DE2109155A1 - 1-furylmethyl-4-phenyl-4-methoxycarbonylpiperidines - - with analgesic activity anorectic activity salt - Google Patents

Abstract

Cpds of formula (I): (where R1 is Me or pref. H; R is Et or pref. H or Me) and their acid addn salts are non-additive strong analgesics. They may be prepd by (a) reacting a 4-(m-R1O-phenyl)-4-methoxycarboxylpi peridine (II) with an R-substd furfuryl halide or alkyl or aryl-sulphonate; (b) reacting (II) with HCHO and R-substd furan; (c) esterification of the corresp free acid etherification of (I;R1=H) both with diazomethane, or (d) partially saponifying (I; R1=acyl) to give (I; R1=H) and opt. methylating this.

Description

1- (Furyl-methyl) -4-phenyl-4-methoxycarbonyl-piperidines, their acid addition salts and processes for their preparation. The invention relates to new 14-turyl-methyl) -4-phenyl-4-methoxycarbonyl-piperidines of the general formula and their acid addition salts with valuable therapeutic properties. In formula I, R denotes a hydrogen atom or a methyl or ethyl group and R 'denotes a hydrogen atom or a methyl group.

The piperidine derivatives according to the invention can be prepared by the following processes: a) Reaction of a 4-phenyl-4-methoxy-carbonyl-piperidine of the formula in which R 'has the meaning given above, with a furyl-methyl derivative of the formula in which R has the abovementioned meaning and X denotes a halogen atom, preferably chlorine or bromine or an alkyl or arylsulfonyloxy group.

The known compounds of the formula II are alkylated with alkylating agents of formula III to the desired compounds of formula 1. One works with the calculated amount or a slight excess of the alkylating agent in used in pure form or in the form of a solution of the unisolated crude product can be. It is expedient to alkylate in the presence of an acid-binding agent, such as triethylamine, dicyclohexylethylamine, sodium carbonate, Potassium carbonate or preferably sodium hydrogen carbonate. It is advisable to use an inert one Solvent or solvent mixture, for example tetrahydrofuran, methylene chloride, Dimethylformamide, dimethyl sulfoxide or, preferably, mixtures of dimethylformamide and tetrahydrofuran. The reaction temperature is variable within wide limits, Temperatures between OOC and the boiling point of the solvent are preferred or medium mixture solution. After the reaction, the reaction products are with Isolated using known methods and optionally in suitable acid addition compounds convicted.

b) Reaction of 4-phenyl-4-methoxycarbonyl-piperidines of the formula II with formaldehyde and a furan derivative of the formula in which R has the meaning given above.

The known compounds of the formula II are used in a known manner with furans of the formula IV and formaldehyde according to Mannich to give the desired piperidine derivatives of the formula I. The reaction takes place in weakly acidic, especially acetic acid Solution in suitable solvents or medium mixtures such as water, alcohols, Tetrahydrofuran, dioxane, preferably in 50% acetic acid. The furans of the formula IV are used in the calculated amount or in a slight excess. formaldehyde can be calculated as paraformaldehyde or preferably as an aqueous solution in the lot or an excess are used. As reaction temperatures temperatures between -100C and the boiling point of the solvent come in Question, preferably one works between 0 and 4000. After the implementation will be the reaction products isolated using known methods and optionally in suitable acid addition compounds transferred.

c) Implementation of a compound of the formula in which R has the abovementioned meaning and R 'and R "denote either both a hydrogen atom or one of the radicals a hydrogen atom and the other a methyl group, with diazomethane.

As starting compounds of the formula V for methylation with diazomethane can l- (furyl-methyl) -4- (m-hydroxyphenyl) -4-carboxypiperidines (R '= R "= H), 1- (furyl-methyl) -4- (m-hydroxyphenyl) -4-methoxycarbonylpiperidines (R '= H; R "= CH3) or 1- (furyomethyl) -4- (m-methoxyphenyl) -4-carboxypiperidines (X '= CH3; Rtt = H) can be used.

