DE1289845B - 4- (4'-Hydroxy-4'-phenylpiperidino) -butyrophenones, their acid addition salts and processes for their preparation - Google Patents

Description

The invention relates to 4- (4'-hydroxy-4'-phenylpiperidino) -butyrophenones of the general formula I.

CO · CH, · CH, · CH,

/ - \ / OH NX
x / \ _Ar

in which R is either a hydrogen or halogen atom and Ar is an unsubstituted phenyl, a p-halophenyl or a p-tolyl radical, their pharmaceutically acceptable acid addition salts and processes for their preparation. , ·

The new organic bases form with a wide variety of inorganic and strong organic Acids suitable for therapeutic use, non-toxic salts, e.g. B. with sulfuric acid, phosphoric acid, Hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfamic acid, citric acid, lactic acid, Maleic acid, malic acid, succinic acid, tartaric acid, cinnamic acid, acetic acid, benzoic acid, gluconic acid and ascorbic acid.

The compounds according to the invention can in a manner known per se by reacting a Aroylalkyl halide of the general formula II

-CO-CH ₂ CH ₂ CH ₂ -halogen (II)

in which halogen means a halogen atom, -with one equivalent of a compound of the general Formula III

Γ

are prepared, where R and Ar have the meaning given above.

The reaction takes place in an inert solvent, z. B. in an aromatic hydrocarbon such as benzene, toluene or xylene, in a lower one Alkanol, such as ethanol, propanol or butanol, or in a lower alkanone, such as acetone or butanone or pentanone. In certain cases, the reaction can be effectively accelerated by increasing the temperature will.

The aroyl alkyl halides can be used in the from C. Van de Westeringh, B. Hermans, F. Raeymaekers and C. Van der Eycken in Ind. Chim. Beige 25, 1073-1076 (1960), described manner.

These intermediates can also be obtained by catalytic debenzylation of the corresponding Prepare l-Benzyl-4-arylpiperidin-4-ols. These alcohols are in turn by treatment of the corresponding aryl magnesium halides or aryl lithium compounds obtained with l-benzyl-4-piperidone and subsequent acid hydrolysis of the adduct.

The 4-arylpiperidin-4-oils can be prepared in such a way that the corresponding 4-aryl-1,2,3,6-tetrahydropyridine Treated with hydrogen bromide and the resulting 4-aryl-4-bromopiperidine to hydrolyze the corresponding 4-arylpiperidin-4-ol sated.

The new compounds according to the invention have valuable pharmacological properties. she are all powerful central nervous system depressants. They also have analgesic, antipyretic and spasmolytic properties.

In the following examples the amounts are given in parts by weight.

example 1

A mixture of 8.7 parts of γ-chlorobutyrophenone, 14.2 parts of 4-phenylpiperidin-4-ol and 0.1 part of potassium iodide in 150 parts of toluene is heated to 100 to 110 ° C. in a closed vessel The solid residue is treated with a mixture of water and ether. The ether layer is separated and added to the filtrate from the original reaction mixture. The combined toluene and ether solution is dried over anhydrous potassium carbonate, filtered and reduced to about one The concentrate is cooled, the resulting precipitate is filtered off and crystallized from diisopropyl ether. This gives l - () <- Benzoyl-propyl) -4-phenylpiperidin-4-ol with a melting point of 129 to 130 ¹¹ C.

The hydrochloride thereof is prepared in such a way that one.die toluene-ether solution after it has been dried treated with anhydrous hydrogen chloride gas. The salt precipitated in this way is filtered off and. recrystallized from 2-propanol. In this way, 1- () '- Benzoyl-propyl) -4-phenylpiperidin-4-ol hydrochloride is obtained having a melting point of about 182 to 184 "C. This compound has the following formula:

OH

CO - CH, - CH, - CH, - N

HCl

B e i s ρ i e 1.2

17 parts of 4- (p-chlorophenyl) -piperidin-4-ol and 9.9 parts of γ-chloro-p-fluorobutyrophenone are obtained according to ^f > 5 example! implemented. 1- [y (p-fluorobenzoyl) -propyl] -4- (p-chlorophenyl) -piperidine-4-oil (melting point 148 to 149.4 ° C.) and the corresponding hydrochloride with a melting point of approximately 226 to 227 are obtained , 5 "C.

