CN109134484A - The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application - Google Patents
The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application Download PDFInfo
- Publication number
- CN109134484A CN109134484A CN201811127461.XA CN201811127461A CN109134484A CN 109134484 A CN109134484 A CN 109134484A CN 201811127461 A CN201811127461 A CN 201811127461A CN 109134484 A CN109134484 A CN 109134484A
- Authority
- CN
- China
- Prior art keywords
- carbon
- alkyl
- branch
- direct
- substituted
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- 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
- A61P31/04—Antibacterial agents
-
- 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
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Cephalotaxine esters and preparation method thereof and pharmaceutical usages.Its general structure is such as shown in (1).The compounds of this invention is widely used in antitumor (pernicious and non-malignant tumors), anti parasitic, antimycotic and antibacterial chemotherapy drug.
Description
Technical field
The invention belongs to chemical syntheses and pharmaceutical technology field, and in particular to a kind of cepehalotaxus fortunei ester with anti-tumor activity
Alkali analog and preparation method thereof and pharmaceutical usage.
Background technique
1970, and Paudler and Powell etc. (Tetrahedron Lett.1970,47,815;Tetrahedron
1972,28,1995) separation identifies four kinds of harringtonines, i.e. harringtonine a from cephalotaxus plant
(Harringtonine, HT), homoharringtonine b (Homoharringtonine, HHT), Deoxyharringtonine c
(Deoxyharringtonine, DHT) and isoharringtonin d (Isoharringtonine, IHT), and find to all have aobvious
The anti-tumor activity of work, wherein it is acute non-lymphocytic for clinical treatment to be loaded into China's pharmacopeia in nineteen ninety by homoharringtonine b
Leukaemia, and clinical application always so far (Chinese Pharmacopoeia nineteen ninety version two, 1990,588;China's coastal port two,
2005,629).
The isolated activity test result of Gin et al. report (Chem.Eur.J.2008,14,4293) shows: tricuspid cephalataxus fortunei ester
The superpower cytotoxicity of alkaloid except show as to hematopoietic cancer cell (HL-60, HL-60/RV+, JURKAT, ALL3, NCEB1,
JEKO, MOLT-3) IC50Value lower than outside 0.1 μM of high pharmaceutical activity, to a variety of solid tumor cancer cells (SKNLP, PC9,
H1650, H1975, H2030, H3255, A431, HeLa, TC71, HTB-15, WD0082) it also shows to be lower than 0.1 μM of IC50Value
High pharmaceutical activity.So cepehalotaxus fortunei aconitines have the efficient anticancer activity of wide spectrum.Self-discovery tricuspid cephalataxus fortunei ester biology
Since alkali, they are always the hot issue of clinic study, as the homoharringtonine of drug candidates and its similar
Object has good potential applicability in clinical practice and potential market.
Although homoharringtonine has been achieved for good effect in terms of clinical treatment leukaemia, bioactivity just
Step result of study shows that this kind of compound also has a very high inhibitory activity to a variety of solid tumors, but the day of homoharringtonine
Right source is rare, chemical synthesis is difficult and hematotoxicity (Leukemia 1998,12,1539) and there are multidrug resistances
The problems such as (i.e. resistance), so that homoharringtonine can be only used to the joint chemotherapy of chronic myelocytic leukemia.From three
Since sharp China fir ester alkali discovery, the structure activity study of this kind of compound is seldom, needs to design, synthesizes more analogs, to
It was found that bioactivity is better than the compound of natural harringtonine.
The invention patent synthesized a series of Cephalotaxine esters, activity test in vitro its dialogue as the result is shown
Blood disease has good inhibiting effect.
Summary of the invention
The purpose of the present invention is to provide the cepehalotaxus fortunei aconitines of a new class of side chain nitrogen atom and its medicinal use
On the way.Cepehalotaxus fortunei aconitines of the present invention can be used for antitumor, antimalarial, anti parasitic, antimycotic and antibacterial chemotherapy
The preparation of drug.
