Abstract:
Diaminocyclohexane platinum complexes having the structural formula ##STR1## wherein: X is a monovalent anion selected from the group consisting of isoascorbate, monosaccharate, saccharate-4-lactone, shikimate, isethionate, 2-aminoethylsulfate, azetidinecarboxylate, proline, hydroxyproline, pipecolinate, cyclopropanecarboxylate, cyclobutanecarboxylate, cyclopentanecarboxylate, cyclopentenecarboxylate, cyclohexanecarboxylate, cyclohexenecarboxylate, bicine, glycine, 2-aminoethanesulfonate, 2-chloroethanesulfonate and 
     Y is a divalent anion selected from the group consisting of iminodiacetate, isocitratelactone, furanedicarboxylate, cyclopropane-1,1-dicarboxylate, isocitratomonoethylester, N-methyliminodiacetate, N-(2-hydroxyethyl)-iminodiacetate, N-benzyliminodiacetate, N-phenyliminodiacetate, N-(2-acetamido)iminodiacetate, cyclohexane-1,1-diacetate, trans-1,2-cyclopropanedicarboxylate, trans-1,2-cyclobutanedicarboxylate, trans-1,2-cyclopentanedicarboxylate and trans-1,2-cyclohexanedicarboxylate 
     and their use in the treatment of tumors.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of U.S. application Ser. No. 636,522, filed Aug. 1, 1984, now abandoned. which, in turn, is a continuation-in-part of application Ser. No. 505,965, filed June 20, 1983, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to certain novel 1,2-diaminocyclohexane platinum complexes and their use in the treatment of tumors. 
     Recently, certain platinum complexes have been shown by Rosenberg, et al. and others to be highly active anti-tumor agents (see U.S. Pat. Nos. 4,177,263 and 4,140,707). For example, the complex cis-dichlorodiamineplatinum-II or &#34;cisplatin&#34; is the chemotherapeutic agent of choice in the treatment of many and varied tumors. 
     There are several drawbacks, however, associated with the use of the platinum complexes to treat tumors. Generally, the platinum complexes have a relatively low solubility in water thereby rendering it difficult to formulate a composition which can effectively deliver the reagent to the site of the tumor in the body. 
     Moreover, many of the platinum complexes are highly nephrotoxic thereby further restricting their use in the absence of precautionary measures to avoid damage to the kidneys when administered to animals afflicted with tumors. 
     Recently, considerable activity has centered on the use of 1,2-diaminocyclohexane complexes of platinum as anti-tumor agents. See, for example, U.S. Pat. Nos. 3,892,790; 3,904,663; 4,115,418; 4,140,707; 4,169,846; 4,175,133; 4,228,090 and 4,256,652 and German Offenlegungschrift No. 30 22 917. 
     Although the complexes described therein possess anti-tumor activity, virtually all are highly insoluble in water and are also relatively highly nephrotoxic. 
     German Offenlegungschrift No. 30 22 957 describes 1,2-diaminocyclohexane/ascorbate complexes of platinum, useful as anti-tumor agents, which comprise mixtures of complexes having varying ratios of ascorbate ion to platinum. Thus, the publication discloses complexes of the formula: ##STR2## wherein n varies from 1.2 to 1.5. The complexes are described as poorly water soluble. 
     in the Proceedings for the American Association for Cancer Research, Vol. 23, page 116, 1982, we describe New Platinum Complexes Containing Ascorbate having good aqueous solubility, useful antitumor activity and decreased nephrotoxicity. Two such complexes, one containing Pt, aminoethylpyrrolidine and ascorbate and the second containing Pt, 1,2-diaminocyclohexane, chloride and ascorbate are capable of suppressing the growth of L1210 cells in vivo. 
     J. Am. Chem. Soc. 1985, 107, 274-276 describes the synthesis of a series of cis-[Pt(RNH 2 ) 2  ] (ascorbate) complexes which are reported to be stable in aqueous or alcoholic solutions and are active in the S180a tumor screen. 
     We have now found that certain other 1,2-diaminocyclohexane (DACH)-platinum-anion complexes are vastly superior to the ascorbate complexes in being relatively non-nephrotoxic, possessing a high degree of antitumor activity, high water-solubility, and no cross resistance to cis(DACH)-dichlorodiamine platinum II. In particular, we have found that the iminodiacetatocyclohexane platinum (II) complexes have marked in vitro cytotoxic activity, good in vivo activity as a single injection which is significantly enhanced when administered intraperitoneally and significantly less nephrotoxicity than cis-platin. 
     Especially preferred embodiments of this invention include the mixed isomer DACH-Pt (II) iminodiacetato complexes and the trans-R,R-DACH-Pt (II) mono-iminodiacetato, mono-N-methyl-iminodiacetato, mono-N-hydroxyethyliminodiacetato, mono-N-phenyliminodiacetato, and mono-N-benzyliminodiacetato complexes. These complexes are especially valuable in that they enhance the cytotoxicity without increased host toxicity. 
     It is an object of the present invention to provide non-nephrotoxic 1,2-diaminocyclohexane (DACH)-platinum-anion complexes containing 1.0 bidentate or 2 monodentate negatively charged organic radicals per molecule of platinum possessing high degrees of anti-tumor activity, high water-solubilities, and no cross resistance to cis-dichlorodiammine platinum II. 
     It is a further object of the invention to provide a method for the preparation of the platinum complexes. 
     It is a further object of the invention to provide a method for preparing DACH-platinum-anion complexes containing stoichiometric ratios of anion to platinum. 
     It is a further object of the invention to provide a pharmaceutical composition particularly adapted for the treatment of animals afflicted with tumors. 
     It is a further object of the invention to provide a therapeutic method for the treatment of animals afflicted with tumors. 
     SUMMARY OF THE INVENTION 
     The above and other objects of the invention are achieved by the hereinbelow described method which enables the production of complexes of DACH-platinum complexes of the following formulae which contain stoichiometric ratios of anion to platinum: ##STR3## wherein: X is a monovalent anion selected from the group consisting of isoascorbate, monosaccharate, saccharate-4-lactone, shikimate, isethionate, 2-aminoethylsulfate, azetidinecarboxylate, proline, hydroxyproline, pipecolinate, cyclopropanecarboxylate, cyclobutanecarboxylate, cyclopentanecarboxylate, cyclopentenecarboxylate, cyclohexanecarboxylate, cyclohexenecarboxylate, bicine, glycine, 2-aminoethanesulfonate, 2-chloroethanesulfonate, and 
