CS242888B2 - Method of diamminoplatinous complexes production - Google Patents

Description

The present invention relates to diaminoplatinum (II) complexes, a process for their preparation, a process for the manufacture of medicaments using such diaminoplatinum (II) complexes for the treatment of cancer, as well as compositions thus formed.

The invention relates to novel diaminoplatinum (IV) complexes and pharmaceutical compositions which utilize such a diaminoplatinum (II) complex for the treatment of cancers such as cancer and cancer, as well as pharmaceutical forms made by the process.

DiaminooFatty comlexes are known from A.P. Zipp and S.G. Zipp in J. Chem. Ed., 54 (12), 739 (1977), which describes the use of cis-diaminodichloride (PDD) for the treatment of cancer.

The article teaches that the platinum compounds frustrate a wide range as intrinsic tumor agents, but they also frustrate serious disadvantages, especially that they are toxic to the kidneys. The method by which the renal toxicity of cis-diaminodichluride to the kidneys is often tended to be by co-leaching with another substance or by concomitantly large fluid or other techniques to achieve roughly adequate kidney flow. A number of other platinum aminocomplexes are known, including the compound of Formula 2, which is shown in the accompanying drawing with a formula overhang.

Wadley Meeical Buuietii, Vol. 7, no. 1, pp. 114 134 Al describes a large number ^{of p} latnatýc ^h diamino complexes suitable к l ^E TIO cancer MEEI them ci.s ^- dijlmiiodlchlori ^dl lj ^t ij ^{characterized.} This article also mentions kidney toxicity as the most serious disadvantage of these compounds.

Also Chem. and Eng. The News of June 6, 1977 at pages 29 and 30 discloses platinum cis-diaminochloride and its use for treating cancer. This publication mentions kidney toxicity as the most serious disadvantage of these compounds.

Also in the article in Cancer Reents Paat 1, Vol. 59, No. 3, pp. 629 and 641 of May and June 1975, ie cis-diп ^ поИсИо ^. Platnate is toxic to the kidneys.

Because PDD is toxic to the kidneys and has a low therapeutic index, other platinum complexes have been sought to treat cancer.

For this purpose, combinations of cis-diiodichloruride lithium with other chemotherapeutic agents were tested. New platinum complexes have also been tested, but have been found to be toxic. It has been found that cis-diclor-bS-cycloethyl ethoxylate is only slightly toxic to the kidneys but is toxic to the spleen.

The so-called platinum mood, a mixture of at least five separate components, has been described as being useful in the treatment of cancer.

Dutch Patent Applications Nos. 73 04 880, 73 04 881, 73 04 882 and 77 03 752 disclose a considerable number of di-complexes, including a compound of Formula 2, which is listed in the formulas.

In all of these core compounds, nitrogen atoms are directly attached to the core. The compounds of the first three Dutch applications were compared with platinum-diaphosphoricide and were found to be more effective. However, none of the patent applications discloses gastrointestinal toxicity. , '; · · Netherlands Patent No. 79 04 740 are .popsάny'diiiiěo ^p litěité complexes' which oharaakeeizuje formula 1 in the summary of formula wherein R .and R nezzávsle each represents hydrogen, a substituted or unsubstituted jlkyloauu, cyklujlkyloauu, asylum or aralkyl, or R _and R ₂ may together form an IT-substituoaiěuuěebo ěesuUsSituuajnou cyklujlkyloalu group, Rg and R nezááásle each represents a hydrogen atom or wherein substituoaaěou

We have found novel diaminoplatnaté complexes of the formula I / ^{CH2C X} C ^H ₂ NH ₂

X ^R 1 ethyl group, or taken together with the carbon atom to which R and

R _{2 is} both bound and cyclohexyl means mmonate, ethyl malonate, hydroxymalonate, carboxyphthalate, bis-chloroacetate, cyclobutane-1, 1-dicarboxylate, or a sodium salt derived from one of the dinitrao or oxalate groups.

