NO742621L - - Google Patents

Description

Procedure in the manufacture of

1, 4-disubstituted piperidines

The present invention relates to a method by producing

ing of new 1,4-disubstituted piperidines with the general formula:

where R is hydrogen, chlorine, bromine, fluorine, lower alkyl, lower alkoxy, trifluoromethyl or p-fluorophenyl, R is hydrogen, chlorine or fluorine,

A is -C(0)-, -C(NOH)-, -CHOH- or -C(OH)(CH^)-, and B is -C(0)-,

-C(NOH)-, -CHOH-, -C(OH)(CH )- or =C-0-CH -CH O, with the pre-

hold that A and B cannot both be -C(0)- except when R is p-fluoro-

phenyl , A cannot be -CHOH- when.B is -C(0)-, and pharmaceutical good-

addable acid addition salts thereof.

The compounds of formula I have been shown, when tested using standard pharmacological methods, to have moderate to strong central nervous system depressant activity. The activity can be demonstrated when the compounds are used in the form of the free bases or as pharmaceutically acceptable acid addition salts. The aforementioned central nervous system depressant activity is an indication that the compounds can be used as psychosedatives. agents, and as such are particularly useful in producing an ant-anxiety effect in a living animal body.

The depressant action of these compounds was determined in pooled mice to which d-amphetamine was subsequently administered according to a modification of the method of Burn and Hobbs (Arch. Intern. Pharmaco-dyn. 113, 290, 1958).

The pharmaceutically acceptable acid addition salts of the free bases of formula I are within the scope of the present invention. The salts are easily prepared using methods known per se. The acids that can be used to prepare the acid addition salts are those whose anions are relatively harmless to the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the free bases are not destroyed by side effects that can be attributed to the anions. The free base is reacted with the calculated amount of organic or inorganic acid in a water-miscible solvent, such as ethanol or isopropanol, with isolation of the salt by concentration and cooling, or the base is reacted with an excess of the acid in a water-immiscible solvent which ethyl ether or isopropyl ether, the desired salt being separated directly. Examples of such organic salts are those produced with maleic acid, fumaric acid, benzoic acid, ascorbic acid, citric acid and malic acid. Examples of such inorganic salts are those produced with hydrochloric acid, hydrogen bromide, sulfuric acid and sulphamic acid.

The term "lower alkyl" includes straight-chain and branched groups with up to 6 carbon atoms, and is exemplified by groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl and hexyl.

It is therefore an aim of the present invention to prepare new 1,4-disubstituted piperidines.

o

The starting materials for the new compounds of formula I are 4-(R-benzoyl)-1-[3-(R-benzoyl)-propyl]-piperidine, 2-(R'-phenyl)-2-{3~[4- (R-benzoyl)-piperidino]-propylj -1,3-dixolane and 4-(R-benzoyl)-piperidine which can be prepared by methods described in US Patent No. 3,576,810, and 4~[4'-( p-fluorophenyl)-benzoyl]-piperidine and 4-(α-hydroxyimino-R-benzyl)-piperidine. 4~[4'-(p-fluorophenyl)-benzoyl]-piperidine is produced simultaneously in the synthesis of 4~(P-fluorobenzoyl)-piperidine from which it is separated by fractional crystallization. 4-(a-hydroxyimino-R-benzyl)-piperidine is prepared by reacting 4-(R-benzoyl)-piperidine with hydroxylamine.

Process The compounds can be prepared by methods which are represented by the following equations where R and R<1> are as indicated above.

Method A: In method A, a suspension of 4~ is heated

(R-benzoyl)-1-[3-(R1-benzoyl)-propyl]-piperidine in a lower alkanol solvent such as absolute ethanol, at a temperature of from

about. 40°C to approx. 6o°C while an excess of sodium borohydride is added in small portions. The reaction is continued at an elevated temperature from approx. 1 hour to approx. 3 hours, and then the excess metal hydride is split by the addition of dilute hydrochloric acid. The bis-hydroxy compound produced in this way is isolated from the reaction mixture by usual acid-base extraction methods.

Method B: A basic aqueous solution of 4"(R-benzoyl)-1-[3-(R<1->benzoyl)-propyl]-piperidine and hydroxylamine is reacted with each other at a temperature of from about 50°C to about 75° C. for from about 4 hours to about 8 hours.The cooled reaction mixture is diluted with about 4 volumes of water, and the bis-hydroxyimino compound that separates from the dilute solution is collected by filtration.

