DE1038049B - Process for the preparation of therapeutically valuable 4-substituted 1, 2-diaryl-3, 5-dioxo-pyrazolidines and their salts - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of 4-substituted l ^ -Diaryl-SjS-dioxo-pyrazolidines, which are suitable as medicaments, especially for the treatment of gout.

The 1,2-diphenyl-4-n-butyl-3,5-dioxo-pyrazolidine was asked as a drug for the treatment of rheumatic diseases gained great importance. It has now been found that analogous compounds with the y-oxo-butyl radical Place of the butyl residue, according to the general formula

, CO-N-Ar ₁

CH ₃ -CO-CH ₂ -CH ₂ -CH! I.

\ I

CO-N-Ar ₂

and their ketals of the general formula

CO-N-Ar ₁

- C - CHo - CHo - CH

II

procedure
for the manufacture of therapeutic

valuable 4-substituted

1,2-diaryl-3,5-dioxo-pyrazolidines

and their salts

^X CO - N - Ar,

Applicant:

J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. F. Zumstein, patent attorney,
Munich 2, Bräuhausstr. 4th

Claimed priority:
Switzerland from September 10, 1954

Dr. Rolf Denss and Dr. Franz Häfliger, Basel (Switzerland), have been named as inventors

where Ar ₁ and Ar _{3 are} phenyl radicals which can be substituted at the same or different positions by halogen, alkyl, alkoxy or alkyl mercapto groups, and R ₁ and R _{2 are} hydrocarbon radicals which can also be linked to form a divalent hydrocarbon radical , also have interesting pharmacological properties with low toxicity. They are particularly suitable for treating gout.

The compounds according to formulas I and II show a much stronger uricosuric effect on humans, than those described in German Patent 814 150. Furthermore, z. B. 1,2-Diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidine according to formula I almost 4 times less toxic (mouse IV) than the corresponding 1,2-diphenyl-4-n-butyl-3,5-dioxo-pyrazolidine according to 40 man of this German patent specification.

The above-defined ketals of the general formula II and the oxo compounds on which they are based General formula I can be prepared by

a) a substituted malonic diester of the general formula

where X is easily split off hydrocarbon radicals, and R ₁ and R ₂ , which have the meanings given above, in a manner known per se in the presence of an alkaline condensing agent on hydrazobenzene or a hydrazobenzene derivative of the general formula

Z ₁ -N- Ar ₁

Z ₂ -N- Ar ₂

where Z ₁ and Z _{2 are} hydrogen or easily split off radicals, in particular acid radicals, and Ar ₁ and Ar _{2 have} the meaning given above, can act or that

b) a substituted malonic acid derivative of the general formula

, CO-Y

co — ο —χ

CH ₃ -C-CH ₂ -CH ₂ -CH

III

R ₁

C — CHg-—

—CH

CO-

O
Ri

O
R,

CO-0 -X

wherein Y is chlorine, bromine or an acyloxy radical and R ₁ and R _{2 have} the meaning given above, in a manner known per se, in the presence of an acid-binding agent on hydrazobenzene or a substituted hy-

«09 600/458

drazobenzene of the general formula IV lets act or that one

c) a substituted malonic acid ester derivative of the general formula

CO-O-X

CH, - C-CH ₂

-CH ₂ -CH

VI

CO-Y

wherein R ₁ , R ₂ , X and Y have the meaning given above, allowed to act in a manner known per se in the presence of an acid-binding agent on hydrazobenzene or a substituted hydrazobenzene of the general formula IV, and the substituted malonic acid ester hydrazide thus obtained the general formula

C. -CH ₂ -CH ₂ / CO - OX -NH O -CH
\ Ar ₂ O R ₂ co - N- Ri Ar ₁

VII

H ₈ C ₁

, CO - N - Ar ₁

CO - N - Ar,

neutral medium and, provided that the γ-oxo group is ketalized is, also Raney nickel in an alkaline medium.

The reaction products can be converted or converted into salts in an analogous manner as described above for the products of the ring closure process is specified.

The following example is intended to explain the production of the new compounds in more detail. In it, parts mean parts by weight; these relate to parts by volume as g to cm ³ .

example

a) 1,2-Diphenyl-4- (3 ', 3'-ethylenedioxybutyl) -3,5-dioxo-pyrazolidine

274 parts of (3,3-ethylenedioxy-butyl) malonic acid diethyl ester are abs in 100 parts by volume. Benzene dissolved and 57 parts of sodium methylate and 184 parts of hydrazobenzene are added. Warming occurs. The reaction mass is refluxed for 15 hours. To

After cooling, it is poured into water, separated off and the aqueous portion is washed twice with benzene. the Benzene solutions are washed 3 times with 2 normal sodium carbonate solution and the combined aqueous solutions with Acidified with 2 normal hydrochloric acid. The precipitated 1,2-diphenyl-4- (3'-3'äthylenedioxy-butyl) -3,5-dioxo-pyrazolidine can be recrystallized from alcohol. Mp. 165 to 167 ° C.

wherein R ₁ , R ₂ , Ar ₁ , Ar ₂ and X have the meaning given above, heated to close the ring, if necessary in the presence of an alkaline condensing agent, and then, if desired, according to any of the three described process modifications a), b) or c ) contained ketal compounds of general formula II by hydrolysis or by transketalization with an oxo compound, eg. B. in the presence of a little hydrogen chloride, converted into free oxo compounds of the general formula I or, if desired, by transketalization with a hydroxyl compound, the radicals R ₁ and R _{2 are} replaced by other defined radicals R ₁ and R ₂ and / or, if desired, compounds of the general formulas I or II converted into their salts with inorganic or organic bases.

