JP3322203B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition.

[0002]

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

[0003]

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[0004] It is known to have anti-leukemia and anti-tumor effects, and its derivative, irinotecan (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
Vol., P. 709 (1994)].

On the other hand, in order to increase the antitumor activity and suppress the side effects of such drugs having strong side effects 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 required 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 liposome [enhancement of effect of anticancer drug 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.

[0006]

As described above, camptothecin compounds have excellent antitumor activity and are extremely useful as pharmaceuticals, but their use is severely restricted due to their strong side effects. There is.

[0007] The present invention provides a pharmaceutical composition comprising a new camptothecin derivative as an active ingredient, which suppresses the occurrence of undesired side effects while maintaining its excellent drug activity. The present invention also provides an antitumor agent comprising the novel camptothecin derivative as an active ingredient.

[0008]

As a result of various studies, the present inventors have found that a novel camptothecin compound having a reactive group and a compound having an amino acid or a peptide bound thereto have excellent antitumor activity. With
The present inventors have found that a camptothecin derivative, which is a final product obtained by combining the derivative with a carboxyl group-containing polysaccharide, has remarkably strong antitumor activity and low toxicity, and thus completed the present invention.

That is, the present invention provides the following general formula:

[0010]

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Wherein R ¹ is a substituted or unsubstituted lower alkyl group; X ¹ is a group represented by the formula: —NHR ² (R ² represents a hydrogen atom or a lower alkyl group) or —OH;
k represents a straight-chain or branched-chain alkylene group in which an oxygen atom may be interposed.] and a camptothecin derivative in which a carboxyl-containing polysaccharide is bonded via an amino acid or a peptide. It is a pharmaceutical composition as an active ingredient.

Further, the present invention is an antitumor agent comprising the camptothecin derivative as an active ingredient.

[0013]

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.

Specific examples thereof include X ^{1 of} compound [I].
And a polysaccharide having a carboxyl group via an amino acid or a peptide.

Further, a part or all of the carboxyl group of the polysaccharide and the amino group of the amino acid or peptide are bonded by an acid amide, and the whole or part of the carboxyl group of the amino acid or peptide and X ^{1 of the} compound [I] are linked. Camptothecin derivatives having an acid amide bond or an ester bond can be mentioned.

More specifically, 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 the amino acid or peptide is linked to the X of the compound [I]. And camptothecin derivatives wherein ^{1 is an} acid amide bond or an ester bond.

Each substituent in the compound represented by the formula [I] which is an active ingredient of the present invention contains the following groups.

The lower alkyl group for R ^{1 and} the lower alkyl group for R ² when X ¹ is --NHR ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert Examples thereof include an alkyl group having 1 to 4 carbon atoms such as -butyl group, and among them, an ethyl group is preferable.

Examples of the substituent of the lower alkyl group represented by R ¹ include a hydroxyl group which may be protected, a mercapto group which may be protected, an amino group which may be protected, and the like. Group or acyl group).

As the “straight-chain or branched-chain alkylene group which may be interposed with an oxygen atom” as Alk,
1 to 6 carbon atoms such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, 1-methylethylene, 1-methylpropylene, and 2-methylpropylene straight or branched chain alkylene group, and -CH ₂ CH ₂ -O-
CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —O—CH ₂ CH
_{2 -, - CH 2 CH (} CH 3) -O-CH 2 CH 2 -, - C
H ₂ CH ₂ —O—CH ₂ CH ₂ —O—CH ₂ CH ₂ —, for example, having 2 to 6 carbon atoms interposed by one or more oxygen atoms
Linear or branched alkylene groups.

Among them, Alk is preferably a straight-chain or branched-chain alkylene group having no oxygen atom interposed, and among them, a straight-chain alkylene group having no oxygen atom interposed, particularly trimethylene group, A tetramethylene group or a pentamethylene group is preferred.

Further, among the compounds [I] which are the active ingredients of the present invention, a compound in which X ¹ -Alk-O- is bonded to the camptothecin skeleton at the 10-position is preferable.

In the compound [I] which is an active ingredient of the present invention, the following formula [Ia] wherein X ¹ is a formula: —NHR ²

[0024]

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Wherein R ¹ , R ² and Alk are as defined above, are preferred.

In the above compound [Ia], R ¹
Is a compound having an unsubstituted lower alkyl group, R ² being a hydrogen atom, Alk being a straight-chain or branched-chain alkylene group (with no oxygen atom interposed), wherein Alk is a straight-chain alkylene having 2 to 4 carbon atoms Compounds that are groups are more preferred.

In the compound [I] which is an active ingredient of the present invention, R ¹ is an ethyl group, X ¹ -Alk-O- is a 3-aminopropyloxy group, and is bonded to the camptothecin skeleton at the 10-position. Compounds are particularly 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 its average molecular weight is from 20,000 to 40.
0000, especially 50,000 to 150,000
It is preferably within the range of [Gel Permeation Chromatography (GPC) Method, Shinsei Kagaku Jikken Koza Vol. 20, page 7, page 7].

A carboxyl group-introduced polysaccharide originally having a carboxyl group is defined as a polysaccharide having no carboxyl group in which some or all of the hydrogen atoms of the hydroxyl groups are carboxy-C _{1-. 4} means substituted with an alkyl group.

In the present invention, the term “polysaccharide having a carboxyl group” refers to 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 groups. Also included are those substituted with a -C _1-4 alkyl group.

The alkyl portion of the carboxy-C _1-4 alkyl group substituted for the hydrogen atom of the hydroxyl group of the above polysaccharide may be either straight-chain or branched.

Preferred examples of the carboxy-C _1-4 alkyl group include carboxymethyl, 1-carboxyethyl, 3-carboxypropyl, 1-methyl-3-carboxypropyl, 2-methyl-3-carboxy. Examples thereof include a propyl group and a 4-carboxybutyl group, and a carboxymethyl group and a 1-carboxyethyl group are particularly preferable.

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

When the above carboxyalkyl groups are introduced, the degree of the introduction is defined as the number of carboxyalkyl groups per sugar residue (including the groups into which peptide chains are further introduced). Can be expressed by the “degree of substitution”. That is,

[0036]

(Equation 1)

Can be expressed as follows. Hereinafter, the degree of substitution may be 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 is contained 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.

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.

The peptide includes not only the peptide derived from the above amino acid but also 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.

The binding direction of the peptide chain is usually from the N-terminus to the carboxyl group of the polysaccharide by an acid amide bond, but a basic amino acid (eg, lysine) is present in the peptide chain. In this case, the binding direction of the peptide chain may be reversed by binding the ε-amino group to the carboxyl group of the polysaccharide and binding the α-amino group to the C-terminal of the peptide chain.

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 the specific peptide 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 are mentioned (where the N-terminal side of these peptides and the peptide chain containing these sequences is introduced into the carboxyl group of the polysaccharide).

Of these peptides, glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine. Or L or D-phenylalanyl-glycine is more preferred.

Of these, glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine or L or D
-Phenylalanyl-glycine is particularly preferred.

As the active ingredient of the present invention, a camptothecin derivative comprising the compound [Ia] and carboxymethylated dextran or pullulan bound via a peptide is preferable.

Among the camptothecin derivatives, in the compound [Ia], R 1 is an unsubstituted lower alkyl group, R 2 is a hydrogen atom, and Alk is a linear or branched alkylene group (no oxygen atom is interposed). Compounds, especially Alk
Is a linear alkylene group having 2 to 4 carbon atoms,
More preferred is a derivative formed by binding to carboxymethylated dextran or pullulan via a peptide.

Among these, the peptide is glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine or L or D
Derivatives which are -phenylalanyl-glycine are particularly preferred.

The active ingredient of the present invention includes compounds [I] wherein R 1 is an ethyl group and X 1 -Alk-O— is an aminopropyloxy group, an aminobutyloxy group or an aminopentyloxy group. , Carboxymethylated dextran or polysaccharides such as pullulan, glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl- Camptothecin derivatives linked via a peptide such as glycyl-glycyl-glycyl-glycine or L or D-phenylalanyl-glycine are more preferred.

Among the derivatives, X 1 -Alk-O- is 3
Particularly preferred is an -aminopropyloxy group, a 4-aminobutyloxy group or a 5-aminopentyloxy group which is bonded to the camptothecin skeleton at the 10-position.

Further, as an active ingredient of the present invention, in the compound [I], R1 is an ethyl group, X1-Alk-O- is a 3-aminopropyloxy group, and the compound is bonded to the camptothecin skeleton at the 10-position. Compound and a polysaccharide such as carboxymethylated dextran or pullulan,
Glycyl-glycyl-L-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine or L
Alternatively, a camptothecin derivative linked via a peptide such as D-phenylalanyl-glycine is particularly preferred.

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 salts.

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 the pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, varies depending on the administration method, age, weight, condition and the like of the patient.
Usually, once each dose of the camptothecin compound [I] [X1
Is a formula: -NHR2, it is 0.02 to 50 mg / kg, especially 0.1 to 10
It is preferable to administer in the range of 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, a camptothecin derivative or a pharmaceutically acceptable salt thereof, which is an active ingredient of the present invention, has excellent antitumor activity in nude mice into which human breast cancer MX-1 cells or human lung cancer LX-1 cells have been subcutaneously implanted. To play.

The camptothecin derivative or the pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has low toxicity.

[0064]

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The camptothecin derivative represented by
Intravenous administration to B / C mice once a day for 3 days (80 mg / kg / da in terms of camptothecin compound hydrochloride)
y) Then, observation was performed for 49 days, but no death was observed.

For this reason, the pharmaceutical composition of the present invention comprises solid tumors [eg, lung cancer, uterine cancer, ovarian cancer, breast cancer, gastrointestinal cancer (colorectal cancer, gastric 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 as 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 group-containing polysaccharide is reacted therewith. The method of making it do is adopted.

By reacting the compound [I] with an amino acid or a peptide, in the formula [I], when X 1 is a formula: —NHR 2, an acid amide bond is formed between the compound and the C-terminal carboxyl group of the amino acid or peptide; When X1 is -OH, an ester bond is formed.

At this time, it is preferable to protect other functional groups in the amino acid or peptide which do not participate in the acid amide bond or the ester bond, for example, the N-terminal amino group or other carboxyl group by a conventional method. .

The 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-methoxybenzyloxycarbonyl group. However, examples of the carboxyl-protecting 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 in a conventional manner, for example, in a suitable solvent (eg, dimethylformamide, acetonitrile, etc.) in the presence of a condensing agent (eg, dicyclohexylcarbodiimide, etc.). Can be done with

When the amino or carboxyl group of the camptothecin compound to which the amino acid or peptide obtained as described above is bonded is protected, if necessary, the protecting group is removed by a conventional method, and then the carboxyl group is removed. The camptothecin derivative is produced by reacting the polysaccharide having the camptothecin derivative. 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, in a suitable solvent (eg, water, ethanol, etc.). A condensing agent (eg, 1- (3-dimethylaminopropyl) -3
-Ethyl carbodiimide hydrochloride).

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-sulfated heparin, the content is preferably 0.1 to 20% by weight,
Particularly preferred is from 10 to 10% by weight.

The average molecular weight (measured by the GPC method) of the camptothecin derivative, which is the active ingredient of the present invention, is preferably 30,000 to 500,000, more preferably 60,000 to 200,000 when the polysaccharide is dextran. preferable.

The camptothecin compound [I] as the active ingredient of the present invention is produced by the method shown in the following reaction formula 1.

[0078]

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Wherein X 2 represents a protecting group —N (R 2) — or a protecting group —O—, and R 1, R 2, X 1 and Alk are the same as described above. Pyranoindolizine (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 desired camptothecin compound [I].

In the above-mentioned production method, the group represented by R1 may be introduced after the Friedlander condensation reaction. That is, instead of the starting compound (1), a compound having hydrogen instead of the group represented by R1 in the compound (1) is used, and the compound is subjected to a Friedlander condensation reaction with the compound (2), and then obtained. The condensation product
Derivatives of the formula: R 1 —CO—X, where X is hydrogen or a reactive group, are described, for example, in Chem. Pharm. Bull
l. 39, 2574-2580 (1991), followed by removal of the protecting group to give compound [I].

In the above reaction formula 1, instead of the aminocarbonyl compound (1), general formula [II]:

[0082]

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[Wherein X3 is R3-N (R2)-or R3
-O-, R3 represents a group obtained by removing the carboxyl hydroxyl group from an amino acid-protected amino acid or a peptide, and R1, R2 and Alk are the same as those described above, and a camptothecin compound [ A compound in which an amino acid or a peptide is bound to I] can also be directly obtained.

In the aminocarbonyl compound (1) as a starting compound used in the above method, the group X2 is a protecting group
When it is N (R2)-, for example, it is produced by a method represented by the following reaction formula 2.

[0085]

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Wherein R 1, R 2 and Alk are as defined above, R 3 is a substituted or unsubstituted lower alkenyl or alkyl group, R 4 is a protected aminoalkyl group, Pr
ot represents a protecting group, T represents a tosyl group or a mesyl group] That is, a protecting group is introduced into an aminoalkanol to obtain a protected aminoalkanol (a), which is tosylated or mesylated to activate a hydroxyl group. Compound (b) is obtained. On the other hand, a Grignard reagent (R3 MgBr) was allowed to act on the hydroxyl-substituted o-nitrobenzaldehyde, and the obtained compound (c) was reacted with the activated protected aminoalkanol (b) prepared above to alkylate the phenolic hydroxyl group. Compound (d) is obtained, which is treated with an oxidizing agent, for example, activated manganese dioxide to give ketone (e), which is then catalytically reduced in the presence of a suitable catalytic reduction catalyst, for example, Pd-C, to give compound (d). (11) is obtained.
Although this compound (11) can be isolated, it can be directly used for the condensation reaction with the compound (2) without isolation and purification.

Further, among the aminocarbonyl compounds (1) in the above reaction formula 1, the compound wherein X 2 is a protecting group —O— is produced, for example, by the method shown in the following reaction formula 3.

[0088]

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Wherein Alk, R1 and R3 are the same as described above, R5 is a lower alkyl group, X3 is a halogen atom, R6 is a hydroxyalkyl group, and R7 is a protected hydroxyalkyl group. A hydroxyalkyl halide is allowed to act on an o-nitrobenzaldehyde dialkyl acetal to hydroxyalkyl a phenolic hydroxyl group, and the hydroxyl group of the hydroxyalkyl group is, for example, t-
After protection with a butyldimethylsilyl group or the like, the obtained acetal is hydrolyzed to obtain an alkoxy-substituted o-nitrobenzaldehyde derivative, which is then reacted with a Grignard reagent in the same manner as in the above-mentioned reaction formula 2 to obtain the compound obtained. (D1) is oxidized in the same manner as in the above Reaction Scheme 2 to give compound (e).
1), which may further catalytic reduction to the compound (l ¹ 1).

In the above reaction formula 2, after removing the amino-protecting group in R 4 of the ketone (e) by a conventional method, the amino-protected amino acid or peptide is removed in the same manner as in the case of compound [I]. To produce a peptide bond, and the product is catalytically reduced in the same manner as ketone (e), or compound (e)
After removing the hydroxyl-protecting group of 1) by a conventional method, the compound is reacted with an amino-protected amino acid or peptide to form an ester bond in the same manner as in the case of compound [I], and the product is converted into a ketone compound (e1). Compound [II] can also be obtained by catalytic reduction in the same manner as in (2).

[0091]

[Experimental example]

EXPERIMENTAL EXAMPLE 1 [Action on Human Breast Cancer MX-1 Cells] (1) Tumor was excised from a passaged MX-1 tumor-bearing nude mouse, cut into small pieces, and a 3 mm square tumor tissue piece was prepared. The mice are implanted subcutaneously on the ventral side.

(2) The major axis and the minor axis of the tumor were measured, and the estimated tumor volume determined according to the following equation (1) was 100-300 m.
At the time of growth to the range of m3, treatment is started with 5 animals per group.

Here, the administered specimen is physiologically converted so as to have a concentration of 0.75 mg / ml in terms of the corresponding camptothecin compound [I] [when X1 is a formula: -NHR2, hydrochloride]. Dilute with saline solution, 7.5mg / kg for single dose
Administer intravenously.

(3) The major axis and minor axis of the tumor are measured until 28 or 31 days after the administration of the sample, and the estimated tumor volume is calculated for each mouse according to the following formula (1).

[0095]

(Equation 2)

(4) The relative tumor volume ratio on each measurement day (tumor volume ratio on each measurement day to the tumor volume on the administration start date) was calculated for each mouse, and the average relative tumor volume ratio for each group was determined.
The growth inhibition rate of the tumor during the experimental period is calculated according to the following equation (2).

[0097]

(Equation 3)

(5) Maximum growth inhibition rate (%) of each administered sample
(The maximum of the growth inhibition rates calculated during the experimental period in each administered sample) is as shown in Table 1 below.

