JPH06228141A - Condensed heterocyclic derivative, its salt, its production and use thereof - Google Patents

Abstract

PURPOSE:To provide a new compound having topoisomerase-inhibitory activity, useful as a carcinostatic. CONSTITUTION:The objective compound of formula I [R' is hydrophilic group- substituted aliphatic hydrocarbon; R<0> is lower alkyl; R<1> and R<2> are each H or lower hydrocarbon; X<1> and X<2> are each O, S(O)k, N-R<3> (k is 0 1 2; R<3> is H or lower hydrocarbon) or methylene; i is 1-3], e.g. 14-aminomethyl-7-ethyl-7- hydroxyl-0H-1,3-dioxolo[4,5-g]pyrano[3',4':6,7]indolizino[1,b]quinolin e-8,11-[7H,13 H]-dione. The compound of the formula I, which gives inhibitory activity on the enzyme involved in topoisomerism in nucleic acid synthesis, has proliferation- suppressive activity on oncocytes.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel fused heterocyclic derivative useful as an antitumor agent, its production method and use.

[0002]

2. Description of the Related Art Camptotheca acuminata
Camptothecin (c isolated and extracted from Nyssaceae)
and its analogs are compounds included in the category of pentacyclic alkaloids, and their main mechanism of action, unlike existing antitumor agents, is topoisomerase I, which plays an important role in the nucleic acid synthesis system. Is the inhibition of. Therefore, cross resistance with existing drugs is not observed, and it is reported to exert a unique and strong antitumor effect. A clinical phase II trial of camptothecin itself was conducted in the United States, but its development as a pharmaceutical product has been discontinued because its toxicity was not as strong as expected. further,
This product is extremely insoluble in water as a basic physical property and has major restrictions on formulation and clinical use [FM Mugg
ia et al., Cancer Chemother. Rep., 56 , 515 (1972)
And CR Hutchinson, Tetrahedron, 37 , 1047 (19
81)]. For the purpose of solving these problems, a derivative of camptothecin which is a 5-ring fused ring system [Japanese Patent Publication No. 3-68007 and WD Kingsbury et al., JM]
ed. Chem., 34 , 98 (1991)] and a derivative extended to a 6-ring condensed ring system [JP-A-2-138186 and ME]
Wall et al., EP-418099-A] are being studied.

[0003]

At present, what is particularly desired in the field of cancer treatment is that it exhibits high selective toxicity to cancer cells by a new mechanism of action, and is clinically easy to handle and excellent in treatment. It is to develop a drug that can be expected to be effective. Conventionally studied camptothecin derivatives are not yet in a practically satisfactory state, for example, they are highly toxic to the digestive organs and bone marrow, or have poor solubility in water.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in view of the above circumstances, a derivative in which a water-soluble substituent is introduced at a specific position of a 6-ring fused ring compound is unexpected. In addition, it specifically inhibits one or two enzymes involved in topoisomerism of nucleic acid synthesis system, exerts high selective toxicity to various tumor cells (especially human lung cancer cells), and is hardly soluble in water. The present invention has been completed by finding that the above-mentioned problem is also overcome and an excellent therapeutic effect is exhibited.

That is, the present invention provides (1) the general formula

[Chemical 7] A lower hydrocarbon group which may have a substituent) or a methylene group which may have a substituent, i represents an integer of 1 to 3, and R ¹ and R ² are each a repeating number of i. It may be different. ] The compound or its salt represented by these, (2) General formula

[Chemical 8] A hydrogen atom or a lower hydrocarbon group which may have a substituent) or a methylene group which may have a substituent,
Is -OR ⁶ (R ⁶ is a hydrogen atom or an organic group having a water-soluble substituent) or

[Chemical 9] (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, a lower hydrocarbon group which may have a substituent, or an organic group having a water-soluble substituent, or forms a heterocyclic ring with an adjacent nitrogen atom. I and j each represent an integer of 1 to 3, and R ¹ , R ² , R ⁴ and R ⁵ may be different from each other in i or j repetitions. Or a salt thereof], a compound of (3) the aliphatic hydrocarbon group is a straight or branched C _1-6 alkyl group (1), (4) a lower alkyl group C A compound of the above (1) which is a _1-6 alkyl group, (5)
The lower hydrocarbon group which may have a substituent represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ is halogen,
Nitro, cyano, hydroxy, carboxy, carbamoyl, N-mono C _1-6 alkylcarbamoyl, N, N-diC _1-6 alkylcarbamoyl, C _1-6 alkoxy, phenoxy, benzyloxy, amino, mono C _1-6 Alkylamino, di-C _1-6 alkylamino, trifluoromethyl,
C _1-5 alkanoyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 alkylthio, sulfamoyl, N-mono C _1-6 alkylsulfamoyl, N, N-diC _1-6 alkylsulfa Moyl, C _1-6 alkylsulfinyl and C _1-6 alkylsulfonyl, optionally substituted C _1-6 alkyl group, C _2-6 alkenyl group, C
_3-6 cycloalkyl group, a compound of the above (1) or (2) which is a phenyl group or a benzyl group, (6) a methylene group which may have a substituent is halogen, nitro, cyano, hydroxy, carboxy , Carbamoyl, N-mono C _1-6 alkylcarbamoyl, N, N-diC _1-6 alkylcarbamoyl, C _1-6 alkoxy, phenoxy, benzyloxy, amino, monoC _1-6 alkylamino, diC
_1-6 alkylamino, trifluoromethyl, C _1-5 alkanoyl, C _1-3 alkoxy-C _1-3 alkyl, C _1-6 alkylthio, sulfamoyl, N-mono C _1-6 alkylsulfamoyl, N, The above-mentioned (1) which is a methylene group optionally having 1 to 3 substituents selected from N-diC _1-6 alkylsulfamoyl, C _1-6 alkylsulfinyl and C _1-6 alkylsulfonyl. or the compound of (2), (7) an organic group having a water-soluble substituent represented by R ⁶ is, R ⁶ ', COR ^6' or CONHR ⁶ '(R ^6' is hydroxy, carboxy, amino, mono C _{1 -6} alkylamino, di-C _1-6 alkylamino, 5 or 6-membered cyclic amino, C _1-3 alkoxy -C _1-3 alkyl, sulfo, sulfino, three to 1 selected from phosphono or dihydroxy ball reel C _1-6 alkyl having a substituent, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 wherein cycloalkyl, phenyl or benzyl group the compound of (2), (8) hetero The ring has hydroxy, carboxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, 5- or 6-membered cyclic amino, C _1-3 alkoxy-C _1-3 alkyl, sulfo, sulfino, phosphono. And pyrrolidine, pyrroline, pyrrole, pyrazole, imidazole, piperine, morpholine, dihydropyridine, tetrahydropyridine, N which may have 1 to 3 substituents selected from dihydroxyboryl.
-Methylpiperazine, N-ethylpiperazine, azacyclopeptane or azacyclooctane (2)
Compound of (9) Y is -OR ^6a , -OCOR ^6a or-
OCONHR ^6a [R ^6a is (1) a hydrogen atom or (2) hydroxy, carboxy, amino, mono-C _1-6 alkylamino, 5- or 6-membered cyclic amino, C _1-3 alkoxy-
C _1-3 alkyl, sulfo, sulfino, phosphono and 1 to 3 substituents substituted C _1-6 alkyl selected from dihydroxy Bo reel, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl or benzyl group], wherein (2)
(10) Y is —NH ₂ , —NHCOR ^6a or —NHC
A compound of the above (2) which is OOR ^6a (R ^6a has the same meaning as in the above (9)), (11) R ¹ and R ² are the same or different and each is a hydrogen atom or a C _1-3 alkyl group, X ¹ And X
² are the same or different, -O-, -S- or -NH-
A compound of the above (1) or (2), wherein i is 1 or 2, and j is an integer of 1 to 3, (12) R ¹ and R ² are both hydrogen atoms, and X ¹ and X ² are both -O. -, The compound of the above (1) or (2), wherein j is 1 or 2, and i is 1.
(13) R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a C _1-3 alkyl group, and Y is —OH, —NH ₂ , —NHC.
A compound of the above (2) which is OR ^6a or —NHCOOR ^6a (R ^6a has the same meaning as the above (9)), (14) R ⁴
And ( ⁵ ) wherein R ⁵ is both a hydrogen atom, and (15) Y is a hydroxyl group or an amino group.
4) the compound, (16) the compound of the above (2) in which Y is an optionally protected amino group, (17) the general formula

