AU627748B2 - Novel selenious acid-platinum complex and anti-tumor agent comprising said complex as effective ingredient - Google Patents

Description

627748 COMMONWEALTH OF AUSTRALIA PATENTS ACT' 1952 C01PLEE PEICAflnI NAME ADDRESS OF APPLICANT: Tsumura Co.

4-10, Nihombashi 3-chome Chuo-ku Tokyo Japan NAME(S) OF INVENTOR(S): Ken Miyarnoto Yuichi Fujil ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

6* Lt 4* 5 COMPLETE SPECIFICATION FOR THE INVENTION ENTITfl 1D: Novel. selenious acid-platinum complex and anti-tumor agent comprising -aid complex as effective ingredient The following statement is a full description of this invention, performing it known to me/us:including the best method of

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TXR-7400 -1a NOVEL SELENIOUS ACID-PLATINUM COMPLEX AND ANTI-TUMOR AGENT COMPRISING SAID COMPLEX AS EFFECTIVE INGREDIENT o e.G

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0 BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a novel selenious acid-platinum complex having Pn anti-tumor activity, which is valuable as a medicine such as an anti-tumor agent.

Description of the Related Art Some platinum complexes, represented by cisplatin, have a prominent anti-tumor effect, and 10 cisplatin is applied to combat diseases. Nevertheless, the toxicity of cisplatin, such as the toxicity to the kidney, is very strong, and a clinical treatment with this complex is hindered by this toxicity. Therefore, the development of a medicine having a toxicity lower than those of the conventional platinum complexes and a high anti-tumor effect is required.

SUMMARY OF THE INVENTION To solve this problem, the present inventions carried out research into platinum complexes containtring 20 selenious acid as a ligand, and as a result, found a selenious acid-platinum complex having a lower tox. city than those of the conventional complexes and a higher anti-tumor activity.

More specifically, in accordance with the present 25 invention, there is provided a novel selenious acid-platinum complex represented by the following general formula: -Pt Se 0 0 2 wherein R 1 and R 2 each stand for NH 3 or together from NH NH

NH

2 C 2 2 or 7 2 NH NH 2 2 Furthermore, in accordance with the present invention, there is provided an anti-tumor agent comprising this platinum complex as an effective ingredient.

.o °DESCRIPTION OF THE PREFERRED EMBODIMENTS "0 The novel selenious acid-platinum complex of the .o present invention (hereinafter referred to as "the compound of the present invention") is prepared, for 0 example, according to the following process.

So A dinitrato-platinum complex having ammonia, 1,2-cyclohexanediamine or 1,2-cyclooctanediamine as a carrier ligand according to the intended compound is 0.07 20 used as the starting material, and the starting complex is brought into contact with an OH type anion exchange .0o" resin to convert the nitro group of the complex to a 0 hydroxyl group, and the complex is reacted with selenium dioxide, whereby the intended platinum complex is obtained.

Other examples of carrier ligands include 0 aminomethylpyrrolidine, aminomethylpiperidine, and o' diaminopentane.

As the dinitrato-platinum complex, there can be mentioned, for example, dinitrodiaminoplatinum, dinitrocyclohexanediaminoplatinum, and diaminocyclooctanediaminoplatinum.

Diaion SA10AOH (supplied by Mitsubishi Kasei) can ij be used as the OH- type anion exchange resin.

The contact method is not particularly critical, so I long as the platinum complex is brought into proper contact with the resin, for example, a batchwise method I

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3- 0 0 o 0 0 0 0 0 0 00 00 0 0 00 ~0 o o 0 and a column method can be adopted, but from the viewpoint of contact efficiency, the column method is preferable.

The reaction with selenium dioxide is preferably realized by adding selecium dioxide to the complex to form a solution and allowing the solution to stand for about 12 to about 36 hours. After the reaction, methanol or the like is added to the reaction mixture to precipitate the formed platinum complex, and the precipitate is recovered by filtration and dried to obtain the intended platinum complex.

The structure of the compound of the present invention is confirmed by elementary analysis, infrared absorption spectrum, and the like.

15 The anti-tumor effect of the compound of the present invention will now be described with reference to the following experiment.

Experiment (Test of Anti-Tumor Effect on Mouse Leukemia L1210 Cells) 20 Six-week-old male CDF 1 mice were implanted intraperitoneally 1 x 10 5 of mouse leukemia L1210 cells, and every four days starting from the following day, the compound obtained in Example 2 or 3 gi'ven hereinafter was administered three times into the abnominal cavity.

