GB2055377A - Cis-platinum(II) amine ascorbate complexes - Google Patents

Abstract

Ascorbate complexes of platinum (II) coordinated to ammonia or monodentate or bidentate amine ligands in a cis configuration represented by the general formula: cis-[Pt(II)A2(X)m(OH)n] wherein A is ammonia or an amine ligand; X is the ascorbate moiety; m is from 1 to 2 and n is from 1 to 0 and the sum of m + n is not greater than 2. The compounds are characterized by pronounced anti-tumor activity, high solubility in water, and low animal toxicity.

Description

SPECIFICATION Cis-platinum(ll) amine ascorbate complexes This invention is concerned with ascorbate complexes of platinum(ll) coordinated to monodentate or bidentate amine ligands in a cis-configuration which are characterized by pronounced anti-tumor activity and low animal toxicity.

Figure lisa reproduction of the infrared spectrum of the cis-diammineplatinum(ll) ascorbate complex of Example I.

Figure2 is a reproduction of the ultraviolet spectrum of the cis-diammineplatinum(ll) ascorbate complex of Example I.

Figure 3 is a reproduction of the nuclear magnetic resonance spectrum of the cis-diammineplatinum(ll) ascorbate complex of Example I.

Figure 4 is a reproduction of the infrared spectrum of the cis-bis(methylamine)platinum(ll) ascorbate complex of Example IV.

Figure 5 is a reproduction of the nuclear magnetic resonance spectrum of the cisbis(methylamine)platinum(ll) ascorbate complex of Example IV.

Figure 6 is a reproduction of the infrared spectrum of the ethylenediamineplatinum(ll) ascorbate complex of Example V.

Figure 7 is a reproduction of the nuclear magnetic resonance spectrum of the ethylenediamineplatinum(ll) ascorbate complex of Example V.

Figure 8 is a reproduction of the infrared spectrum of the diaminocyclohexaneplatinum(ll) ascorbate complex of Example VI.

In 1968 Rosenberg and Van Camp discovered that cis-[Pt(NH3)2C12] showed excellent anti-tumor activity against solid Sarcoma 180 (S180s) in Swiss white mice. (Rosenberg and Van Camp, Nature, 222, 385 (1969)).

This discovery has led to extensive testing of platinum and other transition metal compounds for anti-tumor activity in animals (e.g., Cleare, Coordination Chemistry Reviews, 12, 349 (1974); and Connors and Roberts, ed., Platinum Coordination Complexes in Cancer Chemotherapy, Springer, New York 1974). The neutral cis-[PtA2X2] species which have proven most active against animal tumors are not, as a class, very soluble in water. (J.L. Marx, Science, 192, 774, (1976)). Cleare and Hoeschele indicate solubilities in water or saline at 37etc, ranging from 0.04g 100 ml for [Pt(NH312(malonatel] to 1.38 g 100 ml for [Pt(CH3NH212Cl2]. (Cleare and Hoeschele, Bioinorganic Chemistry, 2, 187 (1973)). Lower solubilities greatly reduce the utility for oral or intravenous administration.

According to this invention novel platinum(ll) amine ascorbate compounds are provided which exhibit excellent activity against the Sarcoma 180 ascites (S180a) tumor in mice. In addition, they have low mammalian toxicity. As a result, the compounds of this invention have favorable therapeutic indices. In addition, with the exception of the diaminocyclohexane platinum(ll) ascorbate compounds, they are highly water soluble, their solubility being greater than lOg 100 ml of water.

The amine platinum(ll) ascorbate compounds of this invention may be represented by the general formula: cis-[Pt(ll)A,(X),(OH),1 (I) wherein A is ammonia (NH3) or a monodentate amine ligand represented by the formula RNH2; R is hydrogen or lower alkyl; A2 is a bidentate diamine ligand; Xis the ascorbate moiety: m is a number having a value of 1 to 2; n is a number having a value of 0 to 1, and the sum of n + m is not greater than 2. The subscripts m and n may have fractional values between their respective limits, in which case formula (I) would represent a mixture of the individual complexes. Whenever the word compound or complex is used to refer to the product of this invention it embraces the individual complexes as well as mixtures of them.

