AU592927B2 - Liposoluble platinum (ii) complex and preparation thereof - Google Patents

Description

c ij I I; ~-n7~ 592927 COMMONWEALTH OF AUSTRALIA Patent Act 1952 COMPLETE SPEC I F I CAT I

(ORIGINAL)

O N Class Int. Class a Application Number S« Lodged a a S Complete Specification Lodged 4 Accepted Published S Priority Related Art Name of Applicant Address of Applicant SUMITOMO PHARMACEUTICALS COMPANY LTD.

S 40, 2-chome, Dosho-machi, Higashi-ku, Osaka, Japan Actual Inventors Mitsuaki Maeda and Takuma Sasaki Address for Service F.B. RICE CO., Patent Attorneys, 28A Montague Street, BALMAIN. 2041.

Complete Specification for the invention entitled: Liposoluble Platinum (II) Complex and Preparation Thereof The following statement is a full description of this invention including the best method of performing it known to us:rci r

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t t S P ECI F I CATIO N Title of the Invention LIPOSOLUBLE PLATINUM (11) COMPLEX AND PREARATION THEREOF Background of the Invention Field of the Invention The present invention relates to a platinum (11) complex. More particularly, the present invention pertains to a platinum (II) complex having excellent antibacterial activity and anticancer activity, in particular, effective to use as an anticancer agent and a process for preparing the same.

Description of the related Art Rece'ntly, a remarkable development has been achieved in medical and pharmaceutical fields, and as a result, diseases conventionally considered to be incurable and showing a high mortality have been protected, restrained or cured (or recovered) to a substantial degreia. under such circumstances, cancer has drawn a great att ention because of its high mortality.'%. However, up to now, there has not yet been proposed an effective 6olution to reduce the mortality of patients suffering from cancer.

,There have been proposed conventional therapeutics for cancer, such as surgical operation in Which the affected part of patients is cut off, irradiation (radiotherapy), chemical therapy (chemotherapy) by administrating S t~ 'r I r medicines. Recently, the immunological therapy (immunotherapy), the interferon therapy, and the utilization of laser such as YAG laser as new technique of the surgical operation have drawn a great attention.

However, the surgical operation and the radiotherapy among others a.e a kind of locally applied techniques of therapy and are effective means for treating patients only if the disease is in its primitive state or there is not metastasis, while these therapeutics are not effective against the progressive cancer those accompanying tit, metastasis in the whole body of patients as well as the systematic diseases such as leukemia and malignant lymphoma in which a specific system in the whole body is gradually affected. On the other hand, the chemotherapy is the only S effective therapeutics against the latter systematic diseases and some of the cancer may be cured by the chemical therapy. It is also recognized that the chemotherapy is an effective tool for treating patients suffering from cancer, in particular, when it is applied as an additional or auxiliary treatment after the surgical operation or it is applied in combination with the radiotherapy and thus, this is one of the therapeutic technique in which a great future development is expected.

Up to now, various kind of anticancer agents have been developed and proposed and each of them differs in its property and the effectiveness thereof varies depending on the kind of cancer. There may be mentioned such as mitomycin C, adriamycin as the medicine against 2 r adenocarcinoma (carcinoma in digestive organs, oophoroma); vincristine, bleomycin against the malignant lymphoma; cytocine arabinoside, L-asparaginase for acute leukemia.

The chemotherapy for the cancer is based on the fact that the cancer may be caused by the parasite such as cancer cells in a human body as encountered in the case of bacteria in the general infectious diseases. In other words, the cancer cells are considered to be normal cells ij which are converted to a variant by some causes and the variant once formed in a body is considered to be the parasite exhibiting autonomous proliferation.

Although cancer cells and normal cells are different r in their biological and biochemical properties from each other, the difference is :simply in a quantitative one, while the qualitative difference between them has not yet been made clear. Therefore, the normal cells may possibly be impaired by the action of chemical agents (medicine) in the chemotherapy and this is revealed as so-called sideeffects due to the medicine (such as anticancer agents).

Thus, it is quite difficult to restrain only the proliferation of cancer cells or destroy only these cells 7 utilizing such medicines.

