FR2534907A1 - DIAMINE-PLATIN COMPLEXES, PROCESS FOR THEIR PREPARATION, PROCESS FOR THE PREPARATION OF A MEDICINAL COMPOSITION USING SUCH PLATINUM DIAMINE COMPLEX FOR THE TREATMENT OF CANCER AND THE COMPOSITION THUS FORMED - Google Patents

Abstract

THIS INVENTION CONCERNS NEW PLATINUM COMPOUNDS, CHARACTERIZED BY THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R AND R ARE BOTH AN ETHYL OR, TOGETHER WITH THE CARBON ATOM TO WHICH THEY ARE BOUND, A CYCLOHEXYL GROUP, R AND R ARE BOTH A HYDROGEN ATOM AND X IS A MALONATE GROUP, AN ETHYLMALONATE GROUP, A HYDROXYMALONATE GROUP, A CARBOXYPHTHALATE GROUP, A BIS-CHLOROACETATE GROUP, A CYCLOBICTARBOX-DINBOX, OR 1,1-DINBOX GROUP AN OXALATE GROUP OR SODIUM SALT OF THESE GROUPS.

Description

2534907-

  The invention relates to novel platinum diamine complexes and a pharmaceutical composition using this diamine platinum complex for the treatment of cancer, for example

  malignant and malignant tumors, as well as a composition

  known thanks to this process. Such platinum diamine complexes are known from the article by AP Zipp and SG Zlpp, J Chem Ed, 54 (12), (1977), which describes the application of cis-diaminodichloride-platinum (PDD) for the treatment of cancer It is mentioned that platinum compounds offer a broad spectrum of activity as antitumor agents but that they also have serious drawbacks, in particular being toxic towards the kidneys, as a method of neutralization. toxicity to the kidneys, a cis-diaminodichloride

  platinum in combination with another substance or is administered

  with a large amount of liquid or other techniques to ensure proper kidney irrigation A number of other platinum amine complexes are known, including compounds of Formula 2

2 u of the formula sheet.

  Wadley Medical Builetin, vol 7, No. 1, p 114-134 discloses a large number of platinum diamine complexes, including the

  platinum cis-diaiminodichloride, for the treatment of cancer.

  Here too, toxlcitis with respect to the kidneys is reported as

  the most important disadvantage of these compounds.

  Chem and Eng News of June 6, 1977, p 29-30 also describes

  Platinum cis-diaminochloride and its application for the treatment of cancer Toxicity to the kidneys is also mentioned as the most important disadvantage

of these compounds.

  In an article published in Canzer Chemotherapy Reports patic I, vol 39, No. 3, May / June 1975, p 629-641, it is reported

  also the toxicity to the kidneys of cis-diaminodichloro

  platinum chloride II Due to the toxicity of PDD

  kidneys and its weak therapeutic indication, we have

  other platinum complexes for the treatment of cancer.

  For this purpose, combinations of platinum cis-diaminodichloride

  Tine (II) with other chemotherapeutic agents were examined; new platinum complexes have also been tested but have proved to be toxic. It has been found, for example, that although platinum (II) cisdichloro-biscyclopentylamine is only slightly toxic to the kidneys, it is toxic to the spleen The so-called "platinum blues", a mixture of different amounts of five or more inseparable constituents, have also been

  described about cancer treatment.

  Dutch patent applications 73 04880; 73 04881; Nos. 04882 and 77 03752 disclose a large number of diamine platinum complexes, especially the compound of formula 2 of the formula sheet.

  nucleus, the nitrogen atoms are directly attached to the nucleus.

  The compounds of the first three Dutch applications were compared to platinum cis-diamino dichloride and found to produce better effects. None of the patent applications discloses anything about the

toxicity to the kidneys.

