DE1470293B2 - Substituted 8- (4'-p-fluorophenyl-4'-oxobutyl) -2,8- diazaspiro- square brackets on 4.5 square brackets to decane-1,3-dione and their acid addition salts or processes for their preparation - Google Patents

Description

2. 2,4 - Dimethyl - 8 - (4 '- ρ - fluorophenyl - 4' - oxobutyl) - 2,8 - diazaspiro [4,5] decane -1,3 - dione and its acid addition salts.

3. A method for the preparation of compounds according to claim 1, characterized in that a substituted succinimide of the general formula II is used in a manner known per se;

(Π)

in which R ₁ and R _{2 have} the meaning given in claim 1, with a compound of the general formula III

χ-CH ₂ -CH, -ca-co

F (III)

in which X stands for chlorine, bromine or iodine, is reacted in the presence of an alkaline condensing agent and optionally the compound thus obtained by reaction with an inorganic one or organic acid is converted into the corresponding acid acetone salt.

4. Medicament consisting of a compound according to claim 1 or 2 and usual auxiliary and Träsersioffen.

Compounds of Formula A

CE ₁ -CK -, - (A)

! in which R is hydrogen, a lower alkyl or \ .z: as Hevlvriiäel, incL ^ Gondere as neuroleptics and

[the benzyl group ·; means and R 'especially For Anti ^ nycl-Cii · ^. in the treatment of various;

Fliior_ stands, _ are from the Austrian patent pcycLicsLti. Diseases used

script 227 690 known (see German Ausiegeschrift [übe.-rasclie.-derweisf: it has now been found that

1234 219). These connections have valuable 45 connections of the common forms

pharmalcodynamic properties jindkörmen d _? .- i -

R ₁ -N

N-CK ₂ -CK ₉ -CK, - CO ■

in which R _{1 is} a lower alkyl or benzyl group; und.R ₂ _eine_lower alkyl] -, _ die_ benzyl- or ^ dje; 55. / 3-phenylethyl group, and their acid addition / dietary salts represent even more effective remedies. ' The compounds of the formula I and their acid addition calcins can be prepared by adding, in a known manner, a substituted succinimide ¹ Cd of the general formula 1

in which R _{1 and} f ^ obigo have meaning, with a compound of the general formula III

X-CH-

K --- CH, -CO

(Π)

: 65 in the X ft '·.' Chlorine, lVrcm or iodine, reacts in the presence of an acidic condensing agent and gives the compound thus obtained by reaction with : i:. ^ L inorganic or organic acid into the corresponding acid addition salt convicted.

When reacting the compounds of the general formula II with the compounds of the general Formula III can be used as an alkaline condensing agent z. B. anhydrous sodium carbonate

turn around; but you can also use an excess of the base of general formula II.

The compounds of general formula I have not yet been described in the literature. It are colorless, solid crystallized substances at room temperature. With inorganic and organic Acids form stable salts that crystallize at room temperature, e.g. B. with hydrochloric acid, hydrobromic acid, Sulfuric acid, methanesulfonic acid, ethanesulfonic acid, _ p-toluenesulfonic acid, succinic acid Maleic acid, fumaric acid, malic acid, tartaric acid, cyclohexanecarboxylic acid or benzoic acid!

The succinic, the general formula U used as starting products can be prepared by known methods, for example as follows:

A compound of the general formula IV 'is used; · ...__. "_;

-CO-N

COO-alkyl

CH

CN (IV)

'CN.' ■■ · -. .

; '2O

25:

like [(l-Benzoyl-4-cyano-piperidyl) -4] -cyanessigsäure- I äthy lester, with a halide of the general! Formula R ₂ - halogen, e.g. B. with Methyljddid, Isöpropylbromid ^ -Butyljodid ^ enzylchlorid or ^ -Phejnyläthylbromid, in the presence of an alkali metal alcoholate. The compound of the general formula V obtained in this way

-CO-N

C — COO — alkyl CN (V) -

35

40:

■ · "CN

is with conc. Hydrochloric acid heated, with hydrolysis, · I decarboxylation and splitting off of the benzoyl group: takes place. If R _{2 is} a branched alkyl or diej 'benzyl group, it is preferred, however, to heat first in 5N hydrochloric acid (to split off the benzoyl group), then in an alkali and finally in a strong mineral acid, such as conc. Salt-; ; ₅₀ acid. The resulting succinic acids of the formula Vl '

