Abstract:
Bisphosphonate compounds are disclosed, particularly bisphosonate conjugates useful in the treatment of soft tissues surrounding bone and bone-related diseases, such as bone cancer and osteoporosis.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application is a continuation-in-part of copending international (PCT) application No. PCT/IB2004/002722, filed Jun. 28, 2004, designating the United States, which application claims priority to U.S. provisional application 60/483,218 filed Jun. 27, 2003. 
     
    
     FIELD OF THE INVENTION  
       [0002]     The present invention is directed to particular bisphosphonate compounds, and in particular, to bisphosphonate conjugates that are useful in the treatment of soft tissues surrounding bone and bone-related diseases, such as bone cancer and osteoporosis.  
       BACKGROUND OF THE INVENTION  
       [0003]     Bisphosphonates represent a class of drugs that have shown very promising therapeutic efficacy in the treatment of a number of diseases associated with abnormally accelerated bone resorption including; osteoporosis, Paget&#39;s disease and hypercalcemia of malignancy. Fleisch H., Ann Med, 29, 55-62 (1997) and Fleisch H., Drugs, 42, 919-944 (1991). More recently bisphosphonates have been shown to be effective at lowering the risk of developing skeletal complications (e.g., pathologic fractures, spinal-cord compression, the need for bone surgery or irradiation) in patients with prostate cancer that had spread to the bone, Saad F et al., J National Cancer Institute 94:1458-1468, 2002; and to inhibit the proliferation of RAS-dependent malignancies, e.g., small cell lung cancer Matsumoto, et al., Am. Soc. of Clin. Oncology, 2003, Abst. No. 2750. Bisphosphonates have also been shown to have antiangiogenic activty, Wood et al, J Pharmacol Exp Ther 2002 September; 302(3):1055-61. Bisphosphonates are commonly used for treatment of myeloma bone disease and against osteolytic metastases of breast cancer, and clinical studies have suggested their use to relieve pain in metastatic prostate cancer.  
         [0004]     Platinum-based agents are widely utilized in chemotherapeutic applications. For example, cisplatin kills tumor cells via formation of covalent, cross- or intrastrand DNA adducts (Sherman et al. Chem. Rev., 87, 1153-81 (1987); Chu, J. Biol. Chem., 269, 787-90 (1994)). Treatment with such platinum-based agents thereby leads to the inhibition of DNA synthesis (Howle et al., Biochem. Pharmacol., 19, 2757-62 (1970); Salles et al., Biochem. Biophys. Res. Commun., 112, 555-63 (1983)). Thus, cells actively synthesizing DNA are highly sensitive to cisplatin (Roberts et al., Prog. Nucl. Acid Res. Mol. Biol., 22, 71-133 (1979); Pinto et al., Proc. Nat. Acad. Sci. (Wash.) 82, 4616-19 (1985)). Such cells generally experience a growth arrest in G 2  and eventually undergo apoptosis. This apoptotic effect is observed at drug concentrations insufficient to inhibit DNA synthesis (Sorenson et al, J. Natl. Cancer Inst., 82, 749-55 (1990)), suggesting that platinum agents act on neoplastic cells via multiple mechanisms. Some cells also demonstrate increased platinum sensitivity when in the G 1  phase of the cell cycle (Krishnaswamy et al., Mutation Res., 293, 161-72 (1993); Donaldson et al., Int. J. Cancer, 57, 847-55 (1994)). Upon release from G 0 /G 1  -S block, such cells remain maximally sensitized through the remainder of the cell cycle.  
         [0005]     U.S. Pat. No. 6,087,349 discloses that bisphosphonates can act as protein-prenyl transferase inhibitors.  
         [0006]     U.S. Pat. No. 4,746,654 discloses bisphosphonates useful as anti-inflammatory agents.  
         [0007]     Australian Patent A-5 1534/85 discloses bisphosphonates useful in treating abnormal calcium and phosphorous metabolism and useful in treating arthritis.  
         [0008]     U.S. Pat. No. 3,683,080 discloses polyphosphonates, in particular diphosphonates useful in inhibiting anomalous deposition and mobilization of calcium phosphate in animal tissue.  
         [0009]     DE 3,719,513-A (Derwent 89-000580/01) discloses diphosphonic acid derivatives useful in treatment of disorders of calcium metabolism.  
         [0010]     WO88/06158 discloses the reaction of activated methylenes with vinylidene diphosphonates.  
         [0011]     International Publication Number WO90/12017 for International Application Number PCT/US90/01106 discloses geminal bisphosphonic acids and derivatives thereof as anti-arthritic agents.  
         [0012]     United States Patent Application No. 20020022603 discloses compositions of zwitterionic phospholipids and bisphosphonates and use of such compositions as bisphosphate delivery systems with reduced GI toxicity.  
         [0013]     United States Patent Application No. 20030032628 discloses pharmaceutical compositions of bisphosphonic acids, and salts thereof, prepared by wet granulation tablet formulation. These pharmaceutical compositions are said to be prepared without the addition of binder; instead, the drug itself acts as a binder.  
         [0014]     United States Patent Application 20020002140 discloses glycosides and orthoester glyco side derivatives of bisphosphonate compounds which are said to have markedly enhanced intestinal absorption and enhanced bioavailability.  
         [0015]     U.S. Pat. No. 5,133,972 discloses transdermal delivery phosphate compounds, and in particular bisphosphonates. Relatedly, U.S. Pat. No. 6,018,679 discloses a method for iontophoretically removing compounds capable of causing skin irritation or other harmful effects.  
         [0016]     U.S. Pat. No. 6,114,316 discloses compositions which combine a tetracycline and a bisphosphonate in synergistic proteinase inhibiting amounts to treat or prevent tissue-destructive conditions related to excess proteinase activity in a biological system.  
         [0017]     U.S. Pat. No. 6,214,812 discloses bisphosphonate conjugates which are said to be capable of releasing antibacterial and/or cytotoxic components upon binding with bone tissue.  
         [0018]     U.S. Pat. No. 6,436,386 discloses hydroxyapatite-targeting polymeric structures, and biologically active conjugates thereof, wherein the hydroxyapatite-targeting moiety may be a bisphosphonate. The conjugates are said to provide a means for tethering a biologically active substances to bone surface.  
         [0019]     Numerous other references may be found in the art describing various types of bisphosphonate compounds, conjugates, formulations, combinations and uses thereof. However there is not disclosed therein a method of synthesizing bisphosphonate complexes comprising platinum, palladium, or like moieties, that are therapeutically useful. Other bisphosphonate complexes known in the art were not known to possess superior properties in respect of their use as therapeutic agents, particularly in respect of their use for the treatment of cancer, more particularly with respect to their use for the treatment of cancers affecting bone tissue.  
       SUMMARY OF THE INVENTION  
       [0020]     The present invention relates to bisphosphonate complexes and their use as targeted cytostatic and/or cytotoxic agents. Desirably the bisphosphonate complexes of the invention may be used to target cells, e.g., cancerous cells, associated with bone.  
         [0021]     In a first aspect the invention relates to a complex according to formula I:  
                         
 
         [0022]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0023]     In a preferred embodiment of said first aspect M is Pt(II).  
         [0024]     In a second aspect, the invention relates to a complex according to formula II:  
                         
 
         [0025]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0026]     In a preferred embodiment of said second aspect M is Pt(II).  
         [0027]     In a third aspect, the invention relates to a complex according to formula III:  
                         
 
 wherein M is Pt(II) or Pd(II); 
 
 or a pharmaceutically acceptable salt thereof. 
 