When converting compounds with active hydrogen atoms (free hydroxyl and free carboxy group) the methylation can be one or two stages take place, with a suitable choice of the stoichiometric ratios as an intermediate stage occurring l- (furyl-methyl) -4- (m-hydroxy phenyl) -4-methoxycarbonylpiperidines can be isolated.

Suitable solvents for the reaction are in particular alcohols, Tetrahydrofuran, dioxane or mixtures of these components. Diazomethane can be gaseous, optionally diluted with inert gas for use or preferably in Solution, for example in ether, can be used. One uses stoichiometric Amounts of diazomethane or a slight excess. Since the reaction is at room temperature occurs almost instantaneously, the easiest way to work is at room temperature, albeit one in principle also at a higher temperature, preferably in the range from 0 to 40.degree can work. The reaction products are isolated, if necessary, by known methods converted into suitable acid addition compounds.

d) Partial saponification of 1- (furyl-methyl) -4- (m-acyloxyphenyl) -4-methoxycarbonylpiperidine of the general formula in which -R has the abovementioned meaning and Ac denotes an acyl group, compounds of the formula I being obtained in which R 'denotes a hydrogen atom; the reaction products can, if appropriate, be methylated to give compounds of the formula 1 in which R 'denotes a methyl group.

Compounds of the formula VI are subjected to selective saponification the phenol ester group while maintaining the methyl ester group. The saponification can be carried out in acidic or alkaline medium. One works in suitable Solvents, for example water, alcohols, tetrahydrofuran, dioxane, preferably in aqueous methanol.

To get the methyl ester group, keep the concentration of hydrogen or. Hydroxyl ions as low as possible, the reaction times as possible short and the reaction temperatures are preferably in the range from 20 to 80.degree. the Reaction products are isolated using known methods and, if necessary converted into suitable acid addition compounds.

The 1- (furyl-methyl) -4-phenyl-4-methoxycarbonyl-piperidines according to the invention of the general formula I are bases and can be physiologically in the customary manner compatible acid addition salts are transferred. Acids suitable for salt formation are for example mineral acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, Hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, or organic Acids such as acetic acid, propionic acid, butyric acid, valeric acid; Pivalic acid, caproic acid, Oapric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, Lactic acid, Tartaric acid, citric acid, malic acid, benzoic acid, phthalic acid, cinnamic acid, salicylic acid, p-hydroxybenzoic acid, ascorbic acid, 8-chlorotheophylline, methanesulfonic acid and the like.

The l- (furyl-methyl) -4-phenyl-4-methoxycarbonylpiperidines according to the invention and their acid addition salts have a therapeutic effect on the central nervous system the end. The compounds according to the invention have a non-morphine-like strength analgesic effectiveness. They are therefore addiction-free analgesics. The connections show in more sensitive pharmacological analgesia Uets7 such as the Hot-Plate-2est (J Pharmacol. Exp. Heran. Vol. 80, p. 300 (1944)) or the writhing test (J. Pharmacol. exp. Therap.

Vol. 154, p. 319 (1966)), a clear dose-dependent analgesic Efficacy in experimental animals such as mice and rats. The lack of an addictive On the other hand, the effect can be determined by the ineffectiveness of the compounds in the Haffner test (German Medical Weekly Volume 55, Page 731 (1929)), due to the missing or weakly pronounced Straub's morphine tail phenomenon and the lack of it or show weak maneuvers in mice.

According to the prevailing doctrine (Adv. Chem. Ser. Vol. 49, p. 162 to 169 (1964)) the ineffectiveness in the Haffner test is a stronger sign that the Compounds do not cause morphine-like addiction symptoms. The intensity the morphine tail phenomenon in the mouse is considered a measure of the addictive effect analgesic substances. Based on the intensity of the morphine tail phenomenon according to work published in the literature, predictions can be made about the Make a substance addictive (I. Shemano and H. Wendel, Toxicol. Appl. Pharmacol. 6, pp. 334 to 339 (1964)). For the by morphine-like substances Triggered maneuvers in mice also seem to be related to intensity and addictive effects (Bulletin, Problems of Drug Dependence 1970, p. 6890).

