JPS63238098A - Novel camptothecin derivative - Google Patents

Abstract

NEW MATERIAL:A compound (salt) expressed by the formula (R<1> represents H or 1-4C alkyl; R<2> represents aldose residue or aldose residue in which COOH group, OH group, etc., is protected with benzoyl group, etc.; bond of R<2> with camptothecin is glycoside bond between oxygen atom. of A ring of camptothecin and carbon atom. of the 1-position of sugar). EXAMPLE:7-Ethylcamptothecin-10-yl beta-D-glucopyranoside. USE:A remedy against malignant tumor. PREPARATION:For example, 7-ethyl-10-hydroxycamptothecin is reacted with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide in the presence of a basic substance, purified with silica gel column chromatography and then protecting groups thereof are eliminated, as necessary, to afford the compound expressed by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel hikoryoku/ptothecin derivatives. More specifically, the present invention is based on the general formula (wherein R1 represents a hydrogen atom or a C1-4 alkyl group, and R2 is an aldose residue or a 1000H group present in the group). Alternatively, the 10H group is a lower aliphatic acyl group whose alkyl group has 1 to 2 carbon atoms, a pensoyl group, a trifluoroacetyl group, a lower alkyl ester group whose alkyl group has 1 to 2 carbon atoms, or A camptothecin derivative represented by a combination of protected aldose residues, in which the bond R and force/ptothecin represents a glycosidic bond between the oxygen atom on the A ring of camptothecin and the sugar-1 carbon atom. or an alkali metal salt, quaternary ammonium salt, or acid addition salt (mineral acid salt or organic acid salt, etc.) of the sugar moiety thereof.

Camptothecin is a deciduous tree (Camptothec).
It is an alkaloid P extracted and isolated from plants such as Aacuminata Nyssaceae, and has a strong nucleic acid synthesis inhibitory effect.The action is rapid and reversible, and is unique in that it shows no cross-resistance with existing anticancer drugs. It is an antitumor substance with a unique mechanism of action, and is effective against murine leukemia L1.
210 and Rat Walker 256 sarcoma and other experimentally transplanted cancers have been recognized as having a strong anticancer effect, but its usefulness as a drug is naturally limited due to its toxic effects. It is in.

The present inventors have so far made numerous attempts to obtain new camptothecin derivatives with improved pharmacological activity and toxicity by chemically modifying natural camptothecin. Among the potent/ptothecin derivatives obtained so far, interesting results have been obtained, particularly for the group of compounds having a hydroxyl group at the 10th position, which show reduced toxicity while maintaining superior antitumor activity. However, these are difficult to administer as medicines because they are poorly soluble in water.

Conventionally, one known method for making camptothecin derivatives water-soluble is to open the E ring (lactone ring) to form a sodium salt of a carboxylic acid. However, it has the disadvantage that it is weakened to a fraction of a second.

The present inventors succeeded in obtaining a glycosylated P derivative of the hydroxyl group on the A ring (9-110-111-1 and 12-positions) without cleavage of the E ring (lactone ring).

The novel glycosyl r derivative according to the present invention can be produced as follows.

, a camptothecin derivative having a hydroxyl group in the A ring is dissolved or suspended in a solvent such as acetone, dioxane, dimethylsulfoxy P, dimethylformamide)+1, dimethylacetamyl, tetrahFlofuran, etc., preferably acetone,
In addition, halo-r-noal P protected by a 4.0-1 group, a trifluoroacetyl group, a lower alkyl ester group having 1 to 2 carbon atoms in an alkyl group, or a combination thereof.
-su (as a halogen atom, chlor or bromine atom,
4.0 to 8.0 equivalents (preferably bromine atoms) are added, stirred vigorously for 6 to 24 hours at room temperature to the boiling temperature of the solvent, and after reaction, insoluble materials are filtered off from the reaction mixture. Then, the product is separated and purified by silica gel column chromatography. In this way, a Cambutycin glucosiP compound having a protecting group at the glyco71 moiety is obtained.

In addition, as an alternative method, a camptothecin derivative having a hydroxyl group in the A ring is hydroxylated to 2.0 to 2.5 equivalents). There is a method in which 2 equivalents of a solution of a halogenoaldose having the above-mentioned protecting group is added to the reaction mixture, and the reaction is carried out at room temperature to 60° C. for a certain period of time.

When the halogen atom at the 1-position and the acetoxy group at the 2-position of the above-mentioned nohalo-r-noal-P-s are in the trans position, an orthoester derivative is produced.

A herodenoal group protected by a thyl group, a lower alkyl ester group having 1 to 2 carbon atoms, or a combination thereof (the halogen atom is a chloro or bromine atom, preferably a bromine atom) is a sugar It can be produced by a known method commonly used in quality chemistry.

That is, the number of carbon atoms in the aldose and the alkyl group is 1 to
The lower acid anhydride of No. 2 is combined with an acidic catalyst (e.g., zinc chloride, sulfuric acid, hydrogen chloride, perchloric acid, etc.) or a basic catalyst (e.g.,
(sodium acetate, pyridine, etc.) to form a mother acyl aldose (hereinafter, acyl refers to a lower acyl group in which the alkyl group has 1 to 2 carbon atoms), and then reacted with hydrogen halide (hereinafter, hydrogen chloride or (represents hydrogen bromide)
No(-acylhalogenoaldose can be produced by reacting an acetic acid solution of

For example, 2,3,4,6-tetra-0-acetyl α-
D-GlucogylanosylpromyY MethodsC
arbohyd, Chem, 2, 221 (I
963), 2,3,4-tri〇-acetyl-α-L-7 copyranosilp OmyP was prepared according to the method described in CarbohydrateResearch 64,2.
97 (I978) and also according to the method described in 2
,3,6.2',3',4',6'-penta-O-acetel-alpha-lomaltosylzolomy)" J J , Am
.

