CN1088703C - Water soluble taxad alcohol derivative - Google Patents
Water soluble taxad alcohol derivative Download PDFInfo
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- CN1088703C CN1088703C CN99116884A CN99116884A CN1088703C CN 1088703 C CN1088703 C CN 1088703C CN 99116884 A CN99116884 A CN 99116884A CN 99116884 A CN99116884 A CN 99116884A CN 1088703 C CN1088703 C CN 1088703C
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Abstract
The present invention relates to water-solubility taxol derivatives containing thiosulfuric acid and salt thereof. The derivatives can be used for treating tumor and cancer. Compared with the existing medicinal single taxol, the present invention has the advantages of keeping the original therapeutic effect, reducing toxic and side effect and high biological availability.
Description
The present invention relates to the novel water soluble taxad alcohol derivative of a class---the Japanese yew alcohol ester of thiosulfuric acid or its salt, described derivative can be used for tumour and treatment for cancer.
Taxol (TAXOL) is the natural plant of the multiple cancer of a kind of effective treatment, now has been widely used in clinical.But because taxol itself is water-soluble hardly, the solubleness in water has caused the restriction that this medicine is used less than 0.004mg/ml, so taxol can only be made the injection use by means of solubility promoter.And this class solubility promoter all has toxic side effect in varying degrees, is that cremophore EL (poly-ethoxy is for Viscotrol C) and ethanol mixed with 1: 1 as solubility promoter commonly used.And cremophore EL is easy to bring out anaphylaxis, and clinical symptom is ypotension, fash and expiratory dyspnea, and ethanol can increase the weight of burden of liver.Therefore, research and development good water solubility, the D51-7059 that toxicity is low, curative effect is high, easy to use, significant.
The object of the present invention is to provide a class to contain the D51-7059 of thiosulfuric acid or its salt.This compound in vivo owing to metabolism discharges the free taxol, has improved its bioavailability as anticarcinogen external stable, has the good anticancer effect.
The present invention's one class water soluble taxad alcohol derivative is to be made of with the ester group form on 2 ' and 7 of taxol the thiosulfuric acid that replaces or its salt, and its structural formula is:
R=CO (CH wherein
2)
mCONH (CH
2)
nS
2O
3M or H,
R '=CO (CH
2)
mCONH (CH
2)
nS
2O
3M or H,
M=2-6, n=2-6, M=hydrogen, sodium, potassium, lithium, ammonium,
M the best is 2 or 3, and n the best is 2 or 3, and M the best is a sodium
R and R ' are CO (CH
2)
mCONH (CH
2)
nS
2O
3During M, can be identical or inequality,
Can only 1 among R and the R ' be H.
The present invention contains the water soluble taxad alcohol derivative of thiosulfuric acid or its salt---and Japanese yew alcohol ester water solubility in the time of 25 ℃ of thiosulfuric acid or its salt is 5-15mg/ml.
The preparation method of water soluble taxad alcohol derivative of the present invention
The Japanese yew alcohol ester of thiosulfuric acid of the present invention or its salt is to be raw material with taxol (natural Japanese yew alcohol preferred), warp and corresponding acid anhydrides such as succinyl oxide or Pyroglutaric acid, perhaps corresponding dicarboxylic acid carboxylic acid halides such as succinic chloride or glutaryl chlorine are reacted into the carboxylic acyloxy taxol in the presence of organic bases, the carboxylic acid of this formation is followed with amino substituted alkyl thiosulfuric acid or its salt such as beta-aminoethyl thiosulfuric acid or its salt or 3-aminopropyl thiosulfuric acid or its reactant salt and obtained the Y-3 series product.Synthetic method of the present invention is simple, and the yield height has the possibility of suitability for industrialized production.Water soluble taxad alcohol derivative preparation method synoptic diagram is referring to figure l.
