CN101735276A - Water-soluble phosphate monoester derivatives and application thereof - Google Patents
Water-soluble phosphate monoester derivatives and application thereof Download PDFInfo
- Publication number
- CN101735276A CN101735276A CN200910259270A CN200910259270A CN101735276A CN 101735276 A CN101735276 A CN 101735276A CN 200910259270 A CN200910259270 A CN 200910259270A CN 200910259270 A CN200910259270 A CN 200910259270A CN 101735276 A CN101735276 A CN 101735276A
- Authority
- CN
- China
- Prior art keywords
- compound
- methyl
- oxygen base
- base
- salt
- 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
Abstract
The invention provides water-soluble phosphate monoester derivatives shown in a general formula I and all possible isomers, salts for medicinal purpose, crystal forms, hydrates, solvent compounds and medicinal compositions. The invention also provides application of the compounds of the invention in preparing a medicament for preventing and treating tumor diseases and diseases related to reduce the TNF-alpha level and/or improve the CAMP level. The medicament has good water solubility, high treatment effect and quick response, and is suitable for patients unsuitable for oral administration.
Description
Technical field
The present invention relates to field of pharmacology, more specifically, relate to a class have good aqueous solubility phosphate monoester derivatives and preparation treatment tumour or with the medicine of TNF α, CAMP level-related disease in application.
Background technology
The sickness rate of cancer constantly rises, and has become serious threat human life's common disease, and its mortality ratio occupies the 2nd in all diseases.Along with molecular biological develop rapidly, people recognize that gradually the overexpression of short proliferating system composition in the cell and the disappearance of depressing proliferation system component are the major causes that causes cell carcinogenesis, simultaneously process such as the signal transduction in the tumour cell, cycle regulating, apoptosis and vasculogenesis and mechanism are also progressively being illustrated.Because the key ingredient of signal transduction pathway is the bigger difference of general existence between normal cell and tumour cell, this difference is low from selectivity for the focus of antitumor drug research and development, side effect big, act on the new type antineoplastic medicine that conventional cell poison class medicines such as DNA, RNA and tubulin transfer at signal transduction pathway in the tumour cell provides reliable theoretical foundation, the antitumor drug of these components of target than traditional antineoplastic thing have that selectivity is strong, advantage such as good effect, toxicity are little.
The reason that causes cell carcinogenesis is very complicated, up to the present, people still fail fully clearly to illustrate the mechanism and the mechanism of its morbidity, but many discoveries that are proved the key enzyme relevant with the tumour cell signal transduction pathway are for selectively acting has indicated direction in the research and development of the new type anticancer medicine of specific target spot.For example, the Brivanib of Bristol-Myers Squibb Co.'s exploitation is a kind of oral vascular endothelial growth factor receptor (vascular endothelial growth factor receptor, VEGFR) Tyrosylprotein kinase and bfgf receptor (fibroblast-growth factor receptor, FGFR) path double inhibitor, be mainly used in disease (Journal of Medicinal Chemistry such as control solid tumor, colorectal carcinoma and liver cancer, 2006,49 (7): 2143-2146; Chinese patent application number: 03816201.6); Enzastaurin is a kind of bisindole maleimide kind anti-cancer drugs by Lilly Co., Eli.'s exploitation, arrestin kinase c-β (proteinkinase C-β optionally, PKC-β) (WO9517182,1995-06-29), be mainly used in the diseases such as neurospongioma, non-Hodgkin lymphoma, non-small cell (type) lung cancer, prostate cancer, solid tumor, colorectal carcinoma, mammary cancer and ovarian cancer of control.
Natural drug has unique effect to treatment and prevention of tumour, can strengthen the susceptibility of a lot of drug-resistant tumor cells to the conventional chemotherapy medicine, as genistein (genistein) analogue Triphendiol (WO2005/049008,2005-06-02) and Phenoxodiol (Chinese patent application number: 97198690.8), to lung cancer, solid tumor, uterus carcinoma, prostate cancer, ovarian cancer, rodent cancer, aleukemic leukemia, squamous cell carcinoma, diseases such as kidney have curative effect (Expert Opin.Investig.Drugs preferably, 2009,18 (4): 469-479).
In addition, " old medicine is newly used " also is another approach of seeking new drug at present, as the Thalidomide with serious teratogenecity (Thalidomide), studies show that at present it has the purposes that reduces the TNF alpha levels and/or improve a lot of inflammation inflammation of CAMP level formation treatment, infectivity, immunology and malignant disease from market exit.Revlimid (Lenalidomide) and Pomalidomide are the derivatives of Thalidomide, reduced the serious adverse reaction of Thalidomide, simultaneously has better therapeutic aspect some refractory disease of treatment, as multiple myeloma, myelodysplastic syndrome, lung cancer, carcinoma of the pancreas, solid tumor, kidney, gastrointestinal cancer, colorectal carcinoma, immunomodulator, soft tissue sarcoma, move disease (Bioorganic ﹠amp such as curling (nuclear) lymphocytic lymphoma, sicklemia, non-Hodgkin lymphoma, myelofibrosis, the anti-host disease of plant; Medicinal Chemistry Letters, 1999,9:1625-1630; Bioorganic ﹠amp; Medicinal ChemistryLetters, 2007,17:5819-5824; Chinese patent application number: 97180299.8).
