JPH06279441A - Ellipticine derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a low toxic new compound useful as an antineoplastic agent, few in side effects, and high in solubility to water. CONSTITUTION:A compound of formula I (R is lower alkyl, lower alkoxy or heteromonocyclic group), e.g. 9-(4-carboxybutylyloxy)ellipticine. The compound of formula I can be obtained by reaction of 9-hydroxyellipticine with a carboxylic acid of the formula R<1>COOH (R<1> is lower alkyl, lower alkoxy or heterocyclic group) to produce a compound of formula II followed by, if necessary, deprotection and then conversion into a salt. The does of the compound of formula I is 0.1-50mg/kg a day. This compound has excellent antineoplastic activity and macrobiotic effect on mice implanted with e.g. mouse sarcoma 180 cells, mouse leukemia cells P388, murine colon 26 cells inducing mouse colon cancer, mouse Lewis lung cancer cells or B16 melanoma cells.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel ellipticine derivative useful as an antitumor agent and a method for producing the same.

[0002]

2. Description of the Prior Art It is known that 2-methyl-9-hydroxyellipticinium acetate can be used as an antitumor agent such as a therapeutic agent for breast cancer (Merck Index, 10th Edition, p. 512). However, this compound has a drawback in that it has no sufficient drug effect, such as no life-prolonging effect in mice transplanted with Lewis lung cancer, and side effects such as tachycardia and strong toxicity. In addition, 9-hydroxy ellipticine hydrochloride has superior antitumor activity as compared to ellipticine, but its low solubility in water makes it unsuitable for clinical use [Alkaloys Chemistry and Pharmacology; Arnold Blossi ed. Academic Press (London); Volume XXV, 141 pages (1
985)]. On the other hand, as a compound having a substituent on the 9-position hydroxy group, a compound substituted with an acetyl group, a propanoyl group or the like is known (US Patent).
3,933,827).

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel ellipticine derivative which has an excellent antitumor effect, has few side effects and toxicity, and / or has high solubility in water.

[0004]

The present invention relates to an ellipticine derivative represented by the following general formula [I] or a pharmaceutically acceptable salt thereof.

[Chemical 5] (In the formula, R is a lower alkyl group having a substituent, a lower alkoxy group which may have a substituent or a heteromonocyclic group.) The ellipticine derivative of the present invention or a pharmaceutically acceptable salt thereof is It is a pharmaceutical compound having an excellent antitumor effect and useful as an antitumor agent.

When R is a lower alkyl group having a substituent in the object compound [I] of the present invention, specific examples thereof include a substituted or unsubstituted lower alkoxy group, an optionally protected carboxyl group, a substituted or Unsubstituted lower alkoxycarbonyl group, substituted or unsubstituted phenyl group, optionally protected aminocarbonyl group, optionally protected amino group, optionally protected amino group, substituted lower alkanoylamino group and protected And lower alkyl groups having 1 to 3 substituents selected from optionally hydroxyl groups, more specifically, lower alkoxy group, lower alkoxy group-substituted lower alkoxy group, optionally protected carboxy lower alkoxy group, Optionally protected carboxyl group, lower alkoxycarbonyl group, lower alkoxy Substituted lower alkoxycarbonyl group, optionally protected carboxy lower alkoxycarbonyl group, optionally protected aminocarbonyl group, optionally protected amino group, optionally protected amino group substituted lower alkanoylamino group And a lower alkyl group having 1 to 3 substituents selected from an optionally protected hydroxyl group. Among them, especially lower alkoxy group, lower alkoxy group-substituted lower alkoxy group, carboxyl group-substituted lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, lower alkoxy group-substituted lower alkoxycarbonyl group, carboxyl group-substituted lower alkoxycarbonyl group, aminocarbonyl Group, a lower alkylaminocarbonyl group, an amino group, a lower alkylamino group, a formylamino group, an amino group-substituted lower alkanoylamino group, and a hydroxyl group
A lower alkyl group having 3 substituents is preferred. Further, when R is a lower alkoxy group which may have a substituent, specific examples thereof include a substituted or unsubstituted lower alkoxy group, an optionally protected carboxyl group, a substituted or unsubstituted lower alkoxycarbonyl group, 1 to 3 substituents selected from an optionally protected aminocarbonyl group, an optionally protected amino group, an optionally protected amino group-substituted lower alkanoylamino group and an optionally protected hydroxyl group And a lower alkoxy group optionally having a lower alkoxy group or a lower alkoxy group substituted with a lower alkoxy group is particularly desirable. Further, when R is a heteromonocyclic group, specific examples thereof include a heteromonocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom and a sulfur atom, and examples thereof include a thiazolyl group and an isothiazolyl group. Alternatively, a thiazolidinyl group and the like can be mentioned. Of these, a thiazolidinyl group is particularly desirable.

