DE1670186B - p-Alkoxy-piperidine-amides and process for their preparation - Google Patents

Description

HN

OR ₄

(III)

R, R ₁

-CH = CH-CO-N

in which R ₁ , R ₂ and R _{3 are} either a substance or chlorine atom, a methyl or methoxy group and R _{4 is} an alkyl radical containing 1 to 3 carbon atoms.

2. Process for the preparation of the compounds according to claim 1, characterized in that reactive acid derivatives of the general formula II are used in a manner known per se

CH = CH = CO-X III)

in which R _{+ has} the meaning given above. implements. As starting compounds of the general for-

mel II come in particular the halides, azides, Anhydrides and imidazolides in question: the ones that are easily and inexpensively accessible are preferably used Acid chlorides. A base such as triethyiamine is generally used to query the acid released in the process or excess p-Alkoxypv ^ cridin der general formula III to.

The production process is explained in more detail in the following examples.

B e i s ρ i e 1 1

1- (3.4.5-trimethoxy-cinnamonyl) -4-methoxy-piperidine

14.2 g of 3,4,5-trimethoxycinnamoyl chloride in 180 ml of benzene are added to a mixture of 13.9 g of 4-methoxypiperidine and 65 ml of benzene. The mixture is refluxed for ¹ Z ₂ hours, cooled and shaken with water. The benzene solution is dried and evaporated. The residue is made from isopropanol

in which R ₁ , R ₂ and R _{3 have} the abovementioned meaning

and X is an easily cleavable reactive

Group represents, with p-alkoxypiperidines of 30 recrystallized.

general formula HI yield: 12g (64.5% of theory) l- (3.4.5-tri-

methoxy - cinnamoyl) - 4 - mcthoxy - piperidine mp 130-131 ⁰ C..

HN

(III)

in which R _{4 has} the meaning given above.

The invention relates to p-alkoxy-piperidin-amides of the general formula I.

RR ₁

CH = CH-CO-N

-OR ₄ (I)

in the R ₁ . R ₂ and R _{3 are} either a hydrogen or chlorine atom. a methyl or methoxy group and R ₄ denotes an alkyl radical containing 1 to 3 carbon atoms, and a process for their preparation.

The compounds of general formula I are new and are characterized by transquillisicrendc, anticonvulsant and sedative effects.

They are produced by methods known per se, by using reactive acid derivatives general formula II

CH = CH-CO-X (II)

in which R ₁ , R ₂ and R, the above meaning B is ρ ie 1 2

Hp-chloro-cinnamoylM-isopropoxy-piperidine

10.05 g (50 m MoDp-chloro-cinnamic acid chloride dissolved in 50 ml of anhydrous tetrahydrofuran. A solution of is at room temperature with stirring 7.16 g (50 mol) of 4-isopropoxypiperidine and 5.05 g (50 mol) of triethylamine in 50 ml of anhydrous tetrahydrofuran slowly added dropwise. After stopping the dropping? the stirring is continued for 2 hours. then the precipitate which has separated out is filtered off with suction and the filtrate is concentrated in vacuo. The residue will be in 100 m! Ether absorbed, the ether solution one after the other with saturated sodium carbonate solution. diluted hydrochloric acid and water, then washed dried and concentrated. The residue is recrystallized from cyclohexane.

Yield: 8.7 g (57% of theory) 1- (p-chlorocinnamoyl) -4-isopropoxypiperidine from Schm. 10 to 110 C.

Example 3

Mp-Chior-cinnamoylM-methoxy-pipcridine

10.05 g (50 m mol) of p-chloro-cinnamic acid chloride. 5.76 g (50 m mol) of 4-methoxypiperidine and 5.05 g (50 m mol) of triethylamine are as described in Example 3, implemented and processed. The crude product obtained is recrystallized from ethanol / water.

Yield: IUg (79% of theory) l- (p-chlorocinnamoyl) - 4 - methoxy - piperidine of m.p. 96 to 98 "C.

Example 4

1- (p-Methoxy-cinnamoyl) -4-methoxy-piperidine

9.8 g (50 m mol) of p-methoxy-ztmtamic acid chloride, 5.76 g (50 m mol) of 4-methoxypiperidine and 5.05 g (50 m mol) of triethylamine are, as described in Example 3, implemented and processed. The crude product obtained is after treatment with activated charcoal recrystallized from benzene / cyclohexane.

Yield: 9.0 g (66% of theory) 1- (p-methoxycinnamoyl) -4-methoxy-piperidine with a melting point of 101 to 103 ⁼ C.

Example 5

! - (m-Methoxy-cinnamon) -4-methoxy-piperidine

9.8 g of m-methoxycinnamic acid chloride, 5.76 g of 4-methoxypiperidine and 5.05 g of triethylamine are, as described in Example 3, reacted and worked up. The crude product is recrystallized from benzene cyclohexane.

Yield: 8.3 g (60% of theory) of I- (m-methoxycinnamoyl) - 4 - methoxy - piperidine mp 57 bis58 C. ^c.

Example 6

1- (3,4-Dimethoxy-cinnamonyl (-4-metho. \ y-piperidine

11.3 g of 3,4-dimethoxycinnamic acid chloride. 5.76 g of 4-methoxypiperidine and 5.05 g of triethylamine are implemented and worked up analogously to Example 3. The crude product is recrystallized from cyclohexane.

Yield: 9.8 g (64% of theory) 1- (3.4-dimethoxy-cinnamic) -4-methoxy-piperidine from m.p. 98 to lOr C.

Example 7

1- (p-Methyl-cinnamoyl) -4-methoxy-piperidine

9.0 g p-methylcinnamic acid chloride, 5.76 g 4-methoxypiperidine and 5.05 g of triethylamine are reacted and worked up analogously to Example 3. The raw product is recrystallized from Benzol'Cyclohexan.