Monodentate amine ligands represented by the formula RNH2 include ammonia (NH3), as well as monoalkyl amines having up to 6 carbons in the alkyl group, such as methylamine, ethylamine, propylamine, isopropylamine, hexylamine and the like. Of the alkyl amines, those having up to 3 carbons are preferred.

Bidentate diamine ligands represented by A2 may be further represented by the formula: R' R2 H2N-CH-CH-NH2 (II) wherein each of R' and R2, when taken separately, is hydrogen or lower alkyl; and R' and R2, when taken together, form the divalent radical: R3 R4 R5 R6 -CH-CH-CH-CH wherein each of R3 - R6, when taken separately is hydrogen or lower alkyl, giving a 1 ,2-diaminocyclohexane ligand as represented by the formula:

By the term "lower alkyl", as employed herein, is meant a linear or branched chain alkyl group of from 1 to about 6 carbons, and preferably from 1 to about 3 carbons, such as methyl, ethyl, propyl. Preferred are diamines where at least one of said R' and R2 are hydrogen, such as ethylenediamine and propylene-1,2diamine.Also preferred are the diamines where R1 and R2, when taken together, are replaced by the radical:

wherein each of R3 - R6 is hydrogen, i.e., 1,2-diaminocyclohexane.

The ascorbate moiety is derived from ascorbic acid, which may be represented by the formula:

wherein carbons numbered 4 and 5 are optically active. There are, then, four optical isomers of ascorbic acid.

The ascorbate moiety of the complex of this invention can be derived from any one of the individual isomers, or from a mixture of any two or more other.

When m in formula (1 ) above is land n is 0, the ascorbate moiety is a divalent moiety which is formed by removal of a hydrogen from each of the hydroxyl groups at C-2 and C-3 ofthefuranone ring. When m is 1 or 2 and n is either 1 or 0, the ascorbate moiety is a monovalent moiety which is probably formed by removal of a hydrogen from the hydroxyl bound to C-3. As a result, platinum is most probably bonded to the ascorbate moiety at C-3.

The compounds of this invention are prepared by contacting in aqueous medium an ascorbate salt with an amine platinum(ll) "diaquo" salt represented by the formula: cis-[PtA2(H2O)2]2(Z (2 U))+u wherein A and A2 are as defined above, Z is an inorganic anion, and u is a number having a value of 0 or 1.

Suitable anions are those which are stable in acid media; they include sulfate, nitrate, and perchlorate, although nitrate is preferred. Anions having a greater complexing ability than water or ascorbate, such as chloride, bromide and iodide are not suitable.

The "diaquo" salt is formed from the stoichiometric reaction of a cis-diamineplatinum(ll) dichloride with a silver salt, preferably silver nitrate, in an aqueous medium at room temperature. Although room temperature is preferred for the reaction, higher or lower temperatures may be employed, e.g., from about O"C to about 50etc. The "diaquo" salt is unstable in solution, and thus freshly prepared solutions should be employed. Alternatively, the "diaquo" salt may be converted to stable solid cis-[PtA2(OH)I2(NO3)2 by reaction with one gram mole of base per atom of platinum. The dimeric complex may be reconverted to a monomer with acid or used directly in the preparation of ascorbate compounds.

The ascorbate salts which are employed are water soluble salts, preferably alkali metal ascorbate salts such as sodium or potassium ascorbate.

