CN102816138A - Preparation method of paclitaxel derivative - Google Patents

Preparation method of paclitaxel derivative Download PDF

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CN102816138A
CN102816138A CN 201210223168 CN201210223168A CN102816138A CN 102816138 A CN102816138 A CN 102816138A CN 201210223168 CN201210223168 CN 201210223168 CN 201210223168 A CN201210223168 A CN 201210223168A CN 102816138 A CN102816138 A CN 102816138A
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preparation
phenyl
hydroxyl
group
baccatin iii
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吴克美
叶仙蓉
王凤
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Institute of Materia Medica of CAMS
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Institute of Materia Medica of CAMS
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Abstract

The invention discloses a novel paclitaxel derivative which contains a secondary amine group at the side chain and has good water-solubility. The paclitaxel derivative is as shown in the general formula (I). The invention provides the compound and its preparation method, a pharmaceutical composition containing the compound and an application of the compound in the preparation of drugs for treating cancers.

Description

The preparation method of D51-7059
Patented claim of the present invention is to divide an application.The application number of original bill is 200610078949.9, and the applying date is on April 28th, 2006, and denomination of invention is: D51-7059, its preparation method and its pharmaceutical composition and purposes.
Technical field
The present invention relates to the verivate of one type of new taxol, its preparation method, the pharmaceutical composition and the compound that contain this compounds are used for preparing the application of treating cancer drug.
Background technology
Taxol obtained (Wani MC, Taylor HL, Wall ME.The isolation and structure of taxol by people such as Wani from yewtree (Taxus brevifolia) separation in 1971; A novel antileukemic and antitumor agent from taus brevifolia.J.Am.Chem.Soc.1971,93,2325); Its complex structure, but antitumous effect mechanism is unique, can promote microtubule polymerization and suppress microtubule depolymerization (Horwitz SB; Fant J, Schiff PB.Promoton of microtubule assembly in vitro by taxol.Nature, 1979; 277,665).Find that through further investigation it has the broad spectrum anticancer activity, the multinational approval listing in the world is used to treat diseases such as ovarian cancer, mammary cancer, lung cancer clinically.But this medicine preparation adopt gather ethoxy for Viscotrol C (cremophore EL) as solubilizing agent, when clinical application, be prone to cause anaphylaxis.Therefore the solvability that improves taxol with develop clinical preparation safely and effectively and become the emphasis of people's research.Docetaxel (taxotere) is the D51-7059 that is synthesized through structure of modification; It has bioavailability preferably; Antitumour activity is superior to taxol, and toxic side effect is less, and water-soluble increase makes it be prone to process preparation; More than 40 country's listings, become a line medication of oncotherapy at present.Patent WO9638138 (Protaxel; Novel taxoids, Biophysica Foundation), WO98/58927 (Bark Nuo Dun Pharm Pur GmbH); CN00115426.5 (water-soluble polyhydroxyl derivative of taxol and preparation method thereof; Fudan University) disclose several kinds of novel solubility D51-7059, be used to treat tumour or other taxol responsive type disease, but do not develop into the clinical treatment medicine so far yet.Therefore, the D51-7059 of research and development good water solubility, high-efficiency low-toxicity still has great importance.
Summary of the invention
The technical problem that the present invention will solve provides a kind of new D51-7059 of good water solubility.
Another technical problem that the present invention will solve provides the method for this new D51-7059 of preparation.
Another technical problem that the present invention will solve provides a kind of pharmaceutical composition, comprising compound and the pharmaceutically acceptable carrier as the general formula (I) of active ingredient.
Another technical problem that the present invention will solve provides the application as antineoplastic agent of a kind of new D51-7059 and compsn thereof.
For solving the problems of the technologies described above, the present invention adopts following technical scheme, and D51-7059 of the present invention is shown in general formula (I):
R wherein 1Be selected from OH, C 2-C 8Acyloxy;
R 2And R 3Independently be selected from (CH 2) nR ', n=0-6 wherein, R ' is selected from C 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, naphthenic base replaces or non-substituted aryl, replaces or non-substituted heterocyclic aryl;
Substituting group on said aryl and the heteroaryl is selected from hydroxyl, methylol, halogen, C 1-5Alkyl, C 1-5Alkoxyl group, C 1-5Alkenyl, acyl group, acyloxy, nitro, amino, C 1-5Alkylamino radical, carboxamido-group, cyanic acid, azido-.
