FR2459247A1 - PLATINUM (II) AMINE CIS-ASCORBATE COMPLEX - Google Patents

Abstract

PLATINUM II ASCORBATE COMPLEX COORDINATED WITH AMMONIA OR WITH MONODENT OR BIDENT AMINE LIGANDS IN A CIS CONFIGURATION REPRESENTED BY THE GENERAL FORMULA: CIS-PT (II) A (X) (OH) IN WHICH IS AMMONIA OR A MONODENT LIGAND ALCOYLAMINE; A IS A LIGAND AMINE BIDENTE; X IS THE ASCORBATE PORTION; M VA FROM 1 TO 2 AND N VA FROM 1 TO 0 AND THE SUM OF MN IS NOT GREATER THAN 2. THE COMPOUNDS ARE CHARACTERIZED BY PROPOSED ANTI-TUMOR ACTIVITY, HIGH SOLUBILITY IN WATER AND LOW TOXICITY TO ANIMALS .

Description

The present invention relates to

  platinum (II) ascorbate complexes coordinated with

  monodentate or bidentate amine ligands in a configu-

  which are characterized by a

  against tumors and low toxicity to

animals.

  - Figure 1 is a reproduction of the

  infrared complex of diammine-cis-ascorbate complex

tine (II) of Example I.

  - Figure 2 is a reproduction of the

  ultraviolet light of the diammin cis-ascorbate complex

platinum (II of Example I.

  FIG. 3 is a reproduction of the

  nuclear magnetic resonance of the goose complex

  platinum-II (platinum) ascorbate of Example I.

  - Figure 4 is a reproduction of the

  infrared bis-cis-ascorbate complex (methyl-

amine) platinum (II) of Example IV.

  - Figure 5 is a reproduction of the

  nuclear magnetic resonance of the cis-complex

  Bis (methylamine) platinum (II) ascorbate of Example IV.

  FIG. 6 is a reproduction of the

  infrared of the ethylenediamine ascorbate complex

  Platinum (II) of Example V. p - Figure 7 is a reproduction of the nuclear magnetic resonance spectrum of the ethylenediamine platinum (II) ascorbate complex of Example V. - Figure 8 is a reproduction of the infrared spectrum of diaminocyclohexa- ascorbate

neplatin (II) of Example VI.

  In 1968, Rosenberg and Van Camp discovered

  green that the cis-Ot (NiH3) 2C12-7 compound exhibited excellent anti-tumor activity against Sarcoma

  180 solid (S180s) in the Swiss white mouse.

  (Rosenberg and Van Camp, Nature, 222, 385 (1969).) This discovery has led to extensive testing with platinum and other transition metal compounds for tumor activity in humans.

  animals (for example, Cleare, Coordination Chemis-

  try Reviews, 12, 349 (1974); and Connors and Roberts,

  ed., Platinum Coordination Complexes in Cancer Chemo-

  Theran, Springer, New York (1974). Neutral cis-tA2X2_7 species which have proved particularly active against animal tumors are generally not very soluble in water. (J.L. Marx, Science, 192, 774 (1976)). Cleare and Hoeschele indicate solubilities in water or saline

  at 37 ° C between 0.04 g / 100 cm3 for Lt (NH) 2 (usually

  lonate7 and 1.38 g / 100 cm3 for LOt (CH3NH2) 2Cl2.

  (Cleare and Hoeschele, Bioinorganic Chemistry, 2, 187

  (1973)). The relatively low solubilities reduce much

  the utility for oral or intra-

  Venous. According to the present invention, there are novel platinum (II) amine ascorbate compounds which exhibit excellent activity against the Sarcoma 180 ascites tumor (S180a) in mice. In addition, they

  have low toxicity to mammals. He is

  The compounds according to the present invention have advantageous therapeutic indices. In addition,

  except for diaminocyclohexane ascorbates

  tine (II), they are very soluble in water, their so-

  lubility being greater than 10 g / 100 cm3 of water.

