JPH02134395A - Novel platinum complexes and antitumor agents - 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] Object of the Invention Page (1976), Journal of Inorganic Biochemistry
rg-anic Biochemistry) Vol. 11, No. 169-149R-di (1979). Among them, cis-dichlorodiamine platinum [
Cisplatin (generic name: cDDP) has excellent anticancer effects and is currently widely used in clinical practice. The present invention relates to a characteristic antitumor agent.

BACKGROUND OF THE INVENTION It is already known that certain platinum complexes have antitumor effects. Examples include JP-A No. 60-87295, JP-A No. 61-265991, JP-A No. 62-24658.
Publication No. 8, Publication No. 62-190192, Publication No. 62-24
No. 6545, No. 63-17894, No. 60-
No. 87295, Journal of Pharmaceutical Science
-utical 5 sciences) Volume 65, Volume 6, Volume 515-528 The platinum complex compounds known so far are usually highly toxic, especially renally toxic, and therefore difficult to administer continuously, but do not produce sufficient clinical therapeutic effects. I can't. For example, the above-mentioned CDDP exhibits excellent medicinal efficacy particularly against malignant tumors of the urinary tract and reproductive organs. When administered to a patient developing such a malignant tumor, it can restore the patient to a state of remission, so it is a useful drug. However, this CDDP has strong renal toxicity, so before administration,
It has the disadvantage that a large amount of water must be administered during administration, and diuretics must be used in conjunction with administration over a long period of time in order to reduce renal toxicity. Further, a platinum complex other than CDDP that does not have the above-mentioned problems has not yet been found.

In view of these circumstances, an object of the present invention is to provide a platinum complex that exhibits novel antitumor activity without side effects.

Means for Solving the Constituent Problems of the Invention The present inventors conducted extensive research in order to find a platinum complex that has excellent antitumor activity and is less toxic.

As a result, we succeeded in synthesizing a novel platinum complex having α-L-xylopyranoside as the amine component. They discovered that this platinum complex has an antitumor effect that is equivalent to or better than CDDP, especially against murine leukemia L-1210, and that acute toxicity and renal toxicity are extremely low, and the present invention was completed. I ended up letting it happen.

That is, the platinum complex of the present invention is a group having the following general formula % structure (in the above formula, R1 and R2 are a hydrogen atom, a lower alkyl group, or a group represented by 10M,
M represents a hydrogen atom or an atom that can become a monovalent cation, and ph represents a phenyl group. )] Representative examples of the compounds represented by the above general formula (1) are listed below, but these examples are not intended to limit the present invention.

-dideoxy-α-L-xylopyranoside) platinum 2° short (benzyl 3,4-diamino-3,4 dideoxy-α-L-xylopyranoside) platinum 3° dithiocyanato (benzyl 3,4-diamino-3,4
-dideoxy-α-L-xylopyranoside) platinum 4° dinitrate (benzyl 6,4-diamino-3,4-
dideoxy-α-L-xylopyranoside) platinum sulfate (benzyl 5,4-diamino 6,4-dideoxy-α-L-xylopyranoside) platinum 6° oxalate (benzyl 3,4-diamino 3,4-dideoquine α-L-xylopyranoside ) Platinum cyclobutane-1,1-dicarboxylade (benzyl 6,4-diamino-3,4-dideoxy-α-L-xylopyranoside) Platinum 8° 4-carboxyphthalate (benzyl 6,4-diamino-6,4- dideoxy-α-L-xylopyranoside)
Platinum malonate (benzyl 3,4-cyacyno-6゜4-dideoxy 7-α-L-xylopyranoside) platinum methyl malonate (benzyl 6,4-diamino-3,
4-dideoxy-α-L-xylopyranoside) platinum 11°ethyl malonate (6,4-diamino-3,
4-dideoxy-α-L-xylopyranoside) platinum 12° dimethyl malonate (benzyl 6,4-diamino-6
, 4-dideoxy-α-L-xylopyranoside) platinum 16°hydroquine malonate (benzyl 5.4-diamino-3,4-dideoxy-α-L-xylopyranoside)
Platinum 4-carboxyphthalate (benzyl 3,4 diamino-3,4-dideoxy-α-L-xylopyranoside) platinum sodium salt 15, hydroxymalonate (benzyl 3,4
-diamino-3,4-dideoxy-α-L-xylopyranoside) platinum sodium salt Note that the compound shop is referred to in the following description.

The platinum complex of the present invention is a novel compound, which acts as an antitumor agent against malignant tumors in humans or various animals, such as Himaru tumor, bladder cancer, kidney and urethral tumors, prenatal cancer, and ovarian cancer. do.

