JPH10168091A - Diammine platinum complex and medicine comprising the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new diammine platinum complex, excellent in antitumor effects, having high safety, capable of effectively acting on a cisplatin-resistant strain and useful as an active ingredient, etc., of a therapeutic agent for malignant tumor. SOLUTION: This new diammine platinum complex is represented by formula I [Ru1 is a (substituted) alkyl, a (substituted) aralkyl or a (substituted) acyl; X is a halogen or two Xs together form a (substituted) malonic acid residue] and is excellent in antitumor effects and has high safety and is useful as a therapeutic agent, etc., for malignant tumor capable of effectively acting on a cisplatin-resistant strain. The diammine platinum complex is obtained by reacting a aqueous solution of potassium iodoplatinate (K2 PtI4 ) prepared by adding potassium iodide to an aqueous solution of chloroplatinic acid with a diamine represented by formula II in a molar amount of 1-10 times based on the K2 PtI4 , providing a platinum complex represented by formula III, then adding silver nitrate thereto, converting the platinum complex into a diaquo complex and subsequently reacting the prepared diaquo complex with a malonic acid derivative or a halogen-containing acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel platinum complex having an excellent antitumor effect and high safety, and a medicament containing the same.

[0002]

2. Description of the Related Art In recent years, malignant tumors have become the leading cause of death, and various antitumor substances have been developed. Among them, cisplatin, an antitumor platinum compound, has a broad antitumor spectrum and occupies an important position in chemotherapy of various tumors.

[0003] However, cisplatin has a problem that it has many side effects such as nephrotoxicity, hematological toxicity, gastrointestinal toxicity and neurotoxicity. Therefore, carboplatin [Latest Medicine, 41 (3), 509 (1986)] was developed to reduce the nephrotoxicity of cisplatin and increase water solubility, but the antitumor effect of carboplatin is not always satisfactory. Was not. Furthermore, as with other anticancer drugs, cisplatin's weak point is that the emergence of resistant cells cannot be avoided.

Therefore, in developing a new antitumor platinum complex, it is desired to create a complex which has excellent antitumor effect and effectively acts on cisplatin-resistant cells. As such an attempt, for example, L12
10 cisplatin-resistant strains show no cross-resistance,
Examples of the synthesis of many platinum complexes having 2-diaminocyclohexane as a ligand [Cancer Research, 37, 34]
55-3457 (1977)].

In addition, Tashiro et al. Induced cisplatin-resistant strains such as an L1210 cisplatin-resistant strain (L1210 / DDP), a P388 cisplatin-resistant strain (P388 / DDP), and a Colon26 cisplatin-resistant strain (Colon26 / DDP). This was used to compare the cross-resistance patterns of various platinum complexes [Cancer and Chemotherapy, 17 (3), PART- (II), 509-514.
(1990)]. In that paper, Tashiro et al.
It has been reported that L1210 / DDP does not show cross-resistance but P388 / DDP shows cross-resistance, etc., and many cisplatin-resistant platinum complexes having trans-1-1,2-diaminocyclohexane as a ligand have been reported. He pointed out that finding a platinum complex having a carrier ligand such that the strain does not show cross-resistance is a stepping stone to overcome cisplatin resistance. As described above, various attempts have been made, but no satisfactory platinum complex has yet been obtained.

[0006]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a platinum complex which has an excellent antitumor effect, is highly safe and effectively acts on cisplatin-resistant strains, and a drug containing the same. It is in.

[0007]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies, and as a result, the diamine platinum complex represented by the following general formula (1) shows excellent antitumor effect and high safety. And found to be effective against cisplatin-resistant strains, and completed the present invention.

That is, the present invention provides the following general formula (1)

[0009]

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[Wherein, R ¹ represents an alkyl group which may have a substituent, an aralkyl group which may have a substituent or an acyl group which may have a substituent; It represents a halogen atom or two X's combine to form an optionally substituted malonic acid residue. And a diamine platinum complex represented by the formula: The present invention also provides a medicine containing the diamine platinum complex represented by the general formula (1) as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The diamine platinum complex of the present invention
Represented by the general formula (1), wherein R ¹Indicated by
The alkyl group may be a linear or branched alkyl group or
Is a cycloalkyl group. Straight or branched chain
As the alkyl group, an alkyl group having 1 to 9 carbon atoms is preferable.
And an alkyl group having 1 to 6 carbon atoms is more preferable. concrete
Include a methyl group, an ethyl group, an n-propyl group,
Pill group, n-butyl group, isobutyl group, sec-butyl
Group, tert-butyl group, n-pentyl group, neopentic
Group, n-hexyl group, n-heptyl group, n-octyl
Group, n-nonyl group and the like. Especially preferred
Or methyl, ethyl, n-propyl, isopropyl
Pill group, n-butyl group, isobutyl group, sec-butyl
Group, tert-butyl group, n-pentyl group, neopentic
And n-hexyl group. Also, a cycloalkyl group
Is a cycloalkyl group having 3 to 7 carbon atoms, specifically,
Is cyclopropyl, cyclobutyl, cyclopentyl
Group, cyclohexyl group, cycloheptyl group and the like.
You.