  The platinum amine ascorbates (II) according to the present invention may be represented by the general formula cis-T> (II) A2 (Xa (OH4-7 (I) wherein A is ammonia (Nm3) or an amine ligand monodentate represented by the formula RNH2; R is hydrogen or a lower alkyl group; A2 is a diaminde bidentate ligand; X is the ascorbate moiety; m is a number having a value of I to 2; n is a number having a value of 0 to 1 and the sum of n + m is not greater than 2. Indices m and n can have fractional values between their

  respective limits, in which case formula (I) represents

  will be a mixture of individual complexes. Whenever the term compound or complex is used for

  designate the product of the present invention, this

  globe the individual complexes as well as their mixtures. The monodentate amine ligands represented by the formula RNE3 include ammonia (NH3) as well as monoalkyl amines having up to 6 atoms

  carbon in the alkyl group, such as methylamines

  ne, ethylamine, propylamine, isopropylamine, hexylamine, etc. Among the alkylamines, it is preferred

  those with up to 3 carbon atoms.

  The amine bidentate ligands represented by A2 may be further represented by the formula R.sub.1 R.sub.2 Xo-8H-8E-M2 (II) in which R.sub.2 and R.sub.2, when taken separately,

  are each hydrogen or a lower alkyl group

  laughing; and RI and R2, when taken together

the divalent radical:

R3 R4R5 R6

* I / I I!

-CO-OE-OH-O-

  o each of R3 to R6, when taken separately,

  is hydrogen or a lower alkyl group,

  a 1,2-diaminocyclohexane ligand as represented

by the formula

4 5

15. R3-CH C R6

- yH- <(III)

H2N NH2

  By the term "lower alkyl group" as used herein is meant a linear or branched chain alkyl group having from 1 to about 6 carbon atoms, and preferably from 1 to about 3 carbon atoms.

  carbon, such as methyl, ethyl, propyl.

  Diamines in which at least one is preferred

  R1 and R2 are hydrogen, like ethyl

  linediamine and propylene-1,2-diamine. The diamines in which R1 and R2, when taken together, are replaced by the radical are also preferred:

R3 R4 R5 R6

1 1 i.

-CH-CH-OH-HI-

  the groups R3 to R6 are each hydrogen,

  that is, 1,2-diaminocyclohexane.

Z459247

  The ascorbate portion is derived from

  ascorbic acid, which may be represented by the formula:

HOH2C- {CH S (IV)

HO OH

  in which the carbon atoms carrying the numbers

  ros 4 and 5 are optically active. So there are four

  active isomers of ascorbic acid. The ascending portion

  The complex of the present invention may be derived from any of the individual isomers, or a mixture of any two or a larger one.

many of them.

  When m in formula (1) above is

  1 and n is O, the ascorbate portion is a di-portion

  which is formed by removing a hydrogen from each of the hydroxyl groups at the 0-2 and 0-3 positions of the furanone ring. When m is 1 or 2 and n is

  1 or 0, the ascorbate portion is a mono-

  slow which is probably formed by kidnapping a

  hydroxyl group hydrogen bonded to 0-3. As a result

  tat, platinum is most likely related to the serving

Ascorbate 0-3.

  The compounds according to the present invention are prepared by bringing an aqueous medium into contact with a salt.

  ascorbate with a "diaquo" salt of amine platinum (II)

  represented by the formula: ## STR3 ## wherein A and A2 are as defined above, Z is an inorganic anion and u is a number having value of 0 or 1. Usable anions are those

  which are stable in acidic environments; they understand

  take the sulphate, nitrate and perchlorate anions, but nitrate is preferred. Anions with a higher complexing capacity than water or lactate, such as chloride, bromide and iodide anions

are not usable.

  The "diaquo" salt is formed by the stoichiometric reaction of a cis-diamine platinum (II) dichloride with a silver salt, preferably nitrate

  of silver, in an aqueous medium at room temperature

  ature. Although room temperature is preferred

  For the reaction, temperature can be used

  higher or lower, for example between about C 000 and about 50 0. "Diaquo" salt is unstable in solution, and thus freshly prepared solutions should be used. Alternatively, the "diaquo" salt can be converted to stable cis-JtA 2 (OH 2 O 2 (NO 3) 2 by reaction with one mole of base per gram atom of platinum The dimer complex can be converted back into a monomer with acid or used

  directly in the preparation of ascorbates.