Chem, Soc, 51, 1820 (I929)
It can be manufactured according to the method described in .

Alternatively, 9-acylaldose and titanium tetrachloride, liquid hydrogen chloride, aluminum chloride, aluminum chloride-phosphorus pentachloride, zinc chloride-thionylchloride P,
It can be produced by the reaction between hydrogen rodanide and acyl hydrogen, or by the reaction between aldose and acyl halide P.

In addition, after reacting anhydrous alkyl group containing hydrogen chloride with a lower alcohol having 1 to 2 carbon atoms to form an acyl aldose (Fischer method), react with penzoylhalai P under water cooling using pyridine as a solvent. 9-Penzoylno-ronoal-P-s can be produced by reacting it with a solution of hydrogen-rhodanide and acetic acid.

Alternatively, 1-acylperbenzoyl al-P
It can also be produced by reacting with anhydrous hydrogen halide in a solvent such as chloroform, ether or acetic acid.

In the case of an aldose (uronic acid) having a carboxyl group in the molecule, its lactone derivative is boiled under reflux in a lower alcohol having anhydrous alkyl groups with 1 to 2 carbon atoms, or sodium methoxy in the corresponding alcohol is prepared. r.

The carboxyl group is protected by a lower alkyl group having 1 to 2 carbon atoms in the alkyl group by reaction with sodium ethoxy P, sodium hydroxide, triethylamine, or triethylammonium hydroxide, and then The hydroxyl group is acylated with 1 to 2 lower acid anhydrides in the presence of the above-mentioned acidic or basic catalyst, and then
By reaction with hydrogen halide-acetic acid solution, alkyl/4'-
Acyl halo-aldose uronates can be produced.

For example, methyl(2,3,4-)so0-acetylα
-D-glucopyranosyl bromide)') cronate is M
ethosCarbohyd, Chem, ,2,
335 (I963).

In addition, in the case of AlP-s (aminoaldose) having an amino group in the molecule, the aminoaldose is heated with an acyl halide to form 0- and -acylaminohalo rnoal P-suhydrohalodane salts, Next, trifluoroacetic anhydride or lower r! with an alkyl group having 1 to 2 carbon atoms! l Anhydride is reacted to form trifluoroacetamide?
Also d low R acyl amido acyl no tameguchi r noal P-
can be manufactured in a variety of ways.

In addition, as an alternative method, 4-acylaminoal
The hydrogen halide salt is reacted with trifluoroacetic anhydride, a lower acid anhydride whose alkyl group has 1 to 2 carbon atoms, or an acyl halide in a solvent such as methylene chloride using pyridine as a catalyst, and then hydrogen halide It can also be produced by reacting with an acetic acid solution.

For example, 3.4.6-) So0-acetyl-2-deoxy-2-trifluoroacetamide P-α-D-glucopyranosyl bromide J, Org.

Chem., 31,507 (I966), J.Or.
It can be produced according to the method described in G. Chem., 32.1821 (I967).

The protective groups for the glycoside compounds of camptothecin, namely lower acyl protecting groups, benzoyl protecting groups, trifluoroacetyl protecting groups, and lower alkyl ester protecting groups, are used to protect the glycoside compounds from methanol, water, or It is removed by mild alkaline hydrolysis with sodium methoxy r-methanol solution or 0.1N aqueous sodium hydroxide solution in acetone. This hydrolysis product is acidified with an ion exchange resin (sulfonic acid-H+ type) or 0.1N hydrochloric acid, and the product is recrystallized from a solvent such as methanol, ethanol, or ethanol-n-hexane, or After separation and purification using exchange resin or reverse phase chromatography, e.g. ODS column, a suitable solvent (e.g. methanol, ethanol, ethanol-n
-hexane, etc.) to obtain a glycoside compound of the lactate/ptothecin derivative.

Furthermore, when the sugar moiety has an amino group, as an acid addition salt (salt of mineral acid or organic acid, etc.) at the amino group,
If the compound has a carboxyl group, it can be obtained as its alkali metal salt or quaternary ammonium salt.

In addition to the hydroxyl group on the A ring, the raw material hy-roxycamptothecin and its derivatives have a hydroxyl group at the 20-position that can be converted into glycosylated P. The hydroxyl group at this position does not undergo glycosylation.

Therefore, no protective group is required for the 20-position hydroxyl group.

Other methods of converting glycosylated P include, for example, high P
A method of reacting roxicamptothecin and its derivatives with the above-mentioned protected halogenoaldose in the presence of silver carbonate or silver oxide (K'6nigs-Knorr reaction),
A method in which aldose acetate is reacted with zinc chloride or p-)luenesulfonic acid as a catalyst under heating, a method in which aldose acetate is reacted in an alkaline solvent (pyridine or quinoli/etc.) containing the above-mentioned protected halogen alkali, etc. Can be mentioned.

Further, as a method for removing the protecting group, a method using 0.5N barium methoxyr in methanol, a method using ammonia-saturated methanol, etc. can be mentioned.

Among camptothecin and A-ring hydroxyl group-substituted products of camptothecin derivatives, which are raw materials for the production of the novel camptothecin derivative according to the present invention, the 9-position substituted product and the 12-position substituted product are:
Camptothecin, or the 9-nitro or 12-nitro form of camptothecin can be produced through reduction and diazotization (see JP-A-59-51289).

10- and roxycamptothecin/or 7-lower alkyl-10-hyP-roxycamptothecin can be obtained by reacting camptothecin or 7-lower alkylcamptothecin with hydrogen peroxide in acetic acid to convert them into N-oxyP forms. Then, the two N-oxy compounds were dissolved in a solvent such as dioxane, acetonitrile, chloroform, methylene chloride, glyme, diglyme, or any mixed solvent thereof, and sulfuric acid,
Treat with mineral acids such as perchloric acid, organic sulfonic acids, etc. under ultraviolet irradiation. (JP-A-58-39683, JP-A-58-59684,
(Refer to Japanese Patent Application Laid-Open No. 58-39685).

