DE1670643A1 - Process for the preparation of pharmacologically active new guanidino-alkyl-cycloimines - Google Patents

Description

is, υ®? -,

EGYESULT GY0GYSZ3R ES TAPSZERGYAR, Budapest X, Kereszturi u _o

30-38 / Unßarn

VRFi ¹ AHRIi] N FOR THE PRODUCTION OF PHARMACOLOGICALLY ACTIVEi-JN NEUhB «. GUANID INO-ALKYIr-CYCLOIMINES

The present invention relates to new Guanicl ino- -alkyl-cycloimines and their salts, a process au their Manufacture and drug preparations that this new Connections included

It was found that the new guanidino-alfc; yl- -cycloirnine of the general formula I.

f CH-CH-NH-C-NH ₂

(CHp) _n I i
K NH R

where R denotes hydrogen or a single-chain or two-chain lower alkyl group and η denotes a whole range from 4 to b, and salts of these compounds, which are particularly valuable pharmacological properties, show the same properties. monoaitecyc.looctan- -Oalze - can be a ßlutdruokseiikurig of longer duration vorrufon, IhZ ¹ Q choral <terietlache Rympathlfirii-block iereiidc UUK «βigt in Tl6j« n a duration of obwa H-Ia!, 61 ο lön * in 6 ₂ / 73 * according to 109812/1736 -

BAD ORIGIN '' ¹ -

a nictitating skin tone ^ increase as a result of the release from Chatecholarainen · They result in a general sympathetic decrease in tone with simultaneous cancellation the reflex mechanisms that increase blood pressure (ζ · Β · carotis) · With oral administration they are better absorbed and have fewer side effects than then GuanethWin (165 mg / kg IV for MSusen) and they have a more favorable therapeutic range of effects · also the other connections of this type show more or more less similar properties.

The new compounds of the formula I _f are prepared according to the invention in such a way that-arainomethyl- cyclo i.min of the formula II which is optionally substituted by an alkyl group

wherein "R and η have the meanings given above, with a compound of the formula III

»-X

where Z for., a Biedere Alkoxy-, Alkylraerkapto-, Araino- or nitroso group, X is hydrogen or together with Z a © third valence bond between dom nitrogen and Oarbonatom liedoutet and Y, and Yg independent fromeinaiKlei » Hydrogen, lower alkyl, nitro «or mean, implements "

109812/1736

The starting materials of the general formula II are new connections

As a compound of the formula III, S-alkyl-isothioureas, O ^ Alky! -Isothioureas, Nitrosoguanidine, qyanamide, l-guanyl-5,5-diniethyi-pyrazole be used·

Polar solvents can be used as the reaction medium or mixtures thereof, but preferably use water

The active ingredients obtained can if necessary be converted into therapeutically usable salts with inorganic or organic acids «The obtained Bases or S ^ lio can be used alone or together with a or more other bioactive agents using in drug manufacturing; common Carriers and auxiliaries converted into medicinal products will.

The inventive method is through the the following examples illustrated in more detail

Example It

71f2o 6 (0.5 mol) oC-aminomethyl-heptauethyleniinine (ng ⁰ = 1.487o | bp 96-lo2 ° CAo torif P of the sulfate salti 262-264 ° C), loo ml of distilled water and Io4.35 β (o 75 mol) of S-methylisothiourea sulfate are introduced into a 250 ml flask equipped with a stirrer and reflux condenser. The mixture is heated to the boiling point in half an hour and refluxed for 4 hours. The methyl mercaptan escaping at the top of the cooler is absorbed.

109812/1736

Dos ho'ito ^ eno Eeηktionagem L och will cool (^ lonsen and 24 hours at room temperature lenz nehalten ^ enteric to 5-6 ° C cooled. The precipitated on we! SEN crystals are filtered ;, on the filter with a little acetone

washed and. dried. The weight of the product is 78.4 c. Depending on the standing, 11.4 g of this product can still be obtained from the mother liquor. In this V / oj to the total amount of the product 89 "4 g, yield 59.6% i Fi 235-237 ⁰ C.

The product is uracrystallized by dissolving it in an equal volume of water and cooling it. 78.9 μ of the product are obtained. F: 239-241 ⁰ C. Yield: 5?, 6 % · The white crystalline product contains 1 mol of crystalline water.

Analysis: O ₉ II ₂₄ N ₄ O ₅ S (3oo, 37)

calculated C % 36.00 H % 8, o5 N% 13.68 S % lo, 67 O% 26, Gl found C % 36.12 H % 8.2o N% 18.61 S # lo, 24 O ^ 27 , o3

On the basis of the spectroscopic (TJV, IR) lines, the product obtained is 1-aza-cyclooctyl- ^ -nethyl- guanide in sulfate * H ₂ O

Example 2:

28.45 g (0.2 mol) oc-aminomethyl-heptaraethyleneirain and 17.2 g (0.2 mol) nitrosoguanidine are in loo ml de st Water redeems the mixture left a day after Stirred for 8 hours on a water bath at 75 ° C. The cooled solution is mixed with dilute sulfuric acid neutralized and, after clarification and filtration, concentrated by vacuum distillation in 5o ml. Leaves the solution 28.2 g of white product, which is ura-

10 9 8 12/1736

BAD INAL

crystallized. 24.5 "S (41, ο% of theory) leg product from F. 239-241 ⁰ C are obtained?