Preferred R 1Be selected from OH, acetoxyl group;
Preferred n=0,1;
Preferred R ' is selected from naphthenic base, halogenated aryl, C 1-5Alkoxy aryl, C 1-5The alkylamino radical aryl,
Preferred R 3It is phenyl;
Preferred when n=1, R ' is the chloro aryl, fluorinated aryl, methoxyl group substituted aryl, dimethylamino substituted aryl; Thiazolidyl;
Preferred when n=0, R ' is pentamethylene, hexanaphthene;
Most preferred chemical combination is selected from following cohort:
Figure BDA00001823845300031
Table 1 D51-7059
Compound R 1 R 2 R 3 R 4
Ⅰ 1 OH To methoxy-benzyl Ph OH
Ⅰ 2 OH Between luorobenzyl Ph OH
Ⅰ 3 OH Benzyl Ph OH
Ⅰ 4 OH The 2-thiazole methyl Ph OH
Ⅰ 5 OH To the dimethyl amido benzyl Ph OH
Ⅰ 6 OH P-chlorobenzyl Ph OH
Ⅰ 7 OH Cyclopentyl Ph OH
Ⅰ 8 OH Cyclohexyl Ph OH
Ⅰ 9 OAc Benzyl Ph OH
Ⅰ 10 OAc P-chlorobenzyl Ph OH
Ⅰ 11 OAc Between luorobenzyl Ph OH
Ⅰ 12 OAc To methoxy-benzyl Ph OH
Ⅰ 13 OAc The 2-thiazole methyl Ph OH
Ⅰ 14 OAc Cyclohexyl Ph OH
Ⅰ 15 OAc Cyclopentyl Ph OH
[0023]Synthetic route is seen in the preparation of the D51-7059 that the present invention relates to
Figure BDA00001823845300041
Preparation with D51-7059 of logical formula I can be through suitable activatory isoserine chain IV (R 3=Ph) the 13-position hydroxyl of parent nucleus obtains in the logical formula II of acidylate; Compound method is referring to document (A.Commercon, D.Bezard, et al.Improved protection and esterification of a precursor of the taxotere and taxol side chains; Tetranedron Letters; 33 (36), 5185-5188,1992).
Particularly, raw material 10-deacetylation baccatin III (II 1, R 1=R 4=OH), baccatin III (II 2, R 1=AcO, R 4=OH) can be from Chinese yew genus plants separation and Extraction (Wani MC; Taylor HL; Et al.The isolation and structure of taxol; A novel antileukemic and antitumor agent from taus brevifolia.J.Am.Chem.Soc.93,2325,1971).Baccatin III also can prepare from 10-deacetylation baccatin III.R 1Be C 2-C 8The compound ii of acyloxy can be from 10-deacetylation baccatin III (II 1, R 1=R 4=OH) synthetic.
Compound ii (R 1=OH or C 2-C 8Acyloxy, R 4=OH) carry out due care in 7-position and 10-position after with activatory isoserine chain IV (R 3=Ph) condensation, hydrolysis synthetic compound (III, R 1=C 2-C 8Acyloxy, or alkyl siloxy, 2,2,2-trichlorine ethoxy carbonyl oxygen base, R 4=alkyl siloxy, 2,2,2-trichlorine ethoxy carbonyl oxygen base).Be raw material with compound (III) again, generate imines with different aldehyde, ketone compound reactions, again through reductive agent NaCNBH 3Reduction is taken off protection base (referring to above-mentioned document) with currently known methods zinc powder/acetic acid then, obtains compound I at last.
Preparing method of the present invention is easy, and yield is higher, can carry out suitability for industrialized production.
The invention still further relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be through the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, process to be suitable for any formulation of human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration; Route of administration can be enteron aisle or non-enteron aisle, like oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be processed ordinary preparation, also process is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is processed tablet, the various vehicle well known in the art that can be widely used comprises thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, TKK 021, vinyl resin, carbomer, Vinylpyrrolidone polymer, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, sodium starch glycolate, sodium hydrogencarbonate and Citric Acid, polyoxyethylene sorbitol fatty ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
For capsule is processed in the administration unit, can the effective constituent The compounds of this invention be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also can the effective constituent The compounds of this invention be processed particle or micropill with thinner, tamanori, disintegrating agent earlier, place hard capsule or soft capsule again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is processed injection, can water, ethanol, Virahol, Ucar 35 or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be Prist, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, enhancing treatment effect, medicine of the present invention or pharmaceutical composition can be used any known medication administration.
