FI76097B - ANALOGIFICANT FARER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA PLATINA-DIAMINKOMPLEX. - Google Patents

Description

1 76097

Analog method for the preparation of therapeutically useful Platin-diamine complexes

Divided by the separated application 820 737 5

The invention relates to an analogous process for the preparation of therapeutically useful platinum-diamine complexes of general formula A

10 Hv Xc «2-NH2, X

H3C \ _Mlζ V \ H3C // \ (Ä) 15 H _C__C_CH, h / \ where X is chlorine, sulphate or oxalate.

These new platinum-diamine complexes can be used to treat cancers such as malignant swellings and malignancies.

It is known from the literature that platinum-diamine complexes are useful in the treatment of cancer.

See. for example, Rosenberg, B., and van Camp. L. Cancer 25 Research 30 (1970) 1799-1802, and Zipp. A. P. and Zipp.

S. G. J. Chem. Ed. 54 (12) (1977) 739, which describe the use of cis-platinum diamine chloride in the treatment of cancer. It has been mentioned that these platinum compounds have a wide spectrum as antitumor agents, but also that they have significant disadvantages, in particular renal toxicity.

A combination of cis-platinum diamine chloride with another substance or the use of large amounts of fluid or other methods to achieve adequate flow through the kidneys has been proposed as a method of counteracting nephrotoxicity.

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Further, platinum-diamine complexes are described in J. Clinical Hematol; Oncol 7 (1) (1977) 114-134; Waldey Medical Bulletin, Vol. 7, No. 1, pages 114-134; Chem. and Eng. News, June 6, 1977, pages 5 29-30, and article in Cancer Chemotherapy

Reports Part 1, 59 (3) (1975) 629-641, It appears from all these literature references that these complexes are toxic to the kidneys.

Important literature regarding platinum-diamine complexes 10 is further represented by Tobe, M.L. and Kohkhar, A.R.

J. Clinical Hematol. Oncol. 7 (1) (1977), Dutch patent applications 7,810,431, 7,903,050 and 7,903,038 and J. Clinical Hematol. Oncol., 7 (1) (1977) 231-241.

Dutch patent application 7,904,740 describes novel platinum-diamine complexes which are well suited for the treatment of cancer and which are of little or no toxicity to the kidneys. This is the so-called divalent platinum. double ligand complexes of formula 6. _ K Λ 20 I4

° n C-NH, X

'V | X «C-ύζ \ a3 wherein the double ligand is substituted or unsubstituted propanediamine. These compounds are little or not toxic to the kidneys due to the nature of the substituents R 1, R 2, R 3 and R 2. Also unpublished Dutch patent application 8,000,032 describes 30 such complexes which are well suited for the treatment of cancer and are not toxic to the kidneys.

A large number of platinum-diamine complexes are known from Dutch patent applications 7,304,880, 7,304,881, 7,304,882 and 7,703,752, including a compound of formula 7.

3 76097 αΝΗ / C1 ^ Pt (7)

Nlf, ^ Cl 5 2

In all compounds having a ring, the nitrogen atoms are directly attached to the ring. The compounds from the first three applications were compared to cis-platinum diamine-10 chloride and proved to be more active. None of these applications mention renal toxicity.

The main application describes the preparation of certain therapeutically useful platinum-diamine complexes of the general formula 1/1 ^ / \> t / U 'C c-_I \

20 R2k / \ / 'X

H - C-C- R, Y

H7 \ R4

The novel compounds of formula A can also be used as intermediates in the preparation of compounds of formula (1) as described in the parent application.

The process according to the invention for the preparation of the compounds of formula (A) is characterized in that PtCl 2 is reacted with NaOH and the compound,

30 of formula B

4,76097 H 2 ch, -nh 2 -HCl H 3 Cl 2, C -NH ~ -HCl H / | f ^ CH3

H H

And, if desired, the compound thus obtained is reacted with silver sulfate or first with silver nitrate and then with an oxalate salt.

The method is described, for example, in Johnson, 15 G.L. Inorg. Synth. VIII, 242-244 and Basolo et al. J. Am. Chem. Soc. 72 (1950) 2433.

The new compounds have high antitumor activity against a large number of cancers, such as L 1210 lymphocytic leukemia.

20 For information on this test method, see Instruction 14, Screening Data Summary Interpretation and Outline of Current Screen, Drug Avaluation Branch National Cencer Institute, Bethesda, Maryland 200.4, 1977, T / C is the survival time for treated (T) versus untreated (C) mice; when T / C> 125 refers to significant antitumor activity.

