CH618167A5 - Process for the preparation of 1-(3-4-m-chlorophenyl-1-piperazinyl)propyl-3,4-diethyl- DELTA (2)-1,2,4-tria zolin-5-one - Google Patents

Description

618167

2

CLAIMS 1. Process for the preparation of l- [3- (4-m.chloro-phenyl-l-piperazinil) -propyl] -3,4-diethyl-A2-l) 2,4-triazolin-5-one of formula (I)

H5C2

2H5

Said process is characterized in that 3,4-di-ethyl-A2-1> 2,4-triazolin-5-one is reacted with a 1-m. chloro-phenyl-4- (3-halogenopropyl) -piperazine in an inert solvent.

The object of this invention is another and new process for the preparation of 1 / 3- (4-m. Chlorophenyl-1-piper-azinyl) -propyl / -3,4-diethyl-A2-1, 2 , 4-triazolin-5-one, of formula (I)

N N

(//

/ \

.N-CH CH CH.-M N

2 2 2

/ V "'

10

H5C2 - t2H5

and its pharmacologically acceptable salts, characterized 15 by the fact that o laN- [3- (4-m. chlorophenyl-1-piperazinyl) -propyl] - N'-propionyl-hydrazine of formula (II)

ç // c n-ch2ch2ch2-n

CD,

C.H CO

2 5I

NH

THE

• ci and its pharmacologically acceptable salts.

20

nh-ch ch ch -n "\ /

r ^ .rx a «

it is reacted with ethyl isocyanate at room temperature in an inert solvent and that 2- [3- (4-m. chlorophenyl-l-piperazi-nyl) -propyl] -4-ethyl-1-propionI-semicarbazide of formula ( III)

C2H5 "CO

NH

c2h5-nh-co-n-ch2ch2ch2n ^ n,

(III)

formed is cycled by heating it in diluted alkaline solution, or 3- (4-m. chlorophenyl-1-piperazinyl) -propyl-hydrazine of formula (IV)

(I) can be used in the form of salt with mineral acids such as, for example, hydrochloric, sulfuric, phosphoric acid, etc., or with mono or pluricarboxylic halitatic acids such as, for example, formic, acetic, lactic, succinic, malonic acid , 25 glutaric, adipic, tartaric, citric, maleic, fumaric, etc., or with aromatic acids such as, for example, benzoic, salicylic, pamoic, etc., or with mandelic, diphenylacetic, benzolytic acid, etc., or with sulfonic acids, such as methanesulfonic acid, benzenesulfonic, toluene sulfonic, etc., or with sulfamic acids, 30 such as cyclamic acid, etc.

(I) revealed some interesting pharmacological properties. Above all, it is interesting to note a modification of the animal behavior, which is typical of tranquilizers and is characterized by sedation, a reduced activity towards the experimenter and a lower motor activity. Furthermore, with (I) a hypotensive and analgesic action is observed; the first is evident both in the normal and experimentally hypertensive rats, the second is evident in the phenylquinone test and in the tail pinch test. Since (I) 40 is scarcely toxic, both in acute and chronic tests, it is possible to hypothesize an interest as an anxiolytic and generally as a tranquilizer in human therapy.

A preparation process of (I) consists in the reaction between the already known 3,4-diethyl-A2-1, 2,4-triazolin-5-one and an appropriate substituted piperazine-45, according to the scheme:

n n ~ ch2ch2ch2-nhnh2

(IV)

vx

C2HS

50

reacted with an alkyl propionyl carbamate of formula (V)

+ X (CH2) 3 - K

CO .. N1I

CaH, CONHCOOR

(V),

with R = lower alkyl,

heating for a few hours in inert solvent in the presence of a dehydrating agent.

2. Process according to claim 1, characterized in that the alkyl propionyl carbamate of formula (V) is propionyl urethane.

According to the Swiss patent No. 589 643, a process is already known for the preparation of l- [3- (4-m. Chlorophenyl-- l-piperazinil) -propyl] -3,4-diethyl-Ao-l, 2 , 4-triazolin-5-one.

55

where X = halogen, or other suitable outgoing group, such as, for example,

OSO..CH,

OSO2C0H4CH3, OCbH4NO2,

etc.

60

For this reaction, it is first necessary to salt the 3,4-dietiI-A2-1> 2,4-triazolin-5-one, for example with an alkaline alcoholate, or with sodiumamide or with sodium hydride, then heat the reaction mixture for a few hours in a solvent such as, for example, dioxane, benzol, alcohol, tetraline, dimethylsulfoxide, dimethylformamide.