A kind of general structure of optically pure Cephalotaxine esters provided by the invention is such as shown in (1):
In formula, R be hydrogen, 1-20 carbon direct-connected perhaps branch alkyl 1-20 carbon direct-connected or branch alkenyl, 1-20
Direct-connected or branch the alkynyl of carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, the alkyl containing phenyl of 1-20 carbon,
The alkyl of the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or polysubstituted benzyl, 1-20
The alkyl of the substituted or unsubstituted circle heterocyclic ring containing 5-7 for the alkyl 1-20 carbon of carbon replaced containing single perhaps multiple halogen atoms,
Direct-connected or branch the alkyl containing single or multiple a hydroxyl of 1-20 carbon, the alkyl can also include one or more miscellaneous original
Son;R1、R2Be respectively hydrogen, halogen, 1-20 carbon direct-connected perhaps branch alkyl 1-20 carbon direct-connected or branch alkenyl, 1-
Direct-connected or branch the alkynyl of 20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, the hydrocarbon containing phenyl of 1-20 carbon
The alkyl of base, the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or polysubstituted benzyl,
The substituted or unsubstituted circle heterocyclic ring containing 5-7 for the alkyl 1-20 carbon of 1-20 carbon replaced containing single perhaps multiple halogen atoms
The alkyl alkyl containing single or multiple a hydroxyl of alkyl, the direct-connected perhaps branch of 1-20 carbon can also be including one or more
A hetero atom;R3、R4Be respectively oxygen, 1-20 carbon direct-connected perhaps branch alkyl 1-20 carbon direct-connected or branch alkenyl,
Direct-connected or branch the alkynyl of 1-20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, the hydrocarbon containing phenyl of 1-20 carbon
The alkyl of base, the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or polysubstituted benzyl,
The substituted or unsubstituted circle heterocyclic ring containing 5-7 for the alkyl 1-20 carbon of 1-20 carbon replaced containing single perhaps multiple halogen atoms
The alkyl alkyl containing single or multiple a hydroxyl of alkyl, the direct-connected perhaps branch of 1-20 carbon can also be including one or more
A hetero atom;Or R3、R4It is the acyl group that direct-connected or branch the alkyl of the carbon containing 1-20 replaces.
Preferably, compound (1) is selected from following compounds, R1、R2、R3、R4Ibid;R5Selected from the direct-connected of 1-20 carbon or branch
The alkyl of chain, direct-connected or branch the alkynyl of the alkenyl 1-20 carbon of the direct-connected perhaps branch of 1-20 carbon, by one or more 1-
The substituted or unsubstituted member containing 3-7 of the alkyl-substituted phenyl of 4 carbon, the alkyl containing phenyl of 1-20 carbon, 1-20 carbon is cyclic annular
The alkyl of substituent group, the alkyl of monosubstituted perhaps polysubstituted benzyl 1-20 carbon replaced containing single or multiple halogen atoms, 1-20
The alkyl of the substituted or unsubstituted circle heterocyclic ring containing 5-7 of carbon, the alkyl can also include one or more hetero atom.
The present invention is further preferred, is selected from following compounds:
The preparation method of Cephalotaxine esters provided by the invention, method one comprise the following steps that
Synthesis step one: general formula be (10) compound and nitromethane under the effect of the catalyst, in atent solvent
Reaction;Wherein R, R1As defined in claim 1;The solvent of the reaction is halogenated hydrocarbons, ether, tetrahydrofuran;Catalyst is
Quinine and its derivative;The reaction carries out within the temperature range of -30 DEG C~30 DEG C, preferably 0 DEG C~25 DEG C, is led to
Formula is the compound of (11).
Synthesis step two: general formula is the compound and zinc powder, acetic acid of (11), is reacted in atent solvent, wherein R, R1Such as
Defined in claim 1;The solvent of the reaction is alcohol or halogenated hydrocarbons;The reaction is in -30 DEG C~30 DEG C, preferably 0 DEG C~25
It is carried out within the temperature range of DEG C, obtains the compound that general formula is (12).
Synthesis step three: general formula is the compound and triethylamine of (12), and acid anhydrides or acyl chlorides is added, anti-in atent solvent
It answers, wherein R, R1As defined in claim 1;The solvent of the reaction is alcohol or halogenated hydrocarbons;The reaction at -30 DEG C~30 DEG C,
It is carried out within the temperature range of preferably 0 DEG C~25 DEG C, obtains the compound that general formula is (13).
