CN1202173A - Amine derivatives of epipodophyllotoxin 2',3'-dideoxyglycosides, preparation method therefor and use thereof as drug and for treating cancer - Google Patents

Amine derivatives of epipodophyllotoxin 2',3'-dideoxyglycosides, preparation method therefor and use thereof as drug and for treating cancer Download PDF

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CN1202173A
CN1202173A CN96198199A CN96198199A CN1202173A CN 1202173 A CN1202173 A CN 1202173A CN 96198199 A CN96198199 A CN 96198199A CN 96198199 A CN96198199 A CN 96198199A CN 1202173 A CN1202173 A CN 1202173A
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compound
epipodophyllotoxin
formula
demethyl
ethylidene
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C·莫尼里特
L·达利
Y·古米斯基
T·艾比尔特
B·希尔
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Pierre Fabre Medicament SA
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Pierre Fabre Medicament SA
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    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract

A compound of general formula (I), wherein X, Y, R1 and R2 are as defined in the description, a preparation method therefor and the use thereof as a drug and for treating cancer, are disclosed.

Description

Epipodophyllotoxin 2 ", 3 " it is as the application of medicine and the application of anticancer therapy thereof for the novel amine derivative of dideoxy glucosides, its preparation method
", 3 " the novel amine derivative of dideoxy glucosides that the present invention relates to epipodophyllotoxin 2, its preparation method, its as the application of medicine with and be used for the application of anticancer therapy.
In the derivative that obtains by natural lignan, there is a class to have the epipodophyllotoxin of podophyllotoxin alkali skeleton.Semisynthetic derivative is wherein arranged, and such as etoposide or Vumon, they generally are used for preparing the medicine for the treatment of cancer.They are counted as the main products in this field.
Etoposide has antineoplastic characteristic, can treat small cell lung cancer and carcinoma of testis especially.
The shortcoming of these products is poorly water-solubles, therefore can run into the difficulty aspect preparation and administrable.
Target of the present invention is a proof, 4 '-position has 2 " deoxidation glucosides structure substituent 4 '-the demethyl epipodophyllotoxin derivatives is by adding one or several nitrogen-atoms; form its adduct and have water miscible compound, make to have solved problem and demonstrated the antitumour activity of being studied.
Patent EP-0 196,618 relate to 4 of following formula '-soluble derivative of demethyl epipodophyllotoxin:
R in the formula 1=Me, X 1=NH 2, NMe 2, X 2=OH
Patent EP-0 415,453 mentioned 4 of following formula '-demethyl epipodophyllotoxin-β-D-altrose glycoside derivates:
R in the formula 1=Me, R 2, R 3=OH and NH 2Or F and NH 2, also see JP 0 161,423.
In other publication, also mentioned the similar derivative thing.See " carbohydrate compound research " (Carbohydr.Res.) 1990,206,219, " pharmaceutical chemistry circular " (Chem.Pharm.Bull) 1986,34,3741, " chemical communication " (Chem.Lett.) 1987,799.
Utilize 2 " deoxidation glucoside be very special.This makes and can obtain than the more lipophilic compound of hydroxy analogs therefore just have wideer anti-tumor activity spectrum.This just makes to have better membrane permeability, can more easily reach on the biological target, such as the noumenal tumour of perfusion difference.In addition, " advantage that the position has amido functional group has given its salifiable possibility, and its water-soluble is enough to prepare better and administration better such as 3.
Therefore the present invention relates to the compound of general formula I
In the formula 3 " position group N (R 1R 2) be in β position (2-deoxidation-D-pectinose base system row) or α position (the 2-deoxy-D-ribose base system row) of ring, R 1And R 2Identical or different, expression hydrogen atom, C 1～C 6Alkyl, these alkyl can form and have as heteroatomic rings such as oxygen and nitrogen, and C 1～C 6Aminoalkyl group, perhaps cyano methyl.
X and Y can be identical or different, expression OH, CH 3, CH 2-NH 2, X and Y can also connect together and form a ring, and such as the 2-methyl isophthalic acid, the 3-diox has so just formed 4,6-ethylidene-3-amino-2, the glucosides dicyclo skeleton of 3-dideoxy-β-D-arabopyranose glycosides or ribopyranose glycosides type.
The invention still further relates to this compound and make the salifiable mineral acid of one or several nitrogen-atoms or organic acid adduct, particularly hydrochloride.
According to a kind of preferred mode, group N (R 1R 2) be group NH 2Or N (CH 3) 2
Group N (R 1R 2) can also be once or twice by methyl, CH 2CN, CH 2-CH 2-NH 2The amino that replaces forms the ring that resembles morpholine.
According to a kind of preferred mode, select to have the compound of Formula I of a glucosides, wherein X and Y form and have OCH (CH 3) OCH 2The ring of chain, such as 4,6-ethylidene-3-amino-2,3-dideoxy-β-D-arabopyranose glycosides or 4,6-ethylidene-3-amino-2,3-dideoxy-β-D-ribopyranose glycosides.
Particularly from following compound, select compound of the present invention:
4-demethyl-4-O-(3-amino-4,6-ethylidene-2,3-dideoxy-β-D-arabopyranose base) epipodophyllotoxin;
4-demethyl-4-O-(3-amino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4-demethyl-4-O-(3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-arabopyranose base) epipodophyllotoxin;
4-demethyl-4-O-(3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4-demethyl-4-O-(3-cyano methyl amino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4-demethyl-4-O-(3-(N-morpholino)-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4-demethyl-4-O-[3-(2-aminoethylamino)-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base] epipodophyllotoxin;
4-demethyl-4-O-(3-amino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin
4-demethyl-4-O-(3,6-diamino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin.
The invention still further relates to the compound that contains at least a general formula I of the present invention and the pharmaceutical composition of appropriate excipients.
This pharmaceutical composition can be taken by injecting pathway or with the form oral route of gelatine capsule, capsule, tablet, and dosage is per 24 hours injection 1～200mg/m 2, oral 5～500mg/m 2
This derivative is taken the various cancers of treatment to the people clinically, such as small cell lung cancer, carcinoma of testis, embryo's tumour, neuroblastoma, kidney, He Jiejinshi and non_hodgkin lymphoma, acute leukemia, colorectal carcinoma, melanoma, placental villi film cancer and mammary cancer.
The invention still further relates to the preparation method of compound of Formula I and they and pharmaceutically useful mineral acid or organic acid adduct.
Therefore the present invention relates to the preparation method of compound of Formula I of the present invention, wherein allow the compound of formula III or formula IV or formula V, in low temperature and inert solvent with 4 '-demethyl-4 '-carbobenzoxy-(Cbz) epipodophyllotoxin and BF 3Etherate or trifluoromethanesulfonic acid trimethyl silyl ester reaction;
In formula III and formula IV, can be α position or β position at 3 substituting groups, NR 1R 2The amino that can be protected by group Z,
In formula V, P represents the protecting group of alcohol, and the product that this condensation obtains is obtained the compound of formula I by deprotection and hydrogenation,
Primary amine 3 of glycosyls is methylated by formaldehyde and sodium cyanoborohydride.
The intermediates preparation of general formula I V is:
Allow the mixture of diacetoxy azido-glucosides VI and dimethyl tertiary butyl silyl chloride in the presence of imidazoles, react; separate the product that reaction thus obtains; every kind of product is carried out deacetylated, the acetal ring with acetaldehyde in the catalysis acidic medium turns to 4, the 6-ethylidene.
Other characteristics of the inventive method are by following explanation, and particularly the synthetic method of reporting on diagram I is shown.
