NO761682L - - Google Patents

Description

The present invention relates to new 4-diphenylbutyl-1-piperidines, their acid addition salts and a process for their production.

The new piperidines have the general formula

wherein R and R are H, alkyl of 1-5 carbon atoms, alkoxy of 1-5 carbon atoms, F, Cl, Br or CF 3 and R 2 is H or acyl of 2-19 carbon atoms. The method according to the invention refers to the production of the new ketones with the formula I, whereby one (a) reacts a 4-benzoylpiperidine having the formula

with a connection with the formula

I I

in which Y is halogen, preferably Br, or another reactive group such as to form the compound and introduces -OH or -OAc in the 4-position of the piperidine group, preferably by bromination to form which is then debrdmerized with e.g. NaOMe in MeOH for I formation of and hydrolyzes to form compound I (R2= H) and optionally acylates the hydroxy compound (R2= acyl) or (bl) converts the 4-benzoylpiperidine•

where X is OH or OAc,

with compound III to form compound I,

(b2) reacts the benzoyl piperidine with the compound

in which Y has the indicated meaning,

for formation of

I I

and selectively reduces to obtain compound I, or (cl) reacts compound III with or an ester thereof to form

transfers the carboxyl group or its ester to the acid chloride and performs a Friedel-Crafts reaction with AlCl₂ and the present benzene derivative to form the compound IV,

(c2) reacts a compound VIII in the same way and reduces the products to form the compound X.

Of the methods described above, (a) is the most appropriate, and the synthesis of all compounds can be carried out according to this method.

The compounds used

IN

is synthesized according to French patent document M 3695 (CA, 66, 115,709).

The benzoyl piperidine

which is known from J. Med. Chem. , 13 (1) (1970), p. 1, and the new 4-benzoyl-4-hydroxypiperidine VII used in the method according to the invention can be prepared according to the following reaction sequence, whereby one starts from

(la) a Friedel-Crafts reaction of

' I ' I

wherein R_ is acetyl or methyl and an R^-substituted benzene in a suitable solvent, such as nitrobenzene, or in an excess of the reactant R^-benzene to give after which the acetyl group is cleaved (XI, R^= CH3CO) with 5-N HCl to form the compound II, (lb) performs a Grignard reaction with 4-cyano-pyridine and a phenylmagnesium bromide to form the 4-benzoylpyridine XII is either hydrogenated over a platinum catalyst to form the 4-piperidylaryl carbinol

wherein R is H,

or is first benzylated or methylated to form the corresponding 1-benzyl (or methyl)-4-aroylpyridine halide and then hydrogenated in the above-mentioned manner to form the compound XIII (R3=benzyl, CH3).

I I

The impure 4-aroylpiperidine XI (R 3 = CHj.,, benzyl) is transferred to the hydrobromide. The compound XI (R3 = H) is then acetylated

The compound XI (R 3 = CH 3 , benzyl, CH 3 CO ) is dissolved in a suitable solvent such as CHCl 3 ^ or CC 4 . and brominated with Br 2 to form

after which the product is recrystallized and treated with NaOMe in MeOH. After addition of water and evaporation of MeOH, the compound can be extracted with ether. The impure compound XV is hydrolyzed in ethanol with concentrated hydrochloric acid to form the compound

The compound XVI (R3= CH3CO) is precipitated with H20. After alkalizing, extraction with CHCl3 or benzene and drying the solution over Na2SC>4, the compound XVI (R3 = CH3, benzyl) can be precipitated in the form of a salt. in

The new compound VII can be prepared by

In (2a), the acetyl group (XVI, R 3 = CH3CO) splits off with. 5-N HCl, j (2b) selectively hydrogenates the benzyl group (XVI, R-, =

benzyl) over a palladium catalyst,

(2c) demethylates (XVI, R., = CH^) with ethyl chloroformate and subjects the product to acid hydrolysis.

In reaction (a), the benzyl piperidine II is reacted with the compound III in a suitable solvent, either a non-polar solvent, such as benzene or xylene, or a polar solvent, such as dimethylformamide or isobutyl acetate. The reaction is preferably carried out in the presence of an acid-binding agent, such as triethylamine or K CO. , possibly in an autoclave at

o

75-150 C.

After the coupling reaction, the products are usually treated with water or 1-N NaOH and extracted with ether, Bu-Me ketone, etc. From the dried solution, the hydrobromides or hydrochlorides can be precipitated and recrystallized. Even the impure product can be used for further reactions.

