CN100341880C - Boric acid and boric acid ester compound ,their preparing method and use in pharmacy - Google Patents
Boric acid and boric acid ester compound ,their preparing method and use in pharmacy Download PDFInfo
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Abstract
The present invention relates to a new boracic acid or boric acid ester compound, a preparation method and pharmacy application thereof. The compound can selectively block the proliferation of tumor cells, induce apoptosis and effectively inhibit the growth of human body tumor cells; the compound changes the polypeptide structure of LDP-341 compounds and has the advantages of stability and easy absorption in bodies.
Description
Technical field:
The invention belongs to the synthetic field of medicine, be specifically related to novel boric acid of a class or boric acid ester compound, preparation method and in pharmaceutically application.
Background technology:
At present, malignant tumour remains one of principal disease that threatens people's life.In China, the sickness rate of malignant tumour even still rising.Though since EPDML progress, the early diagnosis and therapy further improvements in methods, and treatment for cancer and prevention have obtained many achievements in recent years.For example surgical operation and radiocurable continuous maturation, the continuous appearance of new methods of treatment such as gene therapy etc., but also can't replace chemotherapy up to now.On the other hand, because existing cancer therapy drug, though have certain curative effect, they are cell toxicity medicament mostly, have serious toxic side effect.So the PTS of researching and developing new and effective low toxicity is the task of top priority that can't avoid.
In cell, the process need of protein degradation also relates to a kind of covalent bonds of cofactors (ubiquitin) with cell protein of crying.This combination is by the hydrolysis of 26S proteolysis complex body institute.And this 26S proteolysis complex body contains a kind of 20S proteasome (proteasome).This just proteasome catalysis the division and proliferation of cell protein.Cyclin (Cyclins) is a kind of control cell cycle round-robin protein.Its DeR just relates to the catalytic process of above-mentioned cofactors/proteasome.Suppressed the katalysis of proteasome, also just suppressed cyclin and carried out the effect of the outgrowth loop cycle of cell fission.Tumour cell is infinite multiplication owing to the regulatory function of having lost the cell cycle running.So arrestin enzyme body then can stop cell proliferation (but not being to kill cell) effectively.And then the promotion apoptosis, reach the effect of treatment kinds of tumors.Can think that proteasome inhibitor is the novel broad-spectrum anti-cancer drug of a class.Simultaneously, because they are to suppress cell proliferation, rather than kill cell, this class medicine should have lower toxic side effect.Therefore, seek a kind of important new direction of New Policy that proteasome inhibitor has become the cancer therapy drug research and development, and be considered to one of the most great progress of cancer therapy drug research in 20 end of the centurys.
U.S. Pat 5780454 discloses the organic compound of class boric acid and boric acid ester.This series compound is to make by organic synthesis.This series compound is the activity of arrestin enzyme body (proteasome) specifically, optionally blocks the propagation of tumour cell, brings out apoptosis, thereby can be used for the multiple disease of humans and animals such as the treatment of malignant tumour.Its representative compound structure is:
The LDP-341 proteasome inhibitor is researched and developed by U.S. Millennium company, successfully enter third phase clinical trial, U.S. Clinical Cancer Research (2002), 8 (8), 2505-2511 has reported the I clinical trial phase of novel protein enzyme body inhibitor PS-341 treatment malignant tumour.Oncologist (2002), 7 (1), 9-16 has reported the progress of proteasome inhibitor PS-341.Cancer Research (2002), 62 (4), 1083-1086 has reported the pharmaceutical protein enzyme body inhibitor PS-341 that the effect of a kind of T of treatment chronic myeloid leukemia is very strong.Seminars inOncology (2001), 28 (6), 613-619 has reported the antitumous effect of proteasome inhibitor, the development of PS-341.WO 9613266 has reported the synthetic of boric acid and boric acid ester compound and has used.LDP-341 treats the third phase clinical trial of 600 cases of multiple myeloma at present simultaneously in the U.S., Canada and Europe.In treatment adult T cell leukemia's test, shown very strong effect.And be decided to be by U.S. FDA and examine medicine fast.This compound is owing to have good selectivity and significantly low toxic side effect to show stem-winding potential applicability in clinical practice.