     Y is a divalent anion selected from the group consisting of iminodiacetate, isocitratelactone, furanedicarboxylate, cyclopropane-1, 1-dicarboxylate and isocitratomonoethyl ester, N-methyliminodiacetate, N-(2-hydroxyethyl)-iminodiacetate, N-benzyliminodiacetate, N-phenyliminodiacetate, N-(2-acetamido)-iminodiacetate, cyclohexane-1,1-diacetate, trans-1,2-cyclobutanedicarboxylate, trans-1,2-cyclopentanedicarboxylate and trans-1,2-cyclohexanedicarboxylate 
     The present invention is comprised of a central platinum metal coordinated to the DACH molecule and either two identical monodentates or one bidentate. Although cis and trans platinum complexes may be possible, the preferred geometric isomers are the squareplanar cis-platinum(II) complexes. 
     In addition, the DACH molecule contains two chiral centers, and, therefore, exists as either the cis-diastereomer or the trans-diastereomer. Although the cis-diastereomer is optically inactive, the transdiastereomer exists in two enantiometric forms: the trans-R,R-DACH and the trans-S,S-DACH. The trans-DACH are the preferred diastereomers. Especially preferred are the trans-R,R-DACH. It is to be noted that mixtures of the various isomers mentioned hereinabove are contemplated to be within the scope of the present invention. 
     Particularly useful complexes within the scope of the present invention are cis-bis-ascorbato (trans-R,R-DACH) platinum (II) and cis-bis-ascorbato (trans-S,S-DACH) platinum (II). 
     The most preferred embodiments of the present invention are the iminodiacetato derivatives of the trans-DACH-platinum complexdes. Of these, particularly preferred iminodiacetato derivatives are the trans-R,R-DACH-Pt(II) complexes of the above formula wherein: 
     Y is mono-iminodiacetate, mono-N-methyliminodiacetate, mono-N-hydroxyethyliminodiacetate, mono-N-phenyliminodiacetate, and mono-N-benzyliminodiacetate. 
     The method of the invention for preparing the above-described complexes comprises: 
     (a) reacting a water-soluble haloplatinate (II) in an aqueous medium with DACH to produce a di-halo-(DACH)-platinum (II); 
     (b) reacting said product of step (a) with a soluble sulfate salt in an aqueous medium to produce sulfato(DACH)-platinum(II); 
     (c) reacting the product of step (b) with a soluble salt of X or Y to produce said complex of the above formula, and 
     (d) recovering said complex. 
     The present invention also provides a pharmaceutical composition in unit dosage form suitable for administration to an animal afflicted with tumor cells sensitive to a platinum complex of the above formula comprising a therapeutically anti-tumor effective amount of the platinum complex and a pharmaceutically acceptable carrier therefor. 
     The invention also provides a method for the treatment of an animal afflicted with tumor cells sensitive to a platinum complex of the above formula comprising administering to the animal a therapeutically, anti-tumor effective amount of the platinum complex. 
     DETAILED DESCRIPTION OF THE INVENTION 
     The complexes of the invention have the following structural formulae: ##STR4## 
     The stoichiometric mono- and bis-anion-(DACH) platinum complexes of the invention (i.e., containing one divalent anion or two monovalent anions per molecule of platinum) may be prepared by reacting any suitable watersoluble haloplatinate (i.e., K 2  PtCl 4 ) with DACH to produce the intermediate, di-halo-(DACH)platinum(II). The reaction is preferably effected in water at room temperature for a time sufficient to drive the reaction to completion, generally from about 6 to 8 hours. 
     The intermediate di-halo complex is normally a yellow solid precipitate which is advantageously isolated from the reaction mixture by filtering, followed by washing with water, methanol and acetone. Finally, the yellow solid is dried, preferably under vacuum or is left in solution and immediately reacted therein with a sulfate. It is preferred to utilize a sulfate of a metal or cation the halo salt of which is insoluble in water to facilitate isolation of the product. Thus, where the di-halo (DACH) platinum is the di-chloro complex, it is preferred to employ Ag 2  SO 4  thereby facilitating removal of the insoluble by-product, AgCl. The reaction is preferably carried out in an aqueous medium such as water or in the reaction medium from the first step of the method at room temperature. The reaction generally goes to completion in from about 18 to about 24 hours. 
     Following removal of the insoluble by-product halide, the intermediate sulfato (DACH-platinum(II)) is isolated by evaporating the yellow filtrate to dryness, e.g., using a rotary evaporator, as a yellow-brown solid which is washed, e.g., with acetone and dried, preferably, in vacuum. Alternatively, the sulfato-DACH-platinum intermediate is left in solution and reacted therein with a soluble salt of the appropriate anion to yield the platinum complex of the invention. 
     It is preferred to utilize a metal or other cation salt of the anion whose by-product sulfate salt is insoluble in water to facilitate isolation of the platinum complex. For example, the use of the barium salt of the anion yields barium sulfate as a by-product which is readily removable from the reaction medium by filtration. 
     The reaction is preferably conducted in an aqueous medium at about room temperature for a time sufficient to drive the reaction to completion, generally from about 0.3 to about 0.5 hours. 
     The platinum complex may be isolated from the reaction medium by filtering the by-product barium sulfate. The yellow filtrate is evaporated to dryness at 45°-50° C. under reduced pressure, e.g., using a rotary evaporator. The yellow brown solid is then dried, e.g., over P 2  O 5  under vacuum. 
     A reaction sequence for preparing the bis ascorbate complex, for example, is depicted by the following equations wherein: 
     