The diaminoplatinum (II) complexes according to the invention are prepared according to the invention, the compound of the general formula (II)

New to be reacted

Cl

- ^NH4 .

^ / Pt

- NH ₂ . ^ C1 (II), where R _{3 is} a react

R? are as defined above, with AgNO4 in solution, after which the product obtained is left with the compound of formula III

XH (111), wherein X is as defined above, and optionally converted to the sodium salt in a manner known per se.

The invention further relates to a process for the manufacture of pharmaceutical forms in which the compounds are used as active ingredients, and to the medicaments thus obtained.

An extensive research program, conducted by the Naaional Cancer Institute, Bethesda, USA Brussels, BBegie, has shown that it is opposed to cancer.

and the European Organization for Research and Treatment of Cancer, the nins of the invention have high therapeutic efficacy of platinum complexes such as cis-platinum diaminodichloride (PDD), it has been found that the invention has little or no kidney toxicity at all.

Unlike previously known and practically used to combat cancer, the compounds of the novel compound have a significant antitumor effect for a number of different tumor types, such as p 388 lymphocytic leukemia (PS), L-1210 lymphoid leukemia (LE), ependymooiastoma and B16 m / m / m (B1).

As can be seen from the therapeutic effect values given in Table A,

The therapeutic effect of the novel compounds is greater than that of cis-II-platinum (II) -dichloride dichloride (PDD), which is used as a clinical chemmoerotherapeutic agent.

A very serious disadvantage of the practical PDD used as well as other platinum complexes with protruding activity and the hitherto known compounds (with the exception of those described in Dutch Patent Application No. 79 04 740) is, as already mentioned, the high toxicity of these compounds. , the greatest danger is renal toxicity, and in fact represents a limitation of the doses that can be used in practice.

Surprisingly, it has been discovered that the compounds of the present invention do not have the greatest potential. adverse side effects on the kidneys. This is exemplified by histological examination in rats, following treatment with toxic doses, of the compounds described herein, while severe renal impairment is observed in similar assays with a number of PDDs.

The novel compounds also have no deleterious effect on the kidney effect. It is generally recognized that an important method for determining kidney toxicity is related to the assessment of the percentage of blood urea nitrogen (BUN), also referred to as non-protein nitrogen (NPN).

It still appears that the compounds of the present invention do not have a uniform effect on the molar nitrogen content in the blood. Also for doses corresponding to both the amount of LD 50 and the amount of LD 50, the urea nitrogen content in the blood is identical to the control values.

In addition, PDD provides a molar wave nitrogen content in the LD dose,

in a given time you are quadruple than 11.

whereas at the LD ₅₀ dose it increases with a factor that is not increased

Table A

Protirakovářovy ^EFFECTIVE not ^the Mi-Si ³

Compound Strain v / b mice Tumor ^c dose of injection mg / kg T / C ^d (%) formula 4 06 / LE 36,00 246 LE / cSpPDP 24,00 > 500 (3/7) formula 5 BDF ₁ LE 40.00 200 formula 6 BDF1 LE 6.00 207 formula 7 BDF1 LE 128 229 LE / cSpPDP 64 144 formula 8 BDF1 LE 24 214 LE / cisPPDP 18 144 formula 9 BDF1 LE 128 > 643 (4/7) LE / cispPDP 96 150 formula 10 BDF1 LE 128 > 643 (3/7) LE / cisPPDP 96 188 formula 11 BDF1 LE 8 229 formula 12 BDF) LE 80 283 LE / cispPDP 80 231 formula 13 BDF-i LE 30 217 LE / cisPPDP 15 Dec 188 formula 14 BDF1 LE 6 200 LE / cispPDP 6 163 formula 15 BDF ₁ LE / cispPDP 16 230

a: for more detailed information concerning the test procedure and its interpretation, see instruction 14,

Screening Data Interpretation summmry and outline of current screen, Maayland, 20014, 1977 b: 02 = mouse strain 2Γ Β ^ ₃ (BDDp 03 = mouse strain C 57 BL / 6 mouse strain = 06 CP ^ F ^ (CPPjJ , c: PS = P 388 lymphocytic leukemia.e, LE = L1210 lymphoid leukemia, EM = ereodymodlastoma, B) = Bjg.mmlanocarcinoma.

d: the time ratio of the time is přežští přežStí treated (I) for untreated mice (C), terra ^^ ^ u y ^u rod is significant \> s T / C. ¹² 5.

