DE2208434A1 - NEW SUBSTITUTED -2-ARYLAMINOIMIDAZOLINE- (2), THEIR ACID ADDITIONAL SALTS AND PROCESS FOR THE PREPARATION OF THE SAME - Google Patents

Description

Dr. Or. / Al ;>

CH. UIiMIRlIiGRP. SON, Ingelheia on the Rhine

New substituted -2-arylamino-irnidazoline- (2)

their ijHureadditionsalse

and methods of making the same

The invention relates to new substituted 2-aryiaminoimidazoline- (2) of the general formula ^R l

Ii

κ-

309335 / 1U8

and their physiologically compatible acid addition salts with valuable therapeutic properties. In formula I, R ₁ , R ₂ , R- ,, which can be identical or different, denote a hydrogen or fluorine, chlorine or bromine atom or a methyl, ethyl, methoxy, trifluoromethyl or cyano group, R ₄ the groups CH ₃ -G = CH ₂ or

ü -ij- where Rj- is a hydrogen atom. or a methyl

or ethyl group.

The compounds of the formula I are prepared by:

a) Uman'tr.unp: of a 2-Arylami no-i midazol i nn- (2 ^ of the general formula

^K l. . . N

^H H

ir deT R, R, R have the meanings given above , with a halide of the general formula

Shark - GH ₀ _ ρ III

where Hai denotes a chlorine, bromine or iodine atom and R. has the above meaning; or

b) Implementation of a compound of the general formula

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CH,

R,

IV

in which R _n , R ₀ , R ^ and R ,, are defined as indicated above and A is a cyano group or the radical -C ^, ™, where Y is an alkoxy or alkylthio group with up to 4 carbon atoms or one Represents sulfhydryl or amino group, with ethylenediamine or its acid addition salts.

o) Implementation of a metal salt of 2-arylamino-imidazoline the general formula

- IiH

J.1

'N-

Me

where Me denotes a metal cation, preferably an alkali metal cation, with a compound of the formula III.

In the alkylation of 2-arylamino-imidazolines- (2) of the formula II according to process a), the substitution takes place exclusively at the bridging nitrogen atom. Evidence can be provided with the aid of NMR spectroscopy: In the case of a substitution the methylene protons appear at the bridging nitrogen atom of the imidazoline ring as a singlet at about 6 ppm (f-scale). When implementing according to method b) is the constitution of the end compounds is determined by the synthesis. If you work according to method c) you get both

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derivatives substituted on the bridge nitrogen as well as on the imidazoline nitrogen.

The reactions are carried zweckraäßigerweise by heating the reactants -. Optionally in the presence of an organic solvent - to temperatures of about 50 to 15O ⁰ C. The specific reaction conditions depend to a large extent on the reactivity of the reactants, and are expediently precisely defined by preliminary experiments. It is advisable to use the halide in excess in the alkylation according to process a) and to carry out the reaction in the presence of an acid-binding agent. In the case of the reaction according to process b), it is expedient to use ethylene diamine or its acid addition salt used as the reactant in excess.

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The 2-arylamino-imiaazoline- (2) according to the invention of the general Formula I can be phj ^ siologically in the usual way compatible fermentation addition salts are transferred. Acids suitable for forming salts are, for example, hydrochloric acid and hydrogen bromide acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, Propionic acid, butyric acid, valeric acid, caproic acid, capric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, Maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, Malic acid, gluconic acid, galacturonic acid, Benzoic acid, p-hyaroxybenzoic acid, phthalic acid, cinnamic acid, Salicylic acid, ascorbic acid, B-chlorotheophylline and the like.

The compounds of the general formula I according to the invention as well as their acid addition salts have valuable analgesics as well as antihypertensive properties and can therefore be used, for example, in the treatment of the various manifestations of joke states, such as 3. Migraine, application Find. The compounds of general formula I 3 and their Acid addition salts can be oral, enteral or parenteral can be applied. The dosage for oral use is about 0.1 to 80, preferably 1 to 30 ng. The connections of formula I or their acid addition salts can be used with other analgesics or other types of active ingredients, e.g. Spasraolytics, antihypertensive drugs, sedatives, tranquillizers and like. Get used. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories, Solutions, emulsions or powders; in this case, the galenic auxiliaries usually used for their production, Carriers, disintegrants or lubricants or substances to achieve a depot effect are used. The production such galenic forms of administration are conventional Way according to the well-known manufacturing methods «

