NO743683L - - Google Patents

Description

Procedure for the production of new triazolinone derivatives

The present invention relates to a process for the production of 1-[3-((+)-m..chlorophenyl-1-piperazinyl)-propyl]-3,!+-diethyl-<A>9-1,2,<L> r-triazolin-5-one of structural formula I

and its pharmacologically acceptable salts. The compounds of formula I

can be used as a salt with inorganic acids, e.g. hydrochloric acid, sulfuric acid, phosphoric acid etc. or with mono or polybasic aliphatic s-acids, e.g. formic acid, acetic acid, lactic acid, succinic acid, malonic acid, glutaric acid, adipic acid, tartaric acid, citric acid, maleic acid, fumaric acid etc. or with aromatic acids such as benzoic acid, salicylic acid,

pamoic acid, etc., or with sulphonic acids, e.g. rne tan sul. sulfuric acid, benzene sulfonic acid, toluene sulfonic acid, etc. or with sulfamic acid, e.g. cyclamic acid etc. The compounds of formula I exhibit remarkable pharmacological properties. A change in the animal's behavior was observed, which is typical for sedatives, and which is characterized by a sedative effect, a low reactivity to experimental

one

mentator and/or lowering of the motor activity. Furthermore, a hypotensive and analgesic activity was observed after administration of the compound of formula I, the former activity was observed both in normal rats and in experimentally hypertensive rats, and the latter activity was determined by phenylquinone -test or the tail-flick test.

Then the compound of formula. If it shows a low toxic activity in acute as well as chronic tests, it will be understood that the product can have an anxiolytic and a general calming effect in human therapy.

The new compound of formula I is prepared by

the well-known 3,<L>h-diethyl-A0-1,2,<L>i--triazolin-5-one is reacted with a suitable substituted piperazine according to the following reaction scheme:

where X is equal to halogen or another suitable leaving group, e.g. 0S02CH3, 0S02C6HlfCH3, OCgH^NC^, etc.

In this reaction, 3,^-diethyl-^p-1,2,<L>)--triazolin-5-one is first converted into a salt with alkali alcoholate or sodium amide or sodium hydride, and then heated in dioxane, benzene, alcohol, tetralin, dimethylsulfoxide, dimethylformamide for several hours.

The following reactions A and B can be used as alternative methods to the above-mentioned method:

In reaction scheme A, N-m.chlorophenyl-N'-halopropyl-piperazine is obtained from N-nuchlorophenyl-piperazine by adding a 1-bromo-3-chloropropane. First, an alkali salt of 3,^-diethyl-A2-1,2,<1>f-triazolin-5-one is treated with 1-bromo-3-chloropropane in a suitable solvent, e.g. alcohol. Next, 1-(1-(3-chloropropyl)-3 diethyl-A2-1,2,1+-triazolin-5-one is heated for several hours with N-m. chlorophenyl-piperazine in an inert solvent and with HC1 acceptor.

In reaction scheme B, the N-m,chlorophenyl-piperazine-propyl chain is built up on 3,^-diethyl-A2-1, 2,-1+-triazolin-5-one in 3 subsequent steps. In the first step, which is common to reaction scheme A, 1-(3-chloropropyl)-3,1+-diethyl-A2-1,2,^-triazolin-5-one is produced, where - after the product is heated with an excess of diethanol-amine, and 1-(3-t>is-hydroxy-ethylamino-propyl)-3,^--diethyl-A^-1,2,1+-triazolin-5-one are collected. Finally, the m-chlorophenyl-piperazine ring is built up on this compound first with thionyl chloride and then, without isolating the reaction product, with chloraniline.

