FI64145C - FREQUENCY REFRIGERATION FOR 2-ARYLAMINO-2-IMIDAZOLINE DERIVATIVES - Google Patents

Description

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Patent- och registerstyrelsan '' Amok »utlt« d och ucljkmtM pubUcmd 30.06.83 (32) (33) (31) Request * · * »* Stuolkmis — B« fird priorities 03.07.?4 Austria-Österrike (AT) A 5 ^ 7 ^ / 7 ^ (71) Cheraie Linz Aktiengesellscnaft, St.-Peter-Strasse 25 * Linz, Austria-Austria (AT) (72) Rudolf Franzmair, Linz-Ebelsberg, Austria-Austria (AT) (7 * 0 Leitzinger Oy (5 ^) Method for the preparation of 2-arylamino-2-imidazoline derivatives -Förfarande for framställning av 2-arylamino-2-imidazoline derivatives

It is known from Austrian Patents 248,428, 250,344 and 250,345 that 2-arylamino-2-imidazoline derivatives, in particular 2- (21,6'-dichlorophenylamino) -2-imidazoline, have a clear hypotensive effect with a sedative effect.

Belgian patent publication 741 947 further discloses N-aroyl derivatives of this 2-arylamino-2-imidazoline derivative, for example 2-fluorobenzoyl- (2 ', 6'-dichlorophenyl) -amino] -2-imidazoline, which also have these hypotensive and simultaneous sedative effects. .

These N-aroyl derivatives are then obtained by aroylating the free 2-arylamino-2-imidazolines with the corresponding acid chlorides of the aromatic carboxylic acids, the acid group being exchanged for a hydrogen atom bound to the aniline nitrogen.

It has now been found that the aroylation of these 2-arylamino-2-imidazolines with the active amides of aromatic carboxylic acids gives, in very good yields and in considerable purity, aroyl derivatives which have interesting pharmacological properties and in which the acid groups are not in the aniline nitrogen. The structure of these compounds, which differs from that described in Belgian patent publication 741 947, can be demonstrated by various physical studies, e.g. melting point and NMR spectra.

The present invention therefore relates to a process for the preparation of 2-arylamino-2-imidazoline derivatives of the general formula R, H NN-

3 I

C/O

«4 or 10- u 'N-1

J I

C/O

For the preparation of R 4, wherein R 1, R 2 and R 3, which may be the same or different, represent hydrogen, halogen, preferably chlorine or bromine, or a lower alkyl group, provided that at least one of R 1, R 2 and R 3 is always other than hydrogen , and R 1 is a phenyl group optionally substituted by an alkyl group having 1 or 2 carbon atoms, which process is characterized in that the 2-arylamino-2-imidazoline derivative of the general formula II 3 64145 3 ϊ is reacted with the active amides of the general formula III R 4 - C - X (III)

4 rt O

wherein X is a five-membered heterocyclic ring, optionally fused to benzene, having 2 or 3 nitrogen atoms in which at least one nitrogen atom is attached to a hydrogen atom, or a group of the formula 2Xj>? - <NH <iv> R3a wherein R1, R2, R3 and R4 have the same meaning as in formula I, at normal or elevated temperature.

By "active amides" is meant primarily those compounds called "azolides" H.A. According to Staab and W. Rohr, "Synthesis with heterocyclic amides", and W. Foerst, Neuere Methoden der preparative organic chemistry, V, page 53 et seq. By the present invention is meant primarily those azolides of the acids of formula R4.COOH which are analogous to the acetic acid azides of Table I on page 55 of this work. Mention may be made, for example, of 1,2,3-triazole, 1,2,4-triazole and azolides derived from benztriazole and benzimidazole. It is particularly expedient to use imidastolides of the acids of the formula R4COOH. However, an active amide of a compound of formula II containing an acid group bonded to the aniline nitrogen can also be used for the acylation according to the present invention.

4 64145

The different course of acylation with azolides compared to that with acid chlorides is very surprising # since the above-mentioned H.A. According to the work of Staab and W. Rohr, the reactivity of these azolides is similar to that of acid halides and anhydrides.

The reaction of the compounds of formula II with the active amides of formula III can take place in all azole processes under conventional conditions. It is expedient to add a solution of the acylatable 2-arylamino-2-imidazoline of the formula II to the solution of the active amide of the formula III. The reaction may be carried out by allowing the solution to stand at room temperature, but may be heated, conveniently up to the boiling point of the solvent used. Examples of such solvents are toluene, benzene, xylene, chloroform, dimethylformamide, dioxane and tetrahydrofuran. The active amide of the formula III is used in at least an equal molar amount, based on the compound of the formula II, expediently in an excess of 10 to 20%. The reaction time is selected on the basis of the reactivity of the active amide and the reaction temperature.