While all of the above-mentioned methods are used to make modifications to the ring-closing condensation Pyrazolidine derivatives which already contain the carbon structure in the 4-position can be obtained y-oxo-butyl group or ketalized y-oxo-butyl groups also subsequently introduce into existing pyrazolidine derivatives by adding a 1,2-diaryl-3,5-dioxopyrazolidine the general formula

b) 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidine

36.6 parts of 1,2-diphenyl-4- (3 ', 3'-ethylenedioxybutyl) -3,5-dioxo-pyrazolidine are refluxed in 750 parts by volume of acetone with 0.35 parts of p-toluenesulfonic acid for 18 hours. The solution is then filtered, 1500 parts of water are added and the mixture is left to stand at 5 ° C. for 24 hours. The precipitated 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidine is filtered off with suction and washed with 50% acetone . Occasionally is obtained melting at 127.5 to 128.5 ⁰ C crystal form.

Claims (2)

Claims-. 1. Process for the preparation of therapeutically valuable 4-substituted l ^ -Diaryl-S.S-dioxo-pyrazolidines as well as their salts of the general formulas where Ar ₁ and Ar _{2 have} the meaning given above, condensed with a functional derivative or an alkali metal salt of 1,3-dioxobutane (formylacetone) in a manner known per se and simultaneously or subsequently hydrogenated the semicyclic double bond formed during the condensation. As functional derivatives of the non-existent 1,3-dioxobutane in free form, its mono- and diacetals and its enol ethers and enol ethers of 3-monoacetal come into consideration, such as. B. l, l-dimethoxy-butanone- (3), 1,1,3,3-tetramethoxy-butane, l-methoxy-buten- (l) -one- (3) and 1,3,3-trimethoxy- butene (1). Suitable catalysts for the hydrogenation are, for. B. platinum oxide or Raney nickel in the cold in new 55 CH ₃ -CO-CH ₂ -CH ₂ -CH co 2-CH ₂ -CH N -Ar ₁ I. --Ar ₂ II Ar ₂ , CO- ^X CO - N- respectively. co— N- N Ar ₁ C ¹ XJ Γ * C XJ / '\
OO R ₁ R ₂ where Ar ₁ and Ar _{2 are} phenyl radicals which can be substituted in the same or different positions by halogen, alkyl, alkoxy or alkylmecapto groups, and R ₁ and R _{2 are} hydrocarbon radicals which can also be linked to form a divalent hydrocarbon radical, characterized in that one a) a substituted malonic acid diester of the general formula CO-0 -X C Ho - C - - C Ho - ~ C Hg - C H III R » CO-O -X I ₀ where X is easily split off hydrocarbon radicals and R ₁ and R _{2 have} the meaning given above, in a manner known per se in the presence of an alkaline condensing agent on hydrazobenzene or a hydrazobenzene derivative of the general formula Z ₁ -N- Ar ₁ N-Ar, IV 20th in which Z ₁ and Z _{2 are} hydrogen or easily split off radicals, in particular acid radicals, and Ar ₁ and Ar _{2 have} the meaning given above, or by allowing them to act b) a substituted malonic acid derivative of the general formula CO-Y - C - C H2 - C H2 - C H O O CO-Y 30th in which Y is chlorine, bromine or an acyloxy radical and R ₁ and R _{2 have} the meaning given above, in a manner known per se in the presence of an acid-binding agent on hydrazobenzene or a substituted hydrazobenzene of the general formula IV or by allowing 40 c) a substituted one
general formula Malonic acid ester derivative der CO-O-X CH ₃ - C - CH _{2 - CH 2} CH VI R, CO-X in which R ₁ , R ₂ , X and Y have the meaning given above 50 have, in a known manner in the presence of an acid-binding agent on hydrazobenzene or a Lets substituted hydrazobenzene of the general formula IV act and the substituted Malonic acid ester hydrazide of the general formula CO -OX CHo-C-CH ₉ -CH ₉ -CH VII CO -N-NH Ar ₁ Ar ₂ in which R ₁ , R ₂ , Ar ₁ , Ar ₂ and X have the meaning given above, heated to close the ring, if necessary in the presence of an alkaline condensing agent, and then, if desired, according to any of the three process modifications a), b) or c ) obtained ketal compounds of the general formula II by hydrolysis or by transketalization with an oxo compound converted into free oxo compounds of the general formula I or, if desired, by transketalization with a hydroxyl compound, the radicals R ₁ and R _{2 are} replaced by other radicals R ₁ and R ₂ according to the definition and / or if desired, compounds of the general formulas I or II are converted into their salts with inorganic or organic bases. 2. Modification of the method according to claim 1, characterized in that one is a 1,2-diaryl-3,5-dioxo-pyrazolidine the general formula CO-N-Ar ₁ CH, CO-N-Ar ₂ wherein Ar ₁ and Ar _{2 have} the meaning given in claim 1, condensed with a functional derivative or an alkali metal salt of 1,3-dioxobutane in a known manner and at the same time or subsequently hydrogenated the semicyclic double bond formed during the condensation and, if desired, compounds , in which the γ-oxo group is ketalized, converted in a manner known per se by hydrolysis or by transketalization with an oxo compound into compounds having a free γ-oxo group and / or, if desired, the reaction products of the general formula I are converted into their salts with organic or inorganic bases. © 809 600/458 9. 5S