PLATINUM (IV) COMPLEXES

Abstract: New platinum (IV) complexes are now provided, which exhibit antitumor activity as shown by the tests on mouse leukemia, L-1210 cell in mice. These new platinum (IV) complexes contain, 1,2-cyclohexanediamine or 2-(amino­ methyl)cylclohexyl-amine as a ligand.

Description: This invention relates to new platinum(IV) complexes which exhibit antineoplastic or antitumor activity as demonstrated by the test against mousse leukemia L-1210. The platinum(IV) complexes of this invention contains a 1,2-cyclohexanediamine (abbreviated as dach) or 2-(aminomethyl)-cyclohexylamine (abbreviated as amcha) as a ligand. In recent years, a number of platinum(II) complexes, including well-known cisplatin, have been synthetized and have been reported to have antitumor activity. We the present inventors, have synthetized some platinum(II) complexes, as disclosed, for example, in documents JA-A-31648/78, JA-A-35013/80, JA-A-130992/80, JA-A-103192/81, JA-A-156416/82, JA-A-16895/82, JA-A-21697/84, JA-A-34982/85, JA-A-349883/85, JA-A-156416/82, JA-A-109521/85, JA-B-29957/83 and JA-B-196887/85, as well as documents US-C-4,169,846; US-C-4,200,583; US-C-4,256,652; US-C-4,255,347; US-C-4,551,524 and documents EP-C-1126 and EP-C-8936, European Patent Appln.Nos. 83 303659.3 and 84 305304.2. We have also synthetized some organoplatinum(IV) complexes, as disclosed, for example, in documents JA-A-87295/85 and JA-A-109521/85. The document US-C-4 550 187 has also described a method for preparing various stereoisomers of platinum(IV) antineoplastic agents, such as (1S, 2S) - tetrachloro-trans-dach-platinum(IV), (1R, 2R) - tetrachloro-trans-dach-platinum(IV), and tetrachloro-cis-dach-platinum(IV). the following documents, i.e.: _ J. Clin. Hematol. Oncol, vol. 7, n°1, 1977, pages 231-241; L.M HALL et al, entitled "Analogs of sulfato 1,2 diaminocyclohexane platinum (II) (SHP) II: modifications other than leaving ligand" has described for antitumor activity cis-dichloro-trans-dihydroxo-dach platinum(IV), cis-dichloro-trans-dinitro-dach-platinum(IV), cis-malonato-trans-dihydroxo-dach-platinum(IV), and cis-malonato-trans-dinitro-dach platinum(IV). The document EP-A-0 154 589 has also described pure stereoisomers of tetrahalo-dach-platinum(IV), e.g of the types trans-d, trans-ℓ, trans-d,ℓ, and cis, all these isomerically pure compounds being described as active against leukemia. Finally, the document GB-A-2 148 891 has described various platinum-diamine complexes, such as trans-dihydroxo-cis-oxalato-amcha-platinum(IV), cis-dichloro-trans-dihydroxo-amcha-platinum(IV), cis-tetrachloro-amcha-platinum(IV) as having a carcinostatic effect. The compounds disclosed in the last three documents appear to have some toxicity. It is thus the purpose of this invention to obtain new amcha-platinum(IV) or dach-platinum(IV) complexes, exhibiting less toxicity while keeping a substantial antineoplastic or antitumor activity. Now we have succeeded in synthetizing new organoplatinum(IV) compounds having anyone of the following chemical formulae, and having for each chemical structure different stereoisomers, in pure form or admixture. wherein B and B′ taken together denote a group of the formula or a group of the formula or B and B′ each denote a chloro group, and D denotes a chloro group, a nitrato group, or a hydroxo group The amcha ligand may show a configuration selected from cis-ℓ-, cis-d-, trans-ℓ- and trans-d-. In formulae (2) and (3), the dach ligand may adopt three stereo-isomers according to the following steric structure: In formula (1), the amcha ligand may adopt 4 stereo-isomers according to the following steric structure: The platinum(IV) complexes of the formulae (1) to (3) according to this invention, therefore, include some different stereo-isomers as shown above, depending on the configuration 1,2-cyclohexanediamine or 2-(aminomethyl)cyclohexylamine which forms a ligand to the platinum atom. According to particular embodiments of this invention, there are provided five types of the platinum(IV) complexes as described below: (1) A complex of the formula (2) in which the dach moiety is a ligand selected from cis-1,2-cyclohexanediamine, trans-d-1,2-cyclohexanediamine and trans-ℓ-1,2-cyclohexadiamine, (2) A complex of the formula (3) in which the dach moiety is a ligand selected from cis-1,2-cyclohexanediamine, trans-d-1,2-cyclohexanediamine and trans-ℓ-1,2-cyclohexanediamine (3) A complex of the formula (1) in which the amcha moiety is a ligand selected from cis-dℓ-2-(aminomethyl)cyclohexylamine and trans-dℓ-2-(aminomethyl)cyclohexylamine and B, B′ and D are each a chloro group. (4) A complex of the formula (1) in which the amcha moiety is a ligand selected from cis-dℓ-2-(aminomethyl)cyclohexylamine, and B and B′ are each a chloro group, and D is hydroxo group (OH) or a nitrato group (NO₃). (5) A complex of the formula (1) in which the amcha moiety is a ligand selected from cis-dℓ-2-(aminomethyl)cyclohexylamine and trans-dℓ-2-(aminomethyl)cyclohexylamine and B, B′ taken together form a group of the formula and D is a hydroxo group (OH), a chloro group (Cℓ) or a nitrato group (NO₃). With reference to the attached drawings: Fig 1 is infrared absorption spectrum (KBr) of trans-(Cℓ)-oxalato-dichloro-(trans-ℓ-dach)platinum(IV) according to this invention. Fig 2 is infrared absorption spectrum (KBr) of trans-(Cℓ)-malonato-dichloro(trans-ℓ-dach)platinum(IV) according to this invention. Fig 3 is infrared absorption spectrum (KBr) of tetrachloro-(cis-dℓ-amcha)platinum(IV) according to this invention. Fig 4 is infrared absorption spectrum (KBr) of tetrachloro-(trans-dℓ-amcha)platinum(IV) according to this invention. Fig 5 is infrared absorption spectrum (KBr) of trans-(OH)-dichloro-dihydroxo(cis-dℓ-amcha)platinum(IV) according to this invention. Fig 6 is infrared absorption spectrum (KBr) of trans-(OH)-dichloro-dihydroxo(trans-dℓ-amcha)platinum(IV) according to this invention. Fig 7 is infrared absorption spectrum (KBr) of trans-(OH)-oxalato-dihydroxo(cis-dℓ-amcha)platinum(IV) according to this invention. Fig 8 is infrared absorption spectrum (KBr) of trans-(NO₃)-oxalato-dinitrato(cis-dℓ-amcha)platinum(IV) according to this invention. Fig 9 is infrared absorption spectrum (KBr) of trans-(NO₃)-oxalato-dinitro(trans-dℓ-amcha)platinum(IV) according to this invention. Fig 10 is infrared absorption spectrum (KBr) of trans-(Cℓ)-oxalato-dichloro(cis-dℓ-amcha)platinum(IV) according to this invention. The platinum(IV) complex of the general formulae (1) to (3) according to this invention may be prepared by one of the following two processes, (A) and (B). Process (A); In this process, the platinum(II) complex of the general formula (II) wherein the moiety is a dach or amcha ligand, B and B′are as in formula (1), is reacted with chlorine gas or hydrogen peroxide. The starting material, namely the compound of the general formula (II) may be prepared according to a known method, for example, the method disclosed in documents JP-B-41077/85, US-C-4,169,846 and US-C-4,255,347. Process (B); In this process, such a starting compound of the general formulae (1) to (3) where platinum is substituted by two hydroxo groups, which has been obtained in the process (A) above, is reacted with a diluted hydrochloric acid or diluted nitric acid, so that the hydroxo groups present in the starting compound is converted into a chloro group (Cℓ) or nitrato group (NO₃), to give such compounds of the formulae (1) to (3) with Cℓ or NO₃ substituents, according to the invention. The platinum(IV) complexes according to this invention thus obtained can be identified by their infrared absorption spectra as shown in Figures 1 to 10 of the attached drawings. The method for the identification of the compounds is explained below. All the platinum(IV) complexes according to this invention commonly exhibit IR absorption peaks due to the carrier ligand present in the complexes, namely, IR absorption peaks at 3200 to 3100 cm⁻¹ due to νNH₂ at 2900 cm⁻¹ due to νCH and at 1600 cm⁻¹ or thereabout due to νNH₂. By checking the shift of the characteristic infrared absorption peak in a particular platinum(IV) complex, this platinum(IV) complex can be