The Japanese yew alcohol ester of thiosulfuric acid of the present invention or its salt can be used for preparing the pharmaceutical preparation of treatment tumour and cancer, for example can be mixed with to be used for intravenous aqueous injection or powder injection.Embodiment described later is with 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol (Y-3a) and 2 ', and 7-two succinic diamide ethylenebis dithiocarbamate sodium sulfate taxols (Y-3b) are to human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16) model carries out the test of preliminary antitumor curative effect, the result shows that the corresponding dosage group all has significantly antitumor curative effect.
Derivative of the present invention is compared with existing taxol has following advantage and effect, and it is water-soluble by bringing up to greater than 5mg/ml less than 0.004mg/ml, is more than 1250 times of single taxol soluble.The novel D51-7059 of this class is soluble in water, can exempt at present because solubility promoter cremophoer EL and alcoholic acid use the toxic side effect that causes.This compounds enzyme catalysis in blood in vivo resolves into and does not have a pharmacologically active, do not influence the activity of taxol, to rudimentary meta-bolites and the taxol that human body has no adverse reaction, the latter is owing to disengage in vivo, has the high characteristics of bioavailability and increased curative effect.Therefore, use the injection of synthetic derivative preparation of the present invention, can be used for tumour and treatment for cancer.Compare with existing taxol, kept original curative effect, reduced toxic side effect, alleviated patient's misery, have the potentiality that develop into anticarcinogen of new generation.
Describe derivative of the present invention and preparation method thereof below in conjunction with drawings and Examples, but it does not limit the scope of the invention.
Description of drawings:
Fig. 1 water soluble taxad alcohol derivative preparation method synoptic diagram.
Synthetic beta-aminoethyl thiosulfuric acid
2-chloroethyl amine hydrochloride 18.6g and five water Sulfothiorine 39.6g are dissolved in and are heated to 80 ℃ in the 40ml water, stir 6-8 hour.The pH that adjusts reaction solution carries out by dripping saturated sodium bicarbonate aqueous solution once in a while between 6.0～6.5.Filtered while hot, vigorous stirring filtrate is separated out crystallization.Filter and collect crystallization, with cold absolute ethanol washing, dry 20.6g product, yield 82%, 196 ℃ of the fusing points of getting in dry cylinder.
1H NMR(D
2O)δ：3.5ppm(s，CH
2CH
2，4H)。
Synthetic 3-aminopropyl thiosulfuric acid
3-chloro propyl amine hydrochloric acid salt 20.85g and five water Sulfothiorine 39.6g are dissolved in and are heated to 80 ℃ in the 40ml water, stir 6-8 hour.The pH that adjusts reaction solution carries out by dripping saturated sodium bicarbonate aqueous solution once in a while between 6.0～6.5.Filtered while hot, vigorous stirring filtrate is separated out crystallization.Filter and collect crystallization, with cold absolute ethanol washing, dry 21.9g product, the yield 80% of getting in dry cylinder.
Synthetic beta-aminoethyl Sulfothiorine (2a)
With beta-aminoethyl thiosulfuric acid 15.7g, add aqueous sodium hydroxide solution 40ml (concentration 10%) at 0 ℃, after stirring, freezing drying.Get product 17g, yield 95%, it is stand-by to put into moisture eliminator.
Embodiment 4
Synthetic 3-aminopropyl Sulfothiorine (2b)
With 3-aminopropyl thiosulfuric acid 17.1g, add aqueous sodium hydroxide solution 40ml (concentration 10%) at 0 ℃, after stirring, freezing drying.Get product 19g, yield 98%, it is stand-by to put into moisture eliminator.
Embodiment 5
Synthetic beta-aminoethyl thiosulfuric acid tetrabutyl amine salt
With beta-aminoethyl thiosulfuric acid 2g, the hydrogen-oxygen 4-butyl amine aqueous solution (10%) 27ml mixes, stirring reaction is 4 hours under room temperature, reaction mixture extracts 3 times with methylene dichloride 15g, methylene dichloride is all merged, and rotary evaporation gets oily matter, with oil pump take out faint yellow solid product 3.2g, yield 77%, it is stand-by to put into moisture eliminator.
