JPS62190192A - Novel platinum complex - Google Patents

Abstract

NEW MATERIAL:A platinum diamine complex expressed by formula I [R1 and R2 are as follows; R1 is H and R2 is lower cycloalkyl or R1 and R2 link to form a lower cyclic structure consisting of C and N; R3 is H or lower alkyl; m is 0 or 1; X is halogen or two X groups link to represent formula II-VI (R4 and R5 are H or lower alkyl)]. EXAMPLE:cis-Dichloro-N-cyclopentylethylenediamineplatinum. USE:An antitumor agent having low renal toxicity and high solubility in water and stable at room temperature in a vacuum, air etc., without requiring preservation at low temperatures. PREPARATION:For example, a tetrahalogenatoplatinum salt expressed by the formula M2Pt(Hal)4 (M is group capable of being monovalent cation; Hal is halogen) is reacted with an amine expressed by formula VII, preferably at room temperature -90 deg.C to afford the aimed dihalogenato-diamineplatinum expressed by formula VIII.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to platinum complexes having antitumor activity.

[Conventional technology]

Cisplatin is commercially available as a platinum complex that exhibits antitumor activity, and has been applied to many cases due to its remarkable effects. Several other platinum complexes that exhibit antitumor activity have also been reported. However, platinum complexes in which two nitrogen atoms are coordinated (for example, JP-A-4
9-48621. JP 57-156416), Izut
L4-M is a complex in which amine or ammonia is coordinated to a platinum atom.

[Problem that the invention seeks to solve]

As mentioned above, cisplatin is commercially available as a platinum complex cancer drug, but cisplatin has strong renal toxicity, which is a limiting factor for administration.

For this reason, it has the disadvantage that a large amount of water must be administered before and during administration, and administration must be carried out over a long period of time in combination with a diuretic in order to reduce renal toxicity. Furthermore, cisplatin has low solubility in water and has a slow dissolution rate, so it is supplied in an extremely low concentration solution.

For the above reasons, many studies have been carried out to find antitumor platinum complexes that have high solubility in water and low renal toxicity, but so far none has been found that can be put to practical use.

[Means for solving problems]

The present inventors used a ligand of the general formula (wherein R1 and R2 represent a hydrogen atom and R2 represents a lower cycloalkyl group, or R1 and R2 are bonded to each other and consist of a carbon atom and a nitrogen atom. This indicates a lower cyclic structure. Also, R5 indicates a hydrogen atom or a lower alkyl group, and m
indicates O or 1. ), and found that these complexes have antitumor effects and have significantly lower renal toxicity than cisplatin. The present invention was completed based on these findings. That is, the present invention is based on the same general formula. In addition, X is a halogen atom (e.g. chlorine,
A group that represents bromine or has two Xs bonded to each other and has the following structure (in the above formula, R4 and R5 are hydrogen atoms or lower alkyl groups, such as methyl group, ethyl group, n-
It shows propyl group, isopropyl group, n-butyl group, isobutyl group, 5eC-butyl group, tert-butyl group, etc. ) or a group having the structure (in the above formula, n represents 1 or 2).

) is shown. ] This relates to a platinum diamine complex represented by:

In the above general formula (■, when 1 is a hydrogen atom, the lower cycloalkyl group represented by R2 includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc., and R), R2 is bonded to nitrogen When forming a cyclic structure containing atoms, for example, a 3- to 6-membered ring structure containing one nitrogen atom is formed.

Examples of the lower alkyl group represented by R3 include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

Representative examples of the compounds represented by the above general formula (D) are listed below, but these examples are not intended to limit the present invention.