identified about what is the configuration of the leaving groups relative to the platinum(IV) atoms as illustrated below. Trans-(OH)-dichloro-dihydroxo(amcha)platinum(IV) exhibit an IR absorption peak at 3500 cm⁻¹ due to νOH, as shown in Fig. 5 of the attached drawings. Trans-(OH)-oxalato-dihydroxo(amcha)platinum(IV) exhibit an IR absorption peak at 3500 cm⁻¹ due to νOH, and exhibit strong absorption peaks at 1700 cm⁻¹ and 1400 cm⁻¹, due to νC=0 and νC-0, as shown in Fig. 7. Trans-(NO₃)-oxalato-dinitrato(amcha)platinum(IV), as shown in Fig. 9 of the attached drawings, exhibit IR absorption peaks at 1600 cm⁻¹ and 1400 cm⁻¹ due to νC=O and νC-O, and IR absorption peaks at 1550 cm⁻¹, 1280 cm⁻¹ and 950 cm⁻¹ due to νNO₃. Trans-(Cℓ)-oxalato-dichloro(amcha)platinum(IV) exhibit IR absorption peaks at 1700 cm⁻¹ and 1380 cm⁻¹ due to νC=O and νC-O, as shown in Fig.10 of the attached drawings. The new platinum(IV) complexes according to this invention exhibit anti-tumor activity against experimental tumors on mouse, such as L1210, P388 and S180A (ascites-tumor), and therefore are useful in chemotherapeutics of tumors. The new platinum(IV) complexes of this invention can be administered orally, intramuscularly or intravenously. They can be formulated into capsules, powders, pellets or injections. Suitable dosage of the platinum(IV) complexes of this invention is about 1 to 400 mg/kg/day. The production of the novel platinum(IV) complexes of the formula (I) according to this invention is now illustrated with reference to the following examples. The data of elementary analysis and yield of the organo-platinum(IV) complex as produced in the Examples are listed in Table 1 hereinafter. Compound Numbers given in Table 1 are corresponding to the Example Nos. in which the compound indicated was prepared. Example 1 Preparation of trans-(Cℓ)-oxalato-dichloro(cis-dach)platinum(IV). Oxalato(cis-dach)platinum(II) (0,5 g) was suspended in water (5 ml), into which was then passed chlorine gaz for 45 minutes under heating at 70°C on a water bath. The resulting suspension was passed through with air stream for 10 minutes to remove the residual chlorine gas therefrom, so that a transparent, yellow colored reaction solution was obtained. The reaction solution was ice-cooled to deposit a precipitate which was then recovered by filtration. The solid product obtained was dried under reduced pressure, to afford the titled complex. Example 2 Preparation of trans-(Cℓ)-oxalato-dichloro(trans-d-dach)platinum(IV). Oxalato(trans-d-dach)platinum(II) as a starting materiel was reacted with chlorine gas and then processed in the same manner as in Example 1 above, to afford the titled complex. Example 3 Preparation of trans-(Cℓ)-oxalato-dichloro(trans-ℓ-dach)-platinum(IV). Oxalato(trans-ℓ -dach)platinum(II) as a starting materiel was reacted with chlorine gas and then processed in the same manner as in Example 1, to afford the titled complex. Example 4 Preparation of trans-(Cℓ)-malonato-dichloro(cis-dach)platinum(IV). Trans-(OH)-malonato-dihydroxo(cis-dach)platinum(IV) (0,54 g) was suspended in water (20 ml), to which was then added 0.100 N aqueous hydrochloric acid (24 ml). The resulting suspension was stirred at room temperature for 30 minutes and allowed to stand until a transparent reaction solution was formed. The reaction solution was concentrated and the residue was dried under reduced pressure. The dried residue was dissolved in ethanol (30 ml) at 50°C and the solution was filtrated to remove a small amount of colorless, insoluble matter. The filtrate was concentrated and dried under reduced pressure, and a yellow solid residue obtained was washed with a small volume of ethanol and dried, to afford the titled complex. Example 5 Preparation of trans-(Cℓ)-malonato-dichloro(trans-d-dach)platinum(IV). Trans-(OH)-malonato-dihydroxo(trans-d-dach)platinum(IV) as a starting materiel was reacted with hydrochloric acid and then processed in the same manner as in Example 4 above, to afford the titled complex. Example 6 Preparation of