  The ascorbates that are used are water-soluble salts, preferably alkali metal ascorbates such as sodium or potassium ascorbate. The ascorbate is present in the starting reaction mixture in molar excess, that is to say that the molar ratio of ascorbate to salt "diaquo"

  is greater than 1: 1, and is usually included in

  and preferably about 2 moles of ascorbate per gram atom of platinum. The

  preferred proportion may vary, however, between

  1.8 and about 2.2 moles of ascorbate per

  gram of platinum. The concentration of bodies in reaction

  in the aqueous medium does not present a large

  of importance; however, it is preferred that the model

  the reaction medium is about 0.2,

  that is, from about 0.1 to about 0.3

  as regards platinum. The aqueous mixture of the amine diaquo salt and ascorbate is stirred at room temperature for a period of time sufficient to form the compounds of the present invention. If you wish,

  temperatures above or below

  below the ambient temperature, for example

  between about 0 ° and about 30 ° C. The period

  reaction time can vary from a few minutes to

  several hours. At room temperature, the solution becomes a bright yellow after about 15 minutes,

  and then it darkens slowly, turning brown

  yellow after about 8 hours and black after about 24 hours. The solution is constantly acidic, the pH being

  approximately 4.9 at the beginning and falling to a level of

  4.0 to about 4.1, after about an hour, after which it remains substantially constant. The ratio of ascorbate to platinum (after precipitation by 9 volumes of methanol) appears to increase to a maximum of about 2.1: 1 in about 2 hours, after which the ratio decreases. If we use

  reaction lasting more than 7 hours, a decomposition

  PtA2 mesh appears to be starting.

  The ascorbate according to the present invention is recovered from the reaction medium by any suitable technique, preferably precipitation from the solution by means of a non-solvent for the complex, followed by filtration and filtration. drying the precipitate. Alcohols such as ethanol are preferred. When ethanol is used, the composition of the product is influenced by the amount of ethanol used. So the ratio of ascorbate

  platinum increases when the amount of ethanol increases

  from about 3 times to about 6 times the volume of

  reaction mixture. Additional increases

  the amount of ethanol above 6 reaction volumes lead to a reduction in the ratio of

  the ascorbate portion to the platinum portion.

  The exact structure of the ascending complexes

  platinum (II) amine bate according to the present invention

  has not been established with certainty. However,

  that the products obtained as described above

  include a mixture of at least two of the three

  species represented by foxmules:!

CH20H. -H2011

  Hu OCHOH H 0PtA2 tA2 CH OH 4NPFOH tA Separation of individual species is not possible because the compounds decompose sufficiently

  quickly in aqueous solution. Mixtures have typically

  only a ratio of ascorbate to platinum included a459247

  between about 1.2: 1 and about 1.5: 1.

  The infrared spectra of the compounds

  the present invention possess the characteristics

  common areas: 30 m11) Wide straps and shoulders

> 3000 cm-1, due to A NEet 0H.

  2) An intense band at 1720-1730 cm, due to O = O of ascorbate. (This tape is present

  at 1700 cm -1 in sodium ascorbate).

  3) An intense wide band at 1600 cm 1,

due to the curvature of NH2.

  4) Bands at 1140, 1100, 1030, 960 and 930 cm 1, which are thought to be due to C ^ -0 bands

and 7-10 ascorbate.

  The compounds of the present invention are of particular utility in tumor chemotherapy in mammals, having proved

  active against S180a and L1210 in mice. The com

  are administered in the form of aqueous solutions or aqueous slurries. In general, they are active at doses of about

  mg / kg and about 200 mg / kg. The maximum activity is

  for the different compounds, and ranges from about 30 mg / kg for the ethylene-diamine derivative at doses as high as 320 mg / kg for diammine. BDans

  where a toxic dose has been reached, with ethyl-

  nediamine, the maximum effective dose was about a quarter or less of the toxic dose. This represents a clear improvement over cisgt (IaH3) 2012_7, which, with the same determination method, presents

  a maximum activity at 8-10 mg / kg with a toxic dose

  than 16 mg / kg. A greater difference between the effective dose and the toxic dose is preferred by

E459247

  clinicians because it gives a bigger margin

of security.

  The following examples illustrate the

this invention.

