LU84365A1 - PLATINUM-DIAMINE COMPLEXES, PROCESS FOR OBTAINING SAME, APPLICATION OF SUCH A COMPLEX FOR OBTAINING A MEDICAMENT FOR THE TREATMENT OF CANCER AND THE MEDICINAL PRODUCT THUS OBTAINED - Google Patents

Description

t - 1 - The invention relates to new platinum-diamine complexes, a process for obtaining them, a process for the manufacture of a medicament for the treatment of cancer, for example of malignant tumors and tumors, said process using a such complex, as well as a drug obtained by application of said method.

In main patent LU-A-81470, platinum-diamine complexes are described, corresponding to formula (1): 10 R4

Ri -NH9 X

\ \ / cf pt m 15 / / \

15 r2 c-nh2 X

R3 in which R ^ and R2 may represent, independently of one another, a hydrogen atom or an alkyl, cycloalkyl, aryl, or aryalkyl group, substituted or not, and R2 may also represent together a cycloalkyl group substituted or unsubstituted, R3 and R 4 represent, independently of one another, a hydrogen atom or an alkyl, aryl or aryalkyl group, substituted or not and X an anionic group.

Platinum-diamine complexes are known and described in the article by A.P. Zipp and S.G. Zipp, J. Chem. Ed., 54 (12) (1977), page 739, which describes the application of cis-platinum diamine dichloride for the treatment of cancer. These platinum compounds are said to have a broad spectrum as anti-tumor agents, but also to have significant disadvantages, in particular that they are toxic to the kidneys. As a method of counteracting kidney toxicity, it is suggested to combine cis-platinum diamine dichloride with another substance or to use large amounts of liquid, or other techniques ensuring sufficient irrigation. kidneys. In addition, several other platinum-amine complexes are mentioned, among which is the compound corresponding to the formula: - 2 - Λ / ΝΗ2 \ ^ C1 5 ^ v / ^ NH2 ^ * Cl

In "Wadley Medical Bulletin", volume 7, No 1, pages 114 to 134, a large number of platinum-dia-mine complexes are mentioned, including cis-platinum-dichlorodiamine, for the treatment of cancer. Here again, it is said that the toxicity to the kidneys is the most important drawback of these compounds.

In Chem, and Eng. News, June 6, 1977, pages 29 and 30, also describes cis-platinum diamine dichloride and its application in the treatment of cancer. Here again, kidney toxicity is mentioned as the most significant drawback.

The article in "Cancer Chemotherapy Reports", part 1, volume 59, No 3, May-June 1975, pages 629 to 641, also talks about the toxicity of cis-dichlorodiamine-platinum (II) for the 20reins. Because of its toxicity to the kidneys and its low therapeutic index, other platinum complexes have been sought for the treatment of cancer. For this purpose, combinations of cis-dichlorodiamine-platinum (II) with other chemotherapeutic agents have been tried. New platinum complexes have also been tried, but have been found to be too toxic. It has been found, for example, that cis-di-chloro-bis-cyclopentylamine-platinum (II) does little harm to the kidneys but is too toxic to the spleen. In addition, there have been mentioned for the treatment of cancer "platinum blue", which is a mixture of different amounts of at least five inseparable constituents.

According to patent applications NL 73.04.880, 73.04.881, 73.04.882 and 77.03.752, a large number of platinum-diamine complexes are known, among which the compound of formula 35 / \ ^ NH2 ^ -Cl

l I

N / ^^ nh2 ^^ ci

In all compounds with a ring, the nitrogen atoms are attached directly to the ring. The compounds of the first three NL applications cited above have been compared with cis-platinum-diamine chloride and found to have better effects. None of the applications cited above speak of kidney toxicity.

5 In main patent LU-A-81470, new platinum-diamine complexes have been found which are well suited for the treatment of cancer and which have little or no toxicity to the kidneys and these complexes correspond to the formula ( 1) above where R] _, R2, R3, R4 and X have the meanings indicated.

Among these complexes, we preferred the opposites corresponding to formula (2) below: r4

è-NH2 X

15 / v ^ A \ / / \

NC- ΝΗο X

I 2 r3 20 in which R3, R4 and X have the above meaning.

