JPS6310789A - Novel podophyllotoxin derivative - Google Patents

Abstract

NEW MATERIAL:4-Amino-4'-demethyl podophyllotoxin of formula I (R1 and R2 are H or amino, provided that when either one is H, the other is amino). EXAMPLE:4alpha-Amino-4'-demethyl podophyllotoxin. USE:A synthetic raw material for antitumor-active compound indicating individual antitumor activity and providing a compound having excellent novel antitumor activity. PREPARATION:4'-Demethylepipodophyllotoxin bromide of formula II which is a starting material is reacted with an azide compound of the formula; MN3 (M is alkali metal or silver), preferably the azide compound in a molar amount of 1.2-3 times based on the bromide of formula II in a solvent such as THF, etc., preferably at 10-80 deg.C. Then, the resultant compound of formula III (R3 and R4 are H or azide, provided that when either one is H, the other is azide) is reduced with H2 gas in the presence of a catalyst such as Pd/C, etc., in a solvent such as acetone, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to novel podophyllotoxin derivatives which are useful substances for the synthesis of anti-cancer active compounds.

[Conventional technology]

Although it has been known for a long time that podophyllotoxin has anti-inflammatory effects, it has been difficult to apply to humans due to its strong toxicity. Therefore, various semi-synthetic rust conductors were researched to reduce toxicity.

K70pOside and Ten1posida were developed.

[Problem that the invention seeks to solve]

EtoposicLe and Ten1pO5ide have excellent anti-tumor effects against various experiments and cancers, but clinical trials have shown that they are effective against small cell lung cancer, acute leukemia, malignant lymphoma, round tumors, etc.

Satisfactory results have not yet been obtained for other tumors.

[Means for solving problems]

As a result of intensive research into podophyllotoxin derivatives, the present inventors found that a new podophyllotoxin derivative represented by formula (I) not only has an anti-heel tumor effect itself, but also an extremely strong antitumor effect. We have completed the present invention by discovering that this is an excellent compound that can be easily derived into a compound having the following properties.

That is, 1 the present invention provides a novel podophyllotoxin derivative represented by the formula CI Hereinafter, it will be referred to as compound CI). c) The compound (1) of the present invention differs from the podophylloxin visiting conductors that have been studied in the past because it has a newly introduced amino group, which is a basic group.

This is a new compound that is expected to exhibit anti-inflammatory properties different from Ktoposide + Ten1poaide.

The compound (1) of the present invention is the known 4'-demethylepipodophyllotoxin bromide [■] (Japanese Patent Publication No. 43-646
9) as a raw material, 1 is synthesized, for example, through the following reaction route.

(II) (1'/] (in the formula, 1M represents an alkali metal t or silver, R3 and R4
represents a hydrogen atom or an azide group.

One of them is a hydrogen atom and the other is an azide group.

) That is, the compound (If/) is obtained by reacting the compound (n) with a metal azide compound represented by the formula Cu1l). Examples of the metal azide compound represented by formula (III) used in this reaction include sodium azide.

Potassium azide, silver azide, etc. are mentioned, and the amount used is preferably 1 to 5 times the mole of compound (n), particularly preferably 1.2 to 3 times the mole.

The solvent to be used is not particularly limited as long as it does not adversely affect the reaction.1 For example, acetone, tetrahydro7
Ran, ethyl acetate, etc. are mentioned.

The reaction temperature is preferably 0 to 100°C, particularly preferably 10 to 80°C.

Compound (■) is usually obtained as a mixture of stereoisomers of the azide group, but the ratio changes depending on the type of solvent and reaction temperature, so by selecting appropriate reaction conditions, it is possible to preferentially favor the stereoisomer of the azide group. can be obtained.

The stereoisomer mixture of the compound (mV) can be separated by electrical separation and purification methods such as recrystallization and column chromatography, but the mixture can be subjected to the following reduction reaction to form the compound [! ) and then separate.

Next, the compound CI"l is the compound (F/"l is ethyl acetate.