  In the Dutch patent application 79004740 are described platinum diamine complexes which are characterized by formula 1 of the sheet of formulas, wherein R and R 2 are, independently of one another, a hydrogen atom

  or an alkyl, cycloalkyl, aryl or aralkyl group

  substituted and unsubstituted, while R and R 2 may be

  appears a substituted or unsubstituted cycloalkyl group, R 3

  and R 4 are, independently of one another, a hydrogen atom

  gene or substituted alkyl, aryl or aralkyl group or

  unsubstituted and X is an anionic group.

  New diamine diamine complexes have now been found.

  which are characterized by formula 1 of the formula sheet, wherein R 1 and R 2 are both ethyl or together

  with the carbon atom to which they are linked, a cyclo-

  hexyl, R 3 and R 4 are both hydrogen and X is

  a malonate group, an ethyl malonate group, a hydro-

  xymalonate, a carboxyphthalate group, a bis-chloro

  acetate, a cyclobutane-1,1-dicarboxylate group, a dinitrate group, an oxalate group or a sodium salt of one of

these groups.

  The invention furthermore relates to a method for preparing

  of these compounds in a manner known per se, a process for the preparation of a medical composition in which these compounds are used as the active substance, and

  as the shaped medical composition thus obtained.

  An in-depth research program carried out by

  Cancer Institute, Bethesda, U S A and the Organiza-

  European Commission for Research on 11 Cancer Treatment, Brussels, Belgium, has shown that compliant

  this invention exhibit a high therapeutic activity.

  against platinum complexes so far known and used in practice for the fight against

  against cancer, such as platinum cis-diaminodichloride

  tine (PDD); it also appears that the compounds according to the invention have little or no toxicity towards the kidneys. As shown by the therapeutic activity values shown in Table A, the novel compounds show significant antitumor activity against a large number of patients.

  different types of tumors such as lymphocytic leukemia

  P 388 (PS), lymphoid leukemia L-1210 (LE),

  dymoblastoma and melanocarcinoma B 16 (B 1) The tea activity

  of the new related compounds is greater than

  that of platinum cis-diaminodichloride (PDD) which is used

  as an experimental clinical chemotherapeutic agent.

  A very serious drawback of the DP used in the

  as well as all other platinum II complexes endowed with anticancer activity and known hitherto (with the exception of those described in the patent application

  79 04740) is, as already mentioned, the high toxicity

  of these compounds whose toxicity to the kidneys is the most dangerous and in fact limits the dose that may be

used in practice.

  Surprisingly, the compounds according to the invention

  do not have harmful side effects on the kidneys.

  This has been proven by means of histological research on

  rats after treatment with toxic doses of

  poses described below while in a similar study

  with PDD serious damage to the kidneys has been observed.

  The new complexes have no harmful effect on

  kidney activity An important method generally

  known for the determination of toxicity to the kidneys consists of the evaluation of the percentage of urea nitrogen in the blood (blood urea nitrogen, BUN), also designated

  as non-protein nitrogen (non-protein nitrogen, NPN).

  It also appears that the compounds according to the invention

  have no single effect on blood urea nitrogen levels. For both LD 10 and LD 50 doses, BUN levels are On the other hand, the PDD compound already produced LD 10 dose, after the indicated times, a quadruple increase in urea nitrogen, while at an LD 50 dose it is increased by one

factor of not less than 11.

TABLE A

  Anticancer activity in mice bc Compound mouse code tumor dose / injection T / C mg / kg (%) formula 4 06 LE 36.00 246 LE / cis-PDD 24.00> 500 (3/6 formula 5 BDF 1 LE 40 , 00 200 formula 6 BDF 1 LE 6,00 207 formula 7 BDF 1 LE 128,229 (1/6, LE / cis-PDD 64,144 formula 8 BDF 1 LE 24,214 LE / cis-PDD 13,144> 643 (4 / Formula 9 BDF LE 128 643 (4/6, LE / cis-PDD 96 150 Formula 10 BDF 1 LE 128> 643 (3/6, LE / cis-PDD 96 188 TABLE A (continued) Mouse anticompetence activity Compound bc ds / neion T / C mouse code tumor mg / kg () formula 11 BDF 1 LE 8 229 formula 12 BDF 1 LE 80 283 LE / cl-PDD 80 231 ormule 13 BDF 1 LE 30 217 LE / cis-PDD 15 188 Formula 14 BDF LE 6 200 LE / cis-PDD 6 163 Formula 15 BDF 1 LE / cis-PDD 16 230

  a: for more detailed information concerning the technical

  only for testing and interpretation, see Instruction 14, Screening data summary interpretation and outline of current screen,