Preferably using cis-dichloro-1,1-di (aminomethyl) -cycloalkyl-platinum (II) corresponding to formula (3) _____ ^ CH2-NH2 ^ C1 25 (CH2) n Ci '^ Pt {3) in which n is from 2 to 7, preferably from 3 to 5, and is more preferably cis-dichloro-1,1-bis- (aminomethyl) -cyclohexyl-platinum (II) corresponding to formula (4) 30 , - ch2-nh2 .Cl (4) ^ ch2-nh2 ^^ ^ Cl

In formulas (1) and (2), the anionic group X is preferably a chlorine, bromine or iodine atom, a sulphate residue or a substituted or unsubstituted carbox groupelate group, for example oxalate, malonate or substituted malonate .

According to the present invention, use is preferably made of cis-1,1-bis (aminomethyl) cyclohexane-hydroxymalonate of platinum II corresponding to formula 4 ο / \. CH0- NH? .0-C Η \ / XXX <ΐ5> \ X \ CH2-ΝΗ2 ο C ΟΗ 5 Another subject of the invention is a process for obtaining, in itself known manner, this compound, a process for obtaining a medicament in which this compound is used as active substance, and a medicament obtained by this process, which contains an appropriate amount of a complex according to the invention as active ingredient.

Extensive research by the National Cancer Institute, Bethesda, E.U.A. and the European Organization for Research on Cancer Treatment, Brussels, Belgium, have shown that the compounds according to formula (I) have a great therapeutic activity against cancer. Unlike the platinum complexes previously known and used in practice for combating cancer, such as cis-platinum-diamine dichloride (PDD), it has also been found that the compounds according to the invention have a low or even zero toxicity for kidneys.

As shown by the therapeutic activity figures given in Table A, the compounds according to the invention exhibit an advantageous antitumor activity against a large number of different types of tumors, such as p 388 lymphocyte leukemia, L 1210, 1 lymphoid leukemia ependymoblastoma and melanocarcinoma B 16. The therapeutic activity of the compounds according to the invention is greater than that of cis-platinum diamine dichloride (PDD), used as a chemotherapeutic agent in an experimental clinic.

As mentioned above, a very serious drawback of practically applied PDD, as well as all 35 other previously known anticancer platinum complexes, is their high toxicity, the toxicity to the kidneys being the most dangerous and limiting the dose. which can be administered in practice.

Despite considerable research in this area, it has not yet been possible to develop compounds having an anticancer activity comparable to that of PDD but a significantly lower toxicity (for the kidneys).

Surprisingly, the compounds according to the invention have no harmful side effects on the kidneys. This has been demonstrated by a histological examination of rats after treatment with toxic doses of compounds corresponding to formulas (4) and (7): 10 y-V ch2-NH2 Cl \ X 141 \ _ / XCHj-NH ^ 01 0 I)

15 / - ^ / CH? - NHo -c \ / -V

<y V ^ \ (7) '-' \ h2- nh2 ^ -c ^ \ /! s and related compounds of this type while, during a |

20 similar examination of the PDD, we observed

i serious kidney damage. j

The complexes according to the invention have no more harmful effect on the functioning of the kidneys. A generally accepted and important method for the determination of kidney toxicity is to assess the percentage of urea nitrogen (BUN) in the blood, also indicated | as non-protein nitrogen (NPN).

As shown in Table B, the compounds according to the invention have no effect on the blood content of urea nitrogen. As well at doses corresponding to the | DL10 those which correspond to DL ^, the contents j of urea nitrogen of the blood are identical to those of the tee minus. The compound PDD, on the contrary, at the DL- ^ q at the end of the times indicated, already has the effect of quadrupling the content of urea nitrogen while at the DL ^ q the increase coefficient reaches 11.