Diagram 1
[J.C.Florent, C.Monneret are at " Chemical Society's magazine in accordance with known methods in reaction, chemical communication " (J.Chem.Soc.Chem.Comm.) 1987,1171 and B.Abbaci, J.C.Floret and C.Monneret at " French Chemical Society circular " (Buul.Soc.Chim.Fr.) 1989,667], carry out from glucal 1.Condensation nitrine radical ion obtains glucosides class intermediate 2; [C.Kolar and G.Kneissl are " international applications chemistry " (Angew.Chem.Int.) 29 editions according to currently known methods for end group isomery hydroxyl wherein; described in 809 (1990)] protected by silyl in the β position separately; the mixture of two kinds of epimers is provided: 3 and 4, they can use chromatographic separation in this step.Obtain 4 the glycol of 6-position by in the presence of sodium methylate, carrying out alkaline deacetylation: compound 5 and 12.β-nitrine diol compound 5 is in the presence of an acidic catalyst; by means of the acetal of acetaldehyde routinely cyclisation become the ethylidene ring; obtain compound 6; its azido-is reduced into and is amine 7; use carbobenzoxy-(Cbz) (Z) protection again, just become compound 8, for the needs of demethyl epipodophyllotoxin coupling; itself is protected by carbobenzoxy-(Cbz) at the phenol of 4 ' position, and this intermediate is called DMEPT4 '-OZ.Coupling is performed such: pass through F earlier -Ion cracking silyl protecting group is used BF then at low temperatures in identical medium 3Etherate handle.Make group Z separate the compound 10 (NR that protection provides general formula I by hydrogenolysis 1R 2=β NH 2XY=OCH (CH 3) OCH 2).By the effect of formaldehyde and sodium cyanoborohydride, aforesaid primary amine is methylated, obtain the compound 11 (NR of general formula I 1R 2=β NMe 2XY=OCH (CH 3) OCH 2).
α nitrine glucosides intermediate 12 carries out the reaction same with its epimer subsequently, equally by 3, and " triazo-compound 13 of position obtains the compound with DMEPT4 '-OZ coupling, in the case, carries out coupling according to two kinds of technology are easier.
First kind of technology is included under-40 ℃ handles ribopyranose glycosides 13 with trifluoromethanesulfonic acid trimethyl silyl ester (TMSOTf) in methylene dichloride.Second kind of technology is included in the etherate that uses boron trifluoride under-15 ℃ in methylene dichloride.With intermediate 14 catalytic reductions that obtain, obtain being equivalent to NR in the formula then 1R 2=α NH 2XY=OCH (CH 3) OCH 2The compound 15 of general formula I.Carry out NH by formaldehyde and cyano group hydroborate with β 2What compound was identical methylates, and obtains corresponding dimethylamino radical derivative: general formula I (NR 1R 2=α NMe 2XY=OCH (CH 3) OCH 2).Set out by primary amine 15, can under the weak basic condition that has triethylamine DMF solution, make azanylization such as the iodo acetonitrile by enough halo derivatives, obtain NR in the formula 1R 2=α NHCH 2CN; XY=OCH (CH 3) OCH 2The compound 16 of general formula I.By two iodate ethers same primary amine intermediate 15 is carried out cyclisation, form the morpholine ring, obtain derivative 17.Compound 15 by being carried out same alkylation by the iodine ethamine of Z radical protection, is obtained derivative 18, and it can be catalysed and reduced into to being equivalent to NR in the formula 1R 2=α-NHCH 2CH 2NH 2XY=OCH (CH 3) OCH 2The diamino compounds 19 of general formula I.
According to illustrating mode represented in 2 below, obtain the compound that XY in the formula does not form the general formula I of ring.
Diagram 2
Figure A9619819900121
Silylated α triazo-compound 12 carries out optionally tosylation with Tosyl chloride and becomes 21 in pyridine, the tosylate of primary alconol changes iodine derivative 22 into.In this step, 4 secondary alcohol are protected by chloracetate, form functionalized 2-desoxy sugar 23, prepare in low temperature and methylene dichloride, under the general condition with the boron fluoride etherate reaction, with DMEPT4 '-OZ condensation.The intermediate 24 that obtains is the Amberlite IRA410 by handling in alkaline medium; remove the chloracetate blocking group and become compound 25; the catalytic hydrogenation of carrying out makes the situation that reaches be at last; azido-reduction is become 3 " α amino; the Z functional group of 4 ' position is disengaged; and with 6 " carbon reduction is a methyl, thereby obtains being equivalent to NR in the formula 1R 2=3 " α NH 2X=OH; Y=CH 3The derivative 26 of general formula I.The intermediate 24 that obtains previously can be at ambient temperature in DMF and the triazo-compound ionic reaction, obtain 4 " position contain a nitrine acetic ester 3 " α N 3, 6 " N 3Compound 27, by the processing similar to the front, it can be fractured into 4 " alcohol: obtain two azido alcohols 28 by ion exchange resin Amberlite IRA410.Last catalytic reduction step obtains being equivalent to NR in the formula 1R 2=3 " α NH 2X=OH; Y=CH 2NH 2The diamine derivative 29 of compound of Formula I.The salt that is formed by these nitrogenous compounds is such as hydrochloride, can treat that by basis the methanol solution that the stoichiometric methanol hydrochloride solution that pre-determines quantity in salify site is handled nitrogenous compound obtains by traditional mode.Can be randomly produce precipitation in the reaction medium and obtain the crystalline hydrochloride by adding ether.
Mode as symbol also for different synthesis steps is described, has provided following embodiment, but hard-core meaning.
Embodiment 1
General formula I: NR 1R 2=β-NH 2XY=OCH (CH 3) OCH 2
4 '-demethyl-4-O-(3-amino-2,3-dideoxy-4,6-ethylidene-β-D-arabopyranose base) epipodophyllotoxin (compound 10)
Step 1
(50g, 183mmol) heating of the solution in 400mL water is 3 hours with three-O-ethanoyl-D-glucal under 80 ℃.Reaction medium is cooled to 20 ℃ then, add then sodiumazide (17.9g, 275mmol) and acetic acid (38mL, 600mmol).After stirring at ambient temperature 24 hours, with sodium bicarbonate (salt) neutralization medium.(3 * 500mL) extract this phase with ethyl acetate.Merge the organic phase dried over mgso, then concentrating under reduced pressure.Obtain the thick product 2 of 51g, carry out the processing of back immediately.Feature: TLC: cyclohexane/ethyl acetate: 1/1; R f=0.43
C 10H 15N 3O 6M＝273
Step 2
T-butyldimethylsilyl-3-azido--2,3-dideoxy-4,6-two-O-ethanoyl-β-D-arabopyranose glycosides 3 and t-butyldimethylsilyl-3-azido--2,3-dideoxy-4,6-two-O-ethanoyl-β-D-ribopyranose glycosides 4
Under argon gas atmosphere, (16.1g 58mmol) adds 6g imidazoles (87.8mmol) and 13.24g tert-butyldimethylsilyl chloride (87.8mmol) in the solution in being cooled to 0 ℃ anhydrous methylene chloride (200mL) in advance successively to the crude mixture 2 that obtains in step 1.Stirred 15 minutes down and after stirring 19 hours under 20 ℃, reaction medium is poured in the 500mL water at 0 ℃.With 200mL dichloromethane extraction water, use dried over mgso then, concentrating under reduced pressure organic phase, chromatogram purification (cyclohexane/ethyl acetate: 9/1) residue (18.7g) on silica gel.So be separated to 10.7g compound 3 (pulpous states; 48%) and 4.7g compound 4 (pulpous states; 21%); At this moment fraction contains 3 and 4 mixture (3.3g in the middle of; 15%).Feature: 3 TLC: cyclohexane/ethyl acetate: 4/1
R f＝0.45
[α] D20＝-10°(c＝1.4；CHCl 3)
MS：m/z?405(M+NH 4)
C 16H 29N 3O 6SiM＝387
4?R f＝0.52
[α] D 20＝+10°(c＝1；CHCl 3)
MS：m/z?405(M+NH 4) +
C 16H 29N 3O 6SiM＝387
1H?NMR?300MHz?CDCL 3δ
Derivative 3:0,13 (3H, s, S iCH 3); 0,14 (3H, s, S iCH 3);
0,92(9H，s，tBu)；1,72(1H，m，J 2a-1＝9,5Hz，
J 2a-2e＝12,5Hz，J 2a-3＝12,5Hz，H 2a)
2,05(3H，s，COCH 3)；2,15(3H，s，COCH 3)；2,25
(1H，ddd，J 2e-1＝1,5Hz，J 2e-2a＝12,5Hz，J 2e-3
=4,5Hz, H 2e); 3,55-3,62 (2H, m, H 3And H 5);
4,10(1H，dd，J 6-5＝2,5Hz，H 6)；
4,20(1H，dd，J 6-5＝6Hz，J 6-6′＝12Hz，H 6′)；
4,86(1H，t，J＝9,5Hz，H 4)；
4,86 (1H, dd, J 1-2a=9,5Hz, J 1-2e=1,5Hz, H 1). derivative 4:0,1 (6H, s, Si (CH 3) 2); 0,88 (9H, s, tBu);
1,64(1H，ddd，J 2a-2e＝14Hz，J 2a-1＝8,5Hz，
J 2a-3＝3,5Hz，H 2a)；
2,03(1H，ddd，J 2e-2a＝14Hz，J 2e-1＝2Hz，J 2e-3
＝4Hz，H 2e)；
2,05(3H，s，COCH 3)；2,13(3H,s，COCH 3)；
4,05-4,12(1H，m，H 5)；
4,17-4,22(3H，m，H 3，H 6?et?H 6′)；4,89(1H，dd，
J 4-5＝9,5Hz，J 4-3＝3,5Hz，H 4)；
5,02(1H，dd，J 1-2a＝8,5Hz，J 1-2e＝2Hz，H 1).
