CN104860993B - A kind of chromocor compound prodrug and application thereof - Google Patents
A kind of chromocor compound prodrug and application thereof Download PDFInfo
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Abstract
The invention provides a kind of chromocor compound prodrug, its pharmaceutically acceptable salt or solvate, shown in the prodrug such as following formula (I), the present invention is by by the hydrogen sulfate or sulfuric ester, carbonate or carbonic ester of hydroxyl, and phosphate or phosphate substitution, the prodrug of above chromocor compound has been made.The prodrug overcomes the low defect of original chromocor compound poorly water-soluble, bioavailability
Description
Technical field
The present invention relates to a kind of prodrug of chromocor compound and application thereof, belong to field of medicaments.
Background technology
Chromocor compound, is to be present in nature, with 2- phenyl chromone parent nucleus, the class as shown in following formula (A)
Compound.Because have in this kind of compound molecule a ketone carbonyl group, primary oxygen atom have alkalescence, can with strong acid into salt,
It is in yellow more its hydroxy derivatives, therefore is referred to as flavones.
There are some researches prove chromocor compound has multiple biological activities, such as treats cardiovascular system activity, antibacterial and resists
Virus activity, antitumor activity, resisting oxidation free radical activity, anti-inflammatory and antalgic activity and liver-protecting activity etc..
At present, more and more specific chromocor compounds come into drug development process, and achieve Recent Progresses In The Development.Example
A kind of isopentene group flavonoid compound and this compound are such as disclosed in 201110137006.X Chinese patent application
Suppressing the effect of lipase, shown in the molecule such as following formula (B) of the isopentene group flavonoid compound：
This chromocor compound is to separate to obtain from Bai Guimu.
Substitution chromocor compound, and this chemical combination are disclosed in the Chinese patent of Application No. 201410376529.3
The antitumor action of thing.Wherein the patent application is replaced a hydrogen atom of the B phenyl ring of flavones with benzyl, such as following formula
(C) shown in：
Obtaining new compound can be with Bc1-2, Bc1-xLPreferably combined with Mcl-1 albumen, therefore more than preparation
There is good future in the related tumour of albumen.
Chromocor compound glyurallin B are disclosed in the Chinese patent of Application No. 201310112169.1 to be used for
The medicine of tumour is treated, wherein shown in glyurallin B such as following formulas (D),
This compound derives from radix glycyrrhizae.
A Kelading, also known as icariine, epimedium aglucone, are that isolated main work is extracted from Herba Epimedii
Property the new effective monomer that is obtained through enzymatic conversion of composition icariin, shown in its structural formula such as following formula (E)：
A Kela is refer in the Chinese patent application of Application No. 200780039276.9 and is scheduled on prepare abnormal cell
Propagation, the particularly purposes in cancer drug.A Kela is proposed in the Chinese patent of Application No. 03129242.9 to be scheduled on
Prepare the application in SERM.
But, although chromocor compound disclosed above has good pharmaceutical activity, but these compounds have one
Common shortcoming：I.e. dissolubility is poor in water, and after the oral formulations derivatives administration being made, organism utilization rate is very low.Therefore, urgently
The pro-drugs of more than one chromocor compounds to be developed, the prodrug has good water-soluble, bioavailability height.
The content of the invention
It is an object of the present invention to provide the conjunction of a kind of prodrug of chromocor compound, its pharmaceutically acceptable salt or solvent
Thing.
It is a further object of the present invention to provide the prodrug of chromocor compound of the present invention, its pharmaceutically acceptable salt or solvent
The purposes of compound.
One aspect of the present invention provides a kind of chromocor compound prodrug, its pharmaceutically acceptable salt or solvate, should
Shown in prodrug such as following formula (I)：
Wherein：R1、R2And R3Be each independently selected from H, WithIn one or more, one or more of the wherein M in H, Na, K and ammonium, X be selected from Ca or Mg, R5And R6
It is independently selected from H, (C1-6) alkyl, substitution alkyl, substituted alkoxy, cycloalkyl, substituted cycloalkyl, amino, substituted-amino
And the one or more in the cycloalkyl containing hetero atom N or O, described R4Selected from H, halogen atom, hydroxyl, hydroxyl (C1-6)
The alkyl, (C replaced containing one or more halogen atoms1-6) alkyl, alkoxy and (C2-6) one or more in alkenyl.
Preferably, the cycloalkyl containing hetero atom N takes selected from piperidyl, alkyl-substituted piperidyl, piperazinyl and alkyl
One or more in the piperazinyl in generation.
It is highly preferred that described R4Selected from H, halogen atom, hydroxyl, hydroxyl (C1-6) alkyl, contain one or more halogen atoms
(the C of substitution1-6) alkyl and (C2-6) one or more in alkenyl.
