NL8204838A - Antihistaminic, bronchodilatory and/or antiallergic compsn. - contg.4-di:phenyl-methylene-piperidino-1-butyl-phenyl-1-butanol - Google Patents

Abstract

Compsn. with antihistaminic, bronchodilatory and/or antiallergic activity is obtd. by formulating 4-(4-diphenylmethylene) piperidino)-1- (4-t-butylphenyl)-1-butanol of formula (I) ot its salts in a form suitable for therapeutic use: The compsns. may be formulated for oral, s.c., i.m., i.p. or intranasal admin., e.g. as tablets, capsules, solns., suspensions, drops or aerosols. The dosage unit may be 0.01-20 mg/kg; e.g. tablets contg. 1-50mg (I) may be given 1-4 times a day.

Description

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A method of preparing / manufacturing a pharmaceutical composition having antihistamine, bronchodilatory and / or antiallergic action, formed pharmaceutical composition obtained thereby, and method of preparing a compound suitable for use in said method.

The invention relates to a method for preparing / manufacturing a pharmaceutical preparation with antihistamine, bronchodilator and / or antiallergic action, by using an α- (p-tert-butylphenyl) -1-piperidine butanol 5 in the 4-position is substituted by bringing a carbon atom bearing two phenyl groups, or a pharmaceutically acceptable salt thereof, into a form suitable for therapeutic use.

Such a process is known from Dutch patent application 7300873. The compound used as active ingredient is a- (p-tert-butylphenyl) -4- (a-hydroxy-α-phenylbenzyl) -1-piperidine butanol (Example I).

It has been found that 4- (diphenylmethylene) -a- (p-tert-butylphenyl) -1-piperidine butanol, which falls under the formula for the compounds of Dutch patent application 7300873, but not described therein, has higher antihistaminic activity.

French patent application 2,042,313 discloses 4-diphenylmethylene piperidines which are substituted in the 1-position by a hydroxyalkyl, hydroxyalkoxyalkyl or hydrosalkalkoxyalkoxyalkyl group with 1-4 carbon atoms in the alkyl and alkoxy radical, for example 4- (diphenylmethylene) -1 -pipe-ridin-propanol). In addition to antihistamine and bronchodilatory activity, these compounds also have vasodilatory and central nervous system effects. They can be prepared by dehydration of corresponding α, α-diphenyl-N-8204838 * * 2 substituted piperidine methanols.

The compound according to the invention does not affect the central nervous system with all the advantages that it entails, such as the absence of undesired stimulation or depressive states. Also, vasodilatory action has remained, so that it is more selective as antihistamini-cum. And compared to 4- (diphenylmethylene) -1-piperidine methanol according to the mentioned French patent application 2.042.313, its antihistamine action is considerably stronger.

To illustrate the above, a comparative test follows with the compound according to the invention a) and the following known compound according to Dutch patent application 7300873 b) o- (p-tert. Butylphenyl) -4- (ct-hydroxy-α-phenylbenzyl) -1 - 15 piperidine butanol c) 4- (diphenylmethylene) -a- (p-tert.fluorfenyl) -1-piperidine butanol, and according to French patent application 2,042,313 d) 4- (diphenylmethylene) -1-piperdine methanol.

Guinea pigs, put on food and water ad libitum, were injected intradermally with 0.1 ml histamine and then with physiological saline solutions of the test compounds at different concentrations. The emerging stretch marks were made more visible by injection with 1 ml 1% Evans Blue. The animals were sacrificed twenty minutes after this last injection. The diameter of the stretch marks was measured (in mm) and from the mean values, the dose of test compound was calculated to effect a 50% reduction in the mean strip diameter.

30 Connection EDS0 »mS / k§ a) 0.5 b) 1.6 c) 3.8 d) 3.4 35 8204839« -J * 3 ♦

The compound of the formula I according to the invention can be formulated in a customary manner into suitable preparations for oral, intravenous, intravenous, intramuscular, intraperitoneal or intranasal administration, for example tablets, capsules, solutions, suspensions, nasal drops and aerosols. The amount of active compound per dosage unit is generally 0.01 - 20 mg / kg, for example 1-50 mg per tablet when administered 1-4 times daily.

In addition to the active compound, tablets contain a conventional excipient such as lactose, sucrose or corn starch together with a binder such as acacia, corn starch or gelatin, disintegrant such as corn starch, potato starch or alginic acid and / or lubricant such as stearic acid or magnesium stearate. Capsules, for example gelatin capsules, contain an inert carrier, lubricant and inert filler such as lactose, sucrose or corn starch. Suitable carriers for injectable solutions and suspensions are water or oil such as arachis oil, soybean oil or petroleum, and optionally a surfactant, preferably water, aqueous salt solutions, aqueous sugar solutions such as dextrose, and glycols, for example, propylene glycol and polyethylene glycol. Aerosols contain a propellant, for example, nitrogen, carbon dioxide, propane, dichlorofifluoromethane, dichlorodifluoroethane or mixtures of these halogenated hydrocarbons, optionally together with a co-solvent and / or wetting agent.

The compound of the invention of the formula I can be prepared in known or conventional manner, for example by dehydration of α- (p-tert-butylphenyl) -4- (α-hydroxy-α-phenylbenzyl) -1-piperidine butanol of the formula As described in the above-mentioned French Patent Application 2,042,313, reduction of a ketone of the formula 3, or by alkylation of an N-unsubstituted compound of the formula 1 with an α-aryl-m-haloalkanol.

