JPH0867688A - New platinum complex - Google Patents

Abstract

PURPOSE: To obtain a new platinum complex useful as a carcinostatic active substance, having excellent water solubility, strong antitumor activity and low toxicity by reacting a 1,2-diaminocycloalkane with a chloroplatinate and K1 and treating the reaction product with glycolic acid, etc. CONSTITUTION: A compound of formula I (formula II is cycloheptane ring or cyclooctane ring) (e.g. trans-1,2-diaminocyclooctane) is reacted with an aqueous solution containing potassium chloroplatinate and potassium iodide. The prepared precipitate of platinum diiodide complex is collected by filtration and dried under reduced pressure. The platinum diiodide complex is dispersed into water, reacted with silver nitrate at 60-6 deg.C for 1 hour to give cis- dinitratodiaminocyclooctaneplatinum (II). Then the compound is reacted with glycolic acid in the presence of sodium hydroxide to give a new platinum complex of formula III (B is a group of formula IV or two Bs are bonded to form a group of formula V with Pt) having excellent water solubility, strong antitumor activity and low toxicity.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel platinum complex expected as an antineoplastic agent.

[0002]

2. Description of the Related Art Among platinum complexes known as antineoplastic agents, cis-dichlorodiammineplatinum (II) is known.
(Generic name cisplatin) has a remarkable antitumor effect, and is currently widely used in clinical practice. Recently, cis-1,
1-Cyclobutanedicarboxylate-diammineplatinum (II) (generic name carboplatin) (JP-A-49-48)
No. 621) also started to be used clinically, and further cis-O,
Platinum complexes such as O'-glycolate-diammine platinum (II) (JP-A-59-222497) and bis (glycolate) diaminocyclohexane platinum (II) (JP-A-5-9191) have also been developed.

[0003]

However, the antitumor activity of these recently developed platinum complexes is not as high as that of cisplatin. Cisplatin also has insufficient antitumor activity against certain tumors, especially slow growing solid tumors. Cisplatin has strong side effects such as nephrotoxicity and vomiting toxicity, and since it has low solubility in water, only a low concentration of the drug can be supplied, which is a problem in clinical treatment. The emergence of cisplatin resistant strains has also become a problem. For this reason, various cisplatin derivatives have been developed as described above, but none of them are unsatisfactory, for example, the activity becomes low when the toxicity becomes low. Therefore, an object of the present invention is to provide a platinum complex having a strong antitumor activity, few side effects and excellent water solubility.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted earnest studies and synthesized novel platinum (II) complex derivatives, found that these achieve the above objects, and completed the present invention. That is, the present invention has the general formula (1)

[Chemical 9] [In the formula

[Chemical 10] Represents a cycloheptane ring or a 1,2-diaminocyclooctane ring, and B is a formula

[Chemical 11] Or two B together and Pt

[Chemical 12] Indicates. ] It is related with the platinum (II) complex represented by this, and the antineoplastic agent which uses this platinum complex as an active ingredient.

In the formula (1) of the present invention,

[Chemical 13] The diaminocycloheptane ring part or the diaminocycloheptane ring part in which an amino group is bonded to each carbon atom at the 1- and 2-positions of the cycloheptane ring or cyclooctane ring includes geometric isomers and optical isomers, These include the following: That is, 1,2-diaminocycloheptane is cis-1,2-diaminocycloheptane,
Trans-1,2-diaminocycloheptane, trans-1-1,2-diaminocycloheptane, trans-d
-1,2-Diamino-cycloheptane may be mentioned.

1,2-Diaminocyclooctane includes cis-1,2-diaminocyclooctane and trans-1,2.
-Diamino-cyclooctane, trans-l-1,2-
Examples include diaminocyclooctane and trans-d-1,2-diaminocyclooctane. Of the above, preferred are the respective trans isomers, more preferably the optically resolved ones, and particularly preferably the l isomer.

