JPH1072467A - Camptothecin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound which can manifest antitumor action without side-effect and is useful for treatment of solid tumors such as lung cancer by bonding a polysaccharide bearing a carboxyl group through an amino acid or a peptide to camptothecin acid bearing a reactive group. SOLUTION: This compound has a moiety of (A) a compound of formula I [R<1> is a (substituted) lower alkyl; X<1> is a group of the formula: NHR<2> (R<2> is H, a lower alkyl), OH; Alk is a (branched) alkylene which may be bridged with O atoms] and another moiety of (B) a polysaccharide bearing a carboxyl group in which the moieties (A) and (B) are linked to each other through (C1 ) an amino acid or (C2 ) a peptide and also may be in the salt form, typically exemplified by formula II (CM is carboxymethyl). The typified compound is prepared is prepared by reaction of sodium carboxymethylated dextran with 7-ethyl-10- 2'-[2''-(glycyl-glycyl-L-phenyl-alanyglycylamino)ethyloxy]ethyloxy}-(20 S)-camptothecin hydrochloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel camptothecin derivative having enhanced antitumor activity and an intermediate thereof. More specifically, the present invention relates to a novel camptothecin derivative obtained by binding an aminoalkoxy- or hydroxyalkoxy-camptothecin compound to a polysaccharide having a carboxyl group via an amino acid or a peptide, an intermediate thereof, and a method for producing the same. About. The camptothecin derivative of the present invention can be delivered to a target action site in a large amount and selectively, and can exert a desired pharmacological action at the site, and the camptothecin compound has a significantly enhanced antitumor effect. And its side effects are reduced, making it extremely useful as a pharmaceutical.

[0002]

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

Embedded image Irinotecan hydrochloride, which is known to have anti-leukemic and anti-tumor effects
(CPT-11) is already commercially available. However, while this compound has a 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, Vol.
9 (1994)]. On the other hand, in order to increase the antitumor activity and suppress the side effects of such kind of drugs having strong side effects as much as possible, in recent years, a so-called drug delivery system (Drug Delivery System) which delivers a necessary amount of the drug to a necessary tissue has been developed. ) Technology 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 anticancer drug effect and targeting therapy (published by Science Forum Co., Ltd.), p.
(1987)], dextran-conjugated mitomycin [enhancement of anticancer drug effect and targeting therapy (published by Science Forum Co., Ltd.), p. 278 (1987)] and the like.

[0003]

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. Therefore, there is a demand for the development of a new derivative which suppresses the appearance of undesired side effects while maintaining its excellent drug activity.

[0004]

Means for Solving the Problems The present inventors have applied WO 94/19376 by applying the technology of the drug delivery system in order to obtain an excellent camptothecin derivative which has eliminated the problems of the above camptothecin compounds.
As a result of further research on applying the method described in No. 1 to camptothecin-type compounds and applying it to a camptothecin compound having a reactive group, it is possible to bond a polysaccharide having a carboxyl group to the camptothecin compound having a reactive group via an amino acid or a peptide. It has been found that a camptothecin derivative having the above-mentioned effect can be obtained, and the present invention has been completed.

That is, according to the present invention, the following general formula

Embedded image [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 an intervening oxygen atom. Represents a straight-chain or branched-chain alkylene group, which may be represented by a camptothecin compound having an aminoalkoxy group or a hydroxyalkoxy group, and a polysaccharide having a carboxyl group via an amino acid or a peptide. However, it has been found that the obtained camptothecin derivative has remarkably strong antitumor activity and low toxicity.

According to the study of the present inventors, a novel camptothecin compound represented by the above formula [I] and a compound having an amino acid or a peptide bound thereto are useful as intermediates for the final target camptothecin derivative. In addition, it has been found that these camptothecin compounds themselves have excellent antitumor effects.

An object of the present invention is to provide a novel camptothecin derivative comprising a camptothecin compound represented by the formula [I] and a polysaccharide having a carboxyl group bonded via an amino acid or a peptide. Another object of the present invention is to provide a novel intermediate selected from a camptothecin compound represented by the formula [I] and a camptothecin compound obtained by binding an amino acid or a peptide to the compound [I]. Still another object of the present invention is to provide
The present invention provides a method for producing these camptothecin derivatives and intermediates.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The camptothecin derivative of the present invention includes a camptothecin compound [I] and a polysaccharide having a carboxyl group bonded via an amino acid or a peptide. As a specific example, a part or all of the carboxyl group of the polysaccharide and the amino group of the amino acid or the peptide are in an acid amide bond, and all or a part of the carboxyl group of the amino acid or the peptide and X ^{1 of the} compound [I] are May be a compound having an acid amide bond or an ester bond. More specifically, a part or all of a carboxyl group of a polysaccharide and an N-terminal amino group of an amino acid or a peptide are an acid amide bond, and the amino acid or the amino acid Compounds in which the C-terminal carboxyl group of the peptide and X ¹ of the compound [I] have an acid amide bond or an ester bond can be mentioned.

Each substituent in the compound represented by the formula [I] of the present invention contains the following groups. R ¹ and X ¹ have the formula: —NH
The lower alkyl group for R ² to be a R ^2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, an alkyl group having 1 to 4 carbon atoms such as tert- butyl and the like, lower for R ¹ Examples of the substituent of the alkyl group include a hydroxyl group which may be protected, a mercapto group, an amino group and the like (for example, it may be protected with an alkyl group or an acyl group).

The "straight-chain or branched-chain alkylene group in which an oxygen atom may be present" as Alk includes methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and 1-methylethylene. , 1-methylpropylene, 2-methylpropylene and the like straight or branched chain alkylene group having 1-6 carbon atoms, and _{-CH 2 CH 2 -O-CH 2} CH 2 -, - CH 2 C
_{H 2 CH 2 -O-CH 2} CH 2 -, - CH 2 CH (CH 3) -O
_{-CH 2 CH 2 -, - CH} 2 CH 2 -O-CH 2 CH 2 -O-
Examples thereof include a linear or branched alkylene group having 2 to 6 carbon atoms in which one or more oxygen atoms are interposed such as CH ₂ CH ₂ —.

In the above compound [I], X ¹ has the formula: —NH
The following formula which is R ²

Embedded image [Wherein R ¹ , R ² and Alk are as defined above] are preferred. In the above compound [I ′], R ¹ is an unsubstituted lower alkyl group, R ² is a hydrogen atom, and Alk is a carbon atom. Compounds having from 2 to 4 straight-chain alkylene groups (without oxygen atoms) are more preferred. Of the above compound [I], a compound in which 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 is particularly preferable.

The camptothecin compound according to the present invention
[I] and the “polysaccharide having a carboxyl group” bonded via an amino acid or a peptide are those described in WO 94 /
Including the same materials as disclosed in US Pat.
Polysaccharides that inherently have a carboxyl group in their structure
(E.g., hyaluronic acid, pectic acid, alginic acid, chondroitin, heparin, etc.) and polysaccharides that do not originally have a carboxyl group (e.g., pullulan, dextran, mannan, chitin, mannoglucan, chitosan, etc.) Including those that introduced. Among them, dextran is particularly preferred as the polysaccharide, and its average molecular weight is 20,000 to 400,000, especially 5
It is preferably in the range of 0000 to 150,000 [Gel Permeation Chromatography (GPC) Method, Shinsei Kagaku Jikken Koza Vol. 20, page 7]. In the case where a carboxyl group is introduced into a polysaccharide which does not originally have a carboxyl group, the hydrogen atoms of some or all of the hydroxyl groups of the polysaccharide having no carboxyl group are carboxy-C _1-4 alkyl groups. It means what has been replaced. In addition, the “polysaccharide having a carboxyl group” of the present invention includes a polysaccharide originally having no carboxyl group once treated with a reducing agent, and then a hydrogen atom of some or all of the hydroxyl groups is converted to carboxy-C _1-. Also includes those substituted with ₄ alkyl groups.

The alkyl portion of the carboxy-C _1-4 alkyl group which is substituted for the hydrogen atom of the hydroxyl group of the above polysaccharide may be either linear or branched. Carboxy-C
Preferred examples of the _1-4 alkyl group include a carboxymethyl group, a 1-carboxyethyl group, a 3-carboxypropyl group, a 1-methyl-3-carboxypropyl group, a 2-methyl-3-carboxypropyl group, and a 4-carboxy group. A butyl group and the like are mentioned, and a carboxymethyl group and a 1-carboxyethyl group are particularly preferable. In the present invention, it is preferable that the polysaccharide having a carboxyl group is carboxymethylated dextran or pullulan. When the carboxyalkyl group is introduced, the degree of the introduction is defined as the number of carboxyalkyl groups per sugar residue (the peptide chain further includes a group introduced therein). Degree ". That is,

[0014]

(Equation 1) It can be expressed as. Hereinafter, this 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 is preferably 0.3 or more and 0.8 or less. When the polysaccharide is chitin, the degree of substitution is 2 when all of the hydroxyl groups are substituted, preferably from 0.3 to 0.8. Unless the polysaccharide originally has a carboxyl group, it is necessary that at least one carboxyalkyl group be present in the polysaccharide molecule. Therefore, compounds having a substitution degree of 0 in this sense are excluded from the polysaccharide of the present invention. These carboxyl-containing polysaccharides are 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).
Amino acids, L-amino acids, and mixtures thereof), and may be any of neutral amino acids, basic amino acids, and acidic amino acids. Furthermore, not only α-amino acids, but also β-amino acids, γ-amino acids, ε-amino acids and the like are included. Specific examples include glycine, α-alanine, β-alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, proline, oxyproline. , Γ-aminobutyric acid, ε-
Aminocaproic acid and the like.

In addition to the peptides derived from the above-mentioned amino acids, the peptides include those containing a compound other than an amino acid in a part of the chain. For example, a dicarboxylic acid such as succinic acid, a diamine such as ethylene diamine or a diol such as ethylene glycol may be present in or at the terminal of the peptide chain. In addition, the binding direction of the peptide chain is usually linked from the N-terminus to the carboxyl group of the polysaccharide by an acid amide bond,
When a basic amino acid (e.g., lysine) is present in the peptide chain, the ε-amino group is bonded to the carboxyl group of the polysaccharide, and the α-amino group is bonded to the C-terminus of the peptide chain. May be reversed. Such a peptide is one in which two or more amino acids are peptide-bonded, that is, two or more peptide chains, and preferably two to five peptide chains. Examples of specific peptide chains include, for example,-
Gly-Gly-L or D-Phe-Gly-, -L or D
-Phe-Gly-, -L or D-Tyr-Gly-, -L or D-Leu-Gly-, -Gly-Gly-, -Gly-Gly
-Gly-, -Gly-Gly-Gly-Gly- or -Gly-
Gly-Gly-Gly-Gly- and peptide chains containing this sequence in the chain are mentioned (where these peptides and the N-terminal side of the peptide chain containing these sequences are introduced into the carboxyl group of the polysaccharide). Of these peptides,
-Gly-Gly-L or D-Phe-Gly-, -Gly-G
ly-, -Gly-Gly-Gly-, -Gly-Gly-Gly-G
Those which are ly-, -Gly-Gly-Gly-Gly-Gly-, -L or D-Phe-Gly- and -L or D-Leu-Gly- are more preferred. Of these, -Gly
-Gly-L-Phe-Gly, -Gly-Gly-, -Gly-G
Ly-Gly-, -Gly-Gly-Gly-Gly-, -L or D-Phe-Gly- are particularly preferred.

In order to produce the camptothecin derivative of the present invention, a method is generally employed in which an amino acid or a peptide is bound to the compound represented by the formula [I], and then a polysaccharide having a carboxyl group is reacted therewith. Is done.
By reaction of compound [I] with an amino acid or peptide,
When X ^{1 in the} formula [I] is the formula: —NHR ² , an acid amide bond is formed with the C-terminal carboxyl group of the amino acid or peptide, and when X ¹ is —OH, an ester bond is formed. At this time, it is preferable that other functional groups in the amino acid or peptide not participating in the acid amide bond or the ester bond, such as the N-terminal amino group or other carboxyl group, be protected by a conventional method. Such protecting groups are not particularly limited as long as they are generally used for protecting amino acids.Examples of protecting groups for amino group include t-butoxycarbonyl group, p-methoxybenzyloxycarbonyl group, and carboxyl group. Examples of the group-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 by a conventional method, for example, in a suitable solvent in the presence of a condensing agent. It is preferable to use dimethylformamide, acetonitrile, chloroform, methylene chloride and the like as the solvent, and dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the like as the condensing agent.

When the amino group or the camptothecin compound to which the amino acid or peptide is bound as described above is protected, the protecting group is removed by a conventional method, if the amino group is protected, and then reacted with a polysaccharide having a carboxyl group. As a result, the desired camptothecin derivative is produced. 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 bonded to the camptothecin compound [I] form an acid amide bond.

The reaction of a camptothecin compound [I] with an amino acid or peptide bonded to a polysaccharide having a carboxyl group can be carried out according to a conventional method, for example, in a suitable solvent in the presence of a condensing agent. be able to. As a solvent, water, ethanol, dimethylformamide and a mixed solvent thereof are used, and as a condensing agent, 1-
It is preferable to use (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2-ethyloxy-1-ethyloxycarbonyl-1,2-dihydroquinoline and the like.

In the camptothecin derivative of the present invention,
The binding ratio between the polysaccharide and the camptothecin compound [I], which is a medicinal component, is appropriately selected depending on the type of the polysaccharide. In general, the content of the camptothecin compound [I] is preferably set to the following ratio. The polysaccharides are pullulan, dextran,
In the case of chitin, mannoglucan and N-acetyl-de-N-sulphated heparin, the content is preferably 0.1 to 20% by weight, particularly preferably 2 to 10% by weight. The average molecular weight (measured by the GPC method) of the camptothecin derivative of the present invention is 30,000 to 500,000 when the polysaccharide is dextran.
0 is preferable, and especially 60,000 to 200,000 is preferable.

The camptothecin derivative obtained by the above method 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 compound [I] in the present invention
Is produced by the method shown in the following reaction formula 1.

Embedded image [In the formula, 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]

That is, the aminocarbonyl compound (1)
To a known substance, pyranoindolizine (2) (EP-0220)
No. 601-A) and a method known as the Friedlander condensation reaction (Organic Reactions (Org
anic Reactions) 28 , pp37-202, John Willy
& Sons. Inc. New York (cf. 1982)), and then the protecting group is removed to obtain the desired camptothecin compound [I]. In the above production method, the group represented by R ¹ may be introduced after the Friedlander condensation reaction. That is, the starting compound
In place of (1), a compound having hydrogen in place of the group represented by R ¹ in the compound (1) is used.
(2) and a Friedlander condensation reaction, and the resulting condensation product is treated with a derivative represented by the formula: R ¹ —CO—X (X is hydrogen or a reactive group), for example, in Chem. Pharm. B
ull. 39 , 2574-2580 (1991) to give compound [I]. In the above reaction formula 1, instead of the aminocarbonyl compound (1), a compound represented by the general formula [II]:

Embedded image Wherein X ³ represents R ³ —N (R ² ) — or R ³ —O—,
R ³ represents a group obtained by removing a hydroxyl group of a carboxyl group from an amino acid or a peptide protected with an amino group, and R ¹ , R ²
And Alk is the same as described above], a compound in which an amino acid or a peptide is bound to a camptothecin compound [I] can also be directly obtained.