The hydrobromide is dissolved in a suitable solvent, such as CCl^ or CHCl^, and brominated with Br^ to form the compound V

and heated without further purification together with NaOMe in a suitable solvent, such as chloroform or MeOH, under mild conditions, such as at 25-60°C. After addition of water and evaporation of the solvent, the compound VI can be extracted with ether. The impure compound is hydrolyzed in ethanol with concentrated hydrochloric acid, preferably at room temperature. After alkalization, extraction with ether and dilution of the solution over Na 2 SO 3 , the compound I can be precipitated in the form of a salt with pharmaceutically acceptable acids, such as hydrochloric acid or hydrobromic acid, oxalic acid, maleic acid or tartaric acid.

The compounds obtained according to the invention have been subjected to a series of pharmacological tests.

In the following series of pharmacological tests, the new compounds are compared with

The following pharmacological tests have been carried out:

Tests 1-5 and the significance of the coordination of the compounds are described in detail in the following literature.

1. Inhibition of aggressive behaviour

Valzelli, L., AggressiveBehaviour

Eds. Garattini and Sigg, p. 70 (1969)

Valzelli, L., Neuro-Psycho-Pharmacology Ed. Brill, p. 781 (1967)

i-2. Inhibition of climbing van Rossum, J.M. et al, The Neuroleptics, Modern. Problem 1

of Psycho-Psychiatry, vol. 5, p. 26 (1970)

Kneip, P., Arch. Int. Pharmacodyn, 126, 238 (1960) Sandberg, S., Arzneimittelforschung, 9, 203 (1958)

.3. Amphetamine antagonism

Randrup, A. et al., Acta Pharmacol. (Kph), 20, 145 (1963) Randrup, A'., The Neuroleptics, Modern Problems of Psycho--Psychiatry, vol. 5, p. 60 (1970)

4. Cataleptogenic effect

Rossum, J.M. et al, The Neuroleptics, Modern Problems of

Psycho-Psychiatry, vol. 5, p. 26 (1970)

Stille, G., Switzerland. With. Wochenschrift 99, 1645 (1969) 5. Inhibition of conditioned avoidance behavior "Neuroleptics characteristically interrupt the response to the warning stimulus (avoidance) without at the same time interrupting the response to the noxious stimulus (escape) which follows it".

An Introduction to Psycho-Pharmacology,

Eds. Rech and Moore, New York, p. 264 (1971) Courvoisier, S. et al, Arch. Int. Pharmacodyn., _9_2, 305

(1953)

Jacobsen, E., Psychotrophic Drugs,

Eds. Garattini, Ghetti, Amsterdam, p. 119 (1957) Jacobsen and Sonne, Acta Pharmacol. & Toxicol. 11,

pp. 135-147 (1955).

In separate experiments carried out on monkeys, these compounds produce few or no extrapyrimidal side effects, in contrast to, for example, haloperidol and chlorpromazine, which easily and at low doses produce such side effects.

The duration of activity of these compounds is approximately 24 hours, a value comparable to that of pimozide, while the duration of activity of haloperidol and chlorpromazine is approximately 6-8 hours.

The toxicity of the present compounds is rather low, namely from about 350 to over 800 mg/kg. For the sake of comparison

it should be mentioned that the toxicity for haloperidol is 80 mg/kg

and for chlorpromazine 280 mg/kg.

The antipsychotic effect, which is shown by test 3, is confirmed

further through the blocked apomophorin-induced emesin in dog.

Because of these beneficial properties, the new compounds are suitable for the treatment of certain disorders in humans, such as schizophrenia, mania, anxiety and aggression. The general tranquilizing properties also make these new compounds suitable for veterinary medicinal applications.

The new compounds are preferably in the form of their salts, such as hydrochlorides and hydrobromides. This is also the best form for pharmaceutical preparations. Other pharmaceutically acceptable addition salts can be prepared from the hydrochlorides via the bases. For oral use, the compounds are usually administered in the form of tablets.

Tablets can be prepared in a conventional manner by mixing one of the new compounds in the form of an acid addition salt with usual carriers and auxiliary substances such as talc, mag- . nesium stearate, starch, lactose, gelatin and growth glue (gums).

The following composition is suitable for tablet formulations: 0.1-1 g 4-(p-fluorobenzoyl)-4-hydroxy-1-[4,4-(di-p-fluorophenyl)--butyl]-piperidine oxalate 9 g potato starch

1 g of colloidal silicon oxide.

2 g talc

0.2g magnesium stearate

2.5g 5% water solution of gelatin.