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The following examples illustrate the invention without representing it restrict.

example 1 2-f | N- (2,6-dichlorophenyl) -N- (ft-metliaIlyl) -a: nino] -ir;] ida2olin- (2)

ö.9 g (C, 03 mol) 2- (2,6-dichlorophenylamino) -inidazoline- (2) are used together with 15 ml of B-chlorine ^ -methyl-l-proper. in 25 ml absolute methanol for 24 hours in a boiling water bath in Tube heated. The reaction mixture is then concentrated in vacuo and the residue is dissolved in dilute hydrochloric acid. After never) wrongful exudation of the hydrochloric acid solution (ether extracts are discarded) is cleaned over charcoal and niit 5 η sodium hydroxide solution elcalated. The imidazoline base separates here initially oily and crystallized after a while.

It is suctioned off, washed with water and a little ether and dried.

Yield: 4.7 g, corresponding to 55.0 fi of theory, mp 111-112 ⁰ C. The thin-layer chromatogram proving the 2-fN (2,5-dichlorophenyl) -N- (beta-methallyl) amino] - ijnidazolin- (2) as uniform.

Following the procedure of Example 1 were also those in The compounds listed in the table are shown.

Compounds of Formula I.

- C = CH ₂ )

Example Vr. 'R, R ₂ R. Tp ₁ ⁰ C yield >f>

the theory

4-Cl 2-Cii, H 76-79 33.0 2-Cl 6-CK ₃ ri 96-97 66.0 2-Cl 4-CK ₃ H 88-89 44.4 2-CIi ₃ ■ 5-F H 55-57 33.0 2-Cl 3-CK ₃ H 59-62 50.5

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Example no. L ₁ L ₂ ! ·· .-> Γρ, C yield ^

the theory

7 2-C ₂ Hc 6-C ₂ Hc H Cl 30, C

3 2-Br 4-Br 6-Br 175-176 40.0

Example 9

2- £ n- (2-methyl-furylmethyl- (3)) -N- (2, o-dichlorophenyl) -aminoJin ; idazoline- (2)

2.3 g (0.01 mol) of 2- (2,6-Eichlorphenyiasiino) -imidazoline- (2) together with 1.43 6 3-chloroethyl-2-methyliurane and 3 ml of triethylamine in 25 nl of absolute toluene for 3 hours heated under reflux for a long time. After cooling (ice cooling), the precipitate which has separated out is filtered off and dissolved in 1 η HGl. After alkalizing with 2 η sodium hydroxide solution, the imidazoline base is extracted with ether. The combined ether extracts are dried over anhydrous MgSO / and the ether is stripped off in vacuo. The viscous oil remaining as a residue crystallizes after a while. Las crystals are mixed with Fetrolather (40-8O ⁰ C), filtered off with suction, washed with petroleum ether and dried.

Yield: 1.95 g corresponding to 60.2 f. Of theory, T'p. 96-9Ö ⁿ .

Due to the singlet of the 4 methylene protons of the imidazoline ring at about 6.5 ppm (Ύ scale) is the position of the 2-T.iethylfurylmethylrest secured in 2-arylamino-iniidazoline.

The compound dissolves in ethanol, methanol and ether. she is insoluble in HpO. As the hydrochloride, it is also soluble in an equivalent amount of dilute hydrochloric acid.

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-β-

2 - [* - (2-Ethyl-fur _< vlraet ·! \ V L- (3)) -. N- (2,6-Jichlorphenyl) - amiuo] iaida2Olm- (2)

2.3 g (0.01 mol) 2- (2,6-richlorphenylamino) iraidazoline- (2)? are combined with 1.53 g (110 f) 3-chloromethyl-2-ethylfuran vind } ± 1 triethylarain in 25 al of absolute toluene for 5 hours on the return flow? heated. After cooling (ice cooling) * the nutty precipitate containing the new compound is sucked off, washed with toluene and petroleum ether and dissolved in dilute hydrochloric acid. :. The sslssaure I'isun._: varc laehraials extracted with ether (ether extra): te verv.-orfen) and then made alkaline with dilute sodium hydroxide solution. After extracting with ether, the combined ether extracts are dried over anhydrous MgSO. dried and the solvent removed in the Vaicuusa. read viscous oil remaining as residue crystallized after a short time. The yield of pure product is 1.8 g, corresponding to 53 # 2 £ of theory. Mp: 96-93 ° C

Pie stnüfcur of the connection results from the fftüi spectrum, that for the 4 methylene-h is a singlet at about 6.5 ppn having.