Method C: In method C, an ethereal solution of 2-(R'-phenyl)-2-{_3-[4-(R-benzoyl)-piperidino]-propyl}-1,3-dioxolane is added dropwise to an ethereal solution of methylmagnesium iodide at a rate sufficient to maintain mild reflux conditions. After the addition, the mixture is stirred from approx. 1 hour to approx. 3 hours. The reaction mixture is decomposed by adding it to crushed ice. The product is extracted from the cold mixture by solvent extraction, and the dried extracts are concentrated to a residual oil which is boiled briefly under reflux in alcohol containing a mineral acid to hydrolyse the ketal. 4~(α-hydroxy-α-methyl-4-benzyl)-1-[3-(R-benzoyl)-propyl]-piperidine is isolated by acid-base extraction. 2-(R1-phenyl)-2-(3~[4-(R-benzoyl)-piperidino]-propyl)-1,3-dioxolane is also reduced as in method A, using sodium borohydride, whereby one obtains 2- (R"<1>"-phenyl)-2-[3-[4-(α-hydroxy-R-benzyl)-piperidino]-propylj-1,3-dioxolane.

Process D: In process D, a mixture of 4~(α-hydroxyimino-R-benzyl)-piperidine and 2-(R 1-phenyl)-2-(3-chloropropyl)-1,3-dioxolane is boiled in a lower alkanol -solvent such as 1-butanol, under reflux in from approx. 6o to approx. 80 hours. The reaction gives the two stereoisomers of 2-(R-phenyl)-2-{3~[4-(α-hydroxyimino-R-benzoyl)-piperidino]-propy]|-1,3-dioxolane which has been designated as Z the -isomer and the E-isomer, and which are separated from each other by fractional crystallization.

o

Process E: In process E, process D is essentially followed using the same solvent and reaction conditions. The 4-(α-hydroxyimino-R-benzyl)-1-[3-(R1-benzoyl)-propyl]-piperidine is isolated from the reaction mixture and purified from a suitable solvent system such as benzene-isooctane. Method F: In method F, a mixture is reacted of 4™(R-benzoyl)-piperidine and 1-chloro-4-hydroxy-4-(R-phenyl)-pentane with each other in a lower alkanol solvent such as 1-butanol, at reflux temperature in from approx. 20 hours to approx. 30 hours in the presence of sodium bicarbonate. The crude product is placed on a column of aluminum silicate and by using increasing amounts of acetone in benzene followed by increasing amounts of methanol in acetone, several products are separated, among which is the main product in method F, 4-(R_benzoyl)-1-[3- (α-hydroxy-α-methyl-R-benzyl)-propyl]-piperidine.

Method G: In method G, 4~[4'-(p-fluorophenyl)-benzoyl]-1-[3-(p-fluorobenzoyl)-propyl]-piperidine is prepared using the same conditions as stated in method F. The product is isolated from the reaction mixture by conventional means and recrystallized from a suitable solvent such as isopropanol.

Example 1

4~(α-hydroxyimino-p-fluorobenzyl)-1-[3-(α-hydroxyimino-p-fluorobenzyl)-propyl]-piperidine

A mixture of 20.49 (0.05 mol) 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)-propyl]-piperidine hydrochloride, 100 ml of water, 400 ml of ethanol and 92 ml of 6 N sodium hydroxide was heated at 65°C until a clear solution was obtained. A solution of 35 g (0.5 mol) of hydroxylamine hydrochloride in 100 ml of water was added to the reaction mixture. The reaction mixture was heated at 65°C for 6 hours. The reaction mixture was diluted to approx. 4 1 volume of water, and the product that separated was collected by filtration. The collected solid weighed 11 g (53.2%). Recrystallization from ethanol-water gave a light leather colored product melting at 182-183°C. Analysis: Calculated for C22H25<N>3°2<F>2<:>C 65, 82; H 6.28; N 10.47

Found: C 65.79; H 6.36; N 10.37

Example 2

2-(p-fluorophenyl)-2-(3-[4-(p-fluorobenzoyl)-piperidino]-propyl}-1,3-dioxolane

A mixture of 24.49 (0.1 mol) 4-(p-fluorobenzoyl)-piperidine hydrochloride, 24.5 g (0.1 mol) 2-(p-fluorophenyl)-2-(3-chloropropyl)- 1,3-dioxolane and 33.6 g (0.4 mol) of sodium bicarbonate in 450 ml of 1-butanol were heated under reflux for 17 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The crude residue was dissolved in benzene and applied to a magnesium silicate column. Elution with a benzene-acetone gradient gave 16.0 g (24%) of pure product which crystallized. Recrystallization from isooctane gave the pure product melting at 62-64°C.