Most preferably, described R4One or more in H, methoxyl group, trifluoromethyl and isopentene group.
Preferably, wherein one kind in alkylammonium, substitution alkylammonium, aryl ammonium and substituted aryl ammonium of described ammonium or
It is several.
Preferably, wherein shown in the prodrug such as following formula (II)：
Wherein：R1、R2And R3Be each independently selected from H, WithIn one or more, one or more of the wherein M in H, Na, K and ammonium, X be selected from Ca or Mg, R5And R6
It is independently selected from H；The alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alcoxyl of phosphoric acid substitution
Base；The alkoxy of sulfuric acid substitution；The alkoxy of carboxylic acid-substituted；The cycloalkyl and amino, carboxylic of amino, carboxyl or phosphate substitution
One or more in base or the cycloalkyl containing hetero atom N or O of phosphate substitution.
Preferably, shown in the prodrug such as following formula (III)：
Wherein：R1And R3Be each independently selected from H, WithIn one or more, one or more of the wherein M in H, Na, K and ammonium, X be selected from Ca or Mg, R5And R6
It is independently selected from H；The alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alcoxyl of phosphoric acid substitution
Base；The alkoxy of sulfuric acid substitution；The alkoxy of carboxylic acid-substituted；The cycloalkyl and amino, carboxylic of amino, carboxyl or phosphate substitution
One or more in base or the cycloalkyl containing hetero atom N or O of phosphate substitution.
Preferably, wherein shown in the prodrug such as following formula (IV)：
Wherein：R1Selected from H,WithIn
The one or more of one or more, wherein M in H, Na, K and ammonium, X is selected from Ca or Mg；R5And R6It is independently selected from
H；The alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alkoxy of phosphoric acid substitution；The alkane of sulfuric acid substitution
Epoxide；The alkoxy of carboxylic acid-substituted；Amino, the cycloalkyl and amino of carboxyl or phosphate substitution, carboxyl or phosphate substitution
The cycloalkyl containing hetero atom N or O in one or more.
Preferably, shown in the prodrug such as following formula (V)：
Wherein：R1、R2And R3Be each independently selected from H, WithIn one or more, one or more of the wherein M in H, Na, K and ammonium, X be selected from Ca or Mg；R5And R6
It is independently selected from H, the alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alcoxyl of phosphoric acid substitution
Base；The alkoxy of sulfuric acid substitution；The alkoxy of carboxylic acid-substituted；The cycloalkyl and amino, carboxylic of amino, carboxyl or phosphate substitution
One or more in base and the cycloalkyl containing hetero atom N or O of phosphate substitution.
Preferably, wherein shown in the prodrug such as following formula (VI)：
Wherein：R1And R3Be each independently selected from H, WithIn one or more, one or more of the wherein M in H, Na, K and ammonium, X be selected from Ca or Mg；R5And R6
It is independently selected from H, the alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alcoxyl of phosphoric acid substitution
Base；The alkoxy of sulfuric acid substitution；The alkoxy of carboxylic acid-substituted；The cycloalkyl and amino, carboxylic of amino, carboxyl or phosphate substitution
One or more in base or the cycloalkyl containing hetero atom N or O of phosphate substitution.
Preferably, wherein shown in the prodrug such as following formula (VII)：
Wherein：R1Selected from H,WithIn
The one or more of one or more, wherein M in H, Na, K and ammonium, X is selected from Ca or Mg；R5And R6It is independently selected from
H, the alkyl of phosphoric acid substitution；The alkyl of sulfonic acid substitution；The alkyl of carboxylic acid-substituted；The alkoxy of phosphoric acid substitution；The alkane of sulfuric acid substitution
Epoxide；The alkoxy of carboxylic acid-substituted；Amino, the cycloalkyl and amino of carboxyl or phosphate substitution, carboxyl or phosphate substitution
The cycloalkyl containing hetero atom N or O in one or more.
Prodrug, its pharmaceutically acceptable salt or the solvate that another aspect of the present invention provides the present invention are preparing use
Purposes in the medicine for the treatment of malignancy disease.
Preferably, wherein the medicine that described medicine is administered for oral administration or intravenous injection.
The beneficial effects of the present invention are：Female ring of the present invention 3,5 and 7 be hydroxyl, 8 be isopentene group flavones
Compound has an indissoluble in water, the low property of bioavailability, and the present invention is by by hydrogen sulfate or sulfuric ester, the carbonic acid of hydroxyl
Salt or the substitution of carbonic ester and phosphate or phosphate, have been made the prodrug of above chromocor compound.The prodrug overcomes original
The low defect of chromocor compound poorly water-soluble, bioavailability.The profit of the oral formulations being made up of the prodrug in vivo
Former chromocor compound is significantly stronger than with rate.And it is dissolved in the water by the prodrug, it is easier to intravenous form is made.
