DK143901B - METHOD OF ANALOGUE FOR PREPARATION OF 4- (7-BROMO-5-METHOXY-2-BENZOFURANYL) -1-METHYL-1,2,3,6-TETRAHYDROPYRIDINE OR ACID ADDITION SALTS THEREOF - Google Patents

Description

in 143901

The present invention relates to an analogous process for the preparation of the novel 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-1,2,3,6-tetrahydropyridine of the formula CH 3 -o-3 (i)

Br or pharmaceutically acceptable addition salts thereof with inorganic or organic acids.

4- (7-Bromo-5-methoxy-2-benzofuranyl) -1-methyl-1,2,3,6-tetrahydropyridine and its addition salts with inorganic and organic acids have valuable pharmacological properties. As can be seen from the results of the isotopic determination of enzyme activity, in rats and in other experimental animal species, they inhibit the monoamine oxidase, especially selectively and reversibly its A form, after oral or subcutaneous administration of 15 doses of 1.0 mg / kg.

From the specification of Danish patent application no. 1101/74, certain substituted benzofuranyl-tetrahydropyridine and piperidine derivatives having monorine n-oxidase inhibitory activity similar to the general formula 3 J

Y

1 3 4 where R may be hydrogen or methyl, R and R are each

say may mean hydrogen, alkoxy or halogen, and X

and Y individually may mean hydrogen or together form an additional bond. However, the compound of formula I and its acid addition salts is not disclosed in the specification of Danish Patent Application No. 1101/74, and it has been found that the 2 U3901 has a surprisingly good monoamine oxidase inhibitory effect in comparison with those described in the Danish Patent Application. no.

1101/74 known, narrowly analogous compounds, as illustrated below.

5 Following oral administration of 100 mg / kg of the following test substances to rats and killing of the animals 2 hours later, liver and brain homogenates produced a decreased oxidation of the isotope-labeled 5-hydro-tryptamine corresponding to the percentages given below after the test substances. oxidation induced by liver and brain homogenates from untreated control animals: 4- (5-methoxy-2-benzofuranyl) -piperidine hydrochloride (known), liver homogenate 17% / brain homogenate 20%, 4- {5-bromo-2-benzofuranyl) -piperidine hydrochloride (known) 12/9, 1-methyl-4- (5-cyclohexyl-2-benzofuranyl) -piperidine hydrochloride (known) 11/12, 1-methyl-4- (5-methyl-2) -benzofuranyl) -1,2,3,6-tetrahydropyridine hydrochloride (known) 28/35 and 1-methyl-4- (7-bromo-5-methoxy-2-benzofuranyl) -1,2,3,6- tetrahydropyridine hydrochloride 6/4.

At the same time, the compound of formula I and its acid addition salts also causes, in comparison with the very strong MAO-A inhibition, less pronounced inhibition of the uptake of noradrenaline in the heart by rats by oral or subcutaneous administration of doses of 10 to 100 mg / kg. and also inhibits the uptake of 25 serotonin into the midbrain synaptosomes of rats. Furthermore, by intraperitoneal administration to rats at doses of 2 to 40 mg / kg, it antagonizes the hypothermic effect of reserpine.

Along with a favorable therapeutic index, the above-mentioned properties characterize 4- (7-bromo-5-methoxy-2-benzofuranyl) -Ι-ΙΟ methyl-1,2,3,6-tetrahydropyridine of formula I and its pharmaceutically acceptable salts with inorganic and organic acids such as antidepressants, such as can be administered orally or parenterally for the treatment of depression.

The process of the invention is characterized in that a compound of the general formula 3 is partially reduced in the form of a compound of the general formula 3 (L) i- <f ^ n-ch3 z (ii) \ y ^ 0y \ —Y 3

Br represents a monoval anion or the normal equivalent of a polyvalent anion and, if desired, transfers the compound formed to an addition salt with an inorganic organic acid.

The partial reduction of compounds of general formula II is preferably carried out by means of sodium or potassium borohydride in organic-aqueous medium by to a present solution of the starting formula of general formula II in an organic water-miscible solvent, e.g. in a low alkanol such as methanol or ethanol or mixtures thereof with water, little by little, an aqueous solution of sodium borohydride is added and then allowed to react for a further time, maintaining a reactive ion temperature of from ca. 5 to 60 ° C, preferably from room temperature to 35 ° C.

The starting materials for the above process can be prepared from 4- (7-bromo-5-methoxy-2-benzofuranyl) -pyridine. This connection can, for example, is prepared by reacting 3-bromo-5-methoxy-salicylaldehyde with a 4- (halo-methyl) pyridine, especially 4- (chloromethyl) or 4- (bromomethyl) -pyridine, in the presence of a acid-. the same agent, e.g. potassium carbonate, and optionally sodium or potassium iodide under heating in an organic solvent such as dimethylformamide, in addition to the ether formation to the intermediate 2 - [(4-pyridyl) methoxy] -3-bromo-5-methoxybenzaldehyde of the benzofuranrin gene during water decomposition.