Analysis: Calculated for C^H^FgNOg C 69.38; H 6.55; N 3.37

Found: C 69.5-1; H 6.55; N.3,16

Example 3

2-(p-fluorophenyl)-2--[3-[4-(α-hydroxy-p-fluorobenzyl)-piperidino]-propyl}-1,3-dioxolane

in

A mixture of 3.78 g (0.1 mol) of sodium borohydride in 25 ml of anhydrous ethanol was stirred at room temperature. A solution of 8.16 g' (0.02 mol) of 2-(p-fluorophenyl)-2-{3~[4-(P~fluorobenzoyl)-piperidino]-propyl}-1,3-dioxolane in 10 ml of anhydrous ethanol was slowly added dropwise so that a controlled evolution of gas was maintained. After the addition was complete, the mixture was stirred at room temperature for 16 hours. A large excess of water was added and the mixture was extracted several times with benzene. The benzene extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure, and a glass-like residue was obtained. The residue was dissolved in benzene and applied to a magnesium silicate column. Using a benzene-acetone gradient solution, the product was obtained. Recrystallization of the solid product from methanol-isooctane gave 6.59 (78%) of a white,

solid which melted at 114 - 116°C.

Analysis: Calculated for C^H^Fg<N>Og: C 69.04; H 7.00; N 3.36

Found: C 69.07; H 7.08; N 3.33

■ ' ■ Example 4

Z-2-(P-fluorophenyl)-2-{3-[4-(α-hydroxyimino-p-fluorobenzyl)-piperidino-j-propyl}-1,3-dioxolane

A mixture of 15 g (0.058 mol) 4-(α-hydroxyimino-p-fluoro-benzyl)-piperidine, 18.2 g (0.0743 mol) 2-(p-fluorophenyl)-2-(3-chloropropyl) -1,3-dioxolane and 16.8 g (0.2 mol) of sodium bicarbonate in 500 ml of 1-butanol were heated under reflux for 72 hours. On cooling, the reaction mixture solidified. Trituration of the solid with methanol, followed by filtration, gave 11 g of solid. The filtrate was evaporated, whereby a gummy residue was obtained which was triturated with ligroin, whereby a crystalline solid was obtained. The solid was collected by filtration and weighed 7.39- The filtrate was evaporated, and the residue was recrystallized from benzene-isooctane, whereby 5.1 g of impure product was obtained. The total yield of raw product was 23.49 (93.5%). The samples of 11 g and 7.3 g were combined and recrystallized from isopropanol, whereby 5.6 g of product was obtained which melted at 191-192°C. This compound was the Z isomer.

Analysis: Calculated for C24H2gF2N2°3: C 66.96; H 6.56; N 6.51

Found: C 66.97; H 6.55; N 6.42

Example 5

E-2-(p-fluorophenyl)-2-{3-T4-(α-hydroxyimino-p-fluorobenzoyl)-piperidinoyl-propyl}-1,3-dioxolane

The remaining solid from Example 4 was dissolved in benzene and applied to a magnesium silicate column to give pure product (0.5 g) which melted at 161-161.5°C. This compound is the E isomer. Analysis: Calculated for C24H28F2N2°3: C 66.96; H 6.56; N 6.51

Found: C 67.03; H 6.59; N 6.42

Example 6

4-[4'-(p-fluorophenyl)-benzoyl]-1-[3~(p-fluorobenzoyl)-propyl]-piperidine hydrochloride