Among the object compounds [I] of the present invention, a compound which is preferable in terms of efficacy is a lower alkyl group substituted with a carboxyl group in which R may be protected, or a compound represented by the general formula [II] in the general formula [I]. ]

[Chemical 6] (Wherein R is as defined above) is a compound in which the group is an amino acid residue. Examples of the amino acid residue include a group in which a hydroxyl group is removed from a carboxyl group of an amino acid such as glycine, alanine, serine, phenylalanine, valine, lysine, isoleucine, aspartic acid, glutamic acid, asparagine, and glutamine, and particularly aspartic acid, Glutamic acid, asparagine and glutamine residues are preferred. Further, functional groups such as amino group, carboxyl group and hydroxyl group existing in these amino acid residues may be protected by a protective group usually used in this field. Compounds more preferable in view of efficacy include compounds in which R is a carboxyl group-substituted lower alkyl group which may be protected, and particularly preferably a carboxyl group-substituted lower alkyl group.

The most preferable compound in terms of efficacy is 9- (4-
Carboxybutyryloxy) ellipticine. When the group R has an asymmetric carbon atom in its structure, the object compound has optical isomers, but the present invention aims at any of these optical isomers and their racemates and the like. It is included in the range of things.

In the target compound [I] of the present invention, examples of the protected carboxyl group include esterified carboxyl groups. Examples of the ester residue include a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl lower alkyl group and a phenacyl group.
Of these, a lower alkyl group and a phenyl lower alkyl group are preferred ester residues. As the protected amino group, a commonly used amino group-protecting group, for example,
Examples thereof include a formyl group, a lower alkyl group, a lower alkoxycarbonyl group, and an amino group protected by a phenyl lower alkoxycarbonyl group. Of these, an amino group protected with a formyl group or a lower alkyl group is particularly preferable. As the protected hydroxyl group, a commonly used protective group for a hydroxyl group, for example, a lower alkoxycarbonyl group,
Examples thereof include a hydroxyl group protected by a halogeno lower alkoxycarbonyl group, a phenyl lower alkyl group, a tri lower alkylsilyl group, a phenyl lower alkoxycarbonyl group and the like. Of these, a hydroxyl group protected with a phenyl lower alkyl group is particularly preferable.

The object compound [I] of the present invention can be used as a medicine in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmacologically acceptable salt include salts with inorganic acids (hydrochloride, sulfate, etc.), salts with organic acids (lower alkylsulfonate, acetate, etc.), alkali metal salts (sodium salt, Examples thereof include potassium salt) and alkaline earth metal salts (calcium salt). The object compound [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and, for example, tablets, granules, capsules, powders, injections can be prepared by a conventional method. It can be used as an appropriate pharmaceutical preparation such as an agent. The dose of the target compound [I] of the present invention is
Although it depends on the administration method, age, weight and condition of the patient, it is usually about 0.1 to 50 mg / kg per day, preferably about 1 to 10 mg / kg per day.

The object compound [I] of the present invention is prepared by converting 9-hydroxy ellipticine or a salt thereof into the general formula [IV] R ¹ COOH [IV] (wherein R ¹ is a lower alkyl group having a substituent, A lower alkoxy group which may have a group or a heteromonocyclic group, and when the substituent has an amino group, a carboxyl group or a hydroxyl group, they may be protected) Reacting with a compound, a salt thereof or a reactive derivative thereof, the compound of the general formula [III]

[Chemical 7] (Wherein R ¹ has the same meaning as defined above), and when R ¹ has a protected amino group, a protected carboxyl group and / or a protected hydroxyl group, it may be optionally. Can be produced by subjecting the ellipticine derivative [III] to a conventional deprotection reaction to remove the protecting group.

