DE2208434C2 - Substituted 2- (N-furylmethyl-N-phenyl-amino) -2-imidazolines, their acid addition salts, processes for their preparation and compositions containing them - Google Patents

Description

Me® (V)

where Me® denotes a metal cation, preferably an alkali metal cation, and R denotes the one in claim 1 has the meaning mentioned, reacts with a compound of the formula III and optionally the after one of the processes a, b or c obtained end product converted into an acid addition salt

3. Medicinal product consisting of a compound according to claim 1 and customary auxiliaries.

The invention relates to the subject matter characterized in the claims.

In the alkylation of 2-phenylamino-2-imidazolines of the general formula II by process a) the substitution exclusively on the bridging nitrogen atom. The proof can be with the help of the NMR spectroscopy The methylene protons occur when there is a substitution at the bridging nitrogen atom of the imidazoline ring as a singlet at about 6 ppm (r-scale). When implementing according to procedure b) the constitution of the end compounds is determined by the synthesis. If you work according to method c) as follows derivatives substituted on both the bridge nitrogen and the imidazoline nitrogen are obtained.

The reactions are expediently carried out by heating the reactants - if necessary in the presence of an organic solvent - to temperatures of about 50 to 150 ° C. Die spe ^ ie] len The reaction conditions depend to a large extent on the reactivity of the reactants and are expediently durc !. Preliminary tests precisely defined. It is recommended after the alkylation Process a) to use 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 Ethylenediamine used or its acid addition salt to be used in excess.

The 2- (N-furylmethyl-N-phenylamino) -2-imidazolines according to the invention of the general formula I can be physiologically tolerated in a customary manner Acid addition salts are transferred. Drinking suitable for salt formation are e.g. B, hydrochloric acid, hydrogen bromide * acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid) acetic acid Propionic acid, butyric acid, valeric acid, capric 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-hydroxybenzic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid or 8-chlorotheophylline.

The compounds of general formula I according to the invention and their acid addition salts have valuable analgesic properties and can therefore, for example, in the treatment of the various Manifestations of painful conditions, such as B. migraines, find application. The connections of the General formula I and their acid addition salts can be used enterally or parenterally will. The dosage for oral use is about 0.1 to 80, preferably 1 to 30 mg. Suitable Galenic dosage forms are for example

Tablets, capsules, suppositories, solutions, emulsions, or powders; here can be used for their production commonly used pharmaceutical auxiliaries, carrier explosives or lubricants or substances are used to achieve a depot effect. the Such galenic dosage forms are produced in a conventional manner according to the known Manufacturing methods.

Compounds according to the invention were mi substances of the state of the 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
2-imidazoline

Writhing test.
Mouse, sc, ED ₅₁₁
mg / kg

Mouse, p. C,
mg / kg

2- [N 'J-methyl-3-furylmethyD-

N- (2,6-dichIorphenyI) -am ino] -

2- [N- (2-ethyl-3-furyimethyl) -

N- (2,6-dichlorophenyl) -amino] -

2- [N- (3-furylmethyl) -

N- (2.6-dichIorpheny!) - amino] -

2- [N- (2-furylmethyl) -

N- (2,6-dichlorophenyl) -amino] -

2- [N- (2-furylmethyO-

N- (2,6-chloro-6-methylphenyl) -amino] -

2- [N-A! Lyl-N- (2,6-dichlorophenyl) -arnino] - *)

2- [N- (L.i-chlorallyl) -

N- (2.6-dichlorophyl) -ai ino] - *)

2- [N- (trans-chloroai "yl> -

N- (2,6-dichlorophenyl; -ami; j] - *)

2- [N- (3,3-dimethylallyl) -N-

(2,6-diclilorphenyl) -amino] - *)

*) Comparison

0.018 130 0.02 142 0.75 125 0.11 157 1.54 173 1.2
1.4 52
63 1.5 95 2.15 84

The following examples illustrate the invention.

Example I.

2- [N- (2-methyl-3-furylmethyl) -N- (2,6-dichlorophenyl) -amino] -2-imidazoline

23 g (0.01 mol) of 2 (2,6-dichlorophenylamino) -2-imidazoline are refluxed for 3 hours together with 1.43 g of 3-chloromethyl--2-methylfuran and 3 ml of triethylamine in 25 ml of absolute toluene. After cooling (ice cooling), the precipitate which has separated out is filtered off and dissolved in I η HCl. After alkalizing with 2 η sodium hydroxide solution, the imidazoline base is extracted with ether. The combined ether extracts are _{dried over anhydrous MgSO 4} and the ether is stripped off in vacuo. The viscous oil remaining as residue crystallizes out after some time. The crystals are mixed with petroleum ether (40-80 ° C.), filtered off with suction, washed with petroleum ether and dried. Yield; 1.95 g corresponding to 60.2% of theory, mp 96 ~ 98 ° C

Due to the singlet of the 4 methylene protons of the imidazoline at about 6.5 ppm (ir scale), the Position of the 2-methylfurylmethyl radical in the 2 * phenylam> nö'2-iiiiidäzölin secured.