The 11-hydroxy substituted product is obtained by nitration of the B-ring reduced tetrahypyl group of camptothecin.11-2)
It can be produced using the oral cavity as a starting material through oxidation, reduction, and diazotization (see JP-A-59-51287). 11-Hydroxycanzotothecin can be obtained by introducing a lower alkyl group into the 7-position by the method developed by the present inventors. (Refer to Japanese Unexamined Patent Publication No. 158786/1986).

The present invention will be explained in more detail with reference to Examples below.

Example 1 7-ethylcamptothecin-10-12:3'alb
l-Tetra-0-acetyl-β-D-glucobyranoside Method A Ni-ethyl-10-hyP-roxycamptothecin 1.57 g, 2,3,4.6-tetra-0-acetyl-α-D-glucopyranosyl 12.48 fI of bromide and 3.01.9 g of anhydrous potassium carbonate were suspended in 300 g of acetone and boiled and refluxed for 20 hours while stirring vigorously. After the reaction is completed, the solvent is distilled off under reduced pressure, and chloroform and water are added to the residue to remove the roots. Substances insoluble in both layers are filtered off using Celite. The chloroform layer is separated, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.

The concentrate was subjected to medium pressure silica column chromatography (eluting with chloroform and then chloroform/methanol (I00/1)) followed by chloroform-n
- Recrystallization from hexane gave the title compound 0.7111 as colorless needles.

Method B: After dissolving 100 μl of 7-functional 10-hyP roxycamptothecin in 0.1N potassium hydroxide aqueous solution 6.4-, 2,3,4.6-chitler○-acetyl-α-D- Add a 5d solution of Glucopyranosilb Kuchimi R210IV in acetone and allow to react at room temperature for 2 hours. After filtering off the yellow substance that precipitates during the reaction, acetone is distilled off under reduced pressure at a low temperature. Add chloroform and 0.0% to the resulting aqueous solution.
Add 1N hydrochloric acid and shake. Separate the chloroform layer,
Wash with water, dry over magnesium sulfate, and concentrate under reduced pressure.

The concentrate was subjected to medium pressure silica column chromatography (eluting with chloroform and then chloroform/methanol (I00/1)) to give the title compound 50.

M, P, 191-192℃ (decomposition) SIM8: M
H” 723 IRνg product cr': 3450, 2970, 2
930, 1745, 1655°1600, 136
5, 1220, 1030゜'H-NMRδ: 40
0 MHz (CDCL3)i, oa (shi)
2O-CH2Cmu1.40
(t) 7-CH2C is also 1.81-1
．． 98 (m) 2O-CqCH32,
06, 2, 07, 2, 0B, 2.11 (sX4)
2'+ 3:4'=6'-〇 〇 OCR
53,07~3.24 (m) 7-
0H2CH.

3.83 (s) 2O-O
H3,98(dXdXd) 5'-H4,2
2(dXd) 6'-CH(H)-4,3
3(dXd) 6'-CH(H)-
5,20~5.42 (m) 1'-H
, 2'-H, 3'-H.

4'-H 5,25(s) 5-CEi2-5.3
1 (d) 17-CH(H)
-5,75(d) 17-CH(H)-
7,51(dXd) 1l-H7,60(
d)? -H7,64(s)
14-H8,20(d) 12-
E (Example 2 7-nitylcamptothecin-io-yl β-D-glucopyranosyP 7-ethylcamptothecin-10-yl 2'3'4',
6'-tetra-0-acetyl-β-D-glucopyranoside was suspended in 60% of anhydrous methanol, and 2
Add 0.5-methanol solution of 8tin sodium methoxy P-methanol and allow to react at room temperature for 30 minutes. Add 2 d of reaction water, and add an ion exchange resin (sulfonic acid-1 type) to this to make the liquid weakly acidic. The resin was filtered off, washed with methanol, and the filtrate and washings were combined and dried under reduced pressure. The residue was recrystallized from methanol to obtain the title compound 410 as pale yellow needles.

M, P, 232-233℃ (decomposition) BIMB: M
H" 555 IRνKBran-': 3370, 1715,
1645, 1595, 1500° [ 1240, 1160, 1095, 1065, 1040,
1005゜'H-NMRa: aoo ME(Z
(DMso-a,)0.88 (t)
20-□CH2CH31,31-(t) 7-CH
2CH.

1.78~L96 (m) 2O-CH2CH33
,12~3.25 (m) 7-CH2CH3,G
lc, -H3,32~3.39 (m) Glc
, -HX23,jSi ~3.54 (m) G
lc, -HX23.70~3.80 (m) G
lc, -H4,68(dXd)6'-0H 510(d) Glc, -0H 5,14(d) 1'-H(J, Metsu21=,
8-06Hz) 5.16 (d) C)
lc, -0H5,32(s) 5-CH2- 5-43(S) 17-CH2-, Glc--OH
6,50(s) 2O-OR 7,29(s) 14-E( 7,58(dXd)11-H 7,74(d) 9-H 8,11(d) 12-H Example 3 7 -ethylcamptothecin-10-yl 2/, 3IAI
-) Di-0-acetel-β-L-fucopyranoside 7-
Ethyl-10-hydroxycamptothecin 1.57g
, 2.3.4-tri-〇-acetel-α-L-fucopyranosylpromy)'s, s6y and anhydrous potassium carbonate 2,35 J) were suspended in acetone 300-, and while stirring vigorously, Boil to reflux for an hour. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform.
Insoluble material is filtered off using Celite. The filtrate is washed with loloform, and the filtrate and washings are combined and concentrated under reduced pressure. The concentrate was treated with medium pressure silica gel column chromatography.
, (chloroform, then chloroform/methanol (
(eluting at Ioo/1)) and then recrystallized from ethanol to obtain the title compound 1.72JF as colorless needles.