The reduction of the ketone of the formula III is preferably carried out with sodium borohydride in a low alkanol, for example methanol, isopropanol or t-butanol, at 0 ° C to reflux temperature for 0.5-8 hours. However, lithium aluminum hydride or diborane and other solvents such as diethyl ether are also suitable. The ketone of formula 3-5 can also be catalytically hydrogenated with, for example, Raney nickel, palladium, platinum or rhodium as catalyst, in a low alkanol, acetic acid or mixtures thereof with water.

Reduction with aluminum isopropoxide in isopropanol is also possible. Ketones such as those of the formula III are the subject of Dutch patent application 7300869 and can be obtained by alkylation of a corresponding N-unsubstituted compound with a ω-haloalkylaryl ketone in an alcohol or hydrocarbon in the presence of a base as indicated in the aforementioned Dutch patent application 7300869.

The alkylation of an N-unsubstituted compound of the formula 1 and an α-aryl-)) -haloalkanol is carried out in an alcohol or hydrocarbon solvent in the presence of a base, at 70 ° C to reflux temperature for 24 - 72 hours .

20 - Examples of suitable acids for forming non-toxic salts of the compound of the invention of the formula 1 include hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, propionic, glycolic, lactic, grape, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, and dihydroxymalic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-amino-phenoxybenzoic, 2 acetoxybenzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, and β-hydroxyethanesulfonic acid.

82 0 4 8 3 8 l "Λ 5

Example I

a) Preparation of 4- (diphenylmethylene) -α- (p-tert-buty1) -1-piperidinobutyro phenone.

5

A mixture of 24.9 g (0.1 mole) of 4-diphenyl-methylenepiperidine, 28.79 g (0.12 mole) of a-tert-butyl-4-chloro-butyrophenone, 20.0 g of potassium hydrogen carbonate and 0.1 g potassium iodide in a mixture of 200 ml of toluene and 25 ml of water is stirred on a steam bath for 64 hours. Afterwards, the aqueous phase is separated and extracted twice with 50 ml of toluene each time. The extract solutions are combined with the previously obtained organic phase, washed with saturated aqueous sodium chloride solutions, dried over anhydrous magnesium sulfate and filtered. The filtrate is treated with an excess of ethereal hydrogen chloride to form a precipitate. The precipitate is crystallized in butanone containing a little methanol and then in toluene to give 4- (diphenylmethylene) -a- (p-tert-butyl) -1-piperidinobutyrophenone-20 hydrochloride, mp 222-224 ° C.

b) Preparation of 4- (diphenylmethylene) -a- (p-tert-butylphenyl) -1-piperidine butanol.

To a solution of 9.76 g (0.02 mol) 4- (diphenylmethylene) -a- (p-tert.butyl) -1-piperidinobutyrophenone hydrochloride in 50 ml methanol, 1.1 g (0.02 mol) sodium methoxide and then 2.7 g (0.05 mol) of potassium borohydride are added. The mixture is stirred at room temperature for 2 hours and then concentrated to dryness. The solid residue is taken up in 50 ml of a 10 wt.% Aqueous sodium hydroxide solution and stirred for 15 min. After adding 100 ml of chloroform, stirring is continued for a further 30 minutes, after which the aqueous phase is separated and extracted twice with 25 ml of chloroform each time. The extract solutions are combined with the previously obtained organic phase, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered.

The filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized from 70% ethanol to yield 6.8 4- (diphenylmethylene) -a- (p-tert-butylphenyl) -1-piperidinobutanol, m.p. 122. 5-124 ° C is obtained.

Example II

Tablets

Composition: 15 4- (diphenylmethylene) -a- (p-tert-butylphenyl) -1-piperidine butanol 5 mg starch 43 mg lactose 60 mg magnesium stearate. 2 mg.

20

The active compound is mixed with lactose and part of the starch, and the mixture is granulated with the rest of the starch as a paste. The granulate is dried, sieved and mixed with the magnesium stearate and then pressed into tablets weighing 110 mg each.

Example III

30 Capsules composition: 4- (diphenylmethylene) -a- (p-tert.butyl) pheny1-1-piperidine butanol 10 mg 35 talc 5 mg lactose 100 mg 8204838 * "-τ-1 Λ f * 7

The ingredients are forced as dry powders through a fine-mesh sieve and mixed thoroughly. Hard gelatin capsules are filled with the powder mixture. Each capsule contains 115 mg of powder.

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Claims (3)

1. A method of preparing / manufacturing a pharmaceutical composition having antihistamine, bronchodilator and / or antiallergic activity, by a 4- (p-tert-butyl-phenyl) -1-piperidine butanol substituted in the 4-position by bringing a carbon atom bearing two phenyl groups or a pharmaceutically acceptable salt thereof into a form suitable for therapeutic use, characterized in that the active ingredient used is 4- (diphenylmethylene) -a- (p-tert-butylphenyl) - 1-piperidine butanol of the formula 1 to 10 on the formula sheet or a pharmaceutically acceptable salt thereof. A formed pharmaceutical preparation obtained by the method of claim 1. Process for the preparation of a compound suitable for use in the process according to claim 1, characterized in that 4- (diphenylmethylene) -a- (p-tert-butylphenyl) -1-piperidine butanol of the formula 1 or a pharmaceutical acceptable salt thereof is prepared in a manner usual for preparing analogous compounds. 8204838