JPH069642A - 4-desoxy-4-epipodophyllotoxin derivative and its salt - Google Patents

Abstract

PURPOSE:To obtain a new 4-desoxy-4-epipodopyllotoxin derivative useful for treating tumor, having excellent antitumor activity. CONSTITUTION:A compound of formula I [R1 is H or benzyloxycarbonyl; R2 is OH, lower alkyl-substituted piperazinyl, piperidino-substituted piperidino or NR3R4 (R3 and R4 are H or substitutable lower alkyl; substituent group amino which may be substituted with lower alkyl or nitrogen-containing heterocyclic group which may be substituted with lower alkyl); n is 1-6] such as 4- desoxy-4'-dimethyl-O-benzyloxycarbonyl-4-4-(2-oxo-2-hydroxy-1-ethyl)-4- epipodophyllotoxin. A compound of formula I wherein R1 is not H and R2 is OH is obtained by reacting the compound of formula II (R5 is benzyloxycarbonyl) with the compound of formula III [R5 is (CH2)nCH-CH2], reacting the prepared compound formula IV in a proper solvent to give a compound of formula V [R8 is (CH2)nCHO] and oxidizing the compound in an inert solvent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The present invention is a novel 4-desoxy-
The present invention relates to 4-epipodophyllotoxin derivatives and salts thereof. The 4-desoxy-4-epipodophyllotoxin derivative of the present invention has excellent antitumor activity and is useful as an antitumor agent.

[0002]

2. Description of the Related Art Podophyllotoxin derivatives having antitumor activity have been known for a long time, and typical compounds thereof include etoposide and teniposide. However, there are clinical problems such as side effects, and a sufficiently satisfactory compound has not yet been obtained.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a compound having excellent antitumor activity and useful as a therapeutic drug for tumor.

[0004]

As a result of intensive studies on the podophyllotoxin derivative, the present inventors have found a compound having extremely strong antitumor activity and completed the present invention.

The present invention relates to 4-desoxy-4-epipodophyllotoxin derivatives represented by the following general formula (I) and salts thereof.

[0006]

[Chemical 2]

[Wherein R ₁ represents a hydrogen atom or a benzyloxycarbonyl group, R ₂ represents a hydroxyl group, a lower alkyl-substituted piperazinyl group, a piperidino-substituted piperidino group, or the following general formula —N (R ₃ ) (R ₄ ). In the formula, R ₃ and R ₄ are the same or different and each is a hydrogen atom, a lower alkyl group, or a substituted lower alkyl group (the substituent is an amino group which may be substituted with a lower alkyl group. Or a nitrogen-containing heterocycle which may be substituted with a lower alkyl group). n is
Indicates an integer of 1 to 6. ] 4-represented by the general formula (I)
The desoxy-4-epipodophyllotoxin derivative has excellent antitumor activity and is effective in treating tumors.

In the present specification, the lower alkyl group is, for example, a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and the like. A group can be exemplified.

The nitrogen-containing heterocyclic group is a 5-membered or 6-membered heterocyclic group containing one or two nitrogen atoms in its ring structure, and one oxygen atom in the ring structure. It may contain atoms, and examples thereof include heterocyclic groups such as a pyridyl group, a pyrrolyl group, a morpholino group, and a piperidino group.

The salts of the compound of the present invention include pharmaceutically acceptable salts such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, tartaric acid, malic acid, maleic acid, fumaric acid,
Examples thereof include salts with organic acids such as succinic acid and oxalic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid.

The 4-desoxy-4-epipodophyllotoxin derivative of the present invention can be produced, for example, according to the reaction process formulas shown in Chemical formulas 3 to 6 below.

[0012]

[Chemical 3]

[0013]

[Chemical 4]

[0014]

[Chemical 5]

[0015]

[Chemical 6]

In the above Chemical Formulas 3 to 6, R ₅ is a benzyloxycarbonyl group and R ₆ is a general formula — (CH ₂ ) _n C.
H represents a group represented by CH ₂ , and R ₇ represents a group represented by the general formula:-(C
The H _{2) n} CH (OH) group represented by -CH ₂ (OH), R ₈ is the formula - indicates the (CH ₂₎ a group represented by _n CHO. R _2A is a lower alkyl-substituted piperazinyl group, a piperidino-substituted piperidino group, or a general formula —N (R ₃ ).
A group represented by (R ₄ ) is shown. R ₃ , R ₄ and n have the same meaning as described above.