Based on the analysis and the spectroscopic characteristics, the product is l-AzarC ^ clooctyl ^ -methyl- -guanidine-oulfafHpO

Example 3%

28.45 g (0.2 mol) oC-aminomethyl-heptamethyleneimine and 9 »24 S (o» 22 mol) cyanamide are dissolved in 40 ml of water while stirring and heating. A few drops of acetic acid are added to the solution, then the mixture is boiled on a steam bath for 3 hours, an equivalent amount of sulfuric acid being added dropwise. The still hot mixture is clarified, then filtered and dried at room temperature for 24 hours sftien allowed to 5-6 ⁰ C cooled and the product separated by filtration is obtained · 35 "2 g of white crude · After recrystallization

31% pure product (£ 1.6% of theory) are obtained from P. 237-24 ° C.

Based on the analysis and the spectroscopic characteristics, the product is 1-aza-cyclooctyl-2-methyl-guanidine-sulfate-H ₂ O of the formula CqH ₂ J ^ O ₁ -S

Example 4 *

15 »63j (0.1 mol) 1- (2-0ktaazocinyl) ethylamine (bp 1ο1-1ο4 ° 0Λο torr, F. of the sulfate salt 27o-274 ° 0), 2o ml distilled water and 21 g (0.15 mol) of S-methylisothiourea sulfate are placed in a round bottom flask equipped with a stirrer and reflux condenser Mixture is boiled with stirring for 3 hours, then left to stand for 24 hours at 2ο ^{0 C after cooling}

10 9 811/17 3 6

Before filtering, the geraisch is cooled to 5 ° C, the precipitated crystals are filtered and the product is recrystallized from 2.5 parts by volume / weight of 40% aqueous ethanol.In this way, 15t9 ^ & l- Aza-cyclooctyl-2- (1 ^f -methyl) -methyl-guanidine sulfate of the temperature 24 ° -25o ° C.
Yield: 5o.8 %

Analysis: G ₁₀ H ₂₄ N ₄ O ₄ S (296.27)

calculated G % 4o, 57 H % 8.14 N% 18.95 S% lo, 84 O % 21.36 found C% 4o, 9o H% 8.35 N% 18.34 S % lo, 42 O Ji 21 , 00

Example 5s

² 5 | 65 [beta] (0.2 mol) oi-aminomethylhexaniethylenimine (bp 78-84 ° 0 / lo torr, n ^ ° = 1.4365, P. of the "^ fat salt 275-278 ° 0) dissolved in the device of 15 ml of distilled water and 15 ml of ethanol and 41.8 g (0.3 mol) of S-ynethyl isothiourea are added to the mixture The mixture is left to stand for one day at ambient temperature, and finally it is cooled to 5-6 ° C. The crystals which have separated out are filtered off, with them on the filter

/ Washed with a little acetone, then its water is recrystallized from the same volume. There are 29,4o g (54.85% d.Th ·) 1-az a-cy el oh * pi ^ -l-2-rae ttiylguanidinsulf at e RHal th "F * 246- -249 ⁰ C

Analysis: ° 8 ^H 2o ^N 4 ° 4 ^S

calculated C % 35 _f 7o N % 2o, 9o H % 7 »o5 S % 11.94 O #? 3» 3o found 0 % 35.24 N % 2o, 72 H % 7.44 B% 11.27 O % 24, Io

109812/1736

Claims (2)

Claims 1 · Compounds of the general formula I. HH / - ^ ⁿ / CH-CH-NH-G-HH ₂ (CH ₂ VII wherein B is hydrogen or a straight-chain or "branched" one means lower alkyl groups and η for an integer of 4 to 6, and their therapeutically useful salts. 2. Process for the preparation of "compounds of general formula I. HH CH-CH-HH-C-HH ₂ "FA wherein E and η have the meanings given in claim 1, and their salts, characterized in that one an oC-aminomethylcycloimine or a cC-aminomethylcycloimine Derivative of the general formula II wherein E and η have the meanings given ocen, with a compound of the general formula III where Z is a lower alkoxy, alkyl mercapto, amino or Uitroso group, X is hydrogen or together with 1098 12/1736 Z denotes a third valence bond between the nitrogen and carbon atoms, and Y ^ and Y ^ denote, independently of one another, hydrogen, lower alkyl, nitro or nitroso groups, and the reaction is carried out in a polar solvent, preferably in water, and if desired the product obtained is converted into a therapeutically useful salt with an inorganic or organic acid. 109812/17 36