But the water-soluble non-constant of above these medicines is insoluble in the aqueous solution of pH=6.5 as Brivanib, and its solubleness is less than 1 μ g/mL, and Thalidomide is almost insoluble in water, and its solubleness is about 12 μ g/mL.In order to increase the water-soluble of medicine, can in the structure of medicine, introduce hydrophilic radical, in its structure, introduced hydrophilic amino as Revlimid and Pomalidomide etc., but their water-soluble increase is not obvious, even the solubleness as Revlimid also has only slightly soluble in the tart aqueous solution, its solubleness only is about 0.4mg/ml, and the pH value of human body is about 7.4, be weakly alkaline, its solubleness can be littler.Because water-soluble less medicine, solubleness owing to medicine behind the oral administration causes its dissolution rate slow for a short time, be unfavorable for the absorption of medicine, can cause drug absorption slowly, shortcoming such as bioavailability is lower or peak time is long, seriously limited the prospect of its clinical application.
Therefore, this area press for exploitation antitumor or with the active good and water-soluble big medicinal compound of TNF α, CAMP level-related disease.
Summary of the invention
The purpose of this invention is to provide class medicinal compound antitumor or that have good aqueous solubility well with TNF α, CAMP level-related disease activity.
The inventor is through discovering, parent drug Brivanib, Triphendiol, phenoxodiol, Thalidomide, Revlimid, Pomalidomide and the Enzastaurin of poorly water-soluble are prepared as phosphoric acid or methyl acid phosphate prodrug, it has good water-solubility and stability, in blood plasma, can be discharged parent drug by the rapid hydrolysis of phosphoesterase, therefore can improve bioavailability of medicament, increase toxic side effect such as curative effect and minimizing gi tract, particularly be suitable for unsuitable oral patient.
The invention provides the compound of general formula I:
Wherein:
R is selected from the group with following structure:
Or its all possible pharmacologically acceptable salt, crystal formation or hydrate, wherein preferred pharmacologically acceptable salt is sodium, potassium or calcium salt, most preferred pharmacologically acceptable salt is a sodium salt.
With the corresponding medicine of above-mentioned group a-i be: a and c are Brivanib (by the research and development of Bristol-Myers Squibb company); B and d are that Triphendiol and e are Phenoxodiol (by the research and development of Marshall Edwards company); F, g and h are respectively Thalidomide, Revlimid and the Pomalidomide by the research and development of Celgene company; I is the Enzastaurin by the research and development of Eli Lilly company.
The present invention also provides the compound of general formula I I:
Wherein: R
1Be selected from group with following structure:
Or its all possible pharmacologically acceptable salt, isomer, crystal formation, hydrate or solvate.
The present invention also provides the compound of general formula III:
Wherein: R
2Be selected from group with following structure:
Or its all possible pharmacologically acceptable salt, isomer, crystal formation, hydrate or solvate
The present invention also provides the compound of general formula I V:
Wherein: R
3Be selected from group with following structure:
Or its all possible pharmacologically acceptable salt, isomer, crystal formation, hydrate or solvate.
Preferred compound of formula I is selected from:
(1) (R)-1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-base oxygen base also)-third-2-base phosphoric acid;
(2) (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-oxygen base also)-propyl group-2-oxygen base) methyl acid phosphate disodium salt;
(3) (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt;
(4) (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt;
And all possible isomer, pharmacologically acceptable salt, crystal formation, hydrate or solvate.
The present invention also provides compound shown in the general formula I suitable pharmaceutically useful salt, hydrate or solvate, wherein pharmaceutically useful salt includes, but are not limited to compound of Formula I and basic metal or alkaline-earth metal or protonated amines or protonated amino acid etc. and forms metal or amine salt, as lithium, sodium, potassium, magnesium, calcium, barium, zinc and aluminium salt.Preferred salt is sodium, potassium and calcium salt.The salt that The compounds of this invention can be become with mineral acid example hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, Hydrogen bromide and nitric acid and with various organic acids, the salt that is become as toxilic acid, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, citric acid, acetate, lactic acid, methylsulfonic acid, tosic acid, palmitinic acid etc.Some compounds possibility water or various organic solvent crystallization or recrystallizations among the present invention in this case, may form all kinds of SOLVENTS thing.The present invention includes those stoichiometric solvates, comprise hydrate, be also included within the compound that comprises variable water gaging that forms when preparing with lyophylization.
The invention still further relates to the various isomer of compound of Formula I.The isomer of The compounds of this invention comprises tautomer, cis-trans-isomer, conformer, meso compound and has mapping or the optical isomer of non-enantiomorphic relationship.