It's usually several hours.

If a compound of formula IV is used as the active amide of formula III, and if in this group of formula IV and in the compound of formula II the benzene ring substituents R 1, R 2 and R 3 are identical, then it is not necessary to use a compound of formula II equal molar amount or only a small excess. In this case, a considerable sub-amount, expediently using less than half, preferably even only one tenth, of the equivalent amount of the active amide of the formula III is obtained, since during the acylation the active compound of the formula III is released from the active amide.

This modification of the process according to the invention is achieved, for example, simply by boiling the starting materials in an aprotic, inert solvent, such as toluene or xylene.

5 64145

For further work-up, in all variations of the process according to the invention, the solvent is removed after a suitable completion of the reaction, whereby the dry residue can be purified by recrystallization. In some cases it is advisable to triturate the dry residue first with water, possibly while adding a little alkali such as soda or sodium bicarbonate solution, after which either the crystalline phase or the aqueous phase is taken up in an organic solvent.

For the reaction, it is not necessary in all cases to prepare the active amide of the formula III in a separate step.

The azolide of formula III can also be generated in situ from the corresponding azole and the acid chloride of formula R 1 -COCl and used directly further. Thus, for example, it is possible to react an acid chloride of the formula R 1 COCl in tetrahydrofuran with imidazole and, after the reaction has taken place, to add a solution of the compound of the formula II to the reaction solution. The in situ preparation of the imidazole of formula III is also accomplished by reacting an acid of formula R 1 COOH with Ν, Ν'-carbonyldiimidazole.

Active amides in which X represents a group of formula IV are obtained by the method of Belgian Patent Publication 741,947.

The compounds of formula Ia or Ib are homogeneous, highly crystalline products. The structure of these compounds cannot be determined unambiguously in that the question of whether the double bond in the imidazoline ring (Ia) or the exocyclic (Ib) must be left open. They have very interesting pharmaceutical properties. Of particular note are compounds of the formula Ia or Ib in which the phenyl ring is substituted by halogen in the 2- and 6-positions. Such compounds in which R 1 CO represents a benzoyl, m- or p-toluoyl group also have an antihypertensive effect, as do compounds of the formula II, for example 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline and their aroyl derivatives. described in Belgian Patent 741 947, but the sedative effect component is much less clear. A particularly favorable relationship between the antihypertensive effect and the sedative effect is observed in compounds in which R 1 CO is a benzoyl group, with 6 64145 mm being omitted when these compounds are used as hypotensive agents. fatigue as an unpleasant side effect. All of these compounds are excellently absorbed orally, especially those in which R 1 CO is benzoyl.

The same direction of action is also observed with other compounds of formula IVa or IVb, albeit to a different extent.

The absence of a sedative or central nervous system depressant effect is readily ascertained by the presence of the carotid sinus reflex in anesthetized rabbits after administration of said compounds of formula Ia or Ib at 100 micrograms / kg. This reflex is almost completely attenuated by administration of an equal dose of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline. Furthermore, this can also be observed from the unchanged behavior of awake mice when 5 or 10 mg / kg of these benzoyl or p-toluene compounds of formula Ia or Ib are administered.

Said compounds of the formula Ia or Ib in which R 1 CO denotes benzoyl, m- or p-toluene can therefore be administered in medicine as hypotensive substances in all conventional pharmaceutical forms, such as tablets, granules, capsules, suppositories, emulsions, solutions or injections.

Depending on the form of administration, either free bases or salts are used for this purpose. As the salts, salts with, for example, inorganic or organic acids, such as hydrohalides, phosphates, oxalates, 8-chlorophenophyllinate or salts with acidic synthetic resins, can be used.

The method according to the invention is explained in more detail below by means of examples.

The NMR absorbances given in these examples are given as 6 values. Example 1: 1.47 g of benzoic acid (12 mmol) are dissolved in 50 ml of absolute tetrahydrofuran and 1.95 g of N, N'-carbonyldiimidazole are added thereto with stirring. The mixture is allowed to stand for 45 minutes at room temperature. To this is added, with stirring, a solution of 2.30 g of ^ 64145 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in 25 ml of absolute tetrahydrofuran and then allowed to stand for 20 hours at room temperature. The solvent is distilled off under normal pressure and the residue is triturated with about 50 ml of 0.5% sodium bicarbonate solution, whereupon crystallization occurs. Filter, wash the crystals well with water and dry in vacuo over phosphorus pentoxide. 3.31 g of crude 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are obtained, which is recrystallized from isopropanol.