The dosage of The compounds of this invention pharmaceutical composition according to prevent or treat the character and the severity of disease, the individual instances of patient or animal, route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.1-100mg/Kg body weight, and more preferably the 1-60mg/Kg body weight most preferably is the 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or compsn can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Advantage of the present invention; The invention provides a kind of D51-7059 that forms amine salt, the side chain of this verivate contains secondary amine groups, can generate salt with corresponding acid group; Improve the solvability of medicine; It is water-soluble than taxol or Duo like taxol well, increases bioavailability, and is similar with the anti-tumor activity of taxol and docetaxel.
Embodiment
Below embodiment be used for further specifying the present invention, but this and do not mean that any restriction of the present invention.
Preparation example 1 preparation 10-deacetylation-7,10-TROC-baccatin III (II 1, R 1=R 4=TROC).
In the exsiccant reaction flask, add 500mg (0.92mmol) 10-deacetylation crust card fourth III,, be positioned in the icy salt solution and cool off with the dissolving of 10ml anhydrous pyridine.In reaction solution, drip 0.43ml (32mmol) 2,2,2-trichlorine ethoxy dicarbonyl chloride dropwises continued reaction 3 hours, adds the water termination reaction.Reaction solution extracts three times with ETHYLE ACETATE 50ml, merges organic liquor, with 1N hydrochloric acid and saturated sodium-chloride washing, anhydrous sodium sulfate drying.Filter, concentrate yellow oil 1.14g, separate through silicagel column, obtain the 715mg white solid with recrystallizing methanol.Yield 87%, fusing point: 233-235 ℃.
Preparation example 2 preparation 7-TROC-baccatin III (II 2, R 1=OAc, R 4=TROC).
7.38g (12.6mmol) baccatin III, 3.4ml (25.2mmol) 2,2,2-trichlorine ethoxy dicarbonyl chloride, other conditions obtain the 6g white solid with preparation example 1.Yield 63%, fusing point: 232-235 ℃.
Preparation example 3 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-amino-propionyl group]-10-deacetylation-7,10-TROC-baccatin III (III 1, R 1=R 4=TROC, R 3=Ph).
In the exsiccant reaction flask, add 600mg (0.673mmol) 10-deacetylation-7,10-TROC-baccatin III (II 1, R 1=R 4=TROC),, add 345mg (1.08mmol) (4S again with the dissolving of 30ml dry toluene; 5R)-and N-tertbutyloxycarbonyl-2,2-dimethyl--phenyl-5-oxazolidine carboxylic acid, 173mg (0.84mmol) dicyclohexyl carbodiimide; 41mg (0.34mmol) N, the N-dimethyl aminopyridine was 80 ℃ of reactions 4 hours; Water washing reaction liquid, organic layer is concentrated into dried.Add 7ml formic acid to residuum, stirring at room to solid dissolves, and continues room temperature reaction 5 hours.Then the reaction solution adding is contained in the frozen water of 18g sodium hydrogencarbonate, extract three times, merge organic layer, again through saturated sodium-chloride washing, anhydrous sodium sulfate drying with methylene dichloride 60ml.Filter, concentrate yellow oil 700mg, separate through silicagel column, obtain the 520mg white solid with the methanol recrystallization.Yield 72.9%.
Preparation example 4 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-amino-propionyl group]-7-TROC-baccatin III (III 2, R 1=OAc, R 4=TROC, R 3=Ph).
3g (3.95mmol) 7-TROC-baccatin III (II 2, R 1=OAc, R 4=TROC), and 2.0g (6.32mmol) (4S, 5R)-N-tertbutyloxycarbonyl-2; 2-dimethyl--phenyl-5-oxazolidine carboxylic acid, 2.0g (9.8mmol) dicyclohexyl carbodiimide, 0.48g (3.95mmol) N; The N-dimethyl aminopyridine, the same method preparation obtains the 2.7g white solid.Yield 47.7%.
Embodiment 1 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-to methoxy-benzyl amine-propionyl group]-10-deacetylation-baccatin III (I 1, R 1=R 4=OH, R 2=to methoxy-benzyl, R 3=Ph).