The aralkyl group is preferably an aralkyl group having 7 to 19 carbon atoms, and specific examples thereof include a benzyl group, a phenethyl group, a diphenylmethyl group, and a trityl group, with a benzyl group being particularly preferred.

Examples of the acyl group include an alkanoyl group having 1 to 9 carbon atoms, a cycloalkanoyl group having 3 to 7 carbon atoms, a benzoyl group and a 5- to 6-membered heteroaroyl group. Here, examples of the alkanoyl group having 1 to 9 carbon atoms include a formyl group, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group, a hexanoyl group, a heptanoyl group, and an octanoyl group. Among them, carbon number 2
Particularly preferred are alkanoyl groups of ~ 7. In addition, carbon number 3
Examples of the cycloalkanoyl groups to 7 include a cyclopropylcarbonyl group, a cyclopentylcarbonyl group, and a cyclohexylcarbonyl group. Further, as the 5- or 6-membered heteroaroyl group, a heteroaroyl group having a nitrogen atom, an oxygen atom or a sulfur atom as a 5- or 6-membered heteroatom, and specifically, a furoyl group, a thiophenecarbonyl group, a nicotinyl group and the like Is mentioned.

The alkyl group, aralkyl group or acyl group may be substituted with 1 to 3 selected from hydroxy, alkoxy having 1 to 9 carbon atoms and halogen atom. Examples of the substituent-containing alkyl group include a hydroxyethyl group, a methoxymethyl group, a methoxyethyl group,
A chloroethyl group; Examples of the substituent-containing alkanoyl group include a glycoloyl group and a lactoyl group. Examples of the substituent-containing benzoyl group include salicyloyl group, anisoyl group, p-chlorobenzoyl group,
p-hydroxybenzoyl group, p-fluorobenzoyl group and the like.

Among these R ¹ , an alkyl group having 1 to 6 carbon atoms, an aralkyl group having 7 to 14 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a cycloalkanoyl group having 3 to 7 carbon atoms, a benzoyl group or 5 A heteroaroyl group having one nitrogen atom, one sulfur atom or one oxygen atom as a 6-membered heteroatom (these groups include a hydroxy group,
6 may be substituted with an alkoxy group or a halogen atom).

The halogen atom represented by X includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the malonic acid residue formed by two X's include those represented by the following formula (2).

[0017]

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[Wherein, R ² and R ³ may be the same or different and each represent a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or R ² and R ³ are bonded to each other to have 2 to 2 carbon atoms. 5 may form a linear alkylene group)

In the formula (2), the alkyl group represented by R ¹ and R ³ has 1 to 4 carbon atoms, for example, methyl group, ethyl group, n-propyl group, i-propyl group and n-
Butyl group, i-butyl group, sec-butyl group, tert
-Butyl group, and examples of the linear alkylene group having 2 to 5 carbon atoms include an ethylene group, a trimethylene group, a tetramethylene group, and a pentamethylene group. Of these, R
^It is preferred that ² and R ³ form a linear alkylene group having 3 to 5 carbon atoms, particularly a trimethylene group.

The diamine platinum complex of the present invention can be produced, for example, according to the following formula.

[0021]

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Wherein R ¹ and X are the same as above. ]

That is, an aqueous solution of potassium chloroplatinate (K ₂ PtI ₄ ), obtained by adding potassium iodide to an aqueous solution of potassium chloroplatinate, is 1 to 10 times the K ₂ PtI ₄ . The amine (3) is added in a molar amount, preferably 1.2 to 5 times, and reacted at 0 to 60 ° C., preferably 10 to 40 ° C. for 0.5 to 5 hours to obtain a compound (4). Then, the compound (4) is treated with silver nitrate in an aqueous solution to form a diako complex (5). To the aqueous solution of the diako complex (5), a malonic acid derivative or a salt thereof or a halogen atom in an amount of 1 to 3 times the mol of the diako complex is added. Acid or its salt,
By reacting at で 60 ° C., preferably at 10-40 ° C. for 1-8 hours, the desired present compound (1) can be obtained. Compound (1) can be purified and used by a conventional method.

The diamine platinum complex (1) thus obtained has excellent antitumor activity, is highly safe, and effectively acts on cisplatin-resistant strains. Useful as

In order to administer the diamine platinum complex (1) as a therapeutic agent for malignant tumors to mammals including humans, it is usually preferable to combine it with a pharmaceutical carrier to form a pharmaceutical composition. Examples of such a pharmaceutical composition include compositions for injection such as intravenous injection, intramuscular injection, and tumor injection, compositions for oral administration, compositions for rectal administration, and the like, with compositions for injection being particularly preferred.

