JPH04312593A - Novel platinum complex and anti-tumor agent using same - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a novel L-xylopyranoside platinum complex having antitumor activity, and also to an antitumor agent containing the platinum complex as an active ingredient.

0002

BACKGROUND OF THE INVENTION It is already known that certain platinum complexes have antitumor effects. Examples of platinum complexes having antitumor activity are JP-A-60-87295 and JP-A-61-2.
No. 63991, Japanese Patent Application Laid-open No. 62-246588,
JP-A-62-190192, JP-A-62-246
No. 543, JP-A-63-17894, “Journal of Pharmaceutical Science (Jou
rnalof Pharmaceutical Sci
ences)” Volume 65, No. 3, 315-328
(1976), Journal of Inorganic Biochemistry.
Organic Biochemistry)” No. 11
Vol., pp. 139-149 (1979). Among these platinum complexes, cis-dichlorodiamine platinum [generic name: cisplatin (CDDP)] has already been developed using the following formula:

It has the structure [Chemical 3], has excellent anticancer effects, and is currently widely used in clinical practice.

0003

[Problems to be Solved by the Invention] The above-mentioned CDDP exhibits excellent medicinal efficacy particularly against malignant tumors of the urinary tract and reproductive organs. Then, CDD is administered to patients who develop such malignant tumors.
Since administration of P can restore patients to remission,
It is a useful antitumor agent. However, CDDP has the drawback of being highly toxic.

[0004] Similarly to the novel L-xylopyranoside platinum complex of the present invention, platinum complexes are known that are considered to be platinum complexes of L-xylopyranoside and have a chemical structure similar to the novel compound of the present invention. (Unexamined Japanese Patent Publication No. 2-
223591 and JP-A-2-134395). However, the L-xylopyranoside platinum complexes described in these publications do not necessarily exhibit a satisfactory antitumor effect against cisplatin-resistant murine leukemia cells L-1210, as shown in the test examples below.

In view of these circumstances, the object of the present invention is to provide a novel platinum complex that can exhibit high antitumor activity even on cisplatin-resistant murine leukemia cells L-1210 and has low toxicity. It is.

[0006]

[Means for Solving the Problems] The present inventors have conducted extensive research in order to find a platinum complex that has superior antitumor activity and is less toxic. As a result, a novel platinum complex having L-xylopyranoside as an amine component bonded to a platinum atom and having a specific type of substituent group selected as another ligand was obtained, which is represented by the general formula (I) below. succeeded in synthesizing. And this general formula (I
) The novel platinum complex represented by ) has an excellent antitumor effect, which is equivalent to or better than CDDP, especially against mouse leukemia tumor cells L-1210.
It was found that its acute toxicity is extremely low. Based on these findings, we have completed the present invention.

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

[Image Omitted] An L-xylopyranoside platinum complex represented by the formula (wherein R represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aralkyl group) is provided.

In the platinum complex of general formula (I), when R is an alkyl group, it can be an alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, butyl group, etc. It can be a lower alkyl group having 1 to 6 carbon atoms, and is preferably a middle alkyl group having 7 to 10 carbon atoms. When R is a cycloalkyl group, it may have 3 to 6 carbon atoms, such as a cyclopentyl group or a cyclohexyl group. When R is an aralkyl group, it can be a phenyl-(lower)alkyl group, such as a benzyl group or a phenethyl group.

According to the second invention, the following general formula

[
There is provided an antitumor agent containing as an active ingredient: (wherein R represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aralkyl group).

Among the platinum complex compounds of the present invention represented by the above general formula (I), representative examples of compounds are listed in Table 1 below. However, the present invention is not limited to these examples.

[0011]

[Table 1]

The physical properties of a considerable number of the compounds shown in Table 1 are shown in Examples 1 to 5 below, but almost all of the compounds whose physical properties are not shown in the Examples have a melting point of 250. It was higher than ℃.

[0013] Furthermore, compound No. 1 in Table 1 is also referred to in the Examples and Test Examples below.

Among the platinum complexes (I) of the present invention, Compound No. 1 in Table 1 Four compounds, 1, 3, 4 and 10, are particularly preferred.

The novel platinum complex (I) of the present invention can be used to treat malignant tumors in humans or various animals for which cisplatin is clinically used for treatment, such as testicular tumors, bladder cancers, renal pelvis tumors, urethral tumors, prostate cancers, and ovarian tumors. It has anti-tumor activity, acting as an anti-tumor agent against cancer. It is also expected to be effective in treating head and neck cancer, esophageal cancer, lung cancer, stomach cancer, uterine cancer, and kidney cancer.