Embodiment
Following examples are only used for, to of the invention illustrative, the limitation present invention being not used in, in present invention protection
In the range of modification, change, the modification made etc. it is all within the scope of the present invention.
Unless otherwise indicated, " chromocor compound " herein is referred to flavones parent nucleus, in flavones parent nucleus B phenyl ring
Contraposition is with/without substituent, and the hydrogen atom on 8, the A rings of flavones parent nucleus is replaced by isopentene group, and the 3rd, the H of 5 and 7
Shown in the flavone compound that atom is replaced by hydroxyl, such as following formula (F)：
Unless otherwise indicated, term herein " prodrug " is also referred to as " pro-drug ", " prodrug ", " premedicant
Thing ", refer to be that medicine is obtained after modifying for chemical structure it is inactive in vitro or active smaller, in vivo through enzyme or non-
The conversion of enzyme discharges active medicine and plays the compound of drug effect.Pro-drug does not have bioactivity or bioactivity very in itself
It is low, it is changed into active material after metabolism in vivo, this process purpose is to increase the bioavilability of medicine, strengthens target
Tropism, reduces toxicity or the side effect of medicine.By modifying chromocor compound in the present invention, obtained prodrug be in order to
Increase the bioavilability of chromocor compound.
Unless otherwise indicated, term herein " chromocor compound prodrug " is referred to 3,5,7 of formula (F) compound
The class that the hydrogen phosphate or phosphate of hydroxyl, carbonate or carbonic ester and sulfate or sulfate group substitution are obtained is such as
Compound shown in formula (I).
Unless otherwise indicated, term herein " oral administration " refers to medicine by being absorbed into by intestines and stomach after oral
Blood, reaches by blood circulation and locally or systemically organizes, so as to reach the drug administration method of therapeutic purposes.
Unless otherwise indicated, term herein " intravenously administrable " refers to that medicine is directly entered blood circulation by vein
Medication.
Unless otherwise indicated, " HPO (OtBu) herein2Represent " phosphorous acid di tert butyl carbonate ", it is used as and each flavones
The reagent that the hydroxyl of compound is esterified, purchased from splendid remote scientific and technological (Shanghai) Co., Ltd., article number is SY007356.
Unless otherwise indicated, " DIPEA " expressions " DIPEA " herein its as and each flavones
Acid binding agent in compound esterification reaction process, purchased from purchased from splendid remote scientific and technological (Shanghai) Co., Ltd., article number is SY001426.
Unless otherwise indicated, " DMAP " herein represents DMAP, and it is used as each chromocor compound ester
Catalyst during change, purchased from purchased from purchased from splendid remote scientific and technological (Shanghai) Co., Ltd., article number is SY001509.
Unless otherwise indicated, " TMSBr " herein represents bromotrimethylsilane, and it is used as hydrolysis t-butyl phosphate ester,
Purchased from purchased from purchased from splendid remote scientific and technological (Shanghai) Co., Ltd., article number is SY001686.
Unless otherwise indicated, " DCM " herein is represented, it is used as dichloromethane, purchased from Aladdin Reagent Company, commodity
Number be D116146.
Unless otherwise indicated, " DMF " herein represents DMF, and it is used as reaction dissolvent, purchased from purchase
From Aladdin Reagent Company, article number is D111998.
Unless otherwise indicated, " pyridine. sulfur trioxide complex compound " herein, it is used as sulfonating reagent, purchased from Shao Yuan sections
Skill (Shanghai) Co., Ltd., article number is SY001037.
Unless otherwise indicated, " triphosgene " herein refers to trichloromethyl carbonate, and it is used for methyl esterification reagent, purchase
From purchased from splendid remote scientific and technological (Shanghai) Co., Ltd., goods number is SY001885.
Embodiment 1
A Kelading preparation
A Kelading also known as icariine, are to extract isolated from Herba Epimedii, its structure such as following formula (G) institute
Show.
The preparation method of icariine is disclosed in Publication No. CN101302548 patent.This method is with barrenwort
Glycosides is raw material, is hydrolyzed with beta-glucosidase, and the precipitation acetone solution that hydrolysate centrifugation is obtained, centrifugal filtration is obtained
Supernatant.The supernatant that centrifugation is obtained again is recrystallized with water, obtains icariine sterling, and icariine sterling is in yellow
Powdered crystal.Icariin in the present invention is purchased from company of Shanxi Jiahe Plant Chemical Co., Ltd., purity 90%.
