CN101054367A - 3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy - Google Patents
3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy Download PDFInfo
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Abstract
The present invention relates to 2,4-benzo triazine-1,4-dinitrogen oxides dehydrate and its crystal, preparing method and application in tumor radiotheraphy and chemotherapy. The present invention also relates to the method for preparing high-purity 3-amidocyanogen-1,2,4-benzo triazine-1,4-dinitrogen oxides crystal by using 3-amidocyanogen-1,2,4-benzo triazine-1,4-dinitrogen oxides dehydrate.
Description
Technical field
The present invention relates to the radiation and chemotherapy hypersitization medicine in a kind of tumor therapeutic procedure.Specifically, relate to 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate and crystal thereof, preparation method and the application in tumor radiotherapy and chemotherapy; On the other hand, also relate to 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crystal, its preparation method and the application in tumor radiotherapy and chemotherapy.
Background technology
Tumor radiotherapy known today, chemotherapeutics and radiotherapeutic sensitizer drug price all compare expensive, and one of the main reasons is exactly synthetic and complex disposal process, the many and bulk drug price height of middle-chain.3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide (TPZ) are as reliable radiotherapy of a kind of curative effect and chemotherapy sensitizing medicine, and it is clinical to enter for three phases at present.TPZ is a kind of novel tumor chemoradiotherapy sensitizer with biological reducing effect, studies show that TPZ can obviously increase the susceptibility of tumour cell to ray, and a lot of tumours are had tangible effect of enhanced sensitivity, can significantly improve the effect of tumour radiotherapy.The mechanism of action novelty of TPZ, has dual mechanism of action: except that improving in the tumor tissues the effect of anoxic cell to radiation sensitive of the more chemicotherapy sensitizer of research before having, TPZ has the biological reducing effect again simultaneously, it can be in the reduction of the weary oxygen district of tumour, be transformed into meta-bolites with cytotoxic effect, improve killing action greatly to tumour cell, thus TPZ than before some radiotherapeutic sensitizers have better result of treatment.Significant is that the effect of paying of the poison of TPZ is little in addition.
Existing preparation TPZ method is as follows: 1 mole of benzo furazan-1-oxide compound-1-oxide compound and 3 moles of cyanamide disodiums react in 50% methanol aqueous solution, with heat release immediately and difficult control of temperature, self condensation reaction can take place in the too high benzo furazan of what is more important temperature-1-oxide compound, generates the azophenlyene compounds of intractable.In the process that adds the cyanamide disodium, adopt hydronic method, controlled temperature well, but promptly have the thick material of black purple to generate in the short period of time, feasible stirring is difficult to carry out, react the back reluctantly and use the acetate acidifying, obtain red product seldom, and purity is very low.
Disclosing the preparation method of a kind of TPZ in the CN01136096.8 patent application, is to be obtained in 50～60 ℃ of heating with benzo furazan-1-oxide compound in the sodium hydroxide alcoholic solution by cyanamide, uses ethyl alcohol recrystallization after freezing 12 hours, productive rate 40%.This method productive rate is low, and length consuming time is not suitable for suitability for industrialized production, is necessary to study new preparation method for this reason.
Summary of the invention
The dihydrate, its preparation method and the crystal thereof that the purpose of this invention is to provide a kind of TPZ also provide crystal and the preparation method of a kind of TPZ in addition.
Concrete, the invention provides a kind of 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide dihydrate, structural formula is as follows:
The present invention also provides the preparation method of this dihydrate, is to add hot preparation by benzo furazan-1-oxide compound, cyanamide in the sodium hydroxide alcoholic solution, it is characterized by may further comprise the steps:
A) benzo furazan-1-oxide compound is dissolved in methyl alcohol, adds the water of equivalent again, add the cyanamide stirring and make dissolving;
B) under the condition of stirring at room, slowly add solid sodium hydroxide, controlled temperature is no more than 60 ℃;
C) after solid sodium hydroxide all adds dissolving, temperature is risen to 58 ℃-60 ℃ and kept 60 minutes; Cooling is filtered, and discards filtrate, obtains 3-amino-1,2,4-phentriazine-1, the throw out of 4-dinitrogen oxide sodium salt;
D) throw out is water-soluble, filter to collect mother liquor, the cooling back adds acetate, regulates the pH value at 5-7, filter 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crude product;
E) get above-mentioned crude product and add in the entry, heating is dissolved it fully, and cooling gets 3-amino-1,2,4-phentriazine-1, the transparent styloid of the reddish-brown of 4-dinitrogen oxide dihydrate.
