FI77850C - Process for the preparation of 4-benzyloxy or 4-naphthylmethoxypipe ridin derivatives which have antidepressant effect. - Google Patents

Description

77850

The present invention relates to a process for the preparation of 4-benzyloxy or 4-naphthylmethoxypiperidine derivatives having an antidepressant activity and having the formula (I) 10 ° C. 0 "* wherein R is hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl, C 1-4 alkoxycarbonyl, phenethyl, 3-phenylpropyl, or a benzyl group which may be substituted by one halogen or C 1-4 alkyl- alkoxy, X represents one or more hydrogen or halogen atoms or a C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl or methylenedioxy group, or X forms a naphthyl group with the phenyl ring, provided that R and X do not at the same time may represent a hydrogen atom, as well as for the preparation of their pharmaceutically acceptable acid addition salts.

EP patent 15 817 discloses a compound of formula (I) in which R and X simultaneously represent a hydrogen atom. This compound is an anticonvulsant drug, but, unlike the novel compounds prepared according to the invention, it has no antidepressant effect at all.

Preferred compounds of the invention are those in which X represents one or more chlorine atoms or forms a naphthyl radical with the phenyl ring or represents three methoxy radicals.

Of these compounds, mention may be made in particular of those in which R is H.

According to the invention, compounds (I) can be prepared using 2,77850 / λ starting material compound (II) R'N 2 -J-OH, in which R 'is a nitrogen protecting radical, for example 4-nitrobenzoyl radical, optionally substituted benzoyl radical, optionally substituted a benzyl radical or an alkyl radical, and which starting material is reacted with a compound (III) Y-CH 2 -, wherein Y is a reactive radical, for example a chlorine or bromine atom; then either removing the protecting radical R 'if it does not correspond to any radical R, or reducing the optionally substituted benzoyl radical as a protecting radical, or the compound (I) 15 / ^ 2 ° ^ / NH (I> 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 is reacted with a compound R 2, where Z is a reactive group, to attach a radical R.

3

Pharmacological studies on the products (I) 4 * prepared according to the invention have shown their antidepressant activity.

6

The toxicity of the compounds was determined intraperitoneally in mice. The LD 50 value is 30-1000 mg / kg.

8

The antidepressant effect has been determined by testing the effect of 9 compounds against the reserpine-induced precipitation of 10 compounds. (Gouret C. et al., J. Pharmacol. Paris 8, 333-1150, 1977).

12

Mice (males, CD1 Charles River, France, 13-18-22 g) were co-administered the test product or 14 vehicle alone (intraperitoneally) and reserpine 15 (4 mg / kg, subcutaneously). 60 minutes later, the deposition of the dependent eyelid was assessed using an evaluation scale (zero to four) in each mouse. For each dose, a mean estimate and a percentage variation of 77,850 compared to the control group was calculated. For each product, the AD 50 value was determined graphically, i.e., the dose that reduced precipitation by 50% compared to control animals.

The AD 50 value was 4-10 mg / kg intraperitoneally.

5 The antidepressant effect was also determined by testing the potency of head-twitches induced by L-5-hydroxytryptophan. (Van Riezen, H. (1972) Arch. Int. Pharmakology, 198, 256-269).

The experimental procedure was as follows: 10 24 hours before the experiment, the animals were brought to the laboratory where the treatment was to be performed. On the day of the experiment, the mice were weighed and anesthetized. They were then injected with the test products intraperitoneally, followed by subcutaneous injection of L5-HTP 125 suspended in 125 mg / kg Tween. Head jerks were counted 30 minutes after L5-HTP injection for 60 seconds. For each dose, the mean head twitch and the percentage variation from the control group were calculated. The 50% active dose was determined graphically.

The AD 50 value was 0.1-5 mg / kg intraperitoneally.

Pharmacological results indicate that the compounds can be used to treat depressive conditions.

The compounds may be in any form suitable for oral administration, for example tablets, granules, gel beads, drinkable or injectable solutions, etc., combined with any suitable excipient.

The daily dose can be 5-200 mg.

30 Therapeutic comparative trials.

The antidepressant activity of the test compounds was demonstrated by the method described in H. Van Riezen (1972) Arch. Int. Pharmacodyn., 198, 256-269.

4-Benzyloxypiperidine hydrochloride known from EP 15,817 35 was used as a reference compound.

The results are shown in the following table.

