FI70710C - IMMEDIATE FOLLOWING OF THERAPEUTIC ACID 4 (5) SUBSTITUTES - Google Patents

Description

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Process for the preparation of therapeutically active 4 (!>) -Substituted imidazole derivatives

Separated by division of application 802404 - Avdelad fr an trap 802401

The present invention relates to a process for the preparation of novel 4 (S) -benzylimides, as well as their non-toxic, pharmaceutically acceptable acid addition salts. These new imidate ring derivatives have valuable pharmacol op. father a characteristics; in particular, they have an antiulcer effect.

With the imidazole 1i prepared according to the invention, Ia is the general formula ^ 7 fT) H Ra R3 wherein R1, R2 and ^ 3> which may be the same or different are hydrogen, chlorine, bromine, fluorine, methyl, ethyl, methoxy, amino, hydroxy or nitro, R1 is hydrogen or an allyl group having 1 to 7 carbon atoms; ia is an ai k wl group containing 1 to 7 carbon atoms.

The literature (Arch. Pharm, (Weinlieim, Ger.) 1878, 111 (2), 98-10.1, Kurt Wegner et al.) Describes 4- (CK-phenyl) -methyl-methyl-5-methyl. i-imidates so, but have not been described to have pharmacological effects.

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The compounds of formula (I) are bases which form acid addition salts with both organic and inorganic acids. They thus form many pharmaceutically acceptable acid addition salts, such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formats, tartrates, maleates, citrates, benzoates, sulfates, ascorbates and the like.

The following compounds may be mentioned as examples of compounds of formula (i): 4-fc? <.- feny gen. i) -ethoxymethyl-imidazole 4- (2'-methylphenyl)] -methoxymethylimidazole 4- [4- (2-methylphenyl)] - Toxylethylimidates 4 - [C <j- (3'-methylphenyl) 1 - e Toxylethylimidate 4- [1- (4'-methylphenyl) 1- Ethoxymethylimidazole 4- [X- (2'-methoxyphenyl)] -ethoxymethylimidazole 4 - [[X- (3'-methoxyphenyl) 1-ethoxymethyl] imidate sol 4-phenyl (4'-methoxyphenyl) 1-ethoxymethylimidazole 4 - [<X- (2 ', 4', 6'-trimethylphenyl)] - Ethoxymethylimidazole 4 - [<X- (2 ', 6'-dimethylphenyl)] -methoxymethylimidazole 4 - [<X- (2', 6'-dimethylphenyl)] - e Toxylmethylimidates are 5-methyl-4- (<X- phenyl)] - Toximethylimidates are 5-methyl-4 - [<X- (2 ', 6'-dimethyl) phenyl) 1-methoxymethyl-imidazole 1-5-methyl-4- [X- (2 ', 6'-dimethylphenyl)] - ethoxymethylimidazole

Substituents have been found to significantly affect the pharmacological properties of the compounds. Although all the compounds of formula (i) have a substantially satisfactory potency, the compounds in which the phenyl group is 2,6-substituted are the most effective.

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Compounds of formula (i) are prepared by treating a compound of formula (II) with OH .-- N. Ry (II) H K3 in the presence of R1OH acid. Most preferably, the imidazole starting material is simply boiled in a suitable alcohol in the presence of an acid, with suitable acids being inorganic and organic acids, e.g. hydrochloric acid.

As stated above, the compounds of general formula (T) and their non-toxic pharmaceutically acceptable acid addition salts have valuable pharmacological properties. They have been found to have excellent antiulcer effects in mammals. In addition, diuretic, analgesic and anti-inflammatory effects have been observed.

The isomeric compounds of formula (T), their non-toxic pharmaceutically acceptable salts or mixtures thereof may be administered parenterally, intravenously or orally. An effective amount of the derivative is generally combined with a suitable pharmaceutical carrier. As used herein, the term "effective amount" refers to amounts that achieve the desired effect without side effects. The exact amount in a given situation will depend on many factors, such as the mode of administration, the type of breastfeeding, the disease to which the agent is administered, etc., and, of course, the structure of the derivative.