Compound Electron 1, cis-dichloro-N-cyclopentylethylenediamine platinum 2, cis-sulfate-N-cyclopentylethylenediamine platinum-hydrate 3, cis-oxalate-N-cyclopentylethylenediamine platinum 4, cis-4-oxacyclohexane-1,1- dicarboxilard-N-cyclopentylethylenediamine platinum 5, cis-dimethylmalonor)-N-cyclopentylethylenediamine white fluoride 6, cis-dichloro-N-cyclohexylethylenediamine platinum 7, cis-cyclobutane-1,1-dicarboxyl)-N - cyclohexylethylene diamine platinum 8, cismaronor) -N-cyclominoethylpyrrolidine platinum 9,
cis-dichloro-N-cyclopentyl-1,3-propanediamine platinum 10, cis-dichloro-N-cyclopropyl-1,
3-Propanediamine platinum 11, cis-cycloN-cyclohexyl-1,3-
Propanediamine platinum 12, cis-dichloro-N-cyclopentyl-2-methyl=1,3-propanediamine platinum 13, cis-dichloro-N-aminoethylpiperidine platinum The compounds of the present invention can be prepared by known methods such as Indian Journal Opchemistry. -[: IndianJ-Ch
em・, 8. ] 93 (1970)]. For example, the carboxylade complex is MzPt(1-1al)4+(R3CH)mCl-1
2-NH2 [wherein M is a group that can be a monovalent cation, for example,
Na represents Na, and Hal represents a halogen atom.

L, R2, R3 and m are the same as in the general formula above. ] As shown in the reaction formula, a tetrahalogenate platinum salt and an amine are reacted in water, preferably at room temperature to 90°C, to obtain di-logenato diamine platinum represented by (■). Next, as shown in the following formula, <m> is reacted with silver nitrate in water, preferably at room temperature to 90°C, and the produced halogenated steel is separated to obtain a diaco complex aqueous solution. Preferably, the dicarboxylate salt is added to this aqueous solution at room temperature to 90°C.
Compound π can be obtained by reaction at 0°C.

The (v+ sulfate complex) can be obtained by reacting the compound ([) with silver sulfate instead of silver nitrate, preferably at room temperature to 90°C.

The compounds of the present invention (Ill) were analyzed by elemental analysis, infrared absorption spectroscopy, fast atom bombardment mass spectrometry (FAB-MS Pt
=194. The structure was confirmed using CI = 35, etc.

The compounds of the present invention not only have excellent antitumor effects, have low nephrotoxicity, but also have high solubility in water (and are stable both at room temperature, under vacuum and in air, and have no need to be stored at low temperatures). do not have.

〔Example〕

Examples are shown below to clarify aspects of the present invention.

Example 1. (Compound % 1) [Cis-cycloN-cyclopentylethylenediamine platinum] Dissolve 1 g of potassium chloroplatinate in 20 ml of water, dissolve 1.6 g of potassium iodide in 3 ml of water, and add dropwise to this with stirring. . When this is stirred at 40°C for 10 minutes, a black solution of potassium iodide-platinate is obtained. Add 309μ of N-cyclopentylethylenediamine to this solution.
Dissolve the solution in 10 ml of water, add dropwise, and stir at 60°C for 5 minutes.

Separate the precipitated yellow crystals, wash with water and ethanol,
After further washing with ether, it was dried under Makabe and cis-
1.28 g (yield 92.3%) of short-N-cyclopentylethylenediamine platinum crystals are obtained.

1 g of this cis-short-N-cyclopentylethylenediamine platinum is suspended in 20 ml of water, 577111 silver nitrate dissolved in 5 ml of water is added, and the mixture is reacted at 60° C. for 20 minutes with stirring. The solution was cooled to room temperature and then filtered,
Separate the produced silver iodide and wash with water. Combine the p solution and washing solution and add 5 ml of 608rl1g of sodium chloride to this.
of water and stirred for 10 minutes at room temperature. The yellow crystals produced were separated and washed with a small amount of water cooled to 0°C.
After washing with ethanol and drying under vacuum, compound 1 is obtained.

Yield 423 mg Elemental analysis calculated value (%): C, 21,33; I (, 4,09; N
, 7.1]; Pi, 49.49 actual value (inquiry: C
,21,56;H,4,19;N,7.26;Pi,
49.0FAB-MS: (M + H) = 393
Example 2. (Compound % 2) [cis-sulfei)-N-cyclopentylethylenediamine platinum hydrate] In the same manner as in Example 1, P crystal' of cis-short-N-cyclopentylethylenediamine platinum is obtained.

1 g of this crystal was suspended in 80 ml of water, and silver sulfate 529
Add (2) and stir at 60°C for 20 minutes.

After cooling to room temperature, the resulting silver iodide is separated by ttp filtration, and the filtrate is freeze-dried to obtain yellow-white compound 2.