As seen from the above, the development of a new 4 technique for treating cancer is a principal subject to be solved in the medical and pharmaceutic fields and an absolute therapy therefor should be developed. However, it can not be expected to achieve a new drastic development in the surgical therapy and the radiotherapy. Thus, it is 3 3 i,' ii *r II.

i fi more preferable or practical to improve chemotherapy or to develop a new medicine since a significant future development may be expected. It is expected, in particular, as the additional or auxiliary treatment means after the surgical operation of the affected part and it may be used in combination with the radiotherapy.

Furthermore, the chemotherapy may be an effective tool for treating the progressive cancer as well as the systematic diseases. Thus, there is a great need to develop a new therapeutic technique in medical or pharmaceutical science to remedy the patients suffering from these diseases. It must be sa'id, however, that such agents should fulfill such requirement that they affect on the cancer cells specifically and selectively.

An object of this invention is to provide a novel platinum (II) complex having no side-effects which affects on cancer cells specifically and selectively.

An other object of this invention is to provide a method for preparing the platinum (II) complex.

Summary of the Invention We reviewed and made the detailed reexamination of the known platinum (II) complexes which have been utilized as anticancer agent. We had such a notion that the above mentioned problems such as side-effects may be possibly caused from their water solubility. Therefore, we thought that the platinum (II) complex which can act or affect on cancer cells specifically and selectively may be obtained aa:

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'1

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if the complex is liposolubilized. Thus, we obtained different kinds of liposoluible platinum (11) complexes of the present invention.

A liposoluble platinum (11) complex according to the present invention is represented by the following formula Pt R3 T t r~ wherein Ri and R2 each stands for a 2Aigand ammine which may have an organic substituent or may be bonded to each other through a bivalent organic group and R3 represents a bile acid residue.

in the platinum complex according to the, present invention, the organic substituent in the ligand ammine substituted with organic group(s), represented by R1 and R2 and the bivalent organic group through which these two ammine ligands are bonded together may be those used as substituehts of the aminine part (RNH2) of known *diammine platinum (11) complexes in the conventional anticancer agents, Thus, the organic substituent of the ammine ligand (Ri or R2), May be a member selected from a group comprising an alkyl group having from 1 to 5 carbon atoms such as isopropyl group; and a cyc2-oalkyl group having from 3 to 7 carbor, aomo oucxh as cyclcopropyl p-ce1ip 0? tyclohexyl groupn, i4

I

While, the bivalent organic group may be a member selected from the group comprising a cycloalkylene group having from 5 to 8 carbon atoms such as 1, 2-cyclohexylene; an alkylene group having 2 or 3 carbon atom, s, optionally substituted with an alkyl group having from I to 5 carbon atoms, an alkylene group having from 2 to 6 carbon atoms or a phenyl.

group, which includes for example 2, 2-pentamethylenetrimethylene group: *CR2- 4, 4lt 1-etmtyee(ehln)gop 44 4 4 4 C) C2- 1, 2-tatramethylene ttrirnethy:lene) group: C (CH2- Ii and 1, 2-diphenylethylene; and 1/ 2-phenylene group optionally substituted with an alkyl or alkoxyl group having from 1 to 5 carbon atoms or a halogen atom such as 1, 2-phenylene.

When the biva lent organic group is 1, 2-cyclohexylone or the like which possess is -mers Icis- DL-trans p D- S3iUIOSSUSIIN 60:ST BT-20-8 trans and L-trans-form, the liposoluble platinum (1I) complex according to the present invention may be any one of the isomers a'd a mnixture thereof.

As a bile acid residue, an acyloxy part of the bile acid, which is represented by R3 in the formula there may be mentioned a residue of the bile acid such as cholic acids cholic acid, deoxycholic acid, tithocholic acid, chenodeoxycholic acid, ur~odeoxycholic acid, hyodeoxycholic acid) and glyoyrrhizic acid.

