DE1238034B - Process for the preparation of N, N'-bis- [beta-hydroxypropylene- (alpha, gamma)] -piperazinium-bis-p-toluenesulfonate - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 ρ - 6

Number: 1 238 034

File number: Y 773IV d / 12 ρ

Filing date: January 2, 1964

Opened on: April 6, 1967

The invention relates to a method of manufacture of N, N'-bis- [ß-hydroxypropylene- (a, y)] -piperazinium-bis-p-toluenesulfonate the formula

/ CH-2 \ / CH2 CH ₂ \ / CH ₂ \
/ \ ® / \ s / \

HO-CH N N CH-

^ / ^ CH ₂ -CH- / '

OH 2 O - SO ₂

CH ₃

The N ₅ N'-bis [β- hydroxypropylene- (a,) ')] - piper- [5 azinium-bis-p-toluenesulfonate is prepared by either

a) Piperazine with / 3, y-epoxy-a- (p-toluenesulfonyloxy) -propane the formula

CHo - CH - CH ₂ - O - SO ₂

/ V

CH ₃

II Process for the preparation of N, N'-bis - [/? - hydroxypropylene- (a, /)] - piperazinium bis-p-toluenesulfonate

Applicant:

Yamanouchi Seiyaku K. K., Tokyo representative:

O. Schießl, lawyer,

Stamberg, Wittelsbacherstr. 6th

Named as inventor:

Dr. med. Kiyoshi Morisawa, Kanagawa; Dr. Yoshihiko Oka,

Kaichiro Ichikawa,

Noriko Kamoto, Tokyo (Japan)

Claimed priority:

Japan August 8, 1963 (Sho 38-40 702), September 11, 1963 (Sho 38-48 547)

implements or
b) a compound of the general formula

OH

Shark - CH ₂ - CH - CH ₂ - n '

/ CH ₂ - OH

N-CH ₂ -CH-CH ₂ -HaI

III

wherein Hal is a halogen atom, with silver p-toluenesulfonate of the formula

Ag-O-SO ₂ -reacts or

c) a compound of the general formula

/ CH ₂ N. / CH ₂ -CH ₂ HO -CH IV

in aqueous solution with a basic ion exchange resin with p-toluenesulfonic acid has been neutralized, treated or

CH ₂ N

CH - OH ■ 2 shark ⁹

e) a compound of the general formula V is reacted with silver p-toluenesulfonate of the formula IV.

d) a compound of the general formula V The procedure a) is at low temperature with

reacted with p-toluenesulfonic acid or carried out a molar ratio of I: 1. the

709 548/387

The reaction can be carried out in an organic solvent, for example methyl alcohol or ethyl alcohol, be performed. The reaction mixture thus obtained can be distilled to dryness, and if necessary, the residue is purified by recrystallization.

The starting material of the formula II is according to that described in US Pat. No. 2,755,290 Process made.

In the procedure b) can be used as a solvent, for example, acetonitrile or a mixture of Acetonitrile can be used with methyl alcohol. The reaction is protected from by heating Light carried out. It should be in this procedure, the silver sulfonate in an amount of 2 moles per mole the compound of the general formula III can be used. After the implementation, it is deposited The silver halide is filtered off and the filtrate is evaporated to dryness under reduced pressure. Of the residue obtained in this way is recrystallized.

The compounds of general formula III used as starting materials can be prepared according to the in "Journal of Medical and Pharmaceutical Chemistry", Vol. 1, p. 223, described method prepared will.

The implementation according to procedure e) is carried out in accordance with procedure b) described above carried out.

Starting materials of the general formula V can be prepared by allowing a compound of the general formula III to stand for a long time at room temperature or by boiling with water. However, N, N '- bis - [ß - hydroxypropylene - (α, γ)] - piperazinium dihalide is prepared by treating the corresponding sulfonate obtained according to procedures a) and b) through an anion exchange resin layer.