Maryland, 20014,1977.

  b: 02 = mouse code B 6 D 2 F 1 (BDF 1); 03 = mouse code C 57 BL / 6; 06 = mouse code CD 2 F 1 (CDF 1) o c: PS = lymphocyte leukemia P 388; LE = lymphot leukemia L 12 EM = ependymoblastoma; B1 = melanocarcinoma B 16 d: the survival period is the ratio of the survival times of the treated mice (T) to the untreated mice (C); the activity

  therapeutic is significant at T / C 125.

  LE / cis-PDD means cis-PDD resistant.

  The preparation of the aforementioned compounds is illustrated

in the following examples.

  The compounds were prepared according to the method of S C.

  Dhara: Indian J Chem 8, 193 (1970).

Example I

  Cis-dichloro-1,1-di (aminomethyl) cyclohexane platinum (II)

  in formula 3 of the formula sheet.

  A solution of 26.4 g of KI in 20 ml of water was added to a solution of 16 g of K 2 Pt C 14 and the mixture was heated.

  in a water bath for 5 minutes.

  After this, 6.4 g of 1,1-di (aminomethyl) cyclohexane was added and, after stirring the mixture for 5 minutes, the precipitate was filtered off under vacuum and washed three times with hot water. twice with cold ethyl alcohol

and twice with ether.

  11.8 g of this diiodo derivative formed was added to a solution of 6.6 g of Ag NO 3 in 48 ml of water. After stirring the mixture for 10 minutes at 95-100 ° C., the Ag I was filtered off and washed with water 3.28 g of KCl were added to the clear filtrate and the mixture was stirred for 12 minutes. at 95-100 WC After cooling

  mixture, the precipitate was wrung under vacuum and washed with water.

Yield: 6 g.

  Analysis (percent by weight): Calculated: C: 23.53: H: 4.45; N, 6.87; PT: 47, 80

Found: 23.32; 4.46; 6.86, 47.63.

Example II -

  Preparation of cis, 1-di (aminomethyl) -cyclohexane hydroxyl

  platinum (II) malonate of formula 4.

  1.6 g of the dichloro derivative prepared according to Example 1 (formula

  mule 3) were added to a solution of 1.28 g of Ag NO 3 in

25 ml of water.

  After stirring the mixture for 1 hour at 40 ° C., the AgCl

  was filtered off and washed with water.

  A solution of 0.456 g of hydroxymalonic acid and 0.455 g

  of KOH in 10 ml of water was added to the clear filtrate.

  After stirring for 2 hours at room temperature,

  the precipitate was filtered off and dried.

Yield: 77% by weight.

  Analysis: (% by weight): Calculated: C: 29.01; H, 4.43; N, 6.15; Pt: 42.84; 0: 17.58

  Found: 28.77; 4.38; 6.18; 42.96; 17.54.

  Melting point = 248 ° C (decomposition).

Example III

  Cis-4-carboxyphtalato-l, 1-di (aminomethyl) cyclohexane

  platinum (II) having the formula 5.

  1.2 g of the dichloro derivative prepared according to Example 1 (formula 3) were added to a solution of 1 g of Ag NO 3

in 25 ml of water.

  After stirring the mixture for 1 hour at 40 ° C., the C 1 Ag

  was filtered off and washed with water.

  0.63 g of 1,2,4-tricarboxybenzene was added to the filrat

  limpid and the mixture was stirred for 2 hours at room temperature

  The precipitate was filtered off and washed with water. Yield: 0.8 g (45% by weight) Analysis (% by weight): Calculated: C: 36.24; H, 4.29; N: 4.97;

Found: 36.42; 4.13; 4.77.