Schemes A and B are shown below as alternative methods to the above process:

3

618167

to)

h5c2

CO.

C2H5

VM N

ï I

n

THE

nh h5c2.

2H5

n n

I I

CO-

-n-ch ch2ch2-c1

Cl

(THE)

b)

h5c2

, n c2h5

ch2ch2oh hn c0_— n-ch2ch2ch2ci

X

ch2ch2oh

W

11 ^

co.

MEMBERS

-N-cilch en K

sawn

^ ch ch oh

"/ T

2 v

(the)

In scheme A, the N-m. chlorophenyl-N'-halogenopropyl - piperazine is considered to be the sum of 1-bromo-3-chyoro-propane and N-m.-chyorophenyl-piperazine. First of all, a reaction is conducted between an alkaline salt of 3,4-dietsI-A2-1, 2,4 - triazolin-5-one and re-bromo-3-chloropropane in a suitable solvent such as, for example, alcohol . Subsequently l- (3 - chloropropiI) -3,4-diethyl-A2-1, 2,4-triazolin-5-one is heated for a few hours with N-m. chlorophenyl-piperazine in an inert solvent and in the presence of an HCl acceptor.

In scheme B the chain N-m. chlorophenyl-piperazine-pro-pilica is built on 3,4-diethyl-Av-1) 2,4-triazolin-5-one in three successive operations. The first, which is also common to scheme A, consists in the preparation of 1- (3-chloropropyl) - 3,4-diethyl -; \ L, -l, 2,4-triazolin-5-one. The product is then heated with excess of diethanolamine and 1 '- (3-bishydroxy-ethylamino-propyl) -3,4-diethyl - \., - 1,1,4-triazolin-5-one is isolated. Finally, the ring m is built on this compound. chlorophenyl-piperazine, by first treating the product with thionyl chloride and then with c. chloroaniline, even without isolating the reaction product.

so Another convenient method for the synthesis consists in reacting the 1 - (3-morpholinopropyl) -3,4-dietsI - / \ 2_ 1,2,4-triazolin - 5-one with m. chloroaniline. Equimolecular mixtures of the hydrochlorides or hydrobromates of the two compounds, for example, are heated for 200 hours to 200-240 ° C without solvent and the product 55 is isolated as described in Example 6. From 3,4-diethyl - A2 -l, 2,4-triazolin-5-one obtains l- (3-morpholinopropyl) -3,4-- diethyl-Air 1,2,4-triazoIin-5-one, not described in the literature, making a reaction similar to that described in Example 1. The 3,4-diethyl-A2-1,1-triazoIin-5-one can also be transformed into its salt with an alkaline alcoholate or with sodium-amide; and other solvents such as, for example, benzene, alcohols, di-methylsulphoxide, dimethylformamide, can also be used. Another convenient method consists in carrying out the reaction in acetone or 2-butanone solution in 65 presence of solid potassium carbonate.

(I) can be prepared by reacting Pl- (3-aminopro-pil) -3,4-diethyl-A2-1, 2,4-triazolin-5-one with a compound of formula

618167

4

CJK

i 2 s i l

CO ■ N ~ CH2CI, 2CH2NII2

/ CH2CH20H

where Y represents} {

^ CH2CH20H

The reaction is carried out either in solution, for example in an alkanol containing 4 or more carbon atoms and by heating the two basic reagents for a few hours, or without solvent by mixing the two reagents in the form of halides and heating at temperatures of the order of 200 ° C.

L- (3-aminopropyl) -3,4-diethyl -, \ - 1,2,4-triazolin-5-one is not described in the literature. It is conveniently prepared by reacting 1 '1 - (3-chloropropii) -3,4-diethyl-A2-1,2,4-triazolin - 5-one with alcoholic ammonia, or by reacting 3,4-diethyl- - / \ - l, 2,4-triazolin-5-one with N- (3-cIoropropil) -phthalimide, with subsequent hydrazinolysis.

2- [3- (4-m. Chlorophenyl-1-piperaziniI) -propyl] -4-ethyl-1-pro-pionyl-semicarbazide can also be prepared by the action of N-m. cIorofenil-N '- (3-chloropropyl) -piperazine on 1-pro-pionyl-4-ethyl-semicarbazide. As for the cyclization reaction, the simplest method for carrying it out is to heat the compound in a bain-marie with an excess of alkali luita solution. The reaction is completed very quickly in less than 1 hour.

(I) can also be prepared by ethylating l- [3- (4 - m. Chlorophenyl- l-piperazinil) -propyl] -3-ethyl-A2-1,2,4-triazolin - 5-one .