Embodiment 2
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones)
The synthesis and identification of di(2-ethylhexyl)phosphate sodium ester (compound of formula I), synthetic route are as follows：
Compound H 3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzo pyrroles
Mutter -4- ketone) preparation of diethyl phosphate
By compound G 3,5,7- trihydroxies -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzene
And pyrans -4- ketone) (7.4g, 20mmol, 1.0eq) be dissolved in 100ml anhydrous tetrahydro furans (THF), add DIPEA (15ml,
83.7mmol, 4.2eq), stir, add DMAP (0.24g, 2mmol, 10%mol), be cooled to -10 DEG C, be slowly added dropwise
CCl4(3ml, 31mmol, 1.5eq), the anhydrous THF solution 10ml of diethyl phosphite (3.32g, 2.4mmol, 1.2eq) delays
Slow to be warmed to room temperature reaction, (silica gel plate material containing, solvent is ethyl acetate and petroleum ether 1 to thin-layer chromatography：2,254nm uviol lamps show
Color) monitor complete to compound G reactions.Be concentrated under reduced pressure removing THF, adds 200ml dichloromethane and 200ml water, shakes up, point
Liquid.Organic phase with saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous sodium sulfate drying, filters out drier successively, concentrates
To remnants about 50ml, petroleum ether crystallization is slowly added dropwise under stirring.Petroleum ether 110ml is added dropwise altogether, suction filtration obtains compound H sterlings
6.5g, yield:64%.
Compound H carries out magnetic resonance detection, and testing result is as follows：H1-NMR(DMSO,ppm):12.46 (s, 1H),
9.77 (s, 1H), 8.14 (d, J=8.8Hz, 2H), 7.13 (d, J=8.8Hz, 2H), 6.73 (s, 1H), 5.15 (s, 1H), 4.22
(m, 4H), 3.84 (s, 3H), 3.53 (d, J=6.4Hz, 2H), 1.75 (s, 3H), 1.64 (s, 3H), 1.30 (m, 6H).
P31-NMR(DMSO,ppm):-7.0(m)。
Disposing mother liquor, isolate and purify as shown in following formula (1) accessory substance bisphosphate, the accessory substance two as shown in following formula (2)
Phosphate and the accessory substance triguaiacyl phosphate as shown in following formula (3).
Formula (1) compound nuclear magnetic resoance spectrum
H1-NMR(DMSO,ppm):12.24 (s, 1H), 7.93 (d, J=8.8Hz, 2H), 7.19 (d, J=8.8Hz, 2H),
6.83 (s, 1H), 5.16 (s, 1H), 4.07-4.22 (m, 8H), 3.87 (s, 3H), 3.50 (d, J=6.8Hz, 2H), 1.69 (s,
3H), 1.63 (s, 3H), 1.30-1.17 (m, 12H).P31-NMR(DMSO,ppm):- 3.9 (m), -6.0 (m).
Formula (2) compound nuclear magnetic resoance spectrum
H1-NMR(DMSO,ppm):9.41 (s, 1H), 8.12 (d, J=8.8Hz, 2H), 7.35 (s, 1H), 7.13 (d, J=
8.5Hz, 2H), 5.17 (s, 1H), 4.33 (m, 4H), 4.23 (m, 4H), 3.84 (s, 3H), 3.62 (d, J=6.0Hz, 2H),
1.77 (s, 3H), 1.64 (s, 3H), 1.32 (m, 12H).
P31-NMR(DMSO,ppm):-6.49(m),-6.89(m)。
Formula (3) compound nuclear magnetic resoance spectrum
H1- NMR (DMSO, ppm):7.91 (d, J=8.5Hz, 2H), 7.40 (s, 1H), 7.18 (d, J=8.5Hz, 2H),
5.17 (s, 1H), 4.31 (m, 4H), 4.22 (m, 4H), 4.08 (m, 4H), 3.86 (s, 3H), 3.58 (d, J=6.5Hz, 2H),
1.70 (s, 3H), 1.64 (s, 3H), 1.32 (m, 12H), 1.18 (m, 6H)
P31- NMR (DMSO, ppm):- 5.01 (m), -6.97 (m), -7.27 (m).
Compound J 3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzo pyrroles
Mutter -4- ketone) preparation of phosphate
By compound H (1.1g, 1.0eq), sodium iodide 0.3g (2.0eq) is added under anhydrous DCM 30ml, ice-water bath and added
DIPEA 1.3g (5.0eq), are stirred, and reaction is warmed to room temperature naturally after TMSBr1.6g (5.0eq), insulation 30min is added dropwise,
(silica gel plate material containing, solvent is ethyl acetate and petroleum ether 1 to thin-layer chromatography：1,254nm uviol lamp develops the color) monitoring.