LE / cispPDD means resistance to cis-PPP.

The preparation of the above compounds is illustrated by the examples below.

The compounds are produced by the method described by S. C. Dhara in Indian J. Chem. £ 193 (1970).

Example 1

A process for preparing cis-dichloro-1,1-di- (aminomethyl) cyclohexane of platinum (3) given in the formula

To a solution of 16 g of K ₂ PtCl ₄ in 160 ml of water, a solution of 26.4 g of potassium iodide in 20 ml of water is added and the mixture is heated on a water bath for 5 minutes.

6.4 g of 1,1-di- (aminomethyl) cyclohexane are then added and the mixture is stirred for 5 minutes, the precipitate is filtered off with suction and washed three times with hot water, twice with cold ethanol and twice with ether.

11.8 g of the resulting diiodo derivative are added to a solution of 6.6 g of silver nitrate in 48 ml of water.

The mixture is then stirred for 10 minutes at 95-100 ° C and the silver iodide is filtered off and washed with water. 3.28 g of potassium chloride are added to the clear filtrate and the mixture is stirred for 12 minutes at 95-100 ° C. The mixture was cooled, the precipitate was filtered off with suction and washed with water. Yield 6.0 g.

Analysis (% by weight):

calculated: 23.53% C, 4.45% H, 6.87% N, 47.80% Pt, found: 23.32% C, 4.46% H, 6.86% N, 47.63% Pt.

Example 2

A process for the preparation of cis-1,1-di- (aminomethyl) cyclohexanhydroxymalonate (4)

1.6 g of the dichloro derivative of formula 3, prepared according to Example 1, are added to the solution

1.28 g of silver nitrate in 25 ml of water.

After stirring the mixture at 40 ° C for 1 hour, the silver chloride is filtered off and washed with water.

A solution of 0.456 g of hydroxymalonic acid and 0.455 g of potassium hydroxide in 10 ml of water was added to the clear filtrate.

After stirring at room temperature for 2 hours, the precipitate was filtered off and dried.

Yield 77%.

Analysis (% by weight);

calculated: 29.01% C, 4.43% H, 6.15% N, 42.84% Pt, 17.58% O, found: 28.77% C, 4.38% H, 6.18% N, 42.96% Pt, 17.54% O. Melting point: 248 ° C (dec.).

Example 3

Process for the preparation of cis-4-carboxyphthalate-1,1-di (aminomethyl) cyclohexane 5

1.2 g of the dichloro derivative of the formula 3, prepared according to Example 1, are added to a solution of 1 g of silver nitrate in 25 ml of water.

After stirring at 40 ° C for 1 hour, the silver chloride was filtered off and washed with water.

To the clear filtrate was added 0.63 g of 1,2,4-tricarboxybenzene and the mixture was stirred at room temperature for 2 hours. The precipitate is filtered off with suction and washed with water.

Yield 0.8 g (45%).

Analysis (% by weight):

calculated: 36.24%, H 4.29, N 4.97, found: C 36.42, H 4.13, N 4.77.

Appendix 4

Process for producing platinum-1,1-di (aminomethyl) cyclohexane bis (chloroacetate) 6

1.6 g of the dichloro derivative of formula 3, prepared according to Example 1, are added to the solution

1.28 silver nitrate in 25 ml water.

When ^d is no ^H on the ^newly mm ^{di s} c ^{hook nus} te ^pl ot.y at ⁴⁰ ° C, c ^hl ori ^d st from reverse to ^{Rib fil} off and ^p rom ^y is water.