Another available method for the preparation of • the compound of formula I is the reaction of 1-(3-morphoclino-propyl)-.351+-diethyl-A2-1,<2,>)-i-triazolin-5-one and - rn. chloraniline. For example, equimolar mixtures of the hydrochlorins or hydrobromides of the two compounds can be heated for several hours at 200 - 24-0 C without the use of solvent, after which the product is collected as described in example 6. l-(3-mor.folino-propyl) -3,Lf--diethyl-A2-1,2,<1>-i--triazolin-5-one, which has not been previously described, is obtained from 3,lf-diethyl-A2~1,2,h-triazoline -5-one by a reaction similar to that described in example no. 1. 3,1+-diethyl-A2-1,2,^-triazolin-5-one can also be converted to a salt with an alkali alcoholate or sodium amide, other solvents such as e.g. benzene, alcohols, dimethylsulfoxide, dimethylformamide can be used with the same results.

Another method available in the preparation of the compound of formula I consists in carrying out the reaction in acetone or 2-butanone solutions with solid potassium carbonate.

The compound of formula I is also obtained by addition to 1-(3-amino-propyl)-3,<1>+-diethyl-A2-1,2,<1>+-triazolin-5-one of a compound of the following formula W:

The reaction can be carried out either in solution (ie in an alkanol containing<*>+ or more carbon atoms), and heating the two main reagents for several hours, or without any solvent (by mixing the two reagents as halides and heating to 200 °C). 1-(3-aminopropyl)~3,1+-diethyl-A2-1,2,1-!--triazolin-5-one©r not be written in littera.turen. This is produced by reaction of 1-(3~chloropropyl)-3,Lt--diethyl-A2~1,2,)+-triazolin-5'-one with alcoholic ammonium solution, or by reaction of 35!+-diethyl-A0 -1,2,^--triazolin-5-one with N-(3-chloropropyl)-phthalimide and subsequent hydrazinolysis.

The compound of formula I is also obtained by cyclization of 2- [3- (!+-m. chlorophenyl-1-piperazinyl)-propyl]-Li--ethyl-1-propionyl-semicarbazide (VI). or by reaction of N-[3-(^-m. chlorophenyl-l-piperazinyl)-propyl ] ■-N<1->propionyl-hydrazine (VII) with ethyl isocyanate

The compound of formula VI is obtained by reacting the compound of formula VII with ethyl isocyanate as an intermediate and can be easily collected. The most suitable method for preparing the compound of formula VI, which is not described in the literature, is that described above. The compound of formula VI can also be prepared by adding N-m-chlorophenyl-N1-(3-chloropropyl)-piperazine to 1-propionyl-4-ethyl-semicarbazide. The simplest way to carry out the cyclization reaction is to heat the compound of formula VI on a water bath with an excess of dilute alkali solution. The reaction is carried out very easily in the course of l.hour.

The compound of formula I' can also be prepared by reacting 3-('+-m. chlorophenyl-1-piperazinyl)-propyl-hydrazine (VIII) with alkylpropionylcarbamate (IX) such as e.g. propionyl urethane.

where R = lower alkyl.

Equimolar mixtures of the two reagents are heated

for several hours in inert solvent with a dehydrating agent.

The compound of formula I is also prepared by ethylation of 1-[3-(Li--m. chlorophenyl-1-piperazinyl)-propyl]-3-ethyl-A2-1,2,'+-triazolin-5-one (X). The compound of formula (X) is not described in the literature, but can be prepared from 2-[3-(^-m.chlorophenyl-1-piperazinyl)-propyl]-semicarbazide (XI) by condensation with an active derivative of propionic acid, e.g. propionate or thiopropionate or alkyl propionimidate, propionic anhydride, propionamide or propionyl halide, and then by ring formation

or in one step, by reacting the compound of formula XI with a trialkyl orthopropionate.

The ethylation of the compound of formula X is carried out with diethyl sulfate or ethyl halide in an inert or aprotic solvent, or in water and in ethyl alcohol.

Finally, the compound of formula I can be prepared by replacing 3-ethyl-Ag-1,2,^-triazolin-5-one with its precursor, namely 1-propionyl-^-ethyl-semicarbazide (XII).

and by reacting the latter with N-m.-chlorophenyl-N<1->(3-chloropropyl)-piperazine. The reactions are preferably carried out in an inert solvent

with alkali for the ring formation of the open compound.

