DE2112868A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Dr. V / S- ¹ ,! K, Dio ^1. · !. - P. We &

Γ. ^J ~ '' ■ -rjr'iu

Cr. P. , ....., λ--,, .λ Güdel

6 Fra.i!.: U .-: .- '» ^l w Cr. Essiionhelmer Str. 39

S ^ NDOZ A.G.

Basel / Switzerland Case 10G-326Q

Process for manufacturing; new heterocyclic compounds

The invention relates to a process for the preparation of the new compounds of the formula I in which R, represents hydrogen or a lower alkyl group and FU for hydrogen, fluorine, chlorine, bromine, a lower alkyl or lower alkoxy group or an -NK-CO-iU group, v / orin R., means a lower alkyl group, and their acid addition salts, as well as the compounds of the formula I and their acid addition salts.

Erfiridun _: jSr; emäs3 the compounds of the formula I are obtained by compounds of the formula II, v / orin R, has the above meaning, in the presence of an acid-binding agent with compounds of the formula III, where R _{2 has the} above meaning and X { stands for the acid residue of a reactive ester, condenses, and the compounds of formula I obtained are converted, if desired, into their acid addition salts.

As far as R., R ^ and R- stand for lower alkyl groups, exist these preferably have 1-3 carbon atoms.

According to a preferred embodiment of the process, the \ iu.iintz \ ut 'is lower than a di (lower) alkylamide in a solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene, toluene or xylene

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aliphatic monocarboxylic acids such as dimethylformamide or a chlorinated aliphatic hydrocarbon v / ie chloroform or carbon tetrachloride,

Alkali metal carbonates, for example, can be used as acid-binding agents v / ie potassium carbonate or sodium carbonate, tertiary amines such as triethylamine or pyridine or an excess of the compounds the formula. II can be used.

In the compounds of the formula III, X is, for example Chlorine, bromine or the acid residue of an organic sulfonic acid such as an alkylsulfonyloxy or arylsulfonyloxy group, preferably but CMor. This can be used to speed up the reaction The reaction mixture is heated and / or mixed v / ground, preferably at 50-70 ° or at the boiling point of the Reaction mixture and with stirring.

In practice, the method according to the invention can be carried out, for example by adding the compounds of formula II and the acid-binding Agents e.g. an alkali metal carbonate, preferably potassium carbonate, in solvent v / ie toluene or dimethylformamide enters, the compound of the formula III. is added and the reaction mixture is then heated, e.g. with stirring, if necessary to the boiling temperature of the reaction mixture, and after the reaction has ended, the compound of the formula I by known methods isolates and, if necessary, cleans.

The compounds of the formula I can be converted into their acid addition salts and vice versa. ".

Of the compounds of the formula II, the compound of the formula Ha is known. The compounds of the formula lib, in which R,

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stands for a lower alkyl group are new and can be obtained v; ground by one of the compounds of the formula IV, v.'orin R, Has the above meaning, splits off the benzyl group. This cleavage of the benzyl group can be carried out, for example, by the compound of the formula IV is catalytically in a solvent which is inert under the reaction conditions, e.g. in glacial acetic acid hydrogenated, preferably using a Palladia analyzer at slightly increased pressure and slightly increased temperature (e.g. at 5 atmospheres / 60 °).

The starting compounds of formula IV can be prepared, for example d by nan 1-Benzy3 .- '- piperidone in the presence of a AlkalimctaD lamids such Lithimnamid, in a solvent inert under the Keaktionsbedindungen solvent, for example in liquid ammonia and / or cd abs . Ether, abs. Tetrahydrofuran is reacted with γ-lactones of the formula V, in which R ^ has the above meaning, and the resulting reactant product is hydrolyzed, for example with aqueous ammonium chloride solution.

So far the preparation of the starting compounds has not been described these are known or by methods known per se or analogous to those described here or analogous to those known per se Process can be produced.

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The compounds of the formula I and their pharmacologically acceptable ones Acid addition salts have and can have interesting pharmacodynamic properties with low toxicity therefore used as a remedy.

They have analgesic properties that can be found in mice, for example in the "hot plate" test and by inhibiting the phenylbenzoquinone syndrome and in monkeys in the monkey tail test [D. Römer, Proceedings of the International Symposium on Pain, Paris, April 1967 in "Pain", Academic Press, New York, London (I968) pp. I65 - 170] manifest.