Furthermore, the platinum complex (I) of the present invention, like cisplatin, can be used to treat mouse Ehrlich carcinoma, B16 melanoma, P388 leukemia, Sarcoma 180, and CDF1.
Shows anti-tumor activity against breast cancer, Colon Tumore 26 tumor cells.

Next, a method for producing the compound of the present invention will be explained.

The platinum complex of general formula (I) according to the invention is:
For example, it is produced according to the reaction formula below.

(Reaction formula A)

embedded image (wherein, M is a hydrogen atom or an atom that can be a monovalent cation, R is the same as above, and Hal represents a halogen atom, ie, a chlorine, bromine, iodine, or fluorine atom).

In the above reaction scheme A, an aqueous solution of a halogenated monoplatinate of the formula (III), preferably a potassium halogenide platinate, is added to an amino sugar of the formula (II), ie, 3,4-diamino-3 , 4-dideoxy-L-xylopyranose or its derivatives in ethanol, and if the resulting mixture is a heterogeneous solution, add ethanol or water to it to make it a homogeneous solution and react. Platinum complex (IV) can be easily produced.

The amount of the halogenated platinum salt to be used is 1 to 2 times the molar amount of the raw material amino sugar (II). The order of addition may be reversed to the above. This reaction is carried out at room temperature in the dark, and is usually completed in 1 to 7 days, but from 40°C to
By heating to 70°C, the reaction time can be shortened to 1 to 24 hours. Normally, the desired product gradually precipitates from a homogeneous and transparent solution, but if this is collected by filtration, washed with water, ethanol, and ether, and recrystallized with hot water and dimethylformamide as necessary, A platinum complex compound of formula (IV) can be obtained.

(Reaction formula B)

[C7]

Dihalogenoplatinum complex prepared according to reaction formula A (
By reacting IV) with silver nitrate, a platinum complex compound of formula (V) can be produced. This reaction is usually carried out in an aqueous solution at room temperature for 1 to 3 days. The amount of silver nitrate used is the same as that of the compound (IV
) is preferably 1.5 to 2.5 times in mole. After the reaction is complete, excess silver nitrate is precipitated as silver chloride by adding potassium chloride aqueous solution to the reaction solution, and after suction filtration, the filtrate is centrifuged and the supernatant is freeze-dried to form a powder with the formula (V).
A nitrato-type platinum complex compound is obtained. Further, in some cases, compound (V) can be used in the following Reaction Formula C without being isolated.

(Reaction formula C)

[Chemical formula 8]

Next, the nitrato compound (V
) can be reacted with glycolic acid to produce the platinum complex compound of formula (I), which is included in the present invention. In this reaction, glycolic acid is added to an aqueous solution of the nitratoform (V), and the pH is maintained at neutrality with a suitable base, such as an alkali hydroxide, at a temperature of 0 to 100°C, preferably 0°C to room temperature. You can do it for 3 days. The amount of glycolic acid used as a reactant is 0.5 to 2.0 moles, preferably equimolar, to the nitrato compound of formula (V). After completion of the reaction, the reaction solution is concentrated, and the precipitated crystals are collected by filtration, washed successively with acetone and ether, and dried under vacuum to obtain the compound of the present invention of formula (I).

The platinum complex of general formula (I) according to the invention is:
The complex structure was confirmed by elemental analysis, infrared absorption spectrum, secondary ion mass spectrometry (SIMS), etc.

The amino sugar of formula (II), that is, 3,4-diamino-3,4-dideoxy-L-xylopyranose or a derivative thereof, which is the starting material for producing the platinum complex of the present invention, is a new compound; It can be synthesized using the reaction formula shown below.

[0028]

[Chemical formula 9] (In the formula, R shows the same thing as above).

That is, first, Japanese Patent Application Laid-Open No. 18129/1983
According to the method described in Publication No. 0, an epoxide compound of formula (VII) is obtained in 6 steps using a sugar compound of formula (VI) as a starting material. This compound is then ammonolyzed to form the formula (VI
A novel amino sugar of formula (II) is obtained, which is further reduced with hydrogen or sodium hydrosulfite to form formula (II)
New diamino sugars can be produced.

[0030] The diamino sugar compound (II'') in which R is a hydrogen atom in the formula (II) is a reaction formula when R is a benzyl group in the following formula (II'), as shown in the reaction formula below. It can be produced by reducing the compound.

