SE203478C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C07 d12 p: 1/01 PATENT AND REGISTRATION AGENCY tins. 2310/1958 was received on 10/3 1958 published on 26/7 196 THE BRITISH DRUG HOUSES LTD, LONDON, UNITED KINGDOM Aim to produce certain 1-stable-young substituted 4-phenyl-piperidine derivatives with analgesic effect Inventors: V Petrow and 0 Stephenson Priority requested This invention relates to the preparation of certain 1-position-substituted 4-phenylpiperidine derivatives which are valuable because of their analgesic properties.

It is true that piperidine derivatives of the general formula RC6H CO (I) dir R represent a lower alkoxy or lower alkyl radical containing from 1 to 3 carbon atoms and R 'represents a methyl radical, having pronounced analgesic properties. It is further known that the biological properties of such compounds largely depend on the nature of the group R ', and that a change in the group R', from lower alkyl and in particular methyl in general leads to a marked decrease in analgesic activity.

It has now surprisingly been found that by replacing the methyl group (R ') in compounds of the above general formula' I with the 3-aryloxy-2-hydroxypropyl radical (II) ArO • CH, • R2 C (OH). CH, - (II, ddr R2 represents irate or a methyl group) obtain compounds with analgesic action, which can even yam. stone an den of the corresponding compounds, in which R 'represents a methyl group.

The invention therefore relates to a process for preparing piperidine derivatives having analgesic action, characterized in that a piperidine derivative of the formula is reacted with a suitable 3-aryloxy4: 2-epoxypropane of the general formula R2 I -CH, or with a suitable 3-aryloxy-2-hydroxypropyl chloride of the general formula 1 = 1.2 .AsO • CH 2. C (OH). CH ,. Cl in the presence of a chlorvate acceptor to give a piperidine derivative of the general formula R2 ArOC (OH) • CH2 • NC, H, CUR '2 in which formulas Ar ,, m- or p-methoxyphenyl or lower alkoxyphenyl radical having 1-6 carbon atoms in the alkoxy group, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl-, o-, m- or p-fluorophenyl or o -, or p-aminophenyl radical or acyl derivative (Way, denotes vale or a methyl group and R 'denotes a lower alkoxy or lower alkyl group containing 1 to 3 carbon atoms.

According to the invention, for example, the following special novel compounds are prepared: 1- (4'-ethoxycarbonyl-4'-phenyl) piperidino-3-o-toloxypropan-2-ol and its hydrochloride. 1- (4'-Ethoxycarbonyl-4 '-phenyl) -piperidino-3-p-acetamidophenoxypropan-2-ol, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-p-aminophenodroprop-2 -ol-hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-phenoxypropan-2-ol and salts thereof, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-ol O-chlorophenoxypropan-2-ol and its hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-m-tolimd-propan-2-ol and its hydrochloride, 1- (4'-ethoxycarbonyl- 4'-phenyl) -piperidino-3-petholoxy-propan-2-ol and its hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-petoxycarbonylphenoxy-propan-2-ol and its hydrochloride , 1- (4 '- ethoxycarbonyl-4'-phenyl) -piperidino-3-o-fluorophenoxy-propan-2-ol and its hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-2 - Methyl-3-o-toluid-propan-2-ol-hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-o-allylphenoxy-propan-2-ol-hydrolide, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-chlorophenoxypropan-2-ol and its hydrochloride, 1 - (4 '- ethoxycarbonyl-4'-phenyl) -piperidino-3-p-chlorophenoxypropan-2-ol and its hydrochloride, 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-methoxyphenoxypropane-2- ol and its hydrochloride and 1- (4'-ethylcarbonyl-4'-phenyl) -piperidino-2-methyl-3-phenoxypropan-2-ol hydrolide.

In the preparation of compounds in which Ar represents o-, m- or p-aminophenyl, it is desirable to protect the aminophenyl group in the intermediates of the general formulas IV and VI and to later restore the aminophenyl group by known methods.

Condensation of the epoxides (IV) or chlorohydrins (VI) with the piperidine bases (V) can be effected in the absence of solvents or in the absence of solvents, for example ethanol, benzene or petroleum. The resulting products can be isolated directly in the crystalline state or they can also be isolated by standard methods including fractional distillation under reduced pressure.

The invention is further elucidated in the following by some examples of methods for carrying out the method according to the invention.