, M, P, 258-260℃ (decomposition) SIMS
: MH665 IRI/"rcm-' : 3!180, 2970
, 2950, 2B75.1740°ax 1650, 1595, 1360, 1240, 1
215, 1150.

1055°'H-NMR15: 400 MHz (CDC43)
1・04 (t,) 2o-cH2c di1
．． 34 (d) 6m CH31-40 (
t) 7-CH20% 1.81-1.98 (m
) 2O-CHCH32-05,2-11,2,
24(sX3) 2', 3', 4'-0COCH36
,06~3.21(m)7-CCH33,86(s)
2O-OH 4,09(Q) 5'-H 5,20(dXd) 3'-E(5,25(s)
5-CH2-5,27(d) I
LH (Jlt, 2t = 8.06Hz) 5.31. ,
((I) 17-CH(H)-5,3
7(d) 4'-H 5,57(dXd) 2'-H 5,75(d) 17-CH(H)-7,52
(axa) 1l-E (7,61(d)
9-H 7,64(s) 14-H 8,19(d) 12-a Example 4 7-nitylcamptothecin/-10-yl β-L-fucopyranoside 7-ethylcamptothecin-10-yl 2', 3',
4'-) So0-acetyl-β-L-fucopyranoside 1,Ol was suspended in 160 grams of anhydrous methanol, and 0.5-
and react for 40 minutes at room temperature.

The product was post-treated in the same manner as in Example 2 and recrystallized from methanol to obtain the title compound 0.77, P as colorless prism crystals.

M, P, 207-209℃ (minute phosphorus) SIMS: M
H" 539 Engineering Rshi Sakazuki R item on-': 3420 .2970
．． 2930. 2870. 17ro5゜1650,
1595, 1500, 1210, 1070, 1
045°' H-NMRδ: 400 MHz (DM
SO-(I,)0,s8(t)2O
-CH2C di1.19 (d) 6'-C
F(31,32(shi) 7-CD2!l.

1.78-1.96 (m) 2O-CHCH
.

3.02-3.16 (m) 7-CH(H)
CH53,19-3.32 (m) 7-CH(
H) CH33,39-3.58 (m) 3'-
E(,4'-H3,61~3.70 (m)
2'-H3,93(q) 5'-H 4,62(d) 4'-0H4,89(d)
3'～○H5,15(d) 1'
H (J1/, z t ” 7.69Hz) 5.27
(d) 2'-0H5,31(s)
5-CH2-5-46(s) 17-
CH2-6,51(s) 20-CH7,2
9(s) 14-H 7,58(dXd) 1l-E(7,67(ti
) 9-H 8,12(d) 12-H Example 5 3', 4', 6'-tri〇-acetyl-1', 2'-
0-(7-Ethylcamptothecin-10-ylorthoacetyl)-β-D-ma/nobilanosyr 7-Nithyl-10-hyroxycamptothecin 72.3
5g, 2,3,4.6- f Tora-Q-7-1: Chill-
α-romanopyranosylpromy)'13.9011
and anhydrous potassium carbonate 3.52.9 to acetone 450-
and boil under reflux for 6 hours while stirring vigorously. After the reaction is completed, insoluble matter is filtered off using Celite, and the filtrate is washed with acetone.

The filtrate and washing liquids were combined and the solvent was distilled off under reduced pressure to obtain a dark brown tar-like residue. This residue was treated with medium pressure silica sol column chromatography (chloroform/n-hexane (4/1), chloroform, then chloroform/n-hexane (4/1), then chloroform/n-hexane (4/1),
After washing with ether (eluting with methanol (I00/2)), recrystallization from methanol afforded the title compound 0.17II as pale yellow granular crystals.

M, P, 141-144℃ SIMS: MH" 723 IRWKB"on-': 3450, 2970
, 2940 , 2B80.1740°ax 1650 , 1590 , 1565 , 1225 , 1
040°1 δ: 400 MHz (CDC2!l
) 1.04 (t > 2O-CH2C 1.39
(t) 7-CE (2Cmu1.83~1
, 96 (m) 2O-CH,CH.

-5 - 1,97,2,06,2,10,2,13 (sX4)
Orthoacetyl 3'4'6'-0COC)H5 3,14(q) 7-CH,CH33・69
(axaxa) 5'-H3,86(s
) 2O-OH 4-'7 (dXd) 6'-CH
(H)-4,26(dXd) 6'-0H(see)-
4-29(dXd) 2'-H 5,09(axa) 3'-H 5-25(s) 5-CF(2-5,31(d) 17-CH(H)-5.33
(dXd) 4'-H5-46(d
) 1 '-H (J, i, 2t = 2.56 ponds) 5
．． 75 (d) 17-CH(
H)-7,63(dXd) 1l-E( 7,64(s) 14-H 7,79(d) 9-H 8,16(d) 12-H Example 6 Two-ethylcamptothecin-10-yl 2/, 3/
, 6/ , 2// , 3II , 4# ,
6//-Hepta-O-acetyl-β-D-maltoside 7-ethyl-10-hyroxica/zotothecin L57
．． 9 and anhydrous potassium carbonate 2.5511 to a7ton 2
Suspend in 50 g of water and boil and reflux while stirring vigorously.
To this, 2.3, 6.2', 3', 4', 6'-
0-7Sef-α-D-maltosylzolomy)' 10
．． 50 g of acetone solution 5C1mj is added dropwise over 60 minutes and reacted for 6 hours. After the reaction is completed, insoluble matter is filtered off using Celite, and the filtrate is washed with chloroform. After combining the filtration and washing liquids and distilling off the solvent under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography (chloroform, then chloroform/methanol (I00/1
) and then recrystallized from ethanol to give the title compound 1.09.9 as a yellow powder.

M, P, 157-161℃ SIMS: M! ("1011 1Rν"rcm-': 3470, 2965, 1
740, 1650, 1600°ax 1362, 1225, 1025.