Summary of the invention:
Technical problem to be solved by this invention provides novel boric acid and the boric acid ester compound that the new class selectivity is good and toxic side effect is low, and, increase medicine stability and bioavailability in vivo by changing the polypeptide structure of background technology compound L DP-341.They can block tumor cell proliferation as the 20S proteinase inhibitor, the induced tumor apoptosis, thus can be used for the treatment and the prevention of the multiple disease such as the malignant tumour of humans and animals.
Novel boric acid of the present invention and boric acid ester compound have following formula I structure:
Wherein:
R1 and R2 form a ring, two ring or tricyclic structures, and each ring can be saturated or undersaturated 4 to 12 yuan of heterocycles, and can replace 1 to 3 group, is ketone group, hydroxyl, acyl group, acyloxy, alkylsulfonyl, alkyl, alkoxyl group, halogen and aryl etc.Wherein following group is a preferred structure:
Wherein A1 and A2 can be hydrogen independently, methyl, ethyl, methoxyl group, oxyethyl group, chlorine, bromine, fluorine, trifluoromethyl, amido and amide group etc.
R5 and R6 are for being hydrogen independently, aryl, methyl, ethyl, propyl group, methoxyl group, oxyethyl group, chlorine, bromine, fluorine, trifluoromethyl, amide group or amido etc.
R3 is a hydrogen, alkyl, cycloalkyl, aryl or substituted aryl (substituted aryl is A1 and A2), saturated or undersaturated 5 to 10 yuan of heterocycles (substituted aryl is A1 and A2).
R4 is a hydrogen, alkyl, cycloalkyl, aryl or substituted aryl (substituted aryl is A1 and A2), saturated or undersaturated 5 to 10 yuan of heterocycles (substituted aryl is A1 and A2).
X is C (O) NH-,-SO2-NH-, and-CH2NH-,-CH (OH) CH2-,-CH (OH) CH (OH)-,-CH (OH) CH2NH-,-CH=CH-,-C (O) CH2-,-SO2-CH2-, CH2C (O) NH-, or-NH-C (O)-.
Z1 and Z2 are hydroxyls independently, alkyl, and alkoxyl group, aryloxy, or form together and contain the straight chain of two hydroxyls or the compound of cyclization, can be C, also can be N, the heterogeneous ring compound that S or O form.
The representative preferred compound of the present invention has the structure of following compound 1,2,3:
The present invention is by discovering that to the 20S proteasome activity compound 1 has the activity of very strong inhibition 20S proteasome.
Another technical problem to be solved by this invention is the preparation method who discloses above-mentioned novel boric acid and boric acid ester compound.
Novel boric acid disclosed by the invention and boric acid ester compound (formula I) are obtained by the following formula reaction:
R
1, R
2, R
3, R
4, Z
1, Z
2Definition as mentioned above, X is COO.
The embodiment of the invention 1 is described the preparation method of compound 1 in detail, the preparation process of this compound as shown in the formula:
a：1.ClCO
2C
2H
5/(C
2H
5)
3N；2.NaN
3/C
6H
6
B:L-Phenylalanine (L-phenylalanine), H
2O, dioxane, 50 ℃
c：N-Methyl?morpholine，isobutyl?chloroformate，triethylamine，THF
d：phenylboric?acid，H
2O/ether
The preparation technology of compound 1 comprises: phthalic acid monoesters 4 is activated by Vinyl chloroformate in triethylamine and tetrahydrofuran (THF) earlier and the reactant aqueous solution of sodiumazide obtains acylazide; Acylazide got isocyanic ester 5 in 2 hours in reflux in toluene; Resulting isocyanic ester and amino acid under the alkali condition in water and dioxy cyclohexane solution reacting by heating (50 ℃) obtained compound 6 in 4 hours, compound 6 again with known compound boric acid ester 7 usefulness mixed anhydride methods react compound 8,8 again hydrolysis obtain boronic acid compounds 1.
Adopt essentially identical method, the embodiment of the invention 2,3 provides the preparation method of compound 2,3 respectively.
Another technical problem to be solved by this invention is to disclose above-mentioned novel boric acid or the application of boric acid ester compound in the medicine of preparation and 20S proteasome activity diseases related.
The activity of novel boric acid of the present invention or boric acid ester compound energy specificity arrestin enzyme body (20Sproteasome), optionally block the propagation of tumour cell, the induced tumor apoptosis, the multiple diseases such as malignant tumour that can be used for treating and preventing humans and animals.Particularly bone marrow cancer can be suppressed effectively, Lymphocytic leukemia, prostate cancer, the growth of multiple human body tumour cells such as carcinoma of the pancreas and colorectal carcinoma.