The pharmacological activity of the compound of

formula I was determined by the following well-known tests:

Effects on behavior (rats and mice)

Irwin, S. "Pharmacologic techniques in drug evaluation" - Year Book Medical Publishers, Chicago, 196^-, p. 36.

Effects on the conditioned reflex in mice

Bovet, D.; Gatti, G.L. and Frank, M. Sei. Rep. Ist. Super, Sanita, 1961, 1, 127.

Effects on spasms of serotonin (50/.ig/kg) and histamine (16/j.g/kg) in guinea pigs

Konzett, H. and Rossler, R. - Arch. Exp. Path. Pharmacol. , 19<>>+0, 7<1>.

The compound of formula I can be administered either alone or with an excipient all or type of administration and pharmaceutical practice s.

The compound of formula I can be administered orally in the form of tablets, containing starch or lactose as. excipient, or in the form of capsules, either alone or with excipients, or as an elixir or suspension containing a coloring agent or flavouring.

The compound of formula I can be injected intramuscularly or hypodermically. In order to achieve better results in the above-mentioned forms of administration, the compound of formula I can be more effectively used as a sterile aqueous solution in which other components can be dissolved, e.g. salts or■glucose to achieve isotonic solution. The compound of formula I may be administered alone or with other active ingredients.

Psychiatrists will easily choose the most suitable dose for each patient, taking age, weight and the patient's reaction into account.

In general, the daily dose will vary between 50 and 300 mg depending on the case to be treated, and each dose should contain approx. 25 mg of the compound of formula I.

.Example 1

62 g of 3,^-die thyl-^-1, 2,^f-triazolin-5-one was dissolved in 500 ml of anhydrous dioxane. 21 g of Nati in a j<r>0%- in. g oil suspension was added. The mixture was refluxed for 30 minutes, after which 119 g of N-m.-chlorophenyl-N'-(3-chloropropyl)-piperazine were added with stirring. The reaction mixture was refluxed for 20 hours. The solvent was evaporated in vacuo and the residue was collected with 2N HCl solution. The mixture was washed with ethyl ether to remove the hydric oil suspension and made alkaline with 50% K 2 CO 2 solution. The product was extracted with ethyl ether. The ether solution was dried, evaporated to dryness and the product was distilled in vacuo.

115 g of the compound of form] were obtained. IN

with melting point 230°C (0.5 mm Hg). The hydrochloride from isopropyl alcohol has a melting point of 197 - 198°C, the sulfate has a melting point of 178 - 180°C, the phosphate has a melting point of 16k - 166°C, the maleate has a melting point of 122 - 123°G, the benzylate has a melting point of 132 - 133°C, and p- the toluenesulfonate has a melting point of 127 - -129°C

Example 2

To 0.98 g of Na in 20 ml of metbylacohol solution, 6 g of 3,<!>+-diethyl-A2-1,2,<L>i--triazolin-5-one were added and then 6.6 g of 3~ bromochloropropane. The mixture was boiled under reflux to neutral pH, was dissolved in water, extracted with ethyl ether after which the solvent was evaporated and the oily residue was distilled. The boiling point of 1-(3-chloropropyl)-3,If-diethyl-A2-1, 2,<1>+-triazolin-5-one is 121°C at 0.05 mm Hg".

Example 3

1 g 1-(3-chloropropyl)-3,Lf-diethyl-A2-1,2,<1>+-triazolin-5-one, 0.9 g m. chlorophenyl-piperazine and 0,<L>f6 g of triethylamine in 25 ml of toluene was boiled under reflux for 12 hours. 5N NaOH solution was added, the mixture was extracted with ethyl ether and distilled in a stream of steam. The residue from the distillation was extracted with ethyl ether after which hydrochloric acid ether was added to the ether solution. The precipitated hydrochloride obtained and crystallized from isopropyl alcohol was identical to the hydrochloride synthesized in Example 1.

Example

1.5 g of 1-(3-chloropropyl)-3,<1>+-diethyl-A2-1^2,<1>+-triazoliii-5-one and 1.5 g of diethanolamine were heated to 100°C in 15 hours.