Examples The platinum complex of the present invention can be produced by the various methods described below.

(Method A) (Ia) (wherein M is the same as above and Hat represents halogen).

In the above, an aqueous solution of a halogenated potassium platinate, preferably a potassium halogenated platinate, is added to an amino sugar (I
In addition to the ethanol solution of t), if it is a heterogeneous solution, in order to make it a homogeneous solution, by adding ethanol or water to it and reacting, X in general formula (1)
A platinum complex of formula (la) in which is a halogen can be easily produced. The amount of the halogenated platinum salt used is 1 to 2 times the molar amount of the raw material amino sugar (It). The order of addition may be reversed to the above. This reaction is
It is carried out at room temperature and protected from light, and is usually completed in 1 to 7 days, but 40
The reaction time can be shortened to 1 to 24 hours by heating to 1 to 70 degrees Celsius. Normally, the desired product gradually precipitates from a homogeneous and transparent solution, which is collected by filtration, washed with water, ethanol, and ether, and then recrystallized from hot water and dimethylformamide as necessary. Therefore, the compound (Ia) of the present invention can be obtained.

(Method B) React with stirring for 5 hours, add amino sugar ([)
Add equimolar amounts of potassium chloride platinate and adjust the temperature to 0 to 10.
After stirring at 0°C for usually 1 to 48 hours, the generated solid is collected by filtration and washed with water to obtain the compound of the present invention (It+
) (Compound 43) is obtained.

(Method C) H2 ω) (Ia) Potassium chloroplatinate and 4 times the mole of potassium thiocyanate were dissolved in water, and the temperature was preferably 0 to 100°C.
The dihalogenoplatinum complex (1a) is reacted with silver nitrate to form the compound (IC
) (Compound A4) can be produced. This reaction is usually carried out in an aqueous solution at room temperature for 1 to 5 days. The amount of silver nitrate used is preferably 1.5 to 2.5 times the molar amount of compound (Ia). After the reaction is complete, excess silver nitrate is precipitated as silver chloride by adding an aqueous potassium chloride solution to the reaction solution, passing through suction filtration, centrifuging the filtrate, and freeze-drying the supernatant to obtain the compound of the present invention (as a powder). ic> (compound 4
4) is obtained.

(Method D) Sulfate complex (Ia) (Compound Shop 5) can be produced by reacting dihalogenoplatinum complex (Ia) with silver sulfate instead of silver nitrate. The reaction is usually carried out in an aqueous solution at room temperature for 1 to 6 days. The amount of silver sulfate used is based on the compound (Ia
) is preferably 0.9 to 1.2 times in mole.

(Method E) (rc) (Ia) (fd) Compound (re) (Compound &6 to Compound Haruka 16) can be produced by reacting the nidorado compound (IC) with a dicarboxylic acid salt. This reaction is carried out at 0 to 100°C in an aqueous solvent.
What is necessary is just to carry out preferably at 0 degreeC - room temperature for 1 to 3 days. The amount of dicarboxylate used is 0.5 to 2.0 times the mole of the compound (1), preferably equimolar. The initial JpH of the reaction mixture is preferably approximately neutral. However, there is no need to particularly adjust the pH during the reaction.Also, when using the free acid instead of the dicarboxylate, after adding it to the aqueous solvent containing the nidorado compound (IC), add a suitable base, e.g. The pH may be adjusted to neutral using an alkali hydroxide.Also, if the reaction becomes acidic as the reaction progresses, the reaction may be carried out while maintaining the pH neutral using the same base.

The desired product gradually precipitates out, which is collected by filtration, washed with cold water, and recrystallized from hot water and water-methanol as required to obtain the compound of the present invention (e). The structure of the platinum complex of the present invention was confirmed by elemental analysis, infrared absorption spectrum, and secondary ion mass spectrometry (lbIMJ, etc.). It can be synthesized via the formula.

H D-(-1-arabinose epoxide@) (■) (It) (however, phfi phenyl group is shown), that is, 1
First, according to the method described in JP-A-62-181290, D- (known epoxide@) is obtained in 7 steps using -1-arabinose as a starting material. Next, this compound is ammonolyzed to obtain a new amino sugar (M), and by further reducing (substituent), a new diamino sugar can be produced. showed the method.

Next, examples for producing the platinum complex of the present invention will be shown, but the present invention is not limited to the examples shown below.