The compounds of the general formula I according to the invention and their acid addition salts can be used orally, enterally or parenterally. The dosage for oral use is 10 to 300, preferably between 50 and 150 mg. The compounds of the formula I or their acid addition salts can also with other pain relievers or with other types of active ingredients, for Example sedatives, tranquillizers, hypnotics are combined. Suitable galenicals Dosage forms are, for example, tablets, capsules, suppositories, solutions, suspensions or powder; the galenicals usually used for their production can be used here Auxiliaries, carriers, disintegrants or lubricants or substances for achieving a Find depot effect use. The production of such galenic dosage forms takes place in the usual way according to the known manufacturing methods.

The following examples explain the invention without its scope to restrict.

Example 1 (Method a) l-Furfurvl-4- (m-hydroxvohenyl) -4-methoivcarbonvl-uieridine 11.8 g (0.05 mol) 4- (m-hydroxyphenyl) -4-methoxy carbonyl piperidine, 6.2 g (0.075 Mol) NaHCO3 and 6.4 g (0.055 mol) furfuryl chloride are in a mixture of j5 ml of dimethylformamide and 125 ml Tetrahydrofuran 3 hours under Stir and reflux.

The reaction mixture is then evaporated in vacuo and the residue shaken with chloroform and water. The chloroform phase is washed with water, dried with sodium sulfate and evaporated i.V. The residue is with about 20 ml of ethanol with the addition of 10 ml of 5N ethanolic HC1 dissolved and the solution up just added absolute ether to cloud it.

The immediately crystallizing hydrochloride is kept in the refrigerator overnight stored, then vacuumed and washed with ether.

After drying in air and finally at 80 ° C., 14.0 g of the are obtained Title compound (79.5% of theory) with a melting point of 18800. After recrystallization from ethanol / ether the melting point rises to 190 0.

Example 2 (method a) 1- (3-methyl-furfuryl) -4- (m-hydroxvhenv1 ) -4-methoxycarbonyl-piperidine 2.35 g (0.01 mol) 4- (m-hydroxypbenyl) -4-methoxycarbonylpiperidine and 1.26 g of NaHCO 3 are in a mixture of 15 ml of dimethylformamide and 25 ml Tetrahydrofuran with stirring with a solution of 3-methyl-furfuryl bromide in ether (see below) added and refluxed for 3 hours. Then how evaporated as described in Example 1 and shaken with chloroform and water. The evaporation residue of the chloroform phase is used to separate by-products and unreacted starting compound of a column chromatography on silica gel subjected (300 g silica gel, solvent: chloroform / methanol / conc. NH3 90: 10 .- * 0.5). The pure fractions are combined and evaporated down i.V. The residue is crystallized as described in Example 1 as the hydrochloride.

Yield 1.8 g = 50% of theory.

With the mostly very decomposable alkyl homologues of furfuryl chloride or bromides, it is often useful not to isolate these halides, but rather to be used in solution as described above. The one required for the implementation described Ether solution of 3-methyl-furfuryl-bromide is obtained in the following way: 1.4 g (0.0125 Mol) 3-methyl-furfuryl alcohol and 0.315 g of absolute pyridine are in 5 ml of absolute Ether dissolved and with warming and exclusion of moisture at -25 ° C with a solution of 1.09 g (0.004 mol) of phosphorus tribromide in 3 ml of absolute ether within 20 Minutes offset. The mixture is then stirred for a further 15 minutes at this temperature and then used the decanted ethereal solution for the experiment described above.

Example 3 (method a) 1 F furyl-methyl- (3) -1-4- (m-hydroxyphe) ) -4-methowyearbonylpiperidine Following the procedure described in Example 1 is obtained by reacting 4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine and 3-chloromethylfuran the hydrochloride of the above compound in a yield of 82.5 ffi Theory with a melting point of 213 ° C.