The reaction of 9-hydroxy ellipticine or its salt with the free compound [IV] or its salt can be carried out in a suitable solvent in the presence or absence of a condensing agent. Any solvent can be used as long as it does not adversely influence the reaction, and examples thereof include acetone and dimethylformamide. Examples of the condensing agent include dicyclohexylcarbodiimide and 1-ethyl-3-
(3-dimethylaminopropyl) -carbodiimide,
1,1′-carbonyldiimidazole and the like can be mentioned. On the other hand, the reaction of 9-hydroxy ellipticine or its salt with the reactive derivative of compound [IV] or its salt can be carried out in a solvent in the presence or absence of a deoxidizing agent. Examples of the deoxidizing agent include inorganic and organic bases such as alkali metal hydroxides, alkali metal carbonates, pyridine and tri-lower alkylamines. Examples of the reactive derivative of the carboxylic acid compound [IV] include acid halides such as acid chlorides, acid anhydrides and active esters. Any solvent can be used as long as it does not adversely affect the reaction. Any of the above reactions suitably proceeds under cooling to heating (for example, 20 to 50 ° C).

When the carboxylic acid compound represented by the general formula [IV] or its reactive derivative has a protected amino group, carboxyl group or hydroxyl group, the protecting group is an amino group, a carboxyl group or a hydroxyl group protecting group. Any of those commonly used can be used. The amino-protecting group includes a formyl group, a lower alkanoyl group, a lower alkyl group, a lower alkoxycarbonyl group,
A phenyl lower alkoxycarbonyl group is mentioned. Examples of the protective group for the carboxyl group include ester residues such as a lower alkyl group, a halogen lower alkyl group, a phenyl lower alkyl group and a phenacyl group. Examples of the hydroxyl protecting group include a lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, a phenyl lower alkyl group, a tri lower alkylsilyl group, a phenyl lower alkoxycarbonyl group and the like. The amino, carboxyl or hydroxyl protecting group can be removed by subjecting to a conventional deprotection reaction such as reduction, acid treatment or solvolysis, depending on the kind of the protecting group. Since all of the above reactions proceed without racemization, the optically active target compound [I] can be obtained by using the optically active carboxylic acid compound [IV].

In the present specification, the lower alkyl group means methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, secondary butyl group, tertiary butyl group, pentyl group, isopentyl group. 1 to 6 carbon atoms, such as a neopentyl group, a tertiary pentyl group, and a hexyl group
Of straight chain or branched chain, and of these, preferably those having 1 to 4 carbon atoms. The lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a secondary butoxy group, a tertiary butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, It means a straight-chain or branched chain having 1 to 6 carbon atoms such as a tertiary pentyloxy group and a hexyloxy group, and of these, preferably means one having 1 to 4 carbon atoms. . The lower alkanoyl group is an acetyl group, a propionyl group, a butyryl group, an isobutyryl group,
A valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group or the like is meant to mean a linear or branched one having 2 to 6 carbon atoms, and among these, preferably those having 2 to 4 carbon atoms. To do.

[0014]

EXAMPLES Next, the present invention will be described in more detail by way of examples.