Each step of the above reaction process formula will be described below.

<Step A> 1-represented by the general formula (II)
A derivative represented by the general formula (Ia) is obtained by reacting epipodophyllotoxin with a lower alkenylsilane represented by the general formula (III) in the presence of a Lewis acid in a suitable solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, and aprotic solvents such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran and dioxane can be used. As the Lewis acid, for example, titanium tetrachloride, trimethylsilyltrifluoromethanesulfonate, zinc bromide, boron trifluoride ethyl ether, etc. can be used.

The proportion of each reaction product used is such that the compound of general formula (III) is about 1 to 5 times the molar amount of the compound of general formula (II) and the Lewis acid is 0.5 to 0.5 of the compound of general formula (II). It is preferable to use a 3-fold molar amount. The reaction temperature is -100 to 1
The temperature is about 00 ° C, preferably about -20 to 20 ° C. The reaction time is usually about 0.1 to 3 hours.

The 1-epipodophyllotoxin of the general formula (II) is described in Helv. Chim. Acta. , 52 ,
It is a known compound described in 948 (1969), and the lower alkenylsilane of the general formula (III) is also a known and easily available compound.

<Step B> The general formula (I
By oxidizing the derivative represented by a) in an inert solvent, the derivative represented by the general formula (Ib) is obtained.

As the solvent, for example, carbon tetrachloride, acetonitrile, acetic acid, water, pyridine and the like can be used alone or in combination. As the oxidizing agent, for example, ruthenium oxide, sodium periodate, osmium tetroxide, etc. can be used.

The ratio of each reaction product to be used is preferably such that the oxidizing agent is used in an amount of about 0.1 to 2 times the molar amount of the compound of the general formula (Ia). The reaction temperature is about -10 to 80 ° C, preferably about 0 to 20 ° C. The reaction time is usually 0.1 to
It takes about 3 hours.

<Step C> The general formula (I
The derivative represented by the formula (Ic) is obtained by reducing the derivative represented by a) in an inert solvent and then oxidizing it. In this case, as a raw material, in the general formula (Ia), R ₆ is represented by the general formula — (CH ₂ ) _m CH═
A compound that is a group represented by CH ₂ (wherein m represents an integer smaller than n by 1) is used.

As the solvent, for example, carbon tetrachloride, methylene chloride, acetic acid, water, tetrahydrofuran, pyridine and the like can be used alone or in combination. As the reducing agent, for example, borane-dimethyl sulfide, siamilborane-dimethyl sulfide, etc. can be used, and as the oxidizing agent, for example, chromic acid, pyridinium chlorochromate, etc. can be used.

Regarding the use ratio of each reaction product, it is preferable to use a reducing agent in an amount of about 0.5 to 2 times and an oxidizing agent in an amount of about 1 to 3 times the molar amount of the compound of the general formula (Ia). The reaction temperature is about -10 to 50 ° C, preferably about 0 to 20 ° C. The reaction time required for reduction is usually about 0.1 to 3 hours, and the oxidation is usually completed in about 5 to 24 hours.

<Step D> The general formula (I
The derivative represented by the general formula (Ic) can also be obtained by oxidizing the derivative represented by b) in an inert solvent.

As the solvent, for example, carbon tetrachloride, methylene chloride, acetic acid, tetrahydrofuran, diethyl ether, benzene and the like can be used alone or in combination. Examples of the oxidizing agent include potassium permanganate, lead tetraacetate,
Pyridinium chlorochromate etc. can be used.

The ratio of each reaction product to be used is preferably such that the oxidizing agent is used in an amount of about 0.8 to 2 times the molar amount of the compound of the general formula (Ib). The reaction temperature is about 0 to 50 ° C., preferably 0
It is about 20 ° C. The reaction time is usually about 0.1 to 2 hours.