The liposoluble platinum (11) complex of the present invention, represented by the general formula can be prepared according to the following reaction scheme: R1 Cl R1 0112 2+ Pt Pt 2(N032) N~ 120 R2 Cl R2 0H2

(A)(B

R3-M4 Pt R2 R3 (wherein RI R2 and R3 are as defined above and M is an alkali metal) According to this method, a cis-dichioro-diammina platinum (11) complex is firstly converted (nitrified) 7, Eld SMiHIOOSSU 3IN 60:ST 8T-Eo-88, to a diaquo form and then the diaquo form is subjected to the reaction with a desired alkali metal salt of bile acid to produce an objective bile acid derivative of diammine platinum The nitrification may be carried out by means of any conventional nitrifying agents such as silver nitrate (AgNO3). As the alkali metal, in particular, sodium and potassium may be used preferably.

The reaction in which the complex is converted to the diaquo form of the platinum (II) complex is, in general, effected under the light-shielded condition and Sit' proceeds with high yield around room temperature. In addition, it is preferred to heat the complex to a temperature of about 60 to 80 0 C prior to the addition of silver nitrate, in order to facilitate dissolution of the complex into a reaction 'medium. The reaction time somewhat various depending on the reaction temperature, but, in general, the reaction time of about 3 hours is sufficient to achieve a good yield.

The reaction is preferbly carried out under the light-shielded condition as is in the reaction of and is proceeded for from about 10 days to 3 weeks of the reaction time at around a room temperature.

The cis-dichloro-di-(substituted 'or unsubstituted)ammine platinum (II) complexes used as a starting material in the abovementioned process can be obtained by a per se conventional method and, for instance, dichlorocyclohexane- 1,2-diammine platinum (II) complex is disclosed in the 'd S31UIOOSSU8IIW OT:ST 8T-20-88 r

-I

2 article of T, A. Connors, M. Jones et al., Interactions, 1972, 5, p415".

"Chem. Biol.

The platinum (II) complex of the present invention is liposoluble -nd has an activity to supress the growth of the cancer cells or antibacterial activity, so that it is expected to be useful as an anticancer agent which possesses higher specificity and selectivity to the cancer cells or as an antibacterial agent. Moreover, their liposolubility makes it possible to use the complex as a medicine which can affect on the diseased part more specifically and can be released more slowly or steadily when the medicine is combined with a contrast medium as a carrier. A variety of contrast medium such as lipiodol' is widely used for hepar, uterus, tuba or the like for the clinical purpose. The lipiodol is an iodinated poppy fatty acid ethyl ester and has the 12 content of 38 the specific gravity of 1.275 to 1.290, the viscosity of 27 to 43 cS and the median lethal dose (LD5O) of 7 g/Kg when administered intravenously to rabbits. Furthermore, it is also known that the lipiodol is capable of. staying stably at the vicinity of the cancer cells for a long period of time. Therefore, when the lipiodol is used in combination with the liposoluble platinum complex of this invention, the anticancer agent can affect only on the cancer cell and the vicinity thereof more specifically and for longer time duration.

Further, the liposoluble platinum complex of the present invention can be dispersed in physiological saline 4 $9 S3UIDOSSUIIN TT:ST 8T-20-88, I or distilled water which is then subjected to the action of ultrasonic so.that mioells of adequate size is formed. The resulting miceliI solution can be administered intravenously or into a tuifor, so that it affects specifically and staidly only on the cancer cell and the vicinity thereof.

The platinum (11) complex according to the present invention may 'be administered in the dose of 1 mg/day to 3 g/day for an adult intravenously, orally, topically, Vintrarectally or intratumorally. They may be used in the .rI form beof various pharmaceutical .preparations ,such as tablets, suppositories, injections, etc, These preparations may beformUJ.~ted in per se conventional procedures. For instance, a solution or 'a suspension can be, prepared by iidissolving ordispersing the abtive component in a contrast medium such e.s lipiodol or by dispersing in an aqueous solution to fo'rm the micell atccording to any conventional techniques. When the lipiodol is combined with the 1:platinum (II)l complex of the present invention, it is pref erable to; use the platinum (11) complex in an amount ranging f rom 0.1 to 100 mg per 1 to 50 ml of lipiodol.

