NO133448B - - Google Patents

Description

The present invention relates to an analogous process for the production of new α-phenyl-α-(2-piperidyl)-methanol compounds with the general formula:

where R is hydrogen, alkyl with 1-6 carbon atoms or cyclo-

alkyl with 3-6 carbon atoms, R is hydrogen, hydroxy or alkoxy with 1-6 carbon atoms, and R is hydrogen, alkyl with 1-6 carbon atoms or cycloalkyl with 3-6 carbon atoms,

or pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof.

The compounds produced are, in the form of their acid addition salts, solid, crystalline substances. They have a significant pharmacological activity as bronchodilators and they have been shown to have a bronchodilator activity equal to or better than that exhibited by the known bronchodilator aminophylline, in in vivo experiments in guinea pigs and in vitro experiments in an isolated tissue bath using of guinea pig tracheal tissue in doses and concentrations corresponding to the aminophylline standards, as both of these methods are recognized and accepted within pharmacology

given for assessment of bronchodilator activity.

cx-( 3,4-dihydroxypheny 1 )-a-(2-piperidy 1)-methanol pre-

posed as in the following example 1, was tested for bronchodilator activity, and the results compared

with those obtained in the same trial with aminophylline and isoprenaline (3,^t-dihydroxy-α-(isopropylaminomethyl)-benzyl alcohol), a well-known bronchodilator, which is also known as isoproterenol.

(a) Isolated organs

The test compound had approximately the same relaxant activity as isoprenaline when tested on the isolated guinea pig tracheal chain, and approximately 3,000 times the activity of aminophylline.

(b) Anesthetized animals

The test compound inhibited histamine-induced bronchospasm in the anaesthetized, artificially ventilated guinea pig. The test compound had approximately 1/15 the activity of isoprenaline when administered intravenously, and approximately 2000 times the activity of aminophylline. After oral administration, the test compound was active at a dose of 10 mg/kg, while isoprenaline is active at 2.5 mg/kg.

(c) Conscious animals

The test compound reduced the severity of the anaphylactic reaction in guinea pigs sensitized by inhalation of antigen. The test compound had an oral activity of the same magnitude as aminophylline at a dose of 25 mg/kg. It had an activity of the same magnitude as isoprenaline when injected intraperitoneally.

The test compound was entered as the hydrobromide and the isoprenaline as the isoprenaline insu.l f at.

The method according to the present invention is carried out by

(a) a compound of the general formula:

where R, R and R have the meaning given above and B is CO or HCOH, is hydrogenated in the presence of a catalyst, or (b) a polyalkoxy-substituted benzaldehyde of the formula: where Alk is alkyl with 1-6 carbon atoms or cycloalkyl with 3-6 carbon atoms and R is hydrogen or alkoxy with 1-6 carbon atoms, is condensed with picolinic acid or alkyl-substituted picolinic acid with the formula:

li r

where R is hydrogen, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, in the presence of an inert organic solvent with a boiling point above 1<1>40°C to form an α-polyalkoxyphenyl-α-(2 -pyridyl)-methanol compound with the formula:

where Alk, R^ ^5 and R have the meaning indicated above, which compound is oxidized to the corresponding, α-poly-alkoxyphenyl-α-{2-pyridyl)-ketone compound which is dealkylated to form an α-polyhydroxyphenyl-α-( 2-pyridyl)-ketone compound whereupon this compound is hydrogenated in the presence of a catalyst to form an α-polyhydroxy-phenyl-α-(2-piperidyl)-methanol compound, or (c) an alkoxy-substituted p-benzyloxybenzaldehyde of the formula:

where Alk and R^ have the meaning given above, is treated with 2-pyridyllithium or alkyl-substituted pyridyllithium in the presence of an anhydrous, organic solvent at a temperature of between -20°C and +25°C to form an a-(alkoxy- p-benzyloxyphenyl)-α-(2-pyridyl)-methanol compound, and that this compound is debenzylated by hydrogenation in the presence of a palladium catalyst and further hydrogenated in the presence of a platinum catalyst to form an o-(Alkoxy-p-hydroxyphenyl) )-ct-(2-piperidyl)-methanol compound,

after which a compound obtained under (a), (b) or (c) is, if desired, transferred to an acid addition salt or quaternary ammonium salt thereof.