[Chemical 10] [In the formula, R ⁰ , R ¹ , R ² , X ¹ , X ² and i have the same meanings as in the above (1). ] The compound or its salt represented by the general formula,

[Chemical 11] [Wherein R ′ has the same meaning as in the above (1), Z is a hydrogen atom,
Indicates CH ₂ OH, CHO or COOH. ] The method for producing the compound of the above (1), which comprises reacting the compound represented by
(18) General formula

[Chemical 12] [The symbols in the formulas have the same meaning as in (1) above. ] A method for producing a compound of the above (1), which comprises introducing a hydroxy group into the compound represented by the above or a salt thereof, (19) Topoisomerase I inhibitory activity containing the compounds of the above (1) and (2) Agent. (20) An antitumor composition containing the compound of (1) or (2), (21) 14-aminomethyl-7-ethyl-7-hydroxy-10H-1,
3-Dioxolo [4,5-g] pyrano [3 ', 4':
6,7] Indolizino [1,2-b] quinoline-8,1
1 [7H, 13H] -dione or its trifluoroacetate compound (1), (22) 14-aminoethyl-7-ethyl-7-hydroxy-10H-1,3-dioxolo [4,5- g] pyrano [3 ', 4': 6,7]
Indolizino [1,2-b] quinoline-8,11 [7
H, 13H] -dione or its trifluoroacetate compound (1), (23) 7-ethyl-7-hydroxy-14-hydroxymethyl-10H-1,3-
Dioxolo [4,5-g] pyrano [3 ', 4': 6,
7] Indolizino [1,2-b] quinoline-8,11
A compound of the above (1) which is [7H, 13H] -dione,
(24) 14-Aminoethyl-7-ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] pyrano [3 ', 4': 6,7] indolizino [1,2-b]
Quinoline-8,11 [7H, 13H] -dione or its compound (1) which is a hydrochloride thereof, (25) said compound (1) in which the absolute configuration of the substituent R ⁰ on the lactone ring is the S configuration.
And compounds of (2). (26) The compound of (1) or (2), which is a racemic mixture.

In the compounds (I) and (II) of the present invention, there are compounds having absolute configurations S and R due to the formation of asymmetric carbons by the substituents on the lactone ring, but racemates (R and S configurations, etc.) Amount mixtures) and optically active forms of absolute configuration S are preferred. Also, at other positions, an asymmetric center may be present depending on the kind of the substituent, but the absolute configuration thereof may be any of S, R and RS.
When the optically active substance or diastereoisomer exists, it can be easily separated by a usual separation and purification means, if necessary.

In the above formula, R'represents an aliphatic hydrocarbon group substituted with a hydrophilic group, and examples of the hydrophilic group of the aliphatic hydrocarbon group substituted with a hydrophilic group include OR ⁶ (R ⁶ Is the above

[Chemical 13] Examples thereof include a carboxyl group, a sulfonic acid group and a phosphoric acid group. As the aliphatic hydrocarbon group of the aliphatic hydrocarbon group substituted with a hydrophilic group, for example, a linear or branched C _1-11 alkyl group, preferably a C _1-6 alkyl group (for example, Methyl, ethyl, n-propyl, iso-
Propyl, n-butyl, iso-butyl, tert-butyl,
n-pentyl, n-hexyl, etc.), a linear or branched C _2-4 alkenyl group (eg, vinyl, allyl, 2-butenyl, 2-butadienyl, etc.) or a linear or branched C _{A 2-4} alkynyl group (eg, propynyl, propargyl, 2-butynyl, etc.) is used. Preferred examples of such an aliphatic hydrocarbon group are C _1-6 alkyl groups (eg, methyl, ethyl, n-
Propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, n-pentyl, n-hexyl, etc.) and the like.

A preferred example of R'which is an aliphatic hydrocarbon group substituted with a hydrophilic group is represented by the formula:

[Chemical 14] And the like. Examples of the lower alkyl group represented by R ⁰ include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, iso-propyl, butyl, tert.
-Butyl) and the like are used, and among them, for example, a C _1-3 alkyl group (eg, methyl, ethyl, propyl, iso-propyl) is preferable, and particularly, an ethyl group is most preferable.