Example 1. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-o-toloxypropan-2-ol (III: Ar = o-tolyl, R2 = H, R '= OEt). o-Toloxy-1: 2-epoxypropane (5.7 g) was added to a solution of 4-ethoxycarbonyl-4-phenylpiperidine (8.0 g) in light petroleum (10 ml, b.p. 60-80 ° C) and the mixture was heated under aterflOde on angbad for 3 hours.

After cooling, the solution was treated with a small excess of a solution of hydrogen chloride gas in ethanol. Upon dilution of the hot solution with ether, the product is obtained as the crystalline hydrochloride.

This was purified by recrystallization from ethanol, and separated from this solvent as white prismatic crystals, m.p. 188-189 ° C. The hydrochloride was also purified by crystallization from water.

Example 2. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-p-acetamido-phenoxypropan-2-ol (III: Ar = = p-NHAc.13.2 = H, R '= OEt). 4-Ethoxycarbonyl-4-phenylpiperidine (20.6 g) was added to a solution of 1-p-acetanidophenoxy-2: 3-epoxypropane (18.3 g) in 50 ml of ethanol. A slight exotherm occurred and when quenched the mixture was heated on a steam bath for 1 hour.

After removal of the ethanol, the residue solidified. A portion of the product was purified by crystallization from ethyl acetate, bathing at a melting point of 141 145 ° C. 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-p-aminophenoxypropan-2-ol hydrochloride (III: Ar - = p.NH2. C21-14-, R2 = H, R '= OE4 The above acetamido derivative (20 g) was dissolved in 50 ml of ethanol, treated with a solution of 8 g of hydrogen chloride gas in 50 ml of ethanol and the mixture was heated under reflux for 6 hours. from a mixture of ethanol and ethyl acetate to give the product as small white crystals with a narrowing point of about 230 ° C (with probe division).

Example 3. 1- (4'-Ethylcarbonyl-4'-phenyl) -piperidino-3-phenoxypropan-2-ol.

A mixture of 4-ethoxycarbonyl-4-phenyl-piperidine (8.2 g) and 3-phenoxy-1: 2-epoxypropane (5.3 g) in light petroleum (20 ml, b.p. 60-80 ° C) was heated pa angbad for 1 hour. The product crystallized on cooling and was purified by crystallization from aqueous ethanol to give small shiny needles with a melting point of 111 ° C.

The above base was converted to the hydrochloride in concentrated ethanolic solution. The latter compound crystallized from a mixture 3 of ethanol and ether in shiny white prisms with a melting point of 178-179 ° C.

Other salts of 1- (4'-ethoxycarbonyl- 4'-phenyl) -piperidino-3-phenoxypropan-2-ol.

The hydrobromide was separated from ethanol in white needles, m.p. 163-164 ° C.

The acid sulfate was separated from ethanol into granular crystals, m.p. 181-183 ° C. These solidified again and then melted again at 263-264 ° C (with probe division). When the melting point was examined very slowly, the lower melting point was not noted.

The divate phosphate crystallized from aqueous ethanol in white needles, m.p. 174175 ° C.

Hypophosphite was separated from mixtures of ethanol and ether in white needles with a melting point of 114.7-116.5 ° C (corr.).

The sulfamate was precipitated from ethanol in sparingly welded crystals, m.p. 166 ° C.

The glycerophosphate had a melting point of 153-154 ° C after crystallization from a mixture of ethanol and ether.

The methanesulfonate crystallized from ethanol in needles, m.p. 150-151 ° C.

The isethionate is obtained as shiny plates with a melting point of 131-133 ° C after crystallization from a mixture of ethanol and ether.

The lactate had a melting point of 132-133 ° C after crystallization from a mixture of ethanol and ether.

The tartrate was separated from water containing a small amount of ethanol in small white needles with a melting point of 137-138 ° C.

Example 4. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-o-chlorophenoxypropan-2-ol. 3-o-Chlorophenoxy-1: 2-epoxypropane (7.1 g) was added to one% suspension of 4-ethoxycarbonyl-4-phenylpiperidine in light petroleum (10 ml, b.p. 60-80 ° C). The mixture was heated on a steam bath for two hours and the product was separated on cooling. The base was purified by crystallization from aqueous ethanol and had a melting point of 81-83 ° C. The hydrochloride had a melting point of 171-172 ° C after crystallization from a mixture of ethanol and ether.

Example 5. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-m-toloxypropan-2-ol.