Example 11 .

2-f? F- (Furylmothyl- (3)) - ^ - (2 * 6 "dichlorophenylJ-aminoJ" iPidazoliti "- (

2.3 g (0.01 mol) of 2- (2,6-Lichlorphenylajnino) -2-imida8olin together with 1.3 g (110 f.) 3-Chloromethylfuran and 3 πα triethylamine in 25 ml of absolute toluene for 3 hours am?; heated to reflux. Then it is brought to dryness in a vacuum and the residue is dissolved in 1 η hydrochloric acid. Lurch iraxtior.osed

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sr.i at various: pli -. '. orter. the new connection is disconnected from. Made from yarn's product and 7erunreir.i / rangen. Liejeni ^ er »ether extracts which contain the compound (detection by means of thin-layer chromatography on silica gel O in the system: benzene: dioxane: ethanol: conc. NH, = 50i4O: 5: 5 staining: potassium iodoplatinate) are combined, _{dried over anhydrous MgSO 4} and im Reduced vacuum. 1.1 α 2-fN - (? UrylsBethyl- (3)) - * I- (2,6-dichlorophenyl) -aiaino] -2-imides-olin, corresponding to a theoretical yield of 35.5 % . Mp 126 -. 127 ⁰ C

Example 12 2 ~ fN - »(rurylpethyl- (2)) - N- (? _T 6-aichlorphenyl) - aKiinoJ-i.-ai6azoline- (.? )

35 g (0.015 hol) 2- (2,6-Lichlorphenylanino} -inuaazolin- (2) together with 2.1 * j (110 ^) furfuryl chloride and 4.5 nil? Riathylaain in 4C; as absolute toluene 3 After cooling down (ice cooling), the wet lower aclilag is suctioned off and gelatinized in 1 η hydrochloric acid Medium9 2 η VcCIi) fractionated with ether (8 fractions). The ether fractions, which are uniform due to the thin-layer chronato grass, are combined, dried over MgSO. and evaporated to dryness in vacuo, the residue remains; the oil crystallizes after a short time. yield:?. I ₁ g (corresponding to 36.6 £ of theory) Pp 116-113 ⁰ C.

The substance is uniform according to thin-layer chromatography. It is found in an equivalent amount of diluted ZfilznuurB, Ln Athnnol, iiethar.ol, nhlorolorni and; \ ther. On the other hand, they are insoluble in water. Their color is white.

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Following the example above, the following sub-tects can be synthesized:

2-fM - (? Urfuryl- (2)) - N- (2-chloro-4-aethylphenyl) -aoinoJ- imiriazolin- (2)

Yield: 13, d <theory

Γρ. 1C3 - 11O ⁰ C

2-ff ^(T; urylmethyl- (2)) - N- (2-chloro-6-nethylphenyl) -aminoJ- inidazolin- (2) Yield: 44.9 of theory Pp 97-99 ⁰ C.

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2 ~ ΓN- (2.b-DichloΓ phenyl) ~ N- (ß-methall · yl) '»ajalno1-2 ■ -ialdagolln

a) N- (3-MethaiIyI) -N- (2,6-dichlorophenyl) »S-ethyl-isotMuronium-hydro;) oaid

5, θ g (0.016 mol) of N- (2,6-dichlorophenyl) -S «3aethyl-isotliuronium-hydroiodide 1.3 g of soda and 2.9 g of 3-chloro-2-u »ethyi-i-propene become old Heated under reflux in 20 ml of absolute methanol for ο hours with stirring, at this time is a conversion to the N- (ü-Methal.lyl) ~ H- (2,6-aichlor-pheayi) -S-methyl-isothiuroniumhyäro ^ odid almost completely, the inorganic salts are sucked off and the filtrate concentrated to dryness in vacuo. The connection remains behind as vidicoeee Cl, which continues to work raw will.

b) 2- [N- (2, o-Dicniorphenyj.) -: i ~ (3-! E "thailyi) -aaini5] -2" -iffliii * "olia