The Ν, Ν'-bis - [// - hydroxypropylene obtainable according to the invention - (a, y)] - piperazinium - bis - ρ - toluenesulfonate shows an excellent therapeutic effect against transplantable tumors of animals, especially mice and rats, and has low toxicity to animals. The connection can accordingly can be used as anti-tumor agents.

The following Table I shows the antitumor effectiveness and the toxicity of those obtainable according to the invention Compound and, for comparison, the corresponding properties of commercially available Anti-tumor drugs. The compound obtainable according to the invention is denoted by I.

Table I.

link

ED
(ip)

(mg / kg)

Number of administrations T / K

( ⁰ W

LD «,
(i. P-)

(mg / kg)

number of
Administrations

LDv,
ED

I.

Methyl bis (/ j-chloroethyl) amine-N-oxide hydrochloride

N, N-bis (/ i-chloroethyl) -N'-o-propylene phosphoric acid ester diamide

Mitomycin C

Chromomycin A3

Remarks:

15th

30th

25th

3.0

0.01

E 27 +

S 37 +

E 65 +
S 78 -

E 29 +

S 24 + ■

E 21 + -
S 24 + -

E S

394

187

300

8.5

1.6

1. The letter "E" means Ehrlich's carcinoma, and the letter "S" means Crocker's sarcoma 180.

2. TjK (%) is the average tumor weight of mice treated with the drug, expressed as a percentage of the tumor weight of an untreated control mouse.

3. The evaluation is for a T / K value of 0 to 25% by the sign (- +), for 25 to 50% by the sign (-), for 50 to 75% by the sign (±) and expressed for more than 75% by the sign (-).

The ED value is the effective dose at which each compound exhibits an antitumor activity of the magnitude of TjK listed in Table I. Thus, the compound obtainable according to the invention shows a sufficient anti-tumor effect if it is applied seven times in a single dose of one twenty-sixth of the LDo, while the administration of methyl - bis - (ß - chloroethyl) - amine-N-oxide hydrochloride has a TjK value gives at least 65% even when administered seven times in a single dose of one-sixth of the LD50; Chromomycin A3 has no activity at all against solid type tumors.

The maximum tolerated doses for various animals are given in Table II.

Table II Maximum Tolerated Dose (mg / kg)

link Mice (i.p.) Rats (i.p.) Dogs (i.p.) I. 120 250
40
50 100 (approximate)
(SC)
5 (ip)
100 (ip) Methyl bis (/} - chloroethyl) amine N-oxide hydrochloride
N ^ -Bis-i / i-chloräthy ^ -N'-o-propylene phosphoric acid-
ester-diamide

»Ip« means intraperitoneal administration,
"Sc" means subcutaneous administration.

The following examples are intended to illustrate the invention.

example 1

To 15.1 g (0.066 mol) ^, _r -Epoxy-a- (p-toluenesulfonyloxy) propane in 15 ecm methyl alcohol was added a solution of 2.8 g (0.033 mol) anhydrous piperazine in 15 ecm methyl alcohol with stirring and cooling ( 5 to 10 ⁰ C) was added. The reaction mixture was stirred for 3 hours and allowed to stand at room temperature. A crystalline mass appeared which was filtered off and then dissolved in methyl alcohol. The methanol solution was treated with activated charcoal and filtered. Ether was added to the filtrate; as a result, 4.5 g of N, N'-Bi.s - [/ i-hydroxypropylene- (a, 7)] - piperazinium-bis-p-toluenesulfonate precipitate in the form of platelets; M.p. 254 to 255 ⁰ C (decomposition); Yield: 25.2%. The compound is soluble in water and reacts strongly with sodium thiosulfate.

Elemental analysis: C24H34N2O8S2, molecular weight 542.68.

35

Calculated ... C 53.12, H 6.32, N 5.16%;
found ... C 52.85, H 6.30, N 5.22%.