Get 400mg (0.38mmol) III in the preparation example 3 1, 124mg (0.91mmol) aubepine, 36mg (0.152mmol) camphorsulfonic acid is dissolved in anhydrous methylene chloride, stirs 1 hour under the room temperature, adds 20mg (0.3mmol) NaCNBH again 3, reacted 4 hours.Use saturated sodium bicarbonate, salt solution washing, anhydrous sodium sulfate drying.Filter, concentrate, separate, obtain the 120mg white solid through silicagel column.In solid, add Glacial acetic acid min. 99.5 3.7ml, zinc powder 119mg, 50 ℃ were reacted 1 hour.Filter, filtrating is with saturated sodium bicarbonate neutralization, dichloromethane extraction, anhydrous sodium sulfate drying.Filter, concentrate, obtain the 37mg white solid.Yield 12%. 1H-NMR(300MHz?CDCl 3):6.84-8.08(m,14H,Ph-H),5.95(t,1H,J=8.7Hz,H 13),5.57(d,1H,J=7.2Hz,H 2),5.17(s,1H,H 10),4.88(d,1H,J=8.1Hz,H 5),4.79(m,1H,H 7),4.10,4.24(2d,2H,J=8.1Hz,H 20),4.15(m,1H,H 3’),3.79(m,2H,H 2’,H 3),3.74(s,3H,OCH 3),3.70,3.60(2d,2H,J=11.4Hz,NHCH 2).
FAB-MS,m/e(%):828.4(M +,7),302.1(8),168.3(18),121.0(100)。
Embodiment 2 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-luorobenzyl amine-propionyl group]-10-deacetylation-baccatin III (I 2, R 1=R 4=OH, R 2=luorobenzyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with fluorobenzaldehyde replacement 124mg (0.91mmol) aubepine between 113mg (0.91mmol), obtain the 36mg white solid.Yield 12%.
1H-NMR(300MHz?CDCl 3):7.02-8.08(m,14H,Ph-H),5.99(t,1H,J=8.7Hz,H 13),5.57(d,1H,J=7.2Hz,H 2),5.22(s,1H,H 10),4.90(d,1H,J=7.8Hz,H 5),4.78(m,1H,H 7),4.11,4.28(2d,2H,J=9.0Hz,H 20),4.36(m,1H,H 3’),3.97,3.79(m,2H,H 2’,H 3),3.53,3.78(2d,2H,J=13.5Hz,NHCH 2).
FAB-MS,m/e(%):816.7(M +,100),553.6(44),319.1(45),277.3(53)。
Embodiment 3 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-benzyl amine-propionyl group]-10-deacetylation-baccatin III (I 3, R 1=R 4=OH, R 2=benzyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with 0.91mmol phenyl aldehyde replacement 0.91mmol aubepine, obtain the 50mg white solid.Yield 16.6%.
1H-NMR(300MHz CDCl 3):7.29-8.06(m,15H,Ph-H),6.02(t,1H,J=9.3Hz,H 13),5.60(d,1H,J=6.9Hz,H 2),5.18(s,1H,H 10),4.90(d,1H,J=9.3Hz,H 5),4.48(m,1H,H 7),4.13,4.26(2d,2H,J=8.1Hz,H 20),3.92，4.19(m，2H，H 2’，H 3’)，3.79，4.04(2d，2H，J=6.6Hz，NH CH 2 )，3.58(d，?1H,J=12.9Hz,H 3),.
FAB-MS,m/e(%):798.3(M ++1,8),300.7(8),272.1(100),196.1(91)。
Embodiment 4 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-thiazole benzylidene amino-propionyl group]-10-deacetylation-baccatin III (I 4, R 1=R 4=OH, R 2=thiazole methylene radical, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with 0.91mmol thiazole carboxaldehyde replacement 0.91mmol aubepine, obtain the 40mg white solid.Yield 17.5%.
1H-NMR (300MHz CDCl 3): 6.92-8.09 (m, 13H, Ph-H, assorted fragrant hydrogen), 6.00 (t, 1H, H 13), 5.58 (d, 1H, J=7.2Hz, H 2), 5.27 (s, 1H, H 10), 4.89 (d, 1H, J=8.7Hz, H 5), 4.65 (m, 1H, H 7), 4.11,4.28 (2d, 2H, J=8.1Hz, H 20), 4.36 (m, 1H, H 3 '), 4.16 (m, 2H, H 2 ', H 3 '), 3.78 (d, 1H, J=4.5Hz, H 3), 4.12,3.86 (2d, 2H, J=14.1Hz, NHCH 2).