The ascorbate salt is present in the starting reaction mixture in molar excess, i.e., the molar ratio of ascorbate salt to "diaquo" salt is greaterthan 1:1, and ordinarily is in the range offrom 1:1 to about 3:1, and is preferably approximately 2 gram moles of ascorbate salt per gram atom of platinum. The preferred proportion can vary, however, from about 1.8 to about 2.2 moles of ascorbate salt per gram atom of platinum. The concentration of the reactants in the aqueous medium is not highly critical; however it is preferred that the reaction medium be approximately 0.2 molar, i.e. from about 0.1 to about 0.3 molar, with respect to platinum.

The aqueous mixture of the amine diaquo salt and ascorbate salt is stirred at ambient temperature for a period of time sufficient to form the compounds of this invention. If desired, temperatures above or below ambient temperature, e.g., from about 0 C to about 30"C, may be employed. The period of reaction can vary from minutes to several hours. At room temperature, the solution becomes bright yellow after about 15 minutes, and then slowly darkens, becoming yellow-brown after about 8 hours and black after about 24 hours. The solution is acidic throughout, the pH being about 4.9 at the start and falling to about 4.0 to about 4.1 after about one hour, after which it remains essentially constant.The ratio of ascorbate moiety to platinum metal (after precipitation with 9 volumes of ethanol) appears to increase to a maximum of about 1.2:1 in about 2 hours, after which the ratio decreases. If reaction times in excess of about 7 hours are employed, decomposition of the PtA2 units appears to begin.

The ascorbate compound of the invention is recovered from the reaction medium by any suitable technique, preferably by precipitation from solution with a non-solvent for the complex, followed by filtering and drying the precipitate. Alcohols such as ethanol are preferred. When ethanol is employed, the composition of the product is affected by the amount of ethanol employed. Thus, the ratio of ascorbate to platinum increases as the amount of ethanol increases from about 3 to about 6 times the volume of the reaction mixture. Further increases in the amount of ethanol above 6 reaction volumes leads to a decrease in the ratio of ascorbate moiety to platinum moiety.

The exact structure of the amine platinum(ll) ascorbate complexes of this invention has not been conclusively established. However, the products produced as described above are believed to comprise a mixture of at least two of the three species represented by the formulae:

Separation of the individual species is not practical because the compounds decompose fairly rapidly in aqueous solution. The mixtures typically have an ascorbate to platinum ratio of from about 1.2:1 to about 1.5:1.

infrared i infrared spectra of the compounds of this invention possess the following common characteristics: 3road bands and shoulders at > 3000cm-', due to VNH and VOH- 2) A strong peak at 1720-1730 cm~, due to vc=o from ascorbate. (This band occurs at 1 700 cam in sodium ascorbate).

3) A strong broad band at 1600 cm-1, due to NH2 bending.

4) Bands at 1140, 1100, 1030,960 and 930 cm-, believed due to vGe and vGo bands of ascorbate.

The compounds of this invention are of particular utility in tumor chemotherapy in mammals, having been found to be active against S180a and L1210 in mice. The compounds are administered either as aqueous solutions or water slurries. In general, they are active at dosage levels in the range of from about 25 mglkg to about 200 mglkg. Maximum activity varies for the different compounds, and ranges from about 30 mg/kg for the ethylenediamine compound to as high as 320 mglkg for the diammine compound. In the case where a toxic dose was reached, with ethylenediamine, the maximum effective dose occurred around one fourth or less of the toxic dose. This represents a clear improvement over cis-[Pt(NH3)2CI2], for which maximum activity employing the same screening occurs at 8-10 mg/kg with a 16 mg/kg toxic dose.A wider range between the effective dose and the toxic dose is preferred by clinicians because it affords a wider safety margin.

The following examples are illustrative of the present invention.

