CA1256115A - Platinum complexes - Google Patents

Abstract

NOVEL PLATINUM COMPLEXES
Abstact of the Disclosure:
Novel platinum complexes represented by the formula:

(I) wherein A is alkylene having carbon atoms of from 1 to 3;
R1, R2, R3 and R4 are the same or different and are hydrogen or alkyl having carbon atoms of from 1 to 4; X and Y are independently a halogen atom, or combined together to form

Description

~25~ 5 The present invention relates to novel platinum complexes having the general formula (I):

R~ , CH - NH (H) n X
(CH2)m Pt (I) A~ l-(R3)Q ( 1H ) ~ CH-R4 wherein A is alkylene having carbon atoms of from 1 to 3;
S Rl, R2, R3 and R4 are the same or different and are h~drogen or alkyl having carbon atoms of from 1 to 4i X and Y are independently a halogen atom or combined together to form ~ O - C = O O - C' ~ I or ~ , and Q, m and n are O - C = o ~ O - C~
independentl,v 0 or 1, with the proviso that when n is 0, and Y do not si~ultaneously represent a halogen atom.
The above complexes are useful as antitumor agents.
Since Rosenberg et al reported that cisplatin (abbreviated as CDDP hereunder) has antitumor activity (Nature 222, 385 (1969)), many researchers have eagerly investigated to seek platinum complexes with a view to find-ing ones having antitumor activities. For example, some ofthese compounds appear in Japanese Patent Publication No. SS99/84, Japanese Patent Public Disclosure NO. 77694/82, etc.
Although the known platinum complexes includins CDDP
were recognized to exhibit a broad spectrum of antitumor activities, their dosage amounts and the sorts of tumors which could be treated were limited because these complexes have very serious nephrotoxicity. In addition, it is observed that these platinum complexes generally bind to plasma proteins so as to be converted into an inactive form.
The inventors of this invention have studied various platinum complexes in order to identify those having hish antitumor activities and less toxicity. Finally, we found L P~

~2S6~S

the compounds of this invention and confirmed that these complexes are suitable for use as an antitumor agent.
The compounds of this invention are prepared by the following method.
Platinum(II)potassium chloride is reacted with a diamine derivative represented by the formula (II):
Rl R~
CH - NH
(CH2)m (II) A N _ (R3)Q

wherein A, Rl, R2, R3, R4, Q and m are the same as defined above to give the corresponding dichloro compound [formula (I) (n is 0, X and Y are chlorine)]. The resulting dichloro compound is oxidized with hydrogen peroxide to give a novel platinum complex of the formula (I) [n=l, X=Y=Cl] defined above. The above dichloro compound is converted to dini-trate form with use of silver nitrate, and then reacted with a dicarboxylic acid to ~ive a novel platinum complex of the O-C=O , O-C'~
lS formula (I) [n is 0, X and Y are ~ I or ~ ]

defined above.
Diamine derivatives which can be used in this inven-tion include 2-aminomethylpyrrolidine, (S)-2-aminomethyl-. pyrrolidine, (R)-2-aminomethylpyrrolidine, 2--(1-amino-ethyl)pyrrolidine, 2-aminomethyl-l-methylpyrrolidine~