Novel boric acid of the present invention or boric acid ester compound also can be used for treating acquired immune deficiency syndrome (AIDS), psoriasis, cardiovascular system diseases and multiple inflammation etc.
This type of boric acid and boric acid ester compound can be single therapies in tumour or other disease treatment process, can also be and 2 kinds 3 kinds or more multiple medicines thing combination therapy, administration simultaneously, or different precedence administration.Here said combination therapy can be and other Western medicine that herbal medicine merges use, or and hormonotherapy, radiotherapy, immunotherapy, chemotherapy, cold therapy and gene therapy.
Medicament production provided by the invention treatment tumour and other disease, these products contain all suitable additives that this type of boric acid of effective dose and boric acid ester compound and other pharmaceutical industry adopt, and various suitable medicine-feeding way.
Drug manufacture technology comprises that the prodrug that uses nontoxic pharmaceutical industry to accept is raw material, adopts synthetic this type of boric acid of several different methods and boric acid ester compound.Drug manufacture technology also comprises uses solvent that pharmaceutical industry the accepts solvent as this type of boric acid and boric acid ester compound, water for example, mineral oil, edible oil, dimethyl sulfoxide (DMSO) etc.
This type of boric acid and boric acid ester compound can be made into oral administration, local application, inhalation, formulations such as anum administration.Use material that nontoxic pharmaceutical industry accepts as carrier, additives, excipient.Be pointed out that once more administering mode can be a drug combination.Can obey form of administration comprises: tablet, capsule, tincture, lozenge, oral syrup or other all suitable formulations.
This type of boric acid and boric acid ester compound can be made into the formulation that is administered systemically, and comprising: subcutaneous injection, intradermal injection, intramuscular injection, passages through which vital energy circulates injection, intraspinal injection, intrathecal injection, or other any drug administration by injection and instillation.In addition, this type of boric acid and boric acid ester compound preparation still contain other pharmaceutically every non-toxic substance except that containing effective dose.Comprise one or more carriers, thinner, additives, and if necessary, other medicinal component.
This type of boric acid and boric acid ester compound can be made into any type of oral dosage form, comprising: tablet, and lozenge, the soft or hard capsule can be obeyed aqua, tincture, oral administration mixed suspension, pulvis, emulsifying agent etc.Oral dosage form can contain one or more sweeting agents, correctives, and color agent and sanitas are to guarantee that color is perfect and to be convenient to take.
The excipient of this type of boric acid and boric acid ester compound tablet can be the inert thinner, as lime carbonate, and yellow soda ash, calcium lactate, calcium phosphate, sodium phosphate; System granule: W-Gum, alginic acid; Tackiness agent: starch, gelatin or gum arabic; Slipping agent: stearic acid, Magnesium Stearate or talcum powder.Adopt all known technologies, make dressing or the tablet of having no clothes.Coated dosage form comprises enteric coating and slow release formulation.The material that is used for slow release formulation can be glycerine monoester or dialycerides salt.
This type of boric acid and boric acid ester compound capsule can be hard capsule, can also be soft capsules.The material that is used for hard capsule can be a lime carbonate, calcium phosphate or high territory.Be used for the material such as the water of soft capsule, oils comprises peanut oil, sweet oil or liquid paraffin.
The oral water type of this type of boric acid and boric acid ester compound suspension can be formulated with its effective dose and suitable diluent.Its dilution suspensoid can be carbon sodium cellulose glycolate or methylcellulose gum, Vltra tears, alginic acid sodium salt, polyvinylpyrrolidone, tragcanth, gum arabic.Dispersion agent or wetting agent comprise: natural phospholipid, as Yelkin TTS, or the condenses of alkene pyridine oxide compound and lipid acid, as 17 alkyl oxidation of ethylene alkanols, or ethene and fatty acid part esterification condensation thing, or hexitol such as the single oleate of polyoxyethylene sorbitol, or ethylene oxide and fatty acid part fat condensation product, as polyethylene sorbyl alcohol methyl esters hydrochlorate.The oral water type of this type of boric acid and boric acid ester compound suspension also may contain one or more sanitass, as ethyl to or o-hydroxy st-yrax salt; Contain one or more sweeting agents, as sucrose or asccharin.