When a composition for oral administration, especially a solid preparation for oral administration, is prepared, an excipient and, if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, and a flavor are added to the diamine platinum complex of the present invention. After adding an agent, a deodorant and the like, tablets, capsules, powders, granules, fine granules and the like may be prepared in a conventional manner. Excipients include, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methylcellulose, carboxymethylcellulose, glycerin, sodium alginate, gum arabic, etc., and binders such as polyvinyl alcohol, polyvinyl ether, ethyl cellulose, and arabic. Rubber, shellac, sucrose and the like, and lubricants include magnesium stearate, talc and the like. In addition, conventionally known coloring agents and disintegrating agents can be used. The tablets may be coated by a known method.

When preparing an injectable composition, distilled water for injection, a pH adjuster, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the diamine platinum complex of the present invention. Intravenous, intramuscular, and intratumoral injections may be prepared by conventional methods.
Sodium citrate, sodium acetate, sodium phosphate and the like can be used as pH adjusters and buffers, and sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid and the like can be used as stabilizers.

A composition for rectal administration, for example, a suppository, can be produced by a conventional method after adding a base and, if necessary, a surfactant to the diamine platinum complex of the present invention.
As the base, for example, oily bases such as macrogol, lanolin, cocoa oil, fatty acid triglyceride, and Witepsol (manufactured by Dynamite Nobels) can be used.

The dosage of the medicament of the present invention, particularly the therapeutic agent for malignant tumor, varies depending on the usage, patient condition, age, body weight and the like. In the case of an injection, the dose of the diamine platinum complex (1) is 3 to 150 mg / day. It is preferably administered by dividing m ² 1-3 times.

[0030]

EXAMPLES Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

Example 1 (Compound 1) 6.23 g (15 mmol) of potassium chloroplatinate and 24.9 g (150 mmol) of potassium iodide were added to 100 ml of water, and the mixture was stirred at 60 ° C. for 30 minutes. An aqueous solution of potassium platinate was obtained. The aqueous solution was returned to room temperature, and 1.56 g of O-methyl-1,3-diamino-2-propanol was added.
(15 mmol) and stirred at room temperature for 30 minutes. After the reaction, the resulting crystals were collected by filtration, washed successively with water, ethanol and ether, and dried to obtain yellow crystals of cis-diiodo (O-methyl-1,3-diamino-2-propanol) platinum (II). 4.72 g (57% yield) was obtained.

Melting point: 185-200 ° C. (decomposition) Elemental analysis: Calculated: C, 8.68; H, 2.19; N, 5.07 Found: C, 8.73; H, 2.00; N, 5.15

This cis-diiodide (O-methyl-1,3
-Diamino-2-propanol) platinum (II) 2.77 g
(5 mmol) were suspended in 300 ml of water, and 1.7 g of silver nitrate was added thereto.
g (10 mmol) was added, and the mixture was stirred and reacted at room temperature for 3 hours. After the reaction, the generated silver iodide was removed by filtration, and 0.71 of 1,1-cyclobutanedicarboxylic acid was added to the filtrate.
g (5 mmol) dissolved in 10 ml of 1 N sodium hydroxide solution was added, and the mixture was allowed to stand at room temperature overnight. After the reaction, the reaction solution was concentrated to about 2 ml and allowed to stand at 0 ° C., whereby colorless crystals were formed. The resulting crystals are collected by filtration, washed with cold water, dried, and 1,1-cyclobutanedicarboxylato (O-methyl-1,3-diamino-2-propanol) platinum (II) (compound 1) ) 1.12 g (52% yield)
I got

[0034]

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Melting point: 215-230 ° C. (decomposition) Elemental analysis: Calculated: C, 27.21; H, 4.11; N, 6.35 Found: C, 27.28; H, 4.02; N, 6.42 IR (KBr) ν _max cm ^-1 : 3450, 3200, 3120, 1620, 1600

Example 2 (Compound 2) In Example 1, O-methyl-1,3-diamino-2
O-ethyl-1,3-diamino-2-propanol was used in place of -propanol, and cis-diiodo (O-ethyl-1,3-diamino-2
-Propanol) Platinum (II) yellow crystals (57% yield)
I got

Melting point: 210-220 ° C. (decomposition) Elemental analysis: Calculated: C, 10.59; H, 2.94; N, 4.94 Found: C, 10.51; H, 3.15; N, 4.80

This cis-diiodide (O-ethyl-1,3
1,1-cyclobutanedicarboxylate (O-ethyl-1,3-diamino-2-propanol) represented by the following formula in the same manner as in Example 1 except that -diamino-2-propanol) platinum (II) was used. ) Platinum (II) (compound 2) (yield 67%) was obtained.