The crude N- (ii-methallyl) -N- (ü, fe-üiehi3rphenyi) -S-methyi-ieothiuroniuohydrojocid obtained according to a) becomes zaa * ffla§n old i, ö g ethylene axaain at IiJO ⁰ C i / 4 Stund "!, Ing mrhitet, the Ericaiten is dissolved a reaictlonimlec-liung in iß S & li2ifeur warm and a solution with different pH« Wfrt # li (Ibetumpien djw. Alkailficroii alt ^J > n ir * .njf) ii-s.AtiöRif ^ with Xther extracted. Dj * aie a «u * l ⁱⁱ i ':. L * -. ^> ßAiaveffbin & Uß containing Athenre.ction> i: i (Ne.cLweie i, s 2 € sit üeas benzene: dioxane ·. Jcona »NH ₄ OH ·, A <: fe * n-33-« SO ι 40 1 ίϊ t aui Kieeeigel and staining from KaliuffljodpiLatlnat) are concentrated after aeiu unification over MgSO ^ getrocjcnet and La VaJcuaa. The remaining solid Ktiükst - nd wlrci with ether, sucked off and dried Yaicmwtrocjcenechraxik. It proves to be identical to the 2- [H- (2, ^ -

Yield: 0, ö according 17i6% 'aer Thtorie, Pp: 111-112 ⁰ C.

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ι 2208Λ34

2- [S- (2.b-p-chlorophenyl) -N- (ΰ-aethallyl) -amlno-laida «olln- (2)

a) R- (tt-methallyl) -N- (2, b-aichlorophenyl) -guanidine

4.1 g (0.02 mol) of N- (2,6-dichlorophenyl) -guanidine are eusamaen with 2, y g of i-chloro-2-methyl-1-propene and 1, ί> g soda 1h 30 al n-butanol heated under reflux for b hours. After this time the reaction to N- (ß-MethaiIyI) -N- ^, b-dichlorophenyl-guanidine hydrochloride almost completely. The reaction mixture becomes here by suction freed of inorganic salts and concentrated to dryness in a vacuum. Eb still remains contaminated guanidine hydrochloride.

After cleaning AEM on the base it is obtained in a yield of 2 g t corresponding to 39.2 £ theory in crystalline form.

b) 2- [N- (2,6- _< dichlorophenyl) -N- (δ-methaliyl) -aaiino] -2-imida * olin

2.3 g of the synthesized ouanidine hydrochloride and 0,!> g ithylenediaain in 1> ml of amyl alcohol for 20 hours heated with stirring at the return flow. It is then filtered off and concentrated the bare solution to dryness in vacuo. Dissolve the residue in sodium chloride different pH values fractionally extracted with ither (alkalization with 2N sodium hydroxide solution).

Those xether extracts which contain the desired compound are combined, dried over MgSO ^ and freed from the ether in vacuo. The imidazole derivative obtained in this way proves to be identical to the 2- [N- (2,6-dichlorophenyl) -I- (B-mtthmllyl) -amino] -2-imidatolln produced according to Example 1. Yield: 30 % of theory.

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Example 15

2-fN- (2-Hethyl-furylmethyl- (3) -N- (2,6-cichlorophenyl) -aminol-2-imidazoline

11.5 g (0.025 mol) of N '- (2,6-dichlorophenyl) -N' - [2-methylfurylmethyl- (3) JS-methyl-isothiuroniurajodid, prepared by the action of 2-methyl-3-chloromethyl-furan N- (2,6-dichlorophenyl) -S-methyl-isothiuroniura, iadid, are heated to 165-170 ° C. for 15 minutes together with 2.25 g (150 #) 98 tigern ethylenediaini with stirring. The desired Iraidazolin g is obtained of melting point of said renewed after cooling Reaktionsgemisoh in a yield of 6: 99 ⁰ C. It is identical to that described in Example 9 imidazoline. The mixed melting point with authentic product shows no depression and is 99 ^° C. The hydrobromide melts at 236 - 237 ^° C.