From 4- (7-bromo-5-methoxy-2-benzofuranyl) -pyridine, the compounds of the general formula II are obtained in a manner known per se by quaternization with reactive esters of methanol, e.g. those listed below. The quaternization may be carried out in the usual manner in an inert organic solvent, e.g. in methanol, ethyl methyl ketone, ethyl acetate, tetrahydrofuran or dioxane, at room temperature or moderately elevated temperatures up to approx. 100 ° C.

As reactive esters of methanol for the above quaternization, e.g. hydrogen halide esters, especially the bromide and iodide, further lower alkanesulfonic acid esters and arenesulfonic acid esters such as methanesulfonic acid esters or benzenesulfonic acid and p-toluenesulfonic acid esters, as well as esters of other strong acids, e.g. sulfuric acid ester, ie dimethyl sulfate.

The compound of formula I obtained according to the invention can, if desired, be converted into addition salts with inorganic or organic acids if desired in the usual manner. For example, to a solution of the compound in an organic solvent is added the acid desired as a salt component. Preferably, for the reaction, organic solvents are selected in which the resulting salt is heavily soluble so that it can be separated by filtration. Such solvents are e.g. ethyl acetate, methanol, ether, acetone, ethyl methyl ketone, acetone ether, acetone ethanol, methanol ether or ethanol ether.

For use as drug substances, instead of the free base, pharmaceutically acceptable acid addition salts, i.e. salts with such acids, if the anions at the doses available are not toxic. Furthermore, it is advantageous if the salts to be used as drug substances are well crystallizable and not or only slightly hygroscopic. For example, for the salt formation with the compound of formula I, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, acetic, lactic, succinic, fumaric, maleic, malic, tartaric, citric, benzoic, salicylic, phenylacetic, phenylacetic,

5 143 * 01

The active substances are administered orally, rectally or parenterally. The dosage depends on the mode of application, the species, the age and the individual condition. The daily doses of the free base or of pharmaceutically acceptable acid addition salts of the free base are between 0.01 mg / kg and 1.0 mg / kg for warm blooded animals. Suitable dosage unit forms such as dragees, tablets, suppositories or ampoules preferably contain 0.5 to 10 mg of active ingredient.

Dosage unit forms for the oral use contain 10 as active ingredient preferably between 0.5 and 10% of the compound of formula I or a pharmaceutically acceptable salt thereof.

Suitable additional oral dosage unit forms are gelatin capsules as well as soft, closed gelatin capsules and a plasticizer such as glycerol.

As dosage unit forms for rectal use, e.g. suppositories in consideration, which consist of a combination of an active substance with a suppository matrix.

Parenteral ampoules, especially intramuscular administration, preferably contain a water-soluble salt of the active substance at a concentration of preferably 0.1 to 2%, optionally together with suitable stabilizers and buffer substances, in aqueous solution.

The following example illustrates in more detail the process of the invention.

Example.

To a solution of 31.2 g (0.07 mol) of 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-pyridinium iodide in 200 ml of methanol is added dropwise with stirring and external cooling a solution of 10.7 g of sodium borohydride in 60 ml of water so that the reaction temperature does not exceed 35 ° C. Then, the solution is stirred for 20 hours at room temperature. The methanol is then evaporated in vacuo, the remaining aqueous phase is extracted twice with 500 ml of chloroform per ml. Once, the chloroform solution is dried over sodium sulfate, filtered and evaporated. The residue is crystallized from methanol-water to give 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-1,2,3,6-tetrahydropyridine, m.p. 73-77 ° C. The hydrochloride prepared from it with a solution of hydrogen chloride in ether-tetrahydrofuran melts after recrystallization from ethanol at 247-250 ° C.

The starting material can be prepared as follows: a) 75.5 g (0.327 mol) of 3-bromo-5-methoxysalicylaldehyde, 53.6 g (0.327 mol) of 4- (chloromethyl) pyridine hydrochloride, 194 g of potassium carbonate and 15 g of potassium iodide is heated under stirring in 320 ml of dimethylformamide under nitrogen for 20 hours to 150 ° C. The reaction mixture is then cooled to ca.

50 ° C and filtered by suction at this temperature. The filter residue is heated to 100 ° C with 200 ml of dimethylformamide and filtered off by suction and the new filter residue is washed afterwards with dimethylformamide. The combined filtrates are evaporated in vacuo and the residue is then freed from volatiles by heating for 2 hours in high vacuum to 80 ° C. The residue is dissolved in a little methylene chloride and chromatographed on 800 g of alumina (activity II, 25 neutral). The first 2-liter chloroform-eluted fraction is 4- (7-bromo-5-methoxy-2-benzofuranyl) -pyridine, which after recrystallization from ethyl acetate melts at 149-152 ° C.

b) 23.4 g (0.767 mol) of 4- (7-bromo-5-methoxy-2-benzofuranyl) -pyridine are dissolved in 470 ml of ethyl methyl ketone and stirred with II, 5 ml of methyl iodide for 15 hours at ca. 50 ° C. The solution is then cooled to -6 ° C and the separated salt is filtered off by suction. The filter cake is then washed with ether-petroleum ether. The 4- (7-bromo-5-methoxy-2-benzofuranyl) -1-methyl-pyridinium iodide thus obtained melts at 260-265 ° C and can be further processed directly.