[0039]

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Melting point: 235-245 ° C. (decomposition) Elemental analysis: Calculated: C, 29.01; H, 4.43; N, 6.15 Found: C, 28.81; H, 4.50; N, 6.00 IR (KBr) ν _max cm ^-1 : 3450, 3250, 3150, 1660, 1370

Example 3 (Compound 3) In Example 1, O-methyl-1,3-diamino-2
O-methoxymethyl-1,3 instead of propanol
Cis-diiodo (O-methoxymethyl-1,2) was prepared in the same manner as in Example 1 except that -diamino-2-propanol was used.
Yellow crystals of 3- (diamino-2-propanol) platinum (II) (57% yield) were obtained.

Melting point: 180-190 ° C. (decomposition) Elemental analysis: Calculated: C, 10.30; H, 2.42; N, 4.80 Found: C, 10.42; H, 2.20; N, 4.63

This cis-diiodo (O-methoxymethyl-1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 1, except that 1,1,
-Cyclobutanedicarboxylato (O-methoxymethyl-1,3-diamino-2-propanol) platinum (II) crystal (compound 3) (47% yield) was obtained.

[0044]

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Melting point: 230-250 ° C. (decomposition) Elemental analysis: Calculated: C, 28.03; H, 4.28; N, 5.94 Found: C, 28.10; H, 4.50; N, 5.75 IR (KBr) ν _max cm ^-1 : 3450, 3200, 3110, 1630, 1605

Example 4 (Compound 4) In Example 1, O-methyl-1,3-diamino-2
O-methoxyethyl-1,3 instead of propanol
-Diamino-2-propanol was used, and cis-diiodo (O-methoxyethyl-
Crystals of (1,3-diamino-2-propanol) platinum (II) were obtained (yield: 60%).

Melting point: 185-195 ° C. (decomposition) Elemental analysis: Calculated: C, 12.09; H, 2.70; N, 4.69 Found: C, 12.00; H, 2.55; N, 4.77

This cis-diiodo (O-methoxyethyl-1,3-diamino-2-propanol) platinum (II) was used and the other conditions were the same as in Example 1, except that
-Cyclobutanedicarboxylato (O-methoxymethyl-1,3-diamino-2-propanol) platinum (II) crystal (compound 4) was obtained (yield 49%).

[0049]

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Melting point: 225-235 ° C. (decomposition) Elemental analysis: Calculated: C, 29.09; H, 4.57; N, 5.77 Found: C, 29.04; H, 4.50; N, 5.48 IR (KBr) ν _max cm ^-1 : 3500, 3250, 3100, 1620, 1580

Example 5 (Compound 5) 4.15 g (10 mmol) of potassium chloroplatinate and 16.6 g (100 mmol) of potassium iodide were dissolved in 70 ml of water and stirred at room temperature for 1 hour. After the reaction, the reaction solution is heated to 50 ° C.
And concentrated to dryness under reduced pressure. The residue was extracted with 80 ml of ethanol, and insolubles were removed by filtration. 3.53 g (10 mmol) of O-benzyl-1,3-diamino-2-propanol dihydrochloride and 0.80 of sodium hydroxide were added to the filtrate.
g (20 mmol) was added, and the mixture was stirred at room temperature for 60 minutes. After the reaction, the generated crystals were collected by filtration and dried, and cis-diiodide (O
5.75 g (yield 91%) of yellow crystals of -benzyl-1,3-diamino-2-propanol) platinum (II) were obtained.

Melting point: 200-215 ° C. (decomposition) Elemental analysis: Calculated: C, 19.09; H, 2.56; N, 4.45 Found: C, 19.20; H, 2.42; N, 4.38

This cis-diiodo (O-benzyl-1,
3-diamino-2-propanol) platinum (II) 4.40
g (7 mmol) and 2.38 g (14 mmol) of silver nitrate in water 3
Then, the mixture was stirred at room temperature for 6 hours. After the reaction, the generated silver iodide was removed by filtration, and a solution obtained by dissolving 0.994 g (7 mmol) of 1,1-cyclobutanecarboxylic acid in 14 ml of 1 N sodium hydroxide was added to the filtrate, and the mixture was allowed to stand at room temperature overnight. After the reaction, the reaction solution was concentrated to 30 ml, and
The resulting crystals were collected by filtration, dried, and 1,1-cyclobutanedicarboxylato (O-benzyl-1,3-diamino-2-propanol) platinum (I
1.01 g of colorless crystals of I) (compound 5) (25% yield)
I got

[0054]

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Melting point: 230-250 ° C. (decomposition) Elemental analysis: Calculated: C, 37.14; H, 4.29; N, 5.41 Found: C, 37.11; H, 4.22; N, 5.31 IR (KBr) ν _max cm ^-1 : 3450, 3210, 3110, 1660, 1630

Example 6 (Compound 6) In Example 5, O-benzyl-1,3-diamino-
O- (p-fluorobenzyl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride, and cis-diiodo (O- ( Yellow crystals of p-fluorobenzyl) -1,3-diamino-2-propanol) platinum (II) (yield 7
3%).