The compound of the present invention, which has, is widely used in antitumor (pernicious and non-malignant tumors), anti parasitic, antimycotic
With the physiological activity of antibacterial chemotherapy.
Cephalotaxine esters provided by the invention can be used for preparing drug, especially inhibit the drug of tumour.To logical
The experiment of the extracorporeal suppression tumor cell of formula (1) compound represented shows that it has well human leukemia tumor cell line
Inhibitory activity.
Compound in the present invention has the activity for inhibiting leukaemia cell very well, thus can be used for preparing and spread out containing this
Drug of the biology as effective component.
Specific embodiment
Above content of the invention is made further specifically by the specific embodiment of embodiment form again below
It is bright.But this should not be interpreted as to the scope of the above subject matter of the present invention is limited to the following embodiments, it is all based on the present invention it is above-mentioned in
Hold realized technology to all belong to the scope of the present invention.
The preparation of 1 cepehalotaxus fortunei aconitines (15) of embodiment
Under argon gas protection, (14) (4mmol) is dissolved in 5mL CH3NO2It in solution, is stirred at room temperature, is then added and urges thereto
Agent A (0.16mmol), continues to stir, and TLC detection moves to room temperature, reaction system is directly through chromatographic column until raw material point disappearance
PE: EA=4: 1 (0.5%Et3N white, amorphous solid (15) and its table isomers, ratio 99: 1) are obtained, yield 95% is urged
Agent recycling 80%.
Compound (15):1H NMR (400MHz, CDCl3) δ 6.61 (s, 1H), 6.54 (s, 1H), 6.07 (d, J=9.7Hz,
1H), 5.90 (d, J=1.6Hz, 1H), 5.84 (d, J=1.6Hz, 1H), 5.08 (s, 1H), 4.12 (d, J=14.1Hz, 1H),
3.81 (d, J=9.8Hz, 1H), 3.72 (d, J=14.4Hz, 1H), 3.69 (s, 3H), 3.48 (s, 1H), 3.16-3.03 (m,
2H), 3.02-2.89 (m, 1H), 2.69-2.55 (m, 2H), 2.38 (dd, J=13.7,6.5Hz, 1H), 2.12-2.00 (m,
1H), 1.99-1.88 (m, 1H), 1.82-1.69 (m, 2H), 1.47-1.26 (m, 4H), 1.06-0.92 (m, 1H), 0.86 (d, J
=6.4Hz, 3H), 0.84 (d, J=6.4Hz, 4H) ppm.
The preparation of 2 cepehalotaxus fortunei aconitines (16) of embodiment
Compound (15) (2mmol) is dissolved in 3mL AcOH, is placed at 0 DEG C, Zn powder is then added portionwise thereto
(40mmol) moves to room temperature and continues to stir, and TLC, which is detected to raw material point, to disappear, and mixed liquor is filtered through diatomite, and ether washs diatom
Soil obtains filtrate, and 20mL ether is added into filtrate and 10mL is saturated NaCO3Solution, stirs 10min, liquid separation, and water phase is extracted with ether
It takes, merges organic phase, washed with saturated common salt, set anhydrous Na2SO4After drying, vacuum concentration, crude product is through post separation CH2Cl2∶
CH3OH=20: 1 obtains product yield 88%.
Compound (16): 1H NMR (400MHz, CDCl3) δ 6.67 (s, 1H), 6.60 (s, 1H), 5.95 (d, J=
9.7Hz, 1H), 5.87 (s, 1H), 5.85 (s, 1H), 5.05 (s, 1H), 3.79 (d, J=9.7Hz, 1H), 3.67 (s, 3H),
3.18-3.05 (m, 2H), 2.93 (td, J=11.6,7.0Hz, 1H), 2.64-2.58 (m, 2H), 2.40 (dd, J=14.1,
6.9Hz, 1H), 2.34 (d, J=13.3Hz, 1H), 2.22 (d, J=13.4Hz, 1H), 2.05-1.99 (m, 1H), 1.93-1.86
(m, 1H), 1.79-1.72 (m, 3H), 1.55-1.41 (m, 2H), 1.39-1.29 (m, 1H), 1.28-1.21 (m, 3H), 1.01-
0.92 (m, 1H), 0.85 (d, J=6.7,3H), 0.84 (d, J=6.7,3H) ppm.