1H NMR(D
2O)δ(ppm)：0.8～1.2(m，12H)，1.2～2.0(m，16H)，3.0～3.5(m，12H)。
Embodiment 6
Synthetic 2 '-succinyl-taxol (1a)
Method 1: with taxol 0.5g, succinyl oxide 0.12g, DMAP 7mg drops in the reaction flask, vacuum-drying 5 hours, sealing adds anhydrous pyridine 4.8ml with syringe, stirs, in room temperature reaction 3 hours.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.56g, it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,10: 1 then), yield is 85%.
Method 2: with taxol 0.5g, Succinic Acid acyl chlorides 0.19g, DMAP 10mg drops in the reaction flask, vacuum-drying 5 hours, sealing adds anhydrous pyridine 8ml with syringe, stirs, in room temperature reaction 3 hours.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.53g, it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,10: 1 then), yield is 80%.
Embodiment 7
Synthetic 2 '-pentanedioic acid acyl taxol (1b)
Method 1: with taxol 0.5g, Pyroglutaric acid 0.15g, DMAP 7mg drops in the reaction flask, vacuum-drying 5 hours, sealing adds anhydrous pyridine 4.8ml with syringe, stirs, in room temperature reaction 3 hours.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.61g, it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,10: 1 then), yield is 90%.
Method 2: with taxol 0.5g, pentanedioic acid acyl chlorides 0.22g, DMAP 10mg drops in the reaction flask, vacuum-drying 5 hours, sealing adds anhydrous pyridine 8ml with syringe, stirs, in room temperature reaction 3 hours.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.59g, it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,10: 1 then), yield is 80%.
Embodiment 8
Synthetic 2 ', 7-two (succinyl-) taxol (1c)
With taxol 0.5g, succinyl oxide 0.25g, DMAP 7mg drops in the reaction flask, vacuum-drying 5 hours, sealing is injected the dry anhydrous pyridine 4.8ml that heavily steams with syringe, stirs, in stirring at room 35-40 hour.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.76g. it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,8: 1 then).
Embodiment 9
Synthetic 2 ', 7-two (pentanedioic acid acyl) taxol (1d)
With taxol 0.5g Pyroglutaric acid 0.3g, DMAP 7mg drops in the reaction flask, vacuum-drying 5 hours, and sealing is injected the dry anhydrous pyridine 4.8ml that heavily steams with syringe, stirs, in stirring at room 35-40 hour.In reaction mixture, add a large amount of anhydrous diethyl ethers to muddy, add normal hexane to solid again and separate out fully, filter, get thick product 0.71g, it is dissolved in CHCl
3After carry out can getting single straight product behind the rapid column chromatography (leacheate be CHCl
3: CH
3OH, ratio is 20: 1,8: 1 then).
Embodiment 10
Synthetic 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol (Y-3a)
With 2 '-succinyl-taxol 0.2g is dissolved in the anhydrous tetrahydro furan, cryosel is bathed and is cooled to-10 ℃, drip isobutyl chlorocarbonate 0.093ml, splash into triethylamine 0.17ml then, keep under this temperature and reacted five minutes, remove cryosel and bathe, rise to room temperature after 15 minutes, splash into the tetrahydrofuran solution of beta-aminoethyl thiosulfuric acid tetrabutyl amine salt 0.096g, reacted 1 hour, remove by filter Et
3NHCl with the tetrahydrofuran (THF) washing, drains filtrate, and pressurized column chromatography obtains the 4-butyl ammonium of product, developping agent CHCl
3-CH
3OH (being earlier 20: 1, is 10: 1 then).