Example IV

  Cis-1,1-di (aminomethyl) -cyclohexane-bis (chloroacetate) pla

  tine (II) corresponding to formula 6.

  1.6 g of the dichloro derivative prepared according to Example 1 (formula

  mule 3) were added to a solution of 1.28 g of Ag NO 3 in

25 ml of water.

  After stirring the mixture for 1 hour at 40 ° C., the AgCl

  was filtered off and washed with water.

  A solution of 0.73 g of monochloroacetic acid and 4 g of KOH in 25 ml of water was added to the clear filtrate and the mixture was stirred for 2 hours at room temperature.

  The precipitate was drained under vacuum and washed with water.

o

Yield: 1.3 g (65% by weight).

  Analysis (% by weight): Calculated: C, 27.49; H, 4.23; H, 5.34;

Found: 27.4-3; 4.21; 5.55.

Example V

  Cis-1,1-di (aminomethyl) -cyclohexane-malonate of platinum (II)

in Form 15.

  This compound has already been mentioned in the Dutch patent application 79 04740 but its preparation is important for the

following examples.

  1.6 g of the dichloro derivative prepared according to Example I (

  mule 3) were added to a solution of 1.28 g of Ag NO 3 in

ml of water.

  After stirring the mixture for 1 hour at 40 ° C., the AgCl

  was filtered off and washed with water.

  A solution of 0.4 g of malonic acid and 0.455 g of

  KOH in 10 ml of water was added to the clear filtrate.

  After stirring for 2 hours at room temperature,

  the precipitate was filtered off and dried.

  Yield: 1 g (59% by weight) Analysis (% by weight): Calculated: C: 30.07; H, 4.59; H, 6.38; Pt: 44.40; 0: 14,57

  Found: 29.98; 4.54; 6.32; 44.32; 14.57.

Example VI

  Cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate of platinum (II), having the formula 7 was prepared according to the method of Example V.

Yield: 65% by weight.

  Analysis (% by weight): Calcd + 2H 2 O: C, 29.33; H, 5.74; N, 5.70;

Found: 29.23 5.64; 5.71.

Example VII

  Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate

  Tine (II), having the formula 8 was prepared according to the method of Example V. Yield: 87% by weight Analysis (% by weight): Calculated + 1/2 H 20: C: 26.55; H, 4.68; N, 6.19;

Found: 26.67; 4.56; 6.23.

  The sodium salt of this compound having the formula 13

  was prepared according to Example IX.

Example VIII

  Cis-1,1-di (aminomethl) cyclohexane-2-ethyl-malonate from

  Formula II (II) was prepared according to the formula

thode of Example V.

Yield: 64% by weight.

  Analysis (% by weight): Calc + 1.5H 20: C: 31.57; H: 5.50; N: 5.67; 0: 17.79; Pt: 39.43;

  Found: 31.36; 5.47; 5.69; 18.02; 39.58.

Exem Dle IX

  Sodium salt of cis-2,2-diethyl-1,3-diaminopropane-2-hydrochloride

  platinum (II) xymalonate of formula 13.

  0.5 g of the hydroxymalonate derivative prepared according to example

  VII (Formula 8) was suspended in 25 ml of water.

  1.105 ml of 0.1 N NaOH and the mixture was added.

  It was stirred for 30 minutes at room temperature.

  The clear solution was evaporated to dryness and the solution

  the remaining lide was dried. Yield: 0.4 g (72% by weight) Analysis (% by weight) Calcd + 2H 20: C: 23.91; H, 4.61; N, 5.58;

Found: 23.75; 4.44; 5.52.

Example X

  Cis-1-di (aminométhl) cclohexane-, ll-dyclobutanedicarbox-

  platinum (II) late corresponding to formula 12

  2 g of the dichloro compound prepared according to Example I (formula

  mule 3) were added to a solution of 1.6 g Ag NO 3 in

25 ml of water.

  After stirring the mixture for 1 hour at 40 ° C., the C 1 Ag

  was filtered off and washed with water.