Of the methods indicated above, method (a) is a simple hydrogenation of a 2-pyridyl starting compound corresponding to the desired compound.

The starting materials for carrying out step (bN<-> are picolinic acid or an alkyl-substituted picolinic acid and a polyalkoxy-substituted benzaldehyde. a-picolinic acid and alkyl-substituted a-picolinic acids are prepared in a suitable way by oxidation of o-picoline and polyalkylpiperidines with potassium permanganate. Polyalkoxybenzaldehydes are suitably prepared by reducing -tion of the corresponding acid chlorides by the Rosemund method (Ber. 51, 585 (1918)) or with lithium tri-t-butoxyaluminum hydride, or by oxidation of the corresponding benzyl alcohols, e.g. with manganese dioxide. Among the alkyl-substituted picolinic acids which can are used as starting material, for example 6-methyl-picolinic acid, 5-ethylpicolinic acid, 4-n-propylpicolinic acid and 3-riethylpicolinic acid can be mentioned, and among the poly-alkoxy-substituted benzaldehydes which can be used, can be mentioned for example 2,3 -dimethoxybenzaldehyde, 2,4-diethoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, 2,4,6-trimethoxybenzaldehyde, 2,3,4-triethoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde .

In the execution of step (b), picolinic acid or the alkyl-substituted picolinic acid and a suitable polyalkyl-substituted benzaldehyde are condensed to form an α-polyalkyloxyphenyl-α-(2-pyridinyl)-methanol, where the substitution in the phenyl and pyridine rings corresponds to that in the starting materials. The condensation is carried out in the presence of an inert solvent, such as p-cymene, nitrobenzene or anisole, and at a temperature above 140°C, but preferably at the reflux temperature of the solvent used. The reaction product is then selected by conventional isolation and crystallization methods.

The thus formed α-polyalkoxyphenyl-α-(2-pyridinyl)-methanol intermediate is then treated with a strong oxidizing agent such as potassium permanganate, dimethylsulfoxide/acetic anhydride or dry air, to form the corresponding polyalkoxyphenyl-2-pyridyl ketone. The impure alcohol can be oxidized without purification. The oxidation can, when the oxidizing agent is potassium permanganate, be carried out in an aqueous solvent and at a temperature of up to 80°C. The product is recovered by conventional isolation and purification methods and they are then alkylated under treatment with preferably hydrobromic acid to form a polyhydroxyphenyl-2-pyridyl ketone. The dealkylation is carried out by heating the ketone compound in constantly boiling hydrobromic acid under reflux.

In the final step of the reaction sequence, the polyhydroxyphenyl-2-pyridyl ketone compound is hydrogenated in the presence of a catalyst, e.g. Adam's platinum catalyst or platinum on a carbon support. The hydrogenation is carried out in the presence of an inert organic solvent, e.g. methanol, ethanol or acetic acid, at atmospheric pressure and a temperature of 20 - 60°C. The final product, α-polyhydroxyphenyl-α-(2-piperidyl)-methanol, is recovered by conventional isolation and purification methods.

The starting materials for carrying out step (c) are 2-pyridyllithium or alkyl-substituted 2-pyridyllithium, which can be prepared by treating 2-chloro- or 2-bromo-pyridine or an alkyl-substituted 2-chloro- or 2-bromo-pyridine in ether soln. nothing with. freshly cut metallic lithium and 4-benzyloxy-3-methoxybenzaldehyde (or other alkoxy-substituted benzaldehydes), which can be prepared from vanillin by heating with benzyl chloride under reflux.

When carrying out the above-mentioned reaction sequence, 4-benzyloxy-3-methoxybenzaldehyde is added slowly in an anhydrous, inert, organic solvent such as anhydrous ether, at a temperature from 0 - -20°C, to a solution of 2-pyridyllithium or alkyl substituted 2-pyridyllithium in an anhydrous inert organic solvent, e.g. anhydrous ether, also at a temperature from 0 - -20°C, and the resulting mixture is allowed to warm to room temperature. The intermediate, α-(Alkoxy-p-benzyloxyphenyl)-α-(2-pyridyl or alkyl substituted 2-pyridyl)-methanol, is formed by treating the reaction mixture with a mineral acid, e.g. hydrochloric acid, and is recovered by conventional precipitation and crystallization techniques.