The oil type suspension of this type of boric acid and boric acid ester compound can be suspended in its effective dose in the vegetables oil, as peanut oil, and sweet oil, sesame oil, theobroma oil.Or Dormant oils, as liquid paraffin.Said preparation also can contain thinner, as beeswax, and wax, or cetyl alcohol, sweeting agent mentioned above, and correctives and stablizer are as antioxidant vitamin C.
Adopt aforesaid dispersion agent, wetting agent, suspensoid, sanitas, correctives, sweeting agent, and color agent, this type of boric acid and boric acid ester compound also can be made into oil-in-water preparation.
This type of boric acid and boric acid ester compound can be made into oil-in-water emulsifiers.Its oil phase can be aforesaid vegetables oil, as sweet oil, and peanut oil, etc.Can also be liquid paraffin, Dormant oils, or the mixture of two classes.Emulsifying agent can be natural emulsifying agent, as kordofan gum, or tragcanth, natural phospholipid such as soybean phospholipid, Yelkin TTS, lipid acid, the fat of hexitol or half resin are as the sorbose monoester.Also artificial chemical materials, ethylene oxide half fat condenses is as polyethylene sorbyl alcohol monoester salt.The type emulsification preparation of this type of boric acid and boric acid ester compound also can contain sweeting agent and correctives etc.
The syrup of this type of boric acid and boric acid ester compound and tincture can adopt sweeting agent, as propyl alcohol, and propylene glycol, sorbyl alcohol or sucrose.Said preparation also can contain wetting agent, sanitas, correctives, color additives.
The injection of this type of boric acid and boric acid ester compound can adopt aseptic parenteral solution or oily suspension.It can use all dispersion agent, wetting agent or suspensoids that are suitable on the pharmaceutics.Said preparation can be aseptic transparent liquid, uses all thinners that are suitable on the pharmaceutics, as, water, Ringer ' s solution and physiological saline etc.In addition, aseptic lipid also can be used as solvent or suspensoid.It can be synthetic glycerine monoester or two fat, and lipid acid is as oleic acid etc.
This type of boric acid and boric acid ester compound also can be made into suppository, as supp anal etc.Suppository can be combined by a certain amount of Cycolinx and corresponding non-stimulated excipient.Excipient is solid at normal temperatures, but liquefies and the release medicine under anus body temperature.The excipient that is suitable for comprises theobroma oil and macrogol class.
The formulation that is administered systemically of this type of boric acid and boric acid ester compound according to used carrier concentration, can be a suspension type, also lysotype.For easy-to-use or alleviate patient's misery, can add sanitas, buffer reagent and local anesthetic.
This type of boric acid and boric acid ester compound also can be used as animal doctor's medication.Take for ease of animal, the preparation that contains this compounds can add in the animal speech material or in the drinking-water.Also can be made into easily formulation as food or the drink of animal.
First portion test to representative compounds 1 shows that a series of compounds of the present invention have the activity (ki=0.55nM) of very strong inhibition 20S proteasome.Compare with LDP-341 (ki=0.62nM), have same strong activity at least.In addition, this compounds has changed the polypeptide structure of LDP-341 compounds, has more stable in vivo and easier absorbed advantage.From the strong like this external activity of representative compounds 1, can optionally block the propagation of tumour cell fully as LDP-341, bring out apoptosis, suppress human body tumour cell growth effectively, selectivity is good, toxic side effect is low. and, increased medicine stability and bioavailability in vivo by structure of modification.Further biological test well afoot.
Embodiment:
Embodiment 1: compound 1 synthetic
((the 1R-3-methyl isophthalic acid [(2S)-and 1-carbonyl-3-phenyl-2 ((2,4-dicarbapentaborane-1,4-dihydro-2H-quinazoline-3)) propylamine] fourth boric acid
[(1R)-3-methyl-1[(2S)-1-oxo-3-phenyl-2[(2，4-dioxo-1，4-dihydro-2H-quinazolin-3-yl)propyl]amino]butyl]boronic?acid
1. (1g, 5.55mmol) (1.55ml 11.1mmol) is dissolved in the tetrahydrofuran (THF) (15ml), and is cooled to-10 ℃ with three second ammoniums with the phthalic acid monoesters.(0.8ml, 8.33mmol. gained mixture stirred 1 hour under the ice-water bath cooling to be added dropwise to Vinyl chloroformate.(0.9g, aqueous solution 13.87mmol) (5.4ml) also continues to stir 1 hour slowly to drip sodiumazide.Add 50ml water in reaction mixture, and (3 * 10ml) extract compound with toluene.The organic layer that merges was washed with saturated nacl aqueous solution and was used anhydrous sodium sulfate drying again.After the filtration tetrahydrofuran (THF) is evaporated.Toluene solution slowly is heated to backflow.Reflux after 1.5 hours, be cooled to room temperature with solvent evaporation fall isocyanic ester crude product 5 (0.9 gram).