  A solution of 0.677 g of 1,1-cyclobutane dicarboxylic acid

  and 0.547 g of KOH in 10 ml of water was added to

clear filtrate.

  After 2 hours at room temperature and 1 hour at 0 C,

  the white precipitate was filtered off and dried.

Yield: 1.4 g (62% by weight).

  Analysis (% by weight): Calculated + H 20: C: 33.80; H, 5.27; N, 5.63;

Found: 33.98; 5.02 5.77.

Example XI

  Cis-2,2-diethyl-1,3-diaminopropane cyclobutane dicarboxylate

  platinum (II) xylate of formula 9 was prepared according to the method of Example X.

Yield: 64% by weight.

  Analysis (% by weight): Calculated + 2.5H 20: C, 30.46; H: 5.70; N, 5.47; Pt: 38.07;

Found: 030.40; 5.44; 5.37; 38.16.

Example XII

  Cis-11-bis (aminomethyl) cyclohexane platinum (II) nitrate

in Form 11.

25349 07

  4 g of cis-dichloro-1,1-bis (aminomethyl) cyclohexane planin (II) (0.0097 mole) were suspended in 30 ml.

distilled water.

  3.1 g of Ag NO 3 (0.0182 moles) was added and the mixture was then heated for one hour at 40 ° C in the dark. The silver chloride formed was separated by filtration and

  washed with distilled water (10-l).

  The clear filtrate was evaporated under reduced pressure.

  Weight of solid: 4.17 g (93.5% by weight).

  Melting point: explodes at about 240 C

decomposes slowly at times

temperatures below 240 C.

  Analysis (% by weight): Calculated: C: 20.83; H: 3.93; N: 12.14

found: 20.9; 4.1; 11.9.

  1 H NMR spectrum in DMSO-d 6 (Varian T 60) vs. TMS: CH 2 (ring): 1.37 ppm CH <NH 2): 2.30 ppm

H 2 2

  2: 5.67 ppm satellites: 5.20 ppm: 6.18 ppm J 195 pt_ 1 t 95-pt 1 H: 58 HZ

Example XIII

  Cis-1,1-bis (aminomethyl) cyclohexane oxalate (II) 4.1 g of cisdichloro-1,1-bis (aminomethyl) cyclohexane platinum (II) (0.01 mole) was suspended in 30 ml

distilled water.

  3.2 g of Ag NO 3 (0.019 mol) are added thereto and the mixture is then heated for 1 hour at 40 ° C. under the protection of

light.

  The silver chloride formed was separated by filtration and

  washed with distilled water (50 ml).

  2.02 g of potassium oxalate (0.01 mole) was added to the filtrate after which the mixture was stirred for 1 hour.

at room temperature.

  The solid formed was then wrung, washed with water

distilled and dried.

  Dry weight: 3.7 g (87% by weight) Analysis (% by weight) Calculated + 1.5H 20: C: 26.55; H: 4.68; N: 6.19; Pt: 43.13; 0: 19.45; Found: 26.6; 4.6; 6.2; 43.4; 19.2 NMR-H spectrum in DMSO-d 6 (Varian T 60) vs. TMS: CH (ring): 1.32 ppm CH 2 (NH 2): 2.17 ppm NH 2: 5.45 ppm N 2 satellites: 4.83 ppm: 6.08 ppm J 195 pt_H Pt-H 1: 76 Hz

12 2534907

Claims (11)