Next, the compounds represented by the above general formula (1) are exemplified below. Cis-bisglycolate-trans-
1,2-Diaminocycloheptane platinum (II); cis-
Bisglycolate-trans-l-1,2-diaminocycloheptane platinum (II); cis-bisglycolate-
Trans-d-1,2-diaminocycloheptane platinum (II); cis-bisglycolate-cis-1,2-diaminocycloheptane platinum (II); cis- (glycolate-O, O ')-trans-1 , 2-Diaminocycloheptane platinum (II); cis- (glycolate-O,
O ')-trans-l-1,2-diaminocycloheptane platinum (II);

Cis- (Glycolate-O, O ')-trans-d-1,2-diaminocycloheptane platinum (I
I); cis- (glycolate-O, O ')-cis-1,
2-Diaminocycloheptane platinum (II); cis-bisglycolate-trans-1,2-diaminocyclooctane platinum (II); cis-bisglycolate-trans-l-1,2-diaminocyclooctane platinum (II) );
Cis-bisglycolate-trans-d-1,2-diaminocyclooctane platinum (II);

Cis-bisglycolate-cis-1,2-
Diaminocyclooctane platinum (II); cis- (glycolate-O, O ')-trans-1,2-diaminocyclooctane platinum (II); cis- (glycolate-O,
O ')-trans-l-1,2-diaminocyclooctane platinum (II); cis- (glycolate-O, O')-
Trans-d-1,2-diaminocyclooctane platinum (II); and cis- (glycolate-O, O ′)-cis-1,2-diaminocyclooctane platinum (II).

Next, the dosage and formulation of the platinum complex of the present invention when used as an antitumor agent will be described.
The platinum complex of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. To be In order to exert the desired effect as an oral agent, the patient's age,
Although it depends on the body weight and the degree of disease, it is considered appropriate to administer the platinum complex of the present invention in an adult dose of 10 to 600 mg divided into several times a day. The oral preparation is produced by a conventional method using starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like. In addition to the above-mentioned excipients, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a fragrance and the like can be appropriately used in this type of formulation. The platinum complex of the present invention can also be administered as a suspension, emulsion, syrup, or elixir, and these various dosage forms may contain a flavoring agent and a coloring agent.

In order to exert the desired effect as a parenteral agent, it depends on the age, weight and degree of disease of the patient.
Usually, in adults, the weight of the platinum complex of the present invention is 5 to 20 per day.
Intravenous injection up to 0 mg, intravenous drip injection, subcutaneous injection, and intramuscular injection seem to be appropriate. This parenteral preparation is manufactured according to a conventional method,
Generally, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like can be used as the diluent. Further, if necessary, a bactericide, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation may be filled in a vial or the like, frozen, and then water may be removed by an ordinary freeze-drying technique, and a liquid preparation may be re-prepared from the freeze-dried product immediately before use. Further, an isotonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added as needed. Other parenteral agents include external preparations, coating agents such as ointments, suppositories for rectal administration, etc., and they are manufactured by a conventional method.

The platinum complex of the present invention is produced according to the reactions shown in steps A to D below. Step A

Embedded image [In the formula

[Chemical 15] Is the same as above, M represents an alkali metal atom such as Na and K, and Hal represents a halogen atom such as Cl, Br, and I. ]

That is, as shown in the above reaction formula, a halogenated primary platinum salt represented by the formula (3), preferably potassium halogenated primary platinum salt, and a diamine represented by the formula (4), For example, by reacting 1,2-diaminocycloheptane or 1,2-diaminocyclooctane in an aqueous solution, the dihalogenato diamine platinum complex represented by the formula (2) can be obtained. The diamine of formula (4) is 0.5 with respect to the halogenated primary platinum salt of formula (3).
Double mole to double mole, preferably 0.9 mole to 1.
It is used in the range of 2 times mole, and it is stirred at 0 ℃ to 100 ℃.
The reaction is carried out at a temperature of 10.degree. C., preferably 10.degree.