Example 1 (1) To 80 ml of acetone, 1.31 g of 9-hydroxy ellipticine and 6.9 g of anhydrous potassium carbonate were added, and 815 mg of methoxyacetic acid chloride was added dropwise with stirring. After reacting for 5 hours at room temperature, 20 ml of dimethylformamide is added, stirred and filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-methanol) to obtain 823 mg of 9-methoxyacetoxy ellipticine as a yellow powder. Yield: 49% (2) 823 mg of this product was dissolved in 100 ml of a chloroform-methanol (1: 1) mixed solution, 260 mg of methanesulfonic acid was added, the mixture was stirred for 10 minutes, the solvent was distilled off under reduced pressure, and the residue was ether. The precipitated powder is collected by filtration, washed and dried to obtain 988 mg of 9-methoxyacetoxy ellipticine methanesulfonate as a yellow powder. Yield: 93% FAB-MS (m / z): 335 (MH ⁺ , hereinafter M represents a free base) NMR (DMSO-d ₆ ) δ: 2.40 (3H, s),
2.79 (3H, s), 3.21 (3H, s), 3.4
8 (3H, s), 4.45 (2H, s), 7.43 (1
H, dd, J = 2.0, 8.8 Hz), 7.63 (1
H, d, J = 8.8 Hz), 8.18 (1H, d, J =
2Hz), 8.39 (2H, m), 9.84 (1H,
s), 11.81 (1H, NH), 15.1 (1H, b
rs)

Example 2 (1) To 60 ml of dimethylformamide, 500 mg of 2-methoxypropionic acid, 648 mg of 1-hydroxybenzotriazole and 1.19 g of dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 4 hours. Then 9-
Hydroxyelepticin hydrochloride 1.20 g and triethylamine 486 mg are added, and the mixture is stirred at room temperature overnight. 300 ml of ethyl acetate is added to the reaction solution, and after stirring, the insoluble matter is filtered off. The filtrate is washed with a 2% aqueous potassium carbonate solution and saturated brine, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent: chloroform-methanol) to obtain 960 mg of 9- (2-methoxypropionyloxy) ellipticine as a yellow powder. Yield: 69% (2) Using 960 mg of this product and 264 mg of methanesulfonic acid, a reaction treatment was carried out in the same manner as in Example 1- (2) to give a methanesulfonic acid salt of 9- (2-methoxypropionyloxy) ellipticine. 1178 mg are obtained as a yellow powder. Yield: 96% FAB-MS (m / z): 349 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 1.56 (3H, d, J
= 6.8 Hz), 2.39 (3H, s), 2.78 (3
H, s), 3.21 (3H, s), 3.48 (3H,
s), 4.31 (1H, q, J = 6.8Hz), 7.4
1 (1H, dd, J = 2.2, 8.6 Hz), 7.63
(1H, d, J = 8.6 Hz), 8.13 (1H, d,
J = 2.2 Hz), 8.36 (1H, d, J = 7.1H)
z), 8.42 (1H, d, J = 7.1 Hz), 9.9
0 (1H, s), 12.11 (1H, NH)

Examples 3 to 8 By reacting the corresponding starting compounds in the same manner as in Example 1 or 2, the compounds shown in Tables 1 and 2 below are obtained.

[0018]

[Table 1]

[0019]

[Table 2]

Example 9 (1) To 140 ml of dimethylformamide, 2.14 g of glutaric acid monobenzyl ester, 1.30 g of 1-hydroxybenzotriazole and 2.38 g of dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 4 hours. Then, 9.10 g of 9-hydroxy ellipticine is added, and the mixture is stirred at room temperature overnight. Then, the same treatment as in Example 2- (1) is performed to obtain 2.25 g of 9- [4- (benzyloxycarbonyl) butyryloxy] elepticin as a yellow powder. Yield: 60.3% FAB-MS (m / z): 467 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 1.99 (2H, m),
2.56 (2H, t, J = 7Hz), 2.72 (2H,
t, J = 7 Hz), 2.79 (3H, s), 3.21
(3H, s), 5.14 (2H, s), 7.29 (1
H, dd, J = 2.1, 8.6 Hz), 7.39 (5
H, m), 7.56 (1H, d, J = 8.6 Hz),
7.93 (1H, d, J = 6.0 Hz), 8.11 (1
H, d, J = 2.1 Hz), 8.44 (1H, d, J =
(6.0 Hz), 9.7 (1H, s) (2) 1.18 g of this product and 243 mg of methanesulfonic acid are dissolved in 70 ml of 50% methanol aqueous solution, 10% -palladium carbon 1 g is added, and hydrogen is added under normal temperature and normal pressure. Add. The reaction solution is filtered, the filtrate is concentrated under reduced pressure, and ethanol-acetone (1:10) is added to the residue. The precipitated powder is collected by filtration and dried to obtain 592 mg of 9- (4-carboxylbutyryloxy) ellipticine methanesulfonate as a yellow powder. Yield: 49.5% FAB-MS (m / z): 377 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 1.95 (2H, m),
2.39 (3H, s), 2.43 (2H, m), 2.7
4 (2H, m), 2.77 (3H, s), 3.19 (3
H, s), 7.38 (1H, dd, J = 2.0, 8.8)
Hz), 7.60 (1H, d, J = 8.8Hz), 8.
11 (1H, d, J = 2.0 Hz), 8.34 (1H,
t, J = 7 Hz), 8.40 (1H, d, J = 7H)
z), 9.87 (1H, s), 12.07 (1H,
s), 15.0 (2H, br-s)