FAB-MS,m/e(%):804.2(M +,29),559.2(9),278.0(100),202.1(65)。
Embodiment 5 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-to dimethylin benzyl amine-propionyl group]-10-deacetylation-baccatin III (I 5, R 1=R 4=OH, R 2==to dimethylin benzyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, to dimethylin phenyl aldehyde replacement 0.91mmol aubepine, obtain the 35mg white solid with 0.91mmol.Yield 14.7%.
1H-NMR (300MHz CDCl 3): 7.32-8.06 (m, 14H, Ph-H, assorted fragrant hydrogen), 5.95 (m, 1H, H 13), 5.54 (d, 1H, J=6.9Hz, H 2), 5.25 (s, 1H, H 10), 4.86 (d, 1H, J=9.9Hz, H 5), 4.80 (m, 1H, H 7), 4.12-4.33 (m, 3H, H 20, H 2 ', H 3 '), 3.6 (m, 3H, H 3, NHCH 2).
FAB-MS,m/e(%):840.3(M +,24),634.5(18),390.1(25),300.7(100)。
Embodiment 6 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-p-chlorobenzyl amine-propionyl group]-10-deacetylation-baccatin III (I 6, R 1=R 4=OH, R 2=p-chlorobenzyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with 0.91mmol 4-chloro-benzaldehyde replacement 0.91mmol aubepine, obtain the 80mg white solid.Yield 34%.
1H-NMR(300MHz?CDCl 3):7.29-8.12(m,14H,Ph-H,),5.96(t,1H,H 13),5.57(d,1H,J=7.2Hz,H 2),5.30(s,1H,H 10),4.90(d,1H,J=8.7Hz,H 5),4.40(m,1H,H 7),4.09,4.30(2d,2H,J=8.1Hz,H 20),4.16(m,2H,H 2’,H 3’),3.69（m,1H,H 3）,3.75(m,2H,NHCH 2).
FAB-MS,m/e(%):832.2(M +,60),391.2(13),306.0(23),185.1(63),137(42),93.0(100)。
Embodiment 7 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-cyclopentyl amine-propionyl group]-10-deacetylation-baccatin III (I 7, R 1=R 4=OH, R 2=cyclopentyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with 0.91mmol ring valeral replacement 0.91mmol aubepine, obtain the 30mg white solid.Yield 20.5%.
1H-NMR(300MHz CDCl 3):7.31-8.09(m,10H,Ph-H),5.97(t,1H,J=8.7Hz,H 13),5.62(d,1H,J=6.9Hz,H 2),5.28(s,1H,H 10),4.88(d,1H,J=9.3Hz,H 5),4.59(m,1H,H 7),4.09,4.33(2d,2H,J=8.7Hz,H 20),4.18(m,2H,H 2’,H 3’),3.76(d,1H,J=7.2Hz,H 3).
FAB-MS,m/e(%):776.4(M +,29),250.2(100),185.1(45),105.0(62)。
Embodiment 8 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-cyclo-hexylamine-propionyl group]-10-deacetylation-baccatin III (I 8, R 1=R 4=OH, R 2=cyclohexyl, R 3=Ph).
The preparation method identical with embodiment 1, difference are, with 0.91mmol hexamethylene aldehyde replacement 0.91mmol aubepine, obtain the 40mg white solid.Yield 26.8%.
1H-NMR(300MHz CDCl 3):7.29-8.06(m,10H,Ph-H),6.07(t,1H,J=9.0Hz,H 13),6.62(d,1H,J=7.2Hz,H 2),5.21(s,1H,H 10),4.92(d,1H,J=8.1Hz,H 5),4.45(m,1H,H 7),4.14,4.24(2d,2H,J=8.7Hz,H 20),4.21(m,2H,H 2’,H 3’),3.84(d,1H,J=7.2Hz,H 3).
FAB-MS,m/e(%):790.4(M +,32),264.2(100),185.1(66),93.1(75)。
Embodiment 9 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-benzyl amine-propionyl group]-baccatin III (I 9, R 1=OAc, R 4=OH, R 2=benzyl, R 3=Ph).