         [0028]     In a preferred embodiment of said third aspect M is Pt(II).  
         [0029]     In a fourth aspect, the invention relates to a complex according to formula IV:  
                         
 
         [0030]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0031]     In a preferred embodiment of said fourth aspect M is Pt(II).  
         [0032]     In a fifth aspect, the invention relates to a complex according to formula V:  
                         
 
         [0033]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0034]     In a preferred embodiment of said fifth aspect M is Pt(II).  
         [0035]     In a sixth aspect, the invention relates to a complex according to formula VI:  
                         
 
         [0036]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0037]     In a preferred embodiment of said sixth aspect M is Pt(II).  
         [0038]     In a seventh aspect, the invention relates to a complex according to formula VII:  
                         
 
         [0039]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0040]     In a preferred embodiment of said seventh aspect M is Pt(II).  
         [0041]     In a eighth aspect, the invention relates to a complex according to formula VIII:  
                         
 
         [0042]     wherein M is Pt(II) or Pd(II);  
         [0000]     or a pharmaceutically acceptable salt thereof.  
         [0043]     In a preferred embodiment of said eighth aspect M is Pt(II).  
         [0044]     In a ninth aspect, the invention relates to a process for synthesizing a compound according to formula I comprising performing the synthetic procedure described for examples of formula I substantially as herein described. In a preferred embodiment of said ninth aspect M is Pt(II).  
         [0045]     In a tenth aspect, the invention relates to a process for synthesizing a compound according to formula II comprising performing the synthetic procedure described for examples of formula II substantially as herein described. In a preferred embodiment of said tenth aspect M is Pt(II).  
         [0046]     In eleventh aspect, the invention relates to a process for synthesizing a compound according to formula III comprising performing the synthetic procedure described for examples of formula III substantially as herein described. In a preferred embodiment of said aspect M is Pt(II).  
         [0047]     In a twelfth aspect, the invention relates to a method of delivering a cytostaticly and/or cytotoxicly effective amount of platinum or palladium, or of a platinum-containing or a palladium-containing moiety, to a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound according to formula 1, or a pharmaceutically acceptable salt thereof, to said subject in need thereof. Preferably M in formula I is platinum. Also preferably said method comprises delivering said compound at or to bone tissue within said subject. More preferably said method comprises delivering said compound at or to bone tissue on which or in which cancer cells are present. More preferably still said therapeutically effective amount of said compound is an amount effective to treat, i.e., to inhibit and/or to kill, said cancer cells.  
         [0048]     In an thirteenth aspect, the invention relates to a method of delivering a cytostaticly and/or cytotoxicly effective amount of platinum or palladium, or of a platinum-containing or a palladium-containing moiety, to a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound according to formula II, or a pharmaceutically acceptable salt thereof, to said subject in need thereof. Preferably M in formula II is platinum. Also preferably said method comprises delivering said compound at or to bone tissue within said subject. More preferably said method comprises delivering said compound at or to bone tissue on which or in which cancer cells are present. More preferably still said therapeutically effective amount of said compound is an amount effective to treat, i.e., to inhibit and/or to kill, said cancer cells.  
         [0049]     In a fourteenth aspect, the invention relates to a method of delivering a cytostaticly and/or cytotoxicly effective amount of platinum or palladium, or of a platinum-containing or a palladium-containing moiety, to a subject in need thereof, said method comprising administering a therapeutically effective amount of a compound according to formula III, or a pharmaceutically acceptable salt thereof, to said subject in need thereof. Preferably M in formula III is platinum. Also preferably said method comprises delivering said compound at or to bone tissue within said subject. More preferably said method comprises delivering said compound at or to bone tissue on which or in which cancer cells are present. More preferably still said therapeutically effective amount of said compound is an amount effective to treat, i.e., to inhibit and/or to kill, said cancer cells. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0050]      FIG. 1  is a graph showing the adsorption percentages of the test compounds to hydroxyapatite as measured by NMR.  
         [0051]      FIG. 2  is a graph showing the adsorption percentages of the test compounds to hydroxyapatite as measured by  31 P NMR,  1 H NMR, and AAS.  
         [0052]      FIG. 3  is graph illustrating the effects of Example #7 against tumor model DU-145 in athymic nude mice.  
         [0053]      FIG. 4  is graph illustrating the effects of Example #2 against tumor model DU-145 in athymic nude mice.  
         [0054]      FIG. 5  is graph illustrating the effects of Example #4 against tumor model DU-145 in athymic nude mice.  
         [0055]      FIG. 6  is graph illustrating the effects of Examples #1 and #8 against tumor model DU-145 in athymic nude mice. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
       [0056]     The following experimental results are provided for purposes of illustration and are not intended to limit the scope of the invention.  
       EXAMPLE 1  
     cis-Pt(NH 3 ) 2 (MDP)  
       [0057]     a. Materials  
         [0058]     Bisphosphonate (methylenediphosphinic acid (MDP)) was purchased from Tokyo-Kasei, K 2 PtCl 4  was from Tanaka, dimethylacetamide (DMA) and other reagents were Nakarai Tesque. All chemicals were of highest grade available and used without further purification. Water was deionized, doubly distilled, and finally purified by a Milli-Q.  
         [0059]     b. Procedure  
                         