         L=DACH, and 
    
     
         Asc=ascorbate 
    
     
         K.sub.2 PtCl.sub.4 +L→LPtCl.sub.2 +2KCl 
    
     
         LPtCl.sub.2 +Ag.sub.2 SO.sub.4 →LPtSO.sub.4 +2AgCl 
    
     
         LPtSO.sub.4 +Ba(Asc).sub.2 →LPt(Asc).sub.2 +BaSO.sub.4 
    
     It is to be understood that is is within the scope of the method of the present invention to employ similar synthetic procedures to prepare suitable aryl, aralkyl or alkyl N-substituted iminodiacetato DACH platinum complexes. 
     It is likewise apparent that by using similar synthetic procedures mixed isomer DACH,trans-R,R-DACH, trans-S,S-DACH or cis-DACH may be readily prepared and used as the stable amine ligand for the platinum coordination complexes of the present invention. 
     The method of the invention is illustrated by the following non-limiting examples. The products of preparative examples 1-13, 22, 23 and 24 are summarized in Table I. 
     
                                           TABLE 1__________________________________________________________________________COMPOUND NO.     COMPOUND                EXAMPLE NO.__________________________________________________________________________1         cis-bis-dichloro(DACH)Pt(II)                             12         sulfato(DACH)Pt(II)     23         cis-bis-ascorbato(DACH)Pt(II).1H.sub.2 O                             34         cis-bis-ascorbato(trans-R,R--DACH)Pt(II).3H.sub.2 O                             45         cis-bis-ascorbato(trans-S,S--DACH)Pt(II).2H.sub.2 O                             56         cis-bis-ascorbato(cis-DACH)Pt(II).5H.sub.2 O                             67         cis-bis-isoascorbato(DACH)Pt(II).3H.sub.2 O                             78         cis-bis-D-monosaccharato(DACH)Pt(II).3H.sub.2 O                             89         cis-bis-D-saccharato-1,4-lactone(DACH)Pt(II)10        cis-bis-shikimato(DACH)Pt(II).2H.sub.2 O                             1011        iminodiacetato(DACH)Pt(II).2H.sub.2 O                             1112        DL-isocitratolactone(DACH)Pt(II).1H.sub.2 O                             1213        cis-bis-isethionato(DACH)Pt(II).2H.sub.2 O                             1314        cis-bis-2-aminoethylsulfato(DACH)Pt(II)                             1315        cis-bis-L-azetidinecarboxylato(DACH)Pt(II).1H.sub.2 O                             1316        cis-bis-L-prolinato(DACH)Pt(II)                             1317        cis-bis-L-hyroxyprolinato(DACH)Pt(II).1H.sub.2 O                             1318        cis-bis-DL-pipecolinato(DACH)Pt(II).1H.sub.2 O                             1319        furanedicarboxylato(DACH)Pt(II)                             1320        cyclopropane-1,1-dicarboxylato(DACH)Pt(II).H.sub.2 O                             1321        isocitratomonoethylester(DACH)Pt(II).1.5H.sub.2 O                             1322        Cis-bis-cyclohexanecarboxylato                             24     (DACH)Pt(II).1H.sub.2 O23        1,1-cyclohexanediacetato(DACH)                             24     Pt(II).1H.sub.2 O24        Cis-bis-cyclohexenecarboxylato                             24     (DACH)Pt(II).1H.sub.2 O25        Cis-bis-cyclopentanecarboxylato                             24     (DACH)Pt(II).1H.sub.2 O26        Cis-bis-cyclopentenecarboxylato                             24     (DACH)Pt(II).2H.sub.2 O27        trans-DL-1,2-cyclopentanedicar-                             24     boxylato(DACH)Pt(II)28        N--Methyliminodiacetato(DACH)Pt                             24     (II).1H.sub.2 O29        Cis-bis-cyclopropanecarboxylato                             24     (DACH)Pt(II).1H.sub.2 O30        Cis-bis-cyclobutanecarboxylato                             24     (DACH)Pt.1H.sub.2 O31        Cis-bis-ethanesulfonato(DACH)                             24     Pt(II).H.sub.2 O32        Cis-bis-glycinato(DACH)Pt(II).1H.sub.2 O                             2433        Cis-bis-chloroethanesulfonato(DACH)                             24     Pt(II).1H.sub.  2 O34        Cis-bis-bicinato(DACH)Pt(II)                             2435        Iminodiacetato(trans-R,R--DACH)Pt(II).2H.sub.2 O                             2336        Cis-bis-L-prolinato(trans-R,R--DACH)                             22     Pt(II).2H.sub.2 O37        N--Phenyliminodiacetato(DACH)Pt(II).2H.sub.2 O                             2438        N--Benzyliminodiacetato(DACH)Pt(II)                             2439        N--(2-Hydroxyethyl)-iminodiacetato                             24     (DACH)Pt(II).2H.sub.2 O40        trans-1,2-cyclopropanedicarboxylato                             24     (DACH)Pt(II)41        trans-1,2-cyclobutanedicarboxy-                             24     lato(DACH)Pt(II)42        N--(2-Acetamido)-iminodiacetato(DACH)                             24     Pt(II).1/2H.sub.2 O43        trans-1,2-cyclohexanedicarboxylato                             24     (DACH)Pt(II)__________________________________________________________________________ 
    
    
    