[0031]

[Chemical formula 10]

[0032] Production examples of the amino sugar of formula (II) are shown in Reference Production Examples 1 to 5.

Next, an example of producing a platinum complex of general formula (I) according to the present invention will be shown, but the present invention is not limited to the following example.

Example 1 Preparation of glycolate (3,4-diamino-3,4-dideoxy-L-xylopyranose)platinum (compound No. 1) Dichloro(3,4-diamino-3,4-dideoxy-L)
-xylopyranose) platinum (manufactured in Reference Production Example 6 below according to the method described in JP-A-2-223591) was dissolved in 60 ml of water, and 2.5 g (14 mmol) of silver nitrate was dissolved in 60 ml of water. After stirring for 3 days at room temperature in the dark, the precipitated silver chloride was removed by filtration, and 1 ml of 0.5% potassium chloride aqueous solution was added to the filtrate to precipitate excess silver nitrate as silver chloride. Ta. This was centrifuged (190,000 x g, 90 minutes), and the supernatant was lyophilized to give the title compound as a pale yellow crystalline powder.
．． 2 g (yield 96%) was obtained. The physical properties of this material are
It is as shown below.

m. p. >250℃ IR: νKBrmax 3400-3100, 1590
, 1360, 1040, 820 cm-1

Next, 3.2 g (6.9 mmol) of this nitrato compound was added to 60 g of water.
ml, 0.52 g (6.9 mmol) of glycolic acid and 10 ml of 1N sodium hydroxide were added, and the mixture was stirred at room temperature for 2 days. After the reaction, the reaction solution was concentrated to about 10 ml, 500 ml of acetone was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to give 2.1 g of the title compound (yield: 72
%) was obtained. The physical properties of this material are as shown below.

m. p. >250℃ IR: νKBrmax 1630cm-1 SI
MS: (M+H)+=418

Example 2 Glycolato (ethyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside) platinum (compound No.
Production of 3) 1.3 g (2.9 mmol) of dichloro(ethyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside)platinum (produced in Reference Production Example 7 below), 0 silver nitrate
．． A mixture of 99 g (5.8 mmol) and 130 ml of water was stirred in the dark at room temperature for 24 hours. The reaction solution was filtered, and the precipitate on the filter was washed with water. The filtrate and washing solution were combined, and a solution of 0.22 g (2.9 mmol) of glycolic acid dissolved in 5 ml of water and neutralized to pH 7 with 30% NaOH was added, and the mixture was stirred overnight at room temperature in the dark. After concentrating the reaction solution, the residue was dissolved in 10 ml of water, 100 ml of acetone was added, and the mixture was cooled on ice for 3 hours. Filter the precipitated pale yellow crystals,
Washing with acetone and ether and drying yielded 0.0% of the title compound.
7 g (yield 55%) was obtained.

m. p. >250℃ IR: νKBrmax 1620cm-1 SI
MS: (M+H)+=446

Example 3 Glycolate (n-propyl 3,4-diamino-
Production of 3,4-dideoxy-L-xylopyranoside) platinum (Compound No. 4) Dichloro(n-propyl 3,4-diamino-3,4-diamino-3,4-dideoxy-L-xylopyranoside) platinum (produced in Reference Production Example 8 below) ) obtained by the same operation as in Example 1 [formula (V), R=-(CH2)2CH3] 3.0
Dissolve g in 60 ml of water, add 0.47 g of glycolic acid, 1
Add 10ml of N-sodium hydroxide and raise the bath temperature to 60-7.
Heated at 0°C for 5 hours. After air cooling, the reaction mixture was heated to about 10 m
500 ml of acetone was added, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 1.8 g (yield 63%) of the title compound as pale yellowish brown powder crystals.

m. p. 210-215℃ (decomposition) I
R: νKBrmax 1620cm-1 SIM
S: (M+H)+=460

Example 4 Preparation of glycolate (cyclopentyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside)platinum (compound No. 8) Dichloro(cyclopentyl 3,4-diamino-3,4-dideoxy-L) -2.0 g of xylopyranoside platinum (produced in Reference Production Example 9 below), 1.4 g of silver nitrate, 200 m of water
The mixture was stirred in the dark at room temperature for 24 hours. The reaction solution was filtered, and the precipitate on the filter was washed with water. 10 ml of an aqueous solution of glycolic acid (0.31 g) was added to the mixture of the filtrate and washing solution, and the pH was adjusted with 1N sodium hydroxide.
The solution neutralized to 7 was stirred at room temperature in the dark overnight. After concentrating the reaction solution, dissolve the residue in 20 ml of water and add 200 ml of acetone.
ml was added and cooled on ice for 3 hours. The precipitated pale yellow crystals were collected by filtration, washed with acetone and ether, and dried to obtain 1.2 g (yield: 61%) of the title compound.