Example 4 (method a) 1- [2-methyl-furylmethyl- (3)] - 4- (m-hydroxyphenyl) -4-methoxycarbonyl-t> iperidine Following the procedure of Example 1, 4- (m-Hydrozyphenyl) -4-methoxycarbonyl-piperidine is reacted and 2-Nethyl-3-chloromethylfuran the hydrochloride of the above-mentioned compound in a yield of 99% with a melting point of 23,100.

Example 5 (method a) l-r 2-ethyl-furylmethyl- (3) 1-4- (m-hydroxYphenyl) -4-methoxycarbonyl-piperidine Following the procedure of Example 1, starting from 4- (m-hydroxyphenyl ) -4-methoxycarbonyl-piperidine and 2-ethyl-3-chloromethylfuran the hydrochloride of above compound in a yield of 79% with a melting point of 1800C, Example 6 (method b) 1- (5-methyl-furfuryl) -4- (m-hydroxyphenvl) -4-methoxycarbonylpiperidine 2.35 g (0.01 mol) of 4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine are dissolved in 10 ml 50 pointer acetic acid dissolved and with ice cooling and stirring with 1 g of 30% formaldehyde solution (0.01 mol CH2O) and then treated with 0.82 (0.01 mol) 2-methyl-furan.

The mixture is then stirred for a further 15 hours at room temperature. Then diluted one with 50 ml of water and makes in the presence of ice with conc. NH3 ammoniacal. The precipitate is extracted with chloroform, the combined chloroform extracts with Washed with water, dried with sodium sulfate and evaporated down i.V.

The residue is mixed with 20 ml of ethanol with the addition of 0.96 g (0.01 Mol) methanesulfonic acid dissolved. The crystallizing methanesulfonate is over Left in the refrigerator overnight, then vacuumed, washed with ether, first air dried and then at 8000. Yield 3.0 g = 70.5% of theory; Melting point 20300.

After recrystallization from ethanol / ether, the melting point increases to 2040C.

Example 7 (method b) 1- (5-ethyl-furfurs1) -4- (m-hydroxyphenyl) -4-methoxycarboxylic piperidine Following the procedure of Example 6, 4- (m-hydroxyphenyl) -4 methoxycarbonyl-piperidine is obtained reacted with aqueous formaldehyde solution and 2-ethylfuran, the above being referred to Compound as a base in a yield of 93% with a melting point of 118 ° C receives.

Example 8 (method c) l-Furfury1-4- (m-hydroxyphenyl) -4-methoxyearbonsl-piperidine 3.01 g (0.01 mol) of 1-furfuryl-4- (m-hydroxyphenyl) -piperidine-4-carboxylic acid dissolved in 40 ml of methanol and the solution with stirring at room temperature with ethereal Diazomethane solution (0.011 mol diazomethane) added. Then the solution evaporated in vacuo. The residue is treated with chloroform and water with the addition of a few drops of conc. Ammonia shaken. The chloroform phase is separated off, washed with water, dried with sodium sulphate and evaporated down i.V. The residue is crystallized as described in Example 1 as the hydrochloride.

Yield 2.6 g = 76.0% of theory; Melting point 187 ° C. after recrystallization from ethanol / ether 189 to 1900C.

The 1-furfuryl-4- (m-hydroxyphenyl) -piperidine-4-carboxylic acid required as starting material is obtained, for example, by N-alkylation of the known 4- (m-hydroxyphenyl) piperidine-4-carboxylic acid or by saponification of l-furfuryl-4- (m-hydroxyphenyl) -4-ethoxycarbonyl-piperidine in the following way: 0.5 g of 1-furfuryl-4- (m-hydroxyphenyl) -4-ethoxycarbonyl-piperidine hydrochloride [Melting point 203 to 204 ° C, prepared by Implementation of the known 4- (m-Hydroxyphenyl) -4-ethoxycarbonylpiperidine with furfuryl chloride as in the example 1] are refluxed with 20 ml of 10% NaOH for 1 hour. Afterward is cooled and with conc. HC1 (approx. 5 ml) neutralized to pH 6.5. It falls the reaction product, the l-furfuryl-4- (m-hydroxyphenyl) -4-carboxylic acid. she is filtered off with suction after standing overnight and washed with water, then acetone.