     EXAMPLE 1 
     Cis-bis-dichloro(DACH)platinum(II) 
     To an aqueous filtered solution of K 2  PtCl 4  (3.5 g; 8.4 mmole in 50 ml of water) 0.9416 g (8.4 mmole) of DACH was added. The reaction mixture was stirred at room temperature for 6-8 hours. A yellow solid was precipitated, filtered, washed with water, methanol and finally with acetone. The final product was dried under vacuum. 
     Yield=56%. 
     Cis-bis-dichloro(trans-1-DACH)platinum(II); cis-bis-dichloro(trans-d-DACH)platinum(II) and cis-bis-dichloro(cis-DACH)platinum(II) were prepared in an analogous manner using stoichiometric amounts (ca. 1 mmole) of K 2  Ptcl 4  and the respective DACH isomers, i.e., trans-l, trans-d and cis-. 
     EXAMPLE 2 
     Sulfato(DACH)platinum(II) 
     Dichloro(DACH)platinum(II) (DACH being a mixture-, trans-l-, trans-d- or cis-isomer) (1.0 g; 2.6 mmole) was suspended in water (20 ml), and a solution of Ag 2  So 4  (0.75 g; 2.4 mmole) in water (150 ml) was added. The reaction mixture was stirred at room temperature for 24 hours in the dark. The precipitated Agcl was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A yellow-brown produce was obtained and dried over P 2  O 5  under vacuum. 
     Yield: 90%. 
     EXAMPLE 3 
     Cis-bis-ascorbate(DACH)platinum(II).1H 2  O 
     Sulfato(DACH)platinum(II).H 2  O 0.846 g (2 mmole) was dissolved in water (50 ml) and barium ascorbate (0.974 g; 2 mmole in 30 ml of water) was added thereto. The reaction mixture was stirred ca. 20 minutes at room temperature. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow product was obtained, which was then washed with acetone. The product was finally dried under vacuum. 
     Yield=90%. The analytical data for the product is set forth in Table II. 
     Platinum analysis-calculated for C 18  H 28  N 2  O 12  Pt.1H 2  O: Pt28.80%, Found: 28.72%. 
     EXAMPLE 4 
     Cis-bis-ascorbato(trans-R,R-DACH)platinum(II).3H 2  O 
     Sulfato(trans-R,R-DACH)platinum(II) 0.423 g (1 mmole) was dissolved in water (20 ml) and a solution of barium ascorbate (0.478 g; 1 mmole in 10 ml of water) was added thereto. The reaction mixture was stirred for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=85%. The analytical data for the product is set forth in Table II. 
     EXAMPLE 5 
     Cis-bis-ascorbato(trans-S,S-DACH)platinum(II).2H 2  O 
     Sulfato(trans-SS-DACH)platinum(II) 0.423 g (1 mmole) was dissolved in water (20 ml) and a solution of barium ascorbate (0.487; 1 mmole) in 10 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the brown yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A yellow solid was obtained which was then washed with acetone and dried under vacuum. 
     Yield=85%. The analytical data for the product is set forth in Table II. 
     EXAMPLE 6 
     Cis-bis-ascorbato(cis-DACH)platinum(II) 
     Sulfato(cis-DACH)platinum(II) 0.211 g (0.5 mmole) was dissolved in water (10 ml) and a solution of barium ascorbate (0.244 g; 0.5 mmole in 10 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=80%. The analytical data for the product is set forth in Table II. 
     EXAMPLE 7 
     Cis-bis-isoascorbato(DACH)platinum(II).3H 2  O 
     Sulfato(DACH)platinum(II) 0.423 g (1 mmole) was dissolved in water (20 ml) and a solution of barium isoascorbate (0.487 g; 1 mmole in 10 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow product was obtained, which was then washed with acetone. The product was finally dried in vacuo. 
     Yield=85%. The analytical data for the product is set forth in Table II. 
     Platinum analysis-calculated for C 18  H 28  N 2  O 12  Pt.3H 2  O: Pt 27.34%. Found: Pt 27.56%. 
     EXAMPLE 8 
     Cis-bis-D-monosaccharato(DACH)platinum(II).3H 2  O 
     Sulfato(DACH)platinum(II) 1.04 g (2.47 mmole) was dissolved in water (50 ml) and a solution of barium monosaccharate (1.372 g; 2.47 mmole in 80 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=89%. The analytical data for the product is set forth in Table II. 
     Platinum Analysis-calculated for C 18  H 32  N 2  O 16  Pt.3H 2  O: Pt 24.96%. Found: Pt 24.77%. 
     EXAMPLE 9 
     Cis-bis-D-saccharate-1,4-lactone(DACH)platinum(II) 
     Sulfato(DACH)platinum(II) 0.106 g was dissolved in 10 ml of water and barium saccharate-1,4-lactone, prepared in situ by the addition of Ba(OH) 2 .8H 2  O 0.075 g to an aqueous solution of D-saccharic acid 1,4 lactone monohydrate 0.11 g was added thereto and the reaction mixture was stirred for 30 minutes at room temperature. Barium sulfate precipitate was filtered off and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with methanol and acetone. The product was finally dried in vacuo. 
     Yield=82%. The analytical data for the product is set forth in Table II. 
     EXAMPLE 10 
     Cis-bis-shikimato(DACH)platinum(II) 
     Sulfato(DACH)platinum(II) 0.423 g (1 mmole) was dissolved in water (20 ml) and a solution of barium shikimate (0.483 g; 1 mmole in 50 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=80%. The analytical data for the product is set forth in Table II. 
     Platinum Analysis-Calculated for C 20  H 32  N 2  O 10  Pt.2H 2  O Pt 28.20%. Found: Pt 28.76%. 
     EXAMPLE 11 
     Iminodiacetato(DACH)platinum(II) 
     Sulfato(DACH)platinum(II) 1.04 g (2.47 mmole) was dissolved in water (50 ml) and a solution of barium iminodiacetate (0.663 g; 2.57 mmole in 50 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=79%. The analytical data for the product is set forth in Table II. 
     EXAMPLE 12 
     DL-Isocitratolactone(DACH)platinum(II) 
     Sulfato(DACH)platinum(II) 0.106 g (0.25 mmole) was dissolved in water (10 ml) and a solution of barium isocitratolactone (0.766 g; 0.25 mmole in 20 ml of water) was added thereto. The reaction mixture was stirred at room temperature for 20 minutes. Barium sulfate precipitate was filtered off, and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was then washed with acetone and dried in vacuo. 
     Yield=75%. The analytical data for the product is set forth in Table II. 
     The other complexes of the invention, i.e., bis-isethionato, bis-2-aminoethylsulfato, bis-azetidinecarboxylato, bis-prolinato, bis-hydroxyprolinato, bis-pipecolinato, and isocitratomonoethyl ester were prepared in an analogous manner to the methods of Example 9, using stoichiometric amounts (ca. 1 mmole) sulfato(DACH)-platinum(II) and the respective barium salts, i.e., isethionate, 2-aminoethylsulfate, azetidinecarboxylate, proline, hydroxyproline, pipecolinate, and isocitratemonoethyl ester. 
     It will be understood by those skilled in the art that the various isomeric DACH (i.e., trans-S,S-, trans-R,R-, cis-) can be prepared according to the methods of the above examples employing the appropriate DACH isomer. The analytical data for the compounds prepared in Examples 1-13 are set forth in Table II. 
     
                       TABLE II______________________________________   ANALYTICAL DATACOMPOUND  FOUND (%)       CALCULATED (%)NO.       C       H      N      C    H    N______________________________________ 3        32.15   4.32   3.85   31.90                                4.43 4.13 4        30.01   4.53   3.70   30.28                                4.76 3.92 5        31.28   4.38   3.93   31.07                                4.60 4.03 6        28.94   4.01   3.73   28.83                                5.07 3.74 7        30.25   4.19   3.93   30.28                                4.76 3.92 8        27.16   4.23   3.23   27.64                                4.86 3.58 9        29.66   4.15   3.53   29.70                                3.85 3.8510        34.60   5.11   3.75   34.72                                5.20 4.0511        25.35   4.83   8.57   25.20                                4.83 8.8212        28.65   4.13   5.42   28.85                                4.00 5.6113        19.62   4.16   4.19   20.16                                4.70 4.7014        20.28   4.62   8.99   20.36                                4.41 9.5015        31.98   5.20   10.48  31.86                                5.31 10.6216        35.63   5.77   9.87   35.73                                5.58 10.4217        32.75   5.57   9.39   32.69                                5.11 9.5318        37.30   6.21   9.46   37.03                                6.17 9.7019        28.84   3.53   5.33   28.80                                4.00 5.6020        29.37   4.44   5.50   28.94                                4.60 6.1421        30.10   4.46   5.32   30.32                                4.87 5.05______________________________________ 
    
     The in vitro anti-tumor activities of the complexes of the invention are illustrated by the following examples: 
     EXAMPLE 14 
     Wild type L1210 leukemic cells were grown as a suspension culture in McCoy&#39;s 5A medium supplemented with 10% horse serum, glutamine, streptomycin and penicillin at 37° C., 95% relative humidity and 5% CO 2 . Four ml of cell suspension (10 5  cells/ml) are added to culture tubes and the appropriate concentration (0.01, 0.1, 1 or 10 μg/ml final concentration) of drug added to the culture tubes. After 72 hours of incubation, the cell concentration of control and experimental cultures are determined with the aid of a Coulter Counter® Model ZB f  and the percent inhibition calculated. 
     
         ______________________________________COMPOUND NUMBER    ID.sub.50 (μg/ml)______________________________________ 3                 5.0 4                 1.9 5                 4.4 6                 4.0 7                 4.1 8                 2.8 9                 3.010                 2.511                 4.212                 1.013                  0.4314                 4.315                 3.616                 4.017                 2.718                  0.4419                 1.020                  0.4121                 2.0______________________________________ 
    
     The lack of cross-resistance of complexes of the invention to cisdiamminedichloroplatinum(II) is illustrated below: 
     EXAMPLE 15 
     L1210 leukemia cells (L1210/PDD) which are more than 50 fold resistant to cisdiamminedichloroplatinum(II) were grown as suspension cultures in McCoy&#39;s 5A supplemented with 10% horse serum, glutamine, penicillin and streptomycin at 37° C., 95% relative humidity and 5% CO 2 . Four ml of cell suspension were added to culture tubes and the appropriate concentration (0.01, 0.1, 1 or 10 μg/ml final drug concentration) was added. After 96 hours the cell concentration of control and experimental cultures were calculated with the aid of a Coulter Counter® Model ZB f  and the percent inhibition calculated. 
     