CI

CI

%

/

or, in a single step, by reaction of (XI) with a trialkyl orthopro-pionate.

Ethylation is conveniently carried out with diethyl sulphate or ethyl halides in inert or aprotic solvents or 25 in water and ethanol.

Finally, a last method consists in replacing 3,4-di-ethyl-A2-1, 2,4-triazolin-5-one with its precursor, namely I-propionyl-4-ethyl-semicarbazide,

30 C2H5CONHNHCONHC2H5 (XII)

and making the latter react with N-m. chloro - N '- (3-chloropropyl) piperazine.

The reaction is preferably carried out in an inert solvent 35 in the presence of alkalis which causes the cyclization of the open compound.

According to the invention, the process for the preparation of 1 - [3- (4-m. Chlorof enyl- l-piperazinil) -propyl] -3,4-diethyl-A2 - l, 2,4-triazoIin-5 -one of formula (I)

us

50

and its pharmacologically acceptable salts, is characterized in that either N- [3- (4-m. chlorophenyl-l-piperazinil) -propyl] - N'-propionyl-hydrazine of formula (II)

n h ch0c1

• cvh2c1

o N

V

20

H5C2 •

2H5

/ \

45

c //

_N-CH2CH CH2-N N

The latter compound is not described in the literature but can be prepared from 2- [3- (4-m. Chlorophenyl-1-piperazinyl) - propyl j-semicarbazide by condensation with an active derivative of propionic acid such as, for example, an alkyl propionate or thiopropionate or propionimidate, propionic anhydride, propionamidine or a propionyl-halide, followed by cyclization

55

CnH_CO 2 5 |

a

NH-CH2CH2CH2-K

(II)

V (: 0 [-CH2Cn2C, V

K !! "

it is reacted with ethyl isocyanate at room temperature in an inert solvent and that 2- [3- (4-m. chlorophenyl-1-piperazi-65 niI) -propyl] -4-ethyl-1-propionyl-semicarbazide of formula (III)

5

618X67

NH

C-.H.-NH-COr-N-CH ^ CH CH N

N

formed is cycled by heating it in diluted alkaline solution, or 3- (4-m. chlorophenyl-1-piperazinyl) -propyl-hydrazine of formula (IV)

we are reacted with an alkyl propionyl carbamate of formula (V)

C2H5CONHCOOR (V),

with R = lower alkyl,

heating for a few hours in inert solvent in the presence of a dehydrating agent.

(I) can be prepared by cyclization of 2- [3- (4-m. Chlorophenyl-1-piperazinyl) -propyl] -4-ethyl-1-propionyl - semicarbazyl

CI

-NH

\

n c-h.-nh-co-n-ch ch ch n which is chemically equivalent.

The pharmacological effect of the compound object of the present invention has been evaluated following the known procedures reported below:

Effects on behavior (rats and mice)

Irwin, S. "Pharmacologie Techniques In Drug Evaluation" -

Year Book Medicai Publishers, Chicago, 1964, p. 36

Effects on conditional reflexes in mice

Bovet, D .; Gatti, G. L. and Frank, M. - Sci. Reps. Super Ist.

Healthcare, 1961.1, 127.

Effects on spasms caused by serotonin (50 [xg./kg.) And histamine (16 (ig./kg.) In guinea pigs Konzett, H. and Rössler, R. - Arch. Exp. Path. Pharmakol., 1940 , 195.11.

The compound object of the present invention can be administered either alone or in a mixture with an excipient which is chosen according to the route of administration to be used and the current pharmaceutical practice, as is well known in the art.

The compound (I) can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing coloring or flavoring agents.

(I) can be injected parenterally, for example, intramuscularly or subcutaneously. For parenteral administration (I) it can be more effectively used in the form of a sterile aqueous solution which may contain other dissolved substances, for example salts or glucose in an amount sufficient to make the solution isotonic.

(I) can be administered alone or in a mixture with other active substances.

Regarding the dosage, the doctor in any case will easily be able to determine the most suitable one for each individual patient who will vary according to the age, weight and response of the particular patient. In general, the daily dose will be in the range of 50 to 300 mg. depending on the cases treated and a single dose will contain approximately 25 mg. of the active compound (I).