The aminocarbonyl compound (1) as a starting compound used in the above-mentioned method is a compound in which the group X ² is a protecting group —N
In the case of (R ² ) —, it is produced, for example, by a method represented by the following reaction formula 2.

Embedded image [Wherein R ¹ , R ² and Alk are the same as above, R ³ is a substituted or unsubstituted lower alkenyl or alkyl group, R ⁴
Represents a protected aminoalkyl group, Prot represents a protecting group, and 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 obtain a compound (b) having a hydroxyl group activated. On the other hand, the Grignard reagent (R ³ MgBr) is allowed to act on the hydroxyl-substituted o-nitrobenzaldehyde, and the obtained compound (c) is reacted with the activated protected aminoalkanol (b) prepared above to convert the phenolic hydroxyl group into an alkyl. Compound (d) is obtained, which is treated with an oxidizing agent such as activated manganese dioxide to give a ketone (e), which is then catalytically reduced in the presence of a suitable catalytic reducing agent such as Pd-C. compound obtain (1 ^1). Incidentally, the compound (1 ¹⁾ can be isolated, without isolation and purification, it can be used in the condensation reaction of the raw chemical compound (2). In the above reaction formula 2, after removing the amino-protecting group in R ⁴ of the ketone (e) by a conventional method, the compound is reacted with an amino-protected amino acid or peptide in the same manner as in the case of compound [I]. When the product is catalytically reduced in the same manner as the ketone (e), the protecting group at X ² of the aminocarbonyl compound (1) is replaced with a carboxyl group from the amino-protected amino acid or peptide. Can be obtained by converting the compound into a group from which the hydroxyl group has been removed.

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.

Embedded image [Wherein, Alk, R ¹ and R ³ are the same as above, R ⁵ is a lower alkyl group, X ³ is a halogen atom, R ⁶ is a hydroxyalkyl group, and R ⁷ is a protected hydroxyalkyl group]

That is, a phenolic hydroxyl group is hydroxyalkylated by reacting a hydroxyalkyl-substituted o-nitrobenzaldehyde dialkyl acetal with a hydroxyalkyl halide, and the hydroxy group of the hydroxyalkyl group is protected with, for example, a t-butyldimethylsilyl group. 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 a compound (d ¹ ). Similarly, the compound is oxidized to obtain a compound (e ¹ ), and further catalytically reduced to obtain a compound (l ¹¹ ).
In the above reaction formula 3, after removing the hydroxyl-protecting group of the compound (e ¹ ) by a conventional method, the compound is reacted with an amino-protected amino acid or peptide in the same manner as in the case of the compound [I]. The compound [II] can also be obtained by ester-bonding and catalytically reducing the product in the same manner as in the ketone body (e ¹ ).

The camptothecin derivative of the present invention or a pharmacologically acceptable salt thereof has excellent antitumor activity against various tumors. Organ cancer (colorectal cancer, gastric cancer, etc.)].

The camptothecin derivative of the present invention or a pharmaceutically acceptable salt thereof is parenterally (eg, intravenously).
It is preferable to administer to a solution (usually, a solution,
Suspension, emulsion).

The dose of the object of the present invention varies depending on the administration method, age of the patient, weight, condition, etc.
Per day, camptothecin compound [I] [X ¹ has the formula: -NH
If it is R ² is converted to the hydrochloride salt, 0.02 to 5
It is preferable to administer in the range of 0 mg / kg, especially 0.1 to 10 mg / kg.

[0032]

The compounds of the present invention and the method for producing the same will be more specifically described by the following examples, but the present invention is not limited thereto.

Example 1 10- (3'-aminopropyloxy) -7-ethyl- (2
Synthesis of (0S) -camptothecin hydrochloride (1) Synthesis of 3-t-butoxycarbonylaminopropanol 6.0 g of 3-aminopropanol was dissolved in 50 ml of methylene chloride, and di-t-butyl dicarbonate 1 was stirred under ice-cooling and stirring.
8.3 g are added dropwise. 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), 3.2
9 (2H, dd, J = 12Hz and 6Hz), 3.66 (2H, d
d, J = 12 Hz and 6 Hz), 4.80 (1 H, brs)

(2) Synthesis of 3-t-butoxycarbonylaminopropyl tosylate 3-t-butoxycarbonylaminopropanol 10.0
g was dissolved in 100 ml of methylene chloride, 8.66 g of triethylamine and 16.3 g of tosyl chloride were added under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was
After dissolving in 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 15.37 g of 3-t-butoxycarbonylaminopropyl tosylate as a pale yellow oil.
Get. Yield: 82% IR (Neat): ν _max ^{cm -1} = 3400,3340,170
0.1600 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), 3.1
1-3.22 (2H, m), 4.09 (2H, t, J = 6Hz), 4.
5-4.65 (1H, m), 7.36 (2H, d, J = 8Hz), 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 at 78 ° C., 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,
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 1- (5'-hydroxy-2'-nitrophenyl) -2 as a tan powder. 5.09 g of propen-1-ol are 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, b
r), 5.19 (1H, dd, J = 10.5Hz and 1.5Hz),
5.38 (1H, dd, J = 17Hz and 1.5Hz), 5.89
(1H, m), 6.08 (1H, ddd, J = 17Hz, 10.5Hz and 5Hz), 6.80 (1H, dd, J = 9Hz and 3Hz),
7.22 (1H, d, J = 3Hz), 7.97 (1H, d, J = 9H)
z), 9.90 (1H, brs)

(4) 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl]-
Synthesis of 2-propen-1-ol 2.0 g of 1- (5'-hydroxy-2'-nitrophenyl) -2-propen-1-ol was dissolved in 100 ml of dry DMF, and 1 equivalent of sodium iodide and potassium carbonate and 3
Add 1.5 equivalents of -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 caramel-like 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl]-
3.53 g of 2-propen-1-ol are obtained. 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 = 6H)
z), 4.8 (1H, brs), 5.24 (1H, dd, J = 10.5 Hz)
And 1.5 Hz), 5.42 (1 H, dd, J = 17 Hz and 1.5 Hz), 5.92 (1 H, d, J = 5 Hz), 6.08 (1 H, d
dd, J = 17 Hz, 10.5 Hz and 5 Hz), 6.86 (1
H, dd, J = 9 Hz and 3 Hz), 7.25 (1 H, d, J = 3
Hz), 8.04 (1H, d, J = 9Hz)

(5) 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl]-
Synthesis of 2-propen-1-one 1- (5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl) -2-propen-1
Dissolve 9.66 g of ol in 300 ml of chloroform, add 72 g of activated manganese dioxide and heat to reflux. After completion of the reaction, the inorganic substances were removed by filtration through Celite, and the filtrate was concentrated.
After stirring at 0 ° C. for 6 hours, ethyl acetate was added, and the mixture was washed with saturated saline and dried over sodium sulfate. Purification by silica gel column chromatography gave yellow 1- [5 '-(3 "-t
-Butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1-one is obtained, 6.01 g. 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), 4.08-4.16 (2 H, m), 4.67
(1H, brs), 5.85 (1H, d, J = 17.5 Hz), 6.02
(1H, d, J = 10.5 Hz), 6.62 (1H, dd, J = 17.
5 Hz and 10.5 Hz), 6.82 (1 H, d, J = 3 Hz), 7.0
3 (1H, dd, J = 9Hz and 3Hz), 8.17 (1H, d, J
= 9Hz)

(6) 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-aminophenyl]-
Synthesis of propan-1-one 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-nitrophenyl] -2-propen-1
After dissolving 325 mg of -one in 15 ml of ethanol and adding 40 mg of 10% palladium on carbon, the mixture is stirred for 1.5 hours under a hydrogen stream. 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. -1-
Obtain 248 mg. Melting point: 112-115 ° C Yield: 83% IR (Nujol): ν _max ^{cm -1} = 3450,3400,334
0.1,1700,1650 Mass: m / z = 323 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.21 (3
H, t, J = 7 Hz), 1.45 (9 H, s), 1.90-2.01
(2H, m), 2.95 (2H, q, J = 7.5 Hz), 3.33 (2
H, q, J = 6.5 Hz), 3.97 (2H, t, J = 6.5 Hz),
4.48 (1H, brs), 5.96 (2H, brs), 6.62 (1H, brs)
d, J = 9 Hz), 6.95 (1 H, dd, J = 9 Hz and 3 H
z), 7.24 (1H, d, J = 3Hz)

(7-1) 10- (3'-t-butoxycarbonylaminopropyloxy) -7-ethyl- (20S)-
Synthesis of camptothecin 4.54 g of 1- [5 '-(3 "-t-butoxycarbonylaminopropyloxy) -2'-aminophenyl] -propan-1-one was dissolved in 200 ml of ethanol and (4S)-
7,8-dihydro-4-ethyl-4-hydroxy-1H
-Pyrano [3,4-f] indolizine-3,6,10 (4H)-
1.85 g of trione and 134 m of p-toluenesulfonic acid
Add g 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 2.47 g of 10- (3'-t-butoxycarbonylaminopropyloxy) -7-ethyl- (20S) -camptothecin as a pale yellow powder. . Melting point: 196-201 ° C (decomposition) Yield: 64% IR (Nujol): ν _max ^{cm -1} = 3450,3385,174
0,1715,1685,1665,1620 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), 1.4
6 (9H, s), 1.82-1.98 (2H, m), 2.04-2.1
6 (2H, m), 3.12 (2H, q, J = 7.5 Hz), 3.41 (2
H, q, J = 6 Hz), 3.93 (1 H, s), 4.20 (2 H, t, J
= 6Hz), 4.84 (1H, brs), 5.21 (2H, s), 5.29
(1H, d, J = 16Hz), 5.74 (1H, d, J = 16Hz),
7.28 (1H, d, J = 3Hz), 7.43 (1H, dd, J = 9H)
z and 3 Hz), 7.60 (1 H, s), 8.12 (1 H, d, J =
9Hz)

(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} = 3405,3330,173
0.1680,1655 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 H
z), 1.82 (3H, s), 1.80-2.0 (4H, m), 3.1-
3.2 (2H, m), 3.26 (2H, dt, J = 13Hz and 6
Hz), 4.21 (2H, t, J = 6 Hz), 5.26 (2H, s), 5.
42 (2H, s), 6.51 (1H, s), 7.25 (1H, s), 7.4
5 (1 H, d, J = 3 Hz), 7.49 (1 H, dd, J = 9 Hz and 3 Hz), 7.98 (1 H, t, J = 5 Hz), 8.05 (1 H, d,
J = 9Hz)

(8-1) Synthesis of 10- (3'-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride 10- (3'-t-butoxycarbonylaminopropyloxy) -7-ethyl -(20S) -camptothecin 641m
g was dissolved in 10 ml of dioxane, and stirred on an ice bath for 1 hour.
11 ml of 8% hydrochloric acid-dioxane are added dropwise. The mixture was stirred at room temperature, and after the reaction was completed, 15 ml of isopropyl ether was added and stirred. The precipitated powder was collected by filtration, washed with ether, and dried under reduced pressure.
(3'-aminopropyloxy) -7-ethyl- (20S)
563 mg of camptothecin hydrochloride are obtained. Melting point: 218 ° C. or higher (decomposition) Yield: 99% IR (Nujol): ν _max ^{cm −1} = 3370,1745,165
5 Mass: m / z = 450 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.32 (3H, t, J = 8Hz), 1.7
8-1.95 (2H, m), 2.08-2.19 (2H, m), 3.0
-3.1 (2H, m), 3.13-3.25 (2H, m), 4.32
(2H, t, J = 6Hz), 5.32 (2H, s), 5.43 (2H,
s), 7.28 (1H, s), 7.5-7.56 (2H, m), 7.99
(3H, brs), 8.11 (1H, d, J = 10Hz)

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

Example 2 10- (2'-aminoethyloxy) -7-ethyl- (20
Synthesis of S) -camptothecin hydrochloride In the same manner as in Example 1, 10- (2′-aminoethyloxy) -7-ethyl- (20S) -camptothecin hydrochloride as a yellow powder is obtained. Melting point: 249 ° C. or more (decomposition) Yield: 97% IR (Nujol): ν _max ^{cm −1} = 3400, 1745, 165
5,1620 Mass: m / z = 436 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 1.80-1.94 (2H, m), 3.21 (2H, q, J = 7
Hz), 3.27-3.37 (2H, m), 4.45 (2H, t, J =
5Hz), 5.31 (2H, s), 5.43 (2H, s), 7.28 (1
H, s), 7.54-7.58 (2H, m), 8.13 (1H, d, J =
10Hz), 8.31 (3H, brs)

Example 3 10- (5'-aminopentyloxy) -7-ethyl- (2
Synthesis of 0S) -camptothecin hydrochloride In the same manner as in 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} = 3420,1745,166
0,1615 Mass: m / z = 478 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 H
z), 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), 7.48-7.53 (2H, m), 7.98 (3H, brs), 8.
08 (1H, d, J = 9Hz)

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

Example 5 11- (3'-aminopropyloxy) -7-ethyl- (2
Synthesis of (0S) -camptothecin hydrochloride In the same manner as in Example 1, 11- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride is obtained.

