DK154834B - 1,5-Diphenylpyrazoline derivatives - Google Patents

Description

λ DK 154834 Β

The present invention relates to novel 1,5-diphenylpyrazoline derivatives which are intermediates in the preparation of the novel 2-piperazinoalkyl-1,5-diphenylpyrazolin-3-one compounds and their acid addition salts.

Thus, the invention provides intermediates for the preparation of said 2-piperazinoalkyl 1,5-diphenyl-pyrazolin-3-one compounds.

It has now been found that the subject 1,5-diphenylpyrazoline-10 derivatives are valuable intermediates in the preparation of said 2-piperazinoalkyl-1,5-diphenylpyrazolin-3-one compounds which exhibit valuable pharmacological properties. , particularly pronounced antiallergic properties as well as blood pressure lowering properties, and the compounds possess an advantageous efficacy profile with good therapeutic width and low toxicity. These 2-piperazinoalkyl-1,5-diphenylpyrazolin-3-one compounds and their preparation from the subject intermediates are disclosed in Danish Patent Application No. 3723/82 (Danish Patent Application No. 149,947).

The present invention thus relates to 1,5-diphenylpyrazoline derivatives of the general isomeric formulas II and III.

2 DK 154834 B

R 1 represents hydrogen or halogen, R 5 represents hydrogen or halogen, R 1 represents hydrogen or halogen, R 2 represents hydrogen or halogen, Z represents an alkylene group of 2-4. carbon atoms, and Y represents halogen.

As halogen substituents in the phenyl rings may be mentioned especially fluorine, dhl'or or bromine ·

The group Z represents a straight or branched alkylene chain. with 2-4 carbon atoms.

The compounds of formula II or III or mixtures thereof can be reacted in a manner known per se with a compound of formula IV

/ Λ

HN ^ _ / N-R5 IV

wherein R represents an optionally substituted pyridyl group with alkyl having 1-4 carbon atoms or an optionally 15 p-fluoro-substituted phenyl group, to prepare the 3

DK 154834 B

pharmacologically active compounds of formula I

/ ~ \ \ / \

\ -—, / \ il * - · * »<i <*» C

^ u 5 \ 0 '1 R3 wherein R ^, R £, R-j, R ^ and R ^ and Z have the above meaning.

The reaction of the compounds of formula II or III or mixtures thereof with compounds of formula IV can be carried out by ordinary methods for alkylating amines.

The compounds of formula II and II can be obtained in a manner known per se by reacting alkali metal salts of 1,5-diphenylpyrazolin-3-one compounds of formula V

, R 3

Wherein R 1, R 2> R 1 and R 2 are as defined above with compounds of formula VI

Y-Z-Y VI

wherein Z and Y are as defined above, and isolate the prepared compounds of formula II and III as a mixture thereof or as the individual compounds of

4 DK 154834 B

preferably Y is chlorine or bromine.

The reaction is conveniently carried out in a solvent inert to the reaction conditions at temperatures between 0 ° C and the boiling temperature of the solvent.

Usually the temperatures are preferably between 0 ° C

and 100 ° C. As solvents, e.g. lower alcohols such as methanol, ethanol, isopropanol, butanol or tert, -butanol are suitable but also aromatic hydrocarbons such as benzene or toluene, dimethylformamide, sulfolane, hexamethylphosphorotriamine, tetramethylurea or cyclic ethers e.g. dioxane or tetrahydrofuran is suitable.

As the alkali metal salts of the 1,5-diphenylpyrazolin-3-one compounds can be mentioned the lithium, sodium or potassium salts, preferably the sodium salts obtained in situ by the reaction of the compounds of formula I with alkali metal alcoholates or alkali metal hydrides.

In addition to the open alkylation products of formula II, cyclic alkylation products of formula III are obtained by the reaction. Compounds II and III occur in alternating 20 proportions in the reaction mixture depending on the solvents and alkali metal compounds used, the reaction time and the significance of the individual substituents. Thus, e.g. using a lower alcohol and the corresponding alkali metal alcoholate and longer reaction times, e.g. 12-35 hours, predominantly the cyclic compounds III, while using dimethylformamide and alkali metal hydrides and reaction times for e.g. Compounds 1 to 5 hours predominantly occur. Since both compounds II and III or mixtures thereof can be used in the subsequent reaction, a separation of the compounds is not necessary for the further reaction. But of course

DK 154834B

5, the cyclic compounds III can be separated in a manner known per se from the open chain compounds. Thus, for example, cyclic immune salts III, e.g. are readily crystallized by aromatic and / or halogenated hydrocarbons such as benzene, toluene or chloroform.

The alkylation of the 1,5-diphenylpyrazolin-3-one compounds of formula V with the compounds of formula VI usually yields mixtures of the desired N-alkylated compound and in addition the isomeric O-alkylated compound. From this mixture, the N-alkylated compound can be separated chromatographically or by crystallization.

The O-alkylated by-products can be rearranged by simple heating to the N-alkylated Compounds II and the cyclic Immonium Salts III. The rearranging temperature is conveniently between 60 ° C and 200 ° C. Optionally, the rearrangement may be carried out in the presence of an inert solvent conveniently at the boiling temperature of the solvent. Suitable solvents for this purpose are lower boiling alcohols such as methanol, butanol or isopentanol, or aromatic hydrocarbons such as beirzen toluene or xylene. For the thermal rearrangement reaction, the mixtures of cyclic Immonium Compounds III, the N-alkylated Compound II and the corresponding isomeric 0-alkylated Compound directly obtained without the prior separation can also be used.

