DE1470010C - - Google Patents

Description

i 4 / UUlU

The invention relates to N - (/? - guanidinoethyl) -6-azaspiro [2.5] octane (I),

f - CH ₂ - CH ₂ - NH - C = NH

NH ₂ (I)

its pharmaceutically acceptable salts with acids and processes for the preparation of these compounds.

It has been found that these substances have a lasting antihypertensive effect and are effective. are bearable. Compared to guanethidine, equitoxic doses lower the blood pressure in rats more and more persistent.

These connections are made by one in a manner known per se either

a) 6-Azaspiro [2.5] octane with / i-guanidinoethyl halide or with guanidinoacetyl halide and in the latter case with lithium aluminum ' hydride reduced or

b) N - (ß - Ämirioäthyl) - 6 - azaspiro [2,5] bctane with a salt of S-alkyl-isothiourea or with "cyanamide or with alkyl-isdurea

and 'optionally: the compound obtained according to a) or b) converted with acids into a pharmaceutically acceptable salt.

A preferred embodiment of the process according to the invention consists in that the N - (/ S-aminoethyl) -6-azaspiro [2.5] oetane is mixed with the sulfate of the S-methylisothiourea in a molar ratio of 2: 1 ^; Heated in an appropriate solvent such as water or an alcohol for one hour at reflux temperature under nitrogen. In this way one obtains the sulphate of N - (/ S-guanidino-; ether) -6-azaspirö [2.5] octane, from which the base can be obtained after making it alkaline; it can easily be converted into any other pharmaceutically acceptable salt of a mineral acid or an organic acid.

© as "N- ⁱ (j5-Äminoäthyl) -6-azaspirQ [2.5] octane can be prepared by NT (Cyäriömethyl) -> 6-azaspirö [2.5] octane in an inert solvent, such as ether or tetrahydrofuran, with a corresponding reducing agent, such as lithium lithium aluminum hydride, reduced. nvi; - ■; ^ ■ '- ^r ' ^{:: ^;}

The N ^ (Cyanomethyiy6-azaspiro [2,5] octane is obtained by adding equimolar amounts of the underlying azaspiro alkane and a halo-acidic acidity in an aromatic hydrocarbon, e.g. benzene, in the presence of a Alkaline reagent, such as raelium coffee, for a few hours "adf ^; reflux temperature ^r irhitzt ₎ " üni ^: to fix the denatured maleic hydrous acid. y ei; - y ^ -. ■.; :: Λ ν:

The '6-Azasrjiro [2J5] octane obtained; män by reduction of Ö ^ f ^ CS ^ spiroplSOöctanidion ,?)' [^ DimethylenrB -spiroipiperidin-äion-IIIo ^^ extending äurch'Pyrolyse its part of Arhmoniumsälzes the cyclo ^ ropan -jöiessigsäüre-l ,! ! obtained at 250 ibis 300 ° C. ■ -; ^v

Sedspie'l

Ammonia enter until complete dissolution. Then bringing the vessel whose contents are held under ammonia, in a pre-heated to 90 ⁰ C metal bath, the heating is 30 minutes 115 to 125 ° C continued until the water completely evaporated, .. then brings the temperature of the bath to 250 to 260 ⁰ C and holds it for 35 minutes. After: 20 minutes the ammonium salt melts, which is followed by dehydration. The contents of the vessel are allowed to cool, dissolved in 250 ecm boiling ethyl acetate, filtered through activated charcoal, the filtrate is allowed to freeze, air-dry, washed with ethyl acetate and dried in vacuo. 9.9 g (yield 35.6%) of 6-Azäspiro [2.5] octanedione (5.7), which is soluble in alcohols but not very soluble in ether, are obtained; Melting point 165 ° C. .. '' ·.

b) 6-azaspiro [2.5] octane

Into a 1-1 two-necked flask with stirrer and Soxhlet extractor containing 35.7 g (0.257 mol / g) 6-azaspiro [2.5] octanedione (5.7) and on top of which a calcium chloride tube fitted Sitting cooler, 19.5 g (0.51 mol / g) lithium aluminum hydride are placed in 500 ecm of anhydrous ether. By refluxing the ether for 8 hours, the dioh is continuously brought into contact with the reducing agent. The reduction is ended by heating under reflux for 5 and _{2 hours;} then allowed to cool the whole to 0 ⁰ C-hydrolyzed successively with 20 cc of water, 15 cc of 15 ° / oig ^em soda and 70 cc of water, mineral salts dries in the air, washed three times with ether, the ether solution dries a Night over potassium carbonate, filtered, drives off the ether and rectifies the liquid residue in vacuo. 18.5 g (65% yield) of 6-azaspiro [2.5] octane are obtained, which passes over peat at 59 to 60 ° C / 4 and consists of a colorless liquid which is soluble in alcohols, benzene, ether, etc. and at the. Air very quickly absorbs carbon dioxide and water; in "" ² = L4672. ^v ■

The picrate crystallized from alcohol melts at 195 ° C. ■. ■■■■ - '^;'''""V.''.ν'-.;.