A mixture of 9.6 g (0.03 mol) 4-[4'*-(p-fluorophenyl)-benzoyl]-piperidine hydrochloride, 7.35 g (0.03 mol) 2-(p-fluorophenyl) -2-(3-Chloropropyl)-1,3-dioxolane and 10 g (0.12 mol) of sodium bicarbonate in 150 ml of 1-butanol were heated under reflux for 16 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in benzene and extracted with dilute hydrochloric acid. A solid precipitate was obtained which was collected by filtration. The solid was recrystallized from isopropanol, and a white solid was obtained which weighed 11.7 g (81%) and melted at 250-26o°C. Analysis: Calculated for <C>2gH2gClF2N02: C 69.48; H 5.83; N 2.90 ;Found: C 69.09; H 5.84; N 2.67 ; Example 7 ; 4-(a-hydroxyimino-p-fluorobenzyl)-1-[3-(p-fluorobenzoyl)-propyl]-piperidine ; A mixture of 5.5 g (0.0213 mol) 4 -(α-hydroxyimino-p-fluoro-benzyl)-piperidine, 9.0 g (0.045 mol) p-fluorobenzoylpropyl chloride and 8.4 g (0.01 mol) sodium bicarbonate in 100 ml 1-butanol were heated under reflux.for 24 hours. The reaction mixture was cooled and filtered to remove solids. The collected solids were triturated in water and filtered. The collected product was combined with the product filtered from the butanol solution, and the combined weight was 3.1 g. The crude product (38%) was a solid melting at 158-160°C. Recrystallization from benzene-isooctane gave a product melting at 167 -168°C. The material was combined with the product collected from another experiment, and recrystallization of the combined materials gave 3.6 g of product melting at 168.5-172°C. ;Analysis: Calculated for ^ 22^ 2h?2^ 2°2~ C 68'38'H 6>265N 7.25 ;Found: C 68.63; H 6.37; N 7.30 ; Example 8 ; 4 -(α-hydroxy-p-fluorobenzyl)-1-[3-(α-hydroxy-p-fluorobenzyl)-propyl]-piperidine ; To a stirred suspension of 4.3 g ( 0.0116 mol) of 4-(P-fluorobenzoyl)-1-[p-fluorobenzoyl)-propyl]-piperidine in 100 ml of absolute ethanol at 50°C was added in small portions, 1.9 g (0.05 mol) of sodium borohydride . After all the sodium borohydride was added, stirring was continued at 50°C for 1 hour. About. 20 ml of 3 N hydrochloric acid was slowly added dropwise to the mixture. The reaction mixture was stirred up to approx. 400 ml of water and made weakly basic with sodium hydroxide. The mixture was extracted with chloroform, and the chloroform extracts were dried over anhydrous magnesium sulfate. This mixture was filtered, and the filtrate was evaporated under reduced pressure, whereby 4.8 g of oil was obtained which crystallized by trituration in isooctane. The crude product weighed 4.19 (94-95%) and melted at 115-117°C. Recrystallization from isooctane-benzene gave 3.6 g of product melting at 115-H7°C. ;Analysis: Calculated for C^NC>2: C 70.38; H 7.25; N 3.73; Found: C 70.42; H 7.35; N 3.74 ; Example 9 ; 4~(α-hydroxy-α-methyl-p-fluorobenzyl)-1-[3-(P-fluorobenzoyl)-propyl]-piperidine hydrochloride ; A Grignard reagent was prepared By slowly to add 7.19 (0.05 mol) methyl iodide to a stirred mixture of 1.2 g (0.05 mol) magnesium metal in 20 ml ether. After the reaction had begun, the volume of ether was increased to 200 ral. After the addition of the methyl iodide, a solution of 10.39 (0.025 mol) 2-(p-fluorophenyl)-2-{_3-[4-(p-fluorobenzoyl)-piperidino]-propyl]-1,3-dioxolane in 100 ml of ether added to the mixture at a rate such that gentle reflux was maintained. After the addition was complete, the mixture was stirred for 2 hours at room temperature. The mixture was poured onto crushed ice and extracted with ether followed by an extraction with benzene. The combined extracts were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was dissolved in 10 ml of ethanol and 20 ml of dilute hydrochloric acid. The mixture was stirred and heated for 15 minutes. The mixture was cooled and basified with sodium hydroxide solution. The free base was extracted into benzene, and the combined extracts were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was dissolved in anhydrous ether, and an excess of ethereal hydrogen chloride was added. The hydrogen chloride salt which separated was treated with charcoal and recrystallized from isopropanol-isopropyl ether. The salt obtained weighed 5.39 (51%) and melted at 147-149°C. ;Analysis: • Calculated for C22H28ClF2N02'*C 6/+'15' H 6>85=, N 3.40

Found: C 64.30; H 6.59; N 3.24

Example 10

4-(p-Fluorobenzoyl)-1-[3-(a-hydroxy-a-methyl-p-fluorobenzyl)-propyl]-piperidine - oxalate

A mixture of 10.7 g (0.044 mol) 4~(P~fluorobenzoyl)-piperidine, 9.5 g (0.044 mol) 1-chloro-4-hydroxy-4~(p-flu-orphenyl)-pentane and 8.4 g (0.1 mol) of sodium bicarbonate in 200 ml of 1-butanol were stirred under reflux for 24 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The crude product, which weighed 11 g, showed several components by thin-layer chromatography. The oil was dissolved in benzene and applied to a 200 g column of magnesium silicate. Using increasing amounts of acetone in benzene and then increasing amounts of methanol in acetone', several products were separated. The title compound was isolated as 1 g (5.9%)- The free base was treated with 0.32 g of oxalic acid dihydrate and the oxalate salt obtained weighed 1 g and melted at 127-129°C. The salt was recrystallized from isopropanol-isopropyl ether, giving 0.79 g of product melting at 133-135°C. Analysis: Calculated for C25H29F2N°6: C 62>88; H 6.12; N 2.93

Found: C 63.10; H 6.28; N 2.98

Effective amounts of any of the foregoing pharmacologically active compounds can be administered internally to animals, including humans, in a variety of ways, e.g. orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The basic amino compounds, although active, are preferably processed and administered in the form of their pharmaceutically acceptable acid addition salt because of convenient crystallization, increased solubility, and the like.