m. p. >250℃ IR: νKBrmax 1630cm-1 SI
MS: (M+H)+=486

Example 5 Glycolate (benzyl 3,4-diamino-3,
Production of 4-dideoxy-L-xylopyranoside) platinum (compound No. 10) Dinitrato(benzyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside) platinum (JP-A-2-1343
0.65 g (yield: 72%) of the title compound was obtained from 1.0 g of the compound (manufactured according to the method described in Japanese Patent No. 95) in the same manner as in Example 3. m. p. >250℃ IR: νKBrmax 1625cm-1 SI
MS: (M+H)+=508

Next, the preparation of the novel amino sugar compound of formula (II) used in the production of the compound of the present invention will be illustrated.

Reference Production Example 1 Production of benzyl 3-amino-4-azido-3,4-dideoxy-L-xylopyranoside [formula (VIII), R=benzyl group]
6 of the epoxide compound [formula (VII), R=benzyl group] produced by the method described in Publication No. 2-181290
．． 0 g was dissolved in 30 ml of methanol saturated with ammonia and heated at 130 to 140° C. for 5 hours in a sealed tube. After cooling to room temperature, the reaction solution was distilled off under reduced pressure to obtain 5.9 g of a reddish brown oily residue. This residue was purified by silica gel column chromatography using chloroform-methanol (30:1) as a developing solvent to obtain a yellow oil.
This was crystallized from n-hexane to obtain 2.7 g (yield: 42%) of the title compound, an amino sugar, as colorless crystals. The physical properties of this material are as shown below.

m. p. 61-64℃ [α] 25D
-117.6° (c=1.0, CH3OH) High pressure electrophoresis: Mobility 0.93 (ninhydrin coloring, alanine 1.0) Apicel SF-1020 Apparatus: Savant LT-48A Electrolyte: Formic acid Acetic acid-water (25:75:900 solution, pH 1.8)
Pressure: 3000V, time 15 minutes IR: νKBrmax 3325, 3250, 30
50, 2900, 2100, 1590, 145
0, 1350, 1250, 1125, 1095, 1060, 1020, 96
5, 930, 750, 730, 690 cm-1 NMR (100MHZ, CDCl3): δ
2.05, 2.78-3.72, 4.41-4.90
, 7.33

Reference Production Example 2 Benzyl 3,4-diamino-3,4-dideoxy-
L-xylopyranoside [formula (II), R=benzyl group]
Production of the amino sugar obtained in reference production example 1 [formula (VIII),
4.0 g of R=benzyl group] is dissolved in 480 ml of dioxane and 480 ml of triethylamine, and 400 mg of 10% palladium-carbon is added in a nitrogen stream. Hydrogen was introduced into the solution for 35 minutes while stirring at room temperature, and the mixture was further stirred for 3 hours. After the reaction was completed, the catalyst was removed by suction filtration, and the filtrate was distilled off under reduced pressure to obtain 4.1 g of a yellow solid. This solid substance was dissolved in 200 ml of distilled water, and after adjusting the pH to 7 with 1N hydrochloric acid, Amberlite CG-50, ammonia type: H
Pass it through a 300ml mold (7:3) and let it adsorb. distilled water 1
After washing with 2.8 liters of 0.1N ammonia water, it was eluted with 2.8 liters of 0.1N aqueous ammonia, and detected by high-pressure electrophoresis and thin layer chromatography [developing solvent: methyl acetate/isopropyl alcohol/aqueous ammonia (45/105/60)] (ninhydrin The product was collected under reduced pressure, concentrated under reduced pressure, and then lyophilized to obtain 3.5 g of colorless powder. By crystallizing this from methanol/ether, 3.1 g (yield: 87%) of the title compound, amino sugar, was obtained as colorless crystals. The physical properties of this material are as shown below.

m. p. 142-144℃ [α] 25
D -158.6° (c=1.0, CH3OH) high pressure electrophoresis: mobility 1.53 (ninhydrin coloring, alanine 1.0) IR: νKBrmax 3370,
3325, 3275, 3050, 2900, 2
705, 1580, 1340, 1130, 108
5, 1020, 930, 830, 760, 73
0, 690cm-1 NMR (100MHZ,
CD3OD): δ 2.44-2.91, 3.24
~3.56, 4.44~4.83, 7.36