With the said products adding soluble in water 4ml DOWEX-50 ion exchange resin, vigorous stirring 5 hours, carry out ion exchange column dress post then, get the final product aqueous solution with water wash, this aqueous solution is with the mixing solutions of methyl alcohol and the toluene moisture of taking under 25 ℃ of decompressions, products obtained therefrom can be further purified through the thin plate chromatography, and nuclear-magnetism detects no Bu
4N
+Group exists, and thin plate chromatography developping agent proportioning is CHCl
3: CH
3OH=5: 1.Also have the preceding product of a small amount of not exchange to repeat exchange operations.Obtain product 0.19 gram.Electrospray ionization mass spectrum: 1116 (M+1), 1139 (M+Na);
1H NMR (300MHz, CD
3COCD
3) and the document taxol
1H NMR compares, the peak δ (ppm) that product increases: 5.5 (d, 1H), 3.48 (t, 2H), 3.10 (t, 2H), 2.70 (t, 2H), 2.52 (t, 2H).
Embodiment 11
Synthetic 2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b)
With 2 ', 7-two (succinyl-) taxol 0.2g is dissolved in dry DMF 5ml, cryosel is bathed and is cooled to-10 ℃, drips isobutyl chlorocarbonate 0.2ml, splashes into triethylamine 0.35ml then, keep under this temperature and reacted five minutes, remove cryosel and bathe, rise to room temperature after 15 minutes, splash into the anhydrous DMF solution of beta-aminoethyl Sulfothiorine 0.086g, stirring reaction 1 hour adds anhydrous diethyl ether and separates out precipitation.Filter and collect product.Pressurized column chromatography obtains product 0.21 gram, developping agent CHCl
3-CH
3OH (being earlier 20: 1, is 5: 1 then).Electrospray ionization mass spectrum: 1377 (M+1);
1H NMR (300MHz, CD
3COCD
3) and the document taxol
1H NMR compares, the peak that product increases
1H NMR: δ (ppm, CD
3COCD
3): 5.6 (d, 2H), 3.5 (t, 4H), 3.2 (t, 4H), 2.8 (t, 4H), 2.5 (t, 4H).
Embodiment 12
Synthetic 2 ', 7-two (succinic diamide propyl dithiocarbamate sodium sulfate) taxol (Y-3c)
With 2 ', 7-two (succinyl-) taxol 0.2g is dissolved in dry DMF 5ml, cryosel is bathed and is cooled to-10 ℃, drips isobutyl chlorocarbonate 0.2ml, splashes into triethylamine 0.35ml then, keep under this temperature and reacted five minutes, remove cryosel and bathe, rise to room temperature after 15 minutes, splash into the anhydrous DMF solution of 3-aminopropyl Sulfothiorine 0.1g, stirring reaction 1 hour adds anhydrous diethyl ether and separates out precipitation.Filter and collect product.Pressurized column chromatography obtains product 0.23g.Developping agent CHCl
3-CH
3OH (being earlier 20: 1, is 5: 1 then).Electrospray ionization mass spectrum: 1405 (M+1);
1H NMR (300MHz, CD
3COCD
3) and the document taxol
1H NMR compares, the peak that product increases
1H NMR: δ (ppm, CD
3COCD
3): 5.6 (d, 2H), 3.5 (t, 4H), 3.2 (t, 4H), 2.8 (t, 4H), 2.5 (t, 4H), 1.3 (m, 4H).
Embodiment 13
Synthetic 2 ', 7-two (glutaramide propyl dithiocarbamate sodium sulfate) taxol (Y-3d)
With 2 ', 7-two (pentanedioic acid acyl) taxol 0.22g is dissolved in dry DMF 5ml, cryosel is bathed and is cooled to-10 ℃, drips isobutyl chlorocarbonate 0.2ml, splashes into triethylamine 0.35ml then, keep under this temperature and reacted five minutes, remove cryosel and bathe, rise to room temperature after 15 minutes, splash into the anhydrous DMF solution of 3-aminopropyl Sulfothiorine 0.1g, stirring reaction 1 hour adds anhydrous diethyl ether and separates out precipitation.Filter and collect product.Pressurized column chromatography obtains product 0.20g.Developping agent CHCl
3-CH
3OH (being earlier 20: 1, is 5: 1 then).Electrospray ionization mass spectrum: 1433 (M+1);
1H NMR (300MHz, CD
3COCD
3) and the document taxol
1H NMR compares, the peak that product increases
1H NMR: δ (ppm, CD
3COCD
3): 5.6 (d, 2H), 3.5 (t, 4H), 3.2 (t, 4H), 2.8 (t, 4H), 2.5 (t, 4H), 1.5 (m, 4H), 1.1 (m, 4H).
