JPH1171280A - Medicine composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition using a drug delivery system, excellent in antitumor action, reduced in adverse effects, useful as a therapeutic agent for solid tumors, by including a specific camptothecin as an active ingredient. SOLUTION: This composition comprises a camptothecin derivative in which R<6> of a camptothecin of formula I (R<1> to R<5> have a combination in which adjoining two groups of R<1> to R<5> form an alkylene or are two hydrogen atoms, one of the residue is Xn -alkylm -R<6> and the residual two groups are H, etc.; X is O or the like; Alkyl is an alkylene; R<6> is NH2 or the like; (m) and (n) are each 0 or 1) is bonded through an amino acid or a peptide to a carboxyl group- containing polysaccharide or its pharmacologically permissible salt [e.g. a compound of the formula (CM-Dextra.Na is carboxymethyldextran.sodium salt; Gly is glycyl; Phe is phenylalanine)] as an active ingredient. Preferably the objective composition is parenterally administered.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition comprising a novel camptothecin derivative showing enhanced antitumor activity as an active ingredient. More specifically, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a novel camptothecin derivative obtained by binding a camptothecin compound having an aminoalkoxy group or a hydroxyalkoxy group to a polysaccharide having a carboxyl group via an amino acid or a peptide. About. The camptothecin derivative, which is an active ingredient of the present invention, is delivered to a target action site in a large amount and selectively, and can exert a desired pharmacological action at the site, and has an antitumor effect possessed by the camptothecin compound And its side effects are reduced, making it extremely useful as a pharmaceutical.

[0002]

BACKGROUND OF THE INVENTION Camptothecin is a plant alkaloid and has the following chemical structural formula:

[0003]

Embedded image

[0004] It is known to have anti-leukemic and anti-tumor effects, and its derivative, irinotecan hydrochloride (CPT-11), is already commercially available. However, while this compound shows strong antitumor activity in clinical practice, it has strong side effects like other antitumor agents and the like, and its use is restricted [cancer and chemotherapy,
21, 709 (1994)].

[0005] It has also been reported that various camptothecin compounds have been synthesized and have antitumor activity (Japanese Patent Application Laid-Open Nos. 1-279891 and 5-2204).
8, JP-A-6-87746, JP-A-6-22814
No. 1, Tokiohei 4-503505, Tokiohei 4-5020
No. 17).

[0006] On the other hand, in order to increase the antitumor activity and suppress the side effects of such drugs having a strong side effect as much as possible, in recent years, a so-called drug delivery system (hereinafter referred to as a drug delivery system) which delivers a necessary amount of the drug to a necessary tissue has been proposed. The technology of Drug Delivery System) is being studied. In particular, in cancer chemotherapy, there is a problem that a sufficient difference in anticancer drug sensitivity cannot be obtained between tumor cells and normal cells, and a targeted drug delivery system for selectively delivering an anticancer drug to a cancer lesion. Research has been actively conducted, for example, doxorubicin-polysaccharide complex (WO 94/19376), doxorubicin-encapsulated liposomes [enhancement of effect of anticancer agent and targeting therapy (published by Science Forum Co., Ltd.), p. 227 (1987) Dextran-bound mitomycin [enhancement of anticancer drug effect and targeting therapy (published by Science Forum Co., Ltd.), p. 278 (1987)] and the like.

[0007]

As described above, the camptothecin compound has an excellent antitumor effect and is extremely useful as a medicament, but has the problem that its use is severely restricted due to its strong side effects. is there. The present invention provides a pharmaceutical composition comprising, as an active ingredient, a novel camptothecin derivative which suppresses the occurrence of undesired side effects while maintaining its excellent drug activity.

[0008]

The present invention relates to a pharmaceutical composition comprising, as an active ingredient, a camptothecin derivative comprising a camptothecin compound having a reactive group and a polysaccharide having a carboxyl group bound via an amino acid or a peptide.

That is, the following general formula having an aminoalkoxy group, a hydroxyalkoxy group, etc.

[0010]

Embedded image

[In the formula, R ^{1 to} R ⁵ are (A) two adjacent R ^{1 to} R ⁵ are bonded to each other to form an alkylene group, or both are hydrogen atoms; R ¹
One of to R ⁵ is a -X _n -Alk _m -R ^6, another 2
One is a hydrogen atom, or (B) two of R ^{1 to} R ⁵ are bonded to each other to form an alkylene group, and -X _n-
Alk _m and -R ⁶ are substituted, indicates that the remaining three of R ¹ to R ⁵ is a hydrogen atom, an alkyl group or a halogen atom, in the alkylene group in (A) and (B) 1
One or two methylene groups are -O-, -S- or -N
May be replaced by H-, and X is -O- or-
NH-, Alk is an alkylene group, and R ⁶ is-
NH ₂ ,

[0012]

Embedded image

Or --OH, m and n are both 0
Or 1 or m is 1 and n is 0] is a camptothecin derivative wherein R ^{6 of the} camptothecin compound [I] and a polysaccharide having a carboxyl group are bonded via an amino acid or a peptide; It was found to have remarkably strong antitumor activity and low toxicity.

An object of the present invention is to provide a pharmaceutical composition comprising as an active ingredient a novel camptothecin derivative obtained by binding a camptothecin compound represented by the formula [I] and a polysaccharide having a carboxyl group via an amino acid or a peptide. To provide.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of the camptothecin derivative as an active ingredient of the present invention include a camptothecin compound [I] and a polysaccharide having a carboxyl group bonded via an amino acid or a peptide.
As a specific example, a part or all of the carboxyl group of the polysaccharide and the amino group of the amino acid or the peptide are in an acid amide bond, and all or a part of the carboxyl group of the amino acid or the peptide and R ^{6 of the} compound [I] are Can be exemplified by a compound having an acid amide bond or an ester bond. More specifically, a part or all of the carboxyl group of the polysaccharide and the N-terminal amino group of the amino acid or the peptide are an acid amide bond, and the amino acid or the amino acid Compounds in which the C-terminal carboxyl group of the peptide and R ⁶ of compound [I] have an acid amide bond or an ester bond can be mentioned.

Each substituent in the compound represented by the formula [I] includes the following groups.

The adjacent two of R ^{1 to} R ⁵ in FIG.
As an alkylene group formed by bonding one to another (one or two methylene groups may be replaced by —O—, —S— or —NH—), in the general formula [I], A linear or branched alkylene group having 2 to 6 carbon atoms (e.g., an ethylene group, a trimethylene group, a tetramethylene group) formed at the 9-position, the 9-position, the 10-position, the 10-position and the 11-position, or the 11-position and the 12-position; Group, pentamethylene group, hexamethylene group, methylmethylene group, methylethylene group, methyltrimethylene group).

The alkylene group in which one methylene group in the alkylene group is replaced by -O-, -S- or -NH- includes a methylene group at the terminal and a methylene group other than the terminal.
Alkylene groups in which two methylene groups are replaced by -O-, -S- or -NH-, and specifically, a compound represented by the formula-
O-Alk'- (where "Alk '" means an alkylene group; the same applies hereinafter) (e.g., methyleneoxy, ethyleneoxy, trimethyleneoxy, tetramethyleneoxy, Alkyleneamino group represented by formula -NH-Alk'- (for example, methyleneamino group, ethyleneamino group, trimethyleneamino group, tetramethyleneamino group, methylethyleneamino group); Alk '
An alkylenethio group represented by-(for example, a methylenethio group, an ethylenethio group, a trimethylenethio group, a tetramethylenethio group, a methylethylenethio group);
O-Alk "-(where" Alk "is Alk '
Means the same or different alkylene group. The same applies hereinafter) represented by an alkyleneoxyalkyl group (for example,
A methyleneoxymethyl group, an ethyleneoxymethyl group, a trimethyleneoxymethyl group, a methylethyleneoxymethyl group); an alkyleneaminoalkyl group represented by the formula -Alk'-NH-Alk "-(for example, a methyleneaminomethyl group, ethylene An aminomethyl group, a trimethyleneaminomethyl group, a methylethyleneaminomethyl group);
and an alkylenethioalkyl group represented by lk'-S-Alk "-(for example, a methylenethiomethyl group, an ethylenethiomethyl group, a trimethylenethiomethyl group, a methylethylenethiomethyl group).

The alkylene group in which two methylene groups in the alkylene group are replaced by -O-, -S- or -NH- includes a terminal methylene group and a non-terminal methylene group.
Alkylene groups in which two methylene groups are replaced by -O-, -S- or -NH-, and specifically, a compound represented by the formula-
An alkylenedioxy group represented by O-Alk'-O- (for example, a methylenedioxy group, an ethylenedioxy group,
Trimethylenedioxy group, tetramethylenedioxy group,
A methylethylenedioxy group); a formula of —NH—Alk′—N
Alkylenediamino group represented by H- (for example, methylenediamino group, ethylenediamino group, trimethylenediamino group, tetramethylenediamino group, methylethylenediamino group); alkylenedithio group represented by formula -S-Alk'-S- (For example, methylenedithio group, ethylenedithio group, trimethylenedithio group, tetramethylenedithio group, methylethylenedithio group) and the like.