Wherein, the sequencing that reactant is pressed benzo furazan-1-oxide compound, cyanamide and sodium hydroxide adds, and three's mol ratio is 1: 3: 6.
In the step a), preferably add the ratio of 400 ml methanol, be heated to 60 ℃ it is dissolved fully in benzo furazan-1-oxide compound of 1 mole; In the step d), preferably regulating the pH value is 6; In the step e), preferably add the ratio of 500～1500 ml waters in per 10 gram crude products, heating is dissolved it fully.
Obtain the crystal of this dihydrate by method for preparing, it is characterized by the crystal column that takes on a red color, belong to oblique system, spacer is P2
1, unit cell parameters: a=4.775 (1),
Unit cell volume is:
Molecule number Z=2 in the structure cell.
The present invention also provides a kind of 3-amino-1,2, and 4-phentriazine-1, the crystal of 4-dinitrogen oxide, crystal are the transparent column of sorrel, and the diffraction experiment crystallographic dimension is 0.10 * 0.15 * 0.50mm, belongs to rhombic system, and spacer is P2
12
12
1, unit cell parameters: a=4.876 (1), b=7.431 (1),
Unit cell volume is:
Molecule number Z=4 in the structure cell.
This crystal can be by 3-amino-1,2,4-phentriazine-1, and the 4-dinitrogen oxide dihydrate prepares.Specifically, with 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide dihydrate is dissolved in DMF, preferred per 10 gram dihydrates add 100 to 600 milliliters of DMF, and more preferably 200 milliliters, heating makes its dissolving, recrystallization gets 3-amino-1,2,4-phentriazine-1, the crystal of 4-dinitrogen oxide.
The present invention selects for use benzo furazan-1-oxide compound directly to react with cyanamide and sodium hydroxide, and this can make chemical reaction simplify, and overcomes with the cyanamide disodium and synthesizes 3-amino-1,2, the problem that 4-phentriazine-1,4-dinitrogen oxide occur, and can improve the purity of products therefrom.
If adopt the system of methanol-water in the reaction, owing to benzo furazan-1-oxide dissolution is bad, therefore reaction will be the heterogeneous reaction system, and under this condition, the reaction of being carried out will prolong the reaction times, and reaction and incomplete.The contriver finds that benzo furazan-1-oxide compound is soluble in non-polar solvent such as benzene and the toluene, but solubleness is very little in ethanol, and solubleness is also very little in cold methyl alcohol; And in 60 ℃ hot methanol, its solubleness is but very big.Therefore earlier benzo furazan-1-oxide compound is added in the methyl alcohol, be heated to 60 ℃, stirring is dissolved it fully; After treating benzo furazan-1-oxide dissolution, add the water of equal quantities again; Add cyanamide then, stir and make dissolving; Slowly add solid sodium hydroxide again, stir, make dissolving; Can dissolve cyanamide and sodium hydroxide like this, this reaction conditions is equivalent to homogeneous reaction, thereby has avoided reacting in the heterogeneous reaction system, has shortened the reaction times.
Then add cyanamide if in the methanol aqueous solution of benzo furazan-1-oxide compound, add sodium hydrate solid earlier, reaction yield is very low, reason is when temperature raises, under excessive sodium hydroxide condition, add cyanamide, cyanamide is decomposed into formic acid and ammonia very soon, simultaneously cyanamide also aggregates into dimer and tripolymer very soon, and this polymerization also is irreversible reaction, therefore adds cyanamide earlier and then adds the generation that sodium hydrate solid just can be avoided this problem again.
Because benzo furazan-1-oxide compound is easy to take place self condensation reaction being higher than under 60 ℃ of conditions, therefore being defined as 60 ℃ on the temperature of reaction.On the quantitative relationship of reaction, the mol ratio of benzo furazan-1-oxide compound and cyanamide and sodium hydroxide is 1: 3: 6, and temperature is in the time of 58-60 ℃, and productive rate is higher.See Table 1 in differing temps with experimental result under different the feeding intake.