The 1,5-diphenylpyrazolin-3-ones of formula V are well known and can be obtained by well known methods, e.g. prepared by the methods described by Michaelis and Rassmann (Ann. 352, (1907) 158) and by Michaelis and Willert (Ann.

30 358, (1908) 159), e.g. are substituted from the corresponding substituted benzoyl acetic acid esters and corresponding substituted β-acetylphenylhydrazines.

6

DK 154834 B

The following examples illustrate the preparation of the compounds of the invention,

The structure of the subject compounds was determined by spectroscopic studies, in particular by a careful analysis of the IR and NMR spectra.

The IR spectra of the 1,5-diphenylpyrazolin-3-one compounds exhibit at ca. 1630-1680 cm- carbonyl absorption band of the pyrazoline-3-one ring and free of -C = N bands which can be seen in pyrazole derivatives.

EXAMPLE 1 '15-Diphenyl-2- (3-chloropropyl) -pyrazolin-3-one.

Dissolve 47.2 g of 1,5-diphenylpyrazolin-3-one (300 mmol) in 350 ml of dimethylformamide. With stirring, the solution is added portionwise at 80 ° C to 6.6 g of sodium hydride (80%, 220 mmol). The prepared suspension is allowed to cool to 60 ° C and a solution of 34.7 g (220 mmol) of 1-bromo-3-chloropropane in 150 ml of dimethylformamide is added dropwise. The temperature hereby drops to approx. 40 ° C. At this temperature 20 is stirred an additional 12 hours. Subsequently, as much as possible of the dimethylformamide is removed under reduced pressure (oil pump), thereby also removing unreacted bromochloropropane from the reaction mixture. The residue is taken up in methylene chloride and stirred. Thereby precipitates sodium bromide and unreacted d-i-25 phenylpyrazolinone which can be aspirated. The methylene chloride solution is washed with water, dried over sodium sulfate, filtered and the solvent removed under reduced pressure.

60 g of a cool pale yellow oil are obtained containing a mixture of the isomeric 1,5-diphenyl-2- (3-chloropropyl) -30 pyrazolin-3-one and 1,5-diphenyl-3- (3- chloropropoxy) -pyra-

7 DK 154834B

zol. The latter compound is rearranged by one hour heating the mixture to 170 ° C, likewise to 1,5-di-phenyl-2- (3-chloropropyl) -pyrazolin-3-one. The compound prepared can be used for further processing without further purification.

EXAMPLE 2 1,5-Diphenyl-pyrazolo [2,3-b] dihydro-1,3-oxazinium chloride 118 g of 1,5-diphenylpyrazolin-3-one is suspended in methanol and with stirring a solution of 99 g is added. sodium methylate in methanol (30 µg solution). To the prepared solution is added, after 15 minutes, 54 ml of 1-bromo-3-chloropropane are added dropwise and the solution is heated at reflux for 48 hours. Then, the majority of the solvent is distilled off under reduced pressure, the residue is dissolved in dichloromethane and the organic solution is washed twice with 250 ml of water per ml. walk. The wash water is extracted again with 300 ml of methylene chloride and the organic phases are combined, dried over sodium sulfate and filtered. After the solvent is removed under reduced pressure, 150 g of crude 1,5-diphenylpyrazolo [2,3-b] dihydro-1,3-oxazinium chloride are obtained as a yellow crystalline residue. This residue is slurried in 200 ml of acetone, the suspension is heated at reflux for 5 minutes and cooled under 25 stirring. The crystals are filtered off and washed again in the same manner with 250 ml of ethyl acetate. The crystals are then dried in a drying cabinet for 5 hours at 60 ° C. Melting point 208-210 ° C, yield 102 g.

8

DK 154834 B

EXAMPLE 3

Further processing of 1,5-diphenyl-2- (3-chloropropyl) -pyrazolin-3-one to 1,5-diphenyl-2- [3- (4-phenylpiperazin-1-yl) -propyl] -pyrazoline-3 Dissolve 31.3 g of 1,5-diphenyl-2- (3-chloropropyl) -pyrazolin-3-one (prepared analogously to Example 1) in 300 ml of toluene and add to the solution 18.6 g of N-phenylpiperazine and 13.9 g of potassium carbonate. With stirring, the prepared suspension is heated at reflux for 20 hours. After cooling the reaction mixture, shake with water, separate the organic phase and evaporate as much as possible under reduced pressure. The residue is added with dilute hydrochloric acid and the resulting suspension is extracted with methylene chloride.

The clear aqueous phase is added to dilute sodium hydroxide solution for an alkaline reaction and extracted with ethyl acetate.

The organic extract is separated, dried over sodium sulfate and filtered and evaporated under reduced pressure.

The crude 1,5-diphenyl-2- [3- (4-phenylpiperazin-1-yl) -propyl7-pyrazolin-3-one remains as a pale yellow oil (41.2 g).

This residue is dissolved to be converted to the dihydrochloride in isopropanol and the solution is added dropwise to a saturated solution of hydrogen chloride gas in diethyl ether. The crystalline precipitated dihydrochloride is aspirated and washed with isopropanol and ether. Melting point 227-230 ° C, yield 25.7 g.

Claims (1)

Patent Claims: 1,5-Diphenylpyrazoline derivatives of the general isomeric formulas R-, V r "JT I® R4-L ·) R4" Cj r 'in 111 H r3 characterized in that R ^ represents hydrogen or halogen, R 2 represents hydrogen or halogen, represents hydrogen or halogen, and R 2 represents hydrogen or halogen; Z represents an alkylene group of 2-4 carbon atoms; and Y represents halogen.