These are user as a solution or a suspension as mentioned Labove. In th~e case ti.at the platinum (11) complex of the present invention is used in the f'6rm of suspension in distilled weror physiological saline, the preferred amutranges-from 0.1 to 1 mg per 1 to 500 ml of distilled As to cyclohexandiammine derivative of the liposoluble platinum (II)i complex as the active component, it is found 9d S31UI3OSSUd'SIIN 2T:ST 8T-20-88, r

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that it shows higher effects when it is used in the form of suspension in distilled water or in combination with lipiodol. Moreover, the use of the contrast medium makes it possible to perform the diagnosis and the therapy simultaneously so that the effectiveness of treatment for patients can be examined during the treatment The efficacy of the platinum (II) complex according to the invention, in particular, the anticancer activity was examined according to the following procedures using L 1210 CDF1 mouse system. First of all, 1 x 10 4 L 1210 leukemia cells were implanted intraperitoneally to the mice and then a solution of the platinum (II) complex in 0,3 ml of lipiodol was intraperitoneally injected into the mice 24 hours and 5 days after the implantation of the leukemia cells. The platinum (II) complex was administered in three different doses as shown in' the following Table I. In addition, as the controls, mice to which nothing is administered and to which only lipiodol is administered were also examined. Then, the survival time of each group of mice thus treated was determined and the mean survival time (MST) was estimated on the basis of the observed survival time of each mohse. The effectiveness of the platinum (II) complex was represented- by the ratio (T/C) between the mean survival time of the mice to be treated with 'platinum (II) complex and that of the control group of mice and the ratio (CR) between the number of mice completely cured and total number of mice tested. The results obtained are listed in the following Table I.

Cid S31JHI3OSSUKII ET:ST BT-Z2-88 Table I Effect of the Platinuim (11) Complex on the Survival Time of the CDFJ Mi-ce Implanted with L 1210 Cells compound Dose (Mg/Kg X 2) MST T/C Cont rol1 Lipiodol DACHPt (II)- (Chol) 2 DACHPt (II)- (DeOXY) 2 385 1422 285 57 1319 264 53 1280 256 51 10 10 11 .0 9.0 >100 13.0 10 0 >100 11 .0 DACHPt (II)- (Litho) 2 DACHPt (II)- (UrSO) 2 DACHPt (II)- (Cheno) 2 100 100 Toxic 122 100 Toxic >1000 144 )1000 100 0 122 Toxic Toxic 283 toxic Toxic 190 0/6 0/6 1 0 /6' 0/6 0/6 5/6 0/6 3/6 3/6 0/6 0/6 0/6 2/6 0/6 0/ 6 1/6 793 264 53 793 25.5 53 K19.0 in these samples, the platinum administered only one, time.

(11) complex was DACH: Cyclohexane-1, 2-diarnmine Chol: Cholic acid residue (0C0C23H3903) Deoxy: Deoxychoic acid residue (0C0C23!13902) Litho: Lithocholic acid residue. (0C0C2311390) 12 B'd S31UI0GSe8IIW P'T:ST BT-20-8 Urso: Ursodexycholic acid residue (OCOC23H3902) Cheno: Chenodeoxycholic acid residue (OCOC23H3902) In the results shown in Table I, MST and T/C for the control group and the group to which only lipiodol was administered were given 10.0 and 100 respectively and these values were adopted as the standard. It is the matter of course that CR was 0 in these cases. As to the groups to which the liposoluble plIatinum (II) complex according to the present invention is administered, it is observed that mice are sacrificed due to the toxicity of the platinum (II) complex if it was administered in a high dose, however, excellent results were obtained when the complexes were applied in relatively low dose. In particular, the group of mice to which the deoxycholic acid derivative was administered in the amount of: 264 mg/kg shows the value of complete cure ratio (CR) of 5/6, the group administered lithocholic acid derivative in the amount of 1280 mg/kg and 256 mg/kg shows that of 3/6; the group to which 53 mg/kg of the ursodeoxycholic acid derivative is administered shows that of 2/6; that of the group to which 53 mg/kg of' the chenodeoxycholic acid derivative is administered is 1/6.