Example 6 10- [2 '-(2 "-aminoethyloxy) ethyloxy]
Synthesis of -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 1, 10- [2 '-(2 ") in the form of a yellow powder was prepared.
-Aminoethyloxy) ethyloxy] -7-ethyl-
(20S) -Camptothecin hydrochloride is obtained. Melting point: 135 ° C. or more (gradual decomposition) IR (KBr): ν _max ^{cm −1} = 3405,1745,165
5,1615 Mass: m / z = 480 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 1.80-1.94 (2H, m), 2.97-3.06 (2H,
m), 3.20 (2H, 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), 7.2
9 (1H, s), 7.52-7.56 (2H, m), 8.10 (1H,
d, J = 9.5 Hz), 8.04-8.23 (3H, brs)

Example 7 Synthesis of 10- (3'-methylaminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 1, 10- (3'-methyl) Aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride is obtained. Melting point: 180 ° C. or higher (decomposition) Yield: 97% IR (KBr): ν _max ^{cm −1} = 3410,1745,166
0,1615 Mass: m / z = 464 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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 = 6Hz), 5.31 (2H, s), 5.4
3 (2H, s), 7.28 (1H, s), 7.52-7.55 (2H,
m), 8.10 (1H, d, J = 10Hz), 9.00 (2H, brs)

Example 8 10- [3 '-(L-tyrosylamino) propyloxy]-
Synthesis of 7-ethyl- (20S) -camptothecin hydrochloride (1) Synthesis of 10- [3 ′-(t-butoxycarbonyl-L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin 10- ( 3'-aminopropyloxy) -7-ethyl- (2
200 mg of (0S) -camptothecin hydrochloride in dry DMF1
0 ml, and while stirring under ice-cooling, 139 mg of t-butoxycarbonyl-L-tyrosine and 44 ml of triethylamine.
g, 85 mg of N-hydroxysuccinimide, and 1-
95 mg of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are successively added. After adding a catalytic amount of 4-dimethylaminopyridine (DMAP), the mixture was stirred at room temperature, and 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 ′-( 181 mg of t-butoxycarbonyl-L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin are obtained. Yield: 62% IR (Nujol): ν _max ^{cm -1} = 3280,1750,171
0 Mass: m / z = 735 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.92 (3H, t,
J = 7 Hz), 1.31 (3 H, t, J = 7.5 Hz), 1.41 (9
H, s), 1.75-2.02 (4H, m), 2.86-3.10 (4
H, m), 3.3-3.6 (2H, m), 3.8-4.0 (2H, m),
4.24-4.38 (1H, m), 4.78 (1H, brs), 5.00
(2H, s), 5.21 (1H, d, J = 16.5 Hz), 5.26−
5.37 (1H, m), 5.64 (1H, d, J = 16.5Hz),
6.56 (1H, br), 6.81 (2H, d, J = 8.5 Hz), 7.
06 (2H, d, J = 8.5 Hz), 7.12 (1H, d, J = 2.5
Hz), 7.22-7.31 (1H, m), 7.60 (1H, s), 8.
16 (1H, d, J = 9Hz)

(2) Synthesis of 10- [3 '-(L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t-Butoxycarbonyl-L-tyrosylamino) 157 mg of [propyloxy] -7-ethyl- (20S) -camptothecin is dissolved in 5 ml of dioxane, and 2 ml of 18% hydrochloric acid-dioxane is added dropwise with stirring on an ice bath. The mixture was stirred at room temperature, and after the reaction was completed, 20 ml of isopropyl ether was added and stirred. The precipitated powder was collected by filtration, washed with ether, dried under reduced pressure, dissolved in water and freeze-dried to give 10- [3 ′] as a yellow powder.
120 mg of-(L-tyrosylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride are obtained. Melting point: 190 ° C. or higher (decomposition) Yield: 84% IR (Nujol): ν _max ^{cm −1} = 3375,3240,174
0 Mass: m / z = 613 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.32 (3H, t, J = 8Hz), 1.7
5-1.98 (4H, m), 2.93 (2H, d, J = 7 Hz), 3.
14-3.43 (4H, m), 3.87 (1H, t, J = 7Hz),
4.05-4.23 (2H, m), 5.30 (2H, s), 5.43
(2H, s), 6.71 (2H, d, J = 8.5 Hz), 7.03 (2
H, d, J = 8.5 Hz), 7.28 (1 H, s), 7.43-7.5
4 (2H, m), 8.09 (1H, d, J = 9Hz), 8.3 (3H,
m), 8.66 (1H, t, J = 5Hz)

Example 9 10- [3 '-(glycylamino) propyloxy] -7-
Synthesis of ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 8, yellow powdery 10- [3 ′-(glycylamino) propyloxy] -7-ethyl- (20S)
Obtaining camptothecin hydrochloride; Melting point: 190 ° C. or higher (decomposition) Yield: 93% IR (Nujol): ν _max ^{cm −1} = 3355,3225,174
5,1655 Mass: m / z = 507 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.85
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 8Hz),
1.79-1.94 (2H, m), 1.94-2.06 (2H, m),
3.20 (2H, q), 3.37 (2H, q), 3.52-3.60
(2H, m), 4.28 (2H, t, J = 6Hz), 5.29 (2H,
s), 5.43 (2H, s), 7.29 (1H, s), 7.47-7.5
6 (1H, m), 7.51 (1H, s), 8.09 (1H, d, J = 9H
z), 8.20 (3H, m), 8.71 (1H, t, J = 5.5Hz)

Example 10 10- [3 '-(L-serylamino) propyloxy] -7
Synthesis of -ethyl- (20S) -camptothecin hydrochloride (1) Synthesis of 10- [3 '-(t-butoxycarbonyl-L-serylamino) propyloxy] -7-ethyl- (20S) -camptothecin 10- (3 '-Aminopropyloxy) -7-ethyl- (2
(S) -320 mg of camptothecin hydrochloride was treated in the same manner as in Example 8- (1) to give 10-
351 mg of [3 '-(t-butoxycarbonyl-L-serylamino) propyloxy] -7-ethyl- (20S) -camptothecin are obtained. Melting point: 123-129 ° C Yield: 84% IR (Nujol): ν _max ^{cm -1} = 3305, 1750, 170
5 Mass: m / z = 637 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.00 (3H,
t, J = 7 Hz), 1.35 (3 H, t, J = 8 Hz), 1.45 (9
H, s), 1.7-1.95 (2H, m), 2.08-2.20 (2
H, 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 (2 H, t, J = 6 Hz), 4.2-4.3 (1
H, m), 5.05 (2H, s), 5.26 (1H, d, J = 16Hz),
5.70 (1 H, d, J = 16 Hz), 5.74 (1 H, d, J = 8.
5Hz), 7.13-7.24 (1H, m), 7.40 (1H, dd, J
= 9 Hz and 3 Hz), 7.56 (1 H, s), 8.02 (1 H,
d, J = 9Hz)

(2) Synthesis of 10- [3 '-(L-serylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 8- (2), a yellow powder was obtained. 10-
262 mg of [3 '-(L-serylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride are obtained. Melting point: 173-177 ° C (decomposition) Yield: 88% IR (Nujol): ν _max ^{cm -1} = 3350,3240,174
5 Mass: m / z = 537 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.86
(3H, t, J = 7Hz), 1.32 (3H, t, J = 8Hz), 1.7
7-1.95 (2H, m), 1.95-2.07 (2H, m), 3.1
3-3.26 (2H, m), 3.32-3.45 (2H, m), 3.6
8-3.78 (2H, m), 3.78-3.86 (1H, m), 4.2
7 (2H, t, J = 6Hz), 5.30 (2H, s), 5.43 (2
H, s), 7.29 (1H, s), 7.48-7.56 (1H, m), 7.
51 (1H, brs), 8.09 (1H, d, J = 9Hz), 8.17-
8.28 (3H, m), 8.72 (1H, t, J = 5Hz)

Example 11 10- [3 '-(L-phenylalanyl-glycylamino)
Synthesis of propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (1) 10- [3 ′-(t-butoxycarbonyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S Synthesis of 10- (3'-aminopropyloxy) -7-ethyl- (2
200 mg of (0S) -camptothecin hydrochloride in dry DMF2
Of tert-butoxycarbonyl-L-phenylalanylglycine (199 mg), triethylamine (44 mg), N-hydroxybenzotriazole (28 mg) and 1- (3-dimethylaminopropyl) -3-.
118 mg of ethyl carbodiimide hydrochloride are 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. Carbonyl-L-phenylalanyl-glycylamino) propyloxy] -7
228 mg of -ethyl- (20S) -camptothecin are obtained.

Yield: 73% IR (Nujol): ν _max ^{cm -1} = 3300,1750,165
5,1625 Mass: m / z = 754 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.02 (3H,
t, J = 7 Hz), 1.37 (3 H, t, J = 7 Hz), 1.38 (9
H, s), 1.81-1.97 (2H, m), 2.06-1.17 (2
H, m), 2.95 (1H, dd, J = 14Hz and 8Hz), 3.
01-3.16 (2H, m), 3.12 (1H, dd, J = 14Hz
And 6 Hz), 3.39-3.62 (2H, m), 3.93 (2
H, m), 4.12-4.27 (3H, m), 5.03 (1H, d, J =
6.5 Hz), 5.13 (2H, s), 5.26 (1 H, d, J = 16.
5 Hz), 5.71 (1 H, d, J = 16.5 Hz), 6.7 (1 H, b
r), 6.9 (1H, br), 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 = 9Hz)

(2) 10- [3 '-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (2
Synthesis of 0S) -camptothecin hydrochloride 197 mg of 10- [3 ′-(t-butoxycarbonyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin was added to 5 ml of dioxane.
And 18 ml of 18% hydrochloric acid-dioxane was added dropwise with 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 freeze-dried to give 10- [ 3 '-(L
-Phenylalanylglycylamino) propyloxy]-
152 mg of 7-ethyl- (20S) -camptothecin hydrochloride
Get. Melting point: 190 ° C. or more (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 = 7Hz), 1.31 (3H, t, J = 7Hz), 1.7
8-1.93 (2H, m), 1.93-2.06 (2H, m), 2.9
8 (1H, dd, J = 13.5Hz and 7.5Hz), 3.11
(1H, dd, J = 13.5Hz and 6Hz), 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 (2H, t, J = 6Hz), 5.29 (2H, s), 5.43
(2H, s), 7.2-7.35 (6H, m), 7.50 (1H, s),
7.47-7.55 (1H, m), 8.08 (1H, d, J = 9H
z), 8.20 (1H, m), 8.4 (3H, brs), 8.92 (1H, m)

The following Example 1 was performed in the same manner as in Example 11 described above.
2 to 15 compounds are obtained. Example 12 10- [2 '-(L-phenylalanyl-glycylamino)
Ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride

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

Example 14 11- [3 '-(L-phenylalanyl-glycylamino)
Propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride

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

Example 16 10- [3 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride (1) 10- [3 ′-(t-butoxycarbonyl-glycyl-
Synthesis of glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin 10- (3′-aminopropyloxy) -7-ethyl- (2
The compound was synthesized in the same manner as in Example 11- (1) using 650 mg of (0S) -camptothecin hydrochloride, and 10- [3 ′) as a pale yellow powder.
-(T-butoxycarbonyl-glycyl-glycyl-L-
Phenylalanyl-glycylamino) propyloxy]-
714 mg of 7-ethyl- (20S) -camptothecin are obtained. Yield: 62% IR (Nujol): ν _max ^{cm -1} = 3290,1750,165
5,1625 Mass: m / z = 890 (M + Na ⁺ ) NMR (300 MHz, CDCl ₃ -d ₆ DMSO): δ ^TMS =
1.02 (3H, t, J = 7.5 Hz), 1.36 (3H, t, J =
7.5 Hz), 1.43 (9H, s), 1.82-1.98 (2H,
m), 2.12 (2H, m), 3.00 (1H, dd, J = 14.5 Hz
And 10 Hz), 3.05-3.15 (2H, m), 3.19-
3.29 (1 H, 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 (1H,
m), 4.80 (1H, brs), 5.15 (2H, s), 5.28 (1H, brs)
d, J = 16.5 Hz), 5.70 (1 H, d, J = 16.5 Hz),
5.85-5.95 (1H, m), 7.08-7.3 (6H, m),
7.28 (1 H, d, J = 3 Hz), 7.42 (1 H, dd, J = 9 H)
z and 3 Hz), 7.50 (1 H, d, J = 7 Hz), 7.56 (1
H, s), 7.61 (1H, m), 7.66-7.78 (1H, m), 8.
04 (1H, d, J = 9Hz)

(2) 10- [3 '-(glycyl-glycyl-
Synthesis of L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3 '-(t-Butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycylamino) propyl Oxy] -7-ethyl- (20S) -camptothecin 6
Deprotection was carried out in the same manner as in Example 8- (2) using 80 mg, and 10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-yellow powder was obtained.
556 mg of 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 = 7Hz), 1.31 (3H, t, J = 8Hz), 1.7
9-1.93 (2H, m), 1.93-2.05 (2H, m), 2.8
3 (1 H, dd, J = 14 Hz and 10 Hz), 3.05 (1 H,
dd, J = 14 Hz and 4 Hz), 3.1-3.25 (2 H, m),
3.25-3.4 (2H, m), 3.53-3.61 (2H, m),
3.64 (1H, m), 3.69 (1H, m), 3.76 (1H, dd, J
= 16 Hz and 6 Hz), 3.85 (1 H, dd, J = 16 Hz)
And 6 Hz), 4.25 (2 Hz, t, J = 6 Hz), 4.52 (1
H, 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 =
6Hz), 8.09 (1H, d, J = 9Hz), 8.17 (3H, br),
8.36 (1H, t, J = 6Hz), 8.43 (1H, d, J = 8.5)
Hz), 8.65 (1H, t, J = 5Hz)

Example 17 10- [5 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) pentyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Example 8- (2),
10- [5 '-(glycyl-glycyl-L-) as a yellow powder
Phenylalanyl-glycylamino) pentyloxy]-
7-Ethyl- (20S) -camptothecin hydrochloride is obtained. Melting point: 185 ° C or more (decomposition) IR (Nujol): ν _max ^{cm -1} = 3250,1740,166
0 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 H
z), 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 (2H, 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 (1
H, s), 7.47-7.54 (2H, m), 7.85 (1H, t, J =
6 Hz), 8.08 (1 H, d, J = 9 Hz), 8.04-8.20
(3H, br), 8.33 (1H, t, J = 6Hz), 8.42 (1H,
d, J = 8 Hz), 8.64 (1 H, t, J = 6 Hz)

Example 18 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 Example 8- (2),
10- [3 '-(N- (glycyl-glycyl-
L-phenylalanyl-glycyl) -N-methylamino)
Propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride is obtained. Melting point: 190 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3230,1745,165
5 Mass: m / z = 782 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.29-1.34 (3H, m), 1.
80-1.94 (2H, m), 2.00-2.15 (2H, m), 2.
65-2.84 (1H, dd, J = 14Hz and 10Hz),
3.01 (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), 7.49-7.57
(2H, m), 8.08 (1H, dd, J = 9Hz and 3.5Hz),
8.10-8.18 (3H, m), 8.31-8.39 (1H, m),
8.47 (1H, t, J = 5.5Hz), 8.53-8.60 (1
H, m)

Example 19 10- [2 '-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Example 8- (2),
10- [2 '-(glycyl-glycyl-L-) as a yellow powder
Phenylalanyl-glycylamino) ethyloxy] -7
-Ethyl- (20S) -camptothecin hydrochloride is obtained. Melting point: 189 ° C or higher (decomposition) IR (Nujol): ν _max ^{cm -1} = 3210,1745,165
5,1615 Mass: m / z = 754 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.26-1.33 (3H, m), 1.
80-1.93 (2H, m), 2.81 (1H, dd, J = 14Hz
And 10 Hz), 3.06 (1 H, dd, J = 14 Hz and 5
Hz), 3.21 (2H, q, J = 7.5 Hz), 3.54-3.90
(8H, m), 4.26 (2H, t, J = 5.5Hz), 4.52-4.
60 (1H, m), 5.30 (2H, s), 5.43 (2H, s), 7.1
7-7.25 (5H, m), 7.29 (1H, s), 7.50-7.5
6 (2H, m), 8.09 (1H, d, J = 9Hz), 8.12 (3H, m
br), 8.21 (1 H, t, J = 6 Hz), 8.39 (1 H, d, J =
5.5 Hz), 8.40 (1 H, t, J = 5.5 Hz), 8.60 (1
(H, t, J = 5.5Hz)

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} = 3255,1745,165
5,1615 Mass: m / z = 535 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.32 (3H, t, J = 7Hz), 1.7
5-1.99 (6H, m), 2.23 (2H, t, J = 7Hz), 2.
74-2.81 (2H, m), 3.18-3.40 (4H, m), 4.
25 (2H, t, J = 6Hz), 5.30 (2H, s), 5.43 (2
H, s), 7.29 (1H, s), 7.50-7.54 (2H, m), 8.
02 (3H, br), 8.09 (1H, d, J = 9Hz), 8.18 (1
H, t, J = 6Hz)

Example 21 10- [3 ′-{(N- (γ-aminobutyroyl) -γ-aminobutyroyl) amino} propyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11, 10- [3'-
{(N- (γ-aminobutyroyl) -γ-aminobutyroyl) amino} propyloxy] -7-ethyl- (20S)-
Obtain camptothecin hydrochloride. Mp:> 134 ° C. _{(decomposition) IR (KBr): ν max} cm-1 = 1745,1655 Mass: m / z = 620 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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), 2.70-2.8
1 (2H, m), 2.99-3.08 (2H, q), 3.15-3.3
3 (4H, m), 4.24 (2H, t, J = 6Hz), 5.31 (2H,
s), 5.43 (2H, s), 7.30 (1H, s), 7.49-7.5
5 (2H, m), 7.86-8.10 (5H, m), 8.09 (1H,
d, J = 9Hz)