<Step E> The derivative represented by the general formula (Ic) can also be obtained by reacting the derivative represented by the general formula (Ia) with ozone gas in a suitable solvent.

The solvent is not particularly limited as long as it does not participate in the reaction, for example, dichloromethane, 1,2-
Dichloroethane, ethyl acetate, methanol and the like can be used alone or in combination.

Regarding the usage ratio of each reaction product, it is preferable to use ozone gas in an amount of about 1 to 5 times the molar amount of the compound of the general formula (Ia). The reaction temperature is about -80 to -20 ° C, preferably about -70 to -50 ° C. The reaction time is usually
It is about 3 to 24 hours.

<Step F> The derivative represented by the general formula (Id) obtained in step C, step D or step E is oxidized in an inert solvent to obtain the derivative represented by the general formula (Id). be able to.

As the solvent, for example, water, tetrahydrofuran, acetone or the like can be used alone or in combination. As the oxidizing agent, for example, chromic acid, sulfuric acid, etc. can be used.

The proportion of each reaction product used is preferably such that the oxidizing agent is used in an amount of 0.8 to 1.2 times the molar amount of the compound of the general formula (Ic). The reaction temperature is about -10 to 30 ° C, preferably about 0 to 10 ° C. The reaction time is usually 1 to
It takes about 6 hours.

<Step G> The general formula (I
a derivative represented by d) in the presence of a base in an inert solvent,
After reacting with pivaloyl chloride to form an acid anhydride, a compound represented by the general formula HN (R ₃ ) (R ₄ ) (wherein R ₃ and R ₄ are the same as above), a lower alkyl-substituted piperazine or piperidino By reacting with a substituted piperidine, a derivative represented by the general formula (Ie) can be obtained.

As the solvent, for example, carbon tetrachloride, methylene chloride, tetrahydrofuran, ethyl acetate, benzene and the like can be used alone or in combination.

The ratio of each reaction product to the compound of the general formula (Id) is about 1 to 3 times the molar amount of the base, about 1 to 2.5 times the molar amount of pivaloyl chloride, and the general formula HN.
(R ₃ ) (R ₄ ) (wherein R ₃ and R ₄ are the same as above)
It is preferable to use the compound represented by the formula (1), lower alkyl-substituted piperazine or piperidino-substituted piperidine in an amount of about 2 to 3 times the molar amount. The reaction temperature is about -10 to 30 ° C, preferably about -10 to 0 ° C. The reaction time is usually 0.
It takes about 1 to 3 hours.

<Step H> The general formula (I
The derivative represented by d) and the derivative represented by the general formula (Ie) obtained in step G are subjected to catalytic reduction in the presence of a catalyst in an inert solvent to carry out debenzyloxycarbonylation to give a compound represented by the general formula The target compound (If) in which R _{1 in} (I) is a hydrogen atom can be obtained.

The solvent is not particularly limited as long as it does not participate in the reaction and, for example, ethyl acetate, methanol, tetrahydrofuran, acetonitrile, methylene chloride and the like can be used alone or in combination. As the catalyst, for example, palladium black, platinum or the like can be used.

The amount of the catalyst used is represented by the general formula (Id) or (I
It is about 5 to 30% by weight based on the compound represented by e). Hydrogen pressure is about atmospheric pressure to 3 atm, preferably atmospheric pressure to 2
It is about atmospheric pressure. The reaction temperature is about 0 to 40 ° C., preferably room temperature. The reaction time is usually about 1 to 24 hours.

The compound (I
a), (Ib), (Ic), (Id), (Ie), (I
f) and (Ig) are isolated and purified by means usually used in this field such as concentration, filtration, recrystallization and various chromatography.

Of these compounds, the compounds of formulas (Id) and (I
The compounds of e), (If) and (Ig) are the compounds of the present invention.

Further, the compound of the present invention obtained by each of the above reactions is prepared by subjecting it to a solvent such as methylene chloride, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, etc.
The salt form can be obtained by a conventionally known method such as reacting with the organic acid or the inorganic acid at a temperature of about room temperature.

[0046]

EXAMPLES In order to explain the present invention in more detail, examples and reference examples will be given below.