The preparation of 3 cepehalotaxus fortunei aconitines (5) of embodiment
At 0 DEG C, compound (16) (1mmol) is dissolved in 5mL CH2Cl2In solution, Et is then added thereto3N
(3mmol continues to stir, and chloroacetic chloride (1.2mmol) then is added dropwise thereto, is added dropwise and moves to room temperature, and TLC detection is until former
Shots disappear, and full NaHCO is added3Solution quenching reaction, water phase CH2Cl2Extraction merges organic phase, is washed with saturation NaCl,
Set anhydrous Na2SO4After drying.Vacuum concentration, residue column chromatograph PE: EA=8: 1 (0.5%Et3N the unsetting production of white) is obtained
Object, yield 92%.
Compound (5):1H NMR (400MHz, CDCl3) δ 6.69 (s, 1H), 6.65 (s, 1H), 5.97 (d, J=9.6Hz,
1H), 5.92 (s, 1H), 5.86 (s, 1H), 5.04 (s, 1H), 4.66 (s, 1H), 3.83 (s, 1H), 3.80 (d, J=9.8Hz,
1H), 3.67 (s, 3H), 3.48 (ddd, J=14.2,7.7,3.0Hz, 1H), 3.19-3.03 (m, 2H), 2.97-2.87 (m,
1H), 2.65-2.54 (m, 2H), 2.41 (ddd, J=14.2,7.7,3.0Hz, 1H), 2.47-2.32 (m, 1H), 2.07-1.95
(m, 1H), 1.93-1.87 (m, 1H), 1.85 (s, 3H), 1.80-1.71 (m, 2H), 1.56-1.39 (m, 3H), 1.35-1.25
(m, 1H), 1.05-0.91 (m, 1H), 0.85 (d, J=6.7,3H), 0.84 (d, J=6.7,3H) ppm.
The preparation of 4 cepehalotaxus fortunei aconitines (6) of embodiment
With the method for embodiment 3, this title compound (6) faint yellow solid product (yield 88%) is obtained.
Compound (6):1H NMR (400MHz, Chloroform-d) δ 7.28 (t, J=7.2Hz, 2H), 7.21 (m, 1H),
7.16 (d, J=7.2Hz, 2H), 6.61 (s, 1H), 6.34 (s, 1H), 5.80 (d, J=9.7Hz, 1H), 5.76 (s, 2H),
5.03-4.99 (m, 1H), 4.98 (s, 1H), 3.64 (d, J=9.7Hz, 1H), 3.60 (s, 3H), 3.52 (s, 1H), 3.42 (d, J
=15.5Hz, 1H), 3.36 (d, J=15.5Hz, 1H), 3.34 (dd, J=13.8,7.6Hz, 1H), 3.13-2.96 (m, 2H),
2.91-2.79 (m, 1H), 2.57-2.46 (m, 2H), 2.35 (dd, J=14.1,6.8Hz, 1H), 2.16 (dd, J=13.8,
4.5Hz, 1H), 2.00-1.88 (m, 1H), 1.88-1.77 (m, 1H), 1.74-1.65 (m, 2H), 1.44-1.24 (m, 3H),
1.23-1.10 (m, 2H), 0.75 (d, J=6.6,3H) 0.74 (d, J=6.6,3H) ppm.
The preparation of 5 cepehalotaxus fortunei ester alkaloids analog (7) of embodiment
With the method for embodiment 3, this title compound (7) faint yellow solid product (yield 92%) is obtained.
Compound (7):1H NMR (400MHz, CDCl3) δ 6.67 (s, 1H), 6.58 (s, 1H), 6.02 (s, 1H), 5.92
(d, J=9.8Hz, 1H), 5.90 (d, J=1.6Hz, 1H), 5.87 (d, J=1.6Hz, 1H), 5.09 (s, 1H), 3.80 (d, J=
9.7Hz, 1H), 3.68 (s, 3H), 3.37 (dd, J=13.7,7.8Hz, 1H), 3.16-3.07 (m, 2H), 3.06 (s, 1H),
2.94 (td, J=11.5,6.8Hz, 1H), 2.68-2.54 (m, 2H), 2.49-2.36 (m, 2H), 2.04 (dt, J=12.0,
9.5Hz, 1H), 1.90 (ddd, J=12.1,7.8,4.2Hz, 1H), 1.82-1.68 (m, 2H), 1.58-1.39 (m, 3H),
1.28-1.13 (m, 1H), 0.95-0.87 (m, 1H), 0.84 (d, J=6.6Hz, 3H), 0.83 (d, J=6.6Hz, 3H) ppm.