Only a physiological saline was administered to the control group. With respect to each of the groups to which the compounds obtained in Examples 2 and 3 were administered, and to the cont.rol group, the increase in life span was determined ftev the average number of survival days.

The administration dozjrges and increase in life span are shown in Table i.

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1' Iii i*1 000t o 0 0~ 6 #6 t 0 0# 0 6 6# 0 06 666000 0 0 4 Table 1 Increase in Life Span (Z) Administration Dosage 200 mg/kg 10 mg/kg 5 mg/kg Compound obtained in Example 2 188 302 246 Compound obtained in Example 3 169 329 271 It can be seen from the results shown in Table 1 that the compound of the present invention has an excellent antitumor activity. No side effects, such as the toxicity to the kindney, were observed during this 15 experiment.

~Therefore, the compound of the present invention has an excellent anti-tumor action and is valuable as an anti-tumor agent.

When the acute toxicity test of the compounds of the present invention was carried out by using ICR mice, it was found that the LD 5 of the compound obtained in o Example 2 described hereinafter was 30.6 mg/kg, and the 00 LD 50 of the compound obtained in Example 3 described 0,0 hereinafter was 23.4 mg/kg.

o0 0 The administration dosages and preparations of the compound of the present invention will now be described.

o o The compound of the present invention can be administered to humans and animals directly or together 04with a conventional pharmaceutical carrier. The administration form is not particularly critical, and any appropriate form can be selected and adopted. For example, there can be mentioned oral preparations such as tablets, capsules, granules, fine granules and powders, and non-oral preparations such as injections and suppositories.

In the case of oral preparations, to obtain the intended effect, preferably 10 to 600 mg of the compound c Li ~-1CII~ 5

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i U3 00 o 0o o 0o 0 0 0 00 00 00, o 0 000* 01 0 0 1 00 0 0 is dividedly administered several times per day to an adult, although the preferred dosage differs to some extent in accordance with the age and body weight of the patient and the severity of the disease.

Oral preparations can be formed by using, for example, starch, lactose, white sugar, mannitol, carboxymethyl cellulose, corn starch, and inorganic salt or the like by customary procedures.

For oral preparations of this type, a binder a disintegrating agent, a surface active agent, a lubricant, a flowability promoter, a taste improver, a colorant, a perfume and the like can be used in addition to the above-mentioned excipient. Specific examples are described below.

15 (Binder) Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinyl 20 cellulose, and macrogol.

(Disintegrating Agent) Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, and lowly substituted 25 hydroxypropyl cellulose.

(Surface Active Agent) Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid esters, and Polysolbate (Lubricant) Talc, waxes, hydrogenated vegetable oils, sucrose fatty acid esters, magnesium stearate, calcium stearate, aluminum stearate, and polyethylene glycol.

(Flowability Promoter) Light silicic anhydride, dry aluminum hydroxide gel, synthetic aluminum silicate and magnesium silicate.

The compound of the present invention also can be administered in the form of a suspension, an emulsion, a -1 ii I i 6 syrup or an elixir. These preparations may contain a taste improver, an odor improver, a colorant, and the like.

In the case of non-oral preparations, to obtain the intended effect, preferably 5 to 200 mg of the compound of the present invention is administered per day to an adult, by intravenous injection, intravenous drip, hypodermic injection or intramuscular injection, although the preferred dose differs to some extent in accordance with the age and body weight of the patient and the severity of the disease.

°o Non-oral preparations are formed by customary O~ procedures, and as the diluent, generally used are distilled water for injection, a physiological saline solution, an aqueous solution of glucose, a vegetable aoil for injection, sesame oil, peanut oil, soybean oil, 0 corn oil, propylene glycol, and polyethylene glycol.

A fungicide, an antiseptic agent, and a stabilizer may be added according to need. From the viewpoint of stability, preferably a method is adopted in which this oo G non-oral preparation is filled and frozen in a vial, 0 00 0o°. water is removed by a usual freeze-drying technique, and a liquid preparation is formed again from the dry 00 product just before administration. Furthermore, an isotonic agent, a stabilizer, an antiseptic agent a pain-killing agent, and the like can be appropriately added according to need.

As other non-oral preparations, there can be mentioned coating agents such as external lotions and ointments, and suppositories for intrarectal administration. These non-oral preparations can be formed by customary procedures.