10 ml of CHCl 2 and 0.5 g of Al 2 O 3 (II/III) were added to an organic solution. The mixture was filtered, the solvent was evaporated and the oily residue was distilled. 1,<*>+ g 1-(3-bis-hydroxyethylamino-propyl)-3,<L>(--diethyl-A2-i,2,<L>t-triazolin-5-one with boiling point 205 -

210°C at 0.1 mm Hg was obtained.

1.3 g of 1-(3-bis-hydroxyethylamino-propyl)-3, .beta.-diethyl-A2-1,2,<1>+-triazolin-5-one was treated with 1.3 ml of thionyl chloride in 30 minutes at 75°C. Excess thionyl chloride was removed in vacuo and the residue was dissolved in 30 ml of amyl alcohol. 0.75 g m.chloroaniline was added and the mixture was boiled under a stream of nitrogen at 150°C for 8 hours.

The basic layer was extracted and distilled in a steam stream. The residue from the distillation was extracted with ethyl ether and ether saturated with hydrochloric acid. The hydrochloride obtained (melting point 197 - 198UC from isopropyl alcohol) was identical to the hydrochloride which was synthesized in example 1.

Example 5

10 g of 3,Lf-diethyl-A2rl,2,L!--triazolin-5-one was dissolved in

150 ml of dioxane. 3A g of a 50% NaH suspension was added and then 12.5 g of (3-chloropropyl)-morpholine was added.

The mixture was refluxed for 18 hours. The solvent was collected by distillation and the residue was diluted with 2N NaOH and ether. The organic layer was dried and the solvent was removed. 1-(3-Morpholinopropyl)-3,^-diethyl-A2-1,2,<L>f-triazolin-5-one boils at 161°C at 0.3 mm Hg. The hydrochloride has a melting point of 175 - 176°C.

Example 6

An equimolar mixture of 1-(3-morpholinopropyl)-3,1+-diethyl-A2-1,2,1+-triazolin-5-one hydrochloride and m.chloroaniline hydrochloride was heated to 220°C for 1+ hours . The mixture was cooled, NaOH and ethyl ether were added and from the ether solution the compound of formula I was precipitated as hydrochloride with ethereal HCl. The product had a melting point of 197~198°C after crystallization

from isopropyl alcohol.

Example 7

One equivalent of 1-(3-aminopropyl)-3,*+-diethyl-Ap-1,2,^-triazolin-5-one, one equivalent of m„chloro-bis-(2-chloroethyl)-aniline and HCl acceptor, e.g. pyridine was heated I in sopentyl alcohol for 2 hrs. The solvent was distilled in a steam stream and NaOH aqueous solution and ethyl ether were added to the residue. The compound of formula I was precipitated as hydrochloride from the ether layer.

Example 8

Equimolar amounts of 1-(3-amino<p>ro<p>yl)-3,*+-dieth<y>l-Ap-1,2,Li--triazolin-5'-one hydrochloride and k— m Chlorophenylmorpholine hydrochloride was heated to 220°C for h hours. N/10 NaOH solution and ethyl ether were added, and the compound of formula I was precipitated as hydrochloride with ethereal HCl from the organic layer.

Example 9

Equimolar amounts of N-[3-(^-m.-chlorophenyl-l-piperazinyl)• propyl]-N'-propionyl-hydrazine (melting point = 56 - 58°C) and ethyl- . isocyanate was dissolved in dioxane solution at room temperature. After 30 minutes, h% KOH aqueous solution was added and the mixture was heated for 30 minutes in a water bath. The solution was concentrated in vacuo and the residue was extracted with ethyl ether. The ethyl ether was evaporated and the product was distilled in vacuo. The resulting compound of formula I boiled at 220°C at 0.2 mm Hg.

The hydrochloride had a melting point of 197 - 198°C after crystallization from isopropyl alcohol.