E XZMPhE I -

  Synthesis of diamminplatin (II) cis-ascorbate

  A 0.6 M solution of cis-

  Zt (IE3) 2 (H2O) 2 (N03) 2 by the stoichiometric reaction

  (11H) 2C12 7 with silver nitrate in aqueous medium at room temperature. We add

  cm3 of the solution prepared to a

  2.37 g of sodium ascorbate in 10 cm3 of water. The resulting mixture is stirred for 2 hours

  at room temperature, a yellow color is

  progressively evolving. 200 cm3 of ethanol is added

  and the mixture is stirred for a further 2 hours.

  in the air and is then refrigerated overnight. The solid brown-yellow product that has

  formed is filtered off and washed with ethanol.

  It is dissolved in 20 cm3 of water and the solution is slowly added to 200 cm3 of ethanol, with stirring. After

  keeping overnight in a refrigerator, the

  yellow duit is separated by filtration, washed with ethanol

  and dried under vacuum at room temperature to give

  1.06 g of the cis-ascorbate complex of diamminplati-

  ne (II). This procedure is repeated three times

  to obtain additional samples of the cis-

diamminplatin ascorbate (II).

  Analysis:% a) ç N 5w N / Pt C / Pt Found:

Echantil-

on 1 18.73 2.74 5.44

"2 19.00 2.63 5.27 33.99 2.16 9.08

"3 19.21 2.78 5.81 37.75 2.14 8.26

  n 4 20.37 2.81 5.54 39.45 1.96 8.40 Calculated: 18.95 2.65 4.91 34.21 2 9 Pt (NO3) 2C99O14 *

  * Determined using ratios in numbers

  third of platinum carbon corresponding best

to the observed results.

  The infrared spectrum of the cis-complex

  diammine platinum ascorbate (II) thus prepared, which is reproduced in FIG. 1, is characterized by the

following absorption bands.

  Absorption band, Identification Nuiol paste 3450 sh (N shi E 3300 br. 1730 m 1660 m O = 0 1610 s J 1310 sh 2 1100 sh 1070 s CC * 1030 at 1'to 960 m 930 w 860 w 820 w 760 sh 610 m Pt-N ah = shoulder, s = strong, m mean, w = weak;

br = large.

  The ultraviolet spectrum of an aqueous solution of the complex (molarity 2 × 10-4 in platinum) is reproduced in FIG. 2 and the resonance spectrum

  nuclear magnetic is reproduced in Figure 3.

- EXAMPLE II -

  The procedure of the Example is repeated

  I, except that the amount of ethanol used

  Precipitation is modified and 2 to 9 times the volume of the reaction solution is used. of the

  analyzes of diamminplatin (II) cis-ascorbates

  sultants are summarized as follows:

exchanged

  II-A II-B II-O II-D II-E Volumes of ethanol per volume of reaction mixture Product analysis * 38.02, 85 34.50 39.45 Ascorbate / Pt 1.12 1.26 1.55 1.20

  * Insignificant amount of precipitation.

- EXAMPLE III -

  The procedure described in Example I is repeated, except that the reaction time is varied from 1 to 7 hours and 9 volumes are used.

  ethanol to precipitate diammine cis-ascorbate

  platinum (II). The product analyzes are summarized as follows:

ú459247

  Reaction time, Product analysis hours% t Ascorbate / Pt N / Pt C / Pt

I 40.44 1.14 1.99 8.40

2 39.45 1.20 1.96 8.40

4 40.27 - * 1988 8.22

7 42.99 1.02 1.82 7.38

  * Sample too small for determination.

- -

  Synthesis of bis (methylamine) platinum (II) cis-ascorbate 1.065 g of cis-Zt (OH 3 NE 2) 2 ClO 2 7 are suspended in 40 cm 3 of water and 1.10 g of solid AgNO 3 (Ag: Pt = 2: 1). The mixture is stirred at room temperature for 3 hours, protected from light. After filtering the AgO1 and checking with KO1 that there was no more silver, 1.29 g of sodium ascorbate (ascorbate: Pt = 2: 1) was added to the filtrate. and stirred for 2 hours at room temperature. When no more precipitates occur when ethanol is added, all the solvents are removed under vacuum at 30 ° C. The resulting yellow solid is slurried in ethanol, separated by filtration and

  washed with ethanol and then dissolved in 5 cm3 of water.