Crude product productive rate under table 1 differing temps, the different ingredient proportion
| Temperature of reaction (℃) | Benzo furazan-1-oxide compound (mole number) | Cyanamide (mole number) | Sodium hydroxide (mole number) | Crude product productive rate (% is in benzo furazan-1-oxide compound) |
| 55-60 60-62 60-70 55-60 58-60 55-62 55-62 | 1 1 1 1 1 1 1 | 2 2 2 3 3 3 3 | 4 4 6 6 6 6 7 | 48 52 38 68 71 70 61 |
In reaction process, actual what obtain is 3-amino-1,2,4-phentriazine-1, therefore the sodium salt of 4-dinitrogen oxide need carry out acidifying and make it be transformed into product 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide, experiment shows should be selected with the second acid for adjusting pH value 5～6.5.
Crude product productive rate under the different pH values of table 2, the different acidulated condition
| The crude product mole number | Acid | The pH of system | Crude product (% calculates with benzo furazan-1-oxide compound) |
| 0.79 0.79 0.79 0.79 0.79 0.79 0.79 0.79 0.79 0.79 | 0.5mol/l sulfuric acid 1mol/l sulfuric acid 0.5mol/l hydrochloric acid 1mol/l hydrochloric acid acetic acid acetic acid acetic acid acetic acid acetic acid acetic acid | 2.3 1.7 3.3 2.1 2.8 3.2 4.4 5.2 6.2 6.4 | 11 5 33 42 47 55 51 66 88 82 |
With 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crude product 10 restrains in the hot water (70-95 ℃) that is dissolved in 1000 milliliters, places the crystal of separating out 9 grams after cooling off, and contains 2 crystal water in the verified crystallization.Be 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide dihydrate, and it is carried out the monocrystalline X-ray diffraction test, determine its structure.
Tumor growth delay experimental result through isolated cells and animal-transplanted tumor shows that the TPZ dihydrate also can obviously strengthen the anti-knurl effect of simple chemicotherapy in conjunction with chemotherapy or radiotherapy.This dihydrate can be prepared into the preparation of oral or injection, is used to carry out the treatment of the radiation and chemotherapy of tumour.The selected pharmaceutical carrier of above-mentioned preparation is meant pharmaceutical field conventional carrier, for example thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, tensio-active agent etc.Pharmaceutical preparation of the present invention can be applied to the patient who needs treatment by oral, Transdermal absorption or parenteral admin mode.Be used for to be made into conventional solid preparation such as tablet, capsule, oral gel capsule agent etc. when oral, make liquid preparation such as water or syrup etc.Be used for parenteral admin and can be made into injection, and the creme of making according to a conventional method, ointment, plaster, film and sprays etc.The various formulations of medicine of the present invention can for example make activeconstituents mix with one or more carriers according to the preparation of pharmaceutical field ordinary method, make required preparation then.
Method productive rate height, impurity that the present invention adopts are few, adopt water as solvent during recrystallization, and cost is low, and weak point consuming time is easy and simple to handle.The TPZ dihydrate that obtains also has the tumor chemoradiotherapy effect of enhanced sensitivity, can be used for preparing the tumor chemoradiotherapy hypersitization medicine.
Description of drawings
Fig. 1: TPZ dihydrate molecule stereo structure sciagraph
Fig. 2: molecule is along the axial sciagraph of α in the TPZ dihydrate structure cell
Fig. 3: the TPZ dihydrate atomic coordinate parameter and the equivalent temperature factor
Fig. 4: the TPZ dihydrate becomes interatomic bond distance of key and bond angle
Embodiment:
The following examples will be further explained the present invention, but the present invention is not limited only to these embodiment, the scope that these embodiment do not limit the present invention in any way.Those skilled in the art can make various changes or modifications the present invention, but the equivalent form of value doing to change or revise drop on equally within the application's claims institute restricted portion.
Embodiment one: 3-amino-1,2,4-phentriazine-1, the preparation of 4-dinitrogen oxide dihydrate and purifying
136 gram (1mol) benzo furazan-1-oxide compounds are added in 400 milliliters the methyl alcohol, are heated to 60 ℃, stir it is dissolved fully; After the cooling, add the water (400 milliliters) of equivalent again, add 126 gram (3mol) cyanamides, stir and make dissolving; Under the condition of stirring at room, slowly add solid sodium hydroxide 240 grams (6mol), notice that temperature must not be above 65 ℃; After treating that solid sodium hydroxide all adds dissolving, temperature is risen to 58 ℃-60 ℃ ℃ and keep making in 60 minutes reaction to carry out fully obtaining 3-amino-1,2,4-phentriazine-1, the throw out of 4-dinitrogen oxide sodium salt.