Compound may exist with the form of cis-trans-isomer, optical isomer or tautomer among the present invention, the present invention includes the form of its all existence forms, particularly pure isomer.Different isomeric forms can or split with the isomer separation of the means of various routines and other form, and perhaps synthetic method or the three-dimensional method single-minded or asymmetric synthesis that certain isomer can various routines obtains.Since compound of Formula I is to be purpose with medicinal, be appreciated that they preferably provide with pure form, at least 60% purity for example, more suitably 75%, better 85%, best at least 98% purity (% is meant weight percent).The preparation method of pure compound not can be used to be used for the purer form of medicinal compositions.At least contain 1% in these pure inadequately products, be more suitable for 5%, better at least 10% the compound shown in general formula I or its pharmaceutically useful derivative.
The present invention also provides the preparation method of preparation compound of Formula I or its pharmaceutically useful salt, hydrate or solvate, is described respectively at general formula I substructure (general formula I I and general formula III) below, wherein R, R
1, and R
2Has aforesaid definition.
1. the preparation method of general formula I I compound is as follows:
In the solution of trimethyl phosphite 99, add R
1OH.Under the nitrogen protection, ice bath adds phosphoryl chloride down, and stirring reaction is 4 hours under the room temperature.After reaction finishes, add frozen water, have solid to separate out, filter and obtain general formula I I phosphate cpd.This phosphate cpd and acid or alkali reaction can prepare general formula I I pharmacologically acceptable salt.
2. the preparation method of compound of formula III is as follows:
At anhydrous N, in the dinethylformamide solution, add R
2H and sodium hydride stir 30min, add Tetrabutyl amonium bromide, potassiumiodide and di(2-ethylhexyl)phosphate benzyl chloride successively for methyl ester, stirring reaction 12 hours.Reaction finishes, and adds entry, dichloromethane extraction obtains intermediate 3.
In the methanol solution of intermediate 3, add palladium/charcoal of 10%.Feed hydrogen (1atm), stirring reaction 3 hours.Remove by filter palladium/charcoal, evaporated under reduced pressure gets the general formula III phosphate cpd.This phosphate cpd and acid or alkali reaction can prepare the general formula III pharmacologically acceptable salt.
The preparation method of general formula I I and compound of formula III can reference Journal of MedicinalChemistry, 2000,43 (3): 440-448, Journal of Medicinal Chemistry, 2004,47 (1): 188-195 and Bioorganic ﹠amp; Medicinal Chemistry Letters, 2003,13:3669-3672, wherein the preparation method of intermediate 2 can reference Tetrahedron, and 1971,27:3163-3170.The basic salt of general formula I I and compound of formula III or acid-salt can be by the preparations of the routine techniques known to those skilled in the art.
See embodiment about the more detailed data of preparation compound of Formula I.
The present invention also provides a kind of medicinal compositions, comprises compound of Formula I, or its isomer, pharmacologically acceptable salt, hydrate or solvate and pharmaceutically acceptable auxiliary, diluent or carrier.
The pharmaceutical composition of The compounds of this invention, any-mode that can following aspect is granted: in oral, spraying suction, rectal administration, intranasal administration, vagina administration, topical, parenterai administration such as subcutaneous, vein, intramuscular, intraperitoneal, the sheath, in the ventricle, in the breastbone or intracranial injection or input, or by a kind of reservoir medication of outer planting, wherein preferred vein or intramuscular parenterai administration and oral.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration.Form of administration can be solid dosage, liquid dosage form.Liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.Other formulations are lyophilized injectable powder, liquid drugs injection, tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, inclusion compound, implants, patch, liniment etc. for example, injection, tablet and capsules such as wherein preferred lyophilized injectable powder or liquid drugs injection.
It may be noted that in addition, The compounds of this invention is decided by all multifactor at different patients' specific using dosage and using method, comprise patient's age, body weight, sex, the natural health situation, nutritional status, the activity intensity of compound, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the person in charge judges.Here preferred using dosage is between the 0.01-100mg/Kg body weight/day.
Must recognize, the best dosage of compound of Formula I and be at interval by compound property with such as the decision of the external conditionss such as form, path and position of administration, and this best dosage can be determined with conventional technology.Must recognize also simultaneously that the best course of treatment, promptly compound of Formula I is at the nominal dosage of every day in the time, available method well known in the art is determined.
The present invention further provides above-claimed cpd, or its isomer, pharmacologically acceptable salt, crystal formation, hydrate or solvate be used for preparation and treating and/or preventing tumour and/or reduce tumor necrosis factor alpha (TNF α) level and/or improve 3 ', 5 '-application in the medicine of cyclic adenosine monophosphate-C-AMP (CAMP) level-related disease.