  The aqueous solution is added to 200 cm3 of ethanol,

  stirring. After stirring for 30 minutes at

  At room temperature and refrigeration overnight, the pale yellow solid product is filtered off, washed with ethanol and dried under vacuum to give 0.42 g of bis (metbylamine) platinum (II) cis-ascorbate. The product is hydroscopic and breaks down when it is

exposed to light.

ú459247

  Analysis: Calculated: Pt (CH3MH2) 2 (SH8011) * C, 22.35%; H, 3.37%; N, 5.21% Found C, 23.11%; H 3.4 (/ o; N 5.08% * Empirical formula The infrared spectrum of this product is

  reproduced in Figure 4. The identifications of the

  The majors are as follows: Absorbency band Nujol paste 3400 shi 3240 br> 3150 sh 1720 s Identification -? eC 1600 s E2 1350 sh 1140 11m 1100m 1030s 970m 920w 3C-CC -0 860w 820w 750w

  The magnetic resonance spectrum

  Cluster of cis-ascorbate complex of bis (methylamine) -

  platinum (II) is reproduced in FIG.

- EXKLE 5 -

  Synthesis of Ethylenediamine Platinum (II) Ascorbate A 0.25 M solution of (H 2) (H 2 O) 2 (NO 3) 2 is prepared by the stoichiometric reaction.

ú459247

  of C122 with silver nitrate in aqueous medium at room temperature. 48 cm3 of the frankly prepared solution is added to a solution of 4.74 g of sodium ascorbate in 12 cm3 of water. The mixture turns pale green very rapidly, then gradually to yellow after stirring for 2 hours at room temperature. 400 cm3 of ethanol are added.

  and the mixture is stirred for a further 2 hours.

  Then he is put in the refrigerator all night.

* The pale yellow product is separated by filtration, washed with ethanol and redissolved in 40 cm3 of water. After

  filtration for removal of the white matter

  soluble, the solution is added to 400 cm3 of ethanol,

  it is stirred for 2 hours and left to refrigerate.

  manager all night. The cream-colored product is separated by filtration, washed with ethanol and dried

  under vacuum to give 1.12 g of ethylene ascorbate

diamineplatinum (II) solid.

  Analysis: Calculated: Pt (en) C0O9011) * C, 24.09%; H, 3.12e; N, 5.11%; Pt 35.57% Found: 0, 23.59%; H 3.02%; N, 5.38%; Pt 35.44% * Empirical formula (en = ethylenediamine) The infrared spectrum of cis-ascorbate

  Ethylenediamineplatinum (II) is reproduced in FIG.

  6. The identifications of the major bands are

  summed up as follows: a459247 Absorption band, Nulol pulp 5400 sh 3230 br 3140 sh J 1720 s 1610 br 1300 sh 1040 s 960 w 920 w 870 m 810 w 750 sh 650w l 520 w J The plex resonance spectrum is reproduced sure

- EXJELE VI -

  Ascorbate synthesis Ident ificati on

9EH -JO

9C = 0 o RH2 a% - O-2 ko-O

Nuclear Magnetic

Figure 7.

  diaminocyclohexaneplatinum (II) A 0.2M solution of

  X t (DACHXN) (H 2 O) 2 - (NO 3) 2 by the stoichiometric reaction

  gt (DACnN) c12_ with silver nitrate in aqueous medium at room temperature. 1.58 g of sodium ascorbate is added directly to 20 cm 3 of the freshly prepared solution. A small amount of insoluble dark matter is separated by filtration

  and 200 cm3 of ethanol are added. After agitation

  one hour and keeping refrigerated

  overnight, the yellow product is filtered off, washed with ethanol and dried under vacuum to