 
         [0060]     b.1. cis-Pt(NH 3 ) 2 I 2    
         [0061]     According the literature (S. C. Dhara, Indian J. Chem, 1970, 8.), KI 3.3 g (19.8 mmol) was added to K 2 PtCl 4  2 g (4.8 mmol) in 20 ml H 2 O. The solution was stirred in water bath for 5 min and then added to 47 mL of 0.21M aqueous NH 3  solution. After standing at room temperature for about 3 hr the deposited yellow powder was filtered off and washed with hot water, EtOH, and ether. Yield 91%. Elemental analysis: calculated: H, 1.25%, N, 5.80%; observed: H, 1.08%, N, 5.58%. IR: 3260 cm −1 , 3200 cm −1 , 1282 cm −1 , 1270 cm −1 .  
         [0062]     b.2. cis-Pt(NH 3 ) 2 (MDP)  
         [0063]     0.20 g (0.5 mmol) of cis-Pt(NH 3 ) 2 I 2  from step b.1. in dimethylacetamide 5 ml was added to a suspension of 0.149 g (0.48 mmol) of Ag 2 SO 4  in 20 mL H 2 O and stirred for about 4 hr in the dark. After filtration by membrane filter Ba(OH) 2 .8H 2 O 0.15 g (0.48 mmol) and MDP 0.12 g (0.70 mmol) in 20 mL H 2 O was added. After stirring overnight the solution was concentrated by evaporation and the resulting powder was reprecipitated using H 2 O-EtOH. Yield 35%  
         [0064]     Elemental analysis:  
                                                       calculated:   C: 2.98% H: 2.50%, N: 6.95%           observed:   C: 3.14% H: 2.50%, N: 6.83%                      
 
         [0065]     NNMR:  31 P NMR (D 2 O, 85% H 3 PO 4 ) d (ppm)+27.25;  
         [0066]      1 H NMR (D 2 O) d(ppm) 2.349 (t, J=19.91 Hz);  
       EXAMPLE 2  
     Pt(dach)(MDP)  
       [0067]     a. Materials  
         [0068]     1R,2R-1,2-cyclohexanediamine (dach) was purchased from Tokyo-Kasei; K 2 PtCl 4  was purchased from Tanaka; dimethylacetamide (DMA) and other reagents were purchased from Nakarai Tesque. All chemicals were of the highest grade available and were used without further purification. Water was deionized, distilled, and finally purified by Milli-Q.  
         [0069]     b. Procedure  
                         
 
         [0070]     b.1. Pt(dach)I 2    
         [0071]     KI 2.0 g (12 mmol) was added to K 2 PtCl 4  1.25 g (3 mmol) in 20 ml H 2 O. The solution was stirred in a water bath (50° C.) for about 5 min. and then added to 1R,2R-1,2-cyclohexanediamine 0.34 g (3 mmol). The reaction mixture was stirred overnight at room temperature and the deposited yellow powder was filtered off and washed with hot water, then EtOH, and finally diethyl ether. Yield 90%.  
         [0072]     Elemental analysis:  
                                                       calculated:   C: 12.80%, H: 2.51%, N: 4.98%;           observed:   C: 12.66%, H: 2.27%, N: 5.01%.                      
 
         [0073]     b.2. Pt(dach)(MDP)  
         [0074]     0.28 g (0.5 mmol) of Pt(dach)I 2  from step b.1. in dimethylacetamide 5 ml was added to a suspension of 0.149 g (0.48 mmol) of Ag 2 SO 4  in 20 mL H 2 O and stirred for about 4 hr. in the dark. After filtration by membrane filter Ba(OH) 2 .8H 2 O 0.156 g (0.48 mmol) and MDP 0.129 g (0.75 mmol) in 20 mL H 2 O was added. After stirring for about 2 hr., 1 ml of 0.5M H 2 SO 4  aqueous solution was added to the reaction solution mixture over about 5 min. with stirring. The mixture was filtrated and concentrated to about 5 ml by evaporation and the white powder was re-precipitated using MeOH. Yield 35%.  
         [0075]     Elemental analysis:  
                                                       calculated:   C: 17.40%, H: 3.75%, N: 5.80%;           observed:   C: 17.47%, H: 3.44%, N: 5.89%.                      
 
         [0076]     NNMR:  31 P NMR (D 2 O, 85% H 3 PO 4 )_(ppm)+26.1;  1 H NMR (D 2 O)_(ppm) 1.16(t, 2H, dach CH), 1.29(m, 4H, dach), 1.56(d, 2H, dach), 202(d, 2H, dach), 2.37(t, MDP, J=19.91 Hz);  195 Pt NMR (D 2 O, [Pt(en) 2 ]Cl 2 ) (ppm) −4378  
       EXAMPLE 3  
     N-(9-Anthranyl)methyl-1,2-ethanediamine Dihydrochloride (Aten.2HCl)  
       [0077]     a. Materials  
         [0078]     N-(9-Anthranyl)aldehyde was purchased from Tokyo-Kasei; K 2 PtCl 4  was purchased from Tanaka; PdCl 2  was purchased from Kishida Chemical; 2,2′-bipyridine (bpy) was purchased from Wako; DMSO and other reagents were from Nakarai Tesque. All chemicals were of highest grade available and used without further purification. Water was deionized, doubly distilled, and finally purified by a Milli-Q.  
         [0079]     b. Procedure  
                         
 
         [0080]     Ethylendiamine 6.00 g (100 mmol) was added to N-(9-Anthranyl)aldehyde 2.06 g (10 mmol) in 200 ml 1:1 dioxane-CHCl 3  and the solution was refluxed for about 3 hr. After cooling to room temperature, the solution was concentrated by evaporation and 0.45 g (12 mmol) of NaBH 4  in MeOH was added. After stirring overnight 6N HCl was added to adjust the pH to 1 and the liquid was evaporated. Aqueous NaOH was added and the basic solution was extracted with CHCl 3  and dried using Na 2 SO 4 . The CHCl 3  phase was evaporated and the oil residue was treated with MeOH/6N HCl. The resulting yellowish powder was recovered by filtration and recrystallized from EtOH—H 2 O. Yield 2.2 g (65%)  
         [0081]     Elemental analysis C 17 H 2 O N 2 Cl 2 .0.75H 2 O  
                                                       calculated:   C: 60.63%, H: 6.43%, N: 8.32%           observed:   C: 60.40%, H: 6.45%, N: 7.81%                      
 
         [0082]      1 H NMR (D 2 O, 300 MHz) d=3.42 (t, 2H), 3.67 (t, 2H), 5.27 (s, 2H), 7.64 (t, 2H), 7.75 (t, 2H), 8.16 (d, 2H), 8.26 (d, 2H), 8.65 (s, 1H)  
       EXAMPLE 4  
     Pt(bpy)(Aten) Complex  
       [0083]     a. Pt(bpy)Cl 2    
         [0084]     1.411 g (3.4 mmol) of K 2 PtCl 4  in a solution of 10 mL H 2 O, 30 mL DMSO was added to 0.531 g (3.4 mmol) of bpy 50 mL DMSO and the mixture was heated to 80° C. for about 3 hr with stirring. The reaction was stirred overnight and the resulting yellow needles were filtered off and washed with H 2 O and ether. Yield 1.2 g (81%)  
         [0085]     Elemental analysis: C 10 H 8 N 2 Cl 2 Pt  
                                                       calculated:   C: 28.45%, H: 1.91%, N: 6.58%           observed:   C: 28.65%, H: 1.95%, N: 6.64%                      
 