00
50 Reference Production Example 3 3,4-diamino-3,4-dideoxy-L-xylopyranose [Compound (II), R=H
Production of benzyl 3,4- obtained in Reference Production Example 2
1.2 g of diamino-3,4-dideoxy-L-xylopyranoside was dissolved in 6 ml of acetic acid and 30 ml of water, and 0.6 g of 10% palladium-carbonate was dissolved in 30 ml of water in a nitrogen stream.
Suspend and add to l. This solution is heated to 50-60°C, hydrogen is introduced for 105 minutes with stirring, and then stirred for an additional 2 hours at 50-60°C. After the reaction is completed, the catalyst is removed by suction filtration and washed with water.
After neutralizing 70ml with 10% sodium hydroxide, Amberlite CG-50, ammonia type: H type (7:3) 10
Pass through 0 ml and allow to adsorb. After washing with 1 liter of distilled water, 0.
Elution was carried out with 700 ml of 1N ammonia water, followed by high-pressure electrophoresis and thin layer chromatography [Developing solvent: methyl acetate/isopropyl alcohol/aqueous ammonia (45:1
The product is collected under detection (ninhydrin and iodine coloration), concentrated under reduced pressure, and lyophilized to give 0.75 g (100% yield) of the title compound as a pale yellow oil. The physical properties of this material are as follows.

[α]24D -10.7° (c=1.0
, H2O) high-pressure electrophoresis (Avicel SF-1020)
:Mobility (alanine: 1.0) 2.37 (ninhydrin coloring) Equipment: Savant LT-48A electrolyte:
Formic acid-acetic acid-water (25:75:900 solution, pH 1.8
) Voltage: 3000V Time: 15 minutes TLC: Rf
=0.29 Adsorption plate: Silica gel 60F254 Developer: Methyl acetate/isopropyl alcohol/aqueous ammonia (45:105:60) Coloring agent: Ninhydrin and iodine IR: νNaClmax 3250-2850,
1595-1480, 1405-1360, 10
45-940cm-1 NMR (DMSO-d6
): δ 2.26-2.54, 2.84-3.16,
3.38, 3.52-3.76

The 3,4-diamino-3,4-dideoxy-L-xylopyranose obtained in Reference Production Example 3 above is expressed by the following formula shown above.

[Chemical formula 11] It is indicated by.

Reference Production Example 4 Production of ethyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside [Compound (II), R=ethyl group] JP-A-62-18
Ethyl produced according to the method described in Publication No. 1290
2,3-anhydro-4-azido-4-deoxy-L-
6. of ribopyranoside [formula (VII), R=ethyl group].
0 g was dissolved in 60 ml of ammonia-saturated methanol and heated in a sealed tube at 130-140° C. for 5 hours. After cooling to room temperature, the reaction solution was distilled off under reduced pressure to obtain 6.4 g of a reddish brown oily residue. This residue was purified by silica gel column chromatography using chloroform-methanol (30:1) as a developing solvent to obtain ethyl 3-amino-4-azido-3,4-dideoxy-L-xylopyranoside [formula ( VIII), R = ethyl group] was obtained (2.2 g (yield 33%)). Next, add this to 240 ml of dioxane and 240 ml of triethylamine.
10% palladium-carbon2 in a nitrogen stream
Add 00mg. Hydrogen was introduced into the solution for 35 minutes while stirring at room temperature, and the mixture was further stirred for 3 hours. After the reaction was completed, the catalyst was removed by suction filtration, and the filtrate was distilled off under reduced pressure to obtain 1.5 g of a yellow solid. By crystallizing this from methanol/ether, the title compound, ethyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside [compound (II), R=
ethyl group] was obtained (1.3 g (yield 70%)). The physical properties of this material are as shown below.

m. p. 179-183℃ [α] 26
D -158.7° (c=1.0, CH3OH)