In the above formula, R ¹ , R ² , R ⁴ and R ⁵ represent a hydrogen atom or a lower hydrocarbon group which may have a substituent, and a lower hydrocarbon which may have a substituent. Examples of the lower hydrocarbon group in the hydrogen group include C _1-6 alkyl (eg, methyl, ethyl, propyl, iso-propyl,
Butyl, tert-butyl), C _2-6 alkenyl (eg vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl), C _2-6 alkynyl (eg ethynyl, 1-propynyl, propargyl), C _{3 -6} cycloalkyl (eg,
Cyclopropyl, cyclopentyl, cyclohexyl),
Groups such as phenyl and benzyl are used. These R
^The lower hydrocarbon group represented by ¹ , R ² , R ³ and R ⁴ may have 1 to 3 substituents at substitutable positions. Examples of the substituent include, for example, halogen (eg,
Chlorine, bromine, fluorine, iodine), nitro, cyano, hydroxy, carboxy, carbamoyl, N-monoC _1-6 alkylcarbamoyl (eg, N-methylcarbamoyl, N
-Ethylcarbamoyl, N-propylcarbamoyl),
N, N-diC _1-6 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl,
N, N-dipropylcarbamoyl), C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butyroxy), phenoxy, benzyloxy, amino, mono C
_1-6 alkylamino (eg, methylamino, ethylamino, propylamino), diC _1-6 alkylamino (eg,
Dimethylamino, diethylamino, dipropylamino), trifluoromethyl, C _1-5 alkanoyl (eg,
Formyl, acetyl, propionyl), C _1-3 alkoxy-C _1-3 alkyl (eg, methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl),
C _1-6 alkylthio (eg, methylthio, ethylthio),
Sulfamoyl, N-monoC _1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl), N, N-
DiC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl,
N, N-dipropylsulfamoyl), C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl), C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl) and the like are used. R ¹ ,
Preferred examples of R ² , R ⁴ and R ⁵ are hydrogen atom or C
_1-3 alkyl groups (eg methyl, ethyl, propyl, iso
-Propyl) and the like, especially a hydrogen atom is often used.

X ¹ and X ² are represented by the formulas -O-, -S (O) _k-.
(K is an integer of 0, 1 or 2),

[Chemical 15] The methylene group which may have a substituent is shown. Examples of the lower hydrocarbon group represented by R ³ which may have a substituent include a lower hydrocarbon group described in detail for R ¹ , R ² , R ⁴ and R ^5. The number and kind of the substituents which are detailed in R ¹ , R ² , R ⁴ and R ⁵ are also used as the substituents which may be used and which the lower hydrocarbon group may have. However, R ³ is particularly preferably a C _1-3 alkyl group (eg, methyl, ethyl, propyl, iso-propyl) and the like. Also, X ¹ , X ²
As the substituent of the methylene group which may have a substituent represented by, the number and kinds of the substituents described in detail in R ¹ , R ² , R ⁴ and R ⁵ are similarly used. And X ¹
And preferred examples of X ² are —O—, —S—, —
NH- and the like are used, and especially -O- and the like are frequently used.

[0015]

[Chemical 16] And an organic group having a water-soluble substituent represented by R ⁶ is

[Chemical 17] Kill (eg, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl), C _2-6 alkenyl (eg,
Vinyl, 1-methyl vinyl, 1-propenyl, aryl
L, allenyl), C _2-6 alkynyl (eg, ethynyl, 1
Groups such as -propynyl, propargyl), C _3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl), phenyl or benzyl are used, especially C _1-4 alkyl group (eg, methyl, ethyl). , Propyl, iso-propyl, butyl, tert-butyl) or benzyl groups are commonly used. Such a lower hydrocarbon group has 1 to 3 water-soluble substituents at substitutable positions,
For example, hydroxy, carboxy, amino, mono C
_1-6 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino), diC _1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino) 5- or 6-membered cyclic amino (eg, pyrrolyl, piperidino, morpholino, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl), C _1-3 alkoxy-C _1-3 alkyl (eg, methoxymethyl , Ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl), sulfo, sulfino, phosphono, dihydroxyboryl and the like.

Examples of the lower hydrocarbon group represented by R ⁷ and R ⁸ which may have a substituent include lower hydrocarbon groups described in detail in R ¹ , R ² , R ⁴ and R ^5. The lower hydrocarbon group described above is used, and as the substituent that such a lower hydrocarbon group may have, the number of the substituents detailed in R ¹ , R ² , R ⁴ and R ⁵ is used. The same applies to R ⁷ and R ⁸ , but as R ⁷ and R ⁸ , especially a C _1-4 alkyl group (eg, methyl, ethyl, propyl, iso-propyl,
Butyl, tert-butyl) is preferred. Also, R ⁷ and R ⁸
Examples of the organic group having a water-soluble substituent represented by are amide, sulfamoyl, phosphoramide, with adjacent nitrogen atoms,

[Chemical 18] Are used. The heterocyclic ring formed by R ⁷ and R ⁸ together with the adjacent nitrogen atom is preferably a 5- to 8-membered nitrogen-containing heterocycle, for example, pyrrolidine, pyrroline, pyrrole, pyrazole, imidazole, piperidine. , Morpholine, dihydropyridine, tetrahydropyridine, N-methylpiperazine,
Among them, N-ethylpiperazine, azacycloheptane, azacyclooctane and the like are preferably used, and pyrrolidine and morpholine are preferable, and these heterocyclic rings have 1 to 1 substituents at the positions capable of substituting the water-soluble substituent as described for R ⁶ ′. You may have three.

When R ⁷ and R ⁸ are hydrogen atoms, that is, when Y is an amino group, the amino group may be protected by a protector. Examples of the protecting group include "protective group". In Organic Synthesis ”(protective group in organic synthesis) [T.
W. Greene (A Wiley-interscience)], for example, a formyl group, an acetyl group,
Examples include chloroacetyl group, trifluoroacetyl group, benzoyl group, phthaloyl group, 2,2,2-trichloroethyloxycarbonyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group and 7-fluorenyloxycarbonyl group. And preferably t
An ert-butyloxycarbonyl group, a benzyloxycarbonyl group, a trifluoroacetyl group and the like can be mentioned. i and j each represent an integer of 1 to 3.

Next, a method for producing the compounds (I) and (II) of the present invention or a salt thereof will be described. Compound of the present invention (I)
And (II) or a salt thereof can be obtained by subjecting compound (III) or a salt thereof to a radical reaction with compound (IV) or a salt or reactive derivative thereof. As a means of radical reaction, when Z of compound (IV) is a hydrogen atom,
It can be carried out by adding a peroxide in the presence of a strong acid (eg, concentrated sulfuric acid, trifluoroacetic acid, etc.) and generating a radical by a thermal or photoreaction to convert the compound (IV) into a radical. The amount of compound (IV) used is generally about 1 to 200 mol, preferably about 5 to 50 mol, relative to compound (III). As a peroxide,
Examples thereof include benzoyl peroxide and m-chlorobenzoyl peroxide, and they are usually used in an amount of about 1 to 20 mol, preferably about 2 to 5 mol, relative to compound (III) or a salt thereof. This reaction is a compound
(IV) itself may be used as a solvent, or may be carried out in the presence of an appropriate solvent. Examples of the solvent include
Water, alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg, acetonitrile), acetone,
Nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane or a solvent in which these are appropriately mixed is used. As the photoreaction for generating radicals from the peroxide, for example, UV irradiation by a high pressure or low pressure mercury lamp is used, and the reaction temperature in the thermal reaction is, for example, about 20 ° C. to about the boiling point of the reaction solvent (about 150 ° C.).
(Up to 0 ° C), preferably temperatures in the range of about 50 to 100 ° C are used. The reaction time in any reaction is usually in the range of about 0.5 to 100 hours, preferably about 1 to 20 hours.