         [0086]     b. [Pt(bpy)(Aten)]Cl 2  
                         
 
         [0087]     According the literature (Goto, M., et al., Bull. Chem. Soc. Jpn. 2000, 73, 97-105.), to a suspension of Pt(bpy)Cl 2  (0.429, 1.0 mmol) in 20 ml of H 2 O were added 0.44 g (1.3 mmol) Aten.2HCl.0.75H 2 O and 0.16 g (1.5 mmol) Na 2 CO 3  and the mixture was stirred at 80° C. for about 2.5 h. The mixture was then filtered while still hot to remove small amounts of undissolved materials. After cooling to room temperature a pale-yellow precipitate formed which was collected on a filter and dried in a desiccator. Yield 0.56 g (79%)  
         [0088]     Elemental analysis: C 27 H 26 N 4  Cl 2  Pt.2H 2 O  
                                                       calculated:   C: 45.77%, H: 4.27%, N: 7.91%           observed:   C: 45.51%, H: 4.05%, N: 7.61%                      
 
       EXAMPLE 5  
     Pd(bpy)(Aten) Complex  
       [0089]     a. Pd(bpy)Cl 2    
         [0090]     PdCl 2  0.89 g (5.0 mmol) and NaCl 0.58 g (10.0 mmol) were suspended in 50 mL H 2 O and stirred for about 1 hr. After filtration the solution was added to a solution of 0.78 g (5.0 mmol) bpy in 20 mL MeOH and the resulting solution stirred overnight. A yellowish powder precipitated which was recovered and washed with H 2 O and EtOH. Yield 1.56 g (93%)  
         [0091]     Elemental analysis: C 10 H 8 N 2 Cl 2 Pd  
                                                       calculated:   C: 36.01%, H: 2.42%, N: 8.40%           observed:   C: 35.94%, H: 2.14%, N: 8.31%                      
 
         [0092]     b. Pd(bpy)(Aten)]Cl 2  
                         
 
         [0093]     0.33 g (1.0 mmol) of Pd(bpy)Cl 2  from the immediately foregoing step were suspended in 10 mL H 2 O. 0.44 g (1.3 mmol) of Aten.2HCl.0.75H 2 O and 0.16 g (1.5 mmol) Na 2 CO 3  were added and the mixture was then heated to 80° C. for about 2 hr. The solution was filtered while still hot then concentrated by evaporation. A yellow powder was deposited on standing at room temperature. Yield 0.43 g (68%)  
         [0094]     Elemental analysis C 27 H 26 N 4 Cl 2 Pd.3H 2 O  
                                                       calculated:   C: 50.84%, H: 5.06%, N: 8.78%           observed:   C: 50.89%, H: 4.69%, N: 8.80%                      
 
       EXAMPLE 6  
     Pd(bpy)(AtC 3 )  
       [0095]    
       
                 
         
             
             
         
       
     
         [0096]     a. AtC 3 .2HCl  
         [0097]     1,3-diaminepropane 7.41 g (100 mmol) was added to N-(9-Anthranyl)aldehyde 2.06 g (10 mmol) in 200 ml 1:1 dioxane-CHCl 3  and the solution was refluxed for about 3 hr. After cooling to room temperature, the solution was concentrated by evaporation and 0.45 g (12 mmol) of NaBH 4  in MeOH was added. After stirring overnight 6N HCl was added to adjust the pH to 1 and the solution was evaporated. Aqueous NaOH was added and the basic solution was extracted with CHCl 3  and dried by using Na 2 SO 4 . The CHCl 3  phase was evaporated and the oil residue was treated with MeOH/6N HCl. The resulting yellowish powder was recovered by filtration and recrystallized from EtOH—H 2 O. Yield 70%  
         [0098]     Elemental analysis: C 18 H 22 N 2 Cl 2  
                                                       Calculated:   C 64.10% H 6.57% N 8.31%           Observed:   C 64.40% H 6.38% N 7.98%                      
 
         [0099]     NMR:  1 H NMR (CDCl 3 , TMS) d (ppm) 1.64(2H,m), 2.72(2H, t), 2.88(2H, t), 4.66(2H, s), 7.39(4H, m), 7.94(2H, d), 8.25(2H, t), 8.33(1H, s)  
         [0100]     b. [Pd(bpy)(AtC3)]Cl 2    
         [0101]     0.33 g (1.0 mmol) of Pd(bpy)Cl 2  from the immediately foregoing step were suspended in 10 ml H 2 O. 0.44 g (1.3 mmol) of AtC 3 .2HCl and 0.16 g (1.5 mmol) Na 2 CO 3  were added and the mixture was then heated to 80° C. for about 2 hr. The solution was filtered while still hot then concentrated by evaporation. A yellow powder was deposited on standing at room temperature. Yield 0.40 g (58%)  
         [0102]     Elemental analysis: C 28 H 28 N 4 Pd 1 Cl 2 .H 2 O  
                                                               Calculated:   C 54.60%   H 4.91%   N 9.10%           Observed:   C 54.40%   H 4.48%   N 8.98%                      
 
       EXAMPLE 7  
     Pt(bpy)(AtC 3 )  
       [0103]    
       
                 
         
             
             
         
       
     
       Synthesis of [Pt(bpy)(AtC3)]Cl 2    
       [0104]     According the literature (Goto, M., et al., Bull. Chem. Soc. Jpn. 2000, 73, 97-105.), to a suspension of Pt(bpy)Cl 2  (0.42 g, 1.0 mmol) in 20 ml of H 2 O were added 0.44 g (1.3 mmol) AtC 3 .2HCl and 0.16 g (1.5 mmol) Na 2 CO 3  and the mixture was stirred at 80° C. for about 3 h. The mixture was then filtered while still hot to remove small amounts of undissolved materials. After cooling to room temperature a pale-yellow precipitate formed which was collected on a filter and dried in a desiccator. Yield 0.60 g (73%)  
         [0105]     Elemental analysis: C28H28N4Pt1Cl2 
                                                                           calculated:   C:   48.99%   H   4.11%,   N:   8.16%           observed:   C:   49.13%   H   4.37%   N:   8.08%                   48.78       4.29       8.01%                      
 
         [0106]     1H NMR (D2O, DSS)d(ppm) 8.91(1H, d), 8.53(1H,d), 8.35(3H,m), 8.05(2H,t), 7.75(6H,m), 7.18(2H, m), 6.91(1H, d), 6.36(1H, t), 5.55(1H, d), 3.50(4H, m), 3.01(1H, t), 2.51(2H, m)  
       EXAMPLE 8  
     cis-Pt (NH 3 ) 2 (Pyrophosphate)  
       [0107]    
       