Production of platinum (compound, gourd 1) (benzyl 3,4-diamino-5,4-dideoxy-CL)
-L-xy0 pira/'/do (■) 1.0f (4,
2 mmol) was dissolved in ethanol 30-, and to this was added 1.74 f (4.2 mmol) of platinum potassium chloride dissolved in water 35-, and the mixture was stirred at room temperature in the dark for 24 hours. The precipitated yellow crystals were filtered, washed with cold water, ethanol and ether, and then dried under reduced pressure to obtain 2.02 crude crystals of Compound M1. Add this to DMF 20 s
After dissolving in d and filtering, add 50-methanol and cool on ice. The precipitate is collected by filtration, washed with methanol, and dried to obtain 1.9 F (yield: 93 %) was obtained.

The physical properties of this material are as shown below.

m, p,) 300°C [α]25-L65.2° (C = 1.0, DMF
) Elemental analysis value: 012 Hla N2 C120s
Calculated value as Pt (@: C28,58, N5.6
0, N5.56, at 14.06 measured value C@: C
28,33, N3.74, N5.78, C414,19
IR, ν 3450.6250.6170.1560
．． 1-695.1340.1105.1090.103
0.930.745.700 cm-'S engineering MS:
Production of (M+H) = 505 Dissolve 0.83y (2 mmol) of platinum potassium chloride in 20- of water and add 4m of a saturated aqueous solution of potassium iodide.
is added dropwise and reacted at 60° C. for 5 minutes with stirring to obtain a black solution of potassium platinum iodide. Add benzyl 6,4-diamino-6,4-dideoxy-
0.48 f (2 mmol) of α-L-xylopyranoside (b) dissolved in 20-ethanol was added, and the mixture was stirred at room temperature in the dark for 43 hours. The precipitated yellow crystals were separated, washed with cold water, ethanol and ether, and then dried under reduced pressure to obtain crystals of compound M2 (0.84F (yield: 75%)). m, p, of this is 271-275℃ (decomposition)
Met.

The colored crystals were separated, washed with water, and dried under reduced pressure at 60°C for 3 hours to obtain crystals of compound 43. Of (yield 94%
) was obtained. The physical properties of this material are shown below.

m, p, 19? i~196°C (decomposition) Elemental analysis value: C14H1a N40S 82 Calculated value as Pt C%: c 30. I H3,30,N
10.19 Measured value (%): C1.85, N3.25,
N10.28Br IR, ν 6400, 6200, 2100.156
0, 1130, 1090. 1035crR-' 0.85f (2 mmol) of platinum potassium chloride was dissolved in 20ml of water, and potassium thiocyanate was added to this.
．． After adding 7El (8 mmol) and stirring at room temperature for 1 hour,
Add amine sugar (■lO, 48F (2 mmol)).

After stirring at room temperature for 46 hours, 2.0 f (4 mmol) of the dichloroplatinum complex (compound &1) obtained in Example 1 was suspended in 44 Tnt of water, and 1.35 f (8 mmol) of the dichloroplatinum complex (compound &1) obtained in Example 1 was suspended in 44 Tnt of water. 1J mol) was added thereto, and the mixture was stirred for 6 days at room temperature in the dark. Precipitated silver chloride is removed by filtration, and F
2.0 - of 0.5% potassium chloride aqueous solution was added to the solution to precipitate excess silver nitrate as silver chloride. This is centrifuged (
190,000×? , 90 minutes) and the supernatant was lyophilized to give 2.1:1 (96% yield) of Compound M4 as a pale yellow crystalline powder. The physical properties of this material are as shown below.

m, p, 170-173℃ (decomposition) elemental analysis values:
c12 N18 N409 Calculated value as Pt (@2
〇 25.86, H3,26, N 10.05 measurement value (@: C25,98, H3,18, N 10
．． 111 R: vKB' 3400.3250-31
70m-11560, 1485, 1375, 1270,
1050,930,740,700cr! I-'S engineering M
Suspended in S: (M+H) = 558,
0.62 f (2 mlJ mol) of silver sulfate was added, and the mixture was stirred at room temperature in the dark for 3 days. The silver chloride produced is filtered and separated,
The F solution was freeze-dried to give a yellow-white compound of 0.0% of Compound 45.
58f (55% yield) is obtained. The physical properties of this material are
It is as shown below.