1H nucleus magnetic resonance: (CDCl
3, 400MHz) 7.76 (1H, s), 7.70 (1H, m), 7.35 (2H, m), 3.80 (3H, s); Mass spectrum: MS m/z 177 (M
+).
2. above-mentioned intermediate 5 (5mmol) and L-phenyl third amino acid (7.5mmol) are added on the water of equal-volume (10ml), in dioxy hexanaphthene and the sodium hydroxide solution (1M).Its mixture was 50 ℃ of reactions 4 hours.Organic solvent evaporation is fallen.Add 20 ml waters in remaining mixture.Regulate PH to 3 with 10% hydrochloric acid.With the dry compound 6 (1.1g) that gets of the solid filtering of separating out.
1H nucleus magnetic resonance: (DMSO-d
6, 400MHz) 8.50 (1H, br), 7.93 (1H, m), 7.52 (H, m), 7.10 (7H, m), 5.62 (1H, dd, J=6.5,10Hz), 3.50 (1H, d, J=6.5Hz), 3.45 (1H, d, J=10Hz, s); Mass spectrum: MS m/z 311 (M
+).
3. add the compound 6 of equivalent (2.7mmol) and n-formyl sarcolysine base purine in the anhydrous tetrahydro furan (15ml) and be cooled to-20 ℃.Stirred 5 minutes behind the isobutyl chlorocarbonate of adding equivalent.Said mixture (is helped to shift with refrigerative tetrahydrofuran (THF) 20ml) in the chloroformic solution (20ml) of-20 ℃ of boric acid esters 7 that join equivalent.The three second ammoniums that add equivalent again.Stir this mixture to room temperature at-20 ℃.Filter and solvent evaporation is fallen.Add ethyl acetate 100ml in residuum, with the hydrochloric acid of 0.2N, 5% sodium bicarbonate and saturated sodium-chloride liquid were washed and were used anhydrous sodium sulfate drying again.Be evaporated to dried after the filtration.Column chromatography (LH20) separate compound 8 (1g).Mass spectrum: MS (EI) m/z 558 (MH)
+
4. in the water of equal volume (6ml) and ether, add compound 8 (1mmol), add 5 equivalents phenyl-boron dihydroxide (5mmol) doubly again.Stirred 2 hours under the room temperature.Ether layer water extraction 3 times.Reduction vaporization was to doing after the water layer that merges was washed 2 times with ether.With ether residuum is worn away, filtered, the dry compound 1 (0.2g) that gets.
1H nucleus magnetic resonance: (CDCl
3, 400MHz) 7.93 (1H, s), 7.82 (1H, s), 7.49 (1H, s), 7.18 (1H, s), 7.21-7.08 (5H, m), 4.92 (1H, s), 3.6 (1H, s), 3.05 (2H, s), 1.83 (1H, s), 1.5 (2H, s), 1.01 (6H, s);
13C nucleus magnetic resonance (CDCl
3, 400MHz) 175.4 (C=O), 165.9 (C=O), 155.7 (C=O), 140.2 (C), 137.0 (C), 132.1 (CH), 128.4 (CH), 127.9 (CH), 127.5 (CH), 125.7 (CH), 125.4 (C), 124.2 (CH), 56.8 (CH), 44.8 (CH), 34.4 (CH
2), 32.0 (CH
2), 26.4 (CH), 22.4 (CH
3). mass spectrum: MS (EI) m/z 424 (MH)
+
Embodiment 2: compound 2 synthetic
((the 1R-3-methyl isophthalic acid [(2S)-and 1-carbonyl-3-phenyl-2 ((2,4-dicarbapentaborane-1,4-dihydro-2H-talk endlessly pyridine-3)) propylamine] fourth boric acid
[(1R)-3-methyl-1[(2S)-1-oxo-3-phenyl-2[(2，4-dioxo-1，4-dihydro-2H-pteridin-3-yl)propyl]amino]butyl]boronic?acid