[0099]

[Table 1]

Experimental Example 2 [Action on Human Lung Cancer LX-1 Cells] (1) A tumor was removed from a nude mouse bearing LX-1 subculture and cut into small pieces, and a tumor tissue piece of about 3 mm square was prepared. Implanted subcutaneously on the ventral side of a male nude mouse.

(2) The major axis and the minor axis of the tumor were measured, and the estimated tumor volume determined according to the equation (1) of Experimental Example 1 was 10
At the time of growth to the range of 0 to 300 mm 3, treatment is started with 5 animals per group.

Here, the administered sample is a physiological saline solution so as to have a concentration of 4 mg / ml in terms of the corresponding camptothecin compound [I] [in the case where X 1 is the formula: —NHR 2, the hydrochloride salt]. And a single 60 mg / kg iv dose.

(3) The major axis and minor axis of the tumor are measured up to 26 days after the administration of the sample, and the estimated tumor volume is calculated for each mouse according to the formula (1) in Experimental Example 1.

(4) The relative tumor volume ratio on each measurement day (tumor volume ratio on each measurement day to the tumor volume on the administration start day) was calculated for each mouse, and the average relative tumor volume ratio for each group was determined.
The tumor growth inhibition rate during the experimental period is calculated according to the formula (2) in Experimental Example 1.

(5) Maximum growth inhibition rate (%) of each administered sample
(The maximum of the growth inhibition rates calculated during the experimental period, which was the highest for each administered sample) is as shown in Table 2 below.

[0106]

[Table 2]

[0107]

[Production Examples] The compounds which are the active ingredients of the present invention and the production method thereof will be described more specifically by the following production examples.
The active ingredient of the present invention is not limited to these.

Production Example 1 10- (3'-aminopropyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride (1) Synthesis of 3-t-butoxycarbonylaminopropanol 6.0 g of 3-aminopropanol was added to 50 m of methylene chloride.
Then, 18.3 g of di-t-butyl dicarbonate is added dropwise under ice cooling and stirring. After stirring at room temperature for 2 hours, the reaction solution was concentrated and purified by silica gel column chromatography to obtain 13.98 g of 3-t-butoxycarbonylaminopropanol as a colorless oil.

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-butoxycarbonylaminopropyl tosylate 3-t-butoxycarbonylaminopropanol
Was dissolved in 100 ml of methylene chloride, and 8.66 g of triethylamine and tosyl chloride 1 were stirred under ice-cooling and stirring.
Add 6.3 g and stir at room temperature overnight. Concentrate the reaction,
After dissolving the residue in water-ethyl acetate, the organic layer was separated, washed with saturated saline, dried over sodium sulfate, evaporated, and purified by silica gel column chromatography to give a pale yellow oil.
15.37 g of -t-butoxycarbonylaminopropyl tosylate are obtained.

Yield: 82% IR (Neat): ν _max ^{cm -1} = 3400,3340,
1700, 1600 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) Synthesis of 1- (5'-hydroxy-2'-nitrophenyl) -2-propen-1-ol 6.0 g of 5-hydroxy-2-nitrobenzaldehyde
Was dissolved in 90 ml of dry tetrahydrofuran,
Under stirring, 2.3 equivalents of vinylmagnesium bromide are added dropwise. After the temperature was gradually raised and the reaction was completed, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated saline, dried over sodium sulfate, evaporated, and purified by silica gel column chromatography to give a yellow-brown powder. 1- (5 '
-Hydroxy-2'-nitrophenyl) -2-propen-1-ol (5.09 g) is obtained.

Yield: 73% Melting point: 126-130 ° C. IR (Nujol): ν _max ^{cm −1} = 3440, 1600 Mass: m / z = 195 (M ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 2.4
(1H, br), 5.19 (1H, dd, J = 10.5)
Hz and 1.5 Hz), 5.38 (1H, dd, J =
17Hz and 1.5Hz), 5.89 (1H, m),
6.08 (1H, ddd, J = 17Hz, 10.5Hz
And 5 Hz), 6.80 (1 H, dd, J = 9 Hz and 3 Hz), 7.22 (1 H, d, J = 3 Hz),
7.97 (1H, d, J = 9 Hz), 9.90 (1H, d, J = 9 Hz)
brs).

(4) Synthesis of 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1-ol 1- (5'-hydroxy-2 '-Nitrophenyl) -2
-2.0 g of propen-1-ol in 100 m of dry DMF
and 1 equivalent of sodium iodide and 1.5 equivalents of potassium carbonate and 3-t-butoxycarbonylaminopropyl tosylate. After stirring at 50 ° C. for 6 hours, ethyl acetate was added, and the mixture was washed with saturated saline and dried over sodium sulfate. Purified by silica gel column chromatography to obtain a light brown caramelized 1- [5 ′-(3 ″ -t-).
(Butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1-ol 3.53 g
Get.

Yield: 98% IR (Neat): ν _max ^{cm -1} = 3400,1690,
1680 Mass: m / z = 375 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.44
(9H, s), 1.96-2.06 (2H, m), 2.
80 (1H, brs), 3.33 (2H, q, J = 6.
5 Hz), 4.11 (2H, t, J = 6 Hz), 4.8
(1H, brs), 5.24 (1H, dd, J = 10.
5 Hz and 1.5 Hz), 5.42 (1H, dd, J
= 17 Hz and 1.5 Hz), 5.92 (1H, d,
J = 5 Hz), 6.08 (1H, ddd, J = 17H)
z, 10.5 Hz and 5 Hz), 6.86 (1H, d
d, J = 9 Hz and 3 Hz), 7.25 (1H, d,
J = 3 Hz), 8.04 (1 H, d, J = 9 Hz).

(5) Synthesis of 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1-one 1- (5'-(3" 9.66 g of -t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl) -2-propen-1-ol is dissolved in 300 ml of chloroform, and 72 g of activated manganese dioxide is added thereto, followed by heating under reflux. After completion of the reaction, the inorganic substances were removed by filtration through Celite, and the filtrate was concentrated. After stirring at 50 ° C. for 6 hours, ethyl acetate was added.
Wash with saturated saline and dry with sodium sulfate. Purification by silica gel column chromatography yields a yellow 1-
[5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propene-
6.01 g of 1-one are obtained.

Melting point: 65-71 ° C. Yield: 63% IR (Neat): ν _max ^{cm −1} = 3350, 1700 Mass: m / z = 351 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.44
(9H, s), 1.98-2.18 (2H, m), 3.
28-3.37 (2H, q, J = 6.5 Hz), 4.0
8-4.16 (2H, m), 4.67 (1H, br)
s), 5.85 (1H, d, J = 17.5 Hz), 6.
02 (1H, d, J = 10.5 Hz), 6.62 (1
H, dd, J = 17.5 Hz and 10.5 Hz),
6.82 (1H, d, J = 3 Hz), 7.03 (1H,
dd, J = 9 Hz and 3 Hz), 8.17 (1H,
d, J = 9 Hz).

(6) Synthesis of 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-aminophenyl] -propan-1-one 1- [5'-(3" -t -Butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1-one (325 mg) is dissolved in ethanol (15 ml), 10% palladium on carbon (40 mg) is added, and the mixture is stirred under a hydrogen stream for 1.5 hours. The catalyst was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography to give 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-aminophenyl] -propane as a yellow powder. 248 mg of -1-one are obtained.

Melting point: 112-115 ° C. Yield: 83% IR (Nujol): ν _max ^{cm −1} = 3450,340
0,3340,1700,1650 Mass: m / z = 323 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.21
(3H, t, J = 7 Hz), 1.45 (9H, s),
1.90-2.01 (2H, m), 2.95 (2H,
q, J = 7.5 Hz), 3.33 (2H, q, J = 6.
5Hz), 3.97 (2H, t, J = 6.5Hz),
4.48 (1H, brs), 5.96 (2H, br)
s), 6.62 (1H, d, J = 9 Hz), 6.95.
(1H, dd, J = 9 Hz and 3 Hz), 7.24
(1H, d, J = 3 Hz).

(7-1) 10- (3'-tert-butoxycarbonylaminopropyloxy) -7-ethyl- (20
Synthesis of S) -camptothecin 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-aminophenyl] -propane-
Dissolve 4.54 g of 1-one in 200 ml of ethanol,
(4S) -7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] indolizine-3,
1.85 g of 6,10 (4H) -trione and 134 mg of p-toluenesulfonic acid are added, and the mixture is heated to reflux. After completion of the reaction, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 10- (3'-t-) as a pale yellow powder.
2.47 g of butoxycarbonylaminopropyloxy) -7-ethyl- (20S) -camptothecin are obtained.

Melting point: 196-201 ° C. (decomposition) Yield: 64% IR (Nujol): ν _max ^{cm −1} = 3450,338
5,1740,1715,1685,1665,162
0 Mass: m / z = 550 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.03
(3H, t, J = 7.5 Hz), 1.39 (3H, t,
J = 7.5 Hz), 1.46 (9H, s), 1.82-
1.98 (2H, m), 2.04-2.16 (2H,
m), 3.12 (2H, q, J = 7.5 Hz), 3.4
1 (2H, q, J = 6 Hz), 3.93 (1H, s),
4.20 (2H, t, J = 6 Hz), 4.84 (1H,
brs), 5.21 (2H, s), 5.29 (1H,
d, J = 16 Hz), 5.74 (1H, d, J = 16H)
z), 7.28 (1H, d, J = 3 Hz), 7.43
(1H, dd, J = 9 Hz and 3 Hz), 7.60
(1H, s), 8.12 (1H, d, J = 9 Hz).

(7-2) Synthesis of 10- (3′-acetylaminopropyloxy) -7-ethyl- (20S) -camptothecin From the corresponding starting compound, in the same manner as in the above (1) to (7-1), 10- (3'-acetylaminopropyloxy)-
7-Ethyl- (20S) -camptothecin is obtained.

Melting point: 240-245 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3405,333
0, 1730, 1680, 1655 Mass: m / z = 492 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.82 (3H, s), 1.8
0-2.0 (4H, m), 3.1-3.2 (2H,
m), 3.26 (2H, dt, J = 13 Hz and 6H
z), 4.21 (2H, t, J = 6 Hz), 5.26
(2H, s), 5.42 (2H, s), 6.51 (1
H, s), 7.25 (1H, s), 7.45 (1H,
d, J = 3 Hz), 7.49 (1H, dd, J = 9 Hz)
And 3Hz), 7.98 (1H, t, J = 5Hz),
8.05 (1H, d, J = 9 Hz).

(8-1) Synthesis of 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride 10- (3′-t-butoxycarbonylaminopropyloxy) -7-ethyl -(20S) -camptothecin 6
41 mg is dissolved in 10 ml of dioxane, and 11 ml of 18% hydrochloric acid-dioxane is added dropwise while stirring on an ice bath. After stirring at room temperature, the reaction was completed, 15 ml of isopropyl ether was added, and the mixture was stirred. The precipitated powder was collected by filtration, washed with ether, and dried under reduced pressure. The obtained powder was dissolved in water and lyophilized to give 10- (yellow powder). 563 mg of 3'-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride are obtained.

Melting point: 218 ° C. or higher (decomposition) Yield: 99% IR (Nujol): ν _max ^{cm −1} = 3370,174
5,1655 Mass: m / z = 450 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 8 Hz), 1.78-1.95 (2H, m), 2.
08-2.19 (2H, m), 3.0-3.1 (2H,
m), 3.13-3.25 (2H, m), 4.32 (2
H, t, J = 6 Hz), 5.32 (2H, s), 5.4
3 (2H, s), 7.28 (1H, s), 7.5-7.
56 (2H, m), 7.99 (3H, brs), 8.1
1 (1H, d, J = 10 Hz).

(8-2) Synthesis of 10- (3'-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride The product of (7-2) was treated with hydrochloric acid-methanol. 10- (3'-aminopropyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride is obtained. The physicochemical constants of this product are consistent with the product of (8-1).

Production Example 2 10- (2'-aminoethyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 10- (2′-aminoethyloxy) -7-ethyl- (20S) -camptothecin hydrochloride as a yellow powder is obtained.

Melting point: 249 ° C. or higher (decomposition) Yield: 97% IR (Nujol): ν _max ^{cm −1} = 3400, 174
5,1655,1620 Mass: m / z = 436
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-1.94 (2H,
m), 3.21 (2H, q, J = 7 Hz), 3.27-
3.37 (2H, m), 4.45 (2H, t, J = 5H
z), 5.31 (2H, s), 5.43 (2H, s),
7.28 (1H, s), 7.54-7.58 (2H,
m), 8.13 (1H, d, J = 10 Hz), 8.31
(3H, brs).

Production Example 3 10- (5'-Aminopentyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 10- (5′-aminopentyloxy) -7-ethyl- (20S) -camptothecin hydrochloride as a yellow powder is obtained.

Melting point: 179 ° C. or higher (decomposition) Yield: 98% IR (KBr): ν _max ^{cm −1} = 3420,17445,1
660, 1615 Mass: m / z = 478 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.49-1.59 (2H,
m), 1.63-1.73 (2H, m), 1.80-
1.91 (4H, m), 2.77-2.88 (2H,
m), 3.19 (2H, q, J = 8 Hz), 4.21
(2H, t, J = 6 Hz), 5.29 (2H, s),
5.43 (2H, s), 7.28 (1H, s), 7.4
8-7.53 (2H, m), 7.98 (3H, br)
s), 8.08 (1H, d, J = 9 Hz).

Production Example 4 9- (3'-aminopropyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 9- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride is obtained.

Production Example 5 11- (3'-aminopropyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 11- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride is obtained.

Production Example 6 Synthesis of 10- [2 ′-(2 ″ -aminoethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 10- [10 '[2'-
(2 "-aminoethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride is obtained.

Melting point: 135 ° C. or more (gradual decomposition) IR (KBr): ν _max ^{cm −1} = 3405,1741,1
655, 1615 Mass: m / z = 480 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-1.94 (2H,
m), 2.97-3.06 (2H, m), 3.20 (2
H, q, J = 7.5 Hz), 3.75 (2H, t, J =
5.5 Hz), 3.89-3.92 (2H, m), 4.
38-4.40 (2H, m), 5.30 (2H, s),
5.43 (2H, s), 7.29 (1H, s), 7.5
2-7.56 (2H, m), 8.10 (1H, d, J =
9.5 Hz), 8.04-8.23 (3H, brs).

Production Example 7 Synthesis of 10- (3′-methylaminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 10- (3′-methyl) was obtained as a yellow powder. Aminopropyloxy) -7-ethyl- (20S)
Obtaining camptothecin hydrochloride;

Melting point: 180 ° C. or higher (decomposition) Yield: 97% IR (KBr): ν _max ^{cm −1} = 3410,1741,1
660, 1615 Mass: m / z = 464 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-1.94 (2H,
m), 2.15-2.24 (2H, m), 2.57-
2.61 (3H, m), 3.17-3.24 (4H,
m), 4.33 (2H, t, J = 6 Hz), 5.31
(2H, s), 5.43 (2H, s), 7.28 (1
H, s), 7.52-7.55 (2H, m), 8.10.
(1H, d, J = 10 Hz), 9.00 (2H, br)
s).

Production Example 8 Synthesis of 10- [3 ′-(L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (1) 10- [3 ′-(t-Butoxycarbonyl-L) −
Tyrosylamino) propyloxy] -7-ethyl- (2
Synthesis of 0S) -camptothecin 10- (3'-aminopropyloxy) -7-ethyl-
200 mg of (20S) -camptothecin hydrochloride in dry D
Dissolved in 10 ml of MF and stirred under ice-cooling while stirring with 139 mg of t-butoxycarbonyl-L-tyrosine, 44 mg of triethylamine, 85 m of N-hydroxysuccinimide
g, and 1- (3-dimethylaminopropyl) -3-
95 mg of ethyl carbodiimide hydrochloride are added sequentially. After adding a catalytic amount of 4-dimethylaminopyridine (DMAP), the mixture was stirred at room temperature. After completion of the reaction, the solvent was distilled off, extracted with chloroform, and separated and purified by silica gel column chromatography to obtain 10- [3 ′-( t-butoxycarbonyl-L-tyrosylamino) propyloxy] -7
181 mg of -ethyl- (20S) -camptothecin are obtained.

Yield: 62% IR (Nujol): ν _max ^{cm -1} = 3280,175
0.11710 Mass: m / z = 735 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.92
(3H, t, J = 7 Hz), 1.31 (3H, t, J =
7.5 Hz), 1.41 (9H, s), 1.75-2.
02 (4H, m), 2.86-3.10 (4H, m),
3.3-3.6 (2H, m), 3.8-4.0 (2H,
m), 4.24-4.38 (1H, m), 4.78 (1
H, brs), 5.00 (2H, s), 5.21 (1
H, d, J = 16.5 Hz), 5.26-5.37 (1
H, m), 5.64 (1H, d, J = 16.5 Hz),
6.56 (1H, br), 6.81 (2H, d, J =
8.5 Hz), 7.06 (2H, d, J = 8.5H)
z), 7.12 (1H, d, J = 2.5 Hz), 7.2
2-7.31 (1H, m), 7.60 (1H, s),
8.16 (1H, d, J = 9 Hz).