EXAMPLE I Synthesis of cis-Diammineplatinumbil) ascorbate A 0.6 M solution of cis-[Pt(NH3)2(H2O)2](NO3)2 was prepared by the stoichiometric reaction of cis-[Pt(NH3)2C12] with silver nitrate in aqueous medium at room temperature. 10 ml of the freshly prepared solution was added to a solution of 2.37 g of sodium ascorbate dissolved in 10 ml of water. The resulting mixture was stirred for 2 hours at room temperature, with a yellow color gradually developing. 200 ml of ethanol was added and the mixture was stirred for an additional 2 hours in air, and then refrigerated overnight. The crude yellow-brnwn solid product which had formed was filtered and washed with ethanol. It was dissolved in 20 ml of water and the solution was slowly added to 200 ml of ethanol while stirring.After storage overnight in a refrigerator, the yellow product was filtered, washed with ethanol and vacuum dried at room temperature to yield 1.06 g of the cis-diammineplatinum(ll) ascorbate complex.

The procedure was repeated three times to yield additional samples of cis-diammineplatinum(ll) ascorbate.

Analysis: %C %H %N %Pt N/Pt C/Pt Found: Sample 1 18.73 2.74 5.44 Sample 2 19.00 2.63 5.27 33.99 2.16 9.08 Sample 3 19.21 2.78 5.81 37.75 2.14 8.26 Sample4 20.37 2.81 5.54 39.45 1.96 8.40 Calc: 18.95 2.65 4.91 34.21 2 9 Pt(NH3)2CgHg014* * Determined using the whole number ratios of carbon to platinum giving the closest fit with the observed results.

The infrared spectrum of the thus-prepared cis-diammineplatinum(ll) ascorbate complex, which is reproduced in Figure 1, is characterized by the following absorption bands.

Absorption Band, Nujol Mull Assignment 3450 sh VNH, VOH 3300 br 1730 m VC=o 1660m bNH2 1610s 1310sh bNH2 1140 m 1100sh 1070s Vc-c 1030s VC-o 960 m 930 w 860 w 820 w 760sh 610m VPt-N sh=shoulder; s=strong; m=medium; w=weak; br=broad.

The ultraviolet spectrum of an aqueous solution of the complex (2 x 10-4 molar in platinum) is reproduced as Figure 2, and the nuclear magnetic resonance spectrum is reproduced as Figure 3.

EXAMPLE II The procedure of Example I was repeated, except that the amount of ethanol employed as a precipitant was varied from 2 to 9 times the volume of the reaction solution. The analyses of the resulting cis-diammineplatinum(ll) ascorbate products are summarized as follows: Volumes of Ethanol Per Volume Reaction Analysis of Product Sample Mixture %Pt Ascorbate Pt Il-A 2 * Il-B 3 38.02 1.12 Il-C 4 35.85 1.26 Il-D 6 34.50 1.55 Il-E 9 39.45 1.20 * Insignificant amount of precipitation.

EXAMPLE lil The procedure described in Example I was repeated, except that the reaction time was varied from 1 to 7 hours and 9 volumes of ethanol were employed to precipitate the cis-diammineplatinum(ll) ascorbate. The analyses of the products are summarized as follows: Reaction Analysis of Product Time, hr "oPt Ascorbate Pt N Pt C Pt 1 40.44 1.14 1.99 8.40 2 39.45 1.20 1.96 8.40 4 40.27 * 1.88 8.22 7 42.99 1.02 1.82 7.38 *Sample too small for determination EXAMPLE IV Synthesis of Cis-bisZmethylamine)platinumKlil ascorbate 1.065 g of cis-[Pt(CH3NH2)2C12] was suspended in 40 ml of water and 1.10 g of solid AgNO3 (Ag:Pt = 2:1) was added directly. The mixture was stirred at room temperature for 2 hours, protected from light.After filtering off the AgCI and testing with KCI to see that silver was absent, 1.29 g of sodium ascorbate (ascorbate:Pt = 2:1)was added to the filtrate and stirred for 2 hours at room temperature. When no precipitate occurred upon addition of ethanol, all solvents were removed under vacuum at 30so. The resulting yellow solid was slurried in ethanol, filtered, and washed with ethanol, and then dissolved in 5 ml of water. The aqueous solution was added to 200 ml of ethanol while stirring. After stirring for 30 minutes at room temperature and refrigerating overnight, the light yellow solid product was filtered, washed with ethanol, and dried in vacuum to yield 0.42 g of cis-bis(methylamine)platinum(ll) ascorbate. The product was hygroscopic and decomposed when exposed to light.