A mixture of 3-m-toloxy-1: 2-epoxypropane (8.2 g) and 4-ethoxycarbonyl-4-phenylpiperidine (11.7 g) in light petroleum (15 ml, b.p. 60-80 ° C) was heated on a steam bath. for three hours. The base, which was separated on cooling, was purified by crystallization from aqueous ethanol or from light petroleum (b.p. 60-80 ° C) to form white curly needles with a melting point of 80-81 ° C.

The hydrochloride crystallized from a mixture of ethanol and ether in very small shiny needles, m.p. 157-159 ° C.

Example 6. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-p-toloxypropan-2-ol.

To a solution of 4-ethoxycarbonyl-4-phenylpiperidine (12.5 g) in 25 ml of absolute ethanol was added 10.75 g of 2-hydroxy-3-p-toloxypropyl chloride and then 2.85 g of anhydrous sodium carbonate. The mixture was heated on a steam bath under reflux for four hours. It was cooled, diluted with water and the gourmet oil was extracted with chloroform. The chloroform extract was washed with water and the chloroform was distilled off. The remaining oil solidified rapidly. It was purified by crystallization from a mixture of ethanol and light petroleum (b.p. 60-80 ° C) or from aqueous ethanol to give the base as white curly needles, m.p. 111-113 ° C. The hydrochloride crystallized from a mixture of ethanol and ether in small white needles, m.p. 152-154 ° C.

Example 7. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-p-ethoxycarbonylphenoxy-propan-2-ol. 3-β-Ethoxycarbonylphenoxy-1: 2-epoxypropane (9.6 g) was added to a% solution of 4-ethoxycarbonyl-4-phenylpiperidine in petroleum (20 ml, b.p. 6080 ° C) and the mixture was heated on a steam bath for 3 hours . The base solidified on cooling. It crystallized from a mixture of ethanol and petroleum (b.p. 60-80 ° C) in white rippled needles, mp 86-88 ° C.

The hydrochloride was separated from a mixture of ethanol and ether into small white needles, m.p. 174-176 ° C.

Example 8. 1- (4'-Ethoxycarbonyl-4'-phenylypiperidino-3-o-fluoro-phenoxy-propan-2-ol.

This compound was prepared by reacting 3-o-fluorophenoxy-1: 2-epoxypropane (7.9 g) with 4-ethoxycarbonyl-4-phenylpiperidine (11 g) in light petroleum (20 ml, b.p. 60-80 ° C).

It crystallized from ethanol in white needles, m.p. 80-81 ° C.

The hydrochloride was separated from a mixture of ethanol and ether and had a melting point of 159 ° C.

Example 9. 1- (4'-Ethylcarbonyl-4'-phenyl) -piperidino-3-o-allyl-phenoxypropan-2-ol hydrochloride.

To a solution of 4-ethoxycarbonyl- 4-phenylpiperidine (12.7 g) in light petroleum (15 ml, b.p. 60-80 ° C) was added 3-o-allylphenoxy-1: 2-epoxypropane (10.35 g) and the mixture heated on steam bath for 2 hours.

After cooling, the mixture was treated with a small excess of ethanolic hydrochloric acid. The hydrochloride was immediately separated and purified by crystallization from 20 -0/0 ethanol to give small white shiny plates, m.p. 198-200 ° C.

Example 10. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-2-methyl-3-o-toloxy-propan-2-ol hydrochloride.

A mixture of 3-o-toloxy-2-methyl-1: 2-epoxypropane (6.8 g) and 4-ethmycarbonyl-4-phenylpiperidine (8.9 g) in petroleum (20 ml, b.p. 60-80 ° C) was heated on a steam bath for 2 hours. After removal of the solvent, the viscous residue was converted directly to the hydrochloride 4 L of ethanolic solution. It was purified by crystallization from a mixture of ethanol and ether and had a melting point of 177 ° C.

Example 11. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-m-chlorophenoxy-propan-2-ol.

This compound was prepared by condensing 3-m-chlorophenoxy-1: 2-epoxypropane (9.25 g) with 4-ethoxycarbonyl-4-phenylpiperidine (11.7 g) in light petroleum (40 ml, b.p. 60-80 ° C) . It crystallized from aqueous ethanol in white needles, m.p. 89-90 ° C.

The hydrochloride was separated from a mixture of ethanol and ether and had a melting point of 162163 ° C.

Example 12. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-p-chlorophenoxypropan-2-ol.