Reference Example 1: Process A Synthesis of 4-desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin (Compound A) 4′-demethyl -4'-O-benzyloxycarbonyl-4-epipodophyllotoxin 1 g (1.87 mmo
To a solution of l) in 15 ml of dichloromethane was added 426 mg (3.73 mmol) of trimethylallylsilane, and -1
Cooled to 0-0 ° C. 0.6 ml of boron trifluoride ethyl ether was added to this solution and stirred for 1 hour.

After the reaction, 0.6 ml of pyridine was added, and the mixture was added to cold dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and evaporated, purified by column chromatography (silica 50 g, developing solvent: chloroform) and crystallized with ether to give 4-desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-. 1 g (yield 95.7%) of 4-allyl-4-epipodophyllotoxin (Compound A) was obtained.

Melting point 135-137 ° C. [α] _D ²⁰ = −70.03 ° (C = 1.30, DMS
O) ¹ H-NMR (CDCl ₃ ) δ ppm: 7.30-7.
_{43 (5H, m, -OCOOCH 2} Ph), 6.72
(1H, s, 5th H), 6.46 (1H, s, 8th H), 6.31 (2H, s, 2 ', 6'H), 5.
94 (1H, d, J = 1.5Hz, -OC H 2 O-),
5.93 (1H, d, J = 1.5Hz, -OC H 2 O
-), 5.80 (1H, d-d-t, J = 17, 10.
_{5,6.5Hz, -CH 2 C H = CH} 2), 5.25
_{(2H, s, -OCOOC H 2} Ph), 5.12 (1
H, d-d-t, J = 17, _2, 1.5 Hz, -CH2
_{CH = C H 2), 5.11} (1H, d-q, J = 10.
_{5,1.5Hz, -CH 2 CH = C H} 2), 4.58
(1H, d, J = 5Hz, 1st H), 4.25 (2H,
m, 11-position H), 3.68 (6H, s , 3 ' position, 5'-position _{-OC H 3), 3.27 (1H} , m, 4 -position H), 3.0
7 (1H, dd, J = 14.5, 5Hz, 2nd H),
2.93 (1H, m, 3rd H), 2.57 (1H, m, 3H)
_{-C H 2 CH = CH 2)} , 2.42 (1H, m, -C H
₂ CH = CH ₂ ).

[Reference Example 2] Step B 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2,3-dihydroxy-1-propyl) -4-epipodophyllotoxin Synthesis of (Compound B) 4-Desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin 1 g (1.79 mmo) obtained in the same manner as in Reference Example 1.
osmium tetroxide (455 m)
g (1.79 mmol) was added, and the mixture was stirred at room temperature for 1 hour.

After the reaction, a hydrous pyridine solution containing 0.8 g of sodium hydrogen sulfite was added, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, washed with diluted hydrochloric acid and water, and dried. After concentrating the organic layer, the obtained residue was purified by column chromatography (silica 50 g, developing solvent: chloroform: methanol = 20: 1). The residue obtained by concentration was crystallized with ether and 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-
1.0 g of (2,3-dihydroxy-1-propyl) -4-epipodophyllotoxin (Compound B) (yield 94.
2%) was obtained.

Melting point 170.5-172 ° C. [α] _D ²⁰ = −62.25 ° (C = 0.66, DMS
O) ¹ H-NMR (DMSO-d ₆ ) δppm: 7.40
_{(5H, s, -OCOOCH 2 Ph} ), 6.84-6.
94 (1H, br.s, 5th H), 6.44 (1H,
s, 8th H), 6.34, 6.32 (2H, s, 2 '
Position, position 6 'H), 5.96 (2H, s , -OC H 2 O
-), 5.23 (2H, s , -OCOOC H 2 Ph),
_{4.78 (1H, m, -CH 2} CH (O H) CH 2 O
H), 4.58 (1H, d , J = 6.0Hz, 1 -position H), 4.52 (1H, m , -CH 2 CH (OH) CH
_{2 O H), 4.35 (1H} , m, 11α -position H), 4.1
7 (1H, m, 11β-position H), 3.62 (6H, s,
3 'position, 5' position -OC H _3), 3.17-3.69 (4
_{H, m, -CH 2 C H} (OH) C H 2 OH, 4 -position H),
2.94-3.02 (1H, m, 2nd H), 2.19
(1H, m, 3-position H), 1.67 (1H, m , -C H 2
_{CH (OH) CH 2 OH)} , 1.24-1.32 (1
_{H, m, -C H 2 CH} (OH) CH 2 OH).