         ______________________________________           ID.sub.50 (μg/ml)COMPOUND NUMBER   L1210/0  L1210/PDD______________________________________3                 5.0      2.64                 1.9      0.45                 4.4      2.38                 2.8      0.99                 3.0      0.610                2.5      1.211                4.2      1.6cisdiamminedichloro-             0.1      5.5platinum(II)______________________________________ 
    
     The anti-tumor activities of the complexes of the invention are illustrated by the following example: 
     EXAMPLE 16 
     BDF 1  mice were inoculated intraperitoneally with 10 6  L1210 cells. About 24 hours after inoculation of the cells, the mice were injected intraperitoneally with varying dosages of complexes of the present invention. Six mice were used for each dosage level in each experiment with an equal number of control mice inoculated with 10 6  L1210 cells and left untreated with a given complex. The results [%T/C=(survival time of treated animals/survival time of control animals)×100] are set forth below. Long term survival signifies that animals were alive 60 days after inoculation with L1210 cells. 
     
         ______________________________________                              Long TermCOMPOUND NUMBER          DOSE(mg/kg) % T/C   Survivors______________________________________3              50          125     --          60          163     --          75          143     --          90          145     --          100         Toxic   --4              25          128     --          50          184     1/65              25          136     --          50          Toxic   --6              50          Toxic   --          100         Toxic   --7              25          132     --          50          136     --          100          196*   1/6*2/6 animals died of apparent drug toxicity8              12.5        120     --          25          129     --          50          156     --          100         151     --          200         Toxic   --9              12.5        127     --          25          138     --          50          156     --          100         Toxic   --10             50          140     --          100         217     2/611             50          163     --          100          109*   --12             25          133     --          50          145     --          100         Toxic   --*Apparent Toxicity13             5           153     --          10          180     --          20           140*   1/6          50          Toxic   --*2/6 animals died of apparent drug toxicity14             6.25          12.5        In          25          Progress          5015             12.5        157     --          25          148     --          50          161     --          100         Toxic   --16             12.5        144     --          25          165     --          50          165     --          100          162*   --*1 animal died from apparent toxicity17             25          160     --          50          170     --          100         Toxic   --18             12.5        145     --          25          180     --          50          Toxic   --19             6.25        143     --          12.5        136     --          25          136     --          50          Toxic   --______________________________________ 
    
     EXAMPLE 17 
     The procedure of Example 16 was repeated except that the treated animals were injected with multiple doses of the complex as indicated below: 
     
         ______________________________________COMPOUND  DOSE     Day of            Long TermNUMBER    (mg/kg)  Administration                          % T/C Survivors______________________________________ 3        25       1,5,9       176   --     10       1,5,9       123   --     20       1,5,9       196   1/6     30       1,5,9       257   1/6     30       1,5,9,13    273   1/6     2.5      1-9         113   --     5        1-9         142   --     10       1-9         184   --     20       1-9         239   1/6 4        25       1,5,9       218   --     50       1,5,9       144   -- 7        12.5     1,5,9       151   --     25       1,5,9       179   --     50       1,5,9       212   -- 8        25       1,5,9       206   --     50       1,5,9       225   1/610        12.5     1,5,9       139   --     25       1,5,9       149   --     50       1,5,9       222   1/611        25       1,5,9       199   --     50       1,5,9       220   2/612        25       1,5,9       219   --     50       1,5,9       165   --______________________________________ 
    
     EXAMPLE 18 
     The anti-tumor activity of compound number 3 was evaluated against cells sensitive to (L1210/0) and resistant to (L1210/PDD) the standard platinum complex cis-diamminedichloroplatinum(II). 
     
         ______________________________________DOSE(mg/kg)     SCHEDULE     % T/C   SURVIVORS______________________________________L1219/PDD6.25      1,5,9        115     --12.5      1,5,9        124     --25        1,5,9        135     --50        1,5,9        223     3/10100       1,5,9         172*L1210/06.25      1,5,9        117     --12.5      1,5,9        135     --25        1,5,9        181     2/1050        1,5,9        247     1/10100       1,5,9        104     --______________________________________ *Toxicity apparent as excessive loss of weight 
    
     The acute toxicity data obtained with selected complexes of the invention are set forth below: 
     EXAMPLE 19 
     Male albino mice were administered a single intraperitoneal injection of the appropriate test compound and were observed daily for signs of toxicity and survival. Fourteen days after treatment all surviving mice were sacrified and the LD 10 , LD 50  and LD 90  were calculated. 
     
         ______________________________________                       DEATHS/COMPOUND NUMBER DOSE (mg/kg)                       TREATED______________________________________ 3              110         1/6           125         2/6           140         4/6           155         6/6           175         6/6Calculated LD.sub.10 108 mg/kgCalculated LD.sub.50 125 mg/kgCalculated LD.sub.90 150 mg/kg 5               60         0/6            80         2/6           100         5/6           125         6/6           160         5/6Calculated LD.sub.10  70 mg/kgCalculated LD.sub.50  90 mg/kgCalculated LD.sub.90 125 mg/kg 8              100         1/6           125         1/6           158         4/6           200         3/6           250         6/6Calculated LD.sub.10 115 mg/kgCalculated LD.sub.50 155 mg/kgCalculated LD.sub.90 220 mg/kg 9               85         0/6           100         0/6           125         3/6           158         5/6           200         4/6Calculated LD.sub.10 100 mg/kgCalculated LD.sub.50 140 mg/kgCalculated LD.sub.90 185 mg/kg10               50         0/6           100         1/6           125         3/6           160         5/6           200         3/6Calculated LD.sub.10  85 mg/kgCalculated LD.sub.50 130 mg/kgCalculated LD.sub.90 205 mg/kg11               85         1/6           100         3/6           125         5/6           158         4/6           200         6/6Calculated LD.sub.10  80 mg/kgCalculated LD.sub.50 115 mg/kgCalculated LD.sub.90 155 mg/kg______________________________________ 
    
     The potential nephrotoxicity of selected complexes of the invention are set forth below: 
     EXAMPLE 20 
     Male albino mice were administered a single intraperitoneal injection of either the calculated LD 10  or LD 50  of the test compound. Blood was then obtained by retroorbital puncture 96 hours after treatment for determination of blood urea nitroben (BUN) levels (a standard method of screening compounds for potential renal toxicity). 
     