The protecting benzyl group is removed from the intermediate by hydrogenation in an inert organic solvent, e.g. methanol, in the presence of a pre-reduced palladium catalyst or palladium-on-carbon catalyst at room temperature and atmospheric pressure. The thus formed intermediate, α-(Alkoxy-p-hydroxyphenyl)-α-(2-pyridyl or alkyl-substituted 2-pyridyl)-methanol, is recovered by conventional isolation and purification methods and then converted to the final product, α-(Alkoxy-p- hydroxy-phenyl)-α-(2-piperidyl or alkyl-substituted 2-piperidyl)-methanol, first by oxidation and then hydrogenation in the presence of a catalyst as described above in connection with step (b). The end products are extracted by conventional isolation and purification methods.

The compounds produced by the present process can, if desired, be transferred to their pharmaceutically acceptable acid addition salts and quaternary ammonium salts. It can e.g. salts are formed with inorganic acids, such as hydrochlorides, hydrobromides, hydroiodides, sulphates and phosphates. Salts can also be formed with organic acids including monobasic acids, such as acetates or propionates, and especially with organic hydroxy acids and dibasic acids, such as citrates, tartrates, malates and maleates. Pharmaceutically, the salts will not be significantly more toxic than the compound itself, and they can be incorporated into conventional liquid or solid pharmaceutical media. Among the useful quaternary ammonium salts are those formed with such alkyl halides as e.g. methyl iodide and n-hexyl bromide. Such pharmaceutically useful acid addition salts and quaternary ammonium salts are fully equivalent to the bases from which they are derived and their preparation is encompassed by the present process.

The compounds produced by the present method can, either as free bases or in the form of pharmaceutically acceptable acid addition salts or quaternary ammonium salts, be combined with conventional pharmaceutical diluents and carriers to form such dosage forms as tablets, suspensions, solutions, suppositories and the like.

The individual unit dose and frequency of administration are determined not only by the nature and severity of the condition for which the individual seeks healing, but also by the individual's age, weight and sex, his general physical condition and the route of administration. It will therefore be up to the medical expert to determine the exact amount to be administered so that it is non-toxic yet pharmaceutically effective in promoting bronchodilation.

The following examples illustrate the invention.

Example 1 (process b)

A. a -( 3, 4- dimethoxyphenyl)- q-( 2- pyridyl)- methanol.

10 g of picolinic acid were added over the course of 3 hours to a boiling solution of 50 g of 3,4-dimethoxybenzaldehyde in 50 ml of p-cymene. The heating was continued for 3 hours after the addition and the reaction mixture was then allowed to cool. The cooled reaction mixture was extracted twice with 2N hydrochloric acid (total 100 ml). The combined acid extract was washed with 100 ml ether, basified with ammonia solution and then extracted four times with ether (200 ml total). The combined ether extract was concentrated to dryness to give an oil which from a solution in acetone/petroleum ether (b.p. 60-80°C) gave α-(3,4-dimethoxyphenyl)-α-(2-pyridyl)- methanol, m.p. 93 - 95°C. In the description, ether is understood to mean diethyl ether.

B. ( 3,^- dimethoxyphenyl)-( 2- pyridyl)- ketone.-

10 g of ct-(3,^-dimethoxyphenyl)-α-(2-pyridyl)-methanol were suspended by stirring in 200 ml of water and then heated to

10°C. Then 4.7 g of potassium permanganate was added in portions as the pink color disappeared. Excess permanganate was destroyed by addition of ethanol, and the manganese dioxide was removed by filtration. The filter cake was extracted three times with boiling denatured alcohol (total 300 ml) and the filtrate then concentrated under reduced pressure until incipient crystallization. The precipitated white needles were collected by filtration, washed with water and dried in vacuo to give (3,4-dimethoxyphenyl)-(2-pyridyl)-ketone, m.p. 93 - 94°C.