Example 16 (method a)

2- \ N- (2.4-D1-chlorophenyl) -N- (2-methyl-furyl- (3) -methyl) -amino1-2-imidazoline

4.6 g (0.02 mol) of 2- (2,4-dichlorophenylamino) -2-iraidazoline together with 2.86 g (110 %) of 3-chloromethyl-2-methylfuran and 6 ml of triethylamine in 50 ml of absolute toluene Heated under reflux with stirring for 4 hours. After cooling, the precipitated substance is suctioned off, dissolved in a little methanol and the solution is made alkaline with potassium hydroxide solution (egg cooling). The oily imidazoline base which separates out is separated off by centrifugation, taken up in ether and purified by shaking out with water. After the ether solution has been dried over Drierite, it is concentrated in vacuo. The oil remaining in the residue crystallizes out after a short time. A yield of 3.5 g, corresponding to 57.7 # theory of pure imidazoline compound of Pp. 58 - 60 ⁰ C.

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• ft

Enteprechende on catfish (method a) the novel compounds listed in the table were prepared.

Compounds of Formula I.

Beep. R ₁ No.

R ₉ R, R

^{2 3 4}

Pp

Aueb. (H.Th.)

17 2-Cl, 6-CH, H.

H, C

74.5-76.5 ° 41.2

18 2-Cl 4-Br 6-Cl

H ₃ C

181-183 55.8

19 2-CH ₃ O- 5-CH ₃ OH

H ₃ C

27.0

20 2-P 5-F H

H ₃ C

Jfrf oil.

25.7

21 2-CF ₃ HH

22 H HH

H ₃ C

H ₃ C

23 4-CN HH

H ₃ C

159-161

45.4

31.3

8.6

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Beiapl. R ₁ R ₀ R

No. 1 ^

Fp.

Yield

H-C

79-82

48.1

25 2-C1 3-CH ₅ H

H, C

70-73 52.7

2-CH, 5-F

oil

40.0

27 2-CH, 5-Cl H.

oil

50.3

2-Cl H

oil

43.6

2-Cl

4-C1 H

97-99

37.0

2-Cl 3-CH, H.

107-110 ° 27.6

Example 31 (method t)

2-Γ N- (2-chloro-4-methylphenyl) -N- (2-methylfuryl- (3) -methyl) -amino1-2-imiaazoline

10.9 g (0.025 KoI) N «- (2-chloro-4-niethylphenyl) -N ^l - (2-methylfuryl (3) -methyl) -S-niethylisothiuronium oxide, prepared by the action of 2-methyl-3-chloromethylfuran on N- (2-chloro-4-methylphenyl) -S-raethylisothiuronium, iodide, are used together with

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2.5 ml of 98 tiger ethylenediarain (150 %) ^{heated to 165-170 0} G for 15 minutes with stirring. From the reaction mixture worked up after cooling, the desired imidazoline derivative is obtained in a yield of 4.7 g, corresponding to 62.0% of theory.

After chromatography on Al ₂ O, using chloroform as Elutionemittel the melting point of the high-purity substance is (TLC control) 85-87 ⁰ C.

The mixed melting point with material produced according to method a) shows no depression and is also 85 - 87 ^° C.

Example 52 (method c)

2 - ("ff- (2-Methylfuryl- (3) -methyl) -N- (2,6-dichlorophenylamino) 1-2-imidazoline hydrochloride

To a solution of 4.6 g (0.02 mol) of 2- (2,6-dichlorophenylamino) -2-imidazoline in 50 ml of absolute tetrahydrofuran is added 0.87 g (0.02 mol) of an approximately 58% strength Add sodium hydride disperelon at 10 - 20 °. The mixture is stirred at room temperature for 2 hours and a mixture of 2.75 g (105 %) 3-chloromethyl-2-methylfuran and 10 ocm absolute tetrahydrofuran is then added dropwise with stirring at the same temperature. Initially, the reaction is allowed to take place for 2 hours at room temperature and the reaction mixture is then brought to reflux temperature for a further 2 hours. After this time (TLC control) the reaction mixture contains approximately 70 % of the compound substituted on the Iraidazolln-N-Atora in addition to around 10 % of the isomer derivative substituted on the BrUoken-H-atom as well as in addition to the above. 20 j (of the starting imidazoline.

The individual components can be separated using preparative methods Chromatography on silica gel with the benzene: dioxane system: Ethanol: conc. Ammonia = 50:40: 5: 5. The melting points of the two isomeric imldazoline derivatives are 291-292 ° for l- (2-Methylfuryl- (3) -methyl) -2- (2,6-dichlorophenyl-amino) -2-imidazoline hydrochloride and 96-98 ° for 2- [N- (2,6-dichlorophenyl) N- (2-methyl-furyl- (3) -methyl) -araino] -2-imidazoline-ba8e.