Analysis: Calc: Pt(CH3NH2)2(C8H8011)* C, 22.350o; H, 3.370o; N, 5.21to Found: C, 23.11% H, 3.400o; N, 5.080o *Empirical formula The infrared spectrum of this complex is reproduced as Figure 4. The major band assignments are as follows: Absorption Band, Nujol Mull Assignment 3400 sh VNH, VOH 3240 br 3150sh 1720 s VC=o 1600s #NH 1350 sh gNH2 1140 m 1100 m 1030s Vc-c 970 m VC-o 920 w 860 w 820 w 750 w The nuclear magnetic resonance spectrum of the cis-bis(methylamine)platinum(ll) ascorbate complex is reproduced as Figure 5.

EXAMPLE V Synthesis of EthylenediamineplatinumRll) ascorbate A 0.25 M solution of [Pt(en)(H2O)2](NO3)2 was prepared by the stoichiometric reaction of [Pt(en)Cl2] with silver nitrate in aqueous medium at room temperature. 48 ml of the freshly prepared solution was added to a solution of 4.74 g of sodium ascorbate in 12 ml of water. The mixture turned light green very quickly, then gradually yellow after stirring for 2 hours at room temperature. 400 ml of ethanol was added and the mixture was stirred for an additional 2 hours, and then refrigerated overnight. The light yellow product was filtered, washed with ethanol and redissolved in 40 ml of water. After filtering to remove insoluble white material, the solution was added to 400 ml of ethanol, stirred for 2 hours, and refrigerated overnight.The cream colored product was filtered, washed with ethanol, and dried in vacuum to yield 1.12 g of solid ethylenediamineplatinum(ll) ascorbate.

Analysis: Calc: Pt(en)(CgHgO11)* C, 24.09%; H, 3.12%; N, 5.11%; Pt, 35.57% Found: C, 23.59%; H,3.02%; N, 5.38%; Pt, 35.44% *Empirical formula (en=ethylenediamine) The infrared spectrum of cis-ethylenediamineplatinum(ll) ascorbate is reproduced as Figure 6. The major assignments are summarized as follows: Absorption Band, Nujol Mull Assignment 3400sh 3230 br VNH, VOH 3140 sh 1720 s VC=o 1610br #NH2 1300sh #NH2 1135m 1090 m Vc-c 1040s 960 w VC-o 920 w 870 m 810w 750sh 650 w VPt-N 520 w The nuclear magnetic resonance spectrum of the complex is reproduced as Figure 7.

EXAMPLE VI Synthesis of DiaminocyclohexaneplatinumZllJ ascorbate A 0.2 M solution of [Pt(DACHXN)(H20)2](NO3)2 was prepared by the stoichiometric reaction of [Pt(DACHXN)CI2] with silver nitrate in aqueous medium at room temperature. 1.58 9 of sodium ascorbate was added directly to 20 ml of the freshly prepared solution. A small amount of black insoluble material was filtered off and 200 ml of ethanol was added. After stirring for an additional hour and refrigerating overnight, the yellow product was filtered, washed with ethanol, and dried in vacuum to yield 0.189 of diaminocyclohexaneplatinum(ll) ascorbate.

Analysis: Calc: Pt(DACHXN) (C7H8Og)* C,28.62%; H, 4.06%; N, 5.13% Found: C, 28.63%; H,3.72%; N, 4.98% *Empirical Formula (DACHXN = 1,2-diaminocyclohexane) The infrared spectrum of the complex is reproduced in Figure 8.The major band assignments are summarized as follows: Absorption Band, Nujol Mull Assignment 3400 sh 3240 br VNH, VOH 3130sh 1720 s VC=o 1610s 6NH2 1350 sh 5NH2 1150 m 1100 m 1060m Vc-c 1030 m 970 sh VCo 920sh 860 w 820 w 750sh EXAMPLE VII Screening of compounds for anti-tumor activity against S180a The compounds were evaluated for anti-tumor activity against S180 ascites in female CFW Swiss mice by the following procedure.