Melting point: 180-190 ° C. (decomposition) Elemental analysis: Calculated: C, 18.56; H, 2.34; N, 4.33 Found: C, 18.76; H, 2.18; N, 4.19

This cis-diiodo (O- (p-fluorobenzyl) -1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as those of Example 5, except that 1-cyclobutanedicarboxylate (O- (p
-Fluorobenzyl) -1,3-diamino-2-propanol) platinum (II) (compound 6) as colorless crystals (yield 47).
%).

[0059]

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Melting point: 205-220 ° C. (decomposition) Elemental analysis: Calculated: C, 35.89; H, 3.95; N, 5.23 Found: C, 35.74; H, 4.25; N, 5.10 IR (KBr) ν _max cm ^-1 : 3450, 3210, 3120, 1660, 1610

Example 7 (Compound 7) In Example 5, O-benzyl-1,3-diamino-
O- (p-chlorobenzyl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride, and cis-diiodo (O- ( p-chlorobenzyl) -1,3-diamino-
Yellow crystals of 2-propanol) platinum (II) (yield 40
%).

Melting point: 230-240 ° C. (decomposition) Elemental analysis: Calculated: C, 18.10; H, 2.28; N, 4.22 Found: C, 18.15; H, 2.19; N, 4.16

This cis-diiodo (O- (p-chlorobenzyl) -1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as those of Example 5, except that 1-cyclobutanedicarboxylate (O- (p-
Colorless crystals of (chlorobenzyl) -1,3-diamino-2-propanol) platinum (II) (compound 7) (67% yield)
I got

[0064]

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Melting point: 210-225 ° C. (decomposition) Elemental analysis Calculated: C, 34.82; H, 3.84; N, 5.08 Found: C, 34.88; H, 3.74; N, 4.87 IR (KBr) ν _max cm ^-1 : 3400, 3220, 3120, 1640, 1610

Example 8 (Compound 8) In Example 5, O-benzyl-1,3-diamino-
O-acetyl- in place of 2-propanol dihydrochloride
Using 1,3-diamino-2-propanol dihydrochloride,
Otherwise in the same manner as in Example 5, cis-diiodo (O-acetyl-1,3-diamino-2-propanol) platinum (I
Yellow crystals of I) (65% yield) were obtained.

Melting point: 205-220 ° C. (decomposition) Elemental analysis: Calculated: C, 10.34; H, 2.08; N, 4.82 Found: C, 10.19; H, 2.12; N, 4.71

This cis-diiodo (O-acetyl-1,
3-Diamino-2-propanol) platinum (II),
Otherwise in the same manner as in Example 5, colorless crystals of 1,1-cyclobutanedicarboxylate (O-acetyl-1,3-diamino-2-propanol) platinum (II) (compound 8) represented by the following formula (compound 8) 54%).

[0069]

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Melting point: 215-230 ° C. (decomposition) Elemental analysis: Calculated: C, 28.15; H, 3.87; N, 5.97 Found: C, 28.19; H, 3.69; N, 5.99 IR (KBr) ν _max cm ^-1 : 3450, 3250, 3110, 1730, 1640, 16
00

Example 9 (Compound 9) In Example 5, O-benzyl-1,3-diamino-
O- (n-Valeryl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride, and cis-diiodide (O
Yellow crystals of-(n-valeryl) -1,3-diamino-2-propanol) platinum (II) (70% yield) were obtained.

Melting point: 210-220 ° C. (decomposition) Elemental analysis: Calculated: C, 15.42; H, 2.91; N, 4.50 Found: C, 15.46; H, 3.05; N, 4.35

This cis-diiodo (O- (n-valeryl) -1,3-diamino-2-propanol) platinum (I
Using I), and otherwise as in Example 5, 1,1-cyclobutanedicarboxylato (O- (n-valeryl) -1,3-diamino-2-propanol) platinum (II) Colorless crystals of Compound 9 (yield 72%) were obtained.

[0074]

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Melting point: 220-240 ° C. (decomposition) Elemental analysis: Calculated: C, 32.88; H, 4.73; N, 5.48 Found: C, 32.73; H, 4.71; N, 5.40 IR (KBr) ν _max cm ^-1 : 3450, 3280, 3200, 3180, 2950, 17
40, 1710, 1640, 1595, 1380

Example 10 (Compound 10) In Example 5, O-benzyl-1,3-diamino-
O-glycolyl- in place of 2-propanol dihydrochloride
Using 1,3-diamino-2-propanol dihydrochloride,
Otherwise in the same manner as in Example 5, yellow crystals of cis-diiodo (O-glycolyl-1,3-diamino-2-propanol) platinum (II) were obtained (36% yield).