1H-Nlmu δ: 400 animals-z (CDCZs) 1.0
4 (t,) 2O-CH2CH.

1.42 (t) 7-CH2Cmu1.
83-1.96 (m) 2O-CH2CI(
32,02,2,04,2,05,2,07,2',
3', b', 2'-3'.

2.0B, 2.09, 2.11 (sX7)
496”-0COCH33,08~3.26
(m) 7-CH2CH33,82(s)
2O-OH 3,93-4.07 (m) 5'
-H,5"-H4,08(dXd) 6"-CH(
H)-4,19(axa) 4'-a a,27(axa) 6”-
ca(H)-4,31(dXd)6'-C! (H)
-4,55(dXd) 6'-CH(H)-4,8
8(axd) 2'-H 5,08(dXd) 4"-H 5,20(dXd) 2'-H 5-26(s) 5-CH2- 5" (d) 17-ca(
H)-5,38(d) 1'-H(J, I2/=7
．． 697) s, 39 (axd)
3'-H5,40(dXd) 3"-E(5,49(d) 1-T((J+t,21==4
-03ya) 5.75 (d)
17-CH(田)-7,49(dXcl) 1l-
H 7,59(d) 9-H 7,64(s) 14-H 8,19(d) 12-H Example 7 Two-ethylcamptothecin-10-yl β-D-maltocyP 7-ethylcamptothecin-10 -Ile 213/, 6
/, γ: 5″, 4/J 6#-hebutar〇-acetyl-β-D-maltoshi) 1400 Da to anhydrous methanol 45
mj, and add 28ts sodium methoxyde to this.
Add 0.2 parts of methanol solution and react at room temperature for 30 minutes. It was worked up in the same manner as in Example 2 and recrystallized from ethanol to obtain the title compound 269 as colorless needles.

M, P, 220-221℃ (decomposition) SIMS: I
J-I+717 1" affiliated product cnx-': 3375 + 2920 +
1730 + 1650 + 1615 + 1580
, 1500 , 1230 , 1210 , 1140 ,
1060.1020゜'H-1"7MRδ: 400
MHz (DMSO-ds) 0.88 (t, >
2O-CEI2CH11-32(t)
7-CH2C! L11-78~1.95 (m)
2O-CF12CH53,06~3.83 (m)
7-CH, 2CH3, 2'-H, 3'-H.

4'-H, 5'-H, 6'-CH2-.

2"-H, 3"-H, 4'-H, 5'-H.

6'-CH2- 4,53(shi) 6' or 6"-0H4,6
8(t) 6/or 6'-0H4,92(
d) Mal, -0H4,94(d)
Mal, -0H5,09(d) 1'-H
(Jlz, 2zz"3-30H2) 5.24
(d) i O H (J, /, 2/=7
．． 69H2) 5.32 (S) 5-C
H2-5,43(S) 17-CH2-5,5
0(d) Mal, -OH5,56(d)
Mal, -0H5,67(d)
Mal, -0H6-5CL, (s)
20-OH7,29(s) 14-H 7,58(dXd) 1l-H 7,73(d) 9-H 8,11(d) 12-H Example 8 Methyl (7-nityl camptothecin/- 10-yl2',
3', 4'-tri〇-acetyl-β-D-glucopyranosiP)-uronate A method nia-ethyl-10-hyProxica/putote'/
71.3711. Mefk (2,3,4-)di-0-acetyl-α-D-glucopyranosylzolomyr)-uronate 8.34# and anhydrous potassium carbonate 2.42II were suspended in 300 d of acetone, and stirred vigorously. 7 from the table
Boil to reflux for an hour. After the reaction is completed, insoluble matter is filtered off using Celite, and the filtrate is washed with loloform. After combining the filtration and washing liquids and distilling off the solvent under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography (chloroform, then chloroform/methanol (I00/1)).
(eluted with ) and then recrystallized from ethanol to obtain the title compound 85M9 as colorless needles.

Method B Ni-ethyl-10-hydroxycamptothecin 10.0IIfitO,IN Potassium hydroxide aqueous solution 6
After dissolving 40 ml of methyl (2,3,4-)so
-acetyl α-D-glucopyranosylpromyP)-
Uronate 20. Add an acetone 500-solution of O &
React for 4 hours at room temperature. It was then worked up in the same manner as in Method B of Example 1 and recrystallized from ethanol to obtain the title compound 0.6 Ii as colorless needles.

M, P, 179-182℃ (decomposition) SIMS: M
H" 709 1R KB rcm-': 345G, 2955
, 1740, 1645, 1590°ax 1360.1205.1025°' H-NMRδ: 400 MHz (CDC2s)
1.03 (t) 2O-CH2C Muto40 (t) 7-cH2cq 1.81-1.97 (m) 2O-CF
(, CH32,08+2.09.2.12 (sx3
) 2', 3', 4LOCOCHx6・14
(q) 7-C and CH33,73(s)
6'-COOCHs3・9B
(s) 2O-OH4,33(d) 5'
-H 5,24(s) 5-CH2- 5・29 (d) 17-C)I(
H)-5,36~5,49 (m) 1
'-H, 2'-H, 3'-H, 4'-H5・73
(d) 17-CH(H)-7,4
8 (d -D
-glucopyranosyl)-uronate methyl (7-ethylcamptothecin-10-yl 2', 3', 4'-) di-
0-acetyl-β-D-glucopyranoside)-uronate 30jIF was suspended in anhydrous methanol 64, and 2
Add 50 μl of 8% sodium methoxy P-methanol solution and react at room temperature for 60 minutes. An ion exchange resin (sulfonic acid-Hl) is added to the reaction solution to make it weakly acidic. The resin is filtered off, washed with methanol, and the filtrate and washings are combined and dried under reduced pressure. The residue was subjected to medium pressure silica gel column chromatography (eluted with chloroform/methanol (Io/1)), and then recrystallized from ethanol to obtain the title compound 13■ as a colorless to pale yellow amorphous powder.