Reference Production Example 5 Cyclopentyl 3,4-
Production of diamino-3,4-dideoxy-L-xylopyranoside [Compound (II), R = cyclopentyl group]
Cyclopentyl 2,3-anhydro-4-azido-4-deoxy-L-ribopyranoside [formula (VII
), R = cyclopentyl group] was dissolved in 140 ml of methanol saturated with ammonia, and in a sealed tube,
It was heated at 130-150°C for 5 hours. After cooling to room temperature,
The reaction solution was distilled off under reduced pressure to obtain 7.3 g of a reddish brown oily residue. This residue was purified by silica gel column chromatography using chloroform-methanol (20:1) as a developing solvent to obtain cyclopentyl 3-amino-4-azido-3,4-dideoxy-L as a yellow oil.
2.5 g (yield: 32%) of -xylopyranoside [formula (VIII), R = cyclopentyl group] was obtained. Next, mix this with 250 ml of dioxane and 25 ml of triethylamine.
0 ml and add 250 mg of 10% palladium-carbon in a nitrogen stream. Hydrogen was introduced into the solution for 60 minutes while stirring at room temperature, and the mixture was further stirred for 3 hours. After the reaction was completed, the catalyst was removed by suction filtration, and the filtrate was distilled off under reduced pressure to obtain 2.0 g of a yellowish brown solid. By crystallizing this from methanol/ether, 1. 6g (yield 7
1%). The physical properties of this material are as shown below.

m. p. 68-70℃ [α] 26D
-152.9° (c=0.17, CH3OH)

Reference Production Example 6 Production of dichloro(3,4-diamino-3,4-dideoxy-L-xylopyranose)platinum 3,4-diamino-3 obtained in Reference Production Example 3
, 4-dideoxy-L-xylopyranose [formula (II)
, R=H] in 15 m of water.
Platinum potassium chloride (K2PtC
l4) Add an aqueous solution of 1.4 g (3.4 mmol) dissolved in 15 ml of water, and stir for 2 days at room temperature in the dark. A trace amount of precipitate is removed by filtration, and the filtrate is freeze-dried to obtain 1.7 g of a light brown powder. Dissolve this powder in 15 ml of water, add 125 ml of ethanol, cool on ice, and remove the brown precipitate by filtration. The filtrate was concentrated and then lyophilized to give 1.34 g of crystals of the title compound as a pale yellow crystal powder (
yield of 90%). The physical properties of this material are as shown below.

TLC: Rf=0.37 Adsorption plate: Avicel SF developer: Butanol/acetic acid/water (5:2:3
) Color former: 5% stannous chloride/0.1N hydrochloric acid m. p.
>250°C [Starts discoloration at 198°C and turns black (hygroscopic) at about 210°C] [α] 24D -14.5° (c=1.0
, H2O) IR: νKBrmax 3360-330
0, 3180-3100, 1590, 1050,
1035cm-1 SIMS: (M+H)+=4
15

Reference Production Example 7 Dichloro(ethyl 3
, 4-diamino-3,4-dideoxy-L-xylopyranoside) Production of platinum Ethyl obtained in Reference Production Example 4
2.4 g of 3,4-diamino-3,4-dideoxy-L-xylopyranoside [formula (II), R=C2H5] was dissolved in 126 ml of ethanol, and 5.7 g of potassium platinum chloride was dissolved in 118 ml of water. The mixture was stirred for 24 hours at room temperature in the dark. The precipitated yellow crystals were collected by filtration, washed with cold water, ethanol and ether, and 6.0 g of crude crystals were obtained.
I got it. This was dissolved in 20 ml of DMF and filtered, then 60 ml of methanol was added and cooled on ice. The precipitate was collected by filtration while washing with methanol, and dried under reduced pressure to give 5.4 g of the title compound as a yellow crystalline powder (yield: 89%). ) was obtained. The physical properties of this material are as follows.

m. p. >250℃IR: νKBrma
x 3350-2900, 1560, 1095,
1025, 920cm-1 SIMS: (M+
H)+=443

Reference Production Example 8 Dichloro(n
-propyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside) Production of platinum n-propyl 3,4-diamino-3,4-dideoxy-L-xylopyranoside [formula (II), R=(CH2) 2CH3m
．． p. 137-141℃ [α]26D -155
．． 4° (c=1.00, CH3OH)] was treated in the same manner as in Reference Production Example 7 to obtain 3.9 g (yield 91%) of the title compound as a pale yellow crystalline powder. The physical properties of this material are as follows. m. p. >25
0°C IR: νKBrmax 3380, 3250~3
100, 2900, 1560, 1340, 10
95, 1025, 935cm-1 SIMS: (M+
H)+=457

Reference Production Example 9 Dichloro(cyclopentyl
Production of platinum (3,4-diamino-3,4-dideoxy-L-xylopyranoside) Cyclopentyl obtained in Reference Production Example 5 3,4-diamino-3,4-dideoxy-
1.6 g of L-xylopyranoside [formula (II), R = cyclopentyl] was treated in the same manner as in Reference Production Example 7 to obtain 2.8 g (yield 98%) of the title compound as a yellow crystalline powder. The physical properties of this material are as follows.

m. p. >250℃IR: νKBrma
x 3350, 3150, 3100, 2900,
1560, 1090, 1030,, 925cm
-1

Furthermore, the second invention provides an antitumor agent containing the platinum complex of general formula (I) as an active ingredient and a pharmaceutically acceptable carrier.