1.6gTMSBr temperature rising reflux is added after 2 hours 30 minutes, thin-layer chromatography (TCL) monitoring to 3,5- dihydroxy -8-
(3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones) diethyl phosphate disappears.Concentration is removed
DCM is removed, 20ml methanol is added, stirred 10 minutes, concentration is done, adds dry, repetition is concentrated after methanol 20ml is stirred 10 minutes again
Three times, when being concentrated into remnants about 10ml for the last time, suction filtration, filter cake is transferred in 5ml water and stirred evenly, suction filtration, a small amount of frozen water washing, does
It is dry, obtain compound J yellow powder 0.8g, yield:81%.
Compound J carries out magnetic resonance detection, and testing result is as follows：H1-NMR (DMSO, ppm):12.31 (s, 1H),
8.11 (d, J=8.8Hz, 2H), 7.10 (d, J=8.8Hz, 2H), 6.80 (s, 1H), 5.15 (s, 1H), 3.83 (s, 1H), 3.48
(d, J=6.0Hz, 2H), 1.74 (s, 3H), 1.60 (s, 3H), P31-NMR (DMSO, ppm):-6.04(s).
Compound I 3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzo pyrroles
Mutter -4- ketone) preparation of di(2-ethylhexyl)phosphate sodium ester
Sodium hydroxide (27mg, 0.68mmol, 2eq) is dissolved in 4ml methanol aqueous solutions MeOH/H2O(1:1v/v), frozen water
The lower stirring 5min of bath, adds compound J (150mg, 0.34mmol, 1.0eq) and is stirred overnight (PH=8).Not higher than 30 DEG C are drained,
Compound I is obtained, altogether 160mg, yield:97%.
P31-NMR(DMSO,ppm):-0.74(s)
EI-MS:447.1 (100%).
Embodiment 3
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones)
The synthesis and identification of the preparation of sodium sulphate
Compound G (3.68g, 10mmol, 1.0eq) is dissolved in pyridine/dimethylformamide (DMF) (1 of 40ml dryings:
In 1v/v), pyridine. sulfur trioxide complex compound (C is slowly added portionwise5H5NSO3) (4.8g, 30mmol, 6.0eq), addition is finished,
Lucifuge, insulated and stirred is reacted at 50~60 DEG C, and (silica gel plate material containing, solvent is ethyl acetate and petroleum ether 2 to thin-layer chromatography：1,
254nm uviol lamps develop the color) monitoring is wholly absent to compound G, and reaction solution is down to room temperature naturally, and ice bath is down to 0 DEG C, and stirring is lower slow
The slow 30ml water that adds is stirred 30 minutes, is adjusted pH value to 13 with 1mol/l NaOH, is evaporated removing pyridine and DMF, adds
40ml water, the sulfuric acid that 1mol/l is added dropwise is acidified to pH value to 2, then with DCM/ isopropanols (4:1in v/v) extraction, every time
Freezed after 60ml, coextraction 3 times, aqueous phase regulation PH to 6.5, obtain compound L 3,5- dihydroxy -8- (3- methyl-2-butenes
Base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones) sodium sulphate, altogether 3.4g.
The nuclear magnetic resoance spectrum of compound L is as follows：
H1-NMR(DMSO,400MHz)：12.33 (s, 1H), 8.22 (d, J=8.8Hz, 2H), 7.08 (d, J=8.8Hz,
2H), 6.99 (s, 1H), 5.16 (m, 1H), 3.85 (s, 3H), 3.48 (d, J=6.4Hz, 2H), 1.74 (s, 3H), 1.63 (s,
3H)。
The Mass Spectrometer Method result of compound L is EI-MS (-):447.1 (100%).
Embodiment 4
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones)
The synthesis of (4- methylpiperazine-1-yls) -1- formic acid ester hydrochlorides and identification synthetic route are as follows：
The preparation of 4- methyl piperazine -1- formyl chlorides
The dichloromethane 120ml that triphosgene (11.87g, mmol) is dried is added under nitrogen protection, in 250ml reaction bulbs, is stirred
Dissolving is mixed, 0 DEG C is cooled to, the dichloromethane solution 60ml of N methyl piperazine (8g, 8.0mmol) is slowly added dropwise, completion of dropping is protected
Temperature reaction 1h, rear to add the acetonitrile that 20ml is dried, DCM distillations totally, when temperature rises to 70 DEG C, are stopped heating by heating, natural
Cooling, adds the toluene that 50ml is dried, suction filtration, filter cake washs three times with toluene, dry 4- methyl piperazine -1- formyl chloride hydrochloric acid
Salt.Gained 4- methyl piperazine -1- formyl chloride hydrochlorides are transferred in 100ml DCM, 0 DEG C is cooled to, are stirred vigorously lower slow
Point liquid after the potassium bicarbonate aqueous solution of equivalent, stirring 15min is added, aqueous phase is extracted three times with DCM, merge organic phase, saturation food
Salt water washing, anhydrous magnesium sulfate is dried, and is filtered out drier, is concentrated to dryness, obtains 4- methyl piperazine -1- formyl chlorides (9.5g) standby.