Embodiment 14
Preparation 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol (Y-3a) water soluble powder injection
Drop into 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol 40mg in reaction flask, granulesten 1.5 gram, Septochol are received 1.85 grams, add 20 milliliters in acetone, are stirred to molten.To doing, add phosphate buffered saline buffer (pH=7.5) 40ml dissolution residual substance 30 ℃ of vacuum-evaporation, millipore filtration (0.2 micron) filters, and the filtrate lyophilize gets every bottle of water soluble powder injection that contains 40mg 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol.This powder injection can directly add 5% glucose or 10% sodium chloride injection dissolving posterior vein instils.
Embodiment 15
Preparation 2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b) water soluble powder injection
Drop into 2 ' in reaction flask, 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol 40mg, granulesten 1.5 gram, Septochol receive 1.85 grams, add 20 milliliters in acetone, are stirred to molten.Extremely do 30 ℃ of vacuum-evaporation, add phosphate buffered saline buffer (pH=7.5) 40ml dissolution residual substance, millipore filtration (0.2 micron) filters, and the filtrate lyophilize gets every bottle and contains 40mg 2 ', the water soluble powder injection of 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol.This powder injection can directly add 5% glucose or 10% sodium chloride injection dissolving posterior vein instils.
Embodiment 16
2 '-(succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3a) is to human body mastadenoma and murine melanoma clinical trial
1. sample preparation: accurately take by weighing the 13mg sample, put porphyrize in the mortar, add 25ml and dissolve in the physiological saline.In being diluted to physiological saline more as required, the solution of lower concentration, test solution needs fresh preparation every day.
2. animal
2.1. nude mouse and C
57The BL/6 mouse, body weight: 17-19 gram, 6-8 age in week, sex: female
2.2. number of animals: nude mouse test group and positive controls are 6 for every group, and negative control group is 12.C
57BL/6 mouse experiment group and positive controls are 10, and negative control group is 20.
3. knurl source: human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16).
4. dosage setting: 13,5.2 and 2.08mg/kg.
5. dosage regimen: intravenously administrable, once a day, continuous seven days.Negative control group is given corresponding solvent, identical dosage regimen.Positive controls endoxan 30mg/kg (adding dehydrated alcohol 39.6% with Cremophor52.7% is dissolved into 6mg/ml and is diluted to desired concn with physiological saline again) intravenously administrable, once a day, continuous seven days.
6. experiment contrast: negative control is given corresponding solvent.Positive control is endoxan (CTX), prepares with physiological saline.
7. test key step: get the vigorous tumour of growth, prepare into about 1 * 10 with the homogenate method under the aseptic condition
7/ ml cell suspension, with the every mouse armpit of corresponding host subcutaneous vaccination 0.2ml, next day is by the administration of experimental design scheme.Nude mouse places the SPF condition to raise; C
57The BL/6 mouse places cleaning level condition to raise.Experiment finishes the back and dissects each treated animal, cuts open to get tumour and weigh, and calculate by following formula: the average knurl of the average knurl weight-administration of tumor control rate %=[(control group group is heavy)/the average knurl of control group weighs] * 100
8. experimental result: 2 '-(succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3a) with 13,5.2 and the treatment plan of 2.08mg/kg iv * 7qd to human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16) the test of preliminary antitumor curative effect, the result shows that three dosage groups all have significantly antitumor curative effect, the former is respectively 75.64%, 68.17% and 45.55% its tumor control rate, the latter is respectively 55.95%, 46.03% and 31.35%.The result sees table 1 and 2 for details.
