidines and be warming up to stirring at room temperature 8h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=4:1 ~ 2:1).ESI:
1HNMR(500MHz,CDCl
3)δ6.39(d,J＝16.4Hz,1H),6.02(d,J＝16.4Hz,1H),5.78(s,2H),5.62(d,J＝16.1Hz,1H),5.32(d,J＝9.1Hz,1H),5.17(dd,J＝16.2,9.1Hz,1H),5.10(t,J＝6.9Hz,1H),3.31(d,J＝13.9Hz,1H),2.83(d,J＝13.9Hz,1H),2.48(s,2H),2.34(s,3H),2.19(s,3H),2.01(s,3H),1.96(d,J＝5.4Hz,2H),1.93(s,6H),1.87–1.80(m,3H),1.68(s,3H),1.55(s,3H),1.45–1.39(m,4H),1.37(s,3H),1.01(s,3H).；MSESI(m/z):484[M+H]
+。
Embodiment 7:
The preparation of compound 7
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq. tetramethyleneimine and be warming up to stirring at room temperature 24h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=5:1 ~ 1:2).
1HNMR(600MHz,CDCl
3)δ6.47(d,J＝16.4Hz,1H),6.05(d,J＝16.4Hz,1H),5.89(dd,J＝12.0,4.1Hz,2H),5.79(s,1H),5.66(d,J＝16.2Hz,1H),5.36(d,J＝9.1Hz,1H),5.19(dd,J＝16.2,9.1Hz,2H),5.11(t,J＝7.0Hz,1H),3.46(d,J＝13.9Hz,1H),3.10(d,J＝13.9Hz,1H),2.56(t,J＝9.6Hz,7H),2.20(s,6H),2.05(s,3H),1.94(d,J＝0.6Hz,6H),1.69(s,3H),1.59(s,3H),1.45(dd,J＝10.3,4.8Hz,2H),1.38(s,3H),1.02(s,3H).
13CNMR(150MHz,CDCl
3)δ202.66,167.46,159.63,153.92,145.93,131.95,131.35,131.14,129.06,129.02,128.90,124.46,123.39,115.51,82.03,74.43,71.99,65.78,60.63,60.04,44.98,40.74,39.13,30.73,27.85,25.91,25.89,23.36,23.09,20.69,19.37,19.36,18.72,17.88,17.85,14.39；MSESI(m/z):470[M+H]
+。
Embodiment 8:
The preparation of compound 8
20mg compound 11 is dissolved in 2mL tetrahydrofuran (THF), adds 2eq.NaI at 0 DEG C, 0 DEG C is stirred 15min, adds 2eq.N-methylpiperazine and be warming up to stirring at room temperature 24h, remove solvent under reduced pressure, obtain yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=2:1 ~ 1:4).
1HNMR(500MHz,CDCl
3)δ6.42(d,J＝16.4Hz,1H),6.04(d,J＝16.5Hz,1H),5.81(d,J＝12.7Hz,1H),5.78(s,1H),5.59(d,J＝16.1Hz,1H),5.30(d,J＝9.1Hz,1H),5.18(dd,J＝16.1,9.1Hz,1H),5.09(s,1H),3.48(d,J＝13.3Hz,1H),3.01(d,J＝13.7Hz,1H),2.70(d,J＝35.7Hz,12H),2.48(s,3H),2.43(s,3H),2.19(s,3H),2.03(d,J＝12.2Hz,2H),1.94(s,3H),1.87(dd,J＝23.1,13.0Hz,4H),1.68(s,3H),1.44(s,1H),1.37(s,3H),1.25(m,1H),1.09(m,1H),1.02(s,3H)；MSESI(m/z):499[M+H]
+。
Embodiment 9:
The preparation of compound 9
100mgvibsaninB is dissolved in 5mL methylene dichloride, stirs 0.5h at-78 DEG C, then slowly drip 3eq.DAST, react 0.5 ~ 1h at-78 DEG C, add saturated NH
4cl solution (1mL) quencher, placed by reaction flask after stirring 10min and at room temperature continue to stir 5min, DCM dilution, the saturated NaCl solution of organic phase washs 3 times, anhydrous Na SO
4drying, removes solvent under reduced pressure, obtains yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=30:1 ~ 12:1).ESI:441 [M+23]
+,
1hNMR (600MHz, CDCl
3) characteristic signal δ 6.54 (d, J=16.4Hz, 1H), 6.10 (dd, J=14.6, 6.7Hz, 2H), 5.81 (d, J=17.4Hz, 2H), 5.67 (d, J=16.2Hz, 1H), 5.38 (d, J=9.2Hz, 1H), 5.23 (dd, J=16.3, 9.0Hz, 2H), 5.10 (t, J=6.9Hz, 1H), 4.86 – 4.79 (m, 1H), 4.75 (dd, J=10.5, 3.0Hz, 1H), 3.62 – 3.52 (m, 1H), 2.21 (s, 5H), 2.11 – 2.04 (m, 1H), 1.95 (s, 3H), 1.86 – 1.78 (m, 1H), 1.68 (d, J=8.1Hz, 4H), 1.58 (d, J=8.5Hz, 4H), 1.39 (s, 3H), 1.06 (s, 3H).