CH-COOH

"COOH

(VI)

are now esterified, for example by about! 48 hours of refluxing in an over-! Shot of absolute ethanol saturated with hydrogen chloride gas. The resulting dialkyl esters are reacted with amines of the general form; m el R ₁ -NH ₂ as Met hylamin, Äth ylamine, benzyl \ zylamin etc. in succinimides of general research \ mel II übergef ührt. The "it takes place" z. B. in the way

I55 ¹

6oi that the component, dissolved in methanol, in; a pressure vessel for about 24 hours at 22O ⁰ C heated the reaction mixture to dryness! evaporated and the residue is for about ^l / ₂ hours under a weak nitrogen stream at normal! pressure heated to 200 ⁰ C; after another training; execution form, the ester is mixed with an aqueous solution of an excess of the amine of the all-; common formula R ₁ —NH ₂ , heated slowly to! to 260 ° C., the liquid gradually distilling off, and the reaction mixture is then heated to 260 ° C. for about 1 hour. The succinimides! 'of the general ^ formula. II can by distillation! in a vacuum; or by crystallization of their salts

getting cleaned. '^": ™ ~ :: ~~ ~' ^~~~: ~~ .7

The compounds according to the invention are distinguished by valuable pharmacodynamic properties with low toxicity and can therefore be used as medicaments . In particular, they exert peripheral and central effects on the nervous system and have sedative and neuroleptic properties . typical properties to perform the encryption |. lbindungen example, in animal experiments on mice zui iNarkosepotenzierung jund increase der_K.rampf-j ~ threshold you also inhibit "the ~ spontaneous ÄTctlvi-j did of mice n and the amphetamine-encryption! In addition, the substances inhibit the conditional escape reaction of the rat as well as the emotional reactions that occur during stress . Can rbindungen loos aufj due to their sedative and neuroleptic efficacy chischer diseases are used in 'treatment verschiedenster ^l psycho!,
i The port step effected compared to the state of the art is shown in the following test report:

i test report

According to the present invention produced ^ erbindungen are in the following with that of the Austrian patent specification 227 690 known j2 - methyl - 8 - (4 '- ρ - fluorophenyl -4' - oxobutyl) - 2,8 - di-'azaspiro [4,5] decane-1,3-dione compared:

Anesthesia- 'Acute ^: - . ■■ ·. ·. . . ... ·. '■ - ·: ■. · .- ■ - ■ · ■' "■ · '.. pbten2de- toxicity tion *)
ED ₅₀ mg / kg
mouse LD ₅₀ mg / kg
mouse
. substance 2,4-dimethyl-8- (4'-p-fluoro- 193 p. 0. phenyl-4'-oxobutyl) - 2,8-diazaspiro [4,5] decane 1.0 s. C. 350 p. 0. 1,3-dione , ■ ^; ■■■ - ■■ - -1 2-methyl-4-n-butyl- ■ '· .- ■' ■■ "'.:' ■■■ 8- (4'-p-fluorophenyl- 4'-oxobutyl) -2,8-diaza- 1.2 s. C. 247 p. 0. spiro [4,5] decane-1,3-dione .. 2-methyl-4-benzyl- 8- (4'-p-fluorophenyl- 4'-oxobutyl) -2,8-diaza- 1.05 s. C. - ^ spiro [4,5] decane-1,3-dione .. 2-methyl-8- (4'-p-fluoro- phenyl-4'-oxobutyl) - 2,8-diazaspiro [4,5] decane 1,3-dione (compar 4.3 s. C. substance)

*) Potentiation of barbiturate anesthesia

The test substance is administered subcutaneously to mice. 30 minutes later, the animals receive a subliminal dose of the sodium salt of 5-ethyl- ^: 5 - (1 '- methyl) - butyl - 1 - thiobarbituric acid (20 mg / kg! IV), ie a dose that is only used to trigger a! Anesthesia is insufficient. The duration of any sleep that may occur is determined and the ED _{50 is} defined as the dose at which 50% of the animals: Remain motionless in a lateral position for more than 2 minutes. ;

The compounds of the formula I or their physiologically acceptable acid · addition salts can be administered alone or in a suitable drug form with pharmacologically inert adjuvants. !