Cooling is filtered, and discards filtrate, the collecting precipitation thing; Throw out is dissolved in 300 ml waters; Filter, discard filter residue, collect mother liquor.Above-mentioned mother liquor under cooling conditions, is added acetate, and making its pH value is 6, filters, and collects and obtains 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crude product.
Get above-mentioned crude product and restrain the ratio that crude products add 1000 ml waters in per 10, be added in the water, heating is dissolved it fully, and cooling obtains the transparent styloid of reddish-brown, is 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate.
Embodiment two: the test of monocrystalline X-ray diffraction
(1) diffraction experiment: the sample crystal is the transparent column of reddish-brown, and the diffraction experiment crystallographic dimension is 0.05 * 0.20 * 1.00mm, belongs to oblique system, and spacer is P2
1, unit cell parameters: a=4.775 (1),
Unit cell volume is:
Molecule number Z=2 in the structure cell.
Collect diffracted intensity data, Moka radiation, graphite monochromator with MACDIP-2030K face detection instrument, crystal and IP plate are apart from d=100mm, and pipe is pressed 50Kv, pipe stream 60mA, ω scanning, maximum 2 θ angles are 50.0 °, sweep limit is 0-180 °, the backswing angle is 5 °, is spaced apart 5 °, and sweep velocity is 1.5 °/min, each picture scanning 2 times, amount to picked-up 36 width of cloth images, independent point diffraction is 810, but view-point (| F|
2〉=8 σ | F|
2) be 810.
(2) Structure Calculation: on microcomputer, resolve crystalline structure with direct method, on E figure, directly obtain 13 non-hydrogen atom positions, crossover uses method of least squares and difference Fourier method to obtain other non-hydrogen atom position, with least-squares refinement structural parameter and judgement atomic species, calculate the whole hydrogen atoms of acquisition position with geometric calculation and difference Fourier method crossover, final reliable factor R
f=0.061, and Rw=0.059 (w=1/ σ | F|
2).Final definite asymmetry unit stoichiometric equation is C
7H
6N
4O
2.2H
2O, the calculating molecular weight of disregarding water molecules is 178.15, calculating crystalline density is 1.477g/cm
2
The molecule stereo structure sciagraph is seen Fig. 1, and molecule is seen Fig. 2 along the axial sciagraph of α in the structure cell.The atomic coordinate parameter and the equivalent temperature factor are seen Fig. 3, become interatomic bond distance of key and bond angle to see Fig. 4.
(3) analytical results
The result shows: sample is the phentriazine compounds.This compound molecule skeleton constitutes a big conjugate system by six-ring A, B, and molecule is a two dimensional structure and is reddish- brown.Wherein 1,2,1,4 nitrogen-atoms of 4-triazine is all oxidized, forms oxynitrides, and its coordination bond distance average is to comprise 1 RS-27 molecule and 2 crystal water in the next asymmetry unit of 1.305A. crystalline state.Molecular arrangement belongs to first kind spacer under the crystalline state, so this compound should have optically active under crystalline state.Intramolecularly does not have hydrogen bond contact, intermolecular hydrogen bonding: OW1......OW2 (1+x, y, 1+z) 2.8753A, OW1......OW2 (1-x, 1/2+y, 1-z) 2.8421A, OW2......OW1 (x, y, 1+z) 2.7786A, OW2......O13 (x, y, z) 2.7909A.Molecule maintains it in three-dimensional stable alignment with hydrogen bond action power and Van der Waals under the crystalline state.