Embodiment 10:
The preparation of compound 10
100mgvibsaninB is dissolved in 5mL tetrahydrofuran (THF), stirs 0.5h at-10 DEG C, then add 1.2eq.NaH, react 0.5h at-10 DEG C, add 1.5eq.CS
2be warming up to stirring at room temperature 1h after stirring reaction 0.5h, then add 2eqMeI and stir 2h, diluted ethyl acetate, the saturated NaCl solution of organic phase washs 3 times, anhydrous Na SO
4drying, removes solvent under reduced pressure, obtains yellow oil.This oily matter obtains pale yellow oil through silica gel column chromatography (sherwood oil: ethyl acetate=30:1 ~ 10:1).ESI:529 [M+23]
+,
1hNMR (400MHz, CDCl
3) characteristic signal δ 6.53 (d, J=16.4Hz, 1H), 6.28 (d, J=15.9Hz, 1H), 6.15 (dd, J=12.8, 3.9Hz, 1H), 6.09 (d, J=16.4Hz, 1H), 5.79 (s, 1H), 5.65 (d, J=16.1Hz, 1H), 5.35 (d, J=9.4Hz, 3H), 5.25 – 5.18 (m, 2H), 5.10 (t, J=6.9Hz, 1H), 2.53 (d, J=3.0Hz, 3H), 2.21 (d, J=1.3Hz, 6H), 1.94 (d, J=5.2Hz, 4H), 1.66 (s, 3H), 1.59 (s, 3H), 1.38 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H).
Embodiment 11:
The preparation of compound 12:
VibsaninB (0.5g is added in 25mL round-bottomed bottle, 1.2mmol) and the DCM of 10mL drying, add 2,6-lutidine (265 μ L, 2.4mmol) and TESCl (300 μ L, 1.8mmol), this reaction system is at room temperature stirred 6h, adds 1mL water quencher reaction, then add 10mLDCM, organic layer saturated common salt washing (10mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and it is colorless oil (98%) that residuum obtains 623mg compound 1a through silica gel column chromatography (PE/EA=15/1) purifying.
In 10mL round-bottomed bottle, add 1a (100mg, 0.188mmol) and 5mLpyridine be placed in 0 DEG C of ice-water bath and stir 10min, add SOCl
2(30 μ L, 0.376mmol), at 0 DEG C of reaction 30min, adds 10mLEA layering, the saturated CuSO of organic layer
4solution (5mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and it is pale yellow oil (90%) that residuum obtains crude product Compound 1b through Flash silica column chromatography (PE/EA=20/1) purifying.
The compound 1b crude product upper step obtained is dissolved in 8mLAcOH/THF/H
2in O (5/2/1), stirring at room temperature 4h, adds 10mLEA layering, organic layer saturated common salt washing (5mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and residuum obtains 66mg compound 12 for colorless oil (90%) through silica gel column chromatography (PE/EA=10/1) purifying.