This mixture is sufficient for 100 tablets and each has a content of 1-10 mg of the active compound.

The hydrochlorides dissolve easily in water/i-propanol, which makes the compounds particularly valuable as they can be administered parenterally by injection. For parenteral injection, the following solution is suitable: 5-500 mg of 4-(p-methylphenyl)-4-hydroxy-1-[4,4-(di-p-fluorophenyl)--butyl]-piperidine hydrochloride is dissolved in 50 ml water and 50 ml i-propanol, containing 0.6 g NaCl. The obtained solution is filled into ampoules, each of which contains 2 ml of solution and 0.1-10 mg of the active compound. The ampoules are sterilized.

The pharmaceutical compositions can also. contain other therapeutically usable substances than the new diphenylbutyl piperidines.

The invention is illustrated in more detail by means of the following example, in which the indicated temperatures denote degrees Celsius.

Example 1

a) 4-(p-fluorobenzoyl)-l-[4,4-(di-p-fluorophenyl)butyl]-piperidine hydrobromide

A stirred mixture of 6.2 g (0.030 mol) 4-(p-fluorobenzoyl)-piperidine, 9.8 g (0.035 mol) 4-chloro-1,1-(di-p-fluorophenyl)-butane, 10 g of anhydrous sodium carbonate, 0.15 g of potassium iodide and 250 ml of isobutyl acetate are heated under reflux for 85 hours. The mixture is filtered and the filtrate is concentrated under vacuum. The oil obtained as a residue was concentrated in ether and the hydrobromide precipitated with HBr/ethanol. The reaction product was purified by recrystallization in ethanol/ether. Yield 12.8 g, melting-I point 14 7°..

b) 4-bromo-4-(p-fluorobenzoyl)-l-[4,4-(di-p-fluorophenyl)butyl]-piperidine hydrobromide

A solution of 10.6 g (0.020 mol) of 4-(p-fluorobenzoyl)-4-1-[4,4--(di-p-fluorophenyl)butyl]-piperidine in 50 ml of chloroform was treated with 3,4 ml of bromine. The reaction mixture was allowed to stand for 17 hours at room temperature. The solvent and excess bromine were removed under reduced pressure. The residue was dissolved in a solution containing 6.5 g of phenol in 100 ml of methanol and the solution diluted with anhydrous ether to precipitate 4-bromo-4-(p-fluorobenzoyl)-1-[4,4-(di- The p-fluorophenyl)butyl]-piperidine hydrobromide. The reaction product' was purified by recrystallization in methanol/ether. Yield 10 g, melting point 160°.

c) 2-(p-fluorophenyl)-6-[4,4-'(di-p-fluorophenyl)butyl]-2-methoxy-■-1-ox-6-azaspirof"2,5]octane

A solution of 10.0 g (0.019 mol) of 4-bromo-4-(p-fluorobenzoyl)-1-[4,4-(di-p-fluorophenyl)butyl]-piperidine hydrobromide in 35 ml of methanol was added to a solution of sodium methoxide prepared from 3 g of sodium in 35 ml of methanol. The mixture was heated under reflux for 4 hours and the bulk of the methanol removed

under reduced pressure. Water was added and the remaining methanol removed under reduced pressure. The aqueous layer was extracted with ether and the extract dried over sodium carbonate. Removal of the ether gave the impure 2-(p-fluorophenyl)-6-[4,4-(di--p-fluorophenyl)butyl]-2-methoxy-1-ox-6-azaspiro[2,5]octane.

Yield 6.7 g.

d) 4-(p-fluorobenzoyl)-4-hydroxy-l-[4,4-(di-p-fluorophenyl)-butyl]-piperidine-oxalate

A mixture of 4.8 g (0.010 mol) of 2-(p-fluorophenyl)-6-[4,4--(di-p-fluorophenyl)butyl]-2-methoxy-1-ox-6-azaspiro[2 ,5]-octane, 5 ml of concentrated hydrochloric acid and 30 ml of ethanol were stirred for 10 minutes. Water was added and the bulk of the ethanol I removed under reduced pressure. Neutralization with sodium carbonate and extraction with chloroform gave impure 4-(p-fluorobenzoyl)-I -4-hydroxy-1-[4,4-(di-p- fluorophenyl)butyl]piperidine. The base obtained was dissolved in ethanol and the oxalate precipitated with oxalic acid dissolved in ethanol. The reaction product was purified by

recrystallization from ethanol. Yield 4.4 g, melting point 214°.