                 
         
             
             
         
       
     
       Synthesis of cis-Pt(NH 3 ) 2 (Pyrophosphate)  
       [0108]     0.482 g (1 mmol) of cis-Pt(NH 3 ) 2 I 2 . in dimethylacetamide 5 ml was added to a suspension of 0.306 g (0.98 mmol) of Ag 2 SO 4  in 40 mL H 2 O and stirred for about 4 hr in the dark. After filtration by membrane filter Ba(OH) 2 .8H 2 O 0.305 g (1.00 mmol) in 80 mL H 2 O was added and stirred for 30 min. After filtration, pH of the solution was adjusted 34 by NaOH aqueous solution and 1:1 pyrophosphoric acid (2.0 mmol):H 2 O 0.5 g was added and stirred for 1 hr. After filtration the solution was concentrated by evaporation and the resulting powder was precipitated by adding MeOH. The greenish powder was dissolved in hot water. The filtered solution was concentrated in vacuo and MeOH was added. The white powder deposited was washed with ether. Yield 30%  
         [0109]     Elemental analysis: H 8 N 2 O 6 P 2 Pt.1H 2 O  
                                                           calculated:   H: 1.91%,   N: 6.65%           observed:   H: 2.28, 2.27%   N: 6.90, 6.62%                      
 
         [0110]      31 P NMR (D 2 O, 85% H 3 PO 4 ): δ(ppm) 0 ppm  
       EXAMPLE 9  
     Pt(NH 3 )—IP6 Pt(NH 3 ) 2 .IP6.10Na.7H 2 O  
       [0111]    
       
                 
         
             
             
         
       
     
       Synthesis of cis-Pt(NH 3 ) 2 .IP6  
       [0112]     cis-Pt(NH 3 ) 2 I 2  0.483 g (1.0 mmol) dissolved in N,N-dimethylacetamide 5 ml was added to a suspension of AgNO 3  0.340 g (2.0 mmol) in H 2 O 40 ml, and stirred for a overnight in the dark. After filtration by membrane filter, IP6.12Na 1.013 g (1.0 mmol) in H 2 O 30 ml was added and stirred for 3 hrs. The solution was concentrated by evaporation and the resulting powder was reprecipitated by adding MeOH. Yield 54%.  
         [0113]     Elemental analysis: C6H26N2O31P6Pt1Na10 
                                                               calculated:   C 5.84%   H 2.11%   N 2.27%           observed:   C 5.95%   H 2.15%   N 2.12%                      
 
         [0114]      31 P NMR (D 2 O, 85% H 3 PO 4 ) δ (ppm) +7.87(1P), +5.24(2P), +4.92(2P), +3.98(1P)  
         [0115]      195 Pt NMR (D 2 O, Pt(en) 2 Cl 2 )δ(ppm) −2819  
         [0116]     XRF Calculated: P 6.00 Na 10.0 Pt 1.00 Observed: P 6.00 Na 10.9 Pt 0.94  
       EXAMPLE 10  
     Pt(dach)-IP6 
       [0117]    
       
                 
         
             
             
         
       
     
       Synthesis of cis-Pt(dach).IP6  
       [0118]     cis-Pt(dach)I 2  0.563 g (1.0 mmol) dissolved in N,N-dimethylacetamide 5 ml was added to a suspension of AgNO 3  0.340 g (2.0 mmol) in H 2 O 20 ml, and stirred for a overnight in the dark. After filtration by membrane filter, IP6.12Na 1.013 g (1.0 mmol) in H 2 O 30 ml was added and stirred for 3 hrs. The solution was concentrated by evaporation and the resulting powder was reprecipitated by adding MeOH 100 ml. Yield 73%.  
         [0119]     Elemental analysis: C 12 H 44 N 2 O 36 P 6 Pt 1 Na 10  
                                                               calculated:   C 10.26%   H 3.14%   N 2.00%           observed:   C 10.13%   H 2.88%   N 1.71%                      
 
         [0120]     XRF Calculated: P 6.00 Na 10.0 Pt 1.00 Observed: P 6.00 Na 10.3 Pt 1.42  
         [0121]      31 P NMR (D 2 O, 85% H 3 PO 4 )δ(ppm)+7.60(1P), +5.26(2P), +5.00(2P), +4.03(2P)  
         [0122]      195 Pt NMR (D 2 O, Pt(en) 2 Cl 2 )δ(ppm) −3209  
       EXAMPLE 11  
     Pt(NH 3 ) 2 (NDP)  
       [0123]    
       
                 
         
             
             
         
       
     
       Synthesis of cis-Pt(NH 3 ) 2 .NDP  
       [0124]     0.20 g (0.5 mmol) of cis-Pt(NH 3 ) 2 I 2  from step b.1. in dimethylacetamide 5 ml was added to a suspension of 0.149 g (0.48 mmol) of Ag 2 SO 4  in 20 mL H 2 O and stirred for about 4 hr in the dark. After filtration by membrane filter Ba(OH) 2 .8H 2 O 0.15 g (0.48 mmol) and sodium iminodiphosphate (NDP) 0.19 g (0.70 mmol) in 20 ml H 2 O was added. After stirring overnight 1M HClO 4  aqueous solution 1.4 ml was added and the solution was concentrated by evaporation and the resulting powder was reprecipitated using H 2 O-EtOH. Yield 35%  
         [0125]     Elemental Analysis: H 9 N 3 O 6 P 2 Pt 1 .1H 2 O  
                                                           calculated:   H 2.24%   N 10.40%           observed:   H 1.99%   N 10.01%                      
 
         [0126]      31 P NMR (D 2 O, 85% H 3 PO 4 )d(ppm)+10  
       EXAMPLE 12  
     Pt(NH 3 ) 2 (MDPOH)  
       [0127]    
       
                 
         
             
             
         
       
     
       Synthesis of cis-Pt(NH 3 ) 2 .MDPOH  
       [0128]     0.20 g (0.5 mmol) of cis-Pt(NH 3 ) 2 I 2 . in dimethylacetamide 5 ml was added to a suspension of 0.149 g (0.48 mmol) of Ag 2 SO 4  in 20 ml H 2 O and stirred for about 4 hr in the dark. After filtration by membrane filter Ba(OH) 2 .8H 2 O 0.15 g (0.48 mmol) and 60% 1-hydroxyethane-1,1-bis(phosphonic acid) (etidronic acid, MDPOH) 0.24 g (0.70 mmol) in 20 ml H 2 O was added. After stirring overnight the solution was concentrated by evaporation and the resulting powder was reprecipitated using H 2 O-EtOH. Yield 65%  
         [0129]     Elemental analysis: C 2 H 12 N 2 O 7 P 2  μl  
                                                               calculated:   C: 5.54%   H: 2.50%   N: 6.95%           observed:   C: 5.46%   H: 2.30%   N: 6.76%                      
 