Example 1

G. 62 of 3,4-diethyl-A2 "l> 2,4-triazolin-5-one are dissolved in about 500 ml of anhydrous dioxane. 21 g of 50% NaH are added in oil suspension. 30 'to reflux and then add under stirring 119 g of Nm. Chlorophenyl - N' - (3-chloropropyl) -piperazine. The reflux is heated for 20 hours. At the end the solvent is removed under reduced pressure and the mixture is taken again. residue with 2N HCl. It is washed with ether to eliminate the oil of the hydride suspension and alkalinized with 50% K2CO3. It is extracted with ether, dried, the solvent is removed and distilled under reduced pressure. 115 of substance boiling at 230 ° to 0.5 mm. The hydrochloride crystallized from iso-propanol shows mp 197-8 °. The sulphate melts at 178-180 °, the phosphate at 164-6 °, the maleate at 122 -3 °, benzylate at 132-3 °, p.toluensulfonate at 127-9 °.

Example 2

To a solution of 0.98 g. of Na in 20 cm3 of methanol 6 g are added. 3,4-diethyl-A2-1, 2,4-triazolin-5-one and then 6,6 g. of 3-bromochloropropane. It is boiled under reflux to neutral pH, poured into water, extracted with ether, the solvent removed and the residual oil distilled off. L- (3-chloropropyl) - 3,4-diethyl-A2-l, 2,4-triazolin-5-one boils at 121 ° at 0.05 mm.

Example 3

1 g of l- (3-chloropropyl) -3,4-dietsI-A2-l, 2,4-triazolin-5-one, 0,9 g of m. chlorophenyl piperazine and 0.46 g. of triethylamine in 25 cm3 of toluene are boiled under reflux for 12 hours. The solution is taken up with NaOH 5N, extracted with ether, distilled in steam. The residue from the distillation is extracted with ether and the ethereal solution is treated with hydrochloric ether. A hydrochloride precipitates which is crystallized from isopropane and is identical to that prepared in Example 1.

Example 4

1.5 g of l- (3-chloropropyl) -3,4-diethyl-A2-l, 2,4-triazoIin-5 - one and 1,5 g. of diethanolamine are heated to 100 ° for 15 hours. The mixture is taken up in 10 cm3 of CHC13 and the solution is debated with 0.5 g. of A1203 (II / III). It is filtered, the solvent is removed and the residual oil is distilled off. We obtain g. 1,4 of l- (3-bishydroxyethyl-aminopropyl) -3,4-diethyl-A2-l, 2,4-triazolin-5-one which boils at 205-10 ° at 0.1 mm.

1.3 g. of l- (3-bishydroxyethylaminopropyl) -3,4-diethyl-A2 - 1,1,4-triazoIin-5-one are treated with 1.3 cm3 of thionyl chloride for 30 'at 15 °. The excess of thionyl chloride is removed in the rotary evaporator and the residue is dissolved in 30 cm3 of amyl alcohol. 0.57 g are added to the solution. of m. chlorine-aniline and boils at 50 ° in a stream of nitrogen for 8 hours. The basic part is extracted and distilled in vapor. The residue from the distillation is extracted with ether and treated with hydrochloric ether which precipitates a hydrochloride to m.p. 197-8 ° (from isopropanol), identical to that prepared in Example 1.

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618167

Example 5

10 g of 3,4-diethyl-A2-1,2,4-triazolin-5-one dissolve in 150 cm3 of dioxane. 3.4 g are added. of suspension at 50% NaH and then 12.5 g. of 4- (3-chloropropyl) -morpholine. It heats up 18 hours to relapse. The solvent is distilled off and the residue is taken up with 2N NaOH and ether. The organic layer is dried and the solvent is removed.

L- (3-morpholinopropyl) -3,4-diethyl-A2-1,2,4-triazoIin-5 - one boils at 161 ° at 0,3 mm. Hydrochloride shows m.p. 175-6 ° C.

Example 6

An equimolecular mixture of l- (3-morpholinopropyl) -3,4 - diethyl-A2-lj2,4-triazolin-5-one hydrochloride and m. chloroniline hydrochloride is heated to 220 ° for 4 hours. It cools, it is treated with NaOH and ether and from the ether solution it precipitates (I) in the form of hydrochloride with ether HCl. The product shows m.p. 197-8 ° after crystallization from isopropanol.

Example 7

An equivalent of l- (3-aminopropyl) -3,4-diethyl-A2-l, 2,4 - triazolin-5-one, an equivalent of m. chloro-bis- (2-chloroethyl) - aniline and an HCl acceptor such as pyridine, are heated in isopentanol for two hours. The solvent is distilled off in vapor and the residue is taken up in aqueous NaOH and ether. (I) is precipitated in the form of hydrochloride from the ethereal layer.