Table 1. 2 '-succinic diamide ethylenebis dithiocarbamate sodium sulfate taxol (Y-3a)
Curative effect to human body mastadenoma (Bre-04) heteroplastic transplantation model
P
*＜0.01 compares with negative control group
| Group | Dosage (mg/kg) | Dosage regimen | Number of animals (beginning/end) | Body weight (beginning/end) | The knurl weight (X ± SD) | Inhibiting rate (%) |
| Y-3a | 13 | iv×7qd | 6/6 | 18.1/19/2 | 0.238±0.086 ** | 75.64 |
| Y-3a | 5.2 | iv×7qd | 6/6 | 18.4/18.9 | 0.311±0.082 ** | 68.17 |
| Y-3a | 2.08 | iv×7qd | 6/6 | 18.5/19.0 | 0.532±0.108 ** | 45.55 |
| Taxol | 10 | iv×7qd | 6/6 | 18.5/18.7 | 0.178±0.035 ** | 81.78 |
| Positive control CTX | 30 | ip×7qd | 6/6 | 18.3/18.5 | 0.158±0.05 ** | 83.82 |
| Negative control | Coordinative solvent | iv×7qd | 12/12 | 18.4/20.3 | 0.977±0.226 |
Table 2.Y-3a is to murine melanoma (B
16) curative effect of model
P
*＜0.01 compares with negative control group
| Group | Dosage (mg/kg) | Dosage regimen | Number of animals (beginning/end) | Body weight (beginning/end) | The knurl weight (X ± SD) | Inhibiting rate (%) |
| Y-3a | 13 | iv×7qd | 10/10 | 20.2/21.9 | 1.11±0.41 ** | 55.95 |
| Y-3a | 5.2 | iv×7qd | 10/10 | 20.5/22.4 | 1.36±0.23 ** | 46.03 |
| Y-3a | 2.08 | iv×7qd | 10/10 | 20.7/22.9 | 1.73±0.32 ** | 31.35 |
| Taxol | 10 | iv×7qd | 10/10 | 20.1/21.9 | 0.99±0.22 ** | 60.71 |
| Positive control CTX | 30 | ip×7qd | 10/10 | 20.2/19.7 | 0.32±0.09 ** | 87.30 |
| Negative control | Coordinative solvent | iv×7qd | 20/20 | 20.4/25.2 | 2.52±0.39 |
9. test brief summary:
The treatment plan of mole 13mg/kg iv * 7qd such as water-soluble taxol derivative Y-3a high dose group employing of the present invention and taxol 10mg/kg is to human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16) antitumor curative effect show to have suitable antitumous effect, and approaching with the taxol curative effect.Because have certain dose-effect relationship between the dosage, employed dosage is expected further to improve curative effect through adjustment.The LD of Y-3a
50Data are tested.
Embodiment 17
2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b) is to the clinical trial of human body mastadenoma and murine melanoma
1. sample preparation: accurately take by weighing the 16mg sample, put porphyrize in the mortar, add 25ml and dissolve in the physiological saline.In being diluted to physiological saline more as required, the solution of lower concentration, test solution needs fresh preparation every day.
2. animal
2.1. nude mouse and C
57The BL/6 mouse, body weight: 17-19 gram, 6-8 age in week, sex: female
2.2. number of animals: nude mouse test group and positive controls are 8 for every group, and negative control group is 12.C
57BL/6 mouse experiment group and positive controls are 12, and negative control group is 20.
3. knurl source: human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16).
4. dosage setting: 16,6.4 and 2.57mg/kg
5. dosage regimen: intravenously administrable, once a day, continuous seven days.Negative control group is given corresponding solvent, identical dosage regimen.Positive controls endoxan 30mg/kg (adding dehydrated alcohol 39.6% with Cremophor52.7% is dissolved into 6mg/ml and is diluted to desired concn with physiological saline again) intravenously administrable, once a day, continuous seven days.