Step 3
T-butyldimethylsilyl-3-azido--2,3-dideoxy-β-D-arabopyranose glycosides 5
Under argon gas atmosphere, to the derivative 3 that in step 2, obtains (3g, 7.7mmol) sodium methoxide solution (1.9mL) of adding 1M in the solution of anhydrous methanol (40mL).After 1 hour 30 minutes, add H in reaction under 20 ℃ +Resin (Amberlite IRC 50S) is transferred to the pH value with reaction medium and is equaled 7.Filter reaction mixture, concentrating under reduced pressure filtrate obtains 2.27g compound 5 (97%).Feature: TLC: cyclohexane/ethyl acetate: 2/1
R f＝0.36
[α] D20＝-26°(c＝1；CHCl 3)
MS：m/z?304(M+H) +321(M+NH 4) +
Mp＝70～72℃
C 12H 25N 3O 4SiM＝303
Step 4
Tertiary butyl dimethyl methyl is silica-based-3-azido--2, and 3-dideoxy-4,6-O-ethylidene-β-D-arabopyranose glycosides (compound 6)
(0.20g 0.6mmol) adds the diethyl acetal of 0.94mL (6.6mmo1) acetaldehyde in the solution in the 5mL acetonitrile, add 15mg p-methyl benzenesulfonic acid (0.08mmol) then to the compound 5 that obtains in step 3.The stirring reaction medium is 1 hour at ambient temperature, then with the dilution of 20mL ethyl acetate, with the sodium hydrogen carbonate solution washing that the 20mLpH value equals 9, uses the 20mL water washing again.Use the dried over mgso organic phase, concentrating under reduced pressure obtains the thick product of 0.25g then.In the enterprising circumstances in which people get things ready for a trip spectrum of silicon gel purification (cyclohexane/ethyl acetate: 95/5) isolate the pure compound of 0.19g 6 (86%).Feature: TLC: cyclohexane/ethyl acetate: 7/3
R f＝0.89
[α] D20＝-19°(c＝1.1；CHCl 3)
MS：m/z?347(M+NH 4) +
C 14H 27N 3O 4SiM＝329
C???H?????N
Calculate 51.04 8.26 12.75
Survey 51.64 8.43 12.51
Step 5
T-butyldimethylsilyl-3-amino-2,3-dideoxy-4,6-O-ethylidene-β-D-arabopyranose glycosides (compound 7)
(2g 6mmol) adds 50 μ L triethylamines in the solution in the 30mL ethyl acetate, the carbon that adds 0.5g10% then carries palladium to the compound 6 that obtains in step 4.Reaction medium places the hydrogen atmosphere under the normal atmosphere.After stirring at ambient temperature 6 hours, remove by filter catalyzer, the concentrating under reduced pressure organic phase obtains the pure compound of 1.82g 7 (98%).
Feature: TLC: cyclohexane/ethyl acetate: 1/1
R f＝0.23
[α] D20＝-28°(c＝1.3；CHCl 3)
MS：m/z?304(M+H) +
C 14H 29NO 4SiM＝303
Step 6
The amino carbobenzoxy-(Cbz)-2 of t-butyldimethylsilyl-3-, 3-dideoxy-4,6-O-ethylidene-β-D-arabopyranose glycosides (compound 8)
Under argon gas atmosphere, (1.12mL, (1.82g, 6mmol) (1.27mL is in mixture 9.1mmol) at anhydrous methylene dichloride (30mL) and triethylamine 7.88mmol) to add the acetal that obtains 7 be cooled to 0 ℃ in advance in step 5 with Carbobenzoxy Chloride.After stirring 8 hours, reaction medium is poured in the 100mL water, with 100mL dichloromethane extraction water.Use the dried over mgso organic phase, concentrating under reduced pressure, and with the silica gel chromatography residue (cyclohexane/ethyl acetate: 6/1 and 4/1), isolate 1.9g compound 8 (72%) of purifying.Feature: TLC: cyclohexane/ethyl acetate: 1/1
R f＝0.64
[α] D20＝-27°(c＝1.14；
CHCl 3)
MS：m/z?438(M+H) +
Mp＝102℃
C 22H 35NO 6SiM＝437
C????H????N
Calculate 60.38 8.06 3.20
Survey 60.27 8.10 3.29
Step 7
The amino carbobenzoxy-(Cbz)-2 of the 3-of 4-carbobenzoxy-(Cbz) epipodophyllotoxin, 3-dideoxy-4,6-O-ethylidene-β-D-arabopyranose glycosides (compound 9)
To the sugar 8 that in step 6, obtains (2.0g, 4.57mmol) add in the solution in the 100mL anhydrous methylene chloride 5.06mL tetrabutyl ammonium fluoride (the THF solution of 1.1M, 5.5mmol).When TLC confirms compound 8 completely dissolves (stirring 2 hours), reaction medium is cooled to-20 ℃, and (2.57g 4.8mmol), adds 8.44mL boron trifluoride diethyl etherate thing (68.5mmol) then at this moment to add DMEPT4 '-OZ continuously.After 1 hour, pour reaction medium into 200mL saturated sodium bicarbonate solution (adding sodium bicarbonate salt) (pH=9)-20 ℃ of reactions.Use the dried over mgso organic phase, concentrating under reduced pressure, then crude product (6.2g) is purified in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum (methylene dichloride/acetone: 98/2 then 97/3) obtains compound 9 (2.1g, 54%).Feature: TLC: methylene dichloride/acetone: 92/8 R f=0.61
[α] D20＝-74°(c＝1.1；CHCl 3)
MS：m/z?857(M+NH 4) +
Mp＝175℃
C 45H 45NO 15M＝839
C???H???N
Calculate 64.36 5.40 1.67
Survey 64.21 5.30 1.58
Step 8
(0.28g 0.33mmol) adds 30 μ L triethylamines in the solution in the 20mL ethyl acetate, the carbon that adds 150mg10% then carries palladium to compound 9.Reaction medium is placed under the hydrogen atmosphere under the normal atmosphere.After stirring 1 hour 30 minutes at ambient temperature, remove by filter catalyzer, the concentrating under reduced pressure organic phase, carry out chromatogram with silica gel then and purify (methylene chloride: 97/3 then 95/5), obtain the pure compound of 172mg 10 (90%) (recrystallization in methylene dichloride/pentane) feature: TLC: methylene chloride: 95/5 R f=0.31
[α] D20＝-120°(c＝1.05；CHCl 3)
MS：m/z?594(M+Na) +610(M+K) +
Mp＝219℃
C 29H 33NO 11M＝571
C???H???N
Calculate 60.94 5.82 2.45
Survey 60.45 5.78 2.58 1H RMN 300MHz CDCl 3δ 1,36 (3H, d, J=5Hz, CH 3-CH); 1,51 (1H, m, H 2 " a); 2,05 (1H, m, H 2 " e); 2,88 (1H, m, H 3); 3,02 (2H, m, H 3 " etH 4 "); 3,28 (1H, m, J 2-1=5,2Hz, H 2); 3,30 (1H, m, H 5 "); 3,57 (1H, t, J=10Hz, H 6 " a); 3,75 (6H, s, OCH 3); 4,15 (1H, dd, J=5Hz, J=10Hz, H 6 " e); 4,41 (1H, dd, J=9Hz, H 11a); 4,21 (1H, t, J=9Hz, H 11b); 4,59 (1H, d, J=5,2Hz, H 1); 4,75 (1H, q, J=5Hz, H 7 "); 4,85 (1H, dd, J=9Hz, J=2Hz, H 1 "); 4,94 (1H, d, J=3,3Hz, H 4); 5,98 (1H, d, OCH AO); 6,00 (1H, d, OCH BO); 6,24 (2H, s, H 2Et H 6 '); 6,55 (1H, s, H 8); 6,75 (1H, s, H 5).