A solution of 0.73 g of monochloroacetic acid and 0.45 g of potassium hydroxide in 25 ml of water was added to the clear filtrate, and the mixture was stirred at room temperature for 2 hours. The precipitate is filtered off with suction and washed with water.

Yield: 1.3 g (65%).

Analysis (% w / w) calculated: 27.49% C, 4.23% H, 5.34% H, found: 27.43% C, 4.21% H, 5.55% H.

Example 5

A process for the preparation of cis-1,1-di (aminomethyl) cyclohexanemalonate (15)

This compound has already been disclosed in Dutch Patent Application No. 79 04 740, but its preparation is important for the examples below.

1.6 g of the dichloro derivative of formula 3, prepared according to Example 1, are added to the solution

1.28 g of silver nitrate in 25 ml of water.

After one ^h, the ^hook Odin MIC for te ^pl Ota ^40C c ^hl ori ^d with the ^Tribe reverse to the ^dfilt oestrus and ^p ROMs water.

To the clear filtrate was added a solution of 0.4 g malonic acid and 0.455 g potassium hydroxide in 10 ml water.

After stirring at room temperature for 2 hours, the precipitate was filtered off and dried.

Yield 1.0 g (59%).

Analysis (% by weight):

calculated: 30.07% C, 4.59% H, 6.38% H, 44.40% Pt, 14.57% 0, found: 29.98% C, 4.54% H, 6.23% H, 44.32% Pt, 14.57% O.

Example 6

A method for producing cis-2,2-diethyl-l, 3-diamino ^p ro ^p an-2-ethyl malonate platinum of formula 7

The compound was prepared according to the method of Example 5.

Yield 65%.

Analysis (% by weight):

calculated + 2 H ₂ O: 29.33% С, 5.74% Η, 5.70% nalezeno, found: 29.23% С, 5.64% Η, 5.71% Ν.

Example 7

A process for the production of platinum-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate of formula 8

The compound was prepared according to the method of Example 5.

Yield 87%.

Analysis (% by weight);

calculated + 1/2 H ₂ O: C 26.55, H 4.68, N 6.19. Found: C 26.67, H 4.56, N 6.23.

t

The sodium salt of this compound of formula 13 is prepared according to Example 9.

Example 8

A process for the preparation of platinum-1,1-di (aminomethyl) cyclohexane-2-ethyl malonate of formula 10

The compound was prepared according to the method of Example 5.

Yield 64%.

Analysis (% by weight):

calculated + 1.5 H ₂ O: C 31.57, H 5.50, N 5.67, O 17.79, 39.43 Pt, found: C 31.56, H, 47%; N, 5.69; O, 18.02; Pt, 39.58.

Example 9

A process for the preparation of the sodium salt of cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate of formula 13

0.5 g of the hydroxymalonate derivative of formula 8, prepared according to Example 7, is suspended in 25 ml of water.

1.105 ml of 0.1 N sodium hydroxide was added to the suspension, and the mixture was stirred at room temperature for 30 minutes.

The clear solution was evaporated to dryness and the remaining solid was dried.

Yield: 0.4 g (72%).

Analysis (% by weight):

calculated + 2 H ₂ O: C 23.91, H 4.61, N 5.58. Found: C 23.75, H 4.44, N 5.52.

Example 10

Platinum-1,1-di (aminomethyl) cyclohexane-1,1-cyclobutanedicarboxylate 12g

1.6 g of silver nitrate in 25 ml of water.

After stirring at 40 ° C for 1 hour, the silver chloride was filtered off and washed with water.

A solution of 0.677 g of 1,1-cyclobutanedicarboxylic acid and 0.547 g of potassium hydroxide in 10 ml of water was added to the 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%).

Analysis (% by weight):

H, 5.27; N, 5.63. Found: C, 33.98; H, 5.02; N, 5.77.

•

Example 11

Method for the preparation of felt-cis-2,2-diethyl-1,3-diarninopropane-1,1-cyclobutanedicarboxylate 9

The compound was prepared by the method of Example 10.