6. experiment contrast: negative control is given corresponding solvent.Positive control is endoxan (CTX), prepares with physiological saline.
7. test key step: get the vigorous tumour of growth, prepare into about 1 * 10 with the homogenate method under the aseptic condition
7/ ml cell suspension, with the every mouse armpit of corresponding host subcutaneous vaccination 0.2ml, next day is by the administration of experimental design scheme.Nude mouse places the SPF condition to raise; C
57The BL/6 mouse places cleaning level condition to raise.Experiment finishes the back and dissects each treated animal, cuts open to get tumour and weigh, and calculate by following formula: the average knurl of the average knurl weight-administration of tumor control rate %=[(control group group is heavy)/the average knurl of control group weighs] * 100
8. experimental result: 2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b) with 16,6.4 and the treatment plan of 2.57mg/kg iv * 7qd to human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16) antitumor curative effect test, the result shows that three dosage groups all have significantly antitumor curative effect, the former is respectively 76.84%, 69.26% and 44.47% its tumor control rate, the latter is respectively 52.38%, 42.86%, 27.78%.The result sees table 3 and 4 for details.
Table 3. 2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b)
Curative effect to human body mastadenoma (Bre-04) heteroplastic transplantation model
| Group | Dosage (mg/kg) | Dosage regimen | Number of animals (beginning/end) | Body weight (beginning/end) | The knurl weight (X ± SD) | Inhibiting rate (%) |
| Y-3b | 16 | iv×7qd | 8/8 | 18.2/19.3 | 0.226±0.086 ** | 76.84 |
| Y-3b | 6.4 | iv×7qd | 8/8 | 18.3/19.0 | 0.300±0.082 ** | 69.26 |
| Y-3b | 2.57 | iv×7qd | 8/8 | 18.4/19.1 | 0.542±0.108 ** | 44.47 |
| Taxol | 10 | iv×7qd | 8/8 | 18.4/18.6 | 0.179±0.035 ** | 81.66 |
| Positive control CTX | 30 | ip×7qd | 8/8 | 18.2/18.4 | 0.158±0.05 ** | 83.81 |
| Negative control | Coordinative solvent | iv×7qd | 12/12 | 18.3/20.1 | 0.976±0.226 |
P
*＜0.01 compares with negative control group
Table 4. 2 ', 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b)
To murine melanoma (B
16) curative effect of model
P
*＜0.01 compares with negative control group
| Group | Dosage (mg/kg) | Dosage regimen | Number of animals (beginning/end) | Body weight (beginning/end) | The knurl weight (X ± SD) | Inhibiting rate (%) |
| Y-3b | 16 | iv×7qd | 12/12 | 20.1/22.1 | 1.20±0.41 ** | 52.38 |
| Y-3b | 6.4 | iv×7qd | 12/12 | 20.4/22.6 | 1.44±0.23 ** | 42.86 |
| Y-3b | 2.57 | iv×7qd | 12/12 | 20.5/23.1 | 1.82±0.32 ** | 27.78 |
| Taxol | 10 | iv×7qd | 12/12 | 20.3/21.9 | 1.01±0.22 ** | 59.92 |
| Positive control CTX | 30 | ip×7qd | 12/12 | 20.1/19.8 | 0.33±0.09 ** | 86.90 |
| Negative control | Coordinative solvent | iv×7qd | 20/20 | 20.5/25.1 | 2.52±0.39 |
9. test brief summary:
Water-soluble taxol derivative 2 ', the treatment plan of mole 16mg/kg iv * 7qd such as employing of 7-two (succinic diamide ethylenebis dithiocarbamate sodium sulfate) taxol (Y-3b) high dose group and taxol 10mg/kg is to human body mastadenoma heteroplastic transplantation model (Bre-04) and murine melanoma (B
16) antitumor curative effect show to have suitable antitumous effect, and approaching with the taxol curative effect.Owing to have certain dose-effect relationship between the dosage, employed dosage is expected further to improve curative effect through adjusting.The LD of Y-3b
50Data are tested.