! - 6 -

TABLE A

Anti-cancer activity in mice (a) 5: Compound: Type of: Tumor.: Dose / injection: T / C (d) of. (b). .tion, mg / kg. % mouse formula -i —-- 1--1-î -: -----. 04:06. PS. 6/25. 201::: .3.12 .181 10; :. *. 1/56! 153. Same ; 06: LE .12.5 .234. . . 6.25. 180::: 3.12. 145. ditto .03 .EM .6.00. 126 I ,. . same as .02 Bl. 6.00. 208; . . . 3.00. 208d

:::: 1'50: 190 I

. PPD .02 Bl .2,0 .197 j .7: 06 .PS. 25.0. 226 d. . . . 12.5 177 i 20:::::: i:. . . 6.25. 162. same .06 .LE .80.0. 138. same as .03. EM .12.5. 163 d 6.25 130 i::: j

„. 8 .06 .LE. 12.5. 289 I

25 "· i .9 .06. LE 12.5. 323! .11 .06. LE. 12.5. 274 10 .06. LE 12.5. 148. 15. 02. LE. 36.0. 246 3Q. 15. 02 .LE / Cis PDD 24.0.> 500 (3/6 ^! Legend: j (a) for more detailed information on the test method and its interpretation, see Instruction 14, Screening da- 35 ta summary interpretation and outline of current screen, Drug Evaluation Branch, National Cancer Institute, Bethesda, Mary-j land, 20014, 1977.

(b) 02 = mouse code BgD3 (BDF); 03 = mouse code C 57 BL / 6, 06 = mouse code (CDFi) __________________ i - 7 - (c) PS = P 388 lymphocyte leukemia; LE = L1210 lymphoid leukemia; EM = ependymoblastoma; B ^ = melanocarcinoma B 16 (d) ratio between the survival time of the treated mice (T) 5 and that of the untreated mice (C); therapeutic activity is significant if T / C ^ 125.

The formulas (8) to (11) are as follows: CH., .CH0- NH0 Cl 3 \ / 2 2n /

Pt (8) 10 CH3 — CH2 ^ \ cH2- NH ^ € 1 CH -, - CH o CH9-NH0 Cl J \ / 2 2n /

Pt (9) / \ κ \ ch3-ch2 ch2-nh2 Cl 15 / \ yCE0-NH0 Cl (X 2 2-PtX (10,> - ^ nCh2- ^ Cl 20 J — Λ ^ CH2-NH2 ^^^ W \ cH2_

TABLE B

Percentage of urea nitrogen in the blood after administration of platinum complexes (in rats): Compound: Dose: Number of days: Urea nitrogen:: mg / kg: after injection in the blood, _ * _% _ 30 : of formula: 8 (DL, n): 0.10 4 χυ; :: 2: 10::: 4 ·. 15: same: 15 (DL5Q): 0 .10::: 2 .15 35:: 4: 17

Control. .0 "10:: 2 1 9 4: 11 -------------------------------------- ----- 4 ---------------- - 8 - TABLE B (continued)

Percentage of urea nitrogen in the blood after administration of platinum complexes (in rats) 5 ___________: Compound: Dose: Number of days: Urea nitrogen. mg / kg after injection into the blood, * _________ l __________ i ____________________ l _______% __________: PDD: 3 (DL1Q): 0 s 10 10::: 2: 13:: 4: 52:: 7.6 (DL5Q): 0: 10:: : 2: 78::: 4: 148 15 -

The preparation of the compounds mentioned in Tables A

and B is explained by the following examples:

The compounds were prepared according to the method of S.C. Dha-; ra: Indian J. Chem. 8, 193 (197Θ). ! 2o EXAMPLE 1 d

Cis-diiodo-1,1-di (aminomethyl) -cyclohexane-platinum (II) re-, corresponding to formula (6) 3-V yCH2-nh2 / 1 / y ^ (ei

25 \ Xl I

To a solution of 16 g of K2PtCl 4 in 160 ml of water, there is; a solution of 26.4 g of KI in 20 ml of water was added and the mixture was heated in a water bath for 5 minutes. j

Then added 6.4 g of 1,1-di- (aminomethyl) -cyclohe- | 2o xane and, after having stirred the mixture for 5 minutes, one; wrung the precipitate and washed it three times with water | i hot, twice with cold ethyl alcohol and twice j with ether. Yield 22.1g.

| EXAMPLE II

135 Cis-dichloro-1,1-bis- (aminomethyl) -cyclohexane-platinum (II) corresponding to the formula (4) - CH2-HH, / Cl CX> <(4, CH2-NH2 Tl - 9 - Has a solution of 6.6 g of AgNO 4 in 48 ml of water, 11.8 g of the diiod derivative prepared according to Example 1 was added.