The preparation of hydrochloride
To amine 10 (61mg, 0.10mmol) add in the solution in anhydrous methylene chloride (6mL) 0.098M hydrogen chloride methanol solution (1.09mL, 0.106mmol).Stirring reaction medium 10 minutes.The purpose product is settled out after adding ether (20mL).Reclaim the hydrochloride of 56mg (86%) compound 10.Feature: Mp=230 ℃
C 29H 32NO 11ClM＝606
Solubility experiment: 2.56mg in 0.3mL water
C＝0.014M
Embodiment 2
General formula I (NR 1R 2=β NMe 2XY=OCH (CH 3) OCH 2)
4 '-demethyl-4-O (3-dimethylamino-2,3-dideoxy-4,6-ethylidene-β-D-arabopyranose base) epipodophyllotoxin (compound 11)
(0.19g 0.33mmol) adds formaldehyde (13.5 μ L) and sodium cyanoborohydride (85mg) successively in the solution in anhydrous methylene chloride (15mL) to compound 10.After stirring 45 minutes at ambient temperature, add same reactant, continue reaction 45 minutes.With 30mL methylene dichloride diluting reaction medium, water (40mL) washing.Use the dried over mgso organic phase, concentrating under reduced pressure.With silica gel residue is carried out chromatogram purification (methylene chloride: 97/3), obtain 101mg compound 11 (51%).Feature: TLC: methylene chloride: 95/5
R f＝0.4
[α] D20＝-121°(c＝1；CHCl 3)
MS：m/z?600(M+H) +
Mp＝270℃
C 31H 37NO 11M=599 1HRMN 300MHz CDCl3 δ 1,38 (3H, d, J=5Hz, CH 3-CH); 1,55 (1H, m, H 2 " a); 1,96 (1H, m, H 2 " a); 1,96 (1H, m, H 2 " e); 2,33 (3H, s, CH 3-N); 2,91-2,82 (1H, m, H 3); 2,91-2,82 (1H, m, H 3 "); 3,35-3,25 (1H, m, H 5 "); 3,38 (1H, t, J 4 " 5 "=9Hz, J 4 " 3 "=9Hz, H 4 "); 3,58 (1H, t, J 6 " a-5 "=10Hz, J 6 " a-6 " e=10Hz, H 6 " a); 3,75 (3H, s, CH 3O); 4,16 (1H, dd, J 6 " e-5 "=5Hz, J 6 " e-6 " a=10Hz, H 6 " e); 4.21 (1H, t, J 9b-9a=9Hz, J 9b-3=8Hz, H 9b); 4,42 (1H, dd, J 9a-9b=9Hz, J 9a-3=10,5Hz, H 9a); 4,59 (1H, d, J 1-2=5,2Hz, H 1); 4,74 (1H, q, J=5Hz, CH-CH 3); 4,82 (1H, dd, J 1 " 2 " a=9,5Hz, J 1 " 2 " e=2Hz, H 1 "); 4,95 (1H, d, J 4-3=3,2Hz, H 4); 5,97 (1H, d, OCH AO); 6,00 (1H, d, OCH BO); 6,25 (2H, s, H 2 'And H 6 '); 6,55 (1H, s, H 8); 6,76 (1H, s, H 5).
The preparation of hydrochloride
To amine 11 (101mg, 0.17mmol) add in the solution in anhydrous methylene chloride (7mL) 0.098M hydrogen chloride methanol solution (1.72mL, 0.17mmol).Stirring reaction medium 10 minutes.The purpose product is settled out after adding ether (20mL).Reclaim the hydrochloride of 86mg (81%) compound 11.Feature: Mp=199 ℃
C 31H 33NO 11ClM＝635
Solubility experiment: 2.5mg in 0.1mL water
C＝0.038M
Embodiment 3
General formula I (NR 1R 2=α-NH 2XY=OCH (CH 3) OCH 2)
4 '-demethyl-4-O (3-amino-2,3-dideoxy-4,6-ethylidene-β-D-ribopyranose base) epipodophyllotoxin (compound 19)
Step 1
T-butyldimethylsilyl-3-azido--2,3-dideoxy-β-D-ribopyranose glycosides (compound 12)
According to embodiment 1 in step 3 similar methods, but be to use compound 4, obtain compound 12, directly use it for step 2.
Step 2
T-butyldimethylsilyl-3-azido--2,3-dideoxy-4,6-O-ethylidene-β-D-ribopyranose glycosides (compound 13)
(0.25g 0.8mmol) adds the diethyl acetal of 1.1mL (8mmol) acetaldehyde in the solution in the 10mL acetonitrile, add 52mg camphorsulfonic acid (0.24mmol) then to the compound 12 that obtains in step 1.The stirring reaction medium is 9 hours at ambient temperature, uses ethyl acetate (30mL) dilution then, with sodium hydrogen carbonate solution (pH=9) washing, and water (30mL) washing again.Use the dried over mgso organic phase, decompression wave contracts again, obtains the 0.3g crude product.Carry out chromatogram purification (cyclohexane/ethyl acetate: 15/1), isolate the pure compound of 0.15g 13 (55%) with silica gel.Feature: TLC: cyclohexane/ethyl acetate: 4/1
R f＝0.77
[α] D20＝-35°(c＝1.1；CHCl 3)
C 14H 27N 3O 4SiM＝329
Step 3
4 '-the 3-azido--2 of carbobenzoxy-(Cbz) epipodophyllotoxin, 3-dideoxy-4,6-O-ethylidene-β-D-ribopyranose glycosides (compound 14)
First synthetic route:
To DMEPT4 '-OZ (438mg, 0.82mmol), the compound 13 (270mg that obtain in step 2,0.82mmol) and molecular sieve 4A (1.5g) be cooled at 30mL add in the mixture in-40 ℃ the anhydrous methylene chloride trifluoromethanesulfonic acid trimethyl silyl ester (TMSOTf) (446 μ L, 2.46mmol).Reaction is after 1 hour 15 minutes down at-40 ℃, and with triethylamine (342 μ L) neutralization reaction medium, saturated nacl aqueous solution (20mL) washing is used in filtration then.Use the dried over mgso organic phase, concentrating under reduced pressure, the chromatogram thick residue (cyclohexane/ethyl acetate: 65/35), obtain compound 14 (260mg, 45%) of purifying on silica gel then.
Second synthetic route:
To DMEPT4 '-OZ (1.85mg, 3.46mmol), the compound 13 that obtains in step 2 (1.20g, 3.64mmol) be cooled at 100mL add in the mixture in-15 ℃ the anhydrous methylene chloride boron trifluoride diethyl etherate thing (425 μ L, 3.46mmol).Reacted 2 hours down at-15 ℃,, be poured into then in the 200mL saturated sodium bicarbonate solution with 100mL methylene dichloride diluting reaction medium.Use the dried over mgso organic phase, concentrating under reduced pressure, purifying with silica gel chromatography then, (cyclohexane/ethyl acetate: 65/35) thick residue (2.9g) obtains compound 14 (1.19g, 47%) (carrying out recrystallization with ether/hexanaphthene).Feature: TLC: cyclohexane/ethyl acetate: 6/4 R f=0.41
Cyclohexane/ethyl acetate: 65/3 R f=0.27
[α] D20＝-105°(c＝1.05；CHCl 3)
MS：m/z?749(M+NH 4) +
Mp＝139℃
C 37H 37N 3O 13M＝731
Step 4
The 3-amino-2 of epipodophyllotoxin, 3-dideoxy-4,6-ethylidene-β-D-ribopyranose glycosides (compound 15)
(110mg 0.15mmol) adds 20 μ L triethylamines in the solution in the mixture of 10mL ethanol and 5mL ethyl acetate, the carbon that adds 20mg10% then carries palladium to the compound 14 that obtains in step 3.Reaction medium places under the atmospheric hydrogen atmosphere.After stirring 2 hours at ambient temperature, remove by filter catalyzer, the concentrating under reduced pressure organic phase is purified (methylene chloride: 97/3 then 95/5) with silica gel chromatography then, obtains the pure compound of 63mg 15 (72%).