The present invention will now be described in detail with reference to the following examples, that by no means limit the scope of the invention.

Example 1 In 150 ml of distilled water was dissolved 2.5 g of :-i 7 cisdinitrodiaminoplatinum having ammonia as the carrier ligand, while heating, and the solution was passed through a column packed with 100 ma of Diaion and drained out by distilled water. Then 786 mg of selenium dioxide and sodium selenite were incorporated and dissolved in the effluent, about 500 ma of the solution was allowed to stand overnight while intercepting light with an aluminum foil, the solution was concentrated under a reduced pressure by an aspirator, and methanol was added to the concentrate to precipitate a yellow solid. The formed solid was .oo recovered by filtration, thoroughly washed with distilled water, and air-dried to obtain a yellow solid.

.oo From the following physical and chemical S 15 properties, the yellow solid was identified as ocis-diamine-selenitoplatinum

(II).

o Yield: 2.15 g Elementary Analysis: Calculated values: C H 1.70%, N 7.87% Found values: C H 1.78%, N 7.61% 0 Infrared Absorption Spectrum (FT-IR): 00 830 cm 747 cm 715 cm 527 cm Example 2 In 100 ml of distilled water was dissolved 3.72 g of dinitro-(R,R)-cyclohexanediaminoplatinum having cyclohexanediamine as the carrier ligand, while heating, 00 0 and the solution was passed through a column packed with 160 ma of Diaion SA10AOH and drained out by distilled water. Then 895 mg of selenium dioxide was incorporated and dissolved in the effluent, the solution was allowed to stand overnight, and then concentrated under a reduced pressure by an aspirator. When some yellow solid was formed, the concentration was stopped, and methanol was added to the concentrate to precipitate a yellow solid. The formed yellow solid was thoroughly washed with distilled water and air-dried to obtain a yellow solid.

I From the following physical and chemical properties, the yellow solid was identified as 2R) -cyclohexanediamine]-(selenito)-platinum (II).

Yield: 2.60 g (69%) Elementary Analysis: Calculated values: C 16.52%, H 3.23%, n 6.42% Found values: C 16.23%, H 3.45%, N 6.31% Infrared Absorption Spectrum (FT-IR): 833 cm- 1 722 cm- 1 692 cm- 1 519 cm- 1 Example 3 In 100 m2 of distilled water was dissolved 2.00 g of transdinitrocyclooctanediaminoplatinum having cyclooctanediamine as the carrier ligand, while heating, and the solution was passed through a column packed with 15 160 m£ of Diaion SA10AOH and drained out by distilled 0 water. Then 481 mg of selenium dioxide was incorporated and dissolved in the effluent, the solution was allowed to stand overnight, and then concentrated under a reduced pressure by an aspirator. When some yellow solid was 20 formed, the concentration was stopped, and methanol was added to the concentrate to precipitate a yellow solid and the formed solid was recovered by filtration, wasned thoroughly with distilled water, and air-dried to obtain a yellow solid.

From the following physical and chemical properties, the yellow solid was identified as (trans-1,2-cyclooctanediamine)-(selenito)-platinum (II).

Yield: 1.12 g (56%) Elementary Analysis: 30 Calculated values: C 20.70%, H 3.91%, N 6.03% Found values: C 20.51%, H 3.85%, N 6.03% Infrared Absorption Spectrum (FT-IR): 838 cm- 1 730 cm- 1 693 cm- 1 520 cm- 1 Example 4 Corn starch 52 g Crystalline cellulose 40 g Calcium carboxymethyl cellulose 5 g 6 V2 ;i 1 920616,dbletl27,38007.res,8 .4

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1< 9 Light silicic anhydride 0.5 g Magnesium stearate 0.5 g Compound obtained in Example 2 2 g Total 100 g According to the above recipe, ingredients (1) through were homogeneously mixed and compressionmolded by a tableting machine to obtain tablets, each having a weight of 200 mg.

Each tablet contained 4 mg of the compound obtained in Example 2, and 3 to 50 tablets were dividedly administered to an adult several times per day.

oo Example Crystalline cellulose 92.5 g 0ooo 0 000 0 Magnesium stearate 0.5 g I Calcium carboxymethyl cellulose 5 g 0 o Compound obtained in Example 3 2 g Total 100 g According to the above recipe, ingredients (1) and and a part of ingredient were homogeneously mixed, compression-molded, and pulverized, then o o ingredient and the remainder of ingredient (2) o °were added to and mixed with the pulverized product, and the mixture was compression-molded by a tableting 00 machine to obtain tablets each having a weight of 200 mg.