& 459 247

  give 0.18 g of diaminocyclohexane ascorbate

  tine (II). Calculated: Pt (DACHXN) (C7H809) * C, 28.62%; E, 4.06%; N, 5.13% Found: C, 28.63%; H, 3.72%; N, 4.98%. * Empirical formula (DACIN = 1,2diaminocyclohexane) The infrared spectrum of the complex is reproduced in FIG. 8. The identifications of the major bands are summarized as follows: Absorption band, Nujol labeling 3400 ehi H 3240 br NH, 0OH 3130 sh 1720 s' = C0 1610 to 1350 sh 1150 m 1100 m 1060 m 1030 m 970 sh 920 sh 860 w 820 w 750 sh o N2 ô 2 NE2 CC C-0

EXAMPLE VII

  Evaluation of anti-tumor compounds against S180a with respect to activity The compounds are evaluated as follows in

  anti-tumor activity against ascites

  S180 in female Swiss CFW mice.

  CFW mice, weighing an average of 20 g, are subjected to immediate examination and placed in newly prepared cages. On day zero, the mice are inoculated with 0.2 cm 3 of a freshly prepared saline suspension (0.15 M NaCl) containing 1 × 10 7 tumor cells per cm 3, or a total of 2 × 10 6 cells. This

  inoculum is frankly prepared using

  "transfer" to which cells have been injected

  tumors the week before. This inoculum is the end product of a series of steps including (1)

  the removal of the cells from the peri-

  sacrificial transfer mouse, (2) alternating centrifugation and washing

  (2-3 times with cold saline solution) to eliminate

  to destroy blood and other undesirable constituents

  presently and finally (3) the dilution (1: 3) of the packed cell mass with saline solution (the final centrifugation being carried out at 1000 rpm for 2 minutes). A cell count is made on a diluted sample at the 2000 coefficient of this 1: 3 suspension by means of a Coulter Counter. Final dilution is made at 1 x 107

  cells per cm3 based on the average result of the count.

  By day 1, solutions of the compounds tested are preferably

  parried and injected to the mice, each mouse of a group

  pe of four receiving the same compound at the same level

dosing.

  In addition, on this same day, two types of controls (6 mice per group) were used: (1) normal controls (1 group): 0.5 cc of the medium used as a solvent for the test compound, and (2) positive controls (1 group): a known anti-tumor agent cis- / Pt (NH3) 2

  C12_7 in saline at 8 mg / kg, used to determine

  undermine the response of the biological system.

  The effectiveness of a compound is measured by the increase in the survival time of the experimental animals compared with the controls (from

  the day of tumor inoculation (day zero).

  To standardize the results of the trials and allow for comparisons between them, the day of the assessment is arbitrarily chosen as the day corresponding to twice the average survival time (or the average number of days before death) of the tests. normal witnesses. This results in an upper limit

  10IPo practice for% ILS that can be obtained.

  For calculation, surviving mice on the day of

  the assessment are considered dying that day.

The% ILS is the following quantity:

of experi-

  % ILS mean survival time of the mice mentation-1)% average survival time of the control mice x10%

  ILS values of more than 50% represent

  feel a significant activity; those above

  % represent an excellent activity.

  The soluble comolexes of ammine,

  thylamine and ethylene-diamine are administered under

  the form of aqueous solutions. The diamino complex

  water-insoluble cyclohexane is administered in the form of an aqueous slurry. The concentration for a given dose can be calculated as follows Concentration for a given dose (in

mg / cm3) - 0.04 x (Dose in mg / kg).

  Results of preselection tests concerning the antitumor activity of cis-gtA2 (ascorbate) compounds are summarized as follows: Test results of t4A-α, (ascorbate) anti-tumor preselection for compounds against the anti-tumor system. Ascites tumor S180 Compound Medium

Example I H20

(A = NH3)

  Do sea (mg / kg): LS Surviving mice on Day 30 1/4 4/4 3/4 2/4% ILS Positive witnesses Surviving mice on day30 2/6

Example I

(say again)

(A = EH3)

Ex. II-D H20

(ANE3)

Ex. IV

(A = CH3NE2

  Ex. V 3/6 0/6 2/6 H20 2/4 4/4 4/4 3/4 0/4 0/4 3/4 4/4 3/4 3/4 0/4 0/4 1 / 4 1/4. 3/4 H20 H20 3/6

/ ......

you * b V'I

  Results of anti-tumor preselection for compounds.