With 3-amino-1,2,4-phentriazine-1, dihydrate 10 grams of 4-dinitrogen oxide are dissolved in 200 milliliters of N, in dinethylformamide (DMF) solution, be heated to 90-95 ℃, the elimination insolubles is through the rotary evaporation solvent, after the cooling, obtain red crystalline powder 7.5 grams, survey purity greater than 99% through HPLC peak area normalization method.Overall yield behind the purifying is 65% of a theoretical yield.With gained 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide carries out the test of monocrystalline X-ray diffraction, determines its structure, and is specific as follows:
(1) diffraction experiment
The sample crystal is the transparent column of sorrel, and the diffraction experiment crystallographic dimension is 0.10 * 0.15 * 0.50mm, belongs to rhombic system, and spacer is P212121, unit cell parameters: a=4.876 (1), and b=7.431 (1),
Unit cell volume is:
Molecule number Z=4 in the structure cell.
Collect diffracted intensity data, Moka radiation, graphite monochromator with MACDIP-2030K face detection instrument, crystal and IP plate are apart from d=100mm, and pipe is pressed 50Kv, pipe stream 60mA, ω scanning, maximum 2 θ angles are 50.0 °, sweep limit is 0-180 °, the backswing angle is 5 °, is spaced apart 5 °, and sweep velocity is 1.5 °/min, each picture scanning 2 times, amount to picked-up 36 width of cloth images, independent point diffraction is 916, but view-point (| F|2 〉=8 σ | F|2) be 728.
(2) Structure Calculation
On microcomputer, resolve crystalline structure with direct method, on E figure, directly obtain 13 non-hydrogen atom positions, crossover uses the least-squares refinement structural parameter and differentiates atomic species, use geometric calculation and difference Fourier method crossover to calculate and obtain whole hydrogen atoms position, final reliable factor R f=0.066, and Rw=0.064 (w=1/ σ | F|2).Final definite asymmetry unit stoichiometric equation is C7H6N4O2.2H2O, and calculating molecular weight is 178.15, and calculating crystalline density is 1.605g/cm2.
(3) analytical results
The result shows: sample is the phentriazine compounds.This compound molecule skeleton constitutes a big conjugate system with two dimensional structure by six-ring A, the B of two merging, and makes crystal present sorrel.Wherein 1,2,1,4 N atom of 4-triazine is all oxidized, forms oxynitrides, and its coordination bond distance average is that molecular arrangement belongs to first kind spacer under the 1.305A. crystalline state.Intermolecularly under the crystalline state maintain it in three-dimensional stable alignment with Van der Waals force.
Embodiment three: tumour is put/the chemotherapy sensitizing test
Select HeLa (human cervical carcinoma cell S-3 system), CNE-2 (KB cell system), A549 (Lu-csf-1) and the individual tumor cell line of HCT (CCL188) and CNE-2 cell ball, under aerobic and weary oxygen condition, tumour cell is provided with four and treats reagent agent amount (0,1.25,2.5,5 μ M) group, the cell ball is provided with four drug doses (0,7,14,28 μ M) group, 1h is through the 60CO-gammairradiation after the administration, colony-forming test by culturing cell, calculate the survival rate of respectively organizing cell, adopt computer to carry out many targets and click model-fitting, calculate mean lethal dose (D0), oxygen enhancement ratio (OER), enhanced sensitivity is than (SER), the C1.6 equivalence.
The result: four strain tumour cell drug doses are the weary oxygen part D0 value of 0 μ M group (i.e. not administration group), all apparently higher than aerobic part D0 value, the OER value is all greater than 2.5, meet the requirement (OER is between 2.5～3.0) of weary oxygen model, TPZ2H2O is basic, normal, high, and three dosage all have tangible sensitization to four strain tumour cells, SER value (enhanced sensitivity ratio) all greater than 1.4, meets the requirement (SER＞1.4) of radiosensitizer to SER.CNE-2 cell, A549 cell, HeLa cell and HCT cell C1.6 are about respectively: 2.2,1.8,2.1 and 2.0 μ M.Adopt the CNE-2 cell to make cell spheroid and cultivate, the weary oxygen feature of in-vitro simulated tumor tissues is respectively 1.59,1.65,1.77 at the SER of three drug dose groups of 7,14,28 μ M enhanced sensitivity test, and the C1.6 value is about 10 μ M.
Conclusion: TPZ2H2O has significantly radiosensitizing effect to CNE-2 cell, A549 cell, HeLa cell, HCT cell and CNE-2 many cells spheroid, and is dose-effect relationship preferably.Show that TPZ2H2O can be used as radiosensitizer and further studies.