[0020] Formula The Alk in the group represented by -X _n -Alk _m -R ^6, straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms (e.g., methylene group, ethylene group, trimethylene group, tetramethylene Group, pentamethylene group,
Hexamethylene group, methylethylene group, and a methyltrimethylene group), the -X _n -Alk Specific examples of the group represented by _m -R ⁶ is, aminoalkyl group (e.g., aminoethyl group, amino Propyloxy group), piperazinylalkyloxy group (for example, piperazinylethyloxy group, piperazinylpropyloxy group, piperazinylbutyloxy group, piperazinylpentyloxy group), hydroxyalkyloxy group (for example,
Hydroxyethyloxy group, hydroxypropyloxy group, hydroxybutyloxy group, hydroxypentyloxy group), aminoalkylamino group (for example, aminoethylamino group, aminopropylamino group, aminobutylamino group, aminopentylamino group), pipet Radinylalkylamino group (for example, piperazinylethylamino group, piperazinylpropylamino group, piperazinylbutylamino group, piperazinylpentylamino group), hydroxyalkylamino group (for example, hydroxyethylamino group, hydroxy Propylamino group, hydroxybutylamino group, hydroxypentylamino group), aminoalkyl group (for example, aminomethyl group, aminoethyl group, aminopropyl group, aminobutyl group, aminopentyl group), piperazinyl group Group (for example, piperazinylmethyl group, piperazinylethyl group, piperazinylpropyl group, piperazinylbutyl group, piperazinylpentyl group), hydroxyalkyl group (for example, hydroxymethyl group, hydroxyethyl group, A hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group), an amino group, a piperazino group, and a hydroxy group.

Further, an alkylene group (1) formed by bonding two adjacent ones out of R ^{1 to} R ⁵ in (B)
One or two methylene groups are -O-, -S- or -N
A H- may be replaced by), -X _n -Alk _m -R ⁶ in any of the carbon atoms of the alkylene radical
Is a group substituted by 7 in the general formula [I].
And 9-position, 9-position, 10-position and 11-position or between 11-position and a C 2-6 linear or branched alkylene group (for example, ethylene group, trimethylene group, Tetramethylene group, pentamethylene group, hexamethylene group, methylethylene group, methyltrimethylene group), and one methylene group of the alkylene group is replaced by -O-, -S- or -NH-. Specific examples of the alkylene group in which the alkylene group and the two methylene groups are replaced by -O-, -S-, or -NH- include the same as those described above. Further, -X _n -Al substituted on one of these carbon atoms
k _m -R ⁶ are also illustrated the same ones as above.

In the above R ^{1 to} R ⁵ , the alkyl group in the remaining group other than the adjacent alkylene group is a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms (eg, methyl Group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, pentyl group, hexyl group), and the halogen atom includes fluorine, chlorine, bromine and iodine. Can be

Further, as specific camptothecin compound [I], specific examples of the partial structure of ring A and ring B in (A) include the following.

[0024]

Embedded image

[In the formula, X, Alk, R ⁶ , m and n are the same as described above.] Specific examples of the partial structure of the ring A and ring B in (B) include the following.

[0026]

Embedded image

Wherein R ¹¹ , R ²¹ , R ³¹ , R ⁴¹ and R
⁵¹ represents an alkyl group, a halogen atom or a hydrogen atom, and X, Alk, R ⁶ , m and n are the same as described above.] As a preferable combination of R ^{1 to} R ⁵ , (1) R ¹ and R ² are bonded And the trimethylene group and R ³ are 3
An aminopropyloxy group, R ⁴ and R ⁵ are hydrogen atoms. (2) R ¹ is a piperazinomethyl group, R ² and R ⁵ are hydrogen atoms, and R ³ and R ⁴ are bonded to form an ethylenedioxy group. (3) R ¹ Is an aminomethyl group, R ² and R ⁵ are hydrogen atoms,
R ³ and R ⁴ are bonded to form an ethylenedioxy group (4) R ¹ , R ² , R ⁴ and R ⁵ are a hydrogen atom, R ³ is a 3-aminopropyloxy group (5) R ¹ and R ² are bonded An amino-substituted trimethylene group, R ³ is a methyl group, R ⁴ is a fluorine atom, R ⁵ is a hydrogen atom (6) R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen atoms and R ² is an amino group In particular, (1) R ¹ and R ² are bonded to form a trimethylene group and R ³ is 3
An aminopropyloxy group, R ⁴ and R ⁵ are hydrogen atoms. (2) R ¹ is a piperazinomethyl group, R ² and R ⁵ are hydrogen atoms, and R ³ and R ⁴ are bonded to form an ethylenedioxy group. (3) R ¹ And R ² are bonded to form an amino-substituted trimethylene group, R ³ is a methyl group, R ⁴ is a fluorine atom, R ⁵ is a hydrogen atom, (4) R ¹ , R ³ , R ⁴ and R ⁵ are hydrogen atoms, and R ² is Those which are amino groups are preferred.

In the present invention, the “polysaccharide having a carboxyl group” bonded to the camptothecin compound [I] via an amino acid or a peptide is the above-mentioned WO 9
Polysaccharides containing the same substances disclosed in U.S. Pat. No. 4,19,376 and having a carboxyl group in its structure (eg, hyaluronic acid, pectic acid, alginic acid,
Chondroitin, heparin, etc.) and polysaccharides originally having no carboxyl group (eg, pullulan, dextran, mannan, chitin, mannoglucan, chitosan, etc.). Of these, dextran is particularly preferred as the polysaccharide, and has an average molecular weight of 20,000 to 400,000, especially 50,000 to 150,000 [Gel Permeation Chromatography (GPC) Method, Shinsei Kagaku Jikken Koza Vol. 7
Page]. A carboxyl group is introduced into a polysaccharide that does not originally have a carboxyl group. A polysaccharide that does not have a carboxyl group has a part or all of the hydrogen atoms of the hydroxyl groups in a carboxy-C _1-4 alkyl group. Means those substituted with

The “polysaccharide having a carboxyl group” in the present invention includes a polysaccharide that does not originally have a carboxyl group once treated with a reducing agent, and then a part or all of the hydrogen atoms of the hydroxyl group are carboxyl-substituted. Those substituted with a C _1-4 alkyl group are also included.

The alkyl part of the carboxy-C _1-4 alkyl group which is substituted for the hydrogen atom of the hydroxyl group of the above polysaccharide may be either linear or branched. Carboxy-C
Preferred examples of the _1-4 alkyl group include a carboxymethyl group, a 1-carboxyethyl group, a 3-carboxypropyl group, a 1-methyl-3-carboxypropyl group, a 2-methyl-3-carboxypropyl group, and a 4-carboxy group. A butyl group and the like are mentioned, and a carboxymethyl group and a 1-carboxyethyl group are particularly preferable.

In the present invention, it is preferable that the polysaccharide having a carboxyl group is carboxymethylated dextran or pullulan.

When the carboxyalkyl group is introduced, the degree of the introduction can be represented by the "degree of substitution" defined as the number of carboxyalkyl groups per sugar residue. That is,

[0033]

(Equation 1)

Can be expressed as follows. Hereinafter, this degree of substitution is referred to as “degree of carboxymethyl (CM) conversion” when the carboxyalkyl group is a carboxymethyl group.

When the polysaccharide is pullulan, dextran or mannoglucan, the degree of substitution is 3 when all the hydroxyl groups are substituted, and it is preferably 0.3 or more and 0.8 or less.

When the polysaccharide is chitin, the degree of substitution is 2 when all the hydroxyl groups are substituted, and preferably 0.3 or more and 0.8 or less.

Except when the polysaccharide originally has a carboxyl group, at least one polysaccharide molecule is included in the polysaccharide molecule.
It is necessary that two carboxyalkyl groups be present. Therefore, compounds having a substitution degree of 0 in this sense are excluded from the polysaccharide of the present invention.

[0038] These polysaccharides having a carboxyl group can be produced by the method described in WO 94/19376.

The amino acids to be interposed during the binding between the camptothecin compound [I] and the polysaccharide having a carboxyl group include natural amino acids and synthetic amino acids (D
-Amino acids, L-amino acids, and mixtures thereof), and may be any of neutral amino acids, basic amino acids, and acidic amino acids. Furthermore, not only α-amino acids, but also β-amino acids, γ-amino acids, ε-amino acids and the like are included. Specific examples include glycine, α-
Alanine, β-alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine,
Aspartic acid, glutamic acid, lysine, arginine,
Phenylalanine, tyrosine, histidine, tryptophan, proline, oxyproline, γ-aminobutyric acid, ε
-Aminocaproic acid and the like.

In addition to the peptide derived from the above-mentioned amino acids, the peptide also includes a case where a part of the chain contains a compound other than the amino acid. For example, a dicarboxylic acid such as succinic acid, a diamine such as ethylene diamine or a diol such as ethylene glycol may be present in or at the terminal of the peptide chain. In addition, the binding direction of the peptide chain is usually linked from the N-terminus to the carboxyl group of the polysaccharide by an acid amide bond,
When a basic amino acid (for example, lysine) is present in the peptide chain, the ε-amino group is bonded to the carboxyl group of the polysaccharide, and the α-amino group is bonded to the C-terminal carboxyl group of the peptide chain. The binding direction of the chains may be reversed.