Described tumour is including, but not limited to liver cancer, lung cancer, kidney, gastrointestinal cancer, solid tumor, mammary cancer, uterus carcinoma, ovarian cancer, carcinoma of the pancreas, prostate cancer, colorectal carcinoma, neurospongioma, small cell lung cancer, rodent cancer, squamous cell carcinoma, soft tissue sarcoma, multiple myeloma, small cell lung cancer, nonsmall-cell lung cancer, non-Hodgkin lymphoma, aleukemic leukemia, sicklemia, myelodysplastic syndrome, move curling (nuclear) lymphocytic lymphoma etc.; Described reduction TNF alpha levels and/or raising CAMP level-related disease are including, but not limited to septic shock, serious poisonous disease, endotoxin shock, Hemodynamics shock and dense toxicity syndrome, infraction back reperfusion injury, malaria, mycobacterium infects, meningitis, psoriasis, congestive heart failure, fibrotic disease, emaciation, transplant rejection, cancer originality or carcinous illness, asthma, autoimmune disorder, the chance row of AISD infects, rheumatic arthritis, multiple sclerosis, the whole body lupus erythematosus, ENL in the leprosy, radiotherapy damage, cancer originality illness and the damage of hyperoxia alveolar, diseases such as anti-host disease of plant and myelofibrosis.
The present invention has following beneficial effect:
The activity of compound provided by the present invention and parent drug are quite or stronger, the particularly water-soluble parent drug that is far longer than, can avoid after the drug oral administration being destroyed, absorbing and enter the influence that hepatic vein tends to be subjected to " liver sausage circulation ", " first pass effect " again by drug administration by injection by hydrochloric acid in gastric juice or various gastrointestinal enzyme, the low onset of curative effect waits shortcoming slowly, and is fit to unsuitable oral patient.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
The fusing point of compound is measured by RY-1 fusing point instrument, and thermometer is calibration not.1H-NMR is measured by JNM-ECA-400 SUPERCONDUCTING NMR instrument, operating frequency
1H-NMR 400MHz.Mass spectrum is measured by the MicromassZabSpec mass spectrograph.Chromatographic condition (instrument: Agilent 1100 series of high efficiency liquid chromatographs (VWD detector); Chromatographic column: Supelcosil LC-18 post (4.6 * 250mm, 5 μ m); Moving phase: methyl alcohol, 10mM dipotassium hydrogen phosphate solution (phosphoric acid is transferred pH6.8); Sample size: 10 μ l; Flow velocity: 1ml/min).Carlo-Erba 1122 type microelement analyzers.
The preparation of embodiment 1 (R)-1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-base oxygen base also)-third-2-base phosphoric acid (compound 1)
(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2 also with (R)-1-; 4] triazine-6-base oxygen base)-propan-2-ol (741mg; 2mmol, its preparation method reference Journal of MedicinalChemistry, 2006; 49 (7): 2143-2146) join in the tripotassium phosphate ester solution of 40ml; under the nitrogen protection, ice bath slowly adds phosphoryl chloride (0.31ml, 3.0mmol)) down; be warming up to room temperature after adding, stirring reaction 12 hours.After reaction finishes, add frozen water 40ml, stir, there is solid to separate out, filters, filter cake water (20ml * 2) washing, filter cake is dissolved in the aqueous solution that 20ml is dissolved with yellow soda ash (212mg), uses the extraction of ethyl acetate (15ml) and ether (15ml) respectively, water layer hcl acidifying pH=1, there is solid to separate out, filters, filter cake water (10ml * 2) washing, vacuum-drying is spent the night, obtain pulverulent solids 154mg, yield 17.1%, HPLC content are 99.4%.Elemental?analysis：(C
19H
20FN
4O
6P)：Calcd：C，50.67；H，4.48；N，12.44；Found：C，50.49；H，4.56；N，12.52。
1HNMR(CD
3OD)，δ(ppm)：1.40(d，J＝6.6Hz，3H)，2.41(s，3H)，2.45(s，3H)，4.03-4.28(m，2H)，4.96(m，1H)，6.35(m，1H)，6.96(d，J＝7.1Hz，1H)，7.14(d，J＝7.1Hz，1H)，7.61(s，1H)，7.82(s，1H)。ESI-MS：451.1(M+1)。
The preparation of embodiment 2 (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-oxygen base also)-propyl group-2-oxygen base) methyl acid phosphate disodium salt (compound 2)
The preparation of step 1. (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-oxygen base also)-propyl group-2-oxygen base) methyl acid phosphate dibenzyl ester
Under the ice bath nitrogen protection; to (R)-1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole also [1; 2-f] [1; 2; 4] triazine-6-base oxygen base)-propan-2-ol (741mg; anhydrous N 2mmol), add in dinethylformamide (15ml) solution sodium hydride (48mg, 2mmol); stirred 30 minutes; add successively Tetrabutyl amonium bromide (100mg, 0.3mmol); potassiumiodide (50mg, 0.3mmol); slowly drip the di(2-ethylhexyl)phosphate benzyl chloride for methyl ester (978mg; anhydrous N 3mmol), dinethylformamide (10ml) solution, stirring reaction 24 hours.Reaction finishes, and adds entry 40ml dilution, methylene dichloride 60ml extraction, and anhydrous sodium sulfate drying is used in water (30ml) washing 3 times, filters, and removes solvent under reduced pressure.Resistates with flash chromatography on silica gel column purification (cyclohexane/ethyl acetate=16: 1, and cyclohexane/ethyl acetate=8: 1), is obtained the 455mg pulverulent solids, yield 34.5%, fusing point 59-62 ℃.