M, P, 239-241℃ (decomposition) SXMS, M
H583 IRvKB quality picture-': 3420, 2960, 2
870, 1740, 1655°1620, 158
5, 1560, 1525, 1235, 1215
.

1080, 1055, 1030°'H-NMRδ: 400 MHz (DMSO-d,
)0.88 (t) 2O-CH2C
91・28, (t) 7-CH2C
91,78~1.95 (m) 2O-CH2
CH33,10(dXq) 7-CH(H)C
H35,28(dXq) 7-CH(H)CH5
3,36-3.54 (m) 2'-H,3'-
H,4'-H3-66(s) 6'-COO
CH54・27 (a) 5'-H5-3
1(s) 5-C! H2-5・34 (d
) ()ICA, -0H5・43(S)
17-CH2-5・46 (d) 1
'-H (J 1/, 2t = 7-33H2) 5, 5
0 (d) ()1cA, -0H
5,61(d) GlcA, -0H6,50
(s) 2O-OH7,29(s)
14-H 7,58(dXd) 1l-H7,68(d)
9-H 8,12(d) 12-E (Example 10 7-ethylcamptothecin-10-yl β-D-glucopyranosyl Puronic acid rA method: Methyl (7-ethylcamptothecin-10-yl 2', 3', 380 grams of 4'-)di-0-acetyl-β-ri-glucobylanosyl r)-cronate was suspended in 20 grams of acetone, and 0.
Add 62 g of 1X aqueous sodium hydroxide solution and stir at room temperature for 2.
Allow to react for 5 hours. After the reaction is complete, adjust the pH to 4-5 with 1N hydrochloric acid.
After distilling off the acetone under reduced pressure at low temperature, it was treated with reverse phase medium pressure column chromatography (oDS column) (eluted with water/methanol (7/3)) and then ethanol-n Recrystallization from -hexane gave the title compound 282■ as a pale yellow powder.

Method B: 250 glucopyranoside of methyl (7-ethelcamptothecin-10-yl 2',3',4'-tri-acetyl-β-ri-glucopyranoside)-uronate was suspended in 10-glucopyranoside of anhydrous methanol, and 28 % Sodium Methoxy P
-Add 0.2- of methanol solution and react at room temperature for 20 minutes. Then, 0.5 - of a 1N aqueous solution of IJ (hydroxide) was added to the reaction solution, and the mixture was allowed to react at room temperature for 30 minutes. An ion exchange resin (sulfonic acid-H+ type) is added to the reaction solution to make it weakly acidic. The resin is filtered off, washed with methanol, and the filtrate and washings are combined and dried under reduced pressure. The residue was treated with reverse phase medium pressure column chromatography (ODS column) (eluting with water/methanol (6/4)) and then
Recrystallization from ethanol-n-hexane gave the title compound 120 as a pale yellow powder.

M, P, 226-229℃ (decomposition) SIMSm M
H" 569 IRνKBrcm-': 33B5, 1735,
1655, 1620, 1600°ax 1510, 1240, 1220, 1160, 1
105, 1070°1030.

'H-NMRδ: 400 MHz (DMSO-d
, )0.88 (t) 2O-CH2
C di1.30 (t) 7-CH2C di1.78-1.95 (m) 2O-CH2C
H3ro-07~3-47 (m) 7-CH2C
H3+ 2'-H, 3'-H.

4'-H 3,76 (d) 5'-H 5,11-5.25 (br-s) C) lcA,
-0H5,21(d) 1 jin H
(Jl<2z=7-33Hz)5.30 (s
) 5-CH2-5,43(S) 17-
CH2-, GlcA, -0H6,50(s) 2
O-OH 7,29(s) 14-H 7,60(dXd) 1l-H7,73(d)
9-H 8,11(d) 12-H Example 11 7-Nitylcamptothecin-10-yl β-D-glucopyranoside P uronic acid P sodium salt 7-Ethylcamptothecin-10-yl β-D-glucopyranoside uronic acid Dissolve P13° in 5 d of distilled water, and add 20 d of sodium bicarbonate to make a homogeneous solution. After filtering and lyophilizing, Kashihara's compound 1
34 was obtained as a yellow powder.

IR'Ding x i': 3370 + 1735 +
1655 T 1600 + 1510 +1400.
1240.1215.1160.1105.1050
.

1H-NMRδ: 400 MHz (D20 + 1N
HCt) 1, ol (also) 2O-CH2C 曵1.11 (t) 7-CH2C insect 1.
81-2.01 (m) 2O-CH2CH.

2.49 (dXq) 7-CH(H)C
H52,72(dXq) 7-CH(H)CH.

3.612-3-82 (m) 2'-H
,3'-H,4'-H3,97(d) 5-
CH(H)-4,10(a) 5'-E(4
,34(d) ,5-CH(circumflexive)-5,10(
d) 1 F ((, T, /, 2/=7.3
3H2) 5.26 (d) 17-
CH(H)-5,33(d) 17-CH(H
)-6', 80 (S) L4-H
6,87(S) 9-H,1l-H6,98
(s) 12-H Example 12 7-ethylcamptothecin-10-yl 3', 4', 6
'-) Lee O-acetyl-2'-deoxy-2'-trifluoroacetami-P-β-D-glucopyranosyl 7-ethyl-10-hydroxycamptothecin 1.9
After dissolving 6 g in 125 d of 0.1N aqueous potassium hydroxide solution, 4.64. A solution of 9 in 100 parts of acetone was added, and the mixture was allowed to react at room temperature for 2 hours. After filtering off the yellow substance that precipitated during the reaction and washing with filtrate acetone,
The filtrate and washing liquids are combined and the acetate is distilled off under reduced pressure at low temperature.

