DE1670643B2 - 2-GUANIDOMETHYL-PERHYDROAZOCINE, PROCESS FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING 2-GUANIDINOMETHYL-PERHYDROAZOCINE - Google Patents

Description

and its therapeutically acceptable salts.

2. Method of making the connection according to claim 1, characterized in that a-aminomethylperhydroazocin is used in a manner known per se of formula II

(CH ₂ J ₆ CH-CH ₂ -NH ₂ (II)

I NH

either with a compound of the general formula III

ZC-NH ₂

Il

NH

(III)

in which Z is a lower alkoxy, alkyl mercapto, amino or nitroso group, or with Reacts cyanamide in the presence of a polar solvent and optionally the obtained Product with an inorganic or organic acid in a therapeutically acceptable Saiz convicted

3. Pharmaceutical preparations with antihypertensive effects, containing a compound according to Claim 1.

The invention relates to a new guanidino-alkylcycloimine derivative, namely the 2-guanidinomethyl-perhydroazocin and its salts, a process for their Manufacture and pharmaceutical preparations with antihypertensive effects containing this new compound contain.

It has been found that the new compound of formula I

(CH ₂ J ₆ CH-CH ₂ -NH-C-NH ₂ (I)
'NH NH

and therapeutically acceptable salts of this compound show very valuable pharmacological properties. These new compounds have a longer lasting effect on lowering blood pressure. Your characteristic The sympathetic-blocking effect lasts up to 10 days in animals. They trigger an increase in the tone of the nictitating membrane as a result of the release of catecholamines and cause a general decrease in sympathetic tone with simultaneous abolition of the reflex mechanisms that increase blood pressure (e.g. carotid). «: Ip are better absorbed with oral administration,

have fewer side effects than guanethidine (165 mg / kg Lv. in mice) and have one more favorable therapeutic range of effects.

The invention also relates to a process for the preparation of the compounds according to claim 1, which characterized in that α-aminomethyl-perhydroazocin is used in a manner known per se Formula Il

(CH ₂ J ₆ CH-CH ₂ -NH ₂

NH

(H)

either with a compound of the general formula III

ZC-NH ₂
NH

(III)

in which Z is a lower alkoxy, alkyl mercapto, amino or nitroso group, or with cyanamide in Reacts the presence of a polar solvent and optionally the product obtained with a inorganic or organic acid converted into a therapeutically acceptable salt.

The starting compound of the formula II is a new compound.

The polar solvent used as the reaction medium can also be a solvent mixture. Water is preferred.

If desired, the active ingredients obtained can be used therapeutically with inorganic or organic acids compatible salts are transferred. The bases or salts obtained can be used alone or together with one or more other biologically active agents using in the Pharmaceutical production common carriers and auxiliaries in medicinal preparations with antihypertensive agents Effect will be transferred.

Attempt 1

Results of comparative tests between 2-guanidinomethyl perhydroazocin sulfate · H2O and Guanethidine (2-octahydro-1-azocinyl) ethyl guanidine sulfate).

Table I. species 2-guanidinomethyl
perhydroazocin
sulfate H ₂ O (mg / kg) Guanethidine toxicity (LD ₅₀ ) (144-132) Dosie
tion mouse 138 (640-581) 13.3
(14.4-12.2) Mau3 610 (737-665) 105
(118-92) I.v. mouse 700 (2813-2134) 224 ± 47 I.p. mouse 2450 (233-176) 845 ± 60 S. c. rat 202 (968 - 492) 32.5
(36-29.5) P.O. rat 690 (3133-2431) - I.v. rat 2760 852 ± 73 S. c. P.o.

In anesthetized dogs and cats, the compound causes doses of 1-10 mg / kg L v. a two- and sometimes three phase effects on blood pressure. The drop in blood pressure that occurs within a minute is followed by a decrease in blood pressure proportional to the dosage growing, characteristic of guanethidine Blue pressure increase. The measure of secondary blood

Table II Systolic blood pressure values in conscious, hypertonic rats (Hgmm)

The reduction in pressure is determined by the individual sensitivity of the individual animals

In the course of the experiments on nephrogenic hypertonic rats it has been shown that the compound in s.c. or p.o. Dosage greatly and permanently lowers blood pressure

Before the 2-guanidinomethyl 1 4th 142 24 48 120 96 Be
plot perhydroazocin sulfate Η /) Hours after treatment p <0.01 174 3 10mg / kg s.c. 153 152 146 170 Guanethidine p <0.05 162 p <0.05 p <0.01 p <0.01 3 10mg / kg s.c. p <0.05 173 157 48 152 161 171 p <0.05 Hours after treatment p <0.001 P <0, I. Before the 24 72 Be
plot

2-guanidinomethyl 146 150 163 172 perhydroazocine sulfate ■ H ₂ O p <0.001 p <0.001 ρ <0.05 p <0.6 2 x 25 mg / kg p.o. Guanethidine 171 159 167 170 2 x 25 mg / kg p. O. p <0.001 ρ <0.05

Similar effects were seen in hypertensive dogs 35 Table IH observed. The toxicity was 48 hours after the administration

systolic blood pressure decrease still significant (p-value

less than 0.01). link

Attempt 2

Results of comparative tests between 2-guanidinomethyl perhydroazocin sulfate · H2O and 3- [Isoindolinyl (2)] propylguanidine sulfate (DT-PS

12 26 103, example 3).

The experiments were carried out on white mice; the compounds administered intravenously and the LD »values calculated on the basis of the mice which died after 24 hours:

Table IV Ptosis effect

LI) ₅₀ mg / kgi.v.