31.6g • '(0 ^ 2MoVg) ^ OyclQpropane-acetic acid-l,! Are suspended in 30xcm' of water, through the ^ capillary ^{: are left in (a Claeiserik flask with a capillary and a snake condenser with a double jacket}

c) N-cyanomethyl-6-azaspiro [2.5] octane

14.5 g (0.192 mol / g) chloroacetonitrile, 10.2 g (0.095 mol / g) sodium carbonate and 250 ecm benzene are placed in a 1-1 three-necked flask with a dropping funnel, a stirrer and a cooler. A solution of 17.8 g (0.16 mol / g) 6-azaspiro [2.5] octane in 100 ecm benzene is gradually added through the dropping funnel, 0.5 ecm water is added and the mixture is heated : Hours of stirring _{to the} back. The mineral salts are air-dried and washed twice with benzene; dry the benzene solution overnight over sodium sulfate, filter, drive off the benzene from the water bath and rectify in vacuo. In this way, 31 % ! orm eineriTarblosen ^s liquid welchebei 83 ° C / 1 * is 2Torr passes and mblichen organic solvents ilöslidh; τι} ⁹⁴ = 1 ^ 4805 - Γ!?.

d) "N-0S-aminoethyl) - * 6Tazaspiro [2; 53octane

In ^ a 2-KDreihälskcilberi; Tr opftf ^ichter! Cooler with calcium chloride and a stirrer are given: a suspension of "5.3 g (0.138 Mo ^ g) of lithium

aluminum hydride in 500 ecm anhydrous ether and cool the contents of the vessel in an ice bath (with salt) to below 0 ° C. While stirring the mixture at the same time, a solution of 20.8 g (0.138 mol / g) of N-cyanomethyl-6-azaspiro [2.5] octane in 100 ecm of anhydrous ether is added dropwise from the dropping funnel, the rate of addition being controlled in this way that the temperature of the mixture is kept below 0 ° C. The duration of the addition is 15 minutes. The mixture is left stirring for 2 hours in an ice bath are und'dann one night at ambient temperature, cool the contents of the vessel again below 0 ⁰ C., then hydrolysed successively added 7 cc of water, 4 cc of 20% sodium carbonate solution and 22 cc of water, lets the mineral salts air dry, wash them carefully three times with ether and then three times with tetrahydrofuran, dry the ether-tetrahydrofuran solution for a few hours over potassium carbonate, filter, remove the solvents and then rectify the residue in vacuo. 18.2 g (yield 88.5%) of N - (/? - aminoethyl) -6-azaspiro [2.5] octane are obtained in porrn of a colorless liquid which passes over at 62 ° C / 1 torr and «into the is soluble in common organic solvents; nf ^s = 1.4842.

The dipikrate melts after recrystallization in . Water at 243 to 244 ° C /

e) N - (/? - guanidinoethyl) - '6-azaspiro [2.5] octane

Ih a 1-1 three-necked flask with a condenser and a A mixture of 10.5 g is heated with stirring in a stream of nitrogen for 1 hour 40 minutes with stirring

ίο (0.068 mol / g) N - (/? - aminoethyl) -6-azaspiro [2.5] octane and 9.5 g (0.034 mol / g) of the sulfate of S-methylisothiourea in 50 ecm of water. The solution is concentrated to dryness, then the solid residue is rubbed in acetone and dried in air and then under vacuum. In this way, 15.4 g (yield 92.5 ° / ₀ ) of neutral sulfate of N - (/? - guanidinoethyl) -6-azaspiro [2.5] octane, which after recrystallization from 450 ecm of alcohol from white Consists of crystals that are soluble in water. Melting point 275 to 277 ° C with decomposition. The dibromohydrate melts after recrystallization from isopropyl alcohol at about 150 ° C (indistinct melting).

Claims (3)

Claims: 1. N - (/ i-guanidinoethyl) -6-azaspiro [2.5] octane N-CH ₂ -CH, -NH-C = NH and its pharmaceutically acceptable salts with Acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se either a) 6-Azaspird [.2.5] octane with / I-guanidinoethyl halide or with guanidinoacetyl halide and in the latter case mit.Uthiumaluminiumhydrid reduced or - b) N _r (/? - Ämjnoäthy]) - 6-azaspiro [2.5] octane with a salt of S-alkyl-isothiourea or NH ₂ reacts with cyanamide or with alkyl urea .. ■■ '■ and optionally that obtained according to a) or b) Combination with acids converted into a pharmaceutically acceptable salt. - 3. Process for the production of N - (/ i-guanidinoethyl) -6-azaspiroT-2 ₎ 5] octane sulfate, characterized in that one N ~ (/? -Aminoethyl) -6-azaspiroX-2,5] octane reacts in a manner known per se with S-methyiisothiourea sulfate under an inert atmosphere in solution.