Examples 10 to 18 The corresponding raw material compounds were treated in the same manner as in Example 9- (1) to obtain the compounds shown in Tables 3 to 5 below, and the produced compounds were treated as Example 9- (2). The same reaction treatment was performed and the following Tables 6 to 8 were used.
To obtain the compound of By using 1.5 to 3 equivalents of concentrated hydrochloric acid instead of methanesulfonic acid in 9- (2), the hydrochloride of the target compound can be obtained.

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

[0026]

[Table 7]

[0027]

[Table 8]

Example 19 (1) N- (t-butoxycarbonyl) sarcosine 91
8 mg and 9-hydroxy ellipticine 918 mg were treated in the same manner as in Example 9- (1) to obtain 9- (Nt-butoxycarbonyl-N-methylaminoacetoxy) ellipticine 1.05 g as a yellow powder. Yield: 69% FAB-MS (m / z): 434 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 1.46 (9H, s),
2.79 (3H, s), 2.98 (3H, m), 3.2
1 (3H, s), 4.32 (2H, m), 7.31 (1
H, m), 7.60 (1H, m), 7.93 (1H,
d, J = 6.0 Hz), 8.09 (1H, m), 8.4
4 (1H, d, J = 6.0 Hz), 9.7 (1H,
s), 11.5 (1H, br-s) (2) 1.00 g of this product is added to 10 ml of dioxane, and 5 ml of a 15% hydrochloric acid-dioxane solution is further added with stirring under ice cooling. The reaction solution was stirred at room temperature for 3 hours and then 100 m of ether
l was added, the insoluble matter was collected by filtration, washed and dried to obtain 851 mg of dihydrochloride of 9-methylaminoacetoxy ellipticine as a yellow powder. Yield: 91% FAB-MS (m / z): 334 (MH ⁺ ) NMR (D ₂ O) δ: 1.88 (3H, s), 2.01
(3H, s), 2.99 (3H, s), 4.38 (2
H, s), 6.57 (1H, d, J = 8.8 Hz),
6.79 (1H, dd, J = 2.0, 8.8Hz),
7.02 (1H, d, J = 2.0Hz), 7.35 (1
H, d, J = 6.8 Hz), 7.57 (1H, d, J =
6.8 Hz), 8.44 (1H, s)

Examples 20 to 29 The corresponding starting compounds were treated in the same manner as in Example 19- (1) to obtain the compounds shown in Tables 9 to 12 below, and then the produced compounds were used as Examples 19- (2). Reaction treatment is carried out in the same manner as above to obtain the compounds of Tables 13 to 15 below.

[0030]

[Table 9]

[0031]

[Table 10]

[0032]

[Table 11]

[0033]

[Table 12]

[0034]

[Table 13]

[0035]

[Table 14]

[0036]

[Table 15]