Compound 2 (2 with equivalent (2.5mmol), 4-dicarbapentaborane-1,4-dihydro-2H-talks endlessly, and { 2-(2 for pyridine-3-phenyl-propionic acid, 4-Dioxo-1,4-dihydro-2H-pteridin-3-yl)-3-phenyl-propionic acid} and n-formyl sarcolysine base purine add in the anhydrous tetrahydro furan (15ml) and be cooled to-20 ℃.Stirred 5 minutes behind the isobutyl chlorocarbonate of adding equivalent.Said mixture (is helped to shift with refrigerative tetrahydrofuran (THF) 20ml) in the chloroformic solution (20ml) of-20 ℃ of boric acid esters 7 that join equivalent. add three second ammoniums of equivalent again.Stir this mixture to room temperature at-20 ℃.Filter and solvent evaporation is fallen.Add ethyl acetate 100ml in residuum, with the hydrochloric acid of 0.2N, 5% sodium bicarbonate and saturated nacl aqueous solution were washed and were used anhydrous sodium sulfate drying again.Be evaporated to dried after the filtration.Column chromatography (LH20) separate compound intermediate 0.8g).Mass spectrum: MS m/z 313 (MH)
+
In the water of equal volume (6ml) and ether, add above-mentioned intermediate (1mmol), add 5 equivalents phenyl-boron dihydroxide (5mmol) doubly again.Stirred 2 hours under the room temperature.Ether layer water extraction 3 times.Reduction vaporization was to doing after the water layer that merges was washed 2 times with ether.With ether residuum is worn away, filtered, the dry compound 2 (0.15g) that gets.
1H nucleus magnetic resonance: (CDCl
3, 400MHz) 8.17 (1H, s), 7.84 (1H, s), 7.21-7.08 (5H, m), 4.92 (1H, s), 3.6 (1H, s), 3.05 (2H, s), 1.83 (1H, s), 1.5 (2H, s), 1.01 (6H, s);
13C nucleus magnetic resonance (CDCl
3, 400MHz) 175.4 (C=O), 165.9 (C=O), 155.7 (C=O), 155.0 (C), 146.8 (CH), 140.2 (C), 132.9 (CH), 130.3 (CH), 128.4 (CH), 127.9 (CH), 125.7 (CH), 56.0 (CH), 44.8 (CH), 34.4 (CH
2), 32.0 (CH
2), 26.4 (CH), 22.4 (CH
3). mass spectrum: MS (EI) m/z 426 (MH)
+
Embodiment 3: compound 3 synthetic
((the 1R-3-methyl isophthalic acid [(2S)-and 1-carbonyl-3-phenyl-2 ((1-carbonyl-3,4-dihydro-1H-isoquinoline 99.9-2)) propylamine] fourth boric acid
[(1R)-3-methyl-1[(2S)-1-oxo-3-phenyl-2[(1-oxo-3，4-dihydro-1H-isoquinolin-2-yl)propyl]amino]butyl]boronic?acid
Compound 2 (1-carbonyl-3 with equivalent (2.0mmol), 4-dihydro-1H-isoquinoline 99.9-2)-and 3-phenyl-propionic acid { 2-(1-Oxo-3,4-dihydro-1H-isoquinolin-2-yl)-3-phenyl-propionic acid} and n-formyl sarcolysine base purine add in the anhydrous tetrahydro furan (15ml) and be cooled to-20 ℃.Stirred 5 minutes behind the isobutyl chlorocarbonate of adding equivalent.Said mixture (is helped to shift with refrigerative tetrahydrofuran (THF) 20ml) in the chloroformic solution (20ml) of-20 ℃ of boric acid esters 7 that join equivalent. add three second ammoniums of equivalent again.Stir this mixture to room temperature at-20 ℃.Overanxious and solvent evaporation fallen.Add ethyl acetate 100ml in residuum, with the hydrochloric acid of 0.2N, 5% sodium bicarbonate and saturated nacl aqueous solution were washed and were used anhydrous sodium sulfate drying again.Be evaporated to dried after the filtration.Column chromatography (LH20) separate compound intermediate 0.3g).Mass spectrum: MS m/z296 (MH)
+
In the water of equal volume (6ml) and ether, add above-mentioned intermediate (1mmol), add 5 equivalents phenyl-boron dihydroxide (5mmol) doubly again.Stirred 2 hours under the room temperature.Ether layer water extraction 3 times.Reduction vaporization was to doing after the water layer that merges was washed 2 times with ether.With ether residuum is worn away, filtered, the dry compound 3 (0.1g) that gets.