Example 22 Synthesis of camptothecin derivative represented by the following formula

Embedded image [CM / Dextran / Na means carboxymethyl dextran sodium salt] 1.5 g of CM-dextran sodium salt (degree of CM = 0.4) is dissolved in 150 ml of water, and the solution is stirred at 10 ° C. or lower. 75 mg of 10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride obtained in Example 16- (2) are added. 1
About 4 ml of an aqueous solution containing 3 g of-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) was added,
Meanwhile, the pH of the reaction solution is maintained at 7.0 to 6.5 (using 0.1 N hydrochloric acid). After reacting for 2 hours with stirring at 10 ° C or less, the pH was adjusted to 9 (using 0.1 N sodium hydroxide), and after filtration through a filter, 750 ml of ethanol was added to the filtrate, and the resulting precipitate was centrifuged. After collecting and dissolving in 50 ml of water, ion-exchange resin AGMP-50 (Na type, Bio
Rad Co., Ltd.), the fraction containing the desired product is filtered, the precipitate formed by adding ethanol is collected by centrifugation, washed with the solvent, and dried under reduced pressure to obtain 1.17 g of the desired camptothecin derivative. By absorption at 380 nm, 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (Example 1- (8-
The content determined as compound 1) is 1.4%. As a result of analysis by gel permeation column chromatography (GPC), the average molecular weight obtained was 137,000, and the polydispersity Mw / Mn was 2.3. *: GPC analysis conditions: G4000PWXL, 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)

Example 23 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4)
1.0 g was dissolved in 100 ml of water, and 10- [3 '-(glycyl-
Glycyl-L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 120 mg is added. About 10 ml of an aqueous solution containing 3 g of EDC are added while maintaining the pH of the reaction at 7.0-6.5 (using 0.1N hydrochloric acid). Thereafter, in the same manner as in Example 22, 1.03 g of the desired camptothecin derivative is obtained. 380nm
The content determined as 10- (3'-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (compound of Example 1- (8-1)) by absorption at 4.6% was 4.6%.
It is. As a result of analysis by GPC analysis, the average molecular weight obtained was 132,000, and the polydispersity Mw / Mn was 2.3.

Example 24 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4)
In the same manner as in Example 23, from 1.2 g and 130 mg of 10- [3 ′-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Example 11), This gives 1.24 g of the desired camptothecin derivative. 10- by absorption at 380 nm
(3'-aminopropyloxy) -7-ethyl- (20S)
-Camptothecin hydrochloride (compound of Example 1- (8-1))
Is 5.7%. As a result of analysis by GPC analysis, the determined average molecular weight was 139,000,
The polydispersity Mw / Mn is 2.2.

Example 25 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.5)
500 mg and 10- [2 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] -7-
Ethyl- (20S) -camptothecin hydrochloride (Example 19
345 mg of the desired camptothecin derivative is obtained in the same manner as in Example 23 from 50 mg of the compound of the formula (1). By absorption at 380 nm, 10- (2'-aminoethyloxy) -7-
The content determined as ethyl- (20S) -camptothecin hydrochloride (compound of Example 2) is 4.1%. As a result of analysis by GPC analysis, the average molecular weight determined was 169,0.
00, and the polydispersity Mw / Mn is 1.4.

Example 26 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (degree of CM = 0.6)
1.0 g and 10- [3 '-(N- (glycyl-glycyl-L-
Phenylalanyl-glycyl) -N-methylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride (compound of Example 18)
943 mg of the desired camptothecin derivative is obtained in the same manner as described above. The content determined as 10- (3′-methylaminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (compound of 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.

Example 27 Synthesis of camptothecin derivative represented by the following formula

Embedded image As in Example 22, 1.2 g of CM-dextran sodium salt (degree of CM = 0.5) and 10- (3 ′-(glycyl-glycyl-glycyl-glycylamino) propyloxy) obtained in Example 43 described later. From 160 mg of -7-ethyl- (20S) -camptothecin hydrochloride, 1125 mg of the desired camptothecin derivative is obtained as a pale yellow powdery complex. 3
The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride by absorption at 80 nm is 5.3%. As a result of analysis by GPC analysis, the average molecular weight determined was 155,000.
0, and the polydispersity Mw / Mn is 1.46.

Example 28 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4
5) 1154 mg of 10- [3 ′-(γ-aminobutyroylamino) propyloxy] -7-ethyl- obtained in Example 20
Example 23 (150 mg) of (20S) -camptothecin hydrochloride
To give 1100 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-ethyl- (2
The content determined as (OS) -camptothecin hydrochloride (the compound of Example 1- (8-1)) is 2.9%. As a result of analysis by GPC analysis, the average molecular weight determined was 149,00.
0 and the polydispersity Mw / Mn is 1.53.

Example 29 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4
5) 1359 mg was dissolved in 80 ml of water with stirring, and 10- [3 ′-{(N- (γ-aminobutyroyl) -γ-aminobutyroyl) amino} propyloxy obtained in Example 21 under ice cooling. ]
-7-Ethyl- (20S) -camptothecin hydrochloride 135
Add mg. 45 ml of DMF, EEDQ (2-ethoxy-
1-ethoxycarbonyl-1,2-dihydroquinoline) 2
755 mg are added sequentially. After stirring at room temperature for 16 hours, the mixture was poured into 600 ml of ethanol, and 3 ml of 3M saline was added.
A precipitate forms. The resulting precipitate is collected by centrifugation, and
After dissolving in 0 ml, a cation exchange column (Bio-Rad AGM)
P-50, Na type), and the main fraction is collected, filtered through a filter (0.22 μm), and purified by precipitating with 4 volumes of ethanol and 3M saline solution as a precipitant. Furthermore, after dissolving in water,
The operations of filtration through a filter and purification by precipitation from ethanol are repeated, and the obtained precipitate is 90% ethanol, 99.5%
The desired camptothecin derivative 1 in the form of a pale yellow powder is washed with ethanol, acetone and ether sequentially and dried under reduced pressure.
254 mg are obtained. 10- by absorption at 380 nm
(3'-aminopropyloxy) -7-ethyl- (20S)
-The content determined as camptothecin hydrochloride (the compound of Example 1- (8-1)) is 4.9%. As a result of analysis by GPC analysis, the average molecular weight determined was 147,00.
0 and the polydispersity index Mw / Mn is 1.63.

Example 30 Synthesis of camptothecin derivative represented by the following formula

Embedded image [CM ・ Pullulan ・ Na is carboxymethyl pullulan ・
Sodium salt] CM-Pullulan sodium salt (C
M = 0.5) 616 mg and 10- [3 ′ obtained in Example 11.
63 mg of-(L-phenylalanyl-glycylamino) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride are treated in the same manner as in 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 Example 1- (8)) was 4.7%. As a result of analysis by GPC analysis, the obtained average molecular weight was 190,000 and the polydispersity Mw / Mn was 1.8.

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, 7.5 g of sodium iodide and 4.73 g of 3-chloropropanol were added, and 70 ° C was added. And stir for 22 hours. After adding ethyl acetate, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to give 5- (3'-hydroxypropyloxy) -2-nitrobenzaldehyde dimethyl acetal as a pale yellow oil. 39 g are obtained. Yield: 93% NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.60 (1H,
t, J = 5 Hz), 2.08 (2H, quintet, J = 6 Hz), 3.4
4 (6H, s), 3.87 (2H, q, J = 6Hz), 4.22 (2H,
t, J = 6 Hz), 6.01 (1 H, s), 6.91 (1 H, dd, J =
9 Hz and 3 Hz), 7.31 (1 H, d, J = 3 Hz), 7.9
7 (1H, dd, J = 9Hz)

5- (3'-hydroxypropyloxy)-
2-nitrobenzaldehyde dimethyl acetal 6.3
Add 5 g to 70% acetic acid and stir at 60 ° C. for 1.5 hours.
The residue concentrated under reduced pressure was washed with saturated aqueous sodium bicarbonate and saturated saline,
Dry and concentrate under reduced pressure. The residue was dissolved in 50 ml of dry DMF, 4.55 g of t-butyldimethylsilyl chloride and 3.42 g of imidazole were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the solvent, the residue was 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 (2H, quintet, J = 6H
z), 3.80 (2H, t, J = 6 Hz), 4.22 (2H, t, J = 6)
Hz), 7.14 (1H, dd, J = 9Hz and 3Hz), 7.33
(1H, d, J = 3Hz), 8.16 (1H, d, J = 9Hz), 10.
49 (1H, s)

(2) 1- {5 '-[3 "-(t-butyldimethylsilyloxy) propyloxy] -2'-nitrophenyl}
Synthesis of -2-propen-1-one 5.80 g of 5- [3 '-(t-butyldimethylsilyloxy) propyloxy] -2-nitrobenzaldehyde is dissolved in 35 ml of dry THF, and stirred in a dry ice-acetone bath. 1.7 equivalents of vinyl magnesium bromide
Add THF solution. After stirring for 2 hours, 30 ml of 5% hydrochloric acid was added, and the mixture was 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 are 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 (6
H, s), 0.88 (9H, s), 2.00 (2H, quintet, J = 6
Hz), 2.67 (1H, brs), 3.80 (2H, t, J = 6Hz),
4.16 (2H, t, J = 6Hz), 5.24 (1H, dd, J = 1
0.5 Hz and 1.5 Hz), 5.41 (1 H, dd, J = 17 H)
z and 1.5 Hz), 5.90 (1 H, d, J = 5 Hz), 6.08
(1H, ddd, J = 17Hz, 10.5Hz and 1.5Hz),
6.87 (1H, dd, J = 9 Hz and 3 Hz), 7.24 (1
H, d, J = 3 Hz), 8.04 (1 H, d, J = 9 Hz)

1- {5 '-[3 "-(t-butyldimethylsilyloxy) propyloxy] -2'-nitrophenyl} -2
4.98 g of propen-1-ol in chloroform 140
The mixture was dissolved in ml, and 36 g of activated manganese dioxide was added. After filtration of the insolubles, the filtrate was concentrated and purified by silica gel column chromatography to give 1- {5 ′-[3 "-
(t-butyldimethylsilyloxy) propyloxy]-
2'-nitrophenyl} -2-propen-1-one 2.8
7 g 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 =
6Hz), 3.75 (2H, t, J = 6Hz), 4.22 (2H, t, J
= 6 Hz), 5.85 (1 H, d, J = 17.5 Hz), 6.15 (1
H, d, J = 10.5 Hz), 6.65 (1 H, dd, J = 17.5 H)
z and 10.5 Hz), 7.04 (1 H, d, J = 3 Hz), 7.2
5 (1H, dd, J = 9Hz and 3Hz), 8.22 (1H, d, J
= 9Hz)

(3) Synthesis of 10- (3'-hydroxypropyloxy) -7-ethyl- (20S) -camptothecin 1- {5 '-[3 "-(tert-butyldimethylsilyloxy)
Propyloxy] -2′-nitrophenyl} -2-propen-1-one (765 mg) was dissolved in ethanol (10 ml).
156 mg of 0% 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
220 mg of [3,4-f] indolizine-3,6,10 (4H) -trione and 32 mg of p-toluenesulfonic acid were added,
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 343 mg of 7-ethyl-10- (3'-hydroxypropyloxy)-(20S) -camptothecin as a pale yellow powder. Melting point: 233.5-234.5 ° C. Yield: 91% IR (Nujol): ν _max ^{cm -1} = 3380,1750,164
5 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 H
z), 1.76-1.95 (2H, m), 1.97 (1H, quintet,
J = 6.5 Hz), 3.17 (2H, q, J = 7.5 Hz), 3.63
(2H, dt, J = 6.5 Hz and 5 Hz), 4.26 (2H, t,
J = 6.5 Hz), 4.62 (1 H, t, J = 5 Hz), 5.25 (2
H, 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 =
9.5Hz)

Example 32 10- (2′-Hydroxyethyloxy) -7-ethyl-
Synthesis of (20S) -camptothecin (1) Synthesis of 1- {5 ′-[2 ″-(tert-butyldimethylsilyloxy) ethyloxy] -2′-nitrophenyl} -2-propen-1-one 31- 1- {5 ′ in the same manner as in (1) and (2).
-[2 "-(tert-butyldimethylsilyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one IR (Nujol): ν _max ^{cm -1} = 1680 Mass: m / z = 352 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.09 (6H,
s), 0.90 (9H, s), 3.99 (2H, t, J = 5Hz), 4.1
6 (2H, t, J = 5Hz), 5.84 (1H, d, J = 17.5H
z), 6.01 (1H, d, J = 11 Hz), 6.62 (1H, dd, J
= 17.5 Hz and 11 Hz), 6.84 (1 H, d, J = 3 H
z), 7.06 (1 H, dd, J = 10 Hz and 3 Hz), 8.17
(1H, d, J = 9Hz)

(2) Synthesis of 10- (2'-hydroxyethyloxy) -7-ethyl- (20S) -camptothecin 10- (2'-hydroxyethyloxy) ) -7-Ethyl- (20S) -camptothecin is synthesized. Melting point: 251-254 ° C IR (Nujol): ν _max ^{cm -1} = 3470, 1730, 165
5 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 H
z), 1.80-1.93 (2H, m), 3.17 (2H, q, J = 7.
5Hz), 3.83 (2H, q, J = 5Hz), 4.23 (2H, t, J
= 5 Hz), 4.96 (1 H, t, J = 5.5 Hz), 5.27 (2
H, s), 5.42 (2H, s), 6.49 (1H, s), 7.26 (1
H, s), 7.49-7.51 (2H, m), 8.06 (1H, d, J =
9Hz)

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- {5 as in Examples 31- (1) and (2). '-
(2 "-(2"'-(tert-butyldimethylsilyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2
Synthesizing propen-1-one. IR (Nujol): ν _max ^{cm -1} = 1680 Mass: m / z = 396 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 0.06 (6H,
s), 0.89 (9H, s), 3.62 (2H, t, J = 6Hz), 3.7
5 (2H, t, J = 6Hz), 3.87-3.92 (2H, m), 4.
20-4.25 (2H, m), 5.83 (1H, d, J = 17.5H
z), 6.01 (1H, d, J = 10.5 Hz), 6.62 (1H, dd,
J = 17.5 Hz and 10.5 Hz), 6.84 (1 H, d, J
= 3Hz), 7.05 (1H, dd, J = 9Hz and 3Hz), 8.
17 (1H, d, J = 9Hz)

(2) Synthesis of 10- [2 ′-(2 ″ -hydroxyethyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin 1- {1} was obtained in the same manner as in Example 31- (3). 5 '-[2 "-
10- [2 '-(2 "-hydroxyethyloxy) ethyloxy]-from (2"'-(tert-butyldimethylsilyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one 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 H
z), 1.79-1.94 (2H, m), 3.18 (2H, q, J = 7.
5Hz), 3.55 (4H, m), 3.86 (2H, m), 4.34 (2
H, m), 4.63 (1H, brs), 5.27 (2H, s), 5.42 (2
H, s), 6.48 (1H, s), 7.26 (1H, s), 7.48-7.
54 (2H, m), 8.06 (1H, d, J = 10Hz)