The compound dissolves in ethanol, methanol and ether. It is insoluble in water. As is the hydrochloride they are also soluble in an equivalent amount of dilute hydrochloric acid.

Example 2

2- [N- (2-ethyl-3-furylmethyl) -N- (2,6-dichlorophenyl) -amino] -2-imidazoline

2.3 g (0.01 mol) of 2- (2,6-dichlorophenylamino) -imidazoline- (2) together with 1.58 g (110%) of 3-chloromethyl-2-ethylfuran and 3 ml of triethylamine in 25 ml refluxed absolute toluene for 5 hours. After cooling (ice cooling), the precipitate which has separated out, in which the new compound is located, is filtered off with suction, washed with toluene and petroleum ether and dissolved in dilute hydrochloric acid. The hydrochloric acid solution is extracted several times with ether (ether extracts discarded) and then made alkaline with dilute sodium hydroxide solution. After extraction with ether, the combined ether extracts are dried over anhydrous MgSO4 and the solvent is stripped off in vacuo. The viscous oil, which is forbidden as a residue, crystallizes through after a short time. The yield of pure product is 1.8 g, corresponding to 53.2% of theory,
Fp .: 96 to 98 ⁰ C.

The structure of the connection results from the NMR spectrum, which is a singlet for the 4 methylene-Η at about 6.5 ppm (r-scale)

Example 5

2- [N- (2-methyl-3-fury! Methy]) -N- (2,6-dichlorophenyl) -amino] -2-imidazoline

Example 3

2- [N- (3-Furylmethyl) -N- (2,6-dichlorophenyl) -amino] -2-imidazoline

23 g (0.01 mol) of 2- (2,6-dichlorophenylamino) -2-imidazoline are refluxed for 3 hours together with 1.3 g (110%) of 3-chloromethylfuran and 3 ml of triethylamine in 25 ml of absolute toluene . It is then concentrated to dryness in vacuo and the residue is dissolved in 1 η hydrochloric acid. Fractional etherification at different pH values results in the separation of the new compound from the starting product and impurities. Those ether extracts which contain the compound (detection by means of thin-layer chromatography on silica gel G in the system: benzene: dioxane: ethanol: conc. NH3 = 50: 40: 5: 5, color: potassium iodoplatinate) are combined, _{dried over anhydrous MgSO 4} and in vacuo constricted. 1.1 g of 2- [N- (3-F>Tylme'.hyl) -N- (2,6-dichlorophenyl) -amino] -2-imidazoline are obtained, corresponding to a yield of 35.5% of theory. Mp. 126 to 127 ° C.

Example 4

2- [N- (2-furylmethyl) -N- (2,6-dichlorophenyl) -aminoI-2-imidazoline

335 g (0.015 mol) of 2- (2,6-dichlorophenylamino) -2-imidszoline are refluxed for 3 hours together with 2.1 g (110%) of furfuryl chloride and 45 ml of triethylamine in 40 ml of absolute toluene ) the solid precipitate is suctioned off and dissolved in 1 η hydrochloric acid. To separate the starting imidazoline and impurities, acidic acid extraction is carried out several times (ether extracts are discarded) and then at different pH values (blunting with 2 η NaOH) fractionated extraction with ether (8 fractions). The ether fractions which are uniform on the basis of the thin-layer chromatogram are combined, _{dried over MgSO 4} and evaporated to dryness in vacuo. The oil remaining as residue crystallizes out after a short time.
Yield: 1.7 g (corresponding to 36.6% of theory).
Mp. 116 to 118 ° C.

The substance is uniform in thin-layer chromatography. It dissolves in an equivalent amount of dilute hydrochloric acid, in ethanol, methanol, chloroform and ether. On the other hand, it is insoluble in water. Their color is white.

The following substances can be synthesized analogously to the previous example:

2- [N (2 furylmethyl) -N- (2-chloro-
b methylphenyl) -amino] -2-imida £ olin

Yield: 44.9% of theory.

