DE2032748A1 - - Google Patents

Description

LAWYERS

DR JUR. DIPL-CHEM. WALTER BEIL ALFRED HOEPPENER
DR. JUR. DIPL-CHEM. H.-J. WOLFi DR. JUR. HANS CHR. AX

«3 FRANKFURTAMMAIN-HOCHSI

ADELONSTITASSTM,

our Ir. 16424

The 3.A. Paris, France

Basic derivatives of p-hydroxyphenylbutazone _? Process for their production and their use.

The present invention relates to new basic derivatives of p-hydroxyphenylbutazone or l-phenyl-2- (p-hydroxyphenyl) ~ 3 »5-dioxo-4-n-butylpyrazolidine the general formula

OH ₃ (OH ₂ ).

0 -G CM) C

ÜHq "" ""

(D

in the η © ine goose number from 1 to 4 iat and B © inen Hast of a saturated or unsaturated monoainine or sec.

009884/2243

Polyamine (of a sec. J & amines, triamines or tetramines) means, which can be either aliphatic and straight or branched, alicyclic or heterocyclic, where the heterocyclic can include one or more other heteroatoms, as well as their addition salts with pharmaceutical compatible mineral or organic acids.

It applies in particular to the connections in which η = 1 and B denotes a cyclic amino radical, i.e. compounds of the general formula

in which X is the direct bond between the carbon atoms or -0-, -H- or -CBL- means.

CH,

In addition, the invention comprises a method ssur Preparation of the compounds (I>. These can probably be determined as a result of the action of formaldehyde on the Phenolic function of p-Hydroxyphenylbutazona not through the

BATH ORIGINAL

009814/2243

produce classic kanrich reaction. Eb has been found that compounds äaa by reacting the p-IIydroxyphenylbutazons with an amino ether of the general Fonnel

h (CH ₂ OC ₂ H ^) _n or X H-CH ^ OCgH ^ (II),

α it is obtained in an opaque manner, is produced can.

To carry out a method according to the invention η holekule u-Hyctrox, yph - nylnutazon either without Zwipehenmeuiuia oaer in an inert orpanischf.-n solution · ---. K.i.ttel like Chlcroi'crin at Uzutebunpstemt.eratur with one KcJpkül ae? Auiinoätners implemented. Be that way aip compounds (I) in pure; State produced »since the thenol function of p-HyaiOxyphenylbatasone surprisingly not cit üeia A-üinoither reacts.

The mineral ouer or ^ anipchen salts of these new Compounds (I) ornaments according to all known "methods for Preparation of these salts produced, preferably working in an anhydrous medium.

The invention also relates to industrial uses aer compounds (I), especially the use thereof as an active ingredient in anti-inflammatory and antipyretic _s analgeti .see-drugs for humans and animals for the treatment of inflammatory syndromes. The pharmacological investigation of the compounds has shown that they have the following properties:

00988Ä / 2.243

■. BATH ORIGINAL

1) inflammation Hneaiiaende Hig-enochai'ter. with regard to the

of the rat paw produced by carrageenan and in the case of the Erytüem, that of being softened by UV rays was evoked;

2) analytical properties £ ~ (Kontorcionstest, wherein the contortions in the mouse by 2-phenyl-l, 4-benzoquinone caused, electrical stimulation of Zahi.pulr, -) in the rabbit; l'esl; nacli Randall and Selitto (. Arch. int Pharm, 19b7, 111 _r 4, pp 4Oy-41b.) in the rat) J;

3) antipyretic properties (effect on hyperthermia, induced in the rat by injection of dead microbes).

In addition, the compounds (I) are distinguished from aem p-hydroxyphenylbutazone administered in an equimolar dose in a superoetaenaer way by a faster and more permanent V / irKun _e -. rfeit-.rhin -är.d because of their ßasität for Jen Magen better contractual than the pkyaroxypr.enyi r.utazon.

The cevcrzut t'-n VerDin-iiin ^ en are 4- (4 -K ethyl pipe razir.o) -metr.Vi.- ar. j. '. -tvrroiij ^: nometnvi.-l-rjnenyi-l-phenyl-l - ', - r.varox ··' :: er.-] - ',, --a: oxo - ^ - r.-Lutylr yrazolidine.

thanrj ^ zeuti? cne trs-tarate üiit one of the connective amides (Ί.} h. ± -: Wirvstctf contain -: clcne excipients, which are never administered «; j.ies ^r r tr-ar ^ arate on oral, rectal em or perk-atane-Ti η tu are suitable. These pharmacu ti see preparations can consist of other medicinal substances.