Example 34 10- [3 ′-(L-alanyloxy) propyloxy]-
Synthesis of 7-ethyl- (20S) -camptothecin hydrochloride (1) 1- [5 '-(3 "-hydroxypropyloxy) -2'
Synthesis of -nitrophenyl] -2-propen-1-one 1- {5 '-[3 "-(tert-butyldimethylsilyloxy)
Propyloxy] -2'-nitrophenyl} -2-propen-1-one (the compound of Example 31- (2))
The mixture is mixed with 20 ml of HF and 30 ml of 50% acetic acid aqueous solution and stirred and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to give 1- [5 '-(3 "-).
Hydroxypropyloxy) -2'-nitrophenyl]-
1.26 g of 2-propen-1-one are obtained. 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 = 10.5 Hz), 6.62 (1 H, dd, J = 17.5 Hz and 10.5 Hz), 6.84 (1 H, d, J = 3 Hz), 7.04
(1H, dd, J = 9Hz and 3Hz), 8.17 (1H, d, J =
9Hz)

(2) Synthesis of 1- [5 '-(3 "-t-butoxycarbonyl-L-alanyloxy-propyloxy) -2'-nitrophenyl] -2-propen-1-one 1- [5' 1.22 g of-(3 "-hydroxypropyloxy) -2'-nitrophenyl] -2-propen-1-one and t-
2.76 g of butoxycarbonyl-L-alanine was added to THF5
The solution was dissolved in 0 ml, and 3.01 g of DCC was added with stirring under ice cooling. 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-L-alanyloxy-
1.19 g of 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 = 7Hz), 1.43 (9H, s), 2.19 (2H, quintet,
J = 6 Hz), 4.16 (2 H, t, J = 6 Hz), 4.27-4.
42 (3H, m), 4.98 (1H, m), 5.85 (1H, d, J = 1
7.5 Hz), 6.02 (1 H, d, J = 11 Hz), 6.62 (1
H, dd, J = 17.5 Hz and 11 Hz), 6.82 (1 H, d,
J = 3 Hz), 7.04 (1 H, dd, J = 9 Hz and 3 Hz),
8.17 (1H, d, J = 9Hz)

(3) Synthesis of 10- [3 '-(t-butoxycarbonyl-L-alanyloxy) propyloxy] -7-ethyl- (20S) -camptothecin 1- {5'-[3 "-(t- Butoxycarbonyl-L-alanyloxy) propyloxy] -2′-nitrophenyl} -2
1.17 g of propen-1-one is dissolved in 30 ml of ethanol, 206 mg of 10% palladium on 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 30 ml of ethanol, and (4S) -7,
Add 290 mg of 8-dihydro-4-ethyl-4-hydroxy-1H-pyrano [3,4-f] -indolizine-3,6,10 (4H) -trione and 10 mg of p-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 ′-(t-butoxycarbonyl-L-alanyloxy) propyloxy] -7-ethyl- (20S)-as a pale yellow powder.
257 mg of camptothecin are obtained. Melting point: 180 ° C. or higher (decomposition) Yield: 38% IR (Nujol): ν _max ^{cm −1} = 3280,1760,171
5,1660 Mass: m / z = 622 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.25 (3H, t, J = 7.5H)
z), 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), 3.28-3.34 (2
H, m), 4.20-4.37 (3H, m), 5.30 (2H, s), 5.
43 (2H, s), 6.50 (1H, s), 7.27 (1H, s), 7.3
0 (1H, d, J = 7.5Hz), 7.48-7.54 (2H, m),
8.08 (1H, d, J = 9.5Hz)

(4) Synthesis of 10- [3 '-(L-alanyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t-butoxycarbonyl-L-alanyloxy) Propyloxy] -7-ethyl- (20S) -camptothecin (240 mg) was dissolved in dioxane (2 ml), and the mixture was reacted with hydrochloric acid-dioxane (4 ml) while stirring under ice cooling. After the reaction was completed, diisopropyl ether (30 ml) was added. The resulting precipitate was collected by filtration, and 10- [3 ′-(L-alanyloxy) propyloxy] -7-ethyl- (20S)-as a pale yellow powder was obtained.
183 mg of camptothecin hydrochloride are obtained. Yield: 87% IR (Nujol): ν _max ^{cm -1} = 3375,1750,166
0 Mass: m / z = 522 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 1.44 (3H, t, J = 7 Hz), 1.76-1.94 (2
H, m), 2.20 (1H, quintet, J = 6 Hz), 3.20 (2
H, q, J = 7.5 Hz), 4.05-4.20 (1 H, m), 4.3
4 (2H, t, J = 6Hz), 4.40 (2H, t, J = 6Hz), 5.
29 (2H, s), 5.43 (2H, s), 7.28 (1H, s), 7.4
9-7.55 (2H, m), 8.08 (1H, d, J = 10Hz),
8.52-8.73 (3H, m)

Example 35 10- [2 ′-(L-alanyloxy) ethyloxy] -7
Synthesis of -ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 '-[2 "-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] -2'-nitrophenyl}-
Synthesis of 2-propen-1-one In the same manner as in Example 34- (1) and (2), 1- {5 ′
-[2 "-(t-Butoxycarbonyl-L-alanyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one IR (Nujol): ν _max ^{cm -1} = 3370,1750 , 171
5 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 (2H, brt), 5.00 (1H, br), 5.8
5 (1H, d, J = 17 Hz), 6.03 (1H, d, J = 10.5)
Hz), 6.63 (1 H, dd, J = 17.5 Hz and 10.5 H
z), 6.84 (1 H, d, J = 3 Hz), 7.06 (1 H, dd, J =
9 Hz and 3 Hz), 8.18 (1 H, d, J = 9 Hz)

(2) 10- [2 '-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin 10- [2 '-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] in the same manner as in Example 34- (3).
-7-Ethyl- (20S) -camptothecin is synthesized. Melting point: 114-120 ° C IR (Nujol): ν _max ^cm-1 = 3320, 1750, 171
0.1660 Mass: m / z = 608 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.26 (3H, d, J = 7.5H
z), 1.31 (3H, t, J = 7.5Hz), 1.35 (9H, s),
1.80-1.94 (2H, m), 3.19 (2H, q, J = 7.5
Hz), 3.99-4.10 (1H, m), 4.43-4.56 (4
H, m), 5.29 (2H, s), 5.43 (2H, s), 6.49 (1
H, s), 7.27 (1H, s), 7.32 (1H, d, J = 7Hz),
7.49-7.53 (2H, m), 8.08 (1H, d, J = 10H
z)

(3) Synthesis of 10- [2 '-(L-alanyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride In the same manner as in Example 34- (4), 10- [2' − (L−
[Alanyloxy) ethyloxy] -7-ethyl- (20S)
-Synthesize camptothecin hydrochloride. Melting point: 180 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3680, 1750, 1655 Mass: m / z = 508 [(M-Cl ⁻ ) ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 1.45 (3H, d, J = 7 Hz), 1.80-1.94 (2
H, m), 3.21 (2H, q, J = 7.5 Hz), 4.10-4.1
9 (1H, m), 4.50 (2H, m), 4.60-4.65 (2H, m
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.
5Hz), 8.56-8.68 (3H, m)

Example 36 10- {2 '-[2 "-(L-alanyloxy) ethyloxy]
Synthesis of ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride (1) 10- {5 '-[2 "-(2"'-(t-butoxycarbonyl-L-alanyloxy) ethyloxy) ethyloxy]
Synthesis of 2′-nitrophenyl} -2-propen-1-one In the same manner as in Example 34- (1) and (2), 10-
{5 '-[2 "-(2"'-(t-butoxycarbonyl-L-alanyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one is synthesized. IR (Nujol): ν _max ^{cm -1} = 3385,1755,169
0 Mass: m / z = 453 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.38 (3H,
d, J = 7 Hz), 1.44 (9 H, s), 3.74-3.79 (2
H, m), 3.85-3.90 (2H, m), 4.21-4.25 (2
H, m), 4.29-4.35 (3H, m), 5.03 (1H, br),
5.84 (1 H, d, J = 17 Hz), 6.02 (1 H, d, J = 1)
1 Hz), 6.62 (1 H, dd, J = 17.5 Hz and 11 H
z), 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) Synthesis of 10- {2 '-[2 "-(t-butoxycarbonyl-L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin Example 34- (3) 10- {2 '-[2 "-
(t-Butoxycarbonyl-L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin is synthesized. Melting point: 164 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3380, 1750, 170
5,1655 Mass: m / z = 652 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.22 (3H, t, J = 7.5H)
z), 1.31 (3H, t, J = 7.5Hz), 1.37 (9H, s),
1.75-1.94 (2H, m), 3.18 (2H, q, J = 7.5
Hz), 3.73 (2H, t, J = 7 Hz), 3.87 (2H, t, J =
7 Hz), 3.94-4.5 (1 H, m), 4.10-4.35
(4H, m), 5.29 (2H, s), 5.42 (2H, s), 6.48
(1H, s), 7.27 (1H, s), 7.27 (1H, d, J = 6H
z), 7.47-7.54 (2H, m), 8.07 (1H, d, J = 1
0Hz)

(3) 10- {2 '-[2 "-(L-alanyloxy) ethyloxy] ethyloxy} -7-ethyl- (20
S) -Camptothecin hydrochloride 10- {2 '-[2 "-) in the same manner as in Example 34- (4).
(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, 1760, 174
0,1660 Mass: m / z = 552 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 H
z), 1.41 (3H, d, J = 7 Hz), 1.79-1.94 (2
H, m), 3.19 (2H, q, J = 7.5 Hz), 3.78 (2H, t,
J = 7 Hz), 3.89 (2 H, t, J = 7 Hz), 4.00-4.
15 (1H, m), 4.26-4.44 (4H, m), 5.29 (2
H, s), 5.43 (2H, s), 7.28 (1H, s), 7.49-7.
55 (2H, m), 8.08 (1H, d, J = 10Hz), 8.52-
8.70 (3H, m)

Example 37 10- [3 ′-(L-Prolyloxy) propyloxy]-
Synthesis of 7-ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 '-[3 "-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -2'-nitrophenyl}
Synthesis of 2-propen-1-one 1- {5 ′ in the same manner as in Example 34- (1) and (2).
-[3 "-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -2'-nitrophenyl} -2-propen-1-one IR (Neat): ν _max ^{cm -1} = 1750,1700 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 (5H, m), 5.85 (1H, d, J = 1
7.5 Hz), 6.01 (1 H, d, J = 10.5 Hz), 6.62
(1H, dd, J = 17.5Hz and 10.5Hz), 6.82
(1H, d, J = 3Hz), 7.05 (1H, dd, J = 9Hz and 3Hz), 8.17 (1H, d, J = 9Hz)

(2) 10- [3 '-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin 1- {5 '-[3 "-(t-butoxycarbonyl-L-prolyloxy) propyloxy] -2'-nitrophenyl} -2
Using 10- [3 ′-(t-butoxycarbonyl-L-prolyloxy) propyloxy]-as a pale yellow powder, using -propen-1-one in the same manner as in Example 34- (3).
7-Ethyl- (20S) -camptothecin is obtained. Melting point: 136-139 ° C IR (Nujol): ν _max ^{cm -1} = 3280,1755,170
0.1660 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 H
z), 1.36 (9H, s), 1.74-1.94 (6H, m), 2.1
0-2.28 (2H, m), 3.18 (2H, q, J = 7.5Hz),
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 = 9Hz)

(3) Synthesis of 10- [3 '-(L-prolyloxy) propyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [3'-(t-butoxycarbonyl-L-prolyloxy) From propyloxy] -7-ethyl- (20S) -camptothecin, 10- [3 ′-(L-prolyloxy) propyloxy] -7- as a pale yellow powder was obtained in the same manner as in Example 34- (4). Ethyl- (20S) -camptothecin hydrochloride is obtained. IR (Nujol): ν _max ^{cm -1} = 3680, 1750, 166
0,1620 Mass: m / z = 548 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.32 (3H, t, J = 7.5Hz),
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 = 6Hz), 4.42 (2H, t, J = 6H)
z), 5.29 (2H, s), 5.43 (2H, s), 7.28 (1H,
s), 7.50-7.55 (2H, m), 8.09 (1H, d, J = 1
0Hz), 9.00-9.20 (1H, m)

Example 38 10- [2 ′-(L-Prolyloxy) ethyloxy] -7
Synthesis of -ethyl- (20S) -camptothecin hydrochloride (1) 1- {5 '-[2 "-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] -2'-nitrophenyl}-
Synthesis of 2-propen-1-one In the same manner as in Example 34- (1) and (2), 1- {5 ′
-[2 "-(t-Butoxycarbonyl-L-prolyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one IR (Neat): ν _max ^{cm -1} = 1750,1700 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 (3H, 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 (1 H, dd, J = 17.5 Hz and 10.5 Hz), 6.83 (1 H, d, J = 3.5 Hz), 7.04
(1H, dd, J = 9 Hz and 3 Hz), 8.18 (1H, d, J =
9Hz)

(2) 10- [2 '-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin 10- [2 '-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] in the same manner as in Example 34- (3).
-7-Ethyl- (20S) -camptothecin is synthesized. Melting point: 203-205 ° C (decomposition) IR (Nujol): ν _max ^cm-1 = 1755,1735,168
5,1670,1610 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 H
z), 1.37 (9H, s), 1.79-1.94 and 2.16-
2.26 (6H, m), 3.19 (2H, q, J = 7.5Hz), 3.2
8-3.40 (2H, m), 4.20-4.24 (1H, m), 4.4
5-4.56 (4H, m), 5.29 (2H, s), 5.43 (2H,
s), 6.48 (1H, s), 7.27 (1H, s), 7.46-7.5
3 (2H, m), 8.08 (1H, d, J = 9.5Hz)

(3) Synthesis of 10- [2 ′-(L-prolyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin hydrochloride 10- [2 ′ − (L−
Prolyloxy) ethyloxy] -7-ethyl- (20S)
-Synthesize camptothecin hydrochloride. Melting point: 170 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3680, 1750, 165
5 Mass: m / z = 534 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88 (3
H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5Hz),
1.80-2.09 and 2.23-2.35 (6H, m), 3.
17-3.29 (4H, m), 4.40-4.47 (1H, m), 4.
52 (2H, m), 4.62-4.69 (2H, m), 5.30 (2
H, s), 5.43 (2H, s), 7.29 (1H, s), 7.51-7.
55 (2H, m), 8.10 (1H, d, J = 9.5Hz), 9.03
-9.23 and 10.23-10.43 (2H, m)

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]-
Synthesis of 2′-nitrophenyl} -2-propen-1-one 1- {5 ′ in the same manner as in Example 34- (1) and (2).
-[2 "-(2"'-(t-Butoxycarbonyl-L-prolyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2-propen-1-one is synthesized. IR (Neat): ν _max ^{cm -1} = 1750,1700 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 = 18Hz), 6.01 (1H, d,
J = 11 Hz), 6.62 (1 H, dd, 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) Synthesis of 10- {2 '-[2 "-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin Example 34- (3) In the same manner as in 10
-{2 '-[2 "-(t-butoxycarbonyl-L-prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (2
(0S) -Camptothecin is synthesized. IR (Nujol): ν _max ^{cm -1} = 3370,1750,170
0.1655 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 H
z), 1.37 (9H, s), 1.69-1.85 (4H, m), 1.7
9-1.94 (2H, m), 3.18 (2H, q, J = 7.5Hz),
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 (2H, m), 4.30-4.38 (2H, m),
5.29 (2H, s), 5.43 (2H, s), 7.27 (1H, s),
7.47-7.54 (2H, m), 8.07 (1H, d, J = 10H
z)