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones)
The preparation of (4- methylpiperazine-1-yls) -1- formic acid ester hydrochlorides
Added under nitrogen protection, in 100ml reaction bulbs the trihydroxy -8- (3- methyl-2-butenes base) of compound G 3,5,7- -
2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones) (3.7g, mmol), anhydrous tetrahydro furan 37ml, stirring and dissolving, plus
Enter the triethylamine of 2ml dryings, stir, the tetrahydrofuran that 4- methyl piperazine -1- formyl chlorides (1.7g, mmol) are slowly added dropwise is molten
Liquid 5ml, completion of dropping, stirring reaction at room temperature, TLC is monitored to compound G to react completely, suction filtration, and filtrate concentration is dry, residue
Middle addition 10ml water is stirred evenly, filtering, obtains 3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7-
(4H- benzopyran-4-ones) (4- methylpiperazine-1-yls) -1- formic acid esters hydrochloride, crudes, column chromatography obtains 2.2g, yield:
44.5%.
Compound M nmr spectrum H1-NMR (DMSO, ppm):12.38 (s, 1H), 8.14 (d, J=9.2Hz,
2H), 7.14 (d, J=9.2Hz, 2H), 6.58 (s, 1H), 5.11 (s, 1H), 3.84 (s, 1H), 3.61 (t, 4H) 3.43 (d, J=
6.0Hz,2H),2.56(t,4H),2.35(s,3H),1.74(s,3H),1.60(s,3H)。
Embodiment 5
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- chromenes -4-
Ketone) di(2-ethylhexyl)phosphate sodium ester synthesis and identification, synthetic route is as follows：
Compound P (300mg, 0.74mmol) is dissolved in dichloromethane and is cooled to 0 DEG C, Asia is sequentially added under nitrogen protection
Phosphoric acid di tert butyl carbonate (143mg, 0.74mmol), CCl4(1.14g, 7.4mmol), DIPEA (191mg, 1.48mmol), DMAP
(19mg, 0.15mol).Stirred 5 hours at 0 DEG C after mixing, reactant mixture is poured into KH2PO4Saturated aqueous solution in,
Use CH2Cl2After extraction, organic phase MgSO4Drying is concentrated under reduced pressure.Obtain the isolated product Q of residue silicagel column
(352mg, 88%).
Compound Q (300mg, 0.55mmol) is dissolved in dichloromethane and is cooled to 0 DEG C, TMSBr is added under nitrogen protection
(847mg, 5.54mmol).It is stirred at room temperature after mixing 6 hours, the residue being concentrated under reduced pressure to give is obtained with silica gel post separation
Methanol is dissolved in product R, the methanol solution for adding NaOH (44mg, 1.10mmol) is stirred 20 minutes, is concentrated under reduced pressure to give chemical combination
Thing S (153mg, yield 52%).
Compound S nuclear magnetic datas are as follows:
1HNMR(CD3OD,400MHz):8.57 (d, J=8Hz, 1H), 8.50 (d, J=8Hz, 1H), 7.84 (d, J=8Hz,
1H), 7.79 (d, J=8Hz, 1H), 6.68-6.90 (m, 1H), 3.63 (s, 6H), 3.60-3.75 (m, 2H).
Compound P is prepared from according to method disclosed in Publication No. CN103204838 embodiment 1.
Embodiment 7
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- chromenes -4-
Ketone) 4- (4- methylpiperazine-1-yls)-piperidines -1- formic acid esters dihydrochlorides synthesis and identification
Compound P (200mg, 0.49mmol) is dissolved in dichloromethane, sequentially add under nitrogen protection reagent T it is double-(2,
5- dioxypyrrole -1- bases) carbonate (126mg, 0.49mol), triethylamine Et3N(50mg,0.49mmol).45 after mixing
Stirred 8 hours at DEG C, sequentially add reagent V (90mg, 0.49mmol) (4- (4- methylpiperazine-1-yls)-piperidines) and triethylamine
(50mg, 0.49mmol, 1equiv), continues to stir 12 hours, the residue being concentrated under reduced pressure to give silicagel column point at 45 DEG C
From recovery raw material P (50%), obtained product 3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethylbenzenes
Base) -7- (4H- benzopyran-4-ones) 4- (4- methylpiperazine-1-yls)-piperidines -1- formic acid esters (76mg) is dissolved in 1,4- dioxies six
Ring, add HCl (4N, 4.9mmol) Isosorbide-5-Nitrae-dioxane solution, stirring 30 minutes after, be concentrated under reduced pressure to give 3,5- dihydroxy-
8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- benzopyran-4-ones) 4- (4- methyl piperazines -1-
Base)-piperidines -1- formic acid esters dihydrochlorides, product W (84mg, 25%).