The preparation of 6 cepehalotaxus fortunei ester alkaloids analog (8) of embodiment
With the method for embodiment 3, this title compound (8) faint yellow solid product (yield 88%) is obtained.
Compound (8):1H NMR (400MHz, CDCl3) δ 6.67 (s, 1H), 6.58 (s, 1H), 6.03 (s, 1H), 5.92
(d, J=9.8Hz, 1H), 5.87 (d, J=1.4Hz, 1H), 5.86 (d, J=1.4Hz, 1H), 5.09 (s, 1H), 3.80 (d, J=
9.6Hz, 1H), 3.68 (s, 3H), 3.37 (dd, J=13.7,7.8Hz, 1H), 3.15-3.04 (m, 3H), 3.00-2.88 (m,
1H), 2.64-2.44 (m, 4H), 2.10-1.97 (m, 1H), 1.96-1.85 (m, 1H), 1.82-1.69 (m, 2H), 1.58-1.38
(m, 3H), 1.27-1.14 (m, 1H), 0.95-0.88 (m, 1H), 0.85 (d, J=6.6Hz, 3H), 0.84 (d, J=6.6Hz,
3H)ppm.
The preparation of 7 cepehalotaxus fortunei ester alkaloids analog (9) of embodiment
At room temperature, compound (16) (1mmol) is dissolved in the aqueous solution of 5mL formaldehyde (10%), is then added thereto
HCOOH (3mmol), temperature rise to 60 DEG C and continue to stir, and full NaHCO is added until raw material point disappearance in TLC detection3Solution is quenched
Reaction, water phase CH2Cl2Extraction merges organic phase, with saturation NaCl washing, sets anhydrous Na2SO4After drying.Vacuum concentration, it is residual
Excess column chromatographs PE: EA=7: 1 (0.5%Et3N the unsetting product of white, yield 90%) are obtained.
Compound (9):1H NMR (400MHz, CDCl3) δ 6.66 (s, 1H), 6.56 (s, 1H), 5.98 (d, J=9.7Hz,
1H), 5.87 (s, 2H), 5.01 (s, 1H), 3.75 (d, J=9.8Hz, 1H), 3.65 (s, 3H), 3.27-3.13 (m, 1H),
3.14-3.03 (m, 1H), 3.00-2.87 (m, 1H), 2.66-2.53 (m, 2H), 2.40 (dd, J=14.3,6.9Hz, 1H),
2.06-1.99 (m, 1H), 2.00 (s, 6H), 1.98 (s, 1H), 1.94-1.82 (m, 1H), 1.81-1.70 (m, 3H), 1.51-
1.35 (m, 2H), 1.37-1.22 (m, 3H), 1.00-0.91 (m, 1H), 0.83 (d, J=7.0Hz, 3H), 0.82 (d, J=
7.0Hz, 3H) ppm.
13 cepehalotaxus fortunei aconitines anti-tumor biological body outer screening test of embodiment
Using the screening technique of tetrazolium (Methyl-Thiazol-Tetrozolium, MTT) reduction method, it is white to make employment
Blood disease cell line HL-60, action time are 72 hours.It the results are shown in Table 1.