Yield 743■ Elemental analysis calculated values (@: C, 19,22; H, 4,15; N, 6.
40; Pt, 44.60 actual value (%l: C,] 9.
5]; H, 4,02; N, 6.65; Pt, 45.0
FAB-MS: (M+H) =419 Example 3.
(Compound fV & 13) [cis-oxalate-N-cyclopentylethylenediamine platinum] In Example 1, using 305 μm of potassium oxalate instead of sodium chloride, the reaction was carried out at 60° C. for 2 hours with stirring, and the solution was concentrated to 5 ml. After cooling to 0°C, the white crystals formed were separated and washed with a small amount of water cooled to 0°C.
After washing with ethanol and drying under vacuum, compound 3 is obtained.

Yield 515■ Elemental analysis calculated value (%): C, 26,28; H, 3,92; N,
6.8]; Pi, 47.43 actual value (@: C, 26
, (H; H, 3,77; N, 6.99; Pt, 4747
-2FAB-: (M+H) =411 Example 4. (
Compound % 4) [cis-4-oxacyclohexane-1+ 1-dicarboxylade-N-cyclopentylethylenediamine platinum] In Example 1, 4-oxacyclohexane-1,1-dicarboxylic acid 500 μm was used instead of sodium chloride. I
The mixture is dissolved in 6.76 ml of an aqueous solution of N-sodium hydroxide, and reacted at 60° C. for 2 hours with stirring. 5 of the solution
After concentrating to 1 ml, the white crystals formed by cooling to 0°C are collected, washed with a small amount of water cooled to 0°C, washed with ethanol, and dried under vacuum to obtain compound 4. .

Yield 331■ Elemental analysis calculated value (%l: C, 33,94; H, 4,88; N,
5.65; Pt, 39.38 actual value (@: C, 34,
26; H, 5,03; N, 5,41; Pt, 39. O
FAB-MS: (M+H) =495 Example 5. (
Compound %5) [cis-dimethylmalonate-N-cyclopentylethylenediamine platinum] In Example 1, 458 μm of dimethylmalonic acid was added to 6.76 μm of IN aqueous sodium hydroxide solution instead of sodium chloride.
ml, and reacted at 60°C for 2 hours with stirring. After concentrating the solution to 5 ml, it was cooled to 0°C and the resulting white crystals were collected, washed with a small amount of water cooled to 0°C, washed with ethanol, and dried under vacuum to obtain compound 5. get.

Yield 545fIIg Elemental analysis calculation value (%): C, 31,79; H, 4,89; N, 6
．． 18; Pt, 43.03 Actual value (%): C, 31,
94; H, 4, 66; N, 6.29; Pt, 42.8
FAB-MS: (M+H) =453 Example 6. (
Compound 6) [cis-cycloN-cyclohexylethylenediamine platinum] In Example 1, N-cyclohexylethylenediamine 34 was used instead of N-cyclopentylethylenediamine.
Using 31 ng, cis-short-N-
3 sg (yield 95.5%) of cyclohexylethylenediamine platinum is obtained. Using 1 g of this cis-short-N-cyclohexylethylenediamine platinum, 56 sg of silver nitrate is obtained.
Yellow crystals of compound 6 were obtained in the same manner as in Example 1 except that 3111 g and 593 g of sodium chloride were used.

Yield 584ff1g Elemental analysis calculation value (@: C, 23,54; H, 4,44; N, 6
．． 86: Pt, 47.79 Actual value (%): C, 23
,22;I-1,4,51;N,6.77;Pt,4
7.5FAB-MS: (M+H)=407 Example 7
．． (Compound 7) [cis-cyclobutane-1,1-dicarboxy-4-
N-cyclohexylethylenediamine platinum] In Example 6, 488 Ing of cyclobutane-1,1-dicarboxylic acid was used instead of sodium chloride. r] Used by dissolving in 6.60 ml of sodium N hydroxide aqueous solution, 6
The reaction was carried out at 0° C. for 2 hours with stirring.

After concentrating the solution to 5 ml, it was cooled to 0°C, the white crystals formed were collected, and washed with a small amount of water cooled to 0°C.
After washing with ethanol and drying under vacuum, compound 7 is obtained.