1HNMR(DMSO)，δ(ppm)：1.43(d，J＝6.6Hz，3H)，2.34(s，3H)，2.38(s，3H)，4.03-4.28(m，2H)，4.90-5.43(m，7H)，6.35(m，1H)，6.96(d，J＝7.1Hz，1H)，7.14-7.40(m，11H)，7.61(s，1H)，7.82(s，1H)。ESI-MS：661.2(M+1)。
The preparation of step 2. (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-oxygen base also)-propyl group-2-oxygen base) methyl acid phosphate disodium salt
To (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole also [1,2-f] [1,2,4] triazine-6-oxygen base)-and propyl group-2-oxygen base) methyl acid phosphate dibenzyl ester (661mg, in methyl alcohol 1mmol) (30ml), palladium/the charcoal (100mg) of adding 10% feeds hydrogen (1atm), stirring reaction 3 hours.Remove the palladium charcoal by diatomite filtration, with filtrate with yellow soda ash (101mg, water 0.95mmol) (10.0ml) solution removes methyl alcohol under reduced pressure, (5 * 2ml) extract the remaining aqueous solution with ether, with the freeze dried white solid of the aqueous solution, vacuum-drying is spent the night, and uses ether (3 * 4ml) washings again, vacuum-drying, obtain white powder solid 472mg, yield 90%, HPLC content are 99.3%.Elemental?analysis：(C
20H
20FN
4Na
2O
7P)：Calcd：C，45.81；H，3.84；N，10.69；Found：C，45.57；H，4.05；N，10.42。ESI-MS：480.1(M-2Na+1)。
The preparation of embodiment 3 (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt (compound 3)
The preparation of step 1. (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate dibenzyl ester
Adopt and the similarly method preparation of embodiment 2 steps 1, with 3-(1,3-dioxo isoindoline-2-yl)-piperidines-2,6-diketone (2.58g, 10.0mmol, preparation method's reference Bioorganic ﹠amp of this compound; Medicinal Chemistry Letters, 1999,9:1625-1630), sodium hydride (240mg, 10mmol), Tetrabutyl amonium bromide (500mg, 1.5mmol), potassiumiodide (250mg, 1.5mmol), (4.89g 15mmol) reacts, and obtains the 2.26g pulverulent solids for methyl ester to drip the di(2-ethylhexyl)phosphate benzyl chloride, yield 41.2%, fusing point 50-52 ℃.
1HNMR(DMSO)，δ(ppm)：2.11-2.19(m，1H)，2.52-2.69(m，1H)，2.82-2.91(m，1H)，3.02-3.21(m，1H)，4.95-5.48(m，7H)，7.33(m，10H)，7.85-7.99(m，4H)。ESI-MS：549.1(M+1)。
The preparation of step 2 (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt
Adopt and the similarly method preparation of embodiment 2 steps 2; to (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate dibenzyl ester (2.20g; in methyl alcohol 4mmol) (120ml); palladium/the charcoal (400mg) of adding 10% feeds hydrogen (1atm) and removes the protecting group benzyl, again with yellow soda ash (403mg; 3.8mmol) water (40ml) solution reaction; obtain white powder solid 1.36g, yield 91.9%, HPLC content are 99.6%.Elemental?analysis：(C
14H
11N
2Na
2O
8P)：Calcd：C，40.79；H，2.69；N，6.80；Found：C，40.57；H，2.53；N，6.93。ESI-MS：368.0(M-2Na+1)。
The preparation of embodiment 4 (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt (compound 4)
The preparation of step 1. (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate dibenzyl ester
Adopt and the similarly method preparation of embodiment 2 steps 1, with 3-(4-amino-1-oxoisoindoline diindyl-2-yl)-piperidines-2,6-diketone (2.07g, 8.0mmol, preparation method's reference Bioorganic ﹠amp of this compound; Medicinal Chemistry Letters, 1999,9:1625-1630), sodium hydride (192mg, 8mmol), Tetrabutyl amonium bromide (400mg, 1.2mmol), potassiumiodide (200mg, 1.2mmol), drip the di(2-ethylhexyl)phosphate benzyl chloride for methyl ester (3.91g, 12mmol) reaction obtains the 1.96g pulverulent solids, yield 44.5%.