A mixture of 3-p-chlorophenoxy-1: 2-epoxypropane (8.0 g) and 4-ethoxycarbonyl-4-phenylpiperidine (10.0 g) in light petroleum (25 ml, boiling point 6080 ° C) was heated on a steam bath. for 2 hours. The product was excreted on slight cooling. It was purified by crystallization from aqueous ethanol to give white nails, m.p. 103-104 ° C.

The hydrochloride was separated from a mixture of ethanol and ether in white needles, m.p. 165-166 ° C.

Example 13. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-3-o-methcudphenoxypropan-2-ol. 3-o-Methoxyphenoxy-1: 2-epoxypropane (9.0 g) was added to a solution of 4-ethoxycarbonyl-4-phenylpiperidine (11.7 g) in light petroleum (25 ml, b.p. 6080 ° C) containing a few drops of ethanol , and the mixture was heated under reflux for 2 hours. The product, which was separated on cooling, was purified by crystallization from aqueous ethanol to give white needles, m.p. 89-90 ° C.

The hydrochloride was separated from a mixture of ethanol and ether in white needles, m.p. 147-148 ° C.

Example 14. 1- (4'-Ethoxycarbonyl-4'-phenyl) -piperidino-2-methyl-3-phenoxypropan-2-ol hydrochloride.

A mixture of 3-phenoxy-2-methyl-1: 2-epoxypropane (8.2 g) and 4-ethoxycarbonyl-4-phenylpiperidine (11.65 g) in light petroleum (25 ml, b.p. 60-80 ° C) was heated pa angbad i 2 tinunar. After removal of solvent, the oily base was converted directly to the hydrochloride in ethanolic solution. The latter crystallized from a mixture of ethanol and ether in white Alm with a melting point of 171-172 ° C.

Description of experiment.

The analgesic activity was determined in moss as described by Bianchi and Fran-. ceschini (Brit. J. Pharmacol. 1954, 9, 280).

Moss was injected subcutaneously with each of the compounds to be tested and the number of animals in analgesia 30, 60 and 90 minutes after administration was recorded. 90 moss was used for each compound at the following dose levels: 1- (4'-ethoxycarbonyl-4'-phenyl) -piperidino-3-phenoxypropan-2-ol and 1- (4'-ethoxycarbonyl-4 ') -piperidino-3-phenoxypropane at 0.195, 0.39, 0.78, 1.56 and 3.12 mg / kg body weight. Pethidine at 3.12, 6.25, 12.5, 25 and 30 mg / kg body weight.

The compounds were used as the hydrochlorides and dissolved in distilled water.

The injected volumes were constantly healed at 0.5 ml / 20 g body weight and the experiments were performed simultaneously with the three compounds to be tested.

Toxicity tests are also challenged with the three associations.

The following results are obtained with the hydrochlorides of 1- (4 '- ethoxycarbonyl-4'-phenyl) -piperidino-3-phenoxypropan-2-ol \ CO OEt / -O CH, CHOH CH, -N \ / ph 1- ( 4`-ethoxycarbonyl- 4`-phenyl) -piperidino-3-phenoxy-propane COOEt \ -O CH, CH2Cl12-1 ■ T / \>

Claims (4)

Patent claim: 1. was prepared to produce 4-phenyl-piperidine derivatives having analgesic action, characterized in that a piperidine derivative of the formula C61-1, / COR general formula 11.2 I 0 I / \ Ar • O • CH, -CCH, in which formulas Ar represents a phenyl, o, m or p-tolyl, o-, m- or p-methoxyphenyl or lower alkoxyphenyl radical having 1-6 carbon atoms in the alkyd group, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or p-fluorophenyl or o-, m- or p-aminophenyl radical or acyl derivatives hd, R 2 represents vate or a methyl group and R 'represents a lower alkoxy or lower alkyl group containing 1-3 carbon atoms. 2. A kit according to claim 1, characterized in that the chlorine tea acceptor is sodium carbonate or sodium hydro) dd. Salt according to claim 1, characterized in that the condensation of the 3-aryloxy-1: 2-epoxypropane with the piperidine derivative is carried out in the absence of solvent. Salt according to claim 1, characterized in that the condensation of the 3-aryloxy-1: 2-epoxypropane with the piperidine derivative is carried out in the presence of ethanol, benzene or lathe petroleum. Cited publications: Patents from Sweden 166,674; USA. 2,508,653, 2,498,430.