Get 300mg (0.325mmol) III in the preparation example 4 2, phenyl aldehyde 83mg (0.78mmol), camphorsulfonic acid 30mg (0.13mmol) is dissolved in anhydrous methylene chloride, stirs 1 hour under the room temperature, adds 16mg (0.26mmol) NaCNBH again 3, reacted 4 hours.Use saturated sodium bicarbonate, salt solution washing, anhydrous sodium sulfate drying.Filter, concentrate, separate, obtain the 120mg white solid through silicagel column.In solid, add Glacial acetic acid min. 99.5 12ml, zinc powder 380mg, 50 ℃ were reacted 1 hour.Filter, filtrating is with saturated sodium bicarbonate neutralization, dichloromethane extraction, anhydrous sodium sulfate drying.Filter, concentrate, obtain the 103mg white solid.Yield 37.9%.
1H-NMR(300MHz?CDCl 3):7.33-8.09(m,15H,Ph-H),6.27(s,1H,H 10),5.99(t,1H,J=8.7Hz,H 13),5.57(d,1H,J=6.6Hz,H 2),4.91(d,1H,J=9.9Hz,H 5),4.78(m,1H,H 7),4.09,4.25(2d,2H,J=8.7Hz,H 20),4.35(m,1H,H 3’),3.96,3.77(m,2H,H 2’,H 3),3.63-3.73(m,2H,NHCH 2).
FAB-MS,m/e(%):841(M +,8),403.1(13),272.1(46),196.1(72),91.0(100)。
Embodiment 10 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-p-chlorobenzyl amine-propionyl group]-baccatin III (I 10, R 1=OAc, R 4=OH, R 2=p-chlorobenzyl, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with 0.78mmol 4-chloro-benzaldehyde replacement 0.78mmol phenyl aldehyde, obtain the 59mg white solid.Yield 20.8%.
1H-NMR(300MHz?CDCl 3):7.21-8.09(m,14H,Ph-H),6.26(s,1H,H 10),5.94(t,1H,J=8.7Hz,H 13),5.56(d,1H,J=6.9Hz,H 2),5.28(m,1H,H 7),4.93(d,1H,J=9.3Hz,H 5),4.08,4.29(2d,2H,J=8.4Hz,H 20),4.28(m,2H,H 2’,H 3’),4.07(m,H,H 3),3.59-3.80(m,2H,J=6.9Hz,NHCH 2).
FAB-MS,m/e(%):874.2(M ++1,13),391.2(7),246.0(14),137.0(42),93.0(100)。
Embodiment 11 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-luorobenzyl amine-propionyl group]-baccatin III (I 11, R 1=OAc, R 4=OH, R 2=luorobenzyl, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with fluorobenzaldehyde replacement 0.78mmol phenyl aldehyde between 0.78mmol, obtain the 54mg white solid.Yield 19%.
1H-NMR(300MHz?CDCl 3):7.08-8.12(m,14H,Ph-H),6.27(s,1H,H 10),5.96(m,1H,H 13),5.59(d,1H,J=7.2Hz,H 2),4.97(m,1H,H 7),4.94(d,1H,J=9.0Hz,H 5),4.08,4.27(2d,2H,J=8.4Hz,H 20),3.79,4.18(m,2H,H 2’,H 3’),4.11(d,H,J=8.7Hz,H 3),3.63-3.80(m,2H,J=6.9Hz,NHCH 2).
FAB-MS,m/e(%):870.3(M +,16),302.1(6),226.1(14),121.0(100),105.0(29)。
Embodiment 12 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-to methoxy-benzyl amine-propionyl group]-baccatin III (I 12, R 1=OAc, R 4=OH, R 2=to methoxy-benzyl, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with 0.78mmol aubepine replacement 0.78mmol phenyl aldehyde, obtain the 75mg white solid.Yield 26.6%.
1H-NMR(300MHz?CDCl 3):7.02-8.07(m,14H,Ph-H),6.22(s,1H,H 10),5.92(t,1H,H 13),5.63(d,1H,J=7.2Hz,H 2),5.27(m,1H,H 7),4.92(d,1H,J=9.3Hz,H 5),4.08,4.26(2d,2H,J=8.1Hz,H 20),4.09,4.40(m,2H,H 2’,H 3’),3.81(s,3H,OCH 3),3.63(d,H,J=6.9Hz,H 3),3.76(m,2H,NHCH 2).