After stirring the mixture for 10 minutes at 595-100 ° C, the Agl was removed by filtration and washed with water. To the clear filtrate, 3.28 g of KC1 was added and the mixture was stirred for 12 minutes at 95 to 100 ° C. After the mixture had cooled, the precipitate was filtered off and washed with water.

’P0 Yield 6.0g

Analysis (% 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 III

Cis-cyclopentamethylene-malonato-1,1-di (aminomethyl) ~ cyclohexane-platinum (II) corresponding to the formula (7) / -γΗ2 — NHSt / ° 'V “\; 2 () - 'C ^ 2-m2 ^ (7)' o! ! To a solution of 11.55 g of AgNO 4 in 85 ml of water, 20.65 g of the diiodine derivative prepared according to Example I were added.

After stirring the solution for 10 minutes at 95-100 ° C, the Agl was removed by filtration and washed with water. While the filtrate was. still hot, a solution of 5.0323 g of cyclopentamethylene malonic acid in 114.34 ml of 0.51125 N NaOH was added and

I O

; heated the mixture for 12 minutes between 95 and 100 C.

After the mixture has cooled, the precipitate is drained and | we washed it with water. After drying under reduced pressure, one | extracted the product obtained with 4 liters of methanol, the methanolic solution was treated with activated charcoal, filtered, until it was clear and the filtrate was evaporated to dryness under pressure scaled down. The residue was suspended in 500 ml of alcohol, drained and washed with methanol.

Yield 4.75 g Analysis (% by weight): - 10 - calculated C 37.86; H 5.56; N 5.52; Pt 38.46; found 37.50 5.50 5.60 38.19.

Analogously I and II, the following compounds were prepared which are very pale yellow crystalline substances.

EXAMPLE IV

Cis-dichloro- (2-methyl-2-ethyl) -1,3-propane-diamine-platinum (II) corresponding to formula (8) 10 CH, CH0-NEL Cl

Pt (8) CH3-CH2 ^^ 2-NE ^ ^ Cl

Yield: 55% by weight

Analysis (% by weight):! Calculated: C 18.86; H 4.22; N 7.33; Pt 51.04; Cl 18.55 j found: 18.73; 4.14; 7.26; 51.33; 18.69 | EXAMPLE V j

Cis-dichloro-2,2-diethyl-1,3-propanediamine-platinum (II) j corresponding to formula (9) | 20 CH, -CH, CH, -NH, Cl j J / 6 / XPt (9) i ch3-ce 'ch2 ci

Yield: 70% by weight i

Analysis (% by weight):! Calculated: C 21.22; H 4.58; N 7.07; Pt 49.24; Cl 17.89 | found: 21.04; 4.50; 7.02; 49.43; 17.83d EXAMPLE VI!

Cls-dichloro-1,1-di (aminomethyl) -cyclopentane-platinum (II) I

i corresponding to formula (10) 30 / V ^ CH2-NH2 '/ C1 (10> ch2-nh2 cl I Yield: 70% by weight

Analysis (% by weight): calculated: C 21.33; H 4.09; N 7.11; Pt 49.49; Cl 17.98; found: 21.36; 4.10; 7.14; 49.27; 17.91.

EXAMPLE VII

Cis-1,1-di- (aminomethyl) -cyclohexane-platinum (II) sulfate corresponding to formula (11) - 11 - / - \ ^ CH2-NH2 - ^ _ \ K ^ ptso4 (11) \ / \ CH2-NH2 5 2 g of diiod derivative prepared as in Example 1 were suspended in 150 ml of water. After stirring for 20 hours with 1.0 g of Ag2SO4, the Agl * was removed. by filtration and washed with H2O. The clear filtrate was evaporated.

Yield: 1.1 g, about 80% by weight.

Analysis (% by weight) calculated: C 22.17; H 4.19; N 6.46; found: 22.02; 4.62; 6.31. ;

The following compounds are prepared according to the method of G.L. Johnson; Inorg. Synth. VIII, pages 242 to 244.