In producing the antitumor agent of the present invention, the compound of general formula (I) of the present invention is used as an active ingredient, mixed with a pharmaceutically acceptable carrier, and
Furthermore, by adding auxiliary agents if necessary, various types of preparations can be prepared. For example, when the platinum complex of general formula (I) is orally administered, tablets, pills, granules,
It can be a solid preparation such as a powder or capsule, or a liquid preparation such as a solution, suspension, or emulsion. Furthermore, in the case of parenteral administration, it can be made into an injection or a suppository. In this case, the carrier is preferably lactose, starch, dextrin, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, etc. when preparing tablets, pills, granules, powders, and capsules. When preparing an injection, it is preferably dissolved in distilled water or a salt solution such as sodium chloride or potassium chloride, such as physiological saline. When used as a suppository, cacao butter, lauric fat, glycerogelatin, macrogol and the like are preferred. The content of the platinum complex of formula (I) in the preparation is preferably a unit amount convenient for use depending on the patient's age, symptoms, etc. The pharmaceutical dosage of the platinum complex of formula (I) is usually 400 to 800 mg/kg per day when administered orally for tumor treatment in adults, and when administered parenterally,
100-400 mg/kg per day is preferred.

Next, examples will be shown in which the platinum complex of formula (I) according to the present invention is used as an antitumor agent, but the present invention is not limited to the following examples.

Example 6 Injection Compound No. A physiological saline solution of the platinum complex No. 1 was aseptically dispensed into a vial to contain 300 mg of the platinum complex, and the solution was lyophilized to remove water to prepare a dry powder in the vial. During use, 100 ml of physiological saline is added to the vial to form an injection solution.

Example 7 Tablet Compound No. 50g of platinum complex from No.4, 96g of lactose, 27g of crystalline cellulose, 5g of corn starch, 2g of magnesium stearate
g of the mixture (total 180 g) is directly compressed into tablets, each 8 mm in diameter and 180 mg in weight.

When the platinum complex of the general formula (I) of the present invention is used as an antitumor agent, the following effects are brought about. First of all, the platinum complex of general formula (I) exhibits high antitumor activity against murine leukemia tumor cells L-1210. Therefore, the platinum complex of formula (I) is useful as an antitumor agent, for example, for testicular tumors, bladder cancers, renal pelvis tumors, urethral cancers, prostate cancers, ovarian cancers, and the like. It is also expected to be useful as an antitumor compound that is effective in treating head and neck cancer, esophageal cancer, lung cancer, stomach cancer, uterine cancer, and kidney cancer. Second, when the platinum complex of the present invention is administered, it has a large chemotherapeutic coefficient, so it can be safely used over a wide range of doses that exhibit antitumor effects. Thirdly, the platinum complex of the present invention has low acute toxicity to humans and animals and is safe. Its antitumor effect is equal to or greater than that of commercially available CDDP, and also exceeds that of a similar platinum complex. In addition, the safety of the platinum complex of the present invention was evaluated using commercially available C.
Superior to DDP etc.

[0070] In the third aspect of the present invention, a cancer or tumor growing in a mammal (including humans), wherein the cells of the cancer or tumor have the general formula defined above. In a mammal having a cancer or tumor that is susceptible to the platinum complex of the invention of (I),
There is provided a method for inhibiting said cancer or tumor growing in a mammal, comprising administering a platinum complex of general formula (I) in an amount effective to inhibit said cancer or tumor. Ru.

Next, the antitumor activity and acute toxicity of the platinum complex of general formula (I) of the present invention will be explained using test examples.

Test Example 1 Test of antitumor activity against mouse leukemia cells L-1210 1) Measurement of average survival days and survival rate of mice CDF1 mice (male, 5-6 weeks old)
Mouse leukemia cancer cells L-1210 were intraperitoneally transplanted at a rate of 10 5 cells/mouse, and from 1 day after transplantation, a physiological saline solution of each test compound was intraperitoneally administered once a day for 5 consecutive days. It was administered and treated. In addition, to the drug-free group (control group), only physiological saline was administered in the same manner as the drug-administered group. Then, for 60 days after the cancer cell transplantation, the mice in the drug-treated group were allowed to freely drink and drink water and were observed. The average survival days of mice after cancer cell transplantation was determined. The average survival days (T) of the drug-treated group was compared with the average survival days (C) of the control group (approximately 12 to 1
The survival rate of mice (T/C x 100) was calculated in comparison with the previous example (usually dying within 5 days), and the antitumor effect was determined.