1HNMR(600MHz,CDCl
3)δ6.99(d,J＝16.1Hz,1H),6.29(d,J＝16.1Hz,1H),6.06(dd,J＝12.7,4.0Hz,1H),5.91(d,J＝8.9Hz,1H),5.83–5.79(m,1H),5.75(d,J＝16.3Hz,1H),5.39(s,1H),5.27(dd,J＝16.3,9.0Hz,1H),5.19(d,J＝1.7Hz,1H),5.12(t,J＝7.1Hz,1H),4.45–4.36(m,1H),4.20(d,J＝12.5Hz,1H),2.21(d,J＝1.0Hz,3H),2.08(s,3H),2.04–1.98(m,2H),1.95(d,J＝1.0Hz,3H),1.84(dd,J＝12.5,7.0Hz,1H),1.69(s,3H),1.60(s,3H),1.42(td,J＝12.8,5.2Hz,1H),1.05(s,3H).
13CNMR(150MHz,CDCl
3)δ201.43,165.06,158.63,150.44,143.36,141.99,131.78,130.34,130.06,126.80,124.31,124.18,115.33,110.49,74.66,65.66,45.72,40.84,38.82,30.92,29.66,27.52,25.65,23.21,22.76,20.39,17.66；MSESI(m/z):421[M+Na]
+。
Embodiment 12:
The preparation of compound 13:
By compound 12 (20mg, 0.05mmol) and Cl
3cCN (8 μ L, 0.1mmol) is dissolved in 2mLDCM and is placed in 0 DEG C of ice-water bath and stirs 10min, adds PPh
3(26mg, 0.1mmol), reaction is at room temperature stirred 30min, add 100mg silica gel, remove solvent under reduced pressure, residuum obtains 20mg compound 13 for yellow foamy solid (92%) through silica gel column chromatography (PE/EA=12/1) purifying.
1HNMR(600MHz,CDCl
3)δ6.31(dd,J＝16.2,6.6Hz,1H),6.11(dd,J＝12.6,4.2Hz,1H),5.93(t,J＝11.3Hz,1H),5.83–5.80(m,1H),5.73(d,J＝16.3Hz,1H),5.38(d,J＝25.1Hz,1H),5.33–5.24(m,1H),5.20(d,J＝1.7Hz,1H),5.12(ddd,J＝7.0,5.8,1.3Hz,1H),4.53–4.47(m,1H),4.03(d,J＝11.3Hz,1H),2.21(d,J＝1.1Hz,3H),2.08(ddd,J＝13.9,4.2,2.4Hz,1H),2.03(d,J＝12.7Hz,1H),1.95(d,J＝1.1Hz,3H),1.70(s,3H),1.60(s,3H),1.46–1.39(m,1H),1.06(d,J＝7.4Hz,3H).
13CNMR(150MHz,CDCl
3)δ198.98,165.11,158.84,151.29,142.88,142.05,139.15,132.54,131.93,130.06,127.11,124.09,115.29,110.45,74.61,46.88,45.69,40.99,38.84,27.60,25.72,23.21,22.75,20.44,17.73；MSESI(m/z):439[M+Na]
+。
Embodiment 13:
The preparation of compound 14:
VibsaninB (100mg is added in 25mL round-bottomed bottle, 0.24mmol) be placed in-78 DEG C of cold-traps with the DCM of 10mL drying and stir 30min, add the 5mLDCM solution of DAST (95 μ L, 0.72mmol), stir 15min at such a temperature, add the saturated NH of 1mL
4the quencher of Cl solution is reacted, then adds 5mLDCM, organic layer saturated common salt washing (5mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and residuum obtains compound 14 (colorless oil, 20%) through silica gel column chromatography (PE/EA=10/1 ~ 5/1) purifying,
1hNMR (600MHz, acetone-D6) δ 6.97 (d, J=16.2Hz, 1H), 6.20 (dt, J=12.7, 4.3Hz, 1H), 6.15 (d, J=16.2Hz, 1H), 5.88 (dd, J=18.6, 12.6Hz, 2H), 5.74 – 5.70 (m, 1H), 5.30 (s, 1H), 5.18 (dd, J=16.3, 8.9Hz, 1H), 5.11 – 4.96 (m, overlaped, 3H), 4.75 (dd, J=47.3, 10.4Hz, 2H), 2.05 (t, J=4.5Hz, 2H), 1.82 (d, J=1.1Hz, 3H), 1.78 – 1.70 (m, 1H), 1.69 – 1.62 (m, 1H), 1.54 (s, 3H), 1.47 (s, 3H), 1.41 – 1.34 (m, 1H), 0.97 (s, 3H), 0.75 (dd, J=14.5, 7.5Hz, 1H).