CFW mice, averaging 20 g, are immediately inspected and placed in newly prepared cages. On day zero the mice are inoculated with 0.2 ml of a freshly prepared saline suspension (0.15 M NaCI) containing 1 x 107 tumor cells/ml, or a total of 2 x 106 cells. This inoculum is freshly prepared using "transfer" mice which have been injected with tumor cells the previous week. This inoculum is the end-product of a series of steps which involves (1) the removal of the cells from the peritoneal cavity of the sacrificed transfer mouse, (2) alternate centrifugation-washing (2-3 times with cold saline) to remove occasional blood and other undesirable components, and finally (3) dilution (1:3) of the packed cell volume with saline (the final centrifugation being carried out at 1,000 rpm for 2 min.). A cell count is made on a 2,000-fold dilution of this 1:3 suspension by means of a Coulter Counter.Afinal dilution to 1 x 107 cells/mis made based on the averaged count. On day 1, solutions of the test compounds are prepared and the mice injected, with each mouse of a set of four mice being injected with the same test compound at the same dose level.

Also, on this day, two types of controls (6 micessset) are employed: (1) Normal (1 set): 0.5 ml of the solvent medium used for the test compound, and (2) Positive control (1 set): a known anti-tumor agent (cis-[Pt(NH3)2Cl2] in saline at 8 mg kg), used to test the response of the biological system.

The effectiveness of a compound is measured in terms of the increase in life span of the test animals relative to the controls (calculated from the day of tumor inoculation (day zero)). In order to standardize the test data and permit intercomparisons to be made, the day of evaluation is arbitrarily taken as that day corresponding to twice the mean life-span (or average day of death) of the normal controls. This sets a practical upper limit of 100% on the ILS attainable. For calculation purposes, survivors on the day of evaluation are considered to have died on that day. The % ILS is formulated as: %lLS = mean life-span of test mice -1 x 100% mean life-span of control mice ILS values above 50% represent significant activity; those above 75% represent excellent activity.

The soluble ammine, methylamine and ethylenediamine complexes were administered as aqueous solutions. The water-insoluble diaminocyclohexane complex was administered as an aqueous slurry. The concentration for a given dose can be calculated according to: Concentration for a given dose (in mgi'ml) = (0.04) x (Dose in mg/kg).

Anti-tumor screening data for the cis-[PtA2(ascorbate)j compounds are summarized as follows: Anti-tumor screening data for Cis-Pb42 ascorbate compounds vs. the S180 ascites tumor system Positive Controlb Dosea % 30-Day % 30-Day Compound Medium (mg/kg) ILS Survivors ILS Survivors Example I H2O 20 53 1/4 55 2/6 (A=NH3) 40 100 4/4 80 92 3/4 160 15 2/4 Example I H2O 20 88 2/4 77 3/6 (repeated) 40 100 4/4 (A=NH3) 80 100 4/4 160 59 3/4 Example Il-D H2O 10 20 0/4 49 0/6 (A=NH3) 20 24 0/4 40 100 3/4 80 100 4/4 160 100 3/4 320 100 3/4 Example IV H2O 25 24 0/4 78 2/6 (A=CH3NH2) 50 11 0/4 100 93 1/4 200 88 1/4 Example V H2O 30 89 3/4 81 3/6 (A2=en) 60 76 3/4 120 49 1/4 240 -94 0/4 Example VI H2O 25 72 2/4 69 3/6 (A2=DACHXN) slurry 50 99 2/4 100 91 314 200 100 414 a 4 mice. dose for cis-diamineplatinum(ll) ascorbate compounds.

b Positive control = 8 mg kg cis-Pt(NH3)2C12 in saline.