1HNMR(DMSO)，δ(ppm)：2.00-2.14(m，1H)，2.22-2.49(m，1H)，2.59-2.68(m，1H)，2.83-3.05(m，1H)，4.06-4.28(m，2H)，4.92-5.48(m，9H)，6.81(d，J＝7.6Hz，1H)，6.92(d，J＝7.6Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.33(m，10H)。ESI-MS：550.2(M+1)。
The preparation of step 2. (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt
Adopt and the similarly method preparation of embodiment 2 steps 2; to (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2; 6-dioxopiperidine-1-yl) (1.65g in methyl alcohol 3mmol) (90ml), adds palladium/charcoal (300mg) of 10% to the methyl acid phosphate dibenzyl ester; feed hydrogen (1atm) and remove the protecting group benzyl; again with yellow soda ash (302mg, water 2.9mmol) (30ml) solution reaction obtains white powder solid 1.36g; yield 91.9%, HPLC content are 99.2%.Elemental?analysis：(C
14H
14N
3Na
2O
7P)：Calcd：C，40.69；H，3.41；N，10.17；Found：C，40.76；H，3.33；N，10.31。ESI-MS：369.1(M-2Na+1)。
The solubleness of experimental example 5 made compounds, the research in damping fluid and blood plasma
Prodrug is meant that finger is transformed into non-activity or active low with chemical process with activated parent drug, discharges former medicine and brings into play the medicine of therapeutic action through enzymatic or non-enzymatic reaction in vivo.Wherein for the phosphoric acid ester prodrug, generally discharge parent drug through enzyme or chemical hydrolysis in vivo.Mainly be increase medicine water-soluble based on phosphate monoester class prodrug of the present invention simultaneously, therefore, general hydrolysis situation in its solubleness, damping fluid and blood plasma in water of external investigation.
1, the solubleness of prepared compound in water
Take by weighing the testing sample that is ground into fine powder, add in the 10ml volumetric flask, add 10ml water again, powerful jolting was 30 seconds every 5 minutes, observed the dissolving situation in 30 minutes, as did not have visual visible particles of solute, promptly was considered as dissolving fully, saw Table 1.
Made compound and parent drug thereof the solubleness (mg/ml) in water under table 1 room temperature
2, the prepared hydrolysis situation of compound 1 and 2 in phosphoric acid buffer and blood plasma
Storing solution: the 50 μ g/ml aqueous solution
Human plasma: get healthy human blood (adding heparin), centrifugal, get supernatant liquor, standby in the packing deep freezer
PH7.4 phosphoric acid buffer: take by weighing potassium primary phosphate 0.68g, add 0.1mol/l sodium hydroxide solution 39.5ml, be diluted with water to 100ml
Method: human plasma and pH7.4 phosphoric acid buffer 0.8ml are joined respectively in the plastics tubing of two 2ml, put into 37 ℃ of waters bath with thermostatic control and be incubated half an hour, add above storing solution 0.2ml, vortex 20 seconds, sampling 0.1ml continues to be incubated half an hour at 37 ℃.In getting 0.1ml sample, add 0.4ml freezing (30 ℃) methyl alcohol, (4000 commentaries on classics/min), get supernatant liquor and carry out the HPLC analysis in centrifugal 3 minutes.After this respectively 0.5,1,2,4 and 8h take a sample respectively, aftertreatment is the same.The integral area * 100% of integral area/0 of the compound area percentage=different time of different time o'clock.
The hydrolysis situation of table 2 compound 1 and 2 in blood plasma and phosphoric acid buffer
From table 1 and table 2 as can be seen, phosphate monoester derivatives has good solubleness in the aqueous solution, increase more than 1000 times than its corresponding parent drug, and it is stable in the aqueous solution, in human plasma, can be discharged parent drug,, can be prepared into injection owing to have good water-solubility and stability by rapid enzymolysis, have rapid-action, the advantage that good effect, side effect be little, be not subjected to gastrointestinal effects.
The pharmacologically active evaluation of transplanted tumor tumor-inhibiting action in the experimental example 6 mouse bodies
1, experiment material and method
1.1, animal and cell strain
Healthy cleaning level kunming mice, male and female are not limit, body weight 18～22g (Military Medical Science Institute's Experimental Animal Center); Rat liver cancer H22 (Institute of Basic Medical Sciences, A Cademy of Military Medical Sciences).
1.2, experimental technique
1.2.1 set up mouse entity knurl model: select abdominal cavity inoculation 7～9d, the mouse of well-grown H22 liver cancer, aseptic extraction ascites is diluted to 2.5 * 10 with stroke-physiological saline solution
7Individual/the mL tumor cell suspension, abundant mixing, sterilization mouse right fore armpit position, it is subcutaneous to be inoculated in healthy mice right fore armpit, and every 0.2mL inoculates 56.
1.2.2 animal grouping and administration: mouse inoculation is divided into 7 groups at random after 24 hours: model group (physiological saline), Brivanib organizes (30mg/kg), compound 1 and administration 38 of 2 groups of difference and 40mg/kg (mole number is equivalent to Brivanib30mg/kg), Thalidomide group (50mg/kg), compound 4 and 5 groups of 71mg/kg (mole number is equivalent to Thalidomide group 50mg/kg), every group 8, every day, intraperitoneal injection was 1 time, each 0.15ml/10g body weight, successive administration 7 days, because Brivanib is insoluble in physiological saline, according to dosage can't drug administration by injection, therefore adopt gastric infusion.
1.2.3 calculating tumour inhibiting rate: inoculation back the 8th day, mouse is put to death in the back of weighing, and peels off the subcutaneous tumors piece, weighs, and calculates tumour inhibiting rate.Tumour inhibiting rate=(control group knurl weight-experimental group knurl is heavy)/heavy * 100% of control group knurl the results are shown in Table 4.