m, p, 210-217°C (decomposition) [α): 5-1
26.4°-(C=1.0, DMF) Elemental analysis value:
012 N18 N207 S Calculated value as Pt (%
): C27,23, H5,43, N 5.29 Measured value (%1: C27,45, H3,35, N 5.1
4I R: v”r 3375.3175.3075
．． 1570. 1110. 1020. 925. 7
20. 695 cm-" SIMS: (M+H) = 5305) 1.0 f (2 mmol) of the dichloroplatinum complex (compound A1) obtained in Example 1 was added to 80-〇 water in Production Example 4 of 6). 1.0 f (1.8 mmol) of the obtained dinitrate complex (compound 4) was dissolved in 50 g of water, and 0.24 r (1.8 mmol) of disodium oxalate was added to this aqueous solution.
, 8 mmol) and allowed to react for 3 days at room temperature in the dark. The generated crystals were collected, washed successively with cold water and acetone, and then dried under reduced pressure to obtain Compound 0.86F (yield: 92%) as white powdery crystals. The physical properties of this material are as shown below.

m, p, 290-291℃ (decomposition) elemental analysis values:
Calculated value (%) as C14HI3 N207 Pt
: C32,25, H3,48, N 5.37 measurement value (@: C32.38, H3,32, N5
．． 28IR, , x 3360. 3175.307
5.1690.1660. 1600. 1380.
1240. 1200. 1140. 1100. 1
030. 930.895.800.730tyn-'
SIMS: (M+H) = 522 pyranoside) 1 of the dinitrate compound (compound product 4) obtained in Production Example 4 of platinum (compound shop 7)
．． 0 f (1,8 mmol) dissolved in water 60-
1,1-cyclobutanedicarboxylic acid 0.26F (1,8
3.5 mmol) and 1N sodium hydroxide were added, and the mixture was allowed to react at room temperature in the dark for 3 days. The generated crystals were washed with cold water and dried under reduced pressure to obtain compound 0.835' (yield: 80%) of compound Hatsuto 7 as pale yellowish brown powder crystals. The physical properties of this material are as shown below.

m, p, 253.5-255.5°C (decomposition) Elemental analysis value: C1s N24 N207 Calculated value as Pt (%l: C37,57, H4,20, N4.
87 measurement value C@: 0 67.81, H4,1
0, N 4.73I R: vKBr 3400-2
950.1600-1580.1350. 1100
．． 1030. 905. 730.695 cm-' SIMS: (M+H) = 576 Example 8 4-Carboxyphthalate (benzi 1) Preparation of compound from Compound Shop 8 1.0 f (1,8) of dinitrate compound (compound A4)
mmol) in 50 mmol of water and 0.5 mmol of trimellitic acid.
38? A solution prepared by dissolving (1.8 mmol) in water 8- with heating is added, and the mixture is stirred at room temperature in the dark for 2 days. The product is washed with water several times, washed with methanol and dried to obtain 0.85r of light gray crystals of compound J168.
(Yield 76%). The physical properties of this material are as shown below.

m, p, 274-278℃ (decomposition) Elemental analysis value: 021 N22 N209 Calculated value as Pt (as: 0 59.52, H3, 46, N
4.36 measured value (@: c 39.45, H3
, 28, N4.26I R: vKB' 3425
-2900.1700-1540.1340.1030
．． 920.740.695cIn-' SIMS: (M+H) = 6422) Method for producing compound Hatsuyu 14 Compound 320 of compound 7 and compound 8 obtained by this method was mixed with water 2
5-, and dissolve by adding 1N NaOH1-.

After filtration, the tear fluid was freeze-dried to obtain 257W9 (yield 78%) of 4-carboxyphthalate (benzyl 6,4-diamino-3,4-dideoxy-α-L-xylopyranoside) platinum sodium salt (Compound Hatsuto 14). ). The physical properties of this material are as shown below.

m-1)->500℃ Engineering R1νm,, 3375-3180.1570-1
540.1360, t020crR''''1 Dissolve 1.0 f (1.8 mmol) of the dinitrate compound (Compound Shop 4) in water 60-, and add 0.27 f (1.8 mmol) of distrium malonate. ) and stir for 3 days at room temperature in the dark. When the product was washed with water several times and dried, a light gray crystalline powder of compound A9 was obtained.
r (yield 61%) is obtained. The physical properties of this material are shown below.

m, T), 281-283°C (decomposition) Elemental analysis value: Calculated value (%) as 015 N20 N20y Pt: C33,65, H3,77, N
5.23 measurement value (curvature: C33.74, H3.65
, N 5.15I R: vKB' 3380,
5150.5090.1620-1580. 110
．． 1030. 960, 730 m-' S engineering MS: (M+H) = 556, and stirred for 2 days at room temperature in the dark to react.

The produced yellow-white crystals are washed with water several times and dried to obtain compound 0.82F (yield: 83%) of compound 10.