(2) Synthesis of 10- [3 ′-(L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3 ′-(t-Butoxycarbonyl-L-tyrosylamino) Propyloxy] -7-ethyl- (20S)
-157 mg of camptothecin is dissolved in 5 ml of dioxane, and 2 ml of 18% hydrochloric acid-dioxane is stirred on an ice bath.
Is dropped. After stirring at room temperature and adding 20 ml of isopropyl ether after completion of the reaction and stirring, the precipitated powder was collected by filtration, washed with ether, dried under reduced pressure, dissolved in water and freeze-dried to give 10- [3 '-(L- Tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 120 mg is obtained.

Melting point: 190 ° C. or higher (decomposition) Yield: 84% IR (Nujol): ν _max ^{cm −1} = 3375,324
0.1740 Mass: m / z = 613 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 8 Hz), 1.75-1.98 (4H, m), 2.
93 (2H, d, J = 7 Hz), 3.14-3.43
(4H, m), 3.87 (1H, t, J = 7 Hz),
4.05-4.23 (2H, m), 5.30 (2H,
s), 5.43 (2H, s), 6.71 (2H, d, J
= 8.5 Hz), 7.03 (2H, d, J = 8.5H)
z), 7.28 (1H, s), 7.43-7.54 (2
H, m), 8.09 (1H, d, J = 9 Hz), 8.3
(3H, m), 8.66 (1H, t, J = 5 Hz).

Production Example 9 10- [3 '-(Glycylamino) propyloxy]-
Synthesis of 7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 8, 10- [3′-
(Glycylamino) propyloxy] -7-ethyl-
(20S) -Camptothecin hydrochloride is obtained.

Melting point: 190 ° C. or higher (decomposition) Yield: 93% IR (Nujol): ν _max ^{cm −1} = 3355,322
5,1745,1655 Mass: m / z = 507
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
85 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 8 Hz), 1.79-1.94 (2H, m),
1.94-2.06 (2H, m), 3.20 (2H,
q), 3.37 (2H, q), 3.52-3.60 (2
H, m), 4.28 (2H, t, J = 6 Hz), 5.2
9 (2H, s), 5.43 (2H, s), 7.29 (1
H, s), 7.47-7.56 (1H, m), 7.51.
(1H, s), 8.09 (1H, d, J = 9 Hz),
8.20 (3H, m), 8.71 (1H, t, J = 5.
5 Hz).

Production Example 10 10- [3 '-(L-serylamino) propyloxy]
Synthesis of -7-ethyl- (20S) -camptothecin hydrochloride (1) 10- [3 '-(t-butoxycarbonyl-L-
[Cerylamino) propyloxy] -7-ethyl- (20
Synthesis of S) -camptothecin 10- (3'-aminopropyloxy) -7-ethyl-
Using 20 mg of (20S) -camptothecin hydrochloride, treatment was conducted in the same manner as in Production Example 8- (1), to give 10- [3 ′-(t-butoxycarbonyl-L-serylamino) propyloxy] as a pale yellow powder. -7-ethyl- (20
351 mg of S) -camptothecin are obtained.

Melting point: 123-129 ° C. Yield: 84% IR (Nujol): ν _max ^{cm −1} = 3305,175
0.1705 Mass: m / z = 637 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.00
(3H, t, J = 7 Hz), 1.35 (3H, t, J =
8Hz), 1.45 (9H, s), 1.7-1.95
(2H, m), 2.08-2.20 (2H, m), 2.
94-3.15 (2H, m), 3.53-3.64 (2
H, m), 3.66-3.77 (2H, m), 4.12.
(1H, d, J = 4 Hz), 4.18 (2H, t, J =
6 Hz), 4.2-4.3 (1H, m), 5.05 (2
H, s), 5.26 (1H, d, J = 16 Hz), 5.
70 (1H, d, J = 16 Hz), 5.74 (1H,
d, J = 8.5 Hz), 7.13-7.24 (1H,
m), 7.40 (1H, dd, J = 9 Hz and 3H
z), 7.56 (1H, s), 8.02 (1H, d, J
= 9 Hz).

(2) Synthesis of 10- [3 '-(L-serylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 8- (2), a yellow powder was obtained. Of 10
-[3 ′-(L-serylamino) propyloxy] -7
-Ethyl- (20S) -camptothecin hydrochloride 262m
g.

Melting point: 173-177 ° C. (decomposition) Yield: 88% IR (Nujol): ν _max ^{cm −1} = 3350,324
0.1745 Mass: m / z = 537 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
86 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 8 Hz), 1.77-1.95 (2H, m), 1.
95-2.07 (2H, m), 3.13-3.36 (2
H, m), 3.32-3.45 (2H, m), 3.68
-3.78 (2H, m), 3.78-3.86 (1H,
m), 4.27 (2H, t, J = 6 Hz), 5.30
(2H, s), 5.43 (2H, s), 7.29 (1
H, s), 7.48-7.56 (1H, m), 7.51.
(1H, brs), 8.09 (1H, d, J = 9H
z), 8.17-8.28 (3H, m), 8.72 (1
H, t, J = 5 Hz).

Production Example 11 Synthesis of 10- [3 '-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (1) 10- [3'-(t- Butoxycarbonyl-L-
Phenylalanyl-glycylamino) propyloxy]
Synthesis of -7-ethyl- (20S) -camptothecin 10- (3'-aminopropyloxy) -7-ethyl-
200 mg of (20S) -camptothecin hydrochloride in dry D
Dissolved in 20 ml of MF and stirred under ice-cooling while stirring tert-butoxycarbonyl-L-phenylalanylglycine 199 m
g, 44 mg of triethylamine, 28 mg of N-hydroxybenzotriazole and 118 m of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
g is added sequentially. After adding a catalytic amount of 4-dimethylaminopyridine, the mixture was stirred at room temperature. After the reaction was completed, the solvent was distilled off, extracted with chloroform, and separated and purified by silica gel column chromatography to obtain 10- [3 ′-(t-butoxy) as a pale yellow powder. 228 mg of carbonyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin are obtained.

Yield: 73% IR (Nujol): ν _max ^{cm -1} = 3300,175
0,1655,1625 Mass: m / z = 754 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.02
(3H, t, J = 7 Hz), 1.37 (3H, t, J =
7 Hz), 1.38 (9H, s), 1.81-1.97
(2H, m), 2.06-1.17 (2H, m), 2.
95 (1H, dd, J = 14 Hz and 8 Hz);
01-3.16 (2H, m), 3.12 (1H, dd,
J = 14 Hz and 6 Hz), 3.39-3.62 (2
H, m), 3.93 (2H, m), 4.12-4.27.
(3H, m), 5.03 (1H, d, J = 6.5H
z), 5.13 (2H, s), 5.26 (1H, d, J
= 16.5 Hz), 5.71 (1H, d, J = 16.5)
Hz), 6.7 (1H, br), 6.9 (1H, b
r), 7.09-7.17 (1H, m), 7.18-
7.33 (5H, m), 7.35-7.43 (1H,
m), 7.55 (1H, s), 8.04 (1H, d, J
= 9 Hz).

(2) Synthesis of 10- [3 '-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t-butoxycarbonyl- L-phenylalanyl-glycylamino) propyloxy] -7-
197 mg of ethyl- (20S) -camptothecin is dissolved in 5 ml of dioxane, and 2.5 ml of 18% hydrochloric acid-dioxane is added dropwise while stirring on an ice bath. After stirring at room temperature and adding 30 ml of isopropyl ether after completion of the reaction and stirring, the precipitated powder was collected by filtration, washed with ether, dried under reduced pressure, and the obtained powder was dissolved in water and lyophilized to give 10- [ 3 '-(L-phenylalanylglycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (152 mg) is obtained.

Melting point: 190 ° C. or higher (decomposition) Yield: 84% IR (Nujol): ν _max ^{cm −1} = 3230, 1745 Mass: m / z = 654 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.31 (3H, t,
J = 7 Hz), 1.78-1.93 (2H, m), 1.
93-2.06 (2H, m), 2.98 (1H, dd,
J = 13.5 Hz and 7.5 Hz), 3.11 (1
H, dd, J = 13.5 Hz and 6 Hz), 3.1-
3.25 (2H, m), 3.25-3.38 (2H,
m), 3.6-3.71 (1H, m), 3.75-3.
9 (1H, m), 4.09 (1H, m), 4.25 (2
H, t, J = 6 Hz), 5.29 (2H, s), 5.4
3 (2H, s), 7.2-7.35 (6H, m), 7.
50 (1H, s), 7.47-7.55 (1H, m),
8.08 (1H, d, J = 9 Hz), 8.20 (1H,
m), 8.4 (3H, brs), 8.92 (1H,
m).

In the same manner as in Production Example 11, the following Production Example 1
2 to 15 compounds are obtained.

Production Example 12 10- [2 ′-(L-Phenylalanyl-glycylamino) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride.

Production Example 13 9- [3 '-(L-Phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride.

Production Example 14 11- [3 ′-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride.

Production Example 15 10- [3 ′-(L-tyrosyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride.

Production Example 16 Synthesis of 10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (1) 1
Synthesis of 0- [3 '-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin 10- (3'-aminopropyloxy)- 7-ethyl-
Synthesized in the same manner as in Production Example 11- (1) using 650 mg of (20S) -camptothecin hydrochloride, to give 1 as a pale yellow powder.
714 mg of 0- [3 ′-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin are obtained.

Yield: 62% IR (Nujol): ν _max ^{cm -1} = 3290,175
0,1655,1625 Mass: m / z = 890 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ -d ₆ DMSO): δ
^TMS = 1.02 (3H, t, J = 7.5 Hz), 1.3
6 (3H, t, J = 7.5 Hz), 1.43 (9H,
s), 1.82-1.98 (2H, m), 2.12 (2
H, m), 3.00 (1H, dd, J = 14.5 Hz and 10 Hz), 3.05-3.15 (2H, m),
3.19-3.29 (1H, dd, J = 14.5 Hz and 6 Hz), 3.49 (2H, m), 3.65-3.
85 (4H, m), 3.90 (2H, m), 4.18
(2H, t, J = 6 Hz), 4.43-4.54 (1
H, m), 4.80 (1H, brs), 5.15 (2
H, s), 5.28 (1H, d, J = 16.5 Hz),
5.70 (1H, d, J = 16.5 Hz), 5.85 −
5.95 (1H, m), 7.08-7.3 (6H,
m), 7.28 (1H, d, J = 3 Hz), 7.42
(1H, dd, J = 9 Hz and 3 Hz), 7.50
(1H, d, J = 7 Hz), 7.56 (1H, s),
7.61 (1H, m), 7.66-7.78 (1H,
m), 8.04 (1H, d, J = 9 Hz).

(2) Synthesis of 10- [3 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t -Butoxycarbonyl-glycyl-
Deprotection was performed using 680 mg of glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin in the same manner as in Production Example 8- (2), to give 10- [3 ′] as a yellow powder. 556 mg of-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride are obtained.

Melting point: 185 ° C. or more (decomposition) Yield: 88% IR (Nujol): ν _max ^{cm −1} = 3240, 1745 Mass: m / z = 768 [(M−Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.31 (3H, t,
J = 8 Hz), 1.79-1.93 (2H, m), 1.
93-2.05 (2H, m), 2.83 (1H, dd,
J = 14 Hz and 10 Hz), 3.05 (1 H, d
d, J = 14 Hz and 4 Hz), 3.1-3.25
(2H, m), 3.25-3.4 (2H, m), 3.5
3-3.61 (2H, m), 3.64 (1H, m),
3.69 (1H, m), 3.76 (1H, dd, J = 1
6 Hz and 6 Hz), 3.85 (1H, dd, J = 1)
6 Hz and 6 Hz), 4.25 (2H, t, J = 6H)
z), 4.52 (1H, m), 5.28 (2H, s),
5.43 (2H, s), 7.12-7.19 (1H,
m), 7.19-7.27 (5H, m), 7.30 (1
H, s), 7.48-7.57 (2H, m), 7.91.
(1H, t, J = 6 Hz), 8.09 (1H, d, J =
9Hz), 8.17 (3H, br), 8.36 (1H,
t, J = 6 Hz), 8.43 (1 H, d, J = 8.5 H)
z), 8.65 (1H, t, J = 5 Hz).

Production Example 17 Synthesis of 10- [5 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) pentyloxy] -7-ethyl- (20S) -camptothecin hydrochloride Production Example 11- (1) and In the same manner as in Production Example 8- (2), 10- [5 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) pentyloxy] -7-ethyl- (20S) -camptothecin hydrochloride in the form of a yellow powder. Get.

Melting point: 185 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3250,174
0.1660 Mass: m / z = 796 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.56-1.60 (4H,
m), 1.77-1.94 (4H, m), 2.79-
2.89 (1H, m), 3.02-3.23 (5H,
m), 3.58-3.90 (6H, m), 4.20 (2
H, t, J = 6 Hz), 4.49-4.60 (1H,
m), 5.29 (2H, s), 5.43 (2H, s),
7.14-7.27 (5H, m), 7.30 (1H,
s), 7.47-7.54 (2H, m), 7.85 (1
H, t, J = 6 Hz), 8.08 (1H, d, J = 9H)
z), 8.04-8.20 (3H, br), 8.33
(1H, t, J = 6 Hz), 8.42 (1H, d, J =
8 Hz), 8.64 (1 H, t, J = 6 Hz).

Production Example 18 Production of 10- [3 ′-(N- (glycyl-glycyl-L-phenylalanyl-glycyl) -N-methylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Production Example 8- (2), yellow powdery 10- [3 ′-(N- (glycyl-glycyl-L-phenylalanyl-glycyl) -N-methylamino) was obtained. ) Propyloxy] -7-ethyl- (20S)
Obtaining camptothecin hydrochloride;

Melting point: 190 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3230,174
5,1655 Mass: m / z = 782 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.29-1.3
4 (3H, m), 1.80-1.94 (2H, m),
2.00-2.15 (2H, m), 2.65-2.84
(1H, dd, J = 14 Hz and 10 Hz), 3.0
1 (3H, s), 3.06 (1H, dd, J = 14 Hz
And 4 Hz), 3.14-3.25 (2H, m),
3.82-4.40 (8H, m), 4.20-4.30
(2H, m), 4.53-4.64 (1H, m), 5.
28 (2H, s), 5.30 (2H, s), 7.13-
7.27 (5H, m), 7.30 (1H, s), 7.4
9-7.57 (2H, m), 8.08 (1H, dd, J
= 9 Hz and 3.5 Hz), 8.10-8.18 (3
H, m), 8.31-8.39 (1H, m), 8.47.
(1H, t, J = 5.5 Hz), 8.53-8.60
(1H, m).

Production Example 19 Synthesis of 10- [2 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride Production Example 11- (1) and Production In the same manner as in Example 8- (2), 10- [2 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride is obtained as a yellow powder. .

Melting point: 189 ° C. or higher (decomposition) IR (Nujol): ν _max ^{cm −1} = 3210,174
5,1655,1615 Mass: m / z = 754
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.26-1.3
3 (3H, m), 1.80-1.93 (2H, m),
2.81 (1H, dd, J = 14 Hz and 10H
z), 3.06 (1H, dd, J = 14 Hz and 5H
z), 3.21 (2H, q, J = 7.5 Hz), 3.5
4-3.90 (8H, m), 4.26 (2H, t, J =
5.5 Hz), 4.52-4.60 (1H, m), 5.
30 (2H, s), 5.43 (2H, s), 7.17-
7.25 (5H, m), 7.29 (1H, s), 7.5
0-7.56 (2H, m), 8.09 (1H, d, J =
9Hz), 8.12 (3H, br), 8.21 (1H,
t, J = 6 Hz), 8.39 (1 H, d, J = 5.5 H)
z), 8.40 (1H, t, J = 5.5 Hz), 8.6
0 (1H, t, J = 5.5 Hz).

Production Example 20 Synthesis of 10- [3 ′-(γ-aminobutyroylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride -[3'-
(Γ-aminobutyroylamino) propyloxy] -7
-Ethyl- (20S) -camptothecin hydrochloride is obtained.