Yield 0.4 g; Melting point 3050C (dec.).

Example 9 (method c) 1-Furfury1-4- (m-methoxyphenyl) -4-methoxycarbonyl-piperidine 0. q g (2.85 mol) 1-furfuryl-4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine (see Example 1) are dissolved in 10 ml of tetrahydrofuran and the solution with 40 ml of a about 0.02 m of diazomethane solution in ether was added. The reaction mixture remains 4 Stand for days at room temperature under exclusion of moisture. Then Y.V. evaporated and the residue, dissolved in chloroform, over 20 g A1203 (activity level III, neutral) filtered. The filtrate containing the pure substance is i.V.

evaporated and the residue ktsstallisiert analogous to Example 1 as the hydrochloride, Yield 0.65 g = 62.5% of theory; Melting point 16800. The melting point changed not when recrystallizing from ethanol / ether.

Example 10 (Method d) 1-Furfuryl-4- (m-hydroxy-phenyl) -4-meth, oxyearbons-1-peridine 3.9 g (0.01 mol) of 1-furfuryl-4- (m-acetoxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride are dissolved in 100 ml of methanol and 25 ml of 2N NaOH are added to the solution. To Standing for 5 minutes at room temperature, 25 ml of 2 g of ammonium chloride are added and the methanol removed i.V. The residue is made with chloroform and Shaken water, washed the chloroform phase with water, with sodium sulfate dried and evaporated in vacuo.

The residue is as described in Example 1 - as a hydrochloride crystallized.

Yield 2.9 g = 82.5% of theory; Melting point 1900C.

The starting compound is obtained, for example, by alkylation of the well-known 4- (m-acetoxyphenyl) -4-methoxycarbonyi-piperidine with furfuryl chloride analogous to Example 1. The hydrochloride of the compound obtained in this way melts at 15900.

Example 11 (Method d) 1- Burfury1-4- (m-hydrowvphensl) -4-methoxyearbonsl-piperidine 3.9 g (0.01 mol) of 1-furfuryl-4- (m-acetoxyphenyl) -4-methoxycarbonyl-piperidine hydrochloride (see Example 10) are dissolved in 100 ml of methanol and the solution with 25 ml of 2N 1101 offset. The reaction mixture is refluxed for 15 minutes and then evaporated i.V. The residue is as described in Example 10 as the hydrochloride crystallized.

Yield 2.75 g = 75% of theory; Melting point 18900.

Formulation Examples Example A: Tablets 1-furfuryl-4- (m-hydroxyphenyl) -4-methoxycarbonylpiperidine hydrochloride 50.0 mg milk sugar 95.0 mg corn starch 45.0 mg colloidal silica 2.0 mg soluble starch 5.0 mg magnesium stearate 3.0 mg total 200.0 mg Preparation: The active ingredient is mixed with some of the excipients and with a solution the soluble starch granulated in water.

After the granulate has dried, the remainder of the auxiliaries are mixed in and compressing the mixture into tablets.

Example B: Dragees 1-furfuryl-4- (m-hydroxyphenyl) -4-methoxy carbonylpiperidine hydrochloride 75.0 mg lactose 100.0 mg corn starch 65.0 mg colloidal silica 2.0 mg soluble Starch 5.0 mg Magnesium stearate 3.0 mg total 250.0 mg Production: The active ingredient and the excipients are pressed into tablet cores as described in Example A, which are coated with sugar, talc and gum arabic in the usual way.