The compound 60Co gammairradiation of TPZ2H2O BALB/c mouse experiment transplantability mammary cancer and S-180 sarcoma, nude mouse experiment transplantability human lung adenocarcinoma, tangible radiosensitizing effect is all arranged, gross tumor volume, relative tumor proliferation rate and inhibition rate of tumor growth there is obvious restraining effect, and increase with TPZ2H2O dosage and irradiation dose, restraining effect is obvious more.TPZ2H2O all obviously reduces according to penetrating control group (not administration) in each dosage control tumor growth 50% required irradiation dose (TCD50), 10, all greater than 1.4, its C1.6 value is respectively 11.0～16.5mg/kg, 7.0～11.5mg/kg, 12.5～15.0mg/kg to the radiation sensitization of 20mg/kg TPZ2H2O than (SER).The compound 60Co gammairradiation of TPZ2H2O also has tangible radiosensitizing effect to nude mouse experiment transplantability human cervical carcinoma and C57 mouse experiment transplantability melanoma, gross tumor volume and relative tumor proliferation rate (T/C) there is obvious restraining effect, and increase with TPZ2H2O dosage and irradiation dose, restraining effect is obvious more, and tumor growth slack time (TGD) is obviously prolonged.
Embodiment four: the preparation of TPZ dihydrate
1. tablet: TPZ2H2O 85g
Lactose 50g
Starch 35g
Sodium starch glycolate 4g
Magnesium Stearate 1g
HPMC (Vltra tears) is an amount of
Preparation: bulk drug in will writing out a prescription and auxiliary material, comprise that TPZ2H2O, lactose, starch waited 80 mesh sieves, mixing is used the 2%HPMC aqueous solution, granulate drying, whole grain, sodium starch glycolate, the Magnesium Stearate of adding recipe quantity, mixing, compressing tablet obtains tablet, every TPZ2H2O that contains 85mg.
2. gel capsule: TPZ2H2O 85g
Soybean oil 180g
Yelkin TTS 4g
Yellow wax 8g
Hydrogenated vegetable oil 30g
Preparation: hydrogenated vegetable oil and yellow wax are added in the container, with container heating and stir content until fusing.Thorough mixing soybean oil and Yelkin TTS, be added to then in fused hydrogenated vegetable oil/yellow wax mixture, the warm mixture that obtains also stirs, until obtaining uniform mixture, add TPZ2H2O then while stirring in mixture, the suspension that obtains carries out homogenizing.Reprocessing is prepared into gel capsule, every TPZ2H2O that contains 85mg.
3. injection: TPZ2H2O 0.85g
Sodium-chlor 8.70g
Citric acid 0.96g
Sodium hydroxide 0.25g
Add suitable quantity of water to 1000 milliliter, transfer to pH 4.0
Preparation: take by weighing above-mentioned recipe quantity bulk drug and auxiliary material, add water, stir and make dissolving, transfer to pH 4.0, filter, embedding is in ampoule, and sterilization gets finished product, every TPZ2H2O that contains 85mg.
4. granule: TPZ2H2O 85g
Lactose 80g
Starch 90g
HPMC (Vltra tears) is an amount of
Preparation: bulk drug in will write out a prescription and auxiliary material, comprise that TPZ2H2O, lactose, starch waited 80 mesh sieves, mixing, with the dilution of the 2%HPMC aqueous solution is granulated drying, packing, every bag of TPZ2H2O that contains 85mg.
Claims (9)
1. the 3-amino-1,2 shown in the following formula, 4-phentriazine-1, the 4-dinitrogen oxide dihydrate:
2. the crystal of the described dihydrate of claim 1 is characterized by the crystal column that takes on a red color, and belongs to oblique system, and spacer is P2
1, unit cell parameters: a=4.775 (1), b=13.689 (10) β=98.68 (1).Unit cell volume is: V=481.6 (1)
3, molecule number Z=2 in the structure cell.