Next, in the formula (1) which is the target compound, B
There platinum complex is -OCOCH ₂ OH can be prepared as shown in the following Steps B and C. Process B

Embedded image Process C

[Chemical 17]

In step B, the dihalogenate diamine platinum complex of formula (2) is suspended in water, an aqueous solution of silver nitrate is added, and the formed silver halide precipitate is removed by filtration to obtain the compound represented by formula (5). An aqueous solution of the diako complex is obtained.
An appropriate amount of water for suspending the dihalogenato diamine platinum complex of the formula (2) can be used. The amount of silver nitrate used is not particularly limited, but it is preferably used in an amount of 2.5 times or less, more preferably 1.0 to 2.5 times, and particularly preferably 1.0 to 2.5 times the mol of the dihalogenatodiamine platinum complex of formula (2). Preferably, 1.8 to 2 times the molar amount is used. Reaction is 0-10
At a temperature of 0 ° C., preferably 20 to 80 ° C., for 30 minutes or more,
It is preferably performed with stirring for 1 hour or more.

Next, in step C, an aqueous solution of an alkali metal salt of glycolic acid, for example, an aqueous solution of sodium salt is added to the aqueous solution of the diaccomplex of the formula (5) in an appropriate amount and reacted. Generally 1.5 ~
It is preferable to add it in the range of 6 times by mole. Reaction is 0-10
The reaction can be carried out at 0 ° C., but preferably, the reaction is carried out at a temperature of 20 to 70 ° C. for 20 hours or longer, and in the general formula (1), the formula (1-1) in which B is represented by —OCOCH ₂ OH. Can be obtained.

The crude crystals obtained are purified by silica gel chromatography using a methanol-chloroform mixed solvent, or by reprecipitation in an acetone-methanol mixed solvent system or recrystallization with water.

In the formula (1) which is the target compound, two B together form a formula with Pt.

[Chemical 18] The target compound represented by is synthesized by the reaction shown in the following Step D.

Step D

[Chemical 19]

In step D, an aqueous solution of the diako complex of the formula (5) is passed through a column packed with an anion exchange resin (OH type) to obtain a dihydroxydiamine platinum complex of the formula (6). 0.1 to 2 in this aqueous solution
By adding a 2-fold molar amount, preferably 0.5 to 1.5-fold molar amount of glycolic acid and reacting, a target compound of the formula (1-2) is obtained via the compound of the formula (7). The reaction from the compound of formula (7) to the compound of formula (1-2) is completed at 0 to 90 ° C. for several hours to 10 days, but this reaction is a two-step reaction involving the compound of formula (7). And preferably 40 to 70 after reacting at 0 to 40 ° C. for several hours to several days.
It is preferable to complete the reaction by heating at 0 ° C for several hours.

Next, the method for producing the compound of the present invention will be described with reference to Examples.

【Example】

Example 1 cis-bisglycolate-trans-1,2-diamino
Synthesis of cycloheptane platinum (II) (Compound No. 1) 208 mg (0.51 mmol) of potassium chloroplatinate was dissolved in 2 ml of water and 500 mg of potassium iodide was added to 0.5 m of water.
The solution dissolved in 1 is added and reacted at 40 to 41 ° C. for 15 minutes. 103 mg (0.51 mmol) of trans-1,2-diaminocycloheptane hydrochloride was added to 2N Na.
The solution neutralized with OH is added, and the mixture is stirred for one day at room temperature in the dark.

The resulting precipitate of the diiodoplatinum complex is collected by filtration and dried under reduced pressure. 261 mg of the obtained diiodo platinum complex
(0.452 mmol) was dispersed in 2.5 ml of a 20% aqueous solution of ethanol, and silver nitrate was added to 0.3 ml of water.
A liquid in which 6 mg (0.86 mmol) was dissolved was added and the mixture was stirred at 60 to 65 ° C for 1 hour. After cooling, the silver iodide formed was filtered off and the filtrate was dried under reduced pressure to give cis-dinitra-diaminocycloheptane platinum (II) 171 m.
get g. Next, a solution is prepared by dissolving 57.1 mg of glycolic acid in 3.6 ml of 0.2N aqueous sodium hydroxide solution.

112 mg of cis-dinitrate diaminocycloheptane platinum (II) was dissolved in 6 ml of water, and the previously prepared aqueous sodium glycolate solution was added thereto. After reacting for 24 hours at room temperature, water was distilled off under reduced pressure. The obtained crude crystals were recrystallized from a small amount of water to give compound No. One four
8.3 mg was obtained.