4,77850

ANTI - DEPRESSION EFFECT AND TOXICITY

HTP L D 50 ID50 / ED50

Compound ED50 (i.p.) (i.p.) (i.p.) (mg / kg) (mg / kg)

Comparison> 10 (*) 40 <4

From the example “'3 4.5 625 139 5 5.5 70 13 64 80 20 13 5 475 95 17 7 80 11 21 1.5 <100 ^ 66 23 10 ~ 200 ~ 20 24 0.15 50 333 25 0.15 70 466 26 1.3 150 115 27 3; 5 28 2> 1,000> 500 29 2 60 30 31 8 85 10; 34 3.5 160 45 35 0.15 110 733 40 10 275 27 41 1.3 46 1 500 500 48 0.2> 2,000> 10,000 47 0.8 560 700 49 0.5 '; (*) Toxicity difficulties occur at doses above (LD50 = 40 mg / kg) 77850 5

The following examples illustrate the invention. Analyzes and IR and NMR spectra confirm the structures of the compounds.

Example 1c 4- (4-Fluoro-benzyloxy) -piperidine and its Mandate 1.1) 1- (4-Nitrobenzoyl) -4- (4-fluorobenzyloxy) -piperidine The mixture was stirred for 5 hours at 50 ° C. containing 1.6 g of 50% aqueous sodium hydroxide solution, 10 ml of dichloromethane, 2 g (0.008 mol) of 1- (4-nitrobenzoyl) -4-hydroxypiperidine, 2.32 g (0.012 mol) of 4-fluoro- 4 benzyl bromide and 0.15 g (4 x 10 moles) of tetrabutylammonium iodide. The reaction mixture was then diluted with 20 ml of water and 30 ml of dichloromethane and then the organic phase was decanted, washed with water until the washings were neutral, dried (MgSO 4) and evaporated in vacuo. The resulting oily residue crystallized on stirring in ether. 2.23 g of product were obtained, which was purified by dissolving it in 11 ml of dimethylformamide (DMF) and reprecipitating it by adding dropwise 11 ml of water with stirring. Washing with water and drying in vacuo gave 1- (4-nitrobenzoyl) -4- (4-fluorobenzyloxy) piperidine. Sp. 120 ° C.

1.2) 4- (4-fluorobenzyloxy) -piperidine (mandelate)

A mixture of 11.48 g (0.032 mol) of the product obtained in step 1.1), 192 ml of 96% ethanol and 48 ml of 10 M aqueous potassium hydroxide solution was heated to 50 ° C under a nitrogen atmosphere and kept at this temperature for 4 hours at the same time. with stirring. The alcohol was removed by evaporation in vacuo, the residue was taken up in a mixture of 200 ml of water, 72 g of sodium chloride and 35 .mu.l of ether * · ^. · After filtration, the aqueous phase was extracted twice with 200 ml of ether, the combined organic phases were dried (MgSO 4) and evaporated in vacuo. .

6,77850 The oily product thus obtained was converted into d, 1-Mandelate by dissolving it in 100 ml of ether and adding 4.57 g (0.03 mol) of d, 1-mandelic acid. The resulting salt was filtered off and recrystallized from isopropanol. Sp. 146 ° C.

Example 2 4- (3,4,5-Trimethoxy-benzyloxy) -piperidine and its mandelate 2.1) 1- (4-Nitrobenzoyl) -4- (3,4,5-trimethoxy-benzyloxy) -piperidine

A mixture of 0.8 g of 50% aqueous sodium hydroxide solution, 5 ml of dichloromethane, 1 g (0.004 mol) of 1- (4-nitrobenzoyl) -4-hydroxypiperidine, 1.30 g was stirred for 5 hours at 50 ° C. (0.006 mol) 3,4,4--4-trimethoxybenzyl chloride and 0.08 g (2x10 mol) of tetrabutylammonium iodide. The reaction mixture was diluted with 10 ml of water and 15 ml of dichloromethane and the organic phase was then separated by decantation, washed with water until the washings were neutral, dried (MgSO 4) and evaporated to dryness in vacuo. The resulting oily residue crystallized on stirring in ether. 1.36 g (79%) of product were obtained, which was purified by dissolving it in 7 ml of DMF and slowly reprecipitating it by adding 7 ml of water.

Washing with water and drying in vacuo gave 1- (4-nitrobenzoyl) -4- (3,4,5-trimethoxybenzyloxy) piperidine. Sp. 124 ° C.