Although very small amounts of the active compounds prepared according to the invention are effective when it comes to minor therapy, or in the case of administration to animals, including humans, with a relatively low body weight, unit doses are usually 5 mg or more, and may preferably 10, 25 and 50 mg and 500 mg depending of course on the severity of the situation, as 5 mg to 25 mg seems to be optimal per unit dose. The active agents can be combined with other pharmacologically active agents, or with buffers, anti-acids or the like, for administration. It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose will be obtained reproducibly with the dosage form used. Of course, several unit doses can be administered at about the same time.

Pharmaceutical carriers that can be used in the new preparations according to the invention can be solids and liquids. Solid carriers may include, but are not limited to, lactose, starch, magnesium stearate, cornstarch, dicalcium phosphate, gelatin and calcium stearate. Liquid carriers may include, but are not limited to, peanut oil, olive oil, sesame oil, and water.

The following are examples of preparations produced according to the invention: (1) CAPSULES

Capsules with 5 mg, 25 mg and 50 mg active ingredient per capsule was produced. With the higher amounts of active ingredient, the amount of lactose can be reduced.

Other capsule preparations preferably contain a larger dose of active ingredient and are as follows:

In each case, the selected active ingredient is evenly mixed with lactose, starch and magnesium stearate, and the mixture is encapsulated.

(2) TABLETS

A typical composition for a tablet containing 5.0 mg of active ingredient per tablet follows. The composition can be used for other stronger active ingredients by adjusting the weight of dicalcium phosphate.

1, 2, 4 and 5 are mixed homogeneously. 3 is prepared as a 10% paste

in hot. The mixture is granulated with starch paste, and the wet mass is passed through an 8 mesh sieve. The wet granulate is dried and sieved through a 12 mesh sieve. The dried grains are mixed with the calcium stearate and pressed.

Other tablet preparations preferably contain a higher dose

of the active ingredient and is as follows:

The active ingredient, lactose, milo starch and rnai starch are mixed evenly. This mixture is granulated using water as granulation medium. The wet grains are passed through an 8 mesh sieve and dried at 6o - 70°C overnight. The dried grains are passed through a 10 mesh sieve and mixed with the appropriate amount of calcium stearate, and this mixture is then transferred to tablets on a suitable tablet press.

The active ingredient, lactose, dicalcium phosphate, starch and milo-starch are mixed evenly. The mixture is granulated with water, and the wet mass is passed through an 8 mesh sieve. The wet grains are dried at 60 - 70°C overnight. The dried grains are passed through a 10 mesh sieve. These dried grains are mixed with the appropriate weight of calcium stearate, and the lubricated grains are then transferred to tablets on a suitable

tablet press.

in

Claims (1)

Analogy method in the production of therapeutically active substances. 1,4-substituted piperidines of the general formula: where R is hydrogen, chlorine, bromine, fluorine, lower alkyl, lower alkoxy, trifluoromethyl or p-fluorophenyl, R" <*> " is hydrogen, chlorine or fluorine, A is -C(0)-, -C(NOH)-, -CHOH or -C(OH) (CH-.) - , B is -C(0)-, -CHOH-, -C(NOH)-, -C(OH)(CH3 )- or = C- OCH2CH20, with the proviso that A and B cannot both be -C(0)- except when R is p-fluorophenyl, and A cannot be -CHOH when B is -C(0)-, and pharmaceutically acceptable acid addition salts thereof , characterized by ata) a compound with the general formula: where R and A are as indicated above, react with a compound of the formula: where R and B are as indicated above, or b) a compound of the formula: where R and R"*" are as indicated above, is prepared by reducing a compound of the formula: where R and R"*" are as above, with sodium borohydride? or c) a compound of the formula: where R and R"'" are as above, is prepared by treating a compound of the formula: where"R and R<1> are as indicated above, with hydroxylamine, or d) a compound of the formula: where R and R<1> are as above, is prepared by treating a compound of the formula: with methylmagnesium iodide, and the ketal formed is hydrolyzed with acid, or) a compound with the formula: where R and R"^ are as indicated above, is prepared by reducing a compound of formula IX with sodium borohydride, and that the compound obtained is optionally transferred to a pharmaceutically acceptable acid addition salt.