The doses to be used naturally vary depending on the type 4 of the substance used, the administration and the condition to be treated. In general, however, in test animals satisfactory results with a dose of 4 to 30 mg / kg body weight received; this dose can, if necessary, be administered in 2 to 3 portions or as a sustained-release form. For larger mammals, the daily dose is around 30 to 150 mg. For oral applications, the doses contain about 10 to 75 mg of the compounds of the formula I in addition to solid or liquid carriers. Due to their analgesic effectiveness, the substances can be used for treatment used by pain of various origins. The 3- [1- (4-p-fluorophenyl-4-oxobutyl) -4-hydroxy-4-piperidyl] dihydro-2 (3H) - proves to be particularly suitable furanon.

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As a remedy, the new compounds or their physiological Compatible acid addition salts administered alone or in a suitable drug form with pharmacologically indifferent auxiliaries will.

In the following examples, which explain the invention in more detail, however, should not limit their scope in any way, all temperatures are given in .Celsius degrees and are uncorrected. · ■

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SPIE l 1:

A mixture of 18.5 g of dihydro- (4-hydroxy-4-piperidyl) -2 (3K) -furanone, 20.0 g u> - chloro-4-fluorohutyrophenone and 13.8 g potassium carbonate in 300 rr.l toluene is stirred for 3 hours to the boil heated. The inorganic salts are filtered off and the filtrate is washed with water and the organic phase is dried on F.agnesium sulfate and the solvent evaporated. Lian loosens the remaining residue in ethanol and mixed with the calculated amount of ethanolic hydrochloric acid. ! inch addition of Ether crystallizes the hydrochloride of the title compound from m.p. 170-172 °.

Example 2: Dihydro-3-l ^ -hydroxy-1 - (^ - oxo-A-phenylbutyl) -4-

The solution of 20.0 g of dihydro-3- ( ² i-hydroxy-4-piperidyl) -2 (3H) -furanone in 100 ml of dimethylformamide is stirred with the solution within one hour at a temperature of 60 ° of 14.7 g of ur-chlorobutyrophenone in 50 ml of dimethylformamide were added. The reaction mixture is left to react for a further 5 hours at 60 ° C. and the reaction mixture is then diluted with 1 × 0 ml of benzene. The hydrochloride of the excess dihydro-3- (^ -hydroxy.-4-piperidyl) · 2 (3H) -furanone, which crystallizes out after long standing in the refrigerator, is filtered off and washed with ether. The combined filtrates are concentrated on a mixture '/ cn 200 g of ice and 5 ml. Ammonium hydroxide solution poured. It is extracted three times with benzene, the extracts are washed three times with ice water, dried over magnesium sulfate and the solvent is evaporated off. The remaining crude base is dissolved in acetone, close to the calculated f. ^J "ethanolic hydrochloric acid and ether to turbidity rr.it added. The Fiohhydrojhlorid thus obtained is used to

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further Reini ^ uni- au :. ^; ! - "ethanol uncrystallized; reads and enters the pure title substance as hydrochloride vorr. Srnp. 223-225 ° (decomp.) ·

piporidylldihydro-2 i ^ -H-f

Dihydrc-3- ^/ 4-hy.iroxy-4-piperidyl) -2 (3H) -furanone is setr.t according to the method described in Example 2 with ^ -chloro-p-brcn.butyrophonon urr. ^ Esetr.t. Reaction time 14 hours at 60 °. Srr.p. des Ilydrochlorids the title compound 223-220 ° (dec.) (from methanol)

Example ¹ 1 : 3- Γ1- (^ P-Chlorophenyl - ^ - oxobutyl) -4-hydroxy- ^J _ipiperidyl] _dihydro-2 (3H) -furanone

Dihydro-3- ( ² i-hydroxy-4-piperidyl) -2 (3H) -furanone is uretted with 4-chloro-p-chlorobutyrophenone according to the method described in Example 2. Reaction time 14 hours at 60 °. Sn ; p. of the hydrochloric acid of the title compound 199-201 ° (decomp.) (from kethanol / ether)

Example '^:

piperidyi] _aihyaro-2 ^ 3H) -furanori

Dihydro-3- (4-hydroxy-4-piperiayl) -2'3H) uranium is replaced by the method described in Example 2 with 4-chloro-n-fluorotutyrophenone. Reaction time 14 hours at 60 °. Mp. L5l-l63 of the hydrochlorides ^c ( 'dec.) (From methanol / ether).