Melting point:> 152 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3255,174
5,1655,1615 Mass: m / z = 535 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 7 Hz), 1.75-1.99 (6H, m), 2.
23 (2H, t, J = 7 Hz), 2.74-2.81
(2H, m), 3.18-3.40 (4H, m), 4.
25 (2H, t, J = 6 Hz), 5.30 (2H, t, J = 6 Hz)
s), 5.43 (2H, s), 7.29 (1H, s),
7.50-7.54 (2H, m), 8.02 (3H, b
r), 8.09 (1H, d, J = 9 Hz), 8.18
(1H, t, J = 6 Hz).

Production Example 21 10- [3 ′-｛(N- (γ-aminobutyroyl) -γ
-Aminobutyroyl) amino {propyloxy] -7-
Synthesis of ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 11, 10- [3′-
{(N- (γ-aminobutyroyl) -γ-aminobutyroyl) amino} propyloxy] -7-ethyl- (20
S) -Camptothecin hydrochloride is obtained.

Melting point:> 134 ° C. (decomposition) IR (KBr): ν _max ^{cm −1} = 1745, 1655 Mass: m / z = 620 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO) : Δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.58-1.70 (2H,
m), 1.70-1.82 (2H, m), 1.82-
2.02 (4H, m), 2.11 (2H, t, J = 7.
5Hz), 2.18 (2H, t, J = 7.5Hz),
2.70-2.81 (2H, m), 2.99-3.08
(2H, q), 3.15-3.33 (4H, m), 4.
24 (2H, t, J = 6 Hz), 5.31 (2H,
s), 5.43 (2H, s), 7.30 (1H, s),
7.49-7.55 (2H, m), 7.86-8.10
(5H, m), 8.09 (1H, d, J = 9 Hz).

Production Example 22 Synthesis of camptothecin derivative represented by the following formula

[0171]

Embedded image

[CM.Dextran.Na represents sodium carboxymethyl dextran] 1.5 g of CM-dextran sodium salt (degree of CM = 0.4) is dissolved in 150 ml of water and stirred at 10 ° C. or lower. The 10- [3'- obtained in Production Example 16- (2)
(Glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S)
-75 mg of camptothecin hydrochloride are added. 1- (3-
About 4 ml of an aqueous solution containing 3 g of (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) is added, while maintaining the pH of the reaction solution at 7.0 to 6.5 (using 0.1 N hydrochloric acid). After reacting for 2 hours while stirring at 10 ° C. or lower, the pH was adjusted to 9 (using 0.1 N sodium hydroxide), and the mixture was filtered with a filter.
and the resulting precipitate is collected by centrifugation and 50 m
After dissolving in water, the ion exchange resin AGMP-50 (Na t
ype, manufactured by BioRad), the fraction containing the target substance was filtered with a filter, ethanol was added, and the generated precipitate was collected by centrifugation. obtain. 3
The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) by absorption at 80 nm is 1.4%. . As a result of analysis by gel permeation column chromatography (GPC), the obtained average molecular weight is 137,000, and the polydispersity Mw / Mn is 2.3.

*: GPC analysis conditions: G4000PWX
L, 0.2 M phosphate buffer (pH 7.0): acetonitrile = 80:20, or G4000SWXL (manufactured by Tosoh Corporation), 0.2 M phosphate buffer (pH 7.0).

Production Example 23 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0175]

Embedded image

CM-dextran sodium salt (CM
1.0 g was dissolved in 100 ml of water, and 10
The mixture obtained in Production Example 16- (2) was stirred at a temperature of not more than 10 ° C.
-[3 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl-
120 mg of (20S) -camptothecin hydrochloride are added. About 10 ml of an aqueous solution containing 3 g of EDC is added while maintaining the pH of the reaction at 7.0-6.5 (using 0.1 N hydrochloric acid). Hereinafter, in the same manner as in Production Example 22, 1.03 g of a desired camptothecin derivative is obtained. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride (Production Example 1
-The content determined as ((8-1) compound) is 4.6%. As a result of analysis by GPC analysis, the obtained average molecular weight is 132,000, and the polydispersity Mw / Mn is 2.3.

Production Example 24 Synthesis of camptothecin derivative represented by the following formula

[0178]

Embedded image

CM-dextran sodium salt (CM
(Conversion degree = 0.4) 1.2 g and 10- [3 ′-(L-phenylalanyl-glycylamino) propyloxy] -7-
Ethyl- (20S) -camptothecin hydrochloride (Production Example 1
1.24 g of the desired camptothecin derivative is obtained from 130 mg of Compound 1 in the same manner as in Production Example 23. 380
The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) by absorption at nm is 5.7%. . As a result of analysis by GPC analysis, the obtained average molecular weight was 139,000, and the polydispersity Mw /
Mn is 2.2.

Production Example 25 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0181]

Embedded image

CM-dextran sodium salt (CM
500 mg of 10- [2 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino)
From 50 mg of [ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 19), the desired camptothecin derivative 345 was prepared in the same manner as in Production Example 23.
mg. By absorption at 380 nm, 10-
(2′-aminoethyloxy) -7-ethyl- (20
The content determined as S) -camptothecin hydrochloride (the compound of Production Example 2) is 4.1%. As a result of analysis by GPC analysis, the average molecular weight obtained was 169,000, and the polydispersity Mw / Mn was 1.4.

Production Example 26 Synthesis of camptothecin derivative represented by the following formula

[0184]

Embedded image

CM-dextran sodium salt (CM
1.0 g of 10- [3 ′-(N- (glycyl-glycyl-L-phenylalanyl-glycyl)-
N-methylamino) propyloxy] -7-ethyl-
From 100 mg of (20S) -camptothecin hydrochloride (the compound of Production Example 18), 943 mg of a desired camptothecin derivative is obtained in the same manner as in Production Example 23. The content determined as 10- (3′-methylaminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 7) by absorption at 375 nm is 3.3%. As a result of analysis by GPC analysis, the obtained average molecular weight was 129,000 and the polydispersity Mw / Mn was 2.4.

Production Example 27 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0187]

Embedded image

In the same manner as in Production Example 22, 1.2 g of CM-dextran sodium salt (degree of CM = 0.5) and 10- (3 ′-(glycyl-glycyl-glycyl-glycylamino) obtained in Production Example 43 described later. Propyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride 160 mg
1125 mg of the more desired camptothecin derivative is obtained as a pale yellow powdery complex. The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride by absorption at 380 nm is 5.3%. As a result of analysis by GPC analysis, the average molecular weight obtained was 155,000, and the polydispersity Mw / M
n is 1.46.

Production Example 28 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0190]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.45) 1154 mg and 10 obtained in Production Example 20
-[3 '-(γ-aminobutyroylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (150 mg) was treated in the same manner as in Preparation Example 23 to give 1100 mg of the desired camptothecin derivative as a pale yellow powder. obtain.
The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) by absorption at 380 nm is 2.9%. . As a result of analysis by GPC analysis, the average molecular weight obtained is 149,000, and the polydispersity Mw / Mn is 1.53.

Production Example 29 Synthesis of camptothecin derivative represented by the following formula

[0193]

Embedded image

CM-dextran sodium salt (CM
(Chemical degree = 0.45) 1359 mg was dissolved in 80 ml of water with stirring, and 10- [3 '-｛(N
-(Γ-aminobutyroyl) -γ-aminobutyroyl)
Amino {propyloxy] -7-ethyl- (20S)-
135 mg of camptothecin hydrochloride are added. DMF45
ml and 2755 mg of EEDQ (2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline) are sequentially added. After stirring at room temperature for 16 hours, ethanol 600 ml
Pour into it and add 3 ml of 3M saline to precipitate.
The resulting precipitate was collected by centrifugation, dissolved in 150 ml of water, and then dissolved in a cation exchange column (Bio-Rad AGMP-5).
0, Na type), and the main fraction is collected, filtered through a filter (0.22 µm), and purified by precipitation using 4 volumes of ethanol and 3M saline as a precipitant. Furthermore, after dissolving in water,
The operation of filtering and precipitating and purifying from ethanol is repeated, and the obtained precipitate is 90% ethanol, 99.5%
The desired camptothecin derivative 1 was washed with ethanol, acetone and ether sequentially and dried under reduced pressure to obtain a light yellow powder of the desired camptothecin derivative 1.
254 mg are obtained. By absorption at 380 nm, 10
-(3'-aminopropyloxy) -7-ethyl- (2
0S) -Camptothecin hydrochloride (Production Example 1- (8-1)
Is 4.9%. GPC
As a result of the analysis, the average molecular weight obtained was 14
7,000 and the polydispersity Mw / Mn is 1.63.

Production Example 30 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0196]

Embedded image

[CM Pullulan Na represents carboxymethyl pullulan sodium salt] CM-Pullulan sodium salt (degree of CM = 0.5) 6
16-mg and 10- [3 '-(L-phenylalanyl-glycylamino) propyloxy] -7 obtained in Production Example 11
-Ethyl- (20S) -camptothecin hydrochloride 63 mg
Is treated in the same manner as in Production Example 23 to obtain 543 mg of the desired camptothecin derivative as a pale yellow powder. 10- (3'-aminopropyloxy) by absorption at 380 nm
The content determined as -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) was 4.
7%. As a result of analysis by GPC analysis, the average molecular weight obtained is 190,000, and the polydispersity Mw / Mn is 1.8.

Production Example 31 Synthesis of 10- (3′-hydroxypropyloxy) -7-ethyl- (20S) -camptothecin (1) 5- [3 ′-(tert-butyldimethylsilyloxy) propyloxy] -2 Synthesis of -nitrobenzaldehyde 5.33 g of 5-hydroxy-2-nitrobenzaldehyde dimethyl acetal was dissolved in 50 ml of dry DMF, 6.91 g of potassium carbonate and 7.5 of sodium iodide were dissolved.
g, and 4.73 g of 3-chloropropanol, and 7
Stir at 0 ° C. for 22 hours. After adding ethyl acetate, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to give 5-yellow oil as a pale yellow oil.
6.39 g of (3′-hydroxypropyloxy) -2-nitrobenzaldehyde dimethyl acetal are obtained.

Yield: 93% NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.60
(1H, t, J = 5 Hz), 2.08 (2H, quin
tet, J = 6 Hz), 3.44 (6H, s), 3.8
7 (2H, q, J = 6 Hz), 4.22 (2H, t, J
= 6 Hz), 6.01 (1H, s), 6.91 (1H,
dd, J = 9 Hz and 3 Hz), 7.31 (1H,
d, J = 3 Hz), 7.97 (1H, dd, J = 9H)
z) 6.35 g of 5- (3'-hydroxypropyloxy) -2-nitrobenzaldehyde dimethyl acetal was added to 7
Add to 0% acetic acid and stir at 60 ° C for 1.5 hours. The residue concentrated under reduced pressure is washed with saturated aqueous layer solution and saturated saline solution, dried and concentrated under reduced pressure. The residue was dissolved in 50 ml of dry DMF and t
4.55 g of -butyldimethylsilyl chloride and 3.42 g of imidazole are added, and the mixture is stirred at room temperature for 2 hours. After concentrating the solvent, the residue is purified by silica gel column chromatography to obtain 5.82 g of 5- [3 ′-(t-butyldimethylsilyloxy) propyloxy] -2-nitrobenzaldehyde as a pale yellow oil.

Yield: 73% IR (Neat): ν _max ^{cm -1} = 1700 Mass: m / z = 340 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.04
(6H, s), 0.88 (9H, s), 2.03 (2
H, quintet, J = 6 Hz), 3.80 (2H,
t, J = 6 Hz), 4.22 (2H, t, J = 6H)
z), 7.14 (1H, dd, J = 9 Hz and 3H
z), 7.33 (1H, d, J = 3 Hz), 8.16
(1H, d, J = 9 Hz), 10.49 (1H, s).

(2) Synthesis of 1- {5 ′-[3 ”-(t-butyldimethylsilyloxy) propyloxy] -2′-nitrophenyl} -2-propen-1-one 5- [3′- (T-butyldimethylsilyloxy) propyloxy] -2-nitrobenzaldehyde 5.80 g
Is dissolved in 35 ml of dry THF, and 1.7 equivalents of a vinylmagnesium bromide-THF solution are added with stirring on a dry ice-acetone bath. After stirring for 2 hours, 5% hydrochloric acid 3
0 ml, stirred at room temperature, extracted with ethyl acetate, and purified by silica gel column chromatography to give 1-
{5 '-[3 "-(t-butyldimethylsilyloxy)
[Propyloxy] -2'-nitrophenyl} -2-propen-1-ol (5.02 g) is obtained.

Yield: 80% IR (Nujol): ν _max ^{cm −1} = 3420 Mass: m / z = 390 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.04
(6H, s), 0.88 (9H, s), 2.00 (2
H, quintet, J = 6 Hz), 2.67 (1H,
brs), 3.80 (2H, t, J = 6 Hz), 4.1.
6 (2H, t, J = 6 Hz), 5.24 (1H, dd,
J = 10.5 Hz and 1.5 Hz), 5.41 (1
H, dd, J = 17 Hz and 1.5 Hz), 5.90
(1H, d, J = 5 Hz), 6.08 (1H, ddd,
J = 17 Hz, 10.5 Hz and 1.5 Hz), 6.
87 (1H, dd, J = 9 Hz and 3 Hz), 7.2
4 (1H, d, J = 3 Hz), 8.04 (1H, d, J
= 9 Hz).

4.98 g of 1- {5 ′-[3 ″-(t-butyldimethylsilyloxy) propyloxy] -2′-nitrophenyl} -2-propen-1-ol was dissolved in 140 ml of chloroform, and activated. Manganese dioxide 36g
And stirred with heating for 6 hours. After filtering the insoluble matter, the filtrate was concentrated and purified by silica gel column chromatography.
-{5 '-[3 "-(t-butyldimethylsilyloxy) propyloxy] -2'-nitrophenyl} -2-
2.87 g of propen-1-one are obtained.

Yield: 58% IR (Nujol): ν _max ^{cm -1} = 1680 Mass: m / z = 364 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
01 (6H, s), 0.84 (9H, s), 1.93
(2H, quintet, J = 6 Hz), 3.75 (2
H, t, J = 6 Hz), 4.22 (2H, t, J = 6H)
z), 5.85 (1H, d, J = 17.5 Hz), 6.
15 (1H, d, J = 10.5 Hz), 6.65 (1
H, dd, J = 17.5 Hz and 10.5 Hz),
7.04 (1H, d, J = 3 Hz), 7.25 (1H,
dd, J = 9 Hz and 3 Hz), 8.22 (1H,
d, J = 9 Hz).

(3) Synthesis of 10- (3'-hydroxypropyloxy) -7-ethyl- (20S) -camptothecin 1- {5 '-[3 "-(tert-butyldimethylsilyloxy) propyloxy]- 2'-nitrophenyl｝
-2-propen-1-one (765 mg) in ethanol 10
Then, 156 mg of 10% palladium carbon is added, and the mixture is stirred at room temperature and normal pressure under a hydrogen stream. The catalyst is removed by filtration and the solvent is concentrated. The residue was dissolved in 20 ml of ethanol, and (4S) -7,8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] indolinidine-
220 mg of 3,6,10 (4H) -trione and p-
32 mg of toluenesulfonic acid are added, and the mixture is heated to reflux. After completion of the reaction, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to give 7-ethyl-1 as a pale yellow powder.
0- (3'-hydroxypropyloxy)-(20S)
343 mg of camptothecin are obtained.

Melting point: 233.5-234.5 ° C. Yield: 91% IR (Nujol): ν _max ^{cm -1} = 3380,175
0,1645 Mass: m / z = 451 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
89 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.76-1.95 (2H,
m), 1.97 (1H, quintet, J = 6.5H
z), 3.17 (2H, q, J = 7.5 Hz), 3.6
3. (2H, dt, J = 6.5 Hz and 5 Hz);
26 (2H, t, J = 6.5 Hz), 4.62 (1H,
t, J = 5 Hz), 5.25 (2H, s), 5.42
(2H, s), 6.49 (1H, s), 7.26 (1
H, s), 7.45-7.51 (2H, m), 8.05.
(1H, d, J = 9.5 Hz.) Production Example 32 Synthesis of 10- (2'-hydroxyethyloxy) -7-ethyl- (20S) -camptothecin (1) 1- {5 '-[2 "- Synthesis of (tert-butyldimethylsilyloxy) ethyloxy] -2′-nitrophenyl {-2-propen-1-one 1-like in the same manner as in Production Example 31- (1) and (2).
{5 '-[2 "-(tert-butyldimethylsilyloxy) ethyloxy] -2'-nitrophenyl} -2-
Synthesize propen-1-one.

IR (Nujol): ν _max ^{cm -1} = 168
0 Mass: m / z = 352 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.09
(6H, s), 0.90 (9H, s), 3.99 (2
H, t, J = 5 Hz), 4.16 (2H, t, J = 5H)
z), 5.84 (1H, d, J = 17.5 Hz), 6.
01 (1H, d, J = 11 Hz), 6.62 (1H, d
d, J = 17.5 Hz and 11 Hz), 6.84 (1
H, d, J = 3 Hz), 7.06 (1H, dd, J = 1)
0 Hz and 3 Hz), 8.17 (1H, d, J = 9H)
z).