Feature: TLC: methylene chloride: 95/5 R f=0.39
[α] D20＝-100°(c＝1.05；CHCl 3)
MS：m/z?572(M+1) +589(M+NH 4) +
Mp＝217℃
C 29H 33NO 11M=571 1HRMN 300MHz CDCl 3δ: 1,35 (3H, d, J=5Hz, CH 3-CH); 1,73 (1H, m, H 2 " a); 1,90 (1H, m, H 2 " e); 2,83 (1H, m, H 3); 3,22 (1H, dd, J 2-1=5,2Hz, J 2-3=14Hz, H 2); 3,42 (1H, dd, J 4 " 3 "=9,5Hz, J 4 " 5 "=3,5Hz, H 4 "); 3,74 (6H, s, OCH 3); 3,49-3,60 (2H, m, H 3 "Et H 6 "); 3,94-4,02 (1H, m, H 5 "); 4,10-4,20 (2H, m, H 6 "EtH 11b); 4,42 (1H, dd, J 11a-3=9Hz, J 11a-11b=9,5Hz, H 11a); 4,57 (1H, d, J 1-2=5,2Hz, H 1); 4,78 (1H, q, J=5Hz, H 7 "); 4.91 (1H, d, J 4-3=3,4Hz, H 4); 5,38 (1H, dd, J 1 " 2 " e=2Hz, J 1 " 2 " a=9Hz, H 1 "); 5,93 (1H, s, OCH AO); 5,97 (1H, s, OCH BO); 6,25 (2H, s, H 2 'And H 6 '); 6,51 (1H, s, H 8); 6,86 (1H, s, H 5).
The preparation of hydrochloride
To the amine 15 that obtains in step 4 (50mg, add in 0.087mmol) 0.098M hydrogen chloride methanol solution (890 μ L, 0.087mmol).Stirring reaction medium 10 minutes.After adding ether (10mL), filtering the crystallization that obtains is hydrochloride (52mg, 98%).Feature: Mp=175 ℃
C 29H 34NO 11ClM＝607
Solubility experiment: 2.2mg in 0.2mL water
C＝0.02M
Embodiment 4
General formula I: NR 1R 2=α-NMe 2XY=OCH (CH 3) OCH 2
4 '-demethyl-4-O (3-N, N-dimethylamino-2,3-dideoxy-4,6-O-ethylidene-β-D-ribopyranose base) epipodophyllotoxin (compound 20)
(29mg 0.05mmol) adds formaldehyde (10.3 μ L) and sodium cyanoborohydride (12mg) successively in the solution in acetonitrile (1mL) to the compound 15 that obtains in step 4.After stirring 2 hours at ambient temperature.With 20mL methylene dichloride diluting reaction medium, water (20mL) washing.Use the dried over mgso organic phase, concentrating under reduced pressure.Residue reacts under same condition, after same processing, with silica gel residue is carried out chromatogram purification (methylene chloride: 97/3), obtain 29mg compound 20 (95%).Feature: TLC: methylene chloride: 95/5
R f＝0.5
[α] D20＝-85°(c＝1.06；CHCl 3)
MS：m/z?600(M+H) +
Mp＝140℃
C 31H 37NO 11M=599 1H RMN 300MHz CDCl 3δ: 1,35 (3H, d, J=5Hz); 1,55 (1H, m, H 2 " a); 2,20 (1H, m, H 2 " e); 2,36 (3H, s, CH 3N); 2,62 (1H, m, 2,62, H 3 "); 2,85 (1H, m, H 3); 3,23 (1H, dd, J 2-1=5,2Hz, J 2-3=14Hz, H 2), 3,52 (1H, dd, J 4 " 3=3Hz, J 4 " 3 "=9Hz, H 4 "); 3,61 (1H, t, J 6 " a-6 " e=10Hz, J 6 " a-5 "=10Hz, H 6 " a); 3,75 (3H, s, CH 3O); 4,22-4,02 (1H, m, H 5 "); 4,22-4,02 (1H, m, H 6 " e); 4,22-4,02 (1H, m, H 9b); 4,43 (1H, dd, J 9a-9b=9Hz, J 9b-3=10,5Hz, H 9b); 4,62-4,57 (1H, m, J 1-2=5,2Hz, H 1); 4,62-4,57 (3H, m, J=5Hz, CH-CH 3), 4,88 (1H, d, J 4-3=3,4Hz, H 4); 5,96 (1H, d, OCH AO); 5,98 (1H, d, OCH BO); 6,25 (2H, s, H 2And H 6 '); 6,52 (1H, s, H 8); 6,80 (1H, s, H 5).
The preparation of hydrochloride
To amine 20 (59mg, 0.1mmol) in the solution of anhydrous methanol (2mL), add 0.098M hydrogen chloride methanol solution (1mL, 0.1mmol).Stirring reaction medium 10 minutes.After adding ether (20mL), be settled out products therefrom.Reclaim 33mg (53%) crystallization.Feature: Mp=150 ℃
C 31H 38NO 11ClM＝635
Solubility experiment: 2.6mg in 0.1mL water
C＝0.04M
Embodiment 5
General formula I: NR 1R 2=α-NHCH 2CN; XY=OCH (CH 3) OCH 2
4 '-demethyl-4-O (3-cyano methyl amino-2,3-dideoxy-4,6-ethylidene-β-D-ribopyranose base) epipodophyllotoxin (compound 16)
(120mg, (200 μ L 1.47mmol), add 100 μ L iodomethyl cyanides (1.47mmol) then 0.21mmol) to add triethylamine in the solution in dimethyl formamide (4mL) to the compound 15 that obtains in the step 4 of embodiment 3.The stirring reaction medium is 20 hours at ambient temperature, uses 30mL ethyl acetate diluting reaction medium then, water (4 * 30mL) washings again.Use the dried over mgso organic phase, concentrating under reduced pressure.With silica gel residue is carried out chromatogram purification (methylene dichloride/acetone: 92/8), obtain 71mg pure compound 16 (55%) then.Feature: TLC: methylene chloride: 95/5
R f＝0.25
[α] D20＝-86°(c＝0.80；CHCl 3)
MS：m/z?611(M+H) +628(M+NH 4) +
C 31H 34NO 11M=610 1H RMN 300MHz CDCl 3δ: 1,35 (3H, d, J=5Hz, CH 3CH); 1,69 (1H, m, J 2 " a-1=9,5Hz, J 2 " a-2 " e=13Hz, J 2 " a-3=3Hz, H 2 " a); 1,93 (1H, m, H 2 " e); 2,86 (1H, m, H 3); 3,25 (1H, dd, J 2-1=5,2Hz, J 2-3=14Hz, H 2); 3,51-3,56 (2H, m, H 4 "And H 6 " a); 3,56 (2H, m, CH 2CN); 3,76 (6H, s, OCH 3); 3,88 (1H, m, H 5 "); 4,17 (2H, t, J 11a-3=8Hz, J 11a-11b=10Hz, H 3 "And H 11b); 4,14 (1H, dd, J 6a " 6 " b=10Hz, J 6 " b-5 "=5Hz, H 6 " b); 4,41 (1H, dd, J 11a-3=9Hz, J 11a-11b=10Hz, H 11a); 4,60 (1H, d, J 1-2=5,3Hz, H 1); 4,75 (1H, q, J=5Hz, H 7 "); 4,90 (1H, d, J 4-3=3,3Hz, H 4); 5,17 (1H, dd, J 1 " 2 " c=2Hz, J 1 " 2 " a=9,5Hz, H 1 "); 5,99 (1H, s, OCH AO); 6,00 (1H, s, OCH BO); 6,25 (2H, s, H 2And H 6 '); 6,54 (1H, s, H 8); 6,79 (1H, s, H 5).