  Ais (ascorbate) 7 against the Ascite S18 tumor system (continued) Cornpos6 Lllieu Dosea our positive controls Postiitab / k''..L (a & / kg) LS on day 30, surviving mice (2 = in ) 60 76 3/4

49 1/4

  Example VI H20 25 72 2/4 69 3/6 (A2 = DACEXN) boil 50 99 2/4 binds 100 91 3/4

100 4/4

r) -to%

  4 mice per dose for diamine platinum (II) cis-ascorbates.

  b Positive Controls: 8 mg / kg cis-Pt (NH3) 2C12 in saline.

  As is evident from the foregoing, all compounds exhibit excellent activity against the S180a tumor system in

  mice, and all are effective in a range of

  from about 25 to about 200 mg / kg; only the complex of ethylenediamine proves to be toxic in the intervals tested, and only when one reaches

a dose of 240 mg / kg.

EXAMPLE VIII

  Evaluation of the anti-tumor activity of the derivative of

  diammine according to the present invention against the system

me L1210 in the mouse. The activity of the diammin derivative according to the present invention is also determined.

  (Example I) against L1210 lymphoid leukemia in mice, determining the mean survival time compared to control (T / C) mice. The quantity T / 0 * is calculated as follows / C * Average survival time (test)) 100 Average survival time (control) x

  T / C values of 125 or more represent

  feel a notable activity. The results of these

essays are summarized below.

  * T / C is related to% ILS as follows: T / C-100 =% ILS. Determination of anti-tumor activity of the cis-asoorbate compound of diammineplatinum (II) (Example I) against the L1210 tumor system Dosea o / C Toxicity (mg / kg) Surviving mice (, g / kg) on, day Tb 3/6

168 6/6

127 6/6

20 108 6/6

103 6/6

108 6/6

  Dosage regimen - Doses on days 1, 5 and 9 b T = toxic according to NOI criteria (Geran et al., "Protocols for Screening Chemical Agents and

  Natural Products against Tumors and Other Bio-

  logical Systems "(3rd edition), Cancer Chemo-

  Therapy Reports, Part 3, Summer 1972).

  An excellent activity (T / C - 168) is

  observed at a level of 80 mg / kg and a

  (T / O - 127) is observed at 40 mg / kg. Maximum activity is found in the same assay range as with the S180a tumor system. These results compare favorably with those obtained with cis-Ot (NH3) 2012_7, which gives a maximum T / C of 152 mg / kg using the same dosing regimen.

days 1, 5 and 9.

Claims (9)

  1) A cis-ascorbate compound of diamine   tine (II) represented by the general formula; cis / t (II) A2 (x) m (OH) y wherein Pt is in the valence state II and is coordinated with A in a cis configuration; A is ammonia or a monodentate alkylamino ligand;   A2 is a bidentate amine ligand; I is the portion   corbate; m is a number having a value of 1 to 2;   n is a number with a value of 0 & 1, and the sum   me of m + n is not superior & 2.   2) A compound according to claim 1, characterized in that A has the formula RNH2 and R is   selected from hydrogen and a lower alkyl group.   3) A compound according to claim 2,   characterized in that R is hydrogen.   4) A compound according to claim 2,   characterized in that R is a lower alkyl group   laughing. 5) A compound according to claim 4,   characterized in that R is a methyl group.   6) A compound according to claim 1,   characterized in that A2 is represented by the mule: R1 R2 H2N - - CH - NH2   in which R1 and R2, when taken separately,   are each selected from hydrogen and a group   lower coyle; and R1 and R2, when they are caught   seem, form the divalent radical: R3 R4 R5 R6 I! he - CH - cH - CH - cH -   each R 3 R 6, when taken separately, is hydrogen or a lower alkyl group, yielding a 1,2-diaminocyclohexane represented by the formula: R3-CH 1CH-R6 H-CH H2N NH2   67) A compound according to claim 6, characterized in that R and R are each of hydrogen.   8) A compound according to claim 6, characterized in that the groups R3 to R6 are each hydrogen.   9) As a drug useful in particular for the treatment of malignant tumors in a mammal   who has it, a compound according to one of the dications 1 & 8.   10) A pharmaceutical composition containing   as an active ingredient a compound according to one of Claims 1 to 8.