Yield of pure product 2.65 g (77.2% of theory), melting point -160-162 ° C.

Analysis: C ^ gH ^ Cl ^^ O

Calculated: C 57.19 H 3.98 N 12.55 O 5.23 Cl 21.10

Found: 57.4 4.1 12.4 5.2 20.8 pKa: 4.01 (in 70% methylcellosolve at room temperature) UV: λ = 237 nm (sh; e = 22,100) in ethanol IR: (KBr) 3310 cm 1686 cm 1656 cm 1612 cm 1579 cm-1 NMR: (100 MHz, CDCl 3): 3.42 (2H, almost triplet) 4.01 (2H, almost triplet), ca. 4.10 (m, wide, NH, exchange with D20).

The melting point of 2- [N-benzoyl- (2 ', 6'-dichlorophenyl) -amino] -2-imidazoline according to Belgian Patent 741,947 is also 160-161 ° C, but the melting point of the mixture of both compounds is 134-143 ° C.

Other values for the compound of the Belgian patent publication are: pKa value = 6.10 (in 70% methylcellosolve at room temperature) NMR: (100 MHz, CDCl 3): 3.66 (s, 4H), 6.43 (m, broad , NH, exchange with D2O) are also clearly different.

s 64145

Example 2: 4.60 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline (20 mmol) and 4.23 g of p-toluylimidazolidine (23 mmol) are refluxed for 2.5 hours in 60 ml. in absolute toluene. It is then evaporated, the residue is triturated with 40 ml of isopropanol, filtered and dried; 6.27 g of crude 1-p-toluyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline (90.2% of theory) are obtained, melting point = 156-176 ° C, which is recrystallized from isopropanol for purification. . 5.74 g of pure product are obtained (82.7% of theory), melting point: 172-175 ° C.

Analysis: c17H15Cl2N3O

Calculated: C 58.63 H 4.34 Cl 20.36 N 12.06 0 4.59

Found: 58.8 4.6 20.2 11.9 4.9 pKa: 4.18 (in 70% methylcellosolve at room temperature) UV: λ = 236 nm (sh, ε = 20,200) in ethanol IR: (KBr) Δ 310 cm -1, 1689 cm -1, 1650 cm -1, 1620 cm -1 NMR (100 MHz, CDCl 3): 3.48 (2H, almost triplet) 4.07 (2H, almost triplet ca. 4.20) (m, broad, NH, exchange with DjO 2)

Example 3: 1.63 g of imidazole (24 mmol) are dissolved in 10 ml of absolute tetrahydrofuran. A solution of 1.85 g of p-toluyl chloride (12 mmol) in 10 ml of absolute tetrahydrofuran is added dropwise to this solution, and after the addition, the mixture is stirred for a further 2 hours at room temperature. The precipitated imidazole hydrochloride is then filtered off, the crystals are covered with 5 ml of absolute tetrahydrofuran and separated rapidly by suction. The filtrate obtained is added within 5 minutes with stirring to a solution of 2.30 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline (10 mmol) and then allowed to stand for 20 hours at room temperature. It is then evaporated, the residue is treated hot with 25 ml of isopropanol and then allowed to stand for 4 hours at room temperature. Filter, wash with isopropanol and dry. 2.99 g of pure 1-p-toluyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are obtained, which is

II

9,641 45 85.9% of theory, melting point = 172-175 ° C. The product is identical to the product described in Example 2.

Example 4: 3 g of o-toluic acid (22 mmol) are dissolved in 70 ml of absolute tetrahydrofuran, 3.57 g of N, N'-carbonyldiimidazole are added and the mixture is stirred for 1 hour at room temperature. Then a solution of 4.60 g is added. g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in 30 ml of tetrahydrofuran. The mixture is allowed to stand overnight at room temperature. It is then evaporated to dryness in vacuo, the residue is triturated well with 150 ml of water, filtered, washed with water and dried. 6.05 g of crude 1-o-toluyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are thus obtained.

Mp = 160-175 ° C (87.1% of theory).

For purification, recrystallization from isopropanol gives 5.61 g (80.9% of theory) of analytically pure product, m.p. = 179-180 ° C.

pKa: 3.85 (70% methylcellosolve, room temperature) UV: λ = 242 nm (sh, ε = 13 150) in ethanol IR: (KBr) 3 355 cm -1, 1706 cm -1, 1643 cm -1 NMR : (100 MHz, CDCl 3) * 3.94 (2H, almost triplet) 4.05 and about 4.20 (total 3 H, of which 1 H is exchanged with D 2 O, m m 4.05, 2H).