Yield 64%.

Analysis (% by weight):

calculated + 2.5 H2O: C 30.46, H 5.70, N 5.47, Pt 38.07, Found: C 30.40, H 5.44, N 5.37% , 38.16% Pt.

Example 12

Method for preparing cis-1,1-bis- (aminomethyl) cyclohexane nitrate of formula 11 g (0.0097 mol) of cis-dichloro-1,1-bis- (aminomethyl) cyclohexane felt is suspended in 30 ml of distilled water.

To the suspension was added 3.1 g (0.0182 mole) of silver nitrate and then the mixture was refluxed for one nu ^di it at ⁴⁰ ° C, the amine compound act ^{yl and} the light.

The resulting silver chloride is filtered off and washed with 10 ml of distilled water.

The clear solution was evaporated under reduced pressure.

The solid weight was 4.17 g (93.5% by weight).

Melting point: explodes at about ²⁴⁰ ° C, help to rozhádá ^ te ^pl per ot.y after ^{d 240 o} C.

Analysis (% by weight):

calculated: 20.83% C, 3.93% H, 12.14% N, found: 20.9% C, 4.1% H, 11.9% N.

¹ H-NMR-s ^p e ^kt rum in DMSO-d₆ with respect to TMS:

^CH2 (ring) : 1.37 ppm CH, < ^nh ₂ ) : 2.30 ppm NH, : 5.67 ppm side lines : 5.20 ppm : 6.18 ppm ^J 195 Pt- ¹ H : 58 Hz.

Example 13

A process for preparing cis-1,1-bis- (aminomethyl) cyclohexane oxalate (14)

4.1 g (0.01 mol) of cis-dichloro-1,1-bis- (aminomethyl) cyclohexane are suspended in 30 ml of distilled water.

To the suspension was added 3.2 g (0.019 mole) of silver nitrate and then the mixture is heated · ^d h nu ⁱ nu te ^p Lot ⁴⁰ ° C, in ^{No. yl} ou en ^also St. and ^ETL.

The resulting silver chloride is filtered off and washed with 50 ml of distilled water.

To the filtrate was added 2.02 g (0.01 mol) of potassium oxalate, and then the mixture was stirred at room temperature for 1 hour.

The resulting solid is filtered off with suction, washed with distilled water and dried.

The weight after drying is 3.7 g (87% by weight). Analysis (% by weight):

calculated + 1.5 H ₂ O: 26.55 % C, 4.68 % H, 6.19% N, 43.13 % Pt found : 26,6 % c, 4.6 % H, 6.2% N, 43.4 % Pt ¹ H-NMR spectrum in DMSO-dg p regard on TMS: CH ₂ (circle) : 1.32 ppm CH _? (nh ₂ ) : 2.17 ppm ^nh 2 : 5.45 ppm side lines : 4.83 ppm : 6.08 ppm : 76 Hz.

¹ H-NMR spectra in DMSO-dg field from TMS ⁺ (unless otherwise specified) in ppm downstream

Example 3 - Formula 5

CH ₂ (ring): 1.37 (with) ch ₂ (nh ₂ ) 2.39 (with) (wide) nh ₂ 5.46 (with) (wide) Side lines: 5.03 5.79 68 Hz Example 4 - Formula 6 CH ₂ (ring): 1.37 (with) CH ₂ (NH ₂ ): 2.38 (m) (wide) NH ₂ : 5.72 (with) (wide) Side lines: 5.02 6.28 76 Hz

Example 1 - formula 3 ^CH 2 (circle): 1/3 (s) (wide) ^CH 2 (to N): 2.2 (t) nh ₂ three wide signals 4-, 8 4,2 5,5.