Claims (5)
1, the water soluble taxad alcohol derivative of a class thiosulfuric acid or its salt is characterized in that described derivative is to be made of with the ester group form on 2 of taxol ' position and 7 thiosulfuric acid or its salt, and its structural formula is as follows:
R=CO (CH wherein
2)
mCONH (CH
2)
nS
2O
3M or H,
R '=CO (CH
2)
mCONH (CH
2)
nS
2O
3M or H,
M=2-6, n=2-6, M=hydrogen, sodium, potassium, lithium, ammonium,
R and R ' are CO (CH
2)
mCONH (CH
2)
nS
2O
3During M, can be identical or inequality,
Can only 1 among R and the R ' be H.
2, D51-7059 as claimed in claim 1 is characterized in that described derivative has following two kinds substituent structure
(1) R and R ' are CO (CH
2)
mCONH (CH
2)
nS
2O
3M, both are identical;
(2) R is CO (CH
2)
mCONH (CH
2)
nS
2O
3During M, R ' is H
M=2 or 3, n=2 or 3, M=sodium
3, D51-7059 as claimed in claim 1 is characterized in that described taxol is a natural Japanese yew alcohol.
4, the application of D51-7059 as claimed in claim 1 is characterized in that described D51-7059 can be used for preparing the pharmaceutical preparation of treatment tumour and cancer.
5, the application of D51-7059 as claimed in claim 4 is characterized in that described D51-7059 can be mixed with and is used for intravenous aqueous injection or powder injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99116884A CN1088703C (en) | 1999-09-17 | 1999-09-17 | Water soluble taxad alcohol derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99116884A CN1088703C (en) | 1999-09-17 | 1999-09-17 | Water soluble taxad alcohol derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1288890A CN1288890A (en) | 2001-03-28 |
| CN1088703C true CN1088703C (en) | 2002-08-07 |
Family
ID=5279553
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99116884A Expired - Lifetime CN1088703C (en) | 1999-09-17 | 1999-09-17 | Water soluble taxad alcohol derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1088703C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1310898C (en) * | 2004-01-19 | 2007-04-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Taxinol water soluble derivative |
| CN102702140B (en) * | 2012-06-19 | 2014-05-14 | 中国医学科学院生物医学工程研究所 | Preparation method and application of water-soluble paclitaxel compound |
| CN102731442B (en) * | 2012-07-18 | 2014-06-11 | 中国医学科学院生物医学工程研究所 | Preparation method and application of water-soluble docetaxel compounds |
| CN115385875B (en) * | 2022-07-18 | 2023-06-13 | 中国药科大学 | Paclitaxel derivatives, and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | The soluble derivative of taxol |
| US5228324A (en) * | 1987-11-26 | 1993-07-20 | Polska Akademia Nauk-Instytut Podstawowych Problemow Techniki | Method of bending metal objects |
| CN1085553A (en) * | 1992-10-01 | 1994-04-20 | 布里斯托尔-米尔斯·斯奎布公司 | Deoxy taxols |
-
1999
- 1999-09-17 CN CN99116884A patent/CN1088703C/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5228324A (en) * | 1987-11-26 | 1993-07-20 | Polska Akademia Nauk-Instytut Podstawowych Problemow Techniki | Method of bending metal objects |
| CN1059337A (en) * | 1990-08-28 | 1992-03-11 | 弗吉尼亚科技知识产权有限公司 | The soluble derivative of taxol |
| CN1085553A (en) * | 1992-10-01 | 1994-04-20 | 布里斯托尔-米尔斯·斯奎布公司 | Deoxy taxols |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1288890A (en) | 2001-03-28 |
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