Yield 563■ Elemental analysis calculated value f%): C, 35,07; H, 5,05; N,
5.84; Pb2O, 69 actual value (%I: C, 35,
14; H, 4,96; N, 5.67; Pt, 41. IF
AB-MS: (M+H) =479 Example 8. (
Compound Disorder 8) [cis-malonate-N-aminoethylpyrrolidine platinum] In Example 1, N-aminoethylpyrrolidine 275 was used instead of N-cyclopentylethylenediamine, and in the same manner as above, cis-short-N -Aminoethylpyrrolidine 1.30 g of platinum (yield 95.8%) is obtained. 1 g of this cis-short-N-aminoethylpyrrolidine platinum was suspended in 20 ml of water, and 591 μm of silver nitrate was added to 591 μm of silver nitrate.
Dissolve in 1 ml of water, add, and stir at 60°C for 20 minutes. The produced silver iodide is separated by filtration and washed with water. Combine the filtrate and washing liquid, add 370,111 g of malonic acid to this, and add 6.7 g of malonic acid.
Dissolve the mixture in 5 ml of 1N aqueous sodium hydroxide solution, add and react at 50° C. for 8 hours with stirring. 5 ml of solution
After concentrating to
The sample is taken, washed with a small amount of water cooled to 0° C., washed with ethanol, and then dried under vacuum to obtain compound 8.

Yield 244 ■ Elemental analysis calculation directly: C, 26, 28; H, 3, 92; N, 6
．． 81; Pi, 47.43 actual value (@: C, 26,
6]; H, 4,06; N, 6.62; Pi, 46.
8FAB-MS: (M+H)=411 Example 9. (
Compound 9) [cis-dichloro-N-cyclopentyl-1,3-propanediamine platinum] In Practical Example 1, 343 mg of N-cyclopentyl-1,3-propanediamine was used instead of N-cyclopentyldiamine, 1.32 g of cis-short-N-cyclopentyl-1,3-propanediamine platinum (yield: 9
2.7%). Yellow crystals of Compound 9 were obtained in the same manner as in Example 1 except that 1 g of this cis-short-N-cyclopentyl-], 3-propanediamine platinum, 563 cm of silver nitrate, and 593 cm of sodium chloride were used.

Yield 450■ Elemental analysis calculation value (%): C, 23,54; H, 4,44; To, 6
．． 86 ; Pi, 47.79 actual value (Chill: C, 23
,29;H,4,27;N,6.99;Pt,46.9
FAB-MS: (M+H) =407 Example 10.
(Compound 1 K) 0) [cis-cycloN-cyclopropyl-1+ 3-propanediamine White Fluorescence] In Example 1, N-cyclopropyl-1,3-propanediamine 275 using cis-short-N-cyclopropyl-1,3-propanediamine platinum t, z1g (
Yield: 89.2%). This cis-short-N-cyclopropyl-1,3-propanediamine white! Using 1g of silver nitrate and 623cm of sodium chloride,
Otherwise, yellow crystals of Compound 10 are obtained in the same manner as in Example 1.

Yield 350■ Elemental analysis calculated value (%): C, ] 8.96; H, 3,72; N
, 7.37; Pt, 5i, 31 real value (%l: C,]
9.21; H, 4,01; N, 7.55; Pt, 5
0.5FAB-MS: (M+I-1) =379
Example 11, (Compound M1) [cis-cycloN-cyclohexyl-1,3-propanediamine platinum] In Example], instead of N-cyclopentylethylenecyamine, N-cyclohexyl=1.3- Propanediamine 376 using nvt, cis-short-N-cyclohexyl-1,3-propanediamine platinum 1.34
g (yield 91.9%) was obtained. This cis-short-N
-Cyclohexyl-1,3-propanediamine platinum 1g
Yellow crystals of Compound 11 were obtained in the same manner as in Example 1 except that 550 cm of silver nitrate and 579 cm of sodium chloride were used.

Yield 477■ Elemental analysis calculation value (@: C, 25,60; H, 4,77; N, 6
．． 63; Pt, 46.20 actual value (@: C, 25, 4
8; 1, 4.81; N, 6.77; Pi, 47.0
FAB-MS: (M+H)=421 Example 12. (
Compound %] 2) [cis-cycloN-cyclobenzene-2-methyl-
1,3-propanediamine platinum [Example], N
-N-cyclopentyl-2-methyl-1,3-propanediamine 3 instead of cyclopentylethylenecyamine
F6-2-methyl-1,3-propanediamine platinum 1
, 4 og (yield 96.0%). Using this cis-short-N-cyclopentyl-2-methyl-1,3-propanediamine platinum], 55'0111 g of silver nitrate,
Yellow crystals of Compound 12 were obtained in the same manner as in Example 1 except that 579 Qg of sodium chloride was used.