(3) 10- {2 '-[2 "-(L-prolyloxy) ethyloxy] ethyloxy} -7-ethyl- (20
Synthesis of S) -camptothecin hydrochloride 10- {2 ′-[2 ″-] in the same manner as in Example 34- (4).
(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, 1750, 166
0 Mass: m / z = 578 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 H
z), 1.79-2.32 (6H, m), 3.12-3.28 (4H,
m), 3.79 (2H, m), 3.89 (2H, m), 4.28-4.4
6 (5H, m), 5.28 (2H, s), 5.43 (2H, s), 7.30
(1H, s), 7.49-7.54 (2H, m), 8.09 (1H, d,
J = 9.5 Hz), 8.95-9.32 (2 H, m)

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

Embedded image (1) 1- {5 '-[3 "-(Nt-butoxycarbonyl-
Synthesis of O-ethyl-L-β-aspartyloxy) propyloxy] -2′-nitrophenyl} -2-propen-1-one A pale yellow color in the same manner as in Example 34- (1) and (2). Oily 1- {5 '-[3 "-(Nt-butoxycarbonyl-O
-Ethyl-L-β-aspartyloxy) propyloxy] -2′-nitrophenyl} -2-propen-1-one. IR (Neat): ν _max ^{cm -1} = 3370,1740,171
5,1680 NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26 (3H,
t, J = 7Hz), 1.44 (9H, s), 2.17 (2H, quintet,
J = 6 Hz), 2.84 (1 H, dd, J = 16.5 Hz and 5
Hz), 2.97 (1H, dd, J = 16.5Hz and 5Hz),
4.15 (1H, t, J = 5Hz), 4.20 (4H, m), 4.29
(2H, t, J = 6Hz), 4.53-4.57 (1H, m), 5.4
3 (1H, d, J = 8Hz), 5.85 (1H, d, J = 18Hz),
6.02 (1H, d, J = 11 Hz), 6.63 (1H, dd, J = 1)
8 Hz and 11 Hz), 6.83 (1 H, d, J = 3 Hz), 7.
04 (1 H, dd, J = 9 Hz and 3 Hz), 8.18 (1 H, d,
J = 9Hz)

(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)-
Synthesize camptothecin. Melting point: 107-110 ° C IR (Nujol): ν _max ^cm-1 = 3260, 1750, 172
0.1660,1610 Mass: m / z = 694 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.14 (3H, t, J = 7Hz),
1.32 (3H, t, J = 7.5 Hz), 1.36 (9H, s), 1.8
0-1.94 (2H, m), 2.14 (2H, quintet, J = 6H
z), 2.68 (1 H, dd, J = 16 Hz and 8 Hz), 2.8
1 (1 H, dd, J = 16 Hz and 6 Hz), 3.19 (2 H, q,
J = 7.5 Hz), 4.06 (2H, q, J = 7 Hz), 4.23-
4.33 (1H, 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 = 7 Hz), 7.50-7.53 (2H,
m), 8.07 (1H, d, J = 10Hz)

(3) 10- [3 '-(O-ethyl-L-β-
Aspartyloxy) propyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 34- (4), 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, 1750, 166
0,1620 Mass: m / z = 594 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.18 (3H, t, J = 7Hz),
1.32 (3H, t, J = 7.5 Hz), 1.80-1.94 (2
H, m), 2.18 (2H, quintet, J = 6 Hz), 3.00 (1
H, dd, J = 17.5 Hz and 6 Hz), 3.08 (1 H, dd,
J = 17.5 Hz and 6 Hz), 3.20 (2 H, q, J = 7 H
z), 4.16 (1H, m), 4.30 (2H, t, J = 6Hz), 4.3
2 (2H, t, J = 6Hz), 5.30 (2H, s), 5.43 (2H,
s), 7.28 (1H, s), 7.50-7.53 (2H, m), 8.0
9 (1H, d, J = 10Hz), 8.65-8.78 (3H, m)

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

Embedded image (1) 1- {5 '-[2 "-(Nt-butoxycarbonyl-O
-Ethyl-L-β-aspartyloxy) ethyloxy]
Synthesis of 2′-nitrophenyl} -2-propen-1-one 1- {5 ′ in the same manner as in Example 34- (1) and (2).
-[2 "-(Nt-butoxycarbonyl-O-ethyl-L
-Β-aspartyloxy) ethyloxy] -2′-nitrophenyl} -2-propen-1-one is synthesized. IR (Nujol): ν _max ^{cm -1} = 3430,1720,168
0 Mass: m / z = 481 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26 (3H,
t, J = 7 Hz), 1.44 (9 H, s), 2.88 (1 H, dd, J =
17Hz and 5Hz), 3.02 (1H, dd, J = 17Hz and 5Hz), 4.20 (2H, q, J = 7Hz), 4.27 (2H,
m), 4.48 (2H, m), 4.55-4.61 (1H, m), 5.4
5 (1H, brd, J = 8Hz), 5.85 (1H, d, J = 17.5
Hz), 6.02 (1 H, d, J = 10.5 Hz), 6.63 (1 H, d
d, J = 17.5 Hz and 10.5 Hz), 6.85 (1 H, d,
J = 3 Hz), 7.07 (1 H, dd, J = 9 Hz and 3 Hz),
8.19 (1H, d, J = 9Hz)

(2) Synthesis of 10- [2 ′-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy] -7-ethyl- (20S) -camptothecin 10- [2 '-(N-t
-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} = 3310,1745,172
0.1655,1605 Mass: m / z = 680 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.15 (3H, t, J = 7Hz),
1.31 (3H, t, J = 7.5 Hz), 1.37 (9H, s), 1.8
0-1.94 (2H, m), 2.72 (1H, dd, J = 16Hz and 6Hz), 2.84 (1H, dd, J = 16Hz and 6H
z), 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), 7.29
(1H, d, J = 9Hz), 7.50-7.54 (2H, m), 8.0
8 (1H, d, J = 10Hz)

(3) 10- [2 '-(O-ethyl-L-β-
[Aspartyloxy) ethyloxy] -7-ethyl- (2
Synthesis of (0S) -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, 1750, 166
0,1615 Mass: m / z = 580 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.19 (3H, t, J = 7Hz),
1.32 (3H, t, J = 7.5 Hz), 1.80-1.94 (2
H, m), 3.03 (1H, dd, J = 17.5Hz and 6Hz),
3.12 (1H, dd, J = 17.5Hz and 5.5Hz), 3.
21 (2H, q, J = 7.5 Hz), 4.19 (2H, q, J = 7.5
Hz), 4.36 (1H, brm), 4.47-4.53 (4H, m),
5.30 (2H, s), 5.43 (2H, s), 7.29 (1H, s),
7.51-7.54 (2H, m), 8.11 (1H, d, J = 10H
z), 8.67-8.80 (3H, m)

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

Embedded image (1) 1- {5 '-[2 "-(2"'-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl}- 2-
Synthesis of propen-1-one 1- {5 ′ in the same manner as in Example 34- (1) and (2).
-[2 "-(2"'-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -2'-nitrophenyl} -2-propene-1
-One is synthesized. IR (Neat): ν _max ^{cm -1} = 3370,1740,172
0.1680 Mass: m / z = 525 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ ): δ ^TMS = 1.26 (3H,
t, J = 7 Hz), 1.44 (9 H, s), 2.85 (1 H, dd, J =
7 Hz and 5 Hz), 3.01 (1 H, dd, J = 7 Hz and 5 Hz), 3.75 (2 H, m), 3.86-3.90 (2 H, m),
4.22-4.31 (4H, m), 4.20 (2H, q, J = 7H
z), 4.50-4.62 (1H, m), 5.51 (1H, brd, J =
8 Hz), 5.84 (1 H, d, J = 17.5 Hz), 6.01 (1
H, d, J = 10.5 Hz), 6.62 (1 H, dd, J = 17.5 H)
z and 10.5 Hz), 6.86 (1 H, d, J = 3 Hz), 7.0
8 (1 H, dd, J = 9 Hz and 3 Hz), 8.17 (1 H, d, J
= 9Hz)

(2) 10- [2 ′-(2 ″-(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -7-ethyl- (20
Synthesis of S) -camptothecin 10- [2 ′-(2 ″-) in the same manner as in Example 34- (3).
(Nt-butoxycarbonyl-O-ethyl-L-β-aspartyloxy) ethyloxy) ethyloxy] -7-
Ethyl- (20S) -camptothecin is synthesized. Melting point: 164 ° C or higher (decomposition) IR (Nujol): ν _max ^{cm -1} = 3365,1750,165
5 Mass: m / z = 724 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5Hz), 1.15 (3H, t, J = 7Hz),
1.31 (3H, t, J = 7.5 Hz), 1.37 (9H, s), 1.7
9-1.94 (2H, m), 2.66 (1H, dd, J = 16Hz and 6Hz), 2.78 (1H, dd, J = 16Hz and 6H
z), 3.18 (2H, q, J = 7.5 Hz), 3.73 (2H, t, J
= 5Hz), 3.87 (2H, m), 4.07 (2H, q, J = 7.0
Hz), 4.20 (2H, m), 4.30-4.39 (3H, m), 5.
28 (2H, s), 5.42 (2H, s), 6.48 (1H, s), 7.2
6 (1H, d, J = 6Hz), 7.27 (1H, s), 7.49-7.
54 (2H, m), 8.07 (1H, d, J = 10Hz)

(3) 10- {2 '-[2 "-(O-ethyl-L
Synthesis of -β-aspartyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride 10- {2 '-[2 "-
(O-ethyl-L-β-aspartyloxy) ethyloxy] ethyloxy} -7-ethyl- (20S) -camptothecin hydrochloride is synthesized. Melting point: 170 ° C. or more (decomposition) IR (Nujol): ν _max ^{cm −1} = 3375, 1750, 166
0 Mass: m / z = 624 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.19 (3H, t, J = 7Hz),
1.32 (3H, t, J = 7.5 Hz), 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 (2
H, q, J = 7.5 Hz), 3.75 (2H, m), 3.88 (2H,
m), 4.19 (2H, q, J = 7Hz), 4.28-4.35 (5
H, m), 5.29 (2H, s), 5.43 (2H, s), 7.29 (1
H, s), 7.50-7.55 (2H, m), 8.08 (1H, d, J =
10Hz), 8.66-8.82 (3H, m)

Example 43 Synthesis of 7-ethyl-10- [3 '-(glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride (1) 7-ethyl-10- [3' Synthesis of-(t-butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin 7-ethyl-10- (3'-aminopropyloxy) in the same manner as in Example 8- (1). )-(20S) -camptothecin hydrochloride (200 mg) and 2 equivalents of t-butoxycarbonyl-glycyl-glycyl-glycyl-glycine as yellow powder 7
269 mg of -ethyl-10- [3 '-(t-butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin are obtained. Yield: 84% IR (Nujol): ν _max ^{cm -1} = 3290,1750,171
0.1650,1625 Mass: m / z = 778 (M + H ⁺ ) NMR (300 MHz, CDCl ₃ + d ₆ -DMSO): δ ^TMS
= 1.01 (3H, t, J = 7Hz), 1.40 (3H, t, J = 7.
5Hz), 1.43 (9H, s), 1.93 (2H, dq, J = 7.5H
z and 3 Hz), 2.01-2.16 (2H, m), 3.18 (2
H, t, J = 7.5 Hz), 3.47 (2H, m), 3.74 (2H, d,
J = 5.5 Hz), 3.83-3.89 (6 H, m), 4.22 (2
H, t, J = 6Hz), 5.24 (2H, s), 5.29 (1H, d, J
= 16 Hz), 5.64 (1 H, d, J = 16 Hz), 5.88 (1
H, s), 6.55 (1H, m), 7.38 (1H, d, J = 3Hz),
7.47 (1 H, dd, J = 9 Hz and 3 Hz), 7.56 (1
H, s), 7.85 (1H, t), 8.07 (1H, d, J = 9Hz),
8.07-8.17 (3H, m)

(2) Synthesis of 7-ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride -Ethyl-10- [3'-
From 261 mg of (t-butoxycarbonyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin 7-ethyl-10 as a yellow powder
237 mg of-[3 '-(glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride are obtained. Yield: 99% Melting point:> 190 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3195,1750,165
5,1615 Mass: m / z = 678 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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 =
6Hz), 3.70 (2H, q, J = 6Hz), 3.76 (2H, q, J
= 6Hz), 3.84 (2H, q, J = 6Hz), 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 (1 H, 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 (1 H, t, J = 5.5 Hz)

Example 44 Synthesis of 7-ethyl-10- {2 ′-[2 ″-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride (1) 7-ethyl-10- {2 ′-[2 ″-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-
[Glycylamino) ethyloxy] ethyloxy}-(20
Synthesis of (S) -camptothecin 7-ethyl-10- (2′-) as in Example 8- (1).
(2 "-aminoethyloxy) ethyloxy)-(20S)-
400 mg of camptothecin hydrochloride and 2 equivalents of t-butoxycarbonyl-glycyl-glycyl-L-phenylalanylglycine as yellow powdery 7-ethyl-10- {2′-
[2 "-(t-butoxycarbonyl-glycyl-glycyl-
550 mg of L-phenylalanylglycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin are obtained. Yield: 79% Melting point:> 160 ° C (decomposition) IR (Nujol): ν _max ^{cm -1} = 3300,1750,165
5 Mass: m / z = 898 (M + H ⁺ ) NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7Hz), 1.27 (3H, t, J = 7Hz), 1.3
6 (9H, s), 1.83-1.89 (2H, m), 2.78 (1H, d
d, J = 14 Hz and 10 Hz), 3.04 (1 H, dd, J = 1)
4 Hz and 4.5 Hz), 3.18 (2 H, q, J = 7.5 Hz),
3.11-3.80 (8H, m), 3.29 (2H, q, J = 6H
z), 3.84-3.87 (2H, m), 4.34-4.36 (2H,
m), 4.45-4.53 (1H, m), 5.30 (2H, s), 5.4
3 (2H, s), 6.51 (1H, s), 7.00 (1H, t, J = 5.
5Hz), 7.14-7.25 (5H, m), 7.27 (1H, s),
7.52-7.55 (2H, m), 7.83 (1H, t, J = 5.5
Hz), 7.93 (1 H, t, J = 5 Hz), 8.08 (1 H, d, J =
9.5 Hz), 8.17 (1 H, d, J = 8 Hz), 8.29 (1 H,
t, J = 5.5Hz)

(2) Synthesis of 7-ethyl-10- {2 ′-[2 ″-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride Example 8 7-ethyl-10- {2′-
[2 "-(t-butoxycarbonyl-glycyl-glycyl-
L-phenylalanyl-glycylamino) ethyloxy]
7-ethyl-10- {2 '-[2 "-(glycyl-glycyl-L-phenylalanyl-glycylamino) ethyloxy] ethyloxy}-(20S)-as a yellow powder from 550 mg of ethyloxy}-(20S) -camptothecin. 334 mg of camptothecin hydrochloride are obtained Yield: 65% Melting point:> 165 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3225,1750,1655 Mass: m / z = 798 [(M-Cl ⁻ )] ⁺ ] NMR (300 MHz, d ₆ -DMSO): δ ^TMS = 0.88
(3H, t, J = 7.5 Hz), 1.26-1.34 (3H, m), 1.
80-1.94 (2H, m), 2.82 (1H, dd, J = 14Hz
And 10 Hz), 3.06 (1 H, dd, J = 14 Hz and 5.5 Hz), 3.20 (2 H, q, J = 7.5 Hz), 3.29 (2
H, q, J = 6 Hz), 3.55 (2 H, 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), 7.53-7.56 (2H, m), 7.94
(1H, t, J = 5.5Hz), 8.09 (1H, d, J = 9.5H
z), 8.14 (3H, br), 8.32 (1H, t, J = 6 Hz), 8.
38 (1H, d, J = 8.5 Hz), 8.60 (1H, t, J = 5.5)
Hz)

Example 45 Synthesis of camptothecin derivative represented by the following formula

Embedded image In the same manner as in Example 22, 2.3 g of CM-dextran sodium salt (degree of CM = 0.5) and the amount of 7-
Ethyl-10- {2 '-[2 "-(glycyl-glycyl-L
-Phenylalanylglycylamino) ethyloxy] ethyloxy}-(20S) -camptothecin hydrochloride 310 mg
1.83 g of the more desired camptothecin derivative is obtained as a pale yellow powdery complex. The content determined as 7-ethyl-10- (2'-aminoethyloxy-ethyloxy)-(20S) -camptothecin hydrochloride by absorption at 380 nm is 1.6%. As a result of analysis by GPC analysis, the average molecular weight obtained was 200,000, and the polydispersity Mw / M
n is 1.38.