Such a peptide is one in which two or more amino acids are peptide-bonded, that is, one having two or more peptide chains, preferably one having 2 to 5 peptide chains. Examples of specific peptide chains include, for example, glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl. -Glycyl-glycine, L
Or D-phenylalanyl-glycine, L or D-
Tyrosyl-glycine or L- or D-leucyl-glycine and peptide chains containing this sequence in the chain (where the N-terminal side of these peptides and the peptide chain containing these sequences is linked to the carboxyl group of the polysaccharide) .

Among these peptides, glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, More preferably L or D-phenylalanyl-glycine, L or D-leucyl-glycine, and glycyl-glycyl-
L-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, L or D-phenylalanyl-glycine are particularly preferred.

The camptothecin derivatives preferable in terms of efficacy include, among the compounds [I], (1) a trimethylene group in which R ¹ and R ² are bonded, R ³ is a 3-aminopropyloxy group, and R ⁴ and R ⁵ are hydrogen. Atom, (2) R ¹ is an aminomethyl group, R ² and R ⁵ are hydrogen atoms, R ³ and R ⁴ are bonded to an ethylenedioxy group, and (3) R ¹ and R ² are bonded to an amino-substituted trimethylene A group, R ³ is a methyl group, R ⁴ is a fluorine atom,
R ⁵ is a hydrogen atom, or (4) a compound in which R ¹ , R ³ , R ⁴ and R ⁵ are a hydrogen atom, R ² is an amino group and carboxymethylated dextran or pullulan are glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine or L
Or a compound linked via D-phenylalanyl-glycine.

The camptothecin derivative which is the active ingredient of the present invention can be converted into a pharmacologically acceptable salt thereof, if desired. Such salts include alkali metal or alkaline earth metal salts such as sodium, potassium and calcium salts, and amino acid salts such as arginine and lysine.

The camptothecin derivative or the pharmaceutically acceptable salt thereof as the active ingredient of the present invention includes any of inner salts, addition salts, solvates and hydrates thereof.

The camptothecin derivative or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, is preferably administered parenterally (for example, intravenously), and is usually administered in liquid form (for example, solution or suspension). , Emulsion).

The dosage form of the pharmaceutical composition of the present invention is preferably prepared as an injection or infusion by using, for example, distilled water for injection, physiological saline, or aqueous glucose solution.

The dose of the camptothecin derivative or a pharmaceutically acceptable salt thereof as the active ingredient of the present invention varies depending on the administration method, age, weight, condition and the like of the patient.
Usually, once, the camptothecin compound [I] [R ⁶
Is the formula: —NH ₂ , the hydrochloride salt;

[0049]

Embedded image

In the case of the hydrochloride or dihydrochloride], it is 0.02 to 50 mg / kg, especially 0.1
It is preferable to administer in the range of 10 to 10 mg / kg.

The pharmaceutical composition of the present invention can be suitably used especially as an antitumor agent. That is, the camptothecin derivative or the pharmaceutically acceptable salt thereof as the active ingredient of the present invention has excellent antitumor activity. For example, the camptothecin derivative or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, exhibits excellent antitumor activity in nude mice into which human breast cancer MX-1 cells have been subcutaneously transplanted.

For this reason, the pharmaceutical composition of the present invention may be used for solid tumors [for example, lung cancer, uterine cancer, ovarian cancer, breast cancer, gastrointestinal cancer (colorectal cancer, stomach cancer, pancreatic cancer, etc.), liver cancer, kidney cancer, prostate cancer] ,
Head and neck cancer, malignant lymphoma, etc.], and humoral tumors (eg, leukemia).

In order to produce the camptothecin derivative which is the active ingredient of the present invention, an amino acid or a peptide is usually bound to the compound represented by the formula [I], and then the carboxyl-containing polysaccharide is reacted with the amino acid or peptide. The method of making it do is adopted.

By reacting the compound [I] with an amino acid or a peptide, an acid amide bond between the C-terminal carboxyl group of the amino acid or the peptide when R ^{6 in} the formula [I] is of the formula: —NH ₂ or a piperazino group And R ⁶ is —O
In the case of H, an ester bond is formed. At this time, it is preferable that other functional groups in the amino acid or peptide not participating in the acid amide bond or the ester bond, such as the N-terminal amino group or other carboxyl group, be protected by a conventional method. Such a protecting group is not particularly limited as long as it is generally used for protecting an amino acid. Examples of the protecting group for an amino group include a t-butoxycarbonyl group and a p-type group.
-Methoxybenzyloxycarbonyl group and the like, and examples of the protective group for the carboxyl group include a lower alkyl group (for example, a t-butyl group) and a benzyl group.

The above-mentioned acid amide bond and ester bond can be formed according to a conventional method. For example, a condensing agent (for example, dicyclohexylcarbodiimide, 1-amino acid) is dissolved in a suitable solvent (for example, dimethylformamide, tetrahydrofuran, acetonitrile, etc.). (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride).

If the amino or carboxyl group of the camptothecin compound to which the amino acid or peptide obtained as described above is bound is protected, the protecting group is removed by a conventional method, if necessary, and then the carboxyl group is removed. A camptothecin derivative is produced by reacting a polysaccharide having a group. By this reaction, a part or all of the carboxyl group of the polysaccharide and the N-terminal amino group of the amino acid or peptide bound to the camptothecin compound [I] form an acid amide bond.

The reaction of a camptothecin compound [I] with an amino acid or peptide bonded thereto and a polysaccharide having a carboxyl group can be carried out according to a conventional method, for example, using a suitable solvent (eg, water, ethanol, dimethylformamide). Or a mixture thereof) of a condensing agent (for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone, etc.). Can be performed in the presence.

In the camptothecin derivative which is the active ingredient of the present invention, the binding ratio between the polysaccharide and the camptothecin compound [I] which is a medicinal ingredient is appropriately selected depending on the kind of the polysaccharide. The content is preferably set to the following ratio.

When the polysaccharide is pullulan, dextran, chitin, mannoglucan or N-acetyl-de-N-sulfate heparin, the content is preferably 0.1 to 20% by weight,
10% by weight is particularly preferred.

In the present invention, the average molecular weight (measured by GPC method) of the camptothecin derivative as an active ingredient is, for example, 30,000 when the polysaccharide is dextran.
~ 500,000, preferably 60,000-200,
000.

The camptothecin compound [I] as the active ingredient of the present invention includes known compounds (for example, see
No. 279891, JP-A-5-222048, JP-A-6-222
-87746, JP-A-6-228141, JP-T-Hei-4
503505, JP-T-5-502017, etc.), and by a known method, for example, by a method represented by the following reaction formula 1.

[0062]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above, and R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} and R ^{5 ′} are any of them. substituent -X _n -Alk amino group in _m -R ⁶ contained in, except that a piperazino group or a hydroxyl group is protected, each R ^1, R ^2, R ^3, R ⁴ and R
⁵ is the same as That is, pyranosyl indolizine aminocarbonyl compound (1) known substance (2) (EP-0220601- A
) And a process known as the Friedlander condensation reaction (Organic Reactions).
c Reactions) 28, pp37-202, J
ohn Wiley & Sons. Inc. New
York (1982)), and then the protecting group is removed to obtain the camptothecin compound [I].

[0064] In the above process, the formula contained in any of ^{R 1 '~R 5': -X} n -Alk m -R 6 groups, m
Is 1 and n is 1, it can be introduced after the Friedlander condensation reaction. That is, instead of the starting compound (1), a compound in which the corresponding group in the compound (1) is a hydroxyl group (HO—) or an amino group (H ₂ N—) is used, which is referred to as a compound (2) and a Friedlander. After the condensation reaction, the resulting condensation product has the formula: R
_{^{6 '-Alk m -OH (R 6}} ' is a protected amino group, piperazino group, or a hydroxy group, Alk and m are as defined above) protected amino alkanol or hydroxy alkanol or their reactive derivatives represented by ( For example, protected aminoalkyl halide, protected hydroxyalkyl halide) is reacted, and then the protecting group is removed to obtain a desired compound [I].

The starting compound (1) used in the above method is produced, for example, by the method shown in the following reaction formula 2.

[0066]

Embedded image

Wherein R ^{1 ′} , R ^{2 ′} , R ^{3 ′} , R ^{4 ′} and R
^{5 ′} is the same as described above. That is, an oxidizing agent such as
Treatment with pyridinium dichromate gives ketone compound (b), which is then catalytically reduced in the presence of a suitable catalyst, for example, palladium-carbon (Pd-C) to give compound (1).

[0068] Furthermore, the hydroxyl compound in ^{(a), R 1 ',} R 2', R 3 ', R 4' -X n -Alk m -R 6 , which is included in any of and R ^{5 'm} is When 1 and n are 1, the corresponding group is a hydroxyl group (HO-) or an amino group (H
₂ N-), Compound of the general formula:

[0069]

Embedded image

[Wherein Alk and R ⁶ are the same as above]
Or a reactive derivative thereof (for example, a substituted alkyl halide).