The physical properties of this material are shown below.

m, p-255~258°C (decomposed) Elemental analysis value: C16N22 N207 Calculated value as Pt (4): 0 54.97, H4,04, N
5.10 measurement value (@: (! 35.18, H3
,95,N 5.23IR: νKBr 3375.
3150, 3080.1620-1580.1370
．． 1025.910.730.695cm-” S Me: (M+H) = 550 Example 9
(in place of disodium malonate, methylmalonic acid 0.21F is hydroxylated with water 2d and 1N) I
In Example 9, disodium malonate was replaced with 0.24f ethylmalonic acid.
water 1- and 1N-hydroxide) IJum 6.5
It is used after being dissolved in water, and stirred and reacted for 2 days at room temperature in the dark. The resulting pale brown crystalline powder was washed with water in an increased amount of
%). The physical properties of this material are as shown below.

m, p, 236-238°C (decomposition) Elemental analysis value: Calculated value as C17N24 N207 Pt (@: C36,24, H4,29, N 4.9
7 Measured value (%): 0 36.5B, H4,11
, N 4.85I R, νl1lax 3425130
0.5180-5055.1620-1565.137
0.1210.1020, 935.730.695 Confucian
1B Engineering MS: (M+H) = 564 Stir and react for 2 days under light shielding at room temperature. The precipitate is filtered, washed with water, and dried to obtain 0.76 t (yield: 75%) of light brown crystals of compound &12. The physical properties of this material are as shown below.

m-p, 238-241℃ (decomposition) Elemental analysis value: (!17 N24 N207 Calculated value as pt ((transformation): C36,24, H4,29, N
4.97 measured value (%l: c 56.41, H
4,09, N 4.79 engineering R0ν 3400-33
30.3200-2950.1600-1560.13
30.1170.1020, 900.730.695c
m''''1S engineering M8: (M+H) = 564 In Example 9, dimethylmalonic acid 0.24F was dissolved in water 2- and 1N-sodium hydroxide 3Wt and used as a substitute for disodium malonate. 1) Manufacturing method of the compound of Compound Hatsuyu 14 1. of the dinitrate compound (Compound Shop 4) ! Dissolve M (2.7 mmol) in 40 m of water and add 0.32 f of tartronic acid.
(2.7 mmol) was dissolved in 2 m of water, and a solution neutralized to pH 75 with 1N sodium hydroxide 5- was added.

After stirring for 3 days at room temperature in the dark, the mixture is cooled on ice, and the precipitate is washed several times with water and dried to obtain compound 1.13f (yield: 76 cm) of compound A13 as brown crystals. The physical properties of this material are shown below.

m'P, 247-248℃ (decomposition) Engineering R0ν 3360-3050, 1660-158
0.1380-1330, 1110.1030.92
0.730cm-' Elemental analysis value: Calculated value as 015 N20 N208 pt (@: C32,67, H5,66, N
5.08 Measured value (%l: C32,81, H3,48
, N 5.19S engineering MS: (M+H) =
5522) Method for producing compound No. 15 Compound No. 13 obtained by this method was mixed with 0.52 of the compound No. 13 in water.
5m and dissolve by adding 1N sodium hydroxide. After filtration, the lachrymal fluid was lyophilized and treated with hydroxymalonate (benzyl 3,4-diami2-3,4-dideoxy-
α-L-xylopyranoside) platinum sodium salt 0.4
5F (yield: 87 yen) was obtained. The physical properties of this material are as shown below.

m, p, >300℃ IR: vKB” 5350-!1050.1585
．． 1440.1320.1095.102[]m″″1
Epoxide produced by the method described in JP-A-62-181290 @) 6. oy was dissolved in methanol saturated with ammonia, and in a sealed tube, 130 to 14
Heated at 0°C for 5 hours. After cooling to room temperature 1, the reaction solution was distilled off under reduced pressure to obtain a reddish-brown oil with a volume of 5.92. Using this residue as a developing solvent, chloroform-methanol ([0:
Using 1), sheathing was performed by silica gel column chromatography to obtain a yellow oil, which was crystallized with n-hexane to give Amino II (Corporation) 2.7 f (yield 42%) as colorless crystals. Obtained. The physical properties of this material are as shown below.

m, p, 61-64°C [α]. -117,6° (C=1.0, CH30H)
Elemental analysis value: Calculated value as C12N16 N40s (%l: C54,55, H6,10, N21.2
0 measurement value (%1: C54,30, H6,15, N
21.76 High pressure electrophoresis: mobility 0.93, nhydrin coloration, alanine 1.0) Avicel 5F-1020, equipment 5avant LT-48A.