3. the preparation method of the described dihydrate of claim 1 adds hot preparation by benzo furazan-1-oxide compound, cyanamide in the sodium hydroxide alcoholic solution, it is characterized by may further comprise the steps:
A) benzo furazan-1-oxide compound is dissolved in methyl alcohol, preferably is dissolved in the ratio of 400 ml methanol, add the water of equivalent again, add cyanamide and stir and make dissolving in benzo furazan-1-oxide compound of 1 mole;
B) under the condition of stirring at room, slowly add solid sodium hydroxide, controlled temperature is no more than 60 ℃;
C) after solid sodium hydroxide all adds dissolving, temperature is risen to 58 ℃-60 ℃ and kept 60 minutes; Cooling is filtered, and discards filtrate, obtains 3-amino-1,2,4-phentriazine-1, the throw out of 4-dinitrogen oxide sodium salt;
D) throw out is water-soluble, filter to collect mother liquor, the cooling back adds acetate, regulates the pH value 5～6.5, preferably regulate the pH value and be 6 filter 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crude product;
E) crude product is added in the entry, preferably by the per 10 3-amino-1 that restrain, 2,4-phentriazine-1,4-dinitrogen oxide crude product adds the ratio of 500～1500 ml waters, heating is dissolved it fully, cooling gets 3-amino-1,2,4-phentriazine-1, the transparent styloid of the reddish-brown of 4-dinitrogen oxide dihydrate.
4. preparation method according to claim 3 is characterized by the sequencing adding of reactant by benzo furazan-1-oxide compound, cyanamide and sodium hydroxide, and three's mol ratio is 1: 3: 6.
5. preparation method according to claim 3 is characterized by the sequencing adding of reactant by benzo furazan-1-oxide compound, cyanamide and sodium hydroxide, and three's mol ratio is 1: 3: 6, may further comprise the steps:
A) benzo furazan-1-oxide compound is dissolved in methyl alcohol in 1 mole of ratio that adds 400 ml methanol, is heated to 60 ℃ it is dissolved fully, add the water of equivalent again, add the cyanamide stirring and make dissolving;
B) under the condition of stirring at room, slowly add solid sodium hydroxide, controlled temperature is no more than 60 ℃;
C) after solid sodium hydroxide all adds dissolving, temperature is risen to 58 ℃-60 ℃ and kept 60 minutes; Cooling is filtered, and discards filtrate, obtains 3-amino-1,2,4-phentriazine-1, the throw out of 4-dinitrogen oxide sodium salt;
D) throw out is water-soluble, filter to collect mother liquor, the cooling back adds acetate, regulating the pH value is 6, filter 3-amino-1,2,4-phentriazine-1,4-dinitrogen oxide crude product;
E) get above-mentioned crude product and add in the entry in the ratio that per 10 grams add 1000 ml waters, heating is dissolved it fully, and cooling gets 3-amino-1,2,4-phentriazine-1, the transparent styloid of the reddish-brown of 4-dinitrogen oxide dihydrate.
6. 3-amino-1,2,4-phentriazine-1, the crystal of 4-dinitrogen oxide is characterized by crystal and is the transparent column of sorrel, and the diffraction experiment crystallographic dimension is 0.10 * 0.15 * 0.50mm, belongs to rhombic system, and spacer is P2
12
12
1, unit cell parameters: a=4.876 (1), b=7.431 (1), c=20.347 (2) .Unit cell volume is: V=737.24 (14)
3, molecule number Z=4 in the structure cell.
7. the described oxynitride crystalline of claim 6 preparation method is characterized by and may further comprise the steps:
With 3-amino-1,2,4-phentriazine-1, the 4-dinitrogen oxide dihydrate is dissolved in DMF, preferred per 10 gram dihydrates add 100 to 600 milliliters of DMF, and more preferably 200 milliliters, heating makes its dissolving, and recrystallization gets 3-amino-1,2,4-phentriazine-1, the crystal of 4-dinitrogen oxide.
8. the application of the described dihydrate of claim 1 in preparation tumor radiotherapy or chemotherapy sensitizing medicine.
9. claim 2 or the 6 described crystal application in preparation tumor radiotherapy or chemotherapy sensitizing medicine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610072594 CN101054367A (en) | 2006-04-13 | 2006-04-13 | 3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy |
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| CN 200610072594 CN101054367A (en) | 2006-04-13 | 2006-04-13 | 3-Amino-1,2,4-phentriazine-1,4-dinitrogen oxide dihydrate, its preparation method and application in tumour radiotherapy and chemotherapy |
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| CN101683319B (en) * | 2008-09-24 | 2012-09-05 | 杭州民生药业有限公司 | Tirapazamine parenteral hydrous preparation and preparation method thereof |
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