13cNMR (150MHz, acetone-D6) δ 199.20,165.40,159.35,151.20,144.16,143.91,139.97,134.19,131.92,131.26,129.82,129.11,128.03,125.46,116.06,110.18,86.26,85.18,75.36,46.17,41.68,39.47,27.42,25.92,24.09,23.09,20.31,17.76, MSESI (m/z): 423 [M+Na]
+.
Embodiment 14:
The preparation of compound 15:
12 (100mg, 0.25mmol), CeCl is added in 10mL round-bottomed bottle
37H
2o (9mg, 0.025mmol) and 5mLMeOH is placed in-78 DEG C of cold-traps and stirs 10min, adds NaBH in batches
4(30mg, 0.75mmol), stirs 4h by reaction at-78 DEG C, adds the saturated NH of 2mL
4the quencher of Cl solution is reacted, and adds 5mLEA layering, organic layer saturated common salt washing (5mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and the crude product obtained after draining directly carries out next step reaction.
The crude product that upper step obtains is dissolved in 5mLDCM, adds MnO
2(220mg, 2.5mmol), by this reaction system at stirring at room temperature 8h, reaction solution is through diatomite filtration, and filter cake DCM washes (5mL × 3), merges organic layer and washes (5mL × 3) with saturated common salt, anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and the crude product obtained after draining directly carries out next step reaction.
The crude product that upper step obtains is dissolved in 5mLDCM, adds Morpholine (43 μ L, 0.5mmol) and NaBH
3cN (31mg, 0.5mmol), by this reaction system at stirring at room temperature 12h, adds 2mL water quencher reaction, adds 5mLDCM layering, organic layer saturated common salt washing (5mL × 3), anhydrous Na
2sO
4drying, removes solvent under reduced pressure, and the crude product obtained after draining directly carries out next step reaction.
The crude product that upper step obtains is dissolved in 5mLDCM, add PIDA (160mg, 0.5mmol) with TEMPO (0.5mg, 0.05mmol), by this reaction system at stirring at room temperature 4h, remove solvent under reduced pressure, residuum obtains 21mg compound 15 for yellow oil (18%) through silica gel column chromatography (PE/EA=10/1 ~ 3/1) purifying.
1HNMR(600MHz,CDCl
3)δ6.83(d,J＝16.2Hz,1H),6.27(d,J＝16.1Hz,1H),5.90(t,J＝7.8Hz,2H),5.82(s,1H),5.70(d,J＝16.3Hz,1H),5.40(s,1H),5.29–5.18(m,2H),5.13(t,J＝6.8Hz,1H),3.68(d,J＝14.3Hz,6H),3.43(d,J＝13.7Hz,1H),2.88(d,J＝13.6Hz,1H),2.51(s,2H),2.43(s,3H),2.21(s,3H),2.06(d,J＝4.7Hz,2H),2.00(d,J＝13.0Hz,2H),1.95(s,3H),1.87–1.79(m,2H),1.70(s,3H),1.60(s,12H),1.46–1.38(m,2H),1.25(s,6H),1.04(s,3H),0.90–0.85(m,1H).
13CNMR(150MHz,CDCl
3)δ201.20,165.42,159.11,148.61,144.04,142.19,140.24,132.09,131.04,130.28,126.86,124.44,115.52,111.16,74.96,67.13,63.57,54.00,46.03,40.97,39.15,29.92,27.83,25.94,23.46,23.01,20.65,17.94；MSESI(m/z):468[M+H]
+。
Example of formulations 1:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), inject with water routinely, essence filter, injection liquid is made in embedding sterilizing.
Example of formulations 2:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) salt made, be dissolved in sterile water for injection, stirring makes molten, filters with aseptic suction funnel, more aseptic essence filter, be sub-packed in 2 ampoules, after frozen drying, aseptic sealing by fusing obtains powder injection.
Example of formulations 3:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.), add vehicle with excipient weight than the ratio for 9:1, make pulvis.
Example of formulations 4:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.), add vehicle, pelletizing press sheet in itself and excipient weight than the ratio for 1:5-1:10.
Example of formulations 5:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.), oral liquid method for making makes oral liquid routinely.