       EXAMPLE 13  
     In Vitro Assay—Cell Growth Inhibition  
       [0130]     a. Materials &amp; Method  
         [0131]     KB cells were purchased from Human Science Research Resource Bank (Osaka, Japan). The cells were cultured in Earle&#39;s MEM (GIBCO BRL) containing 10% FBS (Bio Whittaker) at 37° C. under 5% CO 2 . After 24 hours the test compounds were added to the cells at the indicated concentrations. 72 hours later the cells were stained with tripan blue and counted manually. IC 50  is calculated as the concentration (aqueous solution) of complex required to inhibit growth of cells by 50%. The results are given in Tables 1, 2 and 3.  
         [0132]     b. Results  
                                                                 TABLE 1                                   5 μM   15 μM   50 μM   150 μM   500 μM                                    cis-Platinum   28.20%   13.80%   6.78%   4.34%   3.52%           (±0.14)   ±1.83   ±0.07   ±0.3   ±0.13       cis-   59.30%   38.20%   23.70%   20.00%   16.43%       Pt(NH 3 ) 2 (MDP)   ±2.96   ±3.81   ±0.67   ±1.05   ±3.17                  
 
         [0133]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 2 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                 1 μg/ml 
                 3 μg/mL 
                 10 μg/mL 
                 30 μg/mL 
                 100 μg/mL 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 [Pt(bpy)(Aten)]Cl 2   
                 93.8% 
                 (±1.7) 
                 81.4% 
                 (±2.7) 
                 75.3% 
                 (±5.9) 
                 73.2% 
                 (±9.1) 
                 32.5% 
               
               
                 (±1.2) 
               
               
                 cis-Pt(NH 3 ) 2 Cl 2   
                 17.0% 
                 (±3.2) 
                 13.4% 
                 (±1.3) 
                 3.0% 
                 (±1.5) 
                 2.2% 
                 (±0.7) 
                 1.6% 
               
               
                 (±0.4) 
               
               
                 [Pd(bpy)(Aten)]Cl 2   
                 86.9 
                 (±7.9) 
                 81.4 
                 (±8.6) 
                 75.1 
                 (±4.0) 
                 44.7 
                 (±2.0) 
                 12.3 
               
               
                 (±3.1) 
               
               
                 ([Pd(bpy)(Npen)]Cl 2 ) 
                 85.6 
                 (±8.6) 
                 81.3 
                 (±11.0) 
                 74.6 
                 (±9.8) 
                 61.4 
                 (±10.7) 
                 2.4 
               
               
                 (±0.3) 
               
               
                   
               
             
          
         
       
     
         [0134]    
       
         
               
               
             
               
               
               
             
           
               
                   
                 TABLE 3 
               
               
                   
                   
               
               
                   
                   
               
               
                   
                 IC 50  (μM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 cis-Pt(NH 3 ) 2 Cl 2   
                 2.75 
               
               
                   
                 cis-Pt(NH 3 ) 2 (MDP) 
                 7.50 
               
               
                   
                 [Pt(bpy)(Aten)]Cl 2   
                 97 μM 
               
               
                   
                 [Pd(bpy)(Aten)]Cl 2   
                 36 μM 
               
               
                   
                   
               
             
          
         
       
     
         [0135]     In a similar fashion a representative number of examples of compounds of the invention were tested for their ability to inhibit the growth/proliferation of cell types representing a number of different cancers. The results are provided in Tables 4-13, below, which provide the Inhibition Constants (IC 50 , μM) for each compound across various cell lines.  
                                                                   TABLE 4                           Breast Cancer Cell Lines            Ex. No.   HBC-4   BSY-1   HBC-5   MCF-7   MDA-MB-231                    1   −4.00   −4.60   −4.47   −4.35   −4.00       8   −4.83   −5.20   −5.57   −4.77   −4.35       2   −4.57   −4.00   −5.18   −4.83   −4.00       4   −4.14   −4.89   −4.12   −4.23   −4.50       5   −4.91   −5.34   −4.98   −5.28   −5.29       9   −4.27   −4.71   −5.16   −4.19   −4.06       10   −5.07   −4.56   −5.40   −5.32   −4.67       11   −4.72   −4.78   −5.09   −4.71   −4.23       7   −5.76   −5.89   −5.89   −5.69   −5.78       6   −5.76   −5.78   −5.89   −5.67   −5.66       12   −4.00   −4.00   −4.00   −4.00   −4.00                  
 
         [0136]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                   
               
               
                 Brain Cancer Cell Lines 
               
             
          
           
               
                 Ex. No. 
                 U251 
                 SF-268 
                 SF-295 
                 SF-539 
                 SNB-75 
                 SNB-78 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.25 
               
               
                 8 
                 −4.64 
                 −5.11 
                 −5.22 
                 −5.17 
                 −4.93 
                 −4.61 
               
               
                 2 
                 −4.00 
                 −4.00 
                 −4.04 
                 −4.72 
                 −4.00 
                 −4.00 
               
               
                 4 
                 −4.84 
                 −4.83 
                 −4.90 
                 −4.82 
                 −4.77 
                 −4.56 
               
               
                 5 
                 −5.00 
                 −5.27 
                 −5.31 
                 −5.36 
                 −5.16 
                 −4.67 
               
               
                 9 
                 −4.00 
                 −4.26 
                 −4.46 
                 −4.00 
                 −5.51 
                 −4.29 
               
               
                 10 
                 −4.69 
                 −4.52 
                 −4.67 
                 −5.14 
                 −4.86 
                 −4.48 
               
               
                 11 
                 −4.50 
                 −4.52 
                 −4.71 
                 −4.54 
                 −4.37 
                 −4.41 
               
               
                 7 
                 −5.66 
                 −5.62 
                 −5.62 
                 −5.75 
                 −5.59 
                 −5.54 
               
               
                 6 
                 −5.68 
                 −5.68 
                 −5.68 
                 −5.79 
                 −5.63 
                 −5.65 
               
               
                 12 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0137]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                   
               
               
                 Colon cancer Cell Lines 
               
             
          
           
               
                 Ex. No. 
                 HCC2998 
                 KM-12 
                 HT-29 
                 HCT-15 
                 HCT-116 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −4.57 
                 −4.43 
                 −4.44 
                 −4.51 
                 −4.58 
               
               
                 2 
                 −4.00 
                 −4.00 
                 −4.72 
                 −4.29 
                 −5.06 
               