Each tablet contained 4 mg of the compound obtained Sin Example 3, and 3 to 50 tablets were dividedly administered several times per day to an adult.

Example 6 Crystalline cellulose 42.5 g 10% Ethanol solution of hydroxypropyl cellulose 50 g Calcium carboxymethyl cellulose 5 g Magnesium stearate 0.5 g Compound obtained in Example 2 2 g Total 100 g According to the above recipe, ingredients 10 and were homogeneously mixed, kneaded by a customary procedure, granulated by an extrusion granulator, dried, and disintegrated. Then ingredients (3) and were mixed with the disintegration product, and the mixture was compression-molded by a tableting machine to obtain tablets each having a weight of 200 mg.

Each tablet contained 4 mg of the compound obtained in Example 2, and 3 to 50 tablets were dividedly administered several times per day to an adult.

Example 7 iKi r, Corn starch 93 g Magnesium stearate 0.5 g S. Calcium carboxymethyl cellulose 5 g Light silicic anhydride 0.5 g Compound obtained in Example 3 1 g Total 100 g According to the above recipe, ingredients (1) through were homogeneously mixed, compression-molded by a compression molding machine, pulverized by a 2 pulverizer, and classified to obtain granules.

One gram of the granules contained 10 mg of the compound obtained in Example 3, and 1 to 20 g of the granules were dividedly administered several times per day to an adult.

Example 8 S, Crystalline cellulose 69 g 10% Ethanol solution of hydroxypropyl cellulose 30 g Compound obtained in Example 2 1 g Total 100 g According to the above recipe, ingredients (1) through were homogeneously mixed, kneaded, granulated by a granulator, dried, and classified to obtain granules.

One gram of the granules contained 10 mg of the compound obtained in Example 2, and 1 to 20 g of the 1 granules were divide day to an adult.

Example 9 11 dly administered several times per

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Corn starch 97.5 g Light silicic anhydride 0.5 g Compound obtained in Example 3 2 g Total 100 g According to the above recipe, ingredients (1) through were homogeneously mixed and filled into 10 capsules No. 2. Each capsule contained 200 mg of the mixture.

Further, each capsule contained 4 mg of the compound obtained in Example 3, and 3 to 50 capsules were dividedly administered several times per day to an 15 adult.

Example Distilled water for injection .o o t.

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Ral a r -i o ;o i o i, ur- to o o o Glucose Compound obtained in Exam: appropriate amount 200 mg )le 2 100 mg 0 D O 0 NC C 0 09 S C Total 5 ml Ingredients and were dissolved in distilled water for an injection, and the solution was poured into ampoules and sterilized at 121 0 C for 15 minutes under pressure to obtain injections.

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Claims (4)

1. A selenious acid-platinum complex represented by the following formula: R 0 Pt 0 2 wherein R1 and R 2 each stand for NH 3 or together form NH NH 2 or 2 or So NH NH *2 2

2. A selenious acid-platinum complex according to 6I claim 1, selected from cis-diamine-selenito-platinum (1R, 2R) -cyclohexanediamine-selenito-platinum and trans-1,2-cyclooctanediamine selenito-platinum (II).

3. An anti-tumor agent comprising as an effective ingredient a selenious acid-platinum complex represented by the following formula: 30 wherein R and R each stand for NH 3 or together form a 4 2 2 ~30 wherein R I and R 2 each stand for NH 3 or together form NH NH 2 or 2 SNH NH -13-

4. An anti-tumor agent according to claim 3, wherein the selenious acid-platinum complex is selected from cis-diamine-selenito-platinum (1R, 2R) cyclohexanediamine-selenito-platinum and (trans- 1, 2-cyclooctanediamine)-(selenito)-platinum (II). Selenious acid-platinum complexes or anti-tumor agents containing them, substantially as hereinbefore described with reference to the examples. I o~ ~ao ooo a o+e ar, oo oo a aa 1 o o sc o r~ s r DATED this 16th day of June, 1992 20 Tsumura Co. By Its Patent Attorneys DAVIES COLLISON CAVE _W1- 0~gi 9206 16,dblet 127,38007.res,13