Further, the anticancer activity'of the platinum (II) complex according to the present invention was examined according to the same procedures as the above mentioned examples for L 1210-CDF1 mouse system. Namely, 1 x 104 of L 1210 leukemia cells were implanted intraperitoneally to the mice and then a suspension of the platinum (II) complex 1'3 S31IDOSS UIIN 8T-20-88e tC in 0. 3 ml of d by ultrasonic w (11) complex wa shown in the controls, mice examined. Ther thus treated w (MST) the rat complete cure r observed surviv are shown in th I re'! Sir istilled water which was treated previously as intraperitoneally injected. The pla~tinum t administered in three different doses as following Table 11. in addition, as the to which nothing is administered were also ithe survival time of each group of mice as determined and the mean survival time io of prolongation of life and the atio (CR) were estimated on the basis of the al time of each mouse. The-obtained results e following Table 1I.

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S31UiI3OSS'IIW 9T:ST 8T-20-88 1 >4 Table 11 4ffect of the Platinum (11) Complex on the Suarvival Timte of the CDF1 Mlice Implanted with L 1210 Cells -7 Compound Dose (mg/IXg x 2) M -0T T/C

U

U

A

1'( .1 Control DACHPt (II)- (Chol) 2 DACHPt (1I)- (Deoxy) 2

'C

DACHPt (II)- (Litho) 2 792 264 53 854 285 57 791 264 53 791 264 as 12 0 17.5 14.0 12 0 1815 9.5 90 21 .0 90 100 120 0 1 94 140 Toxic >1 200 206 106 900 210 Toxic Toxic 900 0/6 3/6 116 0/6 0/6 4/6 2/6 0/6 5/6 2/6 0/6 0/6 5 r DACHPt (II)- (Urso)2 DACHPt (1I)- (MenO)2 791 *)-Toxic 0/6 264 Toxic 0/6 a8 90 >900 4/6 *in the~e samples$ the platinufi (11) complex was administered only one time.

In Table 11, MST and T/C for the control group were given -10.0 and:' 100 respectively and these values were adopted as the ptandards. It is the matter of course that CR was 0 in th~se cases. As to the groups to which the 2T' d S31UIOOSSMaIIW Z-T:G eT-2o-es, r f liposoluble platinum (II) complex according to the present invention is administered, it is observed that mice are sacrificed due to the toxicity of the platinum (II) complex when they was administered in a high dose, however, excellent results were obtained when the complexes were applied in relatively low dose.

In particular, the group of mice to which the cholic acid derivative was administered in the amount of 792 mg/kg shows the CR value of 3/6, the group administered deoxycholic acid derivative in the amount of 285 mg/kg shows that of 4/6; the group to which 264 mg/kg of the lithocholic acid derivative is administered shows that of 5/6; that of the group to which 88 mg/kg of the ursodeoxycholio acid derivative is administered show that of 5/6; that of the group to which 88 mg/kg of the chenodeoxycholic acid derivative is administered shows that of 4/6.

9t*9 ~t S rr F i.

Thus, according to the present invention, it is possible to provide a new platinum (II) complex which has an excellent liposolubility and which is .applicable as anticancer agent or antimicrobial agent. In general, it is usual requirement for not 'only anticancer agents but also for other medicines that medicines must have such properties that they affect specifically on the deseased part and they do not impair normal cells. Since the platinum (II) complex of the present invention is liposoluble, they can be expected to have a high specificity to affected portions. Moreover, if the

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ET Id S3IUI:OSSIU>3IIN zT;sT 8T-2o-88, L, 1 2~V~T~ :1 9 9 it

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lipiodol which, is capable of staving preferentially at the vicinity of the cancer cells for a long period of time is used in combina~tion with the liposoluble platinum (11) complex of this invention, or if the platinum (11) complex is dispersed in distilled water or physiological saline in the form of suspension which is subj ected to the ultrasonic-treatment in order to form micells, it is possible to obtain the anticancer agents which have the excellent specificity and which can be carried specifically to the cancer cells or the vicinity thereof and can be released slowly and can keep steady and long-lasting effects. Namely, the present invention provides very useful anticancer agents having a high specificity and selectivity with little side-effects s~uch as nephrotoxicity of the conventional cysplatine.

The present invention will be explained 'in more detail, by the following illustrative examples which are not limitative.