(2) Synthesis of 10- (2′-hydroxyethyloxy) -7-ethyl- (20S) -camptothecin In the same manner as in Production Example 31- (3), 10- (2′-
(Hydroxyethyloxy) -7-ethyl- (20S)-
Synthesize camptothecin.

Melting point: 251-254 ° C. IR (Nujol): ν _max ^{cm −1} = 3470,173
0,1655 Mass: m / z = 436 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.80-1.93 (2H,
m), 3.17 (2H, q, J = 7.5 Hz), 3.8
3 (2H, q, J = 5 Hz), 4.23 (2H, t, J
= 5Hz), 4.96 (1H, t, J = 5.5Hz),
5.27 (2H, s), 5.42 (2H, s), 6.4
9 (1H, s), 7.26 (1H, s), 7.49-
7.51 (2H, m), 8.06 (1H, d, J = 9H
z).

Production Example 33 Synthesis of 10- [2 '-(2 "-hydroxyethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin (1) 1- {5'-[2"-(2 ") Synthesis of '-(tert-butyldimethylsilyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl {-2-propen-1-one 1-Similar to Production Example 31- (1) and (2)
{5 ′-(2 ″-(2 ″ ′-(tert-butyldimethylsilyloxy) ethyloxy) ethyloxy] -2 ′
-Nitrophenyl} -2-propen-1-one is synthesized.

IR (Nujol): ν _max ^{cm -1} = 168
0 Mass: m / z = 396 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.06
(6H, s), 0.89 (9H, s), 3.62 (2
H, t, J = 6 Hz), 3.75 (2H, t, J = 6H)
z), 3.87-3.92 (2H, m), 4.20-
4.25 (2H, m), 5.83 (1H, d, J = 1
7.5 Hz), 6.01 (1H, d, J = 10.5H)
z), 6.62 (1H, dd, J = 17.5 Hz and 10.5 Hz), 6.84 (1H, d, J = 3 Hz),
7.05 (1H, dd, J = 9 Hz and 3 Hz),
8.17 (1H, d, J = 9 Hz).

(2) 10- [2 ′-(2 ″ -hydroxyethyloxy) ethyloxy] -7-ethyl- (20
Synthesis of S) -camptothecin 1- {5′-
10- [2 'from [2 "-(2"'-(tert-butyldimethylsilyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl {-2-propen-1-one
-(2 "-hydroxyethyloxy) ethyloxy]-
7-Ethyl- (20S) -camptothecin is synthesized.

Melting point: 230-231.5 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 1735,1655 Mass: m / z = 481 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.79-1.94 (2H,
m), 3.18 (2H, q, J = 7.5 Hz), 3.5
5 (4H, m), 3.86 (2H, m), 4.34 (2
H, m), 4.63 (1H, brs), 5.27 (2
H, s), 5.42 (2H, s), 6.48 (1H,
s), 7.26 (1H, s), 7.48-7.54 (2
H, m), 8.06 (1H, d, J = 10 Hz).

Production Example 34 Synthesis of 10- [3 ′-(L-alanyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (1) 1- [5 ′-(3 ″ -hydroxypropyloxy) ) -2′-Nitrophenyl] -2-propen-1-one 1- {5 ′-[3 ″-(tert-butyldimethylsilyloxy) propyloxy] -2′-nitrophenyl}
1.84 g of -2-propen-1-one (the compound of Production Example 31- (2)) is mixed with 20 ml of THF and 30 ml of 50% aqueous acetic acid, and the mixture is stirred and reacted at room temperature overnight. The reaction solution is concentrated under reduced pressure and purified by silica gel column chromatography to obtain 1.26 g of 1- [5 ′-(3 ″ -hydroxypropyloxy) -2′-nitrophenyl] -2-propen-1-one.

Yield: 95% IR (Neat): ν _max ^{cm -1} = 3420, 1675 Mass: m / z = 251 (M ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 2.08
(3H, m), 3.86 (2H, t, J = 6 Hz),
4.23 (2H, t, J = 6 Hz), 5.89 (1H,
d, J = 17.5 Hz), 6.02 (1H, d, J = 1)
0.5Hz), 6.62 (1H, dd, J = 17.5H)
z and 10.5 Hz), 6.84 (1H, d, J = 3
Hz), 7.04 (1H, dd, J = 9 Hz and 3H)
z), 8.17 (1H, d, J = 9 Hz).

(2) 1- [5 '-(3 "-t-butoxycarbonyl-L-alanyloxy-propyloxy)-
Synthesis of 2'-nitrophenyl] -2-propen-1-one 1- [5 '-(3 "-hydroxypropyloxy)-
2'-nitrophenyl] -2-propen-1-one
22 g and t-butoxycarbonyl-L-alanine 2.7
6 g was dissolved in THF 50 ml, and the mixture was stirred under ice-cooling.
Add 3.01 g of CC. After the reaction at room temperature, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1- [5 '-(3 "-t-butoxycarbonyl-).
1.19 g of L-alanyloxy-propyloxy) -2′-nitrophenyl] -2-propen-1-one are obtained.

Yield: 58% IR (Neat): ν _max ^{cm -1} = 3370,1740,
1715 Mass: m / z = 423 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.38
(3H, d, J = 7 Hz), 1.43 (9H, s),
3.19 (2H, quintet, J = 6 Hz);
16 (2H, t, J = 6 Hz), 4.27-4.42
(3H, m), 4.98 (1H, m), 5.85 (1
H, d, J = 17.5 Hz), 6.02 (1H, d, J)
= 11 Hz), 6.62 (1H, dd, J = 17.5H)
z and 11 Hz), 6.82 (1H, d, J = 3H)
z), 7.04 (1H, dd, J = 9 Hz and 3H
z), 8.17 (1H, d, J = 9 Hz).

(3) 10- [3 ′-(t-butoxycarbonyl-L-alanyloxy) propyloxy] -7-
Synthesis of ethyl- (20S) -camptothecin 1.17 g of 1- [5 ′-(3 ″ -tert-butoxycarbonyl-L-alanyloxy-propyloxy) -2′-nitrophenyl] -2-propen-1-one Dissolved in 30 ml of ethanol, added 206 mg of 10% palladium on carbon, stirred under a hydrogen stream at room temperature and normal pressure, removed the catalyst by filtration, concentrated the solvent, dissolved the residue in 30 ml of ethanol, and (4S) -7,8 -Dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] -indolizine-3,6,10 (4H) -trione (290 mg) and p
Add 10 mg of toluenesulfonic acid and heat to reflux.
After completion of the reaction, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography to obtain 10- [3'-
257 mg of (t-butoxycarbonyl-L-alanyloxy) propyloxy] -7-ethyl- (20S) -camptothecin are obtained.

Melting point: 180 ° C. or higher (decomposition) Yield: 38% IR (Nujol): ν _max ^{cm −1} = 3280,176
0, 1715, 1660 Mass: m / z = 622 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.25 (3H,
t, J = 7.5 Hz), 1.32 (3H, t, J = 7.
5Hz), 1.35 (9H, s), 1.78-1.95
(2H, m), 2.08-2.20 (2H, m), 3.
19 (2H, q, J = 7.5 Hz), 3.28-3.3
4 (2H, m), 4.20-4.37 (3H, m),
5.30 (2H, s), 5.43 (2H, s), 6.5
0 (1H, s), 7.27 (1H, s), 7.30 (1
H, d, J = 7.5 Hz), 7.48-7.54 (2
H, m), 8.08 (1H, d, J = 9.5 Hz).

(4) Synthesis of 10- [3 ′-(L-alanyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3 ′-(t-butoxycarbonyl-L-alanyloxy) Propyloxy] -7-ethyl- (20S)
-Dissolve 240 mg of camptothecin in 2 ml of dioxane, add 4 ml of hydrochloric acid-dioxane while stirring under ice-cooling, and react after completion of the reaction, 30 ml of diisopropyl ether
Add. The resulting precipitate was collected by filtration, and 10-
[3 ′-(L-alanyloxy) propyloxy] -7
-Ethyl- (20S) -camptothecin hydrochloride 183m
g.

Yield: 87% IR (Nujol): ν _max ^{cm -1} = 3375,175
0.1660 Mass: m / z = 522 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.44 (3H, t, J = 7H)
z), 1.76-1.94 (2H, m), 2.20 (1
H, quintet, J = 6 Hz), 3.20 (2H,
q, J = 7.5 Hz), 4.05-4.20 (1H,
m), 4.34 (2H, t, J = 6 Hz), 4.40
(2H, t, J = 6 Hz), 5.29 (2H, s),
5.43 (2H, s), 7.28 (1H, s), 7.4
9-7.55 (2H, m), 8.08 (1H, d, J =
10 Hz), 8.52-8.73 (3H, m).

Production Example 35 10- [2 ′-(L-alanyloxy) ethyloxy]
Synthesis of -7-ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 ′-[2 ”-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] -2′-nitrophenyl} -2-propene Synthesis of -1-one 1-one was prepared in the same manner as in Production Example 34- (1) and (2).
{5 ′-[2 ″-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] -2′-nitrophenyl}
-2-propen-1-one is synthesized.

IR (Nujol): ν _max ^{cm -1} = 337
0, 1750, 1715 Mass: m / z = 409 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.39
(3H, d, J = 7.5 Hz), 1.43 (9H,
s), 4.29-4.35 (3H, m), 4.53 (2
H, brt), 5.00 (1H, br), 5.85 (1
H, d, J = 17 Hz), 6.03 (1H, d, J = 1)
0.5Hz), 6.63 (1H, dd, J = 17.5H)
z and 10.5 Hz), 6.84 (1H, d, J = 3
Hz), 7.06 (1H, dd, J = 9 Hz and 3H
z), 8.18 (1H, d, J = 9 Hz).

(2) Synthesis of 10- [2 '-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin [2'-
(T-Butoxycarbonyl-L-alanyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin is synthesized.

Melting point: 114-120 ° C. IR (Nujol): ν _max ^{cm −1} = 3320,175
0, 1710, 1660 Mass: m / z = 608 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.26 (3H,
d, J = 7.5 Hz), 1.31 (3H, t, J = 7.
5Hz), 1.35 (9H, s), 1.80-1.94
(2H, m), 3.19 (2H, q, J = 7.5H
z), 3.99-4.10 (1H, m), 4.43-
4.56 (4H, m), 5.29 (2H, s), 5.4
3 (2H, s), 6.49 (1H, s), 7.27 (1
H, s), 7.32 (1H, d, J = 7 Hz), 7.4
9-7.53 (2H, m), 8.08 (1H, d, J =
10 Hz).

(3) Synthesis of 10- [2 '-(L-alanyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 34- (4), 10- [2' −
(L-alanyloxy) ethyloxy] -7-ethyl-
(20S) -Camptothecin hydrochloride is synthesized.

Melting point: 180 ° C. or higher (decomposition) IR (Nujol): ν _max ^{cm −1} = 3680,175
0.1655 Mass: m / z = 508 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.45 (3H, d, J = 7H)
z), 1.80-1.94 (2H, m), 3.21 (2
H, q, J = 7.5 Hz), 4.10-4.19 (1
H, m), 4.50 (2H, m), 4.60-4.65.
(2H, m), 5.30 (2H, s), 5.43 (2
H, s), 7.29 (1H, s), 7.51-7.55.
(2H, m), 8.10 (1H, d, J = 9.5H)
z), 8.56-8.68 (3H, m).

Production Example 36 Synthesis of 10- {2 ′-[2 ″-(L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin Hydrochloride (1) 10- {5 ′-[2 Synthesis of "-(2"'-(t-butoxycarbonyl-L-alanyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one Preparation Examples 34- (1) and (2) above As in 1
0- {5 ′-[2 ″-(2 ″ ′-(t-butoxycarbonyl-L-alanyloxy) ethyloxy) ethyloxy] -2′-nitrophenyl} -2-propen-1-one is synthesized.

IR (Nujol): ν _max ^{cm -1} = 338
5,1755,1690 Mass: m / z = 453 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.38
(3H, d, J = 7 Hz), 1.44 (9H, s),
3.74-3.79 (2H, m), 3.85-3.90
(2H, m), 4.21-4.25 (2H, m), 4.
29-4.35 (3H, m), 5.03 (1H, b
r), 5.84 (1H, d, J = 17 Hz), 6.02
(1H, d, J = 11 Hz), 6.62 (1H, dd,
J = 17.5 Hz and 11 Hz), 6.85 (1 H,
d, J = 3 Hz), 7.07 (1 H, dd, J = 9 Hz)
And 3 Hz), 8.17 (1 H, d, J = 9 Hz).

(2) 10- {2 '-[2 "-(t-butoxycarbonyl-L-alanyloxy) ethyloxy]
Synthesis of ethyloxy {-7-ethyl- (20S) -camptothecin 10- {2'-
[2 "-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] ethyloxy {-7-ethyl- (2
(OS) -Camptothecin is synthesized.

Melting point: 164 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3380,175
0,1705,1655 Mass: m / z = 652 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.22 (3H,
t, J = 7.5 Hz), 1.31 (3H, t, J = 7.
5Hz), 1.37 (9H, s), 1.75-1.94
(2H, m), 3.18 (2H, q, J = 7.5H
z), 3.73 (2H, t, J = 7 Hz), 3.87
(2H, t, J = 7 Hz), 3.94-4.05 (1
H, m), 4.10-4.35 (4H, m), 5.29
(2H, s), 5.42 (2H, s), 6.48 (1
H, s), 7.27 (1H, s), 7.27 (1H,
d, J = 6 Hz), 7.47-7.54 (2H, m),
8.07 (1H, d, J = 10 Hz).

(3) 10- {2 '-[2 "-(L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride -｛2'-
[2 ″-(L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride is synthesized.

Melting point: 180 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3380,176
0,1740,1660 Mass: m / z = 552 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.41 (3H, d, J = 7H)
z), 1.79-1.94 (2H, m), 3.19 (2
H, q, J = 7.5 Hz), 3.78 (2H, t, J =
7 Hz), 3.89 (2H, t, J = 7 Hz), 4.0
0 to 4.15 (1H, m), 4.26 to 4.44 (4
H, m), 5.29 (2H, s), 5.43 (2H,
s), 7.28 (1H, s), 7.49-7.55 (2
H, m), 8.08 (1H, d, J = 10 Hz), 8.
52-8.70 (3H, m).

Production Example 37 Synthesis of 10- [3 ′-(L-Prolyloxy) propyloxy] -7-ethyl- (20S) -camptothecin Hydrochloride (1) 1- {5 ′-[3 ″-(t- Synthesis of butoxycarbonyl-L-prolyloxy) propyloxy] -2′-nitrophenyl {-2-propen-1-one 1- {5′-one in the same manner as in Production Examples 34- (1) and (2) above.
[3 "-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -2'-nitrophenyl} -2-
Obtain propen-1-one.

IR (Neat): ν _max ^{cm -1} = 175
0.1700 Mass: m / z = 471 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.44
(9H, s), 1.81-2.30 (6H, m), 3.
37-3.54 (2H, m), 4.13-4.37 (5
H, m), 5.85 (1H, d, J = 17.5 Hz),
6.01 (1H, d, J = 10.5 Hz), 6.62
(1H, dd, J = 17.5Hz and 10.5H
z), 6.82 (1H, d, J = 3 Hz), 7.05
(1H, dd, J = 9 Hz and 3 Hz), 8.17
(1H, d, J = 9 Hz).

(2) 10- [3 '-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -7-
Synthesis of ethyl- (20S) -camptothecin 1- {5 ′-[3 ″-(t-butoxycarbonyl-L-
Production Example 3 using prolyloxy) propyloxy] -2′-nitrophenyl {-2-propen-1-one
4-(3)
[3 ′-(t-Butoxycarbonyl-L-prolyloxy) propyloxy] -7-ethyl- (20S) -camptothecin is obtained.

Melting point: 136-139 ° C. IR (Nujol): ν _max ^{cm −1} = 3280,175
5,1700,1660 Mass: m / z = 648 (M
+ H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.36 (9H, s), 1.7
4-1.94 (6H, m), 2.10-2.28 (2
H, m), 3.18 (2H, q, J = 7.5 Hz),
3.27-3.40 (2H, m), 4.15-4.22
(1H, m), 4.24-4.37 (4H, m), 5.
28 (2H, s), 5.42 (2H, s), 6.48
(1H, s), 7.27 (1H, s), 7.48-7.
53 (2H, m), 8.07 (1H, d, J = 9H
z).

(3) Synthesis of 10- [3 '-(L-prolyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t-butoxycarbonyl-L-prolyloxy) Propyloxy] -7-ethyl- (20S)
-From camptothecin, 10- [3 '-(L-prolyloxy) propyloxy] -7-ethyl- (20) as a pale yellow powder was prepared in the same manner as in Production Example 34- (4).
S) -Camptothecin hydrochloride is obtained.