               
                 4 
                 −4.81 
                 −4.77 
                 −4.57 
                 −4.00 
                 −4.37 
               
               
                 5 
                 −5.54 
                 −5.22 
                 −5.25 
                 −5.14 
                 −5.38 
               
               
                 9 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.41 
               
               
                 10 
                 −4.70 
                 −4.23 
                 −4.65 
                 −5.14 
                 −5.33 
               
               
                 11 
                 −4.44 
                 −4.00 
                 −4.38 
                 −4.27 
                 −4.48 
               
               
                 7 
                 −5.70 
                 −5.69 
                 −5.69 
                 −5.56 
                 −5.72 
               
               
                 6 
                 −5.73 
                 −5.67 
                 −5.68 
                 −5.59 
                 −5.76 
               
               
                 12 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0138]    
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                   
               
               
                 Lung cancer Cell Lines 
               
             
          
           
               
                 Ex. No. 
                 NCI-H23 
                 NCI-H226 
                 NCI-H522 
                 NCI-H460 
                 A549 
                 DMS273 
                 DMS114 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
                 −4.64 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −5.20 
                 −4.64 
                 −5.16 
                 −5.22 
                 −4.79 
                 −4.97 
                 −4.85 
               
               
                 2 
                 −4.17 
                 −5.21 
                 −5.18 
                 −4.65 
                 −4.63 
                 −5.00 
                 −4.15 
               
               
                 4 
                 −4.18 
                 −4.83 
                 −4.00 
                 −5.23 
                 −4.69 
                 −4.85 
                 −4.89 
               
               
                 5 
                 −4.88 
                 −5.41 
                 −5.22 
                 −5.86 
                 −4.88 
                 −5.24 
                 −5.28 
               
               
                 9 
                 −4.70 
                 −4.00 
                 −5.69 
                 −4.46 
                 −4.00 
                 −4.29 
                 −4.72 
               
               
                 10 
                 −4.95 
                 −5.08 
                 −5.17 
                 −5.19 
                 −5.21 
                 −6.27 
                 −4.26 
               
               
                 11 
                 −4.68 
                 −4.51 
                 −4.80 
                 −4.90 
                 −4.61 
                 −4.60 
                 −4.55 
               
               
                 7 
                 −5.53 
                 −5.64 
                 −5.77 
                 −5.71 
                 −5.68 
                 −5.68 
                 −5.76 
               
               
                 6 
                 −5.53 
                 −5.54 
                 −5.72 
                 −5.70 
                 −5.69 
                 −5.68 
                 −5.74 
               
               
                 12 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0139]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                   
               
               
                 Melanoma Cell Line 
               
             
          
           
               
                   
                 Ex. No. 
                 LOX-IMVI 
               
               
                   
                   
               
             
          
           
               
                   
                 1 
                 −4.00 
               
               
                   
                 8 
                 −4.85 
               
               
                   
                 2 
                 −4.59 
               
               
                   
                 4 
                 −4.46 
               
               
                   
                 5 
                 −5.15 
               
               
                   
                 9 
                 −4.08 
               
               
                   
                 10 
                 −5.31 
               
               
                   
                 11 
                 −4.66 
               
               
                   
                 7 
                 −5.76 
               
               
                   
                 6 
                 −5.73 
               
               
                   
                 12 
                 −4.00 
               
               
                   
                   
               
             
          
         
       
     
         [0140]    
       
         
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                   
               
               
                 Ovarian cancer Cell Lines 
               
             
          
           
               
                 Ex. No. 
                 OVCAR-3 
                 OVCAR-4 
                 OVCAR-5 
                 OVCAR-8 
                 SK-OV-3 
               
               
                   
               
             
          
           
               
                 1 
                 −4.25 
                 −4.21 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −4.69 
                 −4.83 
                 −4.52 
                 −4.72 
                 −4.65 
               
               
                 2 
                 −4.00 
                 −4.00 
                 −4.51 
                 −4.00 
                 −4.00 
               
               
                 4 
                 −4.13 
                 −4.19 
                 −4.79 
                 −4.37 
                 −4.77 
               
               
                 5 
                 −4.95 
                 −5.06 
                 −5.30 
                 −5.13 
                 −5.10 
               
               
                 9 
                 −4.82 
                 −4.42 
                 −4.00 
                 −4.00 
                 −5.20 
               
               
                 10 
                 −4.90 
                 −5.01 
                 −4.78 
                 −4.57 
                 −4.28 
               
               
                 11 
                 −4.52 
                 −4.63 
                 −4.53 
                 −4.42 
                 −4.43 
               
               
                 7 
                 −5.68 
                 −5.70 
                 −5.80 
                 −5.52 
                 −5.61 
               
               
                 6 
                 −5.67 
                 −5.76 
                 −5.65 
                 −5.56 
                 −5.63 
               
               
                 12 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0141]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                   
               
               
                 Renal cancer 
               
             
          
           
               
                 Ex. No. 
                 RXF-631L 
                 ACHN 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −4.74 
                 −5.37 
               
               
                 2 
                 −4.12 
                 −4.16 
               
               
                 4 
                 −4.89 
                 −4.20 
               
               
                 5 
                 −5.43 
                 −5.22 
               
               
                 9 
                 −4.37 
                 −5.37 
               
               
                 10 
                 −4.39 
                 −5.21 
               
               
                 11 
                 −4.73 
                 −4.76 
               
               
                 7 
                 −5.67 
                 −5.67 
               
               
                 6 
                 −5.67 
                 −5.71 
               
               
                 12 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0142]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                   
               
               
                 Human stomach cancer 
               
             
          
           
               
                 Ex. No. 
                 St-4 
                 MKN1 
                 MKN7 
                 MKN28 
                 MKN45 
                 MKN74 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
                 −4.55 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −4.61 
                 −5.18 
                 −4.76 
                 −4.52 
                 −4.91 
                 −4.50 
               
               
                 2 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −5.51 
                 −4.00 
               
               
                 4 
                 −4.74 
                 −4.00 
                 −4.45 
                 −4.34 
                 −4.68 
                 −4.75 
               
               
                 5 
                 −5.12 
                 −5.28 
                 −5.04 
                 −4.86 
                 −5.08 
                 −5.33 
               
               
                 9 
                 −4.00 
                 −4.42 
                 −4.00 
                 −4.00 
                 −4.14 
                 −4.00 
               
               
                 10 
                 −4.30 
                 −4.89 
                 −4.17 
                 −4.19 
                 −6.21 
                 −4.15 
               
               
                 11 
                 −4.44 
                 −4.60 
                 −4.47 
                 −4.21 
                 −4.60 
                 −4.27 
               