         ______________________________________            RELATIVE   BUNCOMPOUND NUMBER  DOSE       (mg/100 ml)______________________________________3                LD.sub.10  25 ± 6            LD.sub.50  23 ± 65                LD.sub.10  31 ± 3            LD.sub.50  38 ± 98                LD.sub.10  31 ± 8            LD.sub.50   35 ± 129                LD.sub.10  38 ± 8            LD.sub.50   50 ± 1510               LD.sub.10  40 ± 7            LD.sub.50  39 ± 511               LD.sub.10   36 ± 12            LD.sub.50   38 ± 100.09% NaCl       --         32 ± 2cis diamminedichloro            LD.sub.10   53 ± 19platinum(II)     LD.sub.50   67 ± 10______________________________________ 
    
     EXAMPLE 21 
     Cis-bis-2-aminoethanesulfonato(DACH)platinum(II) 
     Sulfato(DACH)platinum(II), 0.211 g, was dissolved in 10 of water and barium-2-amino-ethanesulfonate, prepared in situ by the addition of Ba(OH) 2 .8H 2  O, 0.15 g, to an aqueous solution of 2-aminoethanesulfonic acid, 0.125 g, was added thereto and the reaction mixture was stirred for 30 minutes at room temperature. Barium sulfate precipitate was filtered off and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained which was then washed with methanol and acetone. The product was obtained which was then washed with methanol and acetone. The product was finally dried in vacuo. 
     Yield=80%. 
     The analytical data for the product are set forth in Table III. 
     EXAMPLE 22 
     Cis-bis-L-prolinato(trans-R,R-DACH)platinum(II) 
     Sulfato (trans-R,R-DACH)platinum(II) (0.11 g) was dissolved in 20 ml of water and the barium salt of L-proline, prepared in situ by the addition of Ba(OH) 2 .8H 2  O (0.150 g) to an aqueous solution of L-proline (0.115 g) was added thereto and the reaction mixture was stirred for 20-30 minutes at room temperature. Barium sulfate precipitate was filtered off and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A yellowish-white solid was obtained which was then washed with methanol and acetone. The product was finally dried in vacuo. 
     Yield=75%. 
     The analytical data for the product are set forth in Table III. 
     EXAMPLE 23 
     Iminodiacetato(trans-R,R-DACH)platinum(II)2H 2  O 
     Sulfato(trans-R,R-DACH)platinum(II), 0.423 g, was dissolved in 50 ml of water and barium iminodiacetate prepared in situ by the addition of Ba(OH) 2 .8H 2  O, 0.3 g, to an aqueous solution of iminodiacetic acid, 0.133 g in 100 ml water was added thereto and the reaction mixture was stirred for 20-30 minutes at room temperature. Barium sulfate precipitate was filtered off and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A yellowish-white solid was obtained which was then washed with acetone. The product was then dried in vacuo. Yield=70%. 
     The analytical data for the product are set forth in Table III. 
     EXAMPLE 24 
     Cis-bis-cyclopropanecarboxylato(DACH)platinum(II) 
     Sulfato(DACH)platinum(II), 0.423 g (1 mmole), was dissolved in water (20 ml) and barium cyclopropanecarboxylate, prepared in situ by the addition of Ba(OH) 2 .8H 2  O (0.30 g) to an aqueous solution of cyclopropanecarboxylic acid (0.172 g) (2 mmole), was added thereto and the reaction mixture was stirred for 20-30 minutes at room temperature. Barium sulfate precipitate was filtered off and the yellow filtrate was evaporated to dryness at 45°-50° C. under reduced pressure using a rotary evaporator. A brown yellow solid was obtained, which was purified from methanol. The product was finally dried in vacuo. Yield=70%. The analytical data for the products are set forth in Table III. 
     Other complexes of the invention, i.e. bis-cyclobutanecarboxylate, bis-cyclopentanecarboxylato, bis-cyclopentenecarboxylato, bis-cyclohexanecarboxylato, bis-cyclohexenecarboxylato, cyclopropane-1,1-dicarboxylato, trans-DL-1,2-cyclopentanecarboxylato, cyclohexane-1,1-diacetato, bicinato, chloroethanesulfonato, N-(2-hydroxyethyl)-iminodiacetato, N-(2-acetamido)-iminodiacetato, N-methyliminodiacetato, N-phenyl-iminodiacetato, N-benzyl-iminodiacetato, 3,4-furanedicarboxylato, trans-1,2-cyclopropane dicarboxylato, trans-1,2-cyclobutanedicarboxylato, trans-1,2-cyclopentane dicarboxylato and trans-1,2-cyclohexanedicarboxylato were prepared in an analogous manner to the above mentioned method using stoichiometric amounts (ca/1 mmole) sulfato (DACH) platinum (II), and the respective barium salts (prepared in situ) i.e. cyclobutanecarboxylate, cyclopentanecarboxylate, cyclopentenecarboxylate, cyclohexanecarboxylate, cyclohexenecarboxylate, cyclopropane-1,1-dicarboxylate, trans-DL-1, 2-cyclopentanedicarboxylate, cyclohexane-1,1-diacetate, bicinate, chloroethanesulfonate, N-(2-hydroxy-ethyl)iminodiacetate, N-(2-acetamido)iminodiacetate, N-methyliminoacetate, N-phenyliminoacetate, N-benzyliminodacetate, 3,4-furanedicarboxylate, trans-1,2-cyclopropanedicarboxylate, trans-1,2-cyclobutanedicarboxylate, trans-1,2-cyclopentanedicarboxylate and trans-1, 2-cyclohexanedicarboxylate. 
     
                       TABLE III______________________________________Analytical DataCOMPOUND   Found (%)     Calculated (%)NO.        C      H      N     C     H    N______________________________________22         41.23  6.93   5.46  41.30 6.54 4.8223         36.58  5.75   5.03  36.55 5.71 5.3324         41.20  5.47   4.64  41.56 5.89 4.8525         38.82  5.29   5.04  39.06 6.14 5.0626         37.77  5.52   4.97  37.95 5.62 4.9227         33.43  4.58   5.45  33.50 4.72 6.0128         27.95  5.16   8.58  27.96 4.87 8.8929         33.40  5.31   5.48  33.79 5.23 5.6330         36.61  5.72   5.21  36.55 5.71 5.3331         20.77  5.05   9.51  20.86 4.86 9.7332         25.31  5.32   11.64 25.25 5.05 11.7833         18.26  3.91   3.78  18.46 3.69 4.3034         33.98  5.43   8.33  34.00 5.98 8.8135         25.14  4.37   8.59  25.20 4.83 8.8236         33.41  5.76   9.47  33.50 5.93 9.7737         34.65  4.94   7.99  34.77 4.89 7.6038         38.50  5.20   7.31  38.47 4.71 7.9239         27.96  5.15   7.62  27.69 5.19 8.0740         27.96  4.43   5.57  27.90 4.65 5.9241         31.64  4.83   5.85  31.93 4.43 6.2142         28.34  5.22   10.47 28.45 4.54 11.0043         33.86  5.62   5.40  33.12 5.12 5.52______________________________________ 
    
     In Vitro Cytotoxicity 
     The following compounds were tested for in vitro cytotoxicity according to the protocol described in Example 14. 
     