When Z of compound (IV) is CH ₂ OH, CHO or COOH, it can be carried out in the presence of a metal ion using sulfuric acid, water and a peroxide. The amount of compound (IV) or a salt thereof used is generally about 1 to 100 mol, preferably about 2 to 4 mol, based on compound (III) or a salt thereof.
It is 0 mol. The metal ion may be used generally in an amount of about 1 to 25 mol, preferably about 1 to 5 mol, based on the compound (III) or a salt thereof. Examples of the metal ion include ferrous salts such as ferrous sulfate and ferrous chloride. Examples of the peroxide include hydrogen peroxide, tert-butyl hydroperoxide, etc., and usually about 1 to 20 mol, preferably about 2 to 5 mol, relative to compound (III) or a salt thereof. Used to a degree. This reaction is preferably carried out in the presence of an appropriate solvent, and examples of the solvent include water, alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, Monoglyme, diglyme), nitriles (eg, acetonitrile), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. The reaction temperature is
Usually about -10 ° C to the boiling point of the reaction solvent (about 100 ° C)
The reaction time is usually 0.5 to 100 hours, preferably about 1 to 20 hours.

The compounds (I) and (II) of the present invention or a salt thereof can also be produced by introducing a hydroxy group into the compound (V) or a salt thereof. The reaction for introducing a hydroxy group into compound (V) or a salt thereof can be usually carried out by reacting a metal ion with oxygen (air) or a peroxide in the presence of a base. The metal ion is a compound (V)
Alternatively, it is generally used in an amount of about 0.2 to 50 mol, preferably about 1 to 10 mol, based on the salt thereof. Examples of the metal ions include cupric salts such as cupric chloride and cupric nitrate. Base is a compound
It is generally used in an amount of about 1 to 20 mol, preferably about 1 to 5 mol, based on (V). Examples of the base include metal bases (eg, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate). ), Primary amines (eg, methylamine,
Ethylamine, propylamine), secondary amines (eg, dimethylamine, diethylamine, dipropylamine),
Tertiary amine (eg, trimethylamine, triethylamine, triethanolamine) pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylamino pyridine, 4- (1-pyrrolidinyl) pyridine,
Examples thereof include N, N-dimethylaniline and N, N-diethylaniline.

Examples of the peroxide include hydrogen peroxide and tertiary butyl hydroperoxide.
Usually, it is used in an amount of about 1 to 20 mol, preferably about 2 to 5 mol, relative to compound (V) or a salt thereof.
This reaction is preferably carried out in the presence of an appropriate solvent, and examples of the solvent include water, alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, Monoglyme, diglyme), nitriles (eg, acetonitrile), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. The reaction temperature is, for example, about -20 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about -10 to 50 ° C.
A temperature in the range of is used, and the reaction time is usually in the range of about 1 to 100 hours, preferably about 5 to 48 hours.

In the compounds (I) and (II) or salts thereof, hydroxy, carboxy, amino, mono-C _1-6 alkylamino (as a substituent of R ¹ , R ² , R ⁴ , R ⁵ or Y ( (Eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino), piperidino, sulfo, sulfino, phosphono, dihydroxyboryl, and the like, or a salt thereof, in the case of producing a compound (III) or (IV) ) Or a salt thereof with these substituents protected by a protecting group known per se and then reacted, and then subjected to a deprotection reaction known per se to produce the desired compounds (I) and (II) or a salt thereof. You can also do it. The starting compounds (III), (IV) and (V) or salts thereof can be produced according to a method known in the literature [WD Kingsbury et al., J. Med. Chem.,
34 , 98 (1991); JP-A-2-138186; JP-A-3-
232888; EP-418099-A]. Each of the intermediates of the compound of the present invention produced by the above method and the compounds (I) and (II) of the present invention can be isolated by a conventional separation means such as concentration, solvent extraction,
It can be isolated from the reaction mixture by chromatography, recrystallization and the like.

Raw materials (III), (IV), (V) of the production method of the present invention
The resulting target compounds (I) and (II) may form a salt. As the salt with a base, for example, an alkali metal, alkaline earth metal, non-toxic metal, ammonium or substituted ammonium is used, and specifically, for example, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium. , Trimethylammonium, triethylammonium, triethanolammonium, pyridinium, substituted pyridinium and the like. Examples of salts with acids include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. A salt with an organic acid such as sulfonic acid or camphorsulfonic acid is used.

[0024]

The compounds (I) and (II) or salts thereof of the present invention are
Shows an inhibitory effect on enzymes involved in topoisomerism in nucleic acid synthesis (topoisomerase I inhibitory effect),
It also has a growth inhibitory effect on tumor cells. Therefore,
These compounds can be used alone or in combination with other antitumor agents for the purpose of treating various tumors. For example, the compounds (I) and (II) of the present invention or a pharmacologically acceptable salt thereof can be used in the mouse tumor cell line system (P388, L121).
0, L5178Y, B16 melanoma, MethA, LewisLung Carcinom
a, S180 sarcoma, Erhlich Carcinoma, Colon26 and
38), and human tumor cell line lines (A549, HL60, KB
Tumors of warm-blooded animals [eg, leukemia, melanoma, sarcoma, mastocytoma].
cytoma), carcinoma (carcinoma), neoplasia (neoplasia)]
It can be used as a safe antitumor agent for treating tumors of warm-blooded animals, especially mammals (eg, humans, mice, rats, cats, dogs, rabbits, etc.).

When used as an antitumor agent, the compounds (I) and (II) or salts thereof are used per se or in a pharmaceutically acceptable carrier, excipient, diluent or the like according to a commonly used method. Then, it can be administered orally or parenterally in the form of powder, granules, tablets, capsules, suppositories, injections and the like. The dose depends on the target animal,
Depending on the disease, symptoms, type of compound, administration route, etc., for example, in the case of oral administration, the compound of the present invention is used in the above-mentioned warm-blooded animal at about 1.0 to 500 mg / kg, preferably 10.0 to 200, per day. mg / kg body weight, about 1.0 to 200 mg / day for parenteral administration,
It is preferably 5.0 to 100 mg / kg. The method of administration as an injection includes intramuscular injection, intraperitoneal injection,
Subcutaneous injection, intravenous injection, etc. are used.