2.2) 4- (3,4,5-trimethoxybenzyloxy) -piperidine (mandelate

A mixture of 12 g (0.028 mol) of the product obtained in step 2.1), 168 ml of 96% ethanol and 48 ml of 10 M aqueous potassium hydroxide solution was heated to 50 ° C in the presence of nitrogen-25 gas and kept at this temperature for 4 hours. stirring constantly. The alcohol was removed by evaporation in vacuo, the residue was taken up in a mixture of 70 ml of water, 25.2 g of sodium chloride and 70 ml of chloroform. After filtration, the aqueous phase was extracted twice with 70 ml of chloroform, the combined organic phases were dried (MgSO 4) and evaporated to dryness in vacuo. A pasty solid residue was obtained which was converted to the d, 1-mandelate by dissolving it in 120 ml of methanol, adding 4.26 g (0.028 mol) of d, 1-mandelic acid and filtering after stirring overnight at room temperature. The resulting precipitate was recrystallized from methanol. The product crystallizes with half a molecule of water. Sp. 114 ° C.

Example 3 1-Ethoxycarbonyl-4-benzyloxy-piperidine In a mixture of 6.83 g (0.03 mol) of 4-benzyloxypiperidine, 7, 74 g (0.56 mol) of dry 1 H 2 O 3, 26 ml of water and 26 ml of chloroform were added dropwise with stirring while stirring 3.4 g (0.033 mol) of ethyl chloroformate, and stirring was continued for 1 hour. then 54 ml of chloroform and then the organic phase was separated by decantation and washed 3 times with 20 ml of water and dried (MgSO 4) to evaporate the solvent in vacuo to give a liquid product which was then distilled in vacuo.

30 KpQ 4: 149-151 ° C; n ^ 1 = 1.5178.

77850 8

Example 4 1-Methyl-4- (4-chloro-benzyloxy) -piperidine and its hydrochloride In a 500 ml three-necked flask placed under an argon atmosphere, 4.4 g (0.1 mol) of sodium hydride, 55% strength, were washed 3 times with petroleum ether. an oil mixture. 10.1 g (0.1 mol) of 1-methyl-4-hydroxypiperidine dissolved in 100 ml of DMF were then added. After stirring for 1 hour at room temperature, the reaction mixture was then cooled in an ice bath and 19.3 g (0.12 mol) of p-chlorobenzyl chloride dissolved in 50 ml of DMF were added. After the addition was complete, stirring was continued for an additional 4 hours at room temperature and the reaction mixture was allowed to stand overnight.

The reaction mixture was poured into ice water and extracted with ether 3 times. The organicase was washed once with water and then extracted with dilute HCl (1-2 N). The aqueous phase was then basified with NaOH. It was extracted with ether and the extracts were washed 4 times with water. The organic phase was washed with magnesium sulfate, filtered and concentrated. The resulting oil was distilled twice and a fraction of 94.98 ° C / 0.04 mmHg was collected. The resulting oily product was taken up in ether and its hydrochloride was precipitated by the addition of chlorine-hydrogen gas. The hydrochloride was filtered off and rinsed with ether. The product was dissolved in as little isopropanol as possible while hot and then five times the volume of ethyl acetate was added and the product was left to crystallize. Sp. 149-151 ° C.

Example 5 1-Benzyl-4- (3,4,5-trimethoxybenzyloxypiperidine and its fumarate

In a 250 ml three-necked flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol) of 35 sodium hydride in a 55% oil mixture were washed 3 times with petroleum ether. 9.6 g (0.05 mol) of 1-benzyl-4-hydroxypiperidine dissolved in 30 ml of DMF were then added. When the addition was complete, 9,77850 was stirred for 1 hour at room temperature, then 13 g (80.06 moles) of 3,4,5-trimethoxybenzyl chloride in 30 ml of DMF were added in the same ice bath. Stirring was continued for 5 hours at room temperature and the mixture was allowed to stand overnight. The reaction mixture was poured into ice water and extracted with ether. The product was then extracted with dilute HCl. The aqueous phase was made alkaline with NaOH and then extracted with ether, the extracts washed with water, dried over magnesium sulfate, filtered and concentrated. The oily residue of Saa-10 was taken up in hot pentane. The product crystallized. It was filtered and recrystallized from isopropanol. The obtained base was dissolved in 70 ml of ethanol and 2.9 g (0.025 mol) of fumaric acid 140 dissolved in any ethanol and filtered were added. The salt formed was filtered off and dried. Sp. 160-161 ° C.