Reference Example 3 Synthesis of 4-desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin (compound C) i) Reference to Step D 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2, obtained in the same manner as in 2.
3-dihydroxy-1-propyl) -4-epipodophyllotoxin 1 g (1.69 mmol) benzene 80 m
Lead tetraacetate (795 mg, 1.79 mmol) was added to the 1-solution, and the mixture was stirred at room temperature for 30 minutes.

After the reaction, the mixture was filtered and the filtrate was concentrated, and the obtained residue was purified by column chromatography (silica 70 g, developing solvent: chloroform: methanol = 20: 1) and crystallized with ether to give 4-desoxy. 934 mg (yield 98.7%) of -4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin (Compound C) was obtained.

Ii) Step E 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllotoxin 5.58 g (10 mmo) obtained in the same manner as in Reference Example 1.
50 ml of a solution of l) in dichloromethane at -70 to -60 ° C.
Cooled to. 1 g of ozone gas (1 g / hr) was added to this solution.
I got on for 30 minutes.

After the reaction, nitrogen gas was bubbled for 30 minutes, and then 1
It was washed with 30 ml of an aqueous solution of sodium N-thiosulfate.
The organic layer was washed with water, dried, and concentrated to give a residue, which was crystallized with ether and treated with 4-desoxy-4'-demethyl-
4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin (Compound C) was added to 4.
20 g (yield 75%) was obtained.

Melting point 180-182 ° C. [α] _D ²⁰ = −71.04 ° (C = 1.32, DMS
O) ¹ H-NMR (DMSO-d ₆ ) δppm: 9.73
(1H, s, -C H O ), 7.39 (5H, s, -OC
OOCH ₂ Ph ), 6.88 (1H, s, 5th H),
6.46 (1H, s, 8th H), 6.35 (2H, s,
2 ', 6' position H), 5.96 (2H, s , -OC H 2
O -), 5.23 (2H, s, -OCOOC H 2 P
h), 4.54 (1H, d, J = 3.6Hz, 1st H), 3.96-4.32 (1H, m, 11α H),
3.63 (6H, s, 3 'position, 5'-position -OC H _3),
3.48-3.92 (1H, m, 11β-position H), 2.5
6-3.40 (5H, m, 2, 3, 4 H, -C H
₂ CHO).

Reference Example 4: Step C 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2-formyl-1-ethyl)-
Synthesis of 4-Epipodophyllotoxin (Compound D) 4-Desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-allyl-4-epipodophyllo obtained in the same manner as in Reference Example 1. 4 g of toxin (7.17 mmo
3. To a solution of 1) in 40 ml of tetrahydrofuran, a solution of 2M borane-dimethyl sulfide in tetrahydrofuran 4.
3 ml (8.6 mmol) was added dropwise under ice cooling, and the mixture was reacted at room temperature for 1 hour. The residue obtained by concentrating the reaction solution was dissolved in 80 ml of methylene chloride, 3.0 g (13.9 mmol) of pyridinium chlorochromate was added, and the mixture was stirred at room temperature for 10 minutes.
Stir for hours.

After the reaction, 100 ml of ethyl acetate was added, and the insoluble matter was filtered using Florisil. The residue obtained by concentrating the filtrate was subjected to column chromatography (silica 50
g, developing solvent: hexane: ethyl acetate = 1: 1), purified by crystallization with ether, and 4-desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4-
1.85 g (yield 44.9%) of (2-formyl-1-ethyl) -4-epipodophyllotoxin (Compound D) was obtained.