Melting point: 185-195 ° C. (decomposition) Elemental analysis: Calculated: C, 10.06; H, 2.03; N, 4.69 Found: C, 9.96; H, 2.00; N, 4.81

This cis-diiodo (O-glycolyl-
1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1,1-diamine represented by the following formula was used.
Cyclobutanedicarboxylate (O-glycolyl-1,
Colorless crystals (40% yield) of (3-diamino-2-propanol) platinum (II) (compound 10) were obtained.

[0079]

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Melting point: 220-230 ° C. (decomposition) Elemental analysis: Calculated: C, 27.22; H, 3.74; N, 5.77 Found: C, 27.18; H, 3.69; N, 5.52 IR (KBr) ν _max cm ^-1 : 3350, 3260, 3220, 3110, 1750, 16
40, 1590

Example 11 (Compound 11) In Example 5, O-benzyl-1,3-diamino-
O-cyclopropanecarbonyl-1,3-diamino-2-propanol dihydrochloride is used instead of 2-propanol dihydrochloride, and cis-diiodo (O-cyclopropanecarbonyl-1,3-diamino-2-propanol) is used. Yellow platinum (II) crystals (68% yield) were obtained.

Melting point: 215-225 ° C. (decomposition) Elemental analysis: Calculated: C, 13.85; H, 2.32; N, 4.61 Found: C, 13.98; H, 2.11; N, 4.31

Using this cis-diiodo (O-cyclopropanecarbonyl-1,3-diamino-2-propanol) platinum (II), the procedure of Example 5 was repeated, except that 1,1-
Colorless crystals (88% yield) of cyclobutanedicarboxylato (O-cyclopropanecarbonyl-1,3-diamino-2-propanol) platinum (II) (compound 11) were obtained.

[0084]

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Melting point: 215-225 ° C. (decomposition) Elemental analysis: Calculated: C, 31.52; H, 4.07; N, 5.65 Found: C, 31.44; H, 4.09; N, 5.60 IR (KBr) ν _max cm ^-1 : 3500, 3220, 3150, 1710, 1620, 15
90

Example 12 (Compound 12) In Example 5, O-benzyl-1,3-diamino-
O-pivaloyl- in place of 2-propanol dihydrochloride
Using 1,3-diamino-2-propanol dihydrochloride,
Otherwise in the same manner as in Example 5, yellow crystals of cis-diiodo (O-pivaloyl-1,3-diamino-2-propanol) platinum (II) were obtained (yield: 75%).

Melting point: 220-230 ° C. (decomposition) Elemental analysis: Calculated: C, 15.42; H, 2.91; N, 4.50 Found: C, 15.40; H, 3.01; N, 4.35

This cis-diiodo (O-pivaloyl-
1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1,1-diamine represented by the following formula was used.
Cyclobutanedicarboxylate (O-pivaloyl-1,
Colorless crystals of 3- (diamino-2-propanol) platinum (II) (compound 12) were obtained (yield 53%).

[0089]

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Melting point: 235-250 ° C. (decomposition) Elemental analysis: Calculated: C, 32.88; H, 4.73; N, 5.48 Found: C, 32.79; H, 4.77; N, 5.31 IR (KBr) ν _max cm ^-1 : 3500, 3250, 3090, 1710, 1630, 15
80

Example 13 (Compound 13) In Example 5, O-benzyl-1,3-diamino-
O- (2-furoyl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride, and cis-diiodide (O
Yellow crystals of (-furoyl) -1,3-diamino-2-propanol) platinum (II) were obtained (yield 68%).

Melting point: 195-205 ° C. (decomposition) Elemental analysis: Calculated: C, 15.18; H, 1.91; N, 4.42 Found: C, 15.23; H, 1.62; N, 4.31

This cis-diiodo (O- (2-furoyl) -1,3-diamino-2-propanol) platinum (I
Using I), and otherwise as in Example 5, 1,1-cyclobutanedicarboxylato (O- (2-furoyl) -1,3-diamino-2-propanol) platinum (II) represented by the following formula: Colorless crystals of Compound 13 were obtained (yield 54%).

[0094]

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Melting point: 225-240 ° C. (decomposition) Elemental analysis: Calculated: C, 32.25; H, 4.48; N, 5.37 Found: C, 32.01; H, 4.49; N, 5.47 IR (KBr) ν _max cm ^-1 : 3450, 3250, 3120, 1710, 1630, 16
00

Example 14 (Compound 14) In Example 5, O-benzyl-1,3-diamino-
O- (2-thiophenecarbonyl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride.
Diiodo (O- (2-thiophenecarbonyl) -1,3
Yellow crystals of (-diamino-2-propanol) platinum (II) were obtained (yield 60%).