It can be obtained in high yield by reduction with hydrogen gas at room temperature in the presence of a catalyst such as palladium-carbon in a solvent such as acetone or ethanol.

Naturally, a stereoisomer mixture of the amino group of compound (1) is obtained from the stereoisomer mixture of compound CIV), but it can be easily separated by column chromatography or the like.

〔Example〕

The present invention will be specifically explained below by giving examples of the compounds of the present invention, reference examples of N-benzoyl derivatives as examples of derivatives thereof, and antitumor test examples of these compounds.

Example 1 Synthesis of 4-azido-41-demethylpodophyllotoxin (compound [■]) 4'-demethylepipodophyllotoxin promide tof
was added to 200 d of acetone, silver azide prepared from 6.8 V of silver nitrate and 2.6 f of sodium azide was added, and after refluxing for 1 hour, insoluble materials were separated from P. After evaporating the solvent from Solution F, the residue was separated and purified using silica gel column chromatography. By elution with benzene/ethyl acetate=19, 4α-azido-42-demethylpodophyllotoxin (hereinafter, compound (referred to as Frail)) 2.
2t was obtained and 4β-azido-4'-demethylpodophyllotoxin (hereinafter referred to as compound [■b])5.
I got 4f.

Compound (rl/a) m, p, 214-215°C (decomposition) Engineering R (KBr, cm-') 3450. 2100.
1776H'-NMR (DMSO-(16+ppm)
8.34 (8, IH) 17.06 (III 1H),
6.61 (8, l) 6.26 (al 2H), 6. o
s(a, 2H), 4. ss(m, 3H)14.1
6(t, l)y s, 61(s, 6H), 3.2
1 (dx4, 1H).

2.7-2.9 (m, IH) MS (FAB) 425 (M), 383 [α) D-
224-9° (C=o, s o 2. CHCl3)
Compound [■t)) m, p6211-212°C (decomposition) Engineering R (KBr, c+m-') 3425. 210
0. 1765H'-MMR (DM 80-d6.p
pm ) 8-51 (8, IH) $ 7-1 ('w
lH), 6-6(8,1H).

6-19 (J IH) + 6・05 ((112H)
+ 5-1 (L I H) + 4.54 ((1, IH)
, 4.58 (t, IH) 14.12 (mu, 1a).

3.62 (a, 6H), s, 16 (Axa, 1H
) + z, 9s (m, 1H) MS (FAB) 42
5 (M+), 38! S[α)D −116,7°(C=
Q, 50B, CHCl, ) Example 2 Synthesis of 4α-amino-4'-demethylpodophyllotoxin (hereinafter referred to as compound [1'a)] Compound C1V&
] 2 f was dissolved in 200 d of ethyl acetate.

0.21 l of 10% palladium on carbon was added and hydrogen gas was blown in at room temperature. After the reaction is complete, separate the catalyst from the furnace.

After distilling off the solvent from the p liquid, the residue was recrystallized from methanol to obtain compound (Ia) 1.5 f.

m, p, 235 ~ 236 °C Engineering R (KE r, Ya-1) 3440, 3570, 177
0'11'-MMR (DM80-d6.ppm)a
, sDs+ In)l 7.52ctz+ 1H),
6.4acsr IH).

6, zt (a, l), 5.96 ((1, zH),
4.4s (m, l).

4.03 (Jin, 1H), 4.77 (d, l), s
, bssu, 6H).

5.58 (br, e, 2H), s, o2 (ala
, IH).

2.4 (me IH) MS (FAB) 399 (M+), 58B [α
)2D5-145.2°(C=Q, 5 a a, CH
Cl3) Example 5 4β-amino-4'-demethylpodophyllotoxin (hereinafter referred to as compound CIb). ) synthesis compound (II/
b) Dissolve S t in 200 d of ethyl acetate.