         ______________________________________Compound No.   ID.sub.50 (μg/ml)______________________________________22             0.523             0.624             1.025             0.326             1.327             0.428             1.629             0.330             0.431             3.132             2.533             0.334             1.235             3.036             0.837             1.038             2.339             3.040             0.441             0.542             0.7______________________________________ 
    
     In Vivo Efficacy Studies--Single Dose 
     The following compounds were tested for in vivo oncolytic activity following a single i.p. injection of the drug according to the protocol described in Example 16. 
     
         ______________________________________Compound No.       Dose (mg/kg)   % T/C   LTS______________________________________25          50             163     --       25             178     --       12.5           161     --27          50             183     --       25             159     --       12.5           15828          50             Toxic   --       25             185     --       12.5           161     --29          50             199     1/6       25             176     --       12.5           252     1/630          50             145     --       25             154     --       12.5           149     --26          50             157     --       25             158     --       12.5           185     --31          50             153     --       25             134     --       12.5           109     --32          50             158     --       25             131     --       12.5           128     --33          50             Toxic   --       25             144     --       12.5           188     --34          50             160     --       25             151     --       12.5           165     --36          50             149     --       25             212     1/6       12.5           179     --37          50             108     --       25             156     --       12.5           172     --38          50             158     --       25             170     --       12.5           123     --22          100            170     --       50             140     --24          100            105     --       50             165     --       25             132     --______________________________________ 
    
     In Vivo Efficacy Studies--Multiple Dose 
     The following complexes were tested in vivo oncolytic activity following 3 i.p. injections (days 1, 5, 9) according to the protocol described in Examples 16 and 17. 
     
         ______________________________________Compound No.       Dose (mg/kg)   % T/C   LTS______________________________________25          25             253     --       12.5           246     --       6.25           202     --26          25             300     1/6       12.5           356     1/6       6.25           189     --31          100            295     2/6       50             198     1/637          25             242     1/6       12.5           298     5/6       6.25           246     3/638          25             240     2/6       12.5           287     1/6       6.25           277     --______________________________________ 
    
     T/C calculated for 30 day observation period. Long term survivor data represents survivors/treated 50 days after treatment. 
     EXAMPLE 25 
     Mixed isomer DACH-Pt-(II)-L-complexes listed in Table IV below were prepared in an analogous manner to the methods of Example 8, using the stoichiometric amounts (ca. 1 mmole) sulfato-(DACH)-platinum (II) and the appropriate barium salt. 
     
                       TABLE IV______________________________________Mixed isomer DACH-Pt-(II)-L-ComplexesComplex (L =)         Identifier No.______________________________________bis-ascorbato          1bis-isoascorbato       2bis-monosaccharato     3bis-shikimato          4bis-prolinato          5bis-aminoethylsulfato  6bis-saccharato-1,4-lactone                  7mono-furanedicarboxylato                  8mono-isocitratomonoethylester                  9mono-iminodiacetato   10mono-N--methyliminodiacetato                 11mono-N--hydroxyethyliminodiacetato                 12mono-N--(2-acetamido)iminodiacetato                 13mono-N--phenyliminodiacetato                 14mono-N--benzyliminodiacetato                 15______________________________________ 
    
     EXAMPLE 26 
     Trans-R,R-DACH-Pt(II) complexes listed in Table V below were prepared in a manner analogous to the method of Example 25 using sulfato-(trans-R,R-DACH)-platinum(II) and the appropriate barium salt. 
     
                       TABLE V______________________________________Trans-R,R-DACH-Pt(II)-L-ComplexesComplex (L=)          Identifier No.______________________________________Mono-iminodiacetato   10amono-N--methyliminodiacetato                 11amono-N--hydroxyethyliminodiacetato                 12amono-N--phenyliminodiacetato                 14amono-N--benzyliminodiacetato                 15a______________________________________ 
    
     The analytical data for the products of Examples 25 and 26 are set forth in Table VI below: 
     
                       TABLE VI______________________________________ANALYTICAL DATA    Observed (%)                Calculated (%)Identifier No.      C      H      N     C     H    N______________________________________1          32.15  4.32   3.85  31.90 4.43 4.132          30.25  4.19   3.93  30.28 4.16 3.923          27.16  4.23   3.23  27.64 4.56 3.584          34.60  5.11   3.75  34.72 5.20 4.055          35.63  5.77   9.87  35.73 5.58  10.126          20.28  4.62   8.99  20.36 4.41 9.307          29.66  4.15   3.53  29.70 3.85 3.858          28.84  3.53   5.33  28.80 4.00 5.609          30.10  4.46   5.32  30.32 4.87 5.0510         25.35  4.83   8.57  25.20 4.83 8.8210a        25.27  4.79   8.63  25.20 4.83 8.8211         27.95  5.16   8.58  27.96 4.87 8.8911a        28.00  5.05   8.67  27.96 4.87 8.8912         27.96  5.15   7.62  27.69 5.19 8.0712a        27.75  5.22   8.00  27.69 5.19 8.0713         28.34  5.22    10.74                          28.45 5.54  11.0013a        28.39  5.32    10.85                          28.45 5.54  11.0014         34.65  4.94   7.99  34.77 4.89 7.6014a        34.69  4.88   7.84  34.77 4.89 7.6015         38.50  5.20   7.31  38.47 4.71 7.8215a        38.45  5.16   7.43  38.47 4.71 7.82______________________________________ 
    
     In Vitro Cytotoxicity 
     The complexes listed in Example 25 and 26 were tested for in vitro cytoxicity according to the protocol described in Example 14. The results are shown in Tables VII and VIII below. 
     