C. (3,^-dihydroxyphenyl)-(2-pyridyl)- ketone hydrobromide

10 g of (3,4-dimethoxyphenyl)-(2-pyridyl)-ketone was dissolved in 100 ml of constantly boiling hydrobromic acid and heated under reflux for 3 hours. The dark amber solution was concentrated under reduced pressure and denatured alcohol was evaporated from the residue several times to remove the last traces of water. Crystallization from methanol (300 mL) and ethyl acetate gave (3,4-dihydroxyphenyl)-(2-pyridyl)-ketone hydrobromide, m.p. 225 - 226°C. D. Erythro-α-(3,4-dihydroxyphenyl)-α-(2-piperidyl)-methanol hydrobromide. 20 g of (3,4-dihydroxyphenyl)-(2-pyridyl)-ketone hydrobromide in 600 ml of methanol was hydrogenated at room temperature and atmospheric pressure in the presence of 5 g of Adams platinum catalyst. After taking up the theoretical amount of hydrogen, the catalyst and solvent were removed to give a syrup which solidified by trituration with ethyl acetate (250 ml) and methanol (30 ml).

The solid was collected by filtration, washed with ethyl acetate/methanol (8:1, 50 mL) and dried in vacuo to give erythro-α(3,4-dihydroxyphenyl)-α-(2-piperidyl)-methanol hydrochloride , sm.p. 220°C (decomp.).

Analysis: Calculated for C-^H-LgNO-^Br:

C 47.4, H 6.0, N 4.6, Br 26.3 Found: C 47.5, H 6.1, N 4.6, Br 26.1 Example 2

Using the same method as described in example 1, the following compounds were prepared from 6-methyl-picolinic acid and 3a^-dimethoxybenzaldehyde: A. a-{3,4-dimethoxyphenyl)-a-(6-methyl-2- pyridyl)-methanol, m.p. 99 - 90°C, B. (3,4-dimethoxyphenyl)-(6-methyl-2-pyridyl)-ketone, m.p. 84 - 86°C. C. (3,4-dihydroxyphenyl)-(6-methyl-2-pyridyl)-ketone hydrobromide, m.p. 224°C (decomp.).. D. α-(3,4-dihydroxyphenyl)-α-(6-methyl-2-piperidyl)-methanol hydrobromide, m.p. 2l6°C (decomp.).

Example 3

Using the same method as described in example 1, the following compounds were prepared from picolinic acid and 3,4,5-trimethoxybenzaldehyde:

A. α-(3,4,5-trimethoxyphenyl)-α-(2-pyridyl)-methanol.

B. (3,4,5-trimethoxyphenyl)-(2-pyridyl)-ketone, m.p. 111-112°C. C. (3,4,5-trihydroxyphenyl)-(2-pyridyl)-ketone hydrobromide, m.p. 240°C (decomp.). D. Erythro-α-(3,4,5-trihydroxyphenyl)-α-(2-piperidyl)-methanol hydrobromide, m.p. 130 - 140°C.

Example 4 (process c)

A. α-(4-Benzyloxy-3-methoxyphenyl)-α-(2-pyridyl)-methanol.

12.7 g of small pieces of lithium were suspended in 250 ml of dry ether under nitrogen and it was added 123 g of n-butyl bromide in 100 ml of dry ether over the course of 0.5 hours at a temperature of from

-5° to 0°C. The mixture was stirred for 2.5 hours at this temperature and then cooled to -20°C, after which 95 g of 2-bromopyridine in 50 ml of dry ether were added dropwise. After this addition, the mixture was stirred for 15 minutes and then 145 g of 4-benzyloxy-3-methoxybenzaldehyde in 1.5 liters of dry ether was added during 1 hour at -20°C. After the addition was finished, the reaction mixture was allowed to reach room temperature within 1.5 hours. Treatment of the mixture with 3N hydrochloric acid gave an impure product which separated at the interface between the phases and which was collected by filtration and dried in vacuo over phosphorous benzoxide. Concentration of the ether layer gave a dark brown oil which on trituration with the acidic layer gave a further amount of impure α-(4-benzyloxy-3-methoxy)-α-(2-pyridyl)-methanol, which was recrystallized from ethanol, sm .p. 124 - 125°C