Yield: 8.1 g (62% of theory) l- (p-methylcinnamoyl) - 4 - methoxy - piperidine from m.p. 89 to 91 C.

Example 8

1- (3,5-Dimethoxy-cinnamoyl) -4-methoxy-piperidine

A mixture of 4.2 g of 3,5-dimethoxycinnamic acid. 8.0 g oxalyl chloride and 150 ml absolute benzene It is refluxed for 2 hours. Then it is concentrated in a vacuum. still takes the residue twice with benzene and again narrowed. Finally, again with 200ml of absolute benzene added and slowly stirring a mixture of 2.3 g of 4-methoxypiperidine at room temperature. 2.02 g of triethylamine and 25 ml of absolute benzene tugetropfl. It is left to stand overnight and washed the reaction mixture first with sodium bicarbonate solution. then with 0.5 η hydrochloric acid and finally with water, whereupon it is dried with sodium sulfate. The residue obtained after the benzene has been distilled off is recrystallized from isopropanol. Yield: 4.9 g (81% of theory), melting point 115 to 118.degree.

Example 9 1- (3,5-Dimethoxycinnamoyl) -4-isopropoxypiperidine

In a manner analogous to that described in Example 8, 3,5-dimethoxycinnamic acid chloride is first prepared from 4.2 g of 3,5-dimethoxycinnamic acid and 8 g of oxalyl chloride. A mixture of 2.9 g of 4-isopropoxypiperidine, 2.02 g of triethylamine and 25 ml of benzene is added and the mixture is left to stand at room temperature overnight. Then, as in Example 8, work-up is carried out. After two recrystallizations from cyclohexane, 2.8 g (42% of theory) of 1- (3,5-dimethoxycinnamoyl) -4-isopropoxypiperidine are obtained. ^c C.

Test report

Th 118 = 1- (3,4,5-trimethoxycinnamoyl) -4-meth-

oxy-piperidine,
Ka 17 = 1- (p-methyl-cinnamoyl) -4-methoxy-

piperidine.
Ka 29 = 1- (p -chloro-cinnamoyl) -4-methoxy-

piperidine,

Ka 56 = 1- (p-methoxycinnamoyl) -4-methoxypiperidine,

Ka 57 = 1- (3,4-dimethoxycinnamoyl) -4-methoxy-

piperidine,
Ka 59 = l-fp-chloro-cinnamoylH-isopropoxy-

piperidine,
Ka 96 = 1- (m-methoxy-cinnamoyI) -4-methoxy-

piperidine,
A = 4- (3,4,5-trimethoxy-benzoyl) -morpholm.

The above compounds were made according to the following Methods studied.

1. Muscle relaxing effect (LD ₅₀ ED ₅₀ .
inclined plane)

The toxicity is determined as LD ₅₀ (mg / kg intraperitoneally) 24 hours after the injection of the test substances. The same T .--: re are placed 30 minutes after the injection on an inclined plane covered with fine wire with an incline of 80: those animals that slip within 1 minute are referred to as positive. From this, an ED ₅₀ - according to Li tchfield and Wilcoxon - is determined and the quotient LD ₅₀ / ED _{50 is} calculated. The larger this quotient, the better the specific muscle-relaxing effect.

2. Sedative effect (urethane sleep potentiation)

The potentiation of the narcotic effect of urethane is a measure of the sedative effect of a person

so connection. Here, mice are first injected subcutaneously with the test substances in various doses; 15 minutes later, 1 g / kg urethane is given ip. This is a sub-narcotic dose at which unbuckled animals only take side slides. The doses of the test substances are determined (after a further 15 minutes) at which 50% of the animals assume the supine position (ED ₅₀ ).

3. Anticonvulsant effect (inhibition of the
Pentamethylene octrazole stretching spasm)

10 mice / dose received the test substance ip and 30 minutes later 150 mg / kg pentamethylentetrazole sc. Pentamethylenetetrazole alone leads to tonic clonic cramps in an easily observable stretching spasm of the hind legs. The inhibition of this stretching spasm is assessed and the ED ₅₀ calculated according to L itchfic 1 d and Wilcoxon.

Effective doses in the mouse LD _5n or ED ₅ (I in mg / kg ip

A.
Th
Kn 118 Ka
Ka
Kii 17th Ka
Ka 29 .. 56 .. 57 59 96

Inclined plane LD _sn ED ₅₁₁ 24 hours] (.10 minul 1000 600 645 265 1000 500 100 100 150 150 150 150 350 100 350 200

LD "

ED ₅₁₁ inclined plane

1.7 2.4 2.0 1.0 1.0 1.0 3.5 1.8

Urethane sleep coating ED ₅₁

(30 minuieni

69

5.4
36

9.0
28
33
10
50

inhibition

Pentamethylene

leirazole stretching spasm

ED _5n

(30 minutes)

> 200 30 200 40 50 50 46 50

As can be seen from the table, the compounds according to the invention have a stronger sedating effect Effect as the well-known sedative 4- (3,4,5-Tnmethoxybenzoyl) -morpholine; partly the effect is up a power of ten better. The same applies to the anticonvulsant effect, while the muscle-relaxing effect Effect is roughly in the same order of magnitude. The new! - (3,4,5-trimethoxy-cinnamoylH-methoxy-piperidine, which also has a wider therapeutic range than 4- (3,4,5-trimethoxy-benzoylj-morpholine.

Claims (1)

Patent claims: 1. p-Alkoxy-piperidine-amides of the general formula I. have and X is an easily split off reactive group, with p-alkoxy-piperidines of the general Formula III