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Example 6; ^ ψί ^ Ε ^ Ζ ^ Ζίζΐ ^ ΐ ^ ΐζ ^ ζί ^ Ζ ^^ Ζ ^ ΖΖ ^^ ϊ ^^ Υ ^ Ιζ
4-piperidyl] -2 (3H) -furanone

Dihydro-3- (4-hydroxy-4-piperidyl) -2 (3H) -furanone is prepared by the method described in Example 2 with ^ -chloro-o-methylbutyrophenone ur. set. Reaction time 14 hours at 60 °. Mp. Of the hydrochloride of the title compound 105-167 ° (from methanol / Ether).

Example 7: Dihydro-3- [4-hydroxy-1- (4-oxo-4-m-tolylbutyl) -4-piperidyl] -2 (3H) -furanone

Dlhydro ~ 3- (4-hydroxy-4-piperidyl) -2 (3H) -furanone is after Process described in Example 2 with 4-chloro-m-methylbutyrophenone implemented. Reaction time 5 hours at 60 °. Mp, of the hydrochloride of the title compound 166-170 ° (from methanol / acetone).

Example 3; 3- C1 "C4-o-anisyl-4-oxobutyl) - <'j - hydroxy-4-piperi> dy 1 | dihydro-2 (3H) -_ furarion

Dihydro-3- (4-hydroxy-4-piperidyl) -2 (3H) -i'uranon viird after Process described in Example 2 with 4-chloro-o-methoxybutyrophenone implemented. Reaction time 5 hours at 60 °. M.p. of the hydrochloride of the title compound 165-163 ° (from methanol / Acetone / ether),

Example 9: 3- [1- (4-p-Anisyl-4-oxobutyl) -4-hydroxy-4-piperidyl] ^c jihydro-2 (3H) - f ^u ranon_

Dihydro-3- (4-hydroxy-4-piperidyl) -2 (3H) -furanone is reacted with 4-chloro-p-methoxybutyrophenone according to the method described in Example 2. Reaction time 5 hours at 60 °. M.p. of the hydrochloride of the title compound 212-210 ° (decomp.) (From
Methanol).

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Example 10: Dihydro-3 - [^ - hydroxy-l- (^ -oxo -'- tp-tolylbutyl) -

Dihydro - ^ - (^ - hydroxy-4-piperidyl) -2 (3H) -furanorx is reacted with 4-chloro-p-methylbutyrophenone according to the method described in Example 2. Reaction time 1 hour at βθ °. Mp. Of the title compound 107-109 ° (from benzene / petroleum ether).

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HO

N-CH ₂ -CH ₂ -CH ₂ -CO - ^ *

HO

R.

II

Ha

Man

X-CH ₂ -CH ₂ -CH ₂ -CO- /

III

■ I-CH \\ / 7

IV

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Claims (4)

2112,368 - 11 - 100-3260 Claims: 1. Process for the preparation of new compounds of the formula I, in which R, for hydrogen or a lower alkyl group and Rp for V.'asEcrstof f, fluorine, chlorine, bromine, a lower alkyl or lower alkoxy group or a -IJII-CO- R -.- grrr-pe, where R means a lower alkyl group, and their acid readdit!. ^ N. ^r ; nal ".c, characterized in that compounds of the? orr: .ol II, in which R has the above meaning, in the presence of an acid-binding agent with compounds of the formula III in which R has the above meaning and X stands for the acid residue of a reactive ester, condensed, and the compounds of formula I obtained are, if desired, converted into their acid addition salts. 2. The method according to claim 1, characterized in that one an equivalent excess of the compounds of the formula II is used as the acid-binding agent. 109 «42/1957 ÖAD ORlGfNAt 2112368 - 12 - 100-3260 / FRG 3. Compounds of the formula I in which R, represents hydrogen or a lower alkyl group and Rp for hydrogen, fluorine, chlorine, Bromine, a lower alkyl or lower alkoxy group or a -NH-CO-R ^ .- group, in which R is a lower alkyl group, stand, and their acid addition salts. 4. Remedies characterized in that they have compounds of the formula I. 3700 / US / CZ 109842/1957