2-aminomethyl-1-ethylpyrrolidine, 2-aminomethyl-l,S-dimethylpyrrolidine, l-(2-aminoethyl)pyrrolidine, 2-amino-ethylazetidine, 2-aminomethylaziridine, and the like.
Dicarboxylic acids which are useful in this invention include oxalic acid, l,l-cyclobutanedicarboxylic acid and their salts.
The platinum complex of this invention can be formu-lated by any desirable coventional method with a pharmaceu-tically acceptable carrier and, if necessary, an adjuvant.
For oral administration, the compound of this -- ~125611`5 invention can be formulated into a solid preparation such as tablets, pills, granules, powder, capsules, or the like, or a liquid preparation such as solution, suspension, emulsion or the like. When the preparation is used for parenteral administration, the preparation is formulated into a suppos-itory, injection, an intravenous drip infusion or the like.
When the compound o~ this invention is formulated into tzblets, pills, g_anules, powder or capsules, phar~aceuticzl carriers such as starch, sucrose, crystalline cellulose, kaolin, calcium carbonate, talc, magnesium carbonate and the like are preferably used. For preparation of an injection, it is preferred that the compound is dissolved in distilled water or an aqueous solution of a salt such as sodium chloride. For preparation of an intravenous drip infusion, lS the compound is dissolved in a suitable fluid therapy such as a physiological saline, a glucose-sodium chloride solu-tion or the like. For a suppository, cacao butter, laurin, glycerogelatin, macrogol are preferably used as a base.
The amount of the compound in a formulated prepara-tion is selected so as to be appropriately administered depend-ing on the age and condition of individual patient being treated.
The compound of this invention is preferably adminis-tered orally in a daily dose of from 200 to 400 mg/m2, and parenterally in a daily dose of from 100 to 200 mg/m2.
The compound of this invention has very low toxicity.
For example, when ddY strain male mouse-(5 week old, weigh-ing 26 - 30 g) was intraperitoneally administered, the compound of this invention as an aqueous solution, the LD50 was higher than 80 mg/kg.
As described above, since the compound of this inven-tion has high antitumor activity and low toxicity, and is easily soluble in water, it is very useful as a drug.
This invention is further illustrated in the follow-ing Examples and Experiments, but they should not be inter-preted as limitative of this invention.
Example 1 To a solution of platinum(II) potassium chloride ~256~15 (4.15 g : 0.01 mole) in 100 ml of water was added a solution of 2-aminomethylpyrro1idine (1-00 g : 0.01 mole) in 10 ml of water. The mixture was stirred at room temperature for 1 day. The resulting solid was collected by filtration, washed with water, and dried at 60C under reduced pressure for 3 hours to give 3.00 g of dichloro-(2-aminomethyl-pyrrolidine)platinum(II)- Yield: 82%, m.p. 255 - 270C
(decomposition).
Analysis:
Calcd. for CsH12C12N2Pt: C 16.39, H 3.30, N 7.65 (%) Found: C 16.40, H 3.26, N 7.50 (%) IR spectrum: vmax cm~l: 3420, 3230, 3170 (=NH) To a suspension of the product obtained above (3.00 g : 0.0082 mole) in 300 ml of water was added silver nitrate (2.78 g : 0-0164 mole)- The mixture was stirred at room temperature under light shielding for 3 days. The resulting white precipitate of silver chloride was removed by filtration using a millipore filter (0.22 ~m). The filtrate, which contained the unreacted silver nitrate, was treated with a sodium chloride aqueous solution. The resulting silver chloride was removed by filtration, and the filtrate was evaporated at a temperature below 40C
under reduced pressure into 60 ml. To the above solution was added disodium l,l-cyclobutanedicarboxylate (1.54 g :
0.0082 mole) with stirring, and the mixture was subjected to reaction at room temperature for 4 days.
The resulting white crystalline solid was recovered by filtration, washed with water, and dried at 60C under reduced pressure for 3 hours to give as dried product 1.86 g of 1,1-cyclobutanedicarboxylate(2-aminomethylpyrrolidine) ` platinum(II). Yield: 52~, m.p. 235 - 255C (decomposition).
Analysis:
Calcd. for ;CllHlgN2O4Pt: C 30.20, H 4.15, N 6.40 (%) Found: C 30.00, H 4.11, N 6.61 (%) 35IR spectrum: vmax cm 1: 3080 (=NH), 1640, 1660 (,C=O) ~.