Electrolyte solution formic acid-acetic acid monohydrate (25:75:900 solution, pH 1.8), voltage 3000V, time 15 minutes IR: vKB" 3325.3250.305
0.2900.2100, 1590, 1450,
1350.1250, 1125, 1095.106
0.1020. 965. 930. 750. 73
0.690m-1 NMR (100MH21CDCl3) δ 2.05
, 2.78-3.72, 4.41-4.90.7.
33 Dissolve the amino sugar (IVI 4.Of) obtained in Reference Production Example 1 in dioxane 480- and triethylamine 480-, add 10% a radium-carbon 400 in a nitrogen stream,
Add money. Hydrogen was introduced into the solution for 35 minutes while stirring at room temperature, and the mixture was further stirred for 6 hours. After the reaction was completed, the catalyst was removed by suction filtration, and the lachrymal fluid was distilled under reduced pressure to obtain a yellow solid 4.11. This solid substance was washed with distilled water
After adjusting the pH to 7 with 1N hydrochloric acid, Amberlite CG-50 ammonia type: H type (7:3) 300-
Pass it through and absorb it. After washing with 1 t of distilled water, eluting with 2.8 t of 0.1N ammonia water, high-pressure electrophoresis and thin layer chromatography [Developing solvent: methyl acetate/isopropyl alcohol/aqueous ammonia (45/105/6
The product was collected under reduced pressure, concentrated under reduced pressure, and then lyophilized to obtain 6.5 tons of colorless powder. By crystallizing this with methanol/ether, amino sugar (nl
3.19 (yield 87%) was obtained.

The physical properties of this material are as shown below.

m, p, 142-144°C [α]D -158,6° (C=1.0, (1!I(5
0H) Elemental analysis value: 012 Has Calculated value (%) as N203: C60,48, H7,61, N
11.76 measured value (%I C60,25, H7,72
, N 11.83 High pressure electrophoresis: mobility 1.55, nhydrin coloring, alanine 1.0) X R: vKB' 3370.3325.32
75.3050.2900.2705, 1580,
1340.1130, 1085, 1020.930
．． 830.760.730.690 - 1NMR (10
0MHz, C! DsOD) δ 2.44-2.
91.3.24-3.56.4.44-4.83.7,
56 Method for formulating the antitumor agent of the present invention In producing the antitumor agent of the present invention, various formulations may be prepared by mixing with a carrier used as a pharmaceutical, along with an auxiliary agent if necessary, by a conventional method. can. for example,
When administered orally, it can be in the form of solid preparations such as tablets, emulsions, granules, powders, and capsules, or liquid preparations such as solutions, suspensions, and emulsions. Furthermore, when administered parenterally, it can be administered as an injection or as a school prescription. In this case, the carrier is preferably lactose, starch, dextrin, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium stearate, etc. when preparing tablets, emulsions, 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. In the case of academic regulations, cacao butter, lauric fat, glycerogelatin, macrogol, etc. are preferable. The content of the compound of the present invention in the preparation is desirably a unit amount convenient for use depending on the patient's age, symptoms, etc.

The pharmaceutical dosage of the compound of the present invention is usually 400 to 800 η per day when administered orally for tumor treatment in adults.
/-11.100-4 per day when administered parenterally
00■/I seems to be hitting the mark.

Next, examples will be shown in which the compound according to the present invention is used as an antitumor agent, but the present invention is not limited to the following examples.

Example 14 Injectable Compound Hatsuto 13 compound was aseptically dispensed into vials containing 300~300ml, lyophilized to remove water, and 100ml of physiological saline was added at the time of use. Add it to make an injection.

A mixture of compound 41, compound 50F, lactose 961, crystalline cellulose 279, I-corn starch 52, and magnesium stearate 22 (total 180F) is directly compressed into tablets with a diameter of 8U+ and a weight of 180Wq.

Effects of the Invention When the platinum complex of the present invention is used as an antitumor agent, the following effects are brought about. First of all, murine leukemia (L
-1210) shows high antitumor effects. Therefore, it is useful as an antitumor agent, for example, for antitumor tumors, bladder cancer, renal menstrual/urethral tumors, prostate cancer, ovarian cancer, and the like.

Second, since it has a large chemotherapy coefficient, it can be administered safely over a wide range of doses that exhibit antitumor effects.

Sixth, there is almost no kidney toxicity, so there is no need to worry about side effects. Fourth, it has low acute toxicity to humans and livestock and is safe.

The antitumor effect is equal to or greater than that of commercially available CDDP, and exceeds the effect of a similar platinum complex. In addition, side effects, safety, etc. are superior to commercially available 0DDP and the like.

Next, the effects of the platinum complex of the present invention as an antitumor agent will be explained by conducting tests.