00988 4/2243 BAD ORlQiWAL

hold, with which the Verbinclungen (I) therapeutically compatible are.

For administration by the oral route, those for this Appropriate pharmaceutical forms (tablets, coated tablets, capsules etc.) are used, the unit dose being the active compound is between 100 and 500 mg and the daily dose is 500 to 2000 mg per 24 hours.

For administration by the rectal route, suppositories are used. which contain 100 to 500 mg of active ingredient, x-jobei 1 up to 2 suppositories per 24 hours are prescribed.

For administration percutaneously ointments are used, 2 üie to 10 ° / i> of the active ingredient, with 2 to 3 applications are applied per day.

The following examples serve to explain the Invention. The temperatures are given in degrees Celsius. ■ ■

Example Is

l> -Phenvl-2 ~ p-hydroxyphenyl-3,5- dioxo -4- nbutyl-4-morp hQ-linomethylpyrazolidine.

To a 100 ml flask was placed a solution of 10 g '(0.031 gramol) p-hydroxyphenylbutazone in 45 ml of chloroform. This solution was added with stirring 4y, 5 g (0.031 gram moles) W-Äthoxymebhylniorpholin offset "One Iieö the mixture to stand overnight at Hinge bungs bemperatur and then the chloroform was evaporated on a water bath in vacuo. The residue is crystallized in 50 ml iso-

"009884/2243 bad original

ρropyl alcohol. The mixture was cooled for a few hours, the precipitate was centrifuged off and dried in vacuo over phosphoric anhydria. 3.6 g (yield == 7315 #) of 1-phenyl-2-p-hydroxyphenyL-3, "r-riiox:, - · 4-η-butyl-4-morpholino-methylpyrazolidine were obtained, aas after Umkristalli organization in I sop ropyl alcohol a Scnmelzcunlct of 191 ⁰ G had.

Analysis: G ₃₄ H ₂₉ N ₃ O ₄ (423)

Calculated·. {%) C, 68.15; H 6.86j N 9.93. Found? (*) G 68.10; H 6.885 19.90.

example 2%

1-phenyl-2-p-hydroxyphenyl -3,5-diqxO'-4- n-butyl-4- (4-methyl piperazino) '- methyl p .vrazolidine.

A solution of 9 »4 g (δ, O25 g-ramiaol) p-hydroxyphenylbutazone in 45 ml of chloroform was placed in a 100 ml flask. The solution was admixed with ψ 4.6 g (0.025 Graramol) of 1-ethoxymethyl-4-methylpiperazine with stirring. The solution was left to stand overnight at ambient temperature; the chloroform was then evaporated on a water bath in vacuo and the residue was crystallized by trituration in 20 ml of isopropyl alcohol. The mixture was cooled, the precipitate was centrifuged off and dried in vacuo over phosphoric anhydride. In this way 8 g (yield ^ 63.5 "fa) 1-phenyl-2-p-hydroxyphenyl-3,5-dioxo-4-n-butyl-4 - ('4-methylpiperazino) -methylpyrazolidine were obtained, which after Recrystallization in isopropyl alcohol had a melting point of 155-158 ° C.

009884/2243 ^BA ° ° ^RIQINAL

_ ¹ T _

Analysis: ^Ο 2 $ ^Η 32 ^Η 4 ^Ο 3

Boron «cnn« tt (* V ■ C 6β, 80? Η'7 · 34; Η 12.84. Found: (*) C, 68.78; H 7 »45; K 12.98.

methylpyrazolidine.

A solution of 9 »7 g (0.03 'lrammol) p-riyuroxyptienvloutazon in Ab ml chloroform wurae added with stirring to 3» 9 S (0,03'Gramiuol) N-Xthoxymethylpyrrolidin. The ₃ chi οroform was evaporated in vacuo on a water bath and the brownish, viscous residue dries for a few hours under YaKUiun ^ «. Then it was thinned in 20 ml. Isopropyl alcohol to crystallize. The solution was cooled for one night, the precipitate was centrifuged off and dried in vacuo over phosphoric anhydride. In this way wuraen 2.2 g (Yield = 18 ¹ Jt) l-Paenyl- <ip-hydroxyphenvl-3,5-dioxo-4 ~ n-butyl -4-pyrrolidinomelhvlyyrazoliain .gewonnen, which after recrystallization in Isopropyloxia a melting point of 146-148 C.