If the preparation of the starting compounds is not described, these are known or according to! methods known per se or analogously to those described here or analogously to methods known per se. ! drive can be produced. ■

In the following examples, which explain the invention in more detail, all temperatures are given in degrees Celsius; the melting points are corrected i.
j Example 1

[2,4-Dimethyl-8- (4'-p -fluorophenyl-4 ^ -oxobutyl) -2,8-diazaspiro [4.5] decane-1,3-dione

6.1 g of 2,4 - dimethyl - 2,8 - diazaspiro [4.5] decane | 1,3-dione (0.031 mol) and 3.8 g of 4-bromo-p-fluoro-butyrojphenone (0.015 mol) are in 20 ecm benzene while Heated to 80 ° for 24 hours. The precipitate is filtered off and the filtrate is evaporated ! Dry. The remaining dark oil is in ethanol added and mixed with gaseous hydrogen bromide until the solution is weakly acidic to the Congo j responds. It is precipitated with ether and recrystallized from ethanol / ether. 2,4-dimethyl-8- (4'-p-fluoro- ! phenyl - 4 '- oxo - butyl) - 2,8 - diazaspiro [4,5] decane-1,3-dione-hydrobromide melts at 205 °.

The 2,4-dimethyl-2,8-diazaspiro [4,5] decane-1,3-dione used as the starting product boils at 119 ° / 0.08 mm Hg; Mp. Of the hydrochloride 244 ° L ₅ (from ethanol / ether). Its manufacture is carried out like | Described above from [(I - Benzoyl - 4 - cyano - piperi-j dyl) -4] -cyanoacetic acid ethyl ester, methyl iodide and! Methylamine. . ;

, Example 2 '5 °

2-methyl-4-isopropyl-8- (4'-p-fluorophenyl-:

4'-oxobutyl) -2,8-diazaspiro [4,5] decane-1,3-dione

4.4 g of 2 - methyl - 4 - isopropyl - 2.8 - diazaspiro [4.5] - | decane-1,3-dione and 1.9 g of 4-chloro-p-fluorobutyropheynone are dissolved in 50 ecm abs. Xylene heated to boiling for 18 hours. The precipitate is filtered off, the xylene solution is evaporated off under reduced pressure at 60 ° and the residue is chromatographed on 100 g of neutral aluminum oxide. A yellowish-colored, viscous oil is eluted with a benzene / ether mixture, the oil is taken up in ethanol and the solution is treated with abs. ethanolic hydrochloric acid up to the Congo acid reaction. The resulting crystallized precipitate is then filtered off, the hydrochloric acid filtrate is concentrated to 10 ecm, 5 ecm of water are added and 2 g of sodium phthalene-1,5-disulfonic acid are heated to the boil.

The salt which crystallized out after standing for 18 hours melts at 270 to 272 ° and is pure 2-methyl-4 - isopropyl - 8 - (4 '- ρ - fluorophenyl - 4' - oxobutyl) -2.8 - diazaspiro [4.5] decane - 1,3 - dione - naphthalene-1,5-disulfonate represents. 1 mole of acid binds 2 moles of base. The 2-methyl-4 used as the starting product - Isopropyl - 2,8 - diazaspiro [4,5] decane - 1,3 - dione boils at 123 to 125 ° / 0.09 mm Hg. Its manufacture takes place as described above from [(1-benzoyl-4 - cyanpiperidyl) - 4] - ethyl cyanoacetate, isopropyl bromide and methylamine.

Example 1 3

: 2-methyl-4-n-butyl-8- (4'-p-fluorophenyl-

; 4'-oxobutyl) -2,8-diazaspiro [4,5] decane-1,3-dione

The connection is made by the same procedure as described in the previous example became. Bp 205-210 ° / 0.1 mm Hg; yellow viscous oil which crystallizes on cooling. To the To prepare the maleate, 1.7 g of the distilled compound are dissolved in 8 ecm of ethanol and mixed with 0.5 g maleic acid heated to the boil. After recrystallization from methanol / ether it melts 2 - methyl - 4 - η - butyl - 8 - (4 '- ρ - fluorophenyl - 4' - oxobutyl) - 2,8 - diazaspiro [4,5] decane - 1,3 - dione maleate at 153 to 155 °. 1 molecule of maleic acid binds I base molecule.