               
                 7 
                 −5.61 
                 −5.60 
                 −5.62 
                 −5.64 
                 −5.63 
                 −5.63 
               
               
                 6 
                 −5.51 
                 −5.64 
                 −5.64 
                 −5.57 
                 −5.63 
                 −5.70 
               
               
                 12 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0143]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                   
               
               
                 Prostatic cancer 
               
             
          
           
               
                 Ex. No. 
                 DU-145 
                 PC-3 
               
               
                   
               
             
          
           
               
                 1 
                 −4.00 
                 −4.00 
               
               
                 8 
                 −5.29 
                 −4.45 
               
               
                 2 
                 −4.19 
                 −4.00 
               
               
                 4 
                 −4.33 
                 −4.22 
               
               
                 5 
                 −5.10 
                 −4.90 
               
               
                 9 
                 −4.66 
                 −4.04 
               
               
                 10 
                 −5.03 
                 −4.46 
               
               
                 11 
                 −4.82 
                 −4.63 
               
               
                 7 
                 −5.73 
                 −5.59 
               
               
                 6 
                 −5.63 
                 −5.70 
               
               
                 12 
                 −4.00 
                 −4.00 
               
               
                   
               
             
          
         
       
     
         [0144]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 13 
               
               
                   
               
               
                   
               
               
                 Mean IC 50  (all cell types): 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1 
                 −4.09 
               
               
                   
                 8 
                 −4.83 
               
               
                   
                 2 
                 −4.35 
               
               
                   
                 4 
                 −4.54 
               
               
                   
                 5 
                 −5.18 
               
               
                   
                 9 
                 −4.38 
               
               
                   
                 10 
                 −4.86 
               
               
                   
                 11 
                 −4.55 
               
               
                   
                 7 
                 −5.68 
               
               
                   
                 6 
                 −5.67 
               
               
                   
                 12 
                 −4.00 
               
               
                   
                   
               
             
          
         
       
     
         [0145]     The forgoing data demonstrate that compounds of the invention exhibit significant inhibition of cancerous cells.  
       EXAMPLE 14  
     In Vitro Assay—Adsorption of Pt Complexes to Hydroxyapatite, Ca 10 (PO 4 ) 6 (OH) 2    
       [0146]     Each of a 5, 10, 15, 25, 35, and 100 mg sample of hydroxyapatite (Bio-Rad Macro-Prep Ceramic Hydroxyapatite, type I, 40 μm) was added to 2 ml of HEPES buffer at pD=7.8 and the resulting mixture was shaken for about 24 h at 37° C. Then, 100 μl of each complexes dissolved in HEPES buffer at pD=7.8 was added and the mixtures were shaken for 1.5 h at 37° C. All suspensions were filtered, and these solutions were measured by  31 P NMR (Varian VXR-300S) and Atomic Absorption Spectrometry (Hitachi Z-5710 AAS) of platinum or, for carboplatin, by  1 H NMR. Percentage adsorption to hydroxyapatite was calculated as follows. 
 
From NMR: Binding percentage %=[( A−B )/ A]× 100 
 
From AAS: Binding percentage/%=[( C−D )/ C]× 100 
 
         [0147]     A=the integration intensity of Pt(II) complex  
         [0148]     B=the integration intensity of Pt(II) complex after reacted with hydroxyapatite  
         [0149]     C=the concentration of Pt(II) complex  
         [0150]     D=the concentration of Pt(II) complex after reacted with hydroxyapatite  
         [0151]      FIGS. 1 and 2  depict the adsorption percentages to hydroxyapatite calculated from  31 P NMR,  1 H NMR, and AAS. These results showed that cis-Pt(NH 3 ) 2 (MDP) and Pt(dach)(MDP) adsorb to hydroxyapatite as Pt(II) complexes. Pt(dach)(MDP) adsorbed slightly more than cis-Pt(NH 3 ) 2 (MDP), and both Pt(dach)(MDP) and cis-Pt(NH 3 ) 2 (MDP) adsorbed quite significantly more than carboplatin. When Pt(II) complexes were reacted with 100 mg of hydroxyapatite, the adsorption percentages of cis-Pt(NH 3 ) 2 (MDP) was 69.3%, and that of Pt(dach)(MDP) was 79.6%.  
       EXAMPLE 15  
     In Vivo Tumor Assay  
       [0152]     Male NCr-nude mice, 6-8 weeks of age, were fed ad libitum water (reverse osmosis, 0.17% Cl) and an autoclaved standard rodent (NIH31) diet consisting of: 18% protein; 5% fat; 5% fiber; 8% ash; and 3% minerals. Mice were housed in microisolators on a 12-hour light cycle at 22° C. (72° F.) and 40%-60% humidity. Mice were implanted subcutaneously with 5×10 6  DU145 human prostate cancer cells in the flank. Tumors were monitored initially twice weekly, and then daily as the neoplasms reached the desired size, approximately 100 mm 3  (100 mg). When the DU145 prostate carcinomas attained this size, the animals were pair-matched into the various treatment groups. Estimated tumor weight was calculated using the formula: Tumor Weight (mg)=(w 2 ×L)/2, where w=width and l=length in mm of the tumor.  
         [0153]     Representative compounds of the instant invention were injected intraperitoneally to the animals and found to possess significant antitumor activity. See  FIGS. 3-6 , below.  
         [0154]     The compounds of the instant invention generally can be isolated in the form of their pharmaceutically acceptable acid addition salts, such as the salts derived from using inorganic and organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, D-tartaric, L-tartaric, malonic, methane sulfonic and the like. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter-ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.  
         [0155]     The pharmaceutically acceptable salts can be formed by taking about 1 equivalent of a compound of the invention, (e.g., Compound C, below), and contacting it with about 1 equivalent or more of the appropriate corresponding acid of the salt which is desired. Work-up and isolation of the resulting salt is well-known to those of ordinary skill in the art.  
         [0156]     The compounds of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration. Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one compound of the invention in association with a pharmaceutically acceptable carrier.  
         [0157]     Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.  
         [0158]     Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.  
         [0159]     Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.  
         [0160]     Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as coca butter or a suppository wax.  
         [0161]     Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.  
         [0162]     In general, an effective dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment, all of which are within the realm of knowledge of one of ordinary skill in the art. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight daily are administered to humans and other animals, e.g., mammals.  
         [0163]     A preferred dosage range is 0.01 to 10.0 mg/kg of body weight daily, which can be administered as a single dose or divided into multiple doses.  
         [0164]     While various embodiments of the present invention have been described in detail, it is apparent that further modifications and adaptations of the invention will occur to those skilled in the art. However, it is to be expressly understood that such modifications and adaptations are within the spirit and scope of the present invention. All of the references cited herein are hereby incorporated by reference in their entirety.