1H nucleus magnetic resonance: (CDCl
3, 400MHz) 7.90 (1H, s), 7.46 (1H, s), 7.30 (1H, s), 7.26 (1H, s), 7.21-7.08 (5H, m), 4.92 (1H, s), 3.6 (1H, s), 3.53 (2H, m), 3.09 (2H, s), 2.85 (2H, m), 1.83 (1H, s), 1.5 (2H, s), 1.01 (6H, s);
13C nucleus magnetic resonance (CDCl
3, 400MHz) 175.4 (C=O), 166.1 (C=O), 140.2 (C), 138.7 (C), 133.9 (C), 129.4 (CH), 128.4 (CH), 127.9 (CH), 127.7 (CH), 126.9 (CH), 125.7 (CH), 125.5 (CH), 45.3 (CH
2), 44.8 (CH), 34.4 (CH
2), 32.0 (CH
2), 30.6 (CH
2), 26.4 (CH), 22.4 (CH
3). mass spectrum: MS (EI) m/z 409 (MH)
+
Embodiment 4: compound is to the restraining effect of 20S proteasome
Measure compound to the experimental technique of the restraining effect of 20S proteasome as (Stein etal, Biochemistry, 35,3899-3980,1996 as described in the document; Rock et al, Cell.78,761-771,1994). be summarized as follows:
Proteasome obtains different components by rabbit psoas tissue homogenate by whizzer, obtains precipitation by sulfate of ammoniac (40%-80%), passes through continuous column chromatography (Mono Q and Superose 6) again and separates and obtain, and the rabbit psoas is purchased the Sigma chemical reagents corporation in the U.S..
Zymolyte Suc-Leu-Leu-Val-Tyr-AMC and inhibitor 1 (1-10 μ l, in DMSO) add (20mM HEPES in 2 milliliters the buffered soln, 0.5mM EDTA, 0.035%SDS, pH 7.8). add in 3 milliliters luminoscope (Hitachi 2000) testing tube. 37 ℃ reach balance after (about 5 minutes), add enzyme (1-10 μ l), cut off the reaction process of AMC and locate the fluorescent absorption record, calculate computer by the online of luminoscope institute again and go out speed and Ki. (ki=0.55nM) by 440nm (lex=380nm).Compare with LDP-341 (ki=0.62nM), same strong activity is arranged.
Claims (14)
1, boric acid or boric acid ester compound have following formula I structure:
Wherein:
R1 and R2 form quinazoline, pteridine or isoquinoline 99.9;
R3 is a benzyl;
R4 is an isobutyl-;
X is C (O) NH-;
Z1 and Z2 are hydroxyls independently separately.
2, boric acid according to claim 1 or boric acid ester compound, it is characterized in that described compound for ((the 1R-3-methyl isophthalic acid [(2S)-1-carbonyl-3-phenyl-2 ((2,4-dicarbapentaborane-1,4-dihydro-2H-quinazoline-3)) propylamine] fourth boric acid, have following compound 1 structure:
3, boric acid according to claim 1 or boric acid ester compound, it is characterized in that described compound for ((the 1R-3-methyl isophthalic acid [(2S)-1-carbonyl-3-phenyl-2 ((2, the pyridine-3 of talking endlessly of 4-dicarbapentaborane-1,4-dihydro-2H-)) propylamine] fourth boric acid, have following compound 2 structures:
4, boric acid according to claim 1 or boric acid ester compound, it is characterized in that described compound for ((the 1R-3-methyl isophthalic acid [(2S)-1-carbonyl-3-phenyl-2 ((1-carbonyl-3,4-dihydro-1H-isoquinoline 99.9-2)) propylamine] fourth boric acid, have following compound 3 structures:
5, the preparation method of boric acid according to claim 1 or boric acid ester compound is characterized in that formula I compound is obtained by the following formula reaction:
R
1, R
2, R
3, R
4, Z
1, Z
2Definition as mentioned above, X is COO.