Mp. 224-228 ° C (color decomposition) Elemental analysis Calculated value (%): C 27.91: H 4.68: N
5.92 Found (%): C 27.06: H 4.76: N
5.94 IR (KBr) (cm ^-1 ) 3430, 3400, 3250, 2930, 2320,
1630, 1390, 1305, 1090, 1050,
995, 920, 705

Example 2 Cis-bisglycolate-trans-1,2-diamino
Synthesis of Cyclooctane Platinum (II) (Compound No. 2) 166 mg (0.4 mmol) of potassium chloroplatinate was dissolved in 3 ml of water, and 400 mg of potassium iodide was added to 0.5 ml of water.
The solution dissolved in is added and stirred at 40 to 45 ° C. for 30 minutes. A solution prepared by dissolving 90 mg (0.42 mmol) of trans-1,2-diaminocyclooctane hydrochloride in 0.5 ml of water and neutralizing it with 0.42 ml of 2N NaOH was added, and the mixture was stirred for 1 day at room temperature in the dark.

The resulting precipitate of diiodoplatinum complex is collected by filtration and dried under reduced pressure. Yield 94.5%. 223 mg (0.38 mmol) of the obtained diiodo platinum complex was dispersed in 5 ml of water, 122 mg (0.72 mmol) of silver nitrate was added, and the mixture was stirred at 60 to 65 ° C for 1 hour. Thereafter, the silver iodide formed by cooling was filtered off, and the obtained filtrate was dried under reduced pressure to give cis-
The dinitrate diaminocyclooctane platinum (II) is obtained. Yield 164 mg. Next, 24 mg of glycolic acid was added.
Dissolve in 1.57 ml of 2N sodium hydroxide to make an aqueous sodium salt solution.

69.2 mg of cis-dinitrate diaminocyclooctane platinum (II) was dissolved in 8 ml of water, and the previously prepared aqueous solution of sodium glycolate was added thereto.
After reacting at room temperature for 24 hours, the white precipitate obtained was collected by filtration to obtain compound No. 253.4 mg was obtained. Yield 75.2
%.

Mp. 197-198 ° C (color decomposition) Elemental analysis Calculated value (%): C 29.57: H 4.96: N
5.57 Found (%): C 29.13: H 4.90: N
5.66 IR (KBr) (cm ^-1 ) 3420, 3250, 3210, 2930, 1635,
1400, 1310, 1090, 920, 700

Example 3 Cis-bisglycolate-trans-l-1,2-dia
Minocyclooctane platinum (II) (compound No. 3)
Synthetic potassium chloroplatinate 166 mg (0.4 mmol)
Was dissolved in 2 ml of water and 400 mg of potassium iodide was dissolved in 3 ml of water, and the mixture was added and stirred at 40 to 45 ° C for 15 minutes. To this-
l-1,2-diaminocyclooctane hydrochloride [[α] ²⁰
_{589 = -9.53 ° (C 2,} H 2 O) ] 88.2mg
Is dissolved in water and 4.2 ml of 0.2N NaOH is added to neutralize the solution, and the solution is added to the iodoplatinic acid solution. Stir for 1 day in the dark at room temperature.

The precipitate of the formed diiodoplatinum complex is collected by filtration and dried under reduced pressure. Yield 93%. The obtained diiodine body 22
0 mg (0.372 mmol) was dispersed in 25 ml of 20% hydrous ethanol and 120 mg of silver nitrate (0.71
(Mmmol) and the mixture is stirred at 60 to 65 ° C for 1 hour. After cooling, the silver iodide formed was removed by filtration and the resulting filtrate was dried under reduced pressure to give cis-dinitrate-trans-
l-1,2-diaminocyclooctane platinum (II) 13
9 mg are obtained.

Next, cis-dinitrate-trans-l-
1,2-Diaminocyclooctane platinum (II) 129m
g was dissolved in 6 mg of water and passed through a column packed with anion exchange resin (OH type) Dowex 1-8X. After adding 34 mg of glycolic acid to this solution and reacting for 24 hours, the solution was concentrated and the precipitated crystals were filtered and dried to obtain Compound No.
3 59.6 mg was obtained.