trans-(Cℓ)-malonato-dichloro(trans-ℓ-dach)-platinum(IV). Trans-(OH)-malonato-dihydroxo(trans-ℓ-dach)platinum(IV) as a starting materiel was reacted with aqueous hydrochloric acid and then processed in the same manner as in Example 4, to afford the titled complex. Example 7 Preparation of tetrachloro(cis-ℓ-amcha)platinum(IV). Dichloro(cis-dℓ-amcha)platinum(II) (0,5 g) (see U.S. patent No. 4,255,347) was suspended in water (5 ml), into which was then passed chlorine gas for 45 minutes under heating at 70°C on a water bath. The resulting suspension was passed through with air stream for 10 minutes to remove the remaining chlorine gas therefrom. The resultant yellow and transparent reaction solution was ice-cooled to deposit a precipitate, and this precipitate was recovered by filtration and dried under reduced pressure, to afford the titled complex. Example 8 Preparation of tetrachloro(trans-dℓ-amcha)platinum(IV). Dichloro(trans-dℓ-amcha)platinum(IV) as as starting materiel was reacted with chlorine gas and then processed in the same manner as in Example 7 above, to afford the titled complex. Example 9 Preparation of trans-(OH)-dichloro-dihydroxo(cis-dℓ-amcha)platinum(IV). Dichloro(cis-dℓ-amcha)platinum(II) (0,5 g) was suspended in water (5 ml), to which was then added 30% aqueous hydrogen peroxide (25 ml) under heating at 70°C on a water bath. The resulting suspension was stirred for 45 minutes and allowed to stand. The resultant transparent and yellow reaction solution was concentrated to 3 ml under reduced pressure. The concentration was admixed with ethanol to deposit a precipitate which was recovered by filtration. The titled complex was thus obtained. Example 10 Preparation of trans-(OH)-dichloro-dihydroxo(trans-dℓ-amcha)platinum(IV) Dichloro(trans-dℓ-amcha)platinum(II) as a starting materiel was reacted with aqueous hydrogen peroxide and then processed in the same manner as in Example 9 above, to afford the titled complex. Example 11 Preparation of trans-(NO₃)-dichloro-dinitrato(cis-dℓ-amcha)platinum(IV) Trans-(OH)-dichloro-dihydroxo(cis-dℓ-amcha)platinum(IV) (0,5 g) was suspended in water (5 ml), to which was then added 0.1 N aqueous nitric acid (25 ml). The resulting suspension was stirred at room temperature for 1 hour to effect the reaction. The resultant transparent reaction solution was concentrated under reduced pressure. The solid residue was washed with a small volume of ethanol and dried under reduced pressure, to obtain the titled complex. Example 12 Preparation of trans-(NO₃)-dichloro-dinitrato(trans-dℓ-amcha)platinum(IV) Trans-(OH)-dichloro-dihydroxo(trans-dℓ-amcha)platinum(IV) as a starting material was reacted with aqueous nitric acid and then processed in the same manner as in Example 11 above, to afford the titled complex. Example 13 Preparation of trans-(OH)-oxalato-dihydroxo(cis-dℓ-amcha)platinum(IV) Oxalato(cis-dℓ-amcha)platinum(II) (1.0 g) (see U.S. patent No. 4,255,347) was suspendend in water (10 ml), to which was then added 30% aqueous hydrogen peroxide (50 ml) under heating at 70°C on a water bath, and the resulting suspension was further stirred for 45 minutes to effect the reaction. The resultant clear reaction solution was concentrated to 5 ml under reduced pressure. The concentrate was admixed with ethanol to deposit a colorless precipitate. This precipitate was recovered by filtration and dried under reduced pressure, to afford the titled complex. Example 14 Preparation of trans-(OH)-oxalato-dihydroxo(trans-dℓ-amcha)platinum(IV) Oxalato(trans-dℓ-amcha)platinum(II) as a starting material was reacted with aqueous hydrogen peroxide and then processed in the same manner as in Example 13 above, to afford the titled complex. Example 15 Preparation of trans-(NO₃)-oxalato-dinitrato(cis-dℓ-amcha)platinum(IV) Trans-(OH)-oxalato-dihydroxo(cis -dℓ-amcha)platinum(IV) (1.0 g) was suspended in water (10 mg), to which was then added 0.1 N aqueous nitric acid (50 ml), and the resulting suspension was further stirred at room temperature for 1 hour to effect the reaction. The resultant reaction solution was concentrated under reduced pressure. The concentrate was washed with a