Example 30 (1) 1.72 g of N-benzyloxycarbonyl-L-aspartic acid-α-benzyl ester and 1.20 g of 9-hydroxy ellipticine hydrochloride were treated with Example 19-
By performing the reaction treatment in the same manner as in (1), 9- (O ^1-
1.40 g of benzyl-N-benzyloxycarbonyl-β-L-aspartyloxy) ellipticine are obtained as a yellow powder. Yield: 58% FAB-MS (m / z): 602 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 2.79 (3H, s),
3.19 (5H, s + m), 4.73 (1H, m),
5.10 (2H, s), 5.22 (2H, s), 7.2
1 (1H, dd, J = 2, 8.8H), 7.4 (10
H, m), 7.55 (1H, d, J = 8.8Hz),
7.93 (1H, d, J = 6.4 Hz), 8.09 (1
H, d, J = 2 Hz), 8.1 (1H, br-d),
8.44 (1H, d, J = 6.4Hz), 9.69 (1
H, s), 11.47 (1H, s) (2) 1.19 g of this product was added to a 50% methanol aqueous solution 40
1 and 0.4 ml of concentrated hydrochloric acid are added, and hydrogenation is carried out under atmospheric pressure using 0.6 g of 10% palladium carbon as a catalyst. The catalyst is filtered off and the filtrate is concentrated under reduced pressure. Acetone-ethanol mixed solution (10: 1) was added to the residue, and the powder precipitated after stirring was collected by filtration and dried to give 9- (β-L-aspartyloxy) ellipticine dihydrochloride 0.83 g as a yellow powder. Get as. Yield: 92% FAB-MS (m / z): 378 (MH ⁺ ) NMR (D ₂ O) δ: 1.58 (6H, br-s),
3.19 (1H, dd, J = 5.9, 18.1Hz),
3.31 (1H, dd, J = 5.9, 18.1Hz),
4.36 (1H, t-like, J = 5.9Hz),
6.22 (1H, m), 6.48 (1H, m), 6.5
4 (1H, s), 7.03 (1H, d, J = 7Hz),
7.31 (1H, br-m), 8.08 (1H, s)

Examples 31 to 33 Corresponding raw material compounds were treated in the same manner as in Example 30- (1) to obtain the compounds shown in Table 16 below, and the obtained compounds were used in Example 30- (2). Reaction treatment is carried out in the same manner as above to obtain the compounds of Table 17 below.

[0039]

[Table 16]

[0040]

[Table 17]

Example 34 (1) 1.49 g of 9-hydroxyelepticine hydrochloride, 510 mg of triethylamine, 2.14 g of N-benzyloxycarbonyl-L-aspartic acid-β-benzyl ester in 60 ml of dimethylformamide, 1- Add 338 mg of hydroxybenzotriazole and 1.92 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride. The reaction solution is stirred overnight at room temperature, concentrated under reduced pressure, and a 0.1% aqueous hydrochloric acid solution is added to the obtained residue and stirred. The precipitated powder is collected by filtration, washed with water and then dried. The dry powder is dissolved in a chloroform-methanol mixture (1: 1), activated carbon powder is added, and the mixture is filtered. The filtrate was concentrated under reduced pressure, isopropyl ether was added to the residue, and the precipitated powder was collected by filtration and dried to give 9-.
(O ⁴ -benzyl-N-benzyloxycarbonyl-α
1.90 g of -L-aspartyloxy) ellipticine hydrochloride is obtained as a yellow powder. Yield: 60% FAB-MS (m / z): 602 (MH +) NMR (DMSO-d 6) δ: 2.84 (3H, s),
3.04 (1H, dd, J = 8.0, 16.5Hz),
3.20 (1H, dd, J = 5.5, 16.5Hz),
3.23 (3H, s), 4.87 (1H, m), 5.1
4 (2H, s), 5.19 (2H, s), 7.3 to 7.
4 (11H, m), 7.66 (1H, d, J = 8.5H
z), 8.13 (1H, d, J = 2Hz), 8.20
(1H, d, J = 8.0 Hz), 8.37 (1H, d,
J = 7 Hz), 8.43 (1H, d, J = 7 Hz),
9.92 (1H, s), 12.3 (1H, s) (2) By subjecting 1.50 g of this product to a reaction treatment in the same manner as in Example 30- (2), 9- (α-L-aspara) was obtained. 748 mg of rutileoxy) ellipticine dihydrochloride are obtained as a yellow powder. Yield: 71% FAB-MS (m / z): 378 (MH ⁺ ) NMR (D ₂ O) δ: 1.69 (6H, br-s),
3.1-3.3 (2H, m), 4.65 (1H, t, J
= 4.4 Hz), 6.30 (1H, d, J = 8 Hz),
6.50 (1H, d, J = 8Hz), 6.53 (1H,
s), 7.15 (1H, d, J = 7Hz), 7.43
(1H, d, J = 7Hz), 8.21 (1H, s)