4,70710 The pharmaceutical carrier used may be solid or liquid and may be selected depending on the dosage form. Thus, for example, lactose, sucrose, gelatin and agar may be used as solid carriers, and water, syrup, peanut oil and olive oil may be used as the liquid carrier. The combination of the derivative and the carrier can take many forms, such as tablet, capsule, suppository, solution, emulsion and powder form.

The antihypertensive effect of the imidazole derivatives prepared according to the invention has been demonstrated by sedating anesthetized, normal weight Sprague-Oawley rats. The experimental animals were first anesthetized with urethane. Thereafter, the femoral artery was connected to the blood pressure groove with a polyethylene tube. The test substance was initiated into the femoral vein, and blood pressure and heart rate were recorded using a plotter.

The second experiment used an anesthetized tower Okamoto-Aoki Spontaneous HydDerton Rat (SHR). The test compound was administered orally via a plastic tube to the stomach. Blood pressure was measured from the tail using an indirect bloodless method.

The gastric ulcer inhibitory effect was tested with the compounds of formula (j) using female rats of the SpragueDawley strain, about 10 weeks old and weighing 200 to 750 g. F.before the experiment, the rats, divided into two groups, had been fasting overnight. Another part of the rats was given 20 mg / kg p.o. alone. indomethacin, and for the other part indomethacin 20 mg / kg p.o. and concomitantly the test substance i.p. dosage. Rats were sacrificed after 4 hours, and the gastric ulcer response was counted as wound findings compared to indomethacin-induced wound findings.

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The diuretic effect was studied in rats by collecting their current over a period of 0-5 hours with the compounds i.p. after injection. Prior to the experiment, the rats had been fasting overnight. Immediately before injection, they were given 10 ml of water p.o.

The analgesic effect was studied as follows: 1) Writhing test

The test compounds and the control solvent used were administered p.o. for rats and 45 min. later] ml of 1% acetic acid i.p. The number of seizures was measured over the next 25 min. period. (Koster et al .: Eed.Proc. 18: 412, 1459).

2) Hot plate test

The test compounds and the control solvent used were administered i.p. for dog mice and 30 min. then the tolerated residence time was measured on a plate with a temperature of 55 ° C.

The anti-inflammatory effect was determined by monitoring the inhibition of carrageenan-induced edema by the compounds in rats (Winter C.A. et al., Proc.Soc.Exp.Riol.Med. 111: 544, 1962).

Acute toxicity was studied using NMRI strain female mice, approximately 7 months of age and weighing 30-40 g. The dosage was i.y.

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The following are some examples of the pharmacological properties of the compounds.

When 4- [E 2 - (2 ', 6'-dimethylphenyl)] - ethoxymethyl-imidazole at 45 mg / kg i.v. in mice, subjected to the experiments described above, the compound showed only a very weak hypertensive alert effect. Instead, at a dose of 5 mg / kg, the compound completely prevents the development of an experimental gastric ulcer, at a dose of 0.5 mg / kg partially.

The pharmacological properties of the compounds of the invention are summarized in the following tables.

Examples of compounds having analgesic activity

Analgesic potency x) HP time I daily dose jExtension (%) j Effect mg / kg | w-number) I lii -------- + ------ 1 ----- 1 --- 1 I lii 4 - [<X- (2 ', 6'-dimethyl- j W 100 I 13 j + j

phenyl)] - methoxymethyl III

imidazole j j | | 4 - [<X- (2 ', 4'-dimethyl-N 100 | 0.6] + + |

phenyl) 1-ethoxymethyl-I III

imidazole j III

x) HP = hot plate test W = writhing test

II

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Examples of compounds having a diuretic effect J Dose I Diuretic effect% | I mg / kg I j I j 2,5 h S h | ------------ 1 --- 1 --- j-j 4 - [<? <.- (2 ', 6'-dimethylphenyl) l-J 30.0 j AO | 16 and ethoxymethyl imidazole | | j