Example of formulations 6:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.), add vehicle in itself and excipient weight than the ratio for 5:1, make capsule or granule or electuary.
Example of formulations 7:
By the method first obtained VibsaninB derivative of embodiment 1-13, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.), add vehicle in itself and excipient weight than the ratio for 3:1, make capsule or granule or electuary.
Claims (11)
1. the VibsaninB derivative shown in formula (I) or its pharmaceutical salts,
In formula, lowercase a-d represents independently double bond or singly-bound, uses
represent,
Wherein R
1for-CH
2oH ,-CH
2nH
2,-CHO ,-COOH ,-CH
2x (X=F, Cl, Br) ,-CH=NOR ' ,-CH
2nHOR ' ,-CH
2oC=SSR ' (R ' be H or C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl) ,-CH
2oR " ,-CH
2oC=OR " ,-CH
2(R " is C to NHC=OR " ,-C=OOR "
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls) ,-C=ONR " '
2,-CH
2nR " '
2(R " ' be C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls; Identical and different C
1-10alkyl),
(wherein n=1 – 10, X is CH
2or the heteroatoms such as O, N, S, P, Si, heteroatoms position changeable and can by C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10replace containing heteroatomic ring alkyl, 6 yuan of aryl, 5 to 6 yuan of heteroaryls);
When a is double bond, R
2for O, N, N-OH or N-OMe, S; When a is singly-bound, R
2for H ,-OH, C
1-10alkyl, C
1-10ester group, halogen (F, Cl, Br);
When c is double bond, R
3do not exist; When c is singly-bound, R
3for-OH, halogen (F, Cl, Br), C
1-3alkoxyl group, C
1-10ester group;
When d is double bond, R
4for O, S; When d is singly-bound, R
4for H ,-OH, halogen (F, Cl, Br), C
1-10alkyl amine group, C
1-10ester group, C
1-10unsaturated ester group or containing 6 yuan of aryl ester groups, C
1-10amide group, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls, identical from different C
1-10dialkyl amino, C
1-10alkyl, C
1-3alkoxyl group;
Wherein said C
1-10alkyl, C
1-10alkoxyl group, C
3-C
10cycloalkyl, 5,6 yuan of aryl or heteroaryl are optionally by 1 ~ 3 halogen (F, Cl, Br), hydroxyl, C
1-10alkoxyl group replaces.
2. diterpene VibsaninB derivative as claimed in claim 1 or its pharmaceutical salts, be the diterpene VibsaninB derivative shown in following formula (II), formula (III) or its pharmaceutical salts,
Wherein R
1for-CH
2oH ,-CH
2nH
2,-CHO ,-COOH ,-CH
2x (X=F, Cl, Br) ,-CH=NOR ' ,-CH
2nHOR ' ,-CH
2oC=SSR ' (R ' be H or C
1-10alkyl, C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl) ,-CH
2oR " ,-CH
2oC=OR " ,-CH
2(R " is C to NHC=OR " ,-C=OOR "
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls) ,-C=ONR " '
2,-CH
2nR " '
2(R " ' be C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls; Identical and different C
1-10alkyl),
(wherein n=1 – 10, X is CH
2or the heteroatoms such as O, N, S, P, Si, heteroatoms position changeable and can by C
1-10alkyl; C
3-C
10cycloalkyl, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls replace);
R
4for H ,-OH, halogen (F, Cl, Br), C
1-10alkyl amine group, C
1-10ester group, C
1-10unsaturated ester group or containing 6 yuan of aryl ester groups, C
1-10amide group, C
3-C
10containing heteroatomic ring alkyl; 6 yuan of aryl; 5 to 6 yuan of heteroaryls, identical from different C
1-10dialkyl amino, C
1-10alkyl, C
1-3alkoxyl group.
3. VibsaninB derivative as claimed in claim 2 or its pharmaceutical salts is following compound:
4. VibsaninB derivative as claimed in claim 1 or 2 or its pharmaceutical salts, wherein said pharmaceutical salts refers to pharmacy acceptable salt, refer to the salt formed with organic acid, described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, sulfocyanic acid, tosilate, undecane hydrochlorate.
5. VibsaninB derivative as claimed in claim 3 or its pharmaceutical salts, wherein said pharmaceutical salts refers to pharmacy acceptable salt, refer to the salt formed with organic acid, described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, sulfocyanic acid, tosilate, undecane hydrochlorate.