[0073]

[Equation 1] T: Number of days until death in the drug administration group C: Number of days until death in the non-administration control group

The results are shown in Tables 2 to 4, and Compound No. 3 and no. No. 4 showed an antitumor effect comparable to or superior to that of the control drug CDDP (commercially available product).

[0075] In Tables 2 to 4 and the following tables, the inequality sign (>) attached to the number of survival days and survival rate indicates that there were mice that did not die during the 60-day observation.

[0076]

[Table 2]

[0077]

[Table 3]

[0078]

[Table 4]

2) Measurement of chemotherapy coefficient Furthermore, the dose of the test compound (T/C x 1003
0: calculated from Tables 2 to 4) and the maximum dose of the test compound when the maximum survival rate was shown (T/C x 100max: Tables 2 to 4)
4) was calculated. From these values, the chemotherapy index (CI) of the test compound was calculated using the following formula, and the antitumor effect was determined. The larger the CI value, the more effective it is.

[0080]

[Math 2]

The results are shown in Table 5 below, and the compound of the present invention of formula (I) showed a CI value larger than that of the control drug CDDP (commercially available product), so it has a wide range of effective doses. It has been found.

[0082]

[Table 5]

Test Example 2 Toxicity Test CDF1 strain mice (male) were used as donor animals, and each group consisted of 5 mice (4 weeks old).

As a test method, the platinum complex of the present invention and CDDP were administered to the mice by intraperitoneal injection. Physiological saline was used as the solvent for the injection solution used. Observations were made until day 14 after administration, and acute toxicity value LD50 was determined.

The results are shown in Table 6, and it was found that the compound of the present invention was less toxic than the control drug CDDP (commercially available product).

[0086]

[Table 6]

Test Example 3 Test of antitumor activity of platinum complex against cisplatin-resistant mouse leukemia cells L-1210 (L-1210/CDDP) Mouse leukemia cancer cells L were intraperitoneally administered to CDF1 mice (male, 5 to 6 weeks old). -1210/CD
DPs were transplanted in an amount of 105 cells/mouse, and each test compound was intraperitoneally administered once a day for 5 consecutive days starting one day after transplantation. In addition, the drug-free group (control group) had 0
．． Only 9% physiological saline was administered in the same manner as in the drug administration treatment group. The drug-administered group of mice treated with the test compound was observed for 60 days with free access to water and food. Then, the average number of survival days (T) after cancer cell transplantation for the drug administration treatment group of mice and the average number of survival days (C) for the control group were determined. The survival rate was calculated and the antitumor effect was determined using the following formula.

[0088]

[Equation 3] T: Average number of days of survival until death in drug administration treatment group C
: Average number of days of survival until death in the non-administered control group

0
[089] The results are shown in Tables 7-8. Compound of the present invention (No.
1.No. 3.No. 4 and no. 10) is a platinum complex as another comparative compound [Comparative Compounds A and C (JP-A
-134395) and comparative compound B (JP-A-2
-223591)] showed a survival rate of 125% or more in the control group without drug administration, and
It is recognized that it has a remarkable antitumor effect against 1210.

[0090] The comparative compound A used is disclosed in JP-A-2-1
Compound No. 34395 is published. Comparative compound B is dichloro(benzyl 3,4-diamino-3,4-dideoxy-α-L-xylopyranoside) platinum listed as JP-A-2-223591.
) dichloro(3,4-diamino-3,
4-dideoxy-L-xylopyranose) platinum,
Comparative compound C is compound No. 1 described in JP-A-2-134395. Sulfate (benzyl 3,4-diamino-3,4-dideoxy-α-L-
xylopyranoside) is platinum.

[0091]

[Table 7]

[0092]

[Table 8]

Claims (2)

[Claims] 1. An L-xylopyranoside platinum complex represented by the general formula: [Formula 1] (wherein R represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aralkyl group). 2. It is characterized by containing an L-xylopyranoside platinum complex represented by the general formula [Formula 2] (wherein R represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aralkyl group) as an active ingredient. An anti-tumor agent.