Yield 454■ Elemental analysis calculated value (%l: C, 25.60; H, 4.77; N,
6.63: Pi, 46.20 Actual value (%): C, 25
．． 88: H, 5.01; N, 6.33: Pt. 45
．． 9FAB-MS: (M+H) = 4 2 1 The physical properties of the compound of the present invention are shown in Table].

Table 1 > 2*3240-3150 -6
> 2*3230-3130 -* 10) 3*3200-3140 -]
1) 2*3240-3140 -* *Solubility in physiological saline The solubility of cisplatin in physiological saline is approximately 1.2
Q/ml, the compound of the present invention is clearly highly water-soluble, and also has a high dissolution rate, so even when used as an injection, it is necessary to dissolve the crystals at an appropriate concentration for each use. available for immediate use;
suitable.

Next, the anti-cancer effect of the compounds of the present invention will be explained by giving experimental examples.

Experimental example 1. Antitumor property test against mouse leukemia cells L2]0 (test method) 1 x 10 mouse leukemia Ll2]0 cells were intraperitoneally transplanted into 6-week-old female CD Fl mice, and from the next day onwards, 1 x 10 cells of mouse leukemia Ll2]0 were implanted intraperitoneally, and administered once a day from the next day. The drug was administered intraperitoneally for 5 days. Physiological saline was similarly administered to the drug-untreated group. T/C was calculated from the average survival days of the drug-treated group and the non-treated group using the following formula.

Furthermore, if any mouse died due to acute toxicity of the drug during the test, 50% lethality f (LDso) was calculated by a standard method. Table 2 shows the results of Experimental Example].

In Table 2, max(T/C) indicates the maximum value of (T/C).
pt, dose is the max (T/C) dose (
optimal dosage).

Table 2] 38] 1
6 -4 186 64
172.86 168 4
9.67 136 3
2 43.08 283 1
28 192.09 ] 8
5 32 -10
138 8
38.4] 2 ] 50 32
- As is clear from Table 2, the compound of the present invention has a survival effect on mice inoculated with murine leukemia (L12]0) cells.

Next, the renal toxicity of the compound of the present invention will be explained by giving experimental examples.

Experimental example 2. Kidney toxicity test (test method) The drug was intraperitoneally administered once to 6-week-old male CDF+ mice, and 4 days later, blood was collected and blood urea nitrogen concentration (B
UN)′? : asked.

Table 3 shows the results of Experimental Example 2. The body weight ratio in Table 3 is the ratio of the body weight 48 days after administration to the body weight at the drug administration port. Before administration, administer a dose that is 4 times higher than the oot or dose used in the antitumor test.

Table 3 Physiological saline 1.05 22
．． 7 Cisplatin 16 0.72
92.9] 80
0.74 28.32
20 0.79 11.03
40 0.77
14.14 256 1.
06 24.17 128
1.05 26.28
640 0.79 10.
09 128 1.01
17.710 32
0.96 16.3 As is clear from Table 3, the BUN value in the blood of the compound of the present invention is extremely lower than that of commercially available cisplatin, and is equivalent to that of physiological saline. This indicates that the nephrotoxicity is extremely low.

Therefore, the compound of the present invention serves as an antitumor agent with extremely low nephrotoxicity. Considering these characteristics and high water solubility, when administering intravenously as an injection, it is preferable to administer for a single hour rather than continuously.

〔Effect of the invention〕

The compounds of the present invention have excellent antitumor effects, low nephrotoxicity, and high solubility in water (and can be used as excellent antitumor agents. Furthermore, the compounds of the present invention can be used at room temperature, under vacuum, and in air. Both are stable and do not require particularly low temperature storage.

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc.
shows that these bond together to form a lower cyclic structure consisting of carbon atoms and nitrogen atoms. Further, R_3 represents a hydrogen atom or a lower alkyl group, and m represents 0 or 1. In addition, X represents a halogen atom, or a group in which two Xs are bonded and has the structure ▲There is a mathematical formula, chemical formula, table, etc.▼ (In the above formula, R_4 and R_5 represent a hydrogen atom or a lower alkyl group. ), or ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
Indicates a group having the following structure (in the above formula, n indicates 1 or 2). ] A platinum diamine complex represented by