Example 5 - Formula 15 Dec CH ₂ (circle) : 1,33 (with) с ₂ (NH ₂ ) : 2,13 (with) (wide) ^CH 2 : 4,0-4 , 2 (d) RUN ₂ : 5,20 (with) (wide) side lines : 4,60 : 5,70 ^ «РКн : 66 Hz Example 2 - formula 4 CH ₂ (circle) : 1,30 (with) ch ₂ (nh ₂ ) : 2,15 (with) (wide) H : 4.78 (d)

Example 2 - Formula 4

OH ^NH 2 minor lines ^J 195 _pt -1 _H : 4.05 (d): 5.35 (s) (broad): 4.83

5.97: 68 Hz.

Example 6 - Formula 7

CH ₃ (Et): 0.72 (t) (deformed) CH ₂ (Et): 1.17 (q) (deformed) CH ₃ (Et jnalonate): 0.85 (t) (deformed) CH ₂ (Et malonate): 1.76 (q> (deformed) CH ₂ (NH ₂ ): 2.10 (with) (wide) H: 3.43 (t) nh ₂ 5.23 (with) (wide) Side lines: 4.58 5.88 4t- ^J H 78 Hz • Example 7 - Formula 8 CH ₃ (Et): 0.72 (t) (deformed) CH ₂ (Et): 1.17 (q) (deformed) CH ₂ (NH ₂ ): 2.08 (with) (wide) OH: 4.03 (d) H: 4.87 (d) NH ₂ 5.30 (with) Side lines: 4.71 5.95 74 Hz

Example 8 - Formula 10

CH ₃ (Et) : 0,87 (t) CH ₂ (Et) : 1,73 (q) CH ₂ (circle) : 1,27 (with) (wide) ch ₂ (nh ₂ ) : 2.07 (with) (wide) H : 3,38 (t) nh ₂ : 5,20 (with) (wide) side lines : 4,53 5.77 : 74 Hz

Example 9 - formula 13 in D ₂ O; internal standard: trimethylsilylpropanesulfonic acid sodium salt CH ₃ (Et): 0.8 (t) (deformed)

CH ₂ (Et): 1.27 (q) (deformed)

CH ₂ (NH ₂ ): 1.8-3.0 (m)

H: 4.33 (s).

Example 10 - formula 12 ^CH 2 с ₂ (six-membered circle) (four-membered circle) : 1.33 (s) (wide) : 1.5-2.3 (m) (wide)

Example 10 - v / orec 12

CH ₂ (NH 2) ^NH 2 minor lines ^J195 Pt- ¹ h

Example 11 - Formula 9: 2.72 (t) (deformed): 5.22 (s) (wide): 4.57

5.80: 74 Hz.

CH ₃ (Et)

CH2 (Et)

CH2 (circle)

CH2 (NH2)

ПН2 secondary lines ^J 195

Pt- ¹ !!

: 0.71 (t) (deformed): 1.17 (q) (deformed): 1.55-2.27 (m): 2.70 (t): 5.13 (s) (wide): 4 , 50

5.78: 77 Hz.

A ^sodium salt of s = singlet;

duUet; t = triplet; q = quaternions;

m = multiplet.

Temperatures thaw ° C (in chapters; uncorrected) Example 3 216 change of color 311 decomposition 4 201 5 215 change of color - 6 260 change of color - 7 255 change of color 257 decomposition 8 - 237 decomposition 9 215 change of color 235 decomposition 10 243 Change: to color 249 decomposition 11 260 change of color -

Claims (1)

SUBJECT EZU where Process for producing diaminoplatinum (II) complexes of formula (I) ^R2 NH 2 X is both bonded, denotes a cyclohexyl ethyl group or together a group with a carbon atom to which they are malonate, lis-chloroacetate, ethyl malonate, hydroxymethyl, carbonyl, carbonyl, cyclic, cyclic Oltane-I, I-likarltxylate, linirrate or oxalate group, or sodium salt, derived from any of these groups, characterized by reacting a compound of formula II / 11, where Rj and Rj are as defined above, with silver nitrate in solution, then reacting the obtained product with a compound of formula III XH (111), wherein X is as defined above, and optionally converted to the sodium salt. 3 drawings