Embodiment 6
General formula I: NR 1R 2=α-morpholinyl; XY=OCH (CH 3) OCH 2
4 '-demethyl-4-O (3-N-morpholino-2,3-dideoxy-4,6-ethylidene-β-D-ribopyranose base) epipodophyllotoxin (compound 17)
(60mg, (58 μ L 0.42mmol), add 512mg diiodo-ethyl ether (1.57mmol) then 0.10mmol) to add triethylamine in the solution in dimethyl formamide (2mL) to the compound 15 that obtains in the step 4 of embodiment 3.At ambient temperature and in the dark the stirring reaction medium is 96 hours, uses 30mL ethyl acetate diluting reaction medium then, water (4 * 30mL) washings again.Use the dried over mgso organic phase, concentrating under reduced pressure.Carry out chromatogram purification (methylene dichloride/acetone: 92/8), obtain 46mg pure compound 17 (68%) with silica gel then.Feature: TLC: methylene dichloride/acetone: 92/8
R f＝0.31
[α] D20＝-98°(c＝1.04；
CHCl 3)
C 33H 39NO 12M=641 1H RMN 300MHz CDCl 3δ: 1,33 (3H, d, J=5Hz, CH 3CH); 1,55 (1H, m, J 2 " a-1 "=9,5Hz, J 2 " a-2 " e=13Hz, J 2 " a-3 "=3Hz, H 2 " a); 2,15 (1H, m, H 2 " e); 2,84-2,90 (5H, m, CH 2N et H 3); 2,80 (1H, dd, J 3 " 4 "=3Hz, J 3 " 2 " a=3Hz, J 3 " 2 " e=3Hz, H 3 "); 3,23 (1H, dd, J 2-1=5,2Hz, J 2-3=14Hz, H 2); 3,48 (1H, t, J 6 " a-6 " b=12Hz, J 6 " a-5 "=12Hz, H 6 " a); 3,57 (1H, dd, J 3 " 4 "=3Hz, J 4 " 5 "=9Hz, H 4 "); 3,66-3,76 (10H, m, OCH 3Et OCH 2); 4,08-4,16 (2H, m, H 5 "Et H 6 " b); 4,20 (1H, t, J 11a-3=8Hz, J 11a-11b=9Hz, H 11a); 4,43 (1H, dd, J 11b-3=9Hz, J 11b-11a=9Hz, H 11b); 4,57-4,62 (2H, m, H 1And H 7 "); 4,89 (1H, d, J 4-3=3,4Hz, H 4); 5,20 (1H, dd, J 1 " 2 " e=2Hz, J 1 " 2 " a=9,5Hz, H 1 "); 5,97 (1H, s, OCH AO); 6,00 (1H, s, OCH BO); 6,25 (2H, s, H 2 'And H 6 '); 6,54 (1H, s, H 8); 6,73 (1H, s, H 5).
Embodiment 7
General formula I: NR 1R 2=α-NH 2(CH 2) 2NH 2XY=OCH (CH 3) OCH 2
4 '-demethyl-4-O[3-(2-aminoethylamino)-2,3-dideoxy-4,6-ethylidene-β-D-ribopyranose base] epipodophyllotoxin (compound 18)
(173mg, (127 μ L 0.91mmol), add 0.28g N-carbobenzoxy-(Cbz)-2-iodine ethylamine (0.91mmol) then 0.30mmol) to add triethylamine in the solution in dimethyl formamide (10mL) to the compound 15 that obtains in the step 4 of embodiment 3.The stirring reaction medium is 5 days at ambient temperature, uses 30mL water diluting reaction medium then.After with ethyl acetate (30mL) extraction, (the dried over mgso organic phase is used in 5 * 20mL) washings to water, and concentrating under reduced pressure carries out chromatogram purification (methylene chloride: 97/3), obtain 155mg pure compound 18 (68%) with silica gel then again.Feature: TLC: methylene chloride: 95/5
R f＝0.70
[α] D20＝-74°(c＝1.17；CHCl 3)
MS：m/z749(M+H) +
C 39H 44N 2O 13M＝748
This compound is directly used in following debenzylation step:
(0.15g 0.20mmol) adds triethylamine (30 μ L) in the solution in ethyl acetate and the alcoholic acid mixture (10mL, 1/1), add 10% carbon then and carry palladium (0.1g) to compound 18.Reaction medium is placed under the atmospheric hydrogen atmosphere.
In the presence of atmospheric hydrogen, stirred 1 hour 30 minutes in envrionment temperature system, remove by filter catalyzer, the concentrating under reduced pressure organic phase, on silica gel with chromatogram (the methylene chloride ammonia solution: 97/3), obtain the compound 19 of 107mg (84%) of purifying.Feature: TLC: methylene chloride (ammonia): 95/5
R f＝0.22
[α] D20＝-77°(c＝1；CHCl 3)
Mp＝130℃
C 31H 38NO 11M=614 1H RMN 300MHz CDCl 3δ: 1,33 (3H, d, J=5Hz); 1,55 (1H, m, H 2 " a); 2,15 (1H, m, H 2 " e); 2,33 (3H, m, NH 2Commutative with NH); 2,84-2,90 (5H, m, CH 2-N and H 3); 3.20 (1H, dd, J 3 " 4 "=3Hz, J 3 " 2 " a=3Hz, J 3 " 2 " e=3Hz, H 3 "); 3,23 (1H, dd, H 2); 3,48 (1H, t, J 6 " a-6 " b=12Hz, J 6 " a-5 "=12Hz, H 6 " a); 3,57 (1H, dd, J 4 " 3 "=3Hz, J 4 " 5 "=9Hz, H 4 "); 3,75 (6H, s, OCH 3); 4,08-4,16 (2H, m, H 5 "Et H 6 "B); 4,20 (1H, t, J 11b-3=8, J 11b-11a=9Hz, H 11b); 4,43 (1H, dd, J 11a-3=9Hz, J 11a-11b=9Hz, H 11a); 4,57-4,62 (2H, m, H 1And H 7 "); 4,89 (1H, d, J 4-3=3,4Hz, H 4); 5,20 (1H, dd, J 1 " 2 " e=2Hz, J 1 " 2 " a=9,5Hz, H 1 "); 5,97 and 6,00 (2H, d, OCH 2O); 6,25 (2H, s, H 2 'And H 6 '); 6,54 (1H, s, H 8); 6,73 (1H, s, H 5).
The preparation of hydrochloride
To diamines 19 (64mg, 0.10mmol) in the solution of anhydrous methanol (3mL), add 0.098M hydrogen chloride methanol solution (2.13mL, 0.21mmol).Stirring reaction medium 10 minutes.After adding ether (20mL), be settled out products therefrom.Reclaim 50mg (73%) hydrochloride.Feature: Mp=170 ℃
C 31H 39N 2O 11C 12M＝649
Solubility experiment: 2.0mg in 0.05mL water
C＝0.06M
Embodiment 8
General formula I: NR 1R 2=α-NH 2X=OH; Y=CH 3
4 '-demethyl-4-O-(3-amino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 26)
Step 1
T-butyldimethylsilyl-3-azido--2,3-dideoxy-6-O-p-toluenesulfonyl-β-D-ribopyranose glycosides (compound 21)
With Tosyl chloride (1.55g, 8.15mmol) drips of solution in pyridine (10mL) is added to and is cooled to 0 ℃ in advance, (2.06g is in solution 6.79mmol) glycol 12 that obtains in the step 1 of embodiment 3.After stirring 1 hour under the same temperature, stirred 18 hours down at 20 ℃ again.Use 100mL methylene dichloride diluting reaction medium then, (2 * 100mL) washing organic phases are used the dried over mgso organic phase, concentrating under reduced pressure to water, (cyclohexane/ethyl acetate: 8/2) residue obtains 2.02g compound 21 (65%) to carry out the chromatogram purification with silica gel then.Feature: TLC: cyclohexane/ethyl acetate: 2/1
R f＝0.45
MS：m/z?475(M+H) +
C 19H 31N 3O 6SSiM＝457
Step 2
T-butyldimethylsilyl-3-azido--6-iodo-2,3,6-three deoxidations-β-D-ribopyranose glycosides (compound 22)
(2.65g 17.68mmol) exists down, and (2.02g, 4.42mmol) the solution reflux in acetone (120mL) is 72 hours with the compound 21 that obtains in the step 1 at sodium iodide.After the cooling, with reaction medium concentrating under reduced pressure (30mL), then with the dilution of 100mL methylene dichloride.After with 10% sodium thiosulfate solution washing, use dried over mgso, concentrating under reduced pressure carries out chromatogram purification (cyclohexane/ethyl acetate: 8/2), obtain 1.5g compound 22 (82%) with the residue that obtains with silica gel again.Feature: [α] D20=-30 ° of (c=1.06; CHCl 3)
MS：m/z?431(M+NH 4) +
C 12H 24N 3O 11ISiM＝413
C???H????N
Calculate 34.87 5.81 10.17
Survey 35.07 5.76 10.25
Step 3
T-butyldimethylsilyl-3-azido--6-iodo-4-O-chloracetyl-2,3,6-three deoxidations-β-D-ribopyranose glycosides (compound 23)
(396mL, (1.03g, 2.5mmol) (404 μ L are 5mmol) in the solution in the mixture at methylene dichloride (20mL) and pyridine 5mmol) to be added in the compound 22 that obtains in the preceding step with chloracetyl chlorine.Stirring is after 1 hour down at-10 ℃, and with 30mL methylene dichloride diluting reaction medium, (3 * 20mL) wash water.After the conventional processing, carry out chromatogram purification (cyclohexane/ethyl acetate: 10/1), obtain 1.1g compound 23 (90%) with silica gel.Feature: [α] D20=-14 ° of (c=1.03; CHCl 3)
MS：m/z?507(M+NH 4) +
C 14H 25N 3O 4ClISiM＝489
C????H???N
Calculate 34.35 5.11 8.59
Survey 34.69 5.16 8.22
Step 4
4 '-demethyl-4-O (3-nitrine-6-iodo-2,3,6-three deoxidations-β-D-ribopyranose glycosides) epipodophyllotoxin (compound 24)
To be cooled to-15 ℃ DMEPT 4 '-OZ (1g, 1.85mmol), (1g 2.04mmol) adds the second etherate (BF of boron trifluoride in the mixture in anhydrous methylene chloride (100mL) for the compound 23 that obtains in the preceding step 3Et 2O) (455 μ L, 3.7mmol).,, pour into then in the 200mL saturated sodium bicarbonate aqueous solution after 5 hours-15 ℃ to 0 ℃ reactions with 100mL methylene dichloride diluting reaction medium.Use the dried over mgso organic phase, concentrating under reduced pressure.Thick residue is carried out chromatogram purification (cyclohexane/ethyl acetate: 7/3), obtain 0.8g compound 24 (48%) with silica gel.Feature: TLC: cyclohexane/ethyl acetate: 1/1
R f＝0.58
[α] D20＝-85°(c＝1.26；CHCl 3)
MS：m/z?909(M+NH 4) +
Mp＝143℃
C 37H 35N 3O 13ClIM＝891
Step 5
4 '-demethyl-4-O (3-nitrine-6-iodo-2,3,6-three deoxidations-β-D-ribopyranose base)-4 '-carbobenzoxy-(Cbz) epipodophyllotoxin (compound 25)
(257mg 0.29mmol) adds OH in the solution in methylene chloride (15mL, the 2/1) mixture to nitrine-glucosides 24 -Resin (Amberlite IRA 410).20 ℃ the reaction 3 hours after, filtering reacting medium, concentrating under reduced pressure obtains 0.22g pure compound 25 (94%) then.