Example 2

4-(p-fluorobenzoyl)-4-propionyloxy-1-[4,4-(di-p-fluorophenyl)-butyl]- piperidine hydrochloride 2 g of the impure base from 1d) were dissolved in 20 ml of propionic anhydride and a catalytic amount of 4-dimethylaminopyridine was added. After 10 hours at 20°, the solvent was evaporated. The evaporation residue was dissolved in ethyl acetate/ether and treated

with HCl/ethanol. The hydrochloride obtained was recrystallized from ethanol. The melting point is 246-248°.

Example 3

4-(p-methylphenyl)-4-hydroxy-l-[4,4-(di-p-fluorophenyl)butyl]-piperidine hydrochloride

was synthesized in the same way as in example 1. The hydrochloride has a melting point of 120-122°.

Example 4

1-Acetyl-4-bromo-4-(p-fluorobenzoyl)-piperidine

A solution of 36.0 g (0.145 mol) of 1-acetyl-4-(p-fluorobenzoyl)-piperidine in 175 ml of CHCl 2 was treated with 15 ml of bromine. The mixture was heated under reflux for 1 hour and gave

stand overnight at room temperature. The precipitated 1-acetyl-4-bromo-4-(p-fluoro-benzoyl)-piperidine was collected by filtration and recrystallized from ethanol. Yield 40.6 g, melting point 156-159°.'

Example 5

6- acetyl- 2-( p- fluorophenyl)- 2- methoxy- l- ox- 6- azaspiror 2, 5]-- octane

■ I- . IN

32.8 g (0.10 mol) of 1-acetyl-4-bromo-4-(p-fluorobenzoyl)-piperidine was added to a solution of sodium methoxide prepared from 12.8 g of sodium in 400 ml of methanol. The mixture was heated under reflux for 2 hours. Water was added and the methanol removed under reduced pressure. The aqueous layer was extracted with ether and the extract dried over sodium carbonate. Removal of the ether gave the impure 6-acetyl-2-(p-fluorophenyl)-2-methoxy-1-ox-6-azaspiro[2,5]-octane. Yield 24.2 g.

Example 6

1-acetyl-4-(p-fluorobenzoyl)-4-hydroxypiperidine

A mixture of 21.3 g (0.076-mol) 6-acetyl-2-(p-fluorophenyl)-2-methoxy-1-ox-6-azaspiro[2,5]-octane, 140 ml ethanol and 27 ml concentrated hydrochloric acid was stirred for 15 minutes. Water was added. The precipitated solid was collected by filtration and recrystallized from ethanol/ether to give 19.0 g of 1-acetyl-4-(p-fluorobenzoyl)-4-hydroxy-piperidine. Melting point 146-149°.

Example 7

4-(p-fluorobenzoyl)-4-hydroxy- piperidine hydrochloride

A solution of 18.6 g (0.070 mol) of 1-acetyl-4-(p-fluorobenzoyl)-4-hydroxy-piperidine in 60 ml of 5-N HCl was heated under reflux for 15 hours. The bulk of the water was removed under reduced pressure. Ethanol was added and the solution cooled. The precipitated solid was collected by filtration and recrystallized from ethanol to give 16.5 g of 4-(p-fluoro-benzoyl)-4-hydroxy-piperidine hydrochloride. Melting point 241-243°.

Example 8

4-( p- fluorobenzoyl)- 4- hydroxy-[ 4, 4-( di- p- fluorophenyl) butyl]-- piperidine- oxalate

A stirred mixture of 11.0 g (0.050 mol) 4-(p-fluorobenzoyl)-4-hydroxy-piperidine, 16.9 g (0.060 mol) 4-chloro-1,1-(di-p--fluorophenyl )-butane, 20 g of anhydrous potassium carbonate and 300 ml

in

isobutyl acetate was heated under reflux for 60 hours. The mixture was filtered and the filtrate concentrated in vacuo.; The oil obtained as a residue was dissolved in ethanol and the oxalate precipitated with oxalic acid dissolved in ethanol. The crude product was purified by recrystallization in ethanol. Yield 15.0 g, melting point 214°.

Claims (1)

Starting material for use in the production of a piperidine with the formula where R and R^ are H, alkyl of 1-5 carbon atoms, alkoxy of 1-5 carbon atoms, F, Cl, Br or CF3 and R 2 .is H or acyl of '2-19 carbon atoms, preferably alkanoyl, such as acetyl or stearoyl, and pharmaceutically acceptable acid addition salts thereof, characterized in that it has the general formula: wherein R and R^ have the meanings given above and where X means -OH or -OAC