Mp. 97 to 99 ° C.
Mhlf

11.5 g (0.025 mol) of N'-frpyJ ^ thyl-3-furylmethyl-S-methyl-isothiuronium iodide by the action of 2-methyl-3-chloromethyl-furan on N - ^. e-dich'orphenylJ-S-methyl-isothiuronium iodide, are combined with 2.25 g (150%) 98%

ίο ethylenediamine for 15 minutes at 165-170 ⁰ C was heated with stirring from the worked-up after cooling the reaction mixture obtained the desired imidazoline in a yield of 6 g, mp: S9 ° C. It is identical to the imidazoline described in Example 1. The mixed melting point with the authentic product shows no depression and is 99 ° C. The hydrobromide melts at 236 to 237 ° C.

B e i s ρ i e 1 6

2- [N- (2-MethyI-3-furyI-methyl) -N- (2,6-dichlorophenylamino)] - 2-imidazoline hydrochloride

To a solution of 4.6 g (P "i mol) of 2- (2,6-Dichlorphenyiamirio) -2-iiTiidäzolin in 50 i.il" bsolutcrn tetrahydrofuran is 0.87 g (0.02 mol) of a ca. 58% sodium hydride dispersion at 10-20 °. The mixture is stirred at room temperature for 2 hours and a mixture of 2.75 g (105%) of 3-chloromethyl-2-methylfuran and 10 ecm of absolute tetrahydrofuran is added dropwise with stirring at the same temperature. First allowed to react for 2 hours at room temperature and then the reaction mixture is brought to reflux temperature for a further 2 hours.

After this time (TLC check) the reaction mixture contains approximately 70% of that on the imidazoline nitrogen atom substituted compound in addition to around 10% of the isomeric derivative substituted on the bridge N atom as well as about 20% of the starting imidazoline.

The individual components can be separated using preparative chromatography on silica gel the system benzene: dioxane: ethanol: kcnz. ammonia = 50: 40: 5: 5. The melting points of the two isomeric imidazoline derivatives are 291 to 292 "C for 1 - (2-Methyl-3-furyl-methyl) -2- (2,6-dichlorophenyl-amino) -2-imidazoline hydrochloride and 96 to 93 ° for 2- [N- (2,6-dichlorophenyl) -N- (2-methyl-3-furyl-methyl) -amino] -2-imidazoline-base.

Example A: tablets

2- [N- (2,6-dichlorophenyl) -N- Manufacturing 10 mg (2-methyl-3-furylmethyl) - 65 mg amino] -2-imidazoline 125 mg Milk sugar 40 mg 55 corn starch 3 mg sec. Calcium phosphate cat 3 mg Osuche strength 4 mg Magnesium stearate 250 mg colloidal silica 60 in total

t ^ yyyJ ^
(S-methylphenyiJ-amino ^ -imidazöiiri
Yield: 41.2% of theory.
Mp, 74.5-76.5 ° C

The active ingredient is used with part of the Hiifssiofft. vermycht. intensively with an aqueous solution of the soluble starch is kneaded and granulated in the usual way with the help of a sieve the rest of the excipients mixed and made into tablets of 250 mg compressed

The same process can be used to produce tablet cores, which are then usually prepared with the help of Sugar, talc and gum arabic can be coated.

Example B: ampoules

2- [N- (2,6-dichlorophenyl) -N-

(2-methyl-3-furylmethyl) -

amino] -2-imidazoline

Sodium chloride

least. Water, q. see ad

1.0 mg

18.0 mg

2.0 ml production

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

'Example C: pots

2- [N-f2-chloro-6'methy] phenyl) -N * (2-furylmethyl) -amino] -

2-imidazoline-> hydrobromide 0.02 g

ίο methyl p-hydroxybenzoate 0.07 g

Propyl p-hydroxybenzoate 0.03 g

demineralized water, q. see ad 100 ml

UO 237/47

Claims (2)

Claims; 1. Substituted 2- (N-Fury! Methyl) -N-phenyl-arnino) -2-imidazoIines of the general formula I. (D in which R is a chlorine atom or a methyl group and R ^{1 is} a hydrogen atom or a methyl or ethyl group, as well as their acid addition salts. 2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se a) a substituted 2-phenylamino-2-imidazoline of the general formula II Cl 30th 35 wherein R has the meaning given in claim 1, with a halide of the general Formula III Hal - CH ₃ (in the in which Hai is chlorine, bromine or iodine and R ^{1 has} the meaning given in claim 1; or
b) a compound of the general formula IV (IV) 55 60 in which R and R ¹ are defined as given in claim 1 and R ^{J represents} an alkyl group with up to 4 carbon atoms, with ethylenediamine or its acid additive salts! or IO 15th 20th 25th c) a metal salt of 2-phenylamino-2-imidazoline of the general formula V