6, the preparation method of boric acid according to claim 5 or boric acid ester compound is characterized in that the described compound 1 of claim 2 is made by the following formula preparation process:
Wherein:
a：1.CLCO
2C
2H
5/(C
2H
5)
3N；2.NaN
3/C
6H
6
The b:L-phenylalanine, H
2O, dioxy hexanaphthene, 50 ℃
The c:N-methylmorpholine, isobutyl chloroformate, triethylamine, tetrahydrofuran (THF)
D: phenyl-boron dihydroxide, H
2The O/ ether
Preparation technology comprises: phthalic acid monoesters 4 is activated by Vinyl chloroformate in triethylamine and tetrahydrofuran (THF) earlier and the reactant aqueous solution of sodiumazide obtains acylazide; Acylazide got isocyanic ester 5 in 2 hours in reflux in toluene; Resulting isocyanic ester and amino acid under the alkaline condition in water and dioxy cyclohexane solution reacting by heating, 50 ℃ obtained compound 6 in 4 hours, compound 6 again with known compound boric acid ester 7 usefulness mixed anhydride methods react compound 8,8 again hydrolysis obtain boronic acid compounds 1.
7, the preparation method of boric acid according to claim 5 or boric acid ester compound, it is characterized in that the described compound 2 of claim 3 is by 2 (2, described boric acid ester 7 reactions of pyridine-3-phenyl-propionic acid and claim 6 of talking endlessly of 4-dicarbapentaborane-1,4-dihydro-2H-obtain.
8, the preparation method of boric acid according to claim 5 or boric acid ester compound, it is characterized in that the described compound 3 of claim 4 is obtained by 2 (1-carbonyl-3,4-dihydro-1H-isoquinoline 99.9-2)-3-phenyl-propionic acid and described boric acid ester 7 reactions of claim 6.
9, boric acid according to claim 1 or the boric acid ester compound application in the medicine of preparation and 20S proteasome activity diseases related.
10, the application of boric acid according to claim 9 or boric acid ester compound is characterized in that the activity that this medicine can specificity arrestin enzyme body, optionally blocks the propagation of tumour cell, the induced tumor apoptosis.
11, the application of boric acid according to claim 10 or boric acid ester compound is characterized in that this medicine can suppress bone marrow cancer effectively, Lymphocytic leukemia, prostate cancer, the growth of carcinoma of the pancreas and colorectal carcinoma tumour cell.
12, the application of boric acid according to claim 9 or boric acid ester compound is characterized in that this medicine is used for the treatment of acquired immune deficiency syndrome (AIDS), psoriasis, cardiovascular system diseases and multiple inflammation.
13,, it is characterized in that described medicine adopts any medicine-feeding way, any administering mode according to the application of each described boric acid of claim 9 to 12 or boric acid ester compound.
14,, it is characterized in that described pharmaceutical dosage form is injection, tablet, pill, capsule, paste, creme, patch, pulvis, sprays, implant, suppository or drops according to the application of each described boric acid of claim 9 to 12 or boric acid ester compound.
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| CNB031153852A CN100341880C (en) | 2003-02-13 | 2003-02-13 | Boric acid and boric acid ester compound ,their preparing method and use in pharmacy |
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| CNB031153852A CN100341880C (en) | 2003-02-13 | 2003-02-13 | Boric acid and boric acid ester compound ,their preparing method and use in pharmacy |
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| CN1521171A CN1521171A (en) | 2004-08-18 |
| CN100341880C true CN100341880C (en) | 2007-10-10 |
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| CN102675415B (en) * | 2012-05-11 | 2014-06-18 | 人福医药集团股份公司 | Method for preparing bortezomib |
| CN105601705B (en) * | 2015-12-23 | 2020-04-14 | 国药一心制药有限公司 | Preparation method of bortezomib |
| CN105622658B (en) * | 2016-03-18 | 2018-06-19 | 中国药科大学 | Non-peptide albuminoid enzyme body inhibitor, its pharmaceutical composition, preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996013266A1 (en) * | 1994-10-28 | 1996-05-09 | Proscript, Inc. | Boronic ester and acid compounds, synthesis and uses |
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2003
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996013266A1 (en) * | 1994-10-28 | 1996-05-09 | Proscript, Inc. | Boronic ester and acid compounds, synthesis and uses |
| US5780454A (en) * | 1994-10-28 | 1998-07-14 | Proscript, Inc. | Boronic ester and acid compounds |
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