The influence of table 4 pair tumor-bearing mice growth and tumour (x ± s)
Annotate: compare with model group,
*P＜0.01
2, to the influence of transplanted tumor H22 in the mouse body
As known from Table 4: each group is to the mean number and the standard deviation of tumor-bearing mice growth and effects of tumors, compare with model group, Brivanib, Thalidomide, compound 1,2,3 and 4 can both significantly suppress H22 solid tumor growth effect (P＜0.01), compound 1 (77.3%) and 2 (75.7%) big to quite wherein to the restraining effect of tumour, but significantly greater than Brivanib (42.7%), and Thalidomide (17.8%), compound 3 (21.1%) with 4 (29.1%) to the restraining effect of tumour relative a little less than, but the activity of compound 3 and 4 is better than Thalidomide.Compound 1 and 2 anti-tumor activity significantly are better than its parent drug Brivanib, and the activity of compound 3 also is better than its parent drug Thalidomide, and all has good water-solubility, can be used as better antitumor drug.
Experimental example 7 10mg/ bottle specifications, 1000
Compound 1 10g
N.F,USP MANNITOL 10g
Water for injection adds to 2000ml, and it makes 1000
Press embodiment 7 preparation prescriptions, take by weighing compound 110g, put in the container, add water 1800ml water for injection, and add N.F,USP MANNITOL 10g, and be stirred to dissolving, transfer pH to 6.6～7.0 with 0.1mol/L NaOH, add pin charcoal 1g, 50～60 ℃ were stirred 30 minutes, take off charcoal after, add the injection water to 2000ml, under aseptic condition,, change filtrate branch in the 10ml cillin bottle with 0.22 μ m filtering with microporous membrane degerming, every bottle of 2ml jumps a queue, freeze-drying, inflated with nitrogen, tamponade, packing.
Claims (7)
1. the compound of following general formula I, or its pharmacologically acceptable salt, crystal formation or hydrate:
Wherein:
R is selected from the group with following structure:
2. compound according to claim 1 is characterized in that, described compound is:
(1) (R)-1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-base oxygen base also)-third-2-base phosphoric acid;
(2) (R)-(1-(4-(4-fluoro-2-Methyl-1H-indole base-5-oxygen base)-5-methylpyrrole is [1,2-f] [1,2,4] triazine-6-oxygen base also)-propyl group-2-oxygen base) methyl acid phosphate disodium salt;
(3) (3-(1,3-dioxo isoindoline-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt;
(4) (3-(4-amino-1-oxoisoindoline diindyl-2-yl)-2,6-dioxopiperidine-1-yl) methyl acid phosphate disodium salt;
And pharmacologically acceptable salt, crystal formation or hydrate.
3. according to each described compound of claim 1-2, it is characterized in that the pharmacologically acceptable salt of described compound is and acid or the formed salt of alkali.
4. the pharmaceutical composition that comprises each described compound of claim 1-3.
5. composition according to claim 4 is characterized in that said composition also comprises acceptable accessories or carrier.
6. according to claim 4 or 5 described compositions, it is characterized in that said composition is tablet, capsule, granule, pulvis, dispersion agent, syrup, oral liquid, injection or suppository.
7. each described compound of claim 1-6, or its isomer, pharmacologically acceptable salt, crystal formation, hydrate or solvate be used for preparation treat and/or prevent tumour and/or with tumor necrosis factor alpha (TNF α) level and/or 3 ', 5 '-application in the medicine of cyclic monophosphate (CAMP) level-related disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910259270A CN101735276A (en) | 2009-12-17 | 2009-12-17 | Water-soluble phosphate monoester derivatives and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910259270A CN101735276A (en) | 2009-12-17 | 2009-12-17 | Water-soluble phosphate monoester derivatives and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101735276A true CN101735276A (en) | 2010-06-16 |
Family
ID=42459350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910259270A Pending CN101735276A (en) | 2009-12-17 | 2009-12-17 | Water-soluble phosphate monoester derivatives and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101735276A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019036839A1 (en) * | 2017-08-21 | 2019-02-28 | 诺瑞特国际药业股份有限公司 | Pomalidomide derivative and preparation method therefor |
| JP2019507114A (en) * | 2016-01-08 | 2019-03-14 | セルジーン コーポレイション | Anti-proliferative compounds and their pharmaceutical compositions and uses |
| JP2019094338A (en) * | 2019-01-25 | 2019-06-20 | 株式会社ダイセル | Method for producing phosphorylated equol using enzyme |
| CN110075291A (en) * | 2019-02-01 | 2019-08-02 | 广州中医药大学(广州中医药研究院) | A kind of monophosphate class ester A conjugation Tn anti-tumor vaccine and its application |