Example 8

Equimolecular amounts of 1 (3-aminopro-pil) -3,4-diethyl-A2-1, 2,4-triazolin-5-one hydrochloride and 4-m hydrochloride. chlorophenyl-morpholine are heated to 220 ° for 4 hours. The mixture is then taken up with 10N NaOH and ether. (I) is precipitated from the organic layer in the form of hydrochloride with ethereal HCl.

Example 9

(Invention)

Equimolecular quantities of N- [3- (4-m. Chlorophenyl-1-piper-azinyl) -propyl] -N'-propionyl-hydrazine (mp 56-8 °) and ethyl isocyanate are dissolved in dioxane solution at temperature environment. After half an hour a 4% aqueous solution of KOH is added and half an hour is heated in a water bath. The solution is concentrated under reduced pressure and the residue is extracted with ether. The ether is evaporated and the reaction product is distilled under reduced pressure. The compound (I) thus obtained boils at 220 ° at 0.2 mm.

11 hydrochloride shows m.p. 197-8 ° (from isopropanol).

Example 10

(Invention)

A mole of 3- (4-m. CIorofenil-l-piperazinil) -propiI-hydrazine, 1 mole of ethyl propionylcarbamate, 0.3 moles of P205 and 1500 cm :! of xylene are heated for 5 hours at 115 °. The solution is cooled, filtered and concentrated under reduced pressure. The residue is extracted with ether, the solvent is distilled off and the new residue is distilled under reduced pressure. The compound (I) thus obtained boils at 230 ° at 0.5 mm.

Example 11

5 g of benzaldehyde semicarbazone are suspended in 100 cm3 of anhydrous dioxane. 1.25 g are added. of sodium-amide and heated to 1 hour to reflux. It cools, 9.2 g are added. of 1-m. chlorophenyl-4- (3-chloropropyl) -piperazine in 100 cm3 of dioxane and heated to refluxing under stirring for 18 hours. The solvent is distilled off under reduced pressure and the residue is treated with ice water and benzene. The organic layer is dried and evaporated. There are 15 g left. of an oil which is dissolved in 100 cm3 of a mixture of cyclohexane and ethyl acetate 2: 1. By rest, a small amount of starting substance precipitates and is separated by filtration. The solution is concentrated to 40 cm3. A precipitate is formed which crystallizes from ethanol.

This substance, which is the benzal derivative of l- [3- (4-m. Chlorophenyl-l-piperazinil) -propyl] -semicarbazide shows m.p. 149-151 °.

The semicarbazone is hydrolyzed with oxalic acid, then distilling the benzaldehyde formed in vapor. 2- [3- (4-m. Chlorophenyl-1-piperazinyl) -propyl] -semicarbazide is thus formed which is a unique product in thin layer chromatography and is characterized in the form of oxalate m.p. 175 °.

Example 12

The 2- [3- (4-m. Chlorophenyl-1 - piperazinil) -propyl] -semicarbazide is heated to reflux for 8 hours with an excess of triethyl orthopropionate. It is concentrated under reduced pressure and the l- [3- (4-m. Chlorophenyl-l-piperaziml) -propyl] -3-ethyl-A2-lj2,4 - triazolin-5-one is formed and separated. This substance suspended in an excess of NaOH 2, 5N and an equivalent amount of ethyl sulfate is slowly added under stirring and keeping the temperature below 50 °. It is heated in a bain marie for half an hour and then it cools down. The l- [3- (4 - m. Chlorophenes I-1-piperazinyl) propyl] -3,4-diethyl-A2 "1,2,4-triazo-lin-5-one is extracted with ether and isolated for distillation under reduced pressure.

Example 13

G. 124 of N-m. cIorofenil-N '(3-chloropropyl) -piperazine hydrochloride, g. 96 of 1-propionyl-4-ethyl-semicarbazide, g. 62 of solid KOH, pulverized or in small pieces and g. 2 or 3 of H.O are suspended in mi. 900 of xylene. It is heated to reflux by distilling the azeotrope and recycling the solvent. The reaction is complete in about three hours, when the presence of the chlorobase is no longer highlighted. It is cooled, washed several times with H..O and the layers are separated. The organic layer, bleached on coal, is then concentrated under reduced pressure. The residue is taken up with about m. 600 of isobutanol and treated with gaseous HCl. Precipitates the hydrochloride of l- [3- (4-m. Chloro-phenyl-l-piperazinil) -propyl] -3,4-diethyl-A »-l, 2,4-triazolin-5-one. It is then crystallized from isobutanol. Yield 100 g in pure product.

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V