II II

Examples of compounds having anti-inflammatory activity

Ant i- infl Animator inen potency (dose 100 mg / kg p.o.) I carrageenan | j j effect of induced odeemaj j | inhibition (%) j j --------- j ---- 1 - j-

4- [cK- (2 ', 6'-dimethylphenyl)] - 140 I + 1

methoxymethylimidazole j |

I I I

4 - [<X- (21,6'-dimethylphenyl)] - I 35 | + | ethoxymethylimidazole and j 0 0 71 0

The invention is described in more detail in the following examples.

In the examples showing 1 H-NMk spectrometric shifts, the NMR spectra were taken on a Perkin Elmer R24 instrument using an external tetramethylsilane standard for which the chemical shifts (ε, ppm) shown are tabulated. The letters s, d, t and m are whether it is a singlet, a doublet, a triplet, or a multiplet. The number of hydrogen atoms is also indicated in the same context. The base compounds are run in deuterium methanol, deuterium acetone or deuterium chloroform; the compounds present as hydrochloride are again in deuterium oxide.

Mass spectra were taken on a Perkin Elmer RMU-7 E using a "direct inlet" system. The temperature has been the lowest temperature required to evaporate the compound. The strongest and most structurally relevant fragment ions are included in the examples as m / e values. The intensity of the fragment ion relative to the spike peak is shown in parentheses.

Example 1 4- (oT-Phenyl) -ethoxymethylimidates sol

Dissolve 4 - ((X * -phenyl) -hydroxymethylimidazole (10 (?)) In 40 ml of absolute ethanol, make up to volume with boiling the reaction mixture for 1 hour, evaporate to dryness, add 60 ml of water and dissolve the residue. Basify with sodium carbonate, extract with 3 x 50 ml of chloroform, wash the combined chloroform extracts with water and dry over sodium sulfate, evaporate to dryness, and the crude product thus obtained can be crystallized from ethyl acetate, mp 129-131 ° C.

NMR: 0.85 (t, 3H), 3.15 (q, 2H), 4.9 (s, 1H), 5.1 (s, 1H), 6.45 (s, 1H), 7.0 (s, 5U), 7.25 (s, 1H) .

II 4 - [<X- (2'-Methylphenyl] -1-ethoxymethyl-iridazole 7071 0 9

Example 2

The procedure is as in Example 1, except that 4- [3- (2-'-methyl-phenyl) -hydroxymethylimidazole is used instead of 4- (OC-phenyl) -hydroxymethylimidazole.

NMR: 1.0 (t, 3H), 2.1 (s, 2H), 3.45 (q, 2H), 4.4 (s, 2H), 5.65 (s, 1H), 7.1 (m, 5H), 9.15 (s, 1H) .

Example 3 4- [¢¢ - (21,6'-Dimethylphenyl)] - ethoxymethyl-5-methyl imidazole

Proceed as in Example 1 except that 4- [C 1- (21,61-dimethylphenyl)] - hydroxymethyl-5-methylimidate sol is used.

NMR (HCl salt): 1.05 (1.3H), 1.65 (s, 3H), 2.1 (s, 6H), 3.4 (σ, 2H), 4.65 (s, 2H), 5.95 (s, 1H), 6.95 (s, 3H), 8.5 (s, 1 H).

MS: 244 (38%), 229 (9%), 215 (15%), 199 (39%), 183 (100%), 162 (39%), 139 (29%), 133 (35%), 111 (25%), 109 (17%), 105 (13%).

Example 4 4 - [<X- (2 ', 6'-Dimethylphenyl)] - ethoxymethylimidazole

Proceed as in Example 1 except that 4 - [<X- (2 ', 6'-dimethylphenyl)] - hydroxymethylimidazole is used. The m.p. at 142-147eC. The corresponding hydrochloride is prepared in ethyl acetate-isopropanol and its m.p. is 136-139 ° C.