As is evident in the foregoing, all compounds demonstrated excellent activity against the S180a tumor system in mice, and all proved to be effective within a dosage range of from about 25 mg.kg to 200 mg/kg of the compounds tested; only the ethylenediamine complex was found to be toxic within the ranges tested, and then not until a dosage of 240 mg kg was reached.

EXAMPLE VIII Evaluation of the anti-tumor activity of the diammine compound of this invention in the mouse L 1210 system The diammine compound of this invention (Example I) was also screened for activity against the lymphoid leukemia L1210 system in mice, in which the mean survival time as compared with control mice (T C) was determined. The T C* was calculated as follows: mean mean life-span (Test) mean life-span (Control) x 100 * TiC is related to C/c ILS by the relationship T C-100 = % ILS T/C values of 125 or greater represent significant activity. The data from these tests are summarized below. Anti-tumor screening of cis-diammineplatinum(llJ ascorbate compound (Example!) vs.L 1210 tumor system Dosea T/C Toxicityc (mg/kg) Day Survivors 160 Tb 3/6 80 168 6/6 40 127 6/6 20 108 6/6 10 103 6/6 5 108 6/6 a Dose regimen - Doses on Days 1,5 and 9 b T = Toxic by NCl criteria (Geran, et. al "Protocols for Screening Chemical Agents and Natural Products against Tumors and Other Biological Systems" (3rd ed.), Cancer Chemotherapy Reports, Part 3, Summer, 1972).

Number surviving on Day 5 Excellent activity (T/C - 168) was observed at a level of 80 mg/kg and marginal activity (TIC - 127) was observed at 40 mg/kg. Peak activity was found in the same dose range as with the S180a tumor system.

These results compare favorably with those of cis-[Pt(NH3)2CI2], which produced a maximum T/C of 152 at 5 mg/kg on the same day - 1, 5,9 dose regimen.

Claims (1)

1. A cis-diamineplatinum(ll) ascorbate compound represented by the general formula: cis-[Pt(ll)A,(X),(oH),I wherein Pt is in valence state Il and coordinated to A in a cis configuration; A is amonia or a monodentate alkylamine ligand; A2 is a bidentate amine ligand; Xis the ascorbate moiety; m is a number having a value of from 1 to 2; n is a number having a value of from 0 to 1, and the sum of m + n is not greater than 2.

2. A compound according to Claim 1 wherein A has the formula RNH2, and R is selected from the group consisting of hydrogen or lower alkyl.

3. A compound according to Claim 2 wherein R is hydrogen.

4. A compound according to Claim 2 wherein R is lower alkyl.

5. A compound according to Claim 4 wherein R is methyl.

6. A compound according to Claim 1 wherein A2 is represented by the formula:

wherein each of Ri and R2, when taken separately, is selected from the group consisting of hydrogen and a lower alkyl; and R1 and R2, when taken together, form the divalent radical:

wherein each of R3-R6, when taken separately, is hydrogen or a lower alkyl, giving a 1,2-diaminocyclohexane represented by the formula:

I. VIZ I compouno according to Claim b wherein each ot K' and H Is hydrogen.

8. A compound according to Claim 6 wherein each of R3 - R6 is hydrogen.

9. A pharmaceutical composition for treating malignanttumours in a mammal comprising a complex as claimed in any preceding claim and a pharmaceutically acceptable carrier.

10. The use of a complex as claimed in any of Claims 1 to 8 for treating malignanttumours in a mammal.

11. A cis-diamineplatinum(ll) ascorbate compound represented by the general formula as set out in Claim 1 and substantially as hereinbefore described with reference to any of the Examples.

12. A pharmaceutical composition for treating malignant tumours in a mammal and substantially as hereinbefore described with reference to any of the Examples.