The above-mentioned formulation is carried out according to a method known per se. When producing the above oral preparations, for example, tablets, binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrants (eg, starch, carboxymethylcellulose calcium, etc.), lubricants (eg. , Magnesium stearate, talc, etc.) can be appropriately mixed. In addition, when a parenteral preparation such as an injection is produced, a tonicity agent (eg, glucose, D-sorbitol, D-
Mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.)
And the like can be appropriately mixed.

As a specific example of the production of tablets, for example, the amount of the compound of the present invention is about 1.0 to 50 m per tablet.
g, lactose about 100 to 500 mg, corn starch about 5
0 to 100 mg, hydroxypropyl cellulose about 5
To 20 mg are mixed by a conventional method, granulated, mixed with cornstarch and magnesium stearate, and compressed into tablets, about 100 to 500 mg per tablet, diameter about 3 to 1
Use 0 mm tablets. In addition, as the amount of each tablet used, hydroxypropylmethylcellulose phthalate (about 10 to 20 mg) and castor oil (about 0.5 to 2.0 mg) were dissolved to a concentration of about 5 to 10%. It is also possible to obtain an enteric coated tablet by coating with an acetone-ethanol mixed solution. As a specific example of the preparation of the injection, for example, as a use amount per ampoule, about 2.0 to 50 mg of sodium salt of the compound (I) of the present invention is dissolved in (1) about 2 ml of physiological saline. After injecting into the ampoule, it is sealed and it is about 1
Heat sterilize at 10 ° C for about 30 minutes, or (2) about 10 to 40 mg of mannitol or sorbitol in about 2 ml.
It can also be adjusted by dissolving it in a sterilized distilled water solution, then injecting it into an ampoule, lyophilizing it and sealing it. For use of the lyophilized injection, the ampoule is opened at the time of use and, for example, physiological saline is injected and dissolved at a compound concentration of about 1.0 to 50 mg / ml to give a solution, which is subcutaneously, intravenously or intramuscularly administered. Can be given.

[0028]

EXAMPLES The present invention will be specifically described below with reference to Examples and Examples.

Reference Example 1 7-Ethyl-10H-1,3-dioxolo [4,5-
g] pyrano [3 ', 4': 6,7] indolizino [1,2
-B] quinoline-8,11 [7H, 13H] -dione 4-ethyl-7,8-dihydro-1H-pyrano [3,4
-F] indolizine-3,6,10 (4H) -trione (J. Med. Chem., Vol. 23, 554-560 (1980)) 1,5-
Dioxo (5'-ethyl-2'H, 5'H, 6'H-6
-Oxopyrano) [3 ', 4'-f] -Δ ^{6 (δ)} -tetrahydroindolizine 300 mg was dissolved in acetic acid 12 ml,
200 mg of 2-amino-4,5-methylenedioxybenzaldecht (J. Chem. Soc., 1736 (1951)) was added, and 8
The mixture was stirred at 5 ° C for 20 hours. The reaction solution was concentrated, the residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of chloroform-methanol (100: 1),
170 mg of the title compound are obtained. ¹ H NMR (CDCl ₃ ) 1.09 (3H, t, J = 7.4Hz), 2.10 (2H, m), 3.61 (1H, t, J = 6.4H)
z), 5.25 (2H, s), 5.39 (1H, d, J = 15.2Hz), 5.58 (1H, d, J
= 15.2Hz), 6.19 (2H, s), 7.08 (1H, s), 7.19 (1H, s), 7.3
3 (1H, s), 7.48 (1H, s) .IRmax ^KBr (cm ^-1 ) 1740, 1655, 1600.

Reference Example 2 7-Ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] -pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline -8, 11 [7H, 1
3H] - dissolving the compound 240mg obtained in dione Reference Example 1 in dimethyl formamide 75 ml, added C _u Cl ₂ 414 mg and 25% dimethylamine 0.81 ml, under an oxygen stream, and stirred for 24 hours at room temperature. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography and eluted with a mixed solvent of chloroform-methanol (100: 2) to give 54 mg of the title compound.
Got ¹ H NMR (CDCl ₃ ) 1.04 (3H, t, J = 7.3Hz), 1.92 (2H, q, J = 7.3Hz), 5.25 (2H,
s), 5.31 (1H, d, J = 16.5Hz), 5.76 (1H, d, J = 16.5Hz), 6.
21 (2H, s), 7.18 (1H, s), 7.51 (1H, s), 7.64 (1H, s), 8.21
(1H, s) .IRmax ^KBr (cm ^-1 ) 3400, 1748, 1660, 1600.

Reference Example 3 4 (S) -4-ethyl-4-hydroxy-11-trifluoroacetylaminomethyl-1H-pyrano [3 ',
4 ′: 6,7] Indolizino [1,2-b] -quinoline-3,14 [4H, 12H] -dione In the same manner as in Example 1, camptothecin (100 mg) and 2 were added.
The title compound (63 mg) was obtained from-(trifluoroacetylamino) acetaldehyde (403 mg). ¹ H NMR (DMSO-d ₆ ) 0.90 (3H, t, J = 7.0Hz), 1.89 (2H, q, J = 7.0Hz), 5.01 (2H,
d, J = 4.0Hz), 5.44 (2H, s), 5.46 (2H, s), 6.51 (1H, s),
7.37 (1H, s), 7.68−7.95 (2H, m), 8.20 (1H, d, J = 8.0Hz),
8.36 (1H, d, J = 8.2Hz), 10.10-10.30 (1H, m) .IRmax ^KBr (cm ^-1 ) 3430, 1720, 1655, 1600.

Reference Example 4 11-Benzyloxycarbonylaminomethyl-4
(S) -4-Ethyl-4-hydroxy-1H-pyrano [3 ', 4': 6,7] indolizino [1,2-b]-
Quinoline-3,14 [4H, 12H] -dione In the same manner as in Example 1, camptothecin (77 mg) and 2-
The title compound (73 mg) was obtained from (benzyloxycarbonylamino) acetaldehyde (384 mg). ¹ H NMR (CDCl ₃ ) 1.04 (3H, t, J = 7.6Hz), 1.93 (2H, q, J = 7.6Hz), 4.92 (2H,
d, J = 6.0Hz), 5.11 (2H, s), 5.30 (1H, d, J = 16.6Hz), 5.4
4 (2H, s), 5.70 (1H, d, J = 16.6Hz), 6.94 (1H, t, J = 6.0H
z), 7.34 (5H, s), 7.71 (1H, s), 7.61−7.88 (2H, m), 8.13
-8.31 (2H, m) .IRmax ^KBr (cm ^-1 ) 3400, 1745, 1720, 1655, 1595.