Mp. 201 to 203 ° C. (color decomposition) Optical rotation [α] ²⁰ ₅₈₉ = −7.2 ° (C 0.2% H
₂ O) Elemental analysis calculated value (%): C 29.57: H 4.96: N
5.57 Found (%): C 29.10: H 5.08: N
5.76 IR (KBr) (cm ^-1 ) 3460, 3250, 3220, 2940, 1635,
1430, 1345, 1085, 925, 700

Example 4 cis- (Glycolate-O, O ')-trans-1,2
-Diaminocyclooctane platinum (II) (Compound No.
Synthesis of 4) 69.3 mg (0.15 mmol) of cis-dinitrate-1,2-diaminocyclooctane platinum obtained in Example 2 was dissolved in 7 ml of water to prepare an anion exchange resin (OH type) Dowex 1-X8. Was passed through a column packed with. 11 mg (0.14 mmol) of glycolic acid was added to this solution, and the mixture was reacted with stirring at room temperature for 40 hours. Then 50-60 ° C
Heat and stir for 3 hours. The solution was concentrated and the precipitated yellow crystals were collected by filtration and dried to obtain compound No. 4 19 mg are obtained.
Yield 30%.

Mp. 219 to 220 ° C. Elemental analysis Calculated as C ₁₀ H ₂₀ N ₂ O ₃ Pt ₁ · H ₂ O (%): C 27.97: H 4.73: N
6.52 Found (%): C 27.63: H 5.08: N
6.29 IR (KBr) (cm ^-1 ) 3440, 3425, 2925, 1640, 1475,
1350, 1310, 1190, 1060, 1030,
920, 765, 510, 400

The solubility of the compound of the present invention in water will be described. Test Example 1 Solubility method of the compound of the present invention The solubility of the compound of the present invention in water was determined.

Results The results obtained are shown in Table 1.

[Table 1]

As is clear from the results shown in Table 1, since the solubility of cisplatin in water is about 1.2 mg / ml, the compound of the present invention is obviously highly water-soluble and has a high dissolution rate. . This is preferable because it can be designed into a high-concentration preparation necessary for arterial infusion therapy, and crystals can be dissolved in an appropriate concentration at the time of use for immediate use.

Next, the antitumor effect of typical compounds of the present invention will be explained. Test Example 2 Antitumor Effect of the Compound of the Present Invention Method Lung cancer-derived PC-3 cells at 1 × 10 ⁴ / ml, colon cancer-derived SW1116 cells at 1.75 × 10 ⁴ / ml, and lung cancer-derived LL cells at 1 × 10 4 Colorectal cancer-derived Col at ⁴ / ml
on26 cells were adjusted to 1 × 10 ⁴ / ml, and 96 wel
0.2 ml / well was spread on a flat bottom microplate. After culturing under the conditions of 37 ° C. and 5% CO ₂ for 24 hours, the compound of the present invention No. 1-4 of 5
% Glucose solution and cisplatin (hereinafter referred to as CDDP) physiological saline, and as a control group, 10% each of 5% glucose solution or physiological saline was added, and PC-
72 hours for 3 cells, 96 hours for SW1116 cells, LL
The cells were cultured for 72 hours and the Colon 26 cells were cultured for 72 hours.

After culturing, each well was aerated using an aspirator.
0.05 ml after removing 1 liter of culture solution and fixing with MeOH
%, Methylene blue / 10 mM Tris hydrochloric acid buffer (pH 8.5) solution was added at 100 μl / well,
Stain for 30 minutes at room temperature. The staining solution of each well was extracted using an aspirator and washed with pure water three times. Thereafter, 3% HCl was added at a rate of 200 μl / well, sealed, and left at room temperature for about 24 hours to extract the dye from the cells.

The absorbance (A ₆₆₀ ) of each well at 660 nm was measured with a Dynatec microplate reader, and the growth inhibition rate (%) at each concentration was calculated from the following formula. The inhibition rate was plotted on a logarithmic probability paper to obtain the 50% inhibition concentration (IC ₅₀ ).