B. q-(4-hydroxy-3-methoxyphenyl)-a-(2-pyridyl)-methanol.

A solution of 80 g of α-(4-benzylDoxy-3-methoxyphenyl-α-(2-pyridyl)-methanol in 1.5 liters of methanol was shaken with hydrogen in the presence of pre-reduced palladium-on-carbon catalyst (10%,

40 g) at room temperature and atmospheric pressure, until the theoretical

tical gas quantity was occupied. Removal of the catalyst and concentration of the solution to a volume of approx. 250 ml gave after storage at 0°C α-(4-hydroxy-3-methoxy)-α-(2-pyridyl)-methanol, m.p. 136 - 137°C. Two further yields of produc-

tet was obtained by concentrating the mother liquors. An analytical sample had a m.p. at 137°C.

Analysis: Calculated for C-^H-^NO^: C 67.5, H 5.7, N 6.1

Found: C 67.35, H 5.5, N 6.0.

C. Erythro-α-(4-hydroxy-3-methoxyphenyl)-α-(2-piperidyl)-methanol hydrochloride.

A solution of 25.5 g of α-(4-hydroxy-3-methoxy-phenyl)-α-(2-pyridyl)-methanol in 200 ml of methanol and 23 ml of 5N saline

acid was hydrogenated at room temperature and atmospheric pressure in the near-

be of 3 g of Adam's platinum catalyst. After 3 moles of hydrogen were taken up, the catalyst and solvent were removed to give a solid residue. Recrystallization of this material from a mixture of methanol and ether gave erythro-α-(4-hydroxy-3-methoxyphenyl)-α-(2-piperidyl)-methanol hydrochloride, m.p. 242 -

245°C.

Analysis: Calculated for C^H^qNO-jCI:

C 57.0, H 7.4, N 5.1, Cl 12.95

Found: C 57.1, H 7.4, N 5.1, Cl 13.3

Claims (1)

Analogous process for the preparation of therapeutically effective α-phenyl-α-(2-piperidyl)-methanol compounds with the general formula: where R is hydrogen, alkyl with 1-6 carbon atoms or cycloalkyl with 3-6 carbon atoms, R<1> is hydrogen, hydroxy or alkoxy with 1-6 carbon atoms, and R 2 is hydrogen, alkyl with 1-6 carbon atoms, or cycloalkyl with 3-6 carbon atoms, or pharmaceutically acceptable acid addition salts or quaternary ammonium salts thereof, characterized in that (a) a compound of the general formula: 12 .. where R, R and R have the above meaning, and B is CO or HCOH, is hydrogenated in the presence of a catalyst, or (b) a polyalkyl-substituted benzaldehyde of the formula: where Alk is alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, and R^ is hydrogen or alkoxy of 1-6 carbon atoms, is condensed with picolinic acid or alkyl substituted picolinic acid with the formula: where R^ is hydrogen, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, in the presence of an inert organic solvent with a boiling point above 140°C to form an α-polyalkoxyphenyl-α-(2-pyridyl) -methanol compound with the formula: where Alk, R 3 and R 4 have the above-mentioned meaning, which compound is oxidized to the corresponding α-polyhydroxy-phenyl-α-(2-pyridyl)-ketone compound, which is dealkylated to form an α-polyhydroxyphenyl-α-(2 -pyridyl)-ketone compound, after which this compound is hydrogenated in the presence of a catalyst to form an α-polyhydroxyphenyl-α-(2-piperidyl)-methanol compound, or (c) an alkoxy-substituted p-benzyloxybenzaldehyde of the formula: where Alk and R"^ have the meaning given above, is treated with 2-pyridyllithium or alkyl-substituted pyridyllithium in the presence of an anhydrous, inert, organic solvent at a temperature of between -20 and +25°C to form an -p-benzyloxyphenyl)-α-(2-pyridyl)-methanol compound, which compound is debenzylated by hydrogenation in the presence of a palladium catalyst and further hydrogenated in the presence of a platinum catalyst to form an α-(alkoxy-p-hydroxyphenyl)- α-(2-piperidyl)-methanol compound, after which a compound obtained under (a), (b) or (c) is, if desired, transferred to an acid addition salt or quaternary ammonium salt thereof.