~25~15 The obtained dried product was recrystallized from water to give, as the purified product, 1.61 g of 1,1-cyclobutanedicarboxylate(2-aminomethylpyrrolidine)platinum (II) (compound 1). Total yield: ~5%, m.~. 215 - 220C
(decomposition).
Analysis:
Calca. fo CllElgN2O~t: C 30.20, ~ ~.15, N 6.40 (~) Found: C 30.02, H ~.13, N 6.43 (~) IR spectrum: ~max cm~l: 3100, 3190 (,NH), 1590, 1635 (,C=O) Example 2 To a solution of (S)-proline (25 g : 0.22 mole) and sodium hydroxide (8.7 g : 0.22 mole) in 150 ml of water was slowly added a solution of benzylchloroformate (43.5 g :
0.26 mole) and sodium hydroxide (11.6 g : 0.29 mole) in 75 ml of water with stirring under cGoling on ice over 30 minutes, followed by continuing the stirring at the same temperature for 15 minutes. From the reaction mixture, excess benzylchloroformate was removed by extraction with 150 ml of chloroform. The aqueous layer was acidified with 5N hydrochloric acid, and the resulting oily product was extracted with chloroform. After dryng the chloroform layer over magnesium sulfate, chloroform was removed by evapora-tion to give 52.2 g of (S)-l-carbobenzoxypyrrolidine-2-carboxylic acid as oil. Yield: 96%.
To a solution of the resulting (S)-l-carbobenzoxy-pyrrolidine-2-carboxylic acid (52.2 g : 0.21 mole) and triethylamine (21.2 g : 0.21 mole) in 525 ml of chloroform was added isobutyl chloroformate (28.7 g : 0.21 mole) with stirring under cooling on ice, followed by continuing the stirring for 15 minutes. Dried ammonia gas was bubbled into the mixture for 1 hour and then the mixture was allowed to warm to room temperature and stand overnight. The resulting white precipitate was removed by the filtration, and the filtrate was evaporated under reduced pressure. The residue was dissolved in 200 ml of chloroform and was washed with diluted aqueous hydrochloric acid and water, and dried over `` ~256115 magnesium sulfate. Chloroform was distilled off to give 45.8 g of (S)-l-carbobenzoxypyrrolidine-2-carboxamide.
Yield: 88%.
(S)-1-carbobenzoxypyrrolidine-2-carboxamide (45.8 g :
0.18 mole) was dissolved in 400 ml of absolute methanol and catalytically reduced in a usual manner by addition ol 10 g of 10% pallaci~m on charcoal under 2 hydrogen gas s.eam.
After comple_ion o_ the reaction, tne c-talyst was re.Loved and then the solvent was distilled off under reduced pressure. The residue was crystallized from n-hexane and benzene, and washed with n-hexane to give 18.8 g of (S)-pyrrolidine-2-carboxamide as white solid. Yield: 89%, m.p. 85 - 90C.
To a solution of (S)-pyrrolidine-2-carboxamide (18.8 g : 0.16 mole) in ore liter of dried tetrahydrofuran was slowly added lithium aluminum hydride (33.9 g : 0.89 mole) with stirring under cooling on ice, followed by refluxing the mixture for 48 hours. After cooling, the reaction mixture was treated with water and tetrahydrofuran by usual manner to give oil.
This was distilled under reduced pressure to give 6.07 g of (S)-2-aminomethylpyrrolidine as colorless liquid.
Yield: 37%, b.p. 80 - 85C (20 mmHg). [~]D0 + 10.02 (H2O) (S)-2-aminomethylpyrrolidine was lead to (S)-l,l-cyclobutanedicarboxylate(2-aminomethylpyrrolidine)platinu~.
(II) (Compound 2) by the same manner as described in Exa~ple 1. m.p. 240 - 255-C (decomposition).
Analysis:
Calcd. for CllH18~24Pt: C 30-20, H 4.15, N 6.40 (%) 30 Found: C 30.14, H 4.12, N 6.33 (~) IR spectrum: vmax cm~l: 3100, 3190 (,NH), 1590, 1635 (,C=O) [ ]20 + 39 17 (H2O) Example 3 (R)-proline was lead to (R)-2-aminomethylpyrrolidine by the same manner as in Example 2. b.p. 79 - 85C (20 mmHg) [~]D ~ 8.67 (H2O) ~25611~r;

(R)-2-aminomethylpyrrolidine was further lead to (R)-l,l-cyclobutanedicarboxylate(2-aminomethylpyrrolidine) platinum(II) (Compound 3) by the same manner as described in Example 1. m.p. 248 - 257C (decomposition).
Analysis:
Calcd. for CllHlgN2O4Pt: C 30.20, H 4.15, N 6.40 (%) FounG , C 30.0&, E 4.09, N 5.37 (%) IR spectrum: vmax cm~l: 3100, 3190 (,NH), 1590, 1635 (,C=O) [u]D - 40.10 (H2O) Examples 4 - 18 By the method described in Example 1, various com-pounds (Compounds Nos. 4 - 18) shown in Table 1 were prepared.