Example 46 7-ethyl-10- [3 ′-(glycyl-glycyl-L-
Phenylalanyl-glycyloxy) propyloxy]-
Synthesis of (20S) -camptothecin hydrochloride (1) Preparation of 7-ethyl-10- [3 ′-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-(20S) -camptothecin Synthesis 7-ethyl-10- (3'-hydroxypropyloxy)
-(20S) -camptothecin (50 mg), t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycine (2 equivalents) and a catalytic amount of 4-dimethylaminopyridine were mixed with dry dimethylformamide (2.5 ml).
3 equivalents of N'-dicyclohexylcarbodiimide are added. After reaction at room temperature overnight, the mixture was treated in the same manner as in Example 8- (1) to give 7-ethyl-10- [3 '-(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycyloxy) as a yellow powder. Propyloxy]-(20S) -camptothecin 71 mg is obtained. Yield: 74% IR (Nujol): ν _max ^{cm -1} = 3300,1750,166
0 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 H
z), 1.37 (9H, s), 1.80-1.94 (2H, m), 2.1
1-2.20 (2H, m), 2.72 (1H, dd, J = 14Hz and 10Hz), 3.02 (1H, dd, J = 14Hz and 5H
z), 3.18 (2H, q, J = 7 Hz), 3.52-3.79 (4
H, m), 3.88 (2H, dd, J = 6Hz and 2Hz), 4.3
0 (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), 7.12-7.25 (5 H, m), 7.27 (1 H,
s), 7.51-7.55 (2H, m), 7.88 (1H, t, J = 5
Hz), 8.08 (1H, d, J = 9.5 Hz), 8.32 (1H, t,
J = 5Hz)

(2) 7-ethyl-10- [3 '-(glycyl-glycyl-L-phenylalanyl-glycyloxy)
Synthesis of propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Example 8- (2), 7-ethyl-10- [3′-
(t-butoxycarbonyl-glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-
(20S) -7- as a yellow powder from 58 mg of camptothecin
Ethyl-10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-(2
39 mg of (OS) -camptothecin hydrochloride are obtained. Yield: 72% Melting point:> 167 ° C (decomposition) IR (Nujol): ν _max ^{cm -1} = 3285,1745,165
5 Mass: m / z = 769 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.31 (3H, t, J = 7.5Hz),
1.80-1.93 (2H, m), 2.12-2.20 (2H, m),
2.72 (1H, dd, J = 14Hz and 10Hz), 3.02
(1H, dd, J = 14Hz and 4.5Hz), 3.18 (2H,
q, J = 7.5 Hz), 3.54-3.92 (6 H, m), 4.31
(4H, t, J = 6Hz), 4.51-4.59 (1H, m), 5.2
9 (2H, s), 5.43 (2H, s), 7.13-7.22 (5H,
m), 7.27 (1H, s), 7.51-7.56 (2H, m), 8.0
3 (3H, br), 8.09 (1H, d, J = 9.5 Hz), 8.35
(1H, d, J = 9Hz), 8.51 (1H, t, J = 5.5Hz),
8.60 (1H, t, J = 6Hz)

Example 47 Synthesis of camptothecin derivative represented by the following formula

Embedded image In the same manner as in Example 22, 250 mg of CM-dextran sodium salt (degree of CM = 0.5) and 7 obtained in Example 46 were used.
-Ethyl-10- [3 ′-(glycyl-glycyl-L-phenylalanyl-glycyloxy) propyloxy]-
From 33 mg of (20S) -camptothecin hydrochloride, 196 mg of the desired camptothecin derivative is obtained as a pale yellow powdery complex. By absorption at 380 nm, 7-ethyl-10-
The content determined as (3'-hydroxypropyloxy)-(20S) -camptothecin is 3.6%. As a result of analysis by GPC analysis, the average molecular weight obtained was 182,
000 and the polydispersity index Mw / Mn is 1.48.

Example 48 10- (4′-Aminobutyloxy) -7-ethyl- (20
Synthesis of S) -camptothecin hydrochloride In the same manner as in 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} = 3410,1745,165
5,1615 Mass: m / z = 464 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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 (2H, s), 7.28
(1H, s), 7.50-7.53 (2H, m), 8.00 (3H, b
r), 8.09 (1H, d, J = 10Hz)

Example 49 10- [4 ′-(Glycyl-glycyl-L-phenylalanyl-glycylamino) butyloxy] -7-ethyl-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Example 8- (2),
10- [4 '-(Glycyl-glycyl-L-) as a yellow powder
Phenylalanyl-glycylamino) butyloxy] -7
-Ethyl- (20S) -camptothecin hydrochloride is obtained. Melting point:> 156 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3270,1745,1655,
1615 Mass: m / z = 782 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 H
z), 1.60-1.94 (6H, m), 2.79-2.87 (1H,
m), 3.07 (1H, dd, J = 14Hz, 5Hz), 3.15-3.
23 (4H, m), 3.73-3.90 (6H, m), 4.22 (2
H, t, J = 6 Hz), 4.50-4.58 (1 H, m), 5.30
(2H, s), 5.43 (2H, s), 7.17-7.27 (5H, m),
7.28 (1H, s), 7.50-7.53 (2H, m), 7.87
(1H, t, J = 6Hz), 8.07-8.12 (4H, br), 8.3
9 (1H, t, J = 6Hz), 8.40 (1H, d, J = 8Hz), 8.
60 (1H, t, J = 6Hz)

Example 50 10- {3 ′-[N- (glycyl-L-phenylalanyl-
Synthesis of glycyl-glycyl) -N-methylamino] propyloxy} -7-ethyl- (20S) -camptothecin hydrochloride Analogously to Example 8, 10- {3 ′-[N- (glycyl-
L-phenylalanyl-glycyl-glycyl) -N-methylamino] propyloxy} -7-ethyl- (20S)-
Obtain camptothecin hydrochloride.

Example 51 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4
5) 1116 mg and 7-ethyl-10- obtained in Example 9
[3 ′-(Glycylamino) propyloxy]-(20S)-
95 mg of camptothecin hydrochloride was treated in the same manner as in Example 23 to give the desired camptothecin derivative 111 as a pale yellow powder.
7 mg are obtained. By absorption at 380 nm, 10- (3′-
The content determined as aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Example 1- (8-1)) was 4.8%. As a result of analysis by GPC analysis, the average molecular weight obtained was 143,000, and the polydispersity Mw / Mn was 1.53.

Example 52 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM conversion = 0.6
4) 1400 mg and 182 mg of 10- [5 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) pentyloxy] -7-ethyl- (20S) -camptothecin hydrochloride obtained in Example 17 were treated as in Example 23. The same treatment gives 1330 mg of the desired camptothecin derivative in the form of a pale yellow powder. The content determined as 10- (5′-aminopentyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (compound of Example 3) by absorption at 377 nm was 3.
4%. As a result of analysis by GPC analysis, the obtained average molecular weight was 193,000, and the polydispersity Mw / Mn was 1.5.
6.

Example 53 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM conversion = 0.6
4) In the same manner as in Example 23, 1400 mg and 182 mg of 10- [4 ′-(glycyl-glycyl-L-phenylalanyl-glycylamino) butyloxy] -7-ethyl- (20S) -camptothecin hydrochloride obtained in Example 49 were used. To give 1390 mg of the desired camptothecin derivative in the form of a pale yellow powder. The content determined as 10- (4'-aminobutyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (compound of Example 48) by absorption at 377 nm was 3.8.
%. As a result of analysis by GPC analysis, the obtained average molecular weight was 181,000 and the polydispersity Mw / Mn was 1.76.
It is.

Examples 54 to 69 In the same manner as in Example 22 or 23, camptothecin derivatives shown in Table 1 below were obtained from the corresponding starting compounds shown in Table 1 below.

[Table 1]

Example 70 7-ethyl-10- [3 ′-(glycyl-glycylamino)
Synthesis of propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Example 11, yellow powdery 7-ethyl-1
0- [3 ′-(Glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is obtained. Melting point:> 181 ° C (decomposition) IR (Nujol): ν _max ^{cm -1} = 3300,1750,166
0,1615 Mass: m / z = 564 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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 (2H, d, J = 5.
5Hz), 4.25 (2H, brt), 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, b
r), 8.21 (1H, brt), 8.71 (1H, brd)

Example 71 Synthesis of 7-ethyl-10- [3 ′-(D-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Example 11, a yellow powder was obtained. 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} = 3250,1745,165
5,1610 Mass: m / z = 654 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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
(1H, dd, J = 14Hz, 6Hz), 3.15-3.29 (2H,
m), 3.28-3.36 (2H, m), 3.69 (1H, dd, J = 1
6 Hz, 6 Hz), 3.80 (1 H, dd, J = 16 Hz, 6 Hz),
4.09 (1H, m), 4.25 (2H, t, J = 7Hz), 5.30
(2H, s), 5.43 (2H, s), 7.22-7.35 (6H, m),
7.47-7.55 (2H, m), 8.08 (1H, d, J = 9.5
Hz), 8.19 (1H, brt), 8.25-8.42 (3H, br)

Example 72 Synthesis of 7-ethyl-10- [3 '-(glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride In the same manner as in Example 11, 7-ethyl-10- Ethyl-1
0- [3 ′-(Glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is obtained. Melting point:> 158 ° C. (decomposition) IR (Nujol): ν _max ^{cm −1} = 3250,1750,165
5,1615 Mass: m / z = 621 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7Hz), 1.32 (3H, t, J = 7Hz), 1.8
0-2.20 (4H, m), 3.20 (2H, q, J = 7Hz), 3.
31 (2H, q, J = 7 Hz), 3.61 (2H, q, J = 6 Hz),
3.71 (2H, d, J = 5.5 Hz), 3.84 (2H, d, J = 6
Hz), 4.24 (2H, t, J = 6 Hz), 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 (1 H, d, J = 9 Hz), 8.19 (3
H, br), 8.36 (1H, t, J = 6Hz), 8.80 (1H, t, J
= 5.5Hz)

Example 73 7-Ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Example 8- (2),
This gives 7-ethyl-10- [3 ′-(glycyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride as a yellow powder. Melting point:> 186 ° C (decomposition) IR (Nujol): ν _max ^{cm -1} = 3220,1745,1655,
1615 Mass: m / z = 735 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5Hz), 1.32 (3H, t, J = 7.5H)
z), 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 = 5.5Hz), 4.24 (2
H, t, J = 6Hz), 5.31 (2H, s), 5.43 (2H, s),
7.30 (1H, s), 7.51-7.55 (2H, m), 8.00
(1H, t, J = 6Hz), 8.10 (1H, d, J = 9.5Hz),
8.18 (3H, br), 8.23 (1H, t, J = 6Hz), 8.28
(1H, t, J = 5.5Hz), 8.43 (1H, t, J = 5.5H)
z), 8.82 (1H, t, J = 5.5Hz)

Example 74 7-ethyl-10- [3 ′-(glycyl-glycyl-D-
Phenylalanyl-glycylamino) propyloxy]-
Synthesis of (20S) -camptothecin hydrochloride In the same manner as in Example 11- (1) and Example 8- (2),
This gives 7-ethyl-10- [3 ′-(glycyl-glycyl-D-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride as a yellow powder. Melting point:> 136 ° C (decomposition) IR (Nujol): ν _max ^{cm -1} = 3220,1745,165
5 Mass: m / z = 768 [(M-Cl -) +] NMR (300MHz, d 6 -DMSO): δ TMS = 0.88
(3H, t, J = 7.5 Hz), 1.31 (3H, t, J = 7.5 H
z), 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 = 14Hz, 4.5Hz), 3.14-3.24 (2H,
m), 3.28-3.35 (2H, m), 3.54-4.20 (6H,
m), 4.25 (2H, brt), 4.48-4.58 (1H, m), 5.
29 (2H, s), 5.43 (2H, s), 7.13-7.27 (5
H, m), 7.28 (1H, s), 7.51 (1H, m), 7.50-7.
56 (1H, m), 7.95 (1H, brt), 8.09 (1H, d, J =
9Hz), 8.04-8.17 (3H, br), 8.35 (1H, br
t), 8.39 (1H, brd), 8.59 (1H, brt)

Examples 75 to 78 The compounds shown in Table 2 below are obtained from the product of Example 1 in the same manner as in Example 8 or Example 11.

[Table 2]

Examples 79 to 80 The compounds shown in Table 3 below were obtained from the products of Example 4 or Example 5 in the same manner as in Example 8 or Example 11.

[Table 3]

Example 81 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.6
5) 2220 mg and 7-ethyl-10- obtained in Example 70
[3 ′-(glycyl-glycylamino) propyloxy]-
222 mg of (20S) -camptothecin hydrochloride in Example 23
To give 2310 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-ethyl- (2
The content determined as (OS) -camptothecin hydrochloride (compound of Example 1- (8-1)) is 5.2%. As a result of analysis by GPC analysis, the determined average molecular weight was 166,000.
0, and the polydispersity Mw / Mn is 1.55.

Example 82 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.5
5) 2320 mg and 7-ethyl-10- obtained in Example 71
[3 '-(D-phenylalanyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride 291 mg
Is treated in the same manner as in Example 23 to obtain 1964 mg of the desired camptothecin derivative as a pale yellow powder. 10- (3'-aminopropyloxy) -7 by absorption at 380 nm
-Ethyl- (20S) -camptothecin hydrochloride (Example 1
-The content determined as ((8-1) compound) is 6.7%. As a result of analysis by GPC analysis, the obtained average molecular weight was 184,000, and the polydispersity Mw / Mn was 1.57.