Melting point 153-155 ° C. [α] _D ²⁰ = −69.09 ° (C = 0.38, DMS
O) ¹ H-NMR (CDCl ₃ ) δppm: 9.83 (1
H, s, -C H O) , 7.40 (5H, m, -OCOO
_{CH 2 Ph), 6.83 (1H} , s, 5 -position H), 6.4
5 (1H, s, 8th H), 6.28 (2H, s, 2 ')
Position, position 6 'H), 5.94 (2H, s , -OC H 2 O
-), 5.25 (2H, s , -OCOOC H 2 Ph),
4.58 (1H, d, J = 4.6Hz, 1st H), 4.
37 (1H, m, 11α position), 4.11 (1H, m, 1 position)
1β-position H), 3.67 (6H, s, 3'-position, 5'-position-O
_{C H 3), 3.04-3.10 (1H} , m, 4 -position H),
2.86-3.00 (2H, m, 2nd, 3rd H), 2.
49-2.67 (2H, m, -C H 2 CHO), 1.8
3-2.21 (2H, m, -C H 2 CH 2 CHO).

Example 1 4-desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4- (2-oxo-2-hydroxy-1-ethyl) -4-epipodophyllotoxin ( Synthesis of compound 1) 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-formylmethyl-4-epipodophyllotoxin 1 g (1.
Chromic acid 17 was added to a solution of 78 mmol) in 20 ml of acetone.
A mixed solution of 8 mg (1.78 mmol), concentrated sulfuric acid 0.2 ml and water 0.9 ml was added little by little under ice cooling, and then the mixture was stirred at 0 ° C. for 3 hours.

After the reaction, 1 ml of isopropanol was added to the reaction solution.
Was added and stirred for 1 hour. After stirring, 200m ethyl acetate
50 ml of 1-saturated saline was added for extraction. After drying the organic layer, the solvent was distilled off and the obtained residue was purified by column chromatography (40 g of silica, developing solvent; chloroform: methanol = 10: 1).

The residue obtained by concentrating was crystallized with ether and 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2-oxo-2-hydroxy-1-ethyl). ) -4-Epipodophyllotoxin (Compound 1) was obtained in an amount of 609 mg (yield 59.4%).
The physical property values are shown in Table 1.

Example 2 4-Desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2-oxo-2- (2-morpholino-ethylamino) -1-ethyl) -4 -Synthesis of epipodophyllotoxin (Compound 2) 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4-obtained in the same manner as in Example 1.
(2-oxo-2-hydroxy-1-ethyl) -4-
288 mg (0.5 mmol) of epipodophyllotoxin
And dimethylaminopyridine 74mg (0.6mmol)
To a solution of 5 ml of ethyl acetate in 1 ml of ethyl acetate was added dropwise a solution of 60 mg (0.5 mmol) of pivaloyl chloride in 1 ml of ethyl acetate under ice cooling. After the dropping, to the solution stirred for 30 minutes, 4-
(2-Aminoethyl) morpholine 130 mg (1 mmo
2 ml of an ethyl acetate solution of 1) was added dropwise.

After the reaction, dilute with 50 ml of ethyl acetate,
The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine.
After the organic layer was dried, the solvent was distilled off and the obtained residue was purified by column chromatography (silica 40 g, developing solvent; chloroform: methanol = 10: 1).

The residue obtained was crystallized from ether to give 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4- (2-oxo-2- (2-morpholino-ethylamino). ) -1-Ethyl) -4-epipodophyllotoxin (Compound 2) 270 mg (yield 7
8.5%) was obtained. The physical property values are shown in Table 2.

[Examples 3 to 9] In the same manner as in Example 2, compounds 3 to 9 shown in Tables 3 to 9 below were synthesized.

The compounds in Tables 1 to 9 are compounds represented by the following chemical formula 7.

[0069]

[Chemical 7]

[0070]

[Table 1]

[0071]

[Table 2]

[0072]

[Table 3]

[0073]

[Table 4]

[0074]

[Table 5]

[0075]

[Table 6]

[0076]

[Table 7]

[0077]

[Table 8]

[0078]

[Table 9]

Example 10 4-desoxy-4′-demethyl-4- (2-oxo-2)
Synthesis of 4-hydroxy-1-ethyl) -4-epipodophyllotoxin (compound 10) 4-desoxy-4'-demethyl-4'-O-benzyloxycarbonyl-4 obtained in the same manner as in Example 1. −
(2-oxo-2-hydroxy-1-ethyl) -4-
200 mg of epipodophyllotoxin (0.347 mmo
To 10 ml of methylene chloride solution of 1), 40 mg of 5% palladium-carbon was added, and the mixture was stirred at room temperature for 3 hours under hydrogen pressure (2 atm).