Feature: TLC: cyclohexane/ethyl acetate: 1/1
R f＝0.46
[α] D20＝-57°(c＝1.02；CHCl 3)
MS：m/z?833(M+NH 4) +
Mp＝115℃
C 35H 34N 3O 12IM＝815
Step 6
4 '-demethyl-4-O (3-amino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 26)
(0.20g 0.25mmol) adds 100 μ L triethylamines to compound 25 in preceding step in the solution in ethyl acetate (10mL), the carbon that adds 0.2g10% then carries palladium.In the presence of atmospheric hydrogen, stir 30 hours at ambient temperature after, remove by filter catalyzer, the concentrating under reduced pressure organic phase is carried out the chromatogram (methylene chloride: 92/8), obtain 50mg compound 26 (38%) of purifying with residue with silica gel.
Feature: TLC: methylene chloride: 90/10
R f＝0.33
[α] D20＝-90°(c＝0.5；CHCl 3)
MS：m/z?530(M+H) +
Mp＝140℃
C 27H 31NO 10M＝529
The preparation of hydrochloride
To the amine 26 of front (70mg, 0.14mmol) in the solution of anhydrous methanol (6mL), add 0.098M hydrogen chloride methanol solution (1.44mL, 0.14mmol).Stirring reaction medium 10 minutes.After adding ether (20mL), be settled out products therefrom.Reclaim 40mg (53%) hydrochloride.Feature: Mp=164 ℃
C 27H 32NO 10ClM＝565
Solubility experiment: 2.6mg in 0.2mL water
C＝0.02M
Embodiment 9
General formula I: NR 1R 2=α-NH 2X=OH; Y=CH 2NH 2
4 '-demethyl-4-O (3,6-diamino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 29)
Step 1
4 '-demethyl-4-carbobenzoxy-(Cbz)-4-O (3,6-diazido-4-acetyl azide-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 27)
To the compound 24 that in the step 4 of embodiment 8, obtains (0.45g, 0.51mmol) add in the solution in the 10mL dimethyl formamide sodiumazide (0.1g, 1.5mmol).The stirring reaction medium is 64 hours at ambient temperature, again with 30mL water and the dilution of 30mL ethyl acetate.(4 * 20mL) washing organic phases use dried over mgso to water, concentrating under reduced pressure and carry out chromatogram purification (cyclohexane/ethyl acetate: 7/3), obtain 0.36g compound 27 (90%) with silica gel.Feature: TLC: cyclohexane/ethyl acetate: 6/4
R f＝0.44
[α] D20＝-64°(c＝1；CHCl 3)
MS：m/z?831(M+NH 4) +
Mp＝120℃
C 37H 35N 9O 13M＝813
Step 2
4 '-demethyl-4 '-carbobenzoxy-(Cbz)-4-O (3,6-diazido-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 28)
To nitrine glycoside compounds 27 (70mg, 0.08mmol) the 3mL methylene chloride/methanol mixture (2/1, v/v) add OH in the solution in -Resin (Amberlite IRA 410).Reaction is after 5 hours down at 20 ℃, and filtering reacting medium, concentrating under reduced pressure obtain 59g pure compound 28 (94%).Feature: TLC: cyclohexane/ethyl acetate: 6/4
R f＝0.25
[α] D20＝-53°(c＝1.04；CHCl 3)
Mp＝125℃
C 35H 34N 6O 12IM＝730
Step 3
4 '-demethyl-4-O (3,6-diamino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin (compound 29)
(0.11g 0.15mmol) adds triethylamine (20 μ L) to compound 28 in preceding step in the solution in 10mL ethyl acetate and alcohol mixture (1/1), the carbon that adds 70mg10% then carries palladium.In the presence of atmospheric hydrogen, stir 16 hours at ambient temperature after, remove by filter catalyzer, the concentrating under reduced pressure organic phase obtains 78mg compound 29 (95%).Feature: TLC: methylene chloride: 90/10
R f＝0.06
C 27H 32N 2O 10M＝544
The preparation of hydrochloride
To the diamines 29 of front (78mg, 0.14mmol) in the solution of anhydrous methanol (2mL), add 0.098M hydrogen chloride methanol solution (2.92mL, 0.28mmol).Stirring reaction medium 10 minutes.After adding ether (20mL), be settled out products therefrom.Reclaim 70mg (79%) hydrochloride.Feature: Mp=95 ℃
C 27H 34N 2O 10Cl 2M＝616
Solubility experiment: 2.1mg in 0.05mL water
C＝0.07M
Biological experiment
Tested these compounds by biological experiment, in leukemia P388 mouse body, demonstrated them in the experiment and can be used as carcinostatic agent.This experiment is usually used in the research field of carcinostatic agent at present and [sees the method for antitumor and other biological systems of screening chemicals and natural goods, R.Geran, N.H.Greenberg, M.M.MacDonald, A.M.Schumacher and B.J.Abbott " cancer chemotherapy report " (CancerChemotherapy reports) 1972,3, No.2].
But this experimental model is very responsive to chemotherapy, and a lot of compound exhibits go out good activity, and this makes that this test resolving power is poor.
We have changed the program of test, make it to have more selectivity.By the approach of vein, rather than the approach by peritonaeum injects tumour cell.So just promptly spread in the whole health by blood circulation.Throw in tested compound by the peritonaeum approach then.In order to confirm the activity of this compound, defined two parameters:
Determine 50% effective dosage (ED 50), this expression take compound with untreated with reference to animal mutually specific energy obtain the minimum single dose of tangible animals survived;
Determine to accept the live time that lives forever most of animal behind the shot dosage, the fact that can give heavy dose of compound and observe very long survival time makes the tolerance that may obtain the maximum hospital benefit that compound can reach.
The generation of tumour
Produce leukemia P 388[" American Journal of Pathology " (Am.J.Pathol.) 33,603,1957 in nineteen fifty-five by the chemically induced DBA/2 mouse of 3-MECA].
The pharmacology schedule of operation
Go down to posterity by weekly form, in the peritonaeum of DBA/2 mouse (primitive variety), keep tumour, experimentize with the female mouse CDF1 of the hybridization of heavy 20 ± 2g (the male mouse hybridization of female mouse of bal b/c and XDBA/2) [" cancer chemotherapy report " 3,9,1972] with ascites.Passed through intravenous route implantation tumour cell (106 cells of every mouse) on 0th.With the animal random packet, 2 every group.