1) Average survival days and increased survival rate Cancer cells (
10 L-1210) were transplanted, and from 1 day later, each drug was intraperitoneally administered once a day for 5 consecutive days.

In addition, to the drug-free group (control group), only physiological saline was administered in the same manner as the drug-administered group. Then, the average number of days of survival after cancer cell transplantation was determined, and the survival increase rate (IL19
) was calculated to determine the effect.

T: Number of days in the cage leading to death in the drug administration group C: Number of days leading to death in the non-administration control group The results are shown in Table 1.
Compounds (1) to (to) have antitumor effects, and in particular, compounds (1), (4), (5), and (7) to (6) are equivalent to the control agent 0DDP (commercial product). However, it showed better antitumor effects.

2) Chemotherapy coefficient In addition, the dose (ILS5Q: calculated from Table 1) that shows a 30% survival effect compared to the drug-free group,
The maximum dose Ji (I L
The chemotherapy coefficient (c) was calculated from the following formula to determine the effectiveness. In this case, the larger the CI value, the more effective it is.

The results are shown in Table 2 for compounds (1), (4), (
5) and (2) showed larger values than CDDP (commercial product) and were found to have a wide effective range.

Table 1 Table 1 (continued) Compound 1 25.0 12.5 3.1 1.6 0.4 0.2 18.6 > 30.0 > 30.0 > 300 > 30.0 > 275 > 275 〉275 〉275 0/4 0/4 4/4 4/4 4/4 4/4 0/4 0/4 0/4 Compound 2 25.0 1.6 0.8 0/4 0/4 0/ 4 0/4 0/4 0/4 Compound 3 50.0 25.0 10.6 10.2 8.5 0/4 0/4 0/4 0/4 0/4 Compound 4 3.4 >30. 0 >30.0 >30.0 >30.0 a0 14.6 >275 >275 >275 >275 0/4 4/4 4/4 4/4 4/4 0/4 0/4 0/4 Compound 5 50.0 3.1 1.6 0.8 0.4 0.2 6.0 〉600 ＞50.0 ＞30.0 ＞30.0 ＞30.0 〉275 〉275 〉275 〉275 〉275 0/4 4/4 4/4 4/4 4/4 4/4 0/4 0/4 0/4 Table 1 (continued) Compound 3.8 >30.0 >21.4 11.8 >275 〉167 0/4 4/4 2/4 0/4 0/4 0/4 Compound 100.0 50.0 25.0 3.1 1.6 1.9 > 50.0 > 50.0 > 50. 0 > 30.0 11.0 〉275 〉275 〉275 〉275 0/4 4/4 4/4 4/4 4/4 0/4 0/4 Compound 50.0 25.0 6.3 3.1 1.6 4.0 > 50.0 > 50.0 14, l5 11.7 〉275 〉275 0/4 4/4 4/4 0/4 0/4 0/4 Table 1 (continued) Compound 12 50.0 25.0 12.5 6.3 6.1 1.6 4.2 > 30.0 > 30.0 > 30.0 > 50.0 9.0 〉275 〉275 〉275 〉275 0/ 4 4/4 4/4 4/4 4/4 0/4 Compound 13 100.0 50.0 25.0 12.5 6.6 6.1 1.6 4.7 > 30.0 > 30.0 > 30.0 > 50.0 〉275 〉275 〉275 〉275 0/4 4/4 4/4 4/4 4/4 0/4 0/4 Compound 14 12.5 6.3 1.6 11. 0 14, O 8,5 0/4 0/4 0/4 0/4 0/4 Table 1 (continued) Compound 100.0 50, O 25,0 12,5 6,3 3,1 1,6 >30.0 >30.0 >30.0 >30.0 8.9 >275 >275 >275 >275 0/4 4/4 4/4 4/4 4/4 0/4 0/4 Compound 10 100.0 50.0 5rJ 6.3 6.1 1.6 2.8 > 30.0 >30.0 > 30.0 18.0 15.0 〉275 〉275 〉275 0/4 4/4 4 /4 4/4 0/4 0/4 0/4 Compound 11 50.0 5f1 6.3 3.1 1.6 0.8 2.8 > 50.0 > 50.0 > 30.0 > 30. 0 14.0 〉275 〉275 〉275 〉275 0/4 4/4 4/4 4/4 4/4 0/4 0/4 1st Shishi (continued) Compound 15 100.0 50.0 25.0 6.3 3.1 1.6 4.7 > 50.0 >30.0 >30.0 16.2 8.2 >275 >275 >275 0/4 4/4 4/4 4/4 0/ 4 0/4 0/4 DDP (control agent) 14.9 > 50.0 > 50.0 > 30.0 > 50.0 12.6 〉275 〉275 〉275 〉275 0/4 4/4 4/ 4 4/4 4/4 0/4 0/4 Test drug (mi! /Av'day) Compound 1
0.37 Compound 22.0 Compound 3 13.0 Compound 4 0.23 Compound 50.4 Compound 60.6 Compound 725 Compound 81.1 Compound 91.9 Compound 10 1.8 Compound 11 0.94 Compound 12 17 Compound 13 1.5 Compound 14 3.5 Compound 15 3.5 (Control agent) Table 2 (wh'day) 3.1 25.0 12.5 25.0 6.25 50.0 25.0 50.0 50 .0 25.0 25.0 50.0 6.25 50.0 I 33.8 1.6 1.9 54.6 10.4 20.0 22.7 26.3 27.8 26.6 14. 7 63.6 1.9 13.9 Test Example 2 Toxicity Test (1) Donor Animals ICR mice (male) were used, 5 mice per group (4 weeks old).