Example 83 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.5
5) 2240 mg and 7-ethyl-10- obtained in Example 74
[3 ′-(Glycyl-glycyl-D-phenylalanyl-
Glycylamino) propyloxy]-(20S) -camptothecin hydrochloride (291 mg) is treated in the same manner as in Example 23 to obtain 2005 mg of the desired camptothecin derivative as a pale yellow powder. The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Example 1- (8-1)) by absorption at 380 nm is 5.5%. . As a result of the analysis by GPC analysis,
The required average molecular weight is 148,000, and the polydispersity Mw /
Mn is 1.84.

Example 84 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4
5) 2000 mg and 7-ethyl-10- obtained in Example 72
260 mg of [3 ′-(glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is treated in the same manner as in Example 23 to obtain 1901 mg of the desired camptothecin derivative as a pale yellow powder. By absorption at 380 nm, 10- (3'-aminopropyloxy) -7-
Ethyl- (20S) -camptothecin hydrochloride (Example 1-
The content determined as (the compound of (8-1)) is 5.3%.
As a result of analysis by GPC analysis, the obtained average molecular weight was 138,000, and the polydispersity Mw / Mn was 1.51.

Example 85 Synthesis of camptothecin derivative represented by the following formula

Embedded image CM-dextran sodium salt (CM degree = 0.4
5) 1640 mg and 7-ethyl-10- obtained in Example 73
230 mg of [3 ′-(glycyl-glycyl-glycyl-glycyl-glycylamino) propyloxy]-(20S) -camptothecin hydrochloride is treated in the same manner as in Example 23 to obtain 1700 mg of the desired camptothecin derivative as a pale yellow powder. The content determined as 10- (3′-aminopropyloxy) -7-ethyl- (20S) -camptothecin hydrochloride (the compound of Example 1- (8-1)) by absorption at 380 nm is 4.7%. . As a result of analysis by GPC analysis, the average molecular weight obtained was 149,000, and the polydispersity Mw / M
n is 1.50.

Examples 86 to 92 In the same manner as in Example 22 or Example 23, the compounds shown in Table 4 below were obtained from the corresponding starting compounds.

[Table 4] [CM ・ Pullulan ・ Na is carboxymethyl pullulan ・
Represents sodium salt]

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

[Table 5]

Examples 114 to 158 In the same manner as in Example 22 or Example 23, the compounds shown in Tables 6 to 8 are obtained from the corresponding starting compounds shown in Tables 6 to 8 below.

[Table 6]

[0144]

[Table 7]

[0145]

[Table 8]

Reference Example 1 (1) Dextran [Dextran T-1 manufactured by Pharmacia]
10, average molecular weight: 100,000 (GPC method)] and 29 g of water. To this solution is added 1.45 g of sodium borohydride at 0-5 ° C and stirred at 5 ° C overnight.
Acetic acid was added dropwise to the reaction mixture to adjust the pH to 5, and the mixture was further stirred at room temperature for 3 hours. The pH is adjusted to 7 with 2N sodium hydroxide and, with vigorous stirring, 1.2 l of ethanol are added. After allowing to stand to precipitate insolubles, the supernatant is removed by decantation, and the residue is centrifuged. The residue was dissolved in 0.5 liter of water and lyophilized to give a white powder.
3 g are obtained.

(2) 100 g of the white powder obtained in the above (1)
Was dissolved in 1000 ml of water, and 400 g of sodium hydroxide was added to the solution under ice cooling, followed by stirring for 30 minutes. After returning the reaction solution to room temperature, an aqueous solution of 220 g of monochloroacetic acid 66
0 ml is added dropwise and stirred at 40 ° C. for 18 hours. Reaction solution 1
Cool to below 0 ° 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. Ethanol was added to the filtrate, and the deposited precipitate was collected by filtration, washed with aqueous ethanol and acetone, and dried under reduced pressure at room temperature and 50 ° C. to obtain carboxymethyl dextran (CM-dextran) sodium salt [degree of carboxymethylation ( Neutralization titration): 0.45]
101 g are obtained.

Reference Examples 2 to 7 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 9 below.

[Table 9]

Reference Example 8 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 [carboxy Methylation degree (neutralization titration method): 0.5].

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location C07K 5/103 C07K 5/103 7/06 7/06 C08B 37/00 C08B 37/00 37/02 37/02 // C07K 105: 00

Claims (32)

[Claims] 1. A compound of the general formula [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 an intervening oxygen atom. Represents a straight-chain or branched-chain alkylene group which may be bonded to a polysaccharide having a carboxyl group via an amino acid or a peptide, or a pharmacologically acceptable derivative thereof. Salt. 2. A part or all of a carboxyl group of a polysaccharide and an amino group of an amino acid or a peptide form an acid amide bond, and the whole or part of a carboxyl group of the amino acid or the peptide and X ^{1 of the} compound [I] The compound according to claim 1, which is formed by an acid amide bond or an ester bond, or a pharmaceutically acceptable salt thereof. 3. An acid amide bond between a part or all of the carboxyl group of the polysaccharide and the N-terminal amino group of the amino acid or peptide, and the C-terminal carboxyl group of this amino acid or peptide is linked to X ^{1 of the} compound [I]. 3. The compound according to claim 2, which is formed by an acid amide bond or an ester bond, or a pharmaceutically acceptable salt thereof. 4. X ¹ of the compound [I] is of the formula: —NHR ² (R ² is the same as described above), and the polysaccharide having a carboxyl group is carboxymethylated dextran or pullulan. 4. The compound according to claim 3, which is bound via a peptide, or a pharmaceutically acceptable salt thereof. 5. The compound [I] wherein R ¹ is an unsubstituted lower alkyl group, X ¹ is an amino group, Alk is a linear alkylene group (no oxygen atom is interposed), and the polysaccharide is carboxymethylated. 5. The compound according to claim 4, which is dextran, or a pharmaceutically acceptable salt thereof. 6. The method according to claim 6, wherein the peptide is glycyl-glycyl-L or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, The compound according to claim 5, which is L or D-phenylalanyl-glycine or L or D-leucyl-glycine, or a pharmaceutically acceptable salt thereof. 7. The method according to claim 7, wherein the peptide is glycyl-glycyl-L-
Phenylalanyl-glycine, and R ^{1 of} compound [I]
Is an ethyl group, X ¹ -Alk-O— is a 3-aminopropyloxy group, and is bonded to the camptothecin skeleton at the 10-position, or a pharmaceutically acceptable salt thereof. 8. The peptide is glycyl-glycine, R ¹ of compound [I] is an ethyl group, and X ¹ -Alk-O
The compound according to claim 6, wherein-is a 3-aminopropyloxy group and is bonded to the 10-position of the camptothecin skeleton, or a pharmaceutically acceptable salt thereof. 9. The peptide is glycyl-glycyl-glycine, R ¹ of compound [I] is an ethyl group, and X ^1-
The compound according to claim 6, wherein Alk-O- is a 3-aminopropyloxy group and is bonded to the camptothecin skeleton at the 10-position, or a pharmaceutically acceptable salt thereof. 10. The camptothecin wherein the peptide is glycyl-glycyl-glycyl-glycine, R ¹ of compound [I] is an ethyl group, X ¹ -Alk-O— is a 3-aminopropyloxy group, The compound according to claim 6, which is bonded to the 10-position of the skeleton, or a pharmaceutically acceptable salt thereof. 11. The compound according to claim 1, wherein the peptide is L or D-phenylalanyl-glycine, R ¹ of compound [I] is an ethyl group, and X ¹ -Alk-O— is a 3-aminopropyloxy group. The compound according to claim 6, which is bound to the camptothecin skeleton at position 10, or a pharmaceutically acceptable salt thereof. 12. The polysaccharide having a degree of carboxymethylation of 0.5.
12. The compound or a pharmaceutically acceptable salt thereof according to claim 7, wherein the number is 3 or more and 0.8 or less. 13. A compound of the general formula [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 an intervening oxygen atom. Represents a straight-chain or branched-chain alkylene group, which may be represented by the following formula: 14. The compound or a salt thereof according to claim 13, wherein R ¹ is an unsubstituted lower alkyl group, X ¹ is an amino group, and Alk is a linear alkylene group (no oxygen atom is interposed). 15. R ¹ is an ethyl group, and X ¹ -Alk-O
The compound according to claim 14, wherein-is a 3-aminopropyloxy group and is bonded to the camptothecin skeleton at position 10. 16. A compound of the general formula [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 an intervening oxygen atom. Represented by a linear or branched alkylene group which may be substituted with an amino acid or peptide, or a camptothecin compound or a salt thereof. 17. The compound or a salt thereof according to claim 16, wherein all or a part of the carboxyl group in the amino acid or peptide and X ¹ of the compound [I] are bonded by an acid amide bond or an ester bond. 18. The compound according to claim 17, wherein the C-terminal carboxyl group of the amino acid or peptide and X ¹ of compound [I] are bonded by an acid amide bond or an ester bond or a salt thereof. 19. The compound [I] wherein X ¹ has the formula: —NHR ² (R ²
Is the same as defined above), or a salt thereof. 20. The method according to claim 10, wherein the peptide is glycyl-glycyl-L.
Or D-phenylalanyl-glycine, glycyl-glycine, glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycine, glycyl-glycyl-glycyl-glycyl-glycine, L or D-phenylalanyl-glycine or L or D 20. The compound according to claim 19, which is -leucyl-glycine, or a salt thereof. 21. The compound or a salt thereof according to claim 20, wherein R ¹ is an unsubstituted lower alkyl group, X ¹ is an amino group, and Alk is a linear alkylene group (no oxygen atom is interposed). 22. The method according to claim 22, wherein the peptide is glycyl-glycyl-L.
-Phenylalanyl-glycine, and R of compound [I]
22. The compound or a salt thereof according to claim 21, wherein ¹ is an ethyl group, X ¹ -Alk-O- is a 3-aminopropyloxy group, and is bonded to the camptothecin skeleton at position 10. 23. The peptide is glycyl-glycine, R ¹ of compound [I] is an ethyl group, and X ¹ -Alk-O
22. The compound or a salt thereof according to claim 21, wherein-is a 3-aminopropyloxy group and is bonded to the camptothecin skeleton at position 10. 24. The peptide is glycyl-glycyl-glycine, R ¹ of compound [I] is an ethyl group, and X ¹
-Alk-O- is a 3-aminopropyloxy group,
22. The compound or a salt thereof according to claim 21, which is bound to the camptothecin skeleton at position 10. 25. The camptothecin wherein the peptide is glycyl-glycyl-glycyl-glycine, R ¹ of compound [I] is an ethyl group, X ¹ -Alk-O- is a 3-aminopropyloxy group, 22. The compound or a salt thereof according to claim 21, which is bonded to the skeleton at position 10. (26) the peptide is L or D-phenylalanyl-glycine, R ¹ of compound [I] is an ethyl group, and X ¹ -Alk-O- is a 3-aminopropyloxy group; 22. The compound or a salt thereof according to claim 21, which is bound to the camptothecin skeleton at position 10. 27. 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 an intervening oxygen atom. Represents a linear or branched chain alkylene group which may also have a camptothecin compound formed by bonding a compound represented by the formula: amino acid or peptide, after removing the protecting group, if the amino acid is protected, Reacting with a polysaccharide having a carboxyl group and, if desired, converting the product into a pharmacologically acceptable salt, wherein the compound [I] and the polysaccharide having a carboxyl group are linked via an amino acid or a peptide. A method for producing a camptothecin derivative or a pharmacologically acceptable salt thereof bound. 28. 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 an intervening oxygen atom. Represents a straight-chain or branched-chain alkylene group which may have been reacted with an amino acid or a peptide, and when the amino group or the carboxyl group of the obtained compound is protected, the protecting group Wherein, if desired, the product is converted into a salt.
A method for producing a camptothecin compound or a salt thereof, wherein [I] is bound to an amino acid or a peptide. 29. The general formula [II]: [Wherein, R ¹ is a substituted or unsubstituted lower alkyl group, Alk is a linear or branched alkylene group which may be interposed with an oxygen atom, X ³ is R ³ —N (R ² ) — or R ³ -O-, R
² represents a hydrogen atom or a lower alkyl group; R ³ represents a group obtained by removing a hydroxyl group of a carboxyl group from an amino acid or a peptide protected by an amino group]; and an aminocarbonyl compound represented by the general formula (2): ] Wherein the amino group-protecting group is removed from the resulting compound, and if desired, the product is converted into a salt. 8] [Wherein, X ¹ is a group represented by the formula: —NHR ² or —OH,
Wherein R ¹ , R ² and Alk are the same as described above] and an amino acid or a peptide, and a camptothecin compound or a salt thereof. 30. The general formula (1): [In the formula, R ¹ is a substituted or unsubstituted lower alkyl group, Alk is a linear or branched alkylene group sometimes interposed with an oxygen atom, X ² is a protecting group —N (R ² ) — or a protecting group -O
And R ² represents a hydrogen atom or a lower alkyl group] and an aminocarbonyl compound represented by the general formula (2): Wherein the protecting group is removed from the resulting compound and, if desired, the product is converted into a salt, wherein the product is converted into a salt. [Wherein X ¹ is a group represented by the formula: —NHR ² or —OH, and R ¹ , R ² and Alk are as defined above] or a method for producing a camptothecin compound represented by the formula: 31. General formula (1): [In the formula, R ¹ is a substituted or unsubstituted lower alkyl group, Alk is a linear or branched alkylene group sometimes interposed with an oxygen atom, X ² is a protecting group —N (R ² ) — or a protecting group -O
And R ² represents a hydrogen atom or a lower alkyl group] and an aminocarbonyl compound represented by the general formula (2): With a pyranoindolizine compound represented by the general formula [I]: [Wherein X ¹ is a group represented by the formula: —NHR ² or —OH, and R ¹ , R ² and Alk are the same as described above], and then compound [I] and an amino acid or peptide When the amino group or carboxyl group of the obtained compound is protected, the protecting group is removed,
Further, the obtained compound having an amino acid or peptide is reacted with a polysaccharide having a carboxyl group, and if necessary, the product is converted into a pharmacologically acceptable salt. A method for producing a camptothecin derivative or a pharmaceutically acceptable salt thereof, wherein the polysaccharide having a group is bonded via an amino acid or a peptide. 32. The general formula [II]: [Wherein, R ¹ is a substituted or unsubstituted lower alkyl group, Alk is a linear or branched alkylene group which may be interposed with an oxygen atom, X ³ is R ³ —N (R ² ) — or R ³ -O-, R
² represents a hydrogen atom or a lower alkyl group, R ³ represents a group obtained by removing a hydroxyl group of a carboxyl group from an amino acid or a peptide protected by an amino group] and an aminocarbonyl compound represented by the general formula (2): ] Is reacted with a pyranoindolizine compound represented by the formula, and the protecting group of the amino group is removed from the obtained compound to obtain a compound represented by the general formula
[I]: [Wherein X ¹ is a group represented by the formula: —NHR ² or —OH, and R ¹ , R ² and Alk are the same as those described above], and a camptothecin compound obtained by bonding a compound with an amino acid or a peptide. And reacting the compound with a polysaccharide having a carboxyl group, and if desired, converting the product into a pharmaceutically acceptable salt.
A method for producing a camptothecin derivative or a pharmaceutically acceptable salt thereof, wherein [I] and a polysaccharide having a carboxyl group are bonded via an amino acid or a peptide.