DE2265595C2 - Substituted 2- (N-2-methylallyl-N-phenylamino) -imidazoline- (2), their acid addition salts, processes for their preparation and compositions containing them - Google Patents

Description

the substitution exclusively on the bridging nitrogen atom. The proof can be with the help of the NMR spectroscopy If there is a substitution at the bridging nitrogen atom, the methylene protons of the irnidazoline ring occur as a singlet at about 6 ppm (r-scale). When implementing according to method b) is the Construction of the end compounds is determined by the synthesis.

The reactions are expediently carried out by means of heaters; the reactant - if necessary in Presence of an organic solvent - to temperatures of about 50 to 150 ° C. The special ones Reaction conditions depend to a large extent on the reactivity of the reaction participants and will expediently precisely defined by preliminary tests. It is advisable to use the method for the alkylation a) apply the halide in excess and the reaction in the presence of an acid-binding agent Carry out means. In the case of the reaction according to process b), it is advantageous that as a reactant used ethylenediamine or its acid addition salt to be used in excess.

The 2- (N-2-methylallyl-N-phenylamino) -imidazoline- (2) of the general formula I according to the invention can be converted in the usual way into their physiologically acceptable acid addition salts. For salt formation suitable acids are e.g. B. hydrochloric acid, hydrobromic 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, glueonic acid, galacturonic acid, benzoic acid. p-hydroxybenzoic acid, Phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, 8-chlorotheophylline.

The compounds of general formula I according to the invention and their acid addition salts have valuable analgesic as well as antihypertensive properties and can therefore be used, for example, in the Treatment of the various manifestations of pain conditions, such as B. Migraines, application Find. The compounds of general formula I and their acid addition salts can be enteral or else can be used parenterally. The dosage for oral use is about 0.1 to 80, preferably 1 up to 30 mg. Suitable pharmaceutical dosage forms are, for example, tablets, capsules, suppositories. Solutions, Emulsions or powders; the galenicals usually used for their production can be used here Auxiliaries, carriers, disintegrants or lubricants or substances to achieve a depot effect Use Find. Such galenic dosage forms are produced in a conventional manner according to the known manufacturing methods.

Compounds according to the invention were with substances of the prior art, which from DE-OS 19 58 201 are known, compared with regard to their analgesic potency in the writhing test on mice, the following values were obtained.

link
imidazoline (2)

Wnthing-Tesl
Mouse. see RDio
mg / kg L.D50, mouse
sc, mg / kg 0.33 73 0.7 48 0.9 60 1.2 52 1.4 63 1.5 95 2.15 8 <

2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -2- [N- (2-methyl-4-chlorophenyl) -N- (2-methyl-allyl) -amino] - 2- [N- (2-methyl-6-chlorophenyl) -N (2-methyl-allyl) -amino] -

Comparative compounds from DE-OS 19 58 201:

2- [N-Ally] -N- (2,6-dichlorophenyl) -amino] -2- [N- (cis-3-chloroallyl) -N- (2,6-dichlorophenyl) -amino] - 2- [N- (trans-3-chloro! Lyl) -N- (2,6-dichlorophenyl) -amino] -2- [N- (3,3-dimethylallyl) -N- (2,6-dichlorophenyl) -amino] -

The following examples illustrate the invention.

example 1
2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -imidazoline- (2)

6.9 g (0.03 mol) of 2- (2,6-dichlorophenylamino) -imidazoline- (2) are added together with 15 ml of 3-chloro-2-methyl-1-propene heated in 25 ml of absolute methanol for 24 hours in a boiling water bath in the tube. Then will the reaction mixture was concentrated in vacuo and the residue was dissolved in dilute hydrochloric acid.

After the hydrochloric acid solution has been etherified several times (ether extracts are discarded), it is poured over charcoal cleaned and alkalized with 5 η sodium hydroxide solution. Here, the imidazoline base initially separates out in an oily state crystallizes after a while.

She is vacuumed with water and wenip; Ether washed and dried.

Yield: 4.7 g corresponding to 55.0% of theory. M.p .: 11 f-! 12 ° C.

2- [N- (2,6-dichloro-phenyl) -N- (2-methyl-allyl) -amino] -imidazoline- (2l as uniform.

Further following the procedure of Example 1, the following compound was prepared.

Compound of formula I.

Example no. Ri Rj Ri Mp. ° C dent

% the
theory

2 2-CH ₃ 4-Cl H 78-79 33.0

Example 3

2- [N- (2,6-dichloropharyn!) - N- (2-methyl-ally!) - amino] -2-imidazoline
a) N- (2-methyl-allyl) -N- (2,6-dichlorophenyl) -S-methyl-isothiuronium hydroiodide

5.8 g (0.016 mol) of N- (2,6-dichlorophenyl) -S-niethyl-isothiuronium hydroiodide are mixed with 1.3 g of soda and 2.9 g

3-chloro-2-methyl-1-propene in 20 ml of absolute methanol was refluxed for 6 hours with stirring.