10% palladium-carbon 0.5F was added and hydrogen gas was blown in at room temperature. After the reaction was completed, the same treatment as in Example 2 was carried out to obtain compound Ob) 2.39.

m, P-229~230℃ Engineering R (KBr, H) 3440.1755H” -NMR
(DMso-a6.ppm)a,3(s,IH)
, 6.99 (8, IH), 6.22 (11, IH)
.

5.97 (d, 2H), 4.42 (+1. IH)
, 4.25 (m, 2H).

4.04 ((L, IH), L61 (!l, 6H
), 3.35 (m, l).

2.8 (m, 1H) M8 (FAB) 39? (M”), 3875 [α)
2D5-69.7° (C=o, s 1q, cHcx,
) Reference Example Synthesis of N-benzoyl-4β-amino-4'-demethylpodophyllotoxin (hereinafter referred to as compound (V)) Compound [Ib] 1f was dissolved in 100 d of chloroform,
0.41 l of benzoic acid and 0.71 l of N,N'-dicyclohexylcarbodiimide were added and stirred overnight at room temperature.

After evaporating the solvent from the reaction solution, the residue was separated and purified by silica gel thin layer chromatography (developing solvent: chloroform/methanol = = 9. Rf = = 0.57'), and recrystallized from methanol to form the compound [ ■] Obtained 0.59.

m, p, 179-180℃ Engineering R (KBr+m-') saao, 1770.1650
”-NMR (DM80-d6.ppm)8.71(
al IH), 8.26 (B, IH), 7.9 (
m, 2H)+7-48(m, 5H)l 6-85
(L 1”) + 6-57 (L I H) + 6.29
CB, 2B), 5.99 (al 2H), s, 4
s(m, tH).

4.53((L, 1H), 4.36(7*tH)+
5-76(t+1H)+s, 6s(s, 6H),
s, 4s (m, tH) s, as (m, rH)
MS(FAB) 504(M+H)+, 383,58
2 Anti-axial tumor test example 6 week old female CD ? Mouse leukemia L1210 cells 1×105m were intraperitoneally transplanted into mice (5 mice per group), and drugs at various concentrations were intraperitoneally administered once a day for 5 consecutive days starting from the next day. The drug was dissolved in 35% dimethelsulfoquine and 65% Tween 8G.

It was further diluted 10 times with physiological saline.

The drug-untreated group received vehicle (5.5% DMBO-6.5% T
80-90% physiological saline) was administered in the same manner. Animals were observed for 60 days after tumor implantation, and T/C (%) was determined from the average survival days of the drug-treated group and the drug-untreated group using the following formula.

The test results are shown in the table below. In the table, max (T/C) indicates the maximum value of (T/C), opt and dose are ma
The dose (optimal dose) showing x (T/C) is shown.

As is clear from Table L1210 Gamma 9, the compound of the present invention is effective against murine leukemia L121.
It has a survival effect on mice inoculated with 0 cells, and compound (V) derived therefrom has a very strong survival effect.

〔Effect of the invention〕

The compound of the present invention not only has anti-ulcer activity itself, but is also an extremely useful substance that can be easily derived from a variety of highly novel anti-ulcer active compounds.

Patent Applicant Nippon Kayaku Co., Ltd. 112 Completed Procedural Amendment July 22, 1988 Director General of the Patent Office Kunio Ogawa 1, Indication of rx 1986 Patent Application No. 152636 2, New Title of Invention Podophyllotquine derivative 3, relationship with the amended case Patent applicant: 11-2 Fujimi-chome, Chiyoda-ku, Tokyo (4011)
Representative of Nippon Kayaku Co., Ltd. President and CEO Tsunekazu Sakano 4, Agent 11-2 Fujimi-chome, Chiyoda-ku, Tokyo (Voluntary) 6. No number of inventions increased by amendment 7. Description subject to amendment Detailed description of the invention column Amendment content 1, Specification, page 3 formula [! ] is corrected as “ ”.

that's all

Claims (1)

[Claims] Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 and R_2 represent a hydrogen atom or an amino group, and one of them is a hydrogen atom and the other is an amino group.) 4-Amino-4'-demethylpodophyllotoxin.