DE1695998C3 - N to the power of 2, N to the power of 3-di-spiro-tripiperazinium salts and process for their preparation - Google Patents

Description

CH, CH-

or

and X - means an anion.

The process for the preparation of these new compounds is that one known per se wise

a) a bisquaternary N ² .N ³ -di-spiro-tripiperazinium salt of the general formula

CH, CH-

and X is an anion.

2. Process for the preparation of the salts according to claim 1, characterized in that in in a manner known per se

a) a bisquaternary N ² , N ³ -di-spiro-tripiperazinium salt of the general formula

HN N N NH

HN N N NH

Xj 'HD

with glycerine pi-chlorohydrin of the formula
Cl-CH ₁ -CH CH, (III)

implements and

40

b) if appropriate, then the compound of general formula I obtained in R the group

OH

Cl-CH ₂ -CH -

means by treatment with alkaline agents in the compound of general Formula I, in which R is the group

V-Tl ₁ V_ 11

with glycerine epichlorohydrin of the formula

Cl-CH ₃ -CH-CH ₁ (III)

O
implements and

b) if appropriate, then the compound of the general formula I obtained in which R is the group

OH

Cl - CH ₂ -CH-

mean), by treatment with alkaline agents into the compound of general formula 1, in the R the group

CH.-

-CH-

means converts.

The invention relates to therapeutically active N ² .N ³ -di-spiro-tripiperazinium salts of the general formula

RCH ₁ -N

N-CH ₁ R

means converts.

Both reactions are preferably carried out in an aqueous or aqueous-alcoholic medium; for reaction b) lithium is preferred. hydroxyd used.

For example, it is used to produce the bisquaternary

'N ¹ .N ⁴ - di - (; · - chloro - / f - hydroxypropyl) - N \ N ³ - disiro-tripiperazinium salt the N ² , N ³ -di-spiro-tripiperazinium - dichloride in an aqueous or aqueous-alcoholic medium of the reaction with glycerol epichlorohydrin and the reaction product is isolated by adding a lower alcohol or acetone to the reaction solution.

For conversion into the diepoxy derivative, the bisquaternary N ', N ⁴ -di (y-chloro - ^ - hydroxypropyl) -N ² , N ³ -di-spiro-tripiperazinium-saiz after preliminary isolation in the crystalline state or directly with the reaction solutions treated with a suitable base, preferably with lithium hydroxide, the reaction being carried out in an aqueous or aqueous (I) alcoholic medium or in another suitable solvent. The reaction pro-

duct is isolated by using the reaction mass lower alcohols, acetone or other known methods.

The new compounds have a cancerolyüsche effectiveness. For example, N ', N * -Di- (r-chloro- / J-hydroxypropyl) -N ² , N ³ -di-spiro-tnpiperazinium - diehlorid causes a clear objective remission in clinical trials, possibly up to a complete resolution tumor tissue in the first and second stages in the majority of people with cancer of the larynx, lung cancer, lymphogranulomatosis and other malignant neoplasms. The bisquartaVen N'.N ^ DHfty-epoxypropy!) - N ² , N ³ Tdi-spiro-tripiperazinium salts are not inferior to the previous preparation in terms of their cancerolytic effectiveness, they are only slightly less storable;

A comparison with the prior art shows the superior properties of one of the inventive, Compounds effective as Cytostaticum.

Table 1

The following experiments were carried out on white mice.

connection

N'.N "* - di - (; - chlorine -,; - hydroxypropyl)
N ² , N ^J -di-spiro-tripiperazinium dichloride (A)
N, N'-bis - [/ i-hydroxypropylene - ((/,; -] piperazinium-bis-p-toluenesulfonate (B)
Methyl-bis-l / i-chloroethyl / amine-N-oxide hydrochloride (C)

N, N-Bis - (, <- chloroethyl) -N'-propylenephosphoric acid ester diamide (D)
Mitomycin C

Chromomycin A,

to Virab T K LD ₅₁ , Appointment LD ₄₀ li.p.l rci- li.p.l rei- do chunas- ching- Img kg I / ahf Γ "Ι (mg tg) number E 70 + 1000 1 25th 40 7th S22 ++ 15th 7th E 27 + 394 1 26th S 37 + 30th 7th E65 + 187 I. 6th S 78- 25th 7th E 29 + 300 1 12th S 24+ + 3 7th E21 ++ 8.5 I. 3 S 24+ + 0.01 7th E- 1.6 I. S -

E = honest card. S = Crocker's sarcoma 180.

TK = weight of the treated animal group as a percentage of the weight of the control tumor (without treatment).

I + + ι ^ 1 K = 0 to 25%. I + I = 25 to 50%.

(-1 = f over 75%.

i.p. = Intraperitoneally.

Since the percentage of test animals for the effective dose (ED) is the same in all cases (X), the formation of the quotient LD ₅₀ ZED _x clearly shows that A with regard to the Crocker-Sar ^. koms 180 has better results than B (LD ₅₀ ZED _x is about the same in both cases), because B only achieves a percentage of T / K = 37, while A comes to TK = 22.