After this time, the conversion to N- (2-methyl-a-lyl) -N- (2,6-dichlorophenyl) -S-methyl-isolhiuronium-hydroiodide almost complete. The inorganic salts are suctioned off and the filtrate in vacuo

Concentrated to dryness. The compound remains as a viscous oil, which is further processed raw.

b) 2- [N- (2,6-dichlorophenyl) -N- (2-methylallyl) -amino] -2-imide;! zoline

The crude N- obtained according to a) (2-methyl-allyl) -N- (2,6-dichlorophenyl) -S-methyl-isolhiuroniumhydrojodid are heated together with 1.8 g of ethylenediamine at 150 ⁰ C 'Λ hour. After cooling, the reaction mixture is dissolved in warm 1 η hydrochloric acid and the solution is extracted fractionally with ether at various pH values (blunting or alkalizing with 2 η NaOH). The new ether fractions containing linida / .olin compound (detection in TLC with the benzene to dioxane system to conc. NH4OH to ethanol = 50: 40: 5: 5 on silica gel and staining with potassium iodoplatinate) are dried over MgSO4 and concentrated in vacuo after combining . The remaining solid residue is stirred up with ether, filtered off with suction and dried in a vacuum drying cabinet. It turns out to be identical to the 2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -2-irnidazoline prepared by the method of Example 1.

Yield: 0.8 corresponding to 17.6% of theory

Mp .: 111-112 ⁰ C.

Example 4

2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino-imidazoline- (2)

a) N - (/) '- methyl-allyl) -N- (2,6-dichlorophenyl) - {; uanidine

4.1 g (0.02 mol) of N- (2,6-dichlorophynyl) -guanidine together with 2.9 g of 3-Chl, ir-2-methyl-1-propene and Heated 1.5 g of soda in 30 ml of n-bulanol under reflux for 6 hours. After this time the reaction is to N- (2-methyl-allyl) -N- (2,6-dichlorophenyl) -guanidine-hydrochloride almost completely.

Example A.
• 50 tablets

2-f N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -imidazcline- (2) 10 mg

Milk sugar 65 mg
Corn starch 125 mg

sec. Calcium phosphate 40 mg

soluble starch 3 mg

Magnesium stearate 3 mg

colloidal silica 4 mg

a total of 250 mg

Manufacturing

(, <-, The active ingredient is mixed with some of the excipients, intensively with an aqueous solution of the soluble Kneaded starch and granulated in the usual way using a sieve. The granules will go with the rest the excipients mixed and compressed into tablets of 250 mg.

The same process can be used to produce coated tablets, which are then usually made with the help of

Sugar, talc and gum arabic can be dragieri.

Example 13
Ampoules ϊ

2- [N- (2.6-dichlorophyll) -

N- (2-methyl-allyl) -amino] -imidazoline- (2) 1.0 mg

Sodium chloride 18.0 mg

least. Water q. see ad 2.0 ml io

Manufacturing

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

The reaction mixture is then freed from inorganic salts by suction filtration and in vacuo to 15 Concentrated to dryness. Contaminated guanidine hydrochloride still remains.

After cleaning via the base, a yield of 2.3 g, corresponding to 39.2% of theory, is obtained in crystallized form.

b) 2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -2-imidazoline 20

2.3 g of the synthesized guanidine hydrochloride and 0.5 g of ethylenediamine are in 5 ml of amyl alcohol for 20 hours heated under reflux for a long time with stirring. It is then filtered off and the bare solution in vacuo Concentrated to dryness. After dissolving the residue in 1 η hydrochloric acid, at different pH values with Ether extracted fractionally (alkalization with 2 η sodium hydroxide solution). 25th

Those ether extracts which contain the desired compound are combined, _{dried over MgSO 4} and freed from ether in vacuo. The imidazoline derivative obtained in this way proves to be identical to the 2- [N- (2,6-dichlorophenyl) -N- (2-methyl-allyl) -amino] -2-imidazoline prepared according to Example 1.

Yield: 30% of theory. 30th

Claims (3)

Patent claims:
1. Substituted 2- (N-2-melhyiallyl-N-phenylamino) -iniidazoline- (2) of the general formula I. Ν—, in which Ri is a chlorine atom or a methyl group and R _{2 is} a chlorine atom in the 4- or 6-position, as well as their acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that one is in on known way a) a substituted 2-phenylamino-imidazoline- (2) of the general formula 11 Ν—, in which Ri and Ri have the meaning given in claim 1, with a 2-methylallyl halide of the general formula II! Hal-CH ₂ -C = CH ₂ (JS) CH ₃ in the shark means chlorine, bromine or iodine, converts or
b) a compound of the general formula IV CH ₂ in which Ri and Rj are defined as indicated above and A is a cyano group or the remainder Y -C NH means, where Y is an alkoxy or alkylthio group with up to 4 carbon atoms or a sulfhyryl or amino group, with ethylenediamine or its acid addition salts; and if appropriate, converting the end product obtained by one of processes a or b into an acid addition salt convicted. 3. Medicinal product. ordering from a connection according to claim I and customary auxiliaries. The invention bLMrilil the subject matter characterized in the claims. Hei the alkylation of 2-phenylamino-iniida / olincii- (2) of the general formula II is carried out according to process a)