40

When the above reaction was carried out at a temperature of 0 to 5 ° C., it was initially obtained N, N'-bis- [y- (p-toluenesulfonyloxy) -j3-hydroxypropyl] -piperazine, which was very unstable and when recrystallized from dimethylformamide into pure crystalline Ν, Ν'-bis [y- (p-toluenesulfonyIoxy) - /? - hydroxypropylj-piperazine converted; M.p. 245 to 246 ° C (decomposition); Yield: 52%.

Example 2

_{2.7 g (0.01 mol) of N 5} N '- bis (γ - chloro - β - hydroxypropyl) piperazine were dissolved in 100 ecm of a mixture (8: 2) of acetonitrile and methyl alcohol. To the solution obtained, 5.6 g (0.02 mol) of silver p-toluenesulfonate, dissolved in 25 ecm of the above solvent mixture, were added. The resulting mixture was heated 50 hours at 4O ⁰ C under protection from light. Silver chloride was filtered off and the filtrate was evaporated to dryness under reduced pressure. The product obtained was dissolved in methyl alcohol, the solution treated with activated charcoal and filtered, and the filtrate was treated with ether, whereby 1.1 g of N, N '- bis - [ß - hydroxypropylene - (α, γ)] - piperazinium bis- precipitated p-toluenesulfonate; Mp 255-256 ° C (decomposition); Yield: 20.3%. The product showed no melting point depression when mixed with a sample of the compound prepared according to Example 1 and was further identified by elemental analysis and infrared absorption spectrum.

Example 3

224.2 mg of N, N '- bis - [ß - hydroxypropylene - (α, γ)] - piperazinium dichloride were dissolved in 10 ecm of water, and the resulting solution was passed through a column with 20 ecm of a strongly basic anion exchange resin which an aqueous p-toluenesulfonic acid solution had been passed through, passed at a rate of 1 ecm per minute. It was then eluted with distilled water at the same rate until 250 ecm of eluate was collected. The eluate was evaporated to dryness under reduced pressure on a water bath at 40 to 50 ° C. The crude crystalline product thus obtained was dissolved in methyl alcohol and the resulting solution was worked up in the same manner as in Example 1. 370 mg of N, N'-bis - [/? - hydroxypropylene- (a, y)] - piperazinium-bis-p-toluenesulfonate were obtained; F. 255 to 256 ⁰ C (decomposition); Yield: 82.7%. This compound showed no melting point depression when mixed with a sample of the compound obtained in Example 1, and was further identified by elemental analysis and infrared absorption spectrum.

Claims (1)

Claim: Process for the preparation of N, N'-bis- [ß - hydroxypropylene - (α, γ)] - piperazinium - bisp-toluenesulfonate of the formula /
HIGH CH2 - CH ₂ - CH-OH-2 Ο —SO ₂ CH ₃ characterized in that either in a known manner 7 8 a) Piperazine with / i,} '- epoxy-a- (p-toluenesulfonyloxy) propane of the formula CH ₂ - CH - CH ₂ - O - SO ₂ - <\ ~~ \ - CH ₃ II implements or b) a compound of the general formula Hal-CH ₂ -CH-CH ₂ -NN -CH ₂ -CH-CH ₂ -HaI III in which Hal denotes a halogen atom, with silver p-toluenesulfonate of the formula Ag - Q-SO ₂ - ^ ^ -CH ₃ IV reacts or c) a compound of the general formula / CH ₂ X / CH ₂ -CH _2x / CH _2x HO-CH N N CH-OH-2 Hal = V ^ CH ₂ / NrH ₃ -CH ₃ / ^ CH ₂ / in aqueous solution with a basic ion exchange resin which neutralizes with p-toluenesulfonic acid has been treated or d) a compound of the general formula V is reacted with p-toluenesulfonic acid or e) a compound of the general formula V is reacted with silver p-toluenesulfonate of the formula IV. Documents considered: German Auslegeschrift No. 1111 638; Houben - Weyl, Methods of Organic Chemistry, 4th Edition, Vol. XI / 1 (1957), p. 314 if .; Vol. XI / 2 (1959), pp. 621, 622. 709 548/387 3. 67 © Bundesdruckerei Berlin