IR (Nujol): ν _max ^{cm -1} = 368
0, 1750, 1660, 1620 Mass: m / z =
^{548 [(M-Cl -)} +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 7.5 Hz), 1.81-2.06 (6H, m),
2.19-2.34 (2H, m), 3.17-3.24
(4H, m), 4.05-4.20 (1H, m), 4.
34 (2H, t, J = 6 Hz), 4.42 (2H, t,
J = 6 Hz), 5.29 (2H, s), 5.43 (2
H, s), 7.28 (1H, s), 7.50-7.55
(2H, m), 8.09 (1H, d, J = 10 Hz),
9.00-9.20 (1H, m).

Production Example 38 10- [2 ′-(L-Prolyloxy) ethyloxy]
Synthesis of -7-ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 ′-[2 ”-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] -2′-nitrophenyl} -2-propene Synthesis of -1-one 1-one was prepared in the same manner as in Production Example 34- (1) and (2).
{5 ′-[2 ″-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] -2′-nitrophenyl}
-2-propen-1-one is synthesized.

IR (Neat): ν _max ^{cm -1} = 175
0.1700 Mass: m / z = 435 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.44
(9H, s), 1.86-2.29 (4H, m), 3.
37-3.57 (2H, m), 4.25-4.35 (3
H, m), 4.48-4.53 (2H, m), 5.85
(1H, d, J = 17.5 Hz), 6.02 (1H,
d, J = 10.5 Hz), 6.63 (1H, dd, J =
17.5 Hz and 10.5 Hz), 6.83 (1H,
d, J = 3.5 Hz), 7.04 (1H, dd, J = 9)
Hz and 3 Hz), 8.18 (1H, d, J = 9H)
z).

(2) Synthesis of 10- [2 ′-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin [2'-
(T-Butoxycarbonyl-L-prolyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin is synthesized.

Melting point: 203-205 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 1755,173
5,1685,1670,1610 Mass: m / z = 634 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.37 (9H, s), 1.7
9-1.94 and 2.16-2.26 (6H, m),
3.19 (2H, q, J = 7.5 Hz), 3.28-
3.40 (2H, m), 4.20-4.24 (1H,
m), 4.45-4.56 (4H, m), 5.29 (2
H, s), 5.43 (2H, s), 6.48 (1H,
s), 7.27 (1H, s), 7.46-7.53 (2
H, m), 8.08 (1H, d, J = 9.5 Hz).

(3) Synthesis of 10- [2 '-(L-prolyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Production Example 34- (4), 10- [2' −
(L-prolyloxy) ethyloxy] -7-ethyl-
(20S) -Camptothecin hydrochloride is synthesized.

Melting point: 170 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3680,175
0,1655 Mass: m / z = 534 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-2.09 and 2.
23-2.35 (6H, m), 3.17-3.29 (4
H, m), 4.40-4.47 (1H, m), 4.52
(2H, m), 4.62-4.69 (2H, m), 5.
30 (2H, s), 5.43 (2H, s), 7.29
(1H, s), 7.51-7.55 (2H, m), 8.
10 (1H, d, J = 9.5 Hz), 9.03-9.2
3 and 10.23-10.43 (2H, m).

Production Example 39 Synthesis of 10- {2 ′-[2 ″-(L-prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 ′-[2 "-(2"'-(t-butoxycarbonyl-L-prolyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl {-2-propene-
Synthesis of 1-one 1-one was prepared in the same manner as in Production Example 34- (1) and (2).
{5 ′-[2 ″-(2 ″ ′-(t-butoxycarbonyl-L-prolyloxy) ethyloxy) ethyloxy]
-2'-Nitrophenyl} -2-propen-1-one is synthesized.

IR (Neat): ν _max ^{cm -1} = 175
0.1700 Mass: m / z = 479 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.45
(9H, s), 1.79-2.30 (4H, m), 3.
33-3.59 (2H, m), 3.77 (2H, t, J
= 5 Hz), 3.87 (2H, t, J = 5 Hz), 4.
19-4.26 (2H, m), 4.26-4.36 (3
H, m), 5.84 (1H, d, J = 18 Hz), 6.
01 (1H, d, J = 11 Hz), 6.62 (1H, d
d, J = 18 Hz and 11 Hz), 6.85 (1 H,
d, J = 3 Hz), 7.06 (1 H, dd, J = 9 Hz)
And 3 Hz), 8.17 (1 H, d, J = 9 Hz).

(2) 10- {2 '-[2 "-(t-butoxycarbonyl-L-prolyloxy) ethyloxy]
Synthesis of ethyloxy {-7-ethyl- (20S) -camptothecin 1
0- {2 ′-[2 ″-(t-butoxycarbonyl-L-
Prolyloxy) ethyloxy] ethyloxy {-7-
Ethyl- (20S) -camptothecin is synthesized.

IR (Nujol): ν _max ^{cm -1} = 337
0, 1750, 1700, 1655 Mass: m / z =
678 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.37 (9H, s), 1.6
9-1.85 (4H, m), 1.79-1.94 (2
H, m), 3.18 (2H, q, J = 7.5 Hz),
3.24-3.39 (2H, m), 3.69-3.77
(2H, m), 3.83-3.91 (2H, m), 4.
12-4.21 (1H, m), 4.21-4.28 (2
H, m), 4.30-4.38 (2H, m), 5.29
(2H, s), 5.43 (2H, s), 7.27 (1
H, s), 7.47-7.54 (2H, m), 8.07
(1H, d, J = 10 Hz).

(3) Synthesis of 10- {2 ′-[2 ”-(L-prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in the above Production Example 34- (4) 10- ^ 2'-
[2 ″-(L-Prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride is synthesized.

Melting point: decomposed at 170 ° C. or higher IR (Nujol): ν _max ^{cm −1} = 3370,175
0.1660 Mass: m / z = 578 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.79-2.32 (6H,
m), 3.12-3.28 (4H, m), 3.79 (2
H, m), 3.89 (2H, m), 4.28-4.46.
(5H, m), 5.28 (2H, s), 5.43 (2
H, s), 7.30 (1H, s), 7.49-7.54.
(2H, m), 8.09 (1H, d, J = 9.5H
z), 8.95-9.32 (2H, m).

Production Example 40 10- [3 ′-(O-ethyl-L-β-aspartyloxy) propyloxy] -7-ethyl- (20S) -camptothecin (a camptothecin derivative represented by the following formula) hydrochloride Synthesis of

[0253]

Embedded image

(1) 1- {5 '-[3 "-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) propyloxy] -2'-nitrophenyl}-
Synthesis of 2-propen-1-one In the same manner as in Production Example 34- (1) and (2), pale yellow oily 1- {5 ′-[3 ″-(Nt-butoxycarbonyl-O-ethyl) was obtained. -L-β-aspartyloxy) propyloxy] -2′-nitrophenyl} -2-propen-1-one is synthesized.

IR (Neat): ν _max ^{cm -1} = 337
0, 1740, 1715, 1680 NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26
(3H, t, J = 7 Hz), 1.44 (9H, s),
2.17 (2H, quintet, J = 6 Hz);
84 (1H, dd, J = 16.5 Hz and 5 Hz),
2.97 (1H, dd, J = 16.5 Hz and 5H
z), 4.15 (1H, t, J = 5 Hz), 4.20
(4H, m), 4.29 (2H, t, J = 6 Hz),
4.53-4.57 (1H, m), 5.53 (1H,
d, J = 8 Hz), 5.85 (1 H, d, J = 18 H)
z), 6.02 (1H, d, J = 11 Hz), 6.63
(1H, dd, J = 18 Hz and 11 Hz), 6.8
3 (1H, d, J = 3 Hz), 7.04 (1H, dd,
J = 9 Hz and 3 Hz), 8.18 (1H, d, J =
9 Hz).

(2) Synthesis of 10- [3 ′-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) propyloxy] -7-ethyl- (20S) -camptothecin 10- [3′-
(Nt-butoxycarbonyl-O-ethyl-L-β-
Aspartyloxy) propyloxy] -7-ethyl-
(20S) -Camptothecin is synthesized.

Melting point: 107-110 ° C. IR (Nujol): ν _max ^{cm −1} = 3260,175
0, 1720, 1660, 1610 Mass: m / z = 694 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.14 (3H,
t, J = 7 Hz), 1.32 (3H, t, J = 7.5H)
z), 1.36 (9H, s), 1.80-1.94 (2
H, m), 2.14 (2H, quintet, J = 6H
z), 2.68 (1H, dd, J = 16 Hz and 8H
z), 2.81 (1H, dd, J = 16 Hz and 6H
z), 3.19 (2H, q, J = 7.5 Hz), 4.0
6 (2H, q, J = 7 Hz), 4.23-4.33 (1
H, m), 4.37 (4H, m), 5.29 (2H,
s), 5.43 (2H, s), 6.48 (1H, s),
7.27 (1H, s), 7.31 (1H, d, J = 7H)
z), 7.50-7.53 (2H, m), 8.07 (1
H, d, J = 10 Hz).

(3) 10- [3 '-(O-ethyl-L-
Synthesis of β-aspartyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3′-
(O-Ethyl-L-β-aspartyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride is synthesized.

Melting point: 215 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3690,175
0, 1660, 1620 Mass: m / z = 594
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.18 (3H,
t, J = 7 Hz), 1.32 (3H, t, J = 7.5H)
z), 1.80-1.94 (2H, m), 2.18 (2
H, quintet, J = 6 Hz), 3.00 (1H,
dd, J = 17.5 Hz and 6 Hz), 3.08 (1
H, dd, J = 17.5 Hz and 6 Hz), 3.20
(2H, q, J = 7 Hz), 4.16 (1H, m),
4.30 (2H, t, J = 6 Hz), 4.32 (2H,
t, J = 6 Hz), 5.30 (2H, s), 5.43
(2H, s), 7.28 (1H, s), 7.50-7.
53 (2H, m), 8.09 (1H, d, J = 10H
z), 8.65-8.78 (3H, m).

Production Example 41 10- [2 ′-(O-ethyl-L-β-aspartyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin (camptothecin derivative represented by the following formula)
Synthesis of hydrochloride

[0261]

Embedded image

(1) 1- {5 ′-[2 ”-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy] -2′-nitrophenyl} -2
-Synthesis of propen-1-one 1-
{5 '-[2 "-(Nt-butoxycarbonyl-O-
Ethyl-L-β-aspartyloxy) ethyloxy]
-2'-Nitrophenyl} -2-propen-1-one is synthesized.

IR (Nujol): ν _max ^{cm -1} = 343
0,1720,1680 Mass: m / z = 481 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26
(3H, t, J = 7 Hz), 1.44 (9H, s),
2.88 (1H, dd, J = 17 Hz and 5 Hz),
3.02 (1H, dd, J = 17 Hz and 5 Hz),
4.20 (2H, q, J = 7 Hz), 4.27 (2H,
m), 4.48 (2H, m), 4.55-4.61 (1
H, m), 5.45 (1H, brd, J = 8 Hz),
5.85 (1H, d, J = 17.5 Hz), 6.02
(1H, d, J = 10.5 Hz), 6.63 (1H, d
d, J = 17.5 Hz and 10.5 Hz), 6.85
(1H, d, J = 3 Hz), 7.07 (1H, dd, J
= 9 Hz and 3 Hz), 8.19 (1H, d, J = 9
Hz).

(2) Synthesis of 10- [2 ′-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin Preparation Example 34 -10- [2'-
(Nt-butoxycarbonyl-O-ethyl-L-β-
Aspartyloxy) ethyloxy] -7-ethyl-
(20S) -Camptothecin is synthesized.

Melting point: 111-114 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3310,174
5,1720,1655,1605 Mass: m / z = 680 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.15 (3H,
t, J = 7 Hz), 1.31 (3H, t, J = 7.5H)
z), 1.37 (9H, s), 1.80-1.94 (2
H, m), 2.72 (1H, dd, J = 16 Hz and 6 Hz), 2.84 (1 H, dd, J = 16 Hz and 6 Hz), 3.20 (2H, q, J = 7.5 Hz),
4.07 (2H, q), 4.34-4.47 (5H,
m), 5.29 (2H, s), 5.43 (2H, s),
6.48 (1H, s), 7.27 (1H, s), 7.2
9 (1H, d, J = 9 Hz), 7.50-7.54 (2
H, m), 8.08 (1H, d, J = 10 Hz).

(3) 10- [2 '-(O-ethyl-L-
Synthesis of β-aspartyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [2′-
(O-ethyl-L-β-aspartyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride is synthesized.

Melting point: 160 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3680,175
0, 1660, 1615 Mass: m / z = 580
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.19 (3H,
t, J = 7 Hz), 1.32 (3H, t, J = 7.5H)
z), 1.80-1.94 (2H, m), 3.03 (1
H, dd, J = 17.5 Hz and 6 Hz), 3.12
(1H, dd, J = 17.5 Hz and 5.5 Hz),
3.21 (2H, q, J = 7.5 Hz), 4.19 (2
H, q, J = 7.5 Hz), 4.36 (1H, br)
m), 4.47-4.53 (4H, m), 5.30 (2
H, s), 5.43 (2H, s), 7.29 (1H,
s), 7.51-7.54 (2H, m), 8.11 (1
H, d, J = 10 Hz), 8.67-8.80 (3H,
m).

Production Example 42 10- {2 ′-[2 ”-(O-ethyl-L-β-aspartyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin (represented by the following formula Synthesis of camptothecin derivative) hydrochloride

[0269]

Embedded image

(1) 1- {5 '-[2 "-(2"'-
(Nt-butoxycarbonyl-O-ethyl-L-β-
Aspartyloxy) ethyloxy) ethyloxy]-
Synthesis of 2′-nitrophenyl} -2-propen-1-one 1-like in the same manner as in Production Example 34- (1) and (2).
{5 ′-[2 ″-(2 ″ ′-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -2′-nitrophenyl}-
Synthesize 2-propen-1-one.

IR (Neat): ν _max ^{cm -1} = 337
0, 1740, 1720, 1680 Mass: m / z = 525 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26
(3H, t, J = 7 Hz), 1.44 (9H, s),
2.85 (1H, dd, J = 7 Hz and 5 Hz),
3.01 (1H, dd, J = 7 Hz and 5 Hz),
3.75 (2H, m), 3.86-3.90 (2H,
m), 4.22-4.31 (4H, m), 4.20 (2
H, q, J = 7 Hz), 4.50-4.62 (1H,
m), 5.51 (1H, brd, J = 8 Hz), 5.8
4 (1H, d, J = 17.5 Hz), 6.01 (1H, d, J = 17.5 Hz)
d, J = 10.5 Hz), 6.62 (1H, dd, J =
17.5 Hz and 10.5 Hz), 6.86 (1H,
d, J = 3 Hz), 7.08 (1H, dd, J = 9 Hz)
And 3 Hz), 8.17 (1 H, d, J = 9 Hz).

(2) 10- [2 '-(2 "-(Nt-
Synthesis of butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin 10- [2′-] in the same manner as in Production Example 34- (3).
(2 ″-(Nt-butoxycarbonyl-O-ethyl-
L-β-aspartyloxy) ethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin is synthesized.

Melting point: 164 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3365,175
0,1655 Mass: m / z = 724 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.15 (3H,
t, J = 7 Hz), 1.31 (3H, t, J = 7.5H)
z), 1.37 (9H, s), 1.79-1.94 (2
H, m), 2.66 (1H, dd, J = 16 Hz and 6 Hz), 2.78 (1 H, dd, J = 16 Hz and 6 Hz), 3.18 (2H, q, J = 7.5 Hz),
3.73 (2H, t, J = 5 Hz), 3.87 (2H,
m), 4.07 (2H, q, J = 7.0 Hz), 4.2
0 (2H, m), 4.30-4.39 (3H, m),
5.28 (2H, s), 5.42 (2H, s), 6.4
8 (1H, s), 7.26 (1H, d, J = 6 Hz),
7.27 (1H, s), 7.49-7.54 (2H,
m), 8.07 (1H, d, J = 10 Hz).

(3) Synthesis of 10- {2 ′-[2 ”-(O-ethyl-L-β-aspartyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride Preparation Example 10- {2′-
[2 ″-(O-ethyl-L-β-aspartyloxy)
Ethyloxy] ethyloxy {-7-ethyl- (20
S) -Camptothecin hydrochloride is synthesized.