Example C: Suppositories 1- (5-methyl-furfuryl) -4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine-methanesulfonate 50.0 mg milk sugar 250.0 mg suppository mass q.s. ad 1.7 g Manufacture: The active ingredient and the milk sugar are mixed together and the mixture into the melted Suppository mass evenly suspended. The suspensions are in chilled Molds poured into suppositories weighing 1.7 g.

Example D: Ampoules 1- (5-methyl-furfuryl) -4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine-methanesulfonate 50.0 mg sodium chloride 5.0 mg double-distilled water 5.0 ml Preparation: The active ingredient and the sodium chloride are dissolved in double-distilled water and the solution in Ampoules filled sterile.

Example E: Drops of 1-furfuryl-4- (m-hydroxypbenyl) -4-methoxycarbonylpiperidine hydrochloride 0.070 g methyl p-hydroxybenzoate. 0.07 g propyl p-hydroxybenzoate 0.03 g demineralized water q.s. ad 100.00 ml Manufacturing: The active ingredient and the preservatives are dissolved in demineralized water, the solution is filtered and filled into 100 ml bottles.

- patent claims -

Claims (10)

Claims 1- (Furyl-methyl) -4-phenyl-4-methoxy-carbonyl-piperidines of the general formula in which R 'denotes a hydrogen atom or a methyl group and R denotes a hydrogen atom or a methyl or ethyl group, as well as their acid addition salts. 2. 1-furfuryl-4- (m-hydroxyphenyl) -4-methoxycarbonyl-piperidine and its acid addition salts. 3. 1- (5-methyl-furfuryl) -4- (m-hydroxyphenyl) -4-methoxycarbonylpiperidine and its acid addition salts. 4. Process for the preparation of l- (furylmethyl) -4-phenyl-4-methoxycarbonyl-piperidines of the general formula I and their acid addition salts4, characterized in that a) a substituted 4-phenyl-4-methoxycarbonyl-piperidine of the formula in which R 'has the abovementioned meaning with a furylmethyl derivative of the formula in which R has the abovementioned meaning and X denotes a halogen atom, preferably chlorine or bromine or an alkyl or arylsulfonyloxy group; or b) a substituted 4-phenyl-4-methoxycarbonyl-piperidine of the formula II with formaldehyde and a furan derivative of the formula in which R has the meaning given above; or c) a compound of the formula in which R has the abovementioned meaning and R and R ″ denote a hydrogen atom or a methyl group, where at least one of the radicals must be a hydrogen atom, is reacted with diazomethane; or d) a compound of the formula in which R is defined as given above and Ac denotes an acyl group, partially saponified to l- (furyl-methyl) -4- (m-hydroxyphenyl) -4-methozycarbony1-iperidines and, if desired, - for the purpose of preparing compounds of the formula I, in the R 'denotes a methyl group -methylated; and, if appropriate, the compounds of the general formula I converted into their physiologically acceptable acid addition salts. 5. The method according to claim 4, characterized in that the Performs reactions in the presence of a solvent or solvent mixture. 6. The method according to claim 4 and / or 5, characterized in that that the N-alkylation is carried out in the presence of an acid-binding agent. 7. The method according to claim 6, characterized in that as acid-binding agents amines, metal carbonates, hydrogen carbonates, hydroxides or oxides used. 8. The method according to claim 7, characterized in that as Amines triethylamine, dicyclohexylethylamine as metal carbonates or sodium carbonate Potassium carbonate and, as metal hydrogen carbonate, sodium hydrogen carbonate. 9. Pharmaceutical preparations, characterized in that they as active ingredient one or more compounds of general formula 1 or their Contain physiologically compatible acid addition salts. 10. A process for the preparation of medicaments according to claim 9, characterized in that one or more compounds of the general formula I or their acid addition salts with customary pharmaceutical auxiliaries, carriers, disintegrants or lubricants or substances to achieve a depot effect to give tablets, capsules , Suppositories, coated tablets, powders, solutions or emulsions.