The 2-methyl-4-η-butyl-2,8-diazaspiro [4.5] decane-1,3-dione used as the starting product boils at 112 to 116 ^o / 0.12 mm Hg. It is produced as described above [(1-Benzoyl-4 - cyano - piperidyl) - 4] - ethyl cyanoacetate, n-butyl iodide and methylamine.

Example 4

2-methyl-4-benzyl-8- (4'-p -fluorophenyl-4'-oxobutyl) -2,8-diazaspiro [4,5] decane-1,3-dione

8.9 g of 2-methyl-4-benzyl-2,8-diazaspiro [4.5] decane-1,3-dione and 3.3 g of 4-chloro-p-fluoro-butyrophenone are in 100 ecm abs for 24 hours. Xylene heated to boiling. It is cooled and filtered "from the deposited colorless, crystallized precipitate (mp. 194 to 196 °), which from the Hydrochloride of the unreacted 2-methyl-4-benzyl-2,8-diazaspiro [4,5] decane-1,3-dione consists. The filtrate is washed once with water and then extracted twice with 75 ecm 15% tartaric acid-I each time solution. The combined tartaric acid extracts are made strongly alkaline with saturated potassium carbonate solution and takes up the product j, which has occurred as an oil, in chloroform. The chloroform is washed solution with water, dry it over sodium sulfate and evaporate the chloroform in vacuo Dry. The remaining yellow, viscous oil distills in vacuo at 25070.05 mm Hg. After recrystallization from ethanol, the 2-methyl-4-benzyl-18 melts - (4 '- ρ - fluorophenyl - 4' - oxobutyl) - 2,8 - diazaspiro [4,5] decane-1,3-dione at 95 to 96 °.

The 2-methyl-: 4-benzyl-2,8-diazaspiro [4,5] decane -1,3-dione used as the starting product boils at 150 ° / 0.5 mm Hg; the hydrochloride is clearly hygroscopic and, depending on the crystallization conditions (from methanol or ethanol), melts between 175 and 198 °. The production de r e Verbi invention rfolgt above-described n from [(l-benzoyl-4-cyano-pipefP

dyi) -4] -cyanessigsäureäthyiester, benzyl chloride and Methylamine.

Example 5

2-Benzyl-4-methyl-8- ^(4'-p-r fluorph enyl-4'-oxobutyl) -2,8-diazaspiro [4,5] decane-l, 3-dione

The production takes place according to the same process as already described. The compound forms a hydrochloride with a melting point of 206 ° to 208 ° after recrystallization from ethanol / ether.
; The 2-benzyl-4-methyl-2,8-diazaspiro [4,5] decane -1,3-dione used as the starting product boils at 160 to 170 ° / 0.1 mm Hg. Its preparation takes place as described above from [ (l-Benzoyl-4-cyano-piperi-] dyl) -4] -cyanoacetic acid ethyl ester, methyl iodide and benzyl lamin . .... .._ ..

Example 6

2-methyl-4 - (/ S-phenylethyl) -8- (4'-p-fluorophenyl-4'-oxobutyl) -2,8-diazaspiro [4,5] decane-1,3-dione

The production takes place according to the same process as already described. The connection forms a Naphthalene-1,5-disulfonate with a melting point of 258 ° to 260 ° after recrystallization from water. 1 molecule of acid binds 2 molecules of base.

The 2-methyl-4 - (ß - phenylethyl) - 2,8 - diazaspiro [4.5] decane -1,3 - dione used as the starting product boils at 180 to 190 ° / 0.08 mm Hg (temperature measured in an air bath ). It is of i as described above [(I - benzoyl -A- cyan -piperidyl) -4] -cyanessigsäureäthylester, / 3 Phenyläthylbromid and methylamine heritable provided.

409 525/429

Claims (1)

Patent claims:
1. 8- (4'-p-Fluorophenyl-4'-oxobutyl) -2,8-diazaspiro [4,5] decane-1,3-dione derivatives of the general formula I. N-CH ₂ -CH ₂ -CH ₂ - CO in which R _{1 is} a lower alkyl or benzyl group and R _{2 is} a lower alkyl, benzyl or / 3-phenylethyl group, and their acid addition salts.