Melting point: 170 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3375,175
0.1660 Mass: m / z = 624 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.19 (3H,
t, J = 7 Hz), 1.32 (3H, t, J = 7.5H)
z), 1.79-1.94 (2H, m), 2.99 (1
H, dd, J = 17.5 Hz and 6 Hz), 3.08
(1H, dd, J = 17.5 Hz and 6 Hz), 3.
19 (2H, q, J = 7.5 Hz), 3.75 (2H,
m), 3.88 (2H, m), 4.19 (2H, q, J
= 7 Hz), 4.28-4.35 (5H, m), 5.2
9 (2H, s), 5.43 (2H, s), 7.29 (1
H, s), 7.50-7.55 (2H, m), 8.08
(1H, d, J = 10 Hz), 8.66-8.82 (3
H, m).

Production Example 43 7-Ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20
Synthesis of S) -camptothecin hydrochloride (1) Synthesis of 7-ethyl-10- [3 ′-(t-butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin Production Example 8- 7-ethyl-10- in the same manner as in (1)
7-Ethyl-10- [3 '-(t) as a yellow powder from (3′-aminopropyloxy)-(20S) -camptothecin hydrochloride (200 mg) and 2 equivalents of t-butoxycarbonyl-glycyl-glycyl-glycyl-glycine. -Butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin is obtained 269 mg.

Yield: 84% IR (Nujol): ν _max ^{cm -1} = 3290,175
0, 1710, 1650, 1625 Mass: m / z = 778 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ + d ₆ -DMSO):
δ ^TMS = 1.01 (3H, t, J = 7 Hz), 1.40
(3H, t, J = 7.5 Hz), 1.43 (9H,
s), 1.93 (2H, dq, J = 7.5 Hz and 3
Hz), 2.01-2.16 (2H, m), 3.18
(2H, t, J = 7.5 Hz), 3.47 (2H,
m), 3.74 (2H, d, J = 5.5 Hz), 3.8
3-3.89 (6H, m), 4.22 (2H, t, J =
6Hz), 5.24 (2H, s), 5.29 (1H,
d, J = 16 Hz), 5.64 (1H, d, J = 16H)
z), 5.88 (1H, s), 6.55 (1H, m),
7.38 (1H, d, J = 3 Hz), 7.47 (1H,
dd, J = 9 Hz and 3 Hz), 7.56 (1H,
s), 7.85 (1H, t), 8.07 (1H, d, J
= 9 Hz), 8.07-8.17 (3H, m).

(2) Synthesis of 7-ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride The same method as in Production Example 8- (2) was used. -Ethyl-10-
[3 ′-(t-butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-
7-Ethyl-10- [3 ′-(glycyl-glycyl-) as a yellow powder from (20S) -camptothecin 261 mg
Glycyl-glycylamino) propyloxy]-(20
237 mg of S) -camptothecin hydrochloride are obtained.

Yield: 99% Melting point:> 190 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3195,175
0, 1655, 1615 Mass: m / z = 678
^{[(M-Cl -) +} ] NMR (300MHz, d 6 -DMSO): δ TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-2.02 (4H,
m), 3.20 (2H, q, J = 8 Hz), 3.31
(2H, q, J = 7 Hz), 3.61 (2H, q, J =
6 Hz), 3.70 (2H, q, J = 6 Hz), 3.7
6 (2H, q, J = 6 Hz), 3.84 (2H, q, J
= 6 Hz), 4.24 (2H, t, J = 6 Hz), 5.
31 (2H, s), 5.43 (2H, s), 7.29
(1H, s), 7.51-7.55 (2H, m), 8.
01 (1H, t, J = 5.5 Hz), 8.09 (1H,
d, J = 9.5 Hz), 8.14 (3H, br), 8.
18 (1H, t, J = 6 Hz), 8.40 (1H, t,
J = 6 Hz), 8.74 (1H, t, J = 5.5H)
z).

Production Example 44 Synthesis of 7-ethyl-10- {2 ′-[2 ″-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride (1) Synthesis of 7-ethyl-10- {2 ′-[2 ″-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin Preparation Example 8- (1) 7) -Ethyl-10-
(2 ′-(2 ″ -aminoethyloxy) ethyloxy)
-(20S) -camptothecin hydrochloride 400 mg, t
-Butoxycarbonyl-glycyl-glycyl-L-phenylalanylglycine 2 equivalents of 7-ethyl-10- {2 '-[2 "-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanylglycyl) as a yellow powder. Silamino) ethyloxy] ethyloxy {-(20S)-
550 mg of camptothecin are obtained.

Yield: 79% Melting point:> 160 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3300,175
0.1655 Mass: m / z = 898 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.27 (3H, t,
J = 7 Hz), 1.36 (9H, s), 1.83-1.
89 (2H, m), 2.78 (1H, dd, J = 14H
z and 10 Hz), 3.04 (1H, dd, J = 14)
Hz and 4.5 Hz), 3.18 (2H, q, J =
7.5 Hz), 3.11-3.80 (8H, m),
29 (2H, q, J = 6 Hz), 3.84-3.87
(2H, m), 4.34-4.36 (2H, m), 4.
45-4.53 (1H, m), 5.30 (2H, s),
5.43 (2H, s), 6.51 (1H, s), 7.0
0 (1H, t, J = 5.5 Hz), 7.14-7.25
(5H, m), 7.27 (1H, s), 7.52-7.
55 (2H, m), 7.83 (1H, t, J = 5.5H
z), 7.93 (1H, t, J = 5 Hz), 8.08
(1H, d, J = 9.5 Hz), 8.17 (1H, d,
J = 8 Hz), 8.29 (1H, t, J = 5.5H)
z).

(2) 7-ethyl-10- {2 ′-[2 ”
-(Glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20
Synthesis of S) -camptothecin hydrochloride 7-ethyl-10- as in Production Example 8- (2)
{2 ′-[2 ″-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycylamino)
Ethyloxy] ethyloxy {-(20S) -camptothecin from 550 mg, 7-ethyl-10- as a yellow powder
334 mg of {2 ′-[2 ″-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride are obtained.

Yield: 65% Melting point:> 165 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3225,175
0,1655 Mass: m / z = 798 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.26-1.3
4 (3H, m), 1.80-1.94 (2H, m),
2.82 (1H, dd, J = 14 Hz and 10H
z), 3.06 (1H, dd, J = 14 Hz and 5.
5Hz), 3.20 (2H, q, J = 7.5Hz),
3.29 (2H, q, J = 6 Hz), 3.55 (2H,
t, J = 6 Hz), 3.62-3.80 (6H, m),
3.82-3.89 (2H, m), 4.33-4.37
(2H, m), 4.51-4.58 (1H, m), 5.
30 (2H, s), 5.43 (2H, s), 7.14-
7.25 (5H, m), 7.30 (1H, s), 7.5
3-7.56 (2H, m), 7.94 (1H, t, J =
5.5 Hz), 8.09 (1H, d, J = 9.5H)
z), 8.14 (3H, br), 8.32 (1H, t,
J = 6 Hz), 8.38 (1H, d, J = 8.5H)
z), 8.60 (1H, t, J = 5.5 Hz).

Production Example 45 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0285]

Embedded image

In the same manner as in Production Example 22, 2.3 g of CM-dextran sodium salt (degree of CM = 0.5) and 7-ethyl-10- {2 ′-[2 ″-(7) obtained in Production Example 44. From glycyl-glycyl-L-phenylalanylglycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride (310 mg), 1.83 g of the desired camptothecin derivative is obtained as a pale yellow powdery complex.
By absorption at 80 nm, 7-ethyl-10- (2′-
The content determined as aminoethyloxy-ethyloxy)-(20S) -camptothecin hydrochloride is 1.6%. As a result of analysis by GPC analysis, the average molecular weight obtained is 200,000, and the polydispersity Mw / Mn is 1.38.

Production Example 46 7-ethyl-10- [3 ′-(glycyl-glycyl-L
Synthesis of -phenylalanyl-glycyloxy) propyloxy]-(20S) -camptothecin hydrochloride (1) 7-ethyl-10- [3 '-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-
Synthesis of glycyloxy) propyloxy]-(20S) -camptothecin 7-ethyl-10- (3′-hydroxypropyloxy)-(20S) -camptothecin 50 mg and t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl -2 equivalents of glycine and a catalytic amount of 4-dimethylaminopyridine in 2.5 ml of dry dimethylformamide
And N, N'-dicyclohexylcarbodiimide 3
Add the equivalent. After reaction at room temperature overnight, the mixture was treated in the same manner as in Production Example 8- (1) to give 7-ethyl-10- [3'-
(T-butoxycarbonyl-glycyl-glycyl-L-
Phenylalanyl-glycyloxy) propyloxy]
-71 mg of-(20S) -camptothecin are obtained.

Yield: 74% IR (Nujol): ν _max ^{cm -1} = 3300,175
0.1660 Mass: m / z = 869 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.37 (9H, s), 1.8
0-1.94 (2H, m), 2.11-2.20 (2
H, m), 2.72 (1H, dd, J = 14 Hz and 10 Hz), 3.02 (1 H, dd, J = 14 Hz and 5 Hz), 3.18 (2H, q, J = 7 Hz),
52-3.79 (4H, m), 3.88 (2H, dd,
J = 6 Hz and 2 Hz), 4.30 (4H, t, J =
6Hz), 4.50 (1H, m), 5.29 (2H,
s), 5.43 (2H, s), 6.50 (1H, s),
6.98 (1H, t, J = 6 Hz), 7.12-7.2
5 (5H, m), 7.27 (1H, s), 7.51-
7.55 (2H, m), 7.88 (1H, t, J = 5H
z), 8.08 (1H, d, J = 9.5 Hz), 8.3
2 (1H, t, J = 5 Hz).

(2) Synthesis of 7-ethyl-10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-(20S) -camptothecin hydrochloride Preparation Example 8- (2) Similarly, 7-ethyl-10-
[3 '-(t-Butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-(20S) -camptothecin 58 mg of 7-ethyl-10- [3'-(glycyl- Glycyl-L-phenylalanyl-glycyloxy) propyloxy]-(20S) -camptothecin hydrochloride 39
mg.

Yield: 72% Melting point:> 167 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3285,174
5,1655 Mass: m / z = 769 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.31 (3H, t,
J = 7.5 Hz), 1.80-1.93 (2H, m),
2.12-2.20 (2H, m), 2.72 (1H, d
d, J = 14 Hz and 10 Hz), 3.02 (1H,
dd, J = 14 Hz and 4.5 Hz), 3.18 (2
H, q, J = 7.5 Hz), 3.54-3.92 (6
H, m), 4.31 (4H, t, J = 6 Hz), 4.5.
1-4.59 (1H, m), 5.29 (2H, s),
5.43 (2H, s), 7.13-7.22 (5H,
m), 7.27 (1H, s), 7.51-7.56 (2
H, m), 8.03 (3H, br), 8.09 (1H,
d, J = 9.5 Hz), 8.35 (1H, d, J = 9H)
z), 8.51 (1H, t, J = 5.5 Hz), 8.6
0 (1H, t, J = 6 Hz).

Production Example 47 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0292]

Embedded image

In the same manner as in Production Example 22, 250 mg of CM-dextran sodium salt (CM conversion: 0.5) and 7-ethyl-10- [3 '-(glycyl-glycyl-L- Phenylalanyl-glycyloxy)
From propyloxy]-(20S) -camptothecin hydrochloride (33 mg), 196 mg of the desired camptothecin derivative is obtained as a pale yellow powdery complex. The content determined as 7-ethyl-10- (3′-hydroxypropyloxy)-(20S) -camptothecin by absorption at 380 nm is 3.6%. As a result of the analysis by GPC analysis,
The required average molecular weight is 182,000, and the polydispersity Mw is
/ Mn is 1.48.

Production Example 48 10- (4′-Aminobutyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Production Example 1, 10- (4′-aminobutyloxy) -7-ethyl- (20S) -camptothecin hydrochloride as a yellow powder is obtained.

Melting point:> 200 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3410,174
5,1655,1615 Mass: m / z = 464 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.77-1.93 (6H,
m), 2.90 (2H, t, J = 7 Hz), 3.20
(2H, q, J = 7.5 Hz), 4.24 (2H, t,
J = 6 Hz), 5.31 (2H, s), 5.43 (2
H, s), 7.28 (1H, s), 7.50-7.53
(2H, m), 8.00 (3H, br), 8.09 (1
H, d, J = 10 Hz).

Preparation Example 49 Synthesis of 10- [4 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) butyloxy] -7-ethyl- (20S) -camptothecin hydrochloride Preparation Example 11
-In the same manner as in (1) and Production Example 8- (2), yellow powdery 10- [4 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) butyloxy] -7-
Ethyl- (20S) -camptothecin hydrochloride is obtained.

Melting point:> 156 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3270,174
5,1655,1615 Mass: m / z = 782 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.60-1.94 (6H,
m), 2.79-2.87 (1H, m), 3.07 (1
H, dd, J = 14 Hz, 5 Hz), 3.15-3.2
3 (4H, m), 3.73-3.90 (6H, m),
4.22 (2H, t, J = 6 Hz), 4.50-4.5
8 (1H, m), 5.30 (2H, s), 5.43 (2
H, s), 7.17-7.27 (5H, m), 7.28
(1H, s), 7.50-7.53 (2H, m), 7.
87 (1H, t, J = 6 Hz), 8.07-8.12.
(4H, br), 8.39 (1H, t, J = 6 Hz),
8.40 (1H, d, J = 8 Hz), 8.60 (1H,
t, J = 6 Hz).

Production Example 50 10- {3 ′-[N- (glycyl-L-phenylalanyl-glycyl-glycyl) -N-methylamino] propyloxy} -7-ethyl- (20S) -camptothecin hydrochloride Synthesis 10- {3 ′-[N- (glycyl-L-phenylalanyl-glycyl-glycyl) -N
-Methylamino] propyloxy} -7-ethyl- (2
0S) -Camptothecin hydrochloride is obtained.

Production Example 51 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0300]

Embedded image

CM-dextran sodium salt (CM
1116 mg of 7-ethyl-10- [3 ′-(glycylamino) propyloxy]-(20S) -camptothecin hydrochloride obtained in Production Example 9 was treated in the same manner as in Production Example 23. 1117 mg of the desired camptothecin derivative are obtained in the form of a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy)-
The content determined as 7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) was 4.8.
%. As a result of analysis by GPC analysis, the obtained average molecular weight was 143,000, and the polydispersity Mw / Mn was 1.
53.

Production Example 52 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0303]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.64) 1400 mg and 10 obtained in Production Example 17
-[5 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) pentyloxy] -7-ethyl-
182 mg of (20S) -camptothecin hydrochloride is treated in the same manner as in Production Example 23 to obtain 1330 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 377 nm, 10- (5'-aminopentyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride (Production Example 3
Is 3.4%. GPC
As a result of the analysis, the average molecular weight obtained was 19
3,000, polydispersity Mw / Mn is 1.56.

Production Example 53 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0306]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.64) 1400 mg and 10 obtained in Production Example 49
-[4 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) butyloxy] -7-ethyl-
182 mg of (20S) -camptothecin hydrochloride is treated in the same manner as in Preparation Example 23 to obtain 1390 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 377 nm, 10- (4′-aminobutyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (Production Example 48)
Is 3.8%. GPC
As a result of the analysis, the average molecular weight obtained was 18
1,000, polydispersity Mw / Mn is 1.76.

Production Examples 54 to 69 In the same manner as in Production Example 22 or 23, camptothecin derivatives shown in Table 3 below were obtained from the corresponding starting compounds shown in Table 3 below.

[0309]

[Table 3]

Production Example 70 Synthesis of 7-ethyl-10- [3 ′-(glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Production Example 11, 7-ethyl-10-ethyl yellow powder was obtained. 1
0- [3 ′-(Glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is obtained.

Melting point:> 181 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3300,175
0,1660,1615 Mass: m / z = 564 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-1.93 (2H,
m), 1.93-2.03 (2H, m), 3.15-
3.26 (2H, m), 3.27-3.36 (2H,
m), 3.57-3.64 (2H, m), 3.79 (2
H, d, J = 5.5 Hz), 4.25 (2H, br)
t), 5.31 (2H, s), 5.43 (2H, s),
7.28 (1H, s), 7.49-7.55 (2H,
m), 8.09 (1H, d, J = 9 Hz), 8.05-
8.25 (3H, br), 8.21 (1H, brt),
8.71 (1H, brd).

Production Example 71 7-Ethyl-10- [3 '-(D-phenylalanyl-
Synthesis of [glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Production Example 11, yellow powdery 7-ethyl-1
0- [3 ′-(D-Phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is obtained.

Melting point:> 180 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3250,174
5,1655,1610 Mass: m / z = 654 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.80-1.91 (2H,
m), 1.91-2.02 (2H, m), 2.97 (1
H, dd, J = 14 Hz, 7.5 Hz), 3.10 (1
H, dd, J = 14 Hz, 6 Hz), 3.15-3.2
9 (2H, m), 3.28-3.36 (2H, m),
3.69 (1H, dd, J = 16 Hz, 6 Hz);
80 (1H, dd, J = 16 Hz, 6 Hz), 4.09
(1H, m), 4.25 (2H, t, J = 7 Hz),
5.30 (2H, s), 5.43 (2H, s), 7.2
2-7.35 (6H, m), 7.47-7.55 (2
H, m), 8.08 (1H, d, J = 9.5 Hz),
8.19 (1H, brt), 8.25-8.42 (3
H, br).