Example 1 t C t CC Synthesis of Cyclohexane-l, 2-diammtine Pltndmr (11) Bi schola te Starting from cyclohexane-1 2-dihmmine cons isting of about 65 of trans-isomer and about 35 of cis-isomer, dichlorocyclohexane-1, 2-.diarnmine platinum (11) complex was prepared according to the method disclosed in Chem. Biol.

interactions, 1972, p415. A mixture of 80 ml of distilled water and 570 rg (1.5 mmoles) of VT'd t~Vd S1I3OSSU'8IIH 8T:SI 8I-20-88,

B

dichlorocyclohexane-1, 2-diammine platinum (II) complex was allowed to heat to 70 OC to dissolve most of the complex.

To the solution, after being cooled to room temperature, an aqueous solution of 510 mg (3 mmoles) of silver nitrate in ml of water was added and the mixture was stirred for three hours under light shielded condition. The resulting silver chloride was then filtered off and washed over Celite. The combined filtrate was concentrated to a volume of less than 50 ml at a temperature of lower than 30 OC.

The resultant concentrate was used in the subsequent reaction.

'tI g Thus, an aqueous solution of the complex in the aqua S? form obtained was added to 50 ml of aqueous suspension S which was prepared by dispersing 1.29 g (3 mmoles) of sodium choleate into water. The reaction was carried out under stirring and the light shielded condition for days, the resulting milky white suspension was freeze-dried as it is to give the objective platinum (II) complex.

Rf [Silica gel TLC, CHC13 MeOH 0.41 (cis) 0.20 (trans) I. R. (cm-1) 3350 b) A 2900 2840 (m) 1550 1370 1070 (w) 1030 975 (w) Example 2 The procedures of the Example 1 were repeated except that as the alkali metal salt' of bile acid, sodium ST d SMIUDOSSUKIIN GT:ST ST-20-88, Fr: I 74 r

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deoxycholate, sodim lithocholate, sodium chenodeoxycholate, sodium ursodeoxycholate or sodium hyodeoxycholate *were used instead of sodium cholate and thus the following compounds were prepared *DACHPt (III (Deoky)2: Rf [Silica gel TLC, CHC13 MeO 0.66 (trans) 0.55 (cis) 1. R. (om-1) 3350 2s, b) 900 (Wn 2840 (m) 1550 1380 1030 (w) ttrt ii t 4 4s I I rI t *DACHPt (11) (Litho)2: Rf [Silica gel TLCF CHC13 0,92 (cis) 0,87 1. R. (cm-1) 3380 b) 2920 1560 1390 *DAcipt (11) (Cheno)2: Rf [Silica cel TLC, CHC13 0.75 (trans) '0.61 I. R. (cm-1) 3360 b) 2910 1555 1370 975 835 14eOR (trans)

(V)

(vrS) 2850 (W) 1030 (w)

F

i -i MeOH (41)] (cis) rr r

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(ir

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(in) (vs) (vW) 2850 (i) 1075 (w) *DACHPt (II) (Urso)2: Rf [Silica gel TLC, CHC13 MeO4 (4:1)1 9t dI8 S31HIDOSSUKIN 02:sST eT-Eo-ee., 9T'1 'd 1 i

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I (I a: 0.77 (trzans) P. (cm-1 3360 k(S, b) 1560 (mn) 1010 Mw 0.66 (cis) 2920 (Wn 1380 (vs) 2850 Wm 1040 Mw )ACHPt (11) (Hyo)2: 'Hyo' is hyoaeoxycholic acid [Silica gel. TLC, CHC13 0.6.6 (trans) 0.61 R,(cm-i) 3360 b) 2920 1560 (Wn 1,380 830 (vw) residue (0COC23H4002)) MeOH (cis) (Wn (v s) 2850 (Wn 1030 Mw 2.T Id S31I3OSSUK2IW T2:GI 8T-20-88,

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Claims (23)

1. platinum (11) complex represented by the formula R(I R2 R3 wherein R1 and R2 each stands for a ligand ainmine which may have an organic substituent or may be bonded to each other through a biv:alent organic group and R3 represents a bile 000acid residue,.