6. the preparation method of the VibsaninB derivative in claim 1 or the formula (I) shown in 2 or 3, formula (II), formula (III), is characterized in that the method one of comprises the following steps:
(1) by compound vibsaninB acetylize, compound 1 is obtained; By compound vibsaninB chloro, obtain compound 11, then change into compound 2-8 by 11,
(2) by compound vibsaninB DAST process, compound 9 is obtained,
(3) by compound vibsaninB and NaH/CS
2/ MeI is obtained by reacting compound 10,
(4) the C18 position TBS of compound vibsaninB is protected, then use SOCl
2process, then slough TBS protection obtain compound 12,
(5) DAST and CCl is used respectively by compound 12
3cN process obtains compound 13 and 14,
(6) compound 12 is used NaBH
4reduction, then use MnO
2oxidation, then from different secondary amine generation reduction aminations, finally obtains compound 15 with the oxidation of TEMPO/PIDA system,
7. pharmaceutical composition, wherein containing VibsaninB derivative described in claim 1 or 2 or its pharmaceutical salts, and at least one pharmaceutically acceptable carrier and/or vehicle.
8. pharmaceutical composition, wherein containing VibsaninB derivative according to claim 3 or its pharmaceutical salts, and at least one pharmaceutically acceptable carrier and/or vehicle.
9. the VibsaninB derivative described in claim 1 or 2 or the application of its pharmaceutical salts in preparation treatment or preventing cancer medicine.
10. VibsaninB derivative according to claim 3 or the application of its pharmaceutical salts in preparation treatment or preventing cancer medicine.
11. application as described in claim 9 or 10, is characterized in that wherein said cancer is mammary cancer, lung cancer, small cell lung cancer, nonsmall-cell lung cancer, bronchial adenoma and pleura pulmonary blastoma, brain stem and hypothalamus neurospongioma, cerebellum and cerebral astrocytoma, medulloblastoma, ependymoma, schwann's sheath cancer, neuroderm and Pinealoma, prostate cancer, carcinoma of testis, carcinoma of endometrium, carcinoma of uterine body, cervical cancer, ovarian cancer, carcinoma of vagina, carcinoma vulvae, sarcoma of uterus, anus cancer, colorectal carcinoma, esophagus cancer, carcinoma of gallbladder, cancer of the stomach, duodenal cancer, carcinoma of the pancreas, the rectum cancer, carcinoma of small intestine, tongue cancer, glandula cancer, bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter and urethral carcinoma, cancer eye, liver cancer, cholangiocarcinoma, Combination liver cell cholangiocarcinoma, skin carcinoma, head and neck cancer, vascular tumor, bone tumor, lymphoma, vascular fibroma, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, leiomyosarcoma and rhabdosarcoma, jaw knurl, leukemia, thyroid carcinoma, parathyroid carcinoma.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253240.7A CN105237415A (en) | 2015-05-18 | 2015-05-18 | Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253240.7A CN105237415A (en) | 2015-05-18 | 2015-05-18 | Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105237415A true CN105237415A (en) | 2016-01-13 |
Family
ID=55035289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510253240.7A Pending CN105237415A (en) | 2015-05-18 | 2015-05-18 | Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105237415A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114903926A (en) * | 2022-05-05 | 2022-08-16 | 沈阳药科大学 | Vibsane type total diterpene in coral tree leaves as well as preparation method and application thereof |
| CN115974695A (en) * | 2022-12-13 | 2023-04-18 | 沈阳药科大学 | Preparation method and application of Vibsane diterpenoid compounds in coral trees |
| CN115974695B (en) * | 2022-12-13 | 2024-05-03 | 沈阳药科大学 | Preparation method and application of vibsane diterpenoid compounds in coral tree |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007501278A (en) * | 2003-05-19 | 2007-01-25 | ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー | Method for producing 2-alkynyladenosine derivative |
| WO2013163455A2 (en) * | 2012-04-25 | 2013-10-31 | The Regents Of The University Of California | A drug screening platform for rett syndrome |