Add chloroform and 0.0% to the resulting aqueous solution. Add IN hydrochloric acid and shake. The chloroform layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The concentrate was subjected to medium pressure silica gel column chromatography (chloroform, then chloroform/methanol (Ioo15
) Collect the fractions containing the target product and dry them.

The residue was further subjected to silica gel column chromatography (eluting with chloroform/ether (I/1) then chloroform/methanol (I0/1)) and then recrystallized from chloroform-n-hexane to yield the title compound. 80■ was obtained as a colorless to pale yellow crystalline powder.

M, P, 148-151℃ (decomposition) SIMS: M
H+776 IRνKBrcm-': 3415, 2970,
1745, 1650, 1695°ax 1560, 1505, 1370, 1225, 1
155, 1070.

1030゜'H-NMRδ: 400 MHz (CDCl2)0
．． 96 (t) 20-C'H2C di1
．． 32 (t) 7-CH2C di1.7
9-1.93 (m) 2O-CHCH32,
10=2.11.2-12 (sX3) 3', 4
',6'-0COCH32-93(dXq) 7-
CH(H)CH33,08(dxq) 7-CH(
H) CH34,04(aXdXd)5'-H4,25(dXd)6'-CH(H)-4,33
(br) 2O-OH 4,37(axa) 6'-CH(H)-4,49
(dXdXd)2'-1(4,88(d) 5-CH(H)-5,04(d
) 5-CH(H)-5,26(dXd)
4'-H 5,27(d) 17-CH(H)-5,45(
d) 1'-H 5,47(dXd) 3'-H 5,71(d) 17-CH(dan)-7,35(
axa) 1l-E( 7,49(d) 9-H 7,63(br) 2'-NHCOC!F37.6
5 (s) 14-H8,08(
a) 12-H Example 13 7-nitylcamptothecin/-10-yl 2'-deoxy-2'-trifluoroacetamiP-β-D-glucopyranosyl 7-nitylcamptothecin-10-yl 3',4 ', 6
'-) So0-acetyl-2'-deoxy-2'-trifluoroacetamide-β-D-glucopyranosy P65
Dissolve (1) in 5 d of anhydrous methanol, add 0.1 d of 28% sodium methoxy P-methanol solution to this,
Let react for 30 minutes at room temperature. Ion exchange resin (
Add sulfonic acid (H+ type) to make the liquid weakly acidic.

After filtering off the resin and washing with methanol, combine the filtrate and washing liquid.
Dry under reduced pressure. The residue was crystallized from ethanol-n-hexane to give the title compound 50rI9 as a pale yellow powder.

M, P, 204-206℃ (decomposition) SIMS:
MH650 XRW"cm-': 53B0, 2965,
1730, 1710, 1655°ax 1625.1590.1560.1510.1215.
1185.

1160.1070.

'H-NMRδ: 400 MHz (DMSO-
d, )0.88 (t) 2O-CH2
C 1.30 (t) 7-CH2C 1.78-1.95 (m) 2O-CH2C
E(35,11~5.25 (m) 7-CH,
C) H33,24~3.33 (m) 4'-
H3,43~3.62 (m) 3'-H,5'
-f(,6'-CH(H)-3,78~3.85 (m
) 6'-CH(H)-3,86-3.95 (
m) 2'-H4,80(dXd) 6'-
0E(5,26(d) 1'-H(J, z, 2z=
=8.43Hz)'31 (a) s'
-oH or 4'-0H5,32(s) 5-C
H2- 5,42(s) 17-CH2-5・43
(cl) 3'-oH or 4'-0H6,
49(s) 2o-oH 7.29(s) 14-H7,48(
dXd) 1l-H 7,70(d) 9-H 8,13(d) 12-H 9,37(d) 2'-NFICOCF3 Example 14 7-Nitylcamphtothecin-10-yl 2'-amino-
2'-deoxy-β-D-glucopyranosylhyP-lochloride 7-ethylcamphtothecin-10-yl 2'-deoxy-27-dolifluoroacetamido β-D-glucopyranosyl y4owe was added to 4 ml of water, and 0. 1
Add 1.85% of N aqueous sodium hydroxide solution,
．． Allow to react for 5 hours. After cooling the reaction solution with water, add 0.1N to it.
After acidification by addition of hydrochloric acid 3-, it was subjected to medium pressure reverse phase column chromatography (ODS column) (eluting with water/methanol (773, then 1/1)) and then crystallized from ethanol-n-hexane. The title compound 24■
was obtained as a pale yellow powder.

M, P, 223-226℃ (decomposition) SIMS: M
H" 554 IRν grandchild': 3365, 2970, 29
30, 1730, 1650°1620, 1585
, 1565 , 1510 , 1230 , 1215
.

1160, 1075.

'H-NMRδ: 400 MHz (DMSO-d,
)0.88 (t) 2O-CH2C
1.32 (t) 7-CE (2C 1.78-1.96 (m) 2O-CH2CH3
2,86(t-1ike) 2'-H3-18(q)
7-ca2ca33.22~3j8 (m)
3'-H, 4'-H3, 46-3.79 (m
) 5'-H, 6'-CH(H)-3,73-3
．． 83 (m) 6'-CH(!ri-4,71(
dXd) 6'-0H 5,11(d) 1'-H(J,!,2/
=8.06Hz)5.15~5.22 (br)
3'-OR or 4'-0) H5,24-5.5
4 (br) 3'-OH or 4l-OH
,2LNH2,HCj! 5.31 (s)
5-CH2-5,43(s) 17-C
H2-6,50' (s) 2O-
OH7,29(s) 14-H 7,62(axa) 1l-H 7,78(d) 9-H 8,12(d) 12-H Example 15 Camptothecin-10-ylc 3',4/, 6/-tetra-0-acetyl-β-D-glucopyranoside 10-
HiP Roxica/Ptothecin 900 H9 in 0.1N potassium hydroxide aqueous solution 6811! I! After dissolving in 2
, 3,4.6-tetra-0-acetyl-α-D-glucozeranosyl bromide 2.249 d solution in acetone is added and reacted at room temperature for 2 hours. After filtering off the yellow substance precipitated during the reaction, acetone is distilled off under reduced pressure at low temperature. Chloroform and 0.1N hydrochloric acid are added to the resulting aqueous solution and shaken. The chloroform layer is separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure.