(Equation 1) Results The results are shown in Tables 2 and 3.

[0041]

[Table 2]

[0042]

[Table 3]

From the above Tables 2 and 3, the compounds of the present invention are Co
same as CDDP for lon26 cells, PC-3,
The antitumor activity was stronger than that of CDDP against SW1116 and LL cells. It can be seen that, particularly, it shows an excellent action on PC-3 and SW1116 which are slow growing solid cancer strains.

Further, the antitumor effect of the compound of the present invention on cisplatin-resistant cells will be described. From colorectal cancer according to the method of testing anti-tumor effects method in Test Example 2 against resistant cells of Test Example 3 present compound Colon2
6 cells and their cisplatin resistant cells Colon26 /
The 50% inhibitory concentration (IC ₅₀ ) against DDP was measured, and the resistance index (resistant-index) was calculated from the following formula.

[Formula 2]

Results The results are shown in Table 4.

[Table 4]

As is clear from the results of Test Examples 2 and 3, the compound of the present invention exhibits an excellent antitumor effect against solid cancer, and particularly digestion of slow-growing cancers such as colon cancer and pancreatic cancer. It has an excellent effect on respiratory cancer such as organ cancer and lung cancer, and is useful as a therapeutic agent for these cancers.

The nephrotoxicity of the compound of the present invention will be described. Test Example 4 Experimental Method for Nephrotoxicity of the Compound of the Present Invention in Nude Mice Nude mice (BALB / c-nu, 15 weeks old, ♀) were used to administer the following drugs once into the tail vein. The amount of administration liquid was 0.1 ml per 10 g of mouse body weight. Blood was collected 4 days later, and the urea nitrogen concentration in plasma was measured by Fuji Drychem 5500 using Fuji Drychem slide (BUN-PII). The experiment was conducted with 3 animals in one group. The compounds and solvents used are shown in Table 5 below. However, an appropriate solvent is selected because each compound is stable in the solution. In addition, T122-
The compound name of 208 is cis-bisglycolate-trans-R, R-1,2-diaminocyclohexane.
The Control group represents an untreated group.

[0048]

[Table 5] Results The results are shown in Table 6.

[0049]

[Table 6]

As is clear from the results of Table 6, CDDP
-It can be seen that the compound of the present invention has low nephrotoxicity, as compared with the case where all the animals in the administration group died during the experimental period (4 days after the administration).

[0051]

From the above results, the compound of the present invention shows strong antitumor activity, has low nephrotoxicity, and is highly soluble in water, and is expected to be a new anticancer agent.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kenji Iwata, Kenji Iwata 440-1 Emen, Kuki City, Saitama Prefecture (72) Ken Ken Miyamoto, 2-2-4-101 Oyamada Sakuradai, Machida City, Tokyo

Claims (8)

[Claims] 1. A compound represented by the general formula (1): [In the formula, Represents a cycloheptane ring or a cyclooctane ring, and B represents the formula: Or, two B's together form a formula with Pt: Indicates. ] The platinum (II) complex represented by these. 2. The platinum (II) complex according to claim 1, wherein in the general formula (1), A represents a cyclooctane ring. 3. In the general formula (1), B is represented by the formula: The platinum (II) complex according to claim 2, wherein 4. In the general formula (1), two B together form a formula with Pt: The platinum (II) complex according to claim 2, wherein 5. In the general formula (1), 1, in the cycloheptane ring or cyclooctane ring of
The platinum (I) according to any one of claims 1 to 4, wherein the bond between each carbon atom at the 2-position and the amino group is in the trans form.
I) Complex. 6. In the general formula (1), embedded image 1, in the cycloheptane ring or cyclooctane ring of
The platinum (II) complex according to claim 5, wherein the bond between each carbon atom at the 2-position and the amino group is a trans-l-form. 7. Platinum (II) according to claim 1.
An antineoplastic agent containing a complex as an active ingredient. 8. The antineoplastic agent according to claim 7, which is a therapeutic agent for solid cancer.