For example, the activity of the compound of formula 5 CH, .N NH, »\ / \ / Cl 30 ν \ / c \ X NC_NHC (5) H3c / \ / \ h ^ CH, H h 3 35 against L 1210 lymphocytic leukemia / C = 214 at 120 mg / kg ip) is greater than cis-platinum-5 76097

the activity of diamine chloride (cis-pDD), which is practically used for the treatment of cancer (T / C = 157-186 at a dose of 4-10 mg / kg ip). Among other things, activity was also found in Big Dark Cancer (Melano carcinoma) (T / C = 155 at 5 5 mg / kg ip) and Lewis lung cancer. Examples II

and III showed anti-tumor activity of the following types: r-

Compound_ L 1210__B 16_ 10 Eg No. T / C (mg / kg) T / C (mg / kg) II 207 (30) 168 (8) III 293 (160) 153 (8)

In contrast to the cis-PDD mentioned above, the new compounds have no detrimental effect on renal function (renal toxicity). This can be determined by determining the concentration of urea in the blood, the so-called BUN number (= blood urea nitrogen). Thus, for example, when the compound of formula 5 was administered intraperitoneally to mice, no increase in BUN was observed at doses of 102, 136 and 181 mg / kg.

The preparation of the compounds of the invention is illustrated in more detail by the following examples.

Example I

Cis-dichloro-1-amino-2-aminomethyl-3,3,5-trimethyl-cyclopentane-platinum (II) (formula 5) 1-amino-2-aminomethyl-3,3,5-trimethylcyclopentane .2HCl (2.2 g) and ^ PtCl 2 (4.15 g) were dissolved in 40 ml of water. The mixture was heated to 95-100 ° C and a solution of 1 NaOH in 20 mL of water was added dropwise at-30 ° C so that the pH remained below 6. The precipitate formed was filtered off with suction, washed with water and dried. The product was taken up in 250-300 ml of liquid NH 4 and filtered. After evaporation of NH 4 S, the product was washed with 2N HCl, water and then dried.

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Yield: 3.4 g (85%)

Melting point: 260 ° C Analysis (% by weight):

Calculated: C 26.60; H 4.77; N 6.63; Cl 16.79 δ Found: 25.6 4.8 6.7 16.8 1 H-NMR spectrum in DMSO-d 6 (Varian T-60) for TMS: CH 2 0.93 ppm, CH 2 1, 2-2.4 ppm and NH 2 4.90 ppm (broad) (3.97-61.3).

IR spectrum in C11: 3420 (w), 3250 (m), 3200 (m), 3130 (ra), 10 2960 (m), 2779 (m), 1570 (s), 1450 (s), 1370 ( s), 1200 (s),

1100 (ra), 990 (w), 750 (w) and 320 (s) (Pt-Cl) cm-1. Example II

1-Aramino-2-araoraethyl-3,3,5-triraethylcyclopentaneplatinum (II) sulfate - ", CH" -NHO

15 HX / 2 2 ^ PtSO-.H-O

4 2 CH3 v

CH3 I H

H Λ - / - CH ^ 20 H /

B

3 g of cis-dichloro-1-amino-2-aminomethyl-3,3,5-trimethylcyclopentane platinum (II) were suspended in 100 ml of distilled water. 2.15 g of Ag 2 SO 4 were added and then the mixture was heated at 50 ° C for 3 hours under protection from light.

The silver chloride formed was filtered off and washed with distilled water (20 ml).

The pure filtrate was concentrated in vacuo.

2.5 g of solid were obtained (yield 75% by weight).

Analysis (% by weight):

Calculated: + 1H 2 O; C 23.23; H 4.76; N 6.02; Pt 41.92; S 6.89; O 17.19 Found: 23.54 4.76 6.12 42.25 6.77 7 76097

Example III

1-Amino-2-aminomethyl-3,3,5-trimethylcyclopentane-platinum (II) oxalate

H .CH - NH (X) 0C

> C> \ 1 «Sv / ^

1 ° K

CH3 \ / h \ - / - ch3 H k 15 3 g of cis-dichloro-1-amino-2-aminomethyl-3,3,5-trimethylcyclopentane-platinum (II) were suspended in 30 ml of distilled water. . 2.37 g of AgNO 2 were added and then the mixture was heated at 40 ° C for 1 hour protected from light.

The silver chloride formed was filtered off and washed with distilled water (10 ml),

To the filtrate was added 1.42 g of potassium oxalate, followed by stirring for 2 hours at room temperature.

The resulting solid was collected by suction filtration, washed with distilled water and dried.

2.6 g of solid were obtained (yield 83% by weight).

Analysis (% by weight):

Calculated: C 30.07; H 4.59; N 6.38; Pt 44.40; O 14.57 30 Found: 29.79 4.72 6.22 44.32 14.49.

Claims (2)

An analogous process for the preparation of therapeutically useful platinum diamine complexes of the general formula AH y CH 2 -NH, XH, C \ (a) 10 / \ H3C \ \ HH-C-c-CH- / \ 3 H 'H 15 wherein X is chlorine, sulphate or oxalate, characterized in that K2PtCl4 is reacted with NaOH and a compound of formula BH CH2-NH2-HCl H3C. ^ 20 x. \ yc X -NH ~ - HCl \ H.C \ / H \ _ / 25 H 2 | H H and, if desired, the compound thus obtained are reacted with silver sulfate or first with silver nitrate and then with an oxalate salt. 30