Melting point: 190-200 ° C. (decomposition) Elemental analysis: Calculated: C, 15.57; H, 1.96; N, 4.54 Found: C, 15.39; H, 1.90; N, 4.59

This cis-diiodo (O- (2-thiophenecarbonyl) -1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1-cyclobutanedicarboxylate (O
-(2-thiophenecarbonyl) -1,3-diamino-
Colorless crystals of 2-propanol) platinum (II) (compound 14) were obtained (yield 59%).

[0099]

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Melting point: 190-200 ° C. (decomposition) Elemental analysis: Calculated: C, 31.29; H, 3.38; N, 5.21 Found: C, 31.35; H, 3.29; N, 5.11 IR (KBr) ν _max cm ^-1 : 3450, 3250, 3100, 1695, 1630, 15
80

Example 15 (Compound 15) In Example 5, O-benzyl-1,3-diamino-
O-benzoyl- in place of 2-propanol dihydrochloride
Using 1,3-diamino-2-propanol dihydrochloride,
Otherwise in the same manner as in Example 5, yellow crystals of cis-diiodo (O-benzoyl-1,3-diamino-2-propanol) platinum (II) (46% yield) were obtained.

Melting point: 210-225 ° C. (decomposition) Elemental analysis: Calculated: C, 18.68; H, 2.19; N, 4.36 Found: C, 18.63; H, 2.11; N, 4.29

This cis-diiodo (O-benzoyl-
1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1,1-diamine represented by the following formula was used.
Cyclobutanedicarboxylate (O-benzoyl-1,
Colorless crystals of (3-diamino-2-propanol) platinum (II) (compound 15) (46% yield) were obtained.

[0104]

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Melting point: 245-260 ° C. (decomposition) Elemental analysis: Calculated: C, 36.16; H, 3.79; N, 5.27 Found: C, 36.03; H, 3.72; N, 5.38 IR (KBr) ν _max cm ^-1 : 3500, 3400, 3250, 3090, 1710, 16
30, 1590

Example 16 (Compound 16) In Example 5, O-benzyl-1,3-diamino-
O- (4-hydroxylbenzoyl) -1,3-diamino-2-propanol dihydrochloride was used in place of 2-propanol dihydrochloride, and cis-diiodo (O- ( 4-hydroxylbenzoyl)-
Yellow crystals of 1,3-diamino-2-propanol) platinum (II) were obtained (yield 81%).

Melting point: 225-235 ° C. (decomposition) Elemental analysis: Calculated: C, 18.22; H, 2.14; N, 4.25 Found: C, 18.19; H, 2.01; N, 4.30

This cis-diiodo (O- (4-hydroxylbenzoyl) -1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1-cyclobutanedicarboxylate (O
Colorless crystals (62% yield) of-(4-hydroxylbenzoyl) -1,3-diamino-2-propanol) platinum (II) (compound 16) were obtained.

[0109]

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Melting point: 225-240 ° C. (decomposition) Elemental analysis: Calculated: C, 35.11; H, 3.68; N, 5.12 Found: C, 35.03; H, 3.94; N, 5.01 IR (KBr) ν _max cm ^-1 : 3350, 3220, 3120, 1700, 1620, 15
90

Example 17 (Compound 17) In Example 5, O-benzyl-1,3-diamino-
O- (2-hydroxylbenzoyl) -1,3-diamino-2-propanol dihydrochloride was used instead of 2-propanol dihydrochloride, and cis-diiodo (O- ( 2-hydroxylbenzoyl)-
Yellow crystals of 1,3-diamino-2-propanol) platinum (II) were obtained (yield 77%).

Melting point: 240-250 ° C. (decomposition) Elemental analysis: Calculated: C, 18.22; H, 2.14; N, 4.25 Found: C, 18.18; H, 2.10; N, 4.44

This cis-diiodo (O- (2-hydroxylbenzoyl) -1,3-diamino-2-propanol) platinum (II) was used, and the other conditions were the same as in Example 5, except that 1-cyclobutanedicarboxylate (O
Colorless crystals (20% yield) of-(2-hydroxylbenzoyl) -1,3-diamino-2-propanol) platinum (II) (compound 17) were obtained.