FAB-MS,m/e(%):870.3(M +,13),302.1(5),226.1(12),121.0(100),105.0(28)。
Embodiment 13 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-thiazole benzylidene amino-propionyl group]-baccatin III (I 13, R 1=OAc, R 4=OH, R 2=thiazole methylene radical, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with 0.78mmol thiazole carboxaldehyde replacement 0.78mmol phenyl aldehyde, obtain the 39mg white solid.Yield 14.2%.
1H-NMR(300MHz?CDCl 3):6.88-8.08(m,13H,Ph-H),6.24(s,1H,H 10),6.05(t,1H,H 13),5.60(d,1H,J=6.9Hz,H 2),4.92(d,1H,J=7.2Hz,H 5),4.40(m,1H,H 7),4.13,4.26(2d,2H,J=9.0Hz,H 20),4.10,4.40(m,2H,H 2’,H 3’),3.68(d,H,J=6.9Hz,H 3),3.78(m,2H,J=14.1Hz,NHCH 2).
FAB-MS,m/e(%):846.2(M +,19),278.0(30),202.0(45),132.9(55),105.0(85),97.0(100)。
Embodiment 14 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-cyclo-hexylamine-propionyl group]-baccatin III (I 14, R 1=OAc, R 4=OH, R 2=cyclohexyl, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with 0.78mmol hexamethylene aldehyde replacement 0.78mmol phenyl aldehyde, obtain the 65mg white solid.Yield 23.9%.
1H-NMR(300MHz?CDCl 3):7.30-8.06(m,10H,Ph-H),6.25(s,1H,H 10),5.94(t,1H,H 13),5.56(d,1H,J=7.2Hz,H 2),5.28(m,1H,H 7),4.93(d,1H,J=8.7Hz,H 5),4.09,4.26(2d,2H,J=8.4Hz,H 20),4.33,4.60(m,2H,H 2’,H 3’),3.65(d,H,J=6.9Hz,H 3).
FAB-MS,m/e(%):832.3(M +,20),264.1(80),188.1(100),132.9(24),105.0(99)。
Embodiment 15 preparation 13-[(2 ' R, 3 ' S)-3 '-phenyl-2 '-hydroxyl-3 '-cyclopentyl amine-propionyl group]-baccatin III (I 15, R 1=OAc, R 4=OH, R 2=cyclopentyl, R 3=Ph).
The preparation method identical with embodiment 9, difference are, with 0.78mmol ring valeral replacement 0.78mmol phenyl aldehyde, obtain the 60mg white solid.Yield 22.6%.
1H-NMR(300MHz?CDCl 3):7.32-8.06(m,10H,Ph-H),6.32(s,1H,H 10),5.99(t,1H,H 13),5.58(d,1H,J=6.9Hz,H 2),5.22(m,1H,H 7),4.94(d,1H,J=8.7Hz,H 5),4.09,4.26(2d,2H,J=8.4Hz,H 20),4.37,4.49(m,2H,H 2’,H 3’),3.67(d,H,J=6.9Hz,H 3).
FAB-MS,m/e(%):818.2(M +,12),250.1(61),204.1(12),174.1(100),105.0(92)。
Pharmacological evaluation
Experimental example 1
Synthetic compound of the present invention is carried out the cytotoxicity screening of nine kinds of tumor cell lines and human normal cell line, compare with taxol (taxol) and many seemingly taxols (taxotere).The method that adopts is MTT (tetrazole) method.
The human cancer cell of various logarithmic phases is inoculated in 96 orifice plates; Every hole 800-1500 cell is cultivated dosing after 24 hours, generally at least 5 concentration of each sample; Each concentration is established 3 parallel holes. at RPMI, and 1640 (GIBCO product) (containing 10% calf serum) substratum, 37 ℃, 2%CO 2Cultivation added (Fluka product) in 4 days under the condition, with Bio-Red 450 ELIASAs, detected with the 570nm dual wavelength 450, calculated inhibitory rate of cell growth, and asked IC 50μ M (half-inhibition concentration).Concrete experimental result is (table 2) as follows:
These compounds all have certain CDCC, and especially the effect of compound 4 and compound 13 and taxol are with how close like taxol.