[0071]

[Experimental example] Experimental example 1 [Action on human breast cancer MX-1 cells] A tumor was removed from a nude mouse bearing the passaged MX-1 tumor, cut into small pieces, and a tumor tissue piece having a size of about 3 mm square was prepared. Transplant subcutaneously on the ventral side of nude mice. The major axis and minor axis of the tumor were measured, and the estimated tumor volume determined according to the following equation (1) was
When they grow to the range of 00-300 mm ³ (11
On day), treatment is started with 5 animals per group. The administered sample was the corresponding camptothecin compound [I] [R ⁶ was of the formula: —NH ₂
In the case of, it is converted to a hydrochloride], dissolved in physiological saline, and administered once intravenously. The major axis and minor axis of the tumor are measured daily until 31 days after sample administration, and the estimated tumor volume is calculated for each mouse according to the following formula (1). Mouse 1
The relative tumor volume ratio on each measurement day (tumor volume ratio on each measurement day with respect to the tumor volume on the administration start day) was calculated for each animal, and the average relative tumor volume ratio for each group was determined daily, The tumor growth inhibition rate is calculated according to the following equation (2). The maximum growth inhibition rate% of each administration sample (the maximum growth inhibition rate of each administration sample among the growth inhibition rates calculated during the experiment period) is as shown in Table 1 below.

[0072]

(Equation 2)

[0073]

(Equation 3)

[0074]

[Table 1]

[0075]

[Production example]

 Production Example 1 Synthesis of camptothecin derivative represented by the following formula

[0076]

Embedded image

[Hereinafter, "CM-Dextran Na"
Represents carboxymethyl dextran sodium salt. (1) Synthesis of 3- (t-butoxycarbonylamino) propanol 6.0 g of 3-aminopropanol was added to 50 m of methylene chloride.
and 18.3 g of di-t-butyl dicarbonate is added dropwise under ice-cooling and stirring. After stirring at room temperature for 12 hours,
The reaction mixture was concentrated and separated and purified by silica gel column chromatography to give the title compound as a colorless oil.
98 g are obtained.

Yield: 99.9% IR (neat): ν _max ^{cm -1} = 3380, 1790 Mass: m / z = 176 ([M + H] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1. 45
(9H, s), 1.62-1.72 (2H, m), 3.
0 (1H, brs), 3.29 (2H, dd, J = 12
Hz and 6 Hz), 3.66 (2H, dd, J = 12
Hz and 6 Hz), 4.80 (1H, brs) (2) Synthesis of 3- (t-butoxycarbonylamino) propyl tosylate 3- (t-butoxycarbonylamino) propanol 1
0.0 g was dissolved in 100 ml of methylene chloride, 8.66 g of triethylamine and 16.3 g of tosyl chloride were added under ice-cooling and stirring, and the reaction mixture was stirred at room temperature overnight. After concentrating the reaction mixture and dissolving the residue in water-ethyl acetate, the organic layer is separated, washed with saturated saline, and dried over sodium sulfate. After evaporating the solvent, the residue is separated and purified by silica gel column chromatography to obtain 15.37 g of the title compound as a pale yellow oil.

Yield: 82% IR (neat): ν _max ^{cm -1} = 3400,3340,
1700 Mass: m / z = 352 ([M + Na] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.42
(9H, s), 1.78-1.90 (2H, m), 2.
45 (3H, s), 3.11-3.22 (2H, m),
4.09 (2H, t, J = 6 Hz), 4.5-4.65
(1H, m), 7.36 (2H, d, J = 8 Hz),
7.77-7.83 (2H, m) (3) 5- [3 '-(t-butoxycarbonylamino)
Propyloxy] -1-hydroxy-8-nitro-1,
Synthesis of 2,3,4-tetrahydronaphthalene 1,5-dihydroxy-8-nitro-1,2,3,4-
2.0 g of tetrahydronaphthalene (J. Med. Che
m. , 1973, 16 (3), 254) in 80 ml of dry dimethylformamide, 2 equivalents of potassium carbonate,
Add 1.4 equivalents of sodium iodide and 1.4 equivalents of 3- (t-butoxycarbonylamino) propyl tosylate. After stirring the reaction mixture at 50 ° C. for 24 hours, ethyl acetate is added, washed with saturated saline, and dried over sodium sulfate. The residue is separated and purified by silica gel column chromatography to obtain 3.05 g of the title compound as a pale yellow amorphous powder.

Yield: 87% IR (Melt): ν _max ^{cm -1} = 3360, 1695 Mass: m / z = 384 ([M + NH ₄ ] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.36
(9H, s), 1.57-1.90 (6H, m), 2.
52-2.71 (2H, m), 3.11 (2H, q, J
= 6 Hz), 4.07 (2H, t, J = 6 Hz), 5.
12-5.17 (2H, m), 6.89 (1H, t, J
= 5.5 Hz), 6.96 (1H, d, J = 9 Hz),
7.68 (1H, d, J = 9 Hz) (4) 5- [3 '-(t-butoxycarbonylamino)
Synthesis of propyloxy] -8-nitro-1,2,3,4-tetrahydronaphthalen-1-one 5- [3 ′-(t-butoxycarbonylamino) propyloxy] -1-hydroxy-8-nitro-1 , 2,
2.46 g of 3,4-tetrahydronaphthalene was dissolved in 110 ml of dry methylene chloride, and molecular sieves 3 was dissolved.
A (molecular sieves 3A) 6.
Add 73 g and 1.5 equivalents of pyridinium dichlorochromate and heat to reflux. After completion of the reaction, the reaction mixture was diluted with ether, and the insoluble material was removed by filtration through Celite. The filtrate was concentrated, and separated and purified by silica gel column chromatography to obtain 1.87 g of the title compound as a colorless powder.
Get.

Melting point: 76-77 ° C. Yield: 76% IR (Melt): ν _max ^{cm −1} = 3550, 1700 Mass: m / z = 382 ([M + NH ₄ ] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.44
(9H, s), 2.02-2.20 (4H, m), 2.
68-2.73 (2H, m), 2.92 (2H, t, J
= 6 Hz), 3.36 (2H, q, J = 6.5 Hz),
4.12 (2H, t, J = 6 Hz), 4.78 (1H,
brs), 6.95 (1H, d, J = 9 Hz), 7.3.
9 (1H, d, J = 9 Hz) (5) Synthesis of 8-amino-5- [3 ′-(t-butoxycarbonylamino) propyloxy] -1,2,3,4-tetrahydronaphthalen-1-one 3.55 g of 5- [3 ′-(t-butoxycarbonylamino) propyloxy] -8-nitro-1,2,3,4-tetrahydronaphthalen-1-one was added to ethanol 160
Then, the mixture was dissolved in the same solution, and 420 mg of 10% Pd-C was added. The mixture was stirred under a hydrogen atmosphere for 1.5 hours. Filter off the catalyst,
The filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to yield 3.56 g of a yellow oily crude product.
Get.

The crude product is purified to give 2.70 g of the title compound as a yellow powder.

Melting point: 112 to 115 ° C. Yield: 83% IR (Nujol): ν _max ^{cm −1} = 3440,334
0,1700,1650 Mass: m / z = 335 ([M + H] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.45
(9H, s), 1.92-2.67 (4H, m), 2.
61 (2H, t, J = 6 Hz), 2.87 (2H, t,
J = 6 Hz), 3.35 (2H, q, J = 6.5H)
z), 3.94 (2H, t, J = 6 Hz), 4.85
(1H, brs), 6.10 (2H, brs), 6.4
8 (1H, d, J = 9 Hz), 6.94 (1H, d, J
= 9 Hz) (6) 10- [3 '-(t-butoxycarbonylamino) propyloxy] -7,9-trimethylene- (20
Synthesis of S) -camptothecin 2.03 g of 8-amino-5- [3 ′-(t-butoxycarbonylamino) propyloxy] -1,2,3,4-tetrahydronaphthalen-1-one was added to 85 m of ethanol.
of (4S) -7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] indolizine-3,6,10 (4H) -trione and 800 mg of p- Toluenesulfonic acid (58 mg) is added, and the mixture is refluxed for 17 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was separated and purified by silica gel column chromatography to obtain 850 mg of the title compound as a pale yellow powder.

Melting point: 225 to 227 ° C. (decomposition) Yield: 50% IR (Nujol): ν _max ^{cm −1} = 3440,332
5,1750,1740,1655,1620 Mass: m / z = 562 ([M + H] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.03
(3H, t, J = 7.5 Hz), 1.45 (9H,
s), 1.82-2.18 (6H, m), 3.06-
3.13 (4H, m), 3.41 (2H, q, J = 6H
z), 3.79 (1H, s), 4.24 (2H, t, J
= 6 Hz), 4.9 (1H, br), 5.16 (2H,
s), 5.30 (1H, d, J = 16 Hz), 5.75
(1H, d, J = 16 Hz), 7.51 (1H, d, J)
= 9 Hz), 7.61 (1H, s), 8.06 (1H,
d, J = 9 Hz) (7) 10- (3′-aminopropyloxy) -7,9
Synthesis of -trimethylene- (20S) -camptothecin hydrochloride 836 mg of 10- [3 '-(t-butoxycarbonylamino) propyloxy] -7,9-trimethylene- (20S) -camptothecin is suspended in 30 ml of dioxane and cooled with ice. Under stirring, 18% hydrochloric acid-dioxane 15m
1 is added dropwise. The reaction mixture is stirred at room temperature, and after completion of the reaction, isopropyl ether is added and stirred. The precipitated powder is collected by filtration, washed with ether, dried under reduced pressure, and the obtained yellow powder is dissolved in water and lyophilized to give 620 mg of the title compound as a yellow powder.

Melting point: 194 ° C. or higher (decomposition) Yield: 84% IR (Nujol): ν _max ^{cm −1} = 1740, 1655 Mass: m / z = 462 ([M-Cl] ⁺ ) NMR (300 MHz, d) _6- DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.81-1.9
4 (2H, m), 1.97-2.15 (4H, m),
3.01-3.14 (6H, m), 4.28 (2H,
t, J = 6 Hz), 5.23 (2H, s), 5.43
(2H, s), 7.28 (1H, s), 7.71 (1
H, d, J = 9.5 Hz), 7.95-8.08 (3
H, brs), 8.03 (1H, d, J = 9.5 Hz) (8) 10- [3 ′-(t-butoxycarbonylglycylglycyl-L-phenylalanylglycylamino) propyloxy] -7 , 9-Trimethylene- (20S)-
Synthesis of camptothecin 10- (3'-aminopropyloxy) -7,9-trimethylene- (20S) -camptothecin hydrochloride 158m
g and 49 mg of diisopropylethylamine were dissolved in 5 ml of dimethylformamide with stirring, and a solution of 278 mg of t-butoxycarbonyl-glycylglycyl-L-phenylalanylglycine and 143 mg of N-hydroxysuccinimide in 8 ml of dry dimethylformamide was added thereto. While stirring under ice-cooling.
183 mg of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was separated and purified by silica gel column chromatography to obtain 285 mg of the title compound as a pale yellow powder.

Yield: quantitative yield IR (Nujol): ν _max ^{cm -1} = 3290, 1660 Mass: m / z = 880 ([M + H] ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1. 02
(3H, t, J = 7.5 Hz), 1.43 (9H,
s), 1.85-1.94 (2H, m), 2.02-
2.10 (4H, m), 2.97-3.05 (5H,
m), 3.23 (1H, dd, J = 14 Hz and 5H
z), 3.49 (2H, q, J = 6.5 Hz), 3.6
0-3.80 (6H, m), 4.20 (1H, t, J =
6 Hz), 4.50-4.56 (1H, m), 5.11
(2H, s), 5.29 (1H, d, J = 16.5H)
z), 5.71 (1H, d, J = 16.5 Hz), 5.
85 (1H, brt), 7.08 (1H, m), 7.1
8-7.27 (5H, m), 7.45 (1H, d, J =
7Hz), 7.52 (1H, d, J = 9.5Hz),
7.58 (1H, s), 7.71 (1H, m), 7.9
9 (1H, d, J = 9.5 Hz) (9) 10- [3 ′-(Glycylglycyl-L-phenylalanylglycylamino) propyloxy] -7,9
Synthesis of -trimethylene- (20S) -camptothecin hydrochloride 10- [3 '-(t-Butoxycarbonylglycylglycyl-L-phenylalanylglycylamino) propyloxy] -7,9-trimethylene- (20S) -camptothecin 273 mg is dissolved in 10 ml of dioxane, and 15 ml of 18% hydrochloric acid-dioxane is added dropwise while stirring under ice cooling. The reaction mixture is stirred at room temperature, and after completion of the reaction, isopropyl ether is added, and the mixture is stirred and the precipitated powder is collected by filtration. The obtained powder is washed with ether and dried under reduced pressure. The obtained yellow powder is dissolved in water and freeze-dried to obtain 210 mg of the title compound as a yellow powder.

Melting point: 174 ° C. or higher (decomposition) Yield: 83% IR (Nujol): ν _max ^{cm −1} = 3190,174
5,1650 Mass: m / z = 780 ([M-Cl] ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
89 (3H, t, J = 7 Hz), 1.26-1.32
(2H, m), 1.86-2.04 (6H, m), 2.
79 (1H, dd, J = 14 Hz and 10 Hz),
2.98-3.05 (5H, m), 3.28-3.36
(2H, m), 3.54-3.88 (6H, m), 4.
20 (2H, t, J = 6 Hz), 4.45-4.54
(1H, m), 5.19 (2H, s), 5.43 (2
H, s), 7.11-7.27 (5H, m), 7.35.
(1H, s), 7.71 (1H, t, J = 9.5H)
z), 7.97 (1H, t, J = 5.5 Hz), 8.0
3 (1H, d, J = 9.5 Hz), 8.19 (3H, b
r), 8.35 (1H, t, J = 6 Hz), 8.43
(1H, d, J = 8 Hz), 8.65 (1H, t, J =
5.5 Hz) A camptothecin compound having an amino group obtained by the above synthesis was converted to carboxymethyl dextran (hereinafter, CM).
-Dextran) to give a camptothecin derivative by condensation with a polysaccharide having a carboxyl group. The condensation reaction was carried out using water-soluble carbodiimide (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2).
-Dihydroquinoline) in water or a mixed solvent of water and an organic solvent.

(10) Preparation of camptothecin derivative 500 mg of CM-dextran sodium salt (degree of CM = 0.5) was dissolved in 20 ml of water, and 10- [3 '-(glycylglycyl- L-phenylalanylglycylamino) propyloxy]-
50 mg of 7,9-trimethylene- (20S) -camptothecin hydrochloride are added. 1.5 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added, and the pH of the reaction solution was adjusted to 6.5 using 0.1N hydrochloric acid.
Keep at ~ 7.0. After reacting for 2 hours while stirring at 10 ° C. or lower, the pH is adjusted to 9 using 0.1N sodium hydroxide. The reaction mixture was subjected to ion exchange column chromatography (BioRad AGMP-50, 30 ml, Na
Then, 1.2 ml of 3M saline is added to 30 ml of the fraction containing the target substance, and the mixture is poured into 150 ml of ethanol. The precipitate is centrifuged, added with 20 ml of water and filtered. 3 in the filtrate
0.4 ml of M saline solution is added, and the mixture is stirred and added to 80 ml of ethanol to form a precipitate. Collect the precipitate by centrifugation,
After washing with the solvent, the residue is dried under reduced pressure to obtain 415 mg of the camptothecin derivative represented by the above formula (13). The drug (1- (7), a compound obtained by absorption determined at 380 nm;
The content of 10- (3′-aminopropyloxy) -7,9-trimethylene- (20S) -camptothecin hydrochloride) is 4.4%. As a result of analysis by gel permeation column chromatography (GPC), the obtained average molecular weight is 160,000, and the polydispersity Mw / Mn is 1.57 (GPC analysis conditions: G4000SWXL (manufactured by Tosoh Corporation), 0.2M phosphorus Acid buffer (pH 7.0)).

Production Example 2 Synthesis of camptothecin derivative represented by the following formula

[0090]

Embedded image

(1) Synthesis of 7- (4 ′-(t-butoxycarbonylglycylglycyl-L-phenylalanylglycyl) piperazino) methyl-10,11-ethylenedioxy- (20S) -camptothecin Preparation Example 1 -7-piperazinomethyl- in the same manner as in (8)
From 450 mg of 10,11-ethylenedioxy- (20S) -camptothecin hydrochloride and 2 equivalents of t-butoxycarbonyl-glycylglycyl-L-phenylalanylglycine, 518 mg of the title compound is obtained as a yellow powder.

Yield: 74% IR (Nujol): ν _max ^{cm -1} = 3280,175
0,1655 Mass: m / z = 923 ([M + H] ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
89 (3H, t, J = 7.5 Hz), 1.37 (9H,
s), 1.85-2.1 (2H, m), 2.3-2.6.
(4H, m), 2.75 (1H, dd, J = 14 Hz and 10 Hz), 3.05 (1H, dd, J = 14 Hz)
And 4.5 Hz), 3.3-3.6 (6H, m),
3.58 (1H, dd, J = 21 Hz and 5.5H
z), 3.74 (1H, dd, J = 17 Hz and 5.
5 Hz), 3.9-4.1 (4H, m), 4.44 (4
H, s), 4.58 (1H, m), 5.24 (2H,
s), 5.42 (2H, s), 6.50 (1H, s),
6.97 (1H, t, J = 6 Hz), 7.1-7.3
(6H, m), 7.55 (1H, s), 7.77 (1
H, s), 7.8-7.9 (1H, br), 8.05-
8.2 (2H, m) (2) 7- (4 '-(glycylglycyl-L-phenylalanylglycyl) piperazino) methyl-10,11-
Synthesis of ethylenedioxy- (20S) -camptothecin hydrochloride 7- (4 '-(t-butoxycarbonylglycylglycyl-L-phenylalanylglycyl) piperazino) methyl in the same manner as in Production Example 1- (9) 478 mg of -10,11-ethylenedioxy- (20S) -camptothecin
409 mg of the title compound are obtained in the form of a more yellow powder.

Melting point: 237-239 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3250,174
5,1655 Mass: m / z = 823 ([M-Cl] ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.8-1.99 (2
H, m), 2.79 (1H, dd, J = 14 Hz and 10 Hz), 3.07 (1H, dd, J = 14 Hz and 4 Hz), 3.1-4.3 (16H, m), 4. 47
(4H, s), 4.55-4.70 (1H, m), 5.
44 (2H, s), 5.67 (2H, s), 7.15-
7.32 (6H, m), 7.65 (1H, s), 8.0
5 (1H, s), 8.05-8.20 (3H, br),
8.29 (1H, br), 8.39 (1H, d, J =
8.5 Hz), 8.57 (1 H, t, J = 5.5 Hz) (3) Preparation of camptothecin derivative In the same manner as in Production Example 1- (10), CM-dextran sodium salt (CM conversion = 0) .5) 1.2 g and 7-
168 mg of (4 '-(glycylglycyl-L-phenylalanylglycyl) piperazino) methyl-10,11-ethylenedioxy- (20S) -camptothecin hydrochloride
798 mg of a camptothecin derivative represented by the above formula (14) as a pale yellow powder is obtained. Drug (7-piperazinomethyl-10,11-) determined by absorption at 380 nm
The content of ethylenedioxy- (20S) -camptothecin hydrochloride) is 1.1%. As a result of analysis by gel permeation column chromatography (GPC), the average molecular weight obtained was 169,000, and the polydispersity Mw / Mn was 1.3.
(GPC analysis conditions: G4000SWXL (manufactured by Tosoh Corporation), 0.2 M phosphate buffer (pH 7.0)).

Production Example 3 Synthesis of camptothecin derivative represented by the following formula

[0095]

Embedded image

(1) 7-N- (t-butoxycarbonylglycylglycyl-L-phenylalanylglycyl) aminomethyl-10,11-ethylenedioxy- (20
Synthesis of S) -camptothecin 7-aminomethyl-1 in the same manner as in Production Example 1- (8)
From 222 mg of 0,11-ethylenedioxy- (20S) -camptothecin hydrochloride and 2 equivalents of t-butoxycarbonylglycylglycyl-L-phenylalanylglycine, 232 mg of the title compound is obtained as a yellow powder.

Yield: 58% IR (Nujol): ν _max ^{cm -1} = 3285,175
0,1650 Mass: m / z = 854 ([M + H] ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.35 (9H,
s), 1.78-1.94 (2H, m), 2.74 (1
H, dd, J = 14 Hz and 10 Hz), 2.99
(1H, dd, J = 14 Hz and 4.5 Hz), 3.
4-3.8 (4H, m), 4.34-4.50 (1H,
m), 4.42 (4H, s), 4.66-4.82 (2
H, m), 5.42 (4H, brs), 6.50 (1
H, s), 6.98 (1H, t, J = 6 Hz), 7.1
2-7.28 (5H, m), 7.26 (1H, s),
7.56 (1H, s), 7.80 (1H, s), 7.9
1 (1H, br), 8.14 (1H, d, J = 7.5H
z), 8.32 (2H, t, J = 7.5 Hz), 8.5
8 (1H, m) (2) Synthesis of 7-N- (glycylglycyl-L-phenylalanylglycyl) aminomethyl-10,11-ethylenedioxy- (20S) -camptothecin hydrochloride Production Example 1- (9) 164 mg of the title compound as a yellow powder from 203 mg of 7-N- (t-butoxycarbonylglycylglycyl-L-phenylalanylglycyl) aminomethyl-10,11-ethylenedioxy- (20S) -camptothecin. Get.

[0098] Melting point:> 211 ℃ _{(decomposition) IR (Nujol): ν ma} xcm- 1 = 3220,174
5,1655 Mass: m / z = 754 ([M-Cl] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
88 (3H, t, J = 7 Hz), 1.80-1.93
(2H, m), 2.77 (1H, dd, J = 14 Hz and 10 Hz), 3.00 (1H, dd, J = 14 Hz)
And 4 Hz), 3.6-4.55 (7H, m), 4.
42 (4H, s), 4.65-4.85 (2H, m),
5.42 (2H, s), 5.45 (2H, s), 7.1
3-7.26 (5H, m), 7.27 (1H, s),
7.57 (1H, s), 7.83 (1H, s), 8.0
3-8.16 (3H, br), 8.34-8.40 (2
H, m), 8.54 (1H, br), 8.73 (2H,
br) (3) Preparation of camptothecin derivative CM-dextran sodium salt (degree of CM = 0.
5) Dissolve 772 mg in 50 ml of water and add 25 ml of dimethylformamide. Stir under ice-cooling, and add 7- (N-
(Glycylglycyl-L-phenylalanylglycyl)
(Aminomethyl) -10,11-ethylenedioxy- (2
Add 106 mg of (OS) -camptothecin hydrochloride and 1.57 g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinone. After overnight reaction, the reaction mixture was added to 450 ml of ethanol to form a precipitate.
By treating in the same manner as in (10), a pale yellow powder
To obtain 545 mg of a camptothecin derivative. 3
The content of the drug (7-aminomethyl-10,11-ethylenedioxy- (20S) -camptothecin hydrochloride) determined by absorption at 75 nm is 5.5%. As a result of analysis by gel permeation column chromatography (GPC), the average molecular weight obtained is 165,000, and the polydispersity Mw / Mn is 1.40 (GPC analysis conditions: G40).
00SWXL (manufactured by Tosoh Corporation), 0.2 M phosphate buffer (pH 7.0)).

Production Example 4 10- (3'-aminopropyloxy)-(20S)-
Synthesis of camptothecin hydrochloride (1) 5- [3 '-(t-butoxycarbonylamino)
Synthesis of propyloxy] -2-nitrobenzaldehyde dimethyl acetal 3.0 g of 5-hydroxy-2-nitrobenzaldehyde dimethyl acetal was dried in dimethylformamide 50
3.15 g of sodium iodide and 1.93 g of potassium carbonate and 6.95 g of 3- (t-butoxycarbonylamino) propyl tosylate.
After stirring at 50 ° C. for 3 hours, the temperature is returned to room temperature, and ethyl acetate is added. The extract is washed with saturated saline and dried over sodium sulfate. After evaporating the solvent, the residue is separated and purified by silica gel column chromatography to quantitatively obtain 5.22 g of the title compound as a pale yellow oil.

[0100] ^{_{IR (Neat): ν ma xcm-}} 1 = 336
0.11710 Mass: m / z = 393 ([M + Na] +) NMR (300 MHz, CDCl 3): δ ^TM S = 1.44
(9H, s), 2.02 (2H, quint., J = 6
Hz), 3.33 (2H, dd, J = 13 Hz and 6
Hz), 3.44 (6H, s), 4.11 (2H, t,
J = 6 Hz), 4.7 (1H, brs), 6.01 (1
H, s), 6.90 (1H, dd, J = 9 Hz and 3
Hz), 7.29 (1H, d, J = 3 Hz), 7.97
(1H, d, J = 9 Hz) (2) Synthesis of 10- [3 ′-(t-butoxycarbonylamino) propyloxy]-(20S) -camptothecin 5- [3 ′-(t-butoxycarbonylamino) propyl [Oxy] -2-nitrobenzaldehyde dimethyl acetal (1270 mg) was dissolved in ethanol (20 ml),
120 mg of 10% palladium-carbon is added, and the mixture is stirred under a hydrogen atmosphere for 1.5 hours. The catalyst was removed from the reaction mixture by filtration, and the (4S) -7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] indolizine-3,6,10 (4H ) -Trion 300m
g and 22 mg of p-toluenesulfonic acid are added and stirred overnight at room temperature. The solvent was distilled off from the reaction mixture, and the residue was separated and purified by silica gel column chromatography to obtain 204 mg of the title compound as a pale yellow powder.

[0102] mp: 223-224 ° C. (decomposition) Yield: 34% IR (Nujol): ν ma xcm- 1 = 3360,175
0.1690 Mass: m / z = 522 ([M + H] +) NMR (300 MHz, CDCl 3): δ ^TM S = 1.03
(3H, t, J = 7.5 Hz), 1.46 (9H,
s), 1.8-2.0 (2H, m), 2.08 (1H,
dd, J = 12.5 Hz and 6.5 Hz), 2.10
(1H, dd, J = 12.5 Hz and 6 Hz), 3.
40 (2H, q, J = 6.5 Hz), 4.18 (2H,
t, J = 6 Hz), 4.82 (1H, brs), 5.2
4 (2H, s), 5.29 (1H, d, J = 16H
z), 5.73 (1H, d, J = 16 Hz), 7.12
(1H, d, J = 3 Hz), 7.43 (1H, dd, J
= 9 Hz and 3 Hz), 7.61 (1H, s), 8.
09 (1H, d, J = 9 Hz), 8.20 (1H, d,
J = 9 Hz) (3) 10- (3′-aminopropyloxy)-(20
Synthesis of S) -camptothecin hydrochloride 10- [3 ′-(t-butoxycarbonylamino) propyloxy]-(20S) -camptothecin 352 mg
Is dissolved in dry dioxane-ethanol (7 ml-1 ml), and 5 ml of 19% hydrochloric acid-dioxane is added to this solution under ice-cooling and stirring. After stirring the reaction mixture at room temperature, 10 ml of isopropyl ether is further added, and the precipitated powder is collected by filtration and washed to obtain 339 mg of the title compound as a yellow powder.

[0102] Melting point: 214-218 ℃ _{(decomposition) IR (Nujol): ν ma} xcm- 1 = 3470,328
0,1745 Mass: m / z = 422 ([M-Cl] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
89 (3H, t, J = 7.5 Hz), 1.80-1.9
5 (2H, m), 2.10-2.22 (2H, m),
2.96-3.10 (2H, m), 4.27 (2H,
t, J = 6 Hz), 5.25 (2H, s), 5.42
(2H, s), 7.29 (1H, s), 7.49-7.
55 (2H, m), 8.08 (1H, d, J = 10H
z), 8.19 (3H, brs), 8.54 (1H,
s) Production Example 5 10- [3 '-(Glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy]-(20
Synthesis of S) -camptothecin hydrochloride (1) Synthesis of 10- [3 ′-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanylglycylamino) propyloxy]-(20S) -camptothecin 10- (3 '-Aminopropyloxy)-(20S)-
Dissolve 325 mg of camptothecin hydrochloride in 10 ml of dry dimethylformamide and add 4 equivalents of N-hydroxysuccinimide, 2 equivalents of diisopropylethylamine, and 2 equivalents of Nt-butoxycarbonyl-glycyl-glycyl under ice-cooling and stirring. Add -L-phenylalanylglycine and 4 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. After stirring the reaction mixture at room temperature overnight, the solvent is distilled off. The residue is separated and purified by silica gel column chromatography to quantitatively obtain 597 mg of the title compound as a yellow powder.

[0103] ^{_{IR (Nujol): ν ma xcm-}} 1 = 328
0, 1750, 1660 Mass: m / z = 840 ([M + H] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
88 (3H, t, J = 7 Hz), 1.36 (9H,
s), 1.8-2.04 (4H, m), 2.72-2.
84 (1H, m), 3.00-3.12 (1H, m),
3.24-3.36 (2H, m), 3.50-3.80
(6H, m), 4.18 (2H, t, J = 6 Hz),
4.44-4.54 (1H, m), 5.24 (2H,
s), 5.42 (2H, s), 6.50 (1H, s),
6.99 (1H, t, J = 6 Hz), 7.12-7.2
7 (5H, m), 7.28 (1H, s), 7.48-
7.55 (1H, m), 7.50 (1H, s), 7.8
8-7.96 (1H, m), 8.07 (1H, d, J =
9 Hz), 8.12-8.36 (2H, m), 8.51
(1H, s) (2) 10- [3 ′-(glycyl-glycyl-L-phenylalanylglycylamino) propyloxy]-(2
Synthesis of 0S) -camptothecin hydrochloride 10- (3 ′-(t-butoxycarbonyl-glycyl-
Glycyl-L-phenylalanylglycylamino) propyloxy)-(20S) -camptothecin 580 mg
The above compound was treated in the same manner as in Production Example 4- (3) to obtain 438 mg of the title compound as a yellow powder.

[0104] Yield: 82% mp: 194-199 ° C. _{(decomposition) IR (Nujol): ν ma} xcm- 1 = 3190,174
5,1650 Mass: m / z = 740 ([M-Cl] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
88 (3H, t, J = 7 Hz), 1.80-2.03
(4H, m), 2.79 (1H, dd, J = 14 Hz and 10 Hz), 3.05 (1H, dd, J = 14 Hz)
And 5 Hz), 3.2-3.5 (2H, m), 3.5
2-3.62 (2H, m), 3.62-3.83 (4
H, m), 4.19 (2H, t, J = 6 Hz), 4.4
8-4.58 (1H, m), 5.25 (2H, s),
5.42 (2H, s), 6.5 (1H, brs), 7.
13-7.26 (5H, m), 7.28 (1H, s),
7.49-7.55 (1H, m), 7.50 (1H,
s, J = 9.5 Hz), 7.93 (1H, t, J = 6H)
z), 8.0-8.14 (4H, m), 8.32-8.
41 (2H, m), 8.51 (1H, s), 8.56
(1H, t, J = 5.5 Hz) Production Example 6 Synthesis of camptothecin derivative represented by the following formula

[0105]

Embedded image

CM-dextran sodium salt (CM
513 mg was dissolved in 50 ml of water, and 10- [3 ′-(glycyl-
Glycyl-L-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride 7
7 mg and 1- (3-dimethylaminopropyl) -3
1.54 g of ethylcarbodiimide hydrochloride are added. The internal temperature is 10 ° C or less, and the pH is 6.0 to 6.0 using 0.2N hydrochloric acid.
Stir for 2 hours, keeping at 6.5. The reaction mixture is subjected to ion exchange column chromatography (BioRadAG).
MP-50, 30 ml, Na type), the fraction containing the target substance was filtered, ethanol was added to the filtrate to separate the precipitate, and the precipitate was washed, dried under reduced pressure, and dried under reduced pressure to obtain a pale yellow powdery complex 492.
mg. Drug (10- (3′-aminopropyloxy)-(20S) determined by absorption at 380 nm
-Camptothecin hydrochloride) content is 2.8%. As a result of analysis by gel filtration column chromatography (GPC), the obtained average molecular weight was 179,000 and the polydispersity Mw / Mn was 1.42 (GPC analysis conditions: G4
000SWXL (manufactured by Tosoh Corporation), 0.2 M phosphate buffer (pH = 7.0)).

Production Example 7 Synthesis of camptothecin derivative represented by the following formula

[0108]

Embedded image

(1) (9S) -1- (t-butoxycarbonylglycylglycyl-L-phenylalanylglucylamino) -9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4- Methyl-1H, 12H-benzo [de] pyrano [3 ′, 4 ′: 6,7] indolizino [1,2-b] quinoline-10,13 (9H, 15
Synthesis of H) -dione In the same manner as in Production Example 1- (8), (9S) -1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-
Hydroxy-4-methyl-1H, 12H-benzo [d
e] pyrano [3 ', 4': 6,7] indolizino [1,
2-b] Quinoline-10,13 (9H, 15H) -dione hydrochloride (166 mg) and 2 equivalents of t-butoxycarbonylglycylglycyl-L-phenylalanylglycine give 247 mg of the title compound as a pale yellow amorphous solid. .

[0110] Yield: 82% IR (Nujol): ν ma xcm- 1 = 3290,171
0.1655 Mass: m / z = 854 ([M + H] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
87 (3H, t, J = 7 Hz), 1.37 (9H,
s), 1.8-1.95 (2H, m), 2.05-2.
3 (1H, m), 2.42 (3H, s), 2.5-2.
85 (2H, m), 2.9-3.1 (1H, m), 3.
15-3.4 (2H, m), 3.5-3.8 (6H,
m), 4.4-4.55 (1H, m), 5.26 (2
H, s), 5.42 (2H, s), 5.55-5.65.
(1H, m), 6.53 (1H, s), 6.99 (1
H, t, J = 5 Hz), 7.1-7.3 (5H, m),
7.32 (1H, s), 7.81 (1H, d, J = 11
Hz), 7.8-7.95 (1H, m), 8.1-8.
2 (1H, m), 8.3-8.4 (1H, m), 8.4
-8.5 (1H, m) (2) (9S) -1- (glycylglycyl-L-phenylalanylglucylamino) -9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4- Methyl-
1H, 12H-benzo [de] pyrano [3 ′, 4 ′:
6,7] indolizino [1,2-b] quinoline-10,
Synthesis of 13 (9H, 15H) -dione In the same manner as in Production Example 1- (9), the title compound 193m as a pale yellow powder was obtained from 220 mg of the compound obtained in the above (1).
g.

[0111] Melting point:> 165 ℃ _{(decomposition) IR (Nujol): ν ma} xcm- 1 = 3350,174
5,1660,1615 Mass: m / z = 754
([M-Cl + H] +) NMR (300 MHz, d 6 -DMSO): δ ^TM S = 0.
87 (3H, t, J = 7 Hz), 1.80-1.94
(2H, m), 2.08-2.27 (2H, m), 2.
41 (3H, s), 2.77 (1H, dd, J = 13H
z, 9 Hz), 3.01 (1H, dd, J = 13 Hz,
5Hz), 3.15-3.28 (2H, m), 3.5-
3.91 (6H, m), 4.45-4.56 (1H,
m), 5.25 (2H, s), 5.41 (1H, d, J
= 13 Hz), 5.42 (1H, d, J = 13 Hz),
5.57 (1H, m), 7.12-7.30 (5H,
m), 7.32 (1H, s), 7.80 (1H, d, J
= 11 Hz), 8.0-8.2 (3H, br), 8.3
2 (1H, d, J = 7 Hz), 8.43 (1H, t, J
= 5.5 Hz), 8.50-8.62 (2H, m) (3) Preparation of camptothecin derivative CM-dextran sodium salt (degree of CM = 0.6)
5) 2000 mg and 170 mg of the compound obtained in the above (2)
To obtain 1803 mg of the desired camptothecin derivative as a pale yellow powder. Drug determined by absorption at 376 nm ((9
S) -1-Amino-9-ethyl-5-fluoro-2,3
-Dihydro-9-hydroxy-4-methyl-1H, 12
H-benzo [de] pyrano [3 ', 4': 6,7] indolizino [1,2-b] quinoline-10,13 [9H,
[15H] -dione hydrochloride) content is 3.0%. As a result of analysis by gel filtration column chromatography (GPC), the obtained average molecular weight is 187,000 and the polydispersity Mw / Mn is 1.54 (GPC analysis conditions: G4
000SWXL (manufactured by Tosoh Corporation), 0.2 M phosphate buffer (pH = 7.0)).

Preparation Examples 8 to 24 In the same manner as in any of Preparation Examples 1 to 7, the compounds shown in Table 2 below are obtained.

[0113]

[Table 2]

[Hereinafter, "CM-Pullulan N"
"a" represents carboxymethyl pullulan sodium salt. Production Examples 25 to 41 In the same manner as in any of Production Examples 1 to 7, the compounds shown in Table 3 below are obtained.

[0115]

[Table 3]

Preparation Examples 42 to 59 In the same manner as in any of Preparation Examples 1 to 7, the compounds shown in Table 4 below are obtained.

[0117]

[Table 4]

Production Examples 60 to 76 The compounds shown in Table 5 below are obtained in the same manner as in any of Production Examples 1 to 7.

[0119]

[Table 5]

Preparation Examples 77 to 93 The compounds shown in Table 6 below are obtained in the same manner as in any of Preparation Examples 1 to 7.

[0121]

[Table 6]

Preparation Examples 94 to 110 The compounds shown in Table 7 below are obtained in the same manner as in any of Preparation Examples 1 to 7.

[0123]

[Table 7]

Reference Example 1 (1) Dextran [Dextra, manufactured by Pharmacia]
nT-110, average molecular weight: 100,000 (GP
C) Method] 29 g is dissolved in 290 ml of water. 1.45 g of sodium borohydride is added to this solution at 0 to 5 ° C.
Stir at 5 ° C. overnight. Acetic acid is added dropwise to the reaction mixture to adjust the pH.
And stirred at room temperature for a further 3 hours. Adjust to pH 7 with 2N sodium hydroxide and add 1.2 liters of ethanol with vigorous stirring. After allowing to stand to precipitate insolubles, the supernatant is removed by decantation, and the residue is centrifuged. The residue is dissolved in 0.5 liter of water and freeze-dried to obtain 26.3 g of a white powder.

(2) The white powder 50 obtained in the above (1)
g was dissolved in 500 ml of water, and 200 g of sodium hydroxide was added to the solution under ice cooling, followed by stirring for 30 minutes. After returning the reaction mixture to room temperature, a solution of monochloroacetic acid (110 g) in water (150 ml) was added dropwise, and the mixture was stirred at 40 ° C. for 18 hours. The reaction mixture is cooled to below 10 ° C. and
Adjust to ~ 9. While stirring the reaction mixture vigorously, 8 liters of methanol are added to precipitate insolubles. The insolubles are collected by filtration, dissolved in 5 liters of pure water, and desalted by ultrafiltration. The resulting solution was concentrated under reduced pressure, the concentrated solution was filtered, ethanol was added, the precipitate was collected by filtration, washed with aqueous ethanol and acetone, and dried under reduced pressure at room temperature and 50 ° C. to obtain carboxymethyl dextran ( CM-
Dextran) sodium salt [degree of carboxymethylation (neutralization titration method): 0.5] 50.2 g is obtained.

Reference Example 2 The same procedure as in Reference Example 1 was carried out, except that the amount of monochloroacetic acid was changed, to obtain a compound having a carboxymethylation degree of 0.65.
M-dextran sodium salt is obtained.

[0127]

The camptothecin derivative, which is the active ingredient of the present invention, is delivered in a large amount and selectively to a target site of action by utilizing a drug delivery system, and exhibits a desired pharmacological action at that site. Is what you can do. That is, the camptothecin derivative, which is the active ingredient of the present invention, is extremely useful as a drug having significantly enhanced antitumor activity and reduced side effects as compared with its parent compound, the camptothecin compound.

Therefore, the pharmaceutical composition of the present invention may be used for solid tumors such as lung cancer, uterine cancer, ovarian cancer, breast cancer, gastrointestinal cancer (colorectal cancer, stomach cancer, pancreatic cancer, etc.), liver cancer, kidney cancer, prostate cancer ,
Head and neck cancer, malignant lymphoma, etc.], and humoral tumors (eg, leukemia).

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07D 491/22 C07D 491/22

Claims (15)

[Claims] 1. A compound of the general formula [Wherein, R ^{1 to} R ⁵ are (A) two adjacent R ^{1 to} R ⁵
One is a hydrogen atom even two or form an alkylene group bonded to each other, one of the remaining R ¹ to R ⁵ is a -X _n -Alk _m -R ^6, the other two are hydrogen atom or it is, or (B) among R ¹ to R ^5, although two adjacent bonded to form an alkylene group with one another, is -X _n -Alk _m -R ⁶ in any of the carbon atoms of the alkylene radical Represents that the remaining three of R ^{1 to} R ⁵ are a hydrogen atom, an alkyl group or a halogen atom, and one or two methylene groups in the alkylene group in (A) and (B) are- O-, -S- or -NH-, X may be -O- or -NH-, and A
lk is an alkylene group, R ⁶ is —NH ₂ , Or m and n are both 0 or 1, or m is 1 and n is 0.] wherein R ^{6 of the} camptothecin compound [I] and the carboxyl group-containing polysaccharide are an amino acid or A pharmaceutical composition comprising, as an active ingredient, a camptothecin derivative bound via a peptide or a pharmacologically acceptable salt thereof. 2. A part or all of a carboxyl group of a polysaccharide and an amino group of an amino acid or a peptide are subjected to an acid amide bond, and all or a part of a carboxyl group of the amino acid or a peptide and R ^{6 of the} compound [I] are linked. The pharmaceutical composition according to claim 1, wherein the composition is an acid amide bond or an ester bond. 3. A part or all of the carboxyl group of the polysaccharide and the N-terminal amino group of the amino acid or peptide are acid-amide bonded, and the C-terminal carboxyl group of this amino acid or peptide and R ^{6 of the} compound [I] are linked. 3. The pharmaceutical composition according to claim 2, wherein the composition is an acid amide bond or an ester bond. 4. The compound of formula [I] wherein R ⁶ has the formula: —NH ₂ or 4. The pharmaceutical composition according to claim 3, wherein the polysaccharide having a carboxyl group is carboxymethylated dextran or pullulan, and both components are bound via a peptide. 5. (1) R ¹ and R ² are bonded to each other to obtain a trimethylene group, R ³ is a 3-aminopropyloxy group, R ⁴ and R ⁵
Is a hydrogen atom, (2) R ¹ is a piperazinomethyl group, R ² and R ⁵ are hydrogen atoms, R ³ and R ⁴ are bonded to form an ethylenedioxy group, (3) R ¹ is an aminomethyl group, R ² and R ⁵ is a hydrogen atom, R ³ and R ⁴ are bonded to form an ethylenedioxy group,
(4) R ¹ , R ² , R ⁴ and R ⁵ are a hydrogen atom, R ³ is a 3-aminopropyloxy group, (5) R ¹ and R ² are bonded to an amino-substituted trimethylene group, and R ³ is a methyl group The pharmaceutical composition according to claim 4, wherein R ⁴ is a fluorine atom, R ⁵ is a hydrogen atom, or (6) R ¹ , R ³ , R ⁴ and R ⁵ are a hydrogen atom, and R ² is an amino group. 6. (1) R ¹ and R ² are bonded to each other to obtain a trimethylene group, R ³ is a 3-aminopropyloxy group, R ⁴ and R ⁵
Is a hydrogen atom, (2) R ¹ is an aminomethyl group, R ² and R ⁵
Is a hydrogen atom, R ³ and R ⁴ are bonded to an ethylenedioxy group, (3) R ¹ and R ² are bonded to an amino-substituted trimethylene group, R ³ is a methyl group, R ⁴ is a fluorine atom, and R ⁵ is A hydrogen atom, or (4) R ¹ , R ³ , R ⁴ and R ⁵ are a hydrogen atom, R
The pharmaceutical composition according to claim 4, wherein ² is an amino group. 7. The method according to claim 1, wherein the peptide is glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, The pharmaceutical composition according to claim 5 or 6, which is L or D-phenylalanyl-glycine or L or D-leucyl-glycine. 8. The method according to claim 1, wherein the peptide is glycyl-glycyl-L-.
The pharmaceutical composition according to claim 7, which is phenylalanyl-glycine. 9. The pharmaceutical composition according to claim 7, wherein said peptide is glycyl-glycine. 10. The pharmaceutical composition according to claim 7, wherein said peptide is glycyl-glycyl-glycine. 11. The pharmaceutical composition according to claim 7, wherein said peptide is glycyl-glycyl-glycyl-glycine. 12. The pharmaceutical composition according to claim 7, wherein said peptide is L or D-phenylalanyl-glycine. 13. The polysaccharide having a carboxymethylation degree of 0.1.
The pharmaceutical composition according to claim 8, 9, 10, 11, or 12, which has a value of 3 or more and 0.8 or less. 14. The method according to claim 1, 2, 3, which is an antitumor agent.
4, 5, 6, 7, 8, 9, 10, 11, 12, or 13
The pharmaceutical composition according to any one of the preceding claims. 15. A remedy for lung cancer, uterine cancer, ovarian cancer, breast cancer, gastrointestinal cancer (colorectal cancer, stomach cancer, pancreatic cancer, etc.), liver cancer, renal cancer, prostate cancer, head and neck cancer, malignant lymphoma, leukemia. Certain claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1
15. The pharmaceutical composition according to 1, 12, 13 or 14.