CLAIMS 1. diamine-platinum (II) complexes, characterized by the formula: ## STR1 ## wherein R 1 and R 2 are both ethyl or, together with the carbon atom to which they are bonded, a cyclohexyl group, R 3 and R 4 are both a hydrogen atom and X is a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate group, a bis-chloroacetate group, a cyclobutanel group, 1-dicarboxylate, a dinitrate group or an oxalate group or a sodium salt thereof 2 Platinum diamine complex according to claim 1, characterized by formula 4 below: 4. CH 2 NH 2 O-CH = Pt CH 2 -NH 2 O -C OH -O   3.Diamine platinum complex according to claim 1,   Characterized by Formula 5 below: ## STR2 ## * -C '   R o 4 diamine platinum complex according to claim 1, characterized by the formula 6 below: characterized by formula 7 below: 6 O o CH 2 HH OK 2 N '-C CH 2 CL % / \ H 2 NIH 2   A platinum diamine complex according to claim 1, characterized by formula 7 below: H 55 H 6.The platinum diamine complex according to claim 1, characterized by the formula 8 below: a. A platinum diamine complex according to claim 1, characterized by the following formula 9: 13 8. The platinum diamine complex according to claim 1, characterized by the formula 10 below: O   The platinum diamine complex of claim 1, characterized by formula 11 below: CH 2 N H 2 H 2 <03) 2   The platinum diamine complex according to claim 1, characterized by formula 12 below: 12 O - CHZ NH H 2534907   Platinum diamine complex according to claim 1, characterized by formula 13 below: 02 W 5 C HZ-NH 2 H   A platinum diamine complex according to claim 1, characterized by formula 14 below: A process for the preparation of a medicinal composition for the treatment of cancer using a complex   platinum (II) diamine, characterized in that a compound   to the formula> of the claim R 1, RZ, R 3, R 4 and   X have the meaning mentioned in the   1 is used as platinum (II) diamine complex.   14.Procédé according to claim 13, characterized in that the compound corresponding to formula 4 of the claim   2 is used as platinum (II) complex.   15.Procédé according to claim 13, characterized in that the compound of formula 5 of the claim   -3 is used as platinum (II) diamine complex. 16 2534907   16.Procédé according to claim 13, characterized in that the compound of formula 6 of the claim   4 is used as platinum (II) diamine complex.   17.Procédé according to claim 13, characterized in that the compound of formula 7 of the claim is used as complex diamine platinum (II). 18.Procédé according to claim 13, characterized in that the compound of formula 8 of the claim   6 is used as platinum (II) diamine complex.   Process according to claim 13, characterized in that the compound of formula 9 of claim 7 is used as the diamine complex platinum (II).   20.Procédé according to claim 13, characterized in that the compound having the formula 10 of the claim   8 is used as platinum (II) diamine complex.   Method according to Claim 13, characterized   in that the compound of formula 11 of the claim   Dication 9 is used as platinum diamine complex (II).   22.Procédé according to claim 13, characterized in that the compound of formula 12 of the claim   is used as platinum diamine complex (II>.   Process according to Claim 13, characterized in that the compound having the formula 13 of the claim   It is used as platinum (II) diamine complex.   24.Procédé according to claim 13, characterized in that the compound corresponding to formula 14 of the claim   12 is used as platinum (II) diamine complex.   Process for the preparation of diamine complexes   platinum (II) for the process according to claims 14   at 24, characterized in that a diamine platinum (II) complex corresponding to the formula 1 of claim 1 where R 1, R 2, R 3, R 4 and X have the meaning indicated in   claim 1 is prepared in a manner known per se.   Process according to Claim 25, characterized in that a compound having the formula 4 from claim 2.   Process according to claim 25, characterized in that a compound of formula 5 of the present invention is prepared claim 3.   Process according to Claim 25, characterized in that a compound having the formula 6 of claim 4.   Process according to Claim 25, characterized in that a compound having the formula 7 from claim 5.   30.Procêdé according to claim 25, characterized in that a compound corresponding to the formula 8 of the claim 6.   Process according to Claim 25, characterized in that a compound of formula 9 is prepared of claim 7.   Process according to Claim 25, characterized in that a compound having the formula 10 is prepared of claim 8.   Process according to Claim 25, characterized in that a compound of formula 11 is prepared claim 9.   The process of claim 25 characterized in that a compound of formula 12 is prepared of claim 10.   35.Procédé according to claim 25, characterized in that a compound of formula 13 is prepared of claim 11.   36.Procédé according to claim 25, characterized in that a compound of formula 14 of claim 12 is prepared