Table 1: to the inhibiting rate % of human leukemia tumor cell line HL-60 growth
Claims (7)
1. a kind of optically pure Cephalotaxine esters, it is characterised in that it has the structural compounds as shown in formula (1), R
Indicate the group of last-in-chain(LIC) end part;In formula: R be hydrogen, 1-20 carbon direct-connected perhaps branch alkyl 1-20 carbon direct-connected or branch
The alkenyl of chain, direct-connected or branch the alkynyl of 1-20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, 1-20 carbon
The alkyl of alkyl containing phenyl, the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or takes more
The benzyl in generation, the substituted or unsubstituted of the alkyl 1-20 carbon of 1-20 carbon replaced containing single perhaps multiple halogen atoms contain 5-7
The alkyl of circle heterocyclic ring, direct-connected or branch the alkyl containing single or multiple a hydroxyl of 1-20 carbon, the alkyl can also include one
A or multiple hetero atoms;R1、R2Direct-connected or branch the alkyl of hydrogen, halogen, 1-20 carbon respectively, 1-20 carbon direct-connected or
The alkenyl of person's branch, direct-connected or branch the alkynyl of 1-20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, 1-20
The alkyl of the alkyl containing phenyl of carbon, the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon it is monosubstituted or
Polysubstituted benzyl, 1-20 carbon containing single perhaps multiple halogen atoms replace alkyl 1-20 carbon it is substituted or unsubstituted
The alkyl of the circle heterocyclic ring containing 5-7, direct-connected or branch the alkyl containing single or multiple a hydroxyl of 1-20 carbon, the alkyl can also wrap
Include one or more hetero atom;R3、R4Be respectively oxygen, 1-20 carbon direct-connected perhaps branch alkyl 1-20 carbon direct-connected or
The alkenyl of branch, direct-connected or branch the alkynyl of 1-20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, 1-20 carbon
The alkyl containing phenyl, the alkyl of the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or more
The substituted or unsubstituted of alkyl 1-20 carbon of substituted benzyl, 1-20 carbon replaced containing single perhaps multiple halogen atoms contains
The alkyl of 5-7 circle heterocyclic ring, direct-connected or branch the alkyl containing single or multiple a hydroxyl of 1-20 carbon, the alkyl can also include
One or more hetero atom;Or R3、R4It is the acyl group that direct-connected or branch the alkyl of the carbon containing 1-20 replaces.
。
2. Cephalotaxine esters described in accordance with the claim 1, it is characterised in that: compound (1) is selected from following compounds,
R1、R2、R3、R4Ibid;R5Direct-connected or branch the alkenyl of the alkyl 1-20 carbon of direct-connected perhaps branch selected from 1-20 carbon, 1-
Direct-connected or branch the alkynyl of 20 carbon, by one or more alkyl-substituted phenyl of 1-4 carbon, the hydrocarbon containing phenyl of 1-20 carbon
The alkyl of base, the substituted perhaps unsubstituted cyclic substituents of member containing 3-7 of 1-20 carbon is monosubstituted or polysubstituted benzyl,
The substituted or unsubstituted circle heterocyclic ring containing 5-7 for the alkyl 1-20 carbon of 1-20 carbon replaced containing single perhaps multiple halogen atoms
Alkyl, the alkyl can also include one or more hetero atom.
。
3. Cephalotaxine esters according to claim 2, it is characterised in that it is selected from following compounds:
。
4. the synthetic method of Cephalotaxine esters described in claim 1, it is characterised in that including synthetic method step
It is rapid:
Synthesis step one: the compound and nitromethane that general formula is (10) under the effect of the catalyst, react in atent solvent;
Wherein R, R1As defined in claim 1;The solvent of the reaction is halogenated hydrocarbons, ether, tetrahydrofuran;Catalyst is quinine
Alkali and its derivative;The reaction carries out within the temperature range of -30 DEG C~30 DEG C, preferably 0 DEG C~25 DEG C, obtains general formula and is
(11) compound.
Synthesis step two: general formula is the compound and zinc powder, acetic acid of (11), is reacted in atent solvent, wherein R, R1As right is wanted
It asks defined in 1;The solvent of the reaction is alcohol or halogenated hydrocarbons;The reaction is at -30 DEG C~30 DEG C, preferably 0 DEG C~25 DEG C of temperature
It spends in range and carries out, obtain the compound that general formula is (12).
Synthesis step three: general formula is the compound and triethylamine of (12), and acid anhydrides or acyl chlorides is added, reacts in atent solvent,
Wherein R, R1As defined in claim 1;The solvent of the reaction is alcohol or halogenated hydrocarbons;The reaction is at -30 DEG C~30 DEG C, preferably
It is to carry out within the temperature range of 0 DEG C~25 DEG C, obtains the compound that general formula is (13).
5. according to the method for claim 4, it is characterised in that the catalyst is quinine and its derivative.