(2) Test method Compounds (1) to 0 were intraperitoneally administered to the mice.

Observations were made until day 14 after administration, and LD5oi was determined.

Physiological saline was used as the injection solvent.

The results are as shown in Table 3, compounds (1) to (to)
was found to be less toxic than CDDP (commercially available product).

Table 6 Compound 2 382 Compound 6 535 Compound 4 636 Compound 5 712 Compound 6 67 Compound 7 772 Compound 8 865 Compound 9 536 Compound 10 85!1 Compound 11 671 Compound 12 683 Compound 13 882 Compound 14 55 Compound 15 173 Blood urea nitrogen concentration (BUN) was determined.

In addition, the body weight of the drug-administered mortar and body 1 4 days after drug administration were measured, and the ratio (body 1° 4 days after administration/administration weight to body weight ratio) f was determined.

In addition, in the drug-free control group, physiological saline was intraperitoneally administered at 0.25 μm per mouse.

The results are shown in Table 4. As is clear from Table 4, the compound (1) of the present invention,
It was found that (5) and Q3 had extremely low blood BUN values compared to the control agent CDDP (commercially available product), were equivalent to physiological saline, and had low renal toxicity.

Table 4 The maximum dose (compound 1
:12.5~/#, Compound 5:25/kg, Compound 1
5:50++v/#) was administered intraperitoneally once, and blood was collected 4 days later Compound 1 Compound 5 Compound 13 62.5 0.85 125.0 0.90 250.0 0 .92 28.5 25.6 26.8 Physiological saline 1.10 r-Zoku 7 City Masashiru) December 2, 1988. jl1st, 7th, contents of amendment The chemical structural formula of formula (II) on page 11 is as follows: Commissioner of the Japan Patent Office +! r1. Mr. Bunki! ,・Representation of Patent Application No. 286823 of 1986 2 amended to the title of the invention.

Formula on page 12 The chemical structure of Correct as desired.

3゜ person who makes corrections ・Relationship with 1 list Patent applicant Formula on page 13 The chemical structure of Correct as desired.

4゜1ift of amendment instruction (l219.) 5゜Number of claims increased by supplementary IF...06゜Detailed explanation of the invention in the specification subject to amendment (Formula % Formula %) on page 14) Correct.

The chemical structure of Formula (Ie) on page 14 The chemical structure of Correct the error.

rND14J on the last line of page 30 is rNo13J Supplement II
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5th row 11 from directly below 39th “ 3)” to “ (l　5) ” and correct it.

Page 48, line 6 [1 of [ (l　3) " (l　5) ” and correct it.

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Below

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X represents a halogen atom, -SCN, -NO_3, or two Xs are bonded to ▲ Numerical formula, There are chemical formulas, tables, etc.▼,▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A group having the structure (In the above formula, R_1 and R_2 are
It is a hydrogen atom, a lower alkyl group, or a group represented by -OM, where M represents a hydrogen atom or an atom that can be a monovalent cation, and Ph represents a phenyl group. )] α-L-xylopyranoside platinum complex. 2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, X represents a halogen atom, -SCN, -NO_3, or two Xs are bonded ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼、▲Mathematical formula, chemical formula,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A group having the structure (In the above formula, R_1 and R_2 are
It is a hydrogen atom, a lower alkyl group, or a group represented by -OM, where M represents a hydrogen atom or an atom that can be a monovalent cation, and Ph represents a phenyl group. )] An antitumor agent characterized by containing an α-L-xylopyranoside platinum complex represented by the following as an active ingredient.