Examples 35 to 37 By reacting the corresponding starting compounds in the same manner as in Example 34- (1), the compounds shown in Table 18 below were obtained, and each of the obtained compounds was used in Example 34- (2). Compounds shown in Table 19 below are obtained by carrying out a reaction treatment similar to

[0043]

[Table 18]

[0044]

[Table 19]

Example 38 (1) N- (t-butoxycarbonyl) -D-aspartic acid-α-t-butyl ester (4.17 g) and 9-hydroxyelepticine hydrochloride (3.59 g) were used in Example 19.
By reacting in the same manner as- (1), 9- (N-
t-butoxycarbonyl-O ¹ -t-butyl-β-D-
4.28 g of aspartyloxy) ellipticine are obtained as a yellow powder. Yield: 66.8% FAB-MS (m / z): 534 (MH ⁺ ) NMR (DMSO-d ₆ ) δ: 1.43 (9H, s),
1.45 (9H, s), 2.80 (3H, s), 2.9
5 (1H, m), 3.10 (1H, m), 3.23 (3
H, s), 4.42 (1H, m), 7.29 (1H, d
d, J = 2.2, 9H), 7.43 (1H, d, J = 8)
Hz), 7.58 (1H, d, J = 9 Hz), 7.93
(1H, d, J = 6Hz), 8.11 (1H, d, J =
2.2Hz), 8.44 (1H, d, J = 6Hz),
9.07 (1H, s), 11.47 (1H, s) (2) 1.70 g of this product was added to 20 ml of methylene chloride,
With stirring, 40 ml of trifluoroacetic acid is added. 6 at room temperature
After stirring for an hour, the reaction solution was concentrated, the residue was dissolved in a small amount of water, and then purified with an ion exchange resin IRA-68 (Cl-type, manufactured by Organo Co., Ltd.) packed column (solvent: water) to obtain a predetermined eluate. Are collected and concentrated under reduced pressure. Acetone is added to the residue, and the precipitated powder is collected by filtration, washed, and dried to obtain 995 mg of 9- (β-D-aspartyloxy) ellipticine hydrochloride as a yellow powder. Yield: 75.6% FAB-MS (m / z): 378 (MH ⁺ ) NMR (D ₂ O) δ: 1.67 (3H, s), 1.73
(3H, s), 3.15 (1H, dd, J = 5.9, 1
7.6 Hz), 3.29 (1H, dd, J = 5.4, 1
7.6 Hz), 4.18 (1H, dd, J = 5.4,
5.9 Hz), 6.30 (1 H, d, J = 8 Hz),
6.55 (1H, d, J = 8Hz), 6.68 (1H,
br-s), 7.12 (1H, d, J = 6.8Hz),
7.39 (1H, d, J = 6.8Hz), 8.18 (1
H, s)

[0046]

The ellipticine derivative [I] of the present invention or a pharmaceutically acceptable salt thereof has excellent antitumor activity and is useful as an antitumor agent. For example, the mouse ellipticin derivative of the present invention exhibits significant antitumor action and life-prolonging effect in mice transplanted with mouse sarcoma 180 cells, mouse leukemia cell P388, mouse colon cancer Colon 26 cells, mouse Lewis lung cancer cells and B16 melanoma cells. Furthermore, a phosphorylating enzyme that contributes to phosphorylation of the p53 gene product, such as DNA-activa.
It has a selective inhibitory effect on ted kinase, casein kinase, cdc2 kinase, and thereby inhibits phosphorylation of a mutant p53 gene product that is highly expressed in cancer cells, and selectively induces apoptosis of cancer cells (cell death). ) Is induced. In addition, the ellipticine derivative [I] of the present invention or a pharmacologically acceptable salt thereof has the excellent features of weak side effects on the circulatory system such as tachycardia and low toxicity. For example, 9- (4-carboxylbutyryloxy) ellipticine hydrochloride 80 m
G / kg was intravenously administered to mice once a day for 7 days, and the mice were observed for 7 days, but no death was observed.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koji Oda 4 Inumakata, Urawa City, Saitama Prefecture 3A409