Example 10

1 mol of 3-(Li--m. chlorophenyl-1-piperazinyl)-propyl-hydrazine, 1 mol of ethylpropionylcarbonate, 0.3 mol of PpOc- and 1500 ml of xylene were heated for 5 hours at 115°C. The mixture was cooled, filtered and the solution was concentrated in vacuo. The residue was extracted with

ether, the solvent was distilled off and the residue redistilled in vacuo. The resulting compound was boiled at 230°C at 0.5 mm Hg.

Example II

5 g of benzaldehyde semicarbazone was suspended in 100 ml of anhydrous dioxane. 1.25 g of sodium amide was added and the mixture was refluxed for 1 hour. The mixture was discarded after which 9.2 g of 1-m.chlorophenyl-'+-(3-chloropropyl])-piperazine in 1,100 ml of dioxane were added and the mixture was boiled under reflux and stirring for 18 hours. The solvent was distilled from in vacuo after which ice water and benzene were added to the residue. The organic layer was dried and evaporated. The oil obtained (15 g) was dissolved in 100 ml of cyclohexane-ethyl acetate (2:1) mixture. When the solution was allowed to stand, a small amount of the starting material was precipitated, and the solid material was separated by filtration. The solution was concentrated to <*>+0 ml. A precipitate crystallising from ethyl acetate was obtained. The compound, the benzal derivative of 1-[3-C+-m.chlorophenyl-1-piperazinyl)propyl]-semicarbazide has a melting point of 1'+9 - 1^ 1° C. The semicarbazones were hydrolyzed with oxalic acid and the benzaldehyde obtained under the reaction was distilled in a steam strbm. Thus, 2-[3-(h-m.chlorophenyl-1-piperazinyl)-propyl]-semicarbazide was obtained as a single product shown by thin-layer chromatography and which was analyzed as oxalate. (Melting point 175°C).

Example. 12

2-[3-(^-m-chloro-phenyl-1-piperazinyl)-propyl]-semicarbazide was refluxed with excess triethyl orthopropionate for 8 hours. The mixture was concentrated in vacuo and 1-[3-C-t-m was obtained. chlorophenyl-1-piperazinyl)-propyl]-3-ethyl-Ap-1,2,<L>(--triazolin-5-one) was separated. This compound was slowly suspended in an excess of 2.5 g of NaOH and an equivalent amount of ethyl sulfate was added with stirring keeping the temperature below 50° C. The mixture was heated on a water bath for 30 minutes and then cooled. -3, Lt— diethyl-Ap-1, 2,*+-triazolin-5-one was extracted with ether and isolated by distillation in vacuo.

Example 13

12h g of N-m.chlorophenyl-N'-(3-chloropropyl)-piperazine hydrochloride, 96 g of l-propionyl-^-ethyl-semicarbazide, 62 g of solid KOH in powder form or in small pieces, 2 or 3 g of HpO were suspended in 900 ml xylene. The azeotropic mixture was refluxed and the solvent was recycled. The reaction was carried out over the course of 3 hours, after which the chlorine base was no longer present. The mixture was cooled, washed several times with HO, after which the layers were

parried. The organic layer was decolorized with activated carbon and then concentrated in vacuo. To the residue was added 600 ml of isobutyl alcohol and then gaseous HCl.

The hydrochloride of 1-L3-('+-m.chlorophenyl-1-piperzinyl)-propyl]-3,<L>h-diethyl-Ap-1,2,<1>+-triazolin-5-one was precipitated. It then crystallized out and became isobutyl alcohol. Yield: 100 g.