Example 5: 3 g of m-toluic acid (22 mmol) are dissolved in 70 ml of tetrahydrofuran, 3.57 g of Ν, Ν'-carbonyldiimidazole are added and the mixture is stirred for 1 hour at room temperature. A solution of 4.60 g of 2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in 30 ml of absolute tetrahydrofuran is then added. The mixture is allowed to stand overnight at room temperature. It is then evaporated to dryness in vacuo, the residue is triturated well with 150 ml of water, filtered, washed with water and dried. 6.92 g of crude 1-m-toluyl- (2 *, 6'-dichlorophenylamino) -2-imidazoline are thus obtained, which is recrystallized from benzene: cyclohexane (1: 1) and isopropanol for purification to give 6.21 g ( 89.4% of theory) of analytical grade, mp = 157-158 ° C.

10,641 45 pKa = 4.02 (70% methyl ethyl cellosol, room temperature) UV: λ = 236 nm (sh, ε = 18,700) ethanol IR: (KBr) 3430 cm -1, 1680 cm -1, 1654 cm -1 1 NMR: (100 MHz, CDCl 3) »3.48 (2H, almost triplet) 4.07 (2H, almost triplet), ca 4.2 (m, broad, NH, partially superimposed).

Example 6: 0.65 g (12 mmol) of benzoic acid are dissolved in 20 ml of absolute tetrahydrofuran and 0.86 g of N, N'-carbonyldiimidazole (12 mmol) are added. For the reaction, the mixture is allowed to stand for 30 to 40 minutes at room temperature. To the clear solution is added a solution containing 0.93 g of 2- (2'-chloro-6'-methylphenylamino) -2-imidazoline in 10 ml of absolute tetrahydrofuran and heated at reflux for 3.5 hours. It is then evaporated.

The residue is triturated with 20 ml of 0.5% sodium bicarbonate solution, filtered, washed with water and dried. 1.29 g of crude 1-benzoyl-2- (2'-chloro-6'-methylphenylamino) -2-imidazoline (92.8% of theory) are obtained.

After recrystallization from cyclohexane, 1.11 g of pure product are obtained (79.8% of theory), m.p. = 124-127 ° C.

UV: λ = 234 nm (sh? Ε = 16 600) in ethanol IR: (KBr) 3415 cm -1 (sharp) 1673 cm -1, 1643 cm -1 NMR: (100 MHz, CDCl 3): 3.37 ( 2H, almost triplet) 3.97 (2H, almost triplet) 4.70 (m, broad NH, exchanged with D 2 O)

Example 7: 1.47 g of benzoic acid are dissolved in 50 ml of absolute tetrahydrofuran. To this is added, with stirring, 1.95 g of N, N'-carbonyldiimidazole, the mixture is allowed to stand for 40 minutes at room temperature and a solution of 3.19 g of 2- (2,6'-dibromophenylamino) -2-imidazole is added. and 50 ml of tetrahydrofuran. Allow to stand for 42 hours at room temperature. The solvent is then distilled off under normal pressure and the residue is triturated with 40 ml of 1% sodium bicarbonate solution, whereupon crystallization occurs. crystals

II

11 64145 are filtered off with suction, washed well with water and dried.

4.02 g of crude 1-benzoyl-2- (21,6'-dibromo-phenylamino) -2-imidazoline are thus obtained, which is recrystallized from isopropanol for purification. 3.31 g (78.6% of theory) of pure product are obtained, m.p. = 193-197 ° C.

pKa: 3.67 (in 70% methylcellosolve at room temperature) UV: λ = 240 nm (sh, e = 17,400) λ = 290 nm (sh; ε = 3660) in ethanol IR: (KBr) 3375 cm-1, 1697 cm -1, 1638 cm -1 NMR: (100 MHz, CDCl 3): 3.49 (2H, almost triplet) 4.11 (2H, almost triplet), ca. 4.05 (m, broad, NH, partially obscured) ).

Example 8: 200 mg of 2- (N-benzoyl-N- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline and 15 mg of 2- (2', 6'-dichlorophenylamino) -2-imidazoline boil at reflux for 32 hours in 10 ml of absolute toluene. It is then evaporated to dryness and the residue is recrystallized from 8 ml of isopropanol. 160 mg of pure 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are obtained, melting point = 160-162 ° C, identical to the product of Example 1.