| CN103772176A (en) * | 2014-02-26 | 2014-05-07 | 中国科学院昆明植物研究所 | Vibsane diterpene derivatives as well as pharmaceutical composition and application thereof |
| CN105367421A (en) * | 2014-08-18 | 2016-03-02 | 上海交通大学医学院附属瑞金医院 | Vibsanin B, preparation method and uses thereof |
-
2015
- 2015-05-18 CN CN201510253240.7A patent/CN105237415A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007501278A (en) * | 2003-05-19 | 2007-01-25 | ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー | Method for producing 2-alkynyladenosine derivative |
| WO2013163455A2 (en) * | 2012-04-25 | 2013-10-31 | The Regents Of The University Of California | A drug screening platform for rett syndrome |
| CN103772176A (en) * | 2014-02-26 | 2014-05-07 | 中国科学院昆明植物研究所 | Vibsane diterpene derivatives as well as pharmaceutical composition and application thereof |
| CN105367421A (en) * | 2014-08-18 | 2016-03-02 | 上海交通大学医学院附属瑞金医院 | Vibsanin B, preparation method and uses thereof |
Non-Patent Citations (9)
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114903926A (en) * | 2022-05-05 | 2022-08-16 | 沈阳药科大学 | Vibsane type total diterpene in coral tree leaves as well as preparation method and application thereof |
| CN114903926B (en) * | 2022-05-05 | 2024-01-30 | 沈阳药科大学 | Vibsane type total diterpene in coral leaves, and preparation method and application thereof |
| CN115974695A (en) * | 2022-12-13 | 2023-04-18 | 沈阳药科大学 | Preparation method and application of Vibsane diterpenoid compounds in coral trees |
| CN115974695B (en) * | 2022-12-13 | 2024-05-03 | 沈阳药科大学 | Preparation method and application of vibsane diterpenoid compounds in coral tree |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107667101A (en) | Quinoline as TAM RTK inhibitor | |
| CN106659706A (en) | Platinum compounds, compositions, and uses thereof | |
| CN105985323A (en) | Novel epidermal growth factor receptor inhibitor and application thereof | |
| CN102311449A (en) | Application of gossypol derivative to preparing anti-tumor medicament | |
| CN103038216A (en) | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases | |
| US9029403B2 (en) | Treatment of ovarian cancer with benzylidenebenzohydrazides | |
| CN104557871A (en) | Arylmorpholine compounds with spiro substituents as well as preparation method and use thereof | |
| CN102558178B (en) | Tabersonine derivative, pharmaceutical compositions, preparing method and medical application thereof | |
| CN109575045A (en) | Thienopyrimidines, preparation method, Pharmaceutical composition and its application | |
| CN104557726A (en) | Aromatic heterocyclic derivatives and application thereof in medicaments | |
| CN104557913A (en) | Pyridopyrimidine compounds as well as preparation method and application thereof | |
| CN103936762B (en) | Morpholine quinolines, Preparation Method And The Use | |
| CN105237415A (en) | Vibsanin B derivatives, pharmaceutical compositions thereof, and applications thereof in pharmacy | |
| CN101941953B (en) | Nitrogenous heterocyclic substituted hydrazide compounds as well as preparation methods and applications thereof | |
| CN103664734A (en) | Heterocyclic hydroxamic acid compound as well as pharmaceutical composition and application thereof | |
| CN104418867A (en) | Compound used as PI3K/mTOR inhibitor, preparation method and application | |
| CN102952151B (en) | 3 double β carbolines alkaloid compounds, its preparation method and its pharmaceutical composition and purposes | |
| CN104402861A (en) | Benzene sulfonamide derivatives, preparation method, and treatment application | |
| CN100532381C (en) | Antineoplastic compound, medicament composition and use thereof | |
| CN102838567A (en) | Benzenesulfonyl piperazine compounds or benzoyl piperazine compounds, preparation methods and uses thereof | |
| CN108164476B (en) | Isophthalonitrile compound, application thereof and medicine containing compound | |
| CN104672213A (en) | Amide compound with antitumor activity, and application thereof | |
| WO2013070998A1 (en) | TREATMENT OF OVARIAN CANCER WITH 2-AMINO-4H-NAPHTHO[1,2-b]PYRAN-3-CARBONITRILES | |
| CN109265396A (en) | The new synthetic method and anticancer activity of polycyclic amide compound | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160113 |