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Example 19 To a solution of platinum(II)potassium chloride (4.15 g : 0.01 mole) in 60 ml of water was added a solution of 2-aminomethylazetidine (0.86 g : 0.01 mole) in 10 ml of water, and the mixture was stlrred at room temperature for 4 hours. The resulting solid was collec-ed by -iltration, washed wi_h water and dried 2t 60C uncer reduced pressure for 3 hours _o give 2.64 g of dichloro(2-aminomethylazeti-dine)platinum(II) as white solid. Yield: 75%, m.p. 215 -235C (decomposition).
To the suspension of the above product (1.76 g :0.005 mole) in 3 ml of water was added 18 ml of 31% aqueous hydrogen peroxide with stirring at room temperature. The reaction mixture was subjected to reaction at room tempera-ture for 30 minutes and then at 80C for 1 hour. Aftercooling, the resulting solid was collected by filtration, washed with water and dried at 60C under rèduced pressure for 3 hours to give 1.16 g of cis-dichloro-trans-dihydroxy-(2-aminomethylazetidine)platinum(IV) (Compound 19) as light brown solid. Yield: 60%, m.p. 200 - 220C (decomposition).
Analysis:
Calcd. for C4H12C12N2O2Pt: C 12.44, H 3.13, N 7.25 (%) Found: C 12.61, H 3.16, N 7.13 (~) 2-Aminomethylazetidine used in Example 19 as a start-ing compound was prepared by reducing azetidine-2-carboxv-amide in tetrahydrofuran with lithium aluminum hydride.
Examples 20 - 27 By the method as in Example 19, compounds shown in Table 2 as Compounds 20 - 27 were preared.

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X O Lrl ~ I_ E~ Z ~I ~ r~l Experiment 1 Test of in vivo antitumor activity against Colon 26 carcinoma A small piece of Colon 26 tumor (1 - 2 mm3) was subcutaneously implanted in a lateral region of abdomen of a CDFl/Crj strain male mouse (6 weeks old). Four days after the implantation, mice with the almost same size of tumor were divided into groups of 5 - 6 members each, and each mouse was intraperitoneally administered the test cor.pound.
Ten days after the administration, each of the mice was sacrificed, and the tumor was weighed to calculate the growth inhibitory ratio (GIR) by the following equation:
GIR (g) = C - T x 100 wherein C and T represent the mean weishts of tumor of the control group and the treated group, respectively.
The results are shown in Table 3 below. Cisplatin (CDDP) which is a known compound was used as a comparison.

~2~i5 Table 3 : Antitumor Activity against Colon 26 Carcinoma Compound No. Dose (mg/kg) GIR (%) a7 160 died _ 160 died ._ .

3 40 70 160 died . .

. 120 98 160 died 26 .40 68 68o 63 16 died 12~;6~S

Experiment 2 Tests of in vivo antitumor activity against Colon 26 carcinoma A small piece of Colon 26 tumor (1 - 2 mm3) was subcutaneously implanted in a lateral region of abdomen of a CDFl/Crj strain male mouse (7 weeks old). Four days after the implantation, mice with the almost same size of tumor were divided into groups of 5 - 6 members each, and each mouse W2S intraperi.one211y administered the test compound on day 4, 6, and 8 after implantation in a dose of 40 mg/kg one day. Fourteen days after the implantation, each mouse was sacrificed, and the tumor thereof was weighed to calcu-late the GIR (%) by the following equation.
GIR (~) = C C T x 100 where C and T represent the mean weights of tumor of the control group and the group administered ~he test compound, respectively. - -The results are shown in Table 4.
Table 4 : Antitumor Activity against Colon 26 Carcinoma Compound No. CIR (%) 26 _ 85 Experiment 3 Comparison of in vitro binding property of the test compound relative to the plasma proteins A solution of the test compound was added to plasma obtained from SD strain rat at a ratio of 1:19 by volume 12~6~15 which corresponded to 5 ~g/ml of Pt. The mixture was incubated at 37C under dar~. At a predetermined time, the mixture was sampled, and filtered with a molecular sieve membrane (manufactured by ~mico Centriflow PMS) under centrifugation. The Pt content in the filtrate unbound Pt was assayed by an atomic absorption spectrophotometry.
The results are shown in Table 5.
Table 5 : Percent binding to plasma proteins Incubation Time (hr) Compound No.