small volume of ethanol and dried under reduced pressure, to afford the titled complex. Example 16 Preparation of trans-(NO₃)-oxalato-nitrato(trans-dℓ-amcha)platinum(IV) Trans-(OH)-oxalato-dihydroxo(trans-dℓ-amcha)platinum(IV) as a starting material was reacted with aqueous nitric acid and then processed the same manner as in Example 15 above, to afford the titled complex. Example 17 Preparation of trans-(Cℓ)-oxalato-dichloro(cis-dℓ -amcha)platinum(IV) Oxalato(cis-dℓ-amcha)platinum(II) (1.0 g) was suspended in water (10 ml), into which was then passed chlorine gas for 1 hour under heating at 70°C on a water bath. The resulting suspension was passed through with air stream for 10 minutes to remove the remaining chlorine gas therefrom. The resultant clear and yellow reaction solution was ice-cooled to deposit a precipitate, and the precipitate was recovered by filtration and dried under reduced pressure, to afford the titled complex. Example 18 Preparation of trans-(Cℓ)-oxalato-dichloro(cis-dℓ-amcha)platinum(IV) Oxalato(trans-dℓ-amcha)platinum(IV) as a starting material was reacted with chlorine gas and then processed in a manner similar to Example 17, to afford the titled complex. The elementary analysis value and the yield of the respective platinum(IV) complex according to this invention as obtained in the Examples 1 to 18 above, are summarized in Table 1 below. Experiment 1 Antitumor activity of the platinum(IV) complex of this invention on mice against Leukemia L-1210 is now estimated. To test the anti-tumor activity of the platinum(IV) complexes according to this invention, 10⁵ cells/mouse of Leukemia L-1210 were transplanted by intraperitoneal injection to groups (6 mice in each group) of CDFI mice. On the same day of the transplantation, and 5 days and 9 days after the transplantation of Leukemia L-1210 cells, the platinum(IV) complex under test was administered by intraperitoneal injection to the test mice. The anti-tumor activity of the test platinum(IV) complex was evaluated by means of rate (%) of prolongation of mean survival days of the treated mice, in term of the values of T/C %, i.e., the value of 100 times the mean survival period of the groups of mice treated with the test platinum complex, divided by the mean survival period of the comparative groups of mice which were not treated with the test platinum complex. The test results are as shown in Table 2 below. In Table 2, the T/C (%) values of higher than 125% (the numerical value as underlined) means that the tested platinum complex has a substantial anti-tumor activity. In Table 2, the numerical figure given in parenthesis denotes the number of the mice as entirely cured in each group of mice treated. The term "T" denotes that the incurred decrease in body weight of the treated mice exceeded the lowest limit value (-4 g) for judgement of the toxic effects of the test compound. The test results shown in Table 2 demonstrates that the platinum(IV) complexes of this invention have a significant antitumor activity.

Claims: 1. An antitumor platinum(IV) complex, characterized in that it has a general formula wherein B and B′ taken together denote a group of the formula or a group of the formula or B and B′ each denote a chloro group, and D denotes a chloro group, a nitrato group or a hydroxy group 2. An antitumor platinum(IV) complex, characterized in that it has a general formula 3. An antitumor platinum(IV) complex having a general formula 4. A compound as claimed in claim 1, characterized in that it is trans-(Cℓ)-oxalato-dichloro(trans-dℓ-1-amino-2-aminomethylcyclohexane) platinum(IV) according to the following formula 5. A compound as claimed in claim 2 characterized in that it is trans-(Cℓ)-oxalato-dichloro(trans-ℓ-1,2-diaminocyclohexane)platinum(IV) of the formula 6. A compound as claimed in claim 3 characterized in that it is trans-(Cℓ)-malonato-dichloro(trans-ℓ-1,2-diaminocyclohexane)platinum(IV) of the formula

Inventors: KIDANI, YOSHINORI, NOJI, MASAHIDE
Applicants: KIDANI, YOSHINORI
Application year: 1987
Main classification: C07F15
IPC codes: A61K31, C07F15, A61P35