                       TABLE VII______________________________________Cytoxicity Data of DACH Pt-L Complexes        ID.sub.50 (μg/ml)                      ResistanceComplex (L=)   L1210/0  L1210/DDP  Factor______________________________________bis-ascorbato  5.0      5.0        1.0bis-isoascorbato          4.1      3.8        0.9bis-monosaccharato          2.8      0.9        0.3bis-shikimato  2.5      1.2        0.5bis-prolinato  4.0      2.5        0.6bis-aminoethylsulfato          4.3      3.7        0.9bis-saccharato-          3.0      0.6        0.21,4-lactonemono-furanedicarboxylato          1.0      0.9        0.9mono-isocitratomono-          2.0      1.9        0.9ethylestermono-iminodiacetato          4.2      1.6        0.4mono-N--methyliminodia-          1.6      1.3        0.8cetatomono-N--hydroxyethly-          0.7      0.9        1.3iminodiacetatomono-N--(2-acetamido)-          3.0      1.8        0.6iminodiacetatomono-N--phenylimino-          2.3      2.6        1.1diacetatomono-N--benzylimino-          1.0      0.8        0.8diacetatoDDP            0.1      5.5        55______________________________________ 
    
     
                       TABLE VIII______________________________________Cytotoxicity Data for the trans-R,R-DACH Pt-L Complexes         ID.sub.50 (μg/ml)                          ResistanceComplex (L = )         L1210/0   L1210/DDP  Factor______________________________________mono-iminodiacetatomono-N--methylimino-         0.8       1.9        2.4diacetatomono-N--hydroxyethyl-         1.4       1.8        1.3iminodiacetatomono-N--phenylimino-         0.7       0.6        0.8diacetatomono-N--benzylimino-         1.0       2.4        2.4diacetatoDDP           0.1       5.5        55______________________________________ 
    
     In Vivo Efficacy vs. L1210/0 
     BDF 1  mice were innoculated intraperitoreally with 10 6  L1210 leukemia cells and treatment was begun on the next day (day 1). Two treatment schedules, i.e. single i.p. injection of the drug and i.p. injections on days 1, 5 and 9 according to the protocol described in Examples 16 and 17 were used. 
     The data appears below in Table IX and X. 
     
                       TABLE IX______________________________________In Vivo Efficacy of DACH Iminodiacetato ComplexesAdministered as Single i.p. Injection          Maximal EffectiveComplex (L =)  Dose (mg/Kg)  % T/C______________________________________H.sub.3        50            163CH.sub.3       25            180C.sub.2 H.sub.5 OH          25            180C.sub.6 H.sub.5          12.5          172CH.sub.2 --C.sub.6 H.sub.5          25            170DDP            9             150______________________________________ ##STR5## .sup.(b) DDP = diamminedichloroplatinum II 
    
     
                       TABLE X______________________________________In Vivo Efficacy of DACH-Pt-Iminodiacetato ComplexesAdministered i.p. on Days 1, 5 and 9      Maximal Effective      Long Term.sup.aComplex (L=)      Dose (mg/kg)   % T/C   Survivors______________________________________H.sub.3    50             220     2/6CH.sub.3   12.5           550     5/6C.sub.2 H.sub.5 OH      25             450     4/6C.sub.6 H.sub.5      12.5           537     4/6CH.sub.2 --C.sub.6 H.sub.5      12.5           397     2/6DDP        5              210     1/6______________________________________ .sup.a Long Term Survivors = animals alive 60 days after tumor inoculatio with no visible signs of tumor at sacrifice. 
    
     Table Xi below shows the in vivo efficacy results obtained with trans-R,R-DACH Pt-iminodiacetato complexes. 
     
                       TABLE XI______________________________________In Vivo Efficacy of trans-R,R-DACH Pt-IminodiacetatoComplexes Administered i.p. on Days 1, 5 and 9      Maximal Effective      Long TermComplex (L=)      Dose (mg/kg)   % T/C   Survivors______________________________________H          25             437     2/6CH.sub.3   6.25           700     6/6C.sub.2 H.sub.5 OH      6.25           384     2/6C.sub.6 H.sub.5      6.25           578     4/6CH.sub.2 --C.sub.6 H.sub.5      6.25           620     4/6DDP        5              220     1/6______________________________________ 
    
     The data show that the trans-R,R-DACH complexes are more potent than the mixed isomer DACH complexes and are much more effective than the DDP. 
     MELANOTIC MELANOMA TEST 
     The animals used were BDF 1  mice, all of the same sex, weighing a minimum of 18 g. and all within a 4 g. weight range. There were 6 animals per test group. The mice were inoculated intraperitoneally with 10 6  viable B16 cells (day 0). The test compounds were administered intraperitoneally on days 1, 5 and 9 at various doses. The animals were weighed and survivors were recorded on a regular basis for 60 days. The median survival time and the ratio of survival time for treated (T)/control (C) animals were calculated. The positive control compound was DDP given intraperitoneally at 5 mg/kg. The criterion for efficacy is T/C×100≧125%. The results of the tests appear in Table XII below. 
     
                       TABLE XII______________________________________Efficacy of DACH-Pt-Iminodiacetato Complexes Againsti.p. Inoculated B16 Melanoma      Maximal Effective      Long TermComplex (L = )      Dose (mg/kg)   % T/C   Survivors______________________________________CH.sub.3 (t)      25             210     2/6CH.sub.3 (m)      25             205     0/6C.sub.2 H.sub.5 OH(m)      25             196     2/6C.sub.2 H.sub.5 OH(t)      25             265     4/6C.sub.6 H.sub.5 (t)      25             160     3/6C.sub.6 H.sub.5 (m)      25             215     0/6CH.sub.2 --C.sub.6 H.sub.5 (t)      12.5           252     3/6CH.sub.2 --C.sub.6 H.sub.5 (m)      12.5           207     1/6DDP        5              172     1/6______________________________________ (m) = mixed isomer DACH (t) = transR,R-DACH 
    
     These data show that at least three of the complexes tested were more effective than DDP against B16 and that all of the remaining complexes were at least as effective as DDP against B16. 
     TOXOCOLOGICAL STUDIES 
     The LD 10  and LD 50  values for a single intraperitoneal injection of the test compounds are shown in Table XIII below. 
     
                       TABLE XIII______________________________________Acute Lethality Data for Mixed Isomer DACH Pt.Iminodiacetato Complexes  LD.sub.10        LD.sub.50                LD.sub.90                        RUN (mg/100 ml)  (mg/kg)       (mean + 1 S.D.)______________________________________H        53      107     169   23 ± 4CH.sub.3 49      92      170   22 ± 3C.sub.2 H.sub.5 OH    63      150     301   18 ± 2C.sub.6 H.sub.5    56      81      135   18 ± 1CH.sub.2 --C.sub.6 H.sub.5    81      140     210   27 ± 3DDP      13      15.5    18    80 ± 8Control                        25 ± 2______________________________________ 
    
     The platinum complexes of the invention may be compounded with suitable pharmaceutically acceptable carriers and administered orally, intramuscularly, topically, etc. It is preferred, however, to combine the complex with suitable media, e.g., 5% dextrose, klucel, water, etc., for intravenous administration. Care should be taken, however, to avoid the use of saline as an i.v. medium. 
     Those skilled in the art will be aware of suitable carriers for the complexes of the invention suitable for formulation into capsules, tablets, powders, ointments, pellets, inc. 
     The complexes may also be administered in combination with other anti-tumor agents in a combined chemotherapeutic regimen. 
     The amount of complex included in the pharmaceutical composition and the dosages of complex utilized in the method of treatment of the invention will vary depending in each case upon the condition of the patient, the nature of the tumor undergoing treatment, the anti-tumor activity of the complex, the toxicity and solubility characteristics thereof, etc. Generally, however, an amount of platinum complex ranging from about 25 to about 200 mg/kg is adequate for most applications.