Experiment 4 Test on side-effects BDFl/Crj strain male mice (6 weeks old) were intra-peritoneally administered the test compound, and 1, 3 and 5 days after the administration, 3 mice were saceificed to determine the body weight and the level of urea nitrogen in blood (abbreviated as BUN).
The resutls are shown in Table 6 below.

~2~ 1S

Table 6 : Body weight and BUN

Items for Dose of the Days after Adminstration measurement Compound (mg/kg) 3 5 Control (-) ¦ 23.6 1.0 23.7+1.4 24.4~1.4 weight (c) COm~2Ound(60) ¦ 23.1 1.4 ¦19.9_1.6** l7~g~ *~
(mean SD) No. 3 (60) 23.4+1.5 ~20.1+1.2**~1i.5+0.7**

CDDP (12) 24.6+1.1 22.55+1.1 19.0+1.5**
Control (-) 17.10 + 4.35 . Compound 20.0+2.6 17.7+3.1 15.4+5.5 BUN (mg/dl) No. 2 (60) (mean SD) Compound .~ L _ _ _ _ _ 13.8+7,.6 CDDP (12) 23.3+4.7* 38.5+28.9 65.2+31.5**
* p < 0.05 ** P < O . 01 Formulation of Pharmaceutical Preparation a) Injection:
An aqueous solution of compound No. 1 prepared in the Example was charged in vials by aseptic manipulation so that each vial contains 50 mg of the compound. The content of each vial was dried and sterilized, and the~vials were sealed. When used as an injection, 10 ml of physiological saline was added to the vial to make up the injection.
Alternately, when used as an intravenous drip infu-sion, the preparation was dissolved in a suitable fluid therapy such as a physiological saline or slucose-saline or the like.
b) Tablet:
Compound No. 1 50 g Lactose 96 g Crystalline cellulose 27 g Corn starch 5 g Magnesium stearate 2 g ~25SllS

The above ingredients were intimately mixed and directly compressed by a tableting machine into tablets having a diameter of 8 mm and weiyhing 180 mg each.

From the results obtained by Experiments l and 2 (Tables 3 and 4), it can be seen that the compounds of this inven.ion exhibited a stronger antitumor activity and are efrective over a broader range of aose level in compzrison with those of CDDP.
In addition, although it is generally considered that a platinum complex is binded with plasma proteins to form an inactive substance, the compound of this invention exhibits a significantly lower binding property with plasma proteins than that of CDDP. The compounds of this invention have reduced toxicity and high water-solubility, and are there-fore useful as an antitumor medicine. --

Claims (32)

The embodiments of the invention in which an exclusive property or privilege are claimed are defined as follows:

1. A platinum complex represented by the formula:

(I) wherein A is alkylene having carbon atoms of from 1 to 3;
R1, R2, R3 and R4 are the same or different and are hydrogen or alkyl having carbon atoms of from 1 to 4; X and Y are independently a halogen atom, or combined together to form ; and ?, m and n are independently 0 or 1, with the proviso that when n is 0, X
and Y do not simultaneously represent a halogen atom.

2. A platinum complex according to Claim 1 wherein said compound is represented by the formula:

wherein R1, R2, R3, R4, X, Y, m and n are as defined above and A' is a direct bond or alkylene having carbon atoms of from 1 to 2.

3. A platinum complex according to Claim 1 wherein said compound is represented by the formula:

wherein R1, R2, R3, R4, X, Y, m and n are as defined above and A' is a direct bond or alkylene having carbon atoms of from 1 to 2.