Inoculating back first day of leukemia cell's (acute treatment), drop into antineoplastic compound by peritonaeum approach (ip).Dosage injection solution according to every kg mouse 10mL.The interpretational criteria of anti-tumor activity is the one-tenth current that has prolonged processed animal.The seven day death of 86% mouse behind inoculated tumour.If certain compound can make survival time extend to more than eight days, just think that it is activated.
Following table confirmed water-soluble (is unit with mg/mL) of The compounds of this invention, with ED 50The activity of these compounds of expression, the survival time of representing with fate or T/C%, the latter represents the ratio of the average survival time of the average survival time of the animal groups of being treated and control animals.
Water-soluble mg/mL ???P388 ???ED 50??(mg/Kg) Live time (day) lives forever most ????T/C％
Drop into the control group of tumour cell by vein 6～8 (average 7)
Compound
Etoposide ????0.01 ????10 ????19 ????271
Vumon ????＜0.01 ????20 ????15 ????214
??????15 ????13 ????10 ????21 ????300
??????11 ????25 ????10 ????17 ????242
??????10 ????7 ????10 ????14 ????200
??????20 ????25 ????20 ????18 ????257
Therefore show that compound of the present invention has kept the activity level of reference compound such as etoposide, and have more the water-soluble that helps preparing with administration.

Claims (11)

1. the compound of general formula I, and with pharmaceutically useful mineral acid or organic acid adduct,
" group N (the R of position in the formula, 3 1R 2) be in respect to the β position of encircling (2-deoxidation-D-pectinose base system row) or α position (2-deoxy-D-ribose base system row), R 1And R 2Identical or different, expression hydrogen atom, C 1-C 6Alkyl, these alkyl can form and can have as heteroatomic rings such as oxygen and nitrogen, and C 1-C 6Aminoalkyl group, perhaps cyano methyl.
X and Y can be identical or different, expression OH, CH 3, CH 2-NH 2, X and Y can also connect together and form a ring, such as 2-methyl 1,3 diox, have so just formed 4,6-ethylidene-3-amino-2,3-dideoxy glucosides type two cyclohexanol glycosides skeletons.
2. according to the compound of the general formula I of claim 1, it is characterized in that group NR 1R 2Be group NH 2Or N (CH 3) 2
3. according to the compound of the general formula I of claim 1, it is characterized in that group NR 1R 2By methyl, CH 2CN or CH 2-CH 2-NH 2The amino of Qu Daiing once or twice.
4. according to the compound of the general formula I of one of claim 1 to 3, it is characterized in that X and Y form has OCH (CH 3) OCH 2The ring of chain.
5. according to the compound of the general formula I of one of claim 1 to 4, it is characterized in that it is selected from following compound:
4 '-demethyl-4-O-(3-amino-4,6-ethylidene-2,3-dideoxy-β-D-arabopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-(3-amino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-(3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-arabopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-(3-dimethylamino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-(3-cyano methyl amino-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-(3-(N-morpholino)-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base) epipodophyllotoxin;
4 '-demethyl-4-O-[3-(2-aminoethylamino)-4,6-ethylidene-2,3-dideoxy-β-D-ribopyranose base] epipodophyllotoxin;
4 '-demethyl-4-O-(3-amino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin
4 '-demethyl-4-O-(3,6-diamino-2,3,6-three deoxidations-β-D-ribopyranose base) epipodophyllotoxin.
6. according to the compound of claim 4, it is characterized in that they are the form of hydrochloride.
7. according to the preparation method of the compound of Formula I of claim 1～4, it is characterized in that this method comprises allows the compound of formula III or formula IV or formula V, in low temperature and inert solvent with 4 '-demethyl-4 ' carbobenzoxy-(Cbz) epipodophyllotoxin and BF 3Etherate or trifluoromethanesulfonic acid TMS ester reaction;
Figure A9619819900031
In formula III and formula IV, the substituting group in the 3-position can be α position or β position, NR 1R 2The amino that can be protected by group Z,
In formula V, P represents the protecting group of alcohol, and the protected and hydrogenation of the product that this condensation obtains obtains the compound of formula I,
Primary amine 3 of glycosyls methylates with formaldehyde and sodium cyanoborohydride.
8. the preparation method of general formula I V compound; it is characterized in that; allow the mixture of diacetoxy azido-glucosides VI and tert-butyldimethylsilyl chloride in the presence of imidazoles, react; separate the product that reaction thus obtains; carry out every kind of product deacetylated; changing into the acetal ring of acetaldehyde in the catalysis acidic medium is 4, the 6-ethylidene
Figure A9619819900041
According to the compound of Formula I of claim 1～6 as a kind of medicine.
10. pharmaceutical composition is characterized in that, it contains at least a compound and appropriate excipients according to one of claim 1～6.
11. be used for the application of the medicine of anticancer therapy in preparation according to the compound of Formula I of one of claim 1～4, described medicine is used in particular for treating the cancer of following type, as small cell lung cancer, carcinoma of testis, embryo's tumour, neuroblastoma, kidney, placental villi film cancer, mammary cancer, colorectal carcinoma, melanoma, He Jiejinshi and non_hodgkin lymphoma and acute leukemia.
CN96198199A 1995-10-12 1996-10-11 Amine derivatives of epipodophyllotoxin 2',3'-dideoxyglycosides, preparation method therefor and use thereof as drug and for treating cancer Pending CN1202173A (en)

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CN102115483B (en) * 2009-12-30 2014-12-17 苏州天人合生物技术有限公司 Halogenated dideoxy sugar derivative, preparation method and application thereof
CN109369667A (en) * 2018-12-05 2019-02-22 南通大学 2,3,6- tri- deoxidation glycosyl demethylated podophyllotoxin compounds and its preparation method and application
CN110294764A (en) * 2019-07-15 2019-10-01 中国科学院兰州化学物理研究所 A kind of podophyllotoxin derivative and preparation method thereof of azo key connection
CN112079879A (en) * 2020-08-21 2020-12-15 华润双鹤药业股份有限公司沧州分公司 Novel synthesis method of teniposide intermediate and synthesis method of teniposide

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FR2800374B1 (en) * 1999-10-28 2002-06-28 Adir NEW DERIVATIVES OF 9- (3,5-DIMETHOXYPHENYL) -5,8,8A, 9- TETRAHYDROFURO [3 ', 4': 6.7] NAPHTO [2,3-D] [1,3] DIOXOL-6 ( 5AH) - ONE, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
TWI307341B (en) * 2002-10-11 2009-03-11 Plantaceutica Inc Anticancer compounds
FR2859208B1 (en) 2003-09-02 2006-01-21 Servier Lab NOVEL 9-AMINO-PODOPHYLLOTOXIN DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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JPS6032799A (en) * 1983-07-29 1985-02-19 Microbial Chem Res Found Novel 4'-demethyl-4-epipodophyllotoxin derivative
US5066645A (en) * 1989-09-01 1991-11-19 Bristol-Myers Company Epipodophyllotoxin altroside derivatives

Cited By (7)

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Publication number Priority date Publication date Assignee Title
CN102115483B (en) * 2009-12-30 2014-12-17 苏州天人合生物技术有限公司 Halogenated dideoxy sugar derivative, preparation method and application thereof
CN109369667A (en) * 2018-12-05 2019-02-22 南通大学 2,3,6- tri- deoxidation glycosyl demethylated podophyllotoxin compounds and its preparation method and application
CN109369667B (en) * 2018-12-05 2021-04-13 南通大学 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound and preparation method and application thereof
CN110294764A (en) * 2019-07-15 2019-10-01 中国科学院兰州化学物理研究所 A kind of podophyllotoxin derivative and preparation method thereof of azo key connection
CN110294764B (en) * 2019-07-15 2021-04-20 中国科学院兰州化学物理研究所 Azo bond-connected podophyllotoxin derivative and preparation method thereof
CN112079879A (en) * 2020-08-21 2020-12-15 华润双鹤药业股份有限公司沧州分公司 Novel synthesis method of teniposide intermediate and synthesis method of teniposide
CN112079879B (en) * 2020-08-21 2022-01-14 华润双鹤药业股份有限公司沧州分公司 Novel synthesis method of teniposide intermediate and synthesis method of teniposide

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