Example 6 1- (4-Chloro-benzyl) -4- (3,4,5-trimethoxy-benzyloxy) -piperidine and its fumarate 6.1) 1- (4-chloro-benzoyl) -4-hydroxy-piperidine per liter An Erlenmeyer flask was charged with 30 g (0.296 moles) of 4-hydroxypiperidine, 260 mL of CHCl 3 / 57.3 g (0.414 moles) of CO 2 and 260 mL of water. 51.8 g (0.296 mol) of p-chlorobenzoyl chloride dissolved in 50 ml of CHCl3 were added over 15 minutes while cooling in the same ice bath.

i: J

the thio mixture was stirred overnight at room temperature. The mixture was decanted, extracted with CHCl 3 and washed with water until the pH of the wash water was 6-7. Dried over MgSO 4, filtered and concentrated. The product was recrystallized from ethyl acetate.

6.2) 1- (4-Chlorobenzoyl) -4- (3,4,5-trimethoxy-benzyloxy) -piperidine In a three-necked flask placed under a nitrogen atmosphere, it was washed with petroleum ether 3 times to 0.96 g (0.022 mol).

NaH as a 55% O1 mixture. 4.8 g (0.02 mol) of the product 77850 10 obtained in step 6.1) dissolved in 50 ml of DMF were then added. After the addition was complete, the reaction mixture was stirred for 1 hour at room temperature. The mixture was then cooled in an ice bath and 5.4 g (0.025 mol) of 3,4,5-trimethoxybenzyl chloride dissolved in 10 ml of DMF was added. Stirring was continued for a further 3 hours at room temperature and the reaction mixture was then allowed to stand overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting oily product was dissolved in ether and the solution was filtered. The filtrate was concentrated and poured onto a column packed with alumina (eluent CHCl 3). The product did not crystallize and was used as such in the next step.

6.3 1- (4-Chlorobenzyl) -4- (3,4,5-trimethoxybenzyloxy) piperidine and its fumarate

To a round bottom flask under nitrogen and at room temperature was added 0.38 g (0.01 mol) of AlLiH 2 suspended in 30 ml of dry ether, 7 g (0.0167 mol) of the product obtained in step 2q 6.2) dissolved in 70 ml of dry ether. The reaction mixture was refluxed for 3 hours. The reaction mixture was hydrolyzed with 2.6 mL of isopropanol and 3.3 mL of saturated aqueous NaCl. Filtered and rinsed with ether. The product was extracted into dilute hydrochloric acid. The reaction mixture was then made alkaline with NH 4 OH and extracted with ether. The ether extracts were washed with water, dried over magnesium sulfate, filtered and concentrated. The obtained oily product was dissolved in 30 ml of ethanol, and the solution was filtered, and then 1.2 g (0.0105 mol) of fumaric acid in 60 ml of ethanol was added thereto. The fumarate precipitated slowly. The product was filtered, rinsed with a small amount of ethanol, then with ether and dried. Sp. 178-180 ° C.

The following table shows a number of exemplified compounds.

77850 11

Table jQhc ^ -ο ^ Λ-, m

Compound xr Salt F (° C) 1 4_p H d, l-mandelate ^ 2 3,4 (<o_) H - 137 3 3,4,5- (OMe) 3 H 114 4 2-Me H 112 5 4 - Me H 119 6 3-CF3 H 126

Hydrochloride 7 2-OMe H 170 8 3-OMe H d, 1-Mandate 117 9 4-OMe H 129 10 2-OEt H 135 77850 12

Table (continued)

Compound X r Salt F 1 ° c); ^ - 1 H 3,4- (OMe) 2 H d, 1-mandelate 10 8 12 H Me d, 1-mandelate 118 13 H CO2Et oil pbg („= 149-151 I | 14 3-CF3 CH2CH2OH Hydrochloride 10 2 j

Citrate qd_e 15 3,4,5- (OMe) 3 CH (Me) 2 94 5 16 3,4,5- (OMe) 3 CO 2 Et 64

Fumarate. _ 17 3-CF 3 CH (Me) 2 117

18 3-Me CO 2 Oil OY

j

19 3-CF CO Et 01 jY

1 I

20 3,4,5- (OMe) 3 Me Citrate j 21 4-Cl Me Hydrochloride 149-151 22 3-CF Me Hydrochloride 111-2 | 3 i 23 3,4,5- (OMe) 3 CH2- ^ ~ ^> Fumarate 160-1 2 4 4-Cl H Hydrochloride 157-9 1 25 3,4-Cl2 H Hydrochloride 142.5-144 26 3 ' 4_C12 CH2 ^) Hydrochloride 184-6 27 3,4-Cl2 Me Hydrochloride 119-120 77850 13