[0114]

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Melting point: 240-250 ° C. (decomposition) Elemental analysis: Calculated: C, 35.11; H, 3.68; N, 5.12 Found: C, 35.00; H, 3.51; N, 5.18 IR (KBr) ν _max cm ^-1 : 3350, 3220, 3100, 1670, 1620, 15
90

Test Example 1 Cisplatin-resistant cells L1210 / DDP and P388
/ DDP cross-resistance test: 4 mouse syngeneic tumors (L1210
leukemia, L1210 / DDP, P388 leukemia, P388 / DDP)
WST using a 3-day culture system (addition of 48 hours of drug)
-1 Colorimetric method (a modification of the MTT method, Chem. Pharm. Bull., 4
1, 1118-1122, (1993))
did. Various cell lines containing 10% FCS (fetal calf serum)
RPMI 1640 culture solution (P388 / DDP culture solution is
In addition, it contains 2-Mercaptoethanol at 10 μM)
1 × 10^FiveAdjust to cells / ml and add 100 μl (1 ×
10 ^Fourcells / 100μl / well) in a 96-well culture plate
Seeded. 37 ° C 5% CO_Two24:00 in the incubator
After interculture, 10 μl of each dose of drug was added,
37 ° C 5% CO_TwoCultured for 48 hours in an incubator
did. End of culture for 48 hours (72 hours after start of cell culture)
4 hours before the addition, add 10 μl of WST-1 to each well
4 hours later, the plate was read with a plate reader. D. 45
The absorbance at 0 nm was measured. O.S. of untreated control group.
D. Assuming a value of 100%, cell growth inhibition for each dose of each drug
Calculate the efficiency of each drug treatment group from the linear regression line.₅₀
Values were calculated. Further, L121 of each complex is represented by the following formula.
Resistance to 0 / DDP and P388 / DDP
Factor (RF value) was calculated. Table 1 shows the results.

[0117] RF value ^a) = (L1210 / IC ₅₀ values for DDP) ÷ (IC ₅₀ values for L1210) IC ₅₀ values for the RF values ^{b) = (P388 / DDP)} ÷
(IC ₅₀ value for P388)

[0118]

[Table 1]

[0119] Anti-tumor test for Test Example 2 Mouse leukemia cells L1210: murine leukemia cells L1210 1 × 10 ⁵ cells were transplanted into the abdominal cavity of 6-week-old male CDF ₁ mice, once a day for 5 days from the next day The drug (the compound of the present invention) is administered intraperitoneally, and 3
Observation was performed for 0 days, and the survival rate (LLS: Increase in life spa) was calculated from the average survival days of the drug-treated group and the untreated group according to the following formula.
n).

ILS = (T / C-1) × 100 (%) T = average survival days of drug-treated group C = average survival days of drug-untreated group

Further, based on the ILS value for each dose of each sample, the ILS ₅₀ value (I
The therapeutic index was calculated from the LD ₅₀ value (dose showing an LS value of 50%) and the LD ₅₀ value (50% lethal dose in a single intraperitoneal administration) obtained at the time of dose setting. Table 2 shows the results. In the table, ILS _max is the ILS in the set dose range.
And the dose (mg / kg) are shown in parentheses.

[0122]

[Table 2]

[0123]

Industrial Applicability The diamine platinum complex (1) of the present invention has excellent antitumor effect, high safety, and effectively acts on cisplatin-resistant strains, and thus is useful as a drug, especially as a therapeutic agent for malignant tumors. .

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Hidehiko Kamiya 2-2-21-404, Azuma, Narita City, Chiba Prefecture (72) Inventor Mari Mari Otsuka 4-7-15-704, Yatsu, Narashino City, Chiba Prefecture (72) Inventor Hiroyuki Mizuno 1-24-19 Hiyoshidai, Tomisato-cho, Inba-gun, Chiba Prefecture (72) Inventor Susumu Suto 6-15-5, Tamazo Narita City, Chiba Prefecture

Claims (4)

[Claims] 1. The following general formula (1): [Wherein, R ¹ is an alkyl group which may have a substituent,
X represents an aralkyl group which may have a substituent or an acyl group which may have a substituent, and X represents a halogen atom, or two Xs together have a substituent. To form a malonic acid residue. ] The diamine platinum complex represented by these. 2. R ¹ is a linear or branched alkyl group having 1 to 9 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms,
An aralkyl group having 7 to 19 carbon atoms, an alkanoyl group having 1 to 9 carbon atoms, a cycloalkanoyl group having 3 to 7 carbon atoms, a benzoyl group or a 5- to 6-membered heteroaroyl group (these groups include a hydroxy group, X is a halogen atom, or X is a halogen atom or the following formula (2): (Wherein R ² and R ³ may be the same or different,
Represents a hydrogen atom, an alkyl group having 1 to 9 carbon atoms, or R
² and R ³ may together form a linear alkylene group having 2 to 5 carbon atoms. 2) a group represented by the formula:
The diamine platinum complex according to the above. 3. A medicament comprising the diamine platinum complex according to claim 1 or 2 as an active ingredient. 4. A therapeutic agent for malignant tumors comprising the diamine platinum complex according to claim 1 as an active ingredient.