3- [Isoindolinyl- (2) J-propylguanidine-17 (18,5-I.S, 6) sulfate

2-guanidinomethyl perhydroazocine sulfate · H C)

138 (144-132)

The ptosis exposure studies were on white mice using 10 animals per dose.

link

dose

(mg / kg
po)

Average ptosis after treatment of

3 4

hours

control

3- [isoindolinyl- (2)] propyl-10 guanidine sulfate 40

2-guanidinoniethyl-10

perhydroazocine sulfate · H ₂ O

The ptosis values were determined according to the method of Brodis and coworkers. The adrenergic neuro-blocking effect was on

0.3 0.2 0.3 0.2 0.3 0.3 0.4 0.3 0.2 0.2 0.2 0.3 0.3 0.1 0.3 0.3 0.3 0.2 0.6 U 1.2 - 1.0 1.0

anesthetized cats. The trunk The sympathetic nerve of the neck was stimulated pregangliori with square wave impulses (3–10 V, 0.5–1.0 msec,

25-30 Hz) and the contraction of the nictitan membrane is recorded

Table V
Adrenergic neuroblocking effect

link dose Contraction
inhibition (mg / k «
Lv.) (%) 3- [isoindolinyl- (2)] - prop.yl-
guanidine sulfate 1 5.6 the same 5 29.7 the same 10 36.1 2-guanidinomethyl
perhvdroazocin-
sulfate · H ₂ O 5 100

The studies show that an IV dose of 5.0 mg / kg of the compound 3 {isoindolinyl (2)] propylguanidine sulfate the contraction of the nictitan membrane does not significantly affect a similar dose to the Compound 2-guanidinomethyl-perhydroazocin-sulfate - H2O, on the other hand, causes 100% inhibition.

The table values illustrate the superiority of the 2-guanidinomethyl perhydroazocine of the invention.

The process according to the invention is to be illustrated in more detail by the following examples.

example 1

71.20 g (0.5 mol) Λ-aminomethyl-perhydroazocin (it's = 1.4870; KP 96-102 ° C / 10 torr; melting point of the sulfate salt 262-264 ° C), 100 ml of distilled water and 10435 g (0.75 mol) S-methylisothiourea sulfate are introduced into a 250 ml round-bottom flask equipped with a stirrer and reflux condenser, the mixture is heated to the boiling point within half an hour and refluxed for 4 hours, the methyl mercaptan escaping at the top of the condenser is absorbed.

The homogeneous reaction mixture obtained is allowed to cool and stand for 24 hours at room temperature, then it is cooled to 5-6 ^° C. The precipitated white crystals are filtered off, washed on the filter with a little acetone and dried. 78.4 g of crude product are obtained and, after standing, a further 11.4 g from the mother liquor, so that the total amount of the product is 89.4 g (59.6% ) amounts to; Mp. 235-237 ⁰ C.

The product is recrystallized by dissolving it in an equal volume of water and cooling. 783 g are obtained (52.6% of theory) of the product. Mp. 239-241 ° C. The white crystalline product contains 1 mol of water of crystallization.

Analysis for C ₉ H ₂₄ N ₄ O ₅ S (30037):

Calculated:

C 36.00, H 8.05. N 18.68, S 10.67, O 26.61%,

found: C 36.12. H 8 ^ 0, N 18.61. S 1024. O 27.03%.

Based on the spectroscopic (UV, IR) characteristics, the product obtained is 2-guanidinomethyl perhydioazodn sulfate - H ₂ O.

Example 2

28.45 g (02 mol) «- aminomethyl perhydroazocin and 172 g (02 mol) nitrosoguanidine are distilled in 100 ml Dissolved water, the mixture was left to stand for a day, then 8 hours on a water bath at 75 ° C stirred the cooled solution neutralized with dilute sulfuric acid and after clarifying and filtering concentrated to 50 ml by vacuum distillation. 282 g of a white product precipitate from the solution is crystallized in the usual way. It will be 24.5 g (41.0% of theory) Pure product, melting point 239-24 ° C.

Based on the analysis and the spectroscopic characteristics, the product obtained is 2-guanidinomethyl perhydroazocine sulfate · H2O.

Example 3

28.45 g (02 mol) «- aminomethyl-perhydroazocin and 924 g (022 mol) of dynamide are dissolved in 40 ml of water with stirring and heating, the resulting solution a few drops of acetic acid added, then that The mixture is heated to boiling on the steam bath for 3 hours, an equivalent amount of sulfuric acid being added dropwise. The still hot mixture is clarified, then filtered, left to stand at room temperature for 24 hours, then ^{cooled to 5-6 °} C. and that

The crude product is filtered off. 35.2 g of white are obtained Crude product After recrystallization, 31.0 g of pure product (51.6% of theory) mp 237-240 ° C. are obtained.

Based on the analysis and the spectroscopic characteristics, the product obtained is 2-guanidino methyl perhydroazocin sulfate ^ O of the formula C ₉ H ₂₄ N ₄ O ₅ S.

Example 4

568 g (4.0 mol) of ot-aminomethyl-perhydroazocin are dissolved in 400 ml of distilled water in a 4-1 round bottom flask equipped with a stirrer, the mixture first 500 ml of 8 η-sulfuric acid and then 560 g (4.0 mol ) S-methyl-isothiourea sulfate added with stirring, followed first for 1 hour at 6O ⁰ C and then for 2 hours at 100 ° C for the reaction mixture is cooled to 10-15 ° C and filtered off the precipitated crude product. After recrystallization in water, 970 g (81%) of pure product, melting point 239 ° -241 ° C., are obtained.

On the basis of the analysis and the spectroscopic characteristics, the product obtained is 2-guanidinomethyl perhydroazocine sulfate ■ H ₂ O.

Claims (1)

Patent claims: 1. 2-guanidinomethyl-perhydroazodn of the formula (CH ₂ J ₆ CH-CH ₂ -NH-C-NH ₂ NH NH