6. the application of Cephalotaxine esters described in claim 1, it is characterised in that be used to prepare antitumor, anti-parasitism
Worm, antimycotic and antibacterial chemotherapy drug.
7. the application of Cephalotaxine esters according to claim 7, it is characterised in that be used to prepare antitumor, anti-
Malaria, anti parasitic, antimycotic and antibacterial drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811127461.XA CN109134484A (en) | 2018-09-26 | 2018-09-26 | The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811127461.XA CN109134484A (en) | 2018-09-26 | 2018-09-26 | The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109134484A true CN109134484A (en) | 2019-01-04 |
Family
ID=64812550
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811127461.XA Pending CN109134484A (en) | 2018-09-26 | 2018-09-26 | The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109134484A (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009148654A2 (en) * | 2008-03-03 | 2009-12-10 | Sloan-Kettering Institute For Cancer Research | Cephalotaxus esters, methods of synthesis, and uses thereof |
-
2018
- 2018-09-26 CN CN201811127461.XA patent/CN109134484A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009148654A2 (en) * | 2008-03-03 | 2009-12-10 | Sloan-Kettering Institute For Cancer Research | Cephalotaxus esters, methods of synthesis, and uses thereof |
Non-Patent Citations (2)
Title |
---|
HONGMING LI等: "Enantioselective Nitroaldol Reaction of r-Ketoesters Catalyzed by Cinchona Alkaloids", 《J. AM. CHEM. SOC.》 * |
段行信著: "《实用精细有机合成手册》", 31 January 2000 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2684884B1 (en) | Novel compounds obtained from gamboge resin, and medical uses of the same | |
CN108299458B (en) | Oridonin derivative and preparation method and application thereof | |
JP2009280610A (en) | Compound isolated from gamboge resin having activity in inhibiting growth of tumor/cancer cells and pharmaceutical composition comprising the same | |
Bishara et al. | Salarins D–J, seven new nitrogenous macrolides from the madagascar sponge Fascaplysinopsis sp. | |
CN106928080A (en) | Fused rings γ amino acid derivativges and preparation method thereof and in application pharmaceutically | |
US10493056B2 (en) | Method of use of diterpenoid derivatives as anticancer agents | |
Meesakul et al. | Styryllactones from Goniothalamus tamirensis | |
CN109134484A (en) | The cepehalotaxus fortunei aconitines of side chain nitrogen atom and its preparation and application | |
Miguelez et al. | Simplification of antitumoral phenanthroindolizidine alkaloids: Short synthesis of cytotoxic indolizidinone and pyrrolidine analogs | |
CN102675327B (en) | Harringtonine alkaloid and preparation method and application thereof | |
CN110950880B (en) | Cephalotaxus fortunei ester alkaloid with side chain end containing heterocycle and preparation and application thereof | |
KR20080075911A (en) | Antitumor compounds | |
Luo et al. | Uncommon bis-amide matrine-type alkaloids from Sophora alopecuroides with anti-inflammatory effects | |
CN102746226A (en) | Acridine derivative and preparation method and application thereof | |
CN110407850A (en) | (5R) -5- hydroxy triptolide derivative and its preparation method and application | |
Hu et al. | Regioselective and stereoselective photodimerization of securinine-type and norsecurinine-type alkaloids | |
JP2009274956A (en) | Malignant tumor-treating agent originated from neem seed | |
Charrier et al. | A new derivative detected in accelerated ageing of artesunate-amodiaquine fixed dose combination tablets | |
CN113004268B (en) | Thiazole compound for inhibiting tumor cell growth and application thereof | |
CN111018780B (en) | N-carbonyl-9, 10-dihydroacridine compound and application thereof | |
CN101792449B (en) | Raubasine derivative, preparation and application thereof | |
RU2479582C1 (en) | Labdane-type 6-hydroxynaphthoquinones, having cytotoxic activity on human tumour cells | |
CN106748973A (en) | Two kinds of Azide medicines and its preparation method and application | |
CN116925021A (en) | Dehydrocostuslactone alkylated derivative and salt thereof, pharmaceutical composition and application thereof | |
CN101307041B (en) | Novel taxane halogenation derivates with anti-tumor activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190104 |