DE1670643C3 - 2-guanidomethyl-perhydroazocin, process for its preparation and pharmaceutical preparations containing 2-guanidinomethyl-perhydroazocin - Google Patents

Description

and its therapeutically acceptable salts.

2. Process for the preparation of the compound 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
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 salt convicted.

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

The invention relates to a new guanidino-alkylcycloimine derivative, namely 2-guanidinomethyl-perhydroazocine and its salts, a process for their preparation and pharmaceutical preparations with antihypertensive Effect that this new compound included.

It has been found that the new compound of formula I

(CH ₂ ) ₆ CH-CH ₂ -NH-C-NH ₂ (1)
I μη NH

and therapeutically acceptable salts of this compound show very valuable pharmacological properties. These new compounds have a longer lasting effect on blood pressure lowering. 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). They are better absorbed when administered orally,

have fewer side effects than guanethidine (165 mg / kg i.v. 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 is characterized in that in a known manner oc-aminomethyl-perhydroazocin der Formula II

(CH ₂ I ₆ CH-CH ₂ -NH ₂

NH

(ID

either with a compound of the general formula III

ZC-NH ₁
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 formula II is a new compound.

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

The active ingredients obtained can, if desired be converted into therapeutically acceptable salts with inorganic or organic acids. the Bases or salts obtained can be used alone or together with one or more other biological effective means, using carriers and Aids can be converted into medicinal preparations with antihypertensive effects.

Attempt 1

Results of comparative tests between 2-guanidinomethyl perhydroazocin sulfate · H2O and Guanethidine (^ -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) mouse 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 effect on blood pressure. The drop in blood pressure, which occurs within one minute, is followed by a rise in blood pressure characteristic of guanethidine, which increases proportionally with the dosage. The Degree of Secondary Blood Table II
Systolic blood pressure values in conscious, hypertensive 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. 5 or p.o. Dosage greatly and permanently lowers blood pressure

Before the 2-guanidinomethyl 1 4th 142 150 24 48 161 120 96 I. Be
plot perhydroazocine sulfate · H ₂ O Hours after treatment p <0.01 p <0.001 p <0.00! p <0, l I. 174 3 x 10 mg / kg s.c. 153 152 146 170 172 I. Guanethidine ρ <0.05 162 159 p <0.05 p <0, Eq p <0.01 p <0.6 I. 3 x 10 mg / kg sc p <0.05 p <0.001 I. 173 157 48 152 171 170 ι p <0.05 Hours after treatment Before the 2-guanidinomethyl 24 146 i Be
plot perhydroazocine sulfate · H ₂ O p <0.001 ■, 5 176 2 - 25mg / kg p.o. 72 r. Guanethidine 171 2 x 25 mg / kg p.o. 163 ■ i 172 p <0.05 k 167 ρ <0.05

40

Similar effects were seen in hypertensive dogs 35 Table III

observed. The toxicity was 48 hours after the administration

systolic blood pressure decrease still significant (p-value

less than 0.01). connection

Attempt 2

Results of comparative tests between 2-guanidinomethyl perhydroazocine sulfate · H ₂ O and 3- [isoindolinyI- (2)] propyIguanidine sulfate (DT-PS

12 26 103, example 3).

The experiments were carried out on white mice; the compounds administered intravenously and the LD50 values calculated on the basis of the mice that died after 24 hours:

Table IV
Ptosis effect

LD ₅₀ mg / kg iv

3- [Isoindolinyl (2)] propylguanidine-17 (18.5-15.6) sulfate

2-guanidinomethyl perhydroazocine sulfate · H ₂ O

138 (144-132)

45 The ptosis activity studies were carried out on white mice, 10 animals being used per dose.

connection

Dose mean ptosis after treatment of

(mg / kg 12 3

p.o.) hours

control - 0.3 0.2 0.3 0.2 3- [isoindolinyl- (2)] propyl
guanidine sulfate 10
40 0.4
0.3 0.3
0.1 0.2
0.3 0.2
0.3 2-guanidinomethyl
perhydroazocin
sulfate · H ₂ O 10 0.6 1.1 1.2