Reference Example 5 11-Aminomethyl-4 (S) -4-ethyl-4-hydroxy-1H-pyrano [3 ', 4': 6,7] indolidino [1,2-b] -quinoline-3 , 14 [4H, 12
H] -Dione To a solution of the compound of Reference Example 3 (70 mg) in acetic acid (1.5 ml) was added 47% aqueous hydrogen bromide (0.3 ml), and the mixture was stirred at 100 ° C. for 3 hours. After allowing to cool, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, extracted with chloroform, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the title compound (26 mg). Alternatively, the title compound (16 mg) was obtained from the compound of Reference Example 4 (22 mg) in the same manner as above. ¹ H NMR (DMSO-d ₆ ) 0.91 (3H, t, J = 7.0Hz), 1.89 (2H, q, J = 7.0Hz), 4.46 (2H,
s), 5.38−5.56 (4H, m), 6.43−6.52 (1H, m), 7.37 (1H,
s), 7.64-8.38 (4H, m), 8.20 (1H, d, J = 8.0Hz), 8.36 (1
H, d, J = 8.2Hz), 10.10-10.30 (1H, m) .IRmax ^KBr (cm ^-1 ) 3400, 1750, 1655, 1600.

Reference Example 6 11-Aminomethyl-4 (S) -4-ethyl-4-hydroxy-1H-pyrano [3 ', 4': 6,7] indolidino [1,2-b] -quinoline-3 , 14 [4H, 12
[H] -dione / hydrochloride salt To the compound (5 mg) of Reference Example 5 was added 20% hydrochloric acid-ethanol solution (1 ml), the mixture was stirred at room temperature for 5 hours, and the reaction mixture was concentrated to give the title compound (5 mg). It was ¹ H NMR (DMSO-d ₆ ) 0.90 (3H, t, J = 7.4Hz), 1.89 (2H, q, J = 7.4Hz), 4.58-4.
86 (2H, m), 5.45 (2H, s), 5.65 (2H, s), 7.38 (1H, s), 7.75
−8.00 (2H, m), 8.25 (1H, d, J = 8.2Hz), 8.45 (1H, d, J = 8.
4Hz), 8.62-8.82 (3H, m) .IRmax ^KBr (cm ^-1 ) 3430, 1740, 1650, 1600.

Example 1 14- (Nt-butoxycarbonylamino) methyl-
7-Ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] pyrano [3 ′, 4 ′: 6,7] indolidino [1,2-b] quinoline-8,11 [7H, Thirteen
80 mg of [H] -dione FeSO ₄ .7H ₂ O was dissolved in 2 ml of water, and
100 mg of-(Nt-butoxycarbonyl) aminoacetaldehyde was added, 20 mg of the compound obtained in Reference Example 2 and 1.3 ml of acetic acid were suspended, and 0.27 ml of concentrated sulfuric acid was further added to dissolve. Under ice cooling, 30% H ₂ O _{2 (} 15 mg) was slowly added dropwise, and then the mixture was stirred at room temperature for 1 hour. The reaction solution is ice water 1
It was poured into 0 ml and extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 8 mg of the title compound. ¹ H NMR (CDCl ₃ + CD ₃ OD) 1.03 (3H, t, J = 7.4Hz), 1.48 (9H, s), 1.91 (2H, q, J = 7.4H)
z), 4.75 (2H, d, J = 7.1Hz), 5.27 (1H, d, J = 17.4Hz), 5.
29 (2H, s), 5.68 (1H, d, J = 17.4Hz), 6.21 (2H, s), 7.42 (1
H, s), 7.46 (1H, s), 7.56 (1H, s) .IRmax ^KBr (cm ^-1 ) 3400, 1750-1730, 1660, 1600.

Example 2 14-Aminomethyl-7-ethyl-7-hydroxy-1
OH-1,3-Dioxolo [4,5-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-8,11 [7H, 13H] -dione trifluoroacetic acid Salt 8 mg of the compound obtained in Example 1 was suspended in 1 ml of CH ₂ Cl ₂ , 0.1 ml of CF ₃ COOH was added dropwise, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in water and freeze-dried to obtain 6 mg of the title compound. ¹ H NMR (D ₂ O) 0.71 (3H, t, J = 7.3Hz), 1.72 (2H, q, J = 7.3Hz), 4.50-5.
45 (6H, m), 6.21 (2H, s), 6.69 (1H, s), 7.02 (1H, s), 7.13
(1H, s).

Example 3 14- (Nt-butoxycarbonylamino) ethyl-
7-Ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] pyrano [3 ′, 4 ′: 6,7] indolidino [1,2-b] quinoline-8,11 [7H, Thirteen
H] -Dione The compound (20 mg) of Reference Example 2 and 3 were prepared in the same manner as in Example 1.
The title compound (9 mg) was obtained from-(Nt-butoxycarbonylamino) propionaldehyde (150 mg). ¹ H NMR (CDCl ₃ + CD ₃ OD) 1.03 (3H, t, J = 7.4Hz), 1.48 (9H, s), 1.91 (2H, q, J = 7.4H)
z), 3.30−4.11 (4H, m), 5.21 (2H, s), 5.28 (1H, d, J = 17.
4Hz), 5.74 (1H, d, J = 17.4Hz), 6.19 (2H, s), 7.42−7.66
(3H, m).

Example 4 14-Aminoethyl-7-ethyl-7-hydroxy-1
OH-1,3-Dioxolo [4,5-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-8,11 [7H, 13H] -dione trifluoroacetic acid Salt In the same manner as in Example 2, the title compound (4 mg) was obtained from the compound of Example 3 (6 mg). ¹ H NMR (D ₂ O) 1.03 (3H, t, J = 7.4Hz), 1.97 (2H, q, J = 7.4Hz), 3.30-4.
02 (4H, m), 5.31-6.01 (4H, m), 6.41 (2H, s), 7.58 (1H,
s), 7.63 (1H, s), 7.98 (1H, s).

Example 5 7-Ethyl-7-hydroxy-14- (N-trifluoroacetylamino) methyl-10H-1,3-dioxolo [4,5-g] pyrano [3 ', 4': 6,6] 7] Indolizino [1,2-b] quinoline-8,11 [7H, 13
H] -Dione In the same manner as in Example 1, the compound of Reference Example 2 (40 mg) and 2
The title compound (14 mg) was obtained from-(N-trifluoroacetylamino) acetaldehyde (600 mg). ¹ H NMR (CD ₃ OD + CDCl ₃ ) 1.03 (3H, t, J = 7.4Hz), 1.97 (2H, q, J = 7.4Hz), 4.81-5.
70 (6H, m), 6.22 (2H, s), 7.38−7.67 (3H, m).