4. A platinum complex according to Claim 2 wherein n is 0.

5. A platinum complex according to Claim 2 wherein n is 0; X and Y are

6. A platinum complex cccording to Claim 2 wherein n is 0; X and Y are ; and A' is -(CH2)2-.

7. A platinum complex according to Claim 2 wherein n is 0; X and Y are ; and A' is -CH2-.

8. 1,1-Cyclobutanedicarboxylate(2-aminomethy-pyrrolidine)-platinum (II), according to claim 2.

9. 1,1-Cyclobutanedicarboxylate(2-aminomethylazetidine)-platinum(II), according to Claim 2.

10. A platinum complex according to Claim 2 wherein n is 0; X and Y are

11. A platinum complex according to Claim 2 wherein n is 0; X and Y are ; and A' is -(CH2)2-.

12. A platinum complex according to Claim 2 wherein n is 0; X and Y are ; and A' is -CH2-.

13. A platinum complex according to Claim 2 wherein n is 1; and X and Y are a halogen atom.

14. A platinum complex according to Claim 2 wherein n is 1; and X and Y are chlorine.

15. A platinum complex according to Claim 2 wherein n is 1; X and Y are chlorine; and A' is -(CH2)2-.

16. A platinum complex according to Claim 2 wherein n is 1; X and Y are chlorine; and A' is -CH2-.

17. cis-Dichloro-trans-dihydroxy(2-aminomethylpyrroli-dine)platinum(IV), according to Claim 2.

18. cis-Dichloro-trans-dihydroxy(2-aminomethyl-1-ethylpyrrolidine)platinum(IV), according to Claim 2.

19. cis-Dichloro-trans-dihydroxy(2-(1-aminoethyl)pyrroli-dine]platinum(IV), according to Claim 2.

20. cis-Dichloro-trans-dihvdroxy(2-aminomethylaziridine)-piatnum(IV), accoraigs to Claim 2.

21. cis-Dichloro-trans-dihydroxy(2-aminomethyl-1-methylpyrrolidine)platinum(IV), according to Claim 2.

22. cis-Dichloro-trans-dihydroxy(2-aminomethylazetidine)-platinum(IV), according to Claim 2.

23. A platinum complex according to Claim 3 wherein n is 1; and X and Y are a halogen atom.

24. A platinum complex according to Claim 3 wherein n is 1; and X and Y are chlorine.

25. A platinum complex according to Claim 3 wherein A' is -CH2-.

26. cis-Dichloro-trans-dihydroxy[1-(2-aminoethyl)pyrroli-dine]platinum(IV), according to Claim 3.

27. A process for preparing a platinum complex repre-sented by the formula:

wherein A is alkylene having carbon atoms of from 1 to 3;
R1, R2, R3 and R4 are the same or different and are hydrogen or alkyl having carbon atoms of from 1 to 4; X and Y are independently a halogen atom, or combined together to form or ; and Q, m and n are independently 0 or 1, with the proviso that when n is 0, X and Y do not simultaneously represent a halogen atom, which comprises reacting a diamine derivative of the formula:

wherein A, R1, R2, R3, R4, .alpha. and m are as defined above with platinum(II)potassium chloride to form the corresponding dichloro compound; and (a) oxidizing the dichloro compound with hydrogen peroxide or (b) converting the dichloro compound into the corresponding dinitrate with silver nitrate and then reacting the dinitrate compound with a dicarboxylic acid.

28. A process according to Claim 27 wherein said diamine derivative is reacted with an equimolar of platinum(II)-potassium chloride in an aqueous medium at 0 - 100°C for 4 hours to 3 days.

29. A process according to Claim 27 wherein said dichloro compound is reacted with excess of hydrogen peroxide in an aqueous medium at 0 to 100°C for 0.5 - 10 hours.

30. A process according to Claim 27 wherein said dichloro compound is reacted with twice molar of silver nitrate in an aqueous medium at 1 - 30°C for 1 day to 1 week.

31. A process according to Claim 27 wherein said dinitrate compound is reacted with an aquimolar of dicarboxylic acid in an aqueous medium at 1 - 30°C for 1 hour to 1 week.

32. A process according to Claim 31 wherein said dicarboxylic acid is selected from the group consisting of oxalic acid, 1,1-cyclobutanedicarboxylic acid and the salts thereof.