2. A platinum (1I) complex as set forth in claim 1, wherein said organic substitueft of the ligand ammine is an alJ,.yl group having from 1 to 5, carbon atoms or a cycloa-ky. group having from 3 to 7 carbon atoms,

3. A platinumn (11) complex as set forth in claim 1, wherein said bivalenit organic group is a member selected from the group consisting of a cycloalkylene group having from 5 to 8 carbon atoms; alkylene group having from 2 or 3 carbon atoms, optionally substituted with an alkyl group having from 1 to 5 carbon atoms, ah- alkylene group having from 2 to 6 carbon atoms or a phenyl. group; and 1, 2-phenylene group optionally substituted with an alkyl or alkoxyl group having from I to 5 carbon atoms or a halogen atom. 2:1 BT dS31HIDOSSUKIN T2:ST 8T-20-89,

4. A platinum (11) complex as set forth in claim 1, wherein RI and R2 are unsubstitu~ted ammines.

A platinum (11) complex as set forth in claim 1 wherein R1 and R2 are ligand ammines bonded to each other through a bivalent organic group.

6. A platinum (II) complex as set forth in claim wherein the bivalent organic group is I, 2-cyolohexylene group.

7. A platinum (11) complex as set forth in claim 1 wherein said bile acid residue is a residue of one of cholic acids.

B. A platinum (11) complex as set forth in claim 1, wherein said bile acid residue is a residue of a bile acid selected from a group consisting of oholic acid, deoxycholic acid, lithocholic acid, chenodeoxycholic acid, ursocieoxycholic acid, hyodeoxyoholic acid and glycyrrh.izic acid.

9. Cyclohexane-1, 2-diammine platinum (11) bischolate.

Cyclohexane-l, 2-diammine platinum (11) bisdeoxycholate.

.11. Cyclohexane-l, 2-diammine platinum (1I) bislithocholate. 22 6T dC S31UIDOSSUKIN 22:ST 8T-20-88, U 4

12. Cyclohexane-1, 2-dianrine platinum (11) bischenodeoxycholate.

13. Cyclohexane-1, 2-diammine platinum (11) bisursodeoxycholate,

14. Cyclohexane-1, 2-diammine platinum (11) bi-shyodeoxycholate.

A process for preparing a platinum (II) complex of claim 1 which comprises nitrifying a cis-dichloro-di aminine platinum (1I) complex of the formula-, RI Pt Cl 1 wherein R1 and R2 are as d'f ined in claim 1 with a nitrifying agent to form a: nitrate of a diaqua form thereof; and reacting the resulting diaqua. comp(.und with a compound represented by the formula: R3 -M wherein R3 is as def ined in claim, 1 and M represents an alkali metal.

16. A process according to claim 15, wherein the alkali metal, is sodium. '~JI r2

17. A process according to claim 15, nitrifying agent is silver nitrate.. wherein the 02d S31UIOSIS8IIW E2:ST eT-20-88, J II It FT Fr F F A c

18, A process according to claim 15, wherein R1 and R2 are ligand amminee' bonded to each other through 1, 2- cyclohexylene and said bile acid residue is a residue of a bile acid selected from a group consisting of cholic acid, deoxycholic acid, lithocholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and hyodeoxycholic acid.

19. A pharmaceutical composition useful as anticancer agnet which comprised, an effective amount of a platinum (II) complex of claim 1 as an active ingredient and a pharmaceutically acceptable carrier or diluent.

A method of treating cancerous deseases which comprises administering an effective amount of a platinum (II) complex of claim 1 to a patient.

21.. A method as set forth in claim 20, wherein said platinum (II) complex is incorporated in a lipidol.

22. A method of supressing the growth of the cancer bells which comprises treating the cells with an effictive amount of a platinum (II) complex of claim 1i;

23. A platinum (II) complex defined in claim 1 for use as an active therapeutic substance. Dated this 18 February 1988 SUMITOMO PHARMACEUTICALS COMPANY LTD. Patent Attorneys for the Applicant: F.B. RICE CO. T2 d S3ttd1UIOSSUKIIN E2:ST 8T-20-88,