In addition, A has very little toxicity, as the following table shows:

Table II

Maximum tolerable doses

connection Müusc Rats (i.p.) lip) (mg / kg) (mg / kg) A. 900 1600 B. - 250 C. 120 40 D. 50

According to this, A is more than seven times less toxic than B.

The new salts are well tolerated by the sick, In contrast to the majority of current cytostatics, they do not inhibit blood formation and have a wide therapeutic range. The preparations are intervened in the form of aqueous solutions used and are effective from a daily dose of 30 mg (at the same time the single dose). Even when administered With a dose of 300 mg there is no need to fear serious side effects. The optimal one Daily dose is 50 to 120 mg. Needs for a cure 1.2 to 3.0 g, but in some cases up to 8.0 g total has been administered. The invention Compounds can also be used in combination with the X-ray and radiotherapy as well as with others Cytostatics, including those with the blood formation inhibiting cytostatics are administered.

To obtain therapeutic preparations, the reaction solutions obtained according to Examples 1 and 2 are diluted, which N \ N ⁴ -Di - (- chloro-zZ-hydroxypropyl) - or N \ N ⁴ -Di - (/ i,; '- epoxypropyl) -N ² , N ³ -di-spiro-tripiperazinium-dichloride contain, with ethanol up to a slight cloudiness, add activated charcoal, mix and filter. The filtrate

is passed through a filter candle made of porous Prozcllan through and mixes it with previously through a porcelain plate filtered ethanol in the amounts given in Examples 1 and 2. The precipitated crystalline Precipitate is separated from the mother liquor, washed with ethanol and under conditions dried, which exclude the penetration of microorganisms or mechanical admixtures. If necessary, the dried product is crushed and packed in ampoules or bottles. Before packing the medicine can with sodium chloride or another filler which is inert towards the drug and readily soluble in water been mixed.

Aqueous solutions are prepared from the crystalline powders obtained. which after filtering through Porcelain candles or membrane filters are filled into ampoules or glass bottles and dried in a lyophilic manner be subjected.

The injection solutions of the preparations are prepared immediately before use (ex (empore)) by dissolving the product in the ampoule or bottle, e.g. in sterile water, in a physiological solution or in a glucose solution.

example 1

N'.N ^ -DHv-chloroV-hydroxypropyl) -N ² , N -'- di-spiro-iripiperazinium dichloride

^{30 g of N 2} , N'-di-spiro-iripipcrazinium dichloride, 30 ml of water and 20 ml of glycerol epichlorohydrin are mixed in a stirred flask at 25 to 30 ° C. over the course of 2 hours. The reaction mass is then diluted with 400 ml of ethanol, the precipitate which has separated out is filtered off, washed with ethanol and carefully dried. 40 g of the end product are obtained as a white crystalline powder which contains a molecule of water of crystallization, dissolves easily in water and is practically insoluble in several common organic solvents.

F. 270 to 273 C (decomposition).

Analysis for C _1H H., "CKNi * 2Cl · H ₂ O:

Calculated:

C 43.2. H 7.66. CI 2 ", 34. Cl "14.17.

NIUO. H ₂ O 3.6%;
»Cfound:
"C 43.49. H 7.66. CI 28.03. Cl" 14.15.

N 11.38. H, O 3.00%.

Example 2

N'.N ⁴ -Di - (, ..; - cpoxypropyl) -N ² .N'-di-spirotripiperazinium dichloride

a) The solution of 7.5 g of the N ¹ .N ⁴ - di - (; · - chlorine - 1 '> - hydroxypropyl) -N-, N'-di-spiro-tripipcrazinium dichloride in 8 A 5% aqueous lithium hydroxide solution is gradually added to ml of water at 60 ° C. until the reaction to thymolphthalein remains constant. After the reaction has subsided, the solution is cooled. add ethanol until cloudy and activated charcoal, mix and filter. 100 ml of ethanol are added to the filtrate, the deposited precipitate is filtered off and dried in vacuo without heating. 5.7 g of the end product are obtained as a white crystalline powder which contains two molecules of water of crystallization, easily dissolves in water and practically in alcohol. Chloroform. Acetone and ether is insoluble.
F. 2SO to 285 C (decomposition).

Analysis for C ₁₈ H ₃₄ N ₄ O ^{2 +} 2Cl 2H ₂ O:

Calculated ... C 48.53. H 8.60, Ci 15.90%:
found .... C 48.39. H 8.47, Cl 16.00%.

You can also work as follows: The reaction ^{solution obtained by reacting glycerol epichlorohydrin and N 2} .N ^J -Dispiro-tripiperazinium-dichloride according to Example 1 is gradually added at 60 C until the alkaline reaction to thymolphthalein is maintained, the aqueous lithium hydroxide solution . The reaction solution is treated as indicated above. To isolate the end product, the solution is diluted with 50OmI ethanol. 29.5 g of N ', N ⁴ -Di - (//, _r -epoxypropyl) -N ² , N ^J -dispiro-tripiperazinium dichloride are obtained.

Claims (1)

/ j where R is the group Patent claims: OH k N% N ^ di-spiro-tripiperazinium salts of the general formula RCH ₁ -NNN N-CH ₁ R wherein R is the group ' ^r OH Cl-CH, -CH - or X ₂ - (D ίο Cl-CH ₁ -CH-