Table 2 chemical compounds I 1-15, taxotere, the CDCC (IC of taxol 50μ M)
Numbering The KB nasopharyngeal carcinoma The HCT-8 colorectal carcinoma Bel-7402 liver cancer The A2780 ovarian cancer The A549 adenocarcinoma of lung
Ⅰ 1 3.68 3.16 7.85 2.05 8.14
Ⅰ 2 <0.1 1.82 3.02 0.1 0.57
Ⅰ 3 0.15 2.98 0.38 0.16 0.68
Ⅰ 4 <0.00016 0.83 0.72 0.00049 0.546
Ⅰ 5 0.13 8.74 8.7 0.75 7.11
Ⅰ 6 0.17 2.88 4.28 0.21 1.0
Ⅰ 7 >;10 >;10 >;10 >;10 >;10
Ⅰ 8 5.29 >;10 >;10 5.85 >;10
T1 <0.00016 0.00046 0.0092 <0.00016 0.53
Ⅰ 9 <0.1 0.04 0.86 <0.1 0.21
Ⅰ 10 0.28 0.47 0.75 0.25 0.53
Ⅰ 11 <0.1 <0.1 1.1 0.67 <0.1
Ⅰ 12 <0.1 3.26 1.76 0.72 0.48
Ⅰ 13 0.00042 0.012 0.023 0.00057 0.385
Ⅰ 14 1.2 8.23 8.66 1.27 4.60
Ⅰ 15 5.08 7.52 8.03 6.74 6.70
T2 <0.00016 0.018 0.02 0.00017 0.102
Numbering BGC-823 cancer of the stomach MCF-7 mammary cancer The Hela cervical cancer The KeTr3 kidney The HELF human embryo lung (HEL)
Ⅰ 1 3.52 >;10 1.16 3.48 >;10
Ⅰ 2 0.27 5.6 <0.1 0.77 5.41
Ⅰ 3 0.28 >;10 <0.1 0.54 6.65
Ⅰ 4 0.0045 0.00017 0.00017 0.026 6.41
Ⅰ 5 3.0 >;10 2.68 3.81 >;10
Ⅰ 6 0.34 0.22 0.25 0.99 5.64
Ⅰ 7 >;10 >;10 >;10 >;10 >;10
Ⅰ 8 >;10 >;10 6.09 >;10 >;10
T1 0.0002 <0.00016 <0.00016 <0.00016 0.036
Ⅰ 9 <0.1 0.74 <0.1 0.23 0.75
Ⅰ 10 0.27 0.49 0.14 0.37 0.60
Ⅰ 11 <0.1 0.15 <0.1 <0.1 0.50
Ⅰ 12 0.23 1.0 0.19 1.45 2.35
Ⅰ 13 0.00073 0.00054 0.00041 0.00118 0.069
Ⅰ 14 5.34 >;10 5.75 5.77 >;10
Ⅰ 15 5.25 8.50 4.77 4.98 8.43
T2 <0.00016 <0.00016 <0.00016 0.00021 0.079

Claims (3)

1. prepare the method for D51-7059, it is characterized in that, comprise the steps:
A) activatory isoserine side chain is introduced the 13-position with logical formula II parent nucleus in accordance with known methods;
B) side chain hydrolysis;
C) with different aldehydes or ketones reactions, with the reductive agent reduction, use conventional method deprotection more then, obtain corresponding compounds (I);
R wherein 1Be selected from OH, C 2-C 8Acyloxy;
R 2And R 3Independently be selected from (CH 2) nR ', n=0-6 wherein, R ' is selected from C 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, naphthenic base replaces or non-substituted aryl, replaces or non-substituted heterocyclic aryl;
Substituting group on said aryl and the heteroaryl is selected from hydroxyl, methylol, halogen, C 1-5Alkyl, C 1-5Alkoxyl group, C 1-5Alkenyl, acyl group, acyloxy, nitro, amino, C 1-5Alkylamino radical, carboxamido-group, cyanic acid, azido-.
2. according to the method for claim 1, it is characterized in that described reductive agent is to contain borane reagent.
3. according to the method shown in the claim 2, the described borane reagent that contains is selected from NaCNBH 3, NaBH (OAc) 3
CN 201210223168 2006-04-28 2006-04-28 Preparation method of paclitaxel derivative Pending CN102816138A (en)

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