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- chromenes -4-
Ketone) 4- (4- methylpiperazine-1-yls)-piperidines -1- formic acid esters dihydrochlorides identification
Compound W nuclear magnetic data is as follows:
1HNMR(CDCl3,400MHz):8.34 (d, J=10Hz, 2H), 7.79 (d, J=10Hz, 2H), 6.93 (s, 1H),
5.19 (t, J=8Hz, 1H), 4.25-4.40 (m, 2H), 2.51 (s, 3H), 2.50-3.25 (m, 12H), 1.79-2.19 (m,
2H),1.79(s,3H),1.61(s,3H),1.45-1.61(m,2H)。
Embodiment 8
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- chromenes -4-
Ketone) [1,4 '-two piperidines] -1 '-formic acid ester hydrochloride synthesis and identification
Synthetic method
Compound P (200mg, 0.49mmol) is dissolved in dichloromethane, sequentially add under nitrogen protection reagent T it is double-(2,
5- dioxypyrrole -1- bases) carbonate (126mg, 0.49mmol), triethylamine Et3N(49mg,0.49mmol).45 after mixing
Stirred 8 hours at DEG C, sequentially add reagent X (82mg, 0.49mmol) (Isosorbide-5-Nitrae '-two piperidines) and triethylamine (49mg,
0.49mmol), continue to stir 12 hours at 45 DEG C, the residue being concentrated under reduced pressure to give silica gel post separation reclaims raw material P
(55%) product 3, obtained, 5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- benzos
Pyrans -4- ketone) [Isosorbide-5-Nitrae '-two piperidines] -1 '-formic acid esters (59mg) is dissolved in Isosorbide-5-Nitrae-dioxane, adds the 1 of HCl (4N, 0.5mL),
4- dioxane solutions, after stirring 30 minutes, are concentrated under reduced pressure to give product Z (65mg, yield 20%).
Compound Z nuclear magnetic resonance data is as follows:
1HNMR(CDCl3,400MHz):11.49 (brs, 1H), 8.30 (d, J=8Hz, 2H), 7.78 (d, J=8Hz,
2H),6.62(s,1H),5.10-5.18(m,1H),4.40-4.58(m,2H),3.48(s,3H),2.80-3.30(m,6H),
1.77(s,3H),1.73(s,3H),1.40-2.60(m,12H)。
Embodiment 9
The deliquescent detection of prodrug compound：
The result of dissolubility test of the prodrug of the chromocor compound of synthesis in water is as follows above：Balance dissolving in water
Degree
The result of above dissolubility test shows that the series of the polyhydroxy benzopyran compounds ketone icariine of synthesis is spread out
Biological water-soluble has significant raising, can resist from now on by further to it in immunologic function and immunological regulation, medicine
Research in terms of cancer activity and anti-osteoporosis, and its antitumor drug effect is studied, make every effort to therefrom find the prodrug of high activity,
Go out to have the new compound of good potential applicability in clinical practice to yet-to-be developed.
Embodiment 10
The naturally occurring flavone compound of compound G systems, but the compound is water-soluble very poor, therefore this research is entered to it
Structure of modification is gone, 3 kinds of new precursor compounds, respectively J (phosphate), L (sulfuric acid is prepared for by the method for chemical synthesis
Sodium) and M (hydrochloride).Compound P has similar drug effect to compound G, equally has the property of poorly water-soluble, therefore originally grind
Study carefully and structure of modification also has been carried out to it, 3 kinds of new precursor compounds, respectively S (phosphoric acid are prepared for by the method for chemical synthesis
Ester), W and M (hydrochloride).This experimental study rat is injected intravenously respectively gives G and P and its precursor compound J, L, M, S, W and M
Afterwards, respectively in measurement rat plasma compound P and compound G change in concentration, with this evaluate compound P and compound G and its
Pharmacokinetics behavior of the precursor compound in rat body, is that it deeply develops and laid the foundation.
1. test apparatus
The Qtrap of Applied biosystems LC-MS system API 4000 (contain 2 Taiwan Island Tianjin LC-20AD pumps,
SIL-20AC thermostated autosamplers, CTO-20A column ovens, CBM-20A controllers, ESI and APCI interface ion guns,
Analyst Software 1.5.2 chromatographic work stations)；(bright and beautiful science and technology is stepped in Beijing to be had Targin VX-02 type multitubes turbula shaker
Limit company)；Heraeus Multifuge X3R low-temperature and high-speed centrifuges.