The concentrate was subjected to medium pressure silica gel column chromatography (elution with chloroform and then chloroform/methanol (too/4)), followed by chloroform-n
-Crystallization from hexane gave the title compound 75 da as a colored powder.

M, P, 268-269℃ (decomposition) 8lMS, MH
695 IRy item an-': 3410, 2955, 1
745, 1740, 1655°1600.1500
．． 1575.1360.1255.1150.

1075.1050.

'H-NMRδ+, 400 MHz (CDC1s
)1.04 (t) 20-CF(2CH
31.83~1.97 (m) 2O-C
H, CH32,07,2,08,2-10 (5X3)
2', 3', 4', 6LOCOCH3(
2-08×2) 3.79 (s)
2O-OH3,98(dXdXd) 5'-H
4,23(dXd) 6'-CH(H)-4,3
4(dXd) 6'-CH(H)-5,20-5
．． 43 (m) 5-CH2-, 17-C
See (H)-.

1'-E(, 2 Otsu H, 3'-H, 4'-H5, 74(d
) 17-CH(I()-7,40(d)
9-H 7,52(dXd) 1l-H 7.64(s) 14-H 8,18(d) 12-H 8,27(s) 7-H Example 16 Camptothecin-10-yl β-D - Glucopyranosi P camptothecin-10-yl 2', 3', 4',
50 mg of 6'-tetra-0-acetyl-β-D-glucopyranoside is suspended in 20 ml of anhydrous methanol, 0.1 g of a 28% sodium methoxide-methanol solution is added thereto, and the mixture is allowed to react at room temperature for 30 minutes.

Add an ion exchange resin (sulfonic acid-pi type) to the reaction solution to make the liquid weakly acidic. The resin is filtered off, washed with methanol, and the filtrate and washings are combined and dried under reduced pressure. The residue was recrystallized from ethanol to obtain the title compound 33■ as colorless to pale yellow needles.

M, P, 214-216℃ (decomposition) SIMS: M
H527ERνHr crn'': 3400, 1730
, 1650 , 1620 , 1585°1240.10
75.1040.

'H-NMRδ: 400 MHz (DMSO-
d,)0.88 (t)2O-CH
2Cmu L78~1.98 (m) 2O-C
H2CH33,18~3.28 (m) 4
'-H3,30~3.39 (m) 2'-
H,3'-H3,42~3.58 (m)
5'-H,6'-CH(H)-3,69-3.81
(m) 6'-CH(H) -4,60(d
Xd) 6'-0H5,07(d)
4'-OH5, 12(d) 1'-H(J1/
, 2/ = 6.96Hz) 5.14 (d)
2'-OH or 3'-0H5-28(s)
5-CH2-5,42(8)
17-CH2-,2'-○Hf or 3'-0H6,50
(s) 2O-OF(7,30(s)
14-H 7,59(dXd) 1l-H 7,65(d) 9-H 8,11(d) 12-H 8,55(s) 7-H The present invention provides a novel compound with higher activity than camptothecin. The compounds provided by the present invention, or their salts, have excellent antitumor activity as described below, and can be considered for use as anticancer agents.

The antitumor activity of the above-mentioned compounds provided by the present invention can be determined by
This is illustrated by the experimental example described below.

Experimental Example 1 Antitumor effect on murine leukemia L1210 Experimental method 5 x 105 murine leukemia L1210 were intraperitoneally transplanted into 7-week-old (body weight 17-191) female CDF mice (group I, 6 mice), and 1 day after transplantation. The test substance was administered intraperitoneally on days 5 and 9, and its survival prolonging effect was observed.

The test substance was dissolved in physiological saline or administered in its entirety. The total dosage was as shown in Table 1.

The antitumor effect was expressed as the value (T/C%) obtained by multiplying the ratio of the average survival days (T) of the drug-administered group to the average survival days (C) of the non-drug-administered group by 100 under the above experimental conditions.

Experimental results 7-ethylcamptothecin-10-yl 21.3/, a/; 61-tetra-0-acetyl-β-D-glucopyranosyl (compound 1) and 7-ethylcamptothecin-10- Table 1 shows the results of an antitumor effect test on yl β-D-glucopyranosyl (Compound 2). In addition, as a comparison, the antitumor effect of 7-nitylcamptothecin sodium salt (compound 3) was shown.

Table 1 Compound 1 25 124 Compound 2
12.5 114 compound 3
12.5 124 As seen in the experimental results described above, the novel glycoside derivatives of camptothecin provided by the present invention exhibit excellent antitumor activity against tumors in experimental animals.

Furthermore, among the new glycosylated r derivatives of camptothecin obtained by the present invention, the compound in which the protective group in the sugar moiety has been removed has superior water solubility compared to camptothecin, 7-lower alkylcamptothecin, and their hyP-roxy-substituted derivatives. have.

The compounds provided by the present invention or their salts have excellent antitumor activity and excellent water solubility, and can be used as anti-malignant tumor therapeutic agents.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 represents a hydrogen atom or an alkyl group of C_1_-_4, and R^2 The -COOH or -OH group that is an aldose residue or exists in the group is a lower aliphatic acyl group having 1 to 2 carbon atoms in the alkyl group, a benzoyl group, a trifluoroacetyl group, or an alkyl group. It represents an aldose residue protected by a lower alkyl ester group having 1 to 2 carbon atoms or a combination thereof, and in the formula, the bond between R^2 and camptothecin is between the oxygen atom on the A ring of camptothecin and the 1st position of the sugar. A camptothecin derivative or a salt thereof, which represents a glycosidic bond with a carbon atom.