NMR (HCl salt): 1.1 (t, 3H), 2.15 (s, 6H), 3.4 (q, 2H), 4.6 (s, 2H), 6.0 (s, 1H), 6.85 (s, 1H), 7.05 (m, 3H), 8.65 (s, 1 H).

4 - [<X- (3'-Methylphenyl)] -ethoxymethylimidazole 10 7071 0

Example 5

The procedure is as in Example 1 except that 4- [4- (3'-methylphenyl)] - hydroxymethylimidazole is used. The hydrochloride is prepared in isopropanol-ethyl acetate and melts at 135-140 ° C.

NMR (HCl salt): 1.2 (t, 3H), 2.25 (s, 3H), 3.55 (q, 2H), 4.75 (s, 2H), 5.55 (s, 1H), 7.1 (s, 1H), 8.7 (s, 1 H).

MS: 215 (23 Z), 187 (6 X), 172 (53 X), 171 (100 X), 170 (20%), 155 (7%), 144 (15%), 143 (27%), 97 (20%), 95 (23%), 91 (15%).

Example 6 4- [1- [5c "(3'-Methoxyphenyl)] - ethoxymethylimidazole

The procedure is as in Example 1 except that 4-fo- (3'-methoxyphenyl)] - hydroxymethylimidazole is used.

NMR (HCl salt): 1.05 (t, 3H), 3.4 (q, 2H), 3.6 (s, 3H), 4.75 (s, 2H), 5.45 (s, 1H), 6.9 (m, 5H), 8.65 (s, 1H).

Example 7 4- [ε- (4'-Methoxyphenyl)] - ethoxymethylimidazole

Proceed as in Example 1 except that 4- [O- (4'-methoxyphenyl)] - hydroxymethylimidazole is used.

NMR (HCl salt): 1.0 (t, 3H), 3.3 (q, 2H), 3.55 (s, 3H), 4.7 (s, 2H), 5.4 (s, 1H), 6.95 (m, 5H), 8.6 (s, 1H).

11 4 - [<N- (2 ', 6'-Dimethylphenyl)] - methoxymethylimidazole

Example 8 Τ - - - · -

Dissolve 4- [C <- (2 ', 6'-dimethylphenyl)] - hydroxymethylimidazole (10 r) in 60 ml of inethanol. The hydrochloric acid gas is introduced into the solution while boiling the reaction mixture for 1 hour. Evaporate to dryness. Add 100 ml of water and basify the solution with sodium carbonate. Extract with 3 x 50 ml of chloroform. The combined chloroform layers are washed with water, dried over sodium sulfate and evaporated to dryness. The corresponding hydrochloride, prepared in ethyl acetate-isopropanol, m.p. is 176-179 ° C.

NMR (HCl salt): 2.2 (s, 6H), 3.3 (s, 3H), 4.7 (s, 2H), 6.0 (s, 1H), 6.9 (s, 1H), 7.15 (s, 3H), 8.7 (s, 1H>.

Claims (1)

An analogous process for the preparation of therapeutically valuable imidazole derivatives of the formula ^ / TTV * 1 I% c ^ \ 2r2 (τ) wherein R | ^ 2 ^ 3 »which may be the same or different are hydrogen, chlorine, bromine, fluorine, methyl, ethyl, methoxy, amino, hydroxy or nitro; R 1 is hydrogen or an alkyl group having 1 to 7 carbon atoms and is an alkyl group having 1 to 7 carbon atoms; or for the preparation of their pharmaceutically acceptable acid addition salts, with the limitations 1a that when R 1 and R 3 are simultaneously hydrogen atoms, then R 5 cannot be methyl; characterized in that a compound of the formula R 1, R 2, R 3 and R 2 is as defined above is reacted with a compound of the formula R 1 OH in which R 5 is as defined above; in the presence of an acid to form a compound of formula (I) which, if desired, is converted into a pharmaceutically acceptable acid addition salt. 11