Claims (10)

1.. Procedure for the preparation of 1-[3~(^-m.chlorophenyl-1-piperazinyl)-propyl [-3 ,'+-d i ethyl-Ap-1, 2, Li--triazolin-5-one ( I) and its pharmacologically acceptable salts, characterized in that 35)+-diethyl-Ap-l,2,<l>f-triazolin-5-one is reacted in an inert solvent with a l-m.chlorophenyl.l-<!>+- (3-halopropyl)-piperazine, 2. Procedure for the preparation of 1-[3~ (Li~m. chlorophenyl-1-piperazinyl)-propyl]-3,'+-diethyl-A2-1, 2, h-triazolin-5-one (I) and its pharmacologically acceptable salts, characterized in that 1-bromo-3-chloropropane is added to 3,^--diethyl-Ap-1,2,<1>+-triazolin»5-one, the isolated product is reacted with N-m.chlorophenyl-piperazine in a inert solvent. 3. Procedure for the preparation of 1-[3-(Lf--m. chlorophenyl-1-piperazinyl)-propyl]-3, k- å i ethyl-Ap-1,2,!+-triazolin-5-one (I) and its pharmacologically acceptable salts, characterized in that 1~(3-chloropropyl)-3 j1!— diethyl-Ap-1, 2,^-triazolin-5-one is heated in an over shot of diethanolamine, and that the compound obtained is first mixed with thionyl chloride and then with rn.chloroaniline. h. Process for the preparation of 1-[3-(^--m. chlorophenyl-l-piperazinyl)-propyl]-3,1-(-~diethyl-A0-1,2,Lf-triazolin-5-one (I ) and its pharmacologically acceptable salts, characterized in that 1-(3-morpholino-propyl)-3,^--diethyl-Ap-1,2,!+-triazolin-5-ori halide is heated for several hours with equimolar amounts of rn .the chloraniline salt at temperatures below 200°C. 5. Procedure for the preparation of 1-[3-C+-m.chlorophenyl-1-piperazinyl)-propyl]-3,^-diethyl-Ap-1,2,<1>+-triazolin-5-one (I) and its pharmacologically acceptable salts, characterized in that 1-(3-aminopropyl) 3,<L>h~diethyl-Ap-1,2,<1>+-triazolin-5-one (IV) and a compound of formula are reacted either such as bases or halides. 6. Procedure for the preparation of 1-[Li--m„.chlorophenyl-1-piperazinyl)-propyl]-3,^-diethyl-A2-1,2,<L>i--triazolin-5-one (I ) and its pharmacologically acceptable salts, characterized in that N-[3-(^--m. chloro-phenyl-1-piperazinyl)-propyl]-N'-propionyl-hydrazine is added to ethyl isocyanate at room temperature and in an inert solvent, and that the obtained substituted semicarbazide is cyclized by heating in a dilute alkali solution. 7. Procedure for the preparation of 1-[3-( h- ra. chlorophenyl-l-piperaziriyl)-propyl]-3,14--diethyl-Al-1,2,li--triazolin-5-one (I ) and its pharmacologically acceptable salts, characterized in that 3-(^--m. chloro-phenyl-1-piperazinyl)-propyl-hydrazine is heated in an inert solvent with alkylpropionylcarbamate in the presence of a dehydrating agent. 8. Process for the production of 1-[3-(^-m.chlorophenyl-1-piperazinyl)-propyl]-3,1-i--diethyl-A2-1,2,1+-triazolin-5-one ( I) and its pharmacologically acceptable salts, characterized in that an ethylating agent is added to 1-[3-(^--m. chlorophenyl-1-piperazinyl)-propyl ]-3~ ethyl-Ap-1, 2,!+ -triazolin- 5~one. 9. Process for the preparation of 1-[3-'-+-m.chlorophenyl-1-piperazinyl)-propyl]-3,1'-diethyl-A2-1,2,<1>f-triazolin-5-one ( I) and its pharmacologically acceptable salts, characterized in that 2-[3-( h~m.chloro-phenyl-l-piperazinyl)-propyl]-semicarbazide is heated with a trialkyl orthopropionate for successive ethylation by the method described in example 12. 10. Process for the production of 1-[3-C+-m.chlorophenyl-1-piperazinyl)-propyl]-3,<!>+-diethyl-A2-1,2,<L>i-~triazolin-5~ on (I) and its pharmacologically acceptable salts, characterized in that a 1-m.chlorophenyl-Li-(3-halopropyl)-piperazine is added to 1-propionyl-^-ethyl-semicarbazide in an inert solvent with alkali.