0.3

0.2 0.3

1.0

0.3 0.3 0.2 1.0

The ptosis values were determined according to the method of Brodis and coworkers.
The adrenergic neuroblocking effect was carried out on anesthetized cats. The sympathetic trunk of the neck was stimulated preganglionically with square wave pulses (3–10 V, 0.5–1.0 msec,

25-30 Hz) and the contraction of the membrane is registered nictitans

Table V
Adrenergic neuroblocking effect

connection dose Contraction
inhibition (mg / kg
iv) (%) 3- (isoindolinyl (2)] propyl
guanidine sulfate 1 5.6 the same 5 29.7 the same 10 36.1 2-guanidinomethyl
perhydroazocin
sulfate ■ H ₂ O 5 100

.1 °

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

The tabular 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 t

35

71.20 g (0.5 mol) of a-aminomethyl-perhydroazocin (nf = 1.4870; KP 96-102 ° C / 10 torr _; m.p. of the sulfate salt 262-264 ° C), 100 ml of distilled water and 104, 35 g (0.75 mol) of 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, with the one at the top of the condenser escaping methyl mercaptan 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 unusual white crystals are filtered off, washed on the filter with a little acetone and dried. You get 78.4 g of crude product and from the mother liquor after standing another 11.4 g, so that the total amount of the Product is 89.4 g (59.6%); M.p. 235-237 ° C.

The product is recrystallized by dissolving it in an equal volume of water and cooling. Mar. receives 78.9 g (52.6% of theory) of the product. M.p. 239-241 "C. The white crystalline product contains 1 mole of water of crystallization.

Analysis KJrCH ₂₄ N ₄ O ₅ S (300.37):

Calculated:

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

found:

C 36.12, H8Ä N 18.61, S 10.24, 0 27.03%.

Based on the spectroscopic (UV, IR) characteristics, the product obtained is 2-guanidinomethyl perhydroazocine sulfate · H2O.

Example 2

28.45 g (0.2 mol) of a-aminomethyl-perhydroazocin and 17.2 g (0.2 mol) of nitrosoguanidine are dissolved in 100 ml of distilled water. 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. 28.2 g of a white product precipitate from the solution recrystallized in the usual way. 24.5 g (41.0% of theory) of pure product, melting point 239 ° -24 ° C. are obtained.

On the basis of the analysis and the spectroscopic characteristics, the product obtained is 2-guanidinomethyl perhydroazocine sulfate · H2O.

Example 3

28.45 g (0.2 mol) of ot-aminomethyl-perhydroazocin and 9.24 g (0.22 mol) of dynamide are dissolved in 40 ml of water with stirring and warming, a few drops of acetic acid are added to the resulting solution, then the mixture is left on for 3 hours Steam bath heated to the boil, 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 the crude product filtered off. 35.2 g of white crude product are obtained. 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-guanidinomethyl perhydroazocine sulfate H2O of the formula C ₉ H ₂₄ N ₄ O ₅ S.

Example 4

568 g (4.0 mol) of Λ-aminomethyl-perhydroazocin are distilled in a 4-1 round bottom flask equipped with a stirrer in 400 ml. Water dissolved, the mixture is first 500 ml 8-η sulfuric acid and then 560 g (4.0 mol) of S-methyl-isothiourea sulfate added with stirring, followed first for 1 hour at 6O ⁰ C and then 2 hours at 100 "C for The reaction mixture is ^{cooled to 10-15 °} C. and the precipitated crude product is filtered off. After recrystallization in water, 970 g (81%) pure product, melting point 239-24 ° 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 perhydroazocine of the formula (CH ₂ J ₆ CH-CH ₂ -WH-C-NH ₂ NH (I)