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Example A; Trays .

2-1 N- (Z, 6-i) ichlorpheny I) -N- (ß-methallyl) -amino j iraidazolin- (2)

Lactose

Cornstarch

sec. Calcium phosphate soluble starch magnesium stearate colloidal silica

IO mg 65 mg 125 mg • 40 mg 3 mg 3 mg 4th mg

a total of 250 mg

Manufacturing:

The active ingredient is mixed with a portion of the excipients, Kneaded intensively with an aqueous solution of the soluble starch and in the usual way with the aid of a sieve granulated. The granulate is mixed with the rest of the auxiliary substances and compressed into tablets of 250 μg.

The same process can be used to make dragfee kernels, usually with the help of sugar, talc and gum arabic can be coated.

Example 3: ampoules

2-C N- (2,6-dichlorophenyl) -N- (ß-methallyl) -arainoJ-imidazoline- (2) 1.0 mg

Sodium chloride 18.0 mg

deet. Water q.s. ad 2.0 ml

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Manufacturing:

The active ingredient and sodium chloride are dissolved in water and filled in sterile glass ampoules under nitrogen.

Example G: drops

2-i N- (Zf-chloro-6-methyl-phenyl) -N- (3-methallyl ) -amino ] -imidasoline- (2) -hydrobromide 0.02 g

p-hydroxybenzoearluremethylester 0.07 g

p-Hydroxybenzoic acid propyleater 0.03 g

demineralized water / water to 100 ml

-Patent claims-

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Claims (9)

Claims 1. Substituted 2-arylamino-imida2oline- (2) of the general formula in which R ,, R ₂ * ^R 3 », ^{which can be the same or} different, a hydrogen or fluorine, chlorine or bromine atom or a methyl, ethyl, methoxy, trifluoromethyl or gyamo group, R. the groups CH, - C = CH ₂ or Rc denotes, where R ₁ - denotes a hydrogen atom or a methyl or ethyl group, as well as their acid addition salts. 2. Process for the preparation of compounds of the general Formula I according to claim 1, characterized in that one a) a substituted 2-arylamino-imiaazolin- (2) of the general Formula II in which R ^, R ₂ , R, have the abovementioned meaning, with a halide of the general formula 30983 5/1146 Hal-CH ₂ -R ₄ III in which Hal is chlorine, bromine or iodine and R _{4 is} as defined above ; or b) a compound of the general formula IV R, -N- CH, IV In which R _1, R _2, R * and R ₄ are defined as indicated above and A is a cyano group or the radical -C yyyy, wherein T is an alkoxy or alkylthio group having 4 to bia Kohlenetoffatomen or SuIfhydryi- or Amlnogruppe represents, reacts with ethylenediamine or its Säuxeadditionsealzen ; c) a metal salt of 2-arylamino-imidazoline of the general formula N- - NH - < Me where Me ^ ⁺ 'means a metal cation, preferably an alkali metal cation, with a compound of the formula III 309835/1 U6 and that the end product obtained by one of the processes a or b or c is optionally converted into an acid addition salt. 3. The method according to claim 2, characterized in that the reaction is carried out in the presence of an organic solvent performs. 4. The method of claim 2 and / or 3 »characterized in that one carries out the reaction at a temperature of about 50 150 ⁰ C. 5. The method according to any one of claims 2-4, characterized in that that one the halide of the formula III or the Ä'thylenediamine or its acid addition salt in excess applies. 6. Pharmaceutical preparations, characterized in that they contain one or more compounds of the general as active ingredients Formula I according to claim 1 or its acid addition alloys contain. 7. Process for the preparation of medicaments according to claim 6, characterized in that one or more compounds of the general formula I or their acid addition alloys with customary galenic aids, carriers, explosives Lubricants or substances to achieve a depot effect on tablets, capsules, suppositories, solutions or Powders oompounded. . UV ViAUUP HUi XJggCtl ™ Tr * ™ <m ™ '- ^- ™ yTT ^ ggIimC X. JJiZIUB bCilUCll UlIPBoXO let ™ bonds of the general formula I or d> * ^ n physiological Compatible SJKtreadditionsealzen. 9. Method jrftoh claim 8, dadujjrfn characterized in that one a dosage for oral use of 0.1 - 80, preferably 1 - 30 mg applies. ORIGINAL INSPECTED 309835/1146