Example 6 7-Ethyl-7-hydroxy-14-hydroxymethyl-10H-1,3-dioxolo [4,5-g] pyrano [3 ', 4': 6,7] indolizino [1,2] -B] quinoline-8,11 [7H, 13H] -dione The compound (20 mg) of Reference Example 2 was dissolved in 10 ml of methanol, and 0.15 ml of concentrated sulfuric acid and 30 mg of benzoyl peroxide were added thereto, and the mixture was heated at 70 ° C for 9 hours. It was stirred. The reaction solution was poured into 10 ml of ice water and extracted with chloroform. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (10: 1) to give the title compound (7 mg). ¹ H NMR (CD ₃ OD + CDCl ₃ ) 1.01 (3H, t, J = 7.4Hz), 1.97 (2H, q, J = 7.4Hz), 5.21-5.
80 (6H, m), 6.20 (2H, s), 7.18−7.67 (3H, m).

Example 7 14- (N-benzyloxycarbonylamino) methyl-7-ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] pyrano [3 ', 4': 6 7] Indolizino [1,2-b] quinoline-8,11 [7H, 1
3H] -Dione In the same manner as in Example 1, the title compound (54 mg) was obtained from the compound of Reference Example 2 (150 mg) and 2- (N-benzyloxycarbonylamino) acetaldehyde (1.43 g). ¹ H NMR (CD ₃ OD + CDCl ₃ ) 1.03 (3H, t, J = 7.4Hz), 1.91 (2H, q, J = 7.4Hz), 4.72-4.
83 (2H, m), 5.11 (2H, s), 5.28 (1H, d, J = 16.2Hz), 5.33 (2
H, s), 5.66 (2H, d, J = 16.2Hz), 6.21 (2H, s), 6.91−7.08
(1H, m), 7.34 (5H, s), 7.45 (1H, s), 7.52 (1H, s), 7.58 (1
H, s) .IRmax ^KBr (cm ^-1 ) 3400, 1710, 1650.

Example 8 14- (N-benzyloxycarbonylamino) ethyl-7-ethyl-7-hydroxy-10H-1,3-dioxolo [4,5-g] pyrano [3 ', 4': 6 7] Indolizino [1,2-b] quinoline-8,11 [7H, 1
3H] -dione The compound (43 mg) of Reference Example 2 and 2 were prepared in the same manner as in Example 1.
The title compound (26 mg) was obtained from-(N-benzyloxycarbonylamino) propionaldehyde (125 mg). ¹ H NMR (DMSO-d ₆ ) 0.88 (3H, t, J = 7Hz), 1.87 (2H, q, J = 7Hz), 3.10-4.21 (4
H, m), 4.96 (2H, s), 5.23 (2H, s), 5.43 (2H, s), 6.28 (2H,
s), 6.50 (1H, s), 7.17−7.68 (8H, m).

Example 9 14-Aminoethyl-7-ethyl-7-hydroxy-1
OH-1,3-Dioxolo [4,5-g] pyrano [3 ', 4': 6,7] indolidino [1,2-b] quinoline-8,11 [7H, 13H] -dione hydrochloride The compound of Example 3 (1.0 g) was suspended in 180 ml of methanol, 30 ml of a 4N hydrochloric acid-ethyl acetate solution was added under ice cooling, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and the obtained crude crystals were recrystallized from methanol-diethyl ether to obtain 0.8 g of the title compound as a yellow powder. ¹ H NMR (CD ₃ OD) 0.99 (3H, t, J = 7.3Hz), 1.95 (2H, q, J = 7.3Hz), 3.30-3.
33 (2H, m), 3.43−3.48 (2H, m), 5.26 (2H, s), 5.37 (1H, d,
J = 16.0Hz), 5.58 (1H, d, J = 16.0Hz), 6.24 (1H, s), 6.26
(1H, s), 7.44 (1H, s), 7.52 (1H, s), 7.53 (1H, s). IRmax ^KBr (cm ⁻¹ ) 3450, 173
0, 1655

[0044]

[Formulation example]

Formulation Example 1, Injection The compound of Example 9 is dissolved in distilled water, and the powder obtained by freeze-drying the filtrate obtained by filtration is aseptically sealed in vials in 25 mg increments, sealed, and protected from light after shielding. save.

Formulation Example 2, Tablet Compound of Example 2 25 mg Lactose 98 mg Hydroxypropyl cellulose 3 mg Crystalline cellulose 20 mg Talc 2 mg Magnesium stearate 2 mg The above ingredients were taken and directly compressed into a tablet using a mixing tableting machine to obtain a weight of 15
Make a 0 mg tablet.

[0046]

[Experimental Example] [Table 1] shows the experimental results concerning the topoisomerase I inhibitory action of this compound or a salt thereof. Measurement method: pBR322 DNA (manufactured by Wako Pure Chemical Industries, Ltd.) 0.5 μ
20 μl of buffer [35 mM Tris hydrochloride (p
H8.0), 72 mM KCl, 5 mM MgCl ₂ ,
5 mM dithiothreitol, 5 mM spermidine, 0.
[01% bovine serum albumin] was reacted with 1 unit of calf thorax-derived DNA topoisomerase I (Takara Shuzo), 5 μM concentration of camptothecin, topotecan, and the compound of Example 9 at 37 ° C. for 30 minutes. This reaction solution was analyzed by gel electrophoresis using 0.7% agarose according to a conventional method, and the enzyme activity was determined using the decrease in supercoiled DNA as an index.

[Table 1] -: Negative inhibitory effect +: Positive inhibitory effect positive Camptothecin: Camptothecin

[Chemical 19] Topotecan: Topotecan

[Chemical 20] From Table 1, the compound of the present invention or a salt thereof is superior to camptothecin or topotecan in topoisomerase I.
It can be seen that it has an inhibitory effect.

[0047]

The present invention provides a novel antitumor agent having excellent effects.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 498/22 8415-4C 513/22 8415-4C

Claims (26)