Analysis: ^C 24 ^H 29 ^li 3 ^O 3 ^ ⁰⁷ ^

Calculated: (*) C 70.75; H 7 ₉ 13; M 10, .32. Found: (*) C, 70.61; H 7.31; N 10 "30.

Example 4:

1-phenyl-2-p-hydro3cypiienyl -5,5-dioxo-4-n-batyl-4-piperidino methylpyrazolidine.

009884/2243 _B AD original

In a 100 uJ. ! "as π end ο η KoI ι, en created a solution of 6.1 g (0.019 Grranuiiol) p-Hyciroxyphenylbutazon in 25 ml Introduced chloroform. The solution was dissolved while stirring with 2.7 f. "(0.19 gramol) N-ethoxymethylpii.eridin ver sets. The mixture was kept for 3 days at ambient temperature ditched; the chloroform was then evaporated on a water bath in vacuo, and the residue became j η Apply 2 μl ml of isopropyl oxide; the G-esaiut mixture became frozen for several days. The compound crystallized? became centrifuged and over Phosp'iorsUureanhydrid in a vacuum dried.

In this way, 1.6 g (yield = 20%) of 1-phenyl-2-p-hydroxyphenyl-'3 , ba

methylpyrazoliain obtained, which after recrystallization in 2 ml of methyl alcohol had a melting point of 135 ° C.

Anaxyse: C ₀₁ -HL ₁ N _x O, (4-21)

Calculated!
Found?

C. 71 ,2 B; H 7, 3b; N 9.97 » C. 71 , 27; H 7, 32; N 10, OC

BATH

009884/224

Claims (9)

Claims; 1. Basic derivatives of i ~ ihenyl-2 - (p-hydroxyphenyl) ~ 3 _I 5-dioxo-4-n-butylpyrazolidine of the general formula (I) O = C ₃ (GH ₂ ) Bf- OH G = O (D in which η is an integer from 1 to 4 and B is an Eest of a saturated or unsaturated monoamine or sec "polyamine" which can be either aliphatic and straight branched, alicyclic or heterocyclic ₃ where the heterocycle can comprise one or more other heteroatoms * as well as their addition salts with the pharmaceutically acceptable mineral and organic acids. 2 »Basic derivatives of the general formula 009884/2243 BAD ORIOiNAL - ίο - ^0H O = C C = O CH, (CH ₉ ), CH ₉ - NX · • ⁵ V_J in which X is the direct bond between the carbon atoms. -0-, -N- or -CHp- means, as well as their Addition salary with pharmaceutically acceptable mineral and organic acids. 3. 1-Phenyl-2-p-hydroyphenyl-3 »5-dioxo-4-n-butyl-4-morpholinomethylpyrazolidine. 4. 1-Phenyl-2-p ~ hydroxyphenyl-3 * 5-dioxo-4-n-butyl-4- (4-methylpiperazino) methylpyrazolidine. 5. 1-Phenyl-2-p-hydroxyphenyl-3 »5-dioxo-4-n-butyl-4-pyrrolidinomethylpyrazolidine. 6. 1-Phenyl-a-p-hydroxyphenyl- 1-5-dioxo-4-n-butyl-4-piperidinomethylpyrazolidine. 009884/2243 - Il - 7. A process for the preparation of the Yerbindungen (I) according to claim 1 or 2 "characterized in dai3 one p-Hydroxvphenylbutaaon with a Aminoätner the general Jj ¹ O my: I— \
B (CH ₂ OC ₂ H ^) _n cross XN— CHg-OCgH ^ (II) in aen «n Β» η una X those listed in claims 1 and 2 Have meanings, implements and possibly ρ the received ones Compounds with mineral or organic acids converted into the addition salts in a manner known per se, "preferably in a vase-free medium" 8. The method according to claim 7t, characterized in that that one η molecules of p-hydrophenylbutazone either without Intermediate or in an organic inert solvent Reacts at ambient temperature with a molecule of an amino ether (II). 9. Use of the! Onnectivity according to claim 1-6, particularly in connection with a form suitable for oral, rectal or prekutanem way diluent, and optionally with other acceptable drug substances as active ingredients .to the production of medicaments, " - 10.- Use according to claim 9 »marked thereby- 009884/2243 ORIGINAL BATHROOM net that you can get the compounds in such an amount uses that the drug intended for administration by the oral or endorectal route 100 to 500 mg of the same contains For DAusse S.A. Paris, France (Lawyer) BATH ORIGINAL 009884/2243