After the reaction, 200 ml of methylene chloride was added,
The insoluble material was filtered off. After concentrating the filtrate, the obtained residue was crystallized with 6 ml of acetonitrile to give 4-desoxy-4 ′.
-Demethyl-4- (2-oxo-2-hydroxy-1)
-Ethyl) -4-epipodophyllotoxin (Compound 1
0) was obtained (98 mg, yield 66.3%). The physical property values are shown in Table 10.

Example 11 4-desoxy-4′-demethyl-4- (2-oxo-2)
-(2-morpholino-ethylamino) -1-ethyl)-
Synthesis of 4-Epipodophyllotoxin Hydrochloride (Compound 11) 4-Desoxy-4′-demethyl-4′-O-benzyloxycarbonyl-4-obtained in the same manner as in Example 2.
(2-oxo-2- (2-morpholino-ethylamino)
-1-Ethyl) -4-epipodophyllotoxin 270 m
g in methylene chloride 15 ml solution, 10% palladium-
Carbon (50 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere under 2 atm. After the reaction, the catalyst was filtered off, and 4N-hydrochloric acid /
0.5 ml of ethyl acetate was added.

After the solvent was distilled off, the crystals were crystallized from ether and collected by filtration to give 4-desoxy-4'-demethyl-4- (2-oxo-2- (2-morpholino-ethylamino) -1-ethyl. ) -4-Epipodophyllotoxin hydrochloride (Compound 1
195 mg (yield 84.1%) of 1) was obtained. The physical properties are shown in Table 11.

[Examples 12 to 17] In the same manner as in Example 11, compounds 12 to 17 shown in Tables 12 to 17 below were synthesized.

The compounds shown in Tables 10 to 17 are compounds represented by the following chemical formula 8.

[0085]

[Chemical 8]

[0086]

[Table 10]

[0087]

[Table 11]

[0088]

[Table 12]

[0089]

[Table 13]

[0090]

[Table 14]

[0091]

[Table 15]

[0092]

[Table 16]

[0093]

[Table 17]

[Pharmacological Test 1] P388 mouse leukemia cells were seeded at 1 × 10 ³ cells / well on a 96-well plate and cultured for 24 hours. After dissolving the test compound in dimethylformamide, it was diluted with medium to various concentrations and added to each well to continue the culture.
After contact for 4 days, the plate was fixed with glutaraldehyde and the number of cells was counted by the crystal violet staining method. The cell killing effect of each compound was expressed as the drug concentration (ED ₅₀ ) that reduced the control cell number by 50%. The results are shown in Table 18.

[0095]

[Table 18]

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical indication location C07D 295: 00) 6701-4C (72) Inventor Teruhiro Utsuki 621-2 Iwasawa, Hanno City, Saitama Prefecture (72) Invention Person Yuji Yamada 2-2953-21 Higashisayamagaoka, Tokorozawa, Saitama Prefecture (29) Inventor Yoshiko Yamazaki 2-15-20 Kagiyama, Iruma City, Saitama Prefecture (72) Hideo Yamaguchi 2-3-14 Hanayashiki, Kawanishi City, Hyogo Prefecture

Claims (1)

[Claims] 1. The following general formula: [Wherein R ₁ represents a hydrogen atom or a benzyloxycarbonyl group, R ₂ represents a hydroxyl group, a lower alkyl-substituted piperazinyl group, a piperidino-substituted piperidino group, or a group represented by the following general formula —N (R ₃ ) (R ₄ ). In the formula, R ₃ and R ₄ are the same or different and are a hydrogen atom, a lower alkyl group, or a substituted lower alkyl group (the substituent is an amino group which may be substituted with a lower alkyl group, or a lower alkyl group). Represents a nitrogen-containing heterocycle which may be substituted with an alkyl group). n is
Indicates an integer of 1 to 6. ] 4-desoxy-4 represented by
-Epipodophyllotoxin derivatives and their salts.