| TWI689501B (en) * | 2017-08-21 | 2020-04-01 | 諾瑞特國際藥業股份有限公司 | Pomalidomide derivatives and the preparing method thereof |
| WO2020143779A1 (en) * | 2019-01-11 | 2020-07-16 | 南京诺瑞特医药科技有限公司 | Salt of pomalidomide prodrug |
| WO2020156150A1 (en) * | 2019-01-31 | 2020-08-06 | 南京诺瑞特医药科技有限公司 | Polymorph of pomalidomide prodrug salt |
| JP2021080264A (en) * | 2021-02-15 | 2021-05-27 | 株式会社ダイセル | Method for producing phosphorylated equol using enzyme |
-
2009
- 2009-12-17 CN CN200910259270A patent/CN101735276A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2019507114A (en) * | 2016-01-08 | 2019-03-14 | セルジーン コーポレイション | Anti-proliferative compounds and their pharmaceutical compositions and uses |
| WO2019036839A1 (en) * | 2017-08-21 | 2019-02-28 | 诺瑞特国际药业股份有限公司 | Pomalidomide derivative and preparation method therefor |
| CN109422727A (en) * | 2017-08-21 | 2019-03-05 | 诺瑞特国际药业股份有限公司 | Pomalidomide derivative and preparation method thereof |
| TWI689501B (en) * | 2017-08-21 | 2020-04-01 | 諾瑞特國際藥業股份有限公司 | Pomalidomide derivatives and the preparing method thereof |
| WO2020143779A1 (en) * | 2019-01-11 | 2020-07-16 | 南京诺瑞特医药科技有限公司 | Salt of pomalidomide prodrug |
| CN111434659A (en) * | 2019-01-11 | 2020-07-21 | 南京诺瑞特医药科技有限公司 | Pomalidomide prodrug salt |
| JP2019094338A (en) * | 2019-01-25 | 2019-06-20 | 株式会社ダイセル | Method for producing phosphorylated equol using enzyme |
| WO2020156150A1 (en) * | 2019-01-31 | 2020-08-06 | 南京诺瑞特医药科技有限公司 | Polymorph of pomalidomide prodrug salt |
| CN111499610A (en) * | 2019-01-31 | 2020-08-07 | 南京诺瑞特医药科技有限公司 | Polymorphs of pomalidomide prodrug salt |
| CN110075291A (en) * | 2019-02-01 | 2019-08-02 | 广州中医药大学(广州中医药研究院) | A kind of monophosphate class ester A conjugation Tn anti-tumor vaccine and its application |
| CN110075291B (en) * | 2019-02-01 | 2023-01-06 | 广州中医药大学(广州中医药研究院) | Monophosphoryl ester A conjugated Tn anti-tumor vaccine and application thereof |
| JP2021080264A (en) * | 2021-02-15 | 2021-05-27 | 株式会社ダイセル | Method for producing phosphorylated equol using enzyme |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN101735276A (en) | Water-soluble phosphate monoester derivatives and application thereof | |
| CN110092775A (en) | Target the crystal form of CDK4/6 kinase inhibitor | |
| CN101787064B (en) | Cytarabine derivatives and purposes thereof in resisting cancers and tumors | |
| CN113336768B (en) | Multi-target tyrosine kinase inhibitor | |
| CN110938032A (en) | Organic selenium compound and use thereof | |
| CN110041342B (en) | Selenium-containing compound and application thereof | |
| CN104327097A (en) | Triazole derivatives of rapamycin and application | |
| CN104530081B (en) | The azacyclo-derivant of rapamycin and purposes | |
| CN109467560B (en) | Selenocyanine compound and application thereof | |
| CN113880859B (en) | 2-aryl-4-arylmethylamino pyrimidine compound and application thereof | |
| CN104402861A (en) | Benzene sulfonamide derivatives, preparation method, and treatment application | |
| CN101863901A (en) | 2-(substituted phenyl)-2-(4,5,6,7-thiophane[3,2-c] pyridine-5(4H)-group)-N-substitute-acetamide as well as preparation method and application thereof | |
| CN103864765A (en) | Benzoazepine derivative containing five-membered heterocycle as well as preparation method and application of derivative | |
| CN109846873B (en) | Anti-tumor medicine composition | |
| CN104292211A (en) | Desloratadine nitric oxide donor, and preparation method and application thereof | |
| CN103864776B (en) | A kind of Tegafur derivative containing 1,3,4-thiadiazoles heterocycle and amide group | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN104926804A (en) | Compounds with anti-tumor effect, and preparation method and application of compounds | |
| CN103304556B (en) | Schiff bases compounds containing chromene, Preparation Method And The Use | |
| CN109528664B (en) | Lyophilized powder containing ubenimex-antitumor drug synergistic prodrug derivative and preparation method thereof | |
| CN114957137B (en) | N- (1, 2,3, 6-tetrahydropyrimidine-4-yl) -2-phenylacetamide compound and preparation and application thereof | |
| KR20130130802A (en) | Compositions and methods of using crystalline forms of wortmannin analogs | |
| CN109646429B (en) | Solid dosage form containing ubenimex prodrug derivative and preparation method thereof | |
| CN103880793A (en) | Furan imide-containing compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| DD01 | Delivery of document by public notice |
Addressee: Liao Guochao Document name: Notification of Passing Preliminary Examination of the Application for Invention |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| DD01 | Delivery of document by public notice |
Addressee: Liao Guochao Document name: the First Notification of an Office Action |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100616 |