2.1 pharmacokinetic trial
Healthy male Wistar rat 9,220 ± 20g of body weight is randomly divided into 3 groups, the feed of animal free water.Press
4mg/kg dose intravenous drug administration by injection, respectively at administration before and administration after 0.033,0.083,0.25,0.5,1,2,4,6,8,
12nd, it is intubated extracting vein blood 0.3mL through rat jugular vein after 24 and 36 hours；The blood sample of collection is placed in the plastic tube added with heparin
In, 3000g is centrifuged 10 minutes, and separated plasma, -20 DEG C of preservations are to be measured.
2.2 plasma samples are pre-processed
Total concentration determines (protein precipitation method)
The μ L of Wistar rat plasmas 50 (carrying out suitably diluting according to the height of concentration) are taken, β-grape that 50 μ L newly match somebody with somebody is added
Glycuronide hydrolysis enzyme solutions (20000U/mL, pH value 5.0) are mixed, and 37 DEG C are incubated 1 hour.After hydrolysis terminates, addition is formulated in first
Alcohol：Acetonitrile (1：1, v/v) the μ L of genistein solution 150 of the 500ng/mL in, vortex mixed 2 minutes, 3000g is centrifuged 5 minutes,
The μ L sample introductions of supernatant 10 are taken to determine.
The rat intravenous injection of table 1 gives after G or not total plasma concentration in the same time
The rat intravenous injection of table 2 gives after J not G total plasma concentration in the same time
The rat intravenous injection of table 3 gives after L not G total plasma concentration in the same time
The rat intravenous injection of table 4 gives after M not G total plasma concentration in the same time
The rat intravenous injection of table 5 gives after P or not total plasma concentration in the same time
The rat intravenous injection of table 6 gives after S not P total plasma concentration in the same time
The rat intravenous injection of table 7 gives after W not P total plasma concentration in the same time
The rat intravenous injection of table 8 gives after W not P total plasma concentration in the same time
Claims (12)
1. a kind of chromocor compound prodrug, its pharmaceutically acceptable salt, shown in the prodrug such as following formula (I)：
Wherein：
R1It is selected fromIn one or more；R2And R3It is each independent
Ground be selected from H,In one or more, wherein M be selected from H, Na, K
With the one or more in ammonium, X is selected from Ca or Mg；
R4Selected from H, halogen atom, hydroxyl, hydroxyl C1-6Alkyl, the C replaced containing one or more halogen atoms1-6Alkyl, alkoxy and
C2-6One or more in alkenyl.
2. prodrug according to claim 1, wherein, described R4In H, methoxyl group, trifluoromethyl and isopentene group
It is one or more of.
3. prodrug according to claim 1, wherein described M is selected from alkylammonium, substitution alkylammonium, aryl ammonium and substitution virtue
One or more in base ammonium.
4. shown in prodrug according to claim 1, the wherein prodrug such as following formula (II)：
Wherein：R1It is selected fromIn one or more；R2And R3Respectively
From independently selected from H, In one or more, wherein M is selected from
One or more in H, Na, K and ammonium, X is selected from Ca or Mg.
5. shown in prodrug according to claim 4, the wherein prodrug such as following formula (III)：
6. shown in prodrug according to claim 4, the wherein prodrug such as following formula (IV)：
7. shown in prodrug according to claim 1, the wherein prodrug such as following formula (V)：
Wherein：R1It is selected fromIn one or more；R2And R3Respectively
From independently selected from H, In one or more, wherein M is selected from
One or more in H, Na, K and ammonium, X is selected from Ca or Mg.
8. shown in prodrug according to claim 7, the wherein prodrug such as following formula (VI)：
9. shown in prodrug according to claim 7, the wherein prodrug such as following formula (VII)：
10. the prodrug according to any one of claim 1-9, wherein the one kind of described prodrug in following compound
Or it is several：
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones) phosphoric acid
Two sodium esters；
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- methoxyphenyls) -7- (4H- benzopyran-4-ones) sulfuric acid
Sodium；
3,5- dihydroxy -8- (3- methyl-2-butenes base) -2- (4- trifluoromethyls) -7- (4H- benzopyran-4-ones) phosphorus
Acid disodium ester.
11. the prodrug, its pharmaceutically acceptable salt any one of claim 1-10 are being prepared for treating pernicious swell
Purposes in the medicine of knurl disease.
12. purposes according to claim 11, wherein medicine of the described medicine for oral administration or intravenous injection administration.
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