Claims (9)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R is a lower alkyl group having a substituent, a lower alkoxy group optionally having a substituent or a heteromonocyclic group), or a pharmacologically acceptable salt thereof. 2. R is a substituted or unsubstituted lower alkoxy group, an optionally protected carboxyl group, a substituted or unsubstituted lower alkoxycarbonyl group, a substituted or unsubstituted phenyl group, an optionally protected aminocarbonyl group, Lower alkyl group having 1 to 3 substituents selected from optionally protected amino group, optionally protected amino group-substituted lower alkanoylamino group and optionally protected hydroxyl group; substituted or unsubstituted Lower alkoxy group, optionally protected carboxyl group, substituted or unsubstituted lower alkoxycarbonyl group, optionally protected aminocarbonyl group, optionally protected amino group, optionally protected amino group substitution 1 to 3 substituents selected from a lower alkanoylamino group and an optionally protected hydroxyl group The compound according to claim 1, which is a lower alkoxy group which may have a group; or a heteromonocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom and a sulfur atom. 3. R is a lower alkoxy group, a lower alkoxy group-substituted lower alkoxy group, an optionally protected carboxyl group-substituted lower alkoxy group, an optionally protected carboxyl group, a lower alkoxycarbonyl group, a lower alkoxy group substituted Lower alkoxycarbonyl group, optionally protected carboxyl group-substituted lower alkoxycarbonyl group, optionally protected aminocarbonyl group, optionally protected amino group, optionally protected amino group-substituted lower alkanoylamino A lower alkyl group having 1 to 3 substituents selected from a group and an optionally protected hydroxyl group; a lower alkoxy group; a lower alkoxy group-substituted lower alkoxy group; a thiazolyl group; an isothiazolyl group; or a thiazolidinyl group. The compound according to 1. 4. R is a lower alkoxy group, a lower alkoxy group-substituted lower alkoxy group, a carboxyl group-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkoxy group-substituted lower alkoxycarbonyl group, and a carboxyl group-substituted lower alkoxycarbonyl group. ,
Lower alkyl group having 1 to 3 substituents selected from aminocarbonyl group, lower alkylaminocarbonyl group, amino group, lower alkylamino group, formylamino group, amino group-substituted lower alkanoylamino group and hydroxyl group; lower alkoxy group The compound according to claim 1, which is a lower alkoxy group-substituted lower alkoxy group; or a thiazolidinyl group. 5. R is an optionally protected carboxyl-substituted lower alkyl group, or R is a general formula [I].
In the formula [II] The compound according to claim 1, wherein the group represented by the formula (wherein R has the same meaning as defined above) is an optionally protected amino acid residue. 6. The compound according to claim 1, wherein R is an optionally protected carboxyl group-substituted lower alkyl group. 7. The compound according to claim 1, wherein R is a carboxyl group-substituted lower alkyl group. 8. 9- (4-Carboxybutyryloxy)
Ellipticine or a pharmacologically acceptable salt thereof. 9. 9-Hydroxyellipticine or a salt thereof and a general formula [IV] R ¹ COOH [IV] (In the formula, R ¹ may have a lower alkyl group having a substituent or may have a substituent. A lower alkoxy group or a heteromonocyclic group, and when the substituent has an amino group, a carboxyl group or a hydroxyl group, they may be protected), a carboxylic acid compound thereof, a salt thereof or its reactivity By reacting the derivative, the compound of the general formula [III] (Wherein R ¹ has the same meaning as defined above), and when R ¹ has a protected amino group, a protected carboxyl group and / or a protected hydroxyl group, it may be optionally. The compound of the general formula [I] is characterized in that the protecting group is removed, and if necessary, the product is made into a pharmacologically acceptable salt. (Wherein R is a lower alkyl group having a substituent, a lower alkoxy group optionally having a substituent or a heteromonocyclic group), or a pharmacologically acceptable salt thereof. Manufacturing method.