Example 3

When using 15.3 parts of 4- (p-toluene) -piperidin-4-ol instead of the piperidine compound of Example 3, l - [) '- (p-fluorobenzoyl) propyl] -

4- (p-tolyl) -piperidin-4-ol-hydrochloride with a melting point of about 216 to 218 ^° C.

Example 4

When using 10.3 parts of y-chloro-m-chlorobutyrophenone instead of the γ-chlorobutyrophenone of Example 1, l- | j <- (m-chlorobenzoyl) -

propyl] - 4 - phenylpiperidine - 4 - Oil - hydrochloride with a melting point of about 228.5 to 229.8 ⁰ C.

If you use equivalent amounts of appropriate starting materials and proceed to the rest of the In the manner described above, the compounds listed below are also obtained:

Table 1
Pharmacological data (ED ₅₀ values in mpk se.)

OH

X ^ ti?

X Comparison Hot plate
attempt Erecting
reflex test Mouse ¹ ) Rotarod test anti-
more aggressive IW test Rat ² ) Dog ³ ) R. product: Pento-
barbital test anti-
Amphetamine- anti-
Apomorphine Cl 3-chloro-N- [3'- 2.2 11.0 Potent test 0.35 effect effect H F. (l "-oxyethyl- 0.84 1.5 0.26 1.2 0.60 0.30 0.043 0.06 F. Cl 4 "-piper-azi- 0.46 4.4 0.13 0.40 0.72 0.27 0.080 0.07 F. CH _:) nyl) -propyl] - 0.80 6.0 0.12 1.4 1.3 · 0.18 0.038 0.025 F. phenothiazine 0.09 0.023 0.030 1.3 5.0 0.46 0.75 0.18 0.50 0.16 0.04

Methods: Journal of Medic, and Pharmacol. Chemistry, 1, 286 (1959). ² ) Methods: Drug Research, 11, 819 and 932 (1961). Methods: Drug Research, 9, 765 (1959).

Tabel

pLJ

OH

Jump box test with dogs acute toxicity orally More therapeutic subcutaneous orally when trying • ED ₅₀ orally in dogs > 80 *) index > 1270 > 808 X ED ₅₀ subcutaneous (mg / kg) > 80 *) > 1633 > 258 (mg / kg) 0.099 ■ subcutaneous Cl 0.063 0.31 > 80 *) > 40 *) > 125 > 45 CH ₃ 0.049 > 80 *) Comparative product: 0.89 Perphenazine 0.16 > 20 *)

*) Highest dose tested: No case of mortality.

This table illustrates the following:

1. Strong neuroleptic effectiveness of the invention Butyrophenone derivatives in both modes of administration compared to perphenazine;

2. the relatively low toxicity of these compounds in dogs;

3. the superiority of the compounds according to the invention over the comparison substance ih in terms of the margin of safety (therapeutic index) in the same animals.

Claims (2)

5 6 ■ ... ■ Claims: 1. 4- (4'-Hydrbxy ^ 4'-phenyIpiperidino) -butyrophenones of the general formula I. -CO-CH ₂ -CH ₂ -CH ₂ -N OH Ar ' in which R is either a hydrogen or a halogen atom and Ar is an unsubstituted phenyl, a p-halophenyl or a p-tolyl radical means, as well as their pharmaceutically acceptable acid addition salts. 2. Process for the preparation of 4- (4'-Hydroxy-4'-phenylpiperidino) -butyrophenones of the general formula I, characterized in that a compound is formed in a manner known per se of the general formula II -CO-CH ₂ -CH ₂ -CH ₂ - halogen (II) in which halogen means a halogenator, with at least one equivalent of a compound of the general formula III H-N _Ar (III) converts, where R and Ar have the meaning given above, and the resulting products optionally converted into their pharmaceutically acceptable acid addition salts.