[Claims] 1. A general formula: A lower hydrocarbon group which may have a substituent) or a methylene group which may have a substituent, i represents an integer of 1 to 3, and R ¹ and R ² are each a repeating number of i. It may be different. ] The compound or its salt represented by these. 2. A general formula: A hydrogen atom or a lower hydrocarbon group which may have a substituent) or a methylene group which may have a substituent,
Is —OR ⁶ (R ⁶ is a hydrogen atom or an organic group having a water-soluble substituent) or (R ⁷ and R ⁸ are the same or different and each is a hydrogen atom, an optionally substituted lower hydrocarbon group or an organic group having a water-soluble substituent, or a heterocyclic ring with an adjacent nitrogen atom. I and j each represent an integer of 1 to 3, and R ¹ , R ² , R ⁴ and R ⁵ may be different from each other in i or j repetitions. ] The compound or its salt represented by these. 3. The compound according to claim 1, wherein the aliphatic hydrocarbon group is a linear or branched C _1-6 alkyl group. 4. The compound according to claim 1, wherein the lower alkyl group is a C _1-6 alkyl group. 5. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸
The lower hydrocarbon group which may have a substituent is represented by halogen, nitro, cyano, hydroxy, carboxy, carbamoyl, N-monoC _1-6 alkylcarbamoyl, N, N-diC _1-6 Alkylcarbamoyl, C _1-6 alkoxy, phenoxy, benzyloxy, amino, mono C
_1-6 alkylamino, diC _1-6 alkylamino, trifluoromethyl, C _1-5 alkanoyl, C _1-3 alkoxy-C
_1-3 alkyl, C _1-6 alkylthio, sulfamoyl, N
-Mono C _1-6 alkylsulfamoyl, N, N-diC _1-6
Alkylsulfamoyl, C _1-6 alkylsulfinyl and C _1-6 1 no selected from alkylsulfonyl to 3 substituents substituted C _1-6 alkyl, C _2-6
Alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl,
The compound according to claim 1 or 2, which is a phenyl or benzyl group. 6. A methylene group which may have a substituent,
Halogen, nitro, cyano, hydroxy, carboxy,
Carbamoyl, N-mono C _1-6 alkylcarbamoyl,
N, N-diC _1-6 alkylcarbamoyl, C _1-6 alkoxy, phenoxy, benzyloxy, amino, mono C _1-6
Alkylamino, di-C _1-6 alkylamino, trifluoromethyl, C _1-5 alkanoyl, C _1-3 alkoxy-C
_1-3 alkyl, C _1-6 alkylthio, sulfamoyl, N
-Mono C _1-6 alkylsulfamoyl, N, N-diC _1-6
The compound according to claim 1 or 2, which is a methylene group optionally having 1 to 3 substituents selected from alkylsulfamoyl, C _1-6 alkylsulfinyl or C _1-6 alkylsulfonyl. 7. The organic group having a water-soluble substituent represented by R ⁶ is, R ⁶ ', COR ^6' or CONHR ⁶ '(R ^6' is hydroxy, carboxy, amino, mono-C _1-6 alkylamino, Di C _1-6 alkylamino having 1 to 3 substituents selected from 5- or 6-membered cyclic amino, C _1-3 alkoxy-C _1-3 alkyl, sulfo, sulfino, phosphono or dihydroxyboryl A C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl or benzyl group.
The described compound. 8. The heterocyclic ring is hydroxy, carboxy, amino, mono C _1-6 alkylamino, di C _1-6 alkylamino, 5- or 6-membered cyclic amino, C _1-3 alkoxy-C.
_1-3 alkyl, sulfo, sulfino, phosphono and dihydroxyboryl pyrrolidine optionally having 1 to 3 substituents, pyrroline, pyrrole,
Pyrazole, imidazone, piperidine, morpholine,
The compound according to claim 2, which is dihydropyridine, tetrahydropyridine, N-methylpiperazine, N-ethylpiperazine, azacyclopeptane or azacyclooctane. 9. Y is --OR ^6a , --OCOR ^6a or --OC.
ONHR ^6a [R ^6a is (1) a hydrogen atom or (2) hydroxy, carboxy, amino, mono-C _1-6 alkylamino, 5- or 6-membered cyclic amino, C _1-3 alkoxy-C
_1-3 alkyl, sulfo, sulfino, phosphono, and C _1-6 alkyl _optionally having 1 to 3 substituents selected from dihydroxyboryl, C _2-6 alkenyl,
C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl or benzyl group is shown. ] The compound of Claim 2 which is this. 10. Y is --NH ₂ , --NHCOR ^6a or-
NHCOOR ^6a (R ^6a has the same meaning as in claim 9)
The compound according to claim 2, which is 11. R ¹ and R ² are the same or different and are a hydrogen atom or a C _1-3 alkyl group, and X ¹ and X ² are the same or different and are —O—, —S— or —NH—, i The compound according to claim 1 or 2, wherein is 1 or 2, and j is an integer of 1 to 3. 12. The compound according to claim 1 or 2, wherein R ¹ and R ² are both hydrogen atoms, X ¹ and X ² are both —O—, j is 1 or 2, and i is 1. 13. R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or a C _1-3 alkyl group, and Y is —OH, —NH ₂ , —
NHCOR ^6a or —NHCOOR ^6a (wherein R ^6a is claim 9).
The same meaning as described above). 14. The compound according to claim 13, wherein R ⁴ and R ⁵ are both hydrogen atoms. 15. The compound according to claim 14, wherein Y is a hydroxyl group or an amino group. 16. The compound according to claim 2, wherein Y is an optionally protected amino group. 17. A general formula: [Wherein R ⁰ , R ¹ , R ² , X ¹ , X ² and i are defined as
And 2 have the same meaning as described above. ] The compound or its salt represented by these, and general formula, [In the formula, R'has the same meaning as in claim 1 and Z represents a hydrogen atom, CH ₂ OH, CHO or COOH. ] The compound represented by these, or its salt or reactive derivative is made to react, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 18. A general formula: [The symbols in the formulas have the same meaning as in claim 1. ] The hydroxy group is introduce | transduced into the compound represented by these, or its salt, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 19. A topoisomerase I inhibitory activator containing the compound according to claim 1 or 2. 20. An antitumor composition containing the compound according to claim 1 or 2. 21. 14-Aminomethyl-7-ethyl-7-
Hydroxy-10H-1,3-dioxolo [4,5-
g] pyrano [3 ', 4': 6,7] indolizino [1,
The compound according to claim 1, which is 2-b] quinoline-8,11 [7H, 13H] -dione or a trifluoroacetic acid salt thereof. 22. 14-Aminoethyl-7-ethyl-7-
Hydroxy-10H-1,3-dioxolo [4,5-
g] pyrano [3 ', 4': 6,7] indolizino [1,
The compound according to claim 1, which is 2-b] quinoline-8,11 [7H, 13H] -dione or a trifluoroacetic acid salt thereof. 23. 7-Ethyl-7-hydroxy-14-hydroxymethyl-10H-1,3-dioxolo [4,5]
-G] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-8,11 [7H, 13H]-
The compound according to claim 1, which is a dione. 24. 14-Aminoethyl-7-ethyl-7-
Hydroxy-10H-1,3-dioxolo [4,5-
g] pyrano [3 ', 4': 6,7] indolizino [1,
The compound according to claim 1, which is 2-b] quinoline-8,11 [7H, 13H] -dione or a hydrochloride thereof. 25. The compound according to claim 1, wherein the absolute configuration of the substituent R ⁰ on the lactone ring is S configuration. 26. The compound according to claim 1 or 2, which is a racemic mixture.