Table (continued) X_ R_Salt f (° C) 28 4-Cl CD2Et Oil 29 4 -Cl CH2-f ^ Hydrochloride 171.5-173 3 ^ ^ 2 CH2CH2OH Hydrochloride 115.5-117 4 O 'Pr H Fumarate 140- 141.5 32 3,4,5 (OMe) ^ CH2- ^ J ^ -C1 Fumarate 178-180 3 3 4-OMe CH2CH2 “^ 3 Hydrochloride 165-7 ^ 4- Pr H Fumarate 14 5-6 35 3 ' 4 "() H 170-171.5 36 4-OMe CH2 - <^) - OMe 138_9 f 37 3,4,5- (OMe) 3 CH2p 167.5-168.5 38 4-OMe CH2 * ^) "C1 16 7-8 39 4-OMe CH2" ^ L ^ 152-3 40 4-OMe CH2-p> 137-8 41 2,4-Cl2 CH2CH2OH 106-7 42 3,4,5- (OMe) 3 CH2CH2-7.147-8; ·; t 77850 14

Table (continued)

Compound XR Salt F (° C) 4 3 4-Cl CH2CH2CH2- ^ Jy> Fumarate 148-9 4 4 3,4,5— (OMe) 2 CH2Fumarate 180-181.5 4 5 4-OMe CH2CH2CH2 - <Fumarate 125.5-127 4 6 3,4-Cl 2 CO2Me oil

47 2,4-Cl c02Et Oil Eb = 164-8 ° C

/ 0,001 mm

48 3,4- (j) CO Et oil Eb = 183-5 ° C

/ 0.00 3 mm f 49 4-Br H Hydrochloride 205-7 —------ L ----- il_—

Claims (1)

A process for the preparation of 4-benzyloxy or 4-naphthylmethoxypiperidine derivatives having antidepressant activity and having the formula (I) wherein R is hydrogen, C 1-4 alkyl, hydroxy-C 1-4 alkyl, alkoxycarbonyl, phenethyl, 3-phenylpropyl, or a benzyl group which may be substituted by one halogen or C 1-4 alkoxy, X represents one or more hydrogen or halogen atoms or C a C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl or methylenedioxy group or X forms a naphthyl group with the phenyl ring, provided that R and X cannot simultaneously represent a hydrogen atom, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that a compound of formula (II) R '-] / N-OH (II) v 25 wherein R' is a nitrogen protecting group such as a 4-nitrobenzoyl group, a benzoyl group which may be substituted, a benzyl group which may be substituted, or an alkyl group, is reacted with a compound of formula (III) wherein y is a reactive radical such as chlorine or bromine, after which the protecting group R 'is removed unless it is the same as R, or optionally substituted 16 77850 the benzoyl protecting group is reduced, or a compound of formula (I)! is reacted with a compound R 2, wherein Z is a reactive group capable of introducing a radical R, and the compound of formula (I) thus obtained, if desired, is converted into an acid addition salt with a pharmaceutically acceptable acid. 17 77850 For the preparation of 4-benzyloxy- or 4-naphthylmethoxypiperidines, active as an antidepressant 5 and an active form In (I) £> '- <> 10 color R är väte, C 1-4 -alkyl, hydroxy-C C 1-4 -alkyl, C 1-4 -alkoxycarbonyl, phenethyl, 3-phenylpropyl, or a benzyl group, optionally substituted by halogen or C 1-4 -alkoxy, X is a substituent or a halogenate-halogenate-15 mer or C 1-4 alkyl-, C 1-4 alkoxy-, trifluoromethyl- or methylenedioxy groups or X -bars with phenyl rings and naphthyl groups under the same conditions, in which R 1 and X icke can be used as an enriched atom, as well as a pharmaceutically acceptable drug, Figure 20 for the preparation of formula (II) ΛΛ R'-Yί Y- OH (II) 25 color R 'är en skyddsgrupp förve, säsom en 4-nitrobenzo-ylgrupp, en benzoylgrupp, vilken kan vara substituerad, en benzylgrupp, vilken can be substituted by an alkyl group, having the same meaning as in formula (III) 30 _ Y-CH2- / \ (III) X color Y is not rea ktiv radical, in the case of chlorine or Brom-35 Atom, a different radical group R 'is optionally substituted on the same side as R, or optionally substituted benzoyl radical group reducers, or in the form of a formulation