Example 9: 500 mg of 2- [Nm-toluyl- (2 ', 6'-dichlorophenyl) -amino] -2-imidazoline (1.43 mmol) and 33 mg of 2- (2', 6'-dichlorophenylamino) -2 -imidazoline (0.143 mmol) is heated at reflux for 18 hours in 20 ml of absolute xylene. The solvent is removed in vacuo, the residue is dissolved in hot 3.5 ml of isopropanol and allowed to crystallize slowly. 342 mg (68.4% of theory) of pure 1-m-toluyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are thus obtained, m.p. = 157-158 [deg.] C., which is identical to the product of Example 5.

The starting 2- (Nm-toluyl- (2 ', 6'-dichlorophenyl) amino] -2-imidazoline is prepared by reacting 2- (2', 6'-dichlorophenylamino) -2-imidazoline with m-toluic acid chloride, m.p. = 159-164 ° C.

pKa = 6.68 (in 70% methylcellosolve at room temperature).

12 64145

Example 10 1.52 g or 22 mmol of 1,2,4-triazole are dissolved in 50 ml of anhydrous tetrahydrofuran and a solution of 1.54 g or 11 mmol of benzyl chloride and 20 ml of anhydrous tetrahydrofuran is added dropwise with stirring at room temperature. After completion of the dropwise addition, the mixture was stirred for another hour, the crystalline 1,2,4-triazole hydrochloride was separated by filtration, and the filtrate containing 1-benzoyl-1,2,4-triazolidide was added dropwise to a solution of 2.30 g, or 10 mmol. 2- (2,6-dichlorophenylamino) -2-imidazoline and 40 ml of anhydrous tetrahydrofuran at room temperature after which the mixture is allowed to stand overnight at room temperature. The tetrahydrofuran is removed in vacuo and the residue is recrystallized from isopropanol to give 2.10 g of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline in a yield of 62.9% of theory and a melting point of 160-162 ° C.

Example 11 2.44 g or 11 mmol of 1-benzoylbenzimidazolide and 2.30 g or 10 mmol of 2- (2,6-dichlorophenylamino) -2-imidazoline are refluxed in 50 ml of anhydrous benzene for six hours, after which the benzene is removed in vacuo and the crystalline residue is again crystallized from isopropanol. 2.01 g of 1-benzoyl-2- (2- (6'-dichlorophenylamino) -2-imidazoline are obtained in a yield of 60% of theory and a melting point of 160-162 ° C.

Example 12 2.46 g or 11 mmol of 1-benzoylbenztriazole and 1.84 g or 8 mmol of 2- (2,6-dichlorophenylamino) -2-imidazoline are reacted according to Example 1. 2.15 g of 1-benzoyl-2- (2 ', 6'-dichlorophenylamino) -2-imidazoline are obtained in a yield of 78.1% of theory and a melting point of 160-162 ° C.

Claims (5)

64145 13 A process for the preparation of 2-arylamino-2-imidazoline derivatives of the general formula R 1 R 9 / - S N «n 3 I co K or R 1 H '' 30 - - (. H R 3 CO R 4 in which the formulas R 1, R 2 and R 3, which may be the same or different, represent hydrogen, halogen, preferably chlorine or bromine, or a lower alkyl group, provided that R 1, R 2 and R 3 are always at least one other than hydrogen, and R 4 is a phenyl group optionally substituted by an alkyl group having 1 or 2 carbon atoms, characterized in that the 2-arylamino-2-imidazoline derivative of the general formula II 14 64145 3 H is reacted at normal or elevated temperature with active amides of the general formula III R 4 to C to X (li) II O in which the group X is a five-membered, heterocyclic ring, optionally fused to benzene, having 2 or 3 nitrogen atoms in the molecule, wherein at least one nitrogen atom is attached to a hydrogen atom, or a group -o-1H wherein R1, R2, R3 and R4 have the same meaning as in formula I. Process according to Claim 1, characterized in that the active amide of the formula III is a compound in which X represents a group of the formula IV in which R 1, R 2 and R 3 have the same meaning as in the starting compound of the formula II, the compound of the formula II being used in small amounts, preferably 1/10 equivalent calculated on the compound of formula III in question. h 64145 15 A process for the preparation of 2-arylamino-2-imidazoles according to the form of 3-CO 2 or a single form of R 1, R 2 and R 3, wherein property of an oil, an alkyl group, a halogen, a fatty acid or a bromine group, an alkyl group, an alkyl group, all of which may be attached to the group R 1, R 2 and R 3 are possibly given, or an R 4 or phenyl group, optionally are substituted with an alkyl group of 1 or 2 colaters, which can be substituted with 2-arylamino-2-imidazolyl derivatives of the lower formula II