EXAMPLE VIII 1

~ ~~ I

Cis-dichloro-1 / l-di (aminomethyl) -cyclobutane-platinum (II); having the formula (12) / Λ CH2-NH Cl 20 \ .xT <i2) Χχ ° Η2-NH2 ^ C1 |

2.8 g of 1,1-bis- (aminomethyl) -cyclobutanje, 2 g of HCl and 6.2 g of K2PtCl4 were dissolved in 50 ml of water, heated to 95-100 ° C and added drop by drop 1.2 g of NaOH in 25 ml of water, quickly enough so that the pH is maintained at + 6.

The precipitate formed was filtered off, washed with water and dried. The product was taken up in 250 to 300 ml of liquid NH 3 and filtered. After evaporation of NH3, the product was washed with 2N HCl and with water and dried.

j Yield: 3.7 g, about 65% by weight.

Analysis (% by weight) calculated: C 18.96; H 3.71; N 7.37; Pt 51.31; Cl 18.65 35 found: 18.95; 3.67; 7.37; 51.02; 18.47.

EXAMPLE IX

Cis-dicyloro-2,2-dibenzyl-1,3-propanediamine-platlne (II) corresponding to the formula (13) C, Hc— CH "CH" -NH "Cl 6 5 2 \ / 2 2 \ / 40, C .Pt (13)

L -.................—- X X

c „-CH2 CH2 — NH2 Cl 3 * - 12 -

Yield: 45% by weight Analysis (% by weight): calculated: C 39.24; H 4.26; N 5.38 5 found: 39.81; 4.38; 5.73.

EXAMPLE X

Cis-dichloro-2,2-diisopropyl-1,3-propanediamine-platinum (II) “corresponding to the formula (14) ch3 10 ^ CH CH - NH- Cl

"X \ / V

c Pt / \ / \ ^ CH CH2-NH2 Cl 15 CH- / j J i

Procedure as in Example IX ·

Analysis (% by weight): 1 calculated: C 25.48; H 5.23; N 6.60 i

found: 25.31; 5.39; 6.90. J

20 EXAMPLE XI

Cis-1,1-bis (aminomethyl) cyclohexane-hydroxymalonale of platinum (II) Q

, -V CH - NH- O C H

/ \ / V (15) 25 \ _ / \ pH2-NH2 0 - C OH j 0

1.6 g of the derivative according to Example II (formula 4) were added to a solution of 1.28 g AgNO 4 in 25 ml of water. After stirring the mixture for 1 hour at 40 ° C., AgCl was separated by filtration and washed with water. To the limp filtrate: a solution of 0.456 g of hydroxymalonic acid was added; and 0.455 g KOH in 10 ml of water. After shaking for 2 | hours at room temperature the precipitate was separated by filtration and dried.

Yield: 77% by weight Analysis: (% by weight) calculated: C 29.01; H 4.43; N 6.15; Pt 42.84; O 17.58 found: 29.77; 4.38; 6.18; 42.46; 17.54.

Claims (5)

1. Platinum-diamine complex according to main patent LU 81470 corresponding to formula (1): 5 R4 I 4 R, C-NH „X \ A \ /: R / CX_ 2 | 2 R3 in which R ^ and R2 may represent, independently of one another, a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl, or aryalkyl group, R ^ and R2; can also represent together a substituted or unsubstituted cycloalkyl group 15, R 1 and R 4 represent, independently of one another, a hydrogen atom or an alkyl, aryl group j or substituted or unsubstituted aryalkyl and X an anionic group, characterized in that this complex is cis-l, l-bis (amino- [methyl) cyclohexane-hydroxymalonate platinum II, having the formula ^ j, _ ", CH0-NH0 Ό-CH; : CK X X \ _ / x: H0-NH-, Ko · - C OH 2. s 2. platinum-diamine complex according to claim 1, characterized in that it is cis-l, l-di- (aminomethyl) -j cyclohexane-platinum (II) sulfate corresponding to formula (11) i / \ / CH2-NH2. <X ^ PtS04 i 30 K- 'XcH2-NH2 (11) 3. Method for obtaining a medicament for the treatment of cancer with the use of a platinum-diamine complex as active substance, characterized in that a complex according to any one of the claims is used * 35 1 and 2 in a form suitable for administration. 4. Pharmaceutical composition obtained by the process according to claim 3. 5. Pharmaceutical composition, characterized in that it contains, as active ingredient, an appropriate amount of a platinum-diamine complex according to any one of claims 1 and 2.