Production Example 72 Synthesis of 7-ethyl-10- [3 ′-(glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Production Example 11, a yellow powder of 7- Ethyl-1
0- [3 '-(glycyl-glycyl-glycylamino)
Propyloxy]-(20S) -camptothecin hydrochloride is obtained.

Melting point:> 158 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3250,175
0,1655,1615 Mass: m / z = 621 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7 Hz), 1.32 (3H, t,
J = 7 Hz), 1.80-2.20 (4H, m), 3.
20 (2H, q, J = 7 Hz), 3.31 (2H, q,
J = 7 Hz), 3.61 (2H, q, J = 6 Hz),
3.71 (2H, d, J = 5.5 Hz), 3.84 (2
H, d, J = 6 Hz), 4.24 (2H, t, J = 6H)
z), 5.30 (2H, s), 5.43 (2H, s),
6.56 (1H, s), 7.29 (1H, s), 7.5
1 (1H, s), 7.52 (1H, d, J = 9 Hz),
8.06 (1H, t, J = 6 Hz), 8.19 (1H,
d, J = 9 Hz), 8.19 (3H, br), 8.36
(1H, t, J = 6 Hz), 8.80 (1H, t, J =
5.5 Hz).

Production Example 73 7-Ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]
Synthesis of-(20S) -camptothecin hydrochloride In the same manner as in Production Example 11- (1) and Production Example 8- (2), yellow powdery 7-ethyl-10- [3 ′-(glycyl-glycyl-glycyl) -Glycyl-glycylamino)
Propyloxy]-(20S) -camptothecin hydrochloride is obtained.

Melting point:> 186 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3220,174
5,1655,1615 Mass: m / z = 735 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.32 (3H,
t, J = 7.5 Hz), 1.83-1.91 (2H,
m), 1.94-2.02 (2H, m), 3.16-
3.34 (2H, mt), 3.30 (2H, q, J = 6
Hz), 3.69 (2H, d, J = 5.5 Hz), 3.
74-3.78 (4H, m), 3.85 (2H, d, J
= 5.5 Hz), 4.24 (2H, t, J = 6 Hz),
5.31 (2H, s), 5.43 (2H, s), 7.3
0 (1H, s), 7.51-7.55 (2H, m),
8.00 (1H, t, J = 6 Hz), 8.10 (1H,
d, J = 9.5 Hz), 8.18 (3H, br), 8.
23 (1H, t, J = 6 Hz), 8.28 (1H, t, J
J = 5.5 Hz), 8.43 (1 H, t, J = 5.5 H)
z), 8.82 (1H, t, J = 5.5 Hz).

Production Example 74 7-Ethyl-10- [3 ′-(glycyl-glycyl-D
-Phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Production Example 11- (1) and Production Example 8- (2), 7-ethyl-10- as a yellow powder. [3 ′-(Glycyl-glycyl-D-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is obtained.

Melting point:> 136 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3220,174
5,1655 Mass: m / z = 768 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.
88 (3H, t, J = 7.5 Hz), 1.31 (3H,
t, J = 7.5 Hz), 1.80-1.93 (2H,
m), 1.92-2.04 (2H, m), 2.80 (1
H, dd, J = 14 Hz, 10 Hz), 3.04 (1
H, dd, J = 14 Hz, 4.5 Hz), 3.14 −
3.24 (2H, m), 3.28-3.35 (2H,
m), 3.54-4.20 (6H, m), 4.25 (2
H, brt), 4.48-4.58 (1H, m), 5.
29 (2H, s), 5.43 (2H, s), 7.13-
7.27 (5H, m), 7.28 (1H, s), 7.5
1 (1H, m), 7.50-7.56 (1H, m),
7.95 (1H, brt), 8.09 (1H, d, J =
9 Hz), 8.04-8.17 (3H, br), 8.3
7. 5 (1H, brt), 8.39 (1H, brd),
59 (1H, brt).

Production Examples 75 to 78 The compounds shown in Table 4 below were obtained from the product of Production Example 1 in the same manner as in Production Example 8 or Production Example 11.

[0321]

[Table 4]

Production Examples 79 to 80 The compounds shown in Table 5 below were obtained from the product of Production Example 4 or 5 in the same manner as in Production Example 8 or 11.

[0323]

[Table 5]

Production Example 81 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0325]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.65) 2220 mg and 7-
Ethyl-10- [3 '-(glycyl-glycylamino)
[Proxyoxy]-(20S) -camptothecin hydrochloride (222 mg) was treated in the same manner as in Preparation Example 23 to obtain the desired camptothecin derivative (2310 mg) as a pale yellow powder. 3
The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Production Example 1- (8-1)) by absorption at 80 nm is 5.2%. . As a result of analysis by GPC analysis, the average molecular weight obtained is 166,000, and the polydispersity Mw / Mn is 1.55.

Production Example 82 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0328]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.55) 2320 mg and 7- obtained in Production Example 71
Ethyl-10- [3 ′-(D-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride (291 mg) was treated in the same manner as in Preparation Example 23 to give the desired camptothecin derivative (1964m) as a pale yellow powder.
g. By absorption at 380 nm, 10- (3 ′
-Aminopropyloxy) -7-ethyl- (20S)-
The content determined as camptothecin hydrochloride (the compound of Production Example 1- (8-1)) is 6.7%. As a result of analysis by GPC analysis, the average molecular weight determined was 184,00
0, polydispersity Mw / Mn is 1.57.

Production Example 83 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0331]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.55) 2240 mg and 7- obtained in Production Example 74
Ethyl-10- [3 ′-(glycyl-glycyl-D-phenylalanyl-glycylamino) propyloxy]-
291 mg of (20S) -camptothecin hydrochloride is treated in the same manner as in Production Example 23 to obtain 2005 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride (Production Example 1
The content determined as (-(8-1) compound) is 5.5%. As a result of analysis by GPC analysis, the obtained average molecular weight was 148,000, and the polydispersity Mw / Mn was 1.84.
It is.

Production Example 84 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0334]

Embedded image

CM-dextran sodium salt (CM
Degree of conversion = 0.45) 2000 mg and 7- obtained in Production Example 72
260 mg of ethyl-10- [3 ′-(glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride was treated in the same manner as in Preparation Example 23 to give 1901 mg of the desired camptothecin derivative as a pale yellow powder.
Get. By absorption at 380 nm, 10- (3′-
Aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (compound of Production Example 1- (8-1))
Is 5.3%. As a result of analysis by GPC analysis, the obtained average molecular weight was 138,000,
The polydispersity Mw / Mn is 1.51.

Production Example 85 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0337]

Embedded image

CM-dextran sodium salt (CM
1640 mg of 7- obtained in Production Example 73
Ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-
230 mg of (20S) -camptothecin hydrochloride is treated in the same manner as in Production Example 23 to obtain 1700 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride (Production Example 1
The content determined as-(8-1) compound) is 4.7%. As a result of analysis by GPC analysis, the obtained average molecular weight was 149,000 and the polydispersity Mw / Mn was 1.50.
It is.

Examples 86 to 92 The compounds shown in Table 6 below are obtained from the corresponding starting compounds in the same manner as in Example 22 or 23. Note that C in the table
M · Pulullan · Na represents carboxymethyl pullulan sodium salt. The same applies hereinafter.

[0340]

[Table 6]

Production Examples 93 to 113 In the same manner as in Production Example 11, the compounds shown in Table 7 below were obtained from the corresponding starting compounds shown in Table 5 below.

[0342]

[Table 7]

Production Examples 114 to 158 In the same manner as in Production Example 22 or 23, from the corresponding starting compounds shown in Tables 8 to 10, the following Tables 8 to 10 were prepared.
The compound described is obtained.

[0344]

[Table 8]

[0345]

[Table 9]

[0346]

[Table 10]

Production Example 159 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0348]

Embedded image

CM-dextran sodium salt (CM
5.05) and 10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) obtained in Production Example 16- (2). )-Camptothecin hydrochloride (650 mg) is treated in the same manner as in Preparation Example 23 to obtain 4.989 g of the desired camptothecin derivative. 1 due to absorption at 380 nm
0- (3'-aminopropyloxy) -7-ethyl-
(20S) -camptothecin hydrochloride (Production Example 1- (8-
The content determined as compound (1)) is 5.4%. G
As a result of analysis by PC analysis, the average molecular weight obtained was 1
59000, polydispersity index Mw / Mn is 1.4.

Production Example 160 Synthesis of Camptothecin Derivative Represented by the Following Formula

[0351]

Embedded image

CM-dextran sodium salt (CM
5.21 g of 10− obtained in Production Example 43.
[3 ′-(Glycyl-glycyl-glycyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (679 mg) was treated in the same manner as in Preparation Example 22 to give 5.22 g of the desired camptothecin derivative as a pale yellow powder. Obtained as a complex. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (Production Example 1- (8
The content determined as compound (1)) is 5.6%.
As a result of analysis by GPC analysis, the obtained average molecular weight is 139000, and the polydispersity Mw / Mn is 1.6.

Reference Example 1 (1) Dextran [Dextra, manufactured by Pharmacia]
n T-110, average molecular weight: 100,000 (GPC
Method)], and dissolve 29 g in 290 ml of water. 0
At ｇ5 ° C., add 1.45 g of sodium borohydride and add 5
Stir at C overnight. Acetic acid is added dropwise to the reaction solution to adjust the pH to 5, and the mixture is stirred at room temperature for 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 10 obtained in the above (1)
0 g is dissolved in 1000 ml of water, and 400 g of sodium hydroxide is added to this solution under ice-cooling, followed by stirring for 30 minutes. After returning the reaction solution to room temperature, 660 ml of an aqueous solution of 220 g of monochloroacetic acid is added dropwise, and the mixture is stirred at 40 ° C. for 18 hours. Cool the reaction to below 10 ° C and adjust to pH 8-9 with acetic acid. While stirring the reaction solution vigorously, 8 liters of methanol is added to precipitate insolubles. The insolubles are collected by filtration, dissolved in 5 liters of pure water, and desalted by ultrafiltration. The remaining liquid is concentrated under reduced pressure, and the concentrated liquid is filtered. Add ethanol to the filtrate,
The precipitated precipitate was collected by filtration, washed with aqueous ethanol and acetone, and then dried under reduced pressure at room temperature and 50 ° C.
Carboxymethyl dextran (CM-dextran)
Sodium salt [degree of carboxymethylation (neutralization titration method):
0.45] 101 g are obtained.

Reference Examples 2 to 8 The same procedure as in Reference Example 1 was carried out except that the amount of monochloroacetic acid was changed, to obtain a CM-dextran sodium salt shown in Table 11 below.

[0356]

[Table 11]

Reference Example 9 Pullulan [average molecular weight: 150,000 (GPC method) manufactured by Hayashibara Biochemical Laboratory Co., Ltd.] was treated in the same manner as in Reference Example 1 to give carboxymethyl pullulan (CM-
Pullulan) sodium salt [degree of carboxymethylation (neutralization titration): 0.5].

[0358]

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.

Therefore, 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, gastric cancer, pancreatic cancer, etc.), liver cancer, kidney cancer, prostate cancer] ,
Head and neck cancer, malignant lymphoma, etc.], and humoral tumors (eg, leukemia).

Continuation of the front page (56) References JP-A-2-138186 (JP, A) WO 94/19376 (WO, A1) WO 90/3169 (WO, A1) Zhao, Rulin, et. a l. , Bioorg. Med. Chem. Lett. , Vol. 5, No. 24, p. 3063-3066, 1995 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 491/22 A61K 31/00-31/708 A61P 35/00-35/04 CA (STN) WPI (DIALOG) REGISTRY (STN)

Claims (18)

(57) [Claims] 1. A compound of the general formula [I] [Wherein, R ¹ is a substituted or unsubstituted lower alkyl group, X ¹
Is a group represented by the formula: —NHR ² (R ² represents a hydrogen atom or a lower alkyl group) or —OH, and Alk is a linear or branched group having 1 to 6 carbon atoms which may be interposed with an oxygen atom. X ¹ of the compound [I] represented by the following formula ( ¹⁾ and dextran or pullulan having a carboxyl group are represented by amino acids or 2 to 2
A pharmaceutical composition comprising, as an active ingredient, a camptothecin derivative or a pharmaceutically acceptable salt thereof bound via a peptide consisting of five amino acids . 2. A dextran having a carboxyl group.
Alternatively , part or all of the carboxyl group of pullulan and the amino group of an amino acid or a peptide consisting of 2 to 5 amino acids form an acid amide bond, and this amino acid or 2 to 5 amino acids
All or a part with a compound of the carboxyl group in the peptide comprising the amino acid X ¹ Togasan amide bond or an ester bond to a pharmaceutical composition of claim 1 comprising the [I]. 3. A dextran having a carboxyl group.
Alternatively , a part or all of the carboxyl group of pullulan and an amino acid or the N-terminal amino group of a peptide consisting of 2 to 5 amino acids form an acid amide bond, and this amino acid or 2
C-terminal carboxyl group with a compound of a peptide consisting of 5 amino acids X ¹ Togasan amide bond or an ester bond to a pharmaceutical composition of claim 2 comprising the [I]. 4. X ^{1 of the} compound [I] is of the formula: —NHR
^{2 (R 2} is as defined above), and dextran or pullulan having a carboxyl group is carboxymethylated dextran or pullulan, both components 2
4. The pharmaceutical composition according to claim 3 , which is linked via a peptide consisting of five amino acids . 5. A lower compound wherein R ¹ of compound [I] is substituted with a group selected from the group consisting of an optionally protected hydroxyl group, an optionally protected mercapto group and an optionally protected amino group. The pharmaceutical composition according to claim 4 , which is an alkyl group or an unsubstituted lower alkyl group. 6. A compound [I] wherein R ¹ is an unsubstituted lower alkyl group, X ¹ is an amino group, and Alk is a linear or branched alkylene group having 1 to 6 carbon atoms (an oxygen atom is not interposed). The pharmaceutical composition according to claim 5 , which is 7. A dextran having a carboxyl group.
The pharmaceutical composition according to claim 6 , wherein the pullulan is carboxymethylated dextran. 8. The peptide comprising 2 to 5 amino acids, wherein glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycine. The pharmaceutical composition according to claim 7 , which is glycyl-glycyl-glycyl-glycine or L or D-phenylalanyl-glycine. 9. The compound [I] wherein R ¹ is an ethyl group, Alk
There trimethylene group, a pharmaceutical composition according to claim 8 tetramethylene group or pentamethylene group. 10. The peptide consisting of 2 to 5 amino acids is glycyl-glycyl-L-phenylalanyl-glycine, and X ¹ -Alk-O- of compound [I] is 3-.
The pharmaceutical composition according to claim 9 , which is an aminopropyloxy group and is bonded to the camptothecin skeleton at position 10. 11. The peptide consisting of 2 to 5 amino acids is glycyl-glycine, and X ^1-of compound [I].
Alk-O- is a 3-aminopropyloxy group,
The pharmaceutical composition according to claim 9 , which is bonded to the camptothecin skeleton at position 10. 12. The peptide consisting of 2 to 5 amino acids is glycyl-glycyl-glycine, and X ¹ -Alk-O— of compound [I] is a 3-aminopropyloxy group. The pharmaceutical composition according to claim 9 , which is bound to the camptothecin skeleton at position 10. 13. The peptide consisting of 2 to 5 amino acids is glycyl-glycyl-glycyl-glycine,
The pharmaceutical composition according to claim 9 , wherein X ¹ -Alk-O- of the compound [I] is a 3-aminopropyloxy group and is bonded to the camptothecin skeleton at position 10. 14. The peptide consisting of 2 to 5 amino acids is glycyl-glycyl-glycyl-glycyl-glycine, and X ¹ -Alk-O- of compound [I] is 3-aminopropyl. An oxy group, a camptothecin skeleton 1
The pharmaceutical composition according to claim 9 , which is bonded to the 0 position. 15. The peptide consisting of 2 to 5 amino acids is L or D-phenylalanyl-glycine,
The pharmaceutical composition according to claim 9 , wherein X ¹ -Alk-O- of the compound [I] is a 3-aminopropyloxy group and is bonded to the camptothecin skeleton at position 10. 16. The pharmaceutical composition according to claim 10, wherein dextran having a carboxyl group has a carboxymethylation degree of 0.3 or more and 0.8 or less. 17. The method according to claim 1, which is an antitumor agent .
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1